WO2016084790A1 - Hydronaphthoquinoline derivative - Google Patents

Abstract

The present invention provides a compound represented by general formula (I) which has excellent retinoic acid receptor-related orphan receptor γt inhibitory activity and IL-17 production inhibitory activity, or a pharmaceutically acceptable salt thereof. (In the formula, U represents a phenyl group, pyridyl group, tetrahydrofuryl group, tetrahydropyranyl group or benzyl group which may be independently mono- to tetra-substituted by groups selected from among halogen atoms, C₁-C₆ alkyl groups and C₁-C₆ alkoxy groups, a C₁-C₆ alkyl group, a C₁-C₆ halogenated alkyl group or the like; R¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or the like; R² represents a hydrogen atom or a C₁-C₆ alkyl group; R³ represents a hydrogen atom, a halogen atom, a hydroxyl group or the like; R⁴ represents a hydrogen atom or the like; R⁵ represents a C₁-C₆ alkyl group which may be independently mono- to tetra-substituted by groups selected from among a hydroxyl group and C₁-C₆ alkoxy groups, a hydrogen atom or the like; R⁶ represents a C₁-C₆ alkyl group which may be independently mono- or di-substituted by groups selected from among C₁-C₆ alkylsulfonyl groups and a hydroxyl group, a hydrogen atom, a hydroxyl group or the like; R⁷ represents a hydrogen atom or a fluorine atom; R⁸ represents a hydrogen atom, a fluorine atom or the like; R⁹ represents a hydrogen atom; T represents a single bond, an oxygen atom or a group represented by formula -NH-; Y may be the same or different and each represents a halogen atom or a C₁-C₆ alkyl group; m represents an integer of 0-3; a saturated ring containing a nitrogen atom may be fused with a cyclopropane ring to form a fused ring; and n represents an integer of 1-3.)

Description

Hydronaphthoquinoline derivatives

The present invention has an excellent inhibitory action on retinoic acid receptor-related orphan receptor γt (which may be abbreviated as RORγt in the present specification) and is useful as a therapeutic agent for psoriasis or the like, or an isotope label thereof It relates to compounds or their pharmaceutically acceptable salts.

The cause of many autoimmune diseases is unknown, but it has long been known that many diseases are closely related to T cell abnormalities. In particular, IFN-γ high-producing helper T cells (Th1 cells) have been reported for a long time, but abnormalities in Th1 cells cannot fully explain the pathogenesis of the disease. Was questioned. In 2006, the presence of IL-17 -rich helper T cells (Th17 cells) was reported, suggesting that autoimmune diseases are closely related to abnormalities in Th17 cells. Since then, research on Th17 cells has been conducted energetically, and its relevance has been clarified in several autoimmune diseases, and the importance of Th17 cells has attracted attention. The nuclear receptor RORγt functions in the process of Th17 cell differentiation from naive T cells and in the process of Th17 cells producing IL-17. In naive T cells of RORγt knockout mice, the differentiation into Th17 cells was suppressed, IL-17 production was suppressed, and the development of Experimental Autoimmune Encephalomyelitis, a pathological model of multiple sclerosis, was obtained ( Non-patent document 1). In another pathological model, there is a report that RORγt plays an important role in differentiation into Th17 cells, production of IL-17, and pathogenesis (Non-patent Documents 2-3). From these findings, it is considered that a substance that suppresses the transcriptional activity of RORγt, that is, an RORγt inhibitor may be a therapeutic agent for autoimmune diseases and the like.

Since the cause of autoimmune diseases has not been known so far, immunosuppressants that suppress immunity in general have been used for the treatment. However, this treatment method is not expected to have any effect on the cause of autoimmune disease, but is merely a symptomatic treatment, and therefore, a sufficient therapeutic effect was not observed or remission occurred without remission. Therefore, in order to achieve a sufficient therapeutic effect and remission, a treatment suitable for the cause of the autoimmune disease is required. Recently, abnormalities in Th17 cells with enhanced IL-17 production have been confirmed as the cause of several autoimmune diseases. However, since there is no method that can treat Th17 cell abnormality at present, a new treatment method that can improve Th17 cell abnormality is required.

Non-patent documents 4-7 report a compound having an RORγt inhibitory action. In particular, as a steroid skeleton-like compound having RORγt inhibitory activity, Non-Patent Document 8-11 describes cholesterol derivatives. Non-Patent Document 12 and Patent Document 1 describe digoxin and its derivatives. Patent Documents 2 and 3 describe bile acid derivatives. In these documents, only compounds in which the portion corresponding to the steroid skeleton D ring is a 5-membered carbon ring are described. Non-Patent Document 13 describes ursolic acid. Ursolic acid is a pentacyclic compound.

WO2012 / 074547 WO2013 / 041519 WO2014 / 147016

Cell, 126, 1121-1133 (2006) The Journal of Clinical Investigation, 122, 2252-2256 (2012) Arthritis and Rheumatology, 66, 579-588 (2014) Journal of Medicinal Chemistry 2014,57,5871-5892 Drug Discovery Today 2014,19 (8), 1205-1211 Annual reports in Medicinal Chemistry 2013,48,169-182 Medicinal Chemistry Communications 2013,4,764-776 Journal of Biological Chemistry 2004,279,14033-14038 Journal of Biological Chemistry 2010,285,5013-5025 Biochimica et Biophysica Acta 2010,1801,917-923 Molecular Endocrinology 2010,24,923-929 Journal of Biological Chemistry 2011,286,31409-31417 Journal of Biological Chemistry 2011,286,22707-22710

As a result of intensive studies on a compound having an RORγt inhibitory effect, the inventors have found that a hydronaphthoquinoline compound having a specific chemical structure exhibits selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. It was found to be useful for the prevention and treatment of diseases involving RORγt such as autoimmune diseases. The present inventors have found that this hydronaphthoquinoline compound is useful in the treatment of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, myocardium Treatment of colorectal cancer in which autoimmune diseases such as symptom, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. or IL-17 production is involved in pathogenesis And / or useful as an active ingredient of a medicament for prevention. The present invention has been completed based on the above findings.

The present invention is as follows.
(1) General formula (I)

[Where:
U represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, C Selected from _3- C ₆ cycloalkenyl group, C ₃ -C ₆ halogenated cycloalkyl group, C ₃ -C ₆ halogenated cycloalkenyl group or halogen atom, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group A phenyl group, a pyridyl group, a tetrahydrofuryl group, a tetrahydropyranyl group or a benzyl group, which may be independently substituted by 1 to 4 groups,
R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C ₂ -C ₇ alkylcarbonyloxy group,
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, or
R ² and R ³ together represent an oxo group;
R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkylsulfonyl group and to 1 independently with a group selected from hydroxyl two substituted C ₁ optionally -C ₆ alkyl group,
R ⁵ represents a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group;
A group selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group, a carboxy group, an aminocarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group and a triazolyl group; 4 represents an optionally substituted C ₁ -C ₆ alkyl group; or represents a 2-tetrahydropyranyl group independently substituted with 3 or 4 groups independently selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group Or
R ⁴ and the group represented by the formula —OR ⁵ together represent an oxo group,
R ⁶ is a hydrogen atom, a halogen atom, a hydroxyl group or a C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and 1 to 2 optionally substituted C ₁ -C ₆ alkyl group independently with a group selected from cyano group Indicate
R ⁷ represents a hydrogen atom or a fluorine atom,
R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group,
R ⁹ represents a hydrogen atom, or
R ⁸ and R ⁹ together represent an oxo group;
T represents a single bond, an oxygen atom or a group represented by the formula —NH—,
Y is the same or different and represents a halogen atom or a C ₁ -C ₆ alkyl group,
m represents an integer of 0 to 3,
A saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a condensed ring,
n represents an integer of 1 to 3. Or a pharmaceutically acceptable salt thereof.

In the present invention, the following can be preferably mentioned.
(2) In the general formula (I) of (1),
U represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, C Selected from _3- C ₆ cycloalkenyl group, C ₃ -C ₆ halogenated cycloalkyl group, C ₃ -C ₆ halogenated cycloalkenyl group or halogen atom, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group A phenyl group, a pyridyl group, a tetrahydrofuryl group, a tetrahydropyranyl group or a benzyl group, which may be independently substituted by 1 to 4 groups,
R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C ₂ -C ₇ alkylcarbonyloxy group,
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, or
Together with the carbon atom to which R ² and R ³ are attached, represents a carbonyl group;
R ⁴ represents a hydrogen atom, a (C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group or a C ₁ -C ₆ dihydroxyalkyl group,
R ⁵ represents a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group;
Fluorine atom, a hydroxyl _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkylsulfonyl group, optionally _C 1 -C be 1 to 4 substituents independently a group selected from a carboxy group and an amino group ₆ alkyl group; or 2-tetrahydropyranyl group which is independently substituted with 3 or 4 groups independently selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group, or
Together with the carbon atom to which the group of R ⁴ and the formula —OR ⁵ is attached, represents a carbonyl group,
R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, a (C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group, a C ₁ -C ₆ hydroxyalkyl group or a C ₁ -C ₆ cyanoalkyl group. Show
R ⁷ represents a hydrogen atom or a fluorine atom,
R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group,
R ⁹ represents a hydrogen atom, or
Together with the carbon atom to which R ⁸ and R ⁹ are attached, represents a carbonyl group;
T represents a single bond, an oxygen atom or a group represented by the formula —NH—,
Y is the same or different and represents a halogen atom or a C ₁ -C ₆ alkyl group,
m represents an integer of 0 to 3,
A saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a condensed ring,
A compound wherein n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.
(3) In (1) or (2),
The compound or its pharmaceutically acceptable salt whose general formula (I) is general formula (Ia).

(4) In (1) or (2),
The compound or its pharmaceutically acceptable salt whose general formula (I) is general formula (Ib).

(5) In (1) or (2),
The compound or its pharmaceutically acceptable salt whose general formula (I) is general formula (Ic).

(6) In any one item selected from (1) to (5),
U represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, C _A compound or a pharmaceutically acceptable salt thereof, which is a phenyl group or tetrahydropyranyl group which may be independently substituted with 1 to _{3 3-} C ₆ halogenated cycloalkyl groups or halogen atoms.

(7) In any one item selected from (1) to (5),
U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a tetrahydropyranyl group optionally substituted by one halogen atom. A compound or a pharmaceutically acceptable salt thereof.

(8) In any one item selected from (1) to (5),
U represents 3,3,3-trifluoropropyl group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3,3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyrani Or a pharmaceutically acceptable compound thereof, which is a thio group, 4-fluorotetrahydropyran-2-yl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluorotetrahydropyran-2-yl group Salt.

(9) In any one item selected from (1) to (8),
A compound or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom.

(10) In any one item selected from (1) to (8),
A compound or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

(11) In any one item selected from (1) to (10),
A compound or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or a methyl group.

(12) In any one item selected from (1) to (11),
A compound or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group.

(13) In any one item selected from (1) to (11),
A compound or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a methoxy group.

(14) In any one item selected from (1) to (13),
A compound wherein R ⁴ is a C ₁ -C ₆ alkyl group optionally substituted with 1 or 2 hydrogen atoms or hydroxyl groups, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

(15) In any one item selected from (1) to (14),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group.

(16) In any one item selected from (1) to (15),
R ⁵ represents a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group;
A C ₁ -C ₆ alkyl group or fluorine atom which may be independently substituted with 1 to 3 groups independently selected from a hydroxyl group, a methoxy group, a methylsulfonyl group, an aminocarbonyl group, a tert-butoxycarbonyl group and a triazolyl group; A compound or a pharmaceutically acceptable salt thereof, which is a 2-tetrahydropyranyl group which is independently substituted with 3 or 4 groups independently selected from a hydroxyl group and a hydroxymethyl group.

(17) In any one item selected from (1) to (15),
Compounds wherein R ⁵ is a hydrogen atom, methyl group, 2,3-dihydroxypropyl group, (R) -2,3-dihydroxypropyl group or (S) -2,3-dihydroxypropyl group, or a pharmaceutically acceptable salt thereof Salt.

(18) In any one item selected from (1) to (15),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a methyl group or a (R) -2,3-dihydroxypropyl group.

(19) In any one item selected from (1) to (18),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxymethyl group.

(20) In any one item selected from (1) to (18),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group.

(21) In any one item selected from (1) to (20),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a hydrogen atom.

(22) In any one item selected from (1) to (21),
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom.

(23) In any one item selected from (1) to (22),
A compound or a pharmaceutically acceptable salt thereof, wherein T is a single bond.

(24) In any one item selected from (1) to (23),
A compound or a pharmaceutically acceptable salt thereof, wherein Y is a methyl group.

(25) In any one item selected from (1) to (24),
A compound wherein m is 0 or a pharmaceutically acceptable salt thereof.

(26) In any one item selected from (1) to (25),
A compound wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof.

(27) In any one item selected from (1) to (26),
compounds in which m is 0, n is 1, and the condensed ring formed by condensing a saturated ring containing a nitrogen atom with a cyclopropane ring is a 3-azabicyclo [4.1.0] heptane ring, or Pharmaceutically acceptable salt of

(28) In (1),
The general formula (I) is the general formula (I), and U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group, or a phenyl group or a tetrahydropyranyl group optionally independently substituted by 1 to 3 halogen atoms, R ¹ is a hydrogen atom or a halogen atom, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group, and R ⁴ is a hydrogen atom or A C ₁ -C ₆ alkyl group optionally substituted by 1 to 2 hydroxyl groups, wherein R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, (R) -2,3-dihydroxypropyl Group or (S) -2 3 is a dihydroxypropyl group, or, together a group represented by R ⁴ and the formula -OR ^5, represent oxo group, R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxymethyl group R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group, R ⁹ is a hydrogen atom, T is a single bond, and Y is methyl. A compound or a pharmaceutically acceptable salt thereof, which is a group, m is an integer of 0 to 3, and n is 1 or 2.

(29) In (1),
The general formula (I) is the general formula (I), and U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a halogen atom. A tetrahydropyranyl group which may be substituted by ¹ ; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; and R ³ is a hydrogen atom, a hydroxyl group or a methoxy group. R ⁴ is a hydrogen atom, methyl group, hydroxymethyl group or 2,3-dihydroxypropyl group, R ⁵ is a hydrogen atom, methyl group, 2,3-dihydroxypropyl group, (R) -2,3 A dihydroxypropyl group or a (S) -2,3-dihydroxypropyl group, R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group, R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, T is a single bond, m is 0, n is 1 or 2, and a saturated ring containing a nitrogen atom is A compound or a pharmaceutically acceptable salt thereof, which may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring.

(30) In (1),
General formula (I) is general formula (I), U is 3,3,3-trifluoropropyl group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3,3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 4-fluorotetrahydropyran-2-yl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluoro A tetrahydropyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a hydrogen atom, a hydroxyl group or a methoxy group, and R ⁴ is a hydrogen atom or 2 , 3-a dihydroxypropyl group, ^{R 5} is a hydrogen atom, a methyl group or (R)-2,3-dihydroxypropyl group, ^{R 6} is a hydrogen atom, a hydroxyl group or hydroxymethine A le radical, R ⁷ is hydrogen atom or fluorine atom, R ⁸ is hydrogen atom, R ⁹ is hydrogen atom, T is a single bond, m is 0, Compounds in which n is 1 or 2, and a saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring, or a pharmaceutical thereof Top acceptable salt.

(31) In (1),
The general formula (I) is the general formula (I), and U is a cyclohexyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 5-fluorotetrahydropyran-2-yl group or A (2R, 5R) -5-fluorotetrahydropyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a hydroxyl group or a methoxy group R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group, R ⁵ is a hydrogen atom, a methyl group or a (R) -2,3-dihydroxypropyl group, and R ⁶ is a hydrogen atom An atom, a hydroxyl group or a hydroxymethyl group, R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, T is a single bond, and m is , 0 and n is 1 Is 2, saturated ring containing a nitrogen atom, condensed with the cyclopropane ring, 3-azabicyclo [4.1.0] may compound also form a heptane ring.

(32) In (1),
The general formula (I) is the general formula (Ia), and U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group, or a phenyl group or a tetrahydropyranyl group optionally independently substituted by 1 to 3 halogen atoms, R ¹ is a hydrogen atom or a halogen atom, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group, and R ⁴ is a hydrogen atom hydroxyl group Or a C ₁ -C ₆ alkyl group optionally substituted by 1 or 2 and R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, or a (R) -2,3-dihydroxypropyl group Or (S) -2, - a dihydroxypropyl group, or, taken groups together represented by R ⁴ and the formula -OR ^5, represent oxo group, R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxymethyl group R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group, R ⁹ is a hydrogen atom, T is a single bond, and Y is a methyl group Or a compound or a pharmaceutically acceptable salt thereof, wherein m is an integer of 0 to 3, and n is 1 or 2.

(33) In (1),
The general formula (I) is the general formula (Ia), and U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a halogen atom. A tetrahydropyranyl group which may be substituted by ¹ ; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; and R ³ is a hydrogen atom, a hydroxyl group or a methoxy group. R ⁴ is a hydrogen atom, methyl group, hydroxymethyl group or 2,3-dihydroxypropyl group, R ⁵ is a hydrogen atom, methyl group, 2,3-dihydroxypropyl group, (R) -2,3 A dihydroxypropyl group or (S) -2,3-dihydroxypropyl group, R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group, and R ⁷ is a hydrogen atom or a fluorine atom. , R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, T is a single bond, m is 0, n is 1 or 2, and a saturated ring containing a nitrogen atom , A compound which may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring, or a pharmaceutically acceptable salt thereof.

(34) In (1),
General formula (I) is general formula (Ia), and U is 3,3,3-trifluoropropyl group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3,3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 4-fluorotetrahydropyran-2-yl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluorotetrahydro A pyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a hydroxyl group or a methoxy group, and R ⁴ is a hydrogen atom. or 2,3-a dihydroxypropyl group, ^{R 5} is a hydrogen atom, a methyl group or (R)-2,3-dihydroxypropyl group, ^{R 6} is a hydrogen atom, a hydroxyl group or A Dorokishimechiru group, R ⁷ is hydrogen atom or fluorine atom, R ⁸ is hydrogen atom, R ⁹ is hydrogen atom, T is a single bond, m is 0, Compounds in which n is 1 or 2, and a saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring, or a pharmaceutical thereof Top acceptable salt.

(35) In (1),
The general formula (I) is the general formula (Ia), and U is a cyclohexyl group, 2-tetrahydropyranyl group or (R) -2-tetrahydropyranyl group, 5-fluorotetrahydropyran-2-yl group or A (2R, 5R) -5-fluorotetrahydropyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a hydroxyl group or a methoxy group R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group, R ⁵ is a hydrogen atom, a methyl group or a (R) -2,3-dihydroxypropyl group, and R ⁶ is a hydrogen atom An atom, a hydroxyl group or a hydroxymethyl group, R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, T is a single bond, and m is , 0 and n is 1 or 2, saturated ring containing a nitrogen atom, condensed with the cyclopropane ring, 3-azabicyclo [4.1.0] may compound also form a heptane ring.

(36) In (1),
The general formula (I) is the general formula (Ib) or the general formula (Ic), and U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, (C ₁ -C ₆ alkoxy) -(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ halogenated cycloalkyl group or a phenyl group or tetrahydro which may be independently substituted with 1 to 3 halogen atoms independently A pyranyl group, R ¹ is a hydrogen atom or a halogen atom, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group, R ⁴ is a C ₁ -C ₆ alkyl group optionally substituted by 1 or 2 hydrogen atoms or hydroxyl groups, and R ⁵ is a hydrogen atom, methyl group, 2,3-dihydroxypropyl group, (R) — 2,3-dihydroxypro A group or (S)-2,3-dihydroxypropyl group, or, taken groups together represented by ^{R 4} and the formula -OR ^5, represent oxo group, ^{R 6} is a hydrogen atom, a fluorine atom , A hydroxyl group, a methyl group or a hydroxymethyl group, R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group, R ⁹ is a hydrogen atom, and T is A compound or a pharmaceutically acceptable salt thereof, which is a single bond, Y is a methyl group, m is an integer of 0 to 3, and n is 1 or 2.

(37) In (1),
The general formula (I) is the general formula (Ib) or the general formula (Ic), and U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, or a C ₃ -C ₆ halogenated group. A cycloalkyl group or a tetrahydropyranyl group optionally substituted by one halogen atom, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, A hydroxyl group or a methoxy group, R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group, and R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, (R) -2,3-dihydroxypropyl group or (S) -2,3-dihydroxypropyl group, R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group, and R ⁷ is a hydrogen atom. Or a fluorine atom, R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, T is a single bond, m is 0, n is 1 or 2, nitrogen A compound or a pharmaceutically acceptable salt thereof, wherein a saturated ring containing an atom may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring.

(38) In (1),
General formula (I) is general formula (Ib) or general formula (Ic), and U is 3,3,3-trifluoropropyl group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3, 3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 4-fluorotetrahydropyran-2-yl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluorotetrahydropyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom, a hydroxyl group or a methoxy group. , ^{R 4} is hydrogen atom or a 2,3-dihydroxypropyl group, ^{R 5} is a hydrogen atom, a methyl group or (R)-2,3-dihydroxypropyl group, ^{R 6} is, Atom, a hydroxyl group or a hydroxymethyl group, R ⁷ is hydrogen atom or fluorine atom, R ⁸ is hydrogen atom, R ⁹ is hydrogen atom, T is a single bond, m Is 0, n is 1 or 2, and a saturated ring containing a nitrogen atom is condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring. Good compounds or pharmaceutically acceptable salts thereof.

(39) In (1),
The general formula (I) is the general formula (Ib) or the general formula (Ic), and U is a 3-cyclohexyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 5-fluorotetrahydro A pyran-2-yl group or a (2R, 5R) -5-fluorotetrahydropyran-2-yl group, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a methyl group, and R ³ is , A hydrogen atom, a hydroxyl group or a methoxy group, R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group, and R ⁵ is a hydrogen atom, a methyl group or a (R) -2,3-dihydroxypropyl group. R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group, R ⁷ is a hydrogen atom or a fluorine atom, R ⁸ is a hydrogen atom, R ⁹ is a hydrogen atom, and T is Single bond, m , 0, n is 1 or 2, and a saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a 3-azabicyclo [4.1.0] heptane ring. Compound.

(40)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -tetrahydro-2H-pyran-2-yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone, (2R) -tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a -Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone, [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8 -Methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-7-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone,
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone,
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2,3-dihydroxypropyl) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone,
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4,4-trifluorobutan-1-one,
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone,
(2R) -tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro- 1H-phenanthro [2,1-b] azepin-1-yl] methanone,
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a, 8-dihydroxy-11a, 13a-dimethyloctadecahydro-1H -Phenanthro [2,1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-8,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-7,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(1S) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone,
(Cis-4-fluorocyclohexyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone, or
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl A compound which is octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone or a pharmaceutically acceptable salt thereof.

(41) A compound described in (40) or a pharmaceutically acceptable salt thereof.

(42)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone.

(43) In a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å), diffraction angles 2θ = 4.5, 6.0, 7.5, 10.6, 12.1, 15.2, 16.6, 18.2, 24.4 and 30.7 Crystal of (42) showing a major peak.

(44) (2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexa Decahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone.

(45) In a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms), diffraction angles 2θ = 9.3, 12.5, 13.9, 14.3, 15.2, 15.8, 16.8, 18.9, 20.1 and 21.0 Crystal of (44) showing a major peak.

(46) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone.

(47)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone.

(48) In a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å), diffraction angles 2θ = 5.5, 10.8, 11.0, 14.2, 14.7, 15.5, 16.3, 17.4, 20.3 and 20.6 Crystal of (47) showing a major peak.

(49) {(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a -Dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone.

(50) (2R) -tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-Dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone.

(51) In a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å), diffraction angles 2θ = 9.1, 12.3, 13.6, 14.0, 14.5, 16.0, 16.9, 18.5, 19.7 and 20.7 Crystal of (50) showing the main peak.

(52) [(2R, 5R) -5-Fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2, 11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone.

(53) (2R) -tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-Dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone.

(54) In a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å), diffraction angles 2θ = 13.3, 13.9, 15.0, 16.2, 16.5, 19.1, 19.4, 20.0, 20.4 and 24.2 Crystal of (53) showing a major peak.

(55) A pharmaceutical composition comprising, as an active ingredient, the compound described in any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal thereof.

(56) The pharmaceutical composition according to (55), wherein the pharmaceutical composition has a retinoic acid receptor-related orphan receptor γt inhibitory action.

(57) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for the treatment and / or prevention of a disease that is treated and / or prevented by an retinoic acid receptor-related orphan receptor γt inhibitory action.

(58) For treating and / or preventing a disease in which the pharmaceutical composition treats, improves, reduces and / or prevents symptoms by inhibiting Th17 cell differentiation and / or inhibiting IL-17 production (55) ).

(59) The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic Dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant The pharmaceutical composition according to (55) for the treatment and / or prevention of cellular arteritis, contact dermatitis, optic neuritis or colon cancer.

(60) A pharmaceutical composition for the treatment and / or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease ( 55) The pharmaceutical composition described in 55).

(61) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for the treatment and / or prevention of psoriasis or psoriatic arthritis.

(62) The pharmaceutical composition according to (59) or (60), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(63) A retinoic acid receptor-related orphan receptor comprising the compound described in any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal thereof as an active ingredient Body γt inhibitor.

(64) Use of the compound described in any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal thereof for producing a pharmaceutical composition.

(65) The use according to (64), wherein the pharmaceutical composition is a composition for inhibiting retinoic acid receptor-related orphan receptor γt.

(66) The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic skin Inflammation, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell The use according to (64), which is a composition for the treatment and / or prevention of arteritis inflammation, contact dermatitis, optic neuritis or colon cancer.

(67) A pharmaceutical composition for treating and / or preventing psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease The use according to (64).

(68) The use according to (64), wherein the pharmaceutical composition is a composition for treatment and / or prevention of psoriasis or psoriatic arthritis.

(69) The use according to (66) or (67), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(70) Any one selected from (1) to (54) for use in a method of treating and / or preventing a disease that is treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor γt The compound according to one item or a pharmaceutically acceptable salt thereof or a crystal thereof.

(71) Psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, Type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, The compound described in any one of (1) to (54) or a pharmaceutically acceptable salt thereof for use in a method of treating and / or preventing contact dermatitis, optic neuritis or colorectal cancer Salts or crystals thereof.

(72) For use in a method for the treatment and / or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease (1) ) To (54), or a pharmaceutically acceptable salt or crystal thereof.

(73) The compound according to any one of (1) to (54) or a pharmaceutically acceptable salt thereof for use in a method for treating and / or preventing psoriasis or psoriatic arthritis or Those crystals.

(74) The compound or a pharmaceutically acceptable salt thereof or a crystal thereof according to (71) or (72), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(75) Retinoin for administering a pharmacologically effective amount of the compound described in any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal thereof to a warm-blooded animal Acid receptor-related orphan receptor γt inhibition method.

(76) Diseases in which a pharmacologically effective amount of a compound described in any one of (1) to (42) or a pharmaceutically acceptable salt thereof or a crystal thereof is administered to a warm-blooded animal Treatment and / or prevention method.

(77) The disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell artery (76) The method according to (76), which is inflammation, contact dermatitis, optic neuritis or colon cancer.

(78) The method according to (76), wherein the disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome or chronic obstructive pulmonary disease.

(79) The method according to (76), wherein the disease is psoriasis or psoriatic arthritis.

(80) The method according to (77) or (78), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(81) The method according to any one of (75) to (80), wherein the warm-blooded animal is a human.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl. Preferred is a straight or branched alkyl group having 1 to 3 carbon atoms (C ₁ -C ₃ alkyl group), and more preferred is a methyl group or an ethyl group (C ₁ -C ₂ alkyl group). And even more preferably a methyl group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. A cyclohexyl group is preferred.

In the present invention, the “C ₃ -C ₆ cycloalkenyl group” is a carbon monocyclic group having 3 to 6 carbon atoms including one carbon-carbon double bond. For example, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group. Preferred is a cyclohexenyl group, and more preferred is a 1-cyclohexenyl group.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl or 3-fluoropropyl group. Preferred is a group (C ₁ -C ₃ halogenated alkyl group) in which 1 to 5 “halogen atoms” which are the same or different are bonded to a “C ₁ -C ₃ alkyl group”, more preferably 3 , 3,3-trifluoropropyl group or 3,3-difluoropropyl group.

In the present invention, the “C ₃ -C ₆ halogenated cycloalkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₃ -C ₆ cycloalkyl group”. A group in which one or two fluorine atoms are bonded to a cyclopropyl group or a cyclohexyl group is preferable, and a 2,2-difluorocyclopropyl group, a 3,3-difluorocyclopentyl group, a 3-fluoro group is more preferable. A cyclohexyl group, a 4-fluorocyclohexyl group, or a 3,3-difluorocyclohexyl group.

In the present invention, the “C ₃ -C ₆ halogenated cycloalkenyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₃ -C ₆ cycloalkenyl group”. A 2-fluoro-1-cyclohexenyl group is preferred.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, hexyloxy or 2,3-dimethylbutoxy group. Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C ₁ -C ₄ alkoxy group), and more preferred is a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group). And even more preferred is a methoxy group.

In the present invention, the “(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group” means that one “C ₁ -C ₆ alkoxy group” is the above “C ₁ -C ₆ alkyl group”. It is a group bonded to For example, a methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl or 3-isopropoxypropyl group, preferably A group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₃ alkyl) group) in which _one “C ₁ -C ₄ alkoxy group” is bonded to the “C ₁ -C ₃ alkyl group” And more preferably, a group ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ ) in which _one “C ₁ -C ₂ alkoxy group” is bonded to the “C ₁ -C ₂ alkyl group”. a ₂ alkyl) group), and even more preferably a 1-methoxyethyl group.

In the present invention, the “C ₁ -C ₆ hydroxyalkyl group” is a group in which one hydroxy group is bonded to the “C ₁ -C ₆ alkyl group”. For example, a hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl group. Preferably, one hydroxy group is a group bonded to a “C ₁ -C ₂ alkyl group”, more preferably a hydroxymethyl group or a 2-hydroxyethyl group, and even more preferably a hydroxy group. It is a methyl group.

In the present invention, the “C ₁ -C ₆ dihydroxyalkyl group” is a group in which two hydroxy groups are bonded to the “C ₁ -C ₆ alkyl group”. For example, 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl or 3,4-dihydroxybutyl groups. A group in which two hydroxy groups are bonded to a propyl group or a butyl group is preferable, and a 2,3-dihydroxypropyl group is more preferable.

In the present invention, the “C ₁ -C ₆ cyanoalkyl group” is a group in which one cyano group is bonded to the “C ₁ -C ₆ alkyl group”. For example, a cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl group. A group in which one cyano group is bonded to a “C ₁ -C ₂ alkyl group” is preferable, and a cyanomethyl group is more preferable.

In the present invention, the “C ₁ -C ₆ alkylsulfonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a sulfonyl group. For example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or hexylsulfonyl group. Preferred is a linear or branched alkylsulfonyl group having 1 to 3 carbon atoms (C ₁ -C ₃ alkylsulfonyl group), and more preferred is a methylsulfonyl group or an ethylsulfonyl group (C ₁ -C _2). Alkylsulfonyl group), and more preferably a methylsulfonyl group.

In the present invention, “(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group” means that one “C ₁ -C ₆ alkylsulfonyl group” is the above “C ₁ -C ₆ alkyl group”. A group bonded to “group”. For example, it is a methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, isopropylsulfonylmethyl, methylsulfonylethyl or hexylsulfonylpropyl group, preferably one said “C ₁ -C ₃ alkylsulfonyl group” is the above “ A group ((C ₁ -C ₃ alkylsulfonyl)-(C ₁ -C ₃ alkyl) group) bonded to a “C ₁ -C ₃ alkyl group”, more preferably one of the above “C ₁ -C ₃ alkyl groups”. _{A “2-} alkylsulfonyl group” is a group ((C ₁ -C ₂ alkylsulfonyl)-(C ₁ -C ₂ alkyl) group) bonded to the “C ₁ -C ₂ alkyl group”, and even more preferably, A methylsulfonylmethyl group;

In the present invention, a “C ₂ -C ₇ alkylcarbonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a carbonyl group. For example, an acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group. Preferably, one “C ₁ -C ₃ alkyl group” is a group (C ₂ -C ₄ alkylcarbonyl group) bonded to a carbonyl group, more preferably an acetyl group or a propionyl group (C ₂ —). a C ₃ alkylcarbonyl group), even more preferably more, an acetyl group.

In the present invention, a “C ₁ -C ₆ alkoxycarbonyl group” is a group in which one of the above “C ₁ -C ₆ alkoxy groups” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, 2-methylbutoxycarbonyl, 3-ethylpropoxycarbonyl, hexyloxy A carbonyl or 2,3-dimethylbutoxycarbonyl group. A group in which _one “C ₁ -C ₄ alkoxy group” is bonded to a carbonyl group (C ₁ -C ₄ alkoxycarbonyl group) is preferable, and a t-butoxycarbonyl group is more preferable.

In the present invention, the “C ₂ -C ₇ alkylcarbonyloxy group” is a group in which one carbonyl group bonded to the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom. For example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy, valeryloxy or isovaleryloxy group, and preferably one of the aforementioned “C ₁ -C ₃ alkyl groups” is bonded. A group in which a carbonyl group is bonded to an oxygen atom (C ₂ -C ₄ alkylcarbonyloxy group), more preferably an acetoxy or propionyloxy group (C ₂ -C ₃ alkylcarbonyloxy group), and even more preferably Is an acetoxy group.

In the present invention, the “pyridyl group” is a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, preferably a pyridyl group.

In the present invention, the “tetrahydrofuryl group” is a 2-tetrahydrofuryl group or a 3-tetrahydrofuryl group, preferably a 2-tetrahydrofuryl group, and more preferably (R) -2-tetrahydrofuryl. It is a group.

In the present invention, the “tetrahydropyranyl group” is 2-tetrahydropyranyl group, 3-tetrahydropyranyl group or 4-tetrahydropyranyl group, preferably 2-tetrahydropyranyl group, more preferably Is a (R) -2-tetrahydropyranyl group.

In the present invention, the “triazolyl group” is preferably a 1,2,4-triazolyl group, and more preferably a 1H-1,2,4-triazol-1-yl group.

In the present invention, “phenyl group, pyridyl group, tetrahydrofuryl group which may be independently substituted with 1 to 4 groups independently selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group” , A tetrahydropyranyl group or a benzyl group is selected from a phenyl group, a pyridyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a benzyl group or a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. A phenyl group, a pyridyl group, a tetrahydrofuryl group, a tetrahydropyranyl group or a benzyl group, which are independently substituted with 1 to 4 groups. Preferred is a phenyl group or a tetrahydropyranyl group which may be independently substituted with 1 to 3 halogen atoms, and more preferred is a tetrahydropyranyl group which may be substituted with one fluorine atom. And even more preferably, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluorotetrahydropyran-2 -An yl group.

In the present invention, "C ₁ -C ₆ alkylsulfonyl group 1 independently with a group selected from and two hydroxyl substituted C ₁ -C ₆ alkyl group", a C ₁ -C ₆ alkyl group Or a C ₁ -C ₆ alkyl group which is independently substituted with 1 to 2 groups independently selected from a C ₁ -C ₆ alkylsulfonyl group and a hydroxyl group. Preferably, the “C ₁ -C ₆ alkyl group”, “(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group”, “C ₁ -C ₆ hydroxyalkyl group” or “C ₁ A —C ₆ dihydroxyalkyl group ”, more preferably a methyl group, a methylsulfonylmethyl group, a hydroxymethyl group, or a 2,3-dihydroxypropyl group.

In the present invention, “a group selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group, a carboxy group, an aminocarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group and a triazolyl group” in 1 to 4 optionally substituted _C 1 -C be the ₆ alkyl group independently _"is, C 1 -C ₆ alkyl group or a fluorine atom, a hydroxyl _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkyl a sulfonyl group, a carboxy group, aminocarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, and a C ₁ -C ₆ alkyl radical which is to four substituents independently a group selected from triazolyl group. Preferably, C ₁ may be independently substituted with a group selected from a hydroxyl group, a methoxy group, a methyl sulfonyl group, an aminocarbonyl group, a t-butoxycarbonyl group, and a 1,2,4-triazolyl group. A —C ₆ alkyl group, and more preferably a methyl group or a (R) -2,3-dihydroxypropyl group.

In the present invention, the “2-tetrahydropyranyl group independently substituted with 3 or 4 groups independently selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group” is preferably independently substituted with 3 hydroxyl groups. Or a 2-tetrahydropyranyl group independently substituted with one fluorine atom, two hydroxyl groups and one hydroxymethyl group.

In the present invention, "C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and 1 to 2 optionally substituted C ₁ -C ₆ alkyl group independently with a group selected from cyano group", C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkylsulfonyl group, a C ₁ -C ₆ alkyl radical which is or two substituents independently with a group selected from hydroxyl group and a cyano group. Preferably, the “C ₁ -C ₆ alkyl group”, “(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group”, “C ₁ -C ₆ hydroxyalkyl group” or “C 1 _1- C ₆ cyanoalkyl group ”, more preferably a methyl group or a hydroxymethyl group.

In the present invention, the “saturated ring containing a nitrogen atom” means a ring (group U—T—C (═O) —) corresponding to the steroid skeleton D ring of the tetracyclic compound of the general formula (I). Ring).

In the present invention, “a saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a condensed ring” means that the “saturated ring containing a nitrogen atom” is condensed with a cyclopropane ring. The ring may form a condensed ring such as a 3-azabicyclo [4.1.0] heptane ring (in this case, n is 1).

In the present invention, preferred general formula (I) is general formula (Ia), general formula (Ib) or general formula (Ic), and more preferred general formula (I) is general formula (Ia). .

In the present invention, preferable U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C _{6 is a} cycloalkyl group or a phenyl group or a tetrahydropyranyl group optionally independently substituted by 1 to 3 halogen atoms, and more preferably U is a C ₁ -C ₆ halogenated alkyl group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ halogenated cycloalkyl group or tetrahydropyranyl group optionally substituted by one halogen atom, and still more preferred U is 3,3,3-trifluoropropyl Group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3,3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropi Group, a 4-fluoro tetrahydropyran-2-yl group, 5-fluoro-tetrahydropyran-2-yl group or (2R, 5R) -5- fluoro tetrahydropyran-2-yl group.

In the present invention, preferred R ¹ is a hydrogen atom or a halogen atom, and more preferred R ¹ is a hydrogen atom.

In the present invention, R ² is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

In the present invention, preferred R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group, and more preferred R ³ is a hydrogen atom, a hydroxyl group or a methoxy group.

In the present invention, R ⁴ is preferably a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group.

In the present invention, R ⁵ is preferably a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group; C ₁ which may be independently substituted with a group selected from a hydroxyl group, a methoxy group and an aminocarbonyl group. A —C ₆ alkyl group; or a 2-tetrahydropyranyl group independently substituted with 3 or 4 groups independently selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group, and more preferably R ⁵ is a hydrogen atom, A methyl group or a (R) -2,3-dihydroxypropyl group.

In the present invention, preferred R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group.

In the present invention, R ⁸ is preferably a hydrogen atom.

In the present invention, preferred R ⁹ is a hydrogen atom.

In the present invention, preferred T is a single bond.

In the present invention, Y is preferably a methyl group.

In the present invention, m is preferably 0.

In the present invention, n is preferably 1 or 2.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.). Have.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers since an asymmetric carbon atom exists in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. Examples of the atomic isotope include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention. Isotopically labeled compounds are also encompassed by the compounds of the invention, and any mixture of isotope-labeled compounds in any proportion is also encompassed by the compounds of the invention. The isotope-labeled compound of the present invention can be produced by a method known in the art, for example, by using an isotope-labeled raw material instead of the raw material in the production method of the present invention described later. . A preferred isotope-labeled compound is a compound in which one or more of the hydrogen atoms constituting the compound of the present invention are substituted with deuterium.

“These pharmaceutically acceptable salts” refer to salts that have no significant toxicity and can be used as pharmaceuticals. The compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt, Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, aspartates can be mentioned.

On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-butylamine salts, diisopropylamine salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, trimethylammonium salt And amine salts such as organic salts such as s (hydroxymethyl) aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt.

The compound represented by the general formula (I) of the present invention or its isotope-labeled compound or a pharmaceutically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized. In some cases, adsorbed water is attached or a hydrate is formed, and such a hydrate is also included in the salt of the present invention.

The compound represented by the general formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof may absorb a certain other solvent and become a solvate. Such solvates are also encompassed by the salts of the present invention.

The compound represented by the general formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof is preferably the compound represented by the general formula (I) of the present invention or a pharmacological thereof. It is a salt allowed above, and more preferably a compound represented by the general formula (I) of the present invention.

Another aspect of the present invention relates to crystals of the compounds or salts of the present invention. Here, a crystal means a solid whose internal structure is made up of regularly repeated constituent atoms (or a group thereof) in a three-dimensional manner, and is distinguished from an amorphous solid that does not have such a regular internal structure. .

Even crystals of the same compound may produce crystals (crystal polymorphs) having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions. Any form may be sufficient and the mixture of two or more crystal polymorphs may be sufficient.

The crystal of the present invention absorbs moisture by being left in the atmosphere, and forms a hydrate by adhering water or heating to 25 to 150 ° C. under normal atmospheric conditions. There is a case. Furthermore, the crystal | crystallization of this invention may contain the solvent at the time of crystallization in the adhesion residual solvent or solvate.

In the present specification, the crystal of the present invention may be represented based on powder X-ray diffraction data. However, powder X-ray diffraction is usually measured and analyzed by a technique used in this field. It can be carried out by the method described in the examples. In general, the lattice constant of hydrates and dehydrates changes depending on the attachment and detachment of crystal water, which may change the diffraction angle (2θ) in powder X-ray diffraction. In addition, the intensity of the peak may change due to a difference in crystal growth surface or the like (crystal habit). Therefore, when the crystal of the present invention is represented based on powder X-ray diffraction data, in addition to the crystal having the same diffraction angle and X-ray diffraction diagram of the peak in powder X-ray diffraction, hydrates and dehydrates obtained therefrom Are also included within the scope of the present invention.

The compound represented by the general formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. It is useful for the treatment and / or prevention of RORγt-related diseases such as autoimmune diseases and cancers in which IL-17 production is involved in pathogenesis. Specific diseases include psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstruction Pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colon cancer. Preferred diseases are psoriasis, psoriatic arthritis, ankylosing spondylitis, Sjogren's syndrome or chronic obstructive pulmonary disease (COPD), especially psoriasis or psoriatic arthritis. In addition, the compound represented by the general formula (I) of the present invention, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof selectively prevents abnormalities in Th17 cells, which was impossible with existing treatment methods. The effect which can be treated is expected.

In the present invention, “prevention” means to suppress or delay the onset of a disease that is diagnosed as having a high risk of developing the disease targeted by the present invention due to genetic background or chronic inflammation. To do. In the case of an autoimmune disease, a disease whose onset risk can be diagnosed by single nucleotide polymorphisms (SNPs) or gene mutations is known. In the case of colorectal cancer, it is known that the risk of colorectal cancer is clearly increased due to chronic persistence of colitis. The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action. Prophylactic administration to patients diagnosed with a high risk of onset is expected to have an effect of suppressing or delaying onset.

FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 12. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. The powder X-ray diffraction pattern of the crystal obtained in Example 23. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. 7 is a powder X-ray diffraction pattern of the crystals obtained in Example 71. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. 12 shows a powder X-ray diffraction pattern of the crystal obtained in Example 132. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 133. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. FIG. 12 is a powder X-ray diffraction pattern of the crystals obtained in Example 134. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 160. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. FIG. 6 shows a powder X-ray diffraction pattern of the crystal obtained in Example 165. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 170. FIG. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks. The powder X-ray diffraction pattern of the crystal obtained in Example 177. The vertical axis in the figure indicates the diffraction intensity (Intensity) in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. Numbers 1 to 10 in the figure indicate peak numbers of main peaks.

The compound represented by the general formula (I) of the present invention can be produced according to Method A to Method N described below.

The solvent used in the reaction of each step of the following methods A to N is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting materials to some extent.

In the reaction of each step of Method A to Method N below, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.

In the reaction of each step of Method A to Method N below, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, chromatography (for example, silica gel, alumina, magnesium-silica-based florisil, SO3H-silica (manufactured by Fuji Silysia)). Adsorption column chromatography method; using a carrier such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as distributed column chromatography; a method using ion exchange chromatography; a normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel Usually combined with a suitable eluent) Combining the conventional methods in the separation and purification as appropriate, can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.

In the reaction of each step of the following method A to method N, U, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T, Y, m and n are Shows the same significance as described above. R ¹⁰ represents a C ₁ -C ₆ alkyl group. A methyl group or an ethyl group is preferable, and a methyl group is more preferable. p represents an integer of 0 to 2. L represents a leaving group. P-toluenesulfonyloxy group, methanesulfonyloxy group or chlorine atom is preferred. PRO ¹ represents an amino protecting group used in the field of synthetic organic chemistry. A benzyloxycarbonyl group, a methyloxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group is preferred, and a benzyloxycarbonyl group is more preferred. PRO ² and PRO ³ represent hydroxy-protecting groups used in the field of synthetic organic chemistry. Preferred is an isopropylidene group, acetyl group, benzoyl group or tert-butyldimethylsilyl group, and more preferred is an isopropylidene group, acetyl group or tert-butyldimethylsilyl group. In addition, the amino group, hydroxy group and / or carboxy group which are not clearly specified for protection in the A method to the N method may be protected using a protecting group as necessary. Moreover, when protection is unnecessary, it does not need to protect.

In the method A, among the compounds represented by the general formula (I), R ¹ and R ² are hydrogen atoms, and the group represented by R ⁴ and the formula —OR ⁵ together represents an oxo group, a compound represented by the general formula (II) in which m is 0 and a compound represented by the general formula (I-II) in which R ¹ , R ² and R ⁴ are hydrogen atoms and m is 0 It is a manufacturing method.
(Method A)

Step AI In this step, the compound represented by the general formula (III) is produced by subjecting the compound represented by the general formula (II) to an oximation reaction using a known organic chemical technique. It is a process.

The boiling point of the solvent used for the reaction from 0 ° C. in the presence of a base (sodium acetate, sodium carbonate, etc.) in a solvent (ethanol, water, acetic acid, etc., or a mixed solvent thereof) in the presence of a base (sodium acetate, sodium carbonate, etc.) Up to 50 ° C., preferably from the boiling point of the solvent used in the reaction, by treatment with hydroxylamine. Hydroxylamine hydrochloride is used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of the compound represented by formula (II). The reaction time is 5 minutes to 150 hours, preferably 15 minutes to 100 hours.

The compound represented by the general formula (II) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Step A-II In this step, the compound represented by the general formula (IV) is produced by subjecting the compound represented by the general formula (III) to a Beckmann rearrangement reaction using a known organic chemical technique. It is a process.

In a solvent (benzene, toluene, pyridine, 1,4-dioxane, tetrahydrofuran, dichloromethane or the like or a mixed solvent thereof) in a solvent (from -30 ° C. to the boiling point of the solvent used for the reaction, It is preferably carried out by treating with alkylphosphonic anhydride, polyphosphoric acid, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride, etc. from 0 ° C. to the boiling point of the solvent used in the reaction. The reactant is used in an amount of 0.01 to 30 mol, preferably 0.1 to 10 mol, relative to 1 mol of the compound represented by the general formula (III). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step A-III In this step, the compound represented by the general formula (V) is produced by reducing the compound represented by the general formula (IV) by a known organic chemical method. It is.

The compound represented by the general formula (IV) in a solvent (tetrahydrofuran, 1,4-dioxane, benzene, toluene or the like or a mixed solvent thereof) from −78 ° C. to the boiling point of the solvent used for the reaction, preferably 0 ° C. To the boiling point of the solvent by treating with a reducing agent (lithium aluminum hydride, diborane, lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex or sodium bis (2-methoxyethoxy) aluminum hydride). Is called. The reducing agent is used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of the compound represented by the general formula (IV). If necessary, Lewis acid (tin chloride, trifluoroborane ether complex, etc.) is added. The reaction time is 1 minute to 60 hours, preferably 5 minutes to 24 hours.

Step A-IV In this step, an amidation reaction (when T is a single bond), a carbamation reaction (T is an oxygen atom) using a known organic chemical method for the compound represented by the general formula (V) Or a urea reaction (when T is a group represented by the formula —NH—) to produce a compound represented by the general formula (VI).

In the case of an amidation reaction, the compound represented by the general formula (V) is removed from −30 ° C. in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, N, N-dimethylformamide or the like or a mixed solvent thereof). N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, O- (7-azabenzotriazole-1-) up to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 50 ° C. Yl) -N, N, N ′, N′-tetramethyluronium The reaction is carried out by reacting with a carboxylic acid compound in the presence of a condensing agent such as hexafluoroborate. The condensing agent is used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of the compound represented by the general formula (V). If necessary, a base (triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) is added. The base is used in an excess amount from a catalytic amount. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

In the case of an amidation reaction, the compound represented by the general formula (V) is reacted at −30 ° C. in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, dichloromethane, water, etc. or a mixed solvent thereof). Carboxylic acid halogen compound in the presence of a base (triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, potassium carbonate, sodium bicarbonate, etc.) up to the boiling point of the solvent used in And react. The base is used in a catalytic amount to an excess mole, preferably 0.2 to 2 moles, relative to 1 mole of the compound represented by the general formula (V). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

In the case of carbamate reaction, the compound represented by the general formula (V) is dissolved in a solvent (benzene, toluene, pyridine, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, water, etc. or a mixed solvent thereof) The reaction is carried out at 30 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 50 ° C., by reacting with a haloformate ester or dialkyl dicarbonate. If necessary, a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium hydroxide, etc.) is added. The base is used in an excess amount from a catalytic amount with respect to 1 mol of the compound represented by the general formula (V). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

In the case of the urea reaction, the compound represented by the general formula (V) is reacted from −30 ° C. in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, etc. or a mixed solvent thereof). The reaction is carried out by reacting with an alkyl isocyanate or the like up to the boiling point of the solvent used in the reaction, preferably at 0 to 100 ° C. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step AV This step is a step for producing a compound represented by the general formula (VII) by subjecting the compound represented by the general formula (VI) to an oxidation reaction using a known organic chemical technique. It is.

The compound represented by the general formula (VI) is -30 ° C to 200 ° C, preferably 0 ° C to 120 ° C in a solvent (benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane or the like or a mixed solvent thereof). The reaction is carried out at room temperature by reacting with an aluminum alkoxide in the presence of ketones such as acetone, 2-butanone, cyclohexanone, N-methyl-4-piperidone. The aluminum alkoxide is used in a catalytic amount to an excess mol, preferably 0.2 to 2 mol, relative to 1 mol of the compound represented by the general formula (VI). The ketones are used in an amount of 1 to excess moles, preferably 1 to 10 moles. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step A-VI In this step, the compound represented by the general formula (VIII) is produced by reducing the compound represented by the general formula (VII) by a known organic chemical method. It is.

The compound represented by the general formula (VII) in a solvent (methanol, ethanol, diethyl ether, tetrahydrofuran, 1,4-dioxane or the like or a mixed solvent thereof) is −78 ° C. to 100 ° C., preferably from −78 ° C. The reaction is carried out at room temperature by reacting with a reducing agent such as sodium borohydride. If necessary, 1,2-reduction promoting additives (cerium chloride, etc.) are added. The reducing agent is used in a catalytic amount to an excess mol, preferably 0.25 to 2 mol, relative to 1 mol of the compound represented by the general formula (VII). Further, the reduction promoting additive is used in an amount of 1 to excess mole, preferably 1 to 5 mole. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step A-VII In this step, the compound represented by the general formula (IX) is produced by epoxidizing the compound represented by the general formula (VIII) using a known organic chemical method. It is a process.

The compound represented by the general formula (VIII) is treated with an organic peracid in a solvent (benzene, toluene, methanol, dichloromethane, water or the like or a mixed solvent thereof) from −78 ° C. to room temperature, preferably from −10 ° C. to room temperature. It is carried out by reacting with an oxidizing agent such as alkyl hydroperoxide or hydrogen peroxide. If necessary, a base (sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, etc.) is added. When alkyl hydroperoxide is used, it is carried out in the presence of a metal oxide complex such as aluminum, vanadium, molybdenum or titanium (bis (acetylacetonate) oxovanadium, hexacarbonylmolybdenum, etc.). The base is used in an amount of 1 to excess, preferably 1 to 10 mol per mol of the compound represented by formula (VIII). Further, the metal oxide complex is used in an excess amount, preferably from 0.25 to 2 mol, from a catalytic amount.

Step A-VIII This step is represented by the general formula (X) by subjecting the compound represented by the general formula (IX) to an alkylation reaction or a glycosylation reaction using a known organic chemical technique. This is a process for producing a compound.

In the case of the alkylation reaction, the compound represented by the general formula (IX) is treated with an organic or inorganic base (hydrogenated) in a solvent (N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent thereof). In the presence of sodium, potassium carbonate, potassium t-butoxide, triethylamine, etc.), an additive (triethylbenzylammonium chloride, etc.) is added and the alkyl halide compound, p- It is carried out by treatment with a toluenesulfonyloxyalkyl compound or the like. The alkyl halide compound, p-toluenesulfonyloxyalkyl compound and the like are used in an amount of 1 to excess moles, preferably 1 to 5 moles, relative to 1 mole of the compound represented by the general formula (IX). The reaction time is 1 minute to 72 hours, preferably 5 minutes to 48 hours.

In the case of a glycosylation reaction, an activation reagent containing a compound represented by the general formula (IX) in a solvent (dichloromethane, diethyl ether, toluene, etc.) at −20 ° C. to 100 ° C., preferably −10 ° C. to room temperature. The reaction is carried out by reacting a sugar donor (glycosyl halide, glycosyl imidate, glycosyl phosphate, etc.) in the presence of (protic acid, Lewis acid, etc.). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step A-IX In this step, when R ³ is a hydroxyl group, the compound represented by the general formula (VII) is subjected to a diol-formation reaction using a known organic chemical method to produce a compound represented by the general formula (II It is a process of manufacturing the compound represented by this.

The compound represented by the general formula (VII) in a solvent (tert-butanol, acetone, pyridine, benzene, carbon tetrachloride, water or the like or a mixed solvent thereof) from −78 ° C. to 100 ° C., preferably −10 ° C. To 50 [deg.] C. by reacting with an oxidizing agent such as osmium tetroxide and ruthenium tetroxide. If necessary, a co-oxidant (N-methylmorpholine N-oxide or the like) is added. The oxidizing agent is used in a catalytic amount to an excess mole, preferably 0.1 to 2 moles, relative to 1 mole of the compound represented by the general formula (VII). The reaction time is 10 minutes to 96 hours, preferably 30 minutes to 24 hours.

Step AX In this step, the compound represented by the general formula (I-II) is obtained by subjecting the compound represented by the general formula (X) to an epoxide ring-opening reaction using a known organic chemical technique. Is a process of manufacturing. Conduct reductive epoxide ring-opening reaction with hydride reducing agent, epoxide ring-opening reaction with hetero-reactive agent, epoxide ring-opening reaction with organometallic reagent, etc.

When R ³ is a hydroxyl group, the compound represented by the general formula (X) is -20 ° C. to 150 ° C. in a solvent (acetone, tetrahydrofuran, 1,4-dioxane, water or the like or a mixed solvent thereof), preferably The reaction is carried out by reacting with an acid (perchloric acid, sulfuric acid, etc.) at 0 to 100 ° C. The acid is used in a catalytic amount to an excess mol, preferably 0.25 to 2 mol, per 1 mol of the compound represented by the general formula (X). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step A-XI In this step, the compound represented by the general formula (I-II) is obtained by subjecting the compound represented by the general formula (IX) to a epoxide ring-opening reaction using a known organic chemical method. Is a process of manufacturing. When R ⁵ is a hydrogen atom, the reaction is carried out in the same manner as in the AX process of Method A.

Step A-XII In this step, R ³ is a hydroxyl group, and the compound represented by the general formula (VIII) is subjected to a diolation reaction using a known organic chemical method, whereby the general formula (I-II) It is a process of manufacturing the compound represented by this. When R ⁵ is a hydrogen atom, the reaction is carried out in the same manner as in the A-IX step of Method A.

Step A-XIII In this step, when R ⁵ is a hydrogen atom, the compound represented by the general formula (II) is subjected to a reduction reaction using a known organic chemical method to obtain a compound represented by the general formula (I -II) is a step of producing a compound represented by

The compound represented by the general formula (II) in a solvent (methanol, ethanol, diethyl ether, tetrahydrofuran, 1,4-dioxane or the like or a mixed solvent thereof) from −78 ° C. to 100 ° C., preferably −78 The reaction is carried out by reacting with a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, lithium tri (sec-butyl) borohydride at room temperature from room temperature. The reducing agent is used in a catalytic amount to an excess mol, preferably 0.25 to 3 mol, relative to 1 mol of the compound represented by formula (II). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Method B is a compound represented by the general formula (I) in which R ¹ , R ² , R ⁴ and R ⁵ are hydrogen atoms, R ³ is a hydroxyl group, and m is 0. I-III) is a process for producing a compound represented by
(Method B)

Step BI In this step, a protecting group (benzyloxycarbonyl group, methyloxycarbonyl group, 9-fluorenylmethyloxy) is protected using a known organic chemical method for the compound represented by the general formula (V). In this step, a compound represented by the general formula (XI) is produced by introducing a carbonyl group or the like.

When PRO ¹ is a benzyloxycarbonyl group, the compound represented by the general formula (V) is a solvent (benzene, toluene, pyridine, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, water, etc., or a mixed solvent thereof) The reaction is carried out by reacting with benzyl chloroformate, dibenzyl dicarbonate, etc. at -30 ° C. to the boiling point of the solvent used in the reaction, preferably 0 ° C. to 50 ° C. If necessary, a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium hydroxide, etc.) is added. The base is used in an excess amount from a catalytic amount with respect to 1 mol of the compound represented by the general formula (V). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (V) used in this step is produced according to Step A-III of Method A.

Step B-II In this step, the compound represented by the general formula (XII) is produced by subjecting the compound represented by the general formula (XI) to an oxidation reaction using a known organic chemical technique. It is. This is carried out in the same manner as the AV process of Method A.

Step B-III This step is a step of producing a compound represented by the general formula (XIII) by subjecting the compound represented by the general formula (XII) to a reduction reaction using a known organic chemical technique. It is. This is carried out in the same manner as the A-VI step of Method A.

Step B-IV In this step, the compound represented by the general formula (XIV) is produced by epoxidizing the compound represented by the general formula (XIII) using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

Step BV In this step, the compound represented by the general formula (XV) is produced by subjecting the compound represented by the general formula (XII) to a diolation reaction using a known organic chemical technique. It is a process. This is carried out in the same manner as the A-IX process of Method A.

Step B-VI In this step, the compound represented by the general formula (XVI) is produced by subjecting the compound represented by the general formula (XIII) to a diolation reaction using a known organic chemical method. It is a process. This is carried out in the same manner as the A-IX process of Method A.

Step B-VII In this step, the compound represented by the general formula (XVI) is produced by subjecting the compound represented by the general formula (XIV) to an epoxide ring-opening reaction using a known organic chemical technique. It is a process to do. This is carried out in the same manner as in the AX process of Method A.

Step B-VIII This step is a step of producing a compound represented by the general formula (XVI) by subjecting the compound represented by the general formula (XV) to a reduction reaction using a known organic chemical technique. It is. This is carried out in the same manner as in Step A-XIII of Method A.

Step B-IX In this step, a protective group (isopropylidene group, acetyl group, benzoyl group, etc.) is introduced into the compound represented by the general formula (XVI) using a known organic chemical method. In this step, a compound represented by the general formula (XVII) is produced.

In the case where PRO ² and PRO ³ are isopropylidene groups, the compound represented by the general formula (XVI) is treated with an acid (p) in a solvent (acetone, acetonitrile, tetrahydrofuran, N, N-dimethylformamide or the like, or a mixed solvent thereof). -In the presence of toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, iron chloride, aluminum chloride, etc., from −20 ° C. to the boiling point of the solvent used in the reaction, preferably from 0 ° C. to 50 ° C. Propane, alkyloxypropene, etc.) are reacted. When acetone is used as a solvent, an isopropylidene reagent may not be used. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

When PRO ² and PRO ³ are acetyl groups, the compound represented by the general formula (XVI) is dissolved in a solvent (dichloromethane, N, N-dimethylformamide, pyridine, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof). The reaction is carried out by reacting with an acetylation reagent (acetic anhydride, acetyl chloride, etc.) from −20 ° C. to the boiling point of the solvent used in the reaction, preferably from 0 ° C. to 100 ° C. If necessary, a base (triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.) is added. The base is used in a catalytic amount to an excess mol, preferably 0.2 to 2 mol, relative to 1 mol of the compound represented by the general formula (XVI). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step XX In this step, the compound represented by the general formula (XVIII) is reacted with the compound represented by the general formula (XVII) by a deprotection reaction using a known organic chemical method. It is a manufacturing process.

When PRO ¹ is a benzyloxycarbonyl group, the compound represented by the general formula (XVII) is transitioned in a solvent (ethanol, propanol, methanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane or the like, or a mixed solvent thereof). The reaction is carried out by catalytic hydrogenation in the presence of a metal catalyst (such as palladium carbon) from 0 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 50 ° C. Usually, it is carried out in a hydrogen atmosphere, but if necessary, cyclohexene, 1,4-cyclohexadiene or the like may be used as a hydrogen donor. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step B-XI In this step, the compound represented by the general formula (XVIII) is subjected to an amidation reaction, a carbamation reaction or a ureaation reaction using a known organic chemical method to obtain a compound represented by the general formula (XIX). It is a process of manufacturing the compound represented by these. This is carried out in the same manner as the A-IV step of Method A.

Step B-XII This step is represented by the general formula (I-III) by subjecting the compound represented by the general formula (XIX) to a deprotection reaction using a known organic chemical method. This is a process for producing a compound.

When PRO ² and PRO ³ are isopropylidene groups, the compound represented by the general formula (XIX) is reacted in a solvent (methanol, ethanol, tetrahydrofuran, acetic acid, water, etc. or a mixed solvent thereof) from −20 ° C. to the reaction. The reaction is carried out by reacting with an acid (p-toluenesulfonic acid, hydrochloric acid, acetic acid, etc.) up to the boiling point of the solvent used, preferably at 0 to 100 ° C. The acid is used in a catalytic amount to an excess mol, preferably 0.2 to 2 mol, relative to 1 mol of the compound represented by the general formula (XIX). In the case of acetic acid, it may be used as a solvent. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

When PRO ² and PRO ³ are acetyl groups, the compound represented by the general formula (XIX) is used in a solvent (methanol, ethanol, tetrahydrofuran, water or the like or a mixed solvent thereof) from −20 ° C. It is carried out by reacting with a base (potassium carbonate, sodium methoxide, etc.) up to the boiling point, preferably at 0 ° C. to 50 ° C. The base is used in a catalytic amount to an excess mol, preferably 0.1 to 2 mol, per 1 mol of the compound represented by the general formula (XIX). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

In the method C, among the compounds represented by the general formula (I), R ¹ , R ² and R ⁵ are hydrogen atoms, R ³ is a hydroxyl group and m is 0. This is a method for producing a compound represented by
(Method C)

Step CI This step is a step for producing a compound represented by the general formula (XX) by subjecting the compound represented by the general formula (XIV) to an oxidation reaction using a known organic chemical technique. It is.

In a solvent (acetone, dichloromethane, pyridine or a mixed solvent thereof) of the compound represented by the general formula (XIV), from −30 ° C. to the boiling point of the solvent used for the reaction, preferably from 0 ° C. to the boiling point of the solvent used for the reaction The reaction is carried out by reacting with an oxidizing agent (Jones reagent, pyridinium chlorochromate, desmartin reagent, chromium oxide, etc.). The oxidizing agent is used in an amount of 1 to excess mole, preferably 1 to 10 mole relative to 1 mole of the compound represented by the general formula (XIV). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (XIV) used in this step is produced according to the B-IV step of Method B.

Step C-II This step is represented by the general formula (XXI) by subjecting the compound represented by the general formula (XX) to a nucleophilic addition reaction of an organometallic reagent using a known organic chemical method. This is a process for producing a compound.

A compound represented by the general formula (XX) in a solvent (tetrahydrofuran, diethyl ether or the like or a mixed solvent thereof) at −78 ° C. to 80 ° C., preferably at −78 ° C. to room temperature, is treated with an organometallic reagent (grineer reagent, alkyl This is performed by reacting with a lithium reagent or the like. The organometallic reagent is used in an amount of 1 to excess moles, preferably 1 to 10 moles, relative to 1 mole of the compound represented by the general formula (XX). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step C-III In this step, the compound represented by the general formula (XXII) is produced by subjecting the compound represented by the general formula (XXI) to a epoxide ring-opening reaction using a known organic chemical technique. It is a process to do. When R ³ is a hydroxyl group, the reaction is carried out in the same manner as in the AX process of Method A.

Step C-IV In this step, the compound represented by the general formula (XXIII) is reacted with the compound represented by the general formula (XXIII) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step CV In this step, the compound represented by the general formula (XXIII) is subjected to an amidation reaction, a carbamation reaction or a ureaation reaction using a known organic chemical method to obtain a compound represented by the general formula (I- IV) is a step of producing a compound represented by This is carried out in the same manner as the A-IV step of Method A.

Method D is a compound represented by the general formula ( ^IV ) in which R ¹ , R ⁴ and R ⁵ are hydrogen atoms, R ³ is a hydroxyl group and m is 0 among the compounds represented by the general formula (I). This is a method for producing a compound represented by
(Method D)

Step DI In this step, a protective group (tert-butyldimethylsilyl group, triethylsilyl group, benzyl group, etc.) is introduced into the compound represented by the general formula (XVI) using a known organic chemical method. In this step, the compound represented by the general formula (XXIV) is produced.

When PRO ² is a tert-butyldimethylsilyl group, the compound represented by the general formula (XVI) is −20 ° C. in a solvent (dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide or the like, or a mixed solvent thereof). To 120 ° C., preferably at 0 ° C. to 100 ° C., by reacting with a tert-butyldimethylsilylation reagent (tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl trifluoromethanesulfonate, etc.). If necessary, a base (imidazole, pyridine, 2,6-lutidine, 4-dimethylaminopyridine, sodium hydride, etc.) is added. The base is used in an amount of 1 to excess mol, preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (XVI). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (XVI) used in this step is produced according to the B-VI step, B-VII step or B-VIII step of Method B.

Step D-II In this step, the compound represented by the general formula (XXV) is produced by subjecting the compound represented by the general formula (XXIV) to an oxidation reaction using a known organic chemical technique. It is. This is carried out in the same manner as the CI process in the C method.

Step D-III This step is represented by the general formula (XXVI) by subjecting the compound represented by the general formula (XXV) to a nucleophilic addition reaction of an organometallic reagent using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as in the C-II step of Method C.

Step D-IV In this step, the compound represented by the general formula (XXVII) is reacted with the compound represented by the general formula (XXVII) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step DV In this step, the compound represented by the general formula (XXVII) is subjected to an amidation reaction, a carbamation reaction or a ureaation reaction using a known organic chemical method to obtain a compound represented by the general formula (XXVIII). It is a process of manufacturing the compound represented by these. This is carried out in the same manner as the A-IV step of Method A.

Step D-VI This step is represented by the general formula (IV) by subjecting the compound represented by the general formula (XXVIII) to a deprotection reaction using a known organic chemical method. This is a process for producing a compound.

When PRO ² is a tert-butyldimethylsilyl group, the compound represented by the general formula (XXVIII) is -20 ° C to 120 ° C in a solvent (methanol, ethanol, acetonitrile, tetrahydrofuran, water, etc., or a mixed solvent thereof). Until preferably at 0 to 100 ° C. by reacting with an acid (trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, acetic acid, etc.). The acid is used in a catalytic amount to an excess mol, preferably 0.2 to 2 mol, relative to 1 mol of the compound represented by the general formula (XXVIII). In the case of acetic acid, it may be used as a solvent.

Alternatively, the compound represented by the general formula (XXVIII) is -20 ° C to 120 ° C, preferably 0 ° C to 100 ° C, in a solvent (dichloromethane, chloroform, acetonitrile, tetrahydrofuran, water, or the like). And desilylation reagent (hydrofluoric acid-pyridine, hydrofluoric acid-triethylamine, hydrofluoric acid salt, hydrofluoric acid, tetra n-butylammonium fluoride, etc.). When tetra-n-butylammonium fluoride is used, an acid (such as acetic acid) is added as necessary. The desilylation reagent is used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of the compound represented by the general formula (XXVIII). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Method E is represented by the general formula (I-VI) in which R ¹ , R ² , R ⁴ and R ⁵ are hydrogen atoms and m is 0 among the compounds represented by the general formula (I). This is a method for producing a compound.
(E method)

Step EI In this step, when R ³ is a C ₁ -C ₆ alkoxy group, the compound represented by the general formula (XXIV) is subjected to an alkylation reaction using a known organic chemical method, This is a step for producing a compound represented by the general formula (XXIX). This is carried out in the same manner as the A-VIII step of Method A.

The compound represented by the general formula (XXIV) used in this step is produced according to the DI step of Method D.

Step E-II In this step, the compound represented by the general formula (XXX) is reacted with the compound represented by the general formula (XXIX) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step E-III In this step, the compound represented by the general formula (XXX) is subjected to an amidation reaction, carbamation reaction or urealation reaction using a known organic chemical method, thereby producing a compound represented by the general formula (XXXI). It is a process of manufacturing the compound represented by these. This is carried out in the same manner as the A-IV step of Method A.

Step E-IV This step is represented by the general formula (I-VI) by subjecting the compound represented by the general formula (XXXI) to a deprotection reaction using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as the D-VI step of Method D.

Method F is represented by the general formula (I-VII) in which R ² and R ⁴ are hydrogen atoms, R ³ is a hydroxyl group, and m is 0 among the compounds represented by the general formula (I). A method for producing a compound to be produced.
(F method)

Step FI This step is a step for producing a compound represented by the general formula (XXXII) by subjecting the compound represented by the general formula (X) to an acid treatment. In this step, the compound represented by the general formula (I-II) is also produced.

The compound represented by the general formula (X) in a solvent (acetone, tetrahydrofuran, 1,4-dioxane, water or the like or a mixed solvent thereof) at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction is carried out by reacting an acid (perchloric acid, sulfuric acid, etc.). The acid is used in a catalytic amount to an excess mol, preferably 0.25 to 2 mol, per 1 mol of the compound represented by the general formula (X). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (X) used in this step is produced according to the A-VIII step of Method A.

Step F-II In this step, the compound represented by the general formula (XXXIII) is produced by epoxidizing the compound represented by the general formula (XXXII) using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

Step F-III In this step, the compound represented by the general formula (I-VII) is reacted with the compound represented by the general formula (XXXII) using a known organic chemical method to form a compound represented by the general formula (I-VII). It is a manufacturing process. When R ¹ is a hydroxyl group, the reaction is performed in the same manner as in the A-IX process of Method A.

Step F-IV In this step, the compound represented by the general formula (I-VII) is obtained by subjecting the compound represented by the general formula (XXXIII) to an epoxide ring-opening reaction using a known organic chemical technique. Is a process of manufacturing. This is carried out in the same manner as in the AX process of Method A.

When R ¹ is a fluorine atom, the compound represented by the general formula (XXXIII) is fluorinated in a solvent (dichloromethane or the like) from −20 ° C. to the boiling point of the solvent used in the reaction, preferably from −10 ° C. to room temperature. The reaction is carried out by reacting with hydrogen acid-pyridine, hydrofluoric acid-triethylamine, hydrofluoric acid salt or the like. The reaction agent is used in an amount of 1 to excess mole, preferably 1 to 5 mole relative to 1 mole of the compound represented by the general formula (XXXIII). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Method G is represented by the general formula (I-VIII) in which R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms and m is 0 among the compounds represented by the general formula (I). And a compound represented by formula (I-IX) in which R ² , R ³ and R ⁴ are hydrogen atoms and m is 0.
(G method)

Step GI In this step, the compound represented by the general formula (XXXIV) is produced by epoxidizing the compound represented by the general formula (VI) using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

The compound represented by the general formula (VI) used in this step is produced according to the A-IV step of Method A.

Step G-II In this step, the compound represented by the general formula (I-VIII) is obtained by subjecting the compound represented by the general formula (XXXIV) to an epoxide ring-opening reaction using a known organic chemical technique. Is a process of manufacturing. This is carried out in the same manner as in the AX process of Method A.

Step G-III This step is represented by the general formula (XXXV) by subjecting the compound represented by the general formula (VI) to an alkylation reaction or a glycosylation reaction using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as the A-VIII step of Method A.

Step G-IV In this step, the compound represented by the general formula (XXXVI) is produced by epoxidizing the compound represented by the general formula (XXXV) using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

Step GV In this step, the compound represented by the general formula (I-IX) is obtained by subjecting the compound represented by the general formula (XXXVI) to an epoxide ring-opening reaction using a known organic chemical method. Is a process of manufacturing. This is carried out in the same manner as in the AX process of Method A.

Step G-VI In this step, the compound represented by the general formula (I-VIII) is subjected to an alkylation reaction or a saccharification reaction using a known organic chemical method to produce a compound represented by the general formula (I-IX). It is a process of manufacturing the compound represented by these. This is carried out in the same manner as the A-VIII step of Method A.

Method H is a compound represented by general formula (IX) in which R ² , R ³ and R ⁴ are hydrogen atoms and m is 0 among the compounds represented by general formula (I). It is a manufacturing method.
(Method H)

Step HI In this step, the compound represented by the general formula (XXXVII) is produced by epoxidizing the compound represented by the general formula (XI) by using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

The compound represented by the general formula (XI) used in this step is produced according to the BI step of method B.

Step H-II In this step, the compound represented by the general formula (XXXVIII) is produced by subjecting the compound represented by the general formula (XXXVII) to an epoxide ring-opening reaction using a known organic chemical method. It is a process to do. This is carried out in the same manner as in the AX process of Method A.

Step H-III In this step, the compound represented by the general formula (XXXIX) is reacted with the compound represented by the general formula (XXXVIII) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step H-IV This step is represented by the general formula (XL) by subjecting the compound represented by the general formula (XXXVIII) to an alkylation reaction or a glycosylation reaction using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as the A-VIII step of Method A.

Step HV In this step, the compound represented by the general formula (XXXIX) is subjected to an amidation reaction, carbamation reaction, or ureaation reaction using a known organic chemical method to obtain a compound represented by the general formula (I- This is a process for producing a compound represented by X). When R ⁵ is a hydrogen atom, the reaction is performed in the same manner as in Step A-IV of Method A.

Step H-VI In this step, the compound represented by the general formula (XL) is reacted with the compound represented by the general formula (XL) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step H-VII In this step, the compound represented by the general formula (XLI) is subjected to an amidation reaction, carbamation reaction, or urea formation reaction using a known organic chemical method, whereby the general formula (I- This is a process for producing a compound represented by X). This is carried out in the same manner as the A-IV step of Method A.

Method I is a method for producing a compound represented by the general formula (XL) used in the H-VI step of Method H.
(Method I)

Step II In this step, a hydroxyl group is removed from the compound represented by the general formula (XI) by a known organic chemical method (p-toluenesulfonyloxy group, methanesulfonyloxy group or chlorine). It is a step of producing a compound represented by the general formula (XLII) by converting into atoms and the like.

When a sulfonyloxy group such as an arylsulfonyloxy group or an alkylsulfonyloxy group is introduced as a leaving group, the compound represented by the general formula (XI) is used as a solvent (dichloromethane, chloroform, diethyl ether, tetrahydrofuran, pyridine, etc. In a mixed solvent) at −20 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C., by reacting with a sulfonylation reagent (p-toluenesulfonyl chloride, methanesulfonyl chloride, etc.). If necessary, a base (triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane, etc.) is added. The base is used in an amount of 1 to excess mol, preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (XI). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

In addition, when a chlorine atom is introduced as a leaving group, the compound represented by the general formula (XI) is preferably −20 ° C. to 120 ° C. in a solvent (dichloromethane, chloroform, toluene or the like or a mixed solvent thereof). Is carried out by reacting with a chlorination reagent (thionyl chloride, phosphorus pentachloride, etc.) at 0 to 100 ° C. If necessary, the reaction may be carried out without a solvent, and the reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (XI) used in this step is produced according to the BI step of method B.

Step I-II In this step, the compound represented by the general formula (XLIII) is produced by reacting the compound represented by the general formula (XLII) with an alcohol using a known organic chemical technique. It is a process.

The compound represented by the general formula (XLII) is reacted with an alcohol in a solvent (tetrahydrofuran, 1,4-dioxane, toluene or the like or a mixed solvent thereof) at 0 ° C. to 150 ° C., preferably at room temperature to 120 ° C. To implement. If necessary, an acid (p-toluenesulfonic acid or the like) is added. The acid is used in a catalytic amount to an excess mol, preferably 0.1 to 5 mol, per 1 mol of the compound represented by the general formula (XLII). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step I-III In this step, the compound represented by the general formula (XL) is produced by epoxidizing the compound represented by the general formula (XLIII) using a known organic chemical method. It is a process. This is carried out in the same manner as the A-VII step of Method A.

Method J is a method for producing a compound represented by the general formula (I-XI) in which R ² and R ³ are hydrogen atoms and m is 0 among the compounds represented by the general formula (I). It is.
(J method)

Step JI In this step, the compound represented by the general formula (XLIV) is produced by subjecting the compound represented by the general formula (XXXVIII) to an oxidation reaction using a known organic chemical technique. It is. This is carried out in the same manner as the CI process in the C method.

The compound represented by the general formula (XXXVIII) used in this step is produced according to the H-II step of Method H.

Step J-II This step is represented by the general formula (XLV) by subjecting the compound represented by the general formula (XLIV) to a nucleophilic addition reaction of an organometallic reagent using a known organic chemical method. This is a process for producing a compound. This is carried out in the same manner as in the C-II step of Method C.

Step J-III In this step, the compound represented by the general formula (XLVI) is reacted with the compound represented by the general formula (XLV) by a deprotection reaction using a known organic chemical method. It is a manufacturing process. This is carried out in the same manner as the BX process of Method B.

Step J-IV In this step, the compound represented by the general formula (XLVI) is subjected to an amidation reaction, carbamation reaction, or ureaation reaction using a known organic chemical method, thereby producing a compound represented by the general formula (I- XI) is a step of producing a compound represented by When R ⁵ is a hydrogen atom, the reaction is performed in the same manner as in Step A-IV of Method A.

A compound represented by the general formula (XLVII), a compound represented by the general formula (LIV), a compound represented by the general formula (LIX), or a compound represented by the general formula (LXI), which is produced by the K method to the N method. In the compound represented by the general formula (I), m is 1 to 3 and / or a saturated ring containing a nitrogen atom is obtained. A compound that is condensed with a cyclopropane ring to form a condensed ring can be produced.

Method K is a method for producing a compound represented by the general formula (XLVII) by introducing the substituent Y into the compound represented by the general formula (II).
(K method)

Step KI In this step, the compound represented by the general formula (II) is once converted to trimethylsilyl enol ether using a known organic chemical method and then alkylated using a known organic chemical method. In this step, the compound represented by the general formula (XLVII) is produced by a reaction or a halogenation reaction.

Trimethylsilyl enol ether obtained from the compound represented by the general formula (II) in a solvent (dichloromethane, acetonitrile, N, N-dimethylformamide or the like or a mixed solvent thereof) from −78 ° C. to 120 ° C., preferably − At 20 ° C. to 70 ° C., an alkyl halide (such as methyl iodide) or a halogenating reagent (N-fluorobenzenesulfonimide, N-fluoropyridinium trifluoromethanesulfonate, chloromethyl-4-fluoro-1,4-diazoniabicyclo [ 2,2,2] octane bis (tetrafluoroborate), xenon fluoride, etc.) are reacted. If necessary, a reaction accelerator (titanium tetrachloride, tetra-n-butylammonium fluoride, etc.) is added. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (II) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Method L is a method for producing a compound represented by the general formula (LIV) by introducing the substituent Y into the compound represented by the general formula (VII).
(L method)

Step LI In this step, the compound represented by the general formula (XLIX) is produced by subjecting the compound represented by the general formula (XLVIII) to an imino etherification reaction using a known organic chemical technique. It is a process to do.

The compound represented by the general formula (XLVIII) in a solvent (dichloromethane or the like) from −10 ° C. to the boiling point of the solvent used for the reaction, preferably from 0 ° C. to 50 ° C., is preferably methyl trifluoromethanesulfonate, trimethyloxonium tetra The reaction is carried out by reacting fluoroborate or the like. If necessary, a base (N, N-diisopropylethylamide, triethylamine, etc.) is added. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (XLVIII) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material. For example, it is produced from a compound represented by the general formula (IV).

Step L-II In this step, the compound represented by the general formula (L) is produced by subjecting the compound represented by the general formula (XLIX) to an enol etherification reaction using a known organic chemical technique. It is a process to do.

The compound represented by the general formula (XLIX) is −20 ° C. in a solvent (tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, toluene, benzene, N, N-dimethylformamide, etc. or a mixed solvent thereof). Reaction with alcohol, orthoester (ethyl orthoformate, methyl orthoformate, dimethoxypropane, etc.) in the presence of acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.) at from 0 to 150 ° C, preferably from 0 ° C to 120 ° C To implement. The acid is used in an amount of 1 to excess mol, preferably 1.1 to 5 mol, relative to 1 mol of the compound represented by the general formula (XLIX). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step L-III This step is represented by the general formula (LI) by subjecting the compound represented by the general formula (L) to an alkylation reaction or a halogenation reaction using a known organic chemical method. This is a process for producing a compound.

The compound represented by the general formula (L) is used as a base (n-butyllithium) in a solvent (tetrahydrofuran, diethyl ether or the like or a mixed solvent thereof) at −78 ° C. to 50 ° C., preferably at −78 ° C. to room temperature. , Sec-butyllithium, tert-butyllithium, etc.), followed by alkyl halide (methyl iodide, ethyl iodide, etc.) or halogenated reagent (N-fluorobenzenesulfonimide, chloromethyl-4-fluoro-1) , 4-diazoniabicyclo [2,2,2] octane bis (tetrafluoroborate), etc.). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step L-IV In this step, the compound represented by the general formula (LII) is produced by subjecting the compound represented by the general formula (LI) to a reduction reaction using a known organic chemical technique. It is.

The compound represented by the general formula (LI) is reduced in a solvent (methanol, ethanol or the like or a mixed solvent thereof) from −20 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 70 ° C. It reacts with sodium borohydride etc.). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step LV In this step, the compound represented by the general formula (LII) is subjected to an amidation reaction, carbamation reaction, or urea reaction using a known organic chemical method to obtain a compound represented by the general formula (LIII). It is a process of manufacturing the compound represented by these. This is carried out in the same manner as the A-IV step of Method A.

Step L-VI This step is represented by the general formula (LIV) by subjecting the compound represented by the general formula (LIII) to an acid hydrolysis reaction of enol ether using a known organic chemical method. This is a process for producing a compound.

The compound represented by the general formula (LIII) is −10 ° C. to 150 ° C., preferably 0 in a solvent (tetrahydrofuran, acetone, methanol, ethanol, N, N-dimethylformamide, water, etc., or a mixed solvent thereof). It is carried out by reacting with an acid (hydrochloric acid, sulfuric acid, etc.) at a temperature of from 100 ° C. to 100 ° C. The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Method M is a method for producing a compound represented by the general formula (LIX) by introducing the substituent Y into the compound represented by the general formula (II).
(M method)

Step MI This step introduces a protective group (tert-butyldimethylsilyl group, triethylsilyl group, benzyl group, etc.) to the compound represented by the general formula (LV) using a known organic chemical method. Is a step of producing a compound represented by the general formula (LVI). This is carried out in the same manner as the DI step of the D method.

The compound represented by the general formula (LV) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Step M-II In this step, the compound represented by the general formula (LVI) is subjected to 1,4-addition reaction to an α, β-unsaturated ketone by using a known organic chemical method. This is a process for producing a compound represented by the formula (LVII).

The compound represented by the general formula (LVI) in an organic copper reagent (organolithium) in the presence of trimethylsilyl chloride in a solvent (tetrahydrofuran, diethyl ether, etc.) at −78 ° C. to 50 ° C., preferably at −78 ° C. to room temperature. It is carried out by reacting with a reagent, an organic magnesium reagent and the like and a copper salt). The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

Step M-III In this step, the compound represented by the general formula (LVII) is subjected to a deprotection group reaction using a known organic chemical method, followed by a hydrolysis reaction of silyl enol ether. This is a process for producing a compound represented by the formula (LVIII). Both reactions can be carried out simultaneously according to the case where PRO ^{2 in} the D-VI step of Method D is a tert-butyldimethylsilyl group.

Step M-IV In this step, a compound represented by the general formula (LIX) is produced by introducing an acetyl group into the compound represented by the general formula (LVIII) using a known organic chemical method. It is a process to do. This is carried out in the same manner as when PRO ² and PRO ^{3 in} the B-IX process of Method B are acetyl groups.

Method N is a method for producing a compound represented by the general formula (LXI) by introducing a cyclopropane ring into the compound represented by the general formula (II).
(N method)

Step NI In this step, a compound represented by the general formula (LX) is produced by subjecting the compound represented by the general formula (LV) to cyclopropanation using a known organic chemical method. It is a process to do.

Trimethylsulfoxonium iodide and a base (sodium hydride etc.) in a solvent (dimethyl sulfoxide etc.) in a solvent (dimethyl sulfoxide etc.) at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. The reaction is carried out in the system with the reagent obtained from The reaction time is 10 minutes to 72 hours, preferably 30 minutes to 24 hours.

The compound represented by the general formula (LV) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Step N-II In this step, a compound represented by the general formula (LXI) is produced by introducing an acetyl group into the compound represented by the general formula (LX) using a known organic chemical method. It is a process to do. This is carried out in the same manner as when PRO ² and PRO ^{3 in} the B-IX process of Method B are acetyl groups.

In the above, the protecting group of amino group, hydroxy group and / or carboxy group which may be protected is a protecting group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. It refers to protecting groups commonly used in organic synthetic chemistry (see, for example, T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc.1999 (1999)).

In the above, the “protecting group” of the hydroxy group which may be protected is not particularly limited as long as it is a protecting group of a hydroxy group used in the field of synthetic organic chemistry, but for example, a formyl group, the “C ₂ — C ₇ alkylcarbonyl group ”, C ₂ -C ₇ halogenated alkylcarbonyl group such as 2,2,2-trichloroethylcarbonyl, alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioroyl, methacryloyl, crotonoyl, isocrotonoyl, (E) an “alkylcarbonyl group” such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl; an arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4- Halogenated arylcarbos such as chlorobenzoyl Nyl group, 2,4,6-trimethylbenzoyl, C ₁ -C ₆ alkylated arylcarbonyl group such as 4-toluoyl, C ₁ -C ₆ alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl Nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C ₂ -C ₇ alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl, etc. “Arylcarbonyl group”; C ₂ -C ₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or tri- (C ₁ -C ₆ alkyl) silyl group "Alkoxycarbonyl groups" such as substituted _C 2 -C ₇ alkoxycarbonyl group; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran - “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as 2-yl, 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl or tetrahydro” such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl thiofuranyl group "; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl dimethylsilyl, methyl diisopropylsilyl, methyldi -t- butylsilyl, tri as triisopropylsilyl - _(C 1 -C ₆ alkyl) System Group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, such as phenyl diisopropylsilyl (C ₁ -C ₆ alkyl) diarylsilyl or di - (C ₁ -C ₆ alkyl) "silyl group such as an aryl silyl group A (C ₁ -C ₆ alkoxy) methyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxy such as ethoxymethyl _(C 1 -C ₆ alkoxy) - _(C 1 -C ₆ alkoxy) methyl group, 2,2,2-trichloroethoxymethyl, such as bis (2-chloroethoxy) methyl _{(C 1} - “Alkoxymethyl groups” such as C ₆ halogenated alkoxy) methyl; “Substituted ethyl groups” such as toxiethyl, (C ₁ -C ₆ alkoxy) ethyl groups such as 1- (isopropoxy) ethyl, ethyl halide groups such as 2,2,2-trichloroethyl; benzyl, α- A C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4- Methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4- bromobenzyl, _4-cyano-C 1 -C ₆ alkyl such as _benzyl, C 1 -C ₆ alkoxy, nitro Halogen, "aralkyl group" such as C ₁ -C ₆ alkyl radicals in which an aryl ring is substituted with 1 to 3 aryl groups substituted with a cyano group; vinyloxycarbonyl, "alkenyloxycarbonyl such as allyloxycarbonyl Group "; one or two C ₁ -C ₆ such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl An “aralkyloxycarbonyl group” in which an aryl ring may be substituted with an alkoxy or nitro group, preferably an alkylcarbonyl group, a silyl group or an aralkyl group.

In the above, the “protecting group” of the carboxy group that may be protected is not particularly limited as long as it is a protecting group of the carboxy group used in the field of synthetic organic chemistry, but for example, the above “C ₁ -C ₆ alkyl” group "; vinyl, _C 2 -C ₆ alkenyl groups such as allyl; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, _C 2 -C ₆ alkynyl groups such as 1-butynyl, wherein A “C ₁ -C ₆ halogenated alkyl group”; the “C ₁ -C ₆ hydroxyalkyl group”; a (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl) group such as acetylmethyl; “Aralkyl group”; or the above-mentioned “silyl group”, preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

In the above, the “protecting group” of the amino group that may be protected is not particularly limited as long as it is an amino group protecting group used in the field of synthetic organic chemistry. “Alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “aralkyl group”; “alkenyloxycarbonyl group”; or “aralkyloxycarbonyl group” Or “N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene, etc. A substituted methylene group that forms a Schiff base, preferably an Le carbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group.

Processes that require protection / deprotection are described in known methods (for example, “Protective Groups in Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, 1999, published by Wiley-Interscience Publication)). Method).

The compound of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as drops, suppositories (rectal administration), and external preparations (transdermal administration). These various preparations are pharmaceutical preparation techniques such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, solvents, bases, etc. It can be formulated using adjuvants that can usually be used in the field.

When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.

When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.

When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.

When used as an external preparation, it can be used as an external solid preparation, an external solution (liniment, lotion), a spray, an ointment, a cream, a gel, or a patch. These external preparations can be produced according to a conventional method using solvents, bases, additives, excipients and the like which are usually used for pharmaceuticals.

In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.

The amount of the active ingredient compound contained in the above preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.

The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, particularly humans), but in the case of oral administration, the lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight). The upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight). In the case of intravenous administration, the lower limit is 0.005 mg / kg body weight (preferably 0.05 mg / kg body weight), and the upper limit It is desirable to administer 50 mg / kg body weight (preferably 5 mg / kg body weight) once or several times per day depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, a silica gel 60F ₂₅₄ manufactured by Merck is used as a TLC plate, a solvent used as an elution solvent in column chromatography is used as a developing solvent, and a UV detector or phosphomolybdic acid (ethanol solution) is used as a detection method. ) Was used. Silica gel for columns is Merck SK-85 (230-400 mesh), Yamazen (Hi-Flash ^TM Column), Biotage (SNAP, SNAP Ultra), Moritex (Purif-pack) or Grace (GraceResolv ^™ ) was used. In addition to normal column chromatography, Yamazen (FR50N, Parallel Frac FR-360, W-Prep 2XY), TELEDYNE ISCO (Companion Combi Flash), Moritex (Purif-α2), and Biotage ( The automatic chromatography apparatus of SP-1) was appropriately used.

For purification by preparative TLC, silica gel 60F ₂₅₄ manufactured by Merck & Co., Inc., 1.0 mm thickness, plate 20 × 20 cm was used. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, ml: milliliter, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectra are described with chemical shift values expressed as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, br for broad lines, and m for multiple lines. As a measurement solvent, CDCl ₃ : deuterated chloroform or CD ₃ OD: deuterated methanol was used.

Mass spectrometry (hereinafter referred to as “MS”) was performed by the FAB (Fast Atom Bombardment) method, the EI (Electron Ionization) method, or the ESI (Electron Spray Ionization) method.

For powder X-ray diffraction, several mg of the test substance was collected with a spatula, placed on a non-reflective sample holder, flattened with a medicine-wrapping paper, and then the peak pattern was analyzed under the following analysis conditions.
<Analysis conditions>
Model: Rigaku Rint TTR-III, Sample holder: Non-reflective sample holder Sample: Appropriate amount, X-ray generation conditions: 50kV, 300mA, Wavelength: 1.54 angstrom (copper Kα ray)
Scanning speed: 20 ° / min, scanning range: 2-40 °, sampling width: 0.02 °.

(Example 1)
(Example 1-1)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (α-alcohol)

(Example 1-2)
Cyclohexyl [(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (β-alcohol)

(Process 1)
Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11, 12,12a-tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-1,2,3 , 4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-hexadecahydronaphtho [2,1-f] quinolin-8-ol (10 g) in dichloromethane (100 ml ) And water (100 ml) and sodium bicarbonate (9.9 g) was added. While stirring under ice cooling, cyclohexylcarbonyl chloride (5.2 ml) was added little by little, and the mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was poured into a two-layer solution of ethyl acetate and saturated brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to obtain the title compound (6.1 g).
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.36-5.34 (1H, m), 3.54-3.50 (1H, m), 3.46-3.35 (2H, m), 3.27-3.26 (1H, m), 2.55-2.11 ( 5H, m), 1.89-0.99 (25H, m), 1.43 (3H, s), 0.97 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 6aS, 6bR, 9S, 12aR, 12bS) -9-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline-4 (4aH ) -Yl] methanone To a solution of the compound obtained in Step 1 above (2.84 g) in dichloromethane (50 ml) was added 3-chloroperbenzoic acid (3.68 g) under ice cooling, and the mixture was stirred for 1 hour while warming to room temperature. did. The reaction was stopped by adding a 10% aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give a diastereomeric mixture of the title compound (2.60 g) as a white solid.
Main product
¹ H-NMR (CDCl ₃ ) δ: 3.88 (1H, m), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4Hz), 2.33 (1H, m), 2.33 (1 H, dd, J = 3.0, 11.5 Hz), 2.00-1.08 (28H, m), 1.35 (3H, s), 1.00 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (α-alcohol)
And cyclohexyl [(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] Methanone (β-alcohol)
Lithium borohydride (545 mg) and boron trifluoride diethyl ether complex (0.039 ml) were sequentially added to a tetrahydrofuran (30 ml) solution of the compound (2.60 g) obtained in the above step 2, and the mixture was heated to reflux for 26 hours. Ice pieces and saturated aqueous ammonium chloride solution were added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and a mixture of ethyl acetate and dichloromethane (1: 1) was added to the residue to form a slurry, and the solid was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (α-alcohol) (1.11 g) as a white solid.

The filtrate was further concentrated under reduced pressure, and then purified in turn by silica gel column chromatography [ethyl acetate / hexane] and reverse-phase high performance liquid chromatography [acetonitrile / water containing 0.1% formic acid] to give the title compound (β-alcohol) (35 mg). Obtained as a white solid.
α-alcohol: Example 1-1
MS (ESI) m / z: 418 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 1.86-1.12 (31H m), 1.38 (3H, s), 1.10 (1H, s), 0.92 (3H, s).
β-alcohol: Example 1-2
MS (ESI) m / z: 418 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.13 (1H, brs), 3.41 (1H, m), 3.33 (1H, m), 3.26 (1H, m), 3.04 (1H, br), 2.77 (1H, br ), 2.34 (1H, m), 2.15 (1H, dd, J = 3.4,14.6Hz), 1.84-1.10 (28H, m), 1.37 (3H, s), 0.92 (1H, m), 0.88 (3H, s).

(Example 2)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6,6a, 8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6,6a, 8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone A solution of the compound obtained in Example 1 Step 2 (185 mg) in dioxane (3.0 ml) was mixed with water (0.16 ml) and 0.1 N perchloric acid / 1,4-dioxane solution (0.40 ml at room temperature). ) Were added in order, and the mixture was stirred at the same temperature for 4 hours. Diethyl ether was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed thoroughly with diethyl ether, water and diethyl ether in this order, and dried under reduced pressure to give the title compound (125 mg) as a white solid.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.09 (1H, m), 3.58 (1H, brs), 3.46 (1H, m), 3.36 (1H, m), 3.29 (1H, m), 2.08 (1H, m ), 2.08 (1H, dd, J = 11.3, 12.9 Hz), 1.89-1.17 (29H, m), 1.44 (3H, s), 1.14 (3H, s), 1.10 (1H, s).

(Example 3)
(4aS, 4bR, 6aR, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-8 (2H) -one

(Process 1)
(4aS, 4bR, 6aR, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-8 (2H) -one Example 1 To a solution of the compound (α-alcohol) (400 mg) obtained in Step 3 in dichloromethane (20.0 ml) was added Dess-Martin periodinane (609 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution and 10% aqueous sodium thiosulfate solution were added to the reaction solution to stop the reaction. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Dichloromethane was added to the residue obtained by concentrating the filtrate under reduced pressure to form a slurry, and the solid was collected by filtration. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography [ethyl acetate / dichloromethane], and combined with the collected solid to give the title compound (343 mg) as a white solid.
MS (ESI) m / z: 416 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.42 (1H, m), 3.33 (1H, m), 3.28 (1H, m), 2.65 (1H, d, J = 15.1Hz), 2.40-2.30 (3H, m ), 2.08 (1H, dd, J = 1.5, 15.1 Hz), 1.90-1.15 (27H, m), 1.41 (3H, s), 1.11 (3H, s).

(Example 4)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl acetate

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 3 To a tetrahydrofuran solution of the compound obtained in Step 1 (295 mg) at −78 ° C. was added potassium tri (sec-butyl) borohydride (1.0 M, 1.4 ml), and stirred at the same temperature for 2 hours. The temperature was raised to ° C. and the mixture was further stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. Under ice cooling, hydrogen peroxide solution (30%, 0.8 ml), aqueous potassium hydroxide solution (8M, 0.4 ml) and water (5.0 ml) were added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was neutralized with hydrochloric acid, poured into two layers of ethyl acetate and a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium thiosulfate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (310 mg) as a crude product.
MS (ESI) m / z: 418 (M + H) ^<+> .

(Process 2)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl acetate Above Triethylamine (0.515 ml), 4-dimethylaminopyridine (9.1 mg), and acetic anhydride (0.245 ml) were added sequentially to a suspension of the compound (310 mg) obtained in step 1 in dichloromethane (10 ml) at room temperature. Stir overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (136 mg) as a white solid.
MS (ESI) m / z: 460 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.18 (1H, m), 3.40 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 3.14 (1H, d, J = 1.5Hz), 2.35 (1H, m), 2.04 (3H, s), 1.85 (1H, dd, J = 3.7,15.4Hz), 1.84-1.03 (29H, m), 1.39 (3H, s), 0.88 (3H, s) .

(Example 5)
Cyclohexyl [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 4 To a methanol (10 ml) -tetrahydrofuran (2.0 ml) solution of the compound (115 mg) obtained in Step 2 was added sodium methoxide (1.0 M methanol solution, 0.10 ml) at room temperature, and the mixture was stirred at the same temperature for 12 hours. did. The reaction solution was neutralized and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (103 mg) as a white solid.
MS (ESI) m / z: 418 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.10 (1H, brs), 3.56-3.51 (1H, br), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.71-2.65 (1H, br), 2.34 (1H, m), 1.85-1.05 (30H, m), 1.39 (3H, s), 0.87 (3H, s).

(Example 6)
(2,6-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Il] methanone

(Process 1)
(2,6-difluorophenyl) [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10 , 10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a- Dimethyl-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-ol (5.00 g) and 2,6-difluorobenzoyl chloride (2.60 ml) were used to give the title compound (4.75 g) in the same manner as in Example 1, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.31-7.27 (1H, m), 6.88-6.86 (2H, m), 5.38-5.37 (1H, m), 3.55-3.54 (1H, m), 2.79-2.77 ( 1H, m), 2.56-2.52 (2H, m), 2.36-2.33 (1H, m), 2.25-2.23 (2H, m), 1.99-1.96 (1H, m), 1.90-1.85 (2H, m), 1.78-1.75 (1H, m), 1.70-1.65 (1H, m), 1.54 (3H, s), 1.52-1.39 (9H, m), 1.20-1.07 (2H, m), 1.01 (3H, s).

(Process 2)
(2,6-difluorophenyl) [(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [ 2,1-f] quinolin-4 (4aH) -yl] methanone The title compound (1.83 g) was obtained in the same manner as in Example 1, Step 2 using the compound (2.00 g) obtained in Step 1 above. .
¹ H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.86 (2H, m), 3.90 (1H, m), 3.39-3.30 (2H, m), 3.11 (1H, m), 2.91 (1H , d, J = 4.4 Hz), 2.07-1.15 (19H, m), 1.55 (3H, s), 1.03 (3H, s).

(Process 3)
(2,6-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -yl] methanone To a solution of the compound obtained in Step 2 (200 mg) in tetrahydrofuran (3.0 ml) was added lithium borohydride (60 mg), and the mixture was stirred at 60 to 70 ° C. for 12 hours. Ice pieces and saturated aqueous ammonium chloride solution were added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane], and then purified again by preparative TLC [ethyl acetate / hexane] to give the title compound (19 mg) as a white solid. Obtained.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.23 (1H, m), 6.86 (2H, m), 4.06 (1H, m), 3.46 (1H, s), 3.40-3.33 (2H, m), 3.14 (1H , m), 1.86-1.19 (19H, m), 1.54 (3H, s), 1.08 (1H, s), 0.95 (3H, s), 0.93 (1H, m).

(Example 7)
(2,6-difluorophenyl) [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6,6a, 8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] methanone

(Process 1)
(2,6-difluorophenyl) [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6,6a, 8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] methanone The title compound (132 mg) was obtained as a white solid in the same manner as in Example 2, Step 1, using the compound (200 mg) obtained in Example 6, Step 2.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (DMSO-d ₆ ) δ: 7.43 (1H, m), 7.13 (2H, m), 4.43 (1H, d, J = 3.9Hz), 4.16 (1H, d, J = 5.9Hz), 3.78 (1H, m), 3.69 (1H, s), 3.35-3.28 (2H, m), 3.18 (1H, m), 3.00 (1H, m), 1.83 (1H, m), 1.78-1.23 (14H, m), 1.43 (3H, s), 1.18-1.04 (3H, m), 0.98 (3H, s).

(Example 8)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-Difluorobenzoyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline -6,8-diyl diacetate

(Process 1)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-Difluorobenzoyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline -6,8-Diyldiacetate The title compound (77 mg) was obtained as a white solid in the same manner as in Example 4, Step 2, using the compound (100 mg) obtained in Example 7, Step 1.
MS (ESI) m / z: 548 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.86 (2H, m), 5.13 (1H, m), 4.73 (1H, t, J = 2.9Hz), 3.40-3.32 (2H, m ), 3.13 (1H, m), 2.26 (1H, s), 2.05 (3H, s), 2.00 (3H, s), 1.84 (1H, m), 1.80-1.18 (17H, m), 1.56 (3H, s), 1.10 (3H, s).

(Example 9)
(2,6-difluorophenyl) [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
(2,6-difluorophenyl) [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -6-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone Example 6 To a solution of the compound (250 mg) obtained in Step 2 (250 mg) in dichloromethane (5.0 ml) was added 70% hydrogen fluoride-pyridine (0.51 ml) at 0 ° C. In addition, the mixture was stirred at the same temperature for 1 hour. The reaction was stopped by adding an aqueous sodium hydrogen carbonate solution to the reaction solution. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified in turn by silica gel column chromatography [ethyl acetate / hexane] and reverse phase high performance liquid chromatography [acetonitrile / water containing 0.1% formic acid] to give the title compound (89 mg) Was obtained as a white solid.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.23 (1H, m), 6.89-6.84 (2H, m), 4.25 (1H, m), 4.04 (1H, m), 3.43-3.33 (2H, m), 3.16 (1H, m), 2.08 (1H, m), 1.97 (1H, m), 1.89-1.21 (17H, m), 1.55 (3H, s), 1.13 (1H, brs), 1.06 (3H, d, J = 5.4Hz).

(Example 10)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -Tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone (S form: Rf = higher)
as well as
[(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone (R form: Rf = lower)
(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12, 12a-Hexadecahydronaphtho [2,1-f] quinolin-8-ol (1.85 g) and tetrahydropyran-2-carbonyl chloride (1.14 g) were reacted in the same manner as in Example 1, step 1, Separation and purification by silica gel column chromatography [ethyl acetate / hexane] gave the title compound diastereomer (S form) (923 mg) and the title compound diastereomer (R form) (881 mg).
Diastereomer (S form) (Rf = higher: low polarity)
MS (ESI) m / z: 402 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.34-5.33 (1H, m), 3.98-3.95 (2H, m), 3.48-3.41 (4H, m), 3.28-3.25 (1H, m), 2.29-2.12 ( 3H, m), 1.92-1.48 (17H, m), 1.44 (3H, s), 1.42-1.01 (6H, m), 0.97 (3H, s).
Diastereomer (R form) (Rf = lower: high polarity)
MS (ESI) m / z: 402 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.34-5.32 (1H, m), 4.04-4.02 (1H, m), 3.98-3.96 (1H, m), 3.58-3.26 (5H, m), 2.28-2.16 ( 3H, m), 1.93-1.49 (17H, m), 1.45 (3H, s), 1.29-1.10 (6H, m), 0.97 (3H, s).

(Process 2)
[(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline- 4 (4aH) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound (R form) (457 mg) obtained in Step 1 above, the same as in Step 1 of Example 1 The procedure gave the title compound (492 mg) as a white amorphous.
Main product (α-epoxide)
¹ H-NMR (CDCl ₃ ) δ: 3.99 (1H, m), 3.92 (1 H, dd, J = 2.4, 10.7 Hz), 3.87 (1 H, m), 3.52 (1 H, m), 3.40 (1 H, dt , J = 2.3,11.6Hz), 3.27 (1H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4Hz), 2.03 (1H, dd, J = 11.2,12.7Hz), 2.02 -1.07 (24H, m), 1.36 (3H, s), 1.00 (3H, s).

(Process 3)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -Tetrahydro-2H-pyran-2-yl] methanone To a solution of the compound obtained in Step 2 above (492 mg) in tetrahydrofuran (15 ml) was added lithium borohydride (228 mg) at room temperature and heated to reflux for 9 hours. . After cooling the reaction solution, ice pieces and saturated aqueous ammonium chloride solution were added to stop the reaction. The reaction mixture was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate solution, and extracted three times with dichloromethane / methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (104 mg) as a white solid.
MS (ESI) m / z: 420 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 4.00 (1H, m), 3.94 (1H, dd, J = 2.4,10.7Hz), 3.53 (1H, m), 3.40 (1H, m ), 3.33-3.23 (2H, m), 1.91-1.10 (27H, m), 1.40 (3H, s), 1.07 (1H, s), 0.92 (3H, s).

(Example 11)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2S) -Tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline- 4 (4aH) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone Using the compound (S form) (923 mg) obtained in Example 10, Step 1, Example 1 Step 2 and In a similar manner, the title compound (847 mg) was obtained as a white solid.
Main product (α-epoxide)
¹ H-NMR (CDCl ₃ ) δ: 3.94-3.84 (3H, m), 3.44-3.32 (3H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4Hz), 2.03 (1H , dd, J = 11.2, 12.7 Hz), 2.01-1.09 (24H, m), 1.35 (3H, s), 1.00 (3H, s).

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2S) -Tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Step 1 above (847 mg), the title compound (198 mg) was obtained as a white solid in the same manner as in Step 3 of Example 10. .
MS (ESI) m / z: 420 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 3.95-3.91 (1H, m), 3.93 (1H, dd, J = 3.9,8.8Hz), 3.45-3.39 (2H, m), 3.35 (1H, m), 3.25 (1H, m), 1.89-1.11 (27H, m), 1.39 (3H, s), 1.09 (1H, s), 0.92 (3H, s).

(Example 12)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
(4aS, 4bR, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one Example 1 The compound obtained in Step 1 (6.1 g) was suspended in toluene (150 ml), and cyclohexanone (15 ml) and Aluminum isopropoxide (1.6 g) was added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (6.6 g).
MS (ESI) m / z: 398 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.73-5.71 (1H, m), 3.61-3.60 (2H, m), 3.46-3.43 (1H, m), 3.37-3.34 (2H, m), 2.42-0.98 ( 33H, m).

(Process 2)
Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11, 12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Sodium borohydride at 0 ° C. in ethanol (10 ml) solution of the compound obtained in the above step 1 (300 mg) (57 mg) was added and stirred for 4 hours while warming to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction mixture was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (284 mg) as a white amorphous product.
MS (ESI) m / z: 400 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.25 (1H, d, J = 1.5Hz), 4.11 (1H, m), 3.40 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.33 (1H, m), 2.14 (1H, m), 2.01 (1H, m), 1.91-1.02 (26H, m), 1.40 (3H, s), 0.98 (3H, s), 0.79 (1H, m) .

(Process 3)
Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline -7 (5H) -yl] methanone Using the compound (284 mg) obtained in Step 2 above, the title compound (212 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 416 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.42 (1H, m), 3.33 (1H, m), 3.27 (1H, m), 3.13 (1H, d, J = 4.9Hz), 2.34 (1H, m), 2.20 (1H, d, J = 10.3Hz), 2.07 (1H, m), 1.94 (1H, m), 1.87-1.06 (25H, m), 1.40 (3H, s), 0.96 (3H, s), 0.93 (1H, m).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone The title compound (151 mg) was obtained as a white solid in the same manner as in Example 2, Step 1, using the compound (212 mg) obtained in Step 3 above.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.02 (1H, m), 3.50 (1H, m), 3.42 (1H, d, J = 3.9Hz), 3.40 (1H, m), 3.15 (1H, m) 2.47 (1H, m), 2.11 (1H, m), 1.91-1.13 (27H, m), 1.38 (3H, s), 1.08 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 1, and the peak having a relative intensity of 10 or more when the maximum peak intensity is 100 in FIG. 1 is shown in Table 1.

　(実施例13)
シクロヘキシル[(4aS,4bR,6aR,7R,8S,10aR,10bS,12aS)-6a,7,8-トリヒドロキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル]メタノン

(Example 13)
Cyclohexyl [(4aS, 4bR, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
[(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8- (benzyloxy) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] (cyclohexyl) methanone Example 12, N, N-dimethyl of the compound (1.85 g) obtained in Step 2 Sodium hydride (55 wt%, 2.02 g) was added to a formamide (30 ml) solution at room temperature, and the mixture was stirred at the same temperature for 30 minutes, benzyl bromide (5.50 ml) was added, and the mixture was stirred for 28 hours. Under ice cooling, methanol was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.33 g) as a milky white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.21 (5H, m), 5.36 (1H, d, J = 1.5Hz), 4.58 (1H, d, J = 11.7Hz), 4.52 (1H, d, J = 11.7Hz), 3.91 (1H, m), 3.40 (1H, m), 3.31 (1H, m), 3.25 (1H, m), 2.33 (1H, m), 2.20-1.06 (27H, m), 1.40 (3H, s), 0.99 (3H, s), 0.79 (1H, m).

(Process 2)
[(1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS) -2- (Benzyloxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f ] Quinolin-7 (5H) -yl] (cyclohexyl) methanone Using the compound (1.33 g) obtained in Step 1 above, the title compound (725 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1. It was.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.22 (5H, m), 4.60 (1H, d, J = 11.7Hz), 4.58 (1H, d, J = 11.7Hz), 3.67 (1H, dd, J = 7.8, 9.8Hz), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 3.01 (1H, s), 2.34 (1H, m), 1.98 (1H, m), 1.89 -1.09 (26H, m), 1.41 (3H, s), 1.04 (3H, s), 1.02 (1H, m).

(Process 3)
[(4aS, 4bR, 7S, 8S, 10aR, 10bS, 12aS) -8- (benzyloxy) -7-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9, 10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] (cyclohexyl) methanone (allyl alcohol)
as well as
[(4aS, 4bR, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -8- (benzyloxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] (cyclohexyl) methanone (diol)
Using the compound (725 mg) obtained in Step 2 above, the title compound (allyl alcohol form) (139 mg) and the title compound (diol form) (297 mg) were each converted into a white solid in the same manner as in Step 2 of Example 2. Obtained.
Allyl alcohol
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.79 (1H, m), 4.68 (1H, d, J = 11.7Hz), 4.47 (1H, d, J = 11.7Hz), 4.17 (1H, m), 3.42 (1H, m), 3.35 (1H, m), 3.25 (1H, m), 3.10 (1H, m), 2.77 (1H, d, J = 2.0Hz), 2.35 (1H , m), 2.24 (1H, dm), 2.01 (1H, m), 1.88-1.00 (24H, m), 1.41 (3H, s), 0.96 (3H, s).
Diol body
MS (ESI) m / z: 524 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.33-7.24 (5H, m), 4.59 (1H, d, J = 11.7Hz), 4.49 (1H, d, J = 11.7Hz), 3.87 (1H, brs), 3.57 (1H, brs), 3.40 (1H, m), 3.32 (1H, m), 3.21 (1H, m), 2.44 (1H, d, J = 4.4Hz), 2.33 (1H, m), 1.94-1.12 (29H, m), 1.38 (3H, s), 0.88 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone 10% palladium on carbon catalyst (300 mg) was added to an ethanol (10 ml) -tetrahydrofuran (10 ml) solution of the compound (diol form) (297 mg) obtained in Step 3 above for 6 hours under a hydrogen atmosphere. Stir. The catalyst was filtered off, the filtrate was concentrated, and the resulting residue was solidified with ethanol / hexane to give the title compound (169 mg) as a white solid.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.73 (1H, m), 3.60 (1H, d, J = 2.4Hz), 3.50 (1H, m), 3.39 (1H, m), 3.15 (1H, m) 2.47 (1H, m), 2.04 (1H, br), 1.93-1.11 (27H, m), 1.38 (3H, s), 0.87 (3H, s).

(Example 14)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -6,6a, 7,8-tetrahydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone

(Process 1)
[(4aS, 6aS, 6bR, 9S, 10R, 10aS, 11aS, 12aR, 12bS) -9- (benzyloxy) -10-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinolin-4 (4aH) -yl] (cyclohexyl) methanone Using the compound (allyl alcohol form) (139 mg) obtained in Example 13, Step 3, the same as Example 1, Step 2 The procedure gave the title compound (66 mg) as a white solid.
MS (ESI) m / z: 522 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.24 (5H, m), 4.66 (1H, d, J = 11.7Hz), 4.57 (1H, d, J = 11.7Hz), 3.95 (1H, dd, J = 6.6,9.5Hz), 3.42 (1H, d, J = 4.4Hz), 3.41-3.29 (3H, m), 3.20 (1H, m), 2.33 (1H, m), 2.08-1.99 (2H, m) 1.97 (1H, d, J = 6.8 Hz), 1.78-1.08 (24H, m), 1.34 (3H, s), 1.00 (3H, s).

(Process 2)
[(4aS, 4bR, 6R, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -8- (benzyloxy) -6,6a, 7-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] (cyclohexyl) methanone Using the compound (66 mg) obtained in Step 1 above, the title compound (66 mg) as a white solid was prepared in the same manner as in Example 2, Step 1. Obtained.
MS (ESI) m / z: 540 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.24 (5H, m), 4.66 (1H, d, J = 11.7Hz), 4.43 (1H, d, J = 11.7Hz), 4.05 (1H, d, J = 7.8Hz), 3.86 (1H, brs), 3.61 (1H, m), 3.41 (1H, m), 3.32 (1H, m), 3.21 (1H, m), 3.05 (1H, d, J = 1.5Hz ), 2.37-2.29 (2H, m), 1.99 (1H, m), 1.81-1.13 (26H, m), 1.39 (3H, s), 1.06 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 7R, 8S, 10aR, 10bS, 12aS) -6,6a, 7,8-tetrahydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] methanone Using the compound (66 mg) obtained in Step 2 above, the title compound (48 mg) was obtained as a white solid in the same manner as in Step 13 of Example 13.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.93 (1H, m), 3.80 (1H, d, J = 9.3Hz), 3.70 (1H, m), 3.51 (1H, m), 3.40 (1H, m) 3.16 (1H, dd, J = 3.2, 9.0 Hz), 2.48 (1H, m), 1.92-1.12 (26H, m), 1.41 (3H, s), 1.08 (3H, s).

(Example 15)
(Example 15-1)
Cyclohexyl [(4aS, 4bR, 6aR, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Example 15-2)
Cyclohexyl [(4aS, 4bR, 6aR, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
(4aS, 4bR, 6aR, 7R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-8 (2H ) -One (β-diol)
as well as
(4aS, 4bR, 6aS, 7S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-8 (2H ) -One (α-diol)
Example 12 To a solution of the compound obtained in Step 1 (1.50 g) in acetone (16 ml) -water (4 ml), 4-methylmorpholine-N-oxide (796 mg) and 4% aqueous osmium tetroxide solution (0.80 ml) at room temperature ) Were added in order, and the mixture was stirred at the same temperature for 16 hours. A 10% aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium bicarbonate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (β-diol) (908 mg) and the title compound (α-diol) (237 mg) as white solids, respectively. Got as.
β-diol
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.47 (1H, d, J = 2.9Hz), 3.76 (1H, d, J = 2.9Hz), 3.41 (1H, m), 3.35-3.30 (2H, m), 2.42-2.28 (3H, m), 1.96-1.15 (26H, m), 1.39 (3H, s), 1.05 (1H, m), 0.95 (3H, s).
α-diol
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.11 (1H, d, J = 2.0 Hz), 3.75 (1 H, d, J = 2.0 Hz), 3.41 (1 H, m), 3.33 (1 H, m), 3.27 ( 1H, m), 2.50-2.44 (2H, m), 2.34 (1H, m), 1.95-1.13 (27H, m), 1.41 (3H, s), 1.17 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aR, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone (β-alcohol)
And cyclohexyl [(4aS, 4bR, 6aR, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -Il] methanone (α-alcohol)
To a solution of the compound (β-diol) (908 mg) obtained in Step 1 above in dichloromethane (5.0 ml) was added sodium triacetoxyborohydride (803 mg) at room temperature, and the mixture was stirred at the same temperature for 8 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [dichloromethane / methanol] to give the title compound (β-alcohol) (335 mg) and the title compound (α-alcohol) (204 mg) as white amorphous compounds.
β-alcohol: Example 15-1
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.98 (1H, m), 3.85 (1H, d, J = 3.4Hz), 3.51 (1H, m), 3.40 (1H, m), 3.17 (1H, m) , 2.48 (1H, m), 1.99 (1H, m), 1.89-1.16 (26H, m), 1.39 (3H, s), 1.02 (1H, m), 0.90 (3H, s).
α-alcohol: Example 15-2
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.68 (1H, d, J = 8.8Hz), 3.63 (1H, m), 3.52 (1H, m), 3.41 (1H, m), 3.18 (1H, m) , 2.48 (1H, m), 1.96 (1H, 13.1, 3.4Hz), 1.92-1.14 (26H, m), 1.39 (3H, s), 1.05 (1H, s), 0.87 (3H, s).

(Example 16)
(Example 16-1)
Cyclohexyl [(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone (β-alcohol)

(Example 16-2)
Cyclohexyl [(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone (α-alcohol)

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone (β-alcohol)
And cyclohexyl [(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -Il] methanone (α-alcohol)
Using the compound (α-diol) (237 mg) obtained in Example 15, Step 1, in the same manner as in Example 15, Step 2, the title compound (β-alcohol) (28 mg) and the title compound (α-alcohol) ) (121 mg) was obtained as a white solid.
β-alcohol: Example 16-1
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.69 (1H, m), 3.51 (1H, m), 3.40 (1H, m), 3.31 (1H, d, J = 8.8Hz), 3.16 (1H, m) 2.48 (1H, m), 1.90-1.11 (28H, m), 1.39 (3H, s), 0.92 (3H, s).
α-alcohol: Example 16-2
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.46 (1H, d, J = 3.4Hz), 3.41 (1H, m), 3.18 (1H, m) 2.48 (1H, m), 1.92-1.10 (28H, m), 1.39 (3H, s), 0.91 (3H, s).

(Example 17)
Cyclohexyl [(4aS, 4bR, 6aR, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
(4aS, 4bR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,6,8,9,10,10a , 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-yl acetate Example 1 To a solution of the compound obtained in Step 1 (452 mg) in tetrahydrofuran (10 ml) at 0 ° C. , Triphenylphosphine (891 mg), acetic acid (0.194 ml), and diethyl azodicarboxylate (2.2 M toluene solution, 1.1 ml) were sequentially added, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (410 mg) as a white amorphous.
¹ H-NMR (CDCl ₃ ) δ: 5.39 (1H, dd, J = 1.0,4.9Hz), 5.08 (1H, m), 3.41 (1H, m), 3.33 (1H, m), 3.27 (1H, m ), 2.34 (1H, m), 2.18 (1H, m), 2.08-1.10 (25H, m), 2.01 (3H, s), 1.41 (3H, s), 0.95-0.82 (2H, m), 0.93 ( 3H, s).

(Process 2)
(1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -7- (cyclohexylcarbonyl) -4a, 6a-dimethylhexadecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] Quinolin-2-yl acetate Using the compound (410 mg) obtained in Step 1 above, the title compound (199 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 4.88 (1H, dd, J = 7.6,9.5Hz), 3.43 (1H, m), 3.35 (1H, m), 3.28 (1H, m), 2.81 (1H, s ), 2.35 (1H, m), 2.07-0.97 (28H, m), 2.06 (3H, s), 1.40 (3H, s), 0.95 (3H, s).

(Process 3)
(4aS, 4bR, 6aR, 7R, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a, 8-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7 -Il acetate The title compound (34 mg) was obtained as a white solid in the same manner as in Example 2, Step 1 using the compound (34 mg) obtained in Step 2 above.
¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, d, J = 2.9Hz), 4.10 (1H, m), 3.42 (1H, m), 3.37-3.21 (2H, m), 2.35 (1H, m ), 2.14 (3H, s), 1.89-1.01 (30H, m), 1.38 (3H, s), 0.86 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aR, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone Using the compound (34 mg) obtained in Step 3 above, the title compound (28 mg) was obtained as a white solid in the same manner as in Step 1 of Example 5.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.84 (1H, m), 3.59 (1H, d, J = 3.4Hz), 3.50 (1H, m), 3.38 (1H, m), 3.14 (1H, m) 2.48 (1H, m), 2.16 (1H, m), 1.90-1.10 (27H, m), 1.38 (3H, s), 0.82 (3H, s).

(Example 18)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone

(Process 1)
(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a, 7-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-8 -Il acetate Boron trifluoride diethyl ether complex (0.15 ml) was added to a solution of the compound obtained in Step 2 of Example 17 (165 mg) in benzene (7 ml) at room temperature and stirred at the same temperature for 30 minutes. 5% Aqueous sodium acetate solution was added to the reaction mixture, and the mixture was stirred for 10 min. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was slurried with dichloromethane, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (30 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.55 (1H, m), 3.88 (1H, m), 3.41 (1H, m), 3.36 (1H, m), 3.28 (1H, m), 2.59 (1H, m ), 2.35 (1H, m), 2.05 (1H, m), 2.02 (3H, s), 1.84 (1H, m), 1.79 (1H, d, J = 5.4Hz), 1.78-1.36 (18H, m) 1.39 (3H, s), 1.32 (1H, m), 1.27-1.13 (6H, m), 1.10 (3H, s), 0.84 (1H, m).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone The title compound (23 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5 using the compound (28 mg) obtained in Step 1 above.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.82 (1H, m), 3.50 (1H, m), 3.42 (1H, m), 3.40 (1H, m), 3.17 (1H, m), 2.47 (1H, m), 2.06-1.96 (2H, m), 1.89-1.13 (26H, m), 1.39 (3H, s), 1.08 (3H, s).

(Example 19)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-1,2,3,4 , 4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-ol (33.5 g) in dichloromethane (600 ml) Under ice-cooling, N, N-diisopropylethylamine (24.5 ml) was added to the solution, followed by benzyl chloroformate (17.5 ml), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (29.8 g).
MS (ESI) m / z: 424 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.32-7.28 (5H, m), 5.31-5.31 (1H, m), 5.06-5.06 (2H, m), 3.74-3.73 (1H, m), 3.50-3.47 ( 1H, m), 3.37-3.32 (1H, m), 3.03-3.02 (1H, m), 2.29-2.27 (1H, m), 2.18-2.12 (2H, m), 1.86-0.97 (16H, m), 1.34 (3H, s), 1.52 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a -Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (34.3 g) obtained in Step 1 above, the title compound (34.3 g) was prepared in the same manner as in Step 1 of Example 12. 29.6 g) was obtained.
MS (ESI) m / z: 422 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.70 (1H, s), 5.06 (2H, s), 3.76-3.74 (1H, m), 3.35-3.29 (1H, m) , 3.10-3.07 (1H, m), 2.42-2.26 (4H, m), 2.03-1.99 (2H, m), 1.81-1.80 (1H, m), 1.71-0.91 (11H, m), 1.37 (3H, s), 1.12 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The compound (13.0 g) obtained in Step 2 above was suspended in methanol (300 ml) and cerium chloride heptahydrate. (11.5 g) was added. The reaction solution was cooled to −45 ° C., sodium borohydride (1.17 g) was added, and the mixture was stirred for 4 hours while gradually warming to 0 ° C. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then the filtrate was concentrated to obtain the title compound (14.3 g).
MS (ESI) m / z: 424 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.29-5.29 (1H, m), 5.08-5.08 (2H, m), 4.14-4.12 (1H, m), 3.78-3.76 ( 1H, m), 3.34-3.31 (1H, m), 3.06-3.04 (1H, m), 2.17-2.16 (1H, m), 2.07-2.04 (1H, m), 1.95-1.17 (15H, m), 1.36 (3H, s), 1.01 (3H, s), 0.87-0.84 (2H, m).

(Process 4)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline- 7 (5H) -Carboxylate The title compound (13.1 g) was obtained in the same manner as in Step 1 of Example 1 using the compound (13.1 g) obtained in the above Step 3.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 5.09-5.07 (2H, m), 4.12-4.06 (1H, m), 3.80-3.76 (1H, m), 3.35-3.33 ( 1H, m), 3.16-3.15 (1H, m), 3.08-3.05 (1H, m), 2.26-0.99 (25H, m).

(Process 5)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate Using the compound (29.6 g) obtained in Step 4 above, the title compound (24.3 g) was obtained as a white solid in the same manner as in Example 2, Step 1.
MS (ESI) m / z: 458 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.31 (5H, m), 5.09-5.07 (2H, m), 4.15-4.13 (1H, m), 3.79-3.75 (2H, m), 3.54-3.53 ( 1H, m), 3.35-3.32 (1H, m), 3.05-3.02 (1H, m), 2.30-2.30 (1H, m), 2.20-2.19 (1H, m), 1.82-1.17 (17H, m), 1.35 (3H, s), 1.11 (3H, s).
¹ H-NMR (CD ₃ OD) δ: 7.34-7.24 (5H, m), 5.02 (2H, s), 4.02 (1H, m), 3.76 (1H, m), 3.42 (1H, d, J = 3.4 Hz), 3.32 (1H, m), 2.94 (1H, m), 2.11 (1H, m), 1.85 (1H, m), 1.74-1.10 (16H, m), 1.32 (3H, s), 1.08 (3H , s).

(Example 20)
Cyclohexyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate

(Process 1)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinoline-8 (4H) -carboxylate Example 19 The compound obtained in Step 5 (24.3 g) was suspended in acetonitrile (500 ml) and acetone dimethyl acetal (16.3 ml) and p at 0 ° C. -Toluenesulfonic acid monohydrate (1.01 g) was added, and the mixture was stirred at the same temperature for 3 hours. Triethylamine (8.14 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the resulting residue and stirred for 30 minutes, and then the precipitated solid was collected by filtration. The residue obtained by concentrating the filtrate was dissolved in ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane]. Combined with the previously precipitated solid, the title compound (22.0 g) was obtained as a white solid.
MS (ESI) m / z: 498 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.09-5.09 (2H, m), 4.32-4.30 (1H, m), 3.81-3.76 (2H, m), 3.36-3.34 ( 1H, m), 3.06-3.04 (1H, m), 2.09-2.06 (1H, m), 1.89-1.81 (2H, m), 1.75-1.13 (28H, m).

(Process 2)
(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] Quinoline-13a (4H) -ol The compound obtained in Step 1 above (22.7 g) is dissolved in a mixed solvent of ethanol (150 ml) and tetrahydrofuran (300 ml), and 10% palladium carbon wet (3.00 g) is added. The mixture was stirred at room temperature and normal pressure for 3 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated to give the title compound (16.2 g).
MS (ESI) m / z: 364 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.29-4.24 (1H, m), 3.83-3.82 (1H, m), 2.90-2.88 (1H, m), 2.73-2.70 (1H, m), 1.99-1.98 (1H, m), 1.81-1.07 (20H, m), 1.47 (3H, s), 1.28 (3H, s), 1.15 (3H, s), 1.08 (3H, s).

(Process 3)
Cyclohexyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinoline-8 (4H) -carboxylate To a solution of the compound obtained in Step 2 above (100 mg) in dichloromethane (4.0 ml), potassium carbonate (114 mg) and cyclohexyl chloroformate (58 mg) were sequentially added at room temperature. In addition, the mixture was stirred at the same temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, poured into two layers of ethyl acetate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (134 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.63 (1H, m), 4.28 (1H, m), 4.28 (1H, d, J = 2.9Hz), 3.74 (1H, m), 3.26 (1H, m), 2.99 (1H, m), 2.04 (1H, m), 1.85-1.76 (4H, m), 1.73-1.12 (27H, m), 1.49 (3H, s), 1.31 (3H, s), 1.29 (3H, s).

(Process 4)
Cyclohexyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate The compound (134 mg) obtained in Step 3 above was dissolved in a mixed solution of methanol (5 ml) and tetrahydrofuran (2.5 ml), 4M hydrogen chloride-ethyl acetate solution (0.05 ml) was added, and the mixture was stirred at room temperature. Stir for hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in methanol, and the insoluble material was filtered off. The filtrate was partially concentrated, and the precipitated solid was collected by filtration using diethyl ether to obtain the title compound (109 mg) as a white solid.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.56 (1H, m), 4.03 (1H, dm), 3.75 (1H, m), 3.42 (1H, d, J = 3.9Hz), 3.28 (1H, m) 2.95 (1H, m), 2.11 (1H, m), 1.90-1.77 (3H, m), 1.73-1.11 (24H, m), 1.32 (3H, s), 1.09 (3H, s).

(Example 21)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -N-cyclohexyl-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxamide

(Process 1)
(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -N-cyclohexyl-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] Naphtho [2,1-f] quinoline-8 (4H) -carboxamide Example 20 To a solution of the compound obtained in Step 2 (100 mg) in dichloromethane (4 ml) was added diisopropylamine (0.14 ml) and cyclohexyl isocyanate ( 0.046 ml) was added in order, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (100 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.27 (1H, m), 4.20 (1H, d, J = 7.8Hz), 3.77 (1H, d, J = 5.4Hz), 3.53 (1H, m), 3.23- 3.15 (2H, m), 2.88 (1H, m), 2.03 (1H, m), 1.92-0.99 (28H, m), 1.49 (3H, s), 1.31 (3H, s), 1.29 (3H, s) , 1.10 (3H, s).

(Process 2)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -N-cyclohexyl-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxamide Using the compound (100 mg) obtained in Step 1 above, the title compound (61 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 449 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.02 (1H, m), 3.42 (1H, d, J = 3.9Hz), 3.39 (1H, m), 3.26 (1H, m), 3.19 (1H, m) 2.87 (1H, m), 2.11 (1H, m), 1.86-1.07 (27H, m), 1.30 (3H, s), 1.08 (3H, s).

(Example 22)
Cyclohex-1-en-1-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
Cyclohex-1-en-1-yl [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Example 20 Diisopropylethylamine (0.188 ml) was added at 0 ° C. to a dichloromethane solution of the compound obtained in Step 2 (100 mg). ) And cyclohex-1-ene-1-carbonyl chloride (80 mg) were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (112 mg) as a white solid.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.78 (1H, m), 4.28 (1H, m), 3.77 (1H, d, J = 4.9Hz), 3.41-3.32 (2H, m), 3.24 (1H, m ), 2.28 (1H, m), 2.08-1.95 (4H, m), 1.86-1.77 (2H, m), 1.72-1.17 (19H, m), 1.49 (3H, s), 1.40 (3H, s), 1.29 (3H, s), 1.16 (1H, s), 1.11 (3H, s).

(Process 2)
Cyclohex-1-en-1-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone Using the compound (112 mg) obtained in Step 1 above, the title compound (96 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20. .
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.72 (1H, m), 4.03 (1H, m), 3.45-3.41 (3H, m), 3.14 (1H, m), 2.21 (1H, m), 2.12 ( 1H, m), 2.08-2.04 (2H, m), 1.97 (1H, m), 1.86 (1H, m), 1.75-1.14 (20H, m), 1.40 (3H, s), 1.09 (3H, s) .

(Example 23)
(2R) -tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyltetrahydropyran-2-carboxylate Tetrahydropyran-2-carboxylic acid (300 mg) was dissolved in N, N-dimethylformamide (5 ml), and potassium carbonate (382 mg) and benzyl bromide (0.260 ml) were added to add 75 The mixture was stirred at 0 ° C. for 3 hours and then at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (460 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.32 (5H, m), 5.20 (2H, s), 4.11-4.09 (1H, m), 4.05-4.03 (1H, m), 3.52-3.48 (1H, m), 1.98-1.94 (1H, m), 1.89-1.86 (1H, m), 1.67-1.51 (4H, m).

(Process 2)
Benzyl (2S) -tetrahydropyran-2-carboxylate and benzyl (2R) -tetrahydropyran-2-carboxylate The compound obtained in Step 1 above (460 mg) was optically separated from the isomer under the following conditions, and benzyl (2 2S) -Tetrahydropyran-2-carboxylate (isomer A) (177 mg) and benzyl (2R) -tetrahydropyran-2-carboxylate (isomer B) (174 mg) were obtained, respectively.

Preparative
CHIRALPAK (AS-H) 20x250mm
Eluent: hexane / isopropanol = 99: 1
Flow rate: 20ml / min
Detection wavelength: 254nM
Retention time: Isomer A (2S form): 13.2 minutes, Isomer B (2R form): 16.3 minutes.

analysis
CHIRALCEL (OD-H) 4.6x150um,
Eluent: Hexane / isopropanol = 98: 2
Flow rate: 1.0ml / min
Detection wavelength: 254nM and 210nM
Retention time: Isomer A (2S form): 8.98 min, Isomer B (2R form): 8.38 min.
CHIRALPAK (AS-H) 4.6x150um,
Eluent: Hexane / isopropanol = 98: 2
Flow rate: 1.0ml / min
Detection wavelength: 254nM and 210nM
Retention time: Isomer A (2S form): 8.17 minutes, Isomer B (2R form): 10.8 minutes.

Isomer A (2S form)
[Α] _D ²⁰ -19.1 (c1.02, dichloromethane)
Reference; Journal of the American Chemical Society, 132, 16374 (2010)
CHIRALCEL (OD-H) 4.6x250um,
Eluent: Hexane / isopropanol = 98: 2
Flow rate: 1.0ml / min
Detection wavelength: 215nM
Retention time:
R-isomer: 15.91 min, [α] _D ²⁰ +17.1 (c1.73, CH ₂ Cl ₂ )
S-isomer: 17.44 min.

(Process 3)
(2R) -Tetrahydropyran-2-carboxylic acid The benzyl (2R) -tetrahydropyran-2-carboxylate (105 mg) obtained in Step 2 above was dissolved in ethanol (3 ml), and 10% palladium carbon wet ( 10 mg) was added, and the mixture was stirred at room temperature and normal pressure for 1 hour under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated to give the title compound (55.1 mg).
¹ H-NMR (CDCl ₃ ) δ: 4.13-4.11 (1H, m), 3.99-3.97 (1H, m), 3.57-3.54 (1H, m), 2.08-2.05 (1H, m), 1.95-1.93 ( 1H, m), 1.62-1.59 (4H, m).

(Process 4)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The compound (5.80 g) obtained in Step 3 above was converted to N, N-dimethylformamide ( 100 ml), and under ice-cooling stirring, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate (16.9 g) and N, N-diisopropylethylamine (15.2 ml) was added and stirred at the same temperature for 10 minutes. Subsequently, an N, N-dimethylformamide solution (200 ml) of the compound (16.2 g) obtained in Step 2 of Example 20 was slowly added dropwise, followed by stirring at 0 ° C. for 6 hours. The produced solid was collected by filtration and washed with diethyl ether. The filtrate was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by concentrating the filtrate and the collected solid were purified by silica gel column chromatography [methanol / dichloromethane] to obtain the title compound (12.6 g) as a white solid. .
MS (ESI) m / z: 476 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.27-4.25 (1H, m), 4.10-4.09 (1H, m), 3.98-3.96 (1H, m), 3.83-3.82 (1H, m), 3.61-3.58 (1H, m), 3.51-3.48 (1H, m), 3.40-3.37 (1H, m), 3.27-3.18 (2H, m), 2.01-1.18 (24H, m), 1.47 (3H, s), 1.44 (3H, s), 1.27 (3H, s), 1.13 (3H, s).

(Process 5)
(2R) -tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Acetic acid (50 ml) and water (13 ml) were added to the compound (9.35 g) obtained in Step 4 above, and the mixture was stirred for 3 hours. The reaction mixture was neutralized with an aqueous sodium hydrogen carbonate solution, water (100 ml) was further added, and extraction was performed twice with dichloromethane: methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated to obtain the title compound (8.27 g).
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10-4.09 (1H, m), 4.06-4.04 (1H, m), 3.97-3.96 (1H, m), 3.60-3.58 (1H, m), 3.50-3.48 (1H, m), 3.45-3.44 (1H, m), 3.39-3.37 (1H, m), 3.19-3.17 (1H, m), 2.16-2.13 (1H, m), 1.88-1.17 (26H, m) 1.42 (3H, s), 1.11 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 2, and peaks having a relative intensity of 18 or more when the maximum peak intensity is 100 in FIG. 2 are shown in Table 2.

　(実施例24)
(2S)-テトラヒドロ-2H-ピラン-2-イル[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-トリヒドロキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル]メタノン

(Example 24)
(2S) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinolin-8 (4H) -yl] (tetrahydro-2H-pyran-2-yl) methanone Example 20 Compound (300 mg) obtained in Step 2 and tetrahydropyran-2-carboxylic acid (323 mg ) To give the title compound (329 mg) as a white solid diastereomer mixture (main product R-form) in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 476 (M + H) ^<+> .

(Process 2)
(2S) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The title compound (S form) (5 mg) was prepared in the same manner as in Example 23, Step 5, using the compound (278 mg) obtained in Step 1 above. ) And its (R form) (69 mg) were obtained as white solids, respectively.
Rf = higher (S body) low polarity
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.05-4.01 (2H, m), 3.91 (1H, dd, J = 2.0,11.2Hz), 3.48 (1H, m), 3.44-3.39 (3H, m), 3.16 (1H, m), 2.12 (1H, m), 1.91-1.13 (23H, m), 1.39 (3H, s), 1.09 (3H, s).
Rf = lower (R-form) High polarity Example 23 was agreed.

(Example 25)
[(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2R) -1- (Benzyloxy) hept-6-en-2-ol (2R) -2-[(benzyloxy) methyl] oxirane (7.00 g) and copper iodide (0.49 g) in tetrahydrofuran (350 ml) To the solution, 3-butenylmagnesium bromide (0.5M tetrahydrofuran solution, 100 ml) was added dropwise at -78 ° C. After completion of the dropwise addition, the temperature was slowly raised to room temperature, followed by further stirring for 1 hour. A saturated aqueous ammonia solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (9.37 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.25-7.35 (5H, m), 5.73-5.81 (1H, m), 4.98 (1H, m), 4.93 (1H, m), 4.53 (2H, s), 3.77 -3.82 (1H, m), 3.48 (1H, dd, J = 9.5,3.2Hz), 3.30 (1H, dd, J = 9.5,8.1Hz), 2.30 (1H, d, J = 3.4Hz), 2.01- 2.09 (2H, m), 1.36-1.60 (4H, m).

(Process 2)
(6R) -7- (Benzyloxy) -6-hydroxyheptan-2-one To a solution of the compound (2.02 g) obtained in Step 1 above in tetrahydrofuran-water (7/1: 40 ml) was added palladium chloride (163 mg). Parabenzoquinone (0.991 g) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed twice with 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.06 g) as a colorless oil.
MS (ESI) m / z: 219 (M-OH) ^+
1 H-NMR (CDCl ₃ ) δ: 7.29-7.38 (5H, m), 4.55 (2H, s), 3.80 (1H, m), 3.48-3.51 (1H, m), 3.33 (1H, dd, J = 9.3, 7.8Hz), 2.47 (2H, t, J = 7.3Hz), 2.14 (3H, s), 1.57-1.77 (2H, m), 1.40-1.46 (2H, m).

(Process 3)
(2R, 6R) -2-[(Benzyloxy) methyl] -6-methyltetrahydro-2H-pyran To a solution of the compound obtained in Step 2 above (2.06 g) and triethylsilane (1.52 ml) in dichloromethane (50 ml) In an ice bath, trifluoroborane-diethyl ether complex (1.20 ml) was added, and the mixture was stirred at 0 ° C. for 15 minutes. Saturated brine and water were added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.56 g) as a colorless oil.
MS (ESI) m / z: 221 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.26-7.36 (5H, m), 4.61 (1H, d, J = 12.2Hz), 4.54 (1H, d, J = 12.2Hz), 3.58 (1H, m), 3.44-3.51 (2H, m), 3.39 (1H, dd, J = 10.3,4.4Hz), 1.80-1.84 (1H, m), 1.46-1.60 (3H, m), 1.15-1.27 (2H, m), 1.20 (3H, d, J = 5.9Hz).

(Process 4)
[(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] methanol 20% palladium hydroxide (0.2 g) was added to a solution of the compound (1.56 g) obtained in step 3 above in ethanol (15 ml). In addition, the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The catalyst was removed using Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.66 g) as a colorless oil.
MS (ESI) m / z: 131 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.45-3.60 (4H, m), 2.14-2.24 (1H, m), 1.82-1.87 (1H, m), 1.45-1.61 (3H, m), 1.14-1.28 ( 2H, m), 1.18 (3H, d, J = 6.3 Hz).

(Process 5)
(2R, 6R) -6-Methyltetrahydro-2H-pyran-2-carboxylic acid To a solution of the compound obtained in Step 4 above (0.66 g) in acetonitrile-water (1 / 1,40 ml), iodobenzene diacetate ( 3.6 g) and 2-azaadamantane-N-oxyl (0.15 g) were added, and the mixture was stirred at room temperature for 15 minutes. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was washed twice with dichloromethane. The aqueous layer was acidified with 5N hydrochloric acid, and extracted once with ethyl acetate and dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate] to obtain the title compound (0.53 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.01 (1H, dd, J = 11.7, 2.7 Hz), 3.57-3.65 (1H, m), 2.03-2.11 (1H, m), 1.91-1.98 (1H, m) 1.40-1.66 (3H, m), 1.22-1.29 (1H, m), 1.26 (3H, d, J = 6.2 Hz).

(Process 6)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinolin-8 (4H) -yl] [(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] methanone Example 20 Compound (96.0 mg) obtained in Step 2 The title compound (135 mg) was obtained as a white solid in the same manner as in Step 23 of Example 23 using the compound (57.1 mg) obtained in the above Step 6.
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.30 (1H, m), 3.97 (1H, dd, J = 2.3,10.9Hz), 3.80 (1H, d, J = 5.5Hz), 3.58 (1H, m), 3.47-3.40 (1H, m), 3.35-3.26 (1H, m), 2.07 (1H, m), 1.90-1.18 (28H, m), 1,52 (3H, s), 1.45 (3H, s), 1.31 (3H, s), 1.12 (3H, s).

(Process 7)
[(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (135 mg) obtained in Step 6 above, in the same manner as in Example 23, Step 5, Compound (88 mg) was obtained.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.13 (1H, m), 3.97 (1H, dd, J = 11.0,2.3Hz), 3.60-3.52 (2H, m), 3.43 (1H, m), 3.34-3.26 (1H, m), 2.33 (1H, m), 2.20 (1H, m), 1.90-1.18 (25H, m), 1.44 (3H, s), 1.19 (3H, d, J = 6.3Hz), 1.11 ( 3H, s), 1.08 (1H, s).

(Example 26)
(2-Fluorocyclohex-1-en-1-yl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2-Fluorocyclohex-1-en-1-yl) [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Example 20 Compound (100 mg) obtained in Step 2 and 2,2-difluorocyclohexanecarboxy The title compound (59 mg) was obtained as a pale yellow solid in the same manner as in Example 23, step 4 using ric acid (409 mg).
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.28 (1H, m), 3.78 (1H, d, J = 5.4Hz), 3.43-3.38 (2H, brm), 3.28 (1H, m), 2.19-2.12 (2H , m), 2.04 (1H, m), 1.87-1.77 (2H, m), 1.76-1.13 (22H, m), 1.49 (3H, s), 1.43 (3H, s), 1.29 (3H, s), 1.10 (3H, s).

(Process 2)
(2-Fluorocyclohex-1-en-1-yl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone The compound obtained in the above Step 1 (59 mg) is dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (1 ml), and 1N is obtained at room temperature. Hydrochloric acid (0.5 ml) was added and stirred at the same temperature for 3 hours. The reaction mixture was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane: methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to obtain the title compound (44 mg) as a white solid.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.03 (1H, m), 3.48-3.43 (2H, brm), 3.42 (1H, d, J = 3.9 Hz), 3.17 (1H, m), 2.21-2.13 ( 2H, brm), 2.12 (1H, m), 1.86 (1H, m), 1.80-1.14 (22H, m), 1.42 (3H, s), 1.09 (3H, s).

(Example 27)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -Il] methanone

(Process 1)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-methoxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline- 7 (5H) -carboxylate Example 19 A mixture of the compound obtained in Step 4 (300 mg) in tetrahydrofuran (4 ml) and N, N-dimethylformamide (1 ml) was mixed with methyl iodide (0.637 ml) at room temperature. Sodium hydride (55 wt%, 60 mg) was added in order, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, poured into two layers of ethyl acetate and a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (269 mg) as white Obtained as amorphous.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.75 (1H, m), 3.64 (1H, m), 3.42 (3H, s), 3.32 (1H, m), 3.10 (1H, d, J = 3.4Hz), 3.03 (1H, m), 2.06 (1H, m), 1.94 (1H , m), 1.83 (1H, m), 1.76-1.60 (2H, m), 1.54-1.43 (5H, m), 1.37-1.29 (2H, m), 1.33 (3H, s), 1.26-1.16 (3H , m), 1.14-1.07 (2H, m), 0.97 (3H, s), 0.92 (1H, m).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Carboxylate The title compound (187 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2 using the compound (269 mg) obtained in Step 1 above.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.75 (1H, m), 3.67-3.62 (2H, m), 3.37 (3H, s), 3.31 (1H, m), 3.01 (1H, m), 2.29 (1H, s), 2.19 (1H, m), 1.84-1.52 (7H, m), 1.44-1.33 (6H, m), 1.32 (3H, s), 1.28-1.13 (4H, m), 1.09 (3H, s), 1.04 (1H, s).

(Process 3)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 7 (2H) -diol Using the compound (186 mg) obtained in 2, the title compound (134 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
¹ H-NMR (CD ₃ OD) δ: 3.68 (1H, m), 3.63 (1H, d, J = 3.4Hz), 3.33 (3H, s), 2.87 (1H, m), 2.70 (1H, dd, J = 4.6, 12.9Hz), 2.11 (1H, m), 1.76-1.17 (16H, m), 1.16-0.99 (2H, m), 1.10 (3H, s), 1.04 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -yl] methanone Using the compound obtained in Step 3 above (40 mg) and cyclohexanecarbonyl chloride (0.021 ml), the title compound (43 mg) was obtained as a white solid in the same manner as in Step 22 of Example 22. .
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.67-3.61 (2H, m), 3.41 (1H, m), 3.36 (3H, s), 3.33 (1H, m), 3.23 (1H, m), 2.34 (1H , m), 2.29 (1H, s), 2.19 (1H, m), 1.86-1.52 (12H, m), 1.46-1.31 (7H, m), 1.39 (3H, s), 1.28-1.15 (8H, m ), 1.09 (3H, s), 1.08 (1H, s).

(Example 28)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Example 27, Step 3 (92 mg) and the compound obtained in Example 23, Step 3 (71 mg) The title compound (86 mg) was obtained as a white solid by a method similar to that in Example 23, Step 4.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4,10.7Hz), 3.66-3.61 (2H, m), 3.53 (1H, m), 3.41 (1H , m), 3.36 (3H, s), 3.32-3.22 (2H, m), 2.29 (1H, s), 2.20 (1H, m), 1.89 (1H, m), 1.85-1.31 (17H, m), 1.40 (3H, s), 1.29-1.13 (5H, m), 1.09 (3H, s), 1.04 (1H, s).

(Example 29)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-7-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[tert-butyl (dimethyl) silyl] oxy} -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (250 mg) obtained in Example 23 Step 5 with dichloromethane (10 ml) To a mixed solution of tetrahydrofuran (10 ml), imidazole (176 mg) and tert-butyldimethylchlorosilane (195 mg) were sequentially added at room temperature, and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (309 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.10 (1H, m), 4.00 (1H, m), 3.94 (1H, dd, J = 2.4,10.7Hz), 3.53 (1H, m), 3.41 (1H, m ), 3.37 (1H, d, J = 4.4Hz), 3.34-3.22 (2H, m), 2.65 (1H, s), 2.18 (1H, m), 1.88 (1H, m), 1.84-1.13 (22H, m), 1.40 (3H, s), 1.09 (3H, s), 1.00 (1H, s), 0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s).

(Process 2)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[tert-butyl (dimethyl) silyl] oxy} -6a-hydroxy-7-methoxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The compound obtained in Step 1 above (245 mg) and methyl iodide (0.278 The title compound (133 mg) was obtained as a white solid in the same manner as in Example 27, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, m), 4.00 (1H, m), 3.93 (1H, dd, J = 2.4,10.7Hz), 3.53 (1H, m), 3.47 (3H, s ), 3.40 (1H, m), 3.33-3.21 (2H, m), 2.96 (1H, dd, J = 1.0,3.4Hz), 2.15 (1H, m), 1.88 (1H, m), 1.84-1.13 ( 22H, m), 1.39 (3H, s), 1.11 (1H, s), 1.02 (3H, s), 0.88 (9H, s), 0.06 (3H, s), 0.05 (3H, s).

(Process 3)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-7-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone To a solution of the compound obtained in step 2 above (133 mg) in tetrahydrofuran (5.0 ml) at room temperature with acetic acid (0.27 ml) and fluoride. Tetrabutylammonium (1M tetrahydrofuran solution, 4.71 ml) was added, and the mixture was heated to reflux for 12 hours. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (91 mg) as a white solid.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.06-3.99 (2H, m), 3.96 (1H, dd, J = 2.4, 10.7 Hz), 3.56 (1H, m), 3.52 (3H, s), 3.43 (1H , m), 3.34-3.24 (2H, m), 3.07 (1H, d, J = 3.4Hz), 2.14 (1H, m), 1.99 (1H, d, J = 11.2Hz), 1.90 (1H, m) 1.87-1.17 (22H, m), 1.43 (3H, s), 1.12 (1H, s), 1.04 (3H, s).

(Example 30)
[(4aS, 4bR, 6R, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13bR) -2,2,5a, 7a-tetramethyl-3a, 5,5a, 5b, 6,7,7a, 9,10,11,11a, 11b, 12,13b-Tetradecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinoline-8 (4H) -carboxylate Example 19 Compound obtained in Step 4 (9.76 g The crude product obtained by the same method as in Example 2, Step 1 was reacted by the same method as in Example 20, Step 1, and the product was subjected to silica gel column chromatography [ethyl acetate / hexane]. After separation and purification, the compound (7.44 g) obtained in Example 20, Step 1 and the title compound (olefin) (0.506 g) were obtained as white solids, respectively.
Olefin body
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.76 (1H, dd, J = 2.3,4.7Hz), 5.05 (2H, s), 4.38 (1H, d, J = 5.9Hz ), 4.08 (1H, m), 3.73 (1H, m), 3.34 (1H, m), 3.03 (1H, m), 2.24 (1H, m), 1.81-1.05 (14H, m), 1.49 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 1.09 (3H, s), 0.99 (1H, m).

(Process 2)
Benzyl (3aS, 3bR, 4aS, 5aR, 5bS, 9aS, 11aS, 11bR, 13aS) -2,2,9a, 11b-tetramethyltetradecahydro-3aH- [1,3] dioxolo [5,6] oxyleno [ 4,4a] Naphtho [2,1-f] quinoline-9 (4aH) -carboxylate Using the compound (olefin) (686 mg) obtained in Step 1 above, in the same manner as in Step 1 of Example 1 The title compound (366 mg) was obtained as a white solid.
MS (ESI) m / z: 496 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.04 (2H, s), 4.24 (1H, m), 3.73 (1H, m), 3.40 (1H, d, J = 5.4Hz ), 3.31 (1H, m), 3.13 (1H, d, J = 3.9Hz), 2.98 (1H, m), 2.05 (1H, m), 1.91 (1H, m), 1.77-1.25 (12H, m) 1.53 (3H, s), 1.29 (3H, s), 1.27 (3H, s), 1.16 (3H, s), 1.16-1.09 (2H, m).

(Process 3)
Benzyl (4aS, 4bR, 6R, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -carboxylate Using the compound (366 mg) obtained in Step 2 above, the title compound (71.0 mg) was obtained as a white solid in the same manner as in Step 9 of Example 9.
¹ H-NMR (CD ₃ OD) δ: 7.34-7.25 (5H, m), 5.02 (2H, s), 4.49 (1H, m), 3.99 (1H, m), 3.77 (1H, m), 3.70 ( 1H, d, J = 3.4Hz), 3.32 (1H, m), 2.96 (1H, m), 1.93-1.16 (16H, m), 1.34 (3H, s), 1.24 (3H, d, J = 3.9Hz ).

(Process 4)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13R, 13aS, 13bS) -13-fluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5 , 6] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate The title compound (71.0 mg) was obtained in the same manner as in Example 20, Step 1 using the compound obtained in Step 3 above. 50.0 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 4.51 (1H, m), 4.28 (1H, m), 3.91 (1H, d, J = 4.9Hz), 3.75 (1H, m), 3.33 (1H, m), 3.04 (1H, m), 2.01 (1H, m), 1.84-1.18 (16H, m), 1.54 (3H, s), 1.35 (3H, s), 1.33 (3H, s), 1.25 (3H, d, J = 5.4Hz).

(Process 5)
(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13R, 13aS, 13bS) -13-Fluoro-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [ 2,1-f] quinolin-13a (4H) -ol Using the compound (95.0 mg) obtained in Step 4 above, the title compound (61.0 mg) was converted to a white solid in the same manner as in Example 2, Step 2. Got as.
¹ H-NMR (CDCl ₃ ) δ: 4.51 (1H, m), 4.28 (1H, m), 3.92 (1H, d, J = 5.4Hz), 2.92 (1H, m), 2.83 (1H, m), 1.97 (1H, m), 1.82 (1H, m), 1.75-1.12 (17H, m), 1.54 (3H, s), 1.33 (3H, s), 1.27 (3H, d, J = 5.4Hz), 1.11 (3H, s).

(Process 6)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13R, 13aS, 13bS) -13-Fluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5 , 6] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The compound (61.0 mg) obtained in Step 5 above and tetrahydro The title compound (38.0 mg) was obtained as a white solid in the same manner as in Example 23, Step 4 using pyran-2-carboxylic acid (83.2 mg).
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.52 (1H, m), 4.28 (1H, m), 4.00 (1H, m), 3.94 (1H, m), 3.91 (1H, d, J = 4.9Hz), 3.55 (1H, m), 3.45-3.25 (3H, m), 2.00 (1H, m), 1.88 (1H, m), 1.83-1.16 (21H, m), 1.54 (3H, s), 1.44 (3H, s), 1.33 (3H, s), 1.25 (3H, d, J = 5.4 Hz).

(Process 7)
[(4aS, 4bR, 6R, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound (38.0 mg) obtained in Step 6 above, the same procedure as in Example 23, Step 5 Gave the title compound (28.0 mg) as a white solid.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.50 (1H, m), 4.08 (1H, m), 3.99 (1H, m), 3.94 (1H, dd, J = 3.4,11.2Hz), 3.70 (1H, d, J = 3.4Hz), 3.57 (1H, m), 3.46 (1H, m), 3.36 (1H, m), 3.17 (1H, m), 1.92-1.13 (22H, m), 1.42 (3H, s ), 1.25 (3H, d, J = 3.9Hz).

(Example 31)
(2,6-difluorophenyl) [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 9Z, 10aR, 10bS, 12aS) -9- (hydroxymethylidene) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10 , 10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 Tetrahydrofuran (2.25 g) of the compound (2.25 g) obtained in Step 2 100 ml), lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 12 ml) was added to the solution at −20 ° C. in a nitrogen atmosphere, and the mixture was stirred for 20 minutes. Subsequently, methyl formate (1.65 ml) was added, and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran was distilled off under reduced pressure, 5N hydrochloric acid was added, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (0.97 g).
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 13.7 (1H, m), 7.40-7.31 (5H, m), 5.78 (1H, s), 5.09 (2H, s), 3.78 (1H, m), 3.35 (1H , m), 3.14-3.11 (1H, m), 2.42-2.27 (4H, m), 2.07-2.01 (1H, m), 1.91-1.83 (1H, m), 1.77-0.98 (11H, m), 1.39 (3H, s), 1.01 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 8R, 9S, 10aR, 10bS, 12aS) -8-hydroxy-9- (hydroxymethyl) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9, 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The compound (1.40 g) obtained in the above Step 1 was converted to methanol. (100 ml), sodium borohydride (0.24 g) was added, and the mixture was stirred at room temperature for 10 min. After adding water to the reaction mixture, the methanol was distilled off under reduced pressure and extracted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (0.50 g) as a white solid.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.22 (1H, s), 5.08 (2H, s), 4.10 (1H, m), 3.80-3.73 (2H, m), 3.69 (1H, m), 3.32 (1H, m), 3.05 (1H, m), 2.55 (1H, d, J = 4.9Hz), 2.36 (1H, dd, J = 6.1,3.7Hz), 2.21-2.05 ( 2H, m), 1.94 (1H, m), 1.86-1.63 (4H, m), 1.56-1.15 (7H, m), 1.36 (3H, s), 1.04 (3H, s), 0.97 (1H, m) , 0.88-81 (2H, m).

(Process 3)
Benzyl (1aS, 2S, 3S, 4aR, 4bS, 6aS, 10aS, 10bR) -2-hydroxy-3- (hydroxymethyl) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2 , 1-f] quinoline-7 (5H) -carboxylate Using the compound (1.00 g) obtained in Step 2 above, the title compound (1.00 g) was obtained as a white solid in the same manner as in Example 1, Step 2. Got as.
MS (ESI) m / z: 470 (M + H) ^<+> .

(Process 4)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -carboxylate To a solution of the compound obtained in Step 3 above (1.00 g) in tetrahydrofuran-water (5 / 1,120 ml) was added 70% aqueous perchloric acid (2 ml), Stir at room temperature overnight. The reaction mixture was neutralized with 5N sodium hydroxide. Tetrahydrofuran was distilled off under reduced pressure, ethyl acetate was added, and the precipitated solid was collected by filtration to give the title compound (0.93 g) as a white solid.
MS (ESI) m / z: 488 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.47-7.30 (5H, m), 5.08 (2H, s), 4.09 (1H, m), 3.82-3.64 (4H, m), 3.54 (1H, m), 3.34 (1H, m), 3.04 (1H, m), 2.63 (1H, m), 2.29 (1H, m), 2.21 (1H, m), 2.10-2.04 (1H, m), 1.84-1.65 (3H, m ), 1.60-1.50 (2H, m), 1.35 (3H, s), 1.43-1.10 (10H, m), 1.17 (3H, s), 1.01 (1H, s).

(Process 5)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -7,8-bis (acetyloxy) -9-[(acetyloxy) methyl] -6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The compound obtained in Step 4 above (0.46 g) was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) and 4 -Dimethylaminopyridine (0.12 g) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the disappearance of the raw material, methanol was added at 0 ° C., and azeotropic distillation was performed with toluene to distill off pyridine. 1N Hydrochloric acid was added to the obtained residue, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (0.53 g).
MS (ESI) m / z: 614 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.40-7.26 (5H, m), 5.33 (1H, dd, J = 12.2,3.9Hz), 5.10-5.07 (3H, m), 4.08 (1H, dd, J = 10.7,5.4Hz), 4.01 (1H, dd, J = 10.7,3.4Hz), 3.78 (1H, m), 3.33 (1H, m), 3.05 (1H, m), 2.28 (1H, m), 2.06 ( 3H, s), 2.05 (3H, s), 1.97 (3H, s), 1.34 (3H, s), 1.14 (3H, s), 1.88-1.14 (17H, m).

(Process 6)
(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -9-[(Acetyloxy) methyl] -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] Quinoline-7,8-diyldiacetate The title compound (0.46 g) was prepared in the same manner as in Example 2, Step 2, using the compound obtained in Step 5 above (0.53 g) and 20% palladium hydroxide as the catalyst. Obtained.
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.34 (1H, dd, J = 11.7,3.9Hz), 5.08 (1H, d, J = 3.9Hz), 4.07 (1H, dd, J = 11.2,5.4Hz), 4.01 (1H, dd, J = 11.0,3.2Hz), 2.93-2.82 (2H, m), 2.27 (1H, s), 2.09 (3H, s), 2.06 (3H, s), 1.96 (3H, s) , 1.89-1.82 (1H, m), 1.73-1.57 (6H, m), 1.52-1.32 (5H, m), 1.26-1.15 (3H, m), 1.15 (3H, s), 1.07 (3H, s) , 1.10-1.03 (2H, m).

(Process 7)
(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -9-[(Acetyloxy) methyl] -1- (2,6-difluorobenzoyl) -6a-hydroxy-10a, 12a-dimethyl Octadecahydronaphtho [2,1-f] quinoline-7,8-diyl diacetate The compound (0.10 g) obtained in Step 6 above is dissolved in toluene (10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and difluorobenzene Carboxylic acid chloride (0.040 ml) was added and stirred overnight. The organic layer was separated and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.13 g).
MS (ESI) m / z: 620 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.30-7.24 (1H, m), 6.89 (2H, m), 5.34 (1H, dd, J = 11.7,3.9Hz), 5.09 (1H, d, J = 3.9Hz ), 4.08 (1H, dd, J = 11.0,5.6Hz), 4.02 (1H, dd, J = 11.0,3.4Hz), 3.40 (2H, m), 3.17 (1H, m), 2.30 (1H, m) , 2.11 (3H, s), 2.07 (3H, s), 1.97 (3H, s), 1.94-1.40 (12H, m), 1.56 (3H, s), 1.34-1.20 (5H, m), 1.17 (3H , s).

(Process 8)
(2,6-difluorophenyl) [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (0.13 g) obtained in the above Step 7, the title compound (0.13 g) was prepared in the same manner as in Step 1 of Example 5. 0.10 g) was obtained as a white solid.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.30-7.24 (1H, m), 6.92-6.86 (2H, m), 4.12-4.07 (1H, m), 3.85-3.79 (2H, m), 3.70 (1H, m), 3.56-3.53 (1H, m), 3.43-3.36 (2H, m), 3.17 (1H, m), 2.72 (1H, m), 2.49 (1H, m), 2.23 (1H, m), 2.13 -2.04 (1H, m), 1.89-1.66 (5H, m), 1.58 (3H, s), 1.56-1.14 (11H, m), 1.20 (3H, s), 1.02 (1H, s).

(Example 32)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinoline-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -9-[(Acetyloxy) methyl] -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8-diyl diacetate The same procedure as in Example 31, Step 7, using the compound (0.36 g) obtained in Example 6, Step 6 and cyclohexanecarbonyl chloride (0.31 ml) Gave the title compound (0.30 g) as a white solid.
MS (ESI) m / z: 590 (M + H) ^+
1 H-NMR (CDCl ₃ , 400 MHz) δ: 5.33 (1 H, dd, J = 12.2, 3.9 Hz), 5.08 (1 H, d, 3.9 Hz), 4.08 (1 H, dd, J = 11.2, 5.4 Hz), 3.99 (1H, dd, 11.2,2.9Hz), 3.44 (1H, m), 3.49-3.26 (2H, m), 2.41-2.23 (2H, m), 2.10 (3H, s), 2.06 (3H, s) 1.97 (3H, s), 1.41 (3H, s), 1.97-1.14 (26H, m), 1.13 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone Using the compound (0.30 g) obtained in Step 1 above, the title compound (0.30 g) as a white solid was prepared in the same manner as in Step 1 of Example 5. Obtained.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.12-4.07 (2H, m), 3.81 (1H, m), 3.67 (1H, m), 3.44 (1H, m), 3.36 (1H, m), 3.27-3.20 (2H, m), 2.73 (1H, d, J = 1.5Hz), 2.36 (1H, m), 2.22 (1H, m), 2.08 (1H, m), 1.87-1.09 (26H, m), 1.42 ( 3H, s), 1.18 (3H, s), 0.99 (1H, s).

(Example 33)
Cyclopentyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinoline-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -9-[(Acetyloxy) methyl] -1- (cyclopentylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8-diyldiacetate The same procedure as in Example 31, Step 7 was carried out using the compound (0.16 g) obtained in Example 6, Step 6 and cyclopentanecarbonyl chloride (0.12 ml). The title compound was obtained by the procedure.

(Process 2)
Cyclopentyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone The title compound (0.020 g) was obtained as a solid in the same manner as in Step 1 of Example 5 using the compound obtained in Step 1 above.
MS (ESI) m / z: 450 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.09 (1H, m), 3.93 (1H, m), 3.83-3.79 (1H, m), 3.68 (1H, m), 3.49-3.55 (2H, m), 3.36 (1H, m), 3.30-3.25 (1H, m), 2.88 (1H, m), 2.82 (1H, m), 2.69 (1H, d, J = 1.5Hz), 2.22 (1H, m), 2.08 ( 1H, m), 1.85-1.58 (10H, m), 1.56-1.10 (13H, m), 1.42 (3H, s), 1.18 (3H, s), 0.99 (1H, s).

Example 34
Cyclopentyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (2-hydroxyethyl) -10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bR, 10aR, 10bS, 12aS) -1- (cyclopentylcarbonyl) -10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one (4aS, 4bR, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one (5.0 g) and cyclopentanecarbonyl chloride (2.3 ml) Was used to obtain the title compound (6.7 g) in the same manner as in Step 22 of Example 22.

(Process 2)
tert-butyl [(4aS, 4bR, 10aR, 10bS, 12aS) -1- (cyclopentylcarbonyl) -10a, 12a-dimethyl-8-oxo-1,2,3,4,4a, 4b, 5,6,8 , 9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-9-yl] acetate Compound (0.65 g) obtained in Step 1 above and bromoacetic acid The title compound (0.70 g) was obtained as a diastereomer mixture by the same method as in Example 31, Step 1 using tert-butyl (0.32 ml).
MS (ESI) m / z: 442 (M-tBu) ^<+> .

(Process 3)
Cyclopentyl [(4aS, 4bR, 8S, 9S, 10aR, 10bS, 12aS) -8-hydroxy-9- (2-hydroxyethyl) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8 , 9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Dichloromethane of the compound obtained in Step 2 above (0.70 g) To the (20 ml) solution was added trifluoroacetic acid (10 ml) and stirred at room temperature for 30 minutes. After confirming the disappearance of the raw materials, the solvent was distilled off under reduced pressure, and the resulting crude carboxylic acid was dissolved in tetrahydrofuran (30 ml), methyl chloroformate (0.20 ml) and triethylamine (0.60 ml) were added, and the mixture was stirred at room temperature for 15 minutes. did. After the precipitate was filtered off, methanol (0.2 ml) and sodium borohydride (0.20 g) were added to the filtrate and stirred at room temperature. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography [ethyl acetate-methanol] to obtain the title compound (0.17 g).
MS (ESI) m / z: 430 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.22 (1H, s), 3.90-3.82 (2H, m), 3.72 (1H, m), 3.51 (1H, m), 3.36 (1H, dd, J = 12.0, 3.7Hz), 3.32-3.28 (1H, m), 2.81 (1H, m), 2.19-2.07 (2H, m), 1.44 (3H, s), 1.95-1.38 (21H, m), 1.28-0.79 (6H , m), 1.03 (3H, s).

(Process 4)
Cyclopentyl [(1aS, 2S, 3S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-3- (2-hydroxyethyl) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] Naphtho [2,1-f] quinolin-7 (5H) -yl] methanone The title compound (0.17 g) was prepared in the same manner as in Example 1, Step 2 using the compound (0.17 g) obtained in Step 3 above. )
MS (ESI) m / z: 446 (M + H) ^<+> .

(Process 5)
Cyclopentyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (2-hydroxyethyl) -10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (0.17 g) obtained in Step 4 above, the title compound (0.03 g) was obtained as a white solid in the same manner as in Step 4 of Example 31. Got as.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.89-3.85 (1H, m), 3.78 (1H, dd, J = 10.3,3.9Hz), 3.67 (1H, m), 3.58 (1H, d, J = 3.9Hz ), 3.52 (1H, m), 3.37 (1H, m), 3.29 (1H, m), 2.81 (1H, m), 2.68 (1H, br), 2.20 (1H, m), 1.42 (3H, s) 1.15 (3H, s), 1.86-1.08 (29H, m).

(Example 35)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a, 7,8,9-tetrahydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone

(Process 1)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -9-hydroxy-10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 Compound (1.08 g) obtained in Step 2 and (2S, 8aR)-(-)- The title compound was obtained in the same manner as in Step 31 of Example 31 using (camphorylsulfonyl) oxaziridine (0.76 g).

(Process 2)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -9- (acetyloxy) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The title compound was obtained in the same manner as in Example 31, Step 5 using the compound obtained in Step 1 above. Compound (1.23 g) was obtained as a white solid.
MS (ESI) m / z: 480 (M + H) ^<+> .

(Process 3)
Benzyl (4aS, 4bR, 8R, 10aR, 10bS, 12aS) -9- (acetyloxy) -8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10, 10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (acetate)
And benzyl (4aS, 4bR, 8R, 10aR, 10bS, 12aS) -8,9-dihydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (diol)
Using the compound (1.23 g) obtained in the above Step 2, the title compound (1.23 g) was obtained as a mixture of acetate and diol by the same procedure as in Step 19 of Example 19.

(Process 4)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -3- (acetyloxy) -2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2 , 1-f] quinoline-7 (5H) -carboxylate (acetate)
And benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2,3-dihydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f Quinoline-7 (5H) -carboxylate (diol)
Using the compound (1.23 g) obtained in the above Step 3, the title compound (1.27 g) was obtained as a mixture of acetate and diol in the same manner as in Step 1 of Example 1.

(Process 5)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -7,8,9-tris (acetyloxy) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -carboxylate Using the compound obtained in Step 4 above (1.27 g), the crude product obtained in the same manner as in Step 31 of Example 31 was converted to Step 5 of Example 31. The title compound (0.36 g) was obtained by reacting in the same manner as above.
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.25 (5H, m), 5.50 (1H, dd, J = 10.5,4.1Hz), 5.30-5.26 (1H, m), 5.17 (1H, d, J = 4.4Hz), 5.08 (2H, s), 3.78 (1H, m), 3.35-3.30 (1H, m), 3.05 (1H, m), 2.10-1.12 (19H, m), 2.10 (3H, s), 2.02 (3H, s), 1.96 (3H, s), 1.33 (3H, s), 1.20 (3H, s), 0.88 (1H, m).

(Process 6)
(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8,9-triyl Triacetate The title compound (0.10 g) was obtained in the same manner as in Step 20 of Example 20 using the compound (0.36 g) obtained in the above Step 5 and 20% palladium hydroxide as a catalyst.

(Process 7)
(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7 , 8,9-Triyltriacetate The title compound (123 mg) was obtained in the same manner as in Step 31 of Example 31 using the compound (100 mg) obtained in the above Step 6.

(Process 8)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a, 7,8,9-tetrahydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] methanone The title compound (20 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5 using the compound (123 mg) obtained in Step 7 above.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.85-3.76 (2H, m), 3.56 (1H, d, J = 3.9Hz), 3.58-3.50 (1H, m), 3.46-3.40 (2H, m), 3.20 -3.15 (1H, m), 2.52-2.48 (1H, m), 2.10 (1H, m), 1.93-1.10 (25H, m), 1.41 (3H, s), 1.15 (3H, s).

Example 36
Cyclohexyl [(4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-4,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone

(Process 1)
(3β) -3-{[tert-Butyl (dimethyl) silyl] oxy} androsta-5,15-dien-17-one (3β) -3-hydroxyandrost-5,15-dien-17-one ( 3.8 g) and N, N-dimethylformamide (60 ml) as the solvent were used to give the title compound (2.54 g) as a solid in the same manner as in Example 29, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.53-7.49 (1H, m), 6.05 (1H, dd, J = 6.1,3.2Hz), 5.40-5.36 (1H, m), 3.52-3.46 (1H, m) 2.33-2.19 (4H, m), 1.92-0.99 (21 H, m), 1.08 (3H, s), 1.07 (3H, s), 0.89 (9H, s), 0.07 (6H, s).

(Process 2)
(3β, 15β) -3-{[tert-Butyl (dimethyl) silyl] oxy} -15-methyl-17-[(trimethylsilyl) oxy] androsta-5,16-diene Copper (I) iodide (2.5 g ) And lithium chloride (0.56 g) in tetrahydrofuran (30 ml) at −78 ° C., methylmagnesium bromide (0.96M tetrahydrofuran solution, 14 ml) was added, and the mixture was stirred at −78 ° C. for 30 minutes. Subsequently, chlorotrimethylsilane (1.2 ml) was added, and the mixture was further stirred at the same temperature for 30 minutes. Then, a solution of the compound (1.5 g) obtained in Step 1 above in tetrahydrofuran (15 ml) was added, and the mixture was stirred at -78 ° C for 2 hours. did. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was allowed to return to room temperature, and the insoluble material was filtered off using celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to give the title compound as a crude product.

(Process 3)
(3β, 15β) -3-Hydroxy-15-methylandrost-5-en-17-one p-toluene was added to a solution of the compound obtained in Step 2 above (1.80 g) in methanol (60 ml) and dichloromethane (60 ml). Sulfonic acid monohydrate (70 mg) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compound (902 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.41-5.36 (1H, m), 3.56-3.48 (1H, m), 2.48-2.38 (2H, m), 2.33-2.13 (4H, m), 1.87-1.75 ( 4H, m), 1.71-1.61 (2H, m), 1.54-1.40 (2H, m), 1.12-1.08 (4H, m), 1.10 (3H, d, J = 7.3Hz), 1.04 (3H, s) 1.02 (3H, s).

(Process 4)
(3β, 15β) -15-Methyl-17-oxoandrost-5-en-3-ylacetate The title compound was prepared in the same manner as in Step 31 of Example 31 using the compound (902 mg) obtained in Step 3 above. (1.01 g) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.43-5.39 (1H, m), 4.62-4.56 (1H, m), 2.50-2.12 (5H, m), 2.01 (3H, s), 1.87-1.40 (8H, m), 1.28-0.99 (5H, m), 1.09 (3H, d, J = 7.3Hz), 1.05 (3H, s), 1.01 (3H, s).

(Process 5)
(3β, 15β, 17E) -17- (Hydroxyimino) -15-methylandrost-5-en-3-yl acetate Ethanol (15 ml) of the compound obtained in Step 4 above (1.01 g), dichloromethane (1.5 ml) and water (1.5 ml) were added sodium acetate (962 mg) and hydroxyamine hydrochloride (8.42 g), and the mixture was heated to reflux for 1.5 hours. The reaction solution was cooled to room temperature, and a part of the solvent was distilled off. Water was added to the residue, extracted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give the title compound (919 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.43-5.39 (1H, m), 4.62-4.56 (1H, m), 2.50-2.12 (5H, m), 2.01 (3H, s), 1.87-1.40 (8H, m), 1.28-0.99 (5H, m), 1.09 (3H, d, J = 7.3Hz), 1.05 (3H, s), 1.01 (3H, s).

(Process 6)
(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -4,10a, 12a-trimethyl-2-oxo-1,2,3,4,4a, 4b, 5,7,8,9,10, 10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-yl acetate To a solution of the compound obtained in Step 5 above (919 mg) in tetrahydrofuran (14 ml) in propylphosphonic anhydride (Cyclic trimer) (50% ethyl acetate solution, 0.761 ml) was added and the mixture was heated under reflux for 2 hours. The reaction solution cooled to room temperature was concentrated, ethyl acetate was added, and the resulting solid was collected by filtration to obtain the product. Subsequently, the filtrate was concentrated under reduced pressure, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane]. The previously obtained products were combined to give the title compound (521 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.67 (1H, s), 5.42-5.36 (1H, m), 4.63-4.54 (1H, m), 3.70 (1H, m), 2.60 (1H, dd, J = 17.8, 8.1Hz), 2.39-1.01 (16H, m), 2.01 (3H, s), 1.28 (3H, s), 1.03 (3H, s), 1.02 (3H, d, J = 7.3Hz).

(Process 7)
(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -4,10a, 12a-trimethyl-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-ol The compound (521 mg) obtained in Step 6 above was dissolved in 1,4-dioxane (15 ml), and lithium aluminum hydride was dissolved. (10% tetrahydrofuran solution, 1.7 ml) was added and the reaction was heated to reflux for 2 hours. Sodium sulfate decahydrate was added to the reaction solution under ice cooling until no bubbles appeared. Dichloromethane was added, dried over anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give the title compound (440 mg).
MS (ESI) m / z: 304 (M + H) ^<+> .

(Process 8)
Benzyl (4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-4,10a, 12a-trimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The same procedure as Example 19 Step 1 using the compound (440 mg) obtained in Step 7 above Gave the title compound (424 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.35-5.32 (1H, m), 5.10-5.04 (2H, m), 3.84 (1H, m), 3.55-3.46 (1H, m), 3.32-3.25 (1H, m), 2.99-2.90 (1H, m), 2.31-0.95 (17H, m), 1.44 (3H, s), 0.97 (3H, s), 0.95 (3H, d, J = 6.8Hz).

(Process 9)
Benzyl (4R, 4aS, 4bR, 10aR, 10bS, 12aS) -4,10a, 12a-trimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The title was obtained in the same manner as in Step 1 of Example 12 using the compound (424 mg) obtained in Step 8 above. Compound (353 mg) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.71 (1H, s), 5.11-5.03 (2H, m), 3.89-3.81 (1H, m), 3.31-3.25 (1H, m), 3.05-2.98 (1H, m), 2.44-2.27 (4H, m), 2.11-1.96 (4H, m), 1.72-0.86 (19H, m), 1.47 (3H, s), 1.15 (3H, s), 1.00 (3H, d, J = 7.3 Hz).

(Process 10)
Benzyl (4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-hydroxy-4,10a, 12a-trimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The same procedure as in Step 19 of Example 19 using the compound (353 mg) obtained in Step 9 above Gave the title compound (354 mg) as a solid.
MS (ESI) m / z: 438 (M + H) ^<+> .

(Process 11)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10R, 10aS, 10bR, 12aR) -2-hydroxy-4a, 6a, 10-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1- f] Quinoline-7 (5H) -carboxylate The title compound (316 mg) was obtained as a solid in the same manner as in Example 1, Step 2 using the compound (354 mg) obtained in Step 10 above.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.10-5.03 (2H, m), 4.07-4.00 (1H, m), 3.87-3.80 (1H, m), 3.32-3.26 ( 1H, m), 3.13 (1H, d, J = 4.4Hz), 3.00-2.94 (1H, m), 2.17-1.95 (5H, m), 1.62-0.92 (22H, m), 1.44 (3H, s) , 1.00 (3H, s), 0.98 (3H, d, J = 7.3Hz).

(Process 12)
Benzyl (4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-4,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -Carboxylate The title compound (284 mg) was obtained as a solid in the same manner as in Step 31 of Example 31 using the compound (316 mg) obtained in the above Step 11.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.08-5.03 (2H, m), 4.17-4.09 (1H, m), 3.85-3.79 (1H, m), 3.54-3.50 ( 1H, m), 3.33-3.27 (1H, m), 2.96-2.90 (1H, m), 2.27-2.19 (2H, m), 2.11-1.93 (2H, m), 1.80-0.92 (13H, m), 1.42 (3H, s), 1.12 (3H, s), 0.97 (3H, d, J = 6.8 Hz).

(Process 13)
Benzyl (3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a, 11-pentamethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Using the compound (284 mg) obtained in Step 12 above, the title compound (191 mg) was solidified in the same manner as in Example 1, Step 1. Got as.
MS (ESI) m / z: 512 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.10-5.03 (2H, m), 4.33-4.26 (1H, m), 3.84-3.78 (2H, m), 3.33-3.28 ( 1H, m), 2.98-2.91 (1H, m), 2.14-0.96 (20H, m), 1.50 (3H, s), 1.43 (3H, s), 1.29 (3H, s), 1.14 (3H, s) , 0.97 (3H, d, J = 7.3Hz).

(Process 14)
Benzyl (3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a, 11-pentamethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate The title compound (141 mg) was obtained in the same manner as in Example 20, Step 2 using the compound (191 mg) obtained in Step 13 above. It was.

(Process 15)
Cyclohexyl [(3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a, 11-pentamethylhexadecahydro [1,3] dioxolo [5, 6] Naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Using the compound obtained in Step 14 above (50.0 mg) and cyclohexanecarbonyl chloride (0.027 ml), Example 31 Step 7 and The title compound (64.4 mg) was obtained by a similar method.
MS (ESI) m / z: 488 (M + H) ^<+> .

(Process 16)
Cyclohexyl [(4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-4,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] methanone The title compound (38.0 mg) was obtained as a solid in the same manner as in Step 26 of Example 26 using the compound (64.4 mg) obtained in Step 15 above.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.16-4.10 (1H, m), 3.54-3.50 (1H, m), 3.47-3.43 (1H, m), 3.38-3.31 (1H, m), 3.18-3.12 ( 1H, m), 2.39-2.31 (1H, m), 2.27-2.20 (2H, m), 2.10-2.05 (2H, m), 1.80-0.98 (23H, m), 1.50 (3H, s), 1.12 ( 3H, s), 0.98 (3H, d, J = 6.3 Hz).

(Example 37)
(2R) -Tetrahydro-2H-pyran-2-yl [(4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-4,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a, 11-pentamethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Performed with compound (90.0 mg) obtained in Example 36 Step 14 The title compound (117 mg) was obtained in the same manner as in Example 23, Step 4, using the compound (62 mg) obtained in Step 23 of Example 23.
MS (ESI) m / z: 490 (M + H) ^<+> .

(Process 2)
(2R) -Tetrahydro-2H-pyran-2-yl [(4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-4,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The title compound (62.0) was prepared in the same manner as in Example 23, Step 5, using the compound (117 mg) obtained in Step 1 above. mg).
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.16-4.09 (1H, m), 4.03-3.98 (1H, m), 3.94 (1H, dd, J = 10.7,2.4Hz), 3.60-3.55 (1H, m) , 3.53-3.50 (1H, m), 3.45-3.38 (1H, m), 3.33-3.27 (1H, m), 3.16 (1H, dd, J = 9.8,3.9Hz), 2.28-2.20 (2H, m) , 2.12-2.01 (2H, m), 1.92-1.86 (1H, m), 1.80-0.97 (42H, m), 1.52 (3H, s), 1.12 (3H, s), 0.98 (3H, d, J = 6.8Hz).

(Example 38)
(2,6-difluorophenyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
(2S, 4aR, 4bS, 6aS, 7aS, 8aS, 8bR, 8cR) -2-hydroxy-4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 7a, 8,8a, 8b, 8c, 9-Tetradecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthrene-7 (1H) -one In a solution of trimethylsulfoxonium iodide (5.16g) in dimethylsulfoxide (120ml) Sodium hydride (60 wt%, 0.938 g) was added, and the mixture was stirred at room temperature for 30 minutes. Then, known (3β) -3-hydroxyandrosta-5,15-dien-17-one (3.36 g) was added and the mixture was stirred at room temperature for 4 Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give the title compound (3.82 g).
MS (ESI) m / z: 301 (M + H) ^<+> .

(Process 2)
(2S, 4aR, 4bS, 6aS, 7aS, 8aS, 8bR, 8cR) -4a, 6a-dimethyl-7-oxo-1,2,3,4,4a, 4b, 5,6,6a, 7,7a, 8,8a, 8b, 8c, 9-Hexadecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthren-2-yl acetate Conducted using the compound (3.82 g) obtained in Step 1 above. The title compound (1.58 g) was obtained as a solid in the same manner as in Example 31, Step 5.
MS (ESI) m / z: 343 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.46-5.41 (1H, m), 4.64-4.54 (1H, m), 2.38-0.93 (19H, m) .2.01 (3H, s), 1.03 (3H, s) , 0.95 (3H, s).

(Process 3)
(2S, 4aR, 4bS, 6aS, 7E, 7aS, 8aS, 8bR, 8cR) -7- (hydroxyimino) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a , 7,7a, 8,8a, 8b, 8c, 9-hexadecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthren-2-yl acetate Compound obtained in Step 2 above (1.58 g ) To give the title compound (1.49 g) as a solid in the same manner as in Example 36, step 5.
MS (ESI) m / z: 358 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.44-5.39 (1H, m), 4.62-4.55 (1H, m), 2.42-0.90 (19H, m), 2.01 (3H, s), 1.03 (3H, s) , 0.99 (3H, s).

(Process 4)
(2S, 4aR, 4bS, 6aS, 8aS, 9aS, 9bR, 9cR) -4a, 6a-dimethyl-8-oxo-2,3,4,4a, 4b, 5,6,6a, 7,8,8a, 9,9a, 9b, 9c, 10-Hexadecahydro-1H-cyclopropa [c] naphtho [2,1-f] quinolin-2-yl acetate Performed using the compound (1.38 g) obtained in Step 3 above The title compound (730 mg) was obtained as a solid in the same manner as in Example 36, Step 6.
¹ H-NMR (CDCl ₃ ) δ: 5.45 (1H, brs), 5.43-5.39 (1H, m), 4.64-4.55 (1H, m), 2.38-2.26 (3H, m), 1.89-0.83 (16H, m), 2.01 (3H, s), 1.19 (3H, s), 1.02 (3H, s).

(Process 5)
(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 7,8,8a, 9,9a, 9b, 9c, 10-Hexadecahydro-1H-cyclopropa [c] naphtho [2,1-f] quinolin-2-ol Similar to Example 36, Step 7 using the compound (630 mg) obtained in Step 4 above. To give the title compound (251 mg) as a solid.
MS (ESI) m / z: 302 (M + H) ^<+> .

(Process 6)
(2,6-difluorophenyl) [(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5 , 6,6a, 8,8a, 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone obtained in step 5 above Using the same compound (130 mg) and 2,6-difluorobenzoyl chloride (0.0594 ml), the title compound (43 mg) was obtained as a solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 442 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.28-7.22 (1H, m), 6.91-6.85 (2H, m), 5.39-5.35 (1H, m), 3.62-3.47 (3H, m), 2.99-2.94 ( 1H, m), 2.36-2.28 (2H, m), 2.26-2.18 (1H, m), 1.94 (1H, d, J = 11.2Hz), 1.85-1.79 (3H, m), 1.73-1.64 (2H, m), 1.60 (3H, s), 1.54-1.36 (2H, m), 1.09-1.03 (2H, m), 1.00-0.93 (4H, m), 1.00 (3H, s). 0.50-0.46 (1H, m).

(Process 7)
(4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -7- (2,6-difluorobenzoyl) -4a, 6a-dimethyl-3,4,4a, 4b, 5,6,6a, 7,8 , 8a, 9,9a, 9b, 9c, 10,11-hexadecahydro-2H-cyclopropa [c] naphtho [2,1-f] quinolin-2-one Compound obtained in the above step 6 (65.0 mg) Was used to give the title compound (46 mg) as a solid in the same manner as in Step 1 of Example 12.
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.30-7.23 (1H, m), 6.92-6.85 (2H, m), 5.74 (1H, s), 3.61-3.54 (2H, m), 3.04-3.01 (1H, m), 2.48-2.31 (4H, m), 2.29-2.22 (1H, m), 2.06-1.99 (1H, m), 1.96-1.92 (1H, m), 1.91-1.82 (1H, m), 1.71- 1.36 (4H, m), 1.63 (3H, s), 1.25-0.98 (5H, m), 1.18 (3H, s), 0.55-0.49 (1H, m).

(Process 8)
(2,6-difluorophenyl) [(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6 , 6a, 8,8a, 9,9a, 9b, 9c, 10,11-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone obtained in step 7 above The title compound (46.4 mg) was obtained in the same manner as in Step 19 of Example 19 using the compound (46.0 mg).
MS (ESI) m / z: 442 (M + H) ^<+> .

(Process 9)
(2,6-difluorophenyl) [(1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS) -1-hydroxy-3a, 5a-dimethylhexadecahydrocyclopropa [c] oxyleno [ 4a, 5] Naphtho [2,1-f] quinolin-6 (2H) -yl] methanone The title compound was obtained in the same manner as in Step 1 of Example 1 using the compound obtained in Step 8 above (46.4 mg). (48.0 mg) was obtained as a solid.
MS (ESI) m / z: 458 (M + H) ^<+> .

(Process 10)
(2,6-difluorophenyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Using the compound (48.0 mg) obtained in Step 9 above, in the same manner as in Example 31, Step 4, the title compound (22.0 mg) was obtained as a solid.
MS (ESI) m / z: 476 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.28-7.24 (1H, m), 6.90-6.85 (2H, m), 4.17-4.10 (1H, m), 3.60-3.50 (4H, m), 3.01-2.95 ( 1H, m), 2.30-2.24 (2H, m), 2.03-1.92 (2H, m), 1.80-0.93 (12H, m) .1.58 (3H, s), 1.14 (3H, s), 0.51-0.45 ( 1H, m).

(Example 39)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2- ² H ₂ ) hexadecahydronaphtho [2, 1-f] quinoline-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bR, 8S, 10aR , 10bS, 12aS) -10a, 12a- dimethyl _{^{(2,2- 2 H 2) -1,2,3,4,4a,}} 4b, 5,7,8,9,10 , 10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-ol
(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-2-oxo-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-yl acetate (2.88 g) and lithium aluminum deuteride (1M tetrahydrofuran solution, 25.0 ml) using Example 36 Step 7 The title compound (2.43 g) was obtained as a milky white solid by a method similar to that described above.
MS (ESI) m / z: 292 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.35-5.30 (1H, m), 3.36 (1H, m), 2.25-2.07 (3H, m), 1.85 (1H, m), 1.77 (1H, m), 1.68-1.61 (2H, m), 1.57-0.91 (12H, m), 1.04 (3H, s), 0.97 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 8S, 10aR , 10bS, 12aS) -8- hydroxy-10a, 12a- dimethyl _{^{(2,2- 2 H 2) -3,4,4a,}} 4b, 5,7,8,9, 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 using the compound (2.17 g) obtained in Step 1 above The title compound (2.01 g) was obtained as a white solid by the same method as in Step 1.
MS (ESI) m / z: 426 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.31 (1H, m), 5.07 (1H, d, J = 12.7Hz), 5.05 (1H, d, J = 12.7Hz), 3.49 (1H, m), 3.02 (1H, m), 2.28 (1H, m), 2.22-2.08 (2H, m), 1.85-1.58 (6H, m), 1.55-1.29 (7H, m), 1.33 ( 3H, s), 1.17 (1H, m), 1.07-0.98 (2H, m), 0.94 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 10aR, 10bS , 12aS) -10a, 12a- _{^{dimethyl-8-oxo-(2,2- 2 H 2) -3,4,4a,}} 4b, 5,6,8,9,10, 10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 12 step using compound (2.01 g) obtained in step 2 above The title compound (1.52 g) was obtained as a white solid in the same manner as in 1.
MS (ESI) m / z: 424 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.70 (1H, brs), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.08 (1H, m), 2.44-2.24 (4H, m), 2.05-1.98 (2H, m), 1.83 (1H, m), 1.73-1.59 (4H, m), 1.52-1.41 (2H, m), 1.39-1.16 (3H, m), 1.37 (3H, s), 1.13 (3H, s), 1.05-0.94 (2H, m).

(Process 4)
Benzyl (4aS, 4bR, 8S, 10aR , 10bS, 12aS) -8- hydroxy-10a, 12a- dimethyl _{^{(2,2- 2 H 2) -3,4,4a,}} 4b, 5,6,8,9, 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example using the compound (1.52 g) obtained in Step 3 above The title compound (1.53 g) was obtained as a white amorphous product by the same method as in 19th step 3.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.26 (1H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 4.13 (1H, m), 3.02 (1H, m), 2.15 (1H, m), 2.02 (1H, m), 1.96-1.88 (2H, m), 1.80 (1H, m), 1.72-1.58 (3H, m), 1.54 (1H, m), 1.47-1.11 (8H, m), 1.34 (3H, s), 0.99 (3H, s), 0.88-0.78 (2H, m).

(Process 5)
Benzyl (1aS, 2S, 4aR, 4bS , 6aS, 10aS, 10bR, 12aR) -2- hydroxy -4a, 6a- dimethyl (8,8- _² H ²⁾ tetradecahydro- -1aH- oxireno [4a, 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate Using the compound (1.53 g) obtained in Step 4 above, the title compound (1.59 g) was converted to white in the same manner as in Step 1 of Example 1. Obtained as amorphous.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 4.03 (1H, m), 3.13 (1H, d, J = 4.4Hz), 3.04 (1H, m), 2.20 (1H, d, J = 10.3Hz), 2.06 (1H, m), 1.95 (1H, m), 1.82 (1H, m ), 1.73-1.60 (2H, m), 1.55-1.13 (11H, m), 1.33 (3H, s), 1.09 (1H, m), 0.96 (3H, s), 0.93 (1H, m).

(Process 6)
Benzyl (4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -6a, 7,8- trihydroxy-10a, 12a- dimethyl (2,2- _² H ²⁾ hexa decahydro naphthaldehyde [2,1 -f] Quinoline-1 (2H) -carboxylate Using the compound (500 mg) obtained in Step 5 above, the title compound (414 mg) was obtained as a white solid in the same manner as in Example 2, Step 1.
MS (ESI) m / z: 460 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.34-7.24 (5H, m), 5.02 (2H, s), 4.03 (1H, m), 3.42 (1H, d, J = 3.4Hz), 2.94 (1H, m), 2.11 (1H, m), 1.85 (1H, m), 1.72-1.11 (16H, m), 1.32 (3H, s), 1.08 (3H, s).

(Process 7)
Benzyl (4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -8- ( acetyloxy) -6A, 7- dihydroxy-10a, 12a- dimethyl (2,2- _² H ²⁾ hexa decahydro naphthaldehyde [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (400 mg) obtained in Step 6 above, the title compound (322 mg) was converted to a white solid in the same manner as in Step 2 of Example 4. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.26 (1H, ddd, J = 3.9, 5.4, 12.2Hz), 5.06 (1H, d, J = 12.7Hz), 5.04 (1H , d, J = 12.7Hz), 3.62 (1H, m), 3.01 (1H, m), 2.19 (1H, m), 2.06 (3H, m), 1.88 (1H, d, J = 2.4Hz), 1.84 -1.59 (6H, m), 1.57-1.49 (2H, m), 1.45-1.33 (5H, m), 1.32 (3H, s), 1.25-1.12 (4H, m), 1.11 (3H, s), 1.09 (1H, s).

(Process 8)
(4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -6a, 7- dihydroxy-10a, 12a- dimethyl (2,2- _² H ²⁾ octa decahydro naphthaldehyde [2,1-f] quinoline -8-yl acetate Using the compound (322 mg) obtained in Step 7 above, the title compound (242 mg) was obtained as a white solid in the same manner as in Example 2, Step 2.
¹ H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 3.63 (1H, d, J = 3.4Hz), 2.20-1.76 (4H, m), 2.05 (3H, s), 1.70-1.65 (4H m), 1.57-1.51 (2H, m), 1.47-0.99 (12H, m), 1.13 (3H, s), 1.02 (3H, s).

(Process 9)
(4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -1- ( cyclohexylcarbonyl) -6A, 7- dihydroxy-10a, 12a- dimethyl (2,2- _² H ²⁾ octa decahydro naphthaldehyde [ 2,1-f] quinolin-8-yl acetate Using the compound obtained in Step 8 above (70 mg) and cyclohexanecarbonyl chloride (0.035 ml), the title compound (58 mg) was prepared in the same manner as in Example 1, Step 1. Was obtained as a white solid.
MS (ESI) m / z: 478 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.27 (1H, m), 3.62 (1H, d, J = 3.9Hz), 3.18 (1H, m), 2.49 (1H, m), 2.16 (1H, m) 2.04 (3H, s), 1.92-1.17 (27H, m), 1.41 (3H, s), 1.13 (3H, s).

(Process 10)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2- ² H ₂ ) hexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone Using the compound (58 mg) obtained in Step 9 above, the title compound (45 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5. .
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.03 (1H, m), 3.42 (1H, d, J = 3.9Hz), 3.15 (1H, m), 2.46 (1H, m), 2.11 (1H, m) , 1.87 (1H, m), 1.81-1.13 (26H, m), 1.38 (3H, s), 1.09 (3H, s).

(Example 40)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2 - ² H ₂₎ hexa decahydro naphthaldehyde [2,1-f] quinoline -1 (2H) - yl] methanone

(Process 1)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] (2 , 2- _² H ²⁾ octa decahydro naphthaldehyde [2,1-f] quinolin-8-yl acetate example 39 the compound obtained in step 8 (170 mg) and the compound obtained in example 23 step 3 (99 mg ) To give the title compound (175 mg) as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.25 (1H, m), 4.06 (1H, m), 3.94 (1H, m), 3.59 (1H, d, J = 3.4Hz), 3.46 (1H, m) 3.15 (1H, m), 2.13 (1H, m), 2.01 (3H, s), 1.92-1.80 (3H, m), 1.78-1.47 (11H, m), 1.46-1.31 (3H, m), 1.40 (3H, s), 1.27-1.14 (6H, m), 1.11 (3H, s).

(Process 2)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2 - ² H ₂₎ hexa decahydro naphthaldehyde [2,1-f] quinoline -1 (2H) - yl] methanone using the compound obtained in step 2 (175 mg), the same manner as in example 5 step 1 Gave the title compound (142 mg) as a white solid.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.06 (1H, m), 4.02 (1H, m), 3.94 (1H, dd, J = 2.4,11.2Hz), 3.46 (1H, m), 3.42 (1H, d, J = 3.9Hz), 3.15 (1H, m), 2.12 (1H, m), 1.91-1.82 (2H, m), 1.79-1.28 (17H, m), 1.40 (3H, s), 1.25-1.13 (4H, m), 1.09 (3H, s).

(Example 41)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethyl (2,2- ² H ₂ ) hexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1aS, 2S, 4aR, 4bS , 6aS, 10aS, 10bR, 12aR) -2- methoxy -4a, 6a- dimethyl (8,8- _² H ²⁾ tetradecahydro- -1aH- oxireno [4a, 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate The same procedure as in Example 27, Step 1, using the compound obtained in Step 5 of Example 39 (200 mg) and methyl iodide (0.283 ml). Gave the title compound (187 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.65 (1H, m), 3.42 (3H, s), 3.10 (1H, d, J = 3.9Hz), 3.03 (1H, m), 2.06 (1H, m), 1.94 (1H, m), 1.82 (1H, m), 1.73-1.60 (2H, m), 1.54-1.41 (5H, m), 1.38-1.29 (2H, m), 1.33 (3H, s), 1.27-1.15 (3H, m), 1.14-1.06 (2H, m), 0.97 (3H, s), 0.93 (1H, m).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -6a, 7- dihydroxy-8-methoxy-10a, 12a- dimethyl ^(2,2-2 H ₂₎ hexa decahydro naphthaldehyde [2, 1-f] quinoline-1 (2H) -carboxylate Using the compound (187 mg) obtained in Step 1 above, the title compound (131 mg) was obtained as a white solid in the same manner as in Example 2, Step 1.
MS (ESI) m / z: 474 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.67-3.62 (2H, m ), 3.37 (3H, s), 3.01 (1H, m), 2.28 (1H, s), 2.19 (1H, m), 1.84-1.49 (7H, m), 1.44-1.34 (6H, m), 1.32 ( 3H, s), 1.29-1.12 (4H, m), 1.09 (3H, s), 1.03 (1H, s).

(Process 3)
(4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -8- methoxy-10a, 12a- dimethyl (2,2- _² H ²⁾ hexa decahydro naphthaldehyde [2,1-f] quinoline -6a , 7 (2H) -diol Using the compound (131 mg) obtained in Step 2 above, the title compound (99 mg) was obtained as a white solid in the same manner as in Step 2 of Example 20.
¹ H-NMR (CD ₃ OD) δ: 3.68 (1H, m), 3.62 (1H, d, J = 3.9Hz), 3.32 (3H, s), 2.10 (1H, m), 1.75-1.16 (16H, m), 1.13-0.97 (2H, m), 1.10 (3H, s), 1.02 (3H, s).

(Process 4)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethyl (2,2- ² H ₂ ) hexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (99 mg) obtained in Step 3 above and obtained in Step 3 of Example 23 Using the compound (57 mg), the title compound (92 mg) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.93 (1H, dd, J = 2.4,10.7Hz), 3.66-3.61 (2H, m), 3.41 (1H, m), 3.36 (3H , s), 3.25 (1H, m), 2.29 (1H, s), 2.20 (1H, m), 1.89 (1H, m), 1.85-1.30 (17H, m), 1.40 (3H, s), 1.28- 1.13 (5H, m), 1.09 (3H, s), 1.04 (1H, s).

(Example 42)
1-[(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-Fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] -2-methylpropan-1-one

(Process 1)
(4aS, 4bS, 10aR, 10bS, 12aS) -2-Methoxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,9,10,10a, 10b, 12,12a-dodecahydronaphtho [ 2,1-f] quinoline-8,11-dione (4aS, 4bS, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,9,10,10a, 10b , 12,12a-dodecahydronaphtho [2,1-f] quinoline-2,8,11 (1H) -trione (19.0 g) suspended in dichloromethane (500 ml) and methyl trifluoromethanesulfonate (8.57 ml) In addition, the mixture was stirred overnight at room temperature. An aqueous potassium carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography [ethyl acetate → methanol / dichloromethane] to give the title compound (16.4 g) and The starting lactam body (4.7 g) was obtained.
MS (ESI) m / z: 330 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.71 (1H, s), 3.57 (3H, s), 2.77-2.75 (1H, m), 2.59-2.56 (1H, m), 2.50-1.12 (10H, m) 1.40 (3H, s), 0.92 (3H, s).

(Process 2)
(4aS, 4bS, 10aR, 10bS, 12aS) -8-Ethoxy-2-methoxy-10a, 12a-dimethyl-4,4a, 4b, 5,9,10,10a, 10b, 12,12a-decahydronaphtho [2, 1-f] quinolin-11 (3H) -one The compound (52.4 g) obtained in Step 1 above was dissolved in a mixed solution of tetrahydrofuran (320 ml) and ethanol (320 ml), and ethyl orthoformate (52.4 ml) And p-toluenesulfonic acid monohydrate (33.3 g) were added, and the mixture was stirred at room temperature for 1 hour. 1N aqueous sodium hydroxide solution was added to the reaction solution to make it basic, and the solvent was distilled off, followed by partitioning between ethyl acetate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then the filtrate was concentrated to obtain the title compound (56.2 g).
MS (ESI) m / z: 358 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.15-5.14 (1H, m), 5.06-5.05 (1H, m), 3.76-3.73 (2H, m), 3.57 (3H, s), 2.63-2.55 (2H, m), 2.46-2.23 (5H, m), 2.07-2.01 (2H, m), 1.95-1.85 (3H, m), 1.50-1.43 (2H, m), 1.28 (3H, t, J = 7.1Hz) 1.18-1.15 (1H, m), 1.14 (3H, s), 0.90 (3H, s).

(Process 3)
(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -8-Ethoxy-10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,9,10,10a, 10b, 11,12, 12a-Tetradecahydronaphtho [2,1-f] quinolin-11-ol The compound (56.2 g) obtained in Step 2 above was suspended in ethanol (1000 ml) and sodium borohydride (59.5 g ) Was added and stirred at room temperature overnight. A part of the reaction solution was distilled off, water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain the title compound (44.8 g).
MS (ESI) m / z: 332 (M + H) ^<+> .

(Process 4)
Benzyl (4aS, 4bS, 10aR, 10bS, 11S, 12aS) -8-ethoxy-11-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,9,10,10a, 10b, 11,12 , 12a-dodecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The title compound was prepared in the same manner as in Example 19, Step 1 using the compound (44.8 g) obtained in Step 3 above. Compound (66.5 g) was obtained.
MS (ESI) m / z: 466 (M + H) ^<+> .

(Process 5)
Benzyl (4aS, 4bS, 10aR, 10bS, 11S, 12aS) -11-hydroxy-10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The compound (62.9 g) obtained in Step 4 above was dissolved in tetrahydrofuran (1000 ml), 1N Hydrochloric acid (100 ml) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, neutralized with 1N aqueous sodium hydroxide solution, extracted with dichloromethane, the organic layer was dried, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (26.1 g).
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.32 (5H, m), 5.68 (1H, s), 5.08 (2H, s), 4.34-4.33 (1H, m), 3.82-3.78 (1H, m) 3.31-3.27 (2H, m), 2.50-2.17 (6H, m), 1.99-1.02 (17H, m).

(Process 6)
Benzyl (4aS, 4bS, 10aS, 10bR, 12aS) -10b-fluoro-10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (fluorine)
And benzyl (4aS, 4bS, 10aS, 12aS) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 12,12a-dodecahydronaphtho 2,1-f] quinoline-1 (2H) -carboxylate (olefin)
The compound (26.1 g) obtained in the above Step 5 was dissolved in dichloromethane (600 ml), and 1,8-diazabicyclo [5.4.0] undec-7-ene (16.4 ml) was added. Further, (diethylamino) difluorosulfonium tetrafluoroborate (25.0 g) was added with stirring at −78 ° C., and the mixture was allowed to stand overnight, and the temperature was slowly raised to room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, and the filtrate is concentrated. The resulting residue is separated and purified by silica gel column chromatography [ethyl acetate-hexane] and [ethyl acetate / dichloromethane] to give the title compound (fluorine). (10.6 g) and the title compound (olefin) (8.61 g) were obtained.
Fluorine: (Rf = lower: high polarity)
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.31 (5H, m), 5.84-5.84 (1H, m), 5.09-5.09 (2H, m), 3.80-3.77 (1H, m), 3.40-3.38 ( 1H, m), 3.00-2.98 (1H, m), 2.44-2.35 (6H, m), 2.08-1.43 (10H, m), 1.40 (3H, s), 1.27 (3H, s), 1.25-1.16 ( 1H, m).
Olefin body: (Rf = higher: low polarity)
MS (ESI) m / z: 420 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.33 (5H, m), 5.74-5.74 (1H, m), 5.49-5.47 (1H, m), 5.09 (2H, s), 3.78-3.73 (1H, m), 3.38-3.35 (2H, m), 2.50-2.41 (4H, m), 2.27-1.93 (6H, m), 1.82-1.44 (3H, m), 1.31 (3H, s), 1.23 (3H, s), 1.10-1.07 (1H, m).

(Process 7)
Benzyl (4aS, 4bS, 8S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example using the compound (fluorine) (6.60 g) obtained in Step 6 above The title compound (5.18 g) was obtained by a method similar to that in 19th step 3.
MS (ESI) m / z: 442 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.45-5.44 (1H, m), 5.11-5.05 (2H, m), 4.21-4.19 (1H, m), 3.78-3.76 ( 1H, m), 3.40-3.34 (1H, m), 2.94-2.92 (1H, m), 2.24-2.21 (1H, m), 2.13-2.10 (1H, m), 2.04-1.16 (16H, m), 1.37 (3H, s), 1.15 (3H, s).

(Process 8)
Benzyl (1aS, 2S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1- f] Quinoline-7 (5H) -carboxylate Using the compound (5.18 g) obtained in Step 7 above, the title compound (4.96 g) was obtained in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 458 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.09-5.07 (2H, m), 4.02-4.01 (1H, m), 3.78-3.77 (1H, m), 3.39-3.36 ( 1H, m), 3.23-3.23 (1H, m), 2.96-2.92 (1H, m), 2.12-1.09 (24H, m).

(Process 9)
Benzyl (4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -carboxylate (triol form)
And benzyl (4aS, 4bS, 7R, 8S, 10aS, 10bR, 12aS) -10b-fluoro-7,8-dihydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9, 10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (diol)
Using the compound (2.00 g) obtained in the above Step 8, the title compound (0.93 g) was obtained as a mixture of a triol form and a diol form in the same manner as in Step 4 of Example 31.

(Process 10)
Benzyl (4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -7,8-bis (acetyloxy) -10b-fluoro-6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -carboxylate (tertiary alcohol)
And benzyl (4aS, 4bS, 7R, 8S, 10aS, 10bR, 12aS) -7,8-bis (acetyloxy) -10b-fluoro-10a, 12a-dimethyl-3,4,4a, 4b, 5,7, 8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (olefin)
Using the compound (0.93 g) obtained in the above Step 9, the title compound (tertiary alcohol) (0.67 g) was converted to a white solid by the same procedure as in Step 31 of Example 31, and the title compound (olefin) (0.70 g) were obtained as colorless oils, respectively.
Grade 3 alcohol body
MS (ESI) m / z: 560 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.48 (1H, m), 5.08-5.04 (3H, m), 3.98 (1H, d, J = 35.6Hz), 3.77 (1H , m), 3.39 (1H, m), 2.94 (1H, m), 2.15-2.01 (2H, m), 2.10 (3H, s), 1.97 (3H, s), 1.89-1.40 (14H, m), 1.36 (3H, s), 1.25 (3H, s), 1.12-1.25 (1H, m).

(Process 11)
(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8-diyldiacetate G. The title compound (0.51 g) was obtained in the same manner as in Step 20 of Example 20 using the compound (tertiary alcohol) (1.04 g) obtained in Step 10 above and 20% palladium hydroxide as a catalyst. It was.
MS (ESI) m / z: 426 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.47 (1H, m), 5.05 (1H, m), 3.84 (1H, d, J = 34.2Hz), 3.20 (1H, m), 3.01 (1H, m), 2.30 (1H, m), 2.10 (3H, s), 1.97 (3H, s), 1.37 (3H, s), 1.25 (3H, s), 2.13-1.16 (18H, m).

(Process 12)
(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a-hydroxy-10a, 12a-dimethyl-1- (2-methylpropanoyl) octadecahydronaphtho [2,1- f] Quinoline-7,8-diyldiacetate Using the compound obtained in Step 11 above (100 mg) and isobutyrylcarbonyl chloride (75 mg), the title compound (116 mg) was prepared in the same manner as in Example 31, Step 7. Obtained.
MS (ESI) m / z: 496 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.48 (1H, m), 5.05 (1H, d, J = 3.9Hz), 3.99 (1H, d, J = 35.6Hz), 3.49-3.42 (2H, m), 3.20-3.17 (1H, m), 2.71 (1H, m), 2.17-2.05 (2H, m), 1.87-1.18 (15H, m), 2.10 (3H, s), 1.97 (3H, s), 1.44 ( 3H, s), 1.25 (3H, s), 1.08 (3H, d, J = 6.8Hz), 1.06 (3H, d, J = 6.3Hz).

(Process 13)
1-[(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-Fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] -2-methylpropan-1-one Using the compound (116 mg) obtained in Step 12 above, the title compound (65 mg) was obtained as a white solid in the same manner as in Example 1, Step 1. Got as.
MS (ESI) m / z: 412 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.25 (1H, m), 3.88 (1H, d, J = 35.6Hz), 3.56 (1H, m), 3.48-3.41 (2H, m), 3, 17 ( 1H, m), 2.72 (1H, m), 2.36 (1H, d, J = 2.4Hz), 2.16-1.38 (17H, m), 1.44 (3H, s), 1.26 (3H, s), 1.26-1.22 (1H, m), 1.08 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.3 Hz).

(Example 43)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone

(Process 1)
Cyclohexyl [(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -8-ethoxy-11-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,9,10,10a, 10b, 11, 12,12a-dodecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 42 Conducted using the compound obtained in Step 3 (6.40 g) and cyclohexylcarbonyl chloride (3.15 ml) Example 1 The title compound (8.09 g) was obtained in the same manner as in Step 1.

(Process 2)
(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -1- (Cyclohexylcarbonyl) -11-hydroxy-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a , 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one As in Example 42, Step 5 using the compound (8.09 g) obtained in Step 1 above. The title compound (4.69 g) was obtained by the procedure described above.
MS (ESI) m / z: 414 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.68 (1H, s), 4.33-4.32 (1H, m), 3.56-3.53 (1H, m), 3.46-3.45 (1H, m), 3.38-3.33 (1H, m), 2.50-0.99 (28H, m), 1.70 (3H, s), 1.41 (3H, s).

(Process 3)
(4aS, 4bS, 10aS, 10bR, 12aS) -1- (cyclohexylcarbonyl) -10b-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one (fluorine)
as well as
(4aS, 4bS, 10aS, 12aS) -1- (cyclohexylcarbonyl) -10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 12,12a-dodecahydronaphtho [2,1-f] quinolin-8 (2H) -one (olefin)
The title compound (fluorine) (2.16 g) and the title compound (olefin) (1.67 g) were obtained in the same manner as in Step 42 of Example 42 using the compound (4.69 g) obtained in the above Step 2.
Fluorine: (Rf = lower: high polarity)
MS (ESI) m / z: 416 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.81-5.80 (1H, m), 3.42-3.38 (2H, m), 3.20-3.17 (1H, m), 2.42-1.20 (28H, m), 1.44 (3H, s), 1.25 (3H, s).
Olefin body: (Rf = higher: low polarity)
MS (ESI) m / z: 396 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.70-5.70 (1H, m), 5.45-5.44 (1H, m), 3.58-3.55 (1H, m), 3.50-3.45 (1H, m), 3.26-3.24 ( 1H, m), 2.54-1.03 (32H, m).

(Process 4)
Cyclohexyl [(4aS, 4bS, 8S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Examples were obtained using the compound (fluorine) (500 mg) obtained in Step 3 above. The title compound (402 mg) was obtained as a white solid by the same method as in Step 12 of 12.
MS (ESI) m / z: 418 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.41 (1H, d, J = 1.5Hz), 4.17 (1H, m), 3.43-3.34 (2H, m), 3.13 (1H, m), 2.34 (1H, m ), 2.21 (1H, m), 2.08 (1H, m), 2.01-1.13 (26H, m), 1.41 (3H, s), 1.12 (3H, s).

(Process 5)
Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1 -f] quinolin-7 (5H) -yl] methanone Using the compound (395 mg) obtained in Step 4 above, the title compound (368 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (1H, m), 3.44-3.34 (2H, m), 3.20 (1H, d, J = 2.4Hz), 3.14 (1H, m), 2.35 (1H, m ), 2.07 (1H, m), 1.96 (1H, m), 1.87-1.16 (26H, m), 1.41 (3H, s), 1.07 (3H, s).

(Process 6)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] methanone Using the compound (368 mg) obtained in Step 5 above, the title compound (149 mg) was obtained as a white solid in the same manner as in Example 2, Step 1.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.06 (1H, m), 3.52 (1H, m), 3.44 (1H, m), 3.39 (1H, d, J = 3.9Hz), 3.04 (1H, m) 2.49 (1H, m), 2.19-2.09 (2H, m), 2.00-1.16 (25H, m), 1.42 (3H, s), 1.26 (3H, s).

(Example 44)
(2,6-difluorophenyl) [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2,6-difluorophenyl) [(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -8-ethoxy-11-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,9,10 , 10a, 10b, 11,12,12a-dodecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 42 Compound (6.40 g) obtained in Step 3 and 2,6- The title compound (9.10 g) was obtained in the same manner as in Step 1 of Example 1 using difluorobenzoyl chloride (2.90 ml).

(Process 2)
(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -1- (2,6-difluorobenzoyl) -11-hydroxy-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9 , 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one Example 42 using the compound (9.10 g) obtained in Step 1 above The title compound (4.54 g) was obtained by the same method as in Step 5.
MS (ESI) m / z: 444 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.33-7.24 (1H, m), 6.92-6.88 (2H, m), 5.70-5.68 (1H, m), 4.41-4.39 (1H, m), 3.66-3.62 ( 1H, m), 3.40-3.37 (1H, m), 3.20-3.17 (1H, m), 2.51-1.14 (23H, m).

(Process 3)
(4aS, 4bS, 10aS, 10bR, 12aS) -1- (2,6-difluorobenzoyl) -10b-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10 , 10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one (fluorine)
as well as
(4aS, 4bS, 10aS, 12aS) -1- (2,6-difluorobenzoyl) -10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 12,12a -Dodecahydronaphtho [2,1-f] quinolin-8 (2H) -one (olefin)
The title compound (fluorine) (1.60 g) and the title compound (olefin) (1.32 g) were obtained in the same manner as in Example 42, Step 6 using the compound (4.54 g) obtained in Step 2 above.
Fluorine: (Rf = lower: high polarity)
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.30-7.28 (1H, m), 6.92-6.89 (2H, m), 5.85 (1H, s), 3.44-3.42 (1H, m), 3.35-3.33 (1H, m), 3.22-3.18 (1H, m), 2.44-2.41 (5H, m), 2.16-2.13 (1H, m), 1.91-1.83 (9H, m), 1.61 (3H, s), 1.51-1.49 ( 3H, m), 1.31 (3H, s).
Olefin body: (Rf = higher: low polarity)
MS (ESI) m / z: 426 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.30-7.29 (1H, m), 6.92-6.90 (1H, m), 5.75-5.75 (1H, m), 5.57-5.55 (1H, m), 3.72-3.68 ( 1H, m), 3.42-3.39 (1H, m), 3.20-3.17 (1H, m), 2.51-2.43 (5H, m), 2.21-1.98 (5H, m), 1.79-1.65 (2H, m), 1.56 (3H, s), 1.55-1.52 (1H, m), 1.34 (3H, s), 1.34-1.29 (1H, m), 1.14-1.11 (1H, m).

(Process 4)
(2,6-difluorophenyl) [(4aS, 4bS, 8S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8 , 9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Compound (fluorine) (610 mg) obtained in the above Step 3 ) To give the title compound (431 mg) as a white solid in the same manner as in Step 2 of Example 12.
¹ H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.89-6.85 (2H, m), 5.43 (1H, m), 4.20 (1H, m), 3.39 (1H, m), 3.26 (1H , m), 3.15 (1H, m), 2.24 (1H, m), 2.12-1.19 (17H, m), 1.57 (3H, s), 1.16 (3H, s).

(Process 5)
(2,6-difluorophenyl) [(1aS, 2S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] Naphtho [2,1-f] quinolin-7 (5H) -yl] methanone The title compound (361 mg) was prepared in the same manner as in Step 1 of Example 1 using the compound (431 mg) obtained in Step 4 above. Was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.25 (1H, m), 6.90-6.85 (2H, m), 4.01 (1H, m), 3.39 (1H, m), 3.28 (1H, m), 3.22 (1H , d, J = 2.4Hz), 3.16 (1H, m), 2.12-2.05 (2H, m), 1.96 (1H, m), 1.82-1.39 (12H, m), 1.56 (3H, s), 1.34 1.19 (3H, m), 1.10 (3H, s).

(Process 6)
(2,6-difluorophenyl) [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (361 mg) obtained in Step 5 above, the title compound (52 mg) as a white solid was prepared in the same manner as in Step 2 of Example 2. Obtained.
MS (ESI) m / z: 482 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.41 (1H, m), 7.01 (2H, m), 4.08 (1H, m), 3.47 (1H, m), 3.40 (1H, d, J = 3.9Hz) 3.19-3.13 (2H, m), 2.26-2.14 (2H, m), 2.06-1.51 (12H, m), 1.57 (3H, s), 1.44-1.27 (3H, m), 1.29 (3H, s) .

(Example 45)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bS, 10aS, 10bR, 11S, 12aS) -10b-bromo-1- (cyclohexylcarbonyl) -11-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9 , 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one 1,3-dibromo-5,5-dimethylhydantoin (866 mg) in dichloromethane ( 30 ml) and hydrogen fluoride pyridine (1.41 ml) was added. After stirring the reaction solution for a while, a solution of the compound (olefin compound) obtained in Step 3 of Example 43 (2.14 g) in dichloromethane (50 ml) was slowly added dropwise and stirred for 1 hour. In a separate container, 1,3-dibromo-5,5-dimethylhydantoin (866 mg) was suspended in dichloromethane (20 ml), and a solution prepared by adding hydrogen fluoride pyridine (1.41 ml) was added dropwise to the reaction solution for 30 minutes. Stir. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (936 mg).
MS (ESI) m / z: 494,496 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.77-5.76 (1H, m), 5.16-5.05 (1H, m), 3.76-3.73 (1H, m), 3.48-3.45 (2H, m), 2.78-2.75 ( 1H, m), 2.57-0.87 (31H, m).

(Process 2)
(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -1- (Cyclohexylcarbonyl) -11-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a , 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one The compound obtained in Step 1 above (936 mg) was dissolved in toluene (30 ml) and hydrogenated. Tri n-butyltin (0.993 ml) and 2,2′-azobisisobutyronitrile (18.7 mg) were added, and the mixture was heated and stirred at 100 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed 3 times with 10% aqueous potassium fluoride solution. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (388 mg).
MS (ESI) m / z: 416 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.72-5.70 (1H, m), 5.09-4.97 (1H, m), 3.89-3.86 (1H, m), 3.45-3.38 (2H, m), 2.52-1.03 ( 33H, m).

(Process 3)
Cyclohexyl [(4aS, 4bS, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10 10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The compound (0.25 g) obtained in Step 2 above was treated as Example 19 Step 3 and In a similar manner, the title compound (0.25 g) was obtained as a white solid.
MS (ESI) m / z: 418 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.26 (1H, m), 5.02-4.92 (1H, m), 4.16-4.12 (1H, m), 3.81 (1H, m), 3.49-3.42 (1H, m) , 3.40-3.32 (1H, m), 2.35 (1H, m), 2.25 (1H, m), 2.09-0.86 (26H, m), 1.56 (3H, d, J = 2.4Hz), 1.19 (3H, d , J = 3.9Hz).

(Process 4)
Cyclohexyl [(1aS, 2S, 4aR, 4bS, 5S, 6aS, 10aS, 10bS, 12aR) -5-fluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2 , 1-f] quinolin-7 (5H) -yl] methanone The title compound (0.21 g) was obtained in the same manner as in Step 1 of Example 1 using the compound (0.25 g) obtained in Step 3 above.
MS (ESI) m / z: 434 (M + H) ^<+> .

(Process 5)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone The title compound (60 mg) was obtained in the same manner as in Step 2 of Example 2 using the compound (300 mg) obtained in the above Step 4.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.97-4.86 (1H, m), 4.16-4.10 (1H, m), 3.77 (1H, m), 3.54 (1H, m), 3.49-3.34 (2H, m) 2.39-2.26 (3H, m), 1.28 (3H, d, J = 3.9Hz), 0.82 (1H, s), 1.97-1.15 (29H, m).

Example 46
(2,6-difluorophenyl) [(4aS, 4bS, 6aS, 7S, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(4aS, 4bS, 10aS, 10bR, 11S, 12aS) -10b-bromo-1- (2,6-difluorobenzoyl) -11-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5 , 6,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one Compound obtained in Example 44 Step 3 (olefin) The title compound (0.55 g) was obtained in the same manner as in Example 45, Step 1 using (1.32 g).
MS (ESI) m / z: 524,526 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.32-7.24 (1H, m), 6.94-6.89 (2H, m), 5.78 (1H, m), 5.20 (1H, m), 3.90 (1H, m), 3.45 (1H, m), 3.26-3.20 (1H, m), 2.80 (1H, m), 1.74 (3H, d, J = 2.4), 1.64 (3H, d, J = 4.4Hz), 2.36-1.38 (14H m).

(Process 2)
(4aS, 4bS, 10aR, 10bS, 11S, 12aS) -1- (2,6-difluorobenzoyl) -11-fluoro-10a, 12a-dimethyl-1,3,4,4a, 4b, 5,6,9 , 10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one Example 45 using the compound (0.55 g) obtained in Step 1 above The title compound (0.25 g) was obtained by the same method as in Step 2.
MS (ESI) m / z: 446 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.31-7.22 (1H, m), 6.94-6.86 (2H, m), 5.72 (1H, m), 5.18-5.08 (1H, m), 3.97 (1H, m) , 3.38 (1H, m), 3.22 (1H, m), 2.54-2.37 (3H, m), 2.32 (1H, m), 2.26-2.14 (2H, m), 2.04 (1H, m), 1.97-1.63 (6H, m), 1.74 (3H, d, J = 2.0 Hz), 1.48-1.38 (1H, m), 1.36 (3H, d, J = 4.4 Hz), 1.25-1.05 (2H, m).

(Process 3)
(2,6-difluorophenyl) [(4aS, 4bS, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6 , 8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Compound obtained in the above step 2 (0.37 g) To the title compound (0.21 g) in the same manner as in Example 19, Step 3.

(Process 4)
(2,6-difluorophenyl) [(1aS, 2S, 4aR, 4bS, 5S, 6aS, 10aS, 10bS, 12aR) -5-fluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [ 4a, 5] Naphtho [2,1-f] quinolin-7 (5H) -yl] methanone Using the compound (0.21 g) obtained in Step 3 above, the title compound (0.21 g) was prepared in the same manner as in Step 1 of Example 1. 0.29 g) was obtained.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.28 (1H, m), 6.93-6.87 (2H, m), 5.05-4.95 (1H, m), 4.10-4.05 (1H, m), 3.94 (1H, m) , 3.38 (1H, m), 3.24-3.18 (1H, m), 3.19 (1H, d, J = 4.4Hz), 2.30 (1H, d, J = 10.3Hz), 2.21 (1H, m), 2.12 ( 1H, m), 2.00-1.32 (11H, m), 1.71 (3H, d, J = 2.0 Hz), 1.17 (3H, d, J = 4.4 Hz), 1.18-0.98 (3H, m).

(Process 5)
(2,6-difluorophenyl) [(4aS, 4bS, 6aS, 7S, 8S, 10aR, 10bS, 11S, 12aS) -11-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone The title compound (10 mg) was obtained in the same manner as in Example 2, Step 1 using the compound (290 mg) obtained in Step 4 above. .
MS (ESI) m / z: 482 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.43 (1H, m), 7.06-7.01 (2H, m), 5.05-4.95 (1H, m), 4.09-4.04 (1H, m), 3.71 (1H, m ), 3.52-3.44 (2H, m), 3.12 (1H, m), 2.21 (1H, m), 2.01-1.91 (2H, m), 1.68 (3H, d, J = 2.0Hz), 1.29 (3H, d, J = 3.4 Hz), 1.87-1.22 (16H, m).

(Example 47)
Cyclohexyl [(3R, 4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-3,10a, 12a-trimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
(17E) -9-Fluoro-17- (hydroxyimino) androst-4-en-3-one with 3-ethoxy-9-fluoroandrosta-3,5-dien-17-one (31.0 g) A crude reaction product was obtained using the same method as in Example 36, Step 5. The obtained residue was dissolved in tetrahydrofuran (300 ml), 1N hydrochloric acid (100 ml) was added, and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran was distilled off under reduced pressure, extraction was performed twice with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated to give the title compound (30.0 g) as a white solid.
MS (ESI) m / z: 320 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.85 (1H, d, J = 2Hz), 2.34-2.60 (8H, m), 2.02-1.92 (2H, m), 1.80-1.56 (10H, m), 1.40 ( 1H, m), 1.32 (3H, s), 0.96 (3H, s).

(Process 2)
(4aS, 4bS, 10aS, 10bR, 12aS) -10b-Fluoro-10a, 12a-Dimethyl-1,3,4,4a, 4b, 5,6,9,10,10a, 10b, 11,12,12a- Tetradecahydronaphtho [2,1-f] quinoline-2,8-dione Using the compound (28.5 g) obtained in Step 1 above, the title compound (20.0 g) was prepared in the same manner as in Example 36 Step 6. g) was obtained as a white solid.
MS (ESI) m / z: 320 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.86 (1H, s), 5.81 (1H, m), 2.53-2.36 (7H, m), 2.03 (1H, m), 1.93-1.46 (10H, m), 1.30 (3H, s), 1.22 (3H, s).

(Process 3)
(4aS, 4bS, 10aS, 10bR, 12aS) -10b-fluoro-2-methoxy-10a, 12a-dimethyl-3,4a, 4b, 5,6,9,10,10a, 10b, 11,12,12a- Dodecahydronaphtho [2,1-f] quinolin-8 (4H) -one The title compound (7.50 g) was prepared in the same manner as in Example 42, Step 1 using the compound (20.0 g) obtained in Step 2 above. Was obtained as a white solid.
MS (ESI) m / z: 334 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.85 (1H, brd, J = 2Hz), 3.60 (3H, s), 2.49-2.35 (5H, m), 2.32-2.18 (2H, m), 2.02-1.95 ( 1H, m), 1.88-1.63 (7H, m), 1.55-1.33 (3H, m), 1.30 (3H, s), 1.02 (3H, s).

(Process 4)
(4aS, 4bS, 10aS, 10bR, 12aS) -8-Ethoxy-10b-fluoro-2-methoxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,9,10,10a, 10b, 11, 12,12a-dodecahydronaphtho [2,1-f] quinoline The title compound (2.90 g) was obtained in the same manner as in Example 42, step 2 using the compound (3.74 g) obtained in the above step 3. .
MS (ESI) m / z: 362 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.29 (1H, m), 5.17 (1H, m), 3.83-3.73 (2H, m), 3.61 (3H, s), 2.36-2.25 (5H, m), 2.07 -2.02 (1H, m), 1.96-1.66 (8H, m), 1.50-1.35 (2H, m), 1.30 (3H, t, J = 6.8Hz), 1.07 (3H, s), 1.00 (3H, s ).

(Process 5)
(4aS, 4bS, 10aS, 10bR, 12aS) -8-Ethoxy-10b-fluoro-2-methoxy-3,10a, 12a-trimethyl-3,4,4a, 4b, 5,9,10,10a, 10b, 11,12,12a-dodecahydronaphtho [2,1-f] quinoline To a solution of the compound obtained in Step 4 above (0.58 g) in tetrahydrofuran (50 ml) at −78 ° C. in a nitrogen atmosphere at n-butyllithium ( 2.69M hexane solution, 0.77 ml) was added dropwise. After stirring for 10 minutes at the same temperature, the mixture was stirred for 10 minutes at room temperature. The mixture was cooled again to −78 ° C., methyl iodide (0.15 ml) was added, and the mixture was stirred for 5 minutes. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.58 g) as a diastereomeric mixture.
MS (ESI) m / z: 376 (M + H) ^<+> .

(Process 6)
(4aS, 4bS, 10aS, 10bR, 12aS) -8-ethoxy-10b-fluoro-3,10a, 12a-trimethyl-1,2,3,4,4a, 4b, 5,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline The title compound (0.53 g) was prepared in the same manner as in Example 42, step 3, using the compound (0.58 g) obtained in Step 5 above. Was obtained as a mixture of diastereomers.

(Process 7)
Cyclohexyl [(4aS, 4bS, 10aS, 10bR, 12aS) -8-ethoxy-10b-fluoro-3,10a, 12a-trimethyl-3,4,4a, 4b, 5,9,10,10a, 10b, 11, 12,12a-dodecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 31 using the compound (0.53 g) obtained in Step 6 above and cyclohexanecarbonyl chloride (0.42 ml) In the same manner as in Step 7, the title compound (0.69 g) was obtained as a diastereomer mixture.

(Process 8)
(3R, 4aS, 4bS, 10aS, 10bR, 12aS) -1- (cyclohexylcarbonyl) -10b-fluoro-3,10a, 12a-trimethyl-1,3,4,4a, 4b, 5,6,9,10 , 10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one and
(3S, 4aS, 4bS, 10aS, 10bR, 12aS) -1- (cyclohexylcarbonyl) -10b-fluoro-3,10a, 12a-trimethyl-1,3,4,4a, 4b, 5,6,9,10 , 10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-8 (2H) -one Example 42, step 5 using the compound (0.69 g) obtained in step 7 above The title compound (3R-methyl compound) (0.28 g) and the title compound (3S-methyl compound) (0.18 g) were each obtained as a white solid by the same procedure as described above.
3R-methyl (Rf = higher: low polarity)
MS (ESI) m / z: 430 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.84 (1H, m), 3.61-3.58 (1H, m), 3.25 (1H, m), 2.76 (1H, dd, J = 13.7,8.8Hz), 2.46-2.33 (6H, m), 1.94-1.39 (18H, m), 1.30-1.19 (3H, m), 1.32 (3H, s), 1.27 (3H, s), 0.99 (3H, d, J = 6.3), 0.79 (1H, m).
3S-methyl (Rf = lower: high polarity)
MS (ESI) m / z: 430 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.83 (1H, m), 3.34 (1H, dd, J = 12.7,3.9Hz), 3.19 (1H, m), 3.07 (1H, t, J = 12.4Hz), 2.46-2.33 (6H, m), 2.67-1.98 (3H, m), 1.92-1.77 (6H, m), 1.70-1.65 (3H, m), 1.51-1.41 (5H, m), 1.46 (3H, s ), 1.32-1.18 (4H, m), 1.27 (3H, s), 0.97 (3H, d, J = 6.8 Hz).

(Process 9)
Cyclohexyl [(3R, 4aS, 4bS, 8S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-3,10a, 12a-trimethyl-3,4,4a, 4b, 5,6,8,9, 10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Compound (3R-methyl) obtained in the above Step 8 (0.28 g ) To give the title compound (0.28 g) as a white solid in the same manner as in Example 19, Step 3.
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.44 (1H, m), 4.21 (1H, m), 3.57 (1H, m), 3.19 (1H, m), 2.75 (1H, dd, J = 13.7,8.3Hz ), 2.41 (1H, m), 2.23 (1H, m), 2.11 (1H, m), 2.01 (1H, m), 1.92 (1H, m), 1.86-1.63 (12H, m), 1.58-1.39 ( 6H, m), 1.31-1.21 (4H, m), 1.30 (3H, s), 1.15 (3H, s), 0.97 (3H, d, J = 6.8 Hz), 0.74 (1H, m).

(Process 10)
Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 9R, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-4a, 6a, 9-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinolin-7 (5H) -yl] methanone Using the compound (0.28 g) obtained in Step 9 above, the title compound (0.18 g) was prepared in the same manner as in Example 1, Step 2. Obtained as a white solid.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.58 (1H, dd, J = 13.7,3.9Hz), 3.23 (1H, d, J = 2.9Hz), 3.23-3.18 (1H, m ), 2.75 (1H, dd, J = 13.7, 8.8Hz), 2.45-2.40 (1H, m), 2.09 (1H, m), 1.81-1.62 (13H, m), 1.60-1.39 (7, m), 1.29 (3H, s), 1.33-1.20 (5H, m), 1.09 (3H, s), 0.98 (3H, d, J = 6.3 Hz), 0.77 (1H, m).

(Process 11)
Cyclohexyl [(3R, 4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-3,10a, 12a-trimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone The title compound (50.0 mg) was obtained as a white solid in the same manner as in Step 4 of Example 31 using the compound (180 mg) obtained in Step 10 above. .
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 3.88 (1H, d, J = 36.1Hz), 3.60-3.55 (2H, m), 3.19-3.16 (1H, m), 2.74 (1H , dd, J = 13.7,9.3Hz), 2.11 (1H, m), 2.02-1.97 (1H, m), 1.88-1.62 (14H, m), 1.60-1.38 (6H, m), 1.29 (3H, s ), 1.26 (3H, s), 1.30-1.21 (4H, m), 0.98 (3H, d, J = 6.8 Hz), 0.79 (1H, m).

Example 48
Cyclohexyl [(3S, 4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-3,10a, 12a-trimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(3S, 4aS, 4bS, 8S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-3,10a, 12a-trimethyl-3,4,4a, 4b, 5,6,8,9, 10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Compound obtained in Example 47 Step 8 (3S-methyl) ( The title compound (0.19 g) was obtained as a white solid in the same manner as in Step 19 of Example 19 using 0.18 g).
MS (ESI) m / z: 432 (M + H) ^<+> .

(Process 2)
Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 9S, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-4a, 6a, 9-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinolin-7 (5H) -yl] methanone Using the compound (0.19 g) obtained in the above Step 1, the title compound (0.18 g) was prepared in the same manner as in Example 1, Step 2. Obtained as a white solid.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.33 (1H, dd, J = 12.7,3.9Hz), 3.23 (1H, d, J = 2.4Hz), 3.14 (1H, m), 3,06 (1H, t, J = 12.4Hz), 2.39 (1H, m), 2.13-1.38 (15H, m), 1.43 (3H, s), 1.33-1.20 (9H, m), 1.10 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 0.97-0.91 (1H, m), 0.88 (2H, m).

(Process 3)
Cyclohexyl [(3S, 4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-3,10a, 12a-trimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone The title compound (50 mg) was obtained as a white solid in the same manner as in Step 4 of Example 31 using the compound (180 mg) obtained in Step 2 above.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.25 (1H, m), 3.87 (1H, d, J = 36.1Hz), 3.56 (1H, m), 3.16-3.10 (1H, m), 3.08 (1H, t , J = 12.4Hz), 2.39 (1H, m), 2.35 (1H, d, J = 2.4Hz), 2.17-1.38 (24H, m), 1.43 (3H, s), 1.32-1.18 (4H, m) , 1.25 (3H, s), 0.97 (3H, d, J = 6.8Hz).

(Example 49)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bS, 9Z, 10aS, 10bR, 12aS) -10b-fluoro-9- (hydroxymethylidene) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8 , 9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Compound obtained in Example 42 step 6 (fluorine) ( The title compound (3.22 g) was obtained as a solid in the same manner as in Step 31 of Example 31 using 6.77 g).
MS (ESI) m / z: 468 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.43-7.30 (6H, m), 5.87 (1H, m), 5.09 (2H, s), 3.79 (1H, m), 3.39 (1H, m), 3.01-2.95 (2H, m), 2.50-2.39 (2H, m), 2.08 (1H, d, J = 14.0Hz), 2.01 (1H, m), 1.93-1.47 (9H, m), 1.39 (3H, s), 1.29-1.17 (1H, m), 1.10 (3H, s).

(Process 2)
Benzyl (4aS, 4bS, 8R, 9S, 10aS, 10bR, 12aS) -10b-fluoro-8-hydroxy-9- (hydroxymethyl) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6, 8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (3.22 g) obtained in Step 1 above In the same manner as in Step 2 of Example 31, the title compound (3.25 g) was obtained as a solid.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.43-7.28 (5H, m), 5.37 (1H, s), 5.08 (2H, s), 4.14 (1H, m), 3.80-3.70 (3H, m), 3.37 (1H, m), 2.93 (1H, m), 2.61 (1H, m), 2.34 (1H, m), 2.27-2.14 (2H, m), 2.01-1.93 (1H, m), 1.85-1.47 (10H m), 1.37 (3H, s), 1.37-1.15 (3H, m), 1.18 (3H, s).

(Process 3)
Benzyl (1aS, 2S, 3S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR) -4b-fluoro-2-hydroxy-3- (hydroxymethyl) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a , 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate The title compound (2.00 g) was prepared in the same manner as in Example 1, Step 2 using the compound (3.25 g) obtained in Step 2 above. ) Was obtained as a white solid.
MS (ESI) m / z: 488 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.40-7.26 (5H, m), 5.08 (2H, s), 3.87 (1H, dd, J = 9.3, 6.3Hz), 3.78 (1H, m), 3.68-3.65 (2H, m), 3.37 (1H, m), 3.18 (1H, s), 2.94-2.89 (1H, m), 2.65-2.62 (1H, m), 2.22 (1H, m), 2.07-1.94 (3H , m), 1.85-1.05 (13H, m), 1.37 (3H, s), 1.16 (3H, s).

(Process 4)
Benzyl (4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (tertiary alcohol)
And benzyl (4aS, 4bS, 7R, 8S, 9S, 10aS, 10bR, 12aS) -10b-fluoro-7,8-dihydroxy-9- (hydroxymethyl) -10a, 12a-dimethyl-3,4,4a, 4b , 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (olefin)
Using the compound (2.00 g) obtained in the above Step 3, the title compound was obtained as a mixture of a tertiary alcohol and an olefin in the same manner as in Step 31 of Example 31.

(Process 5)
Benzyl (4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -7,8-bis (acetyloxy) -9-[(acetyloxy) methyl] -10b-fluoro-6a-hydroxy-10a , 12a-Dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (tertiary alcohol)
And benzyl (4aS, 4bS, 7R, 8S, 9S, 10aS, 10bR, 12aS) -7,8-bis (acetyloxy) -9-[(acetyloxy) methyl] -10b-fluoro-10a, 12a-dimethyl- 3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate (olefin body)
The title compound (tertiary alcohol form) (1.04 g) and the title compound (olefin form) (1.50 g) were obtained in the same manner as in Step 31 of Example 31 using the compound obtained in Step 4 above.
Tertiary alcohol
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.28 (5H, m), 5.45 (1H, dd, J = 11.7,4.4Hz), 5.11 (1H, d, J = 4.4Hz), 5.08 (2H, s ), 4.10-4.02 (2H, m), 3.97 (1H, d, J = 39.7Hz), 3.78 (1H, m), 3.39 (1H, m), 2.97-2.94 (1H, m), 2.29 (1H, m), 2.09 (3H, s), 2.08 (3H, s), 1.96 (3H, s), 1.36 (3H, s), 1.28 (3H, s), 2.10-1.49 (12H, m), 1.44-1.40 (1H, m), 1.28-1.13 (2H, m).

(Process 6)
(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -9-[(acetyloxy) methyl] -10b-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2, 1-f] quinoline-7,8-diyl diacetate Similar to Example 19, Step 2, using the compound (tertiary alcohol) (1.04 g) obtained in Step 5 above and 20% palladium hydroxide as the catalyst. The procedure gave the title compound (0.82g) as a solid.

(Process 7)
(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -9-[(acetyloxy) methyl] -1- (cyclohexylcarbonyl) -10b-fluoro-6a-hydroxy-10a, 12a-dimethyl Octadecahydronaphtho [2,1-f] quinoline-7,8-diyl diacetate Similar to Example 31, Step 7, using the compound obtained in Step 6 above (0.45 g) and cyclohexanecarbonyl chloride (0.37 ml). The title compound (0.49g) was obtained by the procedure described above.
¹ H-NMR (CDCl ₃ ) δ: 5.45 (1H, dd, J = 12.0,4.1Hz), 5.11 (1H, d, J = 4.1Hz), 4.02-4.10 (2H, m), 3.98 (1H, d , J = 35.6Hz), 3.48-3.39 (2H, m), 3.20-3.17 (1H, m), 2.38 (1H, m), 2.33-2.25 (1H, m), 2.10-2.02 (2H, m), 1.88-1.63 (12H, m), 2.09 (3H, s), 2.07 (3H, s), 1.96 (3H, s), 1.60-1.38 (6H), 1.43 (3H, s), 1.28 (3H, s) 1.31-1.15 (5H).

(Process 8)
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (0.49 g) obtained in Step 7 above, the title compound (0.25 g) was prepared in the same manner as in Step 5 of Example 5. Obtained as a white solid.
MS (ESI) m / z: 482 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.90 (1H, dd, J = 11.2,4.4Hz), 3.80 (1H, dd, J = 10.5,4.1Hz), 3.59-3.54 (2H, m), 3.50- 3.46 (1H, m), 3.44 (1H, d, J = 4.4Hz), 3.10-3.05 (1H, m), 2.52 (1H, m), 2.21-2.12 (2H, m), 2.03-1.16 (24H, m), 1.45 (3H, s), 1.32 (3H, s).

(Example 50)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl-3 , 4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Examples Using the compound (280 mg) obtained in Step 1 and (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (1.00 g), Example 27 The title compound (316 mg) was obtained as a white solid by the same method as in Step 1.
¹ H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 4.22 (1H, m), 4.04 (1H, dd, J = 6.3,7.8Hz), 3.70 (1H, dd, J = 6.6,8.1Hz) ), 3.57-3.50 (2H, m), 3.41 (1H, dd, J = 5.9,9.8Hz), 3.35 (1H, m), 3.23 (1H, m), 3.15 (1H, m), 2.38-2.32 ( 2H, m), 2.18-2.09 (2H, m), 1.94-1.11 (23H, m), 1.40 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 1.01-0.94 (2H, m), 0.93 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8 , 9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 1 above (316 mg) The title compound (252 mg) was obtained as a white solid by a method similar to that in Example 26, Step 2.
MS (ESI) m / z: 474 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 3.82 (1H, m), 3.69 (1H, m), 3.61 (1H, m), 3.56 (1H, dd, J = 4.1,9.8Hz ), 3.51 (1H, dd, J = 6.3,9.8Hz), 3.41 (1H, m), 3.35 (1H, m), 3.22 (1H, m), 3.16 (1H, m), 2.94 (1H, d, J = 4.4Hz), 2.64 (1H, m), 2.38-2.31 (2H, m), 2.18-2.08 (2H, m), 1.91-1.10 (23H, m), 1.40 (3H, s), 1.02-0.94 (2H, m), 0.93 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-[(2R) -2,3-dihydroxypropoxy] -4a, 6b-dimethyltetradecahydro-1H-oxyleno [4, 4a] Naphtho [2,1-f] quinolin-4 (4aH) -yl] methanone The title compound (121 mg) was prepared in the same manner as in Example 1, Step 2 using the compound (120 mg) obtained in Step 2 above. Was obtained as a white solid.
Main product (α-epoxide)
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.80 (1H, m), 3.67 (1H, m), 3.61-3.44 (4H, m), 3.40 (1H, m), 3.32 (1H, m), 3.19 (1H , m), 2.90 (1H, d, J = 4.4Hz), 2.80 (1H, br), 2.47 (1H, br), 2.33 (1H, m), 2.03-1.94 (3H, m), 1.85-1.05 ( 25H, m), 1.34 (3H, s), 0.99 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone Using the compound (121 mg) obtained in Step 3 above, the title compound (121 mg) was obtained as a white solid in the same manner as in Step 3 of Example 10 (77 mg). Got as.
MS (ESI) m / z: 492 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.76-3.65 (2H, m), 3.54 (1H, dd, J = 4.6,11.0Hz), 3.53-3.47 (2H, m), 3.47 (1H, m), 3.43-3.37 (2H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 51)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl-3 , 4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Examples Example 27 Using the compound (200 mg) obtained in Step 1 and (S)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (1.00 g), Example 27 The title compound (237 mg) was obtained as a white solid by the same method as in Step 1.
¹ H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 4.21 (1H, m), 4.03 (1H, m), 3.71 (1H, m), 3.58-3.50 (2H, m), 3.41 (1H , m), 3.35 (1H, m), 3.23 (1H, m), 3.15 (1H, m), 2.39-2.30 (2H, m), 2.21-2.08 (2H, m), 1.92-1.10 (26H, m ), 1.399 (3H, s), 1.396 (3H, s), 1.02-0.94 (2H, m), 0.93 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6b -Dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinolin-4 (4aH) -yl] methanone Example 1 using the compound (236 mg) obtained in Step 1 above The title compound (190 mg) was obtained as a white solid by the same method as in Step 2.
Main product (α-epoxide)
MS (ESI) m / z: 530 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.01 (1H, dd, J = 6.6, 8.3 Hz), 3.67 (1H, dd, J = 6.3, 8.3 Hz), 3.56 (1H, dd , J = 5.9,9.8Hz), 3.51 (1H, m), 3.41-3.29 (3H, m), 3.18 (1H, m), 2.89 (1H, d, J = 4.4Hz), 2.32 (1H, m) 2.04-1.95 (3H, m), 1.78-1.07 (25H, m), 1.38 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 0.98 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a , 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 2 above (134 mg) and the same procedure as in Step 10 of Example 10. The title compound (84 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.02 (1H, dd, J = 6.3, 7.8Hz), 3.75-3.66 (2H, m), 3.57 (1H, dd, J = 5.6, 9.5Hz), 3.45-3.28 (3H, m), 3.24 (1H, m), 2.34 (1H, m), 1.92-1.08 (31H, m), 1.39 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] methanone Using the compound (84 mg) obtained in Step 3 above, the title compound (64 mg) was obtained as a white solid in the same manner as in Step 26 of Example 26.
MS (ESI) m / z: 492 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.72 (1H, m), 3.67 (1H, m), 3.54 (1H, dd, J = 4.9,11.2Hz), 3.52-3.37 (5H, m), 3.17 ( 1H, dd, J = 2.7,9.0 Hz), 2.47 (1H, m), 1.90-1.08 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 52)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6,6a-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6,6a-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (52 mg) obtained in Example 51, Step 2, the title compound (30 mg) was prepared in the same manner as in Example 2, Step 1. Obtained as a white solid.
MS (ESI) m / z: 508 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.78 (1H, m), 3.68 (1H, m), 3.55 (1H, dd, J = 4.9,11.2Hz) 3.50-3.37 (6H, m), 3.16 (1H , dd, J = 3.4,9.3Hz), 2.48 (1H, m), 1.97 (1H, dd, J = 11.2,12.7Hz), 1.91-1.60 (14H, m), 1.55 (1H, m), 1.48- 1.12 (12H, m), 1.41 (3H, s), 1.07 (3H, s).

(Example 53)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6-fluoro -6a-Hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6b -Dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinolin-4 (4aH) -yl] methanone Example 50 Conducted using the compound (793 mg) obtained in Step 1 The title compound (620 mg) was obtained as a white solid in the same manner as in Example 1, Step 2.
Main product (α-epoxide)
¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.02 (1H, d, J = 6.6,8.3Hz), 3.67 (1H, dd, J = 6.3,8.3Hz), 3.54-3.47 (2H , m), 3.41 (1H, dd, J = 5.9,9.8Hz), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.89 (1H, d, J = 4.4Hz) , 2.32 (1H, m), 2.03-1.93 (3H, m), 1.77-1.07 (25H, m), 1.38 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 0.98 (3H , s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6-fluoro -6a-Hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 9 step using compound (620 mg) obtained in step 1 above In the same manner as in 1, the title compound (319 mg) was obtained as a white solid.
MS (ESI) m / z: 510 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.20 (1H, m), 3.73 (1H, m), 3.68 (1H, m), 3.54 (1H, dd, J = 4.9,11.2Hz), 3.52 (1H, dd, J = 4.9,9.8Hz), 3.50 (1H, m), 3.47 (1H, dd, J = 5.9,11.2Hz), 3.41 (1H, d, J = 6.3,9.8Hz), 3.40 (1H, m ), 3.18 (1H, dd, J = 3.4,9.3Hz), 2.48 (1H, m), 1.92-1.12 (28H, m), 1.40 (3H, s), 1.00 (3H, d, J = 4.9Hz) .

Example 54
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-[(2S, 3S) -2,3,4-trihydroxybutoxy] hexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
{(4S, 5S) -5-[(methoxymethoxy) methyl] -2,2-dimethyl-1,3-dioxolan-4-yl} methyl 4-methylbenzenesulfonate {(4S, 5S) -5-[( Methoxymethoxy) methyl] -2,2-dimethyl-1,3-dioxolan-4-yl} methanol (Journal of the American Chemical Society, 1999, 121, 5829-5830.) (3.01 g) in dichloromethane (100 ml) To the solution, 1,4-diazabicyclo [2.2.2] octane (4.91 g) and p-toluenesulfonyl chloride (4.17 g) were added under ice cooling, and the mixture was stirred for 5 hours while warming to room temperature. The reaction was stopped by adding ice pieces to the reaction solution. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.78 (2H, d, J = 8.3Hz), 7.33 (2H, d, J = 8.3Hz), 4.59 (2H, s), 4.17 (1H, dd, J = 3.7 , 10.5Hz), 4.09 (1H, dd, J = 4.9,10.5Hz), 4.02-3.96 (2H, m), 3.64-3.58 (2H, m), 3.32 (3H, s), 2.43 (3H, s) 1.35 (3H, s), 1.31 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-({(4S, 5S) -5-[(methoxymethoxy) methyl] -2,2-dimethyl-1, 3-Dioxolan-4-yl} methoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 1 Compound (α- The title compound (54 mg) was obtained as a white solid in the same manner as in Example 27, Step 1 using (alcohol) (100 mg) and the compound obtained in Step 1 above (345 mg).
¹ H-NMR (CDCl ₃ ) δ: 4.64 (2H, s), 3.96 (1H, m), 3.90 (1H, m), 3.71 (1H, m), 3.69 (1H, dd, J = 3.4, 10.7 Hz ), 3.62-3.58 (2H, m), 3.55 (1H, dd, J = 4.9,10.3Hz), 3.41 (1H, m), 3.35 (3H, s), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 1.91-1.10 (31H, m), 1.394 (3H, s), 1.392 (3H, s), 1.38 (3H, s), 0.90 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-[(2S, 3S) -2,3,4-trihydroxybutoxy] hexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 2 above (54 mg), the title compound (35 mg) was converted to white using the same procedure as in Step 2 of Example 26. Obtained as a solid.
MS (ESI) m / z: 522 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.74 (1H, m), 3.68 (1H, m), 3.62-3.45 (6H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 ( 1H, m), 1.91-1.09 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

Example 55
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2 , 1-f] Quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-{[(4S, 5S) -2,2,5-trimethyl-1,3- Dioxolan-4-yl] methoxy} hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 1 Compound (α-alcohol) (200 mg) obtained in Step 3 and [( 4S, 5S) -2,2,5-trimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (Tetrahedron, 1987, 43, 2191-2198.) (432 mg) The title compound (188 mg) was obtained as a white solid by the same method as in Step 27.
¹ H-NMR (CDCl ₃ ) δ: 3.84 (1H, m), 3.70 (1H, m), 3.66 (1H, m), 3.56 (1H, dd, J = 5.6,10.0Hz), 3.50 (1H, dd , J = 4.4, 10.0Hz), 3.41 (1H, m), 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.88 (1H, m), 1.84-1.07 (30H, m), 1.39 (3H, s), 1.38 (3H, s), 1.35 (3H, s), 1.27 (3H, d, J = 5.9 Hz), 0.91 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2 , 1-f] quinolin-1 (2H) -yl] methanone Using the compound (188 mg) obtained in Step 1 above, the title compound (129 mg) was obtained as a white solid in the same manner as in Step 26 of Example 26. It was.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.76-3.69 (2H, m), 3.56 (1H, m), 3.50 (1H, m), 3.45-3.37 (3H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 1.13 (3H, d, J = 6.3 Hz), 0.92 (3H, s).

Example 56
tert-butyl {[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline- 8-yl] oxy} acetate

(Process 1)
tert-butyl {[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline- 8-yl] oxy} acetate Similar to Example 27, Step 1, using the compound (α-alcohol) (200 mg), tert-butyl bromoacetate (0.211 ml), and tetrahydrofuran as the solvent obtained in Example 1, Step 3. The title compound (85 mg) was obtained as a white solid.
MS (ESI) m / z: 532 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.98 (1H, d, J = 16.4Hz), 3.94 (1H, d, J = 16.4Hz), 3.74 (1H, m), 3.41 (1H, m), 3.33 ( 1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.91 (1H, m), 1.83-1.09 (29H, m), 1.44 (9H, s), 1.38 (3H, s), 1.05 (1H, s), 0.91 (3H, s).

(Example 57)
{[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl ] Oxy} Acetic Acid

(Process 1)
{[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl Oxy} acetic acid Example 56 A mixture of the compound obtained in Step 1 (80 mg) in methanol (10 ml), tetrahydrofuran (5 ml) and water (2.2 ml) was mixed with 1 N aqueous sodium hydroxide (0.30) at room temperature. ml), and then heated to reflux for 1 hour. The reaction solution was poured into two layers of dichloromethane and 1N hydrochloric acid, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] and crystallized from [diethyl ether / hexane] to give the title compound ( 63 mg) was obtained as a white solid.
MS (ESI) m / z: 476 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.94 (1H, d, J = 16.4Hz), 3.91 (1H, d, J = 16.4Hz), 3.81 (1H, m), 3.50 (1H, m), 3.40 (1H, m), 3.17 (1H, m), 2.47 (1H, m), 1.91-1.09 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 58)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxy-4-methoxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-({(4S, 5S) -5-[(benzyloxy) methyl] -2,2-dimethyl-1,3-dioxolan-4-yl } Methoxy) -10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] (cyclohexyl) methanone Example 1 Compound (835 mg) obtained in Step 1 and {(4S, 5S) -5-[(benzyloxy) methyl] -2,2-dimethyl-1 , 3-Dioxolan-4-yl} methyl 4-methylbenzenesulfonate (Helvetica Chimica Acta, 1981, 64, 687-702.) (5.08 g) was prepared in the same manner as in Example 27, step 1, using the title compound (1.26 g )
MS (ESI) m / z: 634 (M + H) ^<+> .

(Process 2)
[(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-({(4S, 5S) -5-[(benzyloxy) methyl] -2,2-dimethyl-1,3-dioxolane -4-yl} methoxy) -4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinolin-4 (4aH) -yl] (cyclohexyl) methanone In step 1 above Using the obtained compound (1.26 g), the title compound (776 mg) was obtained as a white amorphous substance by the same method as in Step 1 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.24 (5H, m), 4.59 (1H, d, J = 12.2Hz), 4.53 (1H, d, J = 12.2Hz), 3.99-3.87 (2H, m ), 3.59-3.45 (5H, m), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.87 (1H, d, J = 4.4Hz), 2.33 (1H, m) , 1.98 (1H, m), 1.95 (1H, dd, J = 11.7,12.7Hz), 1.91 (1H, m), 1.79-1.05 (25H, m), 1.384 (3H, s), 1.380 (3H, s ), 1.34 (3H, s), 0.97 (3H, s).

(Process 3)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-({(4S, 5S) -5-[(benzyloxy) methyl] -2,2-dimethyl-1,3-dioxolane-4 -Il} methoxy) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] (cyclohexyl) methanone Compound obtained in step 2 above (776 mg) Was used to give the title compound (686 mg) as a white solid in the same manner as in Example 10, Step 3.
¹ H-NMR (CDCl ₃ ) δ: 7.33-7.24 (5H, m), 4.59 (1H, d, J = 12.2Hz), 4.54 (1H, d, J = 12.2Hz), 3.96 (1H, m), 3.91 (1H, m), 3.67 (1H, m), 3.61-3.52 (4H, m), 3.41 (1H, m), 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m) 1.86-1.29 (22H, m), 1.39 (6H, s), 1.38 (3H, s), 1.26-1.08 (8H, m), 1.03 (1H, s), 0.89 (3H, s).

(Process 4)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-{[(4S, 5S) -5- (hydroxymethyl) -2,2-dimethyl-1,3-dioxolane -4-yl] methoxy} -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 3 above (686 mg) The title compound (534 mg) was obtained as a white solid in the same manner as in Example 13, Step 4.
¹ H-NMR (CDCl ₃ ) δ: 3.93-3.84 (2H, m), 3.75 (1H, m), 3.72-3.67 (3H, m), 3.50 (1H, dd, J = 6.8,9.3Hz), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.59 (1H, dd, J = 4.4,7.8Hz), 2.33 (1H, m), 1.90 (1H, m), 1.84- 1.12 (29H, m), 1.39 (9H, s), 1.11 (1H, s), 0.90 (3H, s).

(Process 5)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-{[(4S, 5S) -5- (methoxymethyl) -2,2-dimethyl-1,3-dioxolane -4-yl] methoxy} -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The compound (100 mg) obtained in Step 4 above and methyl iodide ( The title compound (94 mg) was obtained as a white solid in the same manner as in Example 27, step 1 using 0.033 ml).
¹ H-NMR (CDCl ₃ ) δ: 3.94 (1H, m), 3.86 (1H, m), 3.71 (1H, m), 3.58 (1H, dd, J = 5.4,10.3Hz), 3.54 (1H, dd , J = 4.9,10.3Hz), 3.51 (1H, dd, J = 3.8,10.3Hz), 3.48 (1H, dd, J = 6.2,10.3Hz), 3.41 (1H, m), 3.38 (3H, s) 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.88 (1H, m), 1.84-1.53 (13H, m), 1.48-1.12 (16H, m), 1.39 (3H , s), 1.382 (3H, s), 1.379 (3H, s), 1.10 (1H, s), 0.90 (3H, s).

(Process 6)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxy-4-methoxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone To a solution of the compound obtained in Step 5 above (94 mg) in methanol (3 ml) at room temperature, p-toluenesulfonic acid monohydrate ( 4.0 mg) was added and stirred at the same temperature for 5 hours, then heated to 60 ° C. and stirred for 2 hours. After adding triethylamine to the reaction solution, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography [methanol / dichloromethane] to obtain the title compound (80 mg) as a white solid.
MS (ESI) m / z: 536 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.77-3.70 (2H, m), 3.65 (1H, m), 3.57 (1H, dd, J = 5.4,9.8Hz), 3.53-3.37 (5H, m), 3.33 (3H, s), 3.17 (1H, m), 2.47 (1H, m), 1.91-1.10 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 59)
(Example 59-1)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2,3-dihydroxypropyl) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone diastereomer A; (Rf = higher: low polarity)

(Example 59-2)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2,3-dihydroxypropyl) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone diastereomer B; (Rf = lower: high polarity)

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8- (prop-2-en-1-yl) hexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone Example 3 The compound obtained in Step 1 (300 mg) was suspended in tetrahydrofuran (10 ml) and allylmagnesium bromide (17 wt% ether solution, 3.0 ml) was added little by little and stirred at the same temperature for 20 minutes. After adding a saturated aqueous ammonium chloride solution to the reaction solution, the reaction solution was poured into two layers of ethyl acetate and a saturated aqueous ammonium chloride solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (58 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 5.83 (1H, m), 5.15 (1H, dd, J = 2.0,10.3Hz), 5.10 (1H, dd, J = 1.0,17.1Hz), 3.97 (1H, brs ), 3.40 (1H, m), 3.32 (1H, m), 3.24 (1H, m), 2.68 (1H, brs), 2.34 (1H, m), 2.15 (2H, d, J = 7.3Hz), 1.85 -1.04 (30H, m), 1.39 (3H, s), 0.83 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2,3-dihydroxypropyl) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone Using the compound (58 mg) obtained in Step 1 above, the reaction was conducted in the same manner as in Step 15 of Example 15 and separated by silica gel column chromatography [methanol / dichloromethane]. Purification gave the diastereomer A (26 mg) (Rf = higher: low polarity) and diastereomer B (25 mg) (Rf = lower: high polarity) of the title compound as white solids, respectively.
Diastereomer A; (Rf = higher: low polarity): Example 59-1
MS (ESI) m / z: 492 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.41 (1H, m), 3.38 (2H, d, J = 5.4Hz), 3.18 (1H, m) 2.48 (1H, m), 1.89-1.11 (32H, m), 1.40 (3H, s), 0.88 (3H, s).
Diastereomer B; (Rf = lower: high polarity): Example 59-2
MS (ESI) m / z: 492 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.44-3.39 (2H, m), 3.37 (1H, dd, J = 6.1,11.0Hz), 3.19 ( 1H, m), 2.48 (1H, m), 1.89-1.08 (32H, m), 1.39 (3H, s), 0.88 (3H, s).

(Example 60)
Cyclohexyl [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] methanone To a solution of dimethylsulfone (103 mg) in tetrahydrofuran (2 ml) was added lithium diisopropylamide (1.09 M tetrahydrofuran solution, 1.00 ml) at −78 ° C., and the mixture was stirred for 30 minutes. At the same temperature, a suspension of the compound (150 mg) obtained in Example 3, Step 1 in tetrahydrofuran (3 ml) was added little by little, and then the mixture was warmed to 0 ° C. and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, poured into two layers of dichloromethane and a saturated aqueous ammonium chloride solution, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified in turn by silica gel column chromatography [ethyl acetate / hexane] and [methanol / dichloromethane] to give the title compound (25 mg) Was obtained as a white solid.
MS (ESI) m / z: 510 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.90 (1H, s), 3.41 (1H, m), 3.33 (1H, m), 3.27 (1H, m), 3.14 (1H, d, J = 14.6Hz), 3.05 (1H, d, J = 14.6Hz), 3.03 (3H, s), 2.92 (1H, s), 2.34 (1H, m), 1.93 (1H, dd, J = 2.4,14.6Hz), 1.87-1.06 (29H, m), 1.38 (3H, s), 0.87 (3H, s).

(Example 61)
(2,6-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexa Decahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-{[(4-methylphenyl) sulfonyl] oxy} -3,4,4a, 4b, 5,7,8, 9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 Compound (13.6 g) obtained in Step 1 was dissolved in dichloromethane. To the mixture was added 1,4-diazabicyclo [2.2.2] octane (10.8 g) and p-toluenesulfonyl chloride (9.18 g) with stirring under ice cooling, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was diluted with dichloromethane and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give the title compound (18.7 g).
MS (ESI) m / z: 578 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.80-7.79 (2H, m), 7.36-7.30 (7H, m), 5.30-5.29 (1H, m), 5.08 (2H, s), 4.32-4.31 (1H, m), 3.76-3.74 (1H, m), 3.37-3.35 (1H, m), 3.05-3.03 (1H, m), 2.45 (3H, s), 2.33-2.20 (3H, m), 1.83-0.96 ( 18H, m), 0.93 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl-3, 4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate In step 1 above Toluene (20 ml) was added to a mixture of the obtained compound (18.7 g) and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (20.0 ml) under a nitrogen atmosphere. The mixture was stirred with heating at ° C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (8.58 g).
MS (ESI) m / z: 538 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 5.33-5.32 (1H, m), 5.09 (2H, s), 4.20-4.11 (2H, m), 3.77-3.73 (2H, m), 3.60-3.57 (1H, m), 3.46-3.37 (2H, m), 3.19-3.17 (1H, m), 3.06-3.04 (1H, m), 2.46-0.95 (30H, m).

(Process 3)
Benzyl (4aS, 6aS, 6bR, 9S, 12aR, 12bS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6b-dimethyltetradecahydro -1H-Oxyleno [4,4a] naphtho [2,1-f] quinoline-4 (4aH) -carboxylate The same procedure as in Example 1, Step 2 using the compound (8.58 g) obtained in Step 2 above Gave the title compound (8.20 g).
MS (ESI) m / z: 554 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.32 (5H, m), 5.07 (2H, s), 4.24-4.22 (1H, m), 4.07-4.02 (1H, m), 3.74-3.70 (2H, m), 3.57-3.53 (2H, m), 3.46-3.39 (2H, m), 3.00-2.93 (2H, m), 2.04-0.90 (30H, m).

(Process 4)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound obtained in Step 3 above (8.20 g) in the same manner as in Step 1 of Example 1, the title compound ( 6.01 g) was obtained.
MS (ESI) m / z: 556 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.31 (5H, m), 5.08 (2H, s), 4.24-4.23 (1H, m), 4.07-4.04 (1H, m), 3.77-3.72 (3H, m), 3.56-3.54 (1H, m), 3.47-3.44 (1H, m), 3.37-3.27 (1H, m), 3.05-3.02 (1H, m), 1.70-1.10 (30H, m), 0.93 ( 3H, s).

(Process 5)
(4aS, 4bR, 6aR, 8S, 10aR, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-6a (2H) -ol The title compound (144 mg) was obtained in the same manner as in Example 19, Step 1 using the compound (184 mg) obtained in Step 4 above.
MS (ESI) m / z: 422 (M + H) ^<+> .

(Process 6)
(2,6-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy } -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Compound (213 mg) obtained in Step 5 above and 2,6-difluorobenzoyl The title compound was obtained in the same manner as in Example 22, Step 1 using chloride (92.0 mg).

(Process 7)
(2,6-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexa Decahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 6 above, the title compound (223 mg) as a white solid was prepared in the same manner as in Example 23 Step 5. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.31-7.22 (1H, m), 6.93-6.85 (2H, s), 3.87-3.32 (8H, m), 3.20-3.12 (1H, m), 2.58 (1H, d, J = 4.9 Hz), 2.18-2.11 (1H, m), 1.98-1.08 (23 H, m), 1.12 (1 H, d, J = 6.4 Hz), 0.97 (3H, s).

(Example 62)
(2,5-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexa Decahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2,5-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy } -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 61 Compound (213 mg) obtained in Step 5 and 2,5- The title compound was obtained as a crude product in the same manner as in Example 22, Step 1 using difluorobenzoyl chloride (92.0 mg).

(Process 2)
(2,5-difluorophenyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexa Decahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in the above Step 1, the title compound (217 mg) as a white solid was prepared in the same manner as in Example 23, Step 5. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.17-6.94 (3H, s), 3.87-3.32 (8H, m), 3.17-3.10 (1H, m), 2.58 (1H, d, J = 5.4Hz), 2.17 -2.11 (1H, m), 1.98-1.17 (23H, m), 1.11 (1H, d, J = 5.9Hz), 0.97 (3H, s).

(Example 63)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one

(Process 1)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy- 10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one Example 61 Compound (213 mg) obtained in step 5 and isobuty The title compound (246 mg) was obtained by a method similar to that in Example 22, Step 1 using ril chloride (0.0527 ml).

(Process 2)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one The title compound (98.2) was prepared in the same manner as in Example 23, Step 5, using the compound (246 mg) obtained in Step 1 above. mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 3.85-3.26 (9H, m), 2.75-2.66 (1H, m), 2.59 (1H, d, J = 4.9Hz), 2.19-2.13 (1H, m), 1.96 -1.10 (24H, m), 1.09-1.03 (6H, m), 0.94 (3H, s).

(Example 64)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -2-methoxypropan-1-one

(Process 1)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy- 10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] -2-methoxypropan-1-one Example 61 Compound (213 mg) obtained in Step 5 and 2- The title compound was obtained in the same manner as in Example 22, Step 1 using methoxypropanoyl chloride (73.5 mg).

(Process 2)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -2-methoxypropan-1-one The title compound (51.4 mg) was prepared in the same manner as in Example 23, Step 5, using the compound obtained in Step 1 above. Obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.07-4.01 (1H, m), 3.86-3.26 (12H, m), 2.59-2.56 (1H, m), 2.18-2.11 (1H, m), 1.96-1.08 ( 27H, m), 0.95 (3H, s).

Example 65
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4,4-trifluorobutan-1-one

(Process 1)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy- 10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] -4,4,4-trifluorobutan-1-one Example 61 Compound obtained in step 5 ( 211 mg) and 4,4,4-trifluorobutyric acid (89.7 mg) were used to give the title compound (255 mg) as a white solid in the same manner as in Step 23 of Example 23.

(Process 2)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4,4-trifluorobutan-1-one A procedure similar to that in Example 23, Step 5, using the compound (255 mg) obtained in Step 1 above. Gave the title compound (63.5 mg) as a white solid.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.86-3.22 (9H, m), 2.60-2.32 (5H, m), 2.19-2.13 (1H, m), 1.97-1.08 (24H, m), 0.94 (3H, s).

Example 66
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4-difluorobutan-1-one

(Process 1)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy- 10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] -4,4-difluorobutan-1-one Example 61 with the compound (211 mg) obtained in step 5 The title compound was obtained as a crude product in the same manner as in Example 23, Step 4 using 4,4-difluorobutyric acid (65.3 mg).

(Process 2)
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4-difluorobutan-1-one The title compound (151 mg) was prepared in the same manner as in Example 23, step 5, using the compound obtained in the above step 1. Was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 6.09-5.83 (1H, m), 3.86-3.21 (9H, m), 2.59 (1H, d, J = 4.9Hz), 2.46-2.41 (2H, m), 2.20 -2.07 (3H, m), 1.96-1.13 (23H, m), 1.11 (1H, d, J = 5.9Hz), 0.94 (3H, s).

Example 67
(2,2-difluorocyclopropyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2,2-difluorocyclopropyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy} -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 61 Compound (377 mg) obtained in Step 5 and 2,2 -Difluorocyclopropanecarboxylic acid (101 mg) was reacted in the same manner as in Example 23, step 4, and separated and purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compound (diastereomer A: low Polar) (192 mg) and the title compound (Diastereomer B: High polarity) (188 mg) were obtained as white solids, respectively.
Diastereomer A: Low polarity
MS (ESI) m / z: 526 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26-4.20 (1H, m), 4.07-4.03 (1H, m), 3.77-3.68 (2H, m), 3.66-3.37 (4H, m), 3.17-3.11 ( 1H, m), 2.54-2.45 (1H, m), 1.97-1.05 (32H, m), 0.93 (3H, s).
Diastereomer B: High polarity
MS (ESI) m / z: 526 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26-4.20 (1H, m), 4.08-4.03 (1H, m), 3.77-3.68 (2H, m), 3.63-3.38 (4H, m), 3.28-3.22 ( 1H, m), 2.49-2.40 (1H, m), 2.15-2.06 (1H, m), 1.96-1.04 (31H, m), 0.94 (3H, s).

(Process 2)
(2,2-difluorocyclopropyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 1 above (Diastereomer A: Low Polarity) (190 mg) (Example 23 Step 5) In a similar manner, the title compound (111 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 3.86-3.46 (8H, m), 3.19-3.11 (1H, m), 2.58 (1H, d, J = 5.4Hz), 2.54-2.45 (1H, m), 2.18 -2.12 (1H, m), 1.96-1.13 (26H, m), 0.94 (3H, s).

Example 68
(2,2-difluorocyclopropyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2,2-difluorocyclopropyl) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 23 Step using the compound obtained in Example 67 Step 1 (Diastereomer B: High Polarity) (186 mg) The title compound (133 mg) was obtained as a white solid by a method similar to 5.
¹ H-NMR (CDCl ₃ ) δ: 3.86-3.45 (8H, m), 3.29-3.21 (1H, m), 2.58 (1H, d, J = 5.4Hz), 2.49-2.40 (1H, m), 2.19 -2.06 (2H, m), 1.96-1.13 (25H, m), 0.95 (3H, s).

Example 69
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] (6-methylpyridin-2-yl) methanone

(Process 1)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] (6-methylpyridin-2-yl) methanone Example 61 Compound (100 mg) obtained in Step 5 and 6- Example 23 Step using methylpyridine-2-carboxylic acid (97.6 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (305 mg) as condensing agent In the same manner as in 4, the title compound (128 mg) was obtained.

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] (6-methylpyridin-2-yl) methanone Using the compound (128 mg) obtained from Step 1 above, in the same manner as in Example 26 Step 2, the title compound ( 104 mg) was obtained as a solid.
MS (ESI) m / z: 501 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.59-7.55 (1H, m), 7.21-7.17 (1H, m), 7.10-7.07 (1H, m), 3.83-3.31 (9H, m), 3.14-3.08 ( 1H, m), 2.63-2.59 (1H, m), 2.52 (3H, s), 2.25-2.19 (1H, m), 1.92-0.94 (17H, m), 1.52 (3H, s), 0.94 (3H, s).

Example 70
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] (4-methylpyridin-2-yl) methanone

(Process 1)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] (4-methylpyridin-2-yl) methanone Example 61 Compound (100 mg) obtained in Step 5 and 4- Example 23 Step using methylpyridine-2-carboxylic acid (97.6 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (305 mg) as condensing agent In the same manner as in 4, the title compound (128 mg) was obtained.

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] (4-methylpyridin-2-yl) methanone Using the compound (128 mg) obtained from Step 1 above, in the same manner as in Example 26 Step 2, the title compound ( 114 mg) was obtained as a solid.
MS (ESI) m / z: 501 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.40-8.36 (1H, m), 7.30-7.28 (1H, m), 7.09-7.05 (1H, m), 3.82-3.39 (8H, m), 3.37-3.27 ( 1H, m), 3.15-3.05 (1H, m), 2.90-2.58 (1H, m), 2.35 (3H, s), 1.90-1.17 (28H, m), 1.52 (3H, s), 0.94 (3H, s).

Example 71
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone and
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone Example 61 Compound obtained in step 5 ( 726 mg) and tetrahydropyran-2-carbonyl chloride (171 mg) in the same manner as in Step 1 of Example 22, separation and purification by silica gel column chromatography [ethyl acetate / dichloromethane] gave the title compound (R form ) (424 mg) and the title compound (S form) (422 mg).
R body (Rf = higher) low polarity
MS (ESI) m / z: (M + H) +534
¹ H-NMR (CDCl ₃ ) δ: 4.24-4.22 (1H, m), 4.04-3.98 (3H, m), 3.73-3.26 (8H, m), 1.92-0.93 (39H, m).
S body (Rf = lower) high polarity
MS (ESI) m / z: (M + H) +534
¹ H-NMR (CDCl ₃ ) δ: 4.24-4.22 (1H, m), 4.07-4.04 (1H, m), 3.97-3.95 (2H, m), 3.72-3.70 (2H, m), 3.56-3.53 ( 1H, m), 3.45-3.41 (4H, m), 3.29-3.25 (1H, m), 1.92-1.14 (44H, m), 0.93 (3H, s).

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 Step 5 using compound (R form) (200 mg) obtained from Step 1 above The title compound (154 mg) was obtained as a white solid by a method similar to that described above.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.07 (1H, dd, J = 4.1, 8.1Hz), 3.94 (1H, dd, J = 3.4, 10.7Hz), 3.72 (1H, m), 3.67 (1H, m), 3.58-3.38 (6H, m), 3.36 (1H, m), 3.16 (1H, m), 1.90-1.09 (26H, m), 1.40 (3H, s), 0.92 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 3, and peaks having a relative intensity of 16 or more when the maximum peak intensity is 100 in FIG.

　(実施例72)
[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-ジヒドロキシプロポキシ]-6a-ヒドロキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル][(2S)-テトラヒドロ-2H-ピラン-2-イル]メタノン

(Example 72)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone Example 26 using the compound (S form) (18 mg) obtained from Example 71, Step 1 The title compound (11 mg) was obtained as a white solid by the same method as in Step 2.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.04 (1H, dd, J = 2.7,9.5Hz), 3.91 (1H, dd, J = 3.2,11.5Hz), 3.72 (1H, m), 3.67 (1H, m), 3.54 (1H, dd, J = 4.6,11.0Hz), 3.51 (1H, dd, J = 4.6,10.0Hz), 3.50-3.41 (3H, m), 3.47 (1H, dd, J = 5.9, 11.0Hz), 3.40 (1H, dd, J = 6.1, 10.0Hz), 3.17 (1H, m), 1.90-1.09 (26H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 73)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] methanone Example 25 In step 5 The title compound (135 mg) was obtained as a white solid in the same manner as in Example 23, Step 4, using the obtained compound (67 mg) and the compound (130 mg) obtained in Example 61, Step 5.
MS (ESI) m / z: 548 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.23 (1H, m), 4.05 (1H, m), 3.97 (1H, dd, J = 11.0,2.3Hz), 3.68-3.75 (2H, m), 3.53-3.62 (2H, m), 3.38-3.47 (2H, m), 3.25-3.34 (2H, m), 1.09-1.94 (27H, m), 1.43 (3H, s), 1.42 (3H, s), 1.36 (3H , s), 1.19 (3H, d, J = 6.3 Hz) 0.93 (3H, s).

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] [(2R, 6R) -6-methyltetrahydro-2H-pyran-2-yl] methanone Example 23 step using compound (135 mg) obtained in step 1 above The title compound (77 mg) was obtained as a white solid by a method similar to 5.
MS (ESI) m / z: 508 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.97 (1H, dd, J = 10.8, 1.8 Hz), 3.40-3.99 (9H, m), 3.25-3.35 (2H, m), 2.65 (1H, m), 2.23 (1H, m), 1.09-1.93 (26H, m), 1.43 (3H, s), 1.19 (d, J = 6.3 Hz), 0.94 (3H, s).

Example 74
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -6,6-dimethyltetrahydro-2H-pyran-2-yl] methanone

(Process 1)
To a solution of 2-methylhept-6-en-2-ol 5-hexenoic acid methyl ester (6.00 g) in tetrahydrofuran (200 ml) under a nitrogen atmosphere at −78 ° C., methyl lithium (1.1 M diethyl ether solution, 100 ml) The solution was added. The temperature was slowly raised to room temperature, and the mixture was stirred for 1 hour at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the title compound (6.00 g).

(Process 2)
2-Methyl-5- (oxiran-2-yl) pentan-2-ol Using the compound (6.00 g) obtained in Step 1 above, the title compound (2.35 g) was prepared in the same manner as in Example 1, Step 2. Obtained as a colorless oil.
MS (ESI) m / z: 145 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 2.91-2.96 (1H, m), 2.77 (1H, dd, J = 4.9,3.9Hz), 2.49 (1H, dd, J = 5.1,2.7Hz), 1.5-1.62 (7H, m), 1.23 (6H, s).

(Process 3)
(6,6-Dimethyltetrahydro-2H-pyran-2-yl) methanol 10-camphorsulfonic acid (1.89 g) was added to a solution of (2.35 g) obtained in Step 2 above in dichloromethane (50 ml) and stirred at room temperature for 30 minutes. Stir for minutes. 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted once with dichloromethane and ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.25 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 3.68 (1H, m), 3.55 (1H, m), 3.44 (1H, m), 2.16 (1H, dd, J = 7.8,4.4Hz), 1.64-1.70 ( 3H, m), 1.34-1.50 (3H, m), 1.21 (3H, s), 1.21 (3H, s).

(Process 4)
6,6-Dimethyltetrahydro-2H-pyran-2-carboxylic acid Using the compound (1.25 g) obtained in the above Step 3, the title compound (0.95 g) was obtained as a colorless oil in the same manner as in Example 25, Step 5. Obtained as material.
MS (ESI) m / z: 159 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.17 (1H, dd, J = 12.2, 2.9 Hz), 2.07 (1H, m), 1.68-1.80 (2H, m), 1.53 (1H, m), 1.34 1.47 (2H, m), 1.31 (3H, s), 1.25 (3H, s).

(Process 5)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -6,6-dimethyltetrahydro-2H-pyran-2-yl] methanone obtained in step 4 above The title compound (100 mg) was obtained as a white solid in the same manner as in Example 23, Step 4, using the obtained compound (73 mg) and the compound (130 mg) obtained in Example 61, Step 5.
MS (ESI) m / z: 562 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.19-4.25 (2H, m), 4.05 (1H, m), 3.69-3.75 (2H, m), 3.66 (1H, m), 3.38-3.62 (2H, m) , 3.24-3.31 (2H, m), 1.91 (1H, m), 1.09-1.84 (26H, m), 1.42 (3H, s), 1.42 (3H, s), 1.36 (3H, s), 1.22 (3H , s), 1.20 (3H, s), 0.93 (3H, s).

(Process 6)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -6,6-dimethyltetrahydro-2H-pyran-2-yl] methanone Example 23 step using compound (100 mg) obtained in step 5 above The title compound (77 mg) was obtained as a white solid by a method similar to 5.
MS (ESI) m / z: 522 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.21 (1H, dd, J = 10.7,2.4Hz), 3.82 (1H, m), 3.49-3.77 (5H, m), 3.57 (1H, d, J = 4.4Hz ), 3.24-3.32 (2H, m), 2.59 (1H, m), 2.16 (1H, m), 1.89-1.95 (1H, m), 1.08-1.84 (26H, m), 1.42 (3H, s), 1.22 (3H, s), 1.20 (3H, s), 0.94 (3H, s).

(Example 75)
[(2R) -5,5-difluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy ] -6a-Hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Ethyl 2-oxohexe-5-enoate To a solution of diethyl oxalate (14.6 g) in tetrahydrofuran (200 ml) was added 3-butenylmagnesium bromide (0.5 M tetrahydrofuran solution, 200 ml) in a nitrogen atmosphere at -78 ° C. It was. The temperature was slowly raised to room temperature and stirred for 1 hour at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate] to obtain the title compound (15.5 g) as a colorless oily substance.
¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, m), 5.07 (1H, m), 5.02 (1H, m), 4.33 (2H, q, J = 7.2Hz), 2,95 (2H, m ), 2.40 (2H, m), 1.37 (3H, t, J = 7.2Hz).

(Process 2)
Ethyl 2,2-difluorohexe-5-enoate To a solution of the compound obtained in Step 1 above (12.7 g) in dichloromethane (200 ml) at −78 ° C., bis (2-methoxyethylamino) sulfur trifluoride ( 37.63 g) was added, and the mixture was stirred overnight while slowly raising the temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (11.7 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 5.80 (1H, m), 5.08 (1H, m), 5.03 (1H, m), 4.33 (2H, q, J = 7.2Hz), 2.12-2.28 (4H, m ), 1.36 (3H, t, J = 7.2 Hz).

(Process 3)
2,2-Difluorohex-5-en-1-ol The title compound (8 g) was obtained in the same manner as in Example 36, Step 7 using the compound (11.7 g) obtained in Step 2 above.
¹ H-NMR (CDCl ₃ ) δ: 5.84 (1H, m), 5.08 (1H, m), 5.02 (1H, m), 3.72-3.78 (2H, m), 2.28 (1H, m), 1.93-2.76 (3H, m), 1.83-1.87 (2H, m).

(Process 4)
(5,5-difluorotetrahydro-2H-pyran-2-yl) methanol The compound (8.00 g) obtained in the above Step 3 was reacted in the same manner as in Example 1, Step 2, to produce an epoxy compound. After confirmation, 10-camphorsulfonic acid (2.73 g) was added to the reaction solution and stirred at room temperature for 1 hour. To the reaction mixture were added 1N aqueous sodium hydroxide solution and aqueous sodium sulfite solution, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (5.34 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (1H, m), 3.66 (1H, dd, J = 11.7, 2.9 Hz), 3.49-3.61 (3H, m), 2.23-2.31 (1H, m), 1.82 -1.99 (2H, m), 1.68-1.75 (2H, m).

(Process 5)
5,5-Difluorotetrahydro-2H-pyran-2-carboxylic acid Compound (0.43g) obtained in Step 4 above The title compound (0.24g) was obtained as a colorless oil by the same procedure as in Example 25, Step 5. It was.
m / z165 (MH) ^+
1 H-NMR (CDCl ₃ ) δ: 4.07-4.17 (2H, m), 3.65 (1H, m), 2.22-2.32 (2H, m), 1.99-2.10 (2H, m).

(Process 6)
[(2R) -5,5-difluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl -1,3-Dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone obtained in Step 5 above The title compound (90 mg) was obtained as a white solid in the same manner as in Example 23, Step 4, using the obtained compound (77 mg) and the compound (130 mg) obtained in Example 61, Step 5.
MS (ESI) m / z: 570 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.22 (1H, m), 4.11 (1H, dd, J = 9.0,2.7Hz), 4.06 (1H, m), 3.94 (1H, m), 3.69-3.75 (2H , m), 3.51-3.62 (3H, m), 3.39-3.47 (1H, m), 3.34 (1H, m), 3.23 (1H, m), 2.33-2.40 (1H, m), 2.12-2.19 (1H , m), 1.03-2.00 (23H, m), 1.42 (3H, s), 1.42 (3H, s), 1.36 (3H, s), 0.93 (3H, s).

(Process 7)
[(2R) -5,5-difluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy ] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 23 step using compound (90 mg) obtained in step 6 above The title compound (90 mg) was obtained as a white solid by a method similar to 5.
MS (ESI) m / z: 530 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.11 (1H, d), 3.94 (1H, m), 3.82 (1H, m), 3.49-3.77 (7H, m), 3.34 (1H, m), 3.24 (1H , m), 2.30-2.40 (1H, m), 2.10-2.20 (1H, m), 1.07-2.00 (25H, m), 1.42 (3H, s), 0.94 (3H, s).

(Example 76)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-[(2S) -2-hydroxy-3- (methylsulfonyl) propoxy] -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
(2S) -2-hydroxy-3-({(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran 2-ylcarbonyl] octadecahydronaphtho [2,1-f] quinolin-8-yl} oxy) propyl 4-methylbenzenesulfonate Example 71 Step 2 Compound of Compound (340 mg) in Pyridine (4 ml) P-Toluenesulfonyl chloride (158 mg) was added thereto at 0 ° C., and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (290 mg).
MS (ESI) m / z: 648 (M + H) ^<+> .

(Process 2)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-[(2S) -2-hydroxy-3- (methylsulfonyl) propoxy] -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone N, N-dimethylformamide of the compound obtained in Step 1 above (287 mg) To the (5 ml) solution, sodium methanesulfinate (136 mg) and potassium iodide (222 mg) were added at room temperature, and the mixture was stirred at 120 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (64.4 mg) as a white solid.
MS (ESI) m / z: 556 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.38-4.31 (1H, m), 4.06-4.00 (1H, m), 3.99-3.94 (1H, m), 3.80-3.72 (1H, m), 3.60-3.39 ( 5H, m), 3.35-3.18 (3H, m), 3.11-3.03 (4H, m), 2.88-2.84 (1H, m), 1.96-1.06 (29H, m), 0.94 (3H, s).

Example 77
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl-3, 4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 61 steps Example 61, step 2 using the compound (2.31 g) obtained in 1 and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (2.48 ml) Gave the title compound (838 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.07 (2H, s), 4.26-4.19 (1H, m), 4.07-4.02 (1H, m), 3.78-3.67 (2H, m), 3.61-3.50 (2H, m), 3.47-3.29 (2H, m), 3.03-2.96 (1H, m), 2.92 (1H, d, J = 4.4Hz), 2.07-0.93 (30H, m) .

(Process 2)
Benzyl (4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6b- Dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline-4 (4aH) -carboxylate Example 1 Step 2 using the compound obtained in Step 1 above (838 mg) The title compound (823 mg) was obtained by a similar method.

(Process 3)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The title compound was prepared in the same manner as in Example 1, Step 3 using the compound (820 mg) obtained in Step 2 above. 578 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.08 (2H, s), 4.27-4.19 (1H, m), 4.08-4.02 (1H, m), 3.81-3.68 (3H, m), 3.63-3.28 (3H, m), 3.07-3.00 (1H, m), 1.96-1.07 (30H, m), 0.93 (3H, s).

(Process 4)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethylhexadeca Hydronaphtho [2,1-f] quinolin-6a (2H) -ol Using the compound (576 mg) obtained in Step 3 above, the title compound (436 mg) as a white solid was prepared in the same manner as in Example 2, Step 2. Obtained.

(Process 5)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a-hydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound obtained in step 4 above (211 mg) Using the compound (151 mg) obtained in Example 25, Step 3, the title compound (125 mg) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 534 (M + H) ^<+> .

(Process 6)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The same procedure as in Example 23, Step 5, using the compound (123 mg) obtained in Step 5 above Gave the title compound (90.2 mg) as a white solid.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.05-4.00 (1H, m), 3.99-3.94 (1H, m), 3.85-3.39 (8H, m), 3.35-3.26 (2H, m), 2.64-2.60 ( 1H, m), 2.23-2.17 (1H, m), 1.96-1.11 (30H, m), 0.94 (3H, m).

(Example 78)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8- (2-hydroxy-3-methoxypropoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9- [2- (benzyloxy) -3-methoxypropoxy] -4a, 6b-dimethyltetradecahydro-1H-oxyleno [4, 4a] Naphtho [2,1-f] quinoline-4 (4aH) -carboxylate Example 61 The compound (1.73 g) obtained in Step 1 and 2- (benzyloxy) -3-methoxypropan-1-ol ( The title compound (905 mg) was obtained as a yellow oily substance in the same manner as in Example 61, step 2 using Journal of Medicinal Chemistry, 1987, 30, 792) (2.94 g).
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.25 (10H, m), 5.33-5.29 (1H, m), 5.12-5.06 (2H, m), 4.73-4.67 (2H, m), 3.79-3.32 ( 10H, m), 3.19-3.01 (2H, m), 2.40-2.32 (1H, m), 2.21-2.10 (2H, m), 1.93-0.90 (21H, m).

(Process 2)
Benzyl (4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9- [2- (benzyloxy) -3-methoxypropoxy] -4a, 6b-dimethyltetradecahydro-1H-oxyleno [4, 4a] Naphtho [2,1-f] quinoline-4 (4aH) -carboxylate Using the compound (903 mg) obtained in Step 1 above, the title compound (762 mg) was obtained in the same manner as in Example 1, Step 2. It was.

(Process 3)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- [2- (benzyloxy) -3-methoxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -carboxylate Using the compound (760 mg) obtained in Step 2 above, the title compound (533 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.24 (10H, m), 5.11-5.05 (2H, m), 4.72-4.66 (2H, m), 3.81-3.29 (11H, m), 3.07-3.00 ( 1H, m), 1.94-0.88 (27H, m).

(Process 4)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2-hydroxy-3-methoxypropoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-6a (2H ) -Ol The title compound (337 mg) was obtained in the same manner as in Example 13, Step 5 using the compound (528 mg) obtained in Step 3 above.
MS (ESI) m / z: 396 (M + H) ^<+> .

(Process 5)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8- (2-hydroxy-3-methoxypropoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound obtained in Step 4 above (337 mg) and compound obtained in Example 23 Step 3 (111 mg) Was used to give the title compound (73 mg) as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 508 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.07-3.87 (3H, m), 3.77-3.68 (1H, m), 3.59-3.23 (11H, m), 2.48-2.44 (1H, m), 1.95-0.90 ( 33H, m).

(Example 79)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-{[(4S, 5S) -2,2,5-trimethyl-1,3-dioxolan-4-yl] methoxy } -3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 Compound (1.00 g) obtained in Step 1 and [(4S, 5S) -2,2,5-trimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (Tetrahedron, 1987) , 43, 2191-2198.) (2.14 g), and the title compound (929 mg) was obtained as a colorless viscous oil by the same procedure as in Step 27 of Example 27.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.30 (1H, m), 5.07 (1H, d, J = 12.7Hz), 5.05 (1H, d, J = 12.7Hz), 3.76-3.70 (2H, m), 3.67 (1H, m), 3.60 (1H, m), 3.49 (1H, m), 3.35 (1H, m), 3.16 (1H, m), 3.02 (1H, m) , 2.37 (1H, m), 2.20-2.07 (2H, m), 1.90-1.12 (13H, m), 1.39 (3H, s), 1.37 (3H, s), 1.33 (3H, s), 1.28 (3H , d, J = 5.9 Hz), 1.03-0.95 (2H, m), 0.93 (3H, s).

(Process 2)
Benzyl (4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -4a, 6b-dimethyl-9-{[(4S, 5S) -2,2,5-trimethyl-1,3-dioxolane-4 -Yl] methoxy} tetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline-4 (4aH) -carboxylate Conducted using the compound (929 mg) obtained in step 1 above. The title compound (669 mg) was obtained as a white solid in the same manner as in Example 1, Step 2.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.04 (2H, s), 3.83 (1H, m), 3.72 (1H, m), 3.65 (1H, m), 3.55 (1H , m), 3.51 (1H, m), 3.48 (1H, dd, J = 4.1, 10.3Hz), 3.30 (1H, m), 2.97 (1H, m), 2.89 (1H, d, J = 4.4Hz) , 2.01-1.04 (18H, m), 1.38 (3H, s), 1.35 (3H, s), 1.272 (3H, s), 1.266 (3H, d, J = 5.9 Hz), 0.98 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-{[(4S, 5S) -2,2,5-trimethyl-1,3-dioxolane -4-yl] methoxy} hexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 3, Step 3, using the compound (669 mg) obtained in Step 2 above. The procedure gave the title compound (226 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.06 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.84 (1H, m), 3.74 (1H, m), 3.72 (1H, m), 3.66 (1H, m), 3.56 (1H, dd, J = 5.9,10.3Hz), 3.50 (1H, dd, J = 4.4,10.3Hz), 3.30 (1H, m), 3.01 (1H, m), 1.89 (1H, m), 1.79 (1H, m), 1.73-1.08 (19H, m), 1.39 (3H, s), 1.36 (3H, s), 1.31 (3H, s), 1.27 (3H, d, J = 5.9), 0.90 (3H, s).

(Process 4)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-{[(4S, 5S) -2,2,5-trimethyl-1,3-dioxolan-4-yl] Methoxy} hexadecahydronaphtho [2,1-f] quinolin-6a (2H) -ol Using the compound (226 mg) obtained in Step 3 above, the title compound (137 mg ) Was obtained as a white solid.
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.86 (1H, m), 3.74 (1H, m), 3.61 (1H, m), 3.53 (2H, d, J = 4.9Hz), 2.86 (1H, m) , 2.69 (1H, dd, J = 4.9, 13.2Hz), 1.87 (1H, m), 1.71-1.67 (3H, m), 1.65-1.00 (17H, m), 1.33 (3H, s), 1.31 (3H , s), 1.24 (3H, d, J = 6.3 Hz), 1.04 (3H, s), 0.93 (3H, s).

(Process 5)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-{[(4S, 5S) -2,2,5-trimethyl-1,3-dioxolane -4-yl] methoxy} hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone obtained in step 4 above Using the compound (80 mg) and the compound (48 mg) obtained in Example 23, Step 3, the title compound (66 mg) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 548 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4,10.7Hz), 3.84 (1H, m), 3.70 (1H, m), 3.66 (1H, m ), 3.56 (1H, dd, J = 5.9, 10.3Hz), 3.53 (1H, m), 3.50 (1H, dd, J = 4.4, 10.3Hz), 3.41 (1H, m), 3.32-3.22 (2H, m), 1.93-1.84 (2H, m), 1.83-1.08 (24H, m), 1.40 (3H, s), 1.39 (3H, s), 1.36 (3H, s), 1.27 (3H, d, J = 5.9Hz), 1.10 (1H, s), 0.91 (3H, s).

(Process 6)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2S, 3S) -2,3-dihydroxybutoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Step 5 above (66 mg), Example 26 Step 2 and In a similar manner, the title compound (53 mg) was obtained as a white solid.
MS (ESI) m / z: 508 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 2.7,11.0Hz), 3.79-3.72 (2H, m), 3.61-3.56 (2H, m), 3.52-3.43 (3H, m), 3.38 (1H, m), 3.19 (1H, m), 1.94-1.83 (3H, m), 1.83-1.13 (23H, m), 1.43 (3H, s), 1.16 ( 3H, d, J = 6.3 Hz), 0.95 (3H, s).

Example 80
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a -Dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinolin-7 (5H) -yl] methanone Example 12 Compound (100 mg) obtained in Step 3 and [(4R) -2,2-Dimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (101 mg) and tetrabutylammonium iodide (17.8 mg) as additive, similar to Example 27 Step 1 By the procedure, the title compound (55.0 mg) was obtained as a colorless oil.
MS (ESI) m / z: 530 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.29-4.24 (1H, m), 4.06-4.02 (1H, m), 3.82-3.77 (2H, m), 3.68-3.65 (1H, m), 3.54-3.50 ( 1H, m), 3.45-3.39 (1H, m), 3.37-3.30 (1H, m), 3.29-3.23 (1H, m), 3.08 (1H, d, J = 2.9Hz), 2.39-2.31 (1H, m), 2.15 (1H, d, J = 1.0Hz), 2.07-0.84 (27H, m), 1.40 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.96 (3H, s ).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7 -Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example using acetone as a solvent for the compound (55.0 mg) obtained in the above Step 1 The title compound (21.0 mg) was obtained as a solid in the same manner as in 31 step 4.
MS (ESI) m / z: 548 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.28-4.23 (1H, m), 4.06-4.02 (1H, m), 3.80-3.75 (1H, m), 3.67-3.63 (2H, m), 3.58-3.48 ( 2H, m), 3.43-3.38 (1H, m), 3.37-3.30 (1H, m), 3.26-3.22 (1H, m), 2.66 (1H, s), 2.37-2.30 (1H, m), 2.25- 2.16 (1H, m), 1.83-1.05 (26H, m), 1.40 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 1.09 (3H, s).

(Process 3)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (21.0 mg) obtained in the above Step 2, the title compound (8.0 mg) was prepared in the same manner as in Example 26, Step 2. Obtained as a solid.
MS (ESI) m / z: 508 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.82-3.76 (1H, m), 3.76-3.71 (1H, m), 3.63 (1H, d, J = 3.4Hz), 3.56-3.46 (6H, m), 3.44-3.39 (2H, m), 3.33-3.22 (3H, m), 3.17-3.12 (3H, m), 2.51-2.44 (1H, m), 2.16-2.09 (2H, m), 1.88-1.06 (23H , m), 1.39 (3H, s), 1.09 (3H, s).

Example 81
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a -Dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinolin-7 (5H) -yl] methanone Example 12 Compound (200 mg) obtained in Step 3 and [(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (202 mg) and tetrabutylammonium iodide (35.5 mg) as additive, similar to Example 27 Step 1 By the procedure, the title compound (126 mg) was obtained as a colorless oil.
MS (ESI) m / z: 530 (M + H) ⁺
1H-NMR (CDCl ₃ ) δ: 4.29-4.24 (1H, m), 4.07-4.03 (1H, m), 3.84-3.79 (1H, m), 3.79-3.75 (1H, m), 3.63-3.55 (2H , m), 3.45-3.39 (1H, m), 3.37-3.23 (2H, m), 3.08 (1H, d, J = 2.9Hz), 2.39-2.31 (1H, m), 2.09-2.01 (1H, m ), 1.96-1.90 (1H, m), 1.86-0.87 (26H, m), 1.40 (6H, s), 1.34 (3H, s), 0.96 (3H, s).

(Process 2)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7 -Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 31 using acetone as a solvent for the compound obtained in Step 1 above (126 mg) The title compound was obtained in the same manner as in Step 4.

(Process 3)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2S) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The title compound (118 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound obtained in Step 2 above.
¹ H-NMR (CD ₃ OD) δ: 3.81-3.77 (1H, m), 3.73-3.69 (1H, m), 3.62 (1H, d, J = 3.4Hz), 3.59-3.46 (4H, m), 3.44-3.37 (1H, m), 3.33-3.24 (3H, m), 3.18-3.13 (1H, m), 2.51-2.44 (1H, m), 2.16-2.09 (3H, m), 1.87-1.09 (23H , m), 1.39 (3H, s), 1.09 (3H, s).

(Example 82)
1-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one

(Process 1)
Benzyl (2S, 4aR, 4bS, 6aS, 10aS, 10bR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a-dimethyltetradecahydro -1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate Example 19 Compound (5.00 g) obtained in Step 4 and [(4R) -2,2- The title compound was prepared in a manner similar to Example 27 Step 1 using dimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (3.59 g) and tetrabutylammonium iodide (0.840 g) as the additive. (1.59 g) was obtained as a solid.
MS (ESI) m / z: 554 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.31-4.23 (1H, m), 4.04 (1H, dd, J = 8.3,6.3Hz) , 3.81-3.78 (2H, m), 3.77-3.72 (1H, m), 3.67 (1H, dd, J = 9.8,4.9Hz), 3.52 (1H, dd, J = 10.0,6.1Hz), 3.34-3.29 (1H, m), 3.09 (1H, d, J = 2.9Hz), 3.03 (1H, m), 2.07-0.87 (18H, m), 1.39 (3H, s), 1.33 (6H, s), 0.96 ( 3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7- Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 31 using acetone as a solvent for the compound (1.59 g) obtained in Step 1 above The title compound (754 mg) was obtained as a solid by a method similar to 4.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.03 (2H, m), 4.28-4.24 (1H, m), 4.04 (1H, dd, J = 8.3,6.8Hz) , 3.80-3.73 (2H, m), 3.67-3.64 (2H, m), 3.58-3.48 (2H, m), 3.35-3.27 (1H, m), 3.04-2.98 (1H, m), 2.69 (1H, s), 2.26-2.17 (1H, m), 1.85-1.03 (18H, m), 1.41 (3H, s), 1.33 (3H, s), 1.32 (3H, s), 1.10 (3H, s).

(Process 3)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinoline-6a, 7 (2H) -diol The title compound (400 mg) was prepared in the same manner as in Example 2, Step 2 using the compound (754 mg) obtained in Step 2 above. Was obtained as a solid.

(Process 4)
1-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one The compound obtained in Step 3 above (100 mg) and The title compound was obtained in the same manner as in Step 31 of Example 31 using isobutyryl chloride (0.0718 ml).

(Process 5)
1-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] -2-methylpropan-1-one Using the compound obtained in the above Step 4, in the same manner as in Example 31, Step 4, the title compound (12.0 mg) was obtained as a solid.
MS (ESI) m / z: 468 (M + H) ⁺
1H-NMR (CDCl ₃ ) δ: 3.89-3.84 (1H, m), 3.82-3.78 (1H, m), 3.73-3.69 (1H, m), 3.66 (1H, d, J = 3.4Hz), 3.64 3.54 (4H, m), 3.47-3.42 (2H, m), 3.39-3.32 (1H, m), 3.28-3.24 (1H, m), 2.71-2.65 (1H, m), 2.58-2.46 (1H, m ), 2.25-2.16 (1H, m), 1.98-1.94 (1H, m), 1.96-0.96 (13H, m), 1.40 (3H, s), 1.10 (3H, s), 1.04 (6H, dd, J = 7.8,6.8Hz).

Example 83
(2,6-difluorophenyl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2,6-difluorophenyl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl ] Methoxy} -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example 82 Compound (270 mg) obtained in Step 3 and The title compound (67.0 mg) was obtained in the same manner as in Step 31 of Example 31 using 2,6-difluorobenzoyl chloride (0.232 ml).
MS (ESI) m / z: 578 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.27-7.19 (1H, m), 6.89-6.83 (2H, m), 4.29-4.24 (1H, m), 4.04 (1H, dd, J = 8.5,6.6Hz) , 3.82-3.76 (1H, m), 3.67-3.64 (2H, m), 3.58-3.49 (2H, m), 3.42-3.33 (2H, m), 3.17-3.11 (1H, m), 2.27-2.18 ( 1H, m), 1.89-1.06 (17H, m), 1.41 (6H, s), 1.34 (3H, s), 1.12 (3H, s).

(Process 2)
(2,6-difluorophenyl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (67.0 mg) obtained in Step 1 above, in the same manner as in Step 31 of Example 31, The title compound (45.0 mg) was obtained as a solid.
MS (ESI) m / z: 538 (M + H) ⁺
1H-NMR (CDCl ₃ ) δ: 7.27-7.23 (1H, m), 6.90-6.84 (2H, m), 3.90-3.85 (1H, m), 3.85-3.79 (1H, m), 3.74-3.69 (1H , m), 3.67 (1H, d, J = 3.9Hz), 3.64-3.54 (3H, m), 3.48-3.46 (1H, m), 3.42-3.33 (2H, m), 3.17-3.11 (1H, m ), 2.62-2.50 (1H, m), 2.27-1.08 (21H, m), 1.54 (3H, s), 1.12 (3H, s).

(Example 84)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7- Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone obtained in Example 82 step 3 The title compound (200 mg) was obtained as a solid in the same manner as in Step 23 of Example 23 using the obtained compound (300 mg) and tetrahydropyran-2-carboxylic acid (268 mg).
MS (ESI) m / z: 550 (M + H) ⁺
1H-NMR (CDCl ₃ ) δ: 4.30-4.22 (1H, m), 4.05-3.99 (2H, m), 3.95-3.92 (1H, m), 3.80-3.75 (1H, m), 3.67-3.23 (8H , m), 2.68-2.66 (1H, m), 2.25-2.15 (1H, m), 1.89-1.01 (23H, m), 1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s ).

(Process 2)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone Example 23 Step 5 using compound (200 mg) obtained in Step 1 above The title compound (164 mg) was obtained as a white solid by a method similar to that described above.
MS (ESI) m / z: 510 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03-3.98 (1H, m), 3.95-3.92 (1H, m), 3.89-3.85 (1H, m), 3.82-3.78 (1H, m), 3.74-3.69 ( 1H, m), 3.66-3.52 (5H, m), 3.46-3.36 (1H, m), 3.33-3.23 (2H, m), 2.21-2.19 (1H, m), 1.89-1.07 (23H, m), 1.40 (3H, s), 1.09 (3H, s).

Example 85
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8- (2-hydroxyethoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (2S, 4aR, 4bS, 6aS, 10aS, 10bR) -2- (2-tert-butoxy-2-oxoethoxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2 , 1-f] quinoline-7 (5H) -carboxylate Example 19 Step 1 was carried out in the same manner as Example 27 Step 1 using the compound obtained in Step 4 (100 mg) and tert-butyl bromoacetate (0.334 ml). The title compound (86.0 mg) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.07 (2H, s), 3.94-3.90 (1H, m), 3.78-3.71 (1H, m), 3.34-3.29 (1H, m), 3.13 (1H, d, J = 2.9Hz), 3.05-2.99 (1H, m), 2.06-0.84 (18H, m). 1.45 (9H, s), 1.33 (3H, s), 0.96 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8- (2-tert-butoxy-2-oxoethoxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinoline-1 (2H) -carboxylate Using the compound (86.0 mg) obtained in Step 1 above, the title compound (71.0 mg) was obtained as a solid in the same manner as in Step 4 of Example 31. It was.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.05 (2H, s), 4.17 (1H, d, J = 16.6Hz), 3.90 (1H, d, J = 16.6Hz). 3.78-3.72 (2H, m), 3.54 (1H, d, J = 2.9Hz), 3.39 (1H, brs), 3.35-3.27 (1H, m), 3.04-2.98 (1H, m), 2.27-2.19 ( 1H, m), 1.83-1.07 (16H, m), 1.44 (9H, s), 1.32 (3H, s), 1.11 (3H, s).

(Process 3)
tert-Butyl {[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl ] Oxy} acetate The title compound (54.3 mg) was obtained in the same manner as in Step 2 of Example 20 using the compound (71.0 mg) obtained in Step 2 above.

(Process 4)
tert-butyl {[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a, 7-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1- f] Quinolin-8-yl] oxy} acetate Using the compound obtained in Step 3 above (54.3 mg) and cyclohexanecarbonyl chloride (0.0253 ml), the title compound (29.0 mg ) Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.17 (1H, d, J = 17.1Hz), 3.90 (1H, d, J = 17.1Hz), 3.79-3.73 (1H, m), 3.55 (1H, d, J = 2.9Hz), 3.42-3.30 (3H, m), 3.26-3.22 (1H, m), 2.38-2.31 (1H, m), 2.27-2.19 (1H, m), 2.15 (1H, s), 1.80- 1.09 (26H, m), 1.45 (9H, s), 1.39 (3H, s), 1.11 (3H, s).

(Process 5)
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8- (2-hydroxyethoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone A solution of the compound obtained in Step 4 above (29.0 mg) in tetrahydrofuran (1 ml) was cooled to 0 ° C., and lithium borohydride (3.46 mg) was added. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (23 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 3.83-3.78 (1H, m), 3.74-3.69 (2H, m), 3.67-3.61 (3H, m), 3.44-3.38 (1H, m), 3.37-3.30 ( 1H, m), 3.27-3.22 (1H, m), 2.47 (1H, s), 2.37-2.31 (1H, m), 2.24-2.16 (1H, m), 1.96-1.91 (1H, m), 1.81- 1.07 (25H, m), 1.39 (3H, s), 1.10 (3H, s).

Example 86
Cyclohexyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-Il] methanone

(Process 1)
(2S, 4aR, 4bS, 6aS, 7E, 10aS, 10bR) -7- (hydroxyimino) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 7,8 , 9,10,10a, 10b, 11-hexadecahydrochrysen-2-yl acetate (2S, 4aR, 4bS, 6aS, 10aS, 10bR) -4a, 6a-dimethyl-7-oxo-1,2,3, 4,4a, 4b, 5,6,6a, 7,8,9,10,10a, 10b, 11-hexadecahydrochrysen-2-yl acetate (7.53 g) The procedure gave the title compound (7.85 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.38-5.32 (1H, m), 4.62-4.53 (1H, m), 3.29-3.22 (1H, m), 2.35-2.23 (2H, m), 2.17-2.08 ( 1H, m), 2.02-0.95 (17H, m), 2.00 (3H, s), 1.05 (3H, s), 0.99 (3H, s).

(Process 2)
(5aS, 5bR, 9S, 11aR, 11bS, 13aS) -11a, 13a-dimethyl-2-oxo-2,3,4,5,5a, 5b, 6,8,9,10,11,11a, 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepin-9-yl acetate The same procedure as in Example 36, Step 6, using the compound (7.85 g) obtained in Step 1 above Gave the title compound (5.30 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.47 (1H, s), 5.37-5.32 (1H, m), 4.62-4.53 (1H, m), 2.56-2.46 (2H, m), 2.36-2.21 (3H, m), 2.09-2.03 (1H, m), 2.01 (3H, s), 1.91-1.82 (3H, m), 1.67-1.45 (6H, m), 2.01 (3H, s), 1.36-1.02 (6H, m), 1.26 (3H, s), 0.95 (3H, s).

(Process 3)
(5aS, 5bR, 9S, 11aR, 11bS, 13aS) -11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,8,9,10,11,11a, 11b, 12,13, 13a-Hexadecahydro-1H-phenanthro [2,1-b] azepin-9-ol The title compound (4.40) was prepared in the same manner as in Example 36, Step 7 using the compound (5.20 g) obtained in Step 2 above. g) was obtained as a solid.

(Process 4)
Benzyl (5aS, 5bR, 9S, 11aR, 11bS, 13aS) -9-hydroxy-11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,8,9,10,11,11a, 11b , 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Similar to Example 19, Step 1 using the compound (4.40 g) obtained in Step 3 above. The title compound (6.35 g) was obtained by the procedure described above.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.24 (5H, m), 5.35-5.31 (1H, m), 5.07 (2H, s), 3.92 (1H, brs), 3.54-3.44 (1H, m) , 3.20-3.12 (1H, m), 2.37 (1H, s), 2.32-2.25 (2H, m), 2.22-2.14 (1H, m), 1.86-1.78 (2H, m), 1.71-0.89 (15H, m). 1.54 (3H, s), 0.94 (3H, s).

(Process 5)
Benzyl (5aS, 5bR, 11aR, 11bS, 13aS) -11a, 13a-dimethyl-9-oxo-2,3,4,5,5a, 5b, 6,7,9,10,11,11a, 11b, 12 , 13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Using the compound (6.35 g) obtained from Step 4 above, the same procedure as in Step 12 of Example 12 Gave the title compound (1.97 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.71 (1H, s), 5.07 (2H, s), 3.92 (1H, brs), 3.65 to 3.55 (1H, m), 3.18 -3.12 (1H, m), 2.43-2.28 (5H, m), 2.21-2.14 (1H, m), 2.04-1.98 (2H, m), 1.89-1.83 (2H, m), 1.72-0.96 (13H, m), 1.12 (3H, s).

(Process 6)
Benzyl (5aS, 5bR, 9S, 11aR, 11bS, 13aS) -9-hydroxy-11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,7,9,10,11,11a, 11b , 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Using methanol (35 ml) as a solvent for the compound obtained from Step 5 above (1.47 g), The title compound (1.47 g) was obtained in the same manner as in Example 12, Step 2.

(Process 7)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 11aS, 11bR, 13aR) -2-hydroxy-4a, 6a-dimethylhexadecahydrooxyleno [8,8a] phenanthro [2,1-b] azepine-7 ( 1aH) -Carboxylate The title compound (1.42 g) was obtained as an oily substance in the same manner as in Example 1, Step 2 using the compound (1.47 g) obtained from Step 6 above.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.07 (2H, s), 4.03 (1H, s), 3.93 (1H, s), 3.22-3.14 (1H, m), 3.13 (1H, d, J = 3.9 Hz), 2.40-1.99 (5H, m), 1.71-1.00 (19H, m), 0.96 (3H, s).

(Process 8)
Benzyl (3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepine-8-carboxylate Add 70% perchloric acid solution (1 ml) to acetone (100 ml) solution of compound (1.47 g) obtained in step 7 above and stir at room temperature for 18 hours. did. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then acetone was distilled off under reduced pressure. The residue was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (876 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.24 (5H, m), 5.06 (2H, s), 4.32-4.24 (1H, m), 3.98-3.84 (1H, m), 3.77 (1H, d, J = 5.4Hz), 3.24-3.18 (1H, m), 2.39 (1H, s), 2.11-2.03 (1H, m), 1.89-1.81 (2H, m), 1.72-0.97 (17H, m), 1.49 (6H, s), 1.29 (3H, s), 1.09 (3H, s).

(Process 9)
(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -2,2,5a, 7a-Tetramethyloctadecahydro-14aH- [1,3] dioxolo [7,8] phenanthro [2,1 -b] azepine-14a-ol The title compound (714 mg) was obtained as a solid in the same manner as in Example 20, Step 2, using the compound (876 mg) obtained from Step 8 above.

(Process 10)
Cyclohexyl [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8 ] Phenanthro [2,1-b] azepin-8-yl] methanone Using the compound obtained from Step 9 above (40.0 mg) and cyclohexanecarbonyl chloride (46.6 mg) in the same manner as in Example 31, Step 7, The title compound (51.7 mg) was obtained.

(Process 11)
Cyclohexyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-yl] methanone The title compound (21 mg) was obtained as a solid in the same manner as in Step 26 of Example 26 using the compound (51.7 mg) obtained from the above Step 10.
¹ H-NMR (CDCl ₃ ) δ: 4.16-4.08 (1H, m), 3.54-3.32 (3H, m), 2.62-2.55 (1H, m), 2.26-1.03 (31H, m), 1.47 (3H, s), 1.08 (3H, s).

Example 87
(2,6-difluorophenyl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] Azepin-1-yl] methanone

(Process 1)
(2,6-difluorophenyl) [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1, 3] Dioxolo [7,8] phenanthro [2,1-b] azepin-8-yl] methanone Example 86 Using the compound obtained from Step 9 (189 mg) and 2,6-difluorobenzoyl chloride (177 mg) The title compound (259 mg) was obtained in the same manner as in Example 31, Step 7.

(Process 2)
(2,6-difluorophenyl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] azepin-1-yl] methanone The title compound (169 mg) was obtained as a solid in the same manner as in Step 26 of Example 26 using the compound (259 mg) obtained from the above Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.28-7.19 (2H, m), 6.90-6.84 (1H, m), 4.17-4.09 (1H, m), 3.54-3.44 (2H, m), 3.33-3.25 ( 1H, m), 2.80 (1H, m), 2.27-1.01 (20H, m), 1.71 (3H, s), 1.11 (3H, s).

Example 88
Cyclopentyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-Il] methanone

(Process 1)
Cyclopentyl [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8 ] Phenanthro [2,1-b] azepin-8-yl] methanone The procedure similar to that in Example 31, Step 7, using the compound (120 mg) obtained from Example 86, Step 9 and cyclopentanecarbonyl chloride (50.6 mg) Gave the title compound (120 mg).

(Process 2)
Cyclopentyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-yl] methanone The title compound (62 mg) was obtained as a solid in the same manner as in Step 26 of Example 26 using the compound (120 mg) obtained from the above Step 1.
MS (ESI) m / z: 434 (M + H) ⁺
1H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 3.59-3.49 (3H, m), 3.42-3.33 (1H, m), 2.73-2.66 (1H, m), 2.63-2.55 (1H , m), 2.25-2.15 (2H, m), 1.90-1.02 (25H, m), 1.50 (3H, s), 1.08 (3H, s).

Example 89
Cyclobutyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-Il] methanone

(Process 1)
Cyclobutyl [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8 ] Phenanthro [2,1-b] azepin-8-yl] methanone The procedure similar to that in Example 31, Step 7, using the compound (40.0 mg) obtained from Example 9, Step 9 and cyclobutanecarbonyl chloride (0.0377 ml) Gave the title compound (48.7 mg).

(Process 2)
Cyclobutyl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine- 1-yl] methanone The title compound (18.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (48.7 mg) obtained from Step 1 above.
¹ H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 3.53-3.49 (1H, m), 3.35-3.28 (2H, m), 3.16-3.09 (1H, m), 2.63-2.57 ( 1H, m), 2.43-2.35 (1H, m), 2.28 (1H, d, J = 2.4Hz), 2.22-2.08 (3H, m), 2.03-1.92 (1H, m), 1.90-1.82 (2H, m), 1.81-1.73 (2H, m), 1.69-0.95 (16H, m), 1.53 (3H, s), 1.08 (3H, s).

Example 90
2-methyl-1-[(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1 -b] azepine-1-yl] propan-1-one

(Process 1)
1-[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7, 8] Phenanthro [2,1-b] azepin-8-yl] -2-methylpropan-1-one Using the compound (40.0 mg) obtained from Example 86 Step 9 and isobutyryl chloride (33.9 mg) In the same manner as in Example 31, Step 7, the title compound (47.4 mg) was obtained.

(Process 2)
2-methyl-1-[(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1 -b] azepin-1-yl] propan-1-one The title compound (21.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (47.4 mg) obtained from Step 1 above. It was.
¹ H-NMR (CDCl ₃ ) δ: 4.16-4.09 (1H, m), 3.54-3.35 (3H, m), 2.66-2.56 (3H, m), 2.30-2.26 (1H, m), 2.22-2.16 ( 1H, m), 1.89-0.84 (27H, m), 1.49 (3H, s), 1.08 (3H, s), 1.06 (6H, dd, J = 11.7, 6.8 Hz).

Example 91
Tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepine-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (tetrahydro-2H-pyran-2-yl) methanone Example 86 Compound obtained from Step 9 (40 mg) and tetrahydrofuran-2-carboxylic acid (41.4 mg) The title compound (52 mg) was obtained as a mixture of diastereomers by the same method as in Example 23, step 4.

(Process 2)
Tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepin-1-yl] methanone The title compound (12 mg) was obtained in the same manner as in Step 26 of Example 26 using the compound (52 mg) obtained from the above Step 1.
¹ H-NMR (CDCl ₃ ) δ: 4.17-4.08 (1H, m), 4.04-3.98 (1H, m), 3.89-3.82 (1H, m), 3.79-3.67 (1H, m), 3.54-3.49 ( 1H, m), 3.45-3.31 (2H, m), 2.67-2.60 (1H, m), 2.31-2.27 (1H, m), 2.21-2.15 (1H, m), 1.93-1.85 (3H, m), 1.78-0.83 (21H, m), 1.48 (3H, s), 1.08 (3H, s).

(Example 92)
(2R) -tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro- 1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 86 Compound (0.100 g) obtained from Step 9 and (2R) -tetrahydro The title compound (0.030 g) was obtained in the same manner as in Example 23, Step 4 using pyran-2-carboxylic acid (0.041 g).
¹ H-NMR (CDCl ₃ ) δ: 4.33-4.26 (1H, m), 3.98-3.91 (2H, m), 3.77 (1H, d, J = 5.4Hz), 3.46-3.31 (3H, m), 2.66 -2.61 (1H, m), 2.09-2.02 (1H, m), 1.93-1.79 (4H, m), 1.73-1.06 (21H, m), 1.53 (3H, s), 1.49 (3H, s), 1.29 (3H, s), 1.09 (3H, s).

(Process 2)
(2R) -tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro- 1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (20.0 mg) was prepared in the same manner as in Example 23, Step 5, using the compound (30.0 mg) obtained from Step 1 above. Obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.14-4.09 (1H, m), 3.97-3.91 (2H, m), 3.51-3.30 (5H, m), 2.65-2.60 (1H, m), 2.25 (1H, s), 2.23-2.14 (1H, m), 1.93-1.78 (3H, m), 1.74-0.83 (20H, m), 1.52 (3H, s), 1.08 (3H, s).

(Example 93)
(2R) -tetrahydrofuran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepine-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] [(2R) -tetrahydrofuran-2-yl] methanone Example 86 Compound (200 mg) obtained from Step 9 and (R)-(+)-tetrahydrofuran- The title compound (169 mg) was obtained as a solid in the same manner as in Example 31, Step 7 using 2-carbonyl chloride (79.2 mg).
¹ H-NMR (CDCl ₃ ) δ: 4.52-4.44 (1H, m), 4.30-4.26 (1H, m), 4.02 (1H, m), 3.89 (1H, m), 3.77 (1H, d, J = 4.9Hz), 3.48-3.32 (2H, m), 2.62-2.57 (1H, m), 2.13-1.09 (24H, m) .1.55 (3H, s), 1.49 (3H, s), 1.29 (3H, s ), 1.09 (3H, s).

(Process 2)
(2R) -tetrahydrofuran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepin-1-yl] methanone The title compound (143 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (169 mg) obtained from Step 1 above.
¹ H-NMR (CDCl ₃ ) δ: 4.47 (1H, dd, J = 7.8,5.4Hz), 4.15-4.09 (1H, m), 4.02 (1H, m), 3.89 (1H, dm), 3.53-3.49 (1H, m), 3.48-3.31 (2H, m), 2.30-1.11 (24H, m), 1.54 (3H, s), 1.08 (3H, s), 1.01 (1H, m).

Example 94
Pyridin-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1- b] azepine-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (pyridin-2-yl) methanone Example 86 Compound (100 mg) obtained in Step 9 and picolinic acid (97.8 g) and 1-cyano- as a condensing agent 2-Ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) was used in the same manner as in Example 23, step 4, to give the title compound (128 mg).

(Process 2)
Pyridin-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1- b] azepin-1-yl] methanone The title compound (0.042 g) was obtained as a solid in the same manner as in Step 2 of Example 26 using the compound (0.128 g) obtained from the above Step 1.
MS (ESI) m / z: 443 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.54-8.51 (1H, m), 7.73-7.68 (1H, m), 7.44-7.41 (1H, m), 7.26-7.23 (1H, m), 4.18-4.09 1H, m), 3.57-3.44 (2H, m), 3.43-3.34 (1H, m), 3.22-3.14 (1H, m), 2.88-2.81 (1H, m), 2.31-2.17 (2H, m), 1.92-1.84 (2H, m), 1.77-0.99 (15H, m), 1.67 (3H, s), 1.11 (3H, s).

(Example 95)
(6-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (6-methylpyridin-2-yl) methanone Example 86 The compound obtained in Step 9 (100 mg) and 6-methylpyridine-2-carboxylic acid (97.6 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) as a condensing agent in the same manner as in Example 23, step 4, to obtain the title compound. (132 mg) was obtained.

(Process 2)
(6-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (49.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (132 mg) obtained from Step 1 above. .
MS (ESI) m / z: 457 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.59-7.55 (1H, m), 7.22-7.20 (1H, m), 7.10-7.07 (1H, m), 4.17-4.10 (1H, m), 3.54-3.50 ( 1H, m), 3.39-3.31 (1H, m), 3.22-3.14 (1H, m), 2.88-2.82 (1H, m), 2.50 (3H, s), 2.28 (1H, d, J = 2.9Hz) 2.22-2.19 (1H, m), 1.97-1.85 (2H, m), 1.77-1.03 (17H, m), 1.66 (3H, s), 1.11 (3H, s).

Example 96
(5-methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (5-methylpyridin-2-yl) methanone Example 86 Compound obtained from Step 9 (100 mg) and 5-methylpyridine-2-carboxylic acid (54.5 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) as a condensing agent in the same manner as in Example 23, step 4, to obtain the title compound. (132 mg) was obtained.

(Process 2)
(5-methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (32.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (132 mg) obtained from Step 1 above. .
MS (ESI) m / z: 457 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.36-8.33 (1H, m), 7.52-7.48 (1H, m), 7.35-7.32 (1H, m), 4.16-4.09 (1H, m), 3.54-3.50 ( 1H, m), 3.41-3.32 (1H, m), 3.24-3.16 (1H, m), 2.87-2.81 (1H, m), 2.32 (3H, s), 2.27 (1H, d, J = 2.4Hz) 2.22-2.17 (1H, m), 1.95-1.85 (3H, m), 1.76-1.01 (15H, m), 1.50 (3H, s), 1.11 (3H, s).

Example 97
(4-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (4-methylpyridin-2-yl) methanone Example 86 Compound obtained from Step 9 (100 mg) and 4-methylpyridine-2-carboxylic acid (54.5 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) as a condensing agent in the same manner as in Example 23, step 4, to obtain the title compound. (132 mg) was obtained.

(Process 2)
(4-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (59.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (132 mg) obtained from Step 1 above. .
MS (ESI) m / z: 457 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.37-8.35 (1H, m), 7.25-7.22 (1H, m), 7.06-7.03 (1H, m), 4.16-4.09 (1H, m), 3.53-3.49 ( 1H, m), 3.41-3.31 (1H, m), 3.23-3.13 (1H, m), 2.87-2.79 (1H, m), 2.42-2.30 (1H, m), 2.33 (3H, s), 2.25- 2.16 (1H, m), 1.91-1.06 (18H, m), 1.67 (3H, s), 1.10 (3H, s).

Example 98
(3-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (3-methylpyridin-2-yl) methanone Example 86 Compound (100 mg) obtained from Step 9 and 3-methylpyridine-2-carboxylic acid (54.5 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) as a condensing agent in the same manner as in Example 23, step 4, to obtain the title compound. (132 mg) was obtained.

(Process 2)
(3-Methylpyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (46.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (132 mg) obtained from Step 1 above. .
MS (ESI) m / z: 457 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.36-8.33 (1H, m), 7.50-7.46 (1H, m), 7.14-7.10 (1H, m), 4.17-4.09 (1H, m), 3.54-3.50 ( 1H, m), 3.41-3.35 (1H, m), 3.12-3.04 (1H, m), 2.89-2.84 (1H, m), 2.28 (3H, s), 2.28-2.19 (2H, m), 1.92- 1.02 (18H, m), 1.50 (3H, s), 1.11 (3H, s).

Example 99
(3-methoxypyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] Phenanthro [2,1-b] azepin-8-yl] (3-methoxypyridin-2-yl) methanone Example 86 Compound (100 mg) obtained from Step 9 and 3-methylpyridine-2-carboxylic acid (60.8 mg) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (340 mg) as a condensing agent in the same manner as in Example 23, step 4, to obtain the title compound. (136 mg) was obtained.

(Process 2)
(3-methoxypyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (32.0 mg) was obtained as a solid in the same manner as in Example 26, Step 2 using the compound (136 mg) obtained from Step 1 above. .
MS (ESI) m / z: 473 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.14-8.11 (1H, m), 7.20-7.16 (2H, m), 4.16-4.08 (1H, m), 3.80 (3H, s), 3.51 (1H, s) , 3.42-3.36 (1H, m), 3.18-3.09 (1H, m), 2.85-2.80 (1H, m), 2.40-2.33 (1H, m), 2.25-2.15 (1H, m), 1.94-1.82 ( 2H, m), 1.77-1.08 (16H, m), 1.73 (3H, s), 1.10 (3H, s).

(Example 100)
(3-Fluoropyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
(3-Fluoropyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone Example 86 Compound (40.0 mg) obtained from Step 9 and 3-fluoropyridine-2-carboxylic acid (22.4 mg) and 1-cyano- as a condensing agent 2-Ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (68.1 mg) was used in the same manner as in Example 23, step 4, to give the title compound (53.0 mg).

(Process 2)
(3-Fluoropyridin-2-yl) [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone The title compound (9.8 mg) was obtained as a solid in the same manner as in Example 26, Step 2, using the compound (53.0 mg) obtained from Step 1 above. It was.
¹ H-NMR (CDCl ₃ ) δ: 8.38-8.35 (1H, m), 7.44-7.39 (1H, m), 7.29-7.25 (1H, m), 4.17-4.10 (1H, m), 3.55-3.50 ( 1H, m), 3.47-3.41 (1H, m), 3.19-3.14 (1H, m), 2.86-2.80 (1H, m), 2.30 (1H, s), 2.25-2.18 (1H, m), 1.91 0.99 (18H, m), 1.72 (3H, s), 1.11 (3H, s).

(Example 101)
Cyclohexyl {(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepine-1-yl} methanone

(Process 1)
Benzyl (5aS, 5bR, 9S, 11aR, 11bS, 13aS) -11a, 13a-dimethyl-9-{[(4-methylphenyl) sulfonyl] oxy} -2,3,4,5,5a, 5b, 6, 8,9,10,11,11a, 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Example 86 Compound obtained in Step 4 (5.00 The title compound (5.44 g) was obtained as a solid in the same manner as in Example 61, Step 1 using g).
¹ H-NMR (CDCl ₃ ) δ: 7.78-7.76 (2H, m), 7.36-7.26 (7H, m), 5.33-5.27 (1H, m), 5.06 (2H, s), 4.34-4.27 (1H, m), 3.92 (1H, brs), 3.19-3.10 (1H, m), 2.42 (3H, s), 2.42-2.25 (4H, m), 1.80-0.85 (17H, m), 1.53 (3H, s) , 0.90 (3H, s).

(Process 2)
Benzyl (5aS, 5bR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a, 13a-dimethyl-2, 3,4,5,5a, 5b, 6,8,9,10,11,11a, 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Using the compound (1.00 g) obtained in Step 1 above and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (4.47 g), Example 61 Step 2 and In a similar manner, the title compound (513 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.44-7.23 (5H, m), 5.34-5.30 (1H, m), 5.07 (1H, brs), 4.24-4.19 (1H, m), 4.07-4.01 (1H, m), 3.90 (1H, brs), 3.73-3.69 (1H, m), 3.59-3.53 (1H, m), 3.44-3.39 (1H, m), 3.20-3.10 (1H, m), 2.43-2.25 ( 2H, m), 2.20-2.11 (1H, m), 1.92-1.80 (1H, m), 1.69-0.92 (19H, m), 1.54 (3H, s), 1.40 (3H, s), 1.34 (3H, s), 0.92 (3H, s).

(Process 3)
Benzyl (3S, 6aR, 6bS, 11aS, 13aS, 13bR) -3-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a, 13b-dimethylhexadecahydro Oxyleno [8a, 9] phenanthro [2,1-b] azepine-11 (2H) -carboxylate The title compound was prepared in the same manner as in Example 1, Step 2 using the compound obtained in Step 2 above (662 mg). (488 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.05 (2H, s), 4.22-4.17 (1H, m), 4.04-4.00 (1H, m), 3.90 (1H, brs) , 3.70-3.64 (1H, m), 3.58-3.48 (2H, m), 3.45-3.35 (1H, m), 3.17-3.06 (1H, m), 2.91 (1H, d, J = 4.4Hz), 2.44 -2.24 (1H, m), 2.20-2.12 (1H, m), 2.03-1.92 (2H, m), 1.69-0.84 (17H, m), 1.56 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 0.97 (3H, s).

(Process 4)
Benzyl (5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a-hydroxy-11a, 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Using the compound obtained in Step 3 above (488 mg) in the same manner as in Step 1 of Example 1, the title compound ( 369 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.06 (2H, s), 4.23-4.18 (1H, m), 4.03 (1H, m), 3.89 (1H, brs), 3.74 -3.67 (2H, m), 3.60-3.49 (1H, m), 3.46-3.35 (1H, m), 3.23-3.17 (1H, m), 1.93-1.85 (1H, m), 1.83-1.77 (1H, m), 1.68-0.90 (21H, m), 1.54 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Process 5)
(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a, 13a-dimethyloctadeca Hydro-7aH-phenanthro [2,1-b] azepin-7a-ol The title compound was obtained in the same manner as in Step 2 of Example 20 using the compound (369 mg) obtained in Step 4 above.

(Process 6)
Cyclohexyl [(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a-hydroxy-11a , 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone Example using the compound obtained in Step 5 above (39.2 mg) and cyclohexanecarbonyl chloride (0.0183 ml) The title compound (38.0 mg) was obtained as a solid in the same manner as in 31 step 7.
¹ H-NMR (CDCl ₃ ) δ: 4.23-4.18 (1H, m), 4.04-4.01 (1H, m), 3.73-3.63 (2H, m), 3.61-3.33 (6H, m), 2.62-2.55 ( 1H, m), 2.29-2.22 (1H, m), 1.91-0.87 (30H, m), 1.47 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.90 (3H, s) .

(Process 7)
Cyclohexyl {(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [ 2,1-b] azepin-1-yl} methanone The title compound (23 mg) was obtained as a solid in the same manner as in Step 26 of Example 26 using the compound (38 mg) obtained in Step 6 above.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.83-3.77 (1H, m), 3.76-3.66 (2H, m), 3.65-3.59 (2H, m), 3.56-3.54 (1H, m), 3.50-3.42 ( 2H, m), 3.41-3.33 (1H, m), 2.63-2.56 (2H, m), 2.31-2.22 (1H, m), 2.20-2.13 (1H, m), 1.94-1.87 (1H, m), 1.79-0.79 (28H, m), 1.47 (3H, s), 0.91 (3H, s).

(Example 102)
{(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] azepin-1-yl} [(2R) -tetrahydrofuran-2-yl] methanone

(Process 1)
[(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a-hydroxy-11a, 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] [(2R) -tetrahydrofuran-2-yl] methanone Example 101 Compound (282 mg) obtained in Step 5 and ( The title compound (246 mg) was obtained as a solid in the same manner as in Example 31, Step 7 using R)-(+)-tetrahydrofuran-2-carbonyl chloride (90.3 mg).
MS (ESI) m / z: 534 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.50-4.45 (1H, m), 4.23-4.18 (1H, m), 4.06-3.99 (2H, m), 3.92-3.86 (1H, m), 3.73-3.67 ( 2H, m), 3.60-3.50 (1H, m), 3.47-3.32 (3H, m), 2.61-2.56 (1H, m), 2.13-0.90 (26H, m), 1.54 (3H, s), 1.39 ( 3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Process 2)
{(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] azepin-1-yl} [(2R) -tetrahydrofuran-2-yl] methanone Using the compound (246 mg) obtained in Step 1 above, the title compound was prepared in the same manner as in Step 2 of Example 26. (124 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.50-4.45 (1H, m), 4.02 (1H, m), 3.91-3.86 (1H, m), 3.82-3.77 (1H, m), 3.75-3.67 (2H, m), 3.65-3.58 (2H, m), 3.56-3.53 (1H, m), 3.50-3.46 (1H, m), 3.44-3.31 (2H, m), 2.59-2.56 (2H, m), 2.15- 0.87 (27H, m), 0.91 (3H, s).

(Example 103)
{(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a-hydroxy-11a, 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 101 Compound Obtained in Step 5 The title compound (54.1 mg) was obtained in the same manner as in Example 31, step 7 using (43.0 mg) and (2R)-(+)-tetrahydropyran-2-carbonyl chloride (25.7 mg).

(Process 2)
{(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2 , 1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone Similar to Example 23, Step 5, using the compound (54.1 mg) obtained in Step 1 above. To give the title compound (40.0 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 3.97-3.91 (2H, m), 3.81-3.77 (1H, m), 3.75-3.66 (2H, m), 3.64-3.57 (2H, m), 3.56-3.53 ( 1H, m), 3.51-3.46 (1H, m), 3.45-3.38 (3H, m), 3.36-3.30 (1H, m), 2.66-2.61 (1H, m), 2.55 (1H, d, J = 5.4 Hz), 2.15-2.10 (1H, m), 1.93-0.85 (24H, m), 1.51 (3H, s), 0.91 (3H, s).

(Example 104)
2-{[(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -1- (cyclohexylcarbonyl) -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] Azepine-9-yl] oxy} acetamide

(Process 1)
Cyclohexyl [(5aS, 5bR, 9S, 11aR, 11bS, 13aS) -9-hydroxy-11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,8,9,10,11,11a, 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone Example 86 Compound (13.7 g) obtained in Step 3 and cyclohexanecarbonyl chloride (7.93 g ) To give the title compound (13.9 g) as a solid in the same manner as in Example 1, Step 1.
MS (ESI) m / z: 414 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.36-5.30 (1H, m), 3.55-3.42 (2H, m), 3.38-3.29 (1H, m), 2.61-2.54 (1H, m), 2.32-2.23 ( 3H, m), 2.22-2.14 (1H, m), 1.86-0.81 (27H, m), 1.48 (3H, s), 0.94 (3H, s).

(Process 2)
(5aS, 5bR, 9S, 11aR, 11bS, 13aS) -1- (cyclohexylcarbonyl) -11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,8,9,10,11,11a , 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepin-9-yl 4-methylbenzenesulfonate Examples using the compound (13.9 g) obtained in Step 1 above The title compound (15.7 g) was obtained as a colorless solid by the same method as in Step 61.
¹ H-NMR (CDCl ₃ ) δ: 7.79-7.76 (2H, m), 7.32-7.29 (2H, m), 5.33-5.26 (1H, m), 4.35-4.28 (1H, m), 3.52-3.41 ( 2H, m), 3.35-3.29 (1H, m), 3.01 (1H, s), 2.59-2.52 (2H, m), 2.42 (3H, s), 2.42-2.36 (2H, m), 2.32-2.20 ( 3H, m), 1.82-0.88 (42H, m), 1.46 (3H, s), 0.90 (3H, s).

(Process 3)
2-{[(5aS, 5bR, 9S, 11aR, 11bS, 13aS) -1- (cyclohexylcarbonyl) -11a, 13a-dimethyl-2,3,4,5,5a, 5b, 6,8,9,10 , 11,11a, 11b, 12,13,13a-Hexadecahydro-1H-phenanthro [2,1-b] azepin-9-yl] oxy} acetamide The compound obtained in Step 2 above (300 mg) and 2- The title compound (86.0 mg) was obtained as a solid in the same manner as in Example 61, Step 2 using hydroxyacetamide (793 mg).
¹ H-NMR (CDCl ₃ ) δ: 6.55 (1H, s), 5.42-5.32 (2H, m), 3.96 (2H, s), 3.51-3.17 (4H, m), 2.62-2.54 (1H, m) 2.38-2.14 (4H, m), 1.88-0.94 (26H, m), 1.48 (3H, s), 0.94 (3H, s).

(Process 4)
2-{[(3S, 6aR, 6bS, 11aS, 13aS, 13bR) -11- (cyclohexylcarbonyl) -11a, 13b-dimethyloctadecahydrooxyleno [8a, 9] phenanthro [2,1-b] azepine- 3-yl] oxy} acetamide The title compound (78.0 mg) was obtained as a solid in the same manner as in Example 1, Step 2 using the compound obtained in Step 3 above (86.0 mg).
¹ H-NMR (CDCl ₃ ) δ: 6.49 (1H, brs), 5.44 (1H, brs), 3.98-3.90 (3H, m), 3.62-3.55 (1H, m), 3.46-3.38 (2H, m) 3.33.27 (1H, m), 2.93 (1H, d, J = 4.4Hz), 2.58-2.50 (1H, m), 2.30-2.21 (1H, m), 2.17-2.11 (1H, m), 2.05 -1.97 (2H, m), 1.75-0.94 (56H, m), 1.42 (3H, s), 0.99 (3H, s).

(Process 5)
2-{[(5aS, 5bR, 7aR, 9S, 11aR, 11bS, 13aS) -1- (cyclohexylcarbonyl) -7a-hydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] Azepin-9-yl] oxy} acetamide The title compound (19.0 mg) was obtained as a solid in the same manner as in Example 1, Step 3 using the compound (78.0 mg) obtained in Step 4 above.
MS (ESI) m / z: 489 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 6.53 (1H, brs), 5.39 (1H, brs), 4.00-3.89 (3H, m), 3.83-3.74 (1H, m), 3.62-3.26 (4H, m) 2.63-2.58 (1H, m), 2.29-0.79 (31 H, m), 1.47 (3H, s), 0.92 (3H, s).

(Example 105)
Cyclohexyl [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrophenanthro [2,1-b] azocine-1 (2H) -Il] methanone

(Process 1)
(2S, 4aR, 4bS, 6aS, 7E, 10aS, 10bR) -7- (hydroxyimino) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 7,8 , 9,10,10a, 10b, 11-hexadecahydrochrysen-2-yl acetate (2S, 4aR, 4bS, 6aS, 10aS, 10bR) -4a, 6a-dimethyl-7-oxo-1,2,3, 4,4a, 4b, 5,6,6a, 7,8,9,10,10a, 10b, 11-hexadecahydrochrysen-2-yl acetate (3.55 g) The title compound (2.49 g) was obtained by the procedure.
MS (ESI) m / z: 374 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.40-5.32 (1H, m), 4.61-4.55 (1H, m), 3.10 (1H, m), 2.35-0.80 (23H, m) .2.02 (3H, s) , 1.10 (3H, s), 1.00 (3H, s).

(Process 2)
(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -12a, 14a-dimethyl-2-oxo-1,2,3,4,5,6,6a, 6b, 7,9,10,11,12, 12a, 12b, 13,14,14a-octadecahydrophenanthro [2,1-b] azocin-10-yl acetate Example 36 Step 6 using the compound (2.49 g) obtained in Step 1 above The title compound (1.56 g) was obtained as a solid by a similar procedure.
MS (ESI) m / z: 374 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.41 (1H, s), 5.37-5.33 (1H, m), 4.61-4.52 (1H, m), 2.66-2.59 (1H, m), 2.51-2.46 (1H, m), 2.35-2.21 (3H, m), 2.00 (3H, s), 1.85-0.94 (18H, m), 1.17 (3H, s), 0.96 (3H, s).

(Process 3)
(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -12a, 14a-dimethyl-1,2,3,4,5,6,6a, 6b, 7,9,10,11,12,12a, 12b, 13,14,14a-Octadecahydrophenanthro [2,1-b] azocin-10-ol The title compound was prepared in the same manner as in Example 36, step 7 using the compound (886 mg) obtained in Step 2 above. (752 mg) was obtained as a solid.
MS (ESI) m / z: 318 (M + H) ^<+> .

(Process 4)
Cyclohexyl [(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,9,10,11,12,12a, 12b, 13,14,14a-Hexadecahydrophenanthro [2,1-b] azocin-1 (2H) -yl] methanone Compound (250 mg) obtained in Step 3 above and cyclohexanecarbonyl chloride (346 mg) Were used to give the title compound (291 mg) in the same manner as in Example 31, Step 7.
MS (ESI) m / z: 428 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.42-5.35 (1H, m), 3.59-3.51 (1H, m), 3.46-3.36 (1H, m), 3.27-3.16 (1H, m), 2.45-2.21 ( 5H, m), 1.96-0.90 (29H, m), 1.57 (3H, s), 0.99 (3H, s).

(Process 5)
(6aS, 6bR, 12aR, 12bS, 14aS) -1- (cyclohexylcarbonyl) -12a, 14a-dimethyl-1,3,4,5,6,6a, 6b, 7,8,11,12,12a, 12b , 13,14,14a-Hexadecahydrophenanthro [2,1-b] azocin-10 (2H) -one As in Example 12, Step 1 using the compound (280 mg) obtained in Step 4 above. To give the title compound (163 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.71 (1H, s), 3.39 (1H, dd, J = 16.6, 5.9Hz), 3.03 (1H, dd, J = 16.6, 8.3Hz), 2.43-2.27 (6H , m), 2.16-2.09 (1H, m), 2.06-2.00 (1H, m), 1.85-0.94 (26H, m), 1.51 (3H, s), 1.12 (3H, s).

(Process 6)
Cyclohexyl [(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,8,10,11,12,12a, 12b, 13,14,14a-Hexadecahydrophenanthro [2,1-b] azosin-1 (2H) -yl] methanone Example 19 Step using the compound obtained in Step 5 above (163 mg) The title compound (163 mg) was obtained by a method similar to 3.
¹ H-NMR (CDCl ₃ ) δ: 5.27 (2H, s), 4.15-4.09 (1H, m), 3.36 (1H, dd, J = 16.6, 5.9Hz), 3.02 (1H, dd, J = 16.4, 8.1Hz), 2.37-2.30 (1H, m), 2.25-2.13 (2H, m), 2.07-1.97 (2H, m), 1.97-1.90 (1H, m), 1.82-0.73 (27H, m), 1.48 (3H, s), 0.98 (3H, s).

(Process 7)
Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 12aS, 12bR, 14aR) -2-hydroxy-4a, 6a-dimethylhexadecahydro-1aH-oxyleno [8,8a] phenanthro [2,1-b] azocine -7 (5H) -yl] methanone Using the compound (163 mg) obtained in Step 6 above, the title compound (141 mg) was obtained as an oily substance in the same manner as in Step 1 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 4.08-4.02 (1H, m), 3.39 (1H, dd, J = 16.6,6.3Hz), 3.14 (1H, d, J = 4.4Hz), 3.05 (1H, dd , J = 16.8,8.5Hz), 2.38-2.30 (1H, m), 2.28-2.21 (2H, m), 2.11-2.02 (2H, m), 1.89-0.93 (29H, m), 1.48 (3H, s ), 0.97 (3H, s).

(Process 8)
Cyclohexyl [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrophenanthro [2,1-b] azocine-1 (2H) -yl] methanone The title compound (100 mg) was obtained as a solid in the same manner as in Example 31, Step 4 using the compound (141 mg) obtained in Step 7 above.
¹ H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 3.51 (1H, m), 3.37 (1H, dd, J = 16.6,5.9 Hz), 3.10 (1H, dd, J = 16.8, 8.5Hz), 2.36-2.32 (1H, m), 2.28 (1H, d, J = 2.4Hz), 2.24-2.16 (2H, m), 1.86-1.04 (30H, m), 1.47 (3H, s), 1.08 (3H, s).

(Example 106)
(2,6-difluorophenyl) [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrophenanthro [2, 1-b] Azocin-1 (2H) -yl] methanone

(Process 1)
(2,6-difluorophenyl) [(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,9,10 , 11,12,12a, 12b, 13,14,14a-Hexadecahydrophenanthro [2,1-b] azosin-1 (2H) -yl] methanone Compound obtained from Example 105 Step 3 (250 mg ) And 2,6-difluorobenzoyl chloride (0.417 g) were obtained in the same manner as in Example 31, step 7 to give the title compound (300 mg) as a solid.
MS (ESI) m / z: 458 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.33-7.21 (1H, m), 6.96-6.85 (2H, m), 5.37-5.31 (1H, m), 3.53-3.47 (1H, m), 3.30-3.24 ( 2H, m), 2.41-2.38 (1H, m), 2.34-2.26 (2H, m), 2.24-2.16 (1H, m), 1.90-0.84 (19H, m), 1.73 (3H, s), 0.96 ( 3H, s).

(Process 2)
(6aS, 6bR, 12aR, 12bS, 14aS) -1- (2,6-difluorobenzoyl) -12a, 14a-dimethyl-1,3,4,5,6,6a, 6b, 7,8,11,12 , 12a, 12b, 13,14,14a-Hexadecahydrophenanthro [2,1-b] azocin-10 (2H) -one Example 12 using the compound (242 mg) obtained in Step 1 above The title compound (167 mg) was obtained as a solid by the same procedure as in Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.45-7.18 (1H, m), 6.92-6.82 (2H, m), 5.72 (1H, s), 3.35-3.27 (1H, m), 3.20-3.14 (1H, m), 2.48-2.28 (5H, m), 2.19-2.13 (1H, m), 2.09-2.04 (1H, m), 1.77-1.01 (16H, m), 1.75 (3H, s), 1.15 (3H, s).

(Process 3)
(2,6-difluorophenyl) [(6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,8,10 , 11,12,12a, 12b, 13,14,14a-Hexadecahydrophenanthro [2,1-b] azosin-1 (2H) -yl] methanone The compound obtained in Step 2 above (167 mg) Was used to give the title compound (168 mg) in a manner similar to Example 19, Step 3.

(Process 4)
(2,6-difluorophenyl) [(1aS, 2S, 4aR, 4bS, 6aS, 12aS, 12bR, 14aR) -2-hydroxy-4a, 6a-dimethylhexadecahydro-1aH-oxyleno [8,8a] phenanthro [ 2,1-b] Azocin-7 (5H) -yl] methanone Using the compound (168 mg) obtained in Step 3 above, in the same manner as in Example 1, Step 2, the title compound (161 mg) as an oily substance. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.28-7.21 (1H, m), 6.91-6.85 (2H, m), 4.08-4.03 (1H, m), 3.36-3.28 (1H, m), 3.24-3.17 ( 1H, m), 3.15 (1H, d, J = 4.4Hz) .2.46-2.39 (1H, m), 2.31-2.21 (1H, m), 2.16-2.03 (2H, m), 1.76-0.84 (19H, m), 1.71 (3H, s), 1.00 (3H, s).

(Process 5)
(2,6-difluorophenyl) [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrophenanthro [2, 1-b] Azocin-1 (2H) -yl] methanone The title compound (127 mg) was obtained as a solid in the same manner as in Step 31 of Example 31 using the compound (161 mg) obtained in Step 7 above.
¹ H-NMR (CDCl ₃ ) δ: 7.27-7.22 (1H, m), 6.90-6.85 (2H, m), 4.16-4.09 (1H, m), 3.54-3.49 (1H, m), 3.34-3.20 ( 2H, m), 2.43-2.37 (1H, m), 2.28 (1H, d, J = 2.4Hz), 2.26-2.17 (1H, m), 1.92-1.85 (1H, m), 1.76-0.84 (19H, m), 1.71 (3H, s), 1.11 (3H, s).

(Example 107)
(2R) -Tetrahydro-2H-pyran-2-yl [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrofeature Nanslo [2,1-b] azocin-1 (2H) -yl] methanone

(Process 1)
Benzyl (6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,9,10,11,12,12a, 12b , 13,14,14a-Hexadecahydrophenanthro [2,1-b] azocine-1 (2H) -carboxylate Example 19 step using compound (752 mg) obtained in Example 105 step 3 The title compound (667 mg) was obtained as a solid by a method similar to 1.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.34-5.30 (1H, m), 5.09-5.04 (2H, m), 3.60-3.53 (1H, m), 3.53-3.45 ( 1H, m), 3.17-3.08 (1H, m), 2.32-2.26 (2H, m), 2.22-2.14 (1H, m), 2.06-2.00 (1H, m), 1.86-0.93 (19H, m), 1.52 (3H, s), 0.93 (3H, s).

(Process 2)
Benzyl (6aS, 6bR, 12aR, 12bS, 14aS) -12a, 14a-dimethyl-10-oxo-3,4,5,6,6a, 6b, 7,8,10,11,12,12a, 12b, 13 , 14,14a-Hexadecahydrophenanthro [2,1-b] azocine-1 (2H) -carboxylate Similar to Example 12, Step 1 using the compound obtained in Step 1 above (677 mg) The title compound (699 mg) was obtained by the procedure.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.71 (1H, s), 3.65-3.55 (2H, m), 3.08-3.00 (1H, m), 2.45-2.26 (4H, m), 2.21-2.14 (1H, m), 2.10-2.00 (2H, m), 1.89-0.97 (17H, m), 1.55 (3H, s), 1.12 (3H, s).

(Process 3)
Benzyl (6aS, 6bR, 10S, 12aR, 12bS, 14aS) -10-hydroxy-12a, 14a-dimethyl-3,4,5,6,6a, 6b, 7,8,10,11,12,12a, 12b , 13,14,14a-Hexadecahydrophenanthro [2,1-b] azocine-1 (2H) -carboxylate Example 19 Step 3 with the compound (699 mg) obtained in Step 2 above The title compound (700 mg) was obtained by a similar procedure.
MS (ESI) m / z: 452 (M + H) ^<+> .

(Process 4)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 12aS, 12bR, 14aR) -2-hydroxy-4a, 6a-dimethylhexadecahydro-1aH-oxyleno [8,8a] phenanthro [2,1-b] azocine- 7 (5H) -Carboxylate The title compound (755 mg) was obtained as an oily substance in the same manner as in Example 1, Step 2 using the compound (700 mg) obtained in Step 3 above.
MS (ESI) m / z: 468 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.06 (2H, s), 4.04 (1H, brs), 3.65-3.58 (1H, m), 3.14 (1H, d, J = 4.4Hz), 3.09-3.01 (1H, m), 2.20-2.00 (4H, m), 1.79-0.94 (19H, m), 1.51 (3H, s), 0.96 (3H, s).

(Process 5)
Benzyl (6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrophenanthro [2,1-b] azocine-1 ( 2H) -Carboxylate The title compound (752 mg) was obtained as a solid in the same manner as in Example 31, Step 4 using the compound (755 mg) obtained in Step 4 above.
MS (ESI) m / z: 468 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.05 (2H, s), 4.17-4.09 (1H, m), 3.63-3.56 (1H, m), 3.52-3.49 (1H, m), 3.14-3.06 (1H, m), 2.28-2.25 (1H, m), 2.23-2.16 (1H, m), 2.06-2.00 (1H, m), 1.92-1.87 (1H, m), 1.76 1.02 (19H, m), 1.50 (3H, s), 1.08 (3H, s).

(Process 6)
Benzyl (3aS, 5aR, 5bS, 7aS, 13aS, 13bR, 15aS, 15bS) -15a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro [1,3] dioxolo [7,8] phenanthro [2 , 1-b] azocine-8 (4H) -carboxylate The title compound (505 mg) was obtained as a solid in the same manner as in Step 20 of Example 20 using the compound (752 mg) obtained in Step 5 above.
MS (ESI) m / z: 526 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.07 (2H, s), 4.32-4.26 (1H, m), 3.77 (1H, d, J = 5.4Hz), 3.64-3.57 (1H, m), 3.14-3.07 (1H, m), 2.10-1.06 (23H, m), 1.49 (6H, s), 1.29 (3H, s), 1.09 (3H, s).

(Process 7)
(3aS, 5aR, 5bS, 7aS, 13aS, 13bR, 15aS, 15bS) -2,2,5a, 7a-tetramethyloctadecahydro [1,3] dioxolo [7,8] phenanthro [2,1-b] Azocin-15a (4H) -ol The title compound (376 mg) was obtained in the same manner as in Step 2 of Example 20 using the compound (505 mg) obtained in the above Step 6.

(Process 8)
[(3aS, 5aR, 5bS, 7aS, 13aS, 13bR, 15aS, 15bS) -15a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro [1,3] dioxolo [7,8] phenanthro [2 , 1-b] azocin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone (100 mg) obtained in Step 7 above and (R)-(+)- The title compound (115 mg) was obtained as a solid in the same manner as in Example 31, Step 7 using tetrahydropyran-2-carbonyl chloride (75.6 mg).
MS (ESI) m / z: 504 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.32-4.26 (1H, m), 4.03-3.93 (2H, m), 3.77 (1H, d, J = 5.4Hz), 3.46-3.40 (1H, m), 3.33 (1H, dd, J = 16.1,5.9Hz), 3.06 (1H, dd, J = 16.4,9.5Hz), 2.30-2.24 (1H, m), 2.10-2.02 (1H, m), 1.89-1.09 (27H m), 1.49 (3H, s), 1.29 (6H, s), 1.09 (3H, s).

(Process 9)
(2R) -Tetrahydro-2H-pyran-2-yl [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-dimethyloctadecahydrofeature Nanslo [2,1-b] azocin-1 (2H) -yl] methanone The title compound (28.0 mg) was prepared in the same manner as in Example 23, Step 5, using the compound (115 mg) obtained in Step 8 above. Got.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 4.00-3.95 (2H, m), 3.53-3.49 (1H, m), 3.46-3.39 (1H, m), 3.33 (1H, dd, J = 16.4, 6.6Hz), 3.05 (1H, dd, J = 16.8, 9.0Hz), 2.27-2.23 (2H, m), 2.22-2.17 (1H, m), 1.89-1.02 (26H, m) , 1.52 (3H, s), 1.08 (3H, s).

(Example 108)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-8 -Ill β-D-Glucopyranoside

(Process 1)
(4aS, 4bR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,7,8,9 , 10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-8-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside 2, 3,4,6-Tetra-O-benzoyl-1-O- (2,2,2-trichloroethaneimidoyl) -D-glucopyranose (Liebigs Annalen der Chemie, 1984, 7, 1343-1357.) (3.73g And trimethylsilyltrifluoromethanesulfonate (0.1 M dichloromethane solution, 14.0 ml) was added to a solution of the compound (2.00 g) obtained in Step 1 of Example 6 in dichloromethane (30 ml) at −10 ° C. and stirred at the same temperature for 1 hour. . Triethylamine (0.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.06 g) as a white solid.
MS (ESI) m / z: 1008 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.93 (2H, m), 7.88 (2H, m), 7.81 (2H, m), 7.54-7.21 (13H, m), 6.87 (2H , m), 5.87 (1H, t, J = 9.8Hz), 5.59 (1H, t, J = 9.8Hz), 5.47 (1H, dd, J = 7.8, 9.8Hz), 5.18 (1H, m), 4.91 (1H, d, J = 7.8Hz), 4.57 (1H, dd, J = 3.2,12.0Hz), 4.50 (1H, dd, J = 6.1,12.0Hz), 4.13 (1H, m), 3.50 (1H, m), 3.42-3.32 (2H, m), 3.14 (1H, m), 2.19-2.03 (3H, m), 1.90 (1H, m), 1.81-1.16 (12H, m), 1.53 (3H, m) 0.97 (1H, m), 0.89 (1H, m), 0.86 (3H, s).

(Process 2)
(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -4- (2,6-difluorobenzoyl) -4a, 6b-dimethylhexadecahydro-1H-oxyleno [4,4a] naphtho [2, 1-f] quinolin-9-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside same as Example 1, Step 2, using the compound obtained in Step 1 above (200 mg) The title compound (210 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 8.01 (2H, m), 7.91-7.87 (4H, m), 7.79 (2H, m), 7.57 (13H, m), 6.86 (2H, m), 5.84 (1H , t, J = 9.8Hz), 5.58 (1H, t, J = 9.8Hz), 5.46 (1H, dd, J = 7.8,9.8Hz), 4.87 (1H, d, J = 7.8Hz), 4.56 (1H , dd, J = 3.2,12.0Hz), 4.51 (1H, dd, J = 6.1,12.0Hz), 4.13 (1H, m), 3.82 (1H, m), 3.38-3.28 (2H, m), 3.12 ( 1H, m), 2.77 (1H, d, J = 4.4 Hz), 2.08-1.09 (18H, m), 1.47 (3H, s), 0.91 (3H, s).

(Process 3)
(4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -4- (2,6-difluorobenzoyl) -4a, 6b-dimethylhexadecahydro-1H-oxyleno [4,4a] naphtho [2, 1-f] quinolin-9-yl β-D-glucopyranoside Using the compound (924 mg) obtained in Step 2 above, the title compound (524 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5. .
¹ H-NMR (CD ₃ OD) δ: 7.40 (1H, m), 7.03-6.98 (2H, m), 4.29 (1H, d, J = 7.8Hz), 3.87 (1H, m), 3.82 (1H, dd, J = 1.7,11.7Hz), 3.63 (1H, dd, J = 5.4,11.7Hz), 3.43 (1H, m), 3.31-3.19 (4H, m), 3.12 (1H, m), 3.10 (1H , dd, J = 7.8,8.3Hz), 2.96 (1H, d, J = 4.4Hz), 2.11 (1H, t, J = 12.2Hz), 2.09-1.97 (2H, m), 1.83 (1H, m) 1.77-1.20 (18H, m), 1.51 (3H, s), 1.07 (3H, s).

(Process 4)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-8 -Ill β-D-glucopyranoside The title compound (188 mg) was obtained as a white solid in the same manner as in Example 10, Step 3, using the compound (524 mg) obtained in Step 3 above.
MS (ESI) m / z: 610 (M + H) ^+
1 H-NMR (DMSO-d ₆ ) δ: 7.44 (1H, m), 7.15-7.11 (2H, m), 4.88 (1H, d, J = 4.4Hz), 4.86 (1H, m), 4.83 (1H , d, J = 4.4Hz), 4.42 (1H, t, J = 5.4Hz), 4.12 (1H, d, J = 7.8Hz), 3.96 (1H, m), 3.80 (1H, s), 3.63 (1H , dd, J = 4.6,11.0Hz), 3.40 (1H, m), 3.33 (1H, m), 3.19 (1H, m), 3.14 (2H, d, J = 5.4Hz), 3.07 (1H, m) 3.00 (1H, m), 2.85 (1H, m), 1.79-1.02 (20H, m), 1.42 (3H, s), 0.84 (3H, s).

(Example 109)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6,6a-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f ] Quinolin-8-yl β-D-glucopyranoside

(Process 1)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6a-hydroxy-6-iodo-10a, 12a-dimethyloctadecahydronaphtho [2,1 -f] quinolin-8-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside Example 108 Compound (208 mg) obtained in Step 2 in dichloromethane (4.0 ml) -acetonitrile (4.0 ml), sodium iodide (183 mg) and magnesium iodide (339 mg) were sequentially added under ice-cooling, and the mixture was stirred for 15 hours while warming to room temperature. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the title compound (250 mg).

(Process 2)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6,6a-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f ] Quinolin-8-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside Triethylamine (0.281 ml) was added to a solution of the compound obtained in Step 1 above (250 mg) in 2-propanol (15 ml). Hypophosphorous acid aqueous solution (50 wt%, 0.21 ml) and 2,2′-azobisisobutyronitrile (25 mg) were added, and the mixture was stirred at 80 ° C. for 1 hour. After cooling the reaction solution, the precipitated solid was dissolved in dichloromethane, poured into two layers of ethyl acetate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (100 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.94 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.57-7.18 (13H, m), 6.86 (2H , m), 5.86 (1H, t, J = 9.8Hz), 5.59 (1H, t, J = 9.8Hz), 5.47 (1H, dd, J = 7.8, 9.8Hz), 4.89 (1H, d, J = 7.8Hz), 4.59 (1H, dd, J = 3.4,12.1Hz), 4.50 (1H, m), 4.13 (1H, m), 4.04 (1H, m), 3.40-3.30 (3H, m), 3.13 ( 1H, m), 1.96-1.14 (19H, m), 1.52 (3H, s), 1.11 (1H, s), 1.00 (3H, s).

(Process 3)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6,6a-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f ] Quinolin-8-yl β-D-glucopyranoside Using the compound (100 mg) obtained in Step 2 above, the title compound (55 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5.
MS (ESI) m / z: 626 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.40 (1H, m), 7.05-6.96 (2H, m), 4.35 (1H, d, J = 7.8Hz), 4.15 (1H, m), 3.83 (1H, dd, J = 1.5,12.2Hz), 3.63 (1H, dd, J = 5.4,12.2Hz), 3.48-3.39 (2H, m), 3.25-3.18 (2H, m), 3.17-3.10 (2H, m) , 2.03 (1H, t, J = 12.2 Hz), 1.89-1.25 (19H, m), 1.56 (3H, s), 1.12 (3H, s).

(Example 110)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1 -f] quinolin-8-yl β-D-glucopyranoside

(Process 1)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1 -f] quinolin-8-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside 2,3,4,6-tetra-O-benzoyl-1-O- (2,2, Using the same procedure as in Example 108, Step 1, the title compound (102 mg) was obtained as a white solid using 2-trichloroethaneimidoyl) -D-glucopyranose (153 mg) and the compound obtained in Example 9, Step 1 (64 mg). Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.92 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.54-7.46 (3H, m), 7.41-7.30 (7H, m), 7.28-7.21 (3H, m), 6.90-6.83 (2H, m), 5.86 (1H, t, J = 9.8Hz), 5.59 (1H, t, J = 9.8Hz), 5.47 ( 1H, dd, J = 7.8,9.8Hz), 4.90 (1H, d, J = 7.8Hz), 4.58 (1H, dd, J = 3.2,12.0Hz), 4.50 (1H, dd, J = 6.1,12.0Hz) ), 4.16-3.99 (3H, m), 3.43-3.30 (2H, m), 3.14 (1H, m), 2.03-1.17 (19H, m), 1.52 (3H, s), 0.93 (3H, s).

(Process 2)
(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS) -1- (2,6-difluorobenzoyl) -6-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1 -f] Quinolin-8-yl β-D-glucopyranoside Using the compound (102 mg) obtained in Step 1 above, the title compound (51 mg) was obtained as a white solid in the same manner as in Step 1 of Example 5.
MS (ESI) m / z: 628 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.41 (1H, m), 7.01 (2H, m), 4.34 (1H, d, J = 7.3Hz), 4.21 (1H, m), 4.15 (1H, m) , 3.84 (1H, dd, J = 2.0,11.7Hz), 3.63 (1H, dd, J = 5.4,11.7Hz), 3.45 (1H, m), 3.32-3.14 (5H, m), 3.12 (1H, dd , J = 7.3, 8.8Hz), 2.00 (1H, m), 1.94-1.84 (3H, m), 1.81-1.37 (12H, m), 1.55 (3H, s), 1.32-1.21 (2H, m), 1.05 (3H, d, J = 4.9Hz).

(Example 111)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2 , 1-f] quinolin-8-yl β-D-glucopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2 , 1-f] quinolin-8-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside 2,3,4,6-tetra-O-benzoyl-1-O- (2, Using 2,2-trichloroethaneimidoyl) -D-glucopyranose (132 mg) and the compound obtained in Example 10, Step 3 (50 mg), the title compound (69 mg) was prepared in the same manner as in Example 108, Step 1. Obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.93 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.53-7.45 (3H, m), 7.41-7.30 (7H, m), 7.27-7.23 (2H, m), 5.85 (1H, t, J = 9.8Hz), 5.58 (1H, t, J = 9.8Hz), 5.45 (1H, dd, J = 7.8,9.8 Hz), 4.88 (1H, d, J = 7.8Hz), 4.57 (1H, dd, J = 3.4, 12.2Hz), 4.49 (1H, dd, J = 6.1, 12.2Hz), 4.12 (1H, m), 4.04-3.97 (2H, m), 3.93 (1H, dd, J = 2.4,10.7Hz), 3.52 (1H, m), 3.40 (1H, m), 3.30-3.22 (2H, m), 1.94-1.84 ( 2H, m), 1.80-1.04 (24H, m), 1.37 (3H, s), 1.00 (1H, s), 0.79 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2 , 1-f] Quinolin-8-yl β-D-glucopyranoside The title compound (33 mg) was obtained as a white solid in the same manner as in Example 5, Step 1 using the compound (69 mg) obtained in Step 1 above. .
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.32 (1H, d, J = 7.8Hz), 4.12 (1H, m), 4.07 (1H, m), 3.94 (1H, dd, J = 2.9,10.7Hz) , 3.81 (1H, dd, J = 2.0,11.7Hz), 3.62 (1H, dd, J = 5.4,11.7Hz), 3.56 (1H, m), 3.47 (1H, m), 3.35 (1H, m), 3.30 (1H, m), 3.24 (1H, t, J = 8.8Hz), 3.22-3.14 (2H, m), 3.10 (1H, dd, J = 7.8,8.8Hz), 1.90-1.09 (26H, m) 1.40 (3H, s), 0.93 (3H, s).

(Example 112)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- D-Glucopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2, 3,4,6-tetra-O-benzyl-β-D-glucopyranoside (β-glycoside)
as well as
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2, 3,4,6-tetra-O-benzyl-α-D-glucopyranoside (α-glycoside)
2,3,4,6-Tetra-O-benzyl-1-O- (2,2,2-trichloroethaneimidoyl) -D-glucopyranose (656 mg) and the compound obtained in Example 1, step 3 (200 mg ) Using a mixed solution of dichloromethane (9 ml) and acetonitrile (1 ml) as a solvent in the same manner as in Step 108 of Example 108, followed by separation and purification by silica gel column chromatography [ethyl acetate / hexane]. (β-Glycoside) (183 mg) and the title compound (α-glycoside) (149 mg) were obtained as white amorphous, respectively.
β-glycoside: Rf = higher, low polarity
¹ H-NMR (CDCl ₃ ) δ: 7.33-7.09 (20H, m), 4.91 (1H, d, J = 11.2Hz), 4.88 (1H, d, J = 10.7Hz), 4.78 (1H, d, J = 10.7Hz), 4.75 (1H, d, J = 10.7Hz), 4.70 (1H, d, J = 11.2Hz), 4.57 (1H, d, J = 12.2Hz), 4.51 (1H, d, J = 12.2) Hz), 4.50 (1H, d, J = 10.7Hz) 4.45 (1H, d, J = 7.3Hz), 4.06 (1H, m), 3.70 (1H, dd, J = 0.9, 11.0Hz), 3.62 (1H , dd, J = 4.6,11.0Hz), 3.59 (1H, t, J = 9.3Hz), 3.52 (1H, t, J = 9.3Hz), 3.45-3.37 (3H, m), 3.33 (1H, m) 3.25 (1H, m), 2.34 (1H, m), 2.01 (1H, m), 1.84-1.07 (30H, m), 1.38 (3H, s), 0.92 (3H, s).
α-Glycoside: Rf = lower, high polarity
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.09 (20H, m), 4.97 (1H, d, J = 10.7Hz), 4.89 (1H, d, J = 3.4Hz), 4.80 (1H, d, J = 10.7Hz), 4.77 (1H, d, J = 10.7Hz), 4.72 (1H, d, J = 11.7Hz), 4.62 (1H, d, J = 11.7Hz), 4.55 (1H, d, J = 11.7Hz) Hz), 4.44 (1H, d, J = 11.7Hz), 4.43 (1H, d, J = 10.7Hz), 3.98 (1H, m), 3.94 (1H, t, J = 9.5Hz), 3.84 (1H, m), 3.65 (1H, dd, J = 3.9, 10.7Hz), 3.62 (1H, dd, J = 2.2, 10.7Hz), 3.53 (1H, t, J = 9.5Hz), 3.51 (1H, dd, J = 3.4,9.5Hz), 3.41 (1H, m), 3.32 (1H, m), 3.23 (1H, m), 2.34 (1H, m), 1.87-1.06 (30H, m), 1.38 (3H, s) , 1.00 (1H, br), 0.90 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- D-Glucopyranoside The title compound (83 mg) was obtained as a white solid in the same manner as in Example 13, Step 4, using the compound (β-glycoside) (149 mg) obtained in Step 1 above.
MS (ESI) m / z: 580 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.35 (1H, d, J = 7.8Hz), 4.15 (1H, m), 3.85 (1H, dd, J = 2.2,12.0Hz), 3.65 (1H, dd, J = 5.6,12.0Hz), 3.53 (1H, m), 3.43 (1H, m), 3.35-3.18 (4H, m), 3.13 (1H, dd, J = 7.8,8.5Hz), 2.50 (1H, m ), 1.93-1.14 (30H, m), 1.41 (3H, s), 0.96 (3H, s).

(Example 113)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl α- D-Glucopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl α- D-Glucopyranoside The title compound (82 mg) was obtained as a white solid in the same manner as in Example 13, Step 4, using the compound (α-glycoside) (183 mg) obtained in Step 112 of Example 112.
MS (ESI) m / z: 580 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.89 (1H, d, J = 3.9Hz), 4.04 (1H, m), 3.77 (1H, m), 3.65 to 3.60 (2H, m), 3.58 (1H, t, J = 9.3Hz), 3.50 (1H, m), 3.40 (1H, m), 3.31 (1H, dd, J = 3.9,9.3Hz), 3.22 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.94 (3H, s)
(Example 114)
(Example 114-1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl α- D-xisopyranoside

(Example 114-2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- D-xisopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2, 3,4-Tri-O-benzyl-D-xylopyranoside 2,3,4-tri-O-benzyl-1-O- (2,2,2-trichloroethanimidoyl) -D-xylopyranose (Liebigs Annalen der Chemie , 1984, 7, 1343-1357.) (541 mg) and the compound obtained in Example 1 Step 3 (200 mg) in the same manner as Example 108 Step 1 to give the title compound (251 mg) as an isomer mixture. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (15H, m), 4.90 (0.6H, d, J = 10.7Hz), 4.86 (0.4H, d, J = 10.7Hz), 4.84-4.82 (1.4 H, m), 4.79 (0.6H, d, J = 3.9Hz), 4.74-4.68 (2H, m), 4.61 (0.6H, d, J = 12.2Hz), 4.59 (0.6H, d, J = 11.7) Hz), 4.58 (0.4H, d, J = 11.7Hz), 4.38 (0.4H, d, J = 7.8Hz), 4.01 (0.4H, m), 3.95 (0.6H, m), 3.88-3.84 (1H , m), 3.59-3.49 (2.6H, m), 3.43-3.38 (1.6H, m), 3.36-3.29 (1.4H, m), 3.27-3.22 (1H, m), 3.15 (0.4H, dd, J = 10.3,11.7Hz), 2.37-2.31 (1H, m), 1.93-1.07 (30H, m), 1.382 (1.8H, s), 1.377 (1.2H, s), 1.04 (0.6H, s), 1.03 (0.4H, s), 0.93 (1.8H, s), 0.91 (1.2H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl α- D-xisopyranoside (α-glycoside)
as well as
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- D-xisopyranoside (β-glycoside)
The compound (251 mg) obtained in the above Step 1 was reacted in the same manner as in Example 13, Step 4, and separated and purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (α-glycoside) ( 32 mg) and the title compound (β-glycoside) (33 mg) were obtained as white solids, respectively.
α-glycoside; Rf = higher, low polarity: Example 114-1
MS (ESI) m / z: 550 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.83 (1H, d, J = 3.9Hz), 4.02 (1H, m), 3.55-3.37 (6H, m), 3.30 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.89-1.11 (30H, m), 1.39 (3H, s), 0.94 (3H, s).
β-glycoside; Rf = lower, high polarity: Example 114-2
MS (ESI) m / z: 550 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.24 (1H, d, J = 7.3Hz), 4.04 (1H, m), 3.79 (1H, dd, J = 5.4,11.2Hz), 3.50 (1H, m) , 3.46-3.37 (2H, m), 3.24 (1H, t, J = 8.8Hz), 3.18-3.06 (3H, m), 2.47 (1H, m), 1.88-1.11 (30H, m), 1.39 (3H , s), 0.93 (3H, s).

(Example 115)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- L-Glucopyranoside

(Process 1)
2,3,4,6-Tetra-O-benzoyl-1-O- (2,2,2-trichloroethaneimidoyl) -β-L-glucopyranose 2,3,4,6-tetra-O-benzoyl- To a solution of L-glucopyranose (Tetrahedron: Asymmetry, 1994, 5, 2109-2122.) (2.89 g) in dichloromethane (50 ml) at room temperature, trichloroacetonitrile (2.45 ml) and cesium carbonate (316 mg) were added in order, and the same temperature. For 4 hours. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane / ethyl acetate: triethylamine 1% added] to give the title compound (3.22 g) as a white product. Obtained as amorphous.
¹ H-NMR (CDCl ₃ ) δ: 8.61 (1H, s), 8.02-8.00 (2H, m), 7.94-7.91 (4H, m), 7.86-7.83 (2H, m), 7.54 (1H, m) , 7.51-7.46 (2H, m), 7.44-7.38 (3H, m), 7.36-7.32 (4H, m), 7.29-7.26 (2H, m), 6.81 (1H, d, J = 3.4Hz), 6.25 (1H, t, J = 10.0Hz), 5.79 (1H, t, J = 10.0Hz), 5.59 (1H, dd, J = 3.4,10.0Hz), 4.64-4.60 (2H, m), 4.46 (1H, dd, J = 5.1, 12.4 Hz).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2, 3,4,6-tetra-O-benzoyl-β-L-glucopyranoside Example 108 step using the compound obtained in step 1 above (393 mg) and the compound obtained in example 1 step 3 (130 mg) The title compound (188 mg) was obtained as a white amorphous product by the same method as 1.
¹ H-NMR (CDCl ₃ ) δ: 8.02-7.99 (2H, m), 7.93-7.91 (2H, m), 7.89-7.87 (2H, m), 7.81-7.79 (2H, m), 7.54-7.24 ( 12H, m), 5.85 (1H, t, J = 9.8Hz), 5.59 (1H, t, J = 9.8Hz), 5.44 (1H, dd, J = 7.8,9.8Hz), 4.90 (1H, d, J = 7.8Hz), 4.57 (1H, dd, J = 3.4,12.2Hz), 4.50 (1H, dd, J = 5.9,12.2Hz), 4.12 (1H, m), 4.05 (1H, m), 3.40 (1H , m), 3.33 (1H, dt, J = 2.6,12.3Hz), 3.21 (1H, m), 2.33 (1H, m), 1.82-1.01 (30H, m), 1.35 (3H, s), 0.83 ( 1H, s), 0.78 (3H, s).

(Process 3)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl β- L-Glucopyranoside The title compound (92 mg) was obtained as a white amorphous product in the same manner as in Step 1 of Example 5 using the compound (188 mg) obtained in Step 2 above.
MS (ESI) m / z: 580 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.32 (1H, d, J = 7.8Hz), 4.10 (1H, m), 3.83 (1H, dd, J = 1.5,12.0Hz), 3.60 (1H, dd, J = 5.6,12.0Hz), 3.50 (1H, m), 3.40 (1H, m), 3.32-3.14 (4H, m), 3.09 (1H, dd, J = 7.8,8.8Hz), 2.47 (1H, m ), 1.91-1.11 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 116)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-glucopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside)
as well as
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)
3,4,6-Tri-O-acetyl-2-deoxy-2-fluoro-1-O- (2,2,2-trichloroethaneimidoyl) -α-D-glucopyranose (Angewandte Chemie International Edition, 2010, 49,8724-8728.) (163 mg) and the compound (100 mg) obtained in Example 1 Step 3 were reacted in the same manner as in Example 108 Step 1, followed by silica gel column chromatography [ethyl acetate / hexane The title compound (α-glycoside) (77 mg) and the title compound (β-glycoside) (59 mg) were obtained as white solids, respectively.
α-Glycoside: Rf = higher, low polarity
¹ H-NMR (CDCl ₃ ) δ: 5.50 (1H, m), 5.17 (1H, d, J = 3.9Hz), 4.95 (1H, t, J = 9.5Hz), 4.43 (1H, m), 4.22 ( 1H, m), 4.11-4.03 (3H, m), 3.42 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.04 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.92-1.10 (31H, m), 1.38 (3H, s), 0.94 (3H, s).
β-glycoside: Rf = lower, high polarity
¹ H-NMR (CDCl ₃ ) δ: 5.26 (1H, m), 4.98 (1H, dd, J = 9.3, 10.3Hz), 4.62 (1H, dd, J = 2.9, 7.8Hz), 4.23 (1H, dd , J = 5.4,12.2Hz), 4.22 (1H, m), 4.09 (1H, m), 4.07 (1H, dd, J = 2.4,12.2Hz), 3.67 (1H, m), 3.42 (1H, m) , 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.050 (3H, s), 2.046 (3H, s), 2.00 (3H, s), 1.94-1.10 (31H, m ), 1.38 (3H, s), 0.93 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-glucopyranoside The title compound (39 mg) was obtained as a white solid in the same manner as in Example 5, Step 1 using the compound (α-glycoside) (77 mg) obtained in Step 1 above. It was.
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.08 (1H, d, J = 3.9Hz), 4.14 (1H, m), 4.06 (1H, m), (1H, m), 3.81 (1H, m), 3.66-3.60 (2H, m), 3.51 (1H, m), 3.40 (1H, m), 3.27 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.09 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 117)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-glucopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-glucopyranoside Using the compound (β-glycoside) (59 mg) obtained in Step 116 of Example 116, the title compound (40 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5. Got as.
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.57 (1H, dd, J = 2.2,7.6Hz), 4.13 (1H, m), 3.87 (1H, m), 3.81 (1H, dd, J = 1.5,11.7 Hz), 3.62 (1H, dd, J = 5.4,11.7Hz), 3.57-3.48 (2H, m), 3.53 (1H, m), 3.30-3.22 (2H, m), 3.17 (1H, m), 2.47 (1H, m), 1.90-1.10 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 118)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-galactopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-α-D-galactopyranoside (α-glycoside)
as well as
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-β-D-galactopyranoside (β-glycoside)
3,4,6-Tri-O-acetyl-2-deoxy-2-fluoro-1-O- (2,2,2-trichloroethaneimidoyl) -α-D-galactopyranose (Chemistry-A European Journal, 2012 , 18, 8208-8215.) (163 mg) and the compound (100 mg) obtained in Step 1 of Example 1 were reacted in the same manner as in Step 108 of Example 108, followed by silica gel column chromatography [ethyl acetate / Separation and purification with hexane] afforded the title compound (α-glycoside) (18 mg) and the title compound (β-glycoside) (96 mg) as white solids, respectively.
α-Glycoside: Rf = higher, low polarity
¹ H-NMR (CDCl ₃ ) δ: 5.43 (1H, m), 5.35 (1H, m), 5.21 (1H, d, J = 3.4Hz), 4.70 (1H, m), 4.28 (1H, m), 4.09-4.01 (3H, m), 3.41 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.11 (3H, s), 2.03 (3H, s) , 2.00 (3H, s), 1.91-1.11 (31H, m), 1.38 (3H, s), 0.93 (3H, s).
β-glycoside: Rf = lower, high polarity
¹ H-NMR (CDCl ₃ ) δ: 5.37 (1H, m), 5.06 (1H, m), 4.61 (1H, dd, J = 3.9,7.8 Hz), 4.43 (1H, m), 4.14 (1H, dd , J = 6.3,11.2Hz), 4.11 (1H, m), 4.07 (1H, dd, J = 6.8,11.2Hz), 3.88 (1H, m), 3.41 (1H, m), 3.33 (1H, m) , 3.25 (1H, m), 2.34 (1H, m), 2.11 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.97-1.10 (31H, m), 1.38 (3H, s) ), 0.93 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-galactopyranoside Using the compound (α-glycoside) (18 mg) obtained in Step 1 above, the title compound (11 mg) was converted to white in the same manner as in Example 1, Step 1. Obtained as a solid.
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.10 (1H, d, J = 3.9Hz), 4.52 (1H, m), 4.05 (1H, m), 3.94-3.86 (3H, m), 3.68 (1H, dd, J = 5.4,10.5Hz), 3.65 (1H, dd, J = 4.6,10.5Hz), 3.50 (1H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 (1H, m ), 1.89-1.10 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 119)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-galactopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-galactopyranoside Using the compound (β-glycoside) (96 mg) obtained in Example 118, Step 1, the title compound (77 mg) was prepared in the same manner as in Example 5, Step 1. Was obtained as a white solid.
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.53 (1H, dd, J = 3.4,7.8Hz), 4.21 (1H, m), 4.13 (1H, m), 3.84 (1H, t, J = 2.9Hz) , 3.70 (1H, dd, J = 6.3,11.2Hz), 3.68 (1H, dd, J = 5.4,11.2Hz), 3.65 (1H, m), 3.53-3.48 (2H, m), 3.40 (1H, m ), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 120)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-mannopyranoside

(Process 1)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-α-D-mannopyranoside 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-1-O- (2, 2,2-Trichloroethaneimidoyl) -D-mannopyranose (Angewandte Chemie International Edition, 2010, 49, 8724-8728.) (380 mg) and the compound obtained in Example 1 step 3 (200 mg) The title compound (α-glycoside) (351 mg) was obtained as a white solid by the same method as in Example 108, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 5.21 (1H, m), 5.10 (1H, dd, J = 1.5,7.3 Hz), 4.65 (1H, m), 4.22 (1H, dd , J = 5.1,12.1Hz), 4.14-3.99 (3H, m), 3.42 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.07 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.87-1.11 (31H, m), 1.38 (3H, s), 0.92 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-mannopyranoside Using the compound (351 mg) obtained in Step 1 above, the title compound (198 mg) was obtained as a white solid in the same manner as in Step 1 of Example 5.
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.04 (1H, dd, J = 1.5,7.8Hz), 4.48 (1H, m), 4.10 (1H, m), 3.82 (1H, dd, J = 2.0,11.7 Hz), 3.69 (1H, m), 3.65 (1H, dd, J = 5.9,11.7Hz), 3.59 (1H, m), 3.54 (1H, t, J = 9.0Hz), 3.50 (1H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 121)
(Example 121-1)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)

(Example 121-2)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside)

(Process 1)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 3, 4,6-Tri-O-acetyl-2-deoxy-2-fluoro-D-glucopyranoside 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-1-O- (2,2, Using 2-trichloroethaneimidoyl) -α-D-glucopyranose (154 mg) and the compound obtained in Example 5, Step 1 (95 mg), the title compound (156 mg) was prepared in the same manner as Example 108, Step 1. Obtained as an isomer mixture (α-glycoside: β-glycoside = 4: 6).
MS (ESI) m / z: 708 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.45 (0.4H, m), 5.28 (0.6H, m), 5.23 (0.4H, d, J = 3.9Hz), 4.98 (0.6H, dd, J = 9.3, 9.8Hz), 4.97 (0.4H, t, J = 9.8Hz), 4.61 (0.6H, dd, J = 2.9, 7.8Hz), 4.49 (0.4H, m), 4.28-4.04 (3.6H, m), 3.99 (0.4H, m), 3.67 (0.6H, m), 3.65 (0.6H, brs), 3.58 (0.4H, brs), 3.42-3.37 (1H, m), 3.36-3.28 (1H, m), 3.26-3.18 (1H, m), 2.38-2.31 (1H, m), 2.06-2.00 (9H, m), 1.87-1.00 (30H, m), 1.39 (1.2H, s), 1.38 (1.8H, s ), 0.88 (1.2H, s), 0.86 (1.8H, s).

(Process 2)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -1- (cyclohexylcarbonyl) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl 2- Deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside)
The compound obtained in Step 1 above (156 mg) was reacted in the same manner as in Step 5 of Example 5, separated and purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (β-glycoside) ( 45 mg) and the title compound (α-glycoside) (32 mg) were obtained as white solids, respectively.
β-glycoside; Rf = higher, low polarity: Example 121-1
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.64 (1H, dd, J = 2.4, 7.8Hz), 4.23 (1H, m), 3.91 (1H, m), 3.82 (1H, dd, J = 1.7, 12.0 Hz), 3.63 (1H, dd, J = 4.9,12.0Hz), 3.58 (1H, m), 3.50 (1H, m), 3.41 (1H, m), 3.33-3.25 (2H, m), 3.18 (1H , m), 2.48 (1H, m), 1.92-1.07 (30H, m), 1.40 (3H, s), 0.92 (3H, s).
α-glycoside; Rf = lower, high polarity: Example 121-2
MS (ESI) m / z: 582 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.17 (1H, d, J = 3.9 Hz), 4.26 (1H, m), 4.15 (1H, m), 3.81 (1H, m), 3.77 (1H, dd, J = 2.0,12.0Hz), 3.63 (1H, dd, J = 5.6,12.0Hz), 3.57 (1H, m), 3.50 (1H, m), 3.41 (1H, m), 3.30 (1H, m), 3.18 (1H, m), 2.48 (1H, m), 1.89-1.07 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 122)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -Tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 6aS, 6bR, 9S, 10aR, 11aS, 12aR, 12bS) -9-hydroxy-4a, 6b-dimethyltetradecahydro-1H-oxyleno [4,4a] naphtho [2,1-f] quinoline- 4 (4aH) -Carboxylate The title compound (1.04 g) was obtained in the same manner as in Example 1, Step 2, using the compound (1.00 g) obtained in Step 19 of Example 19.
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.07 (2H, s), 3.91 (1H, m), 3.75 (1H, m), 3.33 (1H, m), 3.00 (1H , m), 2.93 (1H, d, J = 4.3 Hz), 2.09-1.06 (19H, m), 1.30 (3H, s), 1.02 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (1.04 g) obtained in 1, the title compound (396 mg) was obtained in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 442 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.30 (5H, m), 5.08 (2H, s), 4.09 (1H, m), 3.78 (1H, m), 3.34 (1H, m), 3.05 (1H , m), 1.87-0.95 (28H, m).

(Process 3)
Benzyl (4aS, 4bR, 6aR, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate 4-Methylmorpholine N-oxide (398 mg) and tetrapropylammonium perruthenate (79.6 mg) were added to a solution of the compound obtained in 2 (1.00 g) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered off through celite and washed with dichloromethane. The filtrate was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.86 g) as a white solid.
MS (ESI) m / z: 440 (M + H) ^<+> .

(Process 4)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Anhydrous cerium chloride (126 mg) was suspended in tetrahydrofuran (5 ml) and stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to 0 ° C., methylmagnesium bromide (0.96 M tetrahydrofuran solution, 0.53 ml) was added, and the mixture was stirred at the same temperature for 1.5 hours, and then the tetrahydrofuran solution (5 ml of the compound (150 mg) obtained in the above step 3 was used. ) Was added at the same temperature for 1 hour, and then the mixture was stirred overnight while gradually warming to room temperature. Further, methylmagnesium bromide (0.96M tetrahydrofuran solution, 5.30 ml) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (87.8 mg) as a white solid.
MS (ESI) m / z: 456 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.30 (5H, m), 5.08 (2H, s), 3.79-3.75 (1H, m), 3.37-3.32 (1H, m), 3.06-3.02 (1H, m), 2.06-0.86 (31H, m).

(Process 5)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 8 (2H) -diol obtained in Step 4 above Using the compound (87.8 mg), the title compound (63.5 mg) was obtained in the same manner as in Step 2 of Example 20.
MS (ESI) m / z: 322 (M + H) ^<+> .

(Process 6)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 using the compound obtained in Step 5 above (62.0 mg) and the compound obtained in Example 23 Step 3 (48.9 mg) The title compound (71.3 mg) was obtained as a white solid by the same method as in Step 4.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.04 (1H, m), 3.97 (1H, m), 3.55 (1H, m), 3.44 (1H, m), 3.33-3.29 (2H, m), 2.06-0.86 (28H, m), 1.42 (3H, s), 1.23 (3H, s), 0.90 (3H, s).

(Example 123)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

　(工程1)
ベンジル(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a-ヒドロキシ-10a,12a-ジメチルテトラデカヒドロ-2H-スピロ[ナフト[2,1-f]キノリン-8,2’-オキシラン]-1(4bH)-カルボキシレート
　窒素雰囲気下、ジメチルスルホキシド(3ml)をトリメチルスルホキソニウムヨージド(300mg)と水素化ナトリウム(60wt%、54.6mg)に滴下して、室温で30分間攪拌した。反応液に実施例122工程3で得られた化合物(400mg)のテトラヒドロフラン溶液(6ml)を加え、1時間攪拌した。反応液に水を加え、ジクロロメタンで抽出後、有機層を無水硫酸ナトリウムで乾燥した。濾液を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー[酢酸エチル/ヘキサン]で精製し、標題化合物(383mg)を白色固体として得た。
MS(ESI)m/z:454(M+H)^+
1H-NMR(CDCl₃)δ:7.36-7.29(5H,m),5.08(2H,s),3.80-3.78(1H,m),3.35-3.28(1H,m),3.05-3.02(1H,m),2.77(1H,s),2.61-2.60(1H,m),2.58-2.57(1H,m),2.32-2.28(1H,m),2.15-2.08(1H,m),1.86-0.99(18H,m),1.36(3H,s),0.95(3H,s)。

(Process 1)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyltetradecahydro-2H-spiro [naphtho [2,1-f] quinoline-8,2'-oxirane ] -1 (4bH) -carboxylate Dimethyl sulfoxide (3 ml) was added dropwise to trimethylsulfoxonium iodide (300 mg) and sodium hydride (60 wt%, 54.6 mg) under a nitrogen atmosphere and stirred at room temperature for 30 minutes. . To the reaction solution was added a tetrahydrofuran solution (6 ml) of the compound (400 mg) obtained in Step 3 of Example 122, and the mixture was stirred for 1 hour. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (383 mg) as a white solid.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.08 (2H, s), 3.80-3.78 (1H, m), 3.35-3.28 (1H, m), 3.05-3.02 (1H, m), 2.77 (1H, s), 2.61-2.60 (1H, m), 2.58-2.57 (1H, m), 2.32-2.28 (1H, m), 2.15-2.08 (1H, m), 1.86-0.99 ( 18H, m), 1.36 (3H, s), 0.95 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -carboxylate The compound (39.0 mg) obtained in Step 1 above was suspended in a mixture of 2-methoxyethanol (2.5 ml) -water (0.25 ml), sodium acetate (141 mg) was added, and The mixture was stirred for 1 hour at 50 ° C. for 2 hours and further at 80 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane: methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (39.8 mg).

(Process 3)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -8-[(acetyloxy) methyl] -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate Acetic anhydride (1 ml) was added to a pyridine (2 ml) solution of the compound (39.8 mg) obtained in Step 2 above, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, toluene was added and the mixture was concentrated again to remove pyridine. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (36.8 mg).
MS (ESI) m / z: 514 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.30 (5H, m), 5.08 (2H, s), 3.94-3.90 (2H, m), 3.80-3.76 (1H, m), 3.34-3.30 (1H, m), 3.07-3.03 (1H, m), 2.11 (3H, s), 1.84-1.10 (22H, m), 1.35 (3H, s), 0.87 (3H, s).

(Process 4)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl] methyl acetate Step 3 The title compound (51.6 mg) was obtained in the same manner as in Step 2 of Example 20 using the compound (71.3 mg) obtained in (1).
MS (ESI) m / z: 380 (M + H) ^<+> .

(Process 5)
{(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydro Naphtho [2,1-f] quinolin-8-yl} methyl acetate Example 23 using the compound obtained in Step 4 above (51.6 mg) and the compound obtained in Example 23 Step 3 (34.5 mg) The title compound (83.5 mg) was obtained in the same manner as in Step 4.
MS (ESI) m / z: 492 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.12-4.10 (1H, m), 3.98-3.97 (1H, m), 3.87-3.84 (2H, m), 3.60-3.57 (1H, m), 3.50-3.48 ( 1H, m), 3.42-3.39 (1H, m), 3.22-3.20 (1H, m), 2.06 (3H, s), 1.88-1.14 (28H, m), 1.44 (3H, s), 0.91 (3H, s).

(Process 6)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound (66.8 mg) obtained in Step 5 above, the title compound (66.8 mg) was prepared in the same manner as in Step 1 of Example 5. 43.6 mg) was obtained as a white solid.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.11-4.10 (1H, m), 3.98-3.96 (1H, m), 3.61-3.57 (1H, m), 3.50-3.48 (1H, m), 3.39-3.36 ( 1H, m), 3.27-3.25 (2H, m), 3.22-3.19 (1H, m), 1.88-1.14 (29H, m), 1.44 (3H, s), 0.90 (3H, s).

(Example 124)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

　(工程1)
ベンジル(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-ジヒドロキシ-10a,12a-ジメチル-8-[(メチルスルファニル)メチル]ヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-カルボキシレート
　実施例123工程1で得られた化合物(65.3mg)のテトラヒドロフラン(3ml)溶液に、ナトリウムチオメトキシド(30.3mg)を加え、50℃で5時間攪拌した。更にナトリウムチオメトキシド(30.3mg)を加え、50℃で2時間攪拌した。反応液を室温に冷却した後、酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濾液を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー[酢酸エチル/ヘキサン]で精製し、標題化合物(45.8mg)を得た。
¹H-NMR(CDCl₃)δ:7.36-7.29(5H,m),5.08(2H,s),4.15(1H,brs),3.80-3.77(1H,m),3.34-3.30(2H,m),3.05-3.02(1H,m),2.59-2.58(2H,m),2.18(3H,s),1.83-1.81(1H,m),1.69-1.09(19H,m),1.35(3H,s),0.86(3H,s)。

(Process 1)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfanyl) methyl] hexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate Sodium thiomethoxide (30.3 mg) was added to a solution of the compound obtained in Example 123, Step 1 (65.3 mg) in tetrahydrofuran (3 ml), and the mixture was stirred at 50 ° C. for 5 hours. Sodium thiomethoxide (30.3 mg) was further added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (45.8 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.08 (2H, s), 4.15 (1H, brs), 3.80-3.77 (1H, m), 3.34-3.30 (2H, m) , 3.05-3.02 (1H, m), 2.59-2.58 (2H, m), 2.18 (3H, s), 1.83-1.81 (1H, m), 1.69-1.09 (19H, m), 1.35 (3H, s) , 0.86 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate To a solution of the compound (45.8 mg) obtained in Step 1 above in dichloromethane (3 ml) was added 3-chloroperbenzoic acid (50.0 mg) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. . The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (54.2 mg).
MS (ESI) m / z: 534 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.33 (5H, m), 5.08 (2H, s), 3.80-3.77 (1H, m), 3.34-3.32 (1H, m), 3.20-3.03 (3H, m), 3.06 (3H, s), 1.98-1.15 (22H, m), 1.35 (3H, s), 0.89 (3H, s).

(Process 3)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] quinoline-6a, 8 (2H) -Diol Using the compound (48.7 mg) obtained in Step 2 above, the title compound (47.7 mg) was obtained in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 400 (M + H) ^<+> .

(Process 4)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylsulfonyl) methyl] hexadecahydronaphtho [2,1-f] quinoline -1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The compound obtained in Step 3 above (36.5 mg) and the compound obtained in Example 23 Step 3 (23.6 mg ) To give the title compound (45.8 mg) in the same manner as in Example 23, step 4.
MS (ESI) m / z: 512 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.95 (1H, brs), 4.06-3.98 (2H, m), 3.54-3.42 (2H, m), 3.33-3.28 (2H, m), 3.18-3.09 (2H, m), 3.05 (3H, s), 3.05-3.01 (1H, m), 1.97-1.12 (26H, m), 1.43 (3H, s), 0.89 (3H, s).

(Example 125)
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -Tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (3.53 g) obtained in Example 122, Step 2, the title compound (2.99 g) was obtained as a white solid in the same manner as in Example 27, Step 1.
MS (ESI) m / z: 456 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.41-7.22 (5H, m), 5.13-5.03 (2H, m), 3.82-3.73 (1H, m), 3.56-3.55 (1H, m), 3.41-3.28 ( 4H, m), 3.09-3.00 (1H, m), 2.00-1.08 (24H, m), 0.98-0.90 (3H, m).

(Process 2)
(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-6a (2H) -ol obtained in step 1 above Using the compound (2.99 g), the title compound (1.65 g) was obtained as a white solid in the same manner as in Step 20 of Example 20.
¹ H-NMR (CD ₃ OD) δ: 3.71-3.58 (1H, m), 3.41-3.25 (4H, m), 2.92-2.82 (1H, m), 2.75-2.65 (1H, m), 1.97-1.86 (1H, m), 1.77-0.99 (22H, m), 0.95 (3H, s).

(Step 3) [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Step 2 above (161 mg) and the compound obtained in Example 23 Step 3 (78.1 mg), The title compound (78 mg) was obtained as a white solid by a method similar to that in Example 23, Step 4.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.06-3.94 (2H, m), 3.63-3.52 (2H, m), 3.47-3.40 (1H, m), 3.37-3.25 (5H, m), 1.99-1.06 ( 30H, m), 0.93 (3H, s).

Example 126
[(2R, 5R) -5-Fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-methoxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl cis-5-fluorotetrahydro-2H-pyran-2-carboxylate Using cis-5-fluorotetrahydro-2H-pyran-2-carboxylic acid (2.96 g) in the same manner as in Example 23 step 1 The title compound (3.73 g) was obtained as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 7.41-7.27 (5H, m), 5.22 (2H, s), 4.60 (1H, m), 4.23 (1H, m), 4.07 (1H, m), 3.64 (1H , m), 2.18 (1H, m), 2.06 (1H, m), 1.94-1.72 (2H, m).

(Process 2)
Benzyl (2S, 5S) -5-fluorotetrahydro-2H-pyran-2-carboxylate and benzyl (2R, 5R) -5-fluorotetrahydro-2H-pyran-2-carboxylate Compound obtained in the above step 1 ( 5.76 g) was optically resolved under the following conditions: benzyl (2S, 5S) -5-fluorotetrahydro-2H-pyran-2-carboxylate (isomer A) (2.36 g) and benzyl (2R, 5R) -5 -Fluorotetrahydro-2H-pyran-2-carboxylate (isomer B) (2.31 g) was obtained as a colorless oil.
CHIRALPAK (AY-H) 20 × 250mm
Eluent: Hexane / ethanol = 7: 3
Flow rate: 20ml / min
Detection wavelength: 254nM
Retention time: Isomer A (2S, 5S) isomer: 9.7 min, Isomer B (2R, 5R) isomer: 14.0 min.

(Process 3)
(2R, 5R) -5-Fluorotetrahydro-2H-pyran-2-carboxylic acid Using the compound (isomer B) (695 mg) obtained in Step 2 above, the title was prepared in the same manner as in Step 23 of Example 23. Compound (431 mg) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.64 (1H, dd, J = 2.0,46.4Hz), 4.28 (1H, m), 4.03 (1H, dd, J = 3.9,10.7Hz), 3.70 (1H, dd , J = 13.2, 38.1 Hz), 2.26 (1H, m), 2.07-1.95 (2H, m), 1.83 (1H, m).

(Process 4)
[(2R, 5R) -5-Fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-8-methoxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Example 125, Step 2 (129 mg) and the compound obtained in Step 3 above (59.3 mg) The title compound (114 mg) was obtained as a white solid by a method similar to that in Example 23, Step 4.
¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, m), 4.13 (1H, m), 4.00 (1H, m), 3.65-3.49 (3H, m), 3.41-3.31 (4H, m), 3.27 (1H, m), 2.27-2.12 (2H, m), 1.95 (1H, m), 1.88-1.13 (24H, m), 1.10 (1H, s), 0.94 (3H, s).

(Example 127)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8- [2- (methylsulfonyl) ethoxy] hexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2- (2-tert-butoxy-2-oxoethoxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5 ] Naphtho [2,1-f] quinoline-7 (5H) -carboxylate Example 19 Sodium hydride (60 wt%, 0.910 g) was added to a solution of the compound (4.00 g) obtained in Step 4 in tetrahydrofuran (90 ml). And tert-butyl bromoacetate (13.3 ml) were added, and the mixture was stirred at 60 ° C. for 7 hours. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.79 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.03 (2H, m), 4.07 (2H, s), 3.92 (1H, m), 3.75 (1H, m), 3.32 (1H, m), 3.13 (1H, d, J = 3.4Hz), 3.03 (1H, m), 2.05 (1H, m), 1.93 (1H, m), 1.82 (1H, m), 1.73-1.62 ( 2H, m), 1.56-0.86 (13H, m), 1.45 (9H, s), 1.33 (3H, s), 0.97 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8- (2-tert-butoxy-2-oxoethoxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinoline-1 (2H) -carboxylate Using the compound (2.79 g) obtained in Step 1 above, the title compound (2.09 g) was converted to white in the same manner as in Example 31, Step 4. Obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.08 (2H, s), 4.20 (1H, d, J = 16.6Hz), 3.92 (1H, d, J = 16.6Hz), 3.81-3.75 (2H, m), 3.57 (1H, brd, J = 2.9Hz), 3.42 (1H, brs), 3.34 (1H, m), 3.03 (1H, m), 2.25 (1H, m), 1.86 -1.15 (17H, m), 1.47 (9H, s), 1.35 (3H, s), 1.14 (3H, s), 1.12 (1H, s).

(Process 3)
tert-Butyl {[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl Oxy} acetate The title compound (1.6 g) was obtained in the same manner as in Example 2, Step 2 using the compound (2.09 g) obtained in Step 2 above.
MS (ESI) m / z: 438 (M + H) ^<+> .

(Process 4)
tert-butyl ({(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2- Ylcarbonyl] octadecahydronaphtho [2,1-f] quinolin-8-yl} oxy) acetate The compound obtained in Step 3 above (1.60 g) and the compound obtained in Example 23 Step 3 (0.714 g) Was used to give the title compound (1.34 g) as a white solid in the same manner as in Step 4 of Example 23.
MS (ESI) m / z: 550 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.16 (1H, m), 4.01 (1H, m), 3.95-3.87 (2H, m), 3.76 (1H, m), 3.56-3.51 (2H, m), 3.41 (1H, m), 3.34 (1H, m), 3.32-3.22 (2H, m), 2.23 (1H, m), 1.91-1.13 (23H, m), 1.44 (9H, s), 1.40 (3H, s ) .1.11 (3H, s), 1.06 (1H, s).

(Process 5)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8- (2-hydroxyethoxy) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone A solution of the compound obtained in Step 4 above (400 mg) in tetrahydrofuran (15 ml) was cooled to 0 ° C. After adding lithium borohydride (47.6 mg), the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (243 mg) as a white solid.
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.94 (1H, m), 3.80 (1H, m), 3.75-3.71 (2H, m), 3.67-3.61 (3H, m), 3.54 (1H, m), 3.41 (1H, m), 3.33-3.23 (2H, m), 2.45 (1H, s), 2.21 (1H, m), 1.93-1.14 (24H, m), 1.41 (3H, s ) .1.10 (3H, s), 1.05 (1H, s).

(Process 6)
2-({(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-yl Carbonyl] octadecahydronaphtho [2,1-f] quinolin-8-yl} oxy) ethyl methanesulfonate To a solution of the compound obtained in Step 5 above (436 mg) in dichloromethane (9.1 ml) was added diisopropylethylamine (0.234). ml) and methanesulfonyl chloride (0.085 ml) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (417 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.37-4.33 (2H, m), 4.00 (1H, m), 3.94 (1H, m), 3.84-3.75 (3H, m), 3.63 (1H, m), 3.54 (1H, m), 3.41 (1H, m), 3.33-3.22 (2H, m), 2.36 (1H, s), 2.21 (1H, m), 1.90-1.13 (26H, m), 1.40 (3H, s ), 1.09 (3H, s) .1.09 (1H, m).

(Process 7)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8- [2- (methylsulfonyl) ethoxy] hexadecahydronaphtho [2,1 -f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone N, N-dimethylformamide (1.8 ml) of the compound obtained in step 6 above (100 mg) To the solution were added sodium methanesulfinate (0.0549 g) and potassium iodide (0.0893 g), and the mixture was stirred at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compound (65 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.03-3.98 (2H, m), 3.94 (1H, m), 3.87-3.79 (2H, m), 3.71 (1H, m), 3.54 (1H, m), 3.41 (1H, m), 3.35-3.24 (3H, m), 3.14 (1H, m), 3.02 (3H, s), 2.22 (1H, m), 1.89-1.05 (25H, m), 1.40 (3H, s ), 1.09 (3H, s).

(Example 128)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8- [2- (1H-1,2,4-triazol-1-yl ) Ethoxy] hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8- [2- (1H-1,2,4-triazol-1-yl ) Ethoxy] hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone 1,2,4-triazole (0.0495 g) To a solution of N, N-dimethylformamide (1.8 ml) in sodium hydride (60 wt%, 0.0287 g) was added and stirred for 10 minutes, and then the compound obtained in Example 127, step 6 (100 mg) was added. Stir for hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (23 mg) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 8.11 (1H, s), 7.94 (1H, s), 4.38-4.28 (2H, m), 4.01 (1H, m), 3.96-3.84 (3H, m), 3.71 (1H, m), 3.57-3.50 (2H, m), 3.41 (1H, m), 3.32-3.21 (2H, m), 2.33 (1H, s), 2.18 (1H, m), 1.92-1.11 (23H , m), 1.40 (3H, s). 1.06 (3H, s), 1.04 (1H, s).

(Example 129)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a- Dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate Example 19 Using the compound obtained in Step 4 (3.00 g) By the same method as in Step 27, the title compound (3.42 g) was obtained as a colorless oil.
MS (ESI) m / z: 554 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.27 (1H, m), 4.04 (1H, dd, J = 8.3,6.3Hz), 3.81 -3.78 (2H, m), 3.75 (1H, m), 3.67 (1H, dd, J = 9.8,4.9Hz), 3.52 (1H, dd, J = 10.0,6.1Hz), 3.32 (1H, m), 3.09 (1H, d, J = 2.9 Hz), 3.03 (1H, m), 2.07-0.87 (18H, m), 1.39 (3H, s), 1.33 (6H, s), 0.96 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinoline-1 (2H) -carboxylate Using the compound (3.42 g) obtained in Step 1 above, the title compound (1.79 g) was obtained as a white solid in the same manner as in Step 4 of Example 31. Got as.
MS (ESI) m / z: 532 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.05 (2H, s), 3.86 (1H, brs), 3.82-3.69 (3H, m), 3.67-3.64 (1H, m) , 3.64-3.52 (3H, m), 3.36-3.28 (1H, m), 3.02-2.99 (1H, m), 2.78-2.63 (1H, m), 2.22-2.15 (2H, m), 1.82-1.07 ( 16H, m), 1.32 (3H, s), 1.09 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7- Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 20, Step 1 using the compound (1.79 g) obtained in Step 2 above. The title compound (2.0 g) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.89 (1H, m), 3.83 (1H, m), 3.80-3.71 (2H, m), 3.69 (1H, d, J = 3.4Hz), 3.66-3.55 (3H, m), 3.34 (1H, m), 3.03 (1H, m), 2.81 (1H, brd, J = 2.9Hz), 2.66 (1H, brs), 2.25-2.17 (2H, m), 1.87-1.14 (21H, m), 1.34 (3H, s), 1.16 (1H, s), 1.12 (3H, s).

(Process 4)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methoxy} -10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinoline-6a, 7 (2H) -diol Using the compound (1.93 g) obtained in Step 3 above, the title compound (1.93 g) was prepared in the same manner as in Step 2 of Example 20. 1.47 g) was obtained.

(Process 5)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -6a, 7- Dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 Obtained in Step 3 To a solution of the obtained compound (0.098 g) in dichloromethane (2 ml) were added oxalyl chloride (0.077 ml) and 1 drop of N, N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, toluene (2 ml), saturated aqueous sodium hydrogen carbonate solution (2 ml), and the compound obtained in Step 4 above (0.219 g) were sequentially added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (0.201 g) as a white solid.
MS (ESI) m / z: 550 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.06-3.98 (2H, m), 3.94 (1H, dd, J = 10.7,2.4Hz), 3.78 (1H, m), 3.67-3.64 (2H, m), 3.57-3.49 (3H, m), 3.44-3.38 (1H, m), 3.34-3.22 (2H, m), 2.68 (1H, s), 2.37-1.06 (24H, m), 1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s), 1.05 (1H, s).

(Process 6)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 using the compound (0.201 g) obtained in Step 5 above The title compound (0.115 g) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 510 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.0,10.7Hz), 3.89 (1H, m), 3.82 (1H, m), 3.73 (1H, m ), 3.68 (1H, d, J = 3.4Hz), 3.65-3.54 (4H, m), 3.49 (1H, d, J = 4.9Hz), 3.43 (1H, m), 3.35-3.25 (2H, m) , 2.80 (1H, br), 2.63 (1H, brs), 2.26-2.17 (2H, m), 1.91 (1H, m), 1.86-1.17 (21H, m), 1.43 (3H, s), 1.14 (1H , s), 1.12 (3H, s).

(Example 130)
{(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a, 8-dihydroxy-11a, 13a-dimethyloctadecahydro-1H -Phenanthro [2,1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 11aS, 11bR, 13aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a- Dimethylhexadecahydrooxyleno [8,8a] phenanthro [2,1-b] azepine-7 (1aH) -carboxylate Example 86 Compound (3.09 g) obtained in Step 7 and (R) -2,2 The title was prepared in the same manner as in Step 27 of Example 27 using 4-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate (9.76 g) and tetra-n-butylammonium iodide (0.252 g). Compound (3.91 g) was obtained as a colorless oil.
MS (ESI) m / z: 568 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.26 (5H, m), 5.07 (2H, s), 4.27 (1H, m), 4.04 (1H, dd, J = 8.3, 6.3Hz), 3.91 (1H , brs), 3.81-3.78 (2H, m), 3.67 (1H, dd, J = 9.8,4.9Hz), 3.52 (1H, dd, J = 9.8,5.9Hz), 3.17 (1H, m), 3.09 ( 1H, d, J = 2.9Hz), 2.38-0.86 (21H, m), 1.40 (3H, s), 1.33 (6H, s), 0.96 (3H, s).

(Process 2)
Benzyl (5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a, 8-dihydroxy-11a, 13a-dimethyloctadecahydro-1H -Phenanthuro [2,1-b] azepine-1-carboxylate Using the compound (3.91 g) obtained in Step 1 above, the title compound (1.53 g) was obtained as a white solid in the same manner as in Step 31 of Example 31. Got as.
MS (ESI) m / z: 546 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.06 (2H, brs), 3.96-3.84 (2H, m), 3.82 (1H, m), 3.71 (1H, m), 3.67 (1H, d, J = 3.9Hz), 3.63-3.53 (3H, m), 3.20 (1H, m), 2.63 (1H, brs), 2.52 (1H, br), 2.39 (1H, br), 2.22 ( 1H, m), 2.02 (1H, m), 1.91 (1H, m), 1.70-1.08 (22H, m), 1.08 (3H, s).

(Process 3)
Benzyl (5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a, 8- Dihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepine-1-carboxylate Using tetrahydrofuran (12 ml) as a solvent for the compound (1.53 g) obtained in the above step 2, Example 20 The title compound (1.98 g, containing impurities) was obtained as a white solid in the same manner as in Step 1 of Example 20.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.06 (2H, s), 4.26 (1H, m), 4.04 (1H, dd, J = 8.3, 6.8Hz), 3.89 (1H , brs), 3.79 (1H, m), 3.67-3.64 (2H, m), 3.59-3.48 (2H, m), 3.20 (1H, m), 2.68 (1H, s), 2.38 (1H, brs), 2.24 (1H, m), 1.90 (1H, m), 1.72-1.05 (19H, m), 1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s).

(Process 4)
(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a, 13a-dimethyl Octadecahydro-7aH-phenanthro [2,1-b] azepine-7a, 8-diol Using the compound obtained in Step 3 above (1.64 g), the title compound (1.64 g) was prepared in the same manner as in Step 2 of Example 20. 1.26 g) was obtained.

(Process 5)
[(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -7a, 8- Dihydroxy-11a, 13a-dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone obtained in step 4 above Using the compound (0.226 g) and the compound (0.0976 g) obtained in Step 23 of Example 23, the title compound (0.124 g) was obtained as a white solid in the same manner as in Step 129 of Example 129.
MS (ESI) m / z: 564 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.04 (1H, dd, J = 8.3,6.8Hz), 3.97-3.92 (2H, m), 3.78 (1H, m), 3.68-3.63 (2H, m), 3.58-3.49 (2H, m), 3.45-3.30 (3H, m), 2.68 (1H, m), 2.62 (1H, m), 2.23 (1H, m), 2.15 (1H, s ), 1.92-1.04 (25H, m), 1.52 (3H, s), 1.41 (3H, s), 1.33 (3H, s), 1.09 (3H, s).

(Process 6)
{(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a, 8-dihydroxy-11a, 13a-dimethyloctadecahydro-1H -Phenanthro [2,1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 using the compound (0.124 g) obtained in Step 5 above The title compound (0.071 g) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 524 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.98-3.92 (2H, m), 3.88 (1H, m), 3.81 (1H, m), 3.71 (1H, dd, J = 11.2,3.9Hz), 3.66 (1H , d, J = 3.4Hz), 3.63-3.54 (3H, m), 3.44-3.39 (2H, m), 3.34 (1H, m), 2.62 (1H, m), 2.22 (1H, m), 1.93- 0.84 (29H, m), 1.52 (3H, s), 1.09 (3H, s).

(Example 131)
{(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 8,8a , 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Example 38 Compound (1.79 g) obtained in Step 5 Was used to give the title compound (2.11 g) as a white solid in the same manner as in Example 19, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.38 (1H, m), 4.33 (1H, dd, J = 2.9,13.7Hz), 3.53 (1H, m), 3.39 (1H , d, J = 13.7Hz), 2.60 (1H, m), 2.38-2.30 (2H, m), 2.23 (1H, m), 1.91-1.23 (13H, m), 1.44 (3H, s), 1.13- 0.84 (4H, m), 0.99 (3H, s), 0.45 (1H, m).

(Process 2)
Benzyl (4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -4a, 6a-dimethyl-2-oxo-2,3,4,4a, 4b, 5,6,6a, 8,8a, 9,9a , 9b, 9c, 10,11-Hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Conducted using the compound (2.11 g) obtained in Step 1 above. The title compound (1.97 g) was obtained as a white solid in the same manner as in Example 12, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.75 (1H, s), 5.10 (1H, d, J = 12.2Hz), 5.06 (1H, d, J = 12.2Hz), 4.32 (1H, dd, J = 2,4,13.7Hz), 3.39 (1H, d, J = 13.7Hz), 2.68 (1H, m), 2.49-2.25 (5H, m), 2.02 (1H, m) , 1.88 (1H, d, J = 10.7Hz), 1.80 (1H, m), 1.73-1.58 (2H, m), 1.47 (3H, s), 1.41-1.25 (2H, m), 1.20-1.01 (3H , m), 1.17 (3H, s), 0.97 (1H, m), 0.88 (1H, m), 0.48 (1H, m).

(Process 3)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 8,8a, 9 , 9a, 9b, 9c, 10,11-Hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Using the compound (1.97 g) obtained in Step 2 above The title compound (1.98 g) was obtained in the same manner as in Example 19, Step 3.

(Process 4)
Benzyl (1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS) -1-hydroxy-3a, 5a-dimethylhexadecahydrocyclopropa [c] oxyleno [4a, 5] naphtho [2, 1-f] quinoline-6 (2H) -carboxylate Using the compound (1.98 g) obtained in Step 3 above, the title compound (1.73 g) was obtained as a white solid in the same manner as in Step 1 of Example 1. It was.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2Hz), 5.06 (1H, d, J = 12.2Hz), 4.32 (1H, dd, J = 2.9, 13.7Hz), 4.07 (1H, m), 3.39 (1H, d, J = 13.7Hz), 3.18 (1H, d, J = 4.4Hz), 2.63 (1H, m), 2.29-2.11 (2H , m), 1.90 (1H, d, J = 11.2Hz), 1.71 (1H, m), 1.58-1.48 (2H, m), 1.46-0.94 (11H, m), 1.44 (3H, s), 1.02 ( 3H, s), 0.87 (1H, m), 0.46 (1H, m).

(Process 5)
Benzyl (1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS) -1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy}- 3a, 5a-Dimethylhexadecahydrocyclopropa [c] oxyleno [4a, 5] naphtho [2,1-f] quinoline-6 (2H) -carboxylate Compound (1.00 g) obtained in Step 4 above and ( R) -2,2-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate (3.17 g) and tetra-n-butylammonium iodide (0.0818 g) using Example 27 Step 1 The title compound (0.522 g) was obtained as a white amorphous product by a method similar to that described above.
MS (ESI) m / z: 566 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.09-5.01 (2H, m), 4.32-4.24 (2H, m), 4.07-4.02 (1H, m), 3.84-3.78 ( 2H, m), 3.70-3.65 (1H, m), 3.55-3.50 (1H, m), 3.36 (1H, d, J = 13.2Hz), 3.10 (1H, d, J = 2.9Hz), 2.61-2.56 (1H, m), 2.19-2.08 (2H, m), 1.85 (1H, d, J = 10.7Hz), 1.67-0.88 (13H, m), 1.40 (3H, s), 1.40 (3H, s), 1.34 (3H, s), 0.98 (3H, s). 0.46-0.40 (1H, m), 0.44-0.42 (1H, m).

(Process 6)
Benzyl (1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Using the compound (0.522 g) obtained in Step 5 above, the title was prepared in the same manner as in Step 4 of Example 31. Compound (502 mg) was obtained.
MS (ESI) m / z: 544 (M + H) ^<+> .

(Process 7)
Benzyl (1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy}- 1,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate The compound (0.502 g) obtained in the above step 6 was used as a solvent. The title compound (0.226 g) was obtained as a white solid in the same manner as in Example 20, Step 1 using tetrahydrofuran (5 ml).
MS (ESI) m / z: 584 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.00 (2H, m), 4.32-4.23 (2H, m), 4.06-4.02 (1H, m), 3.81-3.77 ( 1H, m), 3.67-3.64 (2H, m), 3.58-3.48 (2H, m), 3.35 (1H, d, J = 13.2Hz), 2.70 (1H, brs), 2.61-2.56 (1H, m) 2.33-2.24 (1H, m), 1.98-1.89 (2H, m), 1.74-1.63 (3H, m), 1.44-1.02 (10H, m), 1.41 (3H, s), 1.39 (3H, s) 1.33 (3H, s), 1.11 (3H, s), 0.98-0.93 (1H, m), 0.85-0.80 (1H, m), 0.45-0.39 (1H, m).

(Process 8)
(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a , 6a-Dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinoline-1,11a-diol Example 20 Step 2 using the compound (0.226 g) obtained in Step 7 above The title compound (174 mg) was obtained by a method similar to that described above.
MS (ESI) m / z: 450 (M + H) ^<+> .

(Process 9)
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy}- 1,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] Methanone Using the compound obtained in Step 8 above (0.174 g) and the compound obtained in Example 23 Step 3 (0.101 g) in the same manner as in Example 129 Step 5, the title compound (217 mg) was converted to a white solid. Got as.
MS (ESI) m / z: 562 (M + H) ^<+> .

(Process 10)
{(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound obtained in the above Step 9 (0.217 g ) To give the title compound (0.15 g) as a white solid in the same manner as in Example 23, Step 5.
MS (ESI) m / z: 522 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.05-3.98 (2H, m), 3.97-3.92 (1H, m), 3.90-3.85 (1H, m), 3.84 to 3.78 (1H, m), 3.74 to 3.67 ( 2H, m), 3.65-3.54 (4H, m), 3.48-3.40 (3H, m), 2.84-2.79 (1H, m), 2.32-2.24 (1H, m), 2.00-1.93 (1H, m), 1.93-1.86 (2H, m), 1.75-0.79 (21H, m), 1.42 (3H, s), 1.11 (3H, s), 0.47-0.41 (1H, m).

(Example 132)
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -4a, 6a-dimethyl-2-{[(4-methylphenyl) sulfonyl] oxy} -1,2,3,4,4a, 4b, 5,6,6a, 8,8a, 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Example 131 steps Using the compound (1.00 g) obtained in 1, the title compound (1.36 g) was obtained in the same manner as in Example 61, Step 1.

(Process 2)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a- Dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 8,8a, 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1- f] Quinoline-7-carboxylate The title compound (0.619 g) was obtained as a pale yellow oil in the same manner as in Example 61, Step 2 using the compound (1.36 g) obtained in Step 1 above.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.24 (5H, m), 5.37-5.31 (1H, m), 5.10-5.01 (2H, m), 4.33-4.27 (1H, m), 4.25-4.20 ( 1H, m), 4.06-4.02 (1H, m), 3.74-3.69 (1H, m), 3.60-3.54 (1H, m), 3.45-3.40 (1H, m), 3.39-3.34 (1H, m), 3.21-3.12 (1H, m), 2.59-2.53 (1H, m), 2.40-2.27 (2H, m), 2.22-2.13 (1H, m), 1.91-0.82 (14H, m), 1.40 (3H, s ), 1.40 (3H, s), 1.34 (3H, s), 0.95 (3H, s). 0.44-0.38 (1H, m).

(Process 3)
Benzyl (1aS, 3aS, 5aS, 5bR, 8S, 11aR, 11bR, 11cR) -8-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -3a, 5b- Dimethylhexadecahydrocyclopropa [c] oxyleno [4,4a] naphtho [2,1-f] quinoline-3 (3aH) -carboxylate Example using the compound (0.619 g) obtained in Step 2 above In the same manner as in Step 2, the title compound (0.539 g) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 5.08 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 4.30 (1H, dd, J = 13.7, 2.4Hz), 4.23 (1H, m), 4.05 (1H, m), 3.70 (1H, m), 3.61-3.50 (2H, m), 3.42 (1H, m), 3.35 (1H, d, J = 13.2Hz), 2.97 (1H, d, J = 4.4Hz), 2.56 (1H, d, J = 11.7Hz), 2.21 (1H, m), 2.07-1.96 (2H, m), 1.86-0.81 ( 13H, m), 1.41 (3H, s), 1.37 (3H, s), 1.35 (3H, s), 1.03 (3H, s), 0.96 (1H, s), 0.43 (1H, m).

(Process 4)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a- Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Example 1 using the compound (0.539 g) obtained in Step 3 above The title compound (0.375 g) was obtained as a white solid by the same method as in Step 3.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.06 (1H, d, J = 12.2Hz), 5.02 (1H, d, J = 12.2Hz), 4.28 (1H, dd, J = 13.7, 2.4Hz), 4.23-4.18 (1H, m), 4.03 (1H, t, J = 7.3Hz), 3.74-3.67 (2H, m), 3.60-3.50 (1H, m), 3.45-3.32 ( 2H, m), 2.62-2.56 (1H, m), 1.94-0.92 (19H, m), 1.39 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 0.92 (3H, s) .0.84-0.78 (1H, m), 0.43-0.38 (1H, m).

(Process 5)
(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -4a, 6a -Dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinolin-11a-ol Using the compound (0.175 g) obtained in Step 4 above, the same procedure as in Step 20 of Example 20 Gave the title compound (134 mg).
MS (ESI) m / z: 434 (M + H) ^<+> .

(Process 6)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a- Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Step 5 Using the compound (0.134 g) obtained in Example 23 and the compound (0.0802 g) obtained in Example 23, Step 3, the title compound (0.100 g) was obtained as a white solid in the same manner as in Example 129, Step 5. .
MS (ESI) m / z: 546 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.23-4.18 (1H, m), 4.06-3.98 (3H, m), 3.94 (1H, dd, J = 10.3,2.4Hz), 3.73-3.67 (2H, m) , 3.60-3.50 (1H, m), 3.47-3.36 (3H, m), 2.84-2.78 (1H, m), 1.94-1.82 (4H, m), 1.76-0.92 (21H, m), 1.41 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.92 (3H, s). 0.87-0.82 (1H, m), 0.46-0.39 (1H, m).

(Process 7)
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound (0.100 g) obtained in Step 6 above The title compound (0.091 g) was obtained as a white solid by a method similar to that in Example 23, Step 5.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.83-3.77 (1H, m), 3.76-3.66 (2H, m), 3.65-3.59 ( 2H, m), 3.56-3.53 (1H, m), 3.51-3.39 (3H, m), 2.85-2.80 (1H, m), 2.57-2.53 (1H, m), 2.16-2.07 (1H, m), 1.94-1.84 (5H, m), 1.78-1.05 (17H, m), 1.42 (3H, s), 0.98-0.92 (2H, m), 0.88-0.83 (1H, m), 0.46-0.41 (1H, m ), 0.93 (3H, s).

FIG. 4 shows a powder X-ray diffraction pattern of the title compound, and Table 4 shows peaks having a relative intensity of 30 or more when the maximum peak intensity is 100 in FIG.

　(実施例133)
｛(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-ジヒドロキシプロポキシ]-11a-ヒドロキシ-4a,6a-ジメチルオクタデカヒドロ-7H-シクロプロパ[c]ナフト[2,1-f]キノリン-7-イル｝[(2R,5R)-5-フルオロテトラヒドロ-2H-ピラン-2-イル]メタノン

(Example 133)
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -11a- Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl ] Methanone The title compound (198 mg) was prepared in the same manner as in Example 129, Step 5, using the compound (0.153 g) obtained in Example 5, Step 5, and the compound (0.104 g) obtained in Example 126, Step 3. Was obtained as a white solid.
MS (ESI) m / z: 564 (M + H) ^<+> .

(Process 2)
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone Compound (0.198 Using g), the title compound (0.141 g) was obtained as a white solid in the same manner as in Example 23, Step 5.
MS (ESI) m / z: 524 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 47.3Hz), 4.13-4.05 (2H, m), 4.01-3.96 (1H, m), 3.83-3.77 (1H, m), 3.75 -3.67 (2H, m), 3.65-3.57 (2H, m), 3.56-3.41 (3H, m), 2.83-2.77 (1H, m), 2.63 (1H, s), 2.25-2.07 (3H, m) 1.93-0.81 (22H, m), 1.40 (3H, s), 0.93 (3H, s). 0.46-0.40 (1H, m).

FIG. 5 shows the powder X-ray diffraction pattern of the title compound, and Table 5 shows peaks having a relative intensity of 8 or more when the maximum peak intensity is 100 in FIG.

　(実施例134)
(2R)-テトラヒドロ-2H-ピラン-2-イル[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-トリヒドロキシ-4a,6a-ジメチルオクタデカヒドロ-7H-シクロプロパ[c]ナフト[2,1-f]キノリン-7-イル]メタノン

(Example 134)
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
Benzyl (1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2] , 1-f] quinoline-7-carboxylate Using the compound (18.8 g) obtained in Example 131, Step 4, the title compound (12.5 g) was obtained as a white solid in the same manner as in Example 31, Step 4. It was.
MS (ESI) m / z: 470 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2Hz), 5.05 (1H, d, J = 12.2Hz), 4.32 (1H, dd, J = 2.4,13.7Hz), 4.15 (1H, m), 3.55 (1H, t, J = 2.9Hz), 3.38 (1H, d, J = 13.2Hz), 2.61 (1H, m), 2.35 (1H, d , J = 2.9Hz), 2.27 (1H, m), 2.00-1.93 (2H, m), 1.82 (1H, d, J = 5.9Hz), 1.77-1.04 (12H, m), 1.42 (3H, s) 1.13 (3H, s), 1.10 (1H, s), 0.98 (1H, m), 0.85 (1H, m), 0.45 (1H, m).

(Process 2)
Benzyl (3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H-cyclopropa [c] [1, 3] Dioxolo [5,6] naphtho [2,1-f] quinoline-8-carboxylate Example 20 Step 1 using tetrahydrofuran (200 ml) as a solvent for the compound (12.5 g) obtained in Step 1 above. The title compound (12.2 g) was obtained as a white solid by a method similar to that described above.
MS (ESI) m / z: 510 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2Hz), 5.05 (1H, d, J = 12.2Hz), 4.34-4.29 (2H, m ), 3.82 (1H, d, J = 5.4Hz), 3.38 (1H, d, J = 13.2Hz), 2.62 (1H, m), 2.14 (1H, m), 2.00-1.92 (2H, m), 1.86 (1H, m), 1.74 (1H, m), 1.66-1.20 (9H, m), 1.52 (3H, s), 1.43 (3H, s), 1.32 (3H, s), 1.19 (1H, s), 1.15 (3H, s), 1.08 (1H, m), 0.99 (1H, m), 0.86 (1H, m), 0.45 (1H, m).

(Process 3)
(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -2,2,5a, 7a-tetramethyloctadecahydro-12aH-cyclopropa [c] [1,3] dioxolo [5 , 6] naphtho [2,1-f] quinolin-12a-ol Using the compound obtained in Step 2 above (10.8 g) and 20% palladium hydroxide as the catalyst, the same procedure as in Step 20 of Example 20 was performed. The title compound (7.62 g) was obtained.
MS (ESI) m / z: 376 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.32 (1H, m), 3.82 (1H, d, J = 5.4Hz), 3.29 (1H, dd, J = 9.0,14.4Hz), 3.08 (1H, dd, J = 2.9,14.4Hz), 2.13 (1H, m), 1.95-1.84 (2H, m), 1.67-0.94 (16H, m), 1.53 (3H, s), 1.33 (3H, s), 1.19 (3H, s), 1.00 (3H, s), 0.61 (1H, m), 0.48 (1H, m).

(Process 4)
[(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H-cyclopropa [c] [1, 3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound obtained in Step 3 above (4.5 g) Using the compound (2.3 g) obtained in Example 23, Step 3, the title compound (4.98 g) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 488 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.31 (1H, m), 4.06-4.02 (2H, m), 3.97 (1H, dd, J = 2.4,10.3Hz), 3.81 (1H, d, J = 5.4Hz ), 3.50-3.43 (2H, m), 2.85 (1H, m), 2.15 (1H, m), 1.97-1.08 (20H, m), 1.52 (3H, s), 1.46 (3H, s), 1.32 ( 3H, s), 1.19 (1H, s), 1.15 (3H, s), 0.99 (1H, m), 0.89 (1H, m), 0.47 (1H, m).

(Process 5)
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Using the compound (4.98 g) obtained in Step 4 above, the same procedure as in Example 26 Step 2 Gave the title compound (4.08 g) as a white solid.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.15 (1H, m), 4.06-4.01 (2H, m), 3.97 (1H, dd, J = 2.4,10.3Hz), 3.55 (1H, t, J = 2.9Hz ), 3.50-3.43 (2H, m), 2.84 (1H, m), 2.32 (1H, d, J = 2.4Hz), 2.28 (1H, m), 2.01-1.88 (3H, m), 1.79 (1H, d, J = 6.3Hz), 1.78-1.22 (15H, m), 1.45 (3H, s), 1.19-1.08 (2H, m), 1.13 (3H, s), 1.08 (1H, s), 0.99 (1H , m), 0.88 (1H, m), 0.46 (1H, m).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 6, and the peak having a relative intensity of 9 or more when the maximum peak intensity is 100 in FIG.

　(実施例135)
[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,3-ジフルオロ-6a,7,8-トリヒドロキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル][(2R)-テトラヒドロ-2H-ピラン-2-イル]メタノン

(Example 135)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
(3β, 16α) -3-[(4-Methoxybenzyl) oxy] -17-oxoandrost-5-en-16-yl acetate (3β, 16α) -16-hydroxy-3-[(4-methoxybenzyl ) Oxy] androst-5-en-17-one (10.7 g) was used to give the title compound (13.3 g) as a white solid in the same manner as in Example 31, Step 5.
MS (ESI) m / z: 467 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.27-7.23 (2H, m), 6.87-6.83 (2H, m), 5.42-5.38 (1H, m), 5.35-5.32 (1H, m), 4.47 (2H, s), 3.78 (3H, s), 3.28-3.20 (1H, m), 2.43-2.37 (1H, m), 2.27-2.22 (1H, m), 2.09 (3H, s). 2.09-2.00 (2H, m), 1.97-1.90 (1H, m), 1.87-1.80 (3H, m), 1.69-1.33 (7H, m), 1.06-0.95 (2H, m), 1.01 (3H, s), 0.96 (3H, s).

(Process 2)
(3β, 16α, 17Z) -17- (hydroxyimino) -3-[(4-methoxybenzyl) oxy] androst-5-en-16-yl acetate The compound (11.7 g) obtained in Step 1 above was Was used to give the title compound (12.1 g) in a manner similar to Example 36, Step 5.

(Process 3)
(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-[(4-methoxybenzyl) oxy] -10a, 12a-dimethyl-2-oxo-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-3-yl acetate The compound (12.1 g) obtained in Step 2 above To a tetrahydrofuran (100 ml) solution was added propylphosphonic acid anhydride (cyclic trimer) (50% ethyl acetate solution, 7.47 ml), and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and the organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, pyridine (50 ml) and acetic anhydride (25 ml) were added to the resulting residue, and the mixture was stirred at room temperature. Toluene was added to the reaction mixture, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane, and washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to obtain the title compound (1.31 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.25-7.22 (2H, m), 6.87-6.83 (3H, m), 5.74 (1H, s), 5.34-5.30 (2H, m), 4.46 (2H, s) 3.77 (3H, s), 3.30-3.19 (1H, m), 2.42-0.84 (17H, m) .2.11 (2H, s), 1.16 (3H, s), 0.96 (3H, s).

(Process 4)
(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-[(4-methoxybenzyl) oxy] -10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,7, 8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinolin-3-ol Using the compound (1.31 g) obtained in Step 3 above, Example The title compound (1.16 g) was obtained by a method similar to that in 36-step 7.

(Process 5)
Benzyl (3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3-hydroxy-8-[(4-methoxybenzyl) oxy] -10a, 12a-dimethyl-3,4,4a, 4b, 5,7 , 8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Compound (1.16 g) obtained in Step 4 above Was used to give the title compound (0.96 g) as a white solid in the same manner as in Example 19, Step 1.
MS (ESI) m / z: 560 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (7H, m), 6.87-6.83 (2H, m), 5.32-5.28 (1H, m), 5.08-5.05 (2H, m), 4.46 (2H, s), 4.06-3.99 (1H, m), 3.87 (1H, dd, J = 13.2,4.4Hz), 3.77 (3H, s), 3.32-3.19 (2H, m), 2.97-2.94 (1H, m) , 2.42-2.36 (1H, m), 2.25-2.17 (1H, m), 2.14-2.06 (1H, m), 1.95-1.88 (1H, m), 1.85-1.22 (11H, m), 1.27 (3H, s), 1.04-0.96 (2H, m), 0.94 (3H, s).

(Process 6)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8-[(4-methoxybenzyl) oxy] -10a, 12a-dimethyl-3-oxo-3,4,4a, 4b, 5,7,8 , 9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate dichloromethane (1.2 g) of the compound obtained in step 5 above ( 20 ml), 4-methylmorpholine N-oxide (0.38 g) and tetrapropylammonium perruthenate (0.075 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was directly purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.455 g) as a white solid.
MS (ESI) m / z: 558 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.22 (7H, m), 6.87-6.83 (2H, m), 5.32-5.28 (1H, m), 5.11-5.04 (2H, m), 4.46 (2H, s), 4.42 (1H, d, J = 17.6Hz), 3.82 (1H, d, J = 17.6Hz), 3.77 (3H, s), 3.26-3.20 (1H, m), 3.09-3.04 (1H, m ), 2.53 (1H, dd, J = 19.0,3.4Hz), 2.43-2.37 (1H, m), 2.27-2.06 (3H, m), 1.96-1.90 (1H, m), 1.89-1.75 (2H, m ), 1.72-1.65 (1H, m), 1.60-1.22 (5H, m), 1.39 (3H, s), 1.09-0.94 (2H, m), 0.96 (3H, s).

(Process 7)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-8-[(4-methoxybenzyl) oxy] -10a, 12a-dimethyl-3,4,4a, 4b, 5,7 , 8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate of the compound (0.455 g) obtained in step 6 above (Diethylamino) sulfur trifluoride (2.14 ml) was added to a dichloromethane (8.1 ml) solution, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compound (0.288 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.23 (7H, m), 6.87-6.83 (2H, m), 5.34-5.28 (1H, m), 5.11-5.07 (2H, m), 4.47 (2H, s), 4.13-4.03 (1H, m), 3.78 (3H, s), 3.63-3.49 (1H, m), 3.27-3.21 (1H, m), 3.29-3.19 (1H, m), 2.99-2.92 ( 1H, m), 2.44-2.37 (1H, m), 2.29-1.17 (12H, m), 1.08-0.99 (2H, m), 1.35 (3H, s), 0.96 (3H, s).

(Process 8)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a , 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate To a solution of the compound (0.288 g) obtained in step 7 above in dichloromethane (5 ml), 1 , 3-Dimethoxybenzene (0.194 ml) and trifluoromethanesulfonic acid (0.0218 ml) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compound (0.121 g) as a colorless oil.
MS (ESI) m / z: 460 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.44-7.14 (5H, m), 5.33-5.30 (1H, m), 5.11-5.06 (2H, m), 4.12-4.03 (1H, m), 3.60-3.48 ( 2H, m), 2.99-2.93 (1H, m), 2.34-2.15 (3H, m), 2.11-2.05 (1H, m), 1.85-1.20 (11H, m), 1.09-1.00 (2H, m), 1.35 (3H, s), 0.95 (3H, s).

(Process 9)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -3,3-difluoro-10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 12, Step 1, using the compound (0.121 g) obtained in Step 8 above. The title compound (0.077 g) was obtained as a white solid.
MS (ESI) m / z: 458 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.72 (1H, s), 5.09 (2H, s), 4.12-4.05 (1H, m), 3.54 (1H, m), 3.05 -2.98 (1H, m), 2.43-2.24 (5H, m), 2.05-1.99 (1H, m), 1.98-1.92 (1H, m), 1.86-1.77 (1H, m), 1.72-1.52 (3H, m), 1.46-1.22 (3H, m), 1.38 (3H, s), 1.14 (3H, s), 1.09-1.01 (2H, m).

(Process 10)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a , 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 Step 3 using the compound (0.0770 g) obtained in Step 9 above The title compound (77 mg) was obtained by a method similar to that described above.

(Process 11)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -9,9-difluoro-2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2, 1-f] quinoline-7 (5H) -carboxylate Using the compound (77 mg) obtained in Step 10 above, the title compound (80 mg) was obtained in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 476 (M + H) ^<+> .

(Process 12)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -carboxylate Using the compound (80 mg) obtained in Step 11 above, the title compound (0.063 g) was obtained as a white solid in the same manner as in Example 31, Step 4.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.08 (2H, s), 4.16-4.03 (2H, m), 3.59-3.45 (2H, m), 2.97-2.90 (1H, m), 2.33-2.15 (3H, m), 1.81-1.15 (15H, m), 1.33 (3H, s), 1.09 (3H, s), 0.93 (1H, s).

(Process 13)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -10,10-difluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5 , 6] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Example 20 Step 1 was carried out using tetrahydrofuran (1.3 ml) as a solvent for the compound (0.0630 g) obtained in Step 12 above. In a similar manner, the title compound (0.083 g) was obtained as a white solid.
MS (ESI) m / z: 534 (M + H) ^<+> .

(Process 14)
(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -10,10-difluoro-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [ 2,1-f] quinolin-13a (4H) -ol The title compound (62.3 mg) was obtained in the same manner as in Example 2, Step 2 using the compound (0.0830 g) obtained in Step 13 above.

(Process 15)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -10,10-difluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5 , 6] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Performed with compound (0.0623 g) obtained in step 14 above Using the compound (0.0406 g) obtained in Example 23, Step 3, the title compound (0.023 g) was obtained as a white solid in the same manner as in Example 129, Step 5.
MS (ESI) m / z: 512 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.31-4.25 (1H, m), 4.03-3.93 (3H, m), 3.76 (1H, d, J = 5.4Hz), 3.60-3.51 (1H, m), 3.47 -3.41 (1H, m), 3.17-3.12 (1H, m), 2.34-2.22 (1H, m), 2.15 (1H, s), 2.11-2.02 (1H, m), 1.91-1.05 (19H, m) 0.88-0.82 (1H, m), 1.49 (3H, s), 1.39 (3H, s), 1.29 (3H, s), 1.10 (3H, s).

(Process 16)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,3-difluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The same procedure as in Example 23, Step 5, using the compound obtained in Step 15 (0.0230 g) Gave the title compound (0.021 g) as a white solid.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.17-4.08 (1H, m), 4.04-3.93 (3H, m), 3.61-3.48 (2H, m), 3.47-3.41 (1H, m), 3.18-3.11 ( 1H, m), 2.32-2.18 (3H, m), 1.91-1.21 (21H, m), 1.38 (3H, s) .1.09 (3H, s), 0.90 (1H, s).

(Example 136)
[(4aS, 4bR, 6aR, 8R, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 6aR, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Examples Using the compound (0.500 g) obtained in 122 Step 2, the title compound (0.516 g) was obtained as a white solid in the same manner as in Example 135, Step 6.
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.10-5.04 (2H, m), 3.80-3.73 (1H, m), 3.35-3.27 (1H, m), 3.08-3.02 ( 1H, m), 2.65 (1H, d, J = 15.1Hz), 2.38-2.33 (2H, m), 2.08 (1H, d, J = 15.6Hz), 1.92-1.11 (17H, m), 1.34 (3H , s), 1.11 (3H, s).

(Process 2)
Benzyl (4aS, 4bR, 6aR, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-8-{[tri (propan-2-yl) silyl] oxy} -3,4,4a, 4b, 5,6,6a, 7,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Compound obtained in Step 1 above (0.950 To a solution of g) in dichloromethane (10 ml) were added triethylamine (0.449 ml) and trifluoromethanesulfonic acid triisopropyl ester (0.697 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the title compound (1.29 g).

(Process 3)
Benzyl (4aS, 4bR, 6aR, 9S, 10aR, 10bS, 12aS) -9-fluoro-6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Carboxylate (β-Fluorine)
And benzyl (4aS, 4bR, 6aR, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -Carboxylate (α-Fluorine)
To a solution of the compound obtained in Step 2 above (1.29 g) in N, N-dimethylformamide (30 ml), N-fluoro-N ′-(chloromethyl) triethylenediaminebistetrafluoroborate (0.918 g) was added, and After stirring for 30 minutes, triethylamine (2.6 ml) was added, and the mixture was further stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (β-fluorine) (0.225 g) and the title compound (α -Fluoride) (0.316 g) was obtained as a pale yellow solid.
β-Fluorine: (Rf = higher: low polarity)
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.06 (2H, s), 5.09-4.96 (1H, m), 3.78-3.72 (1H, m), 3.36-3.27 (1H, m), 3.10-3.04 (1H, m), 2.90-2.85 (1H, m), 2.36-2.15 (2H, m), 1.95-1.02 (16H, m), 1.33 (3H, s), 1.06 (3H, s).
α-Fluorine: (Rf = lower: high polarity)
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.22 (5H, m), 5.06 (2H, s), 5.09-4.91 (1H, m), 3.79-3.73 (1H, m), 3.35-3.27 (1H, m), 3.10-3.04 (1H, m), 2.78-2.73 (1H, m), 2.27-2.20 (3H, m), 2.10-2.02 (2H, m), 1.81-1.10 (13H, m), 1.34 ( 3H, s), 1.17 (3H, s).

(Process 4)
Benzyl (4aS, 4bR, 6aR, 8R, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Carboxylate To a solution of the compound (α-fluoride) obtained in Step 3 above (0.316 g) and cerium chloride heptahydrate (0.772 g) in methanol (7 ml) at −78 ° C., sodium borohydride ( 0.0392 g) was added, and the mixture was stirred for 20 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Pyridine (2 ml) and acetic anhydride (1 ml) were added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was stirred at room temperature for 2 hours. 4-Dimethylaminopyridine (0.0929 g) was added, and the mixture was further stirred for 1 day. Toluene was added, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane, and then washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to obtain the title compound (0.133 g) as a white solid.
MS (ESI) m / z: 460 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.08-5.05 (2H, m), 4.75 (1H, m), 4.29 (1H, m), 3.75 (1H, m), 3.30 (1H, m), 3.04 (1H, m), 2.73 (1H, m), 4.29 (1H, m), 3.75 (1H, m), 3.30 (1H, m), 3.04 (1H, m), 2.73 ( 1H, m), 1.89-1.06 (14H, m) .1.32 (3H, s), 0.88 (3H, s).

(Process 5)
(4aS, 4bR, 6aR, 8R, 9R, 10aR, 10bS, 12aS) -9-Fluoro-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 8 (2H) -diol Using the compound (0.133 g) obtained in 4, the title compound (94 mg) was obtained in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 326 (M + H) ^<+> .

(Process 6)
[(4aS, 4bR, 6aR, 8R, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Step 5 above (0.0941 g) and the compound obtained in Step 23 of Example 23 (0.0752 g) The title compound (50 mg) was obtained as a white solid by a method similar to that in Example 129, Step 5.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.75 (1H, m), 4.32-4.22 (2H, m), 4.03-3.93 (2H, m), 3.53 (1H, m), 3.42 (1H, m), 3.31 -3.25 (2H, m), 2.69 (1H, m), 1.90-1.10 (24H, m), 1.41 (3H, s), 0.88 (3H, s).

(Example 137)
[(4aS, 4bR, 6aR, 8R, 9S, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 6aR, 8R, 9S, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Carboxylate The title compound (0.226 g) was obtained in the same manner as in Example 19, Step 3 using the compound (β-fluorine) (0.225 g) obtained in Step 136 of Example 136.
MS (ESI) m / z: 460 (M + H) ^<+> .

(Process 2)
(4aS, 4bR, 6aR, 8R, 9S, 10aR, 10bS, 12aS) -9-fluoro-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 8 (2H) -diol The title compound (27.6 mg) was obtained in the same manner as in Step 2 of Example 20 using the compound (0.0390 g) obtained in 1.
MS (ESI) m / z: 326 (M + H) ^<+> .

(Process 3)
[(4aS, 4bR, 6aR, 8R, 9S, 10aR, 10bS, 12aS) -9-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Using the compound obtained in Step 2 above (0.0276 g) and the compound obtained in Example 23 Step 3 (0.0221 g) The title compound (0.007 g) was obtained as a white solid by a method similar to that in Example 129, Step 5.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.75 (1H, m), 4.04-3.92 (3H, m), 3.58-3.25 (6H, m), 2.09 (1H, m), 1.93-0.97 (23H, m) 1.41 (3H, s), 1.01 (3H, d, J = 2.4Hz).

(Example 138)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -7-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -8- (acetyloxy) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 31 Step 5 using the compound (10.0 g) obtained in Step 3 of Example 19 and In a similar manner, the title compound (11.2 g) was obtained as a colorless oil.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.23-5.17 (2H, m), 5.09-5.03 (2H, m), 3.74 (1H, m), 3.30 (1H, m) , 3.03 (1H, m), 2.18-0.79 (21 H, m), 1.34 (3H, s), 1.00 (3H, s).

(Process 2)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2- (acetyloxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f ] Quinoline-7 (5H) -carboxylate (β-epoxide)
And benzyl (1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS) -2- (acetyloxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1- f] Quinoline-7 (5H) -carboxylate (α-epoxide)
Using the compound (11.2 g) obtained in Step 1 above, the title compound (β-epoxide) (2.4 g) and the title compound (α-epoxide) (6.4 g) were prepared in the same manner as in Step 1 of Example 1. Each was obtained as a white solid.
β-epoxide
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.10 (1H, m), 5.08-5.03 (2H, m), 3.76 (1H, m), 3.33 (1H, m), 3.15 (1H, d, J = 3.4Hz), 3.05 (1H, m), 2.07 (3H, s), 2.07-0.89 (15H, m), 2.07 (3H, s), 1.34 (3H, s), 0.98 ( 3H, s).
α-epoxide
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.05 (2H, s), 4.93 (1H, t, J = 8.8Hz), 3.76 (1H, m), 3.31 (1H, m ), 3.04 (1H, m), 2.87 (1H, s), 2.05 (3H, s). 2.07-1.01 (18H, m), 1.35 (3H, s), 1.05 (3H, s).

(Process 3)
Benzyl (1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS) -2-hydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline- 7 (5H) -carboxylate To a solution of the compound (α-epoxide) obtained in Step 2 above (5.78 g) in tetrahydrofuran (30 ml) -methanol (30 ml), 2N aqueous sodium hydroxide solution (9.00 ml) was added, Stir at room temperature. The reaction mixture was neutralized with 2N hydrochloric acid, and concentrated under reduced pressure, and the resulting residue was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to obtain the title compound (5.71 g) as a white solid.
MS (ESI) m / z: 440 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.05 (2H, s), 3.97 (1H, m), 3.76 (1H, m), 3.31 (1H, m), 3.03 (1H , m), 2.90 (1H, s), 2.04-1.96 (2H, m), 1.91-1.77 (3H, m), 1.69-1.02 (14H, m), 1.34 (3H, s), 1.04 (3H, s) ).

(Process 4)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8- (acetyloxy) -7-fluoro-6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -carboxylate Obtained in Step 3 above after stirring a solution of hafnium tetrafluoride (1.16 g) and tetrabutylammonium dihydrogen trifluoride (1.37 g) in tetrahydrofuran (9 ml) at room temperature for 10 minutes The compound (1.00 g) was added and stirred at the same temperature for 16 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane]. Pyridine (4 ml) and acetic anhydride (2 ml) were added to the resulting mixture of 4-fluoride and 5-fluoride, and the mixture was stirred at room temperature for 3 hours, and then toluene was added and the mixture was concentrated under reduced pressure. The obtained residue was diluted with dichloromethane and washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to obtain the title compound (0.162 g) as a white solid.
MS (ESI) m / z: 502 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.26 (1H, m), 5.10-5.03 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.31 (1H, m), 3.02 (1H, m), 2.20-1.04 (19H, m), 2.07 (3H, s), 1.32 (3H, s), 1.02 (3H, d, J = 3.4 Hz).

(Process 5)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -7-Fluoro-6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl acetate Using the compound (0.162 g) obtained in 4, the title compound (119 mg) was obtained in the same manner as in Example 2, Step 2.
MS (ESI) m / z: 368 (M + H) ^<+> .

(Process 6)
(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -7-Fluoro-6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] Octadecahydronaphtho [2,1-f] quinolin-8-yl acetate Example using the compound (0.119 g) obtained in Step 5 above and the compound (0.0841 g) obtained in Example 23 Step 3 In the same manner as in Step 129, the title compound (0.164 g) was obtained as a white solid.
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 4.34 (1H, m), 4.03-3.91 (2H, m), 3.54 (1H, m), 3.41 (1H, m), 3.34-3.22 (2H, m), 2.07 (3H, s), 2.20-1.14 (25H, m), 1.40 (3H, s), 1.02 (3H, d, J = 2.9 Hz).

(Process 7)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -7-fluoro-6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 26 using tetrahydrofuran (8 ml) and dichloromethane (2 ml) as a solvent for the compound (0.0850 g) obtained in Step 6 above. The title compound (0.073 g) was obtained as a white solid by the same method as in Step 2.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.24 (1H, m), 4.13-3.98 (2H, m), 3.95 (1H, m), 3.54 (1H, m), 3.41 (1H, m), 3.33-3.23 (2H, m), 2.15 (1H, m), 1.90-1.14 (25H, m), 1.40 (3H, s) .0.99 (3H, d, J = 2.9 Hz).

(Example 139)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1aS, 3aS, 5aS, 5bR, 8S, 9aR, 10aS, 11aR, 11bR, 11cR) -8-hydroxy-3a, 5b-dimethylhexadecahydrocyclopropa [c] oxyleno [4,4a] naphtho [2, 1-f] quinoline-3 (3aH) -carboxylate Using the compound (4.00 g) obtained in Example 131, Step 1, the title compound (4.15 g) was obtained in the same manner as in Example 1, Step 2. .
MS (ESI) m / z: 452 (M + H) ^<+> .

(Process 2)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinoline-7-carboxylate Using the compound (4.15 g) obtained in Step 1 above, the title compound (2.06 g) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.09-5.01 (2H, m), 4.29 (1H, dd, J = 13.7,2.4Hz), 4.07 (1H, m), 3.36 (1H, d, J = 13.2Hz), 2.59 (1H, m), 1.94 (1H, m), 1.89-1.80 (2H, m), 1.78-0.89 (17H, m), 1.39 (3H, s), 0.94 (3H, s), 0.82 (1H, m), 0.41 (1H, m).

(Process 3)
(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -4a, 6a-dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinoline-2,11a-diol Using the compound (0.200 g) obtained in the above Step 2, the title compound (141 mg) was obtained in the same manner as in Example 20, Step 2.
MS (ESI) m / z: 320 (M + H) ^<+> .

(Process 4)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (0.141 g) obtained in Step 3 above and compound (0.115 g) obtained in Step 23 of Example 23 Was used to give the title compound (0.137 g) as a white solid in the same manner as in Example 129, Step 5.
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.12-3.98 (3H, m), 3.95 (1H, m), 3.48-3.39 (2H, m), 2.82 (1H, m), 1.93-1.81 (4H, m) 1.76-1.06 (21H, m), 1.42 (3H, s), 0.94 (3H, s). 0.95 (1H, m), 0.85 (1H, m), 0.43 (1H, m).

(Example 140)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone Compound obtained in Example 139 Step 3 (141 mg) and Example 126 obtained in Step 3 Using the compound (0.131 g), the title compound (0.072 g) was obtained as a white solid in the same manner as in Step 129 of Example 129.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.60 (1H, m), 4.16-4.05 (3H, m), 4.01 (1H, m), 3.60 (1H, dd, J = 12.4,35.9Hz), 3.46 (1H , d, J = 13.2Hz), 2.83 (1H, m), 2.26-2.10 (2H, m), 1.95 (1H, d, J = 10.7Hz), 1.91-0.94 (20H, m), 1.43 (3H, s), 0.97 (3H, s), 0.90-0.86 (2H, m), 0.46 (1H, m).

(Example 141)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -11a-hydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1- f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -11a-hydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1- f] Quinoline-7-carboxylate Using the compound (1.00 g) obtained in Example 139, Step 2, the title compound (0.693 g) was obtained as a white solid in the same manner as in Example 27, Step 1.
MS (ESI) m / z: 468 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.07 (1H, d, J = 12.2Hz), 5.03 (1H, d, J = 12.2Hz), 4.29 (1H, dd, J = 13.4,2.7Hz), 3.61-3.55 (1H, m), 3.36 (1H, d, J = 12.7Hz), 3.32 (3H, s), 2.62-2.57 (1H, m), 1.97-1.82 (3H, m), 1.75-0.86 (16H, m), 1.39 (3H, s), 0.93 (3H, s). 0.84-0.79 (1H, m), 0.44-0.38 (1H, m).

(Process 2)
(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-methoxy-4a, 6a-dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinoline-11a -Ol Using the compound (0.150 g) obtained in Step 1 above, the title compound (133 mg) was obtained in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 334 (M + H) ^<+> .

(Process 3)
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -11a-hydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1- f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The compound obtained in Step 2 above (0.107 g) and the compound obtained in Step 23 of Example 23 (0.0836 g) ) To give the title compound (0.132 g) as a white solid in the same manner as in Example 129, step 5.
MS (ESI) m / z: 446 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.61-3.54 (1H, m), 3.48-3.39 (2H, m), 3.32 (3H, s), 2.84-2.79 (1H, m), 1.96-1.83 (4H, m), 1.74-0.93 (21H, m), 1.42 (3H, s), 0.93 (3H, s) .0.87-0.82 (1H, m), 0.46-0.40 (1H, m).

(Example 142)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -11a-hydroxy-2-methoxy-4a , 6a-Dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -11a-hydroxy-2-methoxy-4a , 6a-Dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Example 141 In step 3 with the compound (0.143 g) obtained in step 2 Using the obtained compound (0.127 g), the title compound (0.161 g) was obtained as a white solid in the same manner as in Step 5 of Example 129.
MS (ESI) m / z: 464 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 46.9Hz), 4.14-4.05 (2H, m), 4.00-3.96 (1H, m), 3.63-3.51 (2H, m), 3.46 -3.41 (1H, m), 3.32 (3H, s) .2.83-2.77 (1H, m), 2.24-2.08 (2H, m), 1.95-0.81 (22H, m), 1.40 (3H, s), 0.93 (3H, s), 0.46-0.40 (1H, m).

(Example 143)
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS) -1-methoxy-3a, 5a-dimethylhexadecahydrocyclopropa [c] oxyleno [4a, 5] naphtho [2, 1-f] quinoline-6 (2H) -carboxylate Using the compound (1.00 g) obtained in Example 131, Step 4, the title compound (0.849 g) was obtained as a colorless oil in the same manner as in Example 27, Step 1. Obtained as a thing.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.23 (5H, m), 5.07 (1H, d, J = 12.2Hz), 5.03 (1H, d, J = 12.2Hz), 4.29 (1H, m), 3.65 (1H, m), 3.42 (3H, s), 3.36 (1H, d, J = 13.2Hz), 3.12 (1H, d, J = 3.4Hz), 2.60 (1H, m), 2.21-2.10 (2H , m), 1.86 (1H, d, J = 10.7Hz), 1.67 (1H, m), 1.56-0.93 (12H, m), 1.41 (3H, s), 0.99 (3H, s). 0.84 (1H, m), 0.43 (1H, m).

(Process 2)
Benzyl (1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinoline-7-carboxylate Using the compound (0.849 g) obtained in Step 1 above, the title compound (0.717 g) was obtained as a white solid in the same manner as in Example 31, Step 4. .
MS (ESI) m / z: 484 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.21 (5H, m), 5.06 (1H, d, J = 12.7Hz), 5.02 (1H, d, J = 12.7Hz), 4.29 (1H, dd, J = 13.7, 2.4Hz), 3.68-3.62 (2H, m), 3.38-3.34 (1H, m), 3.37 (3H, s), 2.58 (1H, m), 2.32-2.23 (2H, m), 1.99- 1.90 (2H, m), 1.73-0.94 (14H, m), 1.39 (3H, s), 1.11 (3H, s), 0.83 (1H, m), 0.42 (1H, m).

(Process 3)
(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-methoxy-4a, 6a-dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinoline -1,11a-diol The title compound (145 mg) was obtained in the same manner as in Step 20 of Example 20 using the compound (0.200 g) obtained in Step 2 above.
MS (ESI) m / z: 350 (M + H) ^<+> .

(Process 4)
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (0.145 g) obtained in Step 3 above and obtained in Step 3 of Example 23 Using the compound (0.108 g), the title compound (0.135 g) was obtained as a white solid in the same manner as in Step 129 of Example 129.
MS (ESI) m / z: 462 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.68-3.61 (2H, m), 3.47-3.36 (2H, m), 3.37 (3H, s) .2.84-2.78 (1H, m), 2.32-2.23 (2H, m), 1.99-1.85 (3H, m), 1.78-1.03 (18H, m), 1.42 (3H, s), 1.11 (3H, s), 0.99-0.94 (1H, m), 0.88-0.83 (1H, m), 0.47-0.41 (1H, m).

(Example 144)
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone Example 143 Compound (0.145 g) obtained in Step 3 and Example Using the compound (0.123 g) obtained in 126 Step 3, the title compound (0.176 g) was obtained as a white solid in the same manner as in Example 129, Step 5.
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 47.3Hz), 4.14-4.06 (2H, m), 4.00-3.96 (1H, m), 3.68-3.51 (3H, m), 3.46 -3.42 (1H, m), 3.37 (3H, s), 2.83-2.77 (1H, m), 2.32-2.07 (3H, m), 1.99-1.88 (2H, m), 1.82-1.02 (16H, m) , 1.41 (3H, s), 1.11 (3H, s), 0.99-0.94 (1H, m), 0.88-0.83 (1H, m), 0.47-0.42 (1H, m).

(Example 145)
(2R) -Tetrahydro-2H-pyran-2-yl [(3R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,6a, 7,8-tetrahydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(3β, 16α, 17Z) -17- (Hydroxyimino) androst-5-ene-3,16-diyl diacetate (3β, 16α) -17-oxoandrost-5-ene-3,16-diyldi The title compound (21.7 g) was obtained in the same manner as in Example 36, step 5 using acetate (20.9 g).

(Process 2)
(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-2-oxo-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11,12,12a-Hexadecahydronaphtho [2,1-f] quinoline-3,8-diyl diacetate Using the compound obtained in Step 1 above (21.7 g), Example 36 Step 3 and The title compound (2.24 g, containing impurities) was obtained by a similar procedure.

(Process 3)
(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-1,2,3,4,4a, 4b, 5,7,8,9,10,10a, 10b, 11, 12,12a-Hexadecahydronaphtho [2,1-f] quinoline-3,8-diol The title compound was prepared in the same manner as in Example 36, step 7 using the compound (3.5 g) obtained in Step 2 above. (2.7 g) was obtained.

(Process 4)
Benzyl (3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3,8-dihydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,7,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 19, Step 1 using the compound (2.7 g) obtained in Step 3 above. The title compound (0.581 g) was obtained as a white solid by the above procedure.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.26 (5H, m), 5.38-5.30 (1H, m), 5.14-5.05 (2H, m), 4.10-4.02 (1H, m), 3.92-3.86 ( 1H, m), 3.58-3.44 (1H, m), 3.34-3.25 (1H, m), 3.03-2.95 (1H, m), 2.34-2.28 (1H, m), 2.25-2.10 (2H, m), 1.88-1.81 (2H, m), 1.74-1.25 (11H, m), 1.30 (3H, s), 1.12-0.94 (2H, m), 0.97 (3H, s).

(Process 5)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-3,8-dioxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound obtained in Step 4 above (0.581 g), the title was prepared in the same manner as in Step 1 of Example 12. Compound (0.166 g) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.24 (5H, m), 5.73 (1H, s), 5.12-5.03 (2H, m), 4.43 (1H, d, J = 17.6Hz), 3.81 (1H , d, J = 17.6Hz), 3.17-3.11 (1H, m), 2.63-2.58 (1H, m), 2.45-2.15 (5H, m), 2.07-1.94 (2H, m), 1.87-1.80 (1H m), 1.74-1.61 (3H, m), 1.56-0.97 (4H, m), 1.42 (3H, s), 1.15 (3H, s).

(Process 6)
Benzyl (4aS, 4bR, 8S, 10aR, 10bS, 12aS) -3,8-dihydroxy-10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Using the compound (0.166 g) obtained in Step 5 above, the same procedure as Example 19 Step 3 Gave the title compound (0.167 g).

(Process 7)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2,9-dihydroxy-4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] Quinoline-7 (5H) -carboxylate The title compound (0.174 g) was obtained in the same manner as in Step 1 of Example 1 using the compound (0.167 g) obtained in Step 6 above.

(Process 8)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,6a, 7,8-tetrahydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -Carboxylate The title compound (0.180 g) was obtained in the same manner as in Example 31, Step 4 using the compound (0.174 g) obtained in Step 7 above.

(Process 9)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -10,13a-dihydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinoline-8 (4H) -carboxylate The title compound was prepared in the same manner as in Example 20, Step 1 using tetrahydrofuran (4 ml) as a solvent for the compound (0.180 g) obtained in Step 8 above. Compound (0.098 g) was obtained as a white solid.
Main product (α-alcohol)
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.27 (5H, m), 5.09-5.03 (2H, m), 4.30-4.26 (1H, m), 4.05-3.97 (1H, m), 3.90-3.84 ( 1H, m), 3.78-3.74 (1H, m), 3.30-3.23 (1H, m), 2.97-2.92 (1H, m), 2.15-1.10 (18H, m), 1.49 (3H, s), 1.29 ( 3H, s), 1.27 (3H, s), 1.10 (3H, s).

(Process 10)
Benzyl (3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS) -10- (benzoyloxy) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] Dioxolo [5,6] naphtho [2,1-f] quinoline-8 (4H) -carboxylate (α-benzoate)
And benzyl (3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS) -10- (benzoyloxy) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3 ] Dioxolo [5,6] naphtho [2,1-f] quinoline-8 (4H) -carboxylate (β-benzoate)
To a solution of the compound obtained in Step 9 (913 mg) in dichloromethane (17.8 ml) -pyridine (5.92 ml) was added benzoyl chloride (0.413 ml) at 0 ° C. and stirred at the same temperature for 4 hours. Benzoyl chloride (0.413 ml) was added, and the mixture was further stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / dichloromethane] to give the title compounds as a mixture. The obtained mixture was purified again by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (α-benzoate) (790 mg) and the title compound (β-benzoate) (188 mg) as white solids, respectively.
α-benzoate
MS (ESI) m / z: 618 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 8.01 (2H, d, J = 7.8Hz), 7.57 (1H, t, J = 7.6Hz), 7.44 (2H, t, 7.8Hz), 7.35-7.26 (5H, m), 5.23-5.18 (1H, m), 5.10 (1H, d, J = 12.2Hz), 5.05 (1H, d, J = 12.2Hz), 4.33-4.28 (1H, m), 4.08 (1H, dd , J = 13.4,4.6Hz), 3.79 (1H, d, J = 5.4Hz), 3.57 (1H, dd, J = 12.9,10.0Hz), 2.99 (1H, d, J = 12.7Hz), 2.11-2.04 (1H, m), 1.94-1.85 (4H, m), 1.72-1.16 (12H, m), 1.52 (3H, s), 1.38 (3H, s), 1.31 (3H, s), 1.14 (3H, s ).
β-benzoate
¹ H-NMR (CDCl ₃ ) δ: 7.97-7.95 (2H, m), 7.58-7.55 (1H, m), 7.43-7.40 (2H, m), 7.27-7.22 (5H, m), 5.26-5.23 ( 1H, m), 5.12 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 4.33-4.29 (1H, m), 4.19 (1H, dd, J = 14.4,3.7Hz ), 3.80 (1H, d, J = 4.9Hz), 3.56 (1H, dd, J = 14.4, 2.7Hz), 3.05-3.01 (1H, m), 2.47-2.41 (1H, m), 2.11-2.04 ( 1H, m), 1.89-1.85 (1H, m), 1.75-1.71 (1H, m), 1.67-1.12 (13H, m), 1.56 (3H, s), 1.52 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Process 11)
Benzyl (3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS) -10,13a-dihydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Using the compound (α-benzoate) (731 mg) obtained in Step 10 above, the title compound was prepared in the same manner as in Step 138 of Example 138. (620 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 4.33-4.28 (1H, m ), 4.07-4.02 (1H, m), 3.90 (1H, dd, J = 12.7,4.4Hz), 3.80 (1H, d, J = 5.4Hz), 3.29 (1H, dd, J = 12.7,9.8Hz) , 3.00-2.96 (1H, m), 2.11-2.04 (1H, m), 1.89-1.78 (2H, m), 1.72-1.13 (15H, m), 1.52 (3H, s), 1.31 (3H, s) 1.29 (3H, s), 1.12 (3H, s).

(Process 12)
(3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS) -2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1- f] Quinoline-10,13a (4H) -diol Using the compound (100 mg) obtained in Step 11 above, the title compound (84.0 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.88 (1H, brs), 3.81 (1H, d, J = 4.9Hz), 3.09 (1H, d, J = 13.7Hz), 2.79 (1H, d, J = 13.7Hz), 2.09-2.02 (1H, m), 1.90-1.80 (2H, m), 1.66-1.15 (17H, m), 1.52 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04 (3H, s).

(Process 13)
[(3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS) -10,13a-dihydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (84.0 mg) obtained in Step 12 above and Example 23 Using the compound (50.5 mg) obtained in Step 3, the title compound (66.6 mg) was obtained as a white solid in the same manner as in Step 5 of Example 129.
¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 4.08-3.98 (3H, m), 3.80 (1H, d, J = 5.5Hz), 3.55 (1H, dd, J = 12.7, 4.1Hz), 3.48 (1H, dd, J = 11.3,2.3Hz), 3.43 (1H, dd, J = 12.9,9.0Hz), 3.22-3.18 (1H, m), 2.27-2.24 (1H, m), 2.11-2.03 (1H, m), 1.94-1.19 (22H, m), 1.52 (3H, s), 1.35 (3H, s), 1.31 (3H, s), 1.12 (3H, s).

(Process 14)
(2R) -Tetrahydro-2H-pyran-2-yl [(3R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,6a, 7,8-tetrahydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (66.6 mg) obtained in Step 13 above, the title compound (66.6 mg) was prepared in the same manner as in Step 23 of Example 23. 62.7 mg) was obtained as a white solid.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.11-4.04 (2H, m), 4.00-3.93 (2H, m), 3.67 (1H, dd, J = 12.2,4.9Hz), 3.55-3.49 (1H, m ), 3.46 (1H, d, J = 3.9Hz), 3.20 (1H, t, J = 11.7Hz), 3.13-3.10 (1H, m), 2.20-2.13 (1H, m), 1.91-1.89 (1H, m), 1.84-1.17 (20H, m), 1.35 (3H, s), 1.12 (3H, s).

Example 146
(2R) -Tetrahydro-2H-pyran-2-yl [(3S, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,6a, 7,8-tetrahydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS) -10,13a-dihydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Example 145 Using the compound (β-benzoate) (214 mg) obtained in Step 10 in the same manner as in Step 138 in Example 138 The title compound (185 mg) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.06 (2H, s), 4.30-4.25 (1H, m), 3.91-3.86 (1H, m), 3.77 (1H, d, J = 5.4Hz), 3.70 (1H, dd, J = 13.7,3.4Hz), 3.48 (1H, dd, J = 13.9,6.1Hz), 3.01-2.97 (1H, m), 2.18-2.13 (1H, m ), 2.09-2.02 (1H, m), 1.87-1.81 (1H, m), 1.72-1.66 (1H, m), 1.62-1.10 (14H, m), 1.49 (3H, s), 1.36 (3H, s ), 1.29 (3H, s), 1.10 (3H, s).

(Process 2)
(3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS) -2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1- f] Quinoline-10,13a (4H) -diol Using the compound (359 mg) obtained in Step 1 above, the title compound (281 mg) was obtained as a white solid in the same manner as in Step 2 of Example 20.
MS (ESI) m / z: 380 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.80 (1H, d, J = 5.4Hz), 3.63-3.57 (1H, m), 2.98 (1H, dd, J = 12.4, 4.1Hz), 2.72 (1H, dd, J = 12.0,11.0Hz), 2.10-2.02 (2H, m), 1.89-1.84 (1H, m), 1.72-1.02 (17H, m), 1.52 (3H, s ), 1.32 (3H, s), 1.15 (3H, s), 1.06 (3H, s).

(Process 3)
[(3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS) -10,13a-dihydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (230 mg) obtained in Step 2 above and Example 23 Step The title compound (184 mg) was obtained as a white solid in the same manner as in Example 129, Step 5 using the compound (158 mg) obtained in 3.
¹ H-NMR (CDCl ₃ ) δ: 4.32-4.28 (1H, m), 4.10-4.07 (1H, m), 4.04 (1H, dd, J = 11.0,3.7Hz), 3.98 (1H, dd, J = 10.7, 2.0Hz), 3.79 (1H, d, J = 5.4Hz), 3.59 (1H, dd, J = 14.2, 2.9Hz), 3.52-3.46 (2H, m), 3.31 (1H, d, J = 2.9 Hz), 3.16-3.12 (1H, m), 2.19-2.13 (1H, m), 2.12-2.06 (1H, m), 1.97-1.92 (1H, m), 1.91-1.82 (2H, m), 1.72- 1.14 (18H, m), 1.58 (3H, s), 1.52 (3H, s), 1.31 (3H, s), 1.14 (3H, s).

(Process 4)
(2R) -Tetrahydro-2H-pyran-2-yl [(3S, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -3,6a, 7,8-tetrahydroxy-10a, 12a-dimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (242 mg) obtained in Step 3 above, the title compound (178 mg ) Was obtained as a white solid.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.17 (1H, d, J = 10.3Hz), 4.07-4.03 (1H, m), 4.00 (1H, d, J = 11.7Hz), 3.95-3.91 (1H, m), 3.59 (1H, d, J = 14.2Hz), 3.52 (1H, t, J = 10.3Hz), 3.45 (1H, d, J = 3.4Hz), 3.17-3.12 (1H, m), 2.23- 2.13 (2H, m), 1.89 (1H, brs), 1.76-1.12 (20H, m), 1.46 (3H, s), 1.12 (3H, s).

(Example 147)
(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] hexadecahydronaphtho [2,1-f] quinoline-7 (1H) -one

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[tert-butyl (dimethyl) silyl] oxy} -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 23 The compound (3.00 g) obtained in Step 5 was converted to N, N- Suspend in dimethylformamide (20 ml), add imidazole (1.41 g) and tert-butyldimethylsilyl chloride (1.56 g) at room temperature, stir at the same temperature for 2 hours, add dichloromethane (10 ml), and further for 1 hour Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to stop the reaction. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to a slurry under reduced pressure, and the solid was collected by filtration. The obtained solid was washed with diethyl ether to give the title compound (2.69 g) as a white solid. The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (280 mg) as a white solid.
MS (ESI) m / z: 550 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.13 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.2,10.5Hz), 3.56 (1H, m), 3.43 (1H, m ), 3.40 (1H, d, J = 3.9Hz), 3.36-3.25 (2H, m), 2.67 (1H, s), 2.21 (1H, m), 1.91 (1H, m), 1.87-1.33 (17H, m), 1.43 (3H, s), 1.30-1.16 (5H, m), 1.12 (3H, s), 1.02 (1H, s), 0.89 (9H, s), 0.084 (3H, s), 0.077 (3H , s).

(Process 2)
(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) -8-{[tert-butyl (dimethyl) silyl] oxy} -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro- 2H-pyran-2-ylcarbonyl] hexadecahydronaphtho [2,1-f] quinolin-7 (1H) -one Using the compound (2.97 g) obtained in Step 1 above, Example 3 Step 1 and In a similar manner, the title compound (2.96 g) was obtained as a white solid.
MS (ESI) m / z: 548 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.11 (1H, dd, J = 8.1,11.5Hz), 4.11 (1H, m), 3.97 (1H, m), 3.60 (1H, m), 3.49 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.11 (1H, m), 1.98-1.85 (3H, m), 1.83-1.46 (15H, m), 1.43 (3H, s), 1.38 (1H, m), 1.30-1.14 (4H, m), 0.91 (9H, s), 0.73 (3H, s), 0.10 (3H, s), 0.04 (3H, s).

(Process 3)
(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] hexadecahydronaphtho [2,1-f] quinolin-7 (1H) -one To a solution of the compound (2.87 g) obtained in Step 2 above in tetrahydrofuran (50 ml) was added acetic acid (0.90 ml) and tetra n-butylammonium fluoride at room temperature. (1M tetrahydrofuran solution, 32 ml) was added and stirred at the same temperature for 1 hour, then heated to 50 ° C. and stirred for 15 hours. The reaction mixture was concentrated, poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [methanol / dichloromethane] to give the title compound (746 mg) as a white solid.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.91 (1H, dd, J = 7.8,11.7Hz), 4.10 (1H, m), 3.97 (1H, m), 3.60 (1H, m), 3.50 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.19 (1H, m), 1.96 (1H, m), 1.92-1.45 (17H, m), 1.43 (3H, s), 1.38 (1H , m), 1.30-1.15 (4H, m), 0.73 (3H, s).

(Example 148)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8R, 10aR, 10bS, 12aS) -8- (acetyloxy) -10a, 12a-dimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 To a solution of the compound (2.90 g) obtained in Step 3 in tetrahydrofuran (60 ml) in acetic acid ( 1.18 ml) and triphenylphosphine (3.59 g) were added, and ditert-butyl azodicarboxylate (3.15 g) was added at 0 ° C., followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.83 g) as a white amorphous product.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.42 (1H, m), 5.11 (1H, m), 5.09 (2H, s), 3.77 (1H, m), 3.32 (1H , m), 3.06 (1H, m), 2.20 (1H, m), 2.12-1.15 (15H, m), 2.04 (3H, s), 1.37 (3H, s), 1.01-0.83 (2H, m), 0.96 (3H, s).

(Process 2)
Benzyl (1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2- (acetyloxy) -4a, 6a-dimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f ] Quinoline-7 (5H) -carboxylate Using the compound (2.83 g) obtained in Step 1 above, the title compound (992 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 482 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 4.91 (1H, dd, J = 9.3, 7.3Hz), 3.79 (1H, m), 3.36 (1H, m), 3.07 (1H, m), 2.84 (1H, s), 2.10 (3H, s), 2.06 (1H, m), 1.99 (1H, m), 1.87 (1H, m), 1.79-1.00 (15H, m), 1.37 (3H, s), 0.97 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -8- (acetyloxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -Carboxylate Using the compound (992 mg) obtained in Step 2 above, the title compound (1.00 g) was obtained as a white amorphous product in the same manner as in Step 18 of Example 18.
MS (ESI) m / z: 500 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 4.57 (1H, m), 3.90 (1H, brs), 3.76 (1H, m), 3.37 (1H, m), 3.06 (1H, m), 2.60 (1H, m), 2.12-2.03 (2H, m), 2.05 (3H, s) 1.92-1.14 (16H, m), 1.35 (3H, s), 1.12 (3H, s), 0.86 (1H, m).

(Process 4)
(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl acetate In step 3 above Using the obtained compound (300 mg), the title compound (211 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 366 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.46 (1H, brs), 3.81 (1H, m), 2.90 (1H, m), 2.73 (1H, m), 2.54 (1H, m), 2.05 (1H, m), 1.98 (3H, s), 1.93-1.79 (2H, m), 1.76-1.64 (3H, m), 1.62-1.51 (4H, m), 1.46 (1H, m), 1.38-1.23 (4H, m), 1.20-0.99 (2H, m), 1.16 (3H, s), 1.08 (3H, s), 0.82 (1H, m).

(Process 5)
(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadeca Hydronaphtho [2,1-f] quinolin-8-yl acetate Using the compound obtained in Step 4 above (120 mg) and the compound obtained in Example 23 Step 3 (86 mg), Example 23 Step 4 and In a similar manner, the title compound (168 mg) was obtained as a white solid.
MS (ESI) m / z: 478 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.46 (1H, brs), 4.10 (1H, m), 3.97 (1H, m), 3.81 (1H, m), 3.59 (1H, m), 3.50 (1H, m), 3.40 (1H, m), 3.21 (1H, m), 2.56 (1H, m), 2.04 (1H, m), 1.99 (3H, s), 1.95-1.69 (7H, m), 1.68-1.46 (10H, m), 1.44 (3H, s), 1.29-1.17 (4H, m), 1.15 (3H, s), 0.91 (1H, m).

(Process 6)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (168 mg) obtained in Step 5 above, the title compound (109 mg) was obtained as a white solid in the same manner as in Step 1 of Example 5. Got as.
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, m), 3.85 (1H, d, J = 2.4Hz), 3.59 (1H, m), 3.49 (1H, m) , 3.44 (1H, d, J = 1.0Hz), 3.38 (1H, m), 3.20 (1H, m), 2.09-1.99 (2H, m), 1.93-1.85 (2H, m), 1.83-1.14 (20H , m), 1.43 (3H, s), 1.11 (3H, s).

(Example 149-1)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Example 149-2)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 6aR, 7R, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 (2H)- Carboxylate (β-diol)
And benzyl (4aS, 4bR, 6aS, 7S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate (α-diol)
Using the compound (2.03 g) obtained in Example 19, Step 2, the title compound (β-diol and α-diol) (1.58 g, β: α = 5: 1) in the same manner as in Example 15, Step 1. ) Was obtained as a mixture.
MS (ESI) m / z: 456 (M + H) ^<+> .

(Process 2)
Benzyl (4aS, 4bR, 6aR, 7R, 10aR, 10bS, 12aS) -7- (acetyloxy) -6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -carboxylate (β-acetate)
And benzyl (4aS, 4bR, 6aS, 7S, 10aR, 10bS, 12aS) -7- (acetyloxy) -6a-hydroxy-10a, 12a-dimethyl-8-oxohexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate (α-acetate)
Using the compound (1.58 g) obtained in Step 1 above, the title compound (β-acetate) (874 mg) and the title compound (α-acetate) (236 mg) were each white in the same manner as in Step 2 of Example 4. Obtained as a solid.
β-acetate
MS (ESI) m / z: 498 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.68 (1H, s), 5.09 (2H, s), 3.79 (1H, m), 3.36 (1H, m), 3.14 (1H , m), 2.44 (1H, m), 2.33 (1H, m), 2.23 (3H, s), 2.04-1.96 (2H, m), 1.89-1.28 (13H, m), 1.37 (3H, s), 1.21 (1H, m), 1.02 (3H, s), 0.98 (1H, m).
α-acetate
MS (ESI) m / z: 498 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.30 (1H, s), 5.08 (2H, s), 3.78 (1H, m), 3.33 (1H, m), 3.07 (1H , m), 2.53-2.42 (2H, m), 2.21 (3H, s), 1.95 (1H, m), 1.83 (1H, m), 1.78-1.50 (10H, m), 1.44-1.33 (2H, m ), 1.37 (3H, s), 1.30-1.15 (3H, m), 1.23 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -7- (acetyloxy) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -carboxylate (8S-hydroxy)
And benzyl (4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -7- (acetyloxy) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate (8R-hydroxy)
The compound (α-acetate) (231 mg) obtained in Step 2 above was suspended in methanol (20 ml), sodium borohydride (10 mg) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hr. Ice pieces and saturated aqueous ammonium chloride solution were added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (8S-hydroxy form and 8R-hydroxy form) (211 mg) as a mixture.

(Process 4)
Benzyl (4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -7,8-bis (acetyloxy) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -carboxylate (8S-acetate)
And benzyl (4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -7,8-bis (acetyloxy) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -carboxylate (8R-acetate)
Using the compound (211 mg) obtained in Step 3 above, the title compound (8S-acetate and 8R-acetate) (191 mg, 8S: 8R = 1.1: 1) as a mixture was prepared in the same manner as in Step 4 of Example 4. Obtained.
MS (ESI) m / z: 542 (M + H) ^<+> .

(Process 5)
(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8-diyldiacetate (8S- acetate)
as well as
(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinoline-7,8-diyldiacetate (8R- acetate)
Using the compound (191 mg) obtained in Step 4 above, the title compound (8S-acetate and 8R-acetate) (147 mg) was obtained as a mixture in the same manner as in Step 2 of Example 20.
MS (ESI) m / z: 408 (M + H) ^<+> .

(Process 6)
(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2,1-f] quinoline-7,8-diyl diacetate (8S-acetate)
as well as
(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2,1-f] quinoline-7,8-diyl diacetate (8R-acetate)
Using the compound obtained in Step 5 above (147 mg) and the compound obtained in Step 23 of Example 23 (94 mg), the title compound (8S-acetate and 8R-acetate) was prepared in the same manner as in Step 23 of Example 23. (205 mg) was obtained as a mixture.
MS (ESI) m / z: 520 (M + H) ^<+> .

(Process 7)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (8S-hydroxy)
as well as
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone (8R-hydroxy)
Using the compound (205 mg) obtained in Step 6 above, the title compound (8S-hydroxy compound) (68 mg) and the title compound (8R-hydroxy compound) (51 mg) were prepared in the same manner as in Example 5, Step 1. Obtained as a white solid.
8S-hydroxy compound: Example 149-1
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 1.7, 12.0Hz), 3.72 (1H, m), 3.59 (1H, m), 3.49 (1H, m), 3.38 (1H, m), 3.34 (1H, d, J = 9.3Hz), 3.19 (1H, m), 1.94-1.13 (24H, m), 1.43 (3H, s), 0.95 (3H, s ).
8R-hydroxy compound: Example 149-2
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 4.00-3.94 (2H, m), 3.59 (1H, m), 3.50 (1H, m), 3.49 (1H, d, J = 3.4 Hz), 3.38 (1H, m), 3.20 (1H, m), 1.96-1.37 (19H, m), 1.43 (3H, s), 1.30-1.13 (5H, m), 0.94 (3H, s).

(Example 150)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -Tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -8- (acetyloxy) -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H) -Carboxylate Using the compound (958 mg) obtained in Example 122, Step 2, the title compound (715 mg) was obtained as a white solid in the same manner as in Example 148, Step 1.
MS (ESI) m / z: 484 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.18 (1H, m), 5.05 (2H, s), 3.75 (1H, m), 3.30 (1H, m), 3.14 (1H , d, J = 1.5Hz), 3.02 (1H, m), 2.04 (3H, s), 1.88-1.73 (4H, m), 1.70-1.43 (9H, m), 1.40-1.29 (5H, m), 1.33 (3H, s), 1.18-1.02 (2H, m), 0.88 (3H, s).

(Process 2)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyloctadecahydronaphtho [2,1-f] quinolin-8-yl acetate Compound obtained in Step 1 above (474 mg) was used to give the title compound (348 mg) as a white amorphous product in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 350 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 5.05 (1H, m), 2.97 (1H, m), 2.82 (1H, dd, J = 4.9, 13.2 Hz), 2.01 (3H, s), 1.90 (1H, dd, J = 3.9, 15.6 Hz), 1.87-1.24 (18H, m), 1.21-1.09 (2H, m), 1.13 (3H, s), 0.94 (3H, s).

(Process 3)
(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a-hydroxy-10a, 12a-dimethyl-1-[(2R) -tetrahydro-2H-pyran-2-ylcarbonyl] octadecahydronaphtho [2 , 1-f] quinolin-8-yl acetate Using the compound obtained in Step 2 above (100 mg) and the compound obtained in Step 23 of Example 23 (75 mg) in the same manner as in Step 23 of Example 23 The title compound (161 mg) was obtained as a white solid.
MS (ESI) m / z: 462 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.21 (1H, m), 4.04 (1H, m), 3.99 (1H, dd, J = 2.0,10.7Hz), 3.53 (1H, m), 3.44 (1H, m ), 3.34-3.25 (2H, m), 3.17 (1H, s), 2.07 (3H, s), 1.93-1.07 (26H, m), 1.44 (3H, s), 0.91 (3H, s).

(Process 4)
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -Tetrahydro-2H-pyran-2-yl] methanone Using the compound (161 mg) obtained in Step 3 above, the title compound (104 mg) was obtained as a white solid in the same manner as in Step 5 of Example 5. .
MS (ESI) m / z: 420 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.07 (1H, dd, J = 4.1, 8.1 Hz), 4.03 (1H, m), 3.94 (1H, dd, J = 3.2, 10.5 Hz), 3.56 (1H, m), 3.47 (1H, m), 3.36 (1H, m), 3.18 (1H, m), 1.89-1.07 (26H, m), 1.41 (3H, s), 0.90 (3H, s).

(Example 151)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -10a, 12a-dimethyl-8-oxo-3,4,4a, 4b, 5,6,8,10a, 10b, 11,12,12a-dodecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 To a solution of the compound (5.00 g) obtained in Step 2 in dioxane (60 ml) at 0 ° C., tert-butyldimethylsilyl chloride (180 mg) And 2,3-dichloro-5,6-dicyano-p-benzoquinone (3.50 g) were added, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed successively with water (2 times), 10% aqueous sodium carbonate solution (3 times), water (3 times) and saturated brine (2 times), and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [methanol / dichloromethane], then purified again by silica gel column chromatography [ethyl acetate / hexane], and the title compound (3.59 g) was pale yellow Obtained as a solid.
MS (ESI) m / z: 420 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 7.04 (1H, d, J = 10.3Hz), 6.24 (1H, dd, J = 1.7,10.3Hz), 6.07 (1H, s ), 5.08 (2H, s), 3.77 (1H, m), 3.33 (1H, m), 3.14 (1H, m), 2.50-2.34 (2H, m), 2.14 (1H, m), 1.90-1.13 ( 10H, m), 1.42 (3H, s), 1.20 (3H, s), 1.03 (1H, m).

(Process 2)
Benzyl (4aS, 4bR, 10S, 10aR, 10bS, 12aS) -10,10a, 12a-trimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate To a solution of the compound obtained in Step 1 above (2.89 g) in tetrahydrofuran (50 ml) at room temperature with copper bromide (I) (198 mg), trimethylaluminum (1.08 M hexane solution, 7.0 ml), and trimethylsilyl chloride (1.04 ml) were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.18 g) as a pale yellow solid.
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.70 (1H, s), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 3.78 (1H, m), 3.36 (1H, m), 3.11 (1H, m), 2.72 (1H, dd, J = 4.6,15.9Hz), 2.38-2.31 (2H, m), 2.24-2.10 (2H, m), 2.01 (1H, m), 1.88 (1H, m), 1.81-1.65 (2H, m), 1.59-1.20 (7H, m), 1.40 (3H, s), 1.24 (3H, s), 0.96 (1H, m), 0.93 (3H, d, J = 7.3 Hz).

(Process 3)
Benzyl (4aS, 4bR, 8S, 10S, 10aR, 10bS, 12aS) -8-hydroxy-10,10a, 12a-trimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 19, Step 3, using the compound (2.18 g) obtained in Step 2 above. The title compound (1.76 g) was obtained as a white amorphous product by the above procedure.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.26 (1H, d, J = 1.5Hz), 5.10 (1H, d, J = 12.2Hz), 5.06 (1H, d, J = 12.2Hz), 4.25 (1H, m), 3.77 (1H, m), 3.34 (1H, m), 3.04 (1H, m), 2.17 (1H, m), 2.10 (1H, m), 1.93-1.80 (4H, m), 1.78-1.63 (3H, m), 1.56-1.07 (8H, m), 1.38 (3H, s), 1.10 (3H, s), 0.89 (3H, d, J = 6.8Hz), 0.80 (1H, m).

(Process 4)
Benzyl (1aS, 2S, 4S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-4,4a, 6a-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1- f] Quinoline-7 (5H) -carboxylate Using the compound (1.76 g) obtained in Step 3 above, the title compound (1.61 g) was obtained as a white amorphous product in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.06 (1H, d, J = 12.7Hz), 4.06 (1H, m), 3.76 (1H, m), 3.35 (1H, m), 3.11 (1H, d, J = 3.4Hz), 3.01 (1H, m), 2.02 (1H, m), 1.96-0.89 (17H, m), 1.37 (3H, s), 1.08 (3H, s), 0.92 (3H, d, J = 7.3 Hz).

(Process 5)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -carboxylate Using the compound (1.61 g) obtained in Step 4 above, the title compound (1.03 g) was obtained as a white amorphous product in the same manner as in Step 2 of Example 2.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.06 (1H, d, J = 12.7Hz), 4.32 (1H, m), 3.78 (1H, m), 3.51 (1H, m), 3.35 (1H, m), 3.04 (1H, m), 2.42 (1H, brs), 2.18 (1H, m), 2.01 (1H, m), 1.90 -1.56 (8H, m), 1.52 (1H, m), 1.49-1.38 (3H, m), 1.36 (3H, s), 1.29-1.16 (4H, m), 1.14 (3H, s), 1.10 (3H , d, J = 7.3 Hz), 1.08 (1H, s).

(Process 6)
(4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS) -10,10a, 12a-Trimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 7,8 (2H) -triol Using the compound (1.03 g) obtained in the above Step 5, the title compound (710 mg) was obtained as a white solid by the same method as in Step 20 of Example 20.
MS (ESI) m / z: 338 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.25 (1H, m), 3.43 (1H, d, J = 2.9Hz), 2.96 (1H, m), 2.80 (1H, m), 2.13-2.01 (2H, m), 1.83-1.11 (16H, m), 1.16 (3H, s), 1.14 (3H, d, J = 7.3 Hz), 1.13 (3H, s).

(Process 7)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound obtained in Step 6 above (200 mg) and the compound obtained in Example 23 Step 3 (101 mg), The title compound (141 mg) was obtained as a white amorphous substance by the same method as in Example 23, Step 4.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.33 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.4,10.7Hz), 3.56 (1H, m), 3.51 (1H, brs ), 3.44 (1H, m), 3.36-3.27 (2H, m), 2.35 (1H, d, J = 2.4Hz), 2.19 (1H, m), 2.01 (1H, m), 1.91 (1H, m) , 1.86-1.17 (21H, m), 1.45 (3H, s), 1.14 (3H, s), 1.10 (3H, d, J = 7.8Hz), 1.03 (1H, s).

(Example 152)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 10aR, 10bS, 12aS) -9,10a, 12a-trimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11,12 , 12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 19 In a solution of the compound (5.00 g) obtained in Step 2 in tetrahydrofuran (70 ml) at −70 ° C. Diisopropylamide (1.09M, tetrahydrofuran solution) was added over 5 minutes and then stirred for 30 minutes. After adding methyl iodide (2.95 ml) at the same temperature, the mixture was heated to 0 ° C. and stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.49 g) as a diastereomer mixture.
MS (ESI) m / z: 436 (M + H) ^<+> .

(Process 2)
Benzyl (4aS, 4bR, 9R, 10aR, 10bS, 12aS) -9,10a, 12a-trimethyl-8-oxo-3,4,4a, 4b, 5,6,8,9,10,10a, 10b, 11 , 12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate To a solution of the compound obtained in Step 1 above (2.49 g) in toluene (50 ml) at room temperature, 1,8 -Diazabicyclo [5.4.0] -7-undecene (1.71 ml) was added, and the mixture was refluxed for 36 hours. The reaction mixture was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed successively with 0.5N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.66 g) as a white amorphous product.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.70 (1H, s), 5.08 (2H, s), 3.78 (1H, m), 3.34 (1H, m), 3.11 (1H , m), 2.44 (1H, m), 2.37-2.26 (2H, m), 2.08-1.97 (2H, m), 1.85 (1H, m), 1.78-1.07 (9H, m), 1.39 (3H, s ), 1.18 (3H, s), 1.11 (3H, d, J = 6.3 Hz), 1.05-0.94 (2H, m).

(Process 3)
Benzyl (4aS, 4bR, 8S, 9R, 10aR, 10bS, 12aS) -8-hydroxy-9,10a, 12a-trimethyl-3,4,4a, 4b, 5,6,8,9,10,10a, 10b , 11,12,12a-Tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Similar to Example 19, Step 3, using the compound (1.66 g) obtained in Step 2 above. The title compound (1.53 g) was obtained as a white amorphous product by the above procedure.
MS (ESI) m / z: 438 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.28 (5H, m), 5.23 (1H, s), 5.08 (2H, s), 3.77 (1H, m), 3.67 (1H, m), 3.32 (1H , m), 3.05 (1H, m), 2.15 (1H, m), 2.07 (1H, m), 1.93 (1H, m), 1.83 (1H, m), 1.76-0.99 (12H, m), 1.36 ( 3H, s), 1.05 (3H, d, J = 6.3 Hz), 1.01 (3H, s), 0.90-0.79 (2H, m).

(Process 4)
Benzyl (1aS, 2S, 3R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-3,4a, 6a-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1- f] Quinoline-7 (5H) -carboxylate Using the compound (742 mg) obtained in Step 3 above, the title compound (418 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.78 (1H, m), 3.39 (1H, t, J = 9.5Hz), 3.33 (1H, m ), 3.14 (1H, s), 3.05 (1H, m), 2.00-0.94 (17H, m), 1.36 (3H, s), 1.01 (3H, s), 0.95 (3H, d, J = 6.3Hz) , 0.87 (1H, t, J = 13.4Hz).

(Process 5)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -Carboxylate The title compound (384 mg) was obtained as a white solid in the same manner as in Example 2, Step 1 using the compound (418 mg) obtained in Step 4 above.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.78 (1H, m), 3.68 (1H, m), 3.54 (1H, brs), 3.34 (1H , m), 3.04 (1H, m), 2.34 (1H, d, J = 2.0Hz), 2.18 (1H, m), 1.88-1.15 (17H, m), 1.35 (3H, s), 1.13 (3H, s), 1.08 (1H, s), 1.03 (3H, d, J = 6.3 Hz).

(Process 6)
Benzyl (3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,4,5a, 7a-pentamethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Using the compound (454 mg) obtained in Step 5 above, the title compound (434 mg) was converted to white in the same manner as in Example 1, Step 1. Obtained as a solid.
MS (ESI) m / z: 512 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.83-3.75 (3H, m), 3.34 (1H, m), 3.04 (1H, m), 2.05 (1H, m), 1.87-1.64 (5H, m), 1.60 (1H, m), 1.54-1.10 (11H, m), 1.49 (3H, s), 1.36 (3H, s), 1.32 (3H, s ), 1.13 (3H, s), 1.01 (3H, d, J = 6.3 Hz).

(Process 7)
(3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -2,2,4,5a, 7a-pentamethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2, 1-f] quinolin-13a (4H) -ol Using the compound (434 mg) obtained in Step 6 above, the title compound (304 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 378 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 3.85 (1H, d, J = 5.4Hz), 3.77 (1H, dd, J = 9.3,5.4Hz), 3.20 (1H, m), 3.10 (1H, m) , 2.03-1.94 (2H, m), 1.89-1.81 (2H, m), 1.79-1.59 (6H, m), 1.48-1.22 (8H, m), 1.44 (3H, s), 1.32 (3H, s) 1.29 (3H, s), 1.17 (3H, s), 0.98 (3H, d, J = 6.8 Hz).

(Process 8)
[(3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,4,5a, 7a-pentamethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (150 mg) obtained in Step 7 above and Example 23 Step Using the compound (102 mg) obtained in 3, the title compound (119 mg) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.2,10.5Hz), 3.82-3.80 (2H, m), 3.56 (1H, m), 3.43 (1H , m), 3.35-3.27 (2H, m), 2.05 (1H, m), 1.91 (1H, d, J = 10.3Hz), 1.87-1.16 (21H, m), 1.49 (3H, s), 1.44 ( 3H, s), 1.33 (3H, s), 1.17 (1H, s), 1.13 (3H, s), 1.01 (3H, d, J = 6.3 Hz).

(Process 9)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9,10a, 12a-trimethyl Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The title compound (103 mg) was prepared in the same manner as in Example 23, Step 5, using the compound (116 mg) obtained in Step 8 above. ) Was obtained as a white solid.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.96 (1H, dd, J = 2.4,10.7Hz), 3.67 (1H, m), 3.59-3.52 (2H, m), 3.43 (1H , m), 3.35-3.26 (2H, m), 2.36 (1H, d, J = 2.9Hz), 2.19 (1H, m), 1.95-1.15 (22H, m), 1.89 (1H, d, J = 6.3 Hz), 1.43 (3H, s), 1.13 (3H, s), 1.07 (1H, s), 1.03 (3H, d, J = 6.3 Hz).

(Example 153)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-8,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (1aR, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -4a, 6a-dimethyl-2-oxotetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline-7 ( 5H) -Carboxylate Using the compound (1.16 g) obtained in Step 19 of Example 19 and sodium hydrogen carbonate (665 mg), the title compound (893 mg) was obtained as a white amorphous product by the same method as in Step 3 of Example 3. It was.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 3.78 (1H, m), 3.34 (1H, m), 3.10 (1H, m), 2.99 (1H, s), 2.31 (1H, m), 2.20 (1H, m), 2.13 (1H, m), 2.06 (1H, m), 1.87 -1.78 (2H, m), 1.76-1.64 (2H, m), 1.62-1.09 (9H, m), 1.37 (3H, s), 1.11 (3H, s), 1.03 (1H, d, J = 6.3Hz ).

(Process 2)
Benzyl (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-2,4a, 6a-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] Quinoline-7 (5H) -carboxylate (2S form: Rf = higher)
And benzyl (1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR) -2-hydroxy-2,4a, 6a-trimethyltetradecahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f ] Quinoline-7 (5H) -carboxylate (2R form: Rf = lower)
Methyl magnesium bromide (0.92 M tetrahydrofuran solution, 3.9 ml) was added at 0 ° C. to a tetrahydrofuran (15 ml) solution of the compound (780 mg) obtained in Step 1 above, and the mixture was stirred at the same temperature for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction mixture was poured into two layers of ethyl acetate and saturated brine, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2S form) (293 mg) and the title compound (2R form) (492 mg) as white amorphous compounds, respectively. Obtained.
2S body (Rf = higher: low polarity)
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.10 (1H, d, J = 12.2Hz), 5.07 (1H, d, J = 12.2Hz), 3.78 (1H, m), 3.36 (1H, m), 3.06 (1H, m), 2.82 (1H, s), 2.65 (1H, s), 2.08 (1H, m), 1.99 (1H, m), 1.85 (1H, m), 1.79 -1.09 (14H, m), 1.36 (3H, s), 1.34 (3H, s), 0.99 (3H, s), 0.92 (1H, m).
2R body (Rf = lower: high polarity)
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 3.79 (1H, m), 3.33 (1H, m), 3.05 (1H, m), 2.74 (1H, s), 2.05 (1H, m), 1.96 (1H, m), 1.92-1.79 (2H, m), 1.77-1.64 (2H, m), 1.62-1.51 (2H, m), 1.50-0.98 (11H, m), 1.36 (3H, s), 1.33 (3H, s), 0.96 (3H, s).

(Process 3)
Benzyl (4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -carboxylate To a solution of the compound (2R form) (492 mg) obtained in step 2 above in dioxane (9.0 ml), water and sulfuric acid (3M aqueous solution, 0.362 ml) were added at room temperature, and the mixture was stirred at the same temperature for 8 hours. And then left overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane: methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Dichloromethane was added to the resulting solid to form a slurry, and the solid was collected by filtration to give the title compound (208 mg) as a white solid. The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (108 mg) as a white solid.
MS (ESI) m / z: 472 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7Hz), 5.04 (1H, d, J = 12.7Hz), 3.75 (1H, m), 3.54 (1H, brs), 3.30 (1H, m), 3.25 (1H, dd, J = 1.5,4.9Hz), 3.01 (1H, m), 2.95 (1H, brs), 2.02 (1H, m), 1.87 (1H, m), 1.80 (1H, m), 1.72 (1H, d, J = 4.9Hz), 1.71-1.22 (13H, m), 1.32 (3H, s), 1.26 (3H, s), 1.20- 1.09 (2H, m), 1.04 (3H, s).

(Process 4)
(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -8,10a, 12a-trimethylhexadecahydronaphtho [2,1-f] quinoline-6a, 7,8 (2H) -triol Using the compound (318 mg) obtained in 3, the title compound (229 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20.
MS (ESI) m / z: 338 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 3.28 (1H, brs), 2.90 (1H, m), 2.77 (1H, m), 2.06 (1H, m), 1.90 (1H, m), 1.81-0.97 (21H m), 1.28 (3H, s), 1.09 (3H, s), 1.04 (3H, s).

(Process 5)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-8,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Example using the compound obtained in Step 4 above (100 mg) and the compound obtained in Example 23 Step 3 (70 mg) The title compound (104 mg) was obtained as a white solid by the same method as in Step 23.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 3.4,11.2Hz), 3.59 (1H, m), 3.49 (1H, m), 3.38 (1H, m), 3.19 (1H, m), 3.13 (1H, d, J = 1.5Hz), 2.09 (1H, m), 1.93-1.15 (23H, m), 1.43 (3H, s), 1.20 (3H, s ), 1.07 (3H, s).

(Example 154)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-7,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-{[tert-butyl (dimethyl) silyl] oxy} -6a, 7-dihydroxy-7,10a, 12a-trimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Example 147 Compound (809 mg) tetrahydrofuran (16 ml) obtained in Step 2 ) To the solution was added methylmagnesium bromide (0.92 M tetrahydrofuran solution, 4.0 ml) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into two layers of diethyl ether and saturated aqueous ammonium chloride solution to stop the reaction. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated to a slurry under reduced pressure, and the solid was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (262 mg) as a white solid. The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (237 mg) as a white solid.
MS (ESI) m / z: 564 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.96 (1H, dd, J = 2.4,10.7Hz), 3.79 (1H, dd, J = 5.6,11.5Hz), 3.55 (1H, m ), 3.43 (1H, m), 3.36-3.26 (2H, m), 2.32 (1H, s), 1.97-1.06 (25H, m), 1.42 (3H, s), 1.17 (6H, s), 0.90 ( 9H, s), 0.084 (3H, s), 0.075 (3H, s).

(Process 2)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-7,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone To a solution of the compound obtained in Step 1 above (499 mg) in tetrahydrofuran (20 ml) at room temperature, tetra-n-butylammonium fluoride (1M tetrahydrofuran) Solution, 1.8 ml) was added and stirred at the same temperature for 1 hour. The reaction solution was poured into two layers of chloroform and saturated brine, extracted with chloroform: methanol (10: 1), and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [methanol / dichloromethane], and then purified again by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (302 mg) as a white solid. Obtained.
MS (ESI) m / z: 450 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4,10.7Hz), 3.75 (1H, m), 3.53 (1H, m), 3.41 (1H, m ), 3.34-3.21 (2H, m), 1.93-1.85 (2H, m), 1.82-1.58 (12H, m), 1.52-1.35 (8H, m), 1.40 (3H, s), 1.26 (3H, s ), 1.23-1.08 (5H, m), 1.13 (3H, s).

Example 155
[(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
Benzyl (3aS, 5aS, 5bR, 7aS, 11aS, 11bS, 13aS, 13bS) -5b-fluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinoline-8 (4H) -carboxylate Using the compound (2.37 g) obtained in Step 42 of Example 42, hydrolysis product in the same manner as in Step 4 of Example 31 Got. The title compound (1.55 g) was obtained in the same manner as in Step 20 of Example 20 using the obtained hydrolysis product.
MS (ESI) m / z: 516 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.08 (2H, s), 4.36 (1H, m), 3.92-3.84 (2H, m), 3.77 (1H, m), 3.43 -3.38 (1H, m), 2.93 (1H, m), 2.11-1.95 (5H, m), 1.91-1.21 (12H, m), 1.50 (3H, s), 1.38 (3H, s), 1.32 (3H , s), 1.25 (3H, s).

(Process 2)
(3aS, 5aS, 5bR, 7aS, 11aS, 11bS, 13aS, 13bS) -5b-Fluoro-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2, 1-f] quinolin-13a (4H) -ol The title compound (0.133 g) was obtained in the same manner as in Step 2 of Example 20 using the compound (1.55 g) obtained in Step 1 above.
MS (ESI) m / z: 382 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.36 (1H, m), 3.93-3.84 (2H, m), 2.91 (1H, m), 2.82 (1H, dd, J = 13.2,4.9), 2.05-1.89 ( 5H), 1.77-1.09 (14H, m), 1.51 (3H, s), 1.32 (3H, s), 1.27 (3H, s), 1.09 (3H, s).

(Process 3)
[(3aS, 5aS, 5bR, 7aS, 11aS, 11bS, 13aS, 13bS) -5b-fluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6 ] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (0.12 g) obtained in Step 2 above and Example 23 Using the compound (53 mg) obtained in Step 3, the title compound (0.17 g) was obtained as a white solid in the same manner as in Step 23 of Example 23.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.38-4.34 (1H, m), 4.04 (1H, m), 3.98 (1H, dd, J = 11.0,2.2Hz), 3.93-3.84 (2H, m), 3.59 (1H, m), 3.45 (1H, m), 3.41-3.35 (1H, m), 3.19-3.15 (1H, m), 2.13-2.07 (1H, m), 2.05-1.20 (22H, m), 1.51 (3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.25 (3H, s).

(Process 4)
[(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone The title compound was prepared in the same manner as in Step 23 of Example 23 using the compound (135 mg) obtained in Step 3 above. (88 mg) was obtained as a white solid.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.04 (1H, m), 3.98 (1H, dd, J = 10.7,2.4Hz), 3.88 (1H, d, J = 36.1Hz), 3.60-3.55 (2H, m), 3.44 (1H, m), 3.38 (1H, m), 3.18-3.13 (1H, m), 2.41 (1H, br), 2.16-1.20 (23H, m), 1.45 ( 3H, s), 1.25 (3H, s), 1.13 (1H, d, J = 5.9 Hz).

(Example 156)
[(4aS, 4bR, 6aS, 7S, 8R, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinoline-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
(2α, 3β, 4β, 5α, 17β) -2-Fluorandrostane-3,4,5,17-tetrol (2α, 17β) -2-fluoro-17-hydroxyandrost-4-en-3-one To a solution of (13.6 g) in tetrahydrofuran (400 ml) was added lithium tri-tert-butoxyaluminum hydride (1M tetrahydrofuran solution, 100 ml) in an ice bath, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. In an ice bath, water (2.7 ml), 5N sodium hydroxide solution (2.7 ml) and water (8.1 ml) were added in this order, and the mixture was stirred at room temperature. The precipitated solid was filtered off through Celite. The filtrate was concentrated under reduced pressure to obtain an alcohol form. Using the resulting alcohol form, an epoxy form (13.9 g) was obtained in the same manner as in Step 1 of Example 1. Using the obtained epoxy compound, the title compound (8.00 g) was obtained as a white solid by the same method as in Step 4 of Example 31.
¹ H-NMR (CD ₃ OD) δ: 4.69 (1H, m), 4.07 (1H, m), 3.62-3.53 (2H, m), 2.11 (1H, m), 1.97 (1H, m), 1.86 1.75 (2H, m), 1.68-0.97 (13H, s), 1.19 (3H, s), 0.72 (3H, s).

(Process 2)
(3aR, 4R, 5aR, 5bS, 7aS, 8S, 10aS, 10bS, 12aS, 12bS) -4-Fluoro-2,2,5a, 7a-tetramethylhexadecahydro-12aH-cyclopenta [7,8] phenanthro [ 1,2-d] [1,3] dioxol-8,12a-diol The title compound (4.82 g) was prepared in the same manner as in Step 20 of Example 20 using the compound (5.87 g) obtained in Step 1 above. Was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.32 (1H, m), 3.98 (1H, dd, J = 6.3,2.4Hz), 3.65 (1H, m), 2.11-2.02 (2H, m), 1.88-1.71 (3H, m), 1.65-1.01 (14H, m), 1.53 (3H, s), 1.35 (3H, s), 1.17 (3H, s), 0.75 (3H, s ).

(Process 3)
(3aR, 4R, 5aR, 5bS, 7aS, 10aS, 10bR, 12aS, 12bS) -4-Fluoro-12a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro-8H-cyclopenta [7,8] Phenanthro [1,2-d] [1,3] dioxol-8-one Using the compound (2.83 g) obtained in Step 2 above, the title compound (2.82 g) was prepared in the same manner as in Example 12, Step 1. Was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.33 (1H, m), 3.99 (1H, dd, J = 5.9,2.4Hz), 2.46 (1H, dd, J = 19.0, 8.8Hz), 2.14-2.05 (2H, m), 1.98-1.93 (1H, m), 1.87-1.64 (5H, m), 1.61-1.27 (9H, m), 1.54 (3H, s), 1.36 (3H , s), 1.19 (3H, s) .088 (3H, s).

(Process 4)
(3aR, 4R, 5aR, 5bS, 7aS, 10aS, 10bS, 12aS, 12bS) -4-Fluoro-8- (hydroxyimino) -2,2,5a, 7a-tetramethylhexadecahydro-12aH-cyclopenta [7 , 8] phenanthro [1,2-d] [1,3] dioxol-12a-ol Using the compound (3.06 g) obtained in Step 3 above, the title compound (3.06 g) was prepared in the same manner as in Step 5 of Example 36. 3.17 g) was obtained as a mixture of isomers.
MS (ESI) m / z: 396 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.33 (1H, m), 3.99 (1H, dd, J = 5.9,2.4Hz), 2.70-2.23 (2H, m), 2.14 -2.04 (1H, m), 1.93-1.24 (16H, m), 1.53 (3H, s), 1.36 (3H, s), 1.21-0.89 (6H, m).

(Process 5)
(3aR, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -4-fluoro-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [ 2,1-f] quinolin-13a (4H) -ol To a solution of the compound obtained in Step 4 above (0.45 g) in dichloromethane (25 ml) was added diisobutylaluminum hydride (1.04 M toluene) at −78 ° C. in a nitrogen atmosphere. Solution, 11 ml) was added, followed by stirring at 0 ° C. for 25 minutes. After cooling again to −78 ° C., ethyl acetate (5 ml), methanol (10 ml), and an aqueous Rochelle salt solution (150 ml) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted twice with dichloromethane: methanol (10: 1), and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel chromatography [methanol / ethyl acetate] to obtain the title compound (70 mg) as a white solid.
MS (ESI) m / z: 382 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4,82-4.67 (1H, m), 4.32 (1H, m), 4.00 (1H, dd, J = 6.3,2.4Hz), 2.91 (1H, m), 2.78 (1H, dd, J = 12.7,4.9Hz), 2.01 (1H, m), 1.86-0.95 (18H, m), 1.53 (3H, s), 1.35 (3H, s), 1.14 (3H, s), 1.05 (3H, s).

(Process 6)
[(3aR, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -4-fluoro-13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5 , 6] Naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone Compound (70 mg) obtained in Step 5 above and Examples The title compound (30 mg) was obtained as a white solid in the same manner as in Example 23, Step 4, using the compound (36 mg) obtained in 23 Step 3.
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.81-4.66 (1H, m), 4.32 (1H, m), 4.05-3.94 (3H, m), 3.57 (1H, m), 3.43 (1H, m), 3.35 -3.28 (2H, m), 2.03 (1H, m), 1.93-1.18 (22H, m), 1.52 (3H, s), 1.44 (3H, s), 1.35 (3H, s), 1.12 (3H, s ).

(Process 7)
[(4aS, 4bR, 6aS, 7S, 8R, 9R, 10aR, 10bS, 12aS) -9-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] Quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone By using the compound (30 mg) obtained in Step 6 above, in the same manner as in Step 23 of Example 23. The title compound (27 mg) was obtained as a white solid.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.22 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 10.7,2.4Hz) 3.75 (1H, m), 3.57 (1H, m), 3.43 (1H, m), 3.36-3.27 (2H, m), 2.18 (1H, m), 1.93-1.11 (24H, m), 1.43 (3H, s), 1.16 (3H, s).

Example 157
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2 , 6,6,7,8,9,9- ² H ₈ ) Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Benzyl (4aS, 4bR, 8S, 10aR , 10bS, 12aS) -8- hydroxy-10a, 12a- dimethyl (2,2,6,6,7,8,9,9- ² H ₈₎ -3,4, 4a, 4b, 5,6,8,9,10,10a, 10b, 11,12,12a-tetradecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate Example 39 in step 3 The obtained compound (1.00 g) was suspended in deuterated methanol (10 ml), 1,8-diazabicyclo [5.4.0] -7-undecene (0.02 ml) was added at room temperature, and the mixture was heated to reflux. In the middle of the reaction, heavy methanol (20 ml) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.684 ml) were added little by little, and the mixture was heated to reflux for a total of 50 hours. The reaction mixture was cooled to 0 ° C., anhydrous cerium chloride (640 mg) and sodium deuteride (100 mg) were added, and the mixture was stirred for 4 hours while warming to room temperature. The reaction mixture was diluted with dichloromethane, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (731 mg) as a white amorphous product.
MS (ESI) m / z: 432 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 3.05 (1H, m), 1.92 (1H, dd, J = 3.4,12.7Hz), 1.83 (1H, m), 1.75-1.61 (3H, m), 1.57 (1H, m), 1.47 (1H, m), 1.41-1.29 (3H, m), 1.36 (3H, s), 1.26-1.15 (3H, m), 1.01 (3H, s), 0.88-0.81 (2H, m).

(Process 2)
Benzyl (1aS, 2S, 4aR, 4bS , 6aS, 10aS, 10bR, 12aR) -2- hydroxy -4a, 6a- dimethyl (1a, 2,3,3,8,8,12,12- ² H ₈₎ tetra Decahydro-1aH-oxyleno [4a, 5] naphtho [2,1-f] quinoline-7 (5H) -carboxylate Similar to Example 1, Step 2, using the compound (730 mg) obtained in Step 1 above. The title compound (668 mg) was obtained as a white amorphous product by the above procedure.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7Hz), 5.07 (1H, d, J = 12.7Hz), 3.06 (1H, m), 2.21 (1H, s), 1.96 (1H, dd, J = 3.7,12.9Hz), 1.84 (1H, m), 1.77-0.90 (12H, m), 1.36 (3H, s), 0.99 (3H, s) .

(Process 3)
Benzyl (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2,6,6,7,8,9,9- ² H ₈ ) Hexadecahydronaphtho [2,1-f] quinoline-1 (2H) -carboxylate The title compound was prepared in the same manner as in Example 2, Step 1 using the compound (668 mg) obtained in Step 2 above. Compound (532 mg) was obtained as a white solid.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.36-7.27 (5H, m), 5.04 (2H, s), 2.97 (1H, m), 1.88 (1H, m), 1.73-1.29 (11H, m), 1.34 (3H, s), 1.27-1.13 (2H, m), 1.10 (3H, s).

(Process 4)
Benzyl (3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethyl (3a, 4,4,9,9,13,13,13b- ² H ₈ ) hexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinoline-8 (4H) -carboxylate Using the compound obtained in step 3 above (532 mg), Example 20 The title compound (489 mg) was obtained as a white solid in the same manner as in Step 1.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.09 (1H, d, J = 12.2Hz), 5.07 (1H, d, J = 12.2Hz), 3.04 (1H, m), 1.83 (1H, m), 1.74-1.29 (10H, m), 1.51 (3H, s), 1.36 (3H, s), 1.31 (3H, s), 1.27-1.14 (3H, m), 1.19 (1H, s), 1.12 (3H, s).

(Process 5)
(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -2,2,5a, 7a-tetramethyl (3a, 4,4,9,9,13,13,13b- ² H ₈ ) hexa Decahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-13a (4H) -ol Using the compound (489 mg) obtained in Step 4 above, Example 20 Step 2 and In a similar manner, the title compound (319 mg) was obtained as a pale yellow solid.
MS (ESI) m / z: 372 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 1.76-1.66 (2H, m), 1.62-1.23 (11H, m), 1.44 (3H, s), 1.25 (3H, s), 1.17-1.02 (2H, m ), 1.12 (3H, s), 1.05 (3H, s).

(Process 6)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethyl (3a, 4,4,9,9,13,13,13b- ² H ₈ ) Hexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] Methanone Using the compound obtained in Step 5 above (319 mg) and the compound obtained in Example 23 Step 3 (224 mg), the title compound (370 mg) was obtained as a white solid in the same manner as in Example 23 Step 4. It was.
MS (ESI) m / z: 484 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.4,10.7Hz), 3.43 (1H, m), 3.24 (1H, m), 1.92-1.12 (21H m), 1.49 (3H, s), 1.41 (3H, s), 1.28 (3H, s), 1.09 (3H, s).

(Process 7)
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethyl (2,2 , 6,6,7,8,9,9- ² H ₈ ) Hexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone The compound obtained in Step 6 above (370 mg) Was used to give the title compound (221 mg) as a white solid in a manner similar to Example 23, Step 5.
MS (ESI) m / z: 444 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.09 (1H, m), 3.97 (1H, dd, J = 2.9,10.7Hz), 3.49 (1H, m), 3.18 (1H, m), 1.94-1.14 ( 20H, m), 1.42 (3H, s), 1.11 (3H, s).

(Example 158)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8- (difluoromethoxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8- (difluoromethoxy) -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline- 1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone in a solution of 2,2-difluoro-2- (fluorosulfonyl) acetic acid (0.100 ml) in acetonitrile (5.0 ml) Example 23 The compound obtained in Step 5 (200 mg) and copper iodide (10 mg) were added, followed by stirring at 60 ° C. for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane: methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography [ethyl acetate / hexane] and reverse-phase high-performance liquid chromatography [acetonitrile / water containing 0.1% formic acid] in this order. Purification gave the title compound (12 mg) as a white solid.
MS (ESI) m / z: 486 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 6.29 (1H, t, J = 75.2Hz), 4.66 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.0, 10.7Hz), 3.66 (1H, brs), 3.56 (1H, m), 3.43 (1H, m), 3.35-3.26 (2H, m), 2.24 (1H, m), 2.06 (1H, d, J = 1.5Hz), 1.95 -1.16 (23H, m), 1.43 (3H, s), 1.13 (3H, s), 1.12 (1H, s).

(Example 159)
[(2R, 5S) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(2RS, 5SR) -5-Fluorotetrahydro-2H-pyran-2-yl] methanol (trans form)
as well as
[(2RS, 5RS) -5-Fluorotetrahydro-2H-pyran-2-yl] methanol (cis)
To a dichloromethane solution of 2-fluorohex-5-en-1-ol (1.85 g), 3-chloroperbenzoic acid (4.1 g) was added, and after stirring overnight at room temperature, camphorsulfonic acid (0.73 g) was added, The mixture was further stirred for 20 minutes. A 1N aqueous sodium hydroxide solution was added to make the solution basic, and then an aqueous sodium sulfate solution was added, followed by stirring at room temperature for 15 minutes. Extraction was performed with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane], and the title compound (trans isomer) (0.16 g) and the title compound (cis isomer) (0.30 g) were each colorless. Obtained as an oil.
Trans body
¹ H-NMR (CDCl ₃ ) δ: 4.62-4.46 (1H, m), 4.15 (1H, m), 3.62 (1H, m), 3.52 (1H, dd, J = 11.5,7.1Hz), 3.42 (1H , m), 3.32 (1H, m) 2.30-2.24 (1H, m), 2.01 (1H, br), 1.75-1.61 (2H, m), 1.50-1.41 (1H, m).
Cis body
¹ H-NMR (CDCl ₃ ) δ: 4.67-4.57 (1H, m), 4.21-4.14 (1H, m), 3.68-3.53 (3H, m), 3.53-3.46 (1H, m), 2.24-2.13 ( 1H, m), 2.10 (1H, br), 1.85-1.65 (2H, m), 1.49-1.38 (1H, m).

(Process 2)
(2RS, 5SR) -5-Fluorotetrahydro-2H-pyran-2-carboxylic acid To a solution of the compound obtained in Step 1 (trans isomer) (0.16 g) in acetonitrile (15 ml) -water (15 ml), diacetoxy Iodobenzene (0.85 g) and azaadamantane-N-oxyl (9 mg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was basified with 5N aqueous sodium hydroxide solution and washed twice with dichloromethane. The obtained aqueous layer was acidified with aqueous sodium sulfite solution and 5N hydrochloric acid, and extracted with dichloromethane and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give the title compound (0.13 g) as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 4.68-4.54 (1H, m), 4.21 (1H, m), 4.14-4.12- (1H, m), 3.58-3.50 (1H, m), 2.33-2.17 (2H , m), 1.86-1.76 (2H, m).

(Process 3)
[(2S, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (5R-fluorine: Rf = higher)
as well as
[(2R, 5S) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (5S-fluorine: Rf = lower)
Using the compound (0.32 g) obtained in Example 20 Step 2 and the compound (0.13 g) obtained in Step 2 above, the title compound (5R-fluoride) ( 110 mg) and the title compound (5S-fluorine) (70 mg) were obtained as white solids, respectively.
5R-Fluorine: Rf = higher
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.57 (1H, m), 4.30 (1H, m), 4.16 (1H, dd, J = 6.8,3.9 Hz), 3.92 (1H, m), 3.80 (1H, d , J = 5.4Hz), 3.60-3.44 (2H, m), 3.39 (1H, m), 3.26 (1H, m), 2.24 (1H, m), 2.11-1.13 (22H, m), 1.52 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.13 (3H, s).
5S-Fluorine: Rf = lower
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.60 (1H, m), 4.30 (1H, m), 4.11 (1H, m), 4.06 (1H, dd, J = 7.3,4.4Hz), 3.79 (1H, d , J = 5.4Hz), 3.55 (1H, m), 3.43 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.33 (1H, m), 2.07 (1H, m), 1.92 -1.13 (21H, m), 1.52 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Process 4)
[(2R, 5S) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (5S-fluorine) (70 mg) obtained in Step 3 above, Example 23 Step 5 The title compound (55 mg) was obtained as a white solid by a method similar to that described above.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.66 (1H, m), 4.13-4.05 (3H, m), 3.58-3.52 (2H, m), 3.43 (1H, m), 3.32 (1H, m), 3.24 (1H, m), 2.37-2.27 (2H, m), 2.23-2.17 (1H, m), 1.92-1.03 (21H, m), 1.43 (3H, s), 1.12 (3H, s), 1.03 (1H , s).

(Example 160)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2RS, 5RS) -5-Fluorotetrahydro-2H-pyran-2-carboxylic acid Using compound (cis form) (0.30 g) obtained in Example 159, Step 1, the same as in Example 159, Step 2 The procedure gave the title compound (0.21 g) as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 4.64 (1H, d, J = 46.4Hz), 4.27 (1H, m), 4.05 (1H, t, J = 7.1Hz), 3.69 (1H, dd, J = 38.1 , 13.2Hz), 2.25 (1H, m), 2.06-1.97 (2H, m), 1.84 (1H, m).

(Process 2)
[(2S, 5S) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (5S-fluorine: Rf = higher)
as well as
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (5R-fluorine: Rf = lower)
Using the compound (0.13 g) obtained in Step 1 above and the compound (0.14 g) obtained in Step 2 of Example 20, the title compound (5S-fluorine) ( 70 mg) and the title compound (5R-fluorine) (70 mg) were obtained as white solids, respectively.
5S-Fluorine: Rf = higher
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.58 (1H, brd, J = 47.3Hz), 4.30 (1H, m), 4.07-3.98 (2H, m), 3.80 (1H, d, J = 5.4Hz), 3.59 (1H, dd, J = 33.2,12.7Hz), 3.50-3.42 (2H, m), 3.25 (1H, m), 2.24-2.02 (2H, m), 1.88-1.13 (20H, m), 1.52 ( 3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.19 (1H, s), 1.13 (3H, s).
5R-Fluorine: Rf = lower
MS (ESI) m / z: 494 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 47.3Hz), 4.30 (1H, m), 4.14 (1H, m), 4.01 (1H, brd, J = 10.7Hz), 3.80 ( 1H, d, J = 5.4Hz), 3.64-3.49 (2H, m), 3.40-3.33 (1H, m), 3.29-3.24 (1H, m), 2.25-2.04 (3H, m), 1.88-1.17 ( 19H, m), 1.52 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.17 (1H, s), 1.13 (3H, s).

(Process 3)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (5R-fluorine) (70 mg) obtained in Step 2 above, Example 23 Step 5 The title compound (63 mg) was obtained as a white solid by a method similar to that described above.
MS (ESI) m / z: 454 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 46.9Hz), 4.16-4.11 (2H, m), 4.01 (1H, brd, J = 10.3Hz), 3.6-3.50 (3H, m ), 3.36 (1H, m), 3.26 (1H, m), 2.36-2.10 (5H, m), 1.87-1.07 (20H, m), 1.43 (3H, s), 1.12 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 7, and peaks having a relative intensity of 24 or more when the maximum peak intensity is 100 in FIG.

　(実施例161)
[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-ジヒドロキシ-8-メトキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル][(2R,5R)-5-フルオロテトラヒドロ-2H-ピラン-2-イル]メタノン

(Example 161)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone

(Process 1)
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone The compound obtained in Example 27 Step 3 (0.27 g) and the compound obtained in Example 126 Step 3 (80 mg) was used to give the title compound (70 mg) as a white solid in the same manner as in Example 23, Step 4.
¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 47.8Hz), 4.13 (1H, m), 4.01 (1H, brd, J = 10.7Hz), 3.69-3.51 (4H, m), 3.42-3.32 (1H, m), 3.39 (3H, s), 3.27-3.25 (1H, m), 2.31 (1H, s), 2.26-2.13 (3H, m), 1.90-1.57 (9H, m), 1.51-1.18 (10H, m), 1.43 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Example 162)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
(2RS, 4SR) -2-[(Benzyloxy) methyl] -4-fluorotetrahydro-2H-pyran (cis isomer)
as well as
(2RS, 4RS) -2-[(Benzyloxy) methyl] -4-fluorotetrahydro-2H-pyran (trans form)
To a solution of benzyloxyacetaldehyde (5 g) and 3-buten-1-ol (2.84 ml) in dichloromethane (165 ml) was added tetrafluoroboric acid diethyl ether complex (4.53 ml), and the mixture was stirred at room temperature for 30 minutes. A potassium carbonate aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer is dried over anhydrous magnesium sulfate, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound mixture (6.02 g) as a colorless oil. It was.

(Process 2)
[(2RS, 4SR) -4-fluorotetrahydro-2H-pyran-2-yl] methanol (cis isomer)
as well as
[(2RS, 4RS) -4-fluorotetrahydro-2H-pyran-2-yl] methanol (trans form)
Using the compound obtained in Step 1 above (6.02 g) and 20% palladium hydroxide carbon as a catalyst, the title compound (cis isomer) (0.84 g) and the title compound (trans Body) (0.60 g) was obtained as a colorless oil.
Cis body
¹ H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.14-4.05 (1H, m), 3.65 (1H, dd, J = 11.5,3.2Hz), 3.60 (1H, dd, J = 11.7, 6.8Hz), 3.48-3.39 (2H, m), 2.09-1.99 (2H, m), 1.79-1.46 (2H, m).
Trans body
¹ H-NMR (CDCl ₃ ) δ: 5.10-4.98 (1H, m), 3.91-3.81 (3H, m), 3.69-3.62 (1H, m), 3.53-3.47 (1H, m), 2.09-2.02 ( 1H, m), 1.89-1.58 (3H, m).

(Process 3)
(2RS, 4RS) -4-Fluorotetrahydro-2H-pyran-2-carboxylic acid Compound (trans form) obtained in Step 2 above (0.60 g) in dichloromethane (100 ml) -water (50 ml) two-layer system To the solution were added diacetoxyiodobenzene (3.2 g), AZADOL (registered trademark) (34 mg), and tetrabutylammonium bromide (0.10 g), and the mixture was stirred at room temperature for 2 hours. Sodium sulfite was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and basified with 5N aqueous sodium hydroxide solution. The aqueous layer was washed with dichloromethane, acidified with 5N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.46 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 5.13-5.02 (1H, brd, J = 45.8Hz), 4.40 (1H, dd, J = 12.0,2.7Hz), 4.05-3.99 (1H, m), 3.97-3.90 (1H, m), 2.43-2.34 (1H, m), 1.95-1.76 (3H, m).

(Process 4)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (4R-fluorine)
as well as
[(2S, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a -Tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone (4S-fluorine)
Example 20 Using the compound (100 mg) obtained in Step 2 and the compound (0.10 g) obtained in Step 3 above, in the same manner as in Example 129, Step 5, the title compound (4R-fluoride) ( 34 mg) and the title compound (4S-fluorine) (74 mg) were obtained.
4R-Fluorine
MS (ESI) m / z: 494 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3), 4.41 (1H, dd, J = 10.7,2.4Hz), 4.30 (1H, m), 3.90-3.87 (1H, m) , 3.84 (1H, dd, J = 11.5,2.7Hz), 3.80 (1H, d, J = 5.4Hz), 3.57 (1H, m), 3.33 (1H, m), 3.29-3.25 (1H, m), 2.18-2.04 (2H, m), 1.99-1.13 (21H, m), 1.52 (3H, s), 1.44 (3H, s) 1.31 (3H, s), 1.13 (3H, s).
4S-Fluorine
MS (ESI) m / z: 494 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 5.14-5.03 (1H, m), 4.42-4.38 (1H, m), 4.31-4.29 (1H, m), 3.86-3.78 (3H, m), 3.47 (1H, m), 3.37 (1H, m), 3.26 (1H, m), 2.10-1.17 (23H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.13 (3H , s).

(Process 5)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (4R-fluorine) (130 mg) obtained in Step 4 above, Example 23 Step 5 and In a similar manner, the title compound (70 mg) was obtained as a white solid.
MS (ESI) m / z: 454 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3Hz), 4.41 (1H, dd, J = 11.2, 2.4Hz), 4.14 (1H, m), 3.91-3.80 (2H, m ), 3.59-3.51 (2H, m), 3.36-3.29 (1H, m), 3.28-3.22 (1H, m), 2.30 (1H, br), 2.23-2.05 (2H, m), 1.96-1.16 (21H) , m), 1.43 (3H, s), 1.11 (3H, s), 1.05 (1H, s).

(Example 163)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2 , 5a, 7a-Tetramethyloctadecahydro-8H-cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone obtained in Example 134, step 3. Using the obtained compound (0.2 g) and the compound (0.12 g) obtained in Example 126, Step 3, the title compound (80 mg) was obtained as a white solid in the same manner as in Example 23, Step 4.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.60 (1H, brd, J = 46.9Hz), 4.31 (1H, m) 4.17-4.08 (2H, m), 4.01 (1H, brd, J = 10.3Hz), 3.82 (1H, d, J = 5.4Hz), 3.73 (1H, m), 3.60 (1H, dd, J = 36.1Hz, 12.7Hz), 3.47 (1H, d, J = 13.2Hz), 2.84 (1H, m ), 2.27-2.10 (3H, m), 1.99-1.09 (14H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.03- 0.86 (1H, m), 0.91-0.87 (1H, m), 0.51-0.43 (1H, m).

(Process 2)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Example 23 using the compound obtained in Step 1 above (80 mg) The title compound (74 mg) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.60 (1H, brd, J = 47.3Hz), 4.19-4.08 (3H, m), 4.03-3.98 (1H, m), 3.66-3.54 (2H, m), 3.46 (1H, d, J = 13.2Hz), 2.83 (1H, m), 2.36-2.10 (4H, m), 2.01-1.92 (2H, m), 1.83-1.05 (16H, m), 1.44 (3H, s ), 1.14 (3H, s), 1.03-0.96 (1H, m), 0.91-0.86 (1H, m), 0.51-0.45 (1H, m).
(Example 164)
[(2R, 5S) -5-Fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
Benzyl (2R, 5S) -5-fluorotetrahydro-2H-pyran-2-carboxylate Example 126 Compound (Isomer A) (2.98 g) obtained in Step 2 and 1,8-diazabicyclo [5.4.0] A mixture of -7-undecene (3.73 ml) was stirred at 100 ° C. for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.03 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.43-7.28 (5H, m), 5.20 (2H, s), 4.69-4.50 (1H, m), 4.24-4.10 (2H, m), 3.57-3.48 (1H, m), 2.26-2.02 (2H, m), 1.85-1.72 (2H, m).

(Process 2)
(2R, 5S) -5-Fluorotetrahydro-2H-pyran-2-carboxylic acid The title compound (620 mg) was prepared in the same manner as in Example 23, Step 3 using the compound (1.03 g) obtained in Step 1 above. ) Was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.71-4.52 (1H, m), 4.27-4.18 (1H, m), 4.15-4.08 (1H, m), 3.58-3.49 (1H, m), 2.34-2.16 ( 2H, m), 1.86-1.72 (2H, m).

(Process 3)
[(2R, 5S) -5-Fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2 , 5a, 7a-Tetramethyloctadecahydro-8H-cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone obtained in Example 134, step 3. Using the obtained compound (166 mg) and the compound obtained in Step 2 above (95 mg), the title compound (166 mg) was obtained as a white solid in the same manner as in Step 4 of Example 23.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.67-4.53 (1H, m), 4.31 (1H, m), 4.11 (1H, dd, J = 7.8,3.4Hz), 4.08-4.00 (2H, m), 3.81 (1H, d, J = 5.4Hz), 3.56-3.44 (2H, m), 2.86-2.79 (1H, m), 2.37-2.25 (1H, m), 2.20-2.10 (1H, m), 1.99-1.09 (18H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04-0.97 (1H, m), 0.88-0.81 (1H, m ), 0.54-0.45 (1H, m).

(Process 4)
[(2R, 5S) -5-Fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Example 23 using the compound obtained in Step 3 above (166 mg) The title compound (74 mg) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.58 (1H, m), 4.25 (1H, d, J = 3.4Hz), 4.19 (1H, m), 4.05-3.95 (2H, m), 3.94-3.85 ( 2H, m), 3.74 (1H, s), 3.49-3.43 (2H, m), 3,35-3, 30 (2H, m), 2.69-2.61 (1H, m), 2.17-0.94 (16H, m ), 1.29 (3H, s), 1.01 (3H, s), 0.68-0.63 (1H, m), 0.45-0.37 (1H, m).

Example 165
[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
(2RS, 4SR) -4-Fluorotetrahydro-2H-pyran-2-carboxylic acid Using the compound (cis form) (0.84 g) obtained in Example 162, Step 2, the same as in Example 162, Step 3 By the procedure, the title compound (0.36 g) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.23 (1H, m), 4.07-4.02 (1H, m), 3.55 (1H, m), 2.52 (1H, m), 2.08 (1H, m), 1.88-1.77 (2H, m).

(Process 2)
(4R) -4-benzyl-3-{[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] carbonyl} -1,3-oxazolidine-2-one obtained in step 1 above Triethylamine (0.67 ml), pivaloyl chloride (0.24 ml), and (R) -4-benzyl-2-oxazolidinone (0.30 g) were added to a toluene (20 ml) solution of the compound (240 mg), and the mixture was heated to reflux for 2 days. Water was added to the reaction solution, followed by extraction twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (25 mg) as a colorless oil.
MS (ESI) m / z: 308 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.39-7.20 (5H, m), 5.01 (1H, brd, J = 10.9Hz), 4.92-4.66 (2H, m), 4.29-4.22 (3H, m), 3.58 (1H, m), 3.58 (1H, dd, J = 13.3,3.1Hz), 2.80 (1H, dd, J = 13.5,9.6Hz), 2.44-2.35 (1H, m), 2.14-2.06 (1H, m ), 1.96-1.71 (2H, m).

(Process 3)
(2R, 4S) -4-Fluorotetrahydro-2H-pyran-2-carboxylic acid To a solution of the compound (0.69 g) obtained in Step 2 above in tetrahydrofuran (25 ml) was added lithium hydroxide monohydrate under ice-cooling. (0.19 g) and 30% aqueous hydrogen peroxide (0.85 ml) were added, and the mixture was stirred at room temperature for 1 hour. A sodium sulfite aqueous solution was added to the reaction solution, followed by extraction twice with ethyl acetate and drying over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in dichloromethane and washed with 1N sodium hydroxide. The aqueous layer was acidified with 5N hydrochloric acid, extracted with dichloromethane and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.28 g) as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.23 (1H, m), 4.07-4.02 (1H, m), 3.55 (1H, m), 2.52 (1H, m), 2.08 (1H, m), 1.88-1.77 (2H, m).

(Process 4)
[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2 , 5a, 7a-Tetramethyloctadecahydro-8H-cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone obtained in Example 134, step 3. The title compound (0.11 g) was obtained in the same manner as in Step 23 of Example 23 using the obtained compound (0.10 g) and the compound (0.11 g) obtained in the above Step 3.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.31 (1H, m), 4.16 (1H, m), 3.98-3.91 (2H, m), 3.81 (1H, d, J = 5.4Hz), 3.47 (1H, d, J = 12.7Hz), 3.44-3.39 (1H, m), 2.82 (1H, m), 2.21-2.10 (2H, m), 2.09-2.01 (1H, m), 2.00-1.74 (6H, m), 1.67-1.57 (1H, m), 1.53-1.08 (10H, m), 1.52 (3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.15 ( 3H, s) 1.04-0.98 (1H, m), 0.90-0.86 (1H, m), 0.52-0.46 (1H, m).

(Process 5)
[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Example 23 using the compound (110 mg) obtained in Step 4 above The title compound (100 mg) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.18-4.14 (2H, m), 3.97-3.92 (2H, m), 3.58-3.53 (1H, m), 3.47 (1H, d, J = 12.7Hz), 3.42 (1H, m), 2.82 (1H, m), 2.36 (1H, s), 2.35-2.24 (2H, m), 2.20-2.12 (1H, m), 2.08-1.07 (17H, m), 1.45 (3H, s), 1.13 (3H, s), 1.06 (1H, s), 1.04-0.97 (1H, m), 0.91-0.84 (1H, m), 0.52-0.44 (1H m).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 8, and peaks having a relative intensity of 14 or more when the maximum peak intensity is 100 in FIG.

　(実施例166)
[(2R,4R)-4-フルオロテトラヒドロ-2H-ピラン-2-イル][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-トリヒドロキシ-4a,6a-ジメチルオクタデカヒドロ-7H-シクロプロパ[c]ナフト[2,1-f]キノリン-7-イル]メタノン

(Example 166)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2 , 5a, 7a-Tetramethyloctadecahydro-8H-cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone obtained in Example 134, step 3. The title compound (35 mg) was obtained as a white solid in the same manner as in Example 23, Step 4, using the obtained compound (50 mg) and the compound (56 mg) obtained in Step 162 of Example 162.
MS (ESI) m / z: 506 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3Hz), 4.42 (1H, dd, J = 10.5,2.7Hz), 4.31 (1H, m), 4.02 (1H, m), 3.91-3.81 (3H, m), 3.47 (1H, d, J = 12.7Hz), 2.83 (1H, m), 2.21-1.73 (9H, m), 1.66-1.10 (11H, m), 1.52 (3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04-0.98 (1H, m), 0.90-0.86 (1H, m), 0.52-0.46 (1H, m) .

(Process 2)
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Example 23 using the compound obtained in Step 1 above (35 mg) The title compound (32 mg) was obtained as a white solid by the same method as in Step 5.
MS (ESI) m / z: 466 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.10 (1H, m), 4.41 (1H, dd, J = 10.5,2.7Hz), 4.15 (1H, m), 4.02 (1H, m), 3.92-3,83 (2H, m), 3.55 (1H, m), 3.47 (1H, d, J = 12.7Hz), 2.81 (1H, m), 2.34-2.24 (2H, m), 2.13-1.65 (9H, m), 1.60-1.04 (10H, m), 1.45 (3H, s), 1.13 (3H, s), 1.06 (1H, s), 1.03-0.98 (1H, m), 0.90-0.84 (1H, m), 0.51- 0.45 (1H, m).

(Example 167)
[(2R, 4S) -4-methyltetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
Ethyl 2-[(2S) -4-{[tert-butyl (diphenyl) silyl] oxy} -2-methylbutyl] -1,3-dithian-2-carboxylate tert-butyl [(3S) -4-iodo- To a solution of 3-methylbutoxy] diphenylsilane (10.4 g) and ethyl 1,3-dithiane-2-carboxylate (5.0 g) in dimethylformamide (30 ml) -toluene (100 ml) at 0 ° C., sodium hydride (63 wt% , 1.19 g) was added, and the mixture was stirred at room temperature for 1 hour, and then stirred at 80 ° C for 2 hours. Water was added to the reaction solution, and the organic layer was partially distilled off under reduced pressure. The mixture was extracted 3 times with hexane-ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (10.3 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.70-7.62 (4H, m), 7.45-7.34 (6H, m), 4.25-4.17 (2H, m), 3.72-3.63 (2H, m), 3.41-3.13 ( 2H, m), 2.70-2.59 (2H, m), 2.22-1.21 (7H, m), 1.31 (3H, t, J = 7.0Hz), 1.04 (9H, s), 0.88 (3H, d, J = 6.3Hz).

(Process 2)
Ethyl (4S) -6-{[tert-butyl (diphenyl) silyl] oxy} -4-methyl-2-oxohexanate To a solution of N-bromosuccinimide (20.6 g) in acetonitrile (80 ml) -water (20 ml), A solution of the compound obtained in Step 1 (10 g) in acetonitrile (20 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Dichloromethane (100 ml), hexane (100 ml), and an aqueous sodium sulfite solution were added to the reaction solution, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to obtain the title compound (10.3 g).
¹ H-NMR (CDCl ₃ ) δ: 7.71-7.64 (4H, m), 7.47-7.35 (6H, m), 4.30 (2H, q, J = 7.2Hz), 3.69 (2H, t, J = 6.3Hz ), 2.84 (1H, dd, J = 17.2,5.5Hz), 2.67 (1H, dd, J = 17.4,8.0Hz), 2.34-2.24 (1H, m), 1.63-1.29 (5H, m), 1.04 ( 9H, s), 0.91 (3H, d, J = 6.6 Hz).

(Process 3)
Ethyl (4S) -6-hydroxy-4-methyl-2-oxohexanate Acetic acid (1.4 ml) and tetrabutylammonium fluoride (1M) were added to a solution of the compound (2.60 g) obtained in Step 2 above in tetrahydrofuran (100 ml). Tetrahydrofuran solution, 8 ml) was added. After stirring at room temperature overnight, the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.10 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.33-4.23 (2H, m), 4.07-3.98 (1H, m), 3.82-3.76 (1H, m), 3.61-3.57 (1H, m), 2.09-1.95 ( 1H, m), 1.79-1.55 (4H, m), 1.34 (3H, t, J = 7.2Hz), 0.96 (3H, d, J = 6.7Hz).

(Process 4)
Ethyl (2R, 4S) -4-methyltetrahydro-2H-pyran-2-carboxylate To a solution of the compound obtained in Step 3 above (1.31 g) and triethylsilane (1.21 ml) in dichloromethane (50 ml) under ice-cooling. Boron trifluoride diethyl ether complex (0.96 ml) was added and stirred for 30 minutes. A saturated aqueous ammonium chloride solution (50 ml) and water (50 ml) were added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.75 g) as a colorless oil.
MS (ESI) m / z: 173 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.23 (2H, q, J = 7.2Hz), 4.16-4.11 (1H, m), 3.94 (1H, dd, J = 12.0, 2.2Hz), 3.46 (1H, m ), 2.00-1.94 (1H, m), 1.74-1.64 (1H, m), 1.59-1.52 (1H, m), 1.35-1.17 (2H, m), 1.29 (3H, t, J = 7.3Hz), 0.98 (3H, d, J = 6.8Hz).

(Process 5)
(2R, 4S) -4-Methyltetrahydro-2H-pyran-2-carboxylic acid To a solution of the compound obtained in step 4 above (0.75 g) in ethanol (20 ml) was added 5N aqueous sodium hydroxide solution (10 ml). And stirred at room temperature for 1 hour. A part of the organic layer was distilled off under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The aqueous layer was acidified with 5N hydrochloric acid (15 ml), extracted with dichloromethane and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (0.58 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.16-4.12 (1H, m), 3.96 (1H, dd, J = 11.7,2.4Hz), 3.55-3.50 (1H, m), 2.12-2.06 (1H, m) 1.77-1.66 (1H, m), 1.61-1.55 (1H, m), 1.33-1.14 (2H, m), 1.00 (3H, d, J = 6.8 Hz).

(Process 6)
[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] naphtho [2 , 1-f] quinolin-8 (4H) -yl] [(2R, 4S) -4-methyltetrahydro-2H-pyran-2-yl] methanone The compound (40 mg) obtained in Example 2, Step 2 and the above Using the compound (0.10 g) obtained in Step 5, the title compound (21 mg) was obtained as a white solid in the same manner as in Step 23 of Example 23.
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.34-4.27 (1H, m), 4.04 (1H, dd, J = 11.2,4.4Hz), 3.89 (1H, d, J = 10.7Hz), 3.80 (1H, d , J = 4.9Hz), 3.49-3.35 (3H, m), 3.31-3.24 (1H, m), 2.06 (1H, m), 1.88-1.13 (23H, m), 1.52 (3H, s), 1.43 ( 3H, s), 1.31 (3H, s), 1.13 (3H, s), 0.97 (3H, d, J = 5.4 Hz).

(Process 7)
[(2R, 4S) -4-methyltetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (21 mg) obtained in the above Step 6, the title was prepared in the same manner as in Example 23, Step 5. Compound (19 mg) was obtained as a white solid.
MS (ESI) m / z: 490 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.19-4.11 (1H, m), 4.04 (1H, dd, J = 11.2,4.4Hz), 3.93-3.87 (1H, brm), 3.54 (1H, d, J = 3.9Hz), 3.48-3.34 (3H, m), 3.31-3.24 (1H, m), 2.24-2.14 (1H, m), 1.88-1.11 (25H, m), 1.42 (3H, s), 1.11 (3H , s), 0.97 (3H, d, J = 6.3 Hz).

Example 168
(5R) -5-hydroxy-6-oxo-6-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] hexanoic acid

(Process 1)
(5R) -5- (benzyloxy) -6-{[tert-butyl (dimethyl) silyl] oxy} hexanal {[(2R) -2- (benzyloxy) hex-5-en-1-yl] oxy} To a solution of (tert-butyl) dimethylsilane (4.24 g) in tert-butyl alcohol (198 ml), copper (II) chloride (0.18 g), bis (benzonitrile) palladium (II) dichloride (0.51 g), nitromethane (13.2 ml) ) And sodium nitrite (46 mg) were added, and the mixture was stirred at room temperature for 5 hours under an oxygen atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [ethyl acetate / hexane] to give the title compound (2.40 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 9.73 (1H, t, J = 1.7Hz), 7.35-7.26 (5H, m), 4.71 (1H, d, J = 11.7Hz), 4.55 (1H, d, J = 11.7Hz), 3.71 (1H, dd, J = 10.5, 5.6Hz), 3.59 (1H, dd, J = 10.5, 5.1Hz), 3.46 (1H, m), 2.41-2.38 (2H, m), 1.81 -1.50 (4H, m), 0.90 (9H, s), 0.06 (6H, m).

(Process 2)
(5R) -5- (Benzyloxy) -6-{[tert-butyl (dimethyl) silyl] oxy} hexanoic acid Compound (2.40 g) obtained in Step 1 above in dichloromethane (70 ml) -water (70 ml ) Was added diacetoxyiodobenzene (4.6 g), 2-azaadamantane-N-oxyl (0.22 g), and tetrabutylammonium bromide (0.23 g), and the mixture was stirred at room temperature for 3 hours. After extraction with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (2.5 g) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, m), 7.36-7.27 (3H, m) 7.13-7.09 (1H, m), 4.70 (1H, d, J = 11.7Hz), 4.56 (1H, d, J = 11.7Hz), 3.71 (1H, dd, J = 10.3,5.9Hz), 3.59 (1H, dd, J = 10.5,5.1Hz), 3.47 (1H, m), 2.34 (2H, m), 1.82-1.52 (4H, m), 0.90 (9H, s), 0.04 (6H, s).

(Process 3)
(5R) -5- (Benzyloxy) -6-hydroxyhexanoic acid To a solution of the compound (2.5 g) obtained in Step 2 above in tetrahydrofuran (30 ml) was added 5N hydrochloric acid (5 ml), and the mixture was stirred at room temperature for 1 After stirring for 5 hours, 5N aqueous sodium hydroxide solution was added to make the solution basic, and the mixture was washed with dichloromethane. 5N hydrochloric acid was added to the aqueous layer to make it acidic again, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1.35 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.29 (5H, m), 4.62 (1H, d, J = 11.2Hz), 4.57 (1H, d, J = 11.2Hz), 3.75-3.71 (1H, m ), 3.58-3.51 (2H, m), 2.40-2.33 (2H, m), 1.76-1.55 (4H, m).

(Process 4)
Benzyl (5R) -5- (benzyloxy) -6-hydroxyhexanate Using the compound (1.35 g) obtained in Step 3 above, the title compound (1.45 g) was prepared in the same manner as in Example 23 Step 1. Obtained as a colorless oil.
MS (ESI) m / z: 329 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.12 (2H, s), 4.59 (1H, d, J = 11.7Hz), 4.53 (1H, d, J = 11.7Hz), 3.73-3.66 (1H, m), 3.57-3, 47 (2H, m), 2.36 (2H, t, J = 7.3Hz), 1.90-1.50 (5H, m).

(Process 5)
(2R) -2,6-bis (benzyloxy) -6-oxohexanoic acid Using the compound (1.45 g) obtained in Step 4 above, the title compound (1.25 g ) Was obtained as a pale yellow oil.
MS (ESI) m / z: 343 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 7.40-7.30 (10H, m), 5.11 (2H, s), 4.70 (1H, d, J = 11.2Hz), 4.49 (1H, d, J = 11.2Hz), 4.00 (1H, m), 2.40-2.31 (2H, m), 1.92-1.73 (4H, m).

(Process 6)
Benzyl (5R) -5- (benzyloxy) -6-[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] -6-oxohexanate Example 20 Compound (0.36 g) obtained in Step 2 above and the above Using the compound (0.46 g) obtained in Step 5, the title compound (0.33 g) was obtained as a white solid in the same manner as in Step 23 of Example 23.
MS (ESI) m / z: 688 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.10 (2H, s), 4.63 (1H, d, J = 11.2Hz), 4.38 (1H, d, J = 11.2Hz), 4.31 (1H, m), 4.06 (1H, m), 3.80 (1H, d, J = 5.4Hz), 3.62-3.59 (1H, m), 3.38-3.30 (2H, m), 2.37 (2H, t, J = 7.3Hz), 2.12-2.02 (1H, m), 1.91-1.08 (22H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.13 (3H, s ).

(Process 7)
Benzyl (5R) -5- (benzyloxy) -6-oxo-6-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a- Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] hexanate The title compound was prepared in the same manner as in Example 23, Step 5, using the compound (0.33 g) obtained in Step 6 above. (0.26 g) was obtained as a white solid.
MS (ESI) m / z: 648 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.10 (2H, s), 4.63 (1H, d, J = 11.2Hz) 4.38 (1H, d, J = 11.2Hz), 4.14 (1H, m), 4.05 (1H, dd, J = 8.1,5.1Hz), 3.60 (1H, m), 3.54 (1H, m), 3.38-3.28 (2H, m), 2.41-2.32 (3H, m ), 2.24-2.16 (1H, m), 1.91-1.16 (22H, m), 1.44 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Process 8)
(5R) -5-hydroxy-6-oxo-6-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydro Naphtho [2,1-f] quinolin-1 (2H) -yl] hexanoic acid Using the compound (0.29 g) obtained in Step 7 above, the title compound (0.29 g) was prepared in the same manner as in Step 13 of Example 13. 0.16 g) was obtained as a white solid.
MS (ESI) m / z: 468 [M + H] ^+
1 H-NMR (CD ₃ OD) δ: 4.37 (1H, m), 4.05 (1H, m), 3.45-3.33 (4H, m), 3.21-3.15 (1H, m), 2.37-2.25 (2H, m ), 2.15 (1H, m), 1.92-1.18 (20H, m), 1.45 (3H, s), 1.12 (3H, s).

(Example 169)
4,4,4-trifluoro-1-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2 , 1-f] quinolin-1 (2H) -yl] butan-1-one

(Process 1)
4,4,4-trifluoro-1-[(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1, 3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] butan-1-one Example 20 Compound (0.18 g) obtained in Step 2 and 4,4,4 The title compound (0.22 g) was obtained in the same manner as in Step 4 of Example 23 using -trifluorobutyric acid (105 mg).
MS (ESI) m / z: 488 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.81-3.79 (1H, d, = 4.9Hz), 3.42-3.33 (2H, m), 3.28-3.23 (1H, m), 2.56-2.33 (4H, m), 2.13-2.02 (1H, m), 1.91-1.68 (5H, m), 1.67-1.09 (13H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Process 2)
4,4,4-trifluoro-1-[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2 , 1-f] quinolin-1 (2H) -yl] butan-1-one The title compound (0.18 g) was prepared in the same manner as in Example 23, step 5, using the compound (0.22 g) obtained in Step 1 above. ) Was obtained as a white solid.
MS (ESI) m / z: 448 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.18-4.11 (1H, m), 3.55-3.51 (1H, m), 3.42-3.33 (2H, m), 3.28-3.22 (1H, m), 2.57-2.29 ( 5H, m), 2.25-2.16 (1H, m), 1.91-1.36 (13H, m), 1.42 (3H, s), 1.30-1.10 (5H, m), 1.12 (3H, s), 1.04 (1H, s).

(Example 170)
[(1S) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(1S) -3,3-difluorocyclopentyl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1 , 3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Example 20 Compound (120 mg) obtained in Step 2 and (1S) -3,3-difluoro The title compound (70 mg) was obtained in the same manner as in Example 23, step 4, using cyclopentanecarboxylic acid (74 mg).
MS (ESI) m / z: 496 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.30 (1H, m), 3.80 (1H, d, J = 5.4Hz), 3.46-3.35 (2H, m), 3.29-3.23 (1H, m), 3.12 (1H , m), 2.50-2.35 (1H, m), 2.28-2.13 (2H, m), 2.11-1.13 (22H, m), 1.52 (3H, s), 1.43 (3H, s), 1.32 (3H, s ), 1.13 (3H, s).

(Process 2)
[(1S) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (70 mg) obtained in Step 1 above, the title compound (64 mg) as a white solid was prepared in the same manner as in Example 23, Step 5. Obtained.
MS (ESI) m / z: 456 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.14 (1H, m), 3.53 (1H, m), 3.44-3.34 (2H, m), 3.28-3.22 (1H, m), 3.17-3.07 (1H, m) 2.50-2.34 (1H, m), 2.31-1.17 (25H, m), 1.42 (3H, s), 1.12 (3H, s), 1.03 (1H, s).

FIG. 9 shows the powder X-ray diffraction pattern of the title compound, and Table 9 shows peaks having a relative intensity of 17 or more when the maximum peak intensity is 100 in FIG.

　(実施例171)
[(1R)-3,3-ジフルオロシクロペンチル][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-トリヒドロキシ-10a,12a-ジメチルヘキサデカヒドロナフト[2,1-f]キノリン-1(2H)-イル]メタノン

(Example 171)
[(1R) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone

(Process 1)
[(1R) -3,3-difluorocyclopentyl] [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1 , 3] Dioxolo [5,6] naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Example 20 Compound (120 mg) obtained in Step 2 and (1R) -3,3-difluoro The title compound (80 mg) was obtained as a white solid in the same manner as in Example 23, Step 4 using cyclopentanecarboxylic acid (74 mg).
MS (ESI) m / z: 496 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.35-4.26 (1H, m), 3.80 (1H, d, J = 5.4Hz), 3.43-3.37 (2H, m), 3.29-3.23 (1H, m), 3.13 -3.05 (1H, m), 2.53-2.39 (1H, m), 2.28-2.15 (2H, m), 2.11-1.11 (22H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Process 2)
[(1R) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone Using the compound (80 mg) obtained in Step 1 above, the title compound (74 mg) was converted to a white solid in the same manner as in Example 23, Step 5. Obtained.
MS (ESI) m / z: 456 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.18-4.12 (1H, m), 3.53 (1H, d, J = 3.9Hz), 3.43-3.36 (2H, m), 3.27-3.23 (1H, m), 3.14 -3.05 (1H, m), 2.53-2.39 (1H, m), 2.34-2.14 (4H, m), 2.10-1.04 (22H, m), 1.42 (3H, s), 1.12 (3H, s).

(Example 172)
(Cis-4-fluorocyclohexyl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] methanone

(Process 1)
(Cis-4-fluorocyclohexyl) [(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS) -13a-hydroxy-2,2,5a, 7a-tetramethylhexadecahydro [1,3] dioxolo [5,6] Naphtho [2,1-f] quinolin-8 (4H) -yl] methanone Example 20 Compound (0.10 g) obtained in Step 2 and cis-4-fluorocyclohexanecarboxylic acid (0.12 g) ) To give the title compound (70 mg) as a white solid in the same manner as in Example 129, step 5.
MS (ESI) m / z: 492 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.80 (1H, brd, J = 46.5Hz), 4.30 (1H, m), 3.80 (1H, d, J = 5.5Hz), 3.47-3.35 (2H, m), 3.33-3.26 (1H, m), 2.43 (1H, m), 2.15-2.00 (3H, m), 1.97-1.08 (24H, m), 1.52 (3H, s), 1.43 (3H, s), 1.32 ( 3H, s), 1.13 (3H, s).

(Process 2)
(Cis-4-fluorocyclohexyl) [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] Quinolin-1 (2H) -yl] methanone Using the compound (70 mg) obtained in Step 1 above, the title compound (63 mg) was obtained as a white solid in the same manner as in Step 23 of Example 23.
MS (ESI) m / z: 452 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.80 (1H, brd, J = 4.80), 4.15 (1H, m), 3.53 (1H, br), 3.44-3.34 (2H, m), 3.1-3.26 (1H, m), 2.43 (1H, m), 2.30 (1H, br), 2.20 (1H, m), 2.14-2.03 (2H, m), 1.94-1.15 (24H, m), 1.42 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Example 173)
(Cis-4-fluorocyclohexyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
(Cis-4-fluorocyclohexyl) [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2,5a, 7a-tetramethyloctadecahydro-8H -Cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone Example 134 Compound (125 mg) obtained in Step 3 and cis-4-fluoro The title compound (30 mg) was obtained as a white solid in the same manner as in Example 23, Step 4 using cyclohexanecarboxylic acid (73 mg).
MS (ESI) m / z: 504 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.81 (1H, brd, J = 48.8Hz), 4.31 (1H, m), 3.88 (1H, brd, J = 13.7Hz), 3.82 (1H, d, J = 4.9 Hz), 3.51 (1H, d, J = 13.7Hz), 2.83 (1H, m), 2.44 (1H, m), 2.20-2.05 (3H, m), 1.98 (6H, m), 1.66-1.09 (15H , m), 1.53 (3H, s), 1.44 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.06-0.98 (1H, m), 0.86-0.81 (1H, m), 0.51-0.44 (1H, m).

(Process 2)
(Cis-4-fluorocyclohexyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone The title compound (27 mg) was prepared in the same manner as in Example 23, Step 5, using the compound (30 mg) obtained in Step 1 above. Was obtained as a white solid.
MS (ESI) m / z: 464 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4,81 (1H, brd, J = 48.3Hz), 4.15 (1H, m), 3.88 (1H, brd, J = 13.7Hz), 3.56 (1H, d, J = 3.9Hz), 3.51 (1H, d, J = 13.7Hz), 2.81 (1H, m), 2.44 (1H, m), 2.28 (1H, m), 2.13-2.05 (3H, m), 1.98-1.13 (22H, m), 1.43 (3H, s), 1.13 (3H, s), 1.04-0.99 (1H, m), 0.86-0.80 (1H, m), 0.49-0.45 (1H, m).

(Example 174)
[(1S, 3S) -3-fluorocyclohexyl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
[(1S, 3R, 4R) -4-bromo-3-fluorocyclohexyl] methanol and
[(1S, 3R, 4R) -3-Bromo-4-fluorocyclohexyl] methanol To a solution of N-bromosuccinimide (10.8 g) in dichloromethane (130 ml) was added hydrogen fluoride pyridine (5.27 ml) and at room temperature for 10 minutes. After stirring, a solution of [(1S) -cyclohex-3-en-1-yl] methanol (3.40 g) in dichloromethane (20 ml) was added and stirred at the same temperature for 1 hour. Ice water and an aqueous potassium carbonate solution were added to the reaction solution, followed by extraction twice with dichloromethane, and then the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography [ethyl acetate / hexane] to give a mixture of the title compounds (3.34 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 4.94-4.86 (0.6H, m), 4.86-4.77 (0.4H, m), 4.42 (0.4H, m), 4.37 (0.6H, m), 3.61-3.47 ( 2H, m), 2.28-1.87 (5H, m), 1.69-1.32 (3H, m).

(Process 2)
[(1S, 3S) -3-Fluorocyclohexyl] methanol (1,3-trans form)
as well as
(Cis-4-Fluorocyclohexyl) methanol (1,4-cis)
After adding tributyltin hydride (10.4 ml) and 2,2′-azobisisobutyronitrile (0.026 g) at 100 ° C. to a toluene (200 ml) solution of the mixture (3.34 g) obtained in the above step 1 The mixture was stirred at the same temperature for 1 hour. The reaction solution was cooled to 0 ° C., an aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted twice with ethyl acetate, and then the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (1,3-trans form) (0.83 g) and the title compound (1,4-cis form). ) (0.61 g) was obtained as a colorless oil.
1,3-trans form
¹ H-NMR (CDCl ₃ ) δ: 4.93 (1H, brd, J = 48.3Hz), 3.52-3.46 (2H, m) 2.09-1.88 (3H, m), 1.84-1.76 (1H, m), 1.73- 1.57 (2H), 1.50-1.16 (3H, m), 1.10-0.99 (1H, m).
1,4-cis body
¹ H-NMR (CDCl ₃ ) δ: 4.84 (1H, brd, J = 48.3 Hz), 3.49 (2H, m), 2.05 (2H, m), 1.64-1.33 (8H, m).

(Process 3)
(1S, 3S) -3-Fluorocyclohexanecarboxylic acid Using the compound (1,3-trans form) (0.40 g) obtained in the above Step 2, the title compound ( 0.33 g) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 4.93 (1H, brd, J = 47.7Hz), 2.78 (1H, tt, J = 11.5,3.8Hz), 2.22 (1H, m), 2.03-1.93 (2H, m ), 1.80-1.59 (3H, m), 1.57-1.42 (2H, m).

(Process 4)
[(1S, 3S) -3-fluorocyclohexyl] [(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS) -12a-hydroxy-2,2,5a, 7a-tetramethylocta Decahydro-8H-cyclopropa [c] [1,3] dioxolo [5,6] naphtho [2,1-f] quinolin-8-yl] methanone Compound (160 mg) obtained in Example 134, step 3, and the above Using the compound (93 mg) obtained in Step 3, the title compound (47 mg) was obtained as a white solid in the same manner as in Step 23 of Example 23.
MS (ESI) m / z: 504 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4,97 (1H, brd, J = 48.3Hz), 4.31 (1H, m), 3.96 (1H, m), 3.82 (1H, d, J = 5.4Hz), 3.50 (1H, brd, J = 13.2Hz), 2.89 (1H, m), 2.80 (1H, m), 2.15 (1H, m), 2.05-1.12 (23H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.15 (3H, s), 1.05-0.99 (1H, m), 0.83-0.79 (1H, m), 0.51-0.45 (1H, m).

(Process 5)
[(1S, 3S) -3-fluorocyclohexyl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Using the compound obtained in Step 4 above (47 mg), the title was prepared in the same manner as in Step 5 of Example 23. Compound (43 mg) was obtained as a white solid.
MS (ESI) m / z: 464 [M + H] ^+
1 H-NMR (CDCl ₃ ) δ: 4.97 (1H, brd, J = 47.3Hz), 4.15 (1H, m) 3.95 (1H, m), 3.55 (1H, d, J = 3.9Hz), 3.50 (1H , brd, J = 13.7Hz), 2.89 (1H, m), 2.79 (1H, m), 2.28 (1H, m), 2.05-1.07 (25H, m), 1.42 (3H, s), 1.13 (3H, s), 1.04-0.99 (1H, m), 0.83-0.79 (1H, m), 0.50-0.43 (1H, m).
(Example 175)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone

(Process 1)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS) -14a-hydroxy-2,2,5a, 7a -Tetramethyloctadecahydro-8H- [1,3] dioxolo [7,8] phenanthro [2,1-b] azepin-8-yl] methanone Example 86 Compound (0.200 g) obtained in Step 9 Using the compound (0.157 g) obtained in Example 126, Step 3, the title compound (269 mg) was obtained as a white solid in the same manner as in Example 129, Step 5.

(Process 2)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-Dimethyloctadecahydro-1H-phenanthro [2,1-b] azepin-1-yl] methanone Using the compound (0.269 g) obtained in Step 1 above, in the same manner as in Step 23 of Example 23 The title compound (0.045g) was obtained as a white solid.
MS (ESI) m / z: 468 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.63-4.50 (1H, m), 4.16-4.09 (1H, m), 4.07-3.98 (2H, m), 3.61-3.32 (5H, m), 2.66-2.62 ( 1H, m), 2.26-2.05 (4H, m), 1.90-1.01 (22H, m), 1.51 (3H, s), 1.08 (3H, s).

(Example 176)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-Dimethyloctadecahydrophenanthro [2,1-b] azocin-1 (2H) -yl] methanone

(Process 1)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(3aS, 5aR, 5bS, 7aS, 13aS, 13bR, 15aS, 15bS) -15a-hydroxy-2,2,5a, 7a -Tetramethyloctadecahydro [1,3] dioxolo [7,8] phenanthro [2,1-b] azocin-8 (4H) -yl] methanone Example 107 (0.162 g) with the compound obtained in Step 7 Using the compound (0.123 g) obtained in Example 126, Step 3, the title compound (216 mg) was obtained as a white solid in the same manner as in Example 129, Step 5.

(Process 2)
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(6aS, 6bR, 8aS, 9S, 10S, 12aR, 12bS, 14aS) -8a, 9,10-trihydroxy-12a, 14a-Dimethyloctadecahydrophenanthro [2,1-b] azocin-1 (2H) -yl] methanone Using the compound obtained in Step 1 above (0.216 g), the same as Example 23 Step 5 The title compound (0.118 g) was obtained as a white solid by the procedure.
MS (ESI) m / z: 482 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 4.63-4.51 (1H, m), 4.17-3.98 (3H, m), 3.61-3.45 (2H, m), 3.40-3.34 (1H, m), 3.09-3.01 ( 1H, m), 2.37-1.03 (30H, m), 1.50 (3H, s), 1.09 (3H, s).

(Example 177)
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone

(Process 1)
(3β, 17β) -3- (Methoxymethoxy) androsta-5,15-dien-17-ol (3β) -3- (methoxymethoxy) androsta-5,15-dien-17-one (9.71 g) Was used to give the title compound (9.46 g) as a white solid in the same manner as in Step 3 of Example 19.
¹ H-NMR (CDCl ₃ ) δ: 5.89 (1H, m), 5.68 (1H, m), 5.38 (1H, m), 4.69 (2H, s), 4.33 (1H, m), 3.43 (1H, m ), 3.38 (3H, s), 2.37 (1H, m), 2.28 (1H, m), 2.20 (1H, m), 1.93-1.82 (4H, m), 1.75-1.47 (6H, m), 1.27 ( 1H, s), 1.11-0.98 (2H, m), 1.04 (3H, s), 0.84 (3H, s).

(Process 2)
(3β, 17α) -3- (Methoxymethoxy) androsta-5,15-dien-17-ylbenzoate Using the compound obtained in Step 1 above (9.46 g), the same procedure as in Step 148 of Example 148 Gave the title compound (11.22 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 8.04-8.01 (2H, m), 7.55 (1H, m), 7.45-7.42 (2H, m), 6.25 (1H, dd, J = 1.5,5.9Hz), 6.03 (1H, m), 5.40 (1H, d, J = 5.4Hz), 5.34 (1H, d, J = 2.4Hz), 4.70 (2H, s), 3.43 (1H, m), 3.38 (3H, s) , 2.47 (1H, m), 2.38 (1H, m), 2.32-2.17 (2H, m), 1.93-1.51 (9H, m), 1.11-1.04 (2H, m), 1.07 (3H, s), 0.99 (3H, s).

(Process 3)
(3β, 17α) -3- (Methoxymethoxy) androsta-5,15-dien-17-ol By using the compound (11.3 g) obtained in Step 2 above, the same procedure as in Step 5 of Example 5 was performed. The title compound (7.11 g) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 6.10 (1H, dd, J = 1.0, 5.9 Hz), 5.97 (1 H, m), 5.38 (1 H, m), 4.70 (2 H, s), 4.09 (1 H, dd , J = 2.4,6.3Hz), 3.44 (1H, m), 3.38 (3H, s), 2.38 (1H, m), 2.32-2.25 (2H, m), 2.18 (1H, m), 1.93-1.85 ( 2H, m), 1.79 (1H, m), 1.74-1.50 (6H, m), 1.18 (1H, d, J = 6.3Hz), 1.12-1.01 (2H, m), 1.06 (3H, s), 0.83 (3H, s).

(Process 4)
(2S, 4aR, 4bS, 6aS, 7R, 7aR, 8aR, 8bR, 8cR) -2- (methoxymethoxy) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a , 7,7a, 8,8a, 8b, 8c, 9-hexadecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthren-7-ol Compound obtained in the above step 3 (6.81 g) To a dichloromethane (100 ml) solution were added diethylzinc (1.06 M hexane solution, 29.0 ml) and diiodomethane (2.5 ml) at 0 ° C., and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 2 hours. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to form a slurry by adding dichloromethane and hexane to the resulting residue, and the solid was collected by filtration to give the title compound (1.26 g) as a white solid. The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ethyl acetate / hexane] to give the title compound (5.33 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 5.39 (1H, m), 4.69 (2H, s), 3.91 (1H, dd, J = 3.4, 5.4Hz), 3.43 (1H, m), 3.38 (3H, m ), 2.37 (1H, m), 2.32-2.21 (2H, m), 1.92-1.82 (2H, m), 1.76-1.37 (8H, m), 1.23 (1H, m), 1.10-1.01 (2H, m ), 1.03 (3H, s), 0.93-0.87 (3H, m), 0.92 (3H, s), 0.82 (1H, dd, J = 11.7, 4.9 Hz).

(Process 5)
(2S, 4aR, 4bS, 6aS, 7aR, 8aR, 8bR, 8cR) -2- (methoxymethoxy) -4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 7a, 8 , 8a, 8b, 8c, 9-Tetradecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthrene-7 (1H) -one Using the compound (5.33g) obtained in the above Step 4 The title compound (4.66 g) was obtained as a white solid in the same manner as in Example 3, Step 1.
¹ H-NMR (CDCl ₃ ) δ: 5.41 (1H, m), 4.69 (2H, s), 3.43 (1H, m), 3.38 (3H, s), 2.39 (1H, m), 2.36-2.25 (2H , m), 1.93-1.43 (10H, m), 1.35 (1H, m), 1.27 (1H, m), 1.15 (3H, s), 1.09-1.02 (1H, m), 1.06 (3H, s), 0.95 (1H, m), 0.87-0.84 (2H, m).

(Process 6)
(2S, 4aR, 4bS, 6aS, 7E, 7aR, 8aR, 8bR, 8cR) -N-hydroxy-2- (methoxymethoxy) -4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6 , 6a, 7a, 8,8a, 8b, 8c, 9-tetradecahydrocyclopropa [4,5] cyclopenta [1,2-a] phenanthrene-7 (1H) -imine Compound obtained in step 5 above ( The title compound (4.71 g) was obtained as a white solid in the same manner as in Example 36, step 5 using 4.66 g).
MS (ESI) m / z: 360 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.40 (1H, m), 4.69 (2H, s), 3.43 (1H, m), 3.38 (3H, s), 2.38 (1H, m), 2.32-2.24 (2H , m), 2.08 (1H, m), 1.90 (1H, m), 1.87-1.70 (4H, m), 1.62-1.32 (5H, m), 1.25 (1H, brs), 1.16 (3H, s), 1.09-1.03 (1H, m), 1.06 (3H, s), 0.96 (1H, m), 0.75 (1H, dd, J = 4.4,10.7Hz), 0.70 (1H, m).

(Process 7)
(2S, 4aR, 4bS, 6aS, 8aR, 9aR, 9bR, 9cR) -2- (methoxymethoxy) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 7 , 8a, 9,9a, 9b, 9c, 10-hexadecahydro-8H-cyclopropa [c] naphtho [2,1-f] quinolin-8-one Using the compound (4.71 g) obtained in the above step 6 In the same manner as in Example 36, Step 6, the title compound (4.15 g) was obtained as a white solid.
MS (ESI) m / z: 360 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 5.55 (1H, brs), 5.41 (1H, m), 4.70 (2H, s), 3.44 (1H, m), 3.38 (3H, s), 2.42-2.34 (2H , m), 2.28 (1H, m), 1.91 (1H, m), 1.86 (1H, m), 1.77-1.50 (6H, m), 1.46-1.34 (2H, m), 1.33 (3H, s), 1.26 (1H, m), 1.12-1.03 (3H, m), 1.02 (3H, s), 0.93 (1H, dd, J = 6.3, 11.2 Hz), 0.66 (1H, m).

(Process 8)
(2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR) -2- (methoxymethoxy) -4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 7,8 , 8a, 9,9a, 9b, 9c, 10-hexadecahydro-1H-cyclopropa [c] naphtho [2,1-f] quinoline Examples were obtained using the compound (4.15 g) obtained in Step 7 above. The title compound (4.09 g) was obtained as a white solid in the same manner as in 36-step 7.
¹ H-NMR (CD ₃ OD) δ: 5.42 (1H, m), 4.66 (2H, s), 3.41-3.25 (2H, m), 3.34 (3H, s), 2.91 (1H, d, J = 13.7 Hz), 2.42-2.34 (2H, m), 2.24 (1H, m), 1.95-1.85 (2H, m), 1.72-1.62 (2H, m), 1.60-1.40 (4H, m), 1.15-1.00 ( 3H, m), 1.10 (3H, s), 1.03 (3H, s), 0.84-0.74 (2H, m), 0.74-0.65 (2H, m), 0.07 (1H, brs).

(Process 9)
Benzyl (2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR) -2- (methoxymethoxy) -4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 8,8a, 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Compound obtained in the above step 8 (4.09 g) The title compound (4.87 g) was obtained as a white solid in the same manner as in Example 1, Step 1 using benzyl chloroformate (2.5 ml).
MS (ESI) m / z: 480 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.39 (1H, m), 5.13 (1H, d, J = 12.7Hz), 5.10 (1H, d, J = 12.7Hz), 4.69 (2H, s), 4.50 (1H, br), 3.43 (1H, m), 3.38 (3H, s), 2.92 (1H, br), 2.48 (1H, dd, J = 9.3,14.6Hz), 2.44 -2.34 (2H, m), 2.27 (1H, m), 1.92-1.83 (2H, m), 1.73-1.43 (4H, m), 1.47 (3H, s), 1.36 (1H, m), 1.22-0.97 (4H, m), 1.00 (3H, s), 0.84-0.77 (2H, m), 0.59 (1H, m), 0.13 (1H, m).

(Process 10)
Benzyl (2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-1,2,3,4,4a, 4b, 5,6,6a, 8,8a , 9,9a, 9b, 9c, 10-hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Using the compound (4.87 g) obtained in the above step 9 The title compound (4.53 g) was obtained as a white solid by a method similar to that in Example 26, Step 2.
MS (ESI) m / z: 436 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.39 (1H, m), 5.13 (1H, d, J = 12.7Hz), 5.10 (1H, d, J = 12.7Hz), 4.50 (1H, br), 3.53 (1H, m), 2.93 (1H, br), 2.48 (1H, dd, J = 9.5,14.4Hz), 2.41 (1H, m), 2.32 (1H, m), 2.24 (1H, m), 1.88-1.81 (2H, m), 1.74-1.45 (5H, m), 1.47 (3H, s), 1.36 (1H, m), 1.22-0.97 (4H, m), 1.00 (3H , s), 0.83-0.77 (2H, m), 0.59 (1H, m), 0.13 (1H, m).

(Process 11)
Benzyl (4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR) -4a, 6a-dimethyl-2-oxo-2,3,4,4a, 4b, 5,6,6a, 8,8a, 9,9a , 9b, 9c, 10,11-Hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Conducted using the compound (4.53 g) obtained in Step 10 above. Example 12 The title compound (3.73 g) was obtained as a white amorphous product in the same manner as in Step 1.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.75 (1H, s), 5.15-5.08 (2H, m), 4.51 (1H, br), 3.00 (1H, br), 2.51 -2.31 (7H, m), 2.03 (1H, m), 1.77-1.53 (2H, m), 1.50 (3H, s) 1.32 (1H, m), 1.24-1.07 (3H, m), 1.18 (3H, s), 1.00 (1H, m), 0.86-0.77 (2H, m), 0.62 (1H, m), 0.12 (1H, m).

(Process 12)
Benzyl (2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR) -2-hydroxy-4a, 6a-dimethyl-2,3,4,4a, 4b, 5,6,6a, 8,8a, 9 , 9a, 9b, 9c, 10,11-Hexadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinoline-7-carboxylate Using the compound (4.48 g) obtained in step 11 above The title compound (4.42 g) was obtained as a white solid by a method similar to that in Step 19 of Example 19.
MS (ESI) m / z: 434 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.31 (1H, d, J = 1.5Hz), 5.14-5.08 (2H, m), 4.50 (1H, br), 4.15 (1H , m), 2.94 (1H, br), 2.46 (1H, dd, J = 9.3, 14.6Hz), 2.28-2.19 (2H, m), 2.09 (1H, m), 1.96 (1H, m), 1.71 ( 1H, m), 1.67-1.53 (2H, m), 1.47 (3H, s), 1.43 (1H, m), 1.36 (1H, d, J = 6.3Hz), 1.30-1.09 (4H, m), 1.04 (3H, s), 0.98 (1H, m), 0.86-0.78 (2H, m), 0.75 (1H, t, J = 10.7Hz), 0.59 (1H, m), 0.09 (1H, m).

(Process 13)
Benzyl (1S, 3aR, 3bS, 5aS, 7aR, 8aS, 8bR, 8cR, 10aR, 11aS) -1-hydroxy-3a, 5a-dimethylhexadecahydrocyclopropa [c] oxyleno [4a, 5] naphtho [2, 1-f] quinoline-6 (2H) -carboxylate Using the compound (4.42 g) obtained in Step 12 above, the title compound (4.16 g) was obtained as a white amorphous product in the same manner as in Step 1 of Example 1. It was.
MS (ESI) m / z: 452 (M + H) ^+
1 H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.14-5.08 (2H, m), 4.52 (1H, br), 4.06 (1H, m), 3.16 (1H, d, J = 4.4Hz), 2.96 (1H, br), 2.48 (1H, dd, J = 9.3,14.2Hz), 2.29 (1H, m), 2.23 (1H, d, J = 9.8Hz), 2.15 (1H, m) 1.67-1.00 (12H, m), 1.47 (3H, brs), 1.02 (3H, s), 0.83-0.78 (2H, m), 0.61 (1H, m), 0.11 (1H, m).

(Process 14)
Benzyl (1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2] , 1-f] quinoline-7-carboxylate Using the compound (4.16 g) obtained in Step 13 above, the title compound (3.62 g) was obtained as a white solid in the same manner as in Step 2 of Example 2.
MS (ESI) m / z: 470 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 7.36-7.27 (5H, m), 5.07 (2H, brs), 4.44 (1H, dd, J = 7.8, 14.6Hz), 4.06 (1H, m), 3.46 ( 1H, d, J = 2.9Hz), 2.54 (1H, dd, J = 9.5,14.4Hz), 2.20 (1H, m), 1.97 (1H, m), 1.77-1.62 (2H, m), 1.60-1.07 (11H, m), 1.45 (3H, s), 1.14 (3H, s), 0.91 (1H, t, J = 10.0Hz), 0.80 (1H, m), 0.63 (1H, m), 0.19 (1H, m).

(Process 15)
(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -4a, 6a-dimethyloctadecahydro-11aH-cyclopropa [c] naphtho [2,1-f] quinoline-1,2 , 11a-triol The title compound (207 mg) was obtained as a white solid in the same manner as in Step 20 of Example 20 using the compound (300 mg) obtained in the above Step 14.
MS (ESI) m / z: 336 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.07 (1H, m), 3.46 (1H, d, J = 3.9Hz), 3.23 (1H, m), 2.88 (1H, d, J = 13.7Hz), 2.18 (1H, m), 1.92 (1H, m), 1.73 (1H, m), 1.61-1.03 (11H, m), 1.14 (3H, s), 1.07 (3H, s), 0.80-0.67 (4H, m ), 0.04 (1H, s).

(Process 16)
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone Compound (207 mg) obtained in Step 15 above and compound obtained in Step 3 of Example 23 (162 mg) Was used to give the title compound (126 mg) as a white solid in the same manner as in Example 129, Step 5.
MS (ESI) m / z: 448 (M + H) ^+
1 H-NMR (CD ₃ OD) δ: 4.18-4.11 (2H, m), 4.06 (1H, m), 4.00 (1H, m), 3.54 (1H, m), 3.46 (1H, d, J = 3.4 Hz), 3.08 (1H, m), 2.66 (1H, dd, J = 9.5,13.9Hz), 2.21 (1H, m), 1.96 (1H, m), 1.89 (1H, m), 1.77-1.66 (2H , m), 1.65-1.07 (15H, m), 1.52 (3H, s), 1.15 (3H, s), 0.94 (1H, t, J = 10.0Hz), 0.82 (1H, m), 0.65 (1H, m), 0.23 (1H, m).

The powder X-ray diffraction pattern of the title compound is shown in FIG. 10, and the peak having a relative intensity of 12 or more when the maximum peak intensity is 100 in FIG. 10 is shown in Table 10.

 
　（試験例１）
RORγt遺伝子導入細胞のIL-17産生に対する阻害効果
（１）RORγt遺伝子導入細胞の作製
　マウス（Mus musculus）RORgamma t 蛋白質の全長アミノ酸配列をコードするmRNAの塩基配列（GenBank Accession Number AF163668: http://www.metalife.com/Genbank/5679306）を基に全長蛋白質をコードするmRNAのcDNAをPCR法により取得した。得られたcDNAは、発現ベクターであるpUNOベクター（InvivoGen社）に挿入し、マウスRORγt発現ベクターを構築した。構築したマウスRORγt発現ベクターは、EL4細胞（マウスTリンパ腫細胞株）に導入し、選択培地（DMEM培地にウシ胎児血清、Blasticidin S、ペニシリン、ストレプトマイシンを添加したもの）で培養することでRORγt遺伝子導入細胞を取得した。
（２）IL-17産生阻害作用の評価
　試験化合物のIL-17産生阻害作用は、前述のRORγt遺伝子導入細胞をphorbol 12-Myristate 13-acetate（PMA）とionomycinで刺激した際のIL-17産生で測定した。すなわち、RORγt遺伝子導入細胞を前述の選択培地にて調製し、1穴当たり75000個ずつ96穴平底プレート（Corning社）内に分注した。このとき、種々の濃度の試験化合物を同時に添加した。5%CO₂濃度のインキュベーター中で37℃にて1時間培養した後、PMAを終濃度25ng/mL、ionomycinを終濃度125ng/mL、各穴に添加し合計100μLで5%CO₂濃度のインキュベーター中で37℃にて20時間培養した。その後、培養上清を回収し、上清中のマウスIL-17濃度を、HTRFマウスIL-17キット（Cisbio社）を用いて、EnVison（パーキンエルマー社）にて時間分解蛍光として測定した。試験化合物によるIL-17産生阻害作用については、試験化合物存在下のIL-17産生量に対して試験化合物濃度を片対数プロットしたグラフから、試験化合物非存在下のIL-17産生量の50%に相当するIL-17産生量の試験化合物濃度をIC₅₀値として算出した。IL-17産生阻害作用の結果を
表11に示す。

(Test Example 1)
Inhibitory effects on IL-17 production of RORγt gene-introduced cells (1) Preparation of RORγt gene-introduced cells The nucleotide sequence of mRNA encoding the full-length amino acid sequence of mouse (Mus musculus) RORgamma t protein (GenBank Accession Number AF163668: http: // Based on www.metalife.com/Genbank/5679306), mRNA cDNA encoding the full-length protein was obtained by PCR. The obtained cDNA was inserted into a pUNO vector (InvivoGen) as an expression vector to construct a mouse RORγt expression vector. The constructed mouse RORγt expression vector is introduced into EL4 cells (mouse T lymphoma cell line) and cultured in a selective medium (DMEM medium supplemented with fetal bovine serum, Blasticidin S, penicillin, streptomycin). Cells were obtained.
(2) Evaluation of IL-17 production inhibitory action IL-17 production inhibitory action of the test compound is the result of IL-17 production when RORγt gene-introduced cells are stimulated with phorbol 12-Myristate 13-acetate (PMA) and ionomycin. Measured with That is, RORγt gene-introduced cells were prepared in the above-mentioned selective medium, and dispensed into a 96-well flat bottom plate (Corning) at 75000 cells per well. At this time, various concentrations of test compounds were added simultaneously. After in 5% CO ₂ concentration in the incubator and incubated for 1 hour at 37 ° C., PMA final concentration 25 ng / mL, final concentration ionomycin 125 ng / mL, 5% CO ₂ concentration in the incubator with the addition sum 100μL to each well Incubated for 20 hours at 37 ° C. Thereafter, the culture supernatant was collected, and the mouse IL-17 concentration in the supernatant was measured as time-resolved fluorescence with EnVison (Perkin Elmer) using the HTRF mouse IL-17 kit (Cisbio). About the IL-17 production inhibitory effect by the test compound, from the graph in which the test compound concentration is semilogarithmically plotted against the IL-17 production amount in the presence of the test compound, 50% of the IL-17 production amount in the absence of the test compound The concentration of the test compound corresponding to the amount of IL-17 produced was calculated as the IC ₅₀ value. The results of IL-17 production inhibitory action are shown in Table 11.

 
　本試験において、本発明の化合物は、優れたIL-17産生阻害作用を示した。従って、乾癬、乾癬性関節炎、強直性脊椎炎、多発性硬化症、関節リウマチ、炎症性腸疾患（クローン病や潰瘍性大腸炎など）、シェーグレン症候群、全身性エリテマトーデス、慢性閉塞性肺疾患（COPD）、アトピー性皮膚炎、喘息、一型糖尿病、移植片対宿主病（GvHD）、円形脱毛症、白斑、川崎病、ベーチェット病、糸球体腎炎、心筋症、再生不良性貧血、橋本病、強皮症、巨細胞性動脈炎、接触性皮膚炎、視神経炎などの自己免疫疾患又はIL-17の産生が病態発症に関与している大腸癌の治療剤及び/又は予防剤として有用である。

In this test, the compound of the present invention showed an excellent IL-17 production inhibitory action. Therefore, psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD) ), Atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, strong It is useful as an agent for treating and / or preventing colorectal cancer in which autoimmune diseases such as dermatosis, giant cell arteritis, contact dermatitis, optic neuritis, etc. or IL-17 production is involved in the pathogenesis of the disease.

(Test Example 2)
Inhibitory effect on IL-23-induced mouse psoriasis-like dermatitis model IL-23-induced mouse psoriasis-like dermatitis model is known to be dependent on IL-17 (The Journal of Immunology, 186, 1495- 1502 (2011)) (The Journal of Immunology, 186, 4481-4489 (2011)).

In the experiment, 5 to 10 male mice 7 weeks old or later of BALB / c mice (Charles River Japan) were used. From day 0 to 3, mouse IL-23 (prepared to 50 社 μg / mL with R & D Systems, phosphate buffered saline) was administered intradermally once daily under anesthesia with 1 μg / mouse once daily Induced (The Journal of Experimental Medicine, 203, 2577-2587 (2006)) (Nature, 445, 648-651 (2007)). In the control group, bovine serum albumin (Sigma, prepared in phosphate buffered saline at 50Sigmaμg / mL) was similarly administered intradermally at 1 μg / animal. Evaluation of dermatitis was performed by subtracting the thickness of the auricle before starting IL-23 administration on day 0 from the thickness of the auricle measured using a thickness gauge 24 hours after the last dose of mouse IL-23 (day 4). Thickness was used as an index. The test compound was suspended in 0.5% methylcellulose solution or 9-10% Kollidon® VA64 solution. The test compound or solvent was orally administered twice a day from day 0 to 3. About the dermatitis inhibitory effect by a test compound, it calculated as an inhibition rate (%) according to the following formula. The results of the dermatitis inhibitory effect are shown in Table 12.

Inhibition rate (%) = 100 × (Auricular thickening at the time of solvent administration−Auricular thickening at the time of test compound administration) / (Auricular thickening at the time of solvent administration−Auricular thickening in the control group)

　上述のように本発明の化合物は、皮膚炎阻害効果を有し、乾癬に有効であることが示された。

As described above, the compound of the present invention has a dermatitis inhibitory effect and has been shown to be effective for psoriasis.

Formulation Example 1: Capsule 50 mg of the compound of Example 2 or 3
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
-----------------
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.

Formulation Example 2: Tablet Example 2 or 3 Compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
-----------------
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

The compound represented by the general formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has an excellent retinoic acid receptor-related orphan receptor γt inhibitory action and IL-17 production suppression It has an action and is useful as a medicine.

Claims (48)

Formula (I)

[Where:
U represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, C Selected from _3- C ₆ cycloalkenyl group, C ₃ -C ₆ halogenated cycloalkyl group, C ₃ -C ₆ halogenated cycloalkenyl group or halogen atom, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group A phenyl group, a pyridyl group, a tetrahydrofuryl group, a tetrahydropyranyl group or a benzyl group, which may be independently substituted by 1 to 4 groups,
R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C ₂ -C ₇ alkylcarbonyloxy group,
R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group, or
R ² and R ³ together represent an oxo group;
R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkylsulfonyl group and to 1 independently with a group selected from hydroxyl two substituted C ₁ optionally -C ₆ alkyl group,
R ⁵ represents a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group;
A group selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group, a carboxy group, an aminocarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group and a triazolyl group; 4 represents an optionally substituted C ₁ -C ₆ alkyl group; or represents a 2-tetrahydropyranyl group independently substituted with 3 or 4 groups independently selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group Or
R ⁴ and the group represented by the formula —OR ⁵ together represent an oxo group,
R ⁶ is a hydrogen atom, a halogen atom, a hydroxyl group or a C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and 1 to 2 optionally substituted C ₁ -C ₆ alkyl group independently with a group selected from cyano group Indicate
R ⁷ represents a hydrogen atom or a fluorine atom,
R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group,
R ⁹ represents a hydrogen atom, or
R ⁸ and R ⁹ together represent an oxo group;
T represents a single bond, an oxygen atom or a group represented by the formula —NH—,
Y is the same or different and represents a halogen atom or a C ₁ -C ₆ alkyl group,
m represents an integer of 0 to 3,
A saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a condensed ring,
n represents an integer of 1 to 3. Or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ia).

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ib).

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ic).

5. The method according to claim 1, wherein U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a phenyl group or a tetrahydropyranyl group optionally independently substituted by 1 to 3 halogen atoms Or a pharmaceutically acceptable salt thereof. 5. The method according to claim 1, wherein U is 3,3,3-trifluoropropyl group, cyclohexyl group, 4-fluorocyclohexyl group, (1S) -3,3-difluorocyclopentyl group, 2-tetrahydropyranyl group, (R) -2-tetrahydropyranyl group, 4-fluorotetrahydropyran-2-yl group, 5-fluorotetrahydropyran-2-yl group or (2R, 5R) -5-fluorotetrahydro A compound which is a pyran-2-yl group or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ¹ is a hydrogen atom or a halogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ¹ is a hydrogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ² is a hydrogen atom or a methyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ³ is a hydrogen atom, a hydroxyl group or a methoxy group. The compound or pharmaceutically acceptable compound thereof according to any one of claims 1 to 11, wherein R ⁴ is a C ₁ -C ₆ alkyl group optionally substituted by 1 to 2 hydrogen atoms or hydroxyl groups. Salt. The process according to any one of claims 1 to 12, wherein R ⁵ is a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group;
A C ₁ -C ₆ alkyl group or fluorine atom which may be independently substituted with 1 to 3 groups independently selected from a hydroxyl group, a methoxy group, a methylsulfonyl group, an aminocarbonyl group, a tert-butoxycarbonyl group and a triazolyl group; A compound or a pharmaceutically acceptable salt thereof, which is a 2-tetrahydropyranyl group which is independently substituted with 3 or 4 groups independently selected from a hydroxyl group and a hydroxymethyl group. In any one selected from claims 1 to 12, ^{R 5} is a hydrogen atom, a methyl group, 2,3-dihydroxypropyl group, (R)-2,3-dihydroxypropyl group or (S) -2 , 3-Dihydroxypropyl group or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group, or a hydroxymethyl group. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R ⁸ is a hydrogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R ⁹ is a hydrogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein T is a single bond. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein Y is a methyl group. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein m is 0. 21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein n is 1 or 2. The condensed ring formed by any one of claims 1 to 21, wherein m is 0, n is 1, and a saturated ring containing a nitrogen atom is condensed with a cyclopropane ring is 3- A compound which is an azabicyclo [4.1.0] heptane ring, or a pharmaceutically acceptable salt thereof. [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [( 2R) -tetrahydro-2H-pyran-2-yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] methanone, (2R) -tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a -Dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone, [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8 -Methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-7-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-9- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] methanone,
Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS) -10b-fluoro-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline -1 (2H) -Il] methanone,
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1 -f] quinoline-1 (2H) -yl] methanone,
Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8- (2,3-dihydroxypropyl) -6a, 8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f ] Quinolin-1 (2H) -yl] methanone,
1-[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2, 1-f] quinolin-1 (2H) -yl] -4,4,4-trifluorobutan-1-one,
[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2S) -tetrahydro-2H-pyran-2-yl] methanone,
(2R) -tetrahydro-2H-pyran-2-yl [(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -7a, 8,9-trihydroxy-11a, 13a-dimethyloctadecahydro- 1H-phenanthro [2,1-b] azepin-1-yl] methanone,
[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS) -6a, 8-dihydroxy-8- (hydroxymethyl) -10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 ( 2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a, 7-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(5aS, 5bR, 7aS, 8S, 9S, 11aR, 11bS, 13aS) -9-[(2R) -2,3-dihydroxypropoxy] -7a, 8-dihydroxy-11a, 13a-dimethyloctadecahydro-1H -Phenanthro [2,1-b] azepin-1-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
{(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2-[(2R) -2,3-dihydroxypropoxy] -11a-hydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aR) -2,11a-dihydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] Quinolin-7-yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone,
[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,11a-dihydroxy-2-methoxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [ 2,1-f] quinolin-7-yl] [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-8,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
(2R) -Tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-7,10a, 12a-trimethylhexadeca Hydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone,
[(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2R, 4S) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(2R, 4R) -4-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone,
[(1S) -3,3-difluorocyclopentyl] [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [ 2,1-f] quinolin-1 (2H) -yl] methanone,
(Cis-4-fluorocyclohexyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyloctadecahydro-7H -Cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone, or
(2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl A compound which is octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone or a pharmaceutically acceptable salt thereof. Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Il] methanone. (2R) -tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinolin-1 (2H) -yl] methanone. [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecahydronaphtho [2,1-f] quinoline-1 (2H ) -Yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone. [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS) -8-[(2R) -2,3-dihydroxypropoxy] -6a-hydroxy-10a, 12a-dimethylhexadecahydronaphtho [2,1- f] quinolin-1 (2H) -yl] [(2R) -tetrahydro-2H-pyran-2-yl] methanone. {(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -2-[(2R) -2,3-dihydroxypropoxy] -1,11a-dihydroxy-4a, 6a-dimethylocta Decahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl} [(2R) -tetrahydro-2H-pyran-2-yl] methanone. (2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone. [(2R, 5R) -5-fluorotetrahydro-2H-pyran-2-yl] [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS) -1,2,11a-tri Hydroxy-4a, 6a-dimethyloctadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone. (2R) -Tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS) -1,2,11a-trihydroxy-4a, 6a-dimethyl Octadecahydro-7H-cyclopropa [c] naphtho [2,1-f] quinolin-7-yl] methanone. 32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 32, which has a retinoic acid receptor-related orphan receptor γt inhibitory action. The pharmaceutical composition according to claim 32, for treating and / or preventing a disease which is treated and / or prevented by an inhibitory action of retinoic acid receptor-related orphan receptor γt. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is for the treatment and / or prevention of a disease in which symptoms are treated, ameliorated, reduced and / or prevented by inhibiting Th17 cell differentiation and / or inhibiting IL-17 production. Pharmaceutical composition. The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, Asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell artery 33. A pharmaceutical composition according to claim 32 for the treatment and / or prevention of inflammation, contact dermatitis, optic neuritis or colon cancer. 33. A pharmaceutical composition according to claim 32 for the treatment and / or prevention of psoriasis or psoriatic arthritis. A retinoic acid receptor-related orphan receptor γt inhibitor comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient. Use of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition. The pharmaceutical composition is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma Type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis The use according to claim 39, which is a composition for the treatment and / or prevention of contact dermatitis, optic neuritis or colon cancer. 40. Use according to claim 39, wherein the pharmaceutical composition is a composition for the treatment and / or prevention of psoriasis or psoriatic arthritis. 32. A method according to any one of claims 1 to 31 for use in a method for the treatment and / or prevention of diseases which are treated and / or prevented by retinoic acid receptor-related orphan receptor γt inhibitory action. Or a pharmaceutically acceptable salt thereof. Psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes , Graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact skin 32. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof for use in a method of treating and / or preventing inflammation, optic neuritis or colon cancer. A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof. 45. The method according to claim 44, wherein the disease is treated and / or prevented by an retinoic acid receptor-related orphan receptor γt inhibitory action. The disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, one Type diabetes, graft-versus-host disease (GvHD), alopecia areata, vitiligo, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact 45. The method according to claim 44, wherein the disease is dermatitis, optic neuritis or colorectal cancer. 45. The method of claim 44, wherein the disease is psoriasis or psoriatic arthritis. 48. The method according to any one of claims 44 to 47, wherein the warm-blooded animal is a human.

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