JP2003073380A - Furoisoquinoline derivative, method for producing the same and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent phosphodiesterase IV inhibitor. SOLUTION: The compound having the partial structure represented by the formula 1 or its salt and a compound represented by the formula 2 [in the formulas 1 and 2, R<1> represents an optionally substituted hydrocarbon group or the like; R<2> and R<3> each represents an optionally substituted hydrocarbon or the like; R<4> and R<5> each represents hydrogen atom or the like; R<6> and R<7> each represents an optionally substituted hydrocarbon group; R<8> represents hydrogen atom, -OR<10> (R<10> represents an optionally substituted hydrocarbon group or the like); R<9> represents hydrogen atom or the like; X represents optionally substituted methylene group or the like; and n is 0 or 1] or its salt are provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a phosphodiesterase (PDE) IV inhibitory action, and has inflammatory diseases, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune diseases, depression, Alzheimer's dementia, The present invention relates to a novel furoisoquinoline derivative useful as a prophylactic / therapeutic agent for memory disorders, diabetes, arteriosclerosis, etc., its production method and use.

[0002]

2. Description of the Related Art Today, many hormones and neurotransmitters increase or decrease the intracellular concentration of intracellular second messenger cyclic adenosine-3 ', 5'-monophosphate (cAMP). It regulates those cell functions. The intracellular concentration of this cAMP is controlled by synthase and degrading enzyme. That is, cAMP is produced by adenyl cyclase and degraded by PDE. This degradative enzyme also controls the degradation of cyclic guanosine-3 ', 5'-monophosphate (cGMP). To date, 11 types of isozymes have been identified in PDE [Proceedings of the National Academy of Sciences of the
United States of America (Proceedings
of the National Academy of Sciences of the United
States of America), 97, 3702 (2000).], In various cells such as central, circulatory, respiratory, digestive, reproductive, blood cells, tracheal smooth muscle, etc., they can determine intracellular cAMP and cGMP concentrations. It regulates and controls cell function. It is known that inflammatory cells such as eosinophils, neutrophils, monocytes, T-lymphocytes, and macrophages mainly contain PDE IV, one of the PDE isozymes [Clinical and Experimental]. Allergy (Clinical and Experimental Allergy), Volume 22, 337
P. (1992).]. Drugs mainly classified into three types are used as therapeutic agents for asthma. That is, bronchodilators (for example, β-adrenergic receptor agonists), anti-inflammatory drugs (for example, corticosteroids), and xanthine derivatives (for example, theophylline) that have both bronchodilator and anti-inflammatory effects. is there. Above all, theophylline has been widely used as a therapeutic drug for asthma since ancient times. Then, it became clear that the bronchodilator action of theophylline is based on the PDE inhibitory action, and it has recently attracted attention. However, theophylline is a non-selective PDE inhibitor, and cardiovascular side effects are often observed, requiring strict control of blood levels. Therefore, as a therapeutic drug for inflammatory diseases such as asthma, a drug that selectively inhibits only PDE IV and does not act on other isozymes of PDE is desired. Research results have been reported showing that PDE IV selective inhibitors may be effective therapeutic agents for inflammatory diseases such as asthma [Pulmonary Pharmacology (Pulmonary Phar
macology), vol. 7, p. 1 (1994).]. As a compound having a PDE IV selective inhibitory action,

[Chemical 19] Rolipram (Japanese Patent Application Laid-Open No. 50-157360) and formula

[Chemical 20] SB 207499 [The Journal of Pharmacology and Experimental Therapeutic (The Journal of Pharmacology and
Experimental Therapeutics), 287, 988 (1998).,
Journal of Medicinal Chemistry (Journa
l of Medicinal Chemistry), 41, 821 (1998).] is known. However, it has not been clinically applied until now. In addition, in WO01 / 70746, PD
As a compound having an E IV selective inhibitory action,

[Chemical 21] A compound having a partial structure represented by is disclosed.
Meanwhile, Bulletin De La Societe Chimique De France4
On page 201 (1972), the formula

[Chemical formula 22] [- - - represents a single bond or a double bond] Synthesis of compounds represented by is disclosed. In addition, WO02 / 04455 describes a formula as a therapeutic agent for neurological / cardiac deficiency based on the reuptake inhibitory action of norepinephrine transporter protein.

[Chemical formula 23] [In the formula, R ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C
_4-7 cycloalkylalkyl or benzyl (these may have a specific substituent), R ² is a hydrogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6
Alkynyl, C _3-6 cycloalkyl, C _4-7 cycloalkylalkyl or C _1-6 haloalkyl, R ³ is hydrogen atom, halogen atom, C _1-6 alkyl, C _1-6
Haloalkyl or C _3-6 cycloalkyl (the C
_{1-6 alkyl, C 1-6 haloalkyl, C 3 -6} cycloalkyl may have a specific substituent),
R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, nitro or the like, and R ⁷ represents a hydrogen atom, a halogen atom or the like].

[0003]

[Problems to be Solved by the Invention] A strong selective PDE IV inhibitor can be expected to have a sufficient preventive or therapeutic effect on a wide range of diseases involving inflammation. The present invention provides a novel heterocyclic compound which has a PDE IV selective inhibitory effect, shows a bronchodilator effect and an anti-inflammatory effect by increasing intracellular cAMP concentration, and is further excellent in terms of safety and the like. To do.

[0004]

Means for Solving the Problems As a result of various earnest studies, the present inventors have found that

[Chemical formula 24] [In the formula, ring A, ring B and ring C may each have a substituent] Novel furoisoquinoline compound having a partial structure (hereinafter, may be abbreviated as compound (I)) , Especially 1-position of furoisoquinoline skeleton, 2
Having a great characteristic in terms of chemical structure when a substituent is introduced at the 4-position, 5-position, 6-position, 7-position, 8-position, 9-position, etc.

[Chemical 25] [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,
R ² and R ³ each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group, and R ² and R ³ may have a substituent together with the adjacent carbon atom. An 8-membered ring may be formed, R ⁴ and R ⁵ are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁶ and R ⁷ are each a hydrogen atom or a substituent. R ⁶ and R ⁷ may form a 3- to 8-membered ring which may have a substituent together with the adjacent carbon atom, and R ⁸ is (1) a hydrogen atom,
(2) a hydrocarbon group which may have a substituent, (3) an acyl group, (4) a heterocyclic group which may have a substituent,
(5) Halogen atom, (6) -OR ¹⁰ (R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent) ,
(7) -SR ¹¹ (R ¹¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (8) -S (O) R ¹²
(R ¹² represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent), (9)-
S (O) ₂ R ¹³ (R ¹³ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) or (10) -NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ each represent a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), and R ⁹ represents a hydrogen atom, a cyano group. A hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent, X represents a methylene group or a carbonyl group which may have a substituent, and n is 0 Or 1)], and succeeded in synthesizing for the first time a novel furoisoquinoline compound (hereinafter sometimes abbreviated as compound (I ′)), a salt thereof, a prodrug thereof or a hydrate thereof , These compounds are unique Unexpectedly good PDE based on scholarly structure
It has an inhibitory action, especially PDE IV inhibitory action, and prevents inflammatory diseases, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune diseases, depression, Alzheimer's dementia, memory disorders, diabetes, arteriosclerosis, etc. , And was used as a medicine such as a therapeutic agent. The present inventors have completed the present invention as a result of further studies based on these findings.

That is, the present invention is [1] formula

[Chemical formula 26] A compound having a partial structure represented by (hereinafter sometimes abbreviated as compound (A)) or a salt thereof; [2] Formula

[Chemical 27] [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent] or a salt thereof. ; [3] formula

[Chemical 28] [In the formula, R¹Is a hydrogen atom, or an optionally substituted charcoal
A heterocyclic group which may have a hydrogen halide group or a substituent,
R^TwoAnd R^ThreeEach have a hydrogen atom and a substituent
Represents a hydrocarbon group or an acyl group which may be represented by R^TwoAnd R^Three
Is optionally substituted with an adjacent carbon atom 3
To R may form an 8-membered ring, R^FourAnd R⁵Is it
Hydrocarbons each optionally having a hydrogen atom or a substituent
The base is R⁶And R⁷Are hydrogen atom or substituent
Represents a hydrocarbon group which may have R⁶And R⁷Next to
It may have a substituent with the carbon atom in contact with it 3 No
And may form an 8-membered ring, R⁸Is (1) hydrogen atom,
(2) a hydrocarbon group which may have a substituent, (3) a
A sil group, (4) a heterocyclic group which may have a substituent,
(5) Halogen atom, (6) -OR¹⁰(R¹⁰Is hydrogen
Atoms, optionally substituted hydrocarbon groups, acyl groups
Or represents a heterocyclic group which may have a substituent),
(7) -SR¹¹(R¹¹Has a hydrogen atom and a substituent
Having a hydrocarbon group, an acyl group or a substituent that may be present
(May represent a heterocyclic group), (8) -S (O) R¹²
(R¹²Is a hydrocarbon group which may have a substituent or
Represents a heterocyclic group which may have a substituent), (9)-
S (O)_TwoR^Thirteen(R^ThirteenMay have a substituent
A hydrocarbon group or a heterocyclic group which may have a substituent
Shown) or (10) -NR¹⁴R¹⁵(R¹⁴and
R¹⁵May each have a hydrogen atom or a substituent.
It may have a hydrocarbon group, an acyl group or a substituent.
R represents a heterocyclic group)⁹Is hydrogen atom, cyano group, substituted
Optionally substituted hydrocarbon group, acyl group or substituted
A hydroxyl group which may have a group, and X has a substituent
Optionally a methylene group or a carbonyl group, n is 0 or
Represents 1] or a salt thereof; [4] R¹Indicates either (i) or (ii) below
You: (I) (1) halogen atom, (2) C_1-3Alkylenedi
Oxy group, (3) nitro group, (4) cyano group, (5) halo
C which may be genated_1-6Alkyl group, (6)
C which may be rogenated_2-6An alkenyl group,
(7) C which may be halogenated_2-6Alkynyl
Base, (8) C_3-6Cycloalkyl group, (9) C_{6 -14}
Aryl group, (10) optionally halogenated C
_1-6Alkoxy group, (11) may be halogenated
I C_1-6Alkylthio group, (12) hydroxy group, (1
3) Amino group, (14) Mono-C_1-6Alkylamino
Group, (15) Mono-C _6-14Arylamino group, (16)
The-C_1-6Alkylamino group, (17) di-C_6-14
Arylamino group, (18) formyl, carboxy, cal
Bamoiru, C _1-6Alkyl-carbonyl, C_3-6Shi
Chloroalkyl-carbonyl, C_1-6Alkoxy-Cal
Bonil, C_6-14Aryl-carbonyl, C_7-16
Aralkyl-carbonyl, C_6-14Aryloxy-
Carbonyl, C_7-16Aralkyloxy-Carbonii
Group, nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 containing 1 to 3 heteroatoms selected from
Or 6-membered heterocyclic carbonyl, mono-C_1-6Alkyl-
Carbamoyl, di-C_1-6Alkyl-carbamoyl,
C_6-14Aryl-carbamoyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic carba containing 3 heteroatoms
Moyle, C_1-6Alkyl-thiocarbonyl, C_3-6
Cycloalkyl-thiocarbonyl, C_1-6Alkoxy
-Thiocarbonyl, C_6-14Aryl-thiocarboni
Le, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_7-16
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C _1-6Alkylsulfinyl, C_6-14A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
Group, (19) formylamino, C_1-6Alkyl-carbo
Xamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonyl
Acylamino group selected from amino, (20) C_1-6A
Rukyl-carbonyloxy, C_6-14Aryl-Cal
Bonyloxy, C_1-6Alkoxy-carbonyl
Si, Mono-C_1-6Alkyl-carbamoyloxy, di
-C_1-6Alkyl-carbamoyloxy, C_6-14
Aryl-carbamoyloxy and nicotinoyloxy
Acyloxy group selected from Si, other than (21) carbon atoms
1 selected from nitrogen atom, sulfur atom and oxygen atom
A 4- to 14-membered heterocycle containing 4 heteroatoms
Group, (22) phosphono group, (23) C_6-14Aryl Oki
Si group, (24) di-C_1-6An alkoxy-phosphoryl group,
(25) C_6-14Arylthio group, (26) hydrazino group,
(27) imino group, (28) oxo group, (29) ureido group,
(30) C_1-6Alkyl-ureido group, (31) di-C
_1-6Alkyl-ureido group, (32) oxide group and
(33) 2 to 3 selected from the groups (1) to (32)
A group consisting of groups formed by combining individual groups (hereinafter referred to as substituent A
1 to 5 substituents selected from the group
Each may have C_1-6Alkyl group, C_2-6A
Lucenyl group, C_2-6Alkynyl group, C_3-6Cycloa
Rukiru group, C _3-6Cycloalkenyl group, C_6-14A
Reel base or C_7-16An aralkyl group, (ii) the above
Having 1 to 5 substituents selected from the group A of substituents,
In addition to carbon atom, nitrogen atom, sulfur atom and oxygen source
5 to 5 containing 1 to 4 heteroatoms selected from children
14-membered heterocyclic group; R^TwoAnd R^ThreeAre the following
Indicates any one of (i) to (iii): (i) hydrogen atom, (i
i) 1 to 5 substituents selected from the above-mentioned substituent group A
C which each may have_1-6Alkyl group, C
_2-6Alkenyl group, C_2-6Alkynyl group, C_{Three -6}
Cycloalkyl group, C_3-6Cycloalkenyl group, C
_6-14Aryl group or C_7-16Aralkyl group,
(Iii) the substituent selected from Group A above is 1 to
Formyl, carboxy, carba which may have 5
Moyle, C_1-6Alkyl-carbonyl, C_{3- 6}Shiku
Lower alkyl-carbonyl, C_1-6Alkoxy-carbo
Nil, C_6-14Aryl-carbonyl, C_7-16A
Ralalkyl-carbonyl, C_6-14Aryloxy-ca
Lubonyl, C_7-16Aralkyloxy-carbonyl,
From nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 or containing 1 to 3 heteroatoms selected
6-membered heterocyclic carbonyl, mono-C_1-6Alkyl-cal
Bamoiru, The-C_1-6Alkyl-carbamoyl, C
_6-14Aryl-carbamoyl, nitrogen in addition to carbon atom
1 to 3 selected from atom, sulfur atom and oxygen atom
5 or 6 membered heterocyclic carbamo containing 5 heteroatoms
Il, C_1-6Alkyl-thiocarbonyl, C_3-6Shi
Chloroalkyl-thiocarbonyl, C_1-6Alkoxy-
Thiocarbonyl, C_6-14Aryl-thiocarboni
Le, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_{7- 16}
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_{6- 14}A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
Group; R²And R³Is C with adjacent carbon atoms_1-6Al
Kill, C_6-14Aryl, C_7-16Aralkyl, a
Mino, Mono-C_1-6Alkylamino, mono-C_6
-14Arylamino, di-C_1-6Alkylamino,
The-C_6-14Arylamino and 4 to 10 members
1 to 3 substituents each selected from an aromatic heterocyclic group
May have C_3-8Cycloalkane or 3
May form an 8-membered heterocycle; R^FourAnd R⁵Gazo
Each of (i) a hydrogen atom or (ii) the above substituent group A
Each may have 1 to 5 substituents selected
I C_1-6Alkyl group, C _2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C_Three
-6Cycloalkenyl group, C_6-14Aryl group or
C_7-16An aralkyl group; R⁶And R⁷Respectively
(I) hydrogen atom or (ii) selected from the above substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C _2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C_{Three -6}Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16Represents an aralkyl group, R⁶And R⁷Is adjacent charcoal
C along with elementary atoms_1-6Alkyl, C_6-14Ally
Le, C_7-16Aralkyl, Amino, Mono-C_1-6A
Ruquilamino, Mono-C _6-14Arylamino, di-
C_1-6Alkylamino, di-C_6-14Arylami
And a unit selected from a 4- to 10-membered aromatic heterocyclic group.
C optionally having 1 to 3 substituents_3-8
Forming a cycloalkane or a 3- to 8-membered heterocycle
Well; R⁸Indicates one of the following (i) to (x): (I) a hydrogen atom, (ii) a group selected from the above substituent group A
C optionally having 1 to 5 substituents each_1-6
Alkyl group, C_2-6Alkenyl group, C_2-6Alkini
Lu group, C_{Three -6}Cycloalkyl group, C_3-6Cycloal
Kenyl group, C_6-14Aryl group or C_7-16Ara
Alkyl group, (iii) Substituent selected from Substituent group A
Formyl, carboxy, which may have 1 to 5
Ci, carbamoyl, C_1-6Alkyl-carbonyl, C
_{3- 6}Cycloalkyl-carbonyl, C_1-6Arcoki
Si-carbonyl, C_6-14Aryl-carbonyl, C
_7-16Aralkyl-carbonyl, C_6-14Aryl
Oxy-carbonyl, C_7-16Aralkyl Oxy-ca
Rubonyl, nitrogen atom, sulfur atom and acid other than carbon atom
Contains 1 to 3 heteroatoms selected from elementary atoms
5- or 6-membered heterocyclic carbonyl, mono-C_1-6Al
Kill-carbamoyl, di-C_1-6Alkyl-carbamo
Il, C_6-14Aryl-carbamoyl, carbon atom or less
Besides, 1 selected from nitrogen atom, sulfur atom and oxygen atom
To 5 or 6 membered heterocycles containing 3 to 3 heteroatoms
Carbamoyl, C_1-6Alkyl-thiocarbonyl, C
_3-6Cycloalkyl-thiocarbonyl, C_1-6Al
Coxy-thiocarbonyl, C_6-14Aryl-Thioca
Lubonyl, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_{7- 16}
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_{6- 14}A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
A group, (iv) no substituent selected from the above substituent group A
In addition to the carbon atoms which may be five, nitrogen atoms, sulfur
1 to 1 heteroatoms selected from atoms and oxygen atoms
A 5- to 14-membered heterocyclic ring containing 4, (v) a halogen atom,
(Vi) -OR¹⁰(R¹⁰Is (i ') hydrogen atom, (i
i ′) 1 to 5 substituents selected from the above-mentioned substituent group A
C which each may have_1-6Alkyl group, C
_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6
Cycloalkyl group, C _3-6Cycloalkenyl group, C
_6-14Aryl group or C_7-16Aralkyl group,
(Iii ') There is no 1 substituent selected from the above substituent group A.
Formyl, carbamoyl, C, which may have 5
_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
-Carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl
-Carbonyl, C_6-14Aryloxy-carboni
Le, C_7-16Aralkyloxy-carbonyl, carbon source
Selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring carbonyl, mono-C_1-6Alkyl-carbamoy
Le, the C_1-6Alkyl-carbamoyl, C_6-14
Aryl-carbamoyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hets selected from yellow atom and oxygen atom
5- or 6-membered heterocyclic carbamoyl containing a carbon atom, C
_1-6Alkyl-thiocarbonyl, C_3-6Cycloal
Kill-thiocarbonyl, C_1-6Alkoxy-thiocal
Bonil, C_6-14Aryl-thiocarbonyl, C
_7-16Aralkyl-thiocarbonyl, C_6-14Ants
Oxy-thiocarbonyl, C_7-16Aralkillo
Xy-thiocarbonyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hetero atoms selected from atoms and oxygen atoms
5- or 6-membered heterocyclic thiocarbonyl containing atoms, thi
Ocarbamoyl, Mono-C_1-6Alkyl-thiocarba
Moyle, The-C_1-6Alkyl-thiocarbamoyl, C
_6-14Aryl-thiocarbamoyl, other than carbon atom
1 selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered heterocyclic thio containing 3 heteroatoms
Carbamoyl, sulfamoyl, mono-C_1-6Archi
Rusulfamoyl, Di-C_1-6Alkylsulfamoy
Le, C_6-14Arylsulfamoyl, C_1-6Al
Killsulfonyl, C_6-14Arylsulfonyl, C
_1-6Alkylsulfinyl, C_6-14Arylsul
Finil, C_1-6Alkoxysulfinyl, C
_6-14Aryloxysulfinyl, C_1-6Arco
Xysulfonyl and C_6-14Aryloxysulfo
Acyl group selected from nyl or (iv ') substituent A
It may have 1 to 5 substituents selected from the group
From nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 to 14 members containing 1 to 4 heteroatoms selected
A heterocycle), (vii) -SR¹¹(R¹¹Is
(I ') hydrogen atom, (ii') selected from the above substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C _3-6Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16An aralkyl group, (iii ') from the substituent group A
A group which may have 1 to 5 selected substituents,
Mill, carbamoyl, C_1-6Alkyl-carbonyl,
C_3-6Cycloalkyl-carbonyl, C_1-6Arco
Xy-carbonyl, C_6-14Aryl-carbonyl,
C_7-16Aralkyl-carbonyl, C_6-14Ally
Luoxy-carbonyl, C_7-16Aralkyloxy-
In addition to carbonyl and carbon atom, nitrogen atom, sulfur atom and
Contains 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic carbonyl, mono-C_1-6A
Ruquil-carbamoyl, di-C_1-6Alkyl-carb
Moyle, C_6-14Aryl-carbamoyl, carbon atom
Besides, selected from nitrogen atom, sulfur atom and oxygen atom
5- or 6-membered complex containing 1 to 3 heteroatoms
Carbamoyl ring, C_1-6Alkyl-thiocarbonyl,
C_3-6Cycloalkyl-thiocarbonyl, C_1-6A
Lucoxy-thiocarbonyl, C_6-14Aryl-thio
Carbonyl, C_7-16Aralkyl-thiocarbonyl,
C_6-14Aryloxy-thiocarbonyl, C
_7-16Aralkyloxy-thiocarbonyl, carbon atom
Besides, selected from nitrogen atom, sulfur atom and oxygen atom
5- or 6-membered complex containing 1 to 3 heteroatoms
Ring thiocarbonyl, thiocarbamoyl, mono-C_1-6
Alkyl-thiocarbamoyl, di-C_1-6Alkyl-
Thiocarbamoyl, C_6-14Aryl-thiocarbamo
In addition to carbon and carbon atoms, nitrogen, sulfur and oxygen sources
Containing 1 to 3 heteroatoms selected from the group 5
Or a 6-membered heterocyclic thiocarbamoyl, sulfamoyl,
Mono-C_1-6Alkylsulfamoyl, di-C_1-6
Alkylsulfamoyl, C_6-14Aryl sulfa
Moyle, C_1-6Alkylsulfonyl, C_6-14Ants
Sulfonyl, C_1-6Alkylsulfinyl, C
_6-14Arylsulfinyl, C_1-6Alkoxys
Rufinil, C_6-14Aryloxysulfinyl,
C_1-6Alkoxysulfonyl and C_6-14Ally
An acyl group selected from luoxysulfonyl or (i
v ′) 1 to 5 substituents selected from the above substituent group A
Nitrogen atom, sulfur atom in addition to carbon atoms which may have
And 1 to 4 heteroatoms selected from oxygen atoms
Including 5 to 14 membered heterocycles), (viii) -S (O)
R¹²(R¹²Is (i ′) selected from the above-mentioned substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C_3-6Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16An aralkyl group or (ii ') the substituent group A
A carbon which may have 1 to 5 substituents selected from
Other than atom, selected from nitrogen atom, sulfur atom and oxygen atom
5 to 14 membered complex containing 1 to 4 heteroatoms
A ring), (ix) -S (O)_TwoR^Thirteen(R^ThirteenIs
(I ') the substituent selected from Group A above is 1 to
C which each may have 5_1-6Alkyl group, C
_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6
Cycloalkyl group, C_3-6Cycloalkenyl group, C
_6-14Aryl group or C_7-16Aralkyl group
(Ii ') does not have 1 substituent selected from the above-mentioned substituent group A
In addition to the carbon atoms which may be five, nitrogen atoms, sulfur
1 to 1 heteroatoms selected from atoms and oxygen atoms
5 to 14-membered heterocycle containing 4), (x) -NR
¹⁴R¹⁵(R¹⁴And R¹⁵Each is (i ') water
Elementary atom, (ii ') a substituent selected from the above-mentioned substituent group A
1 to 5 C each may have_1-6Archi
Lu group, C_2-6Alkenyl group, C_2-6An alkynyl group,
C_{3- 6}Cycloalkyl group, C_3-6Cycloalkenyl
Base, C_6-14Aryl group or C_7-16Aralkyl
Group, (iii ') is a substituent selected from Group A of the substituent
Formyl and carbamoy, which may have 5 to 5
Le, C_1-6Alkyl-carbonyl, C_3-6Cycloa
Rukiru-carbonyl, C_1-6Alkoxy-Carbonii
Le, C_6-14Aryl-carbonyl, C_7-16Ara
Rukiru-carbonyl, C_6-14Aryloxy-cal
Bonil, C_7-16Aralkyloxy-carbonyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic carbonyl, mono-C_1-6Alkyl-carb
Moyle, The-C_1-6Alkyl-carbamoyl, C
_6-14Aryl-carbamoyl, nitrogen in addition to carbon atom
1 to 3 selected from atom, sulfur atom and oxygen atom
5 or 6 membered heterocyclic carbamo containing 5 heteroatoms
Il, C_1-6Alkyl-thiocarbonyl, C_3-6Shi
Chloroalkyl-thiocarbonyl, C_1-6Alkoxy-
Thiocarbonyl, C_6-14Aryl-thiocarboni
Le, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_7-16
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_{6-1 Four}Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_{1- 6}Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_6-14A
Reel sulfinyl, C_1-6Alkoxy sulfini
Le, C_6-14Aryloxysulfinyl, C_1-6
Alkoxysulfonyl and C_6-14Aryloxy
An acyl group selected from sulfonyl or (iv ')
Having 1 to 5 substituents selected from the group A of substituents,
In addition to carbon atom, nitrogen atom, sulfur atom and oxygen source
5 to 5 containing 1 to 4 heteroatoms selected from children
Indicates a 14-membered heterocycle) R⁹Is (i) hydrogen atom, (ii) cyano group, (iii)
1 to 5 substituents each selected from the group A of substituents
C which may be_1-6Alkyl group, C_2-6Archeni
Lu group, C_2-6Alkynyl group, C _3-6Cycloalkyl
Base, C_3-6Cycloalkenyl group, C_6-14Aryl
Group or C_7-16An aralkyl group, (iv) the substituent A
May have 1 to 5 substituents selected from the group
I, formyl, carboxy, carbamoyl, C_1-6A
Rukiru-carbonyl, C_3-6Cycloalkyl-carbo
Nil, C_1-6Alkoxy-carbonyl, C_6-14A
Reel-carbonyl, C_7-16Aralkyl-Carboni
Le, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, other than carbon atom
1 selected from nitrogen atom, sulfur atom and oxygen atom
5 or 6-membered heterocyclic ring containing 3 heteroatoms
Lubonyl, Mono-C_1-6Alkyl-carbamoyl, di
-C_1-6Alkyl-carbamoyl, C_6-14Ally
Ru-carbamoyl, nitrogen atom, sulfur atom in addition to carbon atom
And 1 to 3 heteroatoms selected from oxygen atom
A 5- or 6-membered heterocyclic carbamoyl containing, C_1-6
Alkyl-thiocarbonyl, C_3-6Cycloalkyl-
Thiocarbonyl, C_1-6Alkoxy-thiocarboni
Le, C_6-14Aryl-thiocarbonyl, C_7-16
Aralkyl-thiocarbonyl, C_6-14Aryl Oki
Ci-thiocarbonyl, C_{7-1 6}Aralkyl oxy-chi
O-carbonyl, carbon atom, nitrogen atom, sulfur atom and
And 1 to 3 heteroatoms selected from oxygen atoms
Having 5- or 6-membered heterocyclic thiocarbonyl, thiocarba
Moyle, Mono-C_1-6Alkyl-thiocarbamoyl,
The-C_1-6Alkyl-thiocarbamoyl, C_6-14
Aryl-thiocarbamoyl, nitrogen atom other than carbon atom
1 to 3 selected from a child, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thiocarba containing heteroatoms of
Moyle, Sulfamoyl, Mono-C_1-6Alkylsul
Famoyl, The-C_1-6Alkylsulfamoyl, C
_6-14Arylsulfamoyl, C_1-6Alkyls
Lefonil, C_6-14Arylsulfonyl, C_1-6A
Ruquilsulfinyl, C_{6-1 Four}Arylsulfini
Le, sulfino, sulfo, C_1-6Alkoxy sulfi
Nil, C_6-14Aryloxysulfinyl, C
_1-6Alkoxysulfonyl and C_6-14Aryl
An acyl group selected from oxysulfonyl, or (v)
Expression-OR⁹’(R⁹′ Is a hydrogen atom, the substituent group A
Each having 1 to 5 substituents selected from
Good C_1-6Alkyl group, C_2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C
_3-6Cycloalkenyl group, C_6-14Aryl group
Is C_7-16Aralkyl group or the above-mentioned substituent group A
Optionally having 1 to 5 substituents selected from
Lumil, carbamoyl, C_1-6Alkyl-carboni
Le, C_3-6Cycloalkyl-carbonyl, C_1-6A
Lucoxy-carbonyl, C_6-14Aryl-Carbonii
Le, C_7-16Aralkyl-carbonyl, C_6-14A
Reel oxy-carbonyl, C_7-16Aralkyl Oki
In addition to carbonyl and carbon atoms, nitrogen and sulfur atoms
And 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic carbonyl containing, mono-C
_1-6Alkyl-carbamoyl, di-C_1-6Alkyl
-Carbamoyl, C_6-14Aryl-carbamoyl,
From nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 or containing 1 to 3 heteroatoms selected
6-membered heterocyclic carbamoyl, C_1-6Alkyl-thiocal
Bonil, C_3-6Cycloalkyl-thiocarbonyl, C
_1-6Alkoxy-thiocarbonyl, C_6-14Ally
L-thiocarbonyl, C_7-16Aralkyl-Tiocal
Bonil, C_6-14Aryloxy-thiocarbonyl,
C_7-16Aralkyloxy-thiocarbonyl, carbon source
Selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring thiocarbonyl, thiocarbamoyl, mono-C
_1-6Alkyl-thiocarbamoyl, di-C_{1- 6}Al
Kill-thiocarbamoyl, C_6-14Aryl-Thioca
In addition to luvamoyl and carbon atoms, nitrogen atoms, sulfur atoms and
Contains 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic thiocarbamoyl, sulfamo
Il, Mono-C_1-6Alkylsulfamoyl, di-C
_1-6Alkylsulfamoyl, C _6-14Aryls
Rufamoil, C_1-6Alkylsulfonyl, C
_6-14Arylsulfonyl, C_1-6Alkylsulf
Inyl, C_6-14Arylsulfinyl, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
A group represented by the formula:
A methylene group which may have a selected substituent or
A carbonyl group; the above [3], wherein n is 0 or 1
A compound of [5] R^TwoAnd R^ThreeIs C_1-6Alkyl group
A compound described in [3] above; [6] R^FourAnd R⁵Each represents a hydrogen atom
A compound according to [3]; [7] R⁶And R⁷Is C_1-6Alkyl group
A compound described in [3] above; [8] R⁹The compound according to the above [3], wherein is a hydrogen atom;

[9] The compound described in [3] above, wherein n is 0; [10] R ¹ is a formula

[Chemical 29] [In the formula, R¹⁶May have a hydrogen atom or a substituent
C_6-14Aryl group, an amino group which may have a substituent
Group, heterocyclic group which may have a substituent or halogen
Represents a hydrogen atom], R^TwoAnd R^ThreeIs C_1-6
An alkyl group, R ^FourAnd R⁵Are hydrogen atoms,
R⁶And R⁷Is C_1-6An alkyl group, R⁸
Is a hydrogen atom or -OR¹⁰(R¹⁰Is a hydrogen atom,
C which may have a substituent_1-6Alkyl group or reed
R group), R⁹Represents a hydrogen atom and n represents 0,
A compound according to [3]; [11] R¹⁰Are replaced by (1) hydrogen atom and (2) pyridyl.
May be C_1-6Alkyl group or (3) halogen
C substituted with an atom_1-6Alkylsulfonyl, R
¹⁶Is replaced by (1) hydrogen atom and (2) acetylamino group.
Phenyl, (3) (i) C_1-6Alkylsulfonyl group, (i
i) pyridylcarbonyl or (iii) sulfamoyl-C
_1-6A mono- or di-substituted with a substituent selected from an alkyl group.
Optionally substituted amino, (4) pyridyl or (5) halo
The compound according to the above [10], which represents a gen atom; [12] A prodrug of the compound according to [3] above; [13] Expression

[Chemical 30] [In the formula, R ¹⁷ represents a vinyl group or an allyl group which may have a substituent] or a salt thereof, and a salt thereof and a formula R ¹ -CN [wherein R ¹ is A compound represented by [2] having the same meaning as described above, or a salt thereof;

[Chemical 31] [Wherein R ¹ has the same meaning as defined above], or a salt thereof;

[Chemical 32] [Wherein each symbol has the same meaning as described in [3] above] or a salt thereof and a compound represented by the formula R ¹ -CN [wherein R
¹ has the same meaning as described in [3] above] or a salt thereof is reacted; [15] a method for producing a compound according to the above [3]

[Chemical 33] Wherein - - - represents a single bond or a double bond The compound having a partial structure represented by (hereinafter, compound (A-
1)) or a salt thereof; [16] Formula

[Chemical 34] [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom], or a salt thereof. Composition: [17] A pharmaceutical composition comprising the compound according to [3] above or a salt thereof or a prodrug thereof; [18] Formula

[Chemical 35] Wherein - - - represents a single bond or a double bond The compound having a partial structure represented by (hereinafter, compound (A-
2)) or a phosphodiesterase IV inhibitor containing a salt thereof; [19] Formula

[Chemical 36] Wherein - - - represents a single bond or a double bond The compound or inflammatory diseases containing a salt having a partial structure represented by, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis A prophylactic / therapeutic agent for autoimmune disease, depression, Alzheimer-type dementia, memory disorder, diabetes or arteriosclerosis; [20] a phosphodiesterase IV inhibitor [1]
5] to the pharmaceutical composition according to [17]; [21] inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis. The pharmaceutical composition according to the above [15] to [17], which is a prophylactic / therapeutic agent for:

[Chemical 37] Wherein - - - is a single bond or an double bond] phosphodiesterase IV inhibitory method characterized by administering a compound or an effective amount of a salt thereof having a partial structure represented by; [23] Mammals Expression for animals

[Chemical 38] [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom] is administered, and an effective amount of the compound or a salt thereof is administered. A method for inhibiting phosphodiesterase IV, which is characterized by:

[Chemical Formula 39] Wherein - - - represents a single bond or a double bond] inflammatory disease, which comprises administering a compound or an effective amount of a salt thereof having a partial structure represented by, asthma, chronic obstructive Lung disease, rheumatoid arthritis, autoimmune disease, depression,
Method for preventing / treating Alzheimer type dementia, memory disorder, diabetes or arteriosclerosis; [25] Formula for mammals

[Chemical 40] [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom] is administered, and an effective amount of the compound or a salt thereof is administered. A method for preventing / treating inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis characterized by: [26] phosphodiesterase Formulas for producing IV inhibitors

[Chemical 41] Wherein - - - represents a single bond or a double bond The compound having a partial structure represented by or a salt thereof; [27] inflammatory diseases, asthma, chronic obstructive pulmonary disease, rheumatoid Formula for producing a prophylactic / therapeutic agent for rheumatism, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis

[Chemical 42] Wherein - - - represents a single bond or a double bond The compound having a partial structure represented by or a salt thereof; [28] Formula

[Chemical 43] [In the formula, R^2aAnd R^3aEach has a substituent
The aliphatic hydrocarbon group which may be^4aAnd R^5aIs
Carbonization optionally having a hydrogen atom or a substituent
The hydrogen group is^6aAnd R^7aAre hydrogen atoms and
Represents a hydrocarbon group which may have a substituent, R^6a
And R^7aHas substituents on adjacent carbon atoms
R may form a 3- to 8-membered ring, and R^8aIs
(1) Hydrogen atom, (2) Carbonization which may have a substituent
Even if it has a hydrogen group, (3) acyl group, or (4) substituent
Good heterocyclic group, (5) halogen atom, (6) -OR
^10a(R^{1 0a}Is a hydrogen atom, even if it has a substituent
May have a good hydrocarbon group, acyl group or substituent
Represents a good heterocyclic group), (7) -SR^11a(R^11a
Is a hydrogen atom, a hydrocarbon group which may have a substituent,
Shows an acyl group or a heterocyclic group which may have a substituent.
), (8) -S (O) R^12a(R^12aIs a substituent
Optionally having a hydrocarbon group or a substituent
Optionally represents a heterocyclic group), (9) -S (O)_TwoR
^13a(R^13aIs a hydrocarbon which may have a substituent
Indicates a heterocyclic group which may have a basic group or a substituent)
Or (10) -NR ^14aR^15a(R^14aand
R^15aMay each have a hydrogen atom or a substituent.
May have a hydrocarbon group, an acyl group or a substituent
Represents a heterocyclic group), R^9aHas a hydrogen atom and a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent.
A hydroxyl group which may be present] or
The salt;

Further, the present invention is [29] Expression

[Chemical 44] [In the formula, each of ring A, ring B and ring C may have a substituent. ] Or a salt thereof; [30] ring A, ring B and ring C have (1) a hydrocarbon group which may have a substituent, (2) a substituent Optionally heterocyclic group, (3) optionally substituted amino group, (4) acyl group, (5) optionally substituted hydroxyl group, (6) optionally substituted Optionally substituted sulfenyl group, (7) halogen atom, (8) lower alkylenedioxy group, (9) nitro group, (10) cyano group, (11) optionally substituted imino group, (12) oxo group,
(13) an optionally substituted ureido group, (14) an azido group, (15) an optionally substituted amidino group,
(16) a guanidino group which may have a substituent, (17)
The compound according to the above [29], which is 1 to 5 substituents selected from the group consisting of a hydrazino group which may have a substituent and an (18) oxide group; [31] the substituent is a substituent group A The compound according to the above [29], which is a group selected from: [32] the compound (A-1) has the formula

[Chemical formula 45] Wherein - - - is a single bond or a double bond, A ring, B ring and C ring may have a substituent. ] The pharmaceutical composition according to the above [15], which is a compound represented by the following (hereinafter sometimes abbreviated as compound (I-1)); [33] The compound (A-1) has the formula

[Chemical formula 46] The pharmaceutical composition according to [15], which is a compound represented by the formula [wherein the symbols have the same meanings as those described in [3] above (hereinafter sometimes abbreviated as compound (I′-1)). I will provide a. Furthermore, compounds (A), (I), (I ′), (A-
When 1), (I-1), (I'-1), (A-2) or a salt thereof contains an asymmetric carbon in the structure, both the optically active form and the racemic form are within the scope of the present invention. Compounds (A), (I), (I ′), (A-1), (I-1),
The (I′-1), (A-2) or a salt thereof may be a hydrate or an anhydride.

The compounds of the present invention have the formula

[Chemical 47] Has a partial structure represented by

[Chemical 48] [Wherein each symbol has the same meaning as described above]. The molecular weight of the compounds of the present invention is about 1000 or less, preferably about 900 or less, more preferably about 800 or less, and particularly preferably about 700 or less.

In the above formula, ring A, ring B and ring C may have a substitutable number of substituents at substitutable positions. As the substituents on the A ring, the B ring and the C ring, (1) a hydrocarbon group which may have a substituent, (2) a heterocyclic group which may have a substituent, (3) Optionally substituted amino group, (4) acyl group, (5) optionally substituted hydroxyl group, (6) optionally substituted sulfenyl group, (7 ) Halogen atom (eg, fluorine, chlorine, bromine, iodine), (8) lower alkylenedioxy group (eg, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (9) nitro Group, (10) cyano group, (11) optionally substituted imino group, (12) oxo group, (13) optionally substituted ureido group, (14) azido group, (15) an amidino group which may have a substituent, (16) a guanidino group which may have a substituent, (17) Good hydrazino group which may have a group, and (18) oxide groups used.

Examples of the hydrocarbon group of the "hydrocarbon group which may have a substituent" used as the substituents of the A ring, the B ring and the C ring include, for example, an alkyl group, an alkenyl group,
A chain or cyclic hydrocarbon group such as an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group and an aralkyl group is used, and among them, a chain group having 1 to 16 carbon atoms (straight chain or branched chain) or A cyclic hydrocarbon group (eg, aromatic hydrocarbon group, aliphatic cyclic hydrocarbon group) and the like are preferable. Specifically, the following are used. (1) Chain hydrocarbon group: a) Alkyl group [preferably lower alkyl group (for example, C ₁ such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. _-6 alkyl group)], b) alkenyl group [preferably lower alkenyl group (eg, vinyl, allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5
-C _2-6 alkenyl group such as hexenyl)], c) alkynyl group [preferably lower alkynyl group (eg, C _2-6 alkynyl group such as propargyl, ethynyl, 2-butynyl, 2-hexynyl etc.)] (2) Aliphatic cyclic hydrocarbon group: a) a cycloalkyl group [preferably a lower cycloalkyl group (for example, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and a benzene ring; B) cycloalkenyl group [preferably lower cycloalkenyl group (eg, C _3-6 cycloalkenyl such as 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, etc. Group) and may be condensed with a benzene ring] (3) Aromatic hydrocarbon Group: an aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2
-Anthryl, 9-anthryl, 1-phenanthryl,
C _6-14 aryl group such as 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably a phenyl group) (4) Aralkyl group: lower aralkyl group (for example, benzyl, phenethyl, diphenylmethyl, 1 -Naphthylmethyl, 2-naphthylmethyl, 2-phenethyl, 2,2-
C _7-16 aralkyl groups such as diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., preferably benzyl group).

Examples of the substituents on these hydrocarbon groups include (1) halogen atoms (eg, fluorine, chlorine, bromine, iodine), (2) lower alkylenedioxy groups (eg, methylenedioxy, ethylenedioxy). Such as C
_1-3 alkylenedioxy group), (3) nitro group,
(4) cyano group, (5) optionally halogenated lower alkyl group, (6) optionally halogenated lower alkenyl group, (7) optionally halogenated lower alkynyl group, (8 ) A lower cycloalkyl group (for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(9) C _6-14 aryl group (eg, phenyl, 2-naphthyl, etc.), (10) optionally halogenated lower alkoxy group, (11) optionally halogenated lower alkylthio group, (12 ) Hydroxy group, (13) amino group,
(14) Mono-lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (15) mono-C _6-14 aryl An amino group (eg, phenylamino, 2-naphthylamino, etc.),
(16) Di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino), (17) di-C _{6-1 4} arylamino groups (eg, diphenylamino, di (2-naphthyl) amino, etc.), (18) acyl groups, (19) acylamino groups, (20)
Acyloxy group, (21) 4- to 14-membered heterocyclic group (preferably 4- to 10-membered, more preferably 4- to 7-membered heterocyclic group, particularly preferably 5- or 6-membered heterocyclic group) (eg, 4
-Pyridyl, 2-thienyl, 2-furyl, 2-thiazolyl, 3-indolyl, morpholino, 1-piperazinyl,
4- to 14-membered, preferably 4- to 7-membered, containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as piperidino, 1-pyrrolidinyl, 2-isoindolyl and the like, Preferably 5
Or 6-membered heterocyclic group, etc.), (22) phosphono group, (23)
A C _6-14 aryloxy group (eg, phenoxy), (2
4) DiC _1-6 alkoxy-phosphoryl group (eg, dimethoxyphosphoryl, diethoxyphosphoryl), (25) C
_6-14 arylthio group (eg, phenylthio), (26) hydrazino group, (27) imino group, (28) oxo group (except when the oxo group is bonded to a hydrocarbon group to form an acyl group). , (29) ureido group, (30) C _1-6 alkyl-ureido group (eg, methylureido, ethylureido, etc.), (31) di-C _1-6 alkyl-ureido group (eg, dimethylureido, diethylureido) Such),
(32) 1 to 5 selected from the group consisting of (32) an oxide group, (33) a group formed by combining 2 to 3 selected from the groups (1) to (32) (substituent group A), Preferably 1 to 3 is used.

The “optionally halogenated lower alkyl group” in the above-mentioned Substituent group A has, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). And a lower alkyl group (for example, C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) is used. , Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl,
Propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoro Pentyl, hexyl, 6,6,6-trifluorohexyl and the like can be mentioned. Examples of the "optionally halogenated lower alkenyl group" in the Substituent Group A include, for example, a lower group which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). An alkenyl group (for example, a C _2-6 alkenyl group such as vinyl, allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl) is used. The “optionally halogenated lower alkynyl group” in the above-mentioned Substituent group A is, for example, a lower group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). An alkynyl group (eg, a C _2-6 alkynyl group such as propargyl, ethynyl, 2-butynyl, 2-hexynyl, etc.) is used. Examples of the "optionally halogenated lower alkoxy group" in the Substituent Group A include, for example, 1 to 3
Individual halogen atoms (eg, fluorine, chlorine, bromine, iodine)
A lower alkoxy group which may have (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, a C _1-6 alkoxy group such as hexyloxy), such as are used, specific examples, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, trichloromethoxy, 3,3,3-trifluoropropoxy, 4,
4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy and the like are used. The "optionally halogenated lower alkylthio group" in the above-mentioned Substituent group A is, for example, C optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). _1-6
An alkylthio group (for example, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio) is used, and specific examples include methylthio. , Difluoromethylthio, trifluoromethylthio, ethylthio,
Propylthio, isopropylthio, butylthio, 4,4,
4-trifluorobutylthio, pentylthio, hexylthio and the like can be mentioned.

As the "acyl group" in the above-mentioned substituent group A
Is, for example, formyl, carboxy, carbamoyl, C
_1-6Alkyl-carbonyl (eg, acetyl, propio
Nil), C_3-6Cycloalkyl-carbonyl
(Eg cyclopentyl carbonyl, cyclohexyl calc
Bonyl), C_1-6Alkoxy-carbonyl (eg,
Methoxycarbonyl, ethoxycarbonyl, isopropo
Xycarbonyl, tert-butoxycarbonyl, etc.), C
_6-14Aryl-carbonyl (eg, benzoyl, 2-
Naphthoyl, etc.), C_7-16Aralkyl-carbonyl
(Eg phenylacetyl, 3-phenylpropionyl
DO), C_6-14Aryloxy-carbonyl (eg, phenol
Such as enoxycarbonyl and 2-naphthyloxycarbonyl.
DO), C_{7-1 6}Aralkyloxy-carbonyl (eg,
Benzyloxycarbonyl, 2-naphthylmethyloxy
Carbonyl, etc.) 5- or 6-membered heterocyclic carbonyl
(Eg, 1-pyrrolidinylcarbonyl, 4-piperidylca
Rubonyl, 1-piperazinyl carbonyl, 2-morpholin
Nylcarbonyl, 4-pyridylcarbonyl, 3-thieni
Lucarbonyl, 2-furylcarbonyl, 2-thiazolyl
In addition to carbon atoms such as carbonyl, nitrogen atom, sulfur atom,
Contains 1 to 3 heteroatoms selected from oxygen atom, etc.
Having 5- or 6-membered heterocyclic carbonyl), mono-C
_1-6Alkyl-carbamoyl (eg, methylcarbamoyl
, Ethylcarbamoyl), di-C_1-6Alkyl
-Carbamoyl (eg, dimethylcarbamoyl, diethyl
Carbamoyl etc.), C_6-14Aryl-carbamoy
(Eg, phenylcarbamoyl, 2-naphthylcarbamo)
And the like) 5- or 6-membered heterocyclic carbamoyl (eg, 1
-Pyrrolidinylcarbamoyl, 4-piperidylcarbamo
Yl, 1-piperazinylcarbamoyl, 2-morpholini
Lucarbamoyl, 4-pyridylcarbamoyl, 3-thie
Nylcarbamoyl, 2-furylcarbamoyl, 2-thia
In addition to carbon atoms such as zolylcarbamoyl, nitrogen atoms and sulfur atoms
1 to 3 hetero atoms selected from yellow atom, oxygen atom, etc.
5- or 6-membered heterocyclic carbamoyl containing atoms
DO), C_1-6Alkyl-thiocarbonyl (eg, methyl
Thiocarbonyl etc.), C_3-6Cycloalkyl-thio
Carbonyl (eg cyclopentylthiocarbonyl, cycl
Rohexylthiocarbonyl etc.), C_1-6Alkoxy
-Thiocarbonyl (eg, methoxythiocarbonyl, eth
Xythiocarbonyl, propoxythiocarbonyl, buto
Xylthiocarbonyl, etc.), C_6-14Aryl-thio
Carbonyl (eg, phenylthiocarbonyl, 2-naphthyl
Luthiocarbonyl, etc.), C_7-16Aralkyl-Thio
Carbonyl (eg benzylthiocarbonyl, phenethyl
Thiocarbonyl etc.), C_{6- 14}Aryloxy-thio
Ocarbonyl (eg, phenoxythiocarbonyl, 2-na
(Futyloxythiocarbonyl, etc.), C_7-16Aral
Kiroxy-thiocarbonyl (eg, benzyloxythio
Carbonyl, 2-naphthylmethyloxythiocarbonyl
Etc.) 5- or 6-membered heterocyclic thiocarbonyl (eg, 1-
Pyrrolidinyl thiocarbonyl, 4-piperidyl thiocarl
Bonyl, 1-piperazinylthiocarbonyl, 2-morpho
Linylthiocarbonyl, 4-pyridylthiocarbonyl,
3-thienylthiocarbonyl, 2-furylthiocarboni
Other than carbon atoms such as chloro and 2-thiazolylthiocarbonyl
1 selected from nitrogen atom, sulfur atom, oxygen atom, etc.
A 5- or 6-membered heterocyclic thio containing 3 heteroatoms
Carbonyl), thiocarbamoyl, mono-C_1-6
Alkyl-thiocarbamoyl (eg, methylthiocarbamoyl
, Ethylthiocarbamoyl, etc.), di-C_1-6A
Rukyl-thiocarbamoyl (eg, dimethylthiocal
Vamoyl, diethylthiocarbamoyl, etc.), C
_6-14Aryl-thiocarbamoyl (eg, phenylthio
Ocarbamoyl, 2-naphthylthiocarbamoyl
Etc.) 5- or 6-membered heterocyclic thiocarbamoyl (eg, 2-
Pyrrolidinyl thiocarbamoyl, 4-piperidyl thioca
Luvamoyl, 2-piperazinylthiocarbamoyl, 2-
Morpholinyl thiocarbamoyl, 4-pyridyl thiocar
Vamoyl, 3-thienylthiocarbamoyl, 2-furyl
Thiocarbamoyl, 2-thiazolylthiocarbamoyl
Other than carbon atom, nitrogen atom, sulfur atom, oxygen atom, etc.
5 or containing 1 to 3 heteroatoms selected from
Is a 6-membered heterocyclic thiocarbamoyl, etc.), sulfamoy
Le, Mono-C_1-6Alkyl-sulfamoyl (eg,
Tilsulfamoyl, ethylsulfamoyl, etc.), di
-C_1-6Alkyl-sulfamoyl (eg, dimethyls
Rufamoyl, diethylsulfamoyl, etc.), C
_6-14Aryl-sulfamoyl (eg, phenylsulfur
Famoyl etc.), C_1-6Alkylsulfonyl (eg,
Methylsulfonyl, ethylsulfonyl, etc.), C
_6-14Arylsulfonyl (eg, phenylsulfoni
, 2-naphthylsulfonyl, etc.), C_1-6Alkyl
Sulfinyl (eg, methylsulfinyl, ethylsulfin
Inyl, etc.), C_6-14Arylsulfinyl (eg,
Phenylsulfinyl, 2-naphthylsulfinyl
DO), Sulfino, Sulfo, C_1-6Alkoxy sulf
Inyl (eg, methoxysulfinyl, ethoxysulfinyl
Nil), C_6-14Aryloxysulfinyl (eg,
Phenoxysulfinyl), C_1-6Alkoxy sulfo
Nyl (eg, methoxysulfonyl, ethoxysulfonyl)
And C_6-14Aryloxysulfonyl (eg,
(Noxysulfonyl) and the like are used. Among them,
Mill, carboxy, C_1-6Alkyl-carbonyl, C
_1-6Alkoxy-carbonyl, carbamoyl, mono-
C _1-6Alkylcarbamoyl, sulfamoyl, mono
-C_1-6C such as alkyl-sulfamoyl_1-7A
A sil group is preferred.

The "acylamino group" in the above-mentioned Substituent group A is, for example, formylamino, C _1-6 alkyl-
Carboxamide (eg, acetamide, propionamide, etc.), C _6-14 aryl-carboxamide (eg, benzamide, 2-naphthylcarboxamide, etc.), C
_1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, isopropoxycarboxamide, tert-butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), bis (C _{1 -6} alkylsulfonyl) amino (eg, bis (methylsulfonyl) amino, bis (ethylsulfonyl) amino, etc., C _6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, etc.) and the like are used. . Among them, formylamino, C _1-6 alkyl-carboxamide, C
Preferred are C _1-7 acylamino groups such as _1-6 alkoxy-carboxamide, C _1-6 alkylsulfonylamino, bis (C _1-6 alkylsulfonyl) amino.
Examples of the "acyloxy group" in Substituent Group A, for _{example, C 1-6} alkyl - carbonyloxy (e.g., acetyloxy, propionyloxy, _{etc.), C 6- 14} aryl - carbonyloxy (e.g., benzoyloxy, 2 −
Naphthoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy,
tert-butoxycarbonyloxy, etc.), mono-C
_6alkyl - carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), di _{-C 1 -6} alkyl - carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy _{etc.), C 6-14} aryl - carbamoyl Oxy (eg,
Phenylcarbamoyloxy, 2-naphthylcarbamoyloxy and the like), nicotinoyloxy and the like are used. Among them, C _1-6 alkyl-carbonyloxy,
C _1-7 C _2-6 such as alkoxy-carbonyloxy
An acyloxy group is preferred.

In the above-mentioned substituent group A, the above (1) to (3
A group formed by combining two or three selected from the groups of 2)
For example, (33a) Substitution C_1-6Alkyl group [this C_1-6Alkyl
The groups are cyano, carbamoyl, C_1-6Alkyl-cal
Bamoiru, C_1-6Alkyl-carbonyloxy, C
_1-6Alkoxy-carbonyl-C_1-6Alkyl-Mo
Lubamoyl, 5- or 6-membered heterocycle (eg pyridyl etc.
In addition to carbon atoms, selected from nitrogen, sulfur, oxygen, etc.
5 or 6 containing 1 to 3 heteroatoms
Member heterocycle) -C_1-6Alkyl-carbamoyl, C
_1-6Alkylsulfonylamino, C_{1- 6}Alkoxy
-Having a substituent selected from carbonyl, carboxy, etc.
Do], (33b) Substitution C_6-14Aryl group [this C_6-14A
The reel group is amino, optionally halogenated C
_1-6Alkyl-carbonylamino, ureido, C
_1-6Alkylsulfonylamino, (C_1-6Archi
Le) (C_1-6Alkylsulfonyl) amino, C_1-6
Alkoxy-carbonyl-C_1-6Alkylamino, etc.
Having a substituent selected from], (33c) C_1-6Alkoxy-C_6-14Aryl-C
_1-6An alkoxy group, (33d) In addition to carbon atoms having a substituent, nitrogen atoms and sulfur
1 to 4 heteroatoms selected from atoms, oxygen atoms, etc.
5 to 14-membered heterocyclic group containing a child
Is oxo, carboxy-C_1-6Alkyl, C_1-6
Alkyl-carbonyloxy-C_1-6Alkyl, C
_1-6Alkyl, C_1-6Alkoxy-carbonyl-C
_1-6Alkyl, C_1-6Alkyl-carbamoyl-C
_1-6Having a substituent selected from alkyl, etc.], Expression (33e) -NR¹⁸R¹⁹A group represented by [R¹⁸And
And R¹⁹Are (i) 5- or 6-membered heterocycles (eg carbon
In addition to atoms, selected from nitrogen atom, sulfur atom, oxygen atom, etc.
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring) -C_1-6Alkyl, (ii) C_1-6Alkoxy-
Carbonyl-C_1-6Alkyl, (iii) di-C_1-6A
Lucylamino-methylene-sulfamoyl-C_1-6A
Ruquil, (iv) carbamoyl-C_1-6Alkyl, (v)
Rufamoil-C_1-6Alkyl, (vi) C_1-6Archi
Le-sulfonyl, (vii) C_1-6Alkoxy-Carbonii
Le, (viii) di-C_1-6Alkoxy-carbonyl-C
_2-6Alkenyl, (ix) 5- or 6-membered heterocyclic group (eg, charcoal
Other than elementary atom, selected from nitrogen atom, sulfur atom, oxygen atom, etc.
5 or 6 member containing 1 to 3 heteroatoms
Heterocyclic group) [This 5- or 6-membered heterocyclic group is amino, C
_1-6Alkyl-carboxamide, C_1-6Alkyl-
Having a substituent selected from sulfonylamino, etc.
May be present], (x) optionally halogenated C_1-6Al
Kill-carbonyl, (xi) C_1-6Alkylthio-C
_1-6Alkyl-carbonyl, (xii) C_1-6Alkyl
Sulfinyl-C_1-6Alkyl-carbonyl, (xiii)
C _1-6Alkylsulfonyl-C_1-6Alkyl-cal
Bonyl, (xiv) amino-C _1-6Alkyl-carboni
And (xv) optionally halogenated C_1-6Alkyl
-Carbonyl-amino-C_1-6Alkyl-carboni
Le, (xvi) C_6-14Aryl-carbonyl, (xvii)
Ruboxi-C_6-14Aryl-carbonyl, (xviii)
C_1-6Phosphorus optionally esterified with alkyl
No-C_1-6Alkyl-C_6-14Aryl-Carbonii
Le, (xix) C_1-6Has an alkoxy-carbonyl
May be a 5- or 6-membered heterocycle (eg, nitrogen in addition to carbon atom)
1 to 3 selected from atoms, sulfur atoms, oxygen atoms, etc.
5- or 6-membered heterocycle containing heteroatoms of
Nyl, (xx) 5- or 6-membered heterocycle (eg, nitrogen atoms other than carbon atoms)
1 to 3 selected from elementary atom, sulfur atom, oxygen atom, etc.
5- or 6-membered heterocycle containing 6 heteroatoms) -C
_1-6Alkyl-carbonyl, (xxi) C_6-14Ally
Ru-oxy-carbonyl, (xxii) carboxy-C
_1-6Alkyl, (xxiii) carbamoyl, etc.], (33f) Formula —CO—Hal (Hal represents a halogen atom
Group represented by (33g) Substituted sulfamoyl group [This sulfamoyl group
Is carbamoyl-C_{1- 6}Alkyl, 5 or 6 membered compound
Elementary ring-C_1-6Has a substituent selected from alkyl, etc.
], (33h) Formula-C (= O) NR²⁰R²¹Group represented by
[R²⁰And R²¹Are (i) 5- or 6-membered complex, respectively
Rings (eg, other than carbon atoms such as pyridyl and imidazolyl)
1 to selected from nitrogen atom, sulfur atom, oxygen atom, etc.
5- or 6-membered heterocycle containing 3 heteroatoms) -C
_1-6Alkyl, (ii) carboxy-C_1-6Alkyl,
(iii) C_1-6Alkoxy-carbonyl-C_1-6Al
Kill, (iv) J-C_1-6Alkylamino-C_1-6Al
Kill, (v) Carbamoyl-C_1-6Alkyl, (vi) C
_1-6Alkylcarbamoyl-C_{1 -6}Alkyl, (vi
i) 5- or 6-membered heterocycle (eg, carbon atom such as pyridyl)
Other than nitrogen atom, sulfur atom, oxygen atom, etc. 1
To 5 or 6 membered heterocycle containing 3 to 3 heteroatoms
Ring) -C_1-6Alkylcarbamoyl-C_1-6Archi
(Viii) 5- or 6-membered heterocycle (eg pyridyl etc.
In addition to carbon atoms, selected from nitrogen, sulfur, oxygen, etc.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocycle) -amino-C_1-6Alkyl, (ix) sulf
Amoy C_{6- 14}Aryl-C_1-6Alkyl,
(X) C_1-6C which may have alkoxy
_6-14Aryl, (xi) C_1-6Ester with alkyl
Optionally phosphono-C_1-6Alkyl-C
_6-14Aryl, (xii) 4- to 10-membered heterocyclic group
(For example, in addition to carbon atom, nitrogen atom, sulfur atom, oxygen atom, etc.
4 containing 1 to 3 heteroatoms selected from
Ishi 10-membered heterocycle) [This 4- to 10-membered heterocyclic group is
Halogen atom, C_1-6Select from alkyl, oxo, etc.
Optionally have 1 to 2 substituents], (xiii)
C_6-14Aryl-carbamoyl-C_1-6Alkyl
Etc. ], (33i) Halogenated C_1-6Alkyl carboxami
(Eg, 2-chloroacetamide, 2,2-dichloroacetate
Cetamide, 2,2,2-trichloroacetamide
Etc. are used.

The "heterocyclic group which may have a substituent (s)" used as the substituent (s) on the A ring, B ring and C ring is, for example, from a nitrogen atom, a sulfur atom, an oxygen atom, etc. in addition to the carbon atom. A 4- to 14-membered heterocyclic group containing 1 to 4 (preferably 1 to 3) heteroatoms selected is used, and specifically, (a) a 4- to 14-membered aromatic heterocyclic group, (b) ) 4- to 14-membered aliphatic heterocyclic group, (c) 4
A bicyclic or tricyclic fused ring group of a 14-membered heterocycle and a benzene ring is used. Examples of the 4- to 14-membered aromatic heterocyclic group include 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atom.
4 to 14-membered aromatic heterocyclic groups containing 1 to 3 (preferably 1 to 3) are used, and specifically, thiophene,
Furan, indolizine, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, N-oxidized pyridine, pyrazine, pyrimidine, pyridazine, purine, 4H-quinolidine, naphthyridine, isothiazole, isoxazole, flazan and the like can be mentioned. . Among them, pyridine, thiophene, furan and the like are preferably used. The 4- to 14-membered aliphatic heterocyclic group is a 4- to 14-membered one containing 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms. An aliphatic heterocyclic group or the like is used, and specifically, pyrrolidine,
Examples thereof include piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine and imidazolidine. The 2- or 3-cyclic fused ring group of a 4- to 14-membered heterocycle and a benzene ring has 1 or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom.
Or a bicyclic condensed ring group of a heterocycle containing 4 to 4 (preferably 1 to 3) and a benzene ring is used, and specific examples thereof include benzo [b] thiophene, benzofuran, 1H-benzimidazole. , Benzoxazole,
Benzothiazole, 1,2-benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxathiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, Examples thereof include carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, isochroman and dihydrobenzofuran. Examples of the substituent of these heterocyclic groups include the above-mentioned substituent A
1 to 5, preferably 1 to 3 selected from the group is used.

The "optionally substituted amino group" used as the substituents on the A ring, B ring and C ring is the above "hydrocarbon group optionally substituted", the above "Heterocyclic group optionally having substituent (s)", "acyl group" in Substituent Group A (this "acyl group" is further selected from 1 to 5 substituent groups, preferably 1 to 5). Three
An optionally substituted amino group, etc.) may be used. As the “acyl group” used as the substituents of the A ring, the B ring and the C ring, those similar to the “acyl group” in the above-mentioned substituent group A can be used. This "acyl group"
May further have 1 to 5, preferably 1 to 3 substituents selected from the substituent group A. A
“A hydroxyl group which may have a substituent”, “a sulfenyl group which may have a substituent”, and “which may have a substituent” which are used as substituents for the ring, the B ring and the C ring Good imino group ”,“ optionally substituted ureido group ”,
As the substituents of the “optionally substituted amidino group”, “optionally substituted guanidino group” and “optionally substituted hydrazino group”, the above-mentioned “substituted A “hydrocarbon group which may have a group”, the above “heterocyclic group which may have a substituent”, an “acyl group” in the substituent group A (the “acyl group” is a substituent 1 to 5, preferably 1 to 3 substituents selected from Group A) and the like are used.

Examples of the compound in which each of A ring, B ring and C ring has a substituent are, for example,

[Chemical 49] [Wherein R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent], and a compound having a partial structure represented by: The expression

[Chemical 50] A compound represented by the formula [wherein each symbol has the same meaning as defined above] and the like are used.

In the above formula, R ¹ is (1) hydrogen atom, (2)
The hydrocarbon group which may have a substituent or (3) the heterocyclic group which may have a substituent is shown. The "hydrocarbon group which may have a substituent (s)" represented by R ¹ is A
The same "hydrocarbon group optionally having substituent (s)" exemplified as the ring substituent is used. The “heterocyclic group which may have a substituent (s)” represented by R ¹ includes A
The same as the "heterocyclic group which may have a substituent (s)" exemplified as the ring substituent is used. As R ¹ ,
(1) an aromatic hydrocarbon group which may have a substituent,
(2) a heterocyclic group which may have a substituent, (3) an aliphatic cyclic hydrocarbon group which may have a substituent, (4) formula -LR ^1a [wherein, L is Methylene or carbonyl, R ^1a represents a hydrogen atom, an aromatic group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent] The groups represented are preferred.

The "aromatic hydrocarbon group optionally having substituent (s)" and "heterocyclic group optionally having substituent (s)" are as follows.

[Chemical 51] [In the formula, R^1bMay have a hydrogen atom or a substituent
Hydrocarbon group or heterocyclic group which may have a substituent
, D is an aromatic hydrocarbon ring which may have a substituent
Or a heterocycle which may have a substituent, E is a bond
Hand, methylene, oxygen atom, optionally oxidized sulfur source
Child, optionally substituted nitrogen atom or formula-CS
-O-, -CO-O-, -S-CO-,-(CH_Two)_k
-CO-, -NR^1c-CO- (CH_Two)_m-, -NR
^1c-SO_Two-(CH_Two)_m-, -SO _Two-NR^1c−
(CH_Two)_m-, -O-CS-NR^1c-(CH_Two)_m
-, -NR^1c-CO-NR^1c-(CH_Two)_m-,-
NR^1c-CO-CH_Two-(CH _Two)_m-NR^1c−
[In the formula, R^1cMay have a hydrogen atom or a substituent
An alkyl group or an acyl group, k is 0 or 1, m is
Represents an integer of 0 to 3], a group represented by the formula:

[Chemical 52] A group represented by the formula [wherein Hal is a halogen atom and D ring has the same meaning as described above] is preferably used.

The "aromatic hydrocarbon group" which is a preferred group for R ¹ is, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (C _6-14 aryl group). Are used. Examples of the C _6-14 aryl group include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9 -Phenanthryl and the like are used, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable, and phenyl and the like are particularly preferable. As the substituent of the "aromatic hydrocarbon group", 1 to 5, preferably 1 to 3 selected from the above-mentioned Substituent group A is used. Among these substituents, (1) halogen atom, (2) nitro group, (3) C
_1-6 alkyl group (methyl, isopropyl, tert-butyl, etc.) [This C _1-6 alkyl group is a halogen atom,
Cyano, carbamoyl, C _1-6 alkyl-carbamoyl, C _1-6 alkyl-carbonyloxy, C _1-6 alkoxy-carbonyl-C _1-6 alkyl-carbamoyl, a 5- or 6-membered heterocycle (eg, carbon such as pyridyl, etc. Besides atoms, it is selected from nitrogen atom, sulfur atom, oxygen atom, etc. 1
To 5 or 6-membered heterocycle containing 3 to 3 heteroatoms) -C _1-6 alkyl-carbamoyl, C _1-6 alkylsulfonylamino, C _1-6 alkoxy-carbonyl, carboxy and the like. Optionally,], (4) C _3-6 cycloalkyl group (eg cyclohexyl), (5) C _6-14 aryl group (eg phenyl) [this C _6-14 aryl group is amino, carboxy] , C _1-6 alkoxy-carbonyl, carbamoyl,
Mono- or di-C _1-6 alkylcarbamoyl, formylamino, C _1-6 alkyl-carbonylamino optionally having a halogen atom or carboxy (eg, acetylamino, propionylamino, trifluoroacetylamino, pivaloylamino) , C _6-14 aryl-carbonylamino (eg, benzoylamino), C
_1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino), ureido, mono- or di-C
_1-6 alkyl ureido, C _1-6 alkylsulfonylamino (eg, methylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkylsulfonyl) amino (eg,
Methyl (methylsulfonyl) amino etc.), (C _1-6
Alkyl) (C _1-6 alkyl-carbonyl) amino (eg, methyl (acetyl) amino, etc.), C _1-6 alkoxy-carbonyl-C _1-6 alkylamino (eg, 2
-Ethoxycarbonyl-2-propylamino etc.), C
_7-15 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino), C _1-6 alkyl-
Carbonylamino _{-C 1 -6} alkyl - carbonylamino (e.g., acetylamino _{acetylamino), C 1 -6} alkylthio _{-C 1-6} alkyl - carbonylamino (e.g., methylthio _{acetylamino), C 1-6} alkyl - sulfinyl - C _1-6 alkyl-carbonylamino (eg, methylsulfinylacetylamino), C _1-6
Alkyl-sulfonyl-C _1-6 alkyl-carbonylamino (eg, methylsulfonylacetylamino), C
_6-14 aryloxy-carbonylamino (eg, phenoxycarbonylamino), hydroxy-C _1-6 alkyl-carbamoyl (eg, hydroxymethylcarbamoyl, hydroxyethylcarbamoyl) and the like, which may have a substituent group, Especially amino, carboxy,
C _1-6 alkoxy-carbonyl, carbamoyl, mono- or di-C _1-6 alkylcarbamoyl, formylamino, C _1-6 alkyl-carbonylamino optionally having a halogen atom or carboxy (eg, acetylamino, Propionylamino, trifluoroacetylamino, pivaloylamino), C _1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino), ureido, C _1-6 alkylsulfonylamino (eg, methylsulfonylamino), (C _1-6 alkyl). ) (C
_1-6 alkylsulfonyl) amino (e.g., methyl (methylsulfonyl) amino _{etc.), (C 1 -6} alkyl)
(C _1-6 alkyl-carbonyl) amino (eg, methyl (acetyl) amino etc.), C _1-6 alkoxy-carbonyl-C _1-6 alkylamino (eg, 2-ethoxycarbonyl-2-propylamino etc.), It may have a substituent selected from C _7-15 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino) and the like],

[0021] (6) may have a halogen atom or a _{C 1-6} alkoxy _{-C 6-14} aryl _{C 1-6}
Alkoxy group (eg, methoxy, trifluoromethoxy,
Isopropoxy, 2- (4-methoxyphenyl) ethoxy, etc.), (7) C _6-14 aryloxy group (eg, phenoxy), (8) C _optionally having carbamoyl
_1-6 alkylthio group (eg, methylthio, carbamoylmethylthio), (9) C _1-6 alkylsulfinyl group optionally having carbamoyl (eg, methylsulfinyl, carbamoylmethylsulfinyl), (10) C
_6-14 arylthio group (eg, phenylthio), (11)
4- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom in addition to a hydroxy group and (12) carbon atom (eg, pyrrolidinyl, piperidyl, isoindolyl, furyl, Thienyl,
Pyridyl, quinolyl, benzofuranyl, pyrimidinyl,
(Tetrazolyl, imidazolidinyl, isothiazolidinyl, thiadiazolidinyl, azetinyl, etc.) [This heterocyclic group is oxo, carboxy-C _1-6 alkyl, C
_1-6 alkyl-carbonyloxy-C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy-carbonyl-C _1-6 alkyl, C _1-6 alkoxy-carbonyl, carbamoyl-C _1-6 alkyl, It may have a substituent selected from C _1-6 alkyl-carbamoyl-C _1-6 alkyl and the like], (13) carboxy group, (14)
A group represented by the formula —CO—Hal (Hal represents a halogen atom) (eg, chloroformyl), (15) C _1-6 alkyl-carbonyl group (eg, acetyl, etc.), (16) C _1-6
Alkyl-sulfonyl group (eg, methylsulfonyl, etc.), (17) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, etc.), (18) Sulfamoyl group [This sulfamoyl group is C _1-6 alkyl, carbamoyl- C _1-6 alkyl, C _1-6 alkoxy-carbonyl-C _1-6 alkyl, a 5- to 7-membered heterocyclic group optionally having an oxo group (eg, pyridyl, pyrrolidinyl, hexahydroazepinyl, etc. 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom and the like in addition to carbon atom) -C _1-6 alkyl, C _1-6 alkyl-carbonylamino- C
1 to 2 substituents selected from _6-14 aryl and the like
You may have one],

Equation (19) -NR^aR^bA group represented by [R^a
And R^bAre (i) hydrogen atom and (ii) C, respectively._1-6Al
Kill, (iii) 5- or 6-membered heterocycle (eg pyridyl etc.
In addition to carbon atoms, selected from nitrogen, sulfur, oxygen, etc.
5 or 6 containing 1 to 3 heteroatoms
Member heterocycle) -C_1-6Alkyl, (iv) C_1-6Arcoki
Sicarbonyl-C_1-6Alkyl, (v) di-C_1-6
Alkylamino-methylene-sulfamoyl-C_1-6
Alkyl, (vi) carbamoyl-C_1-6Alkyl, (vi
i) Sulfamoyl-C_1-6Alkyl, (viii) C_1-6
Alkyl-sulfonyl, (ix) C_1-6Alkoxy-Cal
Bonyl, (x) di-C_1-6Alkoxy-carbonyl-C
_2-6Alkenyl, (xi) C_6-14Aryl, (xii) 5
Or a 6-membered heterocyclic group (eg, other than carbon atom such as pyridyl)
1 selected from nitrogen atom, sulfur atom, oxygen atom, etc.
A 5- or 6-membered heterocyclic group containing 3 heteroatoms)
[This 5- or 6-membered heterocyclic group is amino, C_1-6Al
Kill-carboxamide, C_1-6Alkyl-sulfonyl
It may have a substituent selected from amino and the like],
(xiii) optionally halogenated C_1-6Alkyl-
Carbonyl, (xiv) C_1-6Alkylthio-C_1-6A
Rukiru-carbonyl, (xv) C_1-6Alkylsulfini
R-C_1-6Alkyl-carbonyl, (xvi) C_1-6A
Rukylsulphonyl-C_1-6Alkyl-carbonyl, (x
vii) Amino-C_1-6Alkyl-carbonyl, (xviii)
C which may be halogenated_1-6Alkyl-carbo
Nyl-amino-C_1-6Alkyl-carbonyl, (xix)
C_6-14Aryl-carbonyl, (xx) carboxy-C
_6-14Aryl-carbonyl, (xxi) C_1-6Archi
Phosphono-C optionally esterified_1-6A
Rukiru-C_6-14Aryl-carbonyl, (xxii) halo
Gen atom, oxo or C_1-6Alkoxy-Carbonii
5- or 6-membered heterocycle which may have a ring
In addition to carbon atoms such as zynyl and pyridyl, nitrogen atoms and sulfur
1 to 3 heteroatoms selected from atoms, oxygen atoms, etc.
5- or 6-membered heterocycle containing a child) -carbonyl, (xxi
ii) 5- or 6-membered heterocycle (eg, carbon atom such as pyridyl)
Other than nitrogen atom, sulfur atom, oxygen atom, etc. 1
To 5 or 6 membered heterocycle containing 3 to 3 heteroatoms
Ring) -C_1-6Alkyl-carbonyl, (xxiv) C
_6-14Aryl-oxy-carbonyl, (xxv) cal
Boxi-C_1-6Alkyl, (xxvi) carbamoyl, (xxv
ii) C which may be halogenated_1-6Alkylcal
Bamoiru, (xxviii) C_1-6Alkyl-carbonyl
C which may have mino_6-14Aryl carbamoy
A (xxix) 5- or 6-membered heterocycle (eg pyridyl, etc.
In addition to carbon atoms, selected from nitrogen, sulfur, oxygen, etc.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocycle) -carbamoyl, (xxx) C_2-6Archeni
R-carbonyl, may have a (xxxi) oxo group
5- or 6-membered heterocycle (eg, carbon atoms such as pyrrolidinyl)
Other than nitrogen atom, sulfur atom, oxygen atom, etc. 1
To 5 or 6 membered heterocycle containing 3 to 3 heteroatoms
Ring) -amino-C_1-6Alkyl-carbonyl, (xxxi
i) (5- or 6-membered heterocycle optionally having an oxo group
(For example, in addition to carbon atoms such as pyrrolidinyl, nitrogen atoms, sulfur
1 to 3 hetero atoms selected from yellow atom, oxygen atom, etc.
5 or 6-membered heterocycle containing atoms)) (C_1-6Al
Kill) Amino-C_1-6Alkyl-carbonyl, (xxxi
ii) (5- or 6-membered heterocycle optionally having an oxo group
(For example, in addition to carbon atoms such as pyrrolidinyl, nitrogen atoms, sulfur
1 to 3 hetero atoms selected from yellow atom, oxygen atom, etc.
5 or 6-membered heterocycle containing atoms)) (C_1-6Al
Kircarbonyl) amino-C_1-6Alkyl-carboni
Le, (xxxiv) C_1-6Alkylthio-C_1-6Archi
Lecarbonyl (sulfur atom may be oxidized),
(Xxxv) C which may be halogenated_1-6Alkyl
Sulfonyl, (xxxvi) sulfamoyl, (xxxvii) C
_1-6Alkylsulfamoyl etc.],

Equation (20) -C (= O) NR^cR^dRepresented by
RU group [R^cAnd R^dAre (i) hydrogen atom and (ii) C, respectively.
_1-6Alkyl, (iii) 5- or 6-membered heterocycle (eg, pyri)
In addition to carbon atoms such as zir and imidazolyl, nitrogen atoms and sulfur
1 to 3 hetero atoms selected from yellow atom, oxygen atom, etc.
5- or 6-membered heterocycle containing atoms) -C_1-6Archi
(Iv) Carboxy-C_1-6Alkyl, (v) C _1-6
Alkoxy-carbonyl-C_1-6Alkyl, (vi) di-
C_1-6Alkylamino-C_1-6Alkyl, (vii) mosquito
Luba Moyle-C_1-6Alkyl, (viii) C_1-6Al
Kircarbamoyl-C_1-6Alkyl, (ix) 5 or
6-membered heterocycle (eg, nitrogen atom in addition to carbon atom such as pyridyl)
1 to 3 selected from a child, a sulfur atom, an oxygen atom, etc.
5- or 6-membered heterocycle containing a hetero atom) -C_1-6
Alkylcarbamoyl-C_1-6Alkyl, (x) 5
Or a 6-membered heterocycle (eg, carbon atoms such as pyridyl, etc.
1 to 3 selected from elementary atom, sulfur atom, oxygen atom, etc.
5- or 6-membered heterocycle containing 6 heteroatoms) -ami
No-C_1-6Alkyl, (xi) sulfamoyl-C
_6-14Aryl-C_1-6Alkyl, (xii) C
_1-6C which may have alkoxy_6-14Ally
Le, (xiii) C_1-6Esterified with alkyl
Moyo Phosphono-C_1-6Alkyl-C_6-14Ally
(Xiv) 4- to 10-membered heterocyclic group (eg, azetini
Ru, pyrrolidinyl, piperidyl, hexahydroazepini
Le, pyridyl, pyrimidinyl, pyrazinyl, pyridazini
1-azabicyclo [2.2.2] oct-3-yl
Other than carbon atom such as nitrogen atom, sulfur atom, oxygen atom, etc.
4 containing 1 to 3 heteroatoms selected from
Ishi 10-membered heterocycle) [This 4- to 10-membered heterocyclic group is
Halogen atom, C_1-6Select from alkyl, oxo, etc.
Optionally have 1 to 2 substituents], (xv) C
_6-14Aryl-carbamoyl-C_1-6Alkyl,
(Xvi) hydroxy-C_1-6Alkyl, (xvii) oki
5- or 6-membered heterocyclic ring optionally having a so group (eg, pyrro
In addition to carbon atoms such as linidyl and pyridyl, nitrogen atoms and sulfur
1 to 3 hetero atoms selected from yellow atom, oxygen atom, etc.
5- or 6-membered heterocycle containing atoms) -carbamoyl-
C_1-6Indicates alkyl and the like. R^cAs a hydrogen atom
preferable. ], (21) cyano group, (22) mono- or di-C
_1-6Alkylcarbamoylthio group (eg, dimethylcalcyl
(Vamoylthio), (23) mono- or di-C_1-6Archi
Ruthiocarbamoyloxy group (eg, dimethylthiocarba
Moyloxy) and the like are preferable.

The "heterocyclic group" shown as a preferable group for R ¹ is pyridyl, thienyl, furyl, imidazolyl, thiazolyl, quinolyl, 1,2-dihydropyridyl, dihydrobenzofuranyl, benzodioxolyl, benzothiazolyl, Piperidyl, piperazinyl and the like are preferable, and pyridyl and 1,2-dihydropyridyl are particularly preferable. As a substituent of this "heterocyclic group",
(1) Halogen atom, (2) C _1-6 alkyl group (eg, methyl, ethyl, etc.) [This alkyl is carboxy, C
_1-6 alkoxy, C _1-6 alkoxy-carbonyl,
Mono-C _1-6 alkyl-amino, di-C _1-6 alkyl-amino, carbamoyl, C _1-6 alkyl-carbamoyl optionally having hydroxy, 4 to 10 members optionally having oxo Heterocyclic group (eg, 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl and quinolyl), 4 to 10 member Heterocycle (eg, 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl and quinolyl) -carbamoyl, carbamoyl-C _{1 -6} may have a substituent selected from alkyl-carbamoyl and the like] (3)
C _1-6 alkoxy group (eg, methoxy), (4) C
_6-14 aryl group (eg, phenyl), (5) C
_7-16 aralkyl group (eg, benzyl) [this C
_7-16 aralkyl is carboxy, C _1-6 alkoxy-carbonyl, carbamoyl, optionally hydroxy C _1-6 alkyl-carbamoyl, 4 to 1
Substitution selected from 0-membered heterocycle (eg, 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl) -carbamoyl, etc. May have a group],
(6) 4- to 10-membered heterocyclic group (eg, 4- to 10-membered containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl, quinolyl, isoquinolyl) Heterocyclic group) [The 4- to 10-membered heterocyclic group is C _1-6 alkyl, C _1-6 alkoxy-carbonyl, carbamoyl, oxo, 4 to 1
Substitution selected from 0-membered heterocyclic group (eg, 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl) May have a group], (7) oxo group, (8) oxide group and the like 1 to 5
And preferably 1 to 3 substituents.

The heterocyclic group having an oxide group as R ¹ is preferably N-oxidized pyridyl or the like.
Shown as preferred groups for R ¹ as "alicyclic hydrocarbon group", for example, cyclopropyl, cyclobutyl, cyclopentyl, C _{3 -6} cycloalkyl group such as cyclohexyl may be used, in particular cyclopentyl,
Cyclohexyl is preferred. This "aliphatic cyclic hydrocarbon group" may have a substituent similar to the substituent that the hydrocarbon group represented by R ¹ may have. R ¹
Examples of the "optionally substituted aromatic hydrocarbon group" and the "optionally substituted heterocyclic group" exemplified by

[Chemical 53] A group represented by [each symbol has the same meaning as defined above] is preferably used.

R^1b“Even if it has a substituent,
The “good hydrocarbon group” is exemplified as the substituent of ring A.
And the same "hydrocarbon group optionally having substituent (s)"
Is used. Among them, (1) C_1-6Alkyl group
(Methyl, isopropyl, tert-butyl, etc.) [This C
_1-6The alkyl group is a halogen atom, cyano or hydroxy.
Shi, C_1-6Alkoxy-carbonyl, di-C_1-6A
Lucylamino, optionally halogenated C_1-6A
Rukyi-carbonyl-amino, carboxy, carbamoy
Le, C_{1 -6}Alkyl-carbamoyl, C_1-6Archi
L-carbonyloxy, C_1-6Alkoxy-Carbonii
R-C_1-6Alkyl-carbamoyl, 5- or 6-membered compound
Elementary ring (excluding carbon atoms such as pyridyl and imidazolyl)
1 selected from nitrogen atom, sulfur atom, oxygen atom, etc.
A 5- or 6-membered heterocycle containing 3 heteroatoms)-
C_1-6Alkyl-carbamoyl, C_1-6Alkylchi
Oh, C_1-6Alkylsulfinyl, C_1-6Alkyl
Sulfonylamino, 5- or 6-membered heterocycle (eg pyridyl
Other than carbon atom such as nitrogen atom, sulfur atom, oxygen atom, etc.
5 containing 1 to 3 heteroatoms selected from
Or 6-membered heterocycle) -C_1-6Alkyl carbamoyl, 5
Or a 6-membered heterocycle (eg, other than carbon atom such as pyridyl)
1 to selected from nitrogen atom, sulfur atom, oxygen atom, etc.
5- or 6-membered heterocycle containing 3 heteroatoms) -a
Mino, Sulfamoyl-C_6-14Aryl, carboxy
Sea C_6-14Aryl, C_1-6Alkoxy-carbo
Nil-C_6-14Aryl, carbamoyl-C_6-14
Aryl, C optionally having hydroxy_{1- 6}Al
Kill-carbamoyl-C_6-14Aryl, 4 to 1
0-membered heterocycle (eg, nitrogen atom in addition to carbon atom such as pyridyl)
1 to 3 selected from a child, a sulfur atom, an oxygen atom, etc.
4- to 10-membered heterocycle containing heteroatoms) -carba
Moyle-C _6-14Substituents selected from aryl etc.
You may have], (2) C_3-6Cycloalkyl group
(Eg cyclohexyl), (3) C_6-14Aryl group
(Eg phenyl) [This C_6-14The aryl group is C
_1-6Alkoxy (eg methoxy), amino, carboxy
Si, optionally halogenated C_1-6Alkyl-Mo
Rubonylamino (eg acetylamino, trifluoroamino)
Cetylamino), C_1-6Alkoxy-carbonylami
No (eg, methoxycarbonylamino), formylami
No, Ureido, C_1-6Alkylsulfonylamino
(Eg, methylsulfonylamino), (C_1-6Archi
Le) (C_1-6Alkylsulfonyl) amino (eg, methyl
(Methylsulfonyl) amino, etc.), C_1-6Arco
Xy-carbonyl-C_1-6Alkylamino (eg, 2-
Ethoxycarbonyl-2-propylamino etc.), C
_{1- 6}Phosphono optionally esterified with alkyl
-C_1-6Alkyl, mono- or di-C_1-6Archi
Le-carbamoyl, C_7-16Aralkyl Oxy-Cal
Bonylamino (eg, benzyloxycarbonylamino)
May have a substituent selected from, etc.] or
(4) C_2-6An alkenyl group and the like are preferable.

The "optionally substituted heterocyclic group" represented by R ^1b is the same as the "optionally substituted heterocyclic group" exemplified as the substituent of ring A. Things are used. Among them, a halogen atom, C _1-6 alkyl, carboxyl-C _1-6 alkyl, C _1-6 alkoxy-carbonyl-C _1-6 alkyl, C _1-6 alkoxy-carbonyl, carbamoyl, oxo, 4 to 1
1 member selected from a 0-membered heterocyclic group (eg, a 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atoms such as pyridyl) Or a 5- to 14-membered heterocyclic group which may be substituted with 2 to 1 substituents and contains 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atom (eg, Azetinyl, pyrrolidinyl,
Piperidyl, isothiazolidinyl, thiadiazolidinyl, hexahydroazepinyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, benzofuranyl, pyrimidinyl, tetrazolyl, imidazolidinyl, pyrazinyl, pyridazinyl, etc.) are preferable. As the aromatic hydrocarbon ring represented by ring D, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms (C _6-14 aryl ring) and the like are used. C
_{As the 6-14} aryl ring, for example, a benzene ring, a naphthalene ring, an anthryl ring, a phenanthryl ring and the like are used, and among them, a benzene ring and a naphthalene ring are preferable, and a benzene ring is particularly preferable. These aromatic hydrocarbon rings may have 1 to 5, preferably 1 to 3 substituents selected from the above-mentioned substituent group A. The heterocycle represented by ring D is, for example, a 5- to 14-membered heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atom. Etc. are used, specifically,
(A) 5 to 14 membered aromatic heterocycle, (b) 5 to 14
A membered aliphatic heterocycle, (c) a bicyclic or tricyclic condensed ring of a 5- to 14-membered heterocycle and a benzene ring and the like are used. The 5
As the to 14-membered aromatic heterocycle, for example, a 5- to 14-membered aromatic ring containing 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom and the like in addition to carbon atom Heterocycle and the like are used, and specifically, thiophene, furan, indolizine, pyrrole,
Imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, N-oxidized pyridine,
Examples thereof include pyrazine, pyrimidine, pyridazine, purine, 4H-quinolidine, naphthyridine, isothiazole, isoxazole, and furazane. Among them, pyridine, thiophene, furan and the like are preferably used. The 5- to 14-membered aliphatic heterocycle contains 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom and the like in addition to carbon atom.
To 14-membered aliphatic heterocycle are used, and specific examples thereof include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine, and imidazolidine. The 2- or 3-cyclic condensed ring of the 5- to 14-membered heterocycle and the benzene ring has 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. Individual)
A bicyclic or tricyclic condensed ring of a heterocycle containing benzene and a benzene ring is used. Specifically, benzo [b] thiophene,
Benzofuran, 1H-benzimidazole, benzoxazole, benzothiazole, 1,2-benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxathiine, indole, isoindole, 1H-indazole, isoquinoline, Examples thereof include quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, isochroman and dihydrobenzofuran. Among them, as the heterocycle represented by D ring,
Pyridine, thiophene, furan, imidazole, thiazole, quinoline, N-oxidized pyridine, 1,2-dihydropyridine, dihydrobenzofuran, benzodioxole, benzothiazole, piperidine, piperazine and the like are preferable, and pyridine and 1,2-dihydropyridine are particularly preferable. Etc. are suitable. Each of these heterocycles has 1 to 5 substituents selected from the above-mentioned Substituent Group A, preferably 1 substituent.
Or may have three.

The "optionally oxidized sulfur" represented by E
"Atom" means S, SO, SO_TwoIs used. At E
As the nitrogen atom which may have a substituent as shown,
For example, even if it has (i) a hydrogen atom and (ii) a substituent
Having one good hydrocarbon group, (iii) acyl group, etc.
A nitrogen atom which may be used is used. Said "has a substituent
“A hydrocarbon group which may be substituted” is a substituent of ring A.
And the "hydrocarbon group which may have a substituent"
Similar ones are used. The "acyl group" is A
Examples of the “acyl group” exemplified as the ring substituent are
This acyl group is further selected from the substituent group A
Having 1 to 5, preferably 1 to 3 substituents
May be. Formulas represented by E: -CS-O-, -CO-
O-, -S-CO-,-(CH_Two)_k-CO-, -NR
^1c-CO- (CH_Two)_m-, -NR^1c-SO_Two−
(CH_Two)_m-, -SO_Two-NR^1c-(CH_Two)
_m-, -O-CS-NR^1c-(CH _Two)_m-, -NR
^1c-CO-NR^1c-(CH_Two)_m-, -NR^1c−
CO-CH_Two-(CH_Two)_m-NR^1c-[Wherein R
^1cIs a hydrogen atom or an alkyl group which may have a substituent
Or an acyl group, k is 0 or 1, m is 0 to 3
In the group represented by^1cIndicated by
Examples of the alkyl group include methyl, ethyl, and
Ropil, isopropyl, butyl, isobutyl, sec-
C such as tyl, tert-butyl, pentyl, hexyl
_1-6An alkyl group or the like is used. R^1cIndicated by
The alkyl group is a substituent selected from the aforementioned substituent group A.
Having 1 to 5, preferably 1 to 3
Good. R^1cThe acyl group represented by
The same as the “acyl group” exemplified as the group is used.
This acyl group is further substituted with a substituent selected from Group A of substituents.
Having 1 to 5, preferably 1 to 3 groups
Good. k represents 0 or 1, and 0 is particularly preferable. m
Represents an integer of 0 to 3, with 0 or 1 being preferred.
Good

Among the above, E is (i) a bond
Hand, (ii) methylene, (iii) O, (iv) S, (v) SO, (v
i) SO_Two, (Vii) -NH-, (viii) -N (C_1-6Al
Kill)-(eg, -N (methyl)-, etc.), (ix) -N (C
_1-6Alkyl-carbonyl)-(eg, -N (acetyl
)-Etc.), (x) -N (C_1-6Alkoxy-carbo
Nyl)-(eg, -N (ethoxycarbonyl)-, etc.),
(xi) -N (C_1-6Alkyl-sulfonyl)-(eg,-
N (methylsulfonyl)-, etc.), (xii) -CO-O
-, (Xiii) -S-CO-, (xiv)-(CH_Two)_k-CO
-(Wherein k represents 0 or 1), (xv)
-NR^f-CO- (CH_Two)_m1-[Wherein R^fIs hydrogen
Atom or C_1-6Alkoxy-carbonyl (eg, meth
(Oxycarbonyl) or nitrogen atom, oxygen other than carbon atom
1 to 3 heteroatoms selected from atoms, sulfur atoms, etc.
Substituted with a heterocyclic group containing a child (eg, pyridyl)
May be C_1-6Alkyl group, m1 is an integer of 0 to 3
A group represented by the formula (xvi) -NR^g-SO_Two−
(CH_Two)_m2-[Wherein R^gIs a hydrogen atom or C_1-
6Alkyl-sulfonyl group (eg, methylsulfonyl)
And m2 represents 0], (xvii) -SO_Two−
NR^h-(CH_Two)_m3-[Wherein R^hIs a hydrogen atom
Is C_{1 -6}Alkyl group (eg methyl), m3 is 0 or
Represents 1] (xviii) -O-CS-NRⁱ
-(CH_Two)_m4-[Wherein RⁱIs a hydrogen atom or C
_1-6An alkyl group (eg methyl), m4 is 0 or 1
Represents], (xix) -NR^j-CO-NR^k−
(CH_Two)_m5-[Wherein R^jIs a hydrogen atom or C _1-6
An alkyl group (eg methyl), R^kIs a hydrogen atom or C
_1-6Alkyl group (eg methyl), m5 is 0 or 1
Represents a group], (xx) -NR^L-CO-CH
_Two(CH_Two)_m6-NR^m-[Wherein R^LIs a hydrogen atom
Or C_1-6An alkyl group (eg methyl), R^mIs hydrogen
Atom or C_1-6An alkyl group (eg, methyl), m6
Represents 0 or 1, and the like.

Examples of the "optionally substituted aromatic hydrocarbon group" and "optionally substituted heterocyclic group" which are exemplified as preferable groups for R ¹ are those represented by the following formulas:

[Chemical 54] A group represented by [each symbol has the same meaning as defined above] is also preferably used. As the halogen atom represented by Hal, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like is used, and among them, a chlorine atom is preferable. The same ring as described above is used as the D ring.

The formula -L exemplified as a preferred group for R ^1.
In the group represented by —R ^1a [wherein each symbol has the same meaning as defined above], L is preferably methylene or carbonyl. ^Examples of the aromatic group represented by R ^1a include
For example, monocyclic or condensed polycyclic aromatic hydrocarbon groups, more specifically phenyl, 1-naphthyl, 2-naphthyl, 1-
C _6-14 aryl groups such as anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl (preferably phenyl, 1-
Naphthyl, 2-naphthyl, etc., particularly preferably phenyl), and the like, 6 to 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group, selected from nitrogen atom, sulfur atom, oxygen atom, etc. in addition to carbon atom 1 One or more (eg 1 to 4, preferably 1 to 3) of one or two heteroatoms 4
A 14-membered aromatic heterocyclic group or the like is used. This 4
As the 14-membered aromatic heterocyclic group, one or more heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, etc., in addition to the carbon atom, may be used (for example, 1 to 4).
, Preferably 1 to 3) monocyclic heterocyclic groups (preferably 5 to 8 members) or condensed aromatic heterocyclic groups thereof, more specifically thiophene, benzo [b] thiophene, benzofuran, 1H -Benzimidazole, benzoxazole, benzothiazole, 1,2-benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, furan, indolizine, xanthene, phenoxathiine, pyrrole, imidazole, triazole,
Thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, feh. Aromatic heterocycles such as nantrisine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine and isochroman (preferably pyridine, thiophene or furan, more preferably pyridine) or these rings (preferably , A monocyclic heterocycle) or one or more (preferably 1 or 2 and more preferably 1) and an aromatic ring (for example, the above-mentioned aromatic hydrocarbon group, etc., preferably Such fused ring group of benzene ring) are used. The substituent of the aromatic group is 1 to 5, preferably 1 to 3 selected from the above-mentioned Substituent group A.
Substituents are used. The aromatic group which may be substituted, represented by R ^1a , includes C _1-6 alkyl,
C _1-6 1 without a substituent to 5 optionally having _{C 6- 14} aryl group (e.g., phenyl), such as alkoxy and the like are preferable.

The "hydroxyl group which may have a substituent (s)" represented by R ^1a is the same as the "hydroxyl group which may have a substituent (s)" exemplified above as the substituent of the ring A. Among them, a hydroxyl group which may have a C _1-6 alkyl group (eg, methyl) is preferable. As the “amino group optionally having substituent (s)” represented by R ^1a , those similar to the “amino group optionally having substituent (s)” exemplified as the substituent of ring A can be used. Examples of the “amino group which may have a substituent” represented by R ^1a include an alkyl group which may have a substituent and an aryl group which may have a substituent. It is preferably an amino group which may have two, particularly a 4- to 10-membered heterocyclic group (a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to carbon atoms). A 10-membered heterocyclic group, for example, C _1-6 alkyl-amino group _optionally substituted with pyridyl),
C _6-14 aryl-amino group, _4- to 10-membered heterocycle (4 to 10-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom, etc. in addition to carbon atom, eg, Pyridyl) -amino group and the like are preferable.

Of these, R ¹ is represented by the formula

[Chemical 55] [In the formula, R ¹⁶ is a hydrogen atom, a C _6-14 aryl group which may have a substituent, an amino group which may have a substituent, or a heterocyclic group which may have a substituent. Or a group represented by a halogen atom]. Particularly, R ¹⁶ is (1) hydrogen atom, (2) phenyl substituted with acetylamino group, (3) (i) C _1-6 alkylsulfonyl group, (ii) pyridylcarbonyl or (iii) sulfamoyl-C _{1 - 6} alkyl which may optionally be mono- or di-substituted with a substituent selected from the group amino, (4) pyridyl or
(5) Halogen atom (fluorine atom, chlorine atom, bromine atom,
Those having an iodine atom) are preferred.

The "hydrocarbon group which may have a substituent (s)" represented by R ² and R ³ is, for example, "a hydrocarbon group which may have a substituent (s). "
The same as is used. Examples of the "hydrocarbon group which may have a substituent" include, for example, a halogen atom, and a hydroxyl group which may have a substituent (for example, C _1-6
Alkyl, C _1-6 alkyl-carbonyl, C _1-6 alkylsulfonyl, C _7-16 aralkyl, etc., which may be substituted with a hydroxyl group, and an amino group which may have a substituent (for example, 1 or An amino group which may be substituted with two C _1-6 alkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl and the like), and a 4- to 10-membered hetero group which may have a substituent. A cyclic group (for example, a 4- to 10-membered heterocyclic group which may have an oxo group and has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, etc. in addition to the carbon atom (eg, Phthalimide, imidazolyl, piperidyl, pyrrolidinyl)), and optionally substituted thio group (for example, C _1-6
A hydrocarbon group which may be substituted with a thio group which may be substituted with alkyl or the like), a C _1-6 alkyl-sulfinyl group, a C _1-6 alkyl-sulfonyl group or the like (in particular, C _1-6 alkyl) Group) is used. Among them, a halogen atom (particularly, bromine atom), hydroxy, C _1-6 alkyl-carbonyloxy (eg, acetoxy), amino, a 4- to 10-membered heterocyclic group optionally having an oxo group (other than carbon atom) C ₁ which may be substituted with a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom and the like (eg, phthalimido, imidazolyl, piperidyl, pyrrolidinyl), etc. _{A -6} alkyl group or the like is preferable, and a C _1-6 alkyl group (eg, methyl, ethyl, etc.) which may be halogenated with a halogen atom (particularly, bromine atom) or the like is preferable,
A methyl group is particularly preferable.

As the "acyl group" represented by R ² and R ³ , the same ones as the "acyl group" exemplified as the substituent of the A ring are used, and among them, C _1-6 alkoxy-
A carbonyl group is preferable, and a methoxycarbonyl group is particularly preferable. The 3- to 8-membered ring formed by R ² and R ³ together with the adjacent carbon atom is, for example, a 3- to 8-membered homocyclic ring or heterocyclic ring. The 3- to 8-membered homocyclic ring formed by R ² and R ³ together with the adjacent carbon atom is:
3- to consisting of carbon atoms is used a cyclic hydrocarbon to 8-membered, particularly, C _{3- 8} cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane), C _3-8 cycloalkene (For example, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene) and the like. Among them, C _3-8 cycloalkane is preferable, and a 5- or 6-membered homocyclic ring such as cyclopentane or cyclohexane (particularly cyclohexane) is particularly preferable. The 3- to 8-membered heterocycle formed by R ² and R ³ together with the adjacent carbon atom is one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom. (For example, 1 to 4, preferably 1 to 3) 5- to 8-membered aliphatic heterocycle (preferably 5- or 6-membered aliphatic heterocycle) and the like are used. More specifically, for example, in addition to carbon atoms and nitrogen atoms such as piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, imidazolidine ring, etc., 1 to 1 hetero atom selected from nitrogen atom, oxygen atom and sulfur atom. 5 to 8 members including 3 (preferably 5 or 6 members)
Aliphatic heterocycles and the like are used. These R ² and R ³
Is a 3- to 8-membered homolog or heterocycle formed with the adjacent carbon atom, has 1 to 5 substituents, preferably the same substituents as the above-mentioned substituents of the heterocycle represented by R ^1. You may have 1 to 3 pieces. As the substituent, C _1-6 alkyl, C _6-14 aryl, C
_7-16 aralkyl, amino, mono-C _1-6 alkylamino, mono-C _6-14 arylamino, di-C _1
-6 alkylamino, di-C _6-14 arylamino,
4- to 10-membered heterocyclic group (eg, 4- to 10-membered (preferably 5- or 6-membered) heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom) 1 to 3 selected from a ring) and the like are preferable. Among the above, each of R ² and R ³ may be C which may be substituted with a halogen atom or the like.
_{A 1-6} alkyl group and a C _1-6 alkoxy-carbonyl group are preferable, and a methyl group and a methoxycarbonyl group are particularly preferable. Further, it is also preferred that R ² and R ³ together with the adjacent carbon atom form a C _3-8 cycloalkane, preferably a 5- or 6-membered homocyclic ring such as cyclopentane or cyclohexane (particularly cyclohexane).

The "hydrocarbon group which may have a substituent (s)" represented by R ⁴ and R ⁵ is "the hydrocarbon group which may have a substituent (s)" exemplified as the substituent of the A ring. The same as is used. Among them, (1) halogen atom, (2) optionally halogenated C _1-6 alkyl, (3) optionally halogenated C _1-6 alkoxy, (4) optionally halogenated 1 to 5 substituents selected from C _1-6 alkylthio, (5) hydroxy, (6) amino, (7) mono-C _1-6 alkylamino, (8) di-C _1-6 alkylamino, etc. A C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group which may be possessed is preferable, and particularly C _1-6.
Alkyl groups (eg, methyl, ethyl, etc.) are preferred. R
^{As 4} and R ⁵ , for example, a hydrogen atom, a C _1-6 alkyl group (eg, methyl, ethyl) and the like are preferable, and a hydrogen atom is particularly preferable.

The "hydrocarbon group which may have a substituent (s)" represented by R ⁶ and R ⁷ is "the hydrocarbon group which may have a substituent (s)" exemplified as the substituents on the ring A. The same ones as described above are used. Among them, a C _1-6 alkyl group (eg, methyl, ethyl, etc.) and the like are preferable, and a methyl group is particularly preferable. The "3- to 8-membered ring which may have a substituent (s) formed by R ⁶ and R ⁷ together with the adjacent carbon atom" is "the substituent formed by R ² and R ³ together with the adjacent carbon atom". May have from 3 to 8
Like are used as membered ring ", among others to 3 which may have a substituent preferably 8-membered homocyclic ring, among others C _{3- 8} cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, Cycloheptane and cyclooctane) are preferable, and a 5- or 6-membered homocyclic ring such as cyclopentane and cyclohexane (particularly cyclopentane) is particularly preferable.

R⁸“It may have a substituent
"Hydrocarbon group" is exemplified as the substituent of ring A.
Similar to "hydrocarbon group optionally having substituent (s)"
Is used. R⁸The hydrocarbon group represented by is C
_1-6Alkyl group (eg, methyl, ethyl, etc.), C
_2-6Alkenyl group (eg, allyl, 2-methyl-2-propyl
Lopenyl, etc.), C_2-6Alkynyl groups (eg propal
Gil etc.), C_3-6Cycloalkyl groups (eg cyclope
C), C_7-16Aralkyl groups (eg, benz
Such as 3-phenylpropyl and 5-phenylpentyl
Etc. are preferable, and especially C_{1- 6}Alkyl groups (especially
Methyl) is preferred. As a substituent of the hydrocarbon group
Is (1) a halogen atom (for example, fluorine, chlorine, odor
(Elemental, iodine), (2) hydroxy group, (3) amino group,
(4) Carboxy, (5) Carbamoyl, (6) C_1-6
Alkoxy-carbonyl (eg, methoxycarbonyl, ether
(Toxycarbonyl, etc.), (7) Mono-C_1-6Archi
Le-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl
(Lubamoyl, etc.), (8) Ji-C_1-6Alkyl-cal
Vamoyl (eg, dimethylcarbamoyl, diethylcarba
Moyl, etc.), (9) carbon source which may have oxo
Other than child, selected from nitrogen atom, sulfur atom, oxygen atom, etc.
4- to 10-membered compounds containing 1 to 3 heteroatoms
A prime ring group (eg, pyridyl, 2-isoindolyl, etc.),
(10) C_6-14Aryl group (eg, phenyl, etc.)
Is preferred. R⁸The “acyl group” represented by is A
Examples of the “acyl group” exemplified as the ring substituent are
This acyl group is further selected from the substituent group A
Having 1 to 5, preferably 1 to 3 substituents
May be. Among them, (1) formyl, (2) C_1-6A
Rukyl-carbonyl group (eg acetyl, propionyl
DO), (3) C_6-14Aryl-carbonyl group (eg,
(4) C _7-16Aralkyl-Carboni
Group (eg, phenylacetyl, etc.), (5) C_{1- 6}Al
Coxy-carbonyl group (eg, methoxycarbonyl, eth
(Xycarbonyl, etc.), (6) carbamoyl group, (7) mono-
Or J-C_1-6Alkyl-carbamoyl group (eg,
Tilcarbamoyl, dimethylcarbamoyl, etc.), (8)
Mono- or di-C_1-6Alkyl-thiocarbamoyl
Groups (eg methylthiocarbamoyl, dimethylthiocarba
Moyle), (9) C_1-6Alkyl-sulfonyl group
(Eg, methylsulfonyl, etc.) or (10) C_1-6Al
Kill-sulfinyl group (eg, methylsulfinyl, etc.)
Are preferred. R⁸"Has a substituent
"May be a heterocyclic group" is exemplified as a substituent of ring A.
The same as the "heterocyclic group which may have a substituent (s)"
Is used. Among them, R⁸And a heterocyclic group represented by
Other than carbon atom, nitrogen atom, sulfur atom, oxygen atom, etc.
4 containing 1 to 4 heteroatoms selected from
Ishi 10-membered aromatic heterocyclic group (eg, tetrazolyl, etc.)
Which is preferable. The substituent of the heterocyclic group may be C
_6-14Aryl groups (eg, phenyl, etc.) are preferred
Yes. R⁸The halogen atom represented by
Child, chlorine atom, bromine atom, iodine atom are used,
However, chlorine atom and the like are preferable.

The "hydrocarbon group which may have a substituent" represented by R ¹⁰ in the formula -OR ^{10 represented} by R ⁸ includes the "substituent having a substituent" exemplified as the substituent of the A ring. The same as the "hydrocarbon group which may be substituted" is used. R
^The hydrocarbon group represented by ¹⁰ includes (i) a C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, butyl, etc.) [this C _1-6 alkyl group is (1) a halogen atom,
(2) Hydroxy group, (3) amino group, (4) carboxy, (5) carbamoyl, (6) C _1-6 alkoxy-carbonyl, (7) mono-C _1-6 alkyl-carbamoyl, (8) di -C _1-6 alkyl - carbamoyl, (9)
A 4- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, etc. in addition to the carbon atom which may have oxo (eg, pyridyl, 2- It may have a substituent selected from, for example, isoindolyl, etc.), (ii) C _2-6 alkenyl group (eg, allyl, 2-methyl-2-propenyl, etc.) [this C _2-6 alkenyl group is C _6-14 aryl (e.g., phenyl) which may have a], _{(iii) C 2-6} alkynyl group (eg, propargyl), _{(iv) C 3- 6} cycloalkyl group (e.g., cyclopentyl, etc. ), (V) C
_{A 7-16} aralkyl group (eg, benzyl, 3-phenylpropyl, 5-phenylpentyl, etc.) and the like are preferable.

R⁸Equation-OR¹⁰Of R¹⁰so
Examples of the “acyl group” shown include formyl and carbonyl.
Luba Moyle, C_1-6Alkyl-carbonyl (eg, acetone
Chill, propionyl, etc.), C_3-6Cycloalkyl-
Carbonyl (eg, cyclopentylcarbonyl, cyclohexyl
Xylcarbonyl, etc.), C_1-6Alkoxy-carbo
Nyl (eg, methoxycarbonyl, ethoxycarbonyl,
Isopropoxycarbonyl, tert-butoxycarbonyl
Etc.), C_6-14Aryl-carbonyl (eg, benzo
Ill, 2-naphthoyl, etc.), C_7-16Aralkyl-
Carbonyl (eg, phenylacetyl, 3-phenylpro
Pionyl etc.), C_6-14Aryloxy-carboni
(Eg, phenoxycarbonyl, 2-naphthyloxyca
Lubonyl etc.), C_7-16Aralkyloxy-carbo
Nyl (eg, benzyloxycarbonyl, 2-naphthylme
Tyloxycarbonyl etc.) 5- or 6-membered heterocyclic car
Bonyl (eg, 1-pyrrolidinylcarbonyl, 4-piperi
Zylcarbonyl, 1-piperazinylcarbonyl, 2-mo
Ruphorinylcarbonyl, 4-pyridylcarbonyl, 3-
Thienylcarbonyl, 2-furylcarbonyl, 2-thia
In addition to carbon atoms such as zolylcarbonyl, nitrogen atoms and sulfur
1 to 3 heteroatoms selected from atoms, oxygen atoms, etc.
A 5- or 6-membered heterocyclic carbonyl containing a child),
No-C_1-6Alkyl-carbamoyl (eg, methylcalcyl
Vamoyl, ethylcarbamoyl, etc.), di-C_1-6A
Rukyl-carbamoyl (eg, dimethylcarbamoyl, di-
Ethylcarbamoyl etc.), C_6-14Aryl-Cal
Vamoyl (eg, phenylcarbamoyl, 2-naphthylca)
Lubamoyl, etc.) 5- or 6-membered heterocyclic carbamoyl
(Eg, 1-pyrrolidinylcarbamoyl, 4-piperidyl
Carbamoyl, 1-piperazinylcarbamoyl, 2-mo
Lufolinylcarbamoyl, 4-pyridylcarbamoyl,
3-thienylcarbamoyl, 2-furylcarbamoyl,
Nitrogen in addition to carbon atoms such as 2-thiazolylcarbamoyl
1 to 3 selected from atoms, sulfur atoms, oxygen atoms, etc.
5- or 6-membered heterocyclic carbamoy containing heteroatoms of
, Etc., C _1-6Alkyl-thiocarbonyl (eg,
Cylthiocarbonyl, etc.), C_3-6Cycloalkyl-
Thiocarbonyl (eg, cyclopentylthiocarbonyl,
Cyclohexylthiocarbonyl etc.), C_1-6Arco
Xy-thiocarbonyl (eg, methoxythiocarbonyl,
Ethoxythiocarbonyl, propoxythiocarbonyl,
Butoxythiocarbonyl etc.), C_6-14Aryl-
Thiocarbonyl (eg, phenylthiocarbonyl, 2-na
(Futylthiocarbonyl, etc.), C_7-16Aralkyl-
Thiocarbonyl (eg, benzylthiocarbonyl, phenene
Cylthiocarbonyl, etc.), C_6-14Aryloxy
-Thiocarbonyl (eg, phenoxythiocarbonyl, 2
-Naphthyloxythiocarbonyl, etc.), C_7-16A
Ralalkyloxy-thiocarbonyl (eg, benzyloxy
Thiocarbonyl, 2-naphthylmethyloxythiocarbo
Nyl, etc.) 5- or 6-membered heterocyclic thiocarbonyl (eg,
1-pyrrolidinylthiocarbonyl, 4-piperidylthio
Carbonyl, 1-piperazinylthiocarbonyl, 2-mo
Ruphorinylthiocarbonyl, 4-pyridylthiocarboni
L, 3-thienylthiocarbonyl, 2-furylthiocal
Carbon atoms such as bonyl and 2-thiazolylthiocarbonyl
Other than nitrogen atom, sulfur atom, oxygen atom, etc. 1
To 5 or 6 membered heterocycles containing 3 to 3 heteroatoms
Thiocarbonyl etc.), thiocarbamoyl, mono-C
_1-6Alkyl-thiocarbamoyl (eg, methylthioca
Luvamoyl, ethylthiocarbamoyl, etc.), di-C
_1-6Alkyl-thiocarbamoyl (eg, dimethyl
Thiocarbamoyl, diethylthiocarbamoyl, etc.),
C_6-14Aryl-thiocarbamoyl (eg, phenyl
Thiocarbamoyl, 2-naphthylthiocarbamoyl
Etc.) 5- or 6-membered heterocyclic thiocarbamoyl (eg, 2-
Pyrrolidinyl thiocarbamoyl, 4-piperidyl thioca
Luvamoyl, 2-piperazinylthiocarbamoyl, 2-
Morpholinyl thiocarbamoyl, 4-pyridyl thiocar
Vamoyl, 3-thienylthiocarbamoyl, 2-furyl
Thiocarbamoyl, 2-thiazolylthiocarbamoyl
Other than carbon atom, nitrogen atom, sulfur atom, oxygen atom, etc.
5 or containing 1 to 3 heteroatoms selected from
Is a 6-membered heterocyclic thiocarbamoyl, sulfamoyl,
Mono-C_{1- 6}Alkyl-sulfamoyl (eg, methyl
Sulfamoyl, ethylsulfamoyl, etc.), di-C
_1-6Alkyl-sulfamoyl (eg, dimethylsulf
Amoyl, diethylsulfamoyl, etc.), C_6-14
Aryl-sulfamoyl (eg, phenylsulfamoy
, Etc., C_1-6Alkylsulfonyl (eg, methyls
Rufonyl, ethylsulfonyl, etc.), C_6-14Ally
Rusulfonyl (eg, phenylsulfonyl, 2-naphthyl)
Sulfonyl etc.), C_1-6Alkylsulfinyl
(Eg methylsulfinyl, ethylsulfinyl
DO), C_6-14Arylsulfinyl (eg, phenyl
Sulfinyl, 2-naphthylsulfinyl, etc.), sulf
Fino, sulfo, C_1-6Alkoxysulfinyl
(Eg, methoxysulfinyl, ethoxysulfinyl
Le), C_6-14Aryloxysulfinyl (eg,
Enoxysulfinyl), C_1-6Alkoxy sulphoni
(Eg, methoxysulfonyl, ethoxysulfonyl)
And C_6-14Aryloxysulfonyl (eg, pheno
Xysulfonyl) is used and the acyl group is
1 to 5 substituents selected from the group A of substituents, preferably
May have 1 to 3. Among them, (i) C
_1-6An alkyl-carbonyl group (eg, acetyl, etc.),
(ii) C_{6- 14}Aryl-carbonyl group (eg, benzoyl
, Etc.), (iii) C_7-16Aralkyl-carbonyl group
(Eg, phenylacetyl, etc.), (iv) C_1-6Arcoki
Si-carbonyl group (eg, methoxycarbonyl, ethoxy
Carbonyl, etc.), (v) mono- or di-C_1-6Al
Kill-thiocarbamoyl group (eg, methylthiocarbamoyl
, Dimethylthiocarbamoyl, etc.), (vi) halogenation
May be C_{1 -6}Alkyl-sulfonyl group
(Eg, methylsulfonyl, etc.) and the like are preferable. R⁸so
Formula shown-OR¹⁰Of R¹⁰Is represented by
“A heterocyclic group which may have” means a substituent on the ring A
And the "heterocyclic group which may have a substituent (s)"
Similar ones are used. Among them, R¹⁰Indicated by
Heterocyclic groups include nitrogen atoms, sulfur atoms, in addition to carbon atoms.
1 to 4 heteroatoms selected from child, oxygen atom, etc.
A 4- to 10-membered aromatic heterocyclic group containing (eg, tetra
Zolyl etc.) [This heterocyclic group is C_6-14Aryl
(Eg, phenyl). ] Etc. are preferred
Yes.

R⁸Equation-SR¹¹Of R¹¹so
As shown in the "hydrocarbon group which may have a substituent (s)"
Are those having "substituent"
The same as the "optional hydrocarbon group" is used. R
¹¹The hydrocarbon group represented by is C_1-6Alkyl
A group (eg, methyl, ethyl, etc.) and the like are preferable. R⁸
Equation-SR¹¹Of R¹¹"Acyl
As "group", R ¹⁰Similar to the "acyl group" shown by
Used from the group A of substituents
1 to 5 substituents, preferably 1 to 3 substituents selected
You may have one. R¹¹With an "acyl group"
As a mono- or di-C_1-6Alkyl-carbamo
Yl group (eg, methylcarbamoyl, dimethylcarbamoy
And the like) are suitable. R⁸Equation-SR
¹¹Of R¹¹"May have a substituent
The "heterocyclic group" is, for example, the "position" exemplified as the substituent of the A ring.
And a heterocyclic group which may have a substituent is used.
To be

[0042] of the formula -S ^{(O) R 12} represented by ^{R 8,} R
^{As the} "hydrocarbon group optionally having substituent (s)" represented by ¹² , those similar to the "hydrocarbon group optionally having substituent (s)" exemplified as the substituent of ring A are used. . As the hydrocarbon group represented by R ¹² , a C _1-6 alkyl group (eg, methyl, ethyl, etc.) and the like are preferable. Yes of formula -S (O) R ¹² represented by R ^8, as "an optionally substituted heterocyclic group" represented by R ^12, the "substituent exemplified as the substituent of ring A The same as the "heterocyclic group which may be used" is used.

R ⁸ of the formula —S (O) ₂ R ¹³
As the “hydrocarbon group optionally having substituent (s)” represented by R ¹³ , the same ones as the “hydrocarbon group optionally having substituent (s)” exemplified as the substituent of ring A are used. To be The hydrocarbon group represented by R ¹³ is preferably a C _1-6 alkyl group (eg, methyl, ethyl, etc.) and the like. Of formula -S (O) ₂ R ¹³ represented by R ^8, as the "optionally substituted heterocyclic group" represented by R ^13, the "substituent exemplified as the substituent of ring A The same as the "heterocyclic group which may have" is used.

R⁸Equation-NR¹⁴R¹⁵Of R
¹⁴And R¹⁵“It may have a substituent
"Hydrocarbon group" is exemplified as the substituent of ring A.
Similar to "hydrocarbon group optionally having substituent (s)"
Is used. R¹⁴And R¹⁵Hydrocarbon represented by
As a group, C_1-6Alkyl group (eg, methyl, ethyl
Etc.) [This C_1-6Alkyl group is C_1-6Alkoxy
-It may have a carbonyl. ] Is suitable
It R⁸Equation-NR¹⁴R¹⁵Of R¹⁴And
And R¹⁵The “acyl group” represented by is R¹⁰Indicated by
The same "acyl group" as described above is used.
The substituent further includes a substituent selected from Group A of substituents 1 to
It may have 5, preferably 1 to 3. Inside
But formyl, C_1-6Alkyl-carbonyl group
(Eg acetyl, propionyl etc.), C_1-6Arco
Xy-carbonyl group (eg, methoxycarbonyl, etoxy)
Carbonyl, etc., carbamoyl group, mono- or di-
-C_1-6Alkyl-carbamoyl group (eg, methylcalcyl
Vamoyl, dimethylcarbamoyl, etc.), C_1-6Al
Kill-sulfonyl group (eg, methylsulfonyl, etc.)
Is preferred. R⁸Equation-NR¹⁴R¹⁵Of R
¹⁴And R¹⁵“It may have a substituent
"Heterocyclic group" is exemplified as the substituent of ring A.
The same as the "heterocyclic group which may have a substituent (s)"
Used. R⁸Equation-NR¹⁴R¹⁵As
Is R¹⁴Is a hydrogen atom, C_{1- 6}Alkyl group (eg,
(Methyl, ethyl, etc.) [This C_1-6Alkyl group is C
_1-6May have an alkoxy-carbonyl
Yes. ], Formyl, C_1-6Alkyl-carbonyl
Group (eg, acetyl, propionyl, etc.), C_1-6A
Lucoxy-carbonyl group (eg, methoxycarbonyl, ether
(Toxycarbonyl, etc.), carbamoyl group, mono-
Or J-C_1-6Alkyl-carbamoyl group (eg,
Tilcarbamoyl, dimethylcarbamoyl, etc.) or
C_1-6Alkyl-sulfonyl group (eg, methylsulfon
Such as Nil) and R¹⁵Is a hydrogen atom, C
_1-6Alkyl (eg methyl, ethyl, propyl, iso
Propyl), C _6-14Aryl (eg, pheny
Le, 2-naphthyl, etc.) or C_7-16Aralkyl
(Eg, benzyl, phenethyl, etc.) is preferable.
Good Above all, R¹⁴Is a hydrogen atom, C_1-6Al
Kill group (eg, methyl, ethyl, etc.) [This C_1-6Al
Kill group is C_1-6Having an alkoxy-carbonyl
Good. ], Formyl, C_1-6Alkyl-carbo
Nyl group (eg, acetyl, propionyl, etc.), C
_1-6Alkoxy-carbonyl group (eg, methoxycarbo group
Nyl, ethoxycarbonyl, etc.), carbamoyl group,
Mono- or di-C_1-6Alkyl-carbamoyl group
(Eg, methylcarbamoyl, dimethylcarbamoyl
DO) or C_1-6Alkyl-sulfonyl group (e.g.,
Such as tylsulfonyl) and R¹⁵Is a hydrogen atom or
Those such as methyl are preferred.

R⁸Is a hydrogen atom or formula-OR
¹⁰(R¹⁰Is a hydrogen atom, or an optionally substituted charcoal
A hydrogen atom group, an acyl group or a compound which may have a substituent
It represents a cyclic group) is preferred. Among them, R⁸as,
Hydrogen atom, hydroxyl group (R¹⁰Is a hydrogen atom),
C which may have a substituent_1-6Alkoxy (R¹⁰But
C which may have a substituent_1-6Is also alkyl
Of) or acyloxy (R¹⁰Is acyl)
Is preferred. In particular, hydrogen atom, hydroxyl group (R¹⁰Is hydrogen
A child), C optionally substituted with pyridyl
_1-6Alkoxy (R ¹⁰Is replaced by pyridyl
Good C_1-6Alkyl) or halogen source
C replaced by child_1-6Alkylsulfonyloxy (R
¹⁰C substituted with a halogen atom_1-6Alkylsul
(Which is sulfonyl) is preferred.

The "hydrocarbon group which may have a substituent (s)" for R ⁹ is the same as the "hydrocarbon group which may have a substituent (s)" exemplified as the substituent of ring A. Things are used. The hydrocarbon group represented by R ⁹ includes C
_{A 1-6} alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and a C _2-6 alkenyl group (eg, 2-methyl-2-propenyl, etc.) are preferable, and especially methyl,
C _1-3 alkyl groups such as isopropyl are preferred. As the substituent of the hydrocarbon group, (1) halogen atom (eg, fluorine, chlorine, bromine, iodine), (2) cyano group, (3) lower alkoxy group (eg, methoxy, ethoxy), (4) Hydroxy group, (5) amino group, (6) mono-lower alkylamino group (eg, mono-C _1-6 alkylamino group such as methylamino, ethylamino, etc.),
(7) Di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, etc.), (8) In addition to a carbon atom which may have oxo, a nitrogen atom, oxygen 4- to 10-membered heterocycles containing 1 to 3 heteroatoms selected from atoms and sulfur atoms (eg piperidino, 2-isoindolyl, etc.), (9)
C _6-14 arylthio (eg, phenylthio etc.),
(10) ureido, (11) carboxy, (12) carbamoyl, (13) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (14) mono-C _1-6 alkyl-carbamoyl (eg. , Methylcarbamoyl, ethylcarbamoyl, etc.), (15) formylamino, (16) C _1-6 alkyl-carboxamide (eg, acetamide, propionamide, etc.) and the like are preferable. As the “acyl group” represented by R ⁹ , the same ones as the “acyl group” exemplified as the substituent of the A ring are used, and specifically, (1) formyl, (2) C _1-6 alkyl A carbonyl group (eg, acetyl, propionyl, etc.),
(3) C _6-14 aryl-carbonyl group (eg, benzoyl etc.), (4) C _7-16 aralkyl-carbonyl group (eg, phenylacetyl etc.), (5) C _1-6 alkoxy-carbonyl group (eg , Methoxycarbonyl, ethoxycarbonyl, etc.), (6) carbamoyl group, (7) mono- or di-C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, dimethylcarbamoyl, etc.), (8) mono- or di- C _1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, dimethylthiocarbamoyl, etc.), (9) C _1-6 alkyl-sulfonyl group (eg, methylsulfonyl, etc.), (10) C _1-6 alkyl-sulfinyl A group (eg, methylsulfinyl, etc.) is used, and formyl is preferable.

[0047] As the "optionally substituted hydroxy group" represented by R ^9, for example, the formula -OR ^{9 '(R 9'} may be a hydrogen atom, an optionally substituted hydrocarbon group Or a group represented by an acyl group) is used.
As the optionally substituted hydrocarbon group represented by R ⁹ ′, those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent of A ring are used. Of these, C _1-6 alkyl and the like are preferable. The acyl group represented by R ⁹ ′ is an “acyl group” represented by R ^10.
The same as those described above are used, among which C _1-6 alkyl-
Carbonyl and the like are preferable. The R ^9, especially hydrogen, cyano group, C _{1 -6} optionally substituted by cyano
An alkyl group, formyl and the like are preferable, and a hydrogen atom is particularly preferable.

X represents (1) a methylene group which may have a substituent or (2) a carbonyl group. As the substituent of the methylene group, a group selected from the above-mentioned Substituent group A and the like are used, and among them, 1 or 2 C _1-6 alkyl groups (eg, methyl, ethyl, etc.), hydroxyl group and the like are preferable.
X is preferably (1) 1 or 2 C _1-6 alkyl groups (eg, methyl, ethyl, etc.), a methylene group optionally having a hydroxyl group, or (2) a carbonyl group, and particularly 1 or A methylene group which may have two methyl groups is preferable, and a methylene group is particularly preferable. n
Represents 0 or 1, and 0 is particularly preferred.

The following compounds are preferable as the compound of the present invention. [Compound (I ′)-I] R ¹ has the formula

[Chemical 56] [Wherein each symbol has the same meaning as defined above] or a group or formula

[Chemical 57] [Wherein each symbol has the same meaning as defined above]
To R^TwoAnd R^ThreeMay each have a substituent
A hydrocarbon group, R^FourAnd R⁵Is a hydrogen atom, R ⁶Oh
And R⁷Each of which may have a substituent
The base is R⁸Is a hydrogen atom or formula-OR¹⁰(R¹⁰Is
Hydrogen atom, optionally substituted hydrocarbon group, acyl group
Group or a heterocyclic group which may have a substituent)
To R⁹Is a hydrogen atom, X is methylene, and n is 0.
A compound (I ') or a salt thereof.

[Compound (I ′)-II] R ¹ is of the formula

[Chemical 58] [In the formula, R ¹⁶ is a hydrogen atom, a C _6-14 aryl group which may have a substituent, an amino group which may have a substituent, or a heterocyclic group which may have a substituent. Or a halogen atom], R ² and R ³ each represent a C _1-6 alkyl group which may have a substituent,
R ⁴ and R ^{5 each} represent a hydrogen atom, and R ⁶ and R ⁷ each represent a C _1-6 alkyl group which may have a substituent,
⁸ represents a hydrogen atom or a formula —OR ¹⁰ (R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group), R ⁹ represents a hydrogen atom, and X represents A compound (I ′) which is methylene and n is 0, or a salt thereof.

[Compound (I ′)-III] R ¹ has the formula

[Chemical 59] [Wherein R ¹⁶ is (1) a hydrogen atom, (2) phenyl substituted with an acetylamino group, (3) (i) a C _1-6 alkylsulfonyl group, (ii) pyridylcarbonyl or (iii) sulfamoyl- R ² and R ³ each represent a group represented by amino, which may be mono- or di-substituted by a substituent selected from C _1-6 alkyl group, (4) pyridyl or (5) halogen atom]. The C _1-6 alkyl group is replaced with R ⁴ and R
⁵ is a hydrogen atom, R ⁶ and R ⁷ are each a C _1-6 alkyl group, R ⁸ is a hydrogen atom or a formula —OR ¹⁰ (R
^10, (1) a hydrogen atom, (2) pyridyl optionally substituted C _{1 -6} alkyl group or (3) shows a C _1-6 alkylsulfonyl substituted with halogen atom), the R ⁹ A compound (I ′) in which X represents methylene and n is 0, which represents a hydrogen atom.

[Compound (I ′)-IV] The compound produced in Examples 1 to 16 or a salt thereof.

Formula used in the pharmaceutical composition of the present invention

[Chemical 60] Wherein - - - represents a single bond or a double bond] The compound having a partial structure represented by, specifically, the formula

[Chemical formula 61] [Wherein, each of the A ring, the B ring and the C ring may have the same substituents as described above] or the like is used, and more specifically, the compound represented by the formula:

[Chemical formula 62] A compound represented by the formula [wherein the symbols have the same meaning as defined above] is used. In addition, the formula

[Chemical formula 63] [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. A group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom] are preferred. The compound of the present invention (A-
1), (I-1) or (I'-1), specifically,
The compound etc. which were manufactured in Examples 1-16 are used.

The production methods of the compounds (I) and (I ') of the present invention are described below. The compound (Ia) is a compound included in the compound (I). The compounds (I) and (I ′) of the present invention can be obtained, for example, by the methods shown in the following reaction schemes 1 and 2 or methods analogous thereto. The compounds (A), (A-1), (I-1) and (I'-
1) can also be manufactured according to the following manufacturing method. Each symbol of the compounds in the following schematic diagrams of reaction formulas has the same meaning as described above unless otherwise specified. Compound (II) in the reaction formula
(VI) and (VII ') to (XIII') include a case where a salt is formed, and examples of the salt include those similar to the salt of compound (I) or (I '). Compound (I
I), (III), (IV), (VI), (VII '), (VII
As I ′), (XI ′) and (XII ′), commercially available products can be easily obtained, or they can be produced by a method known per se or a method analogous thereto.

Unless otherwise specified, the solvents represented by the generic names used in the following reactions include alcohols such as methanol, ethanol, 1-propanol and 2-
Diethyl ether, diisopropyl ether, etc. as ethers such as propanol and tert-butyl alcohol
Diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc., amides such as N, N-dimethylformamide,
N, N-dimethylacetamide, hexamethylphosphoric triamide, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., nitriles, acetonitrile, propionitrile, etc., ketones, acetone , Ethyl methyl ketone and the like, organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like, aromatic amines such as pyridine, 2,6-lutidine and quinoline, and sulfoxides such as dimethyl sulfoxide and the like. . As the bases shown by the generic name used in the following reactions, unless otherwise specified, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like as inorganic bases, sodium carbonate, carbonic acid as basic salts Potassium, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate, etc., aromatic amines such as pyridine and lutidine, and tertiary amines such as triethylamine, tripropylamine, tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine. , 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, sodium hydride as an alkali metal hydride,
Potassium hydride, sodium amide as metal amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc., butyl lithium, tert-butyl lithium as alkyl metal, phenyl lithium etc. as aryl metal, sodium as metal alkoxide Methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like are shown. The product can be used as it is in the reaction solution or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method, and it can be isolated by usual separation means (eg, recrystallization, distillation, chromatography, etc.). Can also be easily purified.

Compound (Ia) [wherein C'ring is R ¹ or R ²
And optionally having a substituent other than R ³ ] are produced by the process shown in Reaction Scheme 1. Reaction formula 1

[Chemical 64] Compound (III) is produced by converting compound (II) into an organometallic compound using magnesium or a base and reacting it with a formylating agent. Examples of the "base" include alkyl metals and aryl metals. The amount of the base used is approximately 1 to approximately 5 mol, preferably approximately 1 to approximately 2 mol, with respect to 1 mol of the compound (II).
Examples of the “formylating agent” include N, N-dimethylformamide, 1-formylpiperidine, 4-formylmorpholine, N-methylformanilide and the like. The amount of the formylating agent used is about 1 per 1 mol of compound (II).
To about 10 mol, preferably about 1 to about 5 mol. This reaction is advantageously carried out using a solvent inert to the reaction. Although such a solvent is not particularly limited as long as the reaction proceeds, a solvent such as ethers and hydrocarbons or a mixed solvent thereof is preferable. The reaction time is usually about 10 minutes to about 48 hours, preferably about 30.
Minutes to about 24 hours. The reaction temperature is usually about -100.
To about 150 ° C, preferably about -80 to about 100
℃.

Compound (V) is produced by reacting compound (III) with compound (IV) [wherein R ²² represents a hydrocarbon group and hal represents halogen] in the presence of a base, if desired. It Examples of the "hydrocarbon group" include:
Chain or cyclic hydrocarbon group _{(e.g., C 1-6} alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, _{etc.), C 3-6} cycloalkyl (For example, cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, etc., C _6-14 aryl (eg,
Phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like)) and the like. The amount of compound (IV) used is approximately 1 to approximately 5 mol, preferably approximately 1 to approximately 2 mol, with respect to 1 mol of the compound (III). Examples of the "base" include inorganic bases, basic salts, aromatic amines, tertiary amines, alkali metal hydrides, alkyl metals, aryl metals, metal amides, metal alkoxides and the like. Can be mentioned. The amount of the base used is approximately 1 to approximately 5 mol, preferably approximately 1 to approximately 2 mol, with respect to 1 mol of the compound (III). This reaction is advantageously carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but examples thereof include alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, water and the like, or a mixture thereof. Solvents and the like are preferred. The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours. The reaction temperature is usually about −100 to about 200 ° C., preferably about −80.
To about 150 ° C.

Compound (Ia) is a compound (V) and a compound (V
It is produced by reacting with I) in the presence of an acid. The amount of compound (VI) used is about 0.5 to about 5 mol, preferably about 0.5 to about 2 mol, relative to 1 mol of compound (V).
It is a mole. As the “acid”, a mineral acid such as sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide or perchloric acid, a boron trifluoride diethyl ether complex, a Lewis acid such as zinc chloride or aluminum chloride and the like can be used. The amount of acid used is compound (V)
It is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol. This reaction is advantageously carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but for example, hydrocarbons,
Organic acids, halogenated hydrocarbons or mixtures thereof are preferred. The reaction time is usually about 10 minutes to about 48 hours, preferably about 15 minutes to about 24 hours. The reaction temperature is usually about −20 to about 150 ° C., preferably about 0.
To about 100 ° C.

The compound (I ') is produced by the process shown in Reaction scheme 2. Reaction formula 2

[Chemical 65] Compound (IX ') is compound (VII') and compound (VIII ')
[In the formula, R²³And R ²⁴Is R⁷Form part of
A hydrocarbon group which may have a substituent, R⁷Same as
And W represents a leaving group.]
It is produced by reacting in the presence of a base. The
Examples of the “leaving group” include hydroxy, halogen atom
(Eg, fluorine, chlorine, bromine, iodine, etc.), halogen
C which may be converted_1-5Alkylsulfonyloxy
(For example, methanesulfonyloxy, ethanesulfonyl
Oxy, trichloromethanesulfonyloxy, etc.), substitution
C which may have a group_6-10Arylsulfonyl
Kisshi etc. are mentioned. "C which may have a substituent
_6-10“Arylsulfonyloxy” is, for example,
C_1-6Alkyl (eg, methyl, ethyl, etc.), C_1-6
Alkoxy (eg, methoxy, ethoxy, etc.) and nitro
C optionally having 1 to 3 substituents selected from
_6-10Arylsulfonyloxy (eg, phenylsulfur
(Honyloxy, naphthylsulfonyloxy, etc.)
As a specific example, benzenesulfonyloxy, m
-Nitrobenzenesulfonyloxy, p-toluenesulfur
Examples include sulfonyloxy and the like. Use of compound (VIII ')
The amount is about 1 to about 5 mol per 1 mol of compound (VII ').
And preferably about 1 to about 2 moles. The "base"
Examples include, for example, inorganic bases, basic salts and aromatic amines.
Amines, tertiary amines, metal hydrides, metal amides
And metal alkoxides. Amount of base used
Is about 1 to about 5 mol with respect to 1 mol of the compound (VII ′),
It is preferably about 1 to about 2 mol. This reaction is a reaction
It is advantageous to work with an inert solvent. like this
The solvent is not particularly limited as long as the reaction proceeds,
For example, alcohols, ethers, hydrocarbons, amides
, Halogenated hydrocarbons, nitriles, ketones, sulfur
Solvents such as rhufoxides or mixed solvents thereof are preferred.
Good The reaction time is usually about 15 minutes to about 48 hours, preferably
It is preferably about 30 minutes to about 24 hours. The reaction temperature is
Usually about -20 to about 150 ° C, preferably about 0 to about
It is 100 ° C.

Instead of the above reaction, the Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be used. The reaction is carried out by reacting compound (VII ') with compound (VII'
In I '), a compound in which W is OH is reacted in the presence of azodicarboxylates (eg, diethylazodicarboxylate etc.) and phosphines (eg, triphenylphosphine, tributylphosphine etc.). Compound (VI
In II ′), the amount of the compound in which W is OH is the compound (V
II ') is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol. The amount of each of the "azodicarboxylates" and "phosphines" to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, relative to 1 mol of compound (VII '). This reaction is advantageously carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but for example, a solvent such as ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, or a mixed solvent thereof or the like. Is preferred. The reaction time is generally about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours. The reaction temperature is usually about -20 to about 2.
The temperature is 00 ° C, preferably about 0 to about 100 ° C.

The compound (X ') is produced by subjecting the compound (IX') to Claisen rearrangement. This reaction is advantageously carried out without solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, alcohols, hydrocarbons, organic acids, ethers, anilines (eg, N, N-
Dimethylaniline, N, N-diethylaniline, etc.),
Phenols (eg, 2,6-dimethylphenol, etc.), halogenated hydrocarbons, mixed solvents thereof, etc. are used. If desired, the reaction may be carried out using an acid catalyst. As the acid catalyst, Lewis acids such as aluminum chloride and boron tribromide are used. In the case of Lewis acid, for example, the amount of the acid catalyst used is usually about 0.1 to about 20 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (IX ′). The reaction time is usually about 30 minutes to about 24 hours, preferably about 1 to about 8
It's time. The reaction temperature is usually about -70 to about 300.
C., preferably about 150 to about 250.degree.

The compound (XI ') can be produced by ring-closing the compound (X') in the presence of a protonic acid, a Lewis acid or iodine. As the protic acid, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and methanesulfonic acid,
Sulfonic acids such as trifluoromethanesulfonic acid and fluorosulfonic acid, Lewis acids such as aluminum chloride, aluminum bromide, titanium chloride (IV), tin chloride (IV), zinc chloride, boron trichloride, boron tribromide, Boron trifluoride or the like is used. Usually, the protonic acid or the Lewis acid is used alone, but both may be combined if desired. When using a protic acid,
The compound (X ') is used in an amount of about 1 to about 200 mol, preferably about 1 to about 100 mol, per 1 mol. When a Lewis acid is used, it is used in an amount of about 1 to about 5 per 1 mol of compound (X ').
The amount used is preferably about 1 to about 3 mol. When iodine is used, it is used in an amount of about 0.05 to about 1 mol, preferably about 0.1 to about 0.5 mol, per 1 mol of compound (X ′). This reaction is advantageously carried out using a solvent inert to the reaction. It is not particularly limited as long as the reaction proceeds as such a solvent, for example, ethers, hydrocarbons,
Solvents such as alcohols, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides and the like, or mixed solvents thereof and the like are preferable. The reaction temperature is generally about −20 to about 150 ° C., preferably about 0 to about 120 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

The compound (XII ′) can be converted into the compound (XI ′) in the same manner as in the production of the compound (III) from the compound (II).
Manufactured from. Compound (XIII '), as in the case of producing compound (V) compound (III) from the compound (IV), the compound (XII') with the compound (IV) wherein, R ²² and hal is the It has the same meaning as]. The compound (I ′) is obtained by converting the compound (V) and the compound (VI) into the compound (I
It is produced from compound (XIII ′) and compound (VI) in the same manner as in the production of a). By the above reaction, a compound (I ′) in which X is methylene can be produced. Further, if desired, the compound thus obtained can be converted into a compound in which X is a methylene or carbonyl having a substituent, by carrying out a functional group conversion based on a reaction known per se.

In each of the above reactions, when the starting compound has amino, carboxy or hydroxy as a substituent,
A protecting group generally used in peptide chemistry and the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include formyl or C _1-6 which may have a substituent, respectively.
Alkyl-carbonyl (eg, acetyl, propionyl, etc.), benzoyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-16 aralkyloxy-carbonyl (eg, benzyloxycarbonyl). Etc.), trityl, phthaloyl and the like are used. These substituents include halogen atoms (for example, fluorine,
Chlorine, bromine, iodine etc.), C _1-6 alkyl-carbonyl (eg acetyl, propionyl, valeryl etc.),
Nitro or the like is used, and the number of substituents is about 1 to 3. As the protective groups of carboxy, for example, each substituent may C _{1 -6} alkyl optionally having (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert
-Butyl etc.), phenyl, trityl, silyl, etc. are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C
_1-6 alkyl-carbonyl (eg acetyl, propionyl, butylcarbonyl etc.), nitro, C _1-6 alkyl (eg methyl, ethyl, tert-butyl etc.),
C _6-14 aryl (eg, phenyl, naphthyl, etc.)
Etc. are used, and the number of substituents is about 1 to 3.
As the hydroxy protecting group, for example, formyl, or C _1-6 alkyl optionally having a substituent (eg, methyl, ethyl, propyl, isopropyl,
Butyl, tert-butyl etc.), phenyl, C _7-16 aralkyl (eg benzyl etc.), C _1-6 alkyl-carbonyl (eg acetyl, propionyl etc.), phenyloxycarbonyl, C _7-16 aralkyloxy-
Carbonyl (eg, benzyloxycarbonyl, etc.),
Tetrahydropyranyl, tetrahydrofuranyl, silyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6 alkyl (eg methyl, ethyl, tert-butyl etc.), C _7-16 aralkyl (eg benzyl etc.), C _6-14 aryl (eg phenyl, naphthyl etc.), nitro etc. are used and substituted Number of groups is 1 to 4
It is about an individual. Further, as a method for removing the protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, ultraviolet light, hydrazine, phenylhydrazine,
A method of treatment with sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium (II) acetate or the like or a reduction reaction is used.

In any case, if desired, a deprotection reaction, an acylation reaction, an alkylation reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a carbon chain extension reaction and a substituent exchange reaction may be carried out individually or respectively. Compounds (A), (I), (I ′), (A-
1), (I-1) or (I'-1) can be synthesized. These reactions are described in, for example, New Experimental Chemistry Course 14, 1
Volume 5, 1977 (Maruzen Publishing), etc. are used. When the desired product is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method. You can also The compound (A), (I), (I '), (A-1), (I-1) or (I' thus obtained
-1) can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization and chromatography. Compound (A),
(I), (I '), (A-1), (I-1) or (I'-1)
When present as configurational isomers (configurational isomers), diastereomers, conformers, etc., each can be isolated by the above-mentioned separation and purification means, if desired. In addition, compounds (A), (I), (I '), (A-1), (I-1) or (I'
When -1) is a racemate, it can be separated into S-form and R-form by a usual optical resolution means. Compound (A), (I), (I '), (A-1), (I-1) or (I'
In the case where a stereoisomer exists in -1), the present invention includes the case where the stereoisomer is present alone and the case where they are a mixture thereof. In addition, compounds (A), (I), (I '), (A-1),
(I-1) or (I'-1) may be a hydrate or a non-hydrate. Compounds (A), (I), (I '), (A-1),
(I-1) or (I'-1) is an isotope (eg, ³ H,
¹⁴ C, ³⁵ S) or the like.

The compounds (A), (I) of the present invention,
Formula used in the production of (I '), (A-1), (I-1) or (I'-1)

[Chemical formula 66] [In the formula, R^2aAnd R^3aEach has a substituent
The aliphatic hydrocarbon group which may be^4aAnd R^5aIs
Carbonization optionally having a hydrogen atom or a substituent
The hydrogen group is^6aAnd R^7aAre hydrogen atoms and
Represents a hydrocarbon group which may have a substituent, R^6a
And R^7aHas substituents on adjacent carbon atoms
R may form a 3- to 8-membered ring, and R^8aIs
(1) Hydrogen atom, (2) Carbonization which may have a substituent
Even if it has a hydrogen group, (3) acyl group, or (4) substituent
Good heterocyclic group, (5) halogen atom, (6) -OR
^10a(R^{1 0a}Is a hydrogen atom, even if it has a substituent
May have a good hydrocarbon group, acyl group or substituent
Represents a good heterocyclic group), (7) -SR^11a(R^11a
Is a hydrogen atom, a hydrocarbon group which may have a substituent,
Shows an acyl group or a heterocyclic group which may have a substituent.
), (8) -S (O) R^12a(R^12aIs a substituent
Optionally having a hydrocarbon group or a substituent
Optionally represents a heterocyclic group), (9) -S (O)_TwoR
^13a(R^13aIs a hydrocarbon which may have a substituent
Indicates a heterocyclic group which may have a basic group or a substituent)
Or (10) -NR ^14aR^15a(R^14aand
R^15aMay each have a hydrogen atom or a substituent.
May have a hydrocarbon group, an acyl group or a substituent
Represents a heterocyclic group), R^9aHas a hydrogen atom and a substituent
Optionally having a hydrocarbon group, an acyl group or a substituent.
A hydroxyl group which may be present] or
The salt is a new compound.

R^2aAnd R^3aIs represented by
"Aliphatic hydrocarbon water" of "aliphatic hydrocarbon group which may have"
Examples of the “primary group” include an alkyl group, an alkenyl group,
Chain hydrocarbons such as alkynyl groups and cycloalkyl groups
Or an aliphatic cyclic hydrocarbon group is used.
1 to 16 chains (straight or branched) or
Aliphatic cyclic hydrocarbon groups are preferred. Specifically,
The ones below are used. (1) Chain hydrocarbon group: alkyl group [preferably lower
Alkyl groups (eg methyl, ethyl, propyl, iso
Propyl, butyl, isobutyl, sec-butyl, tert-
C such as butyl, pentyl, hexyl_1-6Alkyl group
Such)], (2) Aliphatic cyclic hydrocarbon group: cycloalkyl group [preferred
Specifically, a lower cycloalkyl group (for example, cyclopropyl
R, cyclobutyl, cyclopentyl, cyclohexyl
Which C_3-6A cycloalkyl group) and a benzene ring
Which may be condensed] of these "aliphatic hydrocarbon groups"
Examples of the substituent include (1) halogen atom, (2) C
_1-3Alkylenedioxy group, (3) nitro group, (4) c
C which may be rogenated_1-6Alkyl groups, (5)
C_3-6Cycloalkyl group, (6) C_{6 -14}Aryl
Group, (7) optionally halogenated C_1-6Arco
Xy group, (8) optionally halogenated C_1-6A
Rukylthio group, (9) hydroxy group, (10) amino group,
(11) Mono-C_1-6Alkylamino group, (12) mono-
C_{6 -14}Arylamino group, (13) di-C_1-6Al
Killamino group, (14) di-C _6-14Arylamino
Group, (15) formyl, carboxy, carbamoyl, C_1
-6Alkyl-carbonyl, C_3-6Cycloalkyl-
Carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl
-Carbonyl, C_6-14Aryloxy-carboni
Le, C_7-16Aralkyloxy-carbonyl, carbon source
Selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring carbonyl, mono-C_1-6Alkyl-carbamoy
Le, the C_1-6Alkyl-carbamoyl, C_6-14
Aryl-carbamoyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hets selected from yellow atom and oxygen atom
5- or 6-membered heterocyclic carbamoyl containing a carbon atom, C
_1-6Alkyl-thiocarbonyl, C_3-6Cycloal
Kill-thiocarbonyl, C_1-6Alkoxy-thiocal
Bonil, C_6-14Aryl-thiocarbonyl, C
_7-16Aralkyl-thiocarbonyl, C_6-14Ants
Oxy-thiocarbonyl, C_7-16Aralkillo
Xy-thiocarbonyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hetero atoms selected from atoms and oxygen atoms
5- or 6-membered heterocyclic thiocarbonyl containing atoms, thi
Ocarbamoyl, Mono-C_1-6Alkyl-thiocarba
Moyle, The-C_1-6Alkyl-thiocarbamoyl, C
_6-14Aryl-thiocarbamoyl, other than carbon atom
1 selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered heterocyclic thio containing 3 heteroatoms
Carbamoyl, Mono-C_1-6Alkylsulfamoy
Le, the C_1-6Alkylsulfamoyl, C_6-14
Arylsulfamoyl, C_{1- 6}Alkyl sulfoni
Le, C_6-14Arylsulfonyl, C_1-6Alkyl
Sulfinyl, C_6-14Arylsulfinyl, sul
Fino, sulfo, C_1-6Alkoxysulfinyl, C
_6-14Aryloxysulfinyl, C_1-6Arco
Xysulfonyl and C_6-14Aryloxysulfo
Acyl group selected from nyl, (16) formylamino, C
_1-6Alkyl-carboxamide, C_6-14Aryl
-Carboxamide, C_1-6Alkoxy-carboxami
Do, C_1-6Alkylsulfonylamino and C
_6-14Acyl selected from arylsulfonylamino
Amino group, (17) C_1-6Alkyl-carbonyl
Shi, C_6-14Aryl-carbonyloxy, C_1-6
Alkoxy-carbonyloxy, mono-C _1-6Archi
L-carbamoyloxy, di-C_1-6Alkyl-cal
Vamoyloxy, C_6-14Aryl-carbamoyl
Acyloxy selected from xy and nicotinoyloxy
Si group, nitrogen atom other than (18) carbon atom, sulfur atom and
Contains 1 to 3 heteroatoms selected from oxygen atoms
A 4- to 14-membered heterocyclic group, (19) phosphono group, (2
0) C_6-14Aryloxy group, (21) di-C_1-6
Alkoxy-phosphoryl group, (22) C_6-14Aryl
Thio group, (23) hydrazino group, (24) imino group, (25) o
Xo group, (26) ureido group, (27) C_1-6Alkyl-
Ureido group, (28) di-C_1-6Alkyl-ureido
Group, (29) oxide and (30) of the above (1) to (29)
Is it a group formed by combining two or three selected from groups?
Selected from the group consisting of (hereinafter abbreviated as Substituent group B)
Groups are used. Specific examples of these substituents include the above.
Examples of the substituent group A of
It

The "hydrocarbon group which may have a substituent (s)" represented by R ^4a and R ^5a includes R ⁴ and R 5.
⁵ represented by "optionally substituted hydrocarbon group"
The same as is used. The "hydrocarbon group optionally having substituent (s)" for R ^6a and R ^7a is the same as the "hydrocarbon group optionally having substituent (s)" for R ⁶ and R ⁷ . Things are used. The “3- to 8-membered ring optionally having substituent (s)” which R ^6a and R ^7a may form together with the adjacent carbon atom, is R ⁶
And R ⁷ are the same as the “3- to 8-membered ring optionally having substituent (s)” which may be formed together with the adjacent carbon atom.

“A hydrocarbon group which may have a substituent”, an “acyl group”, a “heterocyclic group which may have a substituent”, a “halogen atom” and a “formula” represented by R ^8a. -OR
^10a "," Formula-SR ^11a "," Formula-S (O) R "
^12a "," formula -S _(O) ^{2 R 13 a} "or" formula -N
R ^14a R ^15a ”is“ hydrocarbon group optionally having substituent (s) ”represented by R ⁸ ,“ acyl group ”,“ heterocyclic group optionally having substituent (s) ”,“ halogen ” atom "," formula ^{-OR 10,} "" formula ^{-SR 11} "," the formula -S
^{(O) R 12} "," the same as the formula -S _(O) ^{2 R 13} "or" formula ^-NR 14 ^{R 15} "is used.

[0070] represented by R ^9a "substituent hydrocarbon group which may have a", "acyl group" and "optionally substituted hydroxyl" includes "substituted represented by R ⁹ The same groups as the "hydrocarbon group which may have a group", "acyl group" and "hydroxyl group which may have a substituent" are used.

Examples of the compound (B) include the following compounds.
preferable. (1) R^2aAnd R^3aAre halogen atoms,
C_1-6Alkyl, C _1-6Alkyl-carbonyl,
C_1-6Alkylsulfonyl and C_7-16Aralchi
A hydroxyl group which may be substituted with a substituent selected from
1 or 2 C_1-6Alkyl, C_1-6Alkyl
-Carbonyl and C_6-14Aryl-carbonyl
An amino group which may be substituted with a substituent selected from
Other than carbon atom, nitrogen atom, oxygen atom, sulfur atom, etc.
4 having 1 to 3 heteroatoms selected from
10-membered heterocyclic group, C_1-6Substituted with alkyl
Optionally a thio group, C_1-6Alkyl-sulfinyl group
Or C_1-6Substituted with an alkyl-sulfonyl group
May be C_1-6Represents an alkyl group, R^4a,
R^5a, R^6aAnd R^7aAre hydrogen atoms or
C_1-6Represents an alkyl group, R^8aIs C_1-6Archi
Group, halogen atom, formula-OR^10a(R
^{10 a}Is (i) hydrogen atom, (ii) C_1-6Alkyl group
[This C_1-6Alkyl groups are (1) halogen atoms, (2)
Hydroxy group, (3) amino group, (4) carboxy,
(5) Carbamoyl, (6) C_1-6Alkoxy-carbo
Nil, (7) Mono-C_{1- 6}Alkyl-carbamoyl,
(8) J-C_1-6Alkyl-carbamoyl, (9) oki
In addition to carbon atoms that may have nitrogen atom, sulfur atom
1 to 3 heteroatoms selected from child and oxygen atom
Substitutions selected from 4- to 10-membered heterocyclic groups containing a child
May have a group], (iii) C_3-6Cycloalk
Ru radical, (iv) C _7-16Aralkyl group, (v) C_1-6Al
Kill-carbonyl group, (vi) C_6-14Aryl-carbo
Nyl group, (vii) C_1-6An alkoxy-carbonyl group, (vi
ii) Mono- or di-C_1-6Alkyl-thiocarbamo
Yl group, (ix) optionally halogenated C_1-6Al
A nitrogen source other than a kill-sulfonyl group or (x) carbon atom
1 to 4 selected from child, sulfur atom and oxygen atom
A 4- to 10-membered heterocyclic group containing a hetero atom of
Heterocyclic group is C_6-14May have aryl]
Shown), formula-SR^11a(R^11aIs (i) hydrogen source
Child, (ii) C_1-6Alkyl group or (iii) mono- or
The-C_1-6Alkyl-carbamoyl group), formula
-S (O) R^12a(R^12aIs (i) C_1-6Archi
Group or (ii) mono- or di-C_1-6Alkyl-Mo
And a formula —S (O)._TwoR^13a(R
^13aIs (i) C_1-6Alkyl group or (ii) mono- or
Or J-C_1-6Alkyl-carbamoyl group)
Or formula-NR^14aR^15a(R^14aIs (i) water
Elementary atom, (ii) C_1-6Alkyl group [this C_1-6Archi
Ru group is C_1-6Even if it has an alkoxy-carbonyl
Good], (iii) formyl, (iv) C_1-6Alkyl-cal
Bonyl group, (v) C_1-6An alkoxy-carbonyl group, (v
i) carbamoyl group, (vii) mono- or di-C_1-6A
Rukyl-carbamoyl group or (viii) C_1-6Alkyl
A sulfonyl group, R^15aIs a hydrogen atom or methyl
R)^9aIs (i) hydrogen atom, (ii) C
_1-6Alkyl group [this C_1-6Alkyl groups are (1)
Halogen atom, (2) C_1-6Alkoxy group, (3) hydr
Roxy group, (4) amino group, (5) mono-C_1-6Archi
Luamino group, (6) di-C_1-6Alkylamino group,
(7) Nitrogen source in addition to carbon atom which may have oxo
1 to 3 selected from a child, a sulfur atom and an oxygen atom
A 4- to 10-membered heterocyclic group containing a hetero atom of
(8) C_6-14Arylthio, (9) Ureido, (10)
Carboxy, (11) carbamoyl, (12) C_1-6Al
Coxy-carbonyl, (13) mono-C_1-6Alkyl-
Carbamoyl, (14) formylamino and (15) C
_1-6A substituent selected from alkyl-carboxamide
May have] or (iii) a compound showing a formyl group
Compound (B) (2) Compound (B) produced in Reference Example 4.

Compound (I), (I '), (I-1) or
The prodrug of (I′-1) is a compound (I) produced by a reaction with an enzyme or gastric acid under physiological conditions in vivo.
A compound which is converted to (I '), (I-1) or (I'-1), that is, a compound (I), (I') or (I-1 which is enzymatically oxidized, reduced or hydrolyzed. ) Or (I′-1), a compound (I) which is hydrolyzed by gastric acid or the like,
A compound which changes to (I '), (I-1) or (I'-1). The prodrug of compound (I), (I '), (I-1) or (I'-1) includes compound (I), (I') and (I-1)
Alternatively, a compound in which the amino group of (I′-1) is acylated, alkylated or phosphorylated (for example, compound (I), (I ′),
The amino group of (I-1) or (I'-1) is eicosanoylated,
Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinomethylation, pivaloyloxymethylation, tert-butyl Compound, etc.); Compound (I), (I ′), (I-
1) or a hydroxyl group of (I'-1) is acylated, alkylated, phosphorylated or borated (for example, compound (I), (I '), (I-1) or (I'-1) ) Hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); Compounds (I), (I ′), (I-1 ) Or (I'-1) carboxy group is esterified or amidated (for example, compound (I), (I '), (I-1) or (I'-1) carboxy group is ethyl Esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification,
Pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.) and the like. These compounds are compound (I), (I '), (I-1) or (I'-1) by a method known per se.
Can be manufactured from. In addition, compound (I),
The prodrugs of (I '), (I-1) or (I'-1) are described in Hirokawa Shoten 1990 "Development of Pharmaceuticals" Volume 7 Molecular Design 1
It may be changed to the compound (I), (I '), (I-1) or (I'-1) under physiological conditions as described on pages 63 to 198.

Compounds (A), (I), (I '), (A-
As the salt of 1), (I-1), (I'-1) or (B), for example, a pharmacologically acceptable salt and the like are used.
Examples thereof include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt. Suitable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,
Examples thereof include salts with dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
Examples thereof include salts with phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone. Examples thereof include salts with acids and p-toluenesulfonic acid. Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc. To be Among them, pharmaceutically acceptable salts are preferable, and examples thereof include compounds (I) or (I ′) having a basic functional group, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphorus. Examples thereof include salts with inorganic acids such as acids, for example, salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. , If it has an acidic functional group,
For example, alkali metal salts such as sodium salt and potassium salt,
Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts and the like.

Expression

[Chemical formula 67] Wherein - - - represents a single bond or a double bond], or a salt thereof having a partial structure represented by the PDE inhibitory action, in particular having a PDE IV inhibitory activity, diseases caused by PDE It can be used as a preventive / therapeutic agent.
As the salt of the compound (A-2), the above compound (A),
(I), (I '), (A-1), (I-1), (I'-
Examples thereof include those similar to the salt of 1) or (B). Among them, the compounds (A), (I), (I ′), (A-1) of the present invention included in the above compound (A-2) or a salt thereof.
(I-1), (I'-1) or a salt thereof (including prodrugs of compounds (I), (I-1), (I ') and (I'-1)) (hereinafter, referred to as "the present invention") Abbreviated as compound)
Has an excellent PDE inhibitory action, especially PDE IV inhibitory action, and is low in toxicity and safe, so that inflammatory diseases in mammals (eg, human, mouse, dog, rat, cow, etc.), Autoimmune disease, diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, central hypofunction after cerebrovascular obstruction, cerebrovascular dementia, Alzheimer's dementia, memory Disorder, obesity, heart failure, pulmonary fibrosis, allergic disease, angina, myocardial infarction,
Prevention of hypertension, pulmonary hypertension, renal disease, cerebral dysfunction, immunodeficiency, ophthalmology, sexual dysfunction in men or women, etc.
It can be used as a therapeutic agent and a PDE inhibitor. Inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, cerebrovascular obstruction Subsequent hypofunction of the central nervous system, cerebrovascular dementia, Alzheimer's dementia, memory impairment, obesity, heart failure, pulmonary fibrosis, allergic diseases (for example, atopic dermatitis,
Prophylactic / therapeutic agent for allergic rhinitis, urticaria, etc., PDE
It can be used as an IV inhibitor. The route of administration is oral,
It may be parenteral. Specific examples of the dosage form include, for example, tablets (including sugar-coated tablets and film-coated tablets),
Pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, injections, inhalants, ointments, eye drops, aerosols, eye ointments,
A plaster, a suppository, a troche, a poultice, a liniment and the like are used. These formulations are prepared according to a conventional method (for example, the method described in the Japanese Pharmacopoeia, etc.). In the preparation of the present invention, the content of the compound of the present invention varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, based on the whole preparation.
More preferably, it is about 0.5 to 20% by weight.
Specifically, the method for producing tablets is as follows: a pharmaceutical product as it is, an excipient, a binder, a disintegrating agent or other appropriate additives are uniformly mixed and granulated by a suitable method, A lubricant, etc. is added and compression-molded, or the medicine is used as it is, or an excipient, a binder, a disintegrating agent or other suitable additive is added and uniformly mixed,
It can also be manufactured by direct compression molding, or by directly molding granules as they are, or by adding appropriate additives and mixing them uniformly, and then compression molding. In addition, a colorant, a flavoring agent and the like can be added to the present agent, if necessary. Furthermore, this agent can be coated with a suitable coating agent. The manufacturing method of the injection is a fixed amount of the drug, in the case of an aqueous solvent, water for injection, physiological saline,
In the case of a non-aqueous solvent such as Ringer's solution, it can be usually dissolved, suspended or emulsified in vegetable oil or the like to give a fixed amount, or a fixed amount of a drug can be taken and sealed in a container for injection. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose and the like can be used. As the carrier for injection, for example,
Distilled water, physiological saline, glucose solution, infusion solution, etc. are used. In addition, additives generally used in preparations can be added as appropriate. The dose of these preparations varies depending on the age, body weight, symptoms, administration route, number of administrations, etc. 0.01 to 100 mg / kg, preferably 0.1 to 50 mg / kg, more preferably 0.5 to 10 mg / kg daily 1 or 2
It is recommended to administer in divided doses orally.

Although the compound of the present invention exhibits an excellent PDE IV inhibitory action even when used as a single agent, it is further used in combination with other pharmaceutical ingredients other than the compound of the present invention (hereinafter abbreviated as concomitant drug) (multidrug). It can also be used together. Examples of such concomitant drugs include anti-asthma agents (eg, fluticasone propionate, beclomethasone propionate, theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.), antiallergic agents (eg, fexofenadine, epinastine, ebastine, etc.) , Anticholinergic agents (eg, ipratropium bromide, flutropium bromide, oxitropium bromide, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, loxoprofen sodium, etc.), antibacterial agents (eg, cefixime, cefdinir, etc.) Ofloxacin, tosufloxacin tosylate, levofloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.), antidiabetic agents (eg, pioglitazone, etc.) Nateglinide, voglibose, acarbose, etc.)
And so on. When the compound of the present invention and the concomitant drug are used in combination, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be simultaneously administered to the administration subject. , You may administer at a time lag. The dose of the concomitant drug may be similar to the dose clinically used, and the administration subject, administration route, disease,
It can be appropriately selected depending on the combination and the like. The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such a dosage form include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) identical two preparations obtained by separately formulating the compound of the present invention and a concomitant drug Simultaneous administration by the administration route, (3) administration of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time lag, (4) compound of the present invention Simultaneous administration of two kinds of preparations obtained by separately formulating the drug and the concomitant drug through different administration routes, (5) Different two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration with a time lag in the administration route (for example, administration of the compound of the present invention → concomitant drug in the order or administration in the reverse order) and the like can be mentioned. Hereinafter, these administration forms will be collectively referred to as the concomitant drug of the present invention. The concomitant drug of the present invention has low toxicity, and for example, the compound of the present invention or (and) the concomitant drug is mixed with a pharmaceutically acceptable carrier according to a method known per se, to obtain a pharmaceutical composition such as a tablet ( As a sugar-coated tablet, film-coated tablet, powder, granule, capsule (including soft capsule), solution, injection, suppository, sustained-release agent, etc., orally or parenterally (eg, topical, rectal, intravenous) Can be safely administered. Injections are administered intravenously, intramuscularly, subcutaneously, in organs, intranasally, intracutaneously, eye drops, intracerebrally, rectally, intravaginally and intraperitoneally, inside tumors, in the vicinity of tumors, or directly into the lesion. It can be administered.

As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, those similar to those used in the above-mentioned pharmaceutical composition of the present invention can be used. . The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the preparation, but it is usually about 0.01 to 100% by weight, preferably about 0.1 to about 50% by weight based on the whole preparation. %, More preferably about 0.5 to about 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1% to the whole preparation.
It is about 1 to about 50% by weight, more preferably about 0.5 to about 20% by weight. The content of additives such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. Is.
Also, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.

These formulations can be produced by a method known per se which is generally used in the formulation process. For example, the compound of the present invention or a concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose). ,
Dextrin, etc.), stabilizers (eg, ascorbic acid,
Sodium pyrosulfite etc.), surfactants (eg polysorbate 80, macrogol etc.), solubilizers (eg glycerin, ethanol etc.), buffers (eg phosphoric acid and its alkali metal salts, citric acid and its alkali metals) Salt, etc.), isotonicity agent (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjuster (eg,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizing agents (eg, propylene) Glycols, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) in aqueous injections, or vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., and solubilizing agents such as propylene glycol. Alternatively, it can be emulsified and molded into an oil-based injection to prepare an injection. To prepare a preparation for oral administration, according to a method known per se, the compound of the present invention or the concomitant drug is, for example,
Excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg,
Starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and then, if necessary, taste masking. For the purpose of enteric or sustained release, an oral administration preparation can be prepared by coating by a method known per se. As the coating agent, for example,
Hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (Rohm, Germany, methacrylic acid) -Acrylic acid copolymerization) and pigments (eg red iron oxide, titanium dioxide, etc.) are used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
For example, in the case of a suppository, the compound of the present invention or the concomitant drug can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. As the oily base used in the composition, for example, glycerides of higher fatty acids [eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, migliols (manufactured by Dynamite Nobel, Germany) ) And the like], or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Examples of the aqueous base include polyethylene glycols, propylene glycol,
Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like. Examples of the sustained-release preparation include sustained-release microcapsules. The sustained-release microcapsules can be prepared by a method known per se, but for example, it is preferable that the sustained-release microcapsules are molded into a sustained-release preparation and administered. The compound of the present invention is a solid preparation (eg, powder, granule,
It is preferably molded into a preparation for oral administration such as tablets and capsules or a preparation for rectal administration such as suppositories. Particularly preferred is a preparation for oral administration. The concomitant drug can be made into the dosage forms described above depending on the type of drug.

In the following, [1] an injection of the compound of the present invention or a concomitant drug and its preparation, [2] a sustained release preparation or an immediate release preparation of the compound of the present invention or a concomitant drug, and its preparation, [3] The sublingual tablet, buccal or buccal disintegrant of the compound of the present invention or the concomitant drug and its preparation will be specifically described. [1] Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate. The injection can be obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or a salicylate in water. Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol. The concentration of the compound of the present invention or the concomitant drug in the injection is about 0.5 to about 50 w / v%, preferably about 3 to about 20 w / v%. The concentration of benzoate and / or salicylate is about 0.5 to about 50.
Preferred is w / v%, preferably about 3 to about 20 w / v%. In addition, this product contains additives commonly used for injections,
For example, stabilizers (ascorbic acid, sodium pyrosulfite etc.), surfactants (polysorbate 80, macrogol etc.), solubilizers (glycerin, ethanol etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its Alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin, etc.), pH adjusters (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, Benzoic acid, etc.), dissolving agents (concentrated glycerin, meglumine, etc.),
A solubilizing agent (propylene glycol, sucrose, etc.), a soothing agent (glucose, benzyl alcohol, etc.) and the like can be appropriately added. These additives are generally added in the proportions usually used for injections. The pH of the injection is pH
It can be adjusted to 2 to 12, preferably 2.5 to 8.0 by adding a regulator. The injectable preparation can be obtained by dissolving both the compound of the present invention or the concomitant drug and optionally the benzoate and / or salicylate, and optionally the above-mentioned additive in water. These may be dissolved in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injectable solution. The aqueous solution for injection is preferably heated, and can be provided as an injectable solution by performing, for example, filter sterilization, high-pressure heat sterilization, and the like in the same manner as an ordinary injectable solution. The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes. Furthermore, it may be a preparation in which the solution has antibacterial properties so that it can be used as a multiple-dose preparation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof A sustained-release preparation obtained by coating the core containing the compound of the present invention or the concomitant drug with a film-forming agent such as a water-insoluble substance or a swelling polymer, if desired. Release formulations are preferred. For example, a once-daily type sustained release preparation for oral administration is preferable. As the water-insoluble substance used for the film forming agent, for example, ethyl cellulose,
Cellulose ethers such as butyl cellulose, cellulose acetates such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid /
Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkylmethacrylate copolymer, poly (methacrylic acid anhydride), glycidylmethacrylate copolymer, especially Eudragit RS-100, RL-10.
0, RS-30D, RL-30D, RL-PO, RS-
Such as PO (ethyl acrylate / methyl methacrylate / trimethyl chloride / ammonium ethyl methacrylate copolymer) and Eudragit NE-30D (methyl methacrylate / ethyl acrylate copolymer), etc., such as Eudragit (ROHM Pharma) Acrylic acid polymers, hydrogenated castor oil (eg, Lovely wax (Freund's industry), etc.), hardened oil, carnauba wax, fatty acid glycerin ester, waxes such as paraffin, polyglycerin fatty acid ester, etc. may be mentioned. As the swelling polymer, a polymer having an acidic dissociative group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as small intestine or large intestine. Polymers having acidic dissociative groups are preferred. Polymers having such acidic dissociative groups and exhibiting pH-dependent swelling include, for example, carbomer 934.
P, 940, 941, 974P, 980, 1342, etc.
Polycarbophil, calcium polycarbophil (all of which are manufactured by BF Goodsrich), Hibiswako 103,
104, 105, 304 (all manufactured by Wako Pure Chemical Industries, Ltd.)
And cross-linked polyacrylic acid polymers such as The film forming agent used in the sustained-release preparation may further contain a hydrophilic substance. Examples of the hydrophilic substance include pullulan,
Dextrin, polysaccharides that may have a sulfuric acid group such as alkali metal alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, Examples thereof include polyvinyl alcohol and polyethylene glycol. The content of the water-insoluble substance in the film agent of the sustained-release preparation is about 30.
To about 90% (w / w), preferably about 35 to about 8
0% (w / w), more preferably about 40 to 75% (w
/ w), content of swelling polymer is about 3 to about 30%
(W / w), preferably about 3 to about 15% (w / w).
The coating agent may further contain a hydrophilic substance, in which case the content rate of the hydrophilic substance in the coating agent is about 50% (w / w)
Below, preferably about 5 to about 40% (w / w), more preferably about 5 to about 35% (w / w). Where the above% (w /
w) indicates the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohols such as methanol and ethanol) from the coating agent solution. Sustained-release preparations are prepared by preparing a core containing a drug as illustrated below, and then using the obtained core as a coating agent solution in which a water-insoluble substance or a swelling polymer is dissolved by heating or dissolved or dispersed in a solvent. It is manufactured by coating.

I. Preparation of Nucleus Containing Drugs The form of the drug-containing core (hereinafter sometimes simply referred to as a core) coated with the film-forming agent is not particularly limited, but is preferably formed into particles such as granules or fine particles. When the core is a granule or a fine granule, its average particle size is preferably about 1
50 to about 2,000 μm, more preferably about 50
It is from 0 to about 1,400 μm. The core can be prepared by an ordinary manufacturing method. For example, a drug is mixed with an appropriate excipient, a binder, a disintegrant, a lubricant, a stabilizer and the like, and the mixture is prepared by a wet extrusion granulation method, a fluidized bed granulation method or the like. The drug content of the nucleus is about 0.5 to about 95% (w /
w), preferably about 5 to about 80% (w / w), more preferably about 30 to about 70% (w / w). As the excipient contained in the core, for example, saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferable. As the binder, for example, polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. Examples of disintegrants include carboxymethyl cellulose calcium (ECG
505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropyl cellulose, polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose are preferable. Examples of lubricants and anti-agglomeration agents include talc and magnesium stearate, and lubricants such as polyethylene glycol. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as the stabilizer. In addition to the above-mentioned production method, the core may be prepared by spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on an inert carrier particle, which is the core of the core, while the drug It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method, in which a mixture of this and an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those manufactured from sucrose, lactose, starch, crystalline cellulose and waxes can be used, and the average particle size thereof is about 100 μm to about 1.5.
It is preferably 00 μm. The surface of the core may be coated with a protective agent in order to separate the drug contained in the core from the coating agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance or the like is used. The protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose. The protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid or maleic acid as a stabilizer, and a lubricant such as talc. When a protective agent is used, its coating amount is about 1 to about 1 with respect to the nucleus.
5% (w / w), preferably about 1 to about 10% (w / w),
More preferably, it is about 2 to about 8% (w / w). The protective agent can be coated by a conventional coating method, and specifically, the core can be spray-coated with the protective agent by, for example, a fluidized bed coating method, a pan coating method or the like.

II. Coating of the core with a coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. To produce a sustained release formulation. Examples of the method for coating the core with the coating agent liquid include a spray coating method. The composition ratio of the water-insoluble substance, the swelling polymer or the hydrophilic substance in the coating agent liquid is appropriately selected so that the content of each component in the coating is the above content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), and more preferably to the core (excluding the coating amount of the protective agent). About 5 to 3
It is 5% (w / w). As the solvent for the coating agent liquid, water or an organic solvent may be used alone or a mixture of both may be used. The mixing ratio of water and the organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be varied in the range of 1 to 100%, and preferably 1 to about 30%.
The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance, and for example, lower alcohols such as methanol, ethanol, 2-propanol and 1-butanol, lower alkanones such as acetone, acetonitrile, chloroform, dichloromethane and the like. Is used.
Of these, lower alcohols are preferable, and ethanol and 2-
Propanol is especially preferred. Water and a mixed liquid of water and an organic solvent are preferably used as the solvent of the film forming agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid or maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method, and specifically, it is carried out by spray coating the core with a coating agent solution by, for example, a fluidized bed coating method, a pan coating method or the like. You can If necessary at this time, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. are plasticized. You may add as an agent. After coating with the coating agent, an antistatic agent such as talc may be mixed if necessary. The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). Oral administration agents, parenteral administration agents such as injection agents are used, and oral administration agents are preferred. The immediate-release preparation may usually contain, in addition to the active ingredient drug, a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the field of formulation. . The formulation excipient used is not particularly limited as long as it is an excipient that is commonly used as a formulation excipient. For example, as an excipient for an oral solid preparation, lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.),
Powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid,
Examples thereof include magnesium carbonate, calcium carbonate, L-cysteine, etc., and preferably corn starch, mannitol, etc. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4w based on the total amount of the immediate release preparation.
/ w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to about 97 w / w%. The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60% with respect to the total amount of the immediate release preparation. When the immediate release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
Examples of such a disintegrant include carboxymethyl cellulose calcium (manufactured by Gotoku Yakuhin, ECG-505),
Croscarmellose sodium (for example, Asahi Kasei Corporation)
Made, acdysol), crospovidone (eg BASF
Colydon CL), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), sodium carboxymethyl starch (Kimura Sangyo, Explotab), partially pregelatinized starch (PCS, manufactured by Asahi Kasei Co., Ltd.) is used, for example, to disintegrate the granules by contacting with water, absorbing water, swelling, or forming a channel between the active ingredient constituting the nucleus and the excipient. Any thing can be used. These disintegrants may be used alone or in combination of two or more.
The amount of the disintegrant to be added is appropriately selected depending on the type and amount of the drug used, the design of the release preparation, etc., but is, for example, about 0.05 to about 30 w / w%, preferably the total amount of the immediate release preparation. Is about 0.5 to about 15 w / w%. When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, in addition to the composition described above, if desired, it may further contain additives conventionally used in solid preparations. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin), lubricants (for example, , Polyethylene glycol, magnesium stearate, talc,
Light silicic anhydride (for example, Aerosil (Japan Aerosil)), surfactants (for example, anionic surfactants such as sodium alkylsulfate, polyoxyethylene fatty acid ester and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative) Nonionic surfactants such as), colorants (for example, tar dyes, caramel, red iron oxide, titanium oxide, riboflavins), if necessary, corrigents (for example, sweeteners, flavors, etc.), adsorbents, Preservatives, wetting agents, antistatic agents and the like are used. Further, an organic acid such as tartaric acid, citric acid, succinic acid or fumaric acid may be added as a stabilizer. As the binder, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used. The quick-release preparation can be prepared by mixing the above-mentioned components, and if necessary, further kneading and molding, based on the usual manufacturing technology for preparations. The above-mentioned mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when forming an immediate release preparation in the form of particles, by the same method as the method for preparing the core of the sustained release preparation, a vertical granulator, a universal kneader (manufactured by Hata Tekko Co., Ltd.), a flower It can be prepared by mixing using a layer granulator FD-5S (manufactured by Powrex) or the like, and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like. The immediate-release preparation and the sustained-release preparation thus obtained are formulated as they are or separately separately with a formulation excipient by a conventional method, and then administered simultaneously or in combination with an arbitrary administration interval interposed. Alternatively, both of them may be used as they are or as appropriate, together with a pharmaceutical excipient, etc. in one oral administration formulation (eg, granules, fine granules, tablets,
It may be formulated into a capsule or the like). Both preparations may be made into granules or fine granules and filled in the same capsule or the like to give a preparation for oral administration.

[3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation, orally rapid disintegrating agent may be a solid preparation such as a tablet, or an oral mucous membrane adhesive tablet ( the film)
May be As the sublingual tablet, buccal or buccal disintegrant, a formulation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, an auxiliary agent such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer and a stabilizer may be contained. In addition, in order to facilitate absorption and increase bioavailability, β-cyclodextrin or β-cyclodextrin derivative (eg, hydroxypropyl-β
-Cyclodextrin, etc.) and the like. Examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Examples of the isotonicity agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, with mannitol being particularly preferred. As a hydrophilic carrier, crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid,
Examples thereof include swelling hydrophilic carriers such as dicalcium phosphate and calcium carbonate, and crystalline cellulose (eg, microcrystalline cellulose) is particularly preferable. Examples of the water-dispersible polymer include gum (eg, tragacanth gum, acacia gum, guar gum), alginate (eg, sodium alginate), cellulose derivative (eg, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose), gelatin. , Water-soluble starch, polyacrylic acid (eg carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, alginate , Gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferred. As the stabilizer, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine,
Examples thereof include sodium sulfite, and citric acid and ascorbic acid are particularly preferable.

Sublingual tablets, buccal or buccal disintegrants are
It can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
Furthermore, if desired, the above-mentioned lubricant, isotonicity agent, hydrophilic carrier, water-dispersible polymer, stabilizer, colorant, sweetener,
You may mix auxiliary agents, such as a preservative. Sublingual tablets, buccal tablets, or rapidly disintegrating buccal tablets can be obtained by mixing the above components at the same time or with a time lag and compression molding. In order to obtain an appropriate hardness, it may be produced by moistening / wetting with a solvent such as water or alcohol as needed before and after the tableting process, followed by molding and drying. When forming into a mucous membrane-attached tablet (film), the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipient, etc. are dissolved in a solvent such as water. And cast the resulting solution (cast)
The film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, a sweetener and the like may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film an appropriate elasticity, and bioadhesive polymers (eg, polycarbophil, carbopol) to enhance adhesion of the film to the mucosal lining of the oral cavity. May be. Casting is performed by pouring the solution onto a non-adhesive surface and applying a uniform thickness (preferably 10 to 1000) with a coating tool such as a doctor blade.
This is accomplished by spreading it to the micron range) and then drying the solution to form a film. The film thus formed may be dried at room temperature or under heating and cut into a desired surface area. As a preferable intraoral quick disintegrating agent, solid rapid diffusion administration consisting of a network of the compound of the present invention or the concomitant drug and a water-soluble or water-diffusible carrier which is inactive with the compound of the present invention or the concomitant drug Agents. The reticulate body is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or a concomitant drug in a suitable solvent. It is preferable that, in addition to the compound of the present invention or the concomitant drug, the composition of the quick disintegrating agent in the oral cavity contains a matrix forming agent and a secondary component. Examples of the matrix-forming agent include gelatins, dextrins, animal proteins such as soybeans, wheat and psyllium seed proteins or vegetable proteins; gum substances such as gum arabic, guar gum, agar and xanthan; polysaccharides. Alginic acids; Carboxymethyl celluloses; Carrageenans; Dextranes; Pectins; Synthetic polymers such as polyvinylpyrrolidone; Substances derived from gelatin-Arabic gum complex; Further, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and amino acids having 2 to 12 carbon atoms such as L-phenylalanine are included. One or more matrix forming agents may be introduced into the solution or suspension prior to solidification. Such a matrix forming agent may be present in addition to the surfactant, or the surfactant may be excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusional state of the compound of the present invention or the concomitant drug in its solution or suspension.

The composition may contain secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavors, sweeteners or taste masking agents. Suitable colorants include red, black and yellow iron oxides and FD & Eberd & Eberard FD &
FD such as C Blue No. 2 and FD & C Red No. 40
& C dye. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations thereof. Suitable pH
Modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbent materials and microencapsulated apomorphine. The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound of the present invention or the concomitant drug, and the period of about 1 minute to about 60 minutes, preferably about 1 minute. Minutes to about 15 minutes, more preferably about 2 minutes to
A formulation capable of dissolving 90% or more of the compound of the present invention or a concomitant drug (in water) in about 5 minutes (the above-mentioned sublingual tablet, buccal, etc.) or about 1 to 1 when placed in the oral cavity An intraoral quick disintegrating agent that disintegrates within about 60 seconds, preferably within about 1 to about 30 seconds, more preferably within about 1 to about 10 seconds is preferred. The content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the isotonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 1
0 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10%.
Is about 30% by weight. The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1
Is about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent and a preservative, if necessary.

The dose of the concomitant drug of the present invention varies depending on the kind, age, body weight, symptom, dosage form, administration method, administration period and the like of the compound of the present invention. ) Per person, as a compound of the present invention and a concomitant drug, usually about 0.01 to about 100 each day.
0 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / Kg is intravenously administered once to several times a day. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.
It is possible to set any amount of the concomitant drug as long as side effects do not pose a problem. The daily dose as a concomitant drug depends on the degree of symptoms, age of the subject, sex, body weight,
Sensitivity difference, timing of administration, interval, properties of pharmaceutical preparation, preparation,
It depends on the type, the type of active ingredient, etc., and is not particularly limited, but the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration,
The amount is preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg, and this is usually administered in 1 to 4 divided doses per day. When the concomitant drug of the present invention is administered, it may be administered at the same time, but the compound of the present invention may be administered after the concomitant drug is administered first, or the compound of the present invention may be administered first. However, the concomitant drug may be administered thereafter. When administered at a time lag, the time lag varies depending on the active ingredient to be administered, the dosage form, and the method of administration. The method includes administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, within 1 minute to 1 day after the administration of the compound of the present invention,
Preferably, the concomitant drug is administered within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour.

[0086]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further described in detail by the following Reference Examples, Examples, Formulation Examples and Test Examples.
These examples are merely implementations, are not intended to limit the invention, and may vary without departing from the scope of the invention. "Room temperature" in the following Reference Examples and Examples usually indicates about 10 ° C to about 35 ° C. %, Yield is mol /
mol% and others indicate weight%. The basic silica gel is NH-DM102 manufactured by Fuji Silysia Chemical Ltd.
0 was used. OH and NH in proton NMR spectrum
Those that cannot be confirmed by broadening such as proton are not described in the data. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz (hertz) Hertz) CDCl ₃ : Deuterated chloroform DMSO-d ₆ : Deuterated dimethyl sulfoxide ¹ H NMR: Proton Nuclear magnetic resonance

Transformant Escherichia coli BL21 / pPD obtained in Test Example 1 described later
E4D3 has been deposited with the deposit number F at the Institute of Biotechnology, National Institute of Advanced Industrial Science and Technology (NIBH) since March 8, 2000.
ERM BP-7075 as deposit number IFO to the Foundation / Fermentation Research Institute (IFO) from February 24, 2000
Deposited as 16383. The gene manipulation method using Escherichia coli followed the method described in Molecular Cloning. The sequence numbers in the sequence listing in this specification show the following sequences. [SEQ ID NO: 1] This shows the base sequence of the primer used in Test Example 1. [SEQ ID NO: 2] This shows the base sequence of the primer used in Test Example 1. [SEQ ID NO: 3] Escherichia coli (Escheric) obtained in Test Example 1
hia coli) cDNA carried by BL21 / pPDE4D3
The base sequence of A is shown. [SEQ ID NO: 4] Escherichia coli (Escheric) obtained in Test Example 1
hia coli) cDNA carried by BL21 / pPDE4D3
The amino acid sequence encoded by the nucleotide sequence of A is shown.

[0088]

Examples Reference Example 1 Benzoic acid 5-bromo-2-methoxyphenyl ester guaiacol (125 g, 1.01 mol) pyridine (300 mL)
The solution was ice-cooled, and benzoyl chloride (149
g, 1.06 mol) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, 2 M hydrochloric acid (twice), and water, and concentrated to give benzoic acid 2-methoxyphenyl ester (234 g) as a solid. 229 g of this acetic acid
Dissolve in (700 mL) and bromine (176 g, 1.10 mol) at 15 ° C.
Solution of acetic acid (100 mL) was added dropwise over 1.5 hours at room temperature.
It was stirred for 15.5 hours. Bromine (24 g, 0.1
A 5 mol) acetic acid (10 mL) solution was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated under reduced pressure to give the title compound (267 g, yield 89%).
Got Melting point 74-78 ° C. ¹ H NMR (CDCl ₃ ) δ 3.80 (3H, s), 6.89 (1H, d, J = 8.
6 Hz), 7.32 (1H, d, J = 2.5 Hz), 7.36 (1H, dd, J =
8.6, 2.5 Hz), 7.46-7.56 (2H, m), 7.59-7.70 (1H, m),
8.16-8.24 (2H, m).

Reference Example 2 5-bromo-2-methoxyphenol benzoic acid 5-bromo-2-methoxyphenyl ester (261
g, 0.850 mol) in tetrahydrofuran (100 mL) / methanol (100 mL) suspension in 5 M aqueous sodium hydroxide solution.
(350 mL, 1.75 mol) was added, and the mixture was stirred at room temperature for 1 hr.
The reaction mixture was acidified with 2 M hydrochloric acid (500 mL, 1.00 mol), and sodium hydrogencarbonate (10 g, 0.12 mol) was added to neutralize the mixture. The resulting mixture was ethyl acetate / hexane (1: 1)
The mixture was extracted twice. The combined organic layers were washed with water and concentrated under reduced pressure. The residue was recrystallized from hexane to give the title compound (14
8 g, yield 86%) was obtained. Melting point 66-67 ° C. ¹ H NMR (CDCl ₃ ) δ 3.88 (3H, s), 5.65 (1H, br s), 6.
71 (1H, d, J = 8.5 Hz), 6.97 (1H, dd, J = 8.5, 2.5
Hz), 7.07 (1H, d, J = 2.5 Hz).

Reference Example 3 2,3-Dihydro-7-methoxy-2,2-dimethyl-4-benzofurancarboxaldehyde 5-bromo-2-methoxyphenol (102 g, 0.502 mol)
3-chloro-2-methyl-1-propene (55 mL, 0.56 mol) and potassium carbonate (83.3 g, 0.603 mol) were added to the N, N-dimethylformamide (400 mL) solution of, and the mixture was heated at 75 ° C under a nitrogen atmosphere at 75 ° C. Stir for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with a hexane / ethyl acetate (1: 1) mixed solution. The combined organic layers were washed twice with water, treated with activated carbon, filtered, and concentrated under reduced pressure to give 4-bromo-1-methoxy-2-[(2-methyl-2
-Propenyl) oxy] benzene (130 g) was obtained as an oil. This was dissolved in N, N-diethylaniline (100 mL) and stirred under a nitrogen atmosphere at 200 ° C. for 5.5 hours. The reaction mixture was dissolved in diisopropyl ether and treated with 1 M hydrochloric acid (2
Washed with water, treated with activated carbon, filtered, and concentrated under reduced pressure.
3-Bromo-6-methoxy-2- (2-methyl-2-propenyl) phenol (129 g) was obtained as an oil. Dissolve this in ethanol (200 mL) and use concentrated hydrochloric acid (50 mL) in ethanol.
(50 mL) solution was added, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was concentrated under reduced pressure, hexane was added, and the aqueous layer was separated. The organic layer is washed with water, 1 M aqueous sodium hydroxide solution (3 times), water, treated with activated carbon, filtered, and concentrated under reduced pressure to give 4-bromo-2,3-.
Dihydro-7-methoxy-2,2-dimethylbenzofuran (113
g) was obtained as an oil. This 1.37 g was dissolved in tetrahydrofuran (15 mL), cooled to -78 ° C under a nitrogen atmosphere, and 1.6 M n-butyllithium / hexane solution (4.0 mL,
6.4 mmol) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes. N, N-dimethylformamide (1.2 mL, 15 mmo
l) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane / ethyl acetate 20: 1)
After recrystallization from ethyl acetate-hexane, the title compound (741 mg, yield 59%) was obtained. Melting point 89-90 ° C. ¹ H NMR (CDCl ₃ ) δ1.54 (6H, s), 3.39 (2H, s), 3.96
(3H, s), 6.88 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J =
8.4 Hz), 9.90 (1H, s).

Reference Example 4 2,3-Dihydro-7-methoxy-2,2-dimethyl-4- (2-methyl-1)
-Propenyl) benzofuran 2,3-dihydro-7-methoxy-2,2-dimethyl-4-benzofurancarboxaldehyde (10.4 g, 50.4 mmol) and isopropyltriphenylphosphonium iodide (23.8 g,
55.1 mmol) in tetrahydrofuran (100 mL) suspension with sodium hydride (66% oil dispersion) (1.99 g, 55 mmol).
Was added and the mixture was heated under reflux for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate.
The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane / ethyl acetate (4: 1) mixture was added to the residue,
The insoluble material was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (after hexane / ethyl acetate 100: 1).
It was subjected to 10: 1) to give the title compound (11.0 g, yield 94%). Oil. ¹ H NMR (CDCl ₃ ) δ1.51 (6H, s), 1.81 (3H, d, J = 1.
1 Hz), 1.87 (3H, d, J = 1.1 Hz), 2.94 (2H, s), 3.86
(3H, s), 6.03 (1H, s), 6.70 (2H, s).

Example 1 1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline 2,3-dihydro-7- Methoxy-2,2-dimethyl-4- (2-methyl-1)
-Propenyl) benzofuran (2.09 g, 9.00 mmol) and benzonitrile (1.21 g, 11.7 mmol) in acetic acid (3 mL)
Concentrated sulfuric acid (1.2 mL) was added dropwise to the solution at 10 ° C, and the solution was added at the same temperature for 30
Stir for minutes. The reaction mixture was poured into ice water and washed with diisopropyl ether. The aqueous layer was basified with 5 M aqueous sodium hydroxide solution and extracted twice with a tetrahydrofuran / diisopropyl ether (1: 1) mixture. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound.
(1.37 g, yield 45%) was obtained. Melting point 128-129 ° C. ¹ H NMR (CDCl ₃ ) δ 1.28 (6H, s), 1.57 (6H, s), 2.59
(2H, s), 3.01 (2H, s), 3.69 (3H, s), 6.62 (1H, s),
7.36-7.45 (3H, m), 7.49-7.60 (2H, m).

Example 2 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinolin-4-ol 1,2,8,9- Tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline (3.70 g, 11.0
A 48% hydrobromic acid (25 mL) solution of (mmol) was heated under reflux for 13 hours. After cooling, the reaction mixture was neutralized with concentrated aqueous ammonia and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The precipitated crystals were washed with diisopropyl ether and recrystallized from ethanol-ethyl acetate to give the title compound (2.17 g, yield 61%). Softening point 187 ° C. ¹ H NMR (CDCl ₃ ) δ 1.25 (6H, s), 1.54 (6H, s), 2.53
(2H, s), 3.00 (2H, s), 6.56 (1H, s), 7.30-7.33 (3H,
m), 7.43-7.50 (2H, m).

Example 3 4-Ethoxy-1,2,8,9-tetrahydro-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline 1,2,8,9- Tetrahydro-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinolin-4-ol (638 mg, 1.99 m
mol) in N, N-dimethylformamide (6 mL) was added iodoethane (0.19 mL, 2.4 mmol) and sodium hydride (66% oil dispersion) (87 mg, 2.4 mmol) at room temperature.
Stir for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate,
It was filtered and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 20: 1 followed by 1
0: 1) and crystallized from hexane to give the title compound (4
(65 mg, yield 67%) was obtained. Melting point 120-122 ° C. ¹ H NMR (CDCl ₃ ) δ 1.29 (6H, s), 1.32 (3H, t, J = 7.
0 Hz), 1.57 (6H, s), 2.60 (2H, s), 3.00 (2H, s),
3.93 (2H, q, J = 7.0 Hz), 6.63 (1H, s), 7.39-7.42
(3H, m), 7.52-7.57 (2H, m).

Example 4 3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) benzenamine N A suspension of-(3-cyanophenyl) -2,2,2-trifluoroacetamide (5.89 g, 27.5 mmol) in toluene (25 mL) and acetic acid (12 mL) was cooled with ice and concentrated sulfuric acid (3.0 mL). , Then
2,3-dihydro-7-methoxy-2,2-dimethyl-4- (2-methyl-
A solution of 1-propenyl) benzofuran (5.81 g, 25.0 mmol) in toluene (25 mL) was added dropwise, and the mixture was stirred at 80 ° C for 1 hr.
Ethanol (20 mL) was added dropwise to the obtained mixture at the same temperature, and the mixture was stirred for 1 hr. The reaction mixture was ice-cooled, water was added,
It was neutralized with concentrated aqueous ammonia and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was suspended in ethanol (30 mL), 2 M aqueous sodium hydroxide solution (30 mL, 60 mmol) was added, and the mixture was heated under reflux for 1 hr.
The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 3: 1 followed by 1: 1) and crystallized from ethyl acetate-hexane to give the title compound (4.47 g, yield 51%). Melting point 163-165 ° C. ¹ H NMR (CDCl ₃ ) δ 1.26 (6H, s), 1.56 (6H, s), 2.58
(2H, s), 3.00 (2H, s), 3.20-4.00 (2H, br), 3.71 (3
H, s), 6.68-6.76 (1H, m), 6.69 (1H, s), 6.84-6.92
(2H, m), 7.17 (1H, t, J = 7.7 Hz).

Example 5 N- [3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) Phenyl] -4
-Pyridinecarboxamide 3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) benzenamine (701 mg, 2.00 mmol) and 4-dimethylaminopyridine (611 mg, 5.00 mmol) in N, N-dimethylformamide (10 mL) were added to isonicotinoyl chloride hydrochloride (7 mL).
12 mg, 4.00 mmol) was added, and the mixture was stirred at room temperature for 20 minutes.
Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was recrystallized from ethanol-diethyl ether to give the title compound (800 mg, yield 8
8%). Melting point 247-249 ° C. ¹ H NMR (CDCl ₃ ) δ1.21 (6H, s), 1.57 (6H, s), 2.51
(2H, s), 3.00 (2H, s), 3.73 (3H, s), 6.68 (1H, s),
7.25-7.33 (1H, m), 7.42 (1H, t, J = 7.9 Hz), 7.66
(2H, d, J = 6.2 Hz), 7.74 (1H, t, J = 1.7 Hz), 7.9
0-7.98 (1H, m), 8.73 (1H, br s), 8.76 (2H, d, J =
6.2 Hz).

Example 6 N- [3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) Phenyl] methanesulfonamide 3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) benzenamine (2.11 g, 6.02 mmol) in pyridine (15 mL),
Methanesulfonyl chloride (0.51 mL, 6.6 mmol) under ice cooling
Was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was dissolved in toluene, concentrated under reduced pressure, and crystallized from ethyl acetate-diethyl ether to give the title compound (2.28 g, yield 88%). Melting point 211-215 ° C. ¹ H NMR (CDCl ₃ ) δ1.34 (6H, s), 1.58 (6H, s), 2.60-
2.81 (5H, m), 3.02 (2H, s), 3.73 (3H, s), 6.66 (1
H, s), 7.21-7.44 (3H, m), 7.53 (1H, br s).

Example 7 3-[(Methylsulfonyl) [3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline)
-6-Yyl) phenyl] amino] propanesulfonamide 3-chloro-1-propanesulfonamide (788 mg, 5.00 mm
ol) in toluene (10 mL) was added with N, N-dimethylformamide dimethyl acetal (0.73 mL, 5.5 mmol), and the mixture was stirred at 60 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a mixture (1.15 g) containing 3-chloro-N-[(dimethylamino) methylene] -1-propanesulfonamide. 600 mg of this mixture, N- [3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline-6
-Yl) phenyl] methanesulfonamide (806 mg, 1.88
mmol) and sodium iodide (282 mg, 1.88 mmol)
Sodium hydride (66% oil dispersion) (89 mg, 2.4 mmol) was added to the N, N-dimethylformamide (4 mL) suspension of, and the mixture was stirred at room temperature for 10 minutes and at 80 ° C for 4 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 1: 1 followed by ethyl acetate) to give N-[(dimethylamino) methylene] -3-[(methylsulfonyl) [3- (1,2,8 , 9-Tetrahydro-4-methoxy-2,2,8,8
-Tetramethylfuro [3,2-f] isoquinolin-6-yl) phenyl] amino] propanesulfonamide (1.05 g) was obtained as an amorphous substance. This was dissolved in 2 M hydrochloric acid and heated under reflux for 40 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is ethyl acetate
Crystallization from hexane gave the title compound (820 mg, yield 79
%) Melting point 165-167 ° C. ¹ H NMR (CDCl ₃ ) δ 1.29 (6H, s), 1.57 (6H, s), 1.89-
2.05 (2H, m), 2.59 (2H, s), 2.96 (3H, s), 3.01 (2
H, s), 3.21 (2H, t, J = 7.3 Hz), 3.73 (3H, s), 3.9
1 (2H, t, J = 6.6 Hz), 5.38 (2H, br s), 6.62 (1H,
s), 7.39-7.56 (3H, m), 7.57-7.61 (1H, m).

Example 8 6- (3-Bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline 3- Bromobenzonitrile (4.47 g, 24.6 mmol) and
2,3-dihydro-7-methoxy-2,2-dimethyl-4- (2-methyl-1
A solution of -propenyl) benzofuran (5.70 g, 24.5 mmol) in toluene (20 mL) was heated to 85 ° C and concentrated sulfuric acid (3.0 m
L, 56 mmol) in acetic acid (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture and washed with diisopropyl ether. The organic layer was extracted with 2 M hydrochloric acid. The combined aqueous layers were ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10: 1) and crystallized from hexane to give the title compound (2.88 g, yield 28%). Melting point 128-130 ° C. ¹ H NMR (CDCl ₃ ) δ 1.27 (6H, s), 1.57 (6H, s), 2.58
(2H, s), 3.01 (2H, s), 3.71 (3H, s), 6.56 (1H, s),
7.27 (1H, t, J = 7.8 Hz), 7.46 (1H, dt, J = 7.8, 1.
3 Hz), 7.54 (1H, ddd, J = 7.8, 2.0, 1.1 Hz), 7.72
(1H, t, J = 1.7 Hz).

Example 9 1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6- [3- (4-pyridinyl) phenyl] furo [3,2-f ] Isoquinoline 6- (3-Bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline (3.
34 g, 8.06 mmol) and 4-pyridinylboronic acid (1.49
g, 12.1 mmol) N, N-dimethylformamide (20 mL)
Sodium carbonate (1.41 g, 13.3 mmol) in water was added to the suspension.
(10 mL) solution and tetrakis (triphenylphosphine) palladium (0) (466 mg, 0.403 mmol) were added, and the mixture was stirred at 120 ° C for 6 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10: 1 followed by 2: 1) and crystallized from ethyl acetate-hexane to give the title compound (1.95 g, yield 59%). Melting point 125-127 ° C. ¹ H NMR (CDCl ₃ ) δ1.30 (6H, s), 1.58 (6H, s), 2.62
(2H, s), 3.03 (2H, s), 3.69 (3H, s), 6.62 (1H, s),
7.48-7.57 (1H, m), 7.55 (2H, d, J = 6.2 Hz), 7.61
(1H, dt, J = 7.6, 1.7 Hz), 7.69 (1H, dt, J = 7.4,
1.7 Hz), 7.83 (1H, t, J = 1.7 Hz), 8.66 (2H, d, J
= 6.2 Hz).

Example 10 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-6- [3- (4-
Pyridinyl) phenyl] furo [3,2-f] isoquinolin-4-ol 1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6- [3- (4- Pyridinyl) phenyl] furo [3,2-f] isoquinoline (1.11 g, 2.69 mmol) in 48% hydrobromic acid (13 mL)
Was added, and the mixture was stirred at 105 ° C for 17 hours. The reaction mixture was ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with a mixed solution of ethyl acetate-tetrahydrofuran. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol-diethyl ether to give the title compound (766
mg, yield 71%) was obtained. Melting point 221-223 ° C. ¹ H NMR (CDCl ₃ ) δ 1.29 (6H, s), 1.56 (6H, s), 2.59
(2H, s), 3.02 (2H, s), 6.60 (1H, s), 7.35 (2H, d, J
= 6.2 Hz), 7.45-7.54 (1H, m), 7.57-7.68 (3H, m),
8.44 (2H, d, J = 6.2 Hz).

Example 11 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-4- [2- (2-
Pyridinyl) ethoxy] -6- [3- (4-pyridinyl) phenyl]
Furo [3,2-f] isoquinoline 1,2,8,9-tetrahydro-2,2,8,8-tetramethyl-6- [3- (4-
Pyridinyl) phenyl] furo [3,2-f] isoquinolin-4-ol (598 mg, 1.50 mmol), 2- (2-hydroxyethyl) pyridine (277 mg, 2.25 mmol) and triphenylphosphine (787 mg, 3.00 tetrahydrofuran) (6 m)
L) Diisopropyl azodicarboxylate in solution under ice cooling
(0.59 mL, 3.0 mmol) was added dropwise at room temperature for 30 minutes at 60 ° C.
It was stirred for 1 hour. To the resulting mixture was added 2- (2-hydroxyethyl) pyridine (0.17 mL, 1.5 mmol), triphenylphosphine (394 mg, 1.50 mmol) and diisopropyl azodicarboxylate (0.30 mL, 1.5 mmol), and 6
The mixture was stirred at 0 ° C for 1.5 hours. The reaction mixture was ice-cooled, 1 M
It was acidified with hydrochloric acid and washed twice with ethyl acetate. The aqueous layer was neutralized with concentrated aqueous ammonia and extracted twice with ethyl acetate. The combined organic layers were washed with 1 M aqueous sodium hydroxide solution (twice) and water, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10:
1, 5: 1, 3: 1 followed by 1: 1) and recrystallized from diethyl ether-hexane to give the title compound (348 mg, yield 46%).
Got Melting point 110-113 ° C. ¹ H NMR (CDCl ₃ ) δ 1.29 (6H, s), 1.56 (6H, s), 2.60
(2H, s), 3.00 (2H, s), 3.17 (2H, t, J = 7.0 Hz), 4.
28 (2H, t, J = 7.0 Hz), 6.66 (1H, s), 7.06 (1H, dd
d, J = 7.6, 4.9, 1.2 Hz), 7.11-7.17 (1H, m), 7.45-
7.61 (5H, m), 7.67 (1H, dt, J = 7.0, 1.9 Hz), 7.78
-7.81 (1H, m), 8.45 (1H, ddd, J = 5.0, 1.9, 0.9 H
z), 8.63 (2H, d, J = 6.2 Hz).

Example 12 N- [3 '-(1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl ) [1,1'-Biphenyl] -4-yl] acetamide 6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [ 3,2-f] isoquinoline (20
7 mg, 0.500 mmol), 4 '-(4,4,5,5-tetramethyl-1,3,2-
Dioxaborolan-2-yl) acetanilide (144 mg, 0.
551 mmol), sodium carbonate (133 mg, 1.25 mmol) and tetrakis (triphenylphosphine) palladium (0)
(12 mg, 0.010 mmol) 1,2-dimethoxyethane (1.5 m
A suspension of L), ethanol (0.8 mL) and water (0.8 mL) was stirred under a nitrogen atmosphere at 85 ° C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate-basic silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (218 mg, yield 93%). Melting point 231-234 ° C. ¹ H NMR (CDCl ₃ ) δ1.31 (6H, s), 1.58 (6H, s), 2.13
(3H, s), 2.63 (2H, s), 3.03 (2H, s), 3.69 (3H, s),
6.67 (1H, s), 7.40-7.61 (7H, m), 7.68-7.76 (2H,
m).

Example 13 6- (3-Bromophenyl) -1,2,8,9-tetrahydro-2,2,8,8-
Tetramethylfuro [3,2-f] isoquinolin-4-ol 6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [ 3,2-f] isoquinoline (2.
48 g of hydrobromic acid (30 mL) was added to 08 g (5.02 mmol), and the mixture was stirred at 105 ° C. for 14.5 hours. The reaction mixture was ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with chloroform. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (1.09 g, yield 54%). Melting point 236-239 ° C. ¹ H NMR (CDCl ₃ ) δ1.24 (6H, s), 1.54 (6H, s), 2.54
(2H, s), 3.00 (2H, s), 5.60-5.80 (1H, br), 6.50 (1
H, s), 7.19 (1H, t, J = 7.8 Hz), 7.33-7.38 (1H,
m), 7.43-7.48 (1H, m), 7.61 (1H, t, J = 1.7 Hz).

Example 14 N- [3 '-(1,2,8,9-tetrahydro-4-hydroxy-2,2,8,8-
Tetramethylfuro [3,2-f] isoquinolin-6-yl) [1,1'-
Biphenyl] -4-yl] acetamide 6- (3-bromophenyl) -1,2,8,9-tetrahydro-2,2,8,8-
Tetramethylfuro [3,2-f] isoquinolin-4-ol (1.00
g, 2.50 mmol), 4 '-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acetanilide (718 mg, 2.75
mmol), sodium carbonate (662 mg, 6.25 mmol) and tetrakis (triphenylphosphine) palladium (0) (5
8 mg, 0.050 mmol) 1,2-dimethoxyethane (12 m
A suspension of L), ethanol (6 mL) and water (6 mL) was stirred at 85 ° C for 21 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate-basic silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (1.12 g, yield 99%). Melting point 272-275 ° C. ¹ H NMR (DMSO-d ₆ ) δ1.17 (6H, s), 1.46 (6H, s), 2.0
6 (3H, s), 2.52 (2H, s), 2.99 (2H, s), 6.58 (1H,
s), 7.37-7.44 (1H, m), 7.51 (1H, t, J = 7.7 Hz),
7.59-7.72 (6H, m), 9.03 (1H, s), 10.04 (1H, s).

Example 15 Trifluoromethanesulfonic acid 6- [4 '-(acetylamino)
[1,1'-Biphenyl] -3-yl] -1,2,8,9-tetrahydro-2,
2,8,8-Tetramethylfuro [3,2-f] isoquinolin-4-yl ester N- [3 '-(1,2,8,9-tetrahydro-4-hydroxy-2,2,8,8 -
Tetramethylfuro [3,2-f] isoquinolin-6-yl) [1,1'-
Biphenyl] -4-yl] acetamide (546 mg, 1.20 mmo
To a solution of l) in pyridine (6 mL) was added dropwise trifluoromethanesulfonic anhydride (0.51 mL, 3.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 5: 1, 2: 1 followed by 1: 1), and crystallized from ethyl acetate-hexane to give the title compound (595 mg,
The yield was 85%). Melting point 233-235 ° C. ¹ H NMR (CDCl ₃ ) δ1.31 (6H, s), 1.58 (6H, s), 2.18
(3H, s), 2.65 (2H, s), 3.07 (2H, s), 7.02 (1H, s),
7.32 (1H, br s), 7.34-7.51 (2H, m), 7.57 (4H, s),
7.60-7.65 (1H, m), 7.69-7.71 (1H, m).

Example 16 N- [3 '-(1,2,8,9-tetrahydro-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) [1, 1'-biphenyl] -4-
Ile] acetamide trifluoromethanesulfonic acid 6- [4 '-(acetylamino)
[1,1'-Biphenyl] -3-yl] -1,2,8,9-tetrahydro-2,
2,8,8-Tetramethylfuro [3,2-f] isoquinolin-4-yl ester (470 mg, 0.801 mmol), triethylamine (0.3
4 mL, 2.4 mmol), palladium (II) acetate (4.5 mg, 0.02
0 mmol) and triphenylphosphine (10.5 mg, 0.04
Formic acid (60 μL, 1.6 mmol) was added to a solution of (00 mmol) in N, N-dimethylformamide (1.5 mL), and the mixture was placed under a nitrogen atmosphere.
The mixture was stirred at ℃ for 4.5 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate-basic silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane /
The mixture was subjected to ethyl acetate 1: 1 and then 1: 2) and crystallized from ethyl acetate-hexane to give the title compound (340 mg, yield 97%). Melting point 140-152 ° C. ¹ H NMR (CDCl ₃ ) δ 1.31 (6H, s), 1.53 (6H, s), 2.17
(3H, s), 2.67 (2H, s), 2.99 (2H, s), 6.53 (1H, d, J
= 8.1 Hz), 7.04 (1H, d, J = 8.1 Hz), 7.40-7.49 (3
H, m), 7.54 (4H, s), 7.55-7.62 (1H, m), 7.66-7.69
(1H, m).

The compounds prepared in the above examples are shown in Table 1 below.

[Table 1]

Formulation Example 1 (1) Compound of Example 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Example 1 Using a mixture of 10.0 mg of the compound obtained in 1), 60.0 mg of lactose and 35.0 mg of corn starch in 0.03 ml of 10% aqueous gelatin solution (3.0 mg as gelatin),
After granulating through a 1 mm mesh sieve, it was dried at 40 ° C. and sieved again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The obtained central tablets were coated with sugar coating with a suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets. Formulation Example 2 (1) Compound of Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Obtained in Example 1 10.0 mg of the obtained compound and 3.0 mg of magnesium stearate, 0.07 ml of an aqueous solution of soluble starch
After granulating (7.0 mg as soluble starch) it was dried and mixed with 70.0 mg lactose and 50.0 mg corn starch. The mixture was compressed to give tablets. Formulation Example 3 (1) Compound of Example 1 5.0 mg (2) Salt 20.0 mg (3) Distilled water 5.0 mg obtained in Example 1 and total salt 2 ml and salt 20.0 mg
Was dissolved in distilled water, and water was added to make the total amount 2.0 ml.
The solution was filtered and filled under aseptic conditions into 2 ml ampoules. The ampoule was sterilized and then sealed to obtain a solution for injection.

Formulation Example 4 1500 g of the compound obtained in Example 1, 2025 g of lactose and 556.5 g of corn starch were uniformly mixed in a fluidized bed granulation dryer (FD-5S, Powrex Co., Ltd.), and then the mixture was kept in the machine. An aqueous solution in which 126 g of hydroxypropyl cellulose was dissolved was sprayed to granulate, and then dried in a fluidized bed granulation dryer. The obtained granulated product was crushed using a power mill with a punching screen having a diameter of 1.5 mm to obtain a sized powder. Take 3927 g of this sized powder, add 210 g of croscarmellose sodium and 63 g of magnesium stearate, and mix with a tumbler mixer to give granules for tableting. The granules have a diameter of 6.5 with a tablet machine.
A plain tablet was obtained by tableting at a weight of 300 mg using a mm 2 frame.
The obtained uncoated tablets were hydroxypropylmethylcellulose 2910 (TC-5) in a Doria coater coating machine.
Then, Macrogol 6000 was dissolved and a liquid in which titanium oxide and ferric sesquioxide were dispersed was sprayed to obtain about 13500 tablets, a film tablet of the following formulation containing 100 mg per tablet. Tablet formulation: Composition Compound amount (mg) (1) Compound of Example 1 100.0 (2) Lactose 135.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxy Propyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 (3 ) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 5 The compound obtained in Example 1 was prepared according to the method described in Formulation Example 4. About 13500 film tablets of the following formulation containing 25 mg per tablet were obtained. Tablet formulation: Composition Compounding amount (mg) (1) Compound of Example 1 25.0 (2) Lactose 210.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxy Propyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 (3 ) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0

Formulation Example 6 According to the method described in Formulation Example 4, about 13500 film tablets of the following formulation containing 5 mg each of the compound obtained in Example 1 were obtained. Tablet formulation: Composition Compound amount (mg) (1) Compound of Example 1 5.0 (2) Lactose 230.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxy Propyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 (3 ) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 7 The compound obtained in Example 1 was prepared according to the method described in Formulation Example 4. About 13500 film tablets of the following formulation containing 1 mg per tablet were obtained. Tablet formulation: Composition Compounding amount (mg) (1) Compound of Example 1 1.0 (2) Lactose 234.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxy Propyl cellulose 8.4 (6) Magnesium stearate 4.5 Total (naked tablet) 300.0 Film tablet formulation: (1) Naked tablet 300.0 (film component) (2) Hydroxypropyl methylcellulose 2910 7.485 (3 ) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 8 White petrolatum 40 g Cetanol 10 g Salami beeswax 5 g Sorbitan sesquioleate 5 g Lauromoclogold 0.5 g Methyl paraoxybenzoate 0.1 g Propyl paraoxybenzoate 0.1 g Purified water Appropriate amount Pharmacopoeial ointment of the above composition ( 00g) in advance 70
A solution obtained by heating 1 ° C of the compound obtained in Example 1 in 20 ml of methanol and heating the solution was added to the solution. The mixture was heated and mixed at the same temperature for 10 minutes to remove residual methanol, and cooled to room temperature to obtain a water-absorbing ointment.

Test Example 1 Measurement of PDE IV inhibitory action (1) Claw of gene encoding human brain-derived PDE 4D3
Training PDE 4D3 from human brain cDNA library by PCR
The encoding gene was cloned. 1ng brain Q
UICK-Clone^TMNem using cDNA (Clontech) as a template
oz et al. reported (FEBS Letters 384, 97-102 (1996))
Primer prepared with reference to the existing PDE 4D3 gene nucleotide sequence
-Set: 5'-ccacgatagctgctcaaacaagag-3 '(SEQ ID NO:
No. 1) and 5'-atagaaaccccaagtccaataaac-3 '(SEQ ID NO:
No .: 2), 20 pmol each, and TaKaRa EX Taq
(Takara Shuzo), PCR reaction using MiniCycler^TM(MJ
 RESERCH) (reaction conditions: 94 ° C for 0.5 minutes)
For 30 minutes at 55 ° C for 0.5 minutes and 72 ° C for 4 minutes
Le). The PCR product was subjected to agarose gel electrophoresis,
A 2.4 kb DNA fragment was recovered. The fragment is PfuDNA
After smoothing with polymerase (STRATAGENE), Zero Blunt P
Using the CR Cloning Kit (Invitrogen), PDE 4D3 remains
The gene was cloned. (2) Construction of E. coli expression vector The plasmid obtained in (1) above was transformed with the restriction enzyme EcoRI.
(Takara Shuzo) and then agarose gel electrophoresis
A DNA fragment of about 2.4 kb was recovered. The DNA fragment
After digesting the enzyme with the restriction enzyme EcoRI (Takara Shuzo), BAP (Takara Shuzo)
Brewing) treated pGEX4T-3 (Pharmacia)
I ligated. The obtained cDNA fragment has the sequence number
No .: 3 has a base sequence represented by
Represented by SEQ ID NO: 4 at positions 74 to 2092 in the column
The encoded amino acid sequence is encoded
Was found (FIGS. 1 to 3). This cDNA fragment is
E. coli BL21 (Funakoshi Co., Ltd.)
Escherichia coli transformed with Escherichia coli (Escherichia coli) expressing the PDE 4D3 gene
ia coli) BL21 / pPDE4D3 was obtained. (3) Expression of recombinant human brain-derived PDE 4D3 in E. coli and
Refining E. coli BL21 / pPDE4D3 obtained in (2) above
Was used to obtain recombinant human brain-derived PDE 4D3. Big
Expression and purification in Enterobacter is by GST Gene Fusio
n System (Pharmacia) attached protocol
It was carried out according to Le. As a result, the target set of about 76 kDa
Replaced human brain-derived PDE 4D3 from 1 L of E. coli culture
I was able to obtain 4 mg. (4) Measurement of PDE IV inhibitory action For 96-well plate (OPTI plate, Packard)
Buffer solution [0.5 M Tris-HCl (pH 7.5),
83 mM MgCl_Two, 17 mM EGTA] 10μ
1. Recombinant human brain-derived PDE 4D3 obtained in (1) above
(0.0034 mg / ml) 10 μl, ultrapure water 65 μ
l, 5 μl of inhibitor sample, [^ThreeH] cAMP 10 μl
Was added and reacted at 30 ° C. for 30 minutes. After the reaction,
SPA beads solution [18mg / ml Yttrium sili
cate beads, 18mM ZnSO_Four] 50 μl was added,
After leaving at room temperature for about 20 minutes, scintillation cow
Measurement (Topcount, Packard)
Decided Radioactivity (1020 cpm) without addition
In contrast, when recombinant human brain-derived PDE 4D3 was added,
It showed a radioactivity of 28245 cpm. Various in this reaction
Concentration of PDE IV Inhibitor Rolipram (BIOMOL Resear
ch Laboratories, Inc.)
Was inhibited and rolipram was able to induce this enzymatic reaction at about 100 nM.
50% inhibition. Using this assay system, the compounds of the present invention
Recombinant human brain-derived PDE inhibitory activity (IC _FiftyThe value
It was measured. The results are shown in Table 2.

[0113]

[Table 2]

Test Example 2 Inhibitory Effect on Antigen-induced Airway Stenosis in Guinea Pigs (1) Preparation of Rabbit Anti-Ovalbumin (OA) Serum White Rabbit (body weight about 3 kg; New Zealand White:
Kitayama Labes was immunized intramuscularly with 1.0 ml of an emulsion of 0.5 ml of 10% OA (Grade III, Sigma) solution and 0.5 ml of Freund's complete adjuvant (Wako Pure Chemical Industries). This operation was repeated once a week for a total of 4 times. Whole blood was collected one week after the final immunization. The collected blood was allowed to stand at room temperature for 1 hour or longer, and then left to stand in the refrigerating room for a whole day and night. The next day, the serum portion was collected and centrifuged (3000 rpm, 10 min), and the supernatant was stored as antiserum at -20 ° C. (2) Antigen-induced airway narrowing reaction The airway narrowing reaction was measured by a modified method of the Konzet-Rossler method. A male Hartley guinea pig weighing 400 to 500 g (Japan SLC, Shizuoka) was intravenously administered with 1.0 ml of 8 to 16 times diluted anti-OA serum under ether anesthesia and used in the experiment 16 to 24 hours later. did. Anesthetize with urethane (1.2 g / kg, ip) (manufactured by Aldrich), intubate the trachea cannula into the trachea, and in order to stop spontaneous breathing, galamine triethiodide (1 mg / kg, iv) ( Sigma) was administered. The animal breathes 70 times with an artificial respirator (Harvard model 683).
/ Min, artificial ventilation with a tidal volume of 2-3 ml and an initial load pressure of 10 cmH ₂ O, and the endotracheal pressure from the side branch of the tracheal cannula,
It was measured via a differential pressure transducer. Mepyramine maleate (1.0 mg / kg) (manufactured by Sigma) and propranolol (1.0 mg / kg) (manufactured by Sigma) were intravenously administered 2 minutes after the administration of galamine triethiodide, and further 2 minutes later, the OA antigen (1.0 (mg / kg) was intravenously administered to induce airway stenosis reaction. Example compound 1 mg / kg was dissolved in 25% dimethylacetamide, 25% polyethylene glycol 400, 50% physiological saline and intravenously administered 5 minutes before the antigen induction. Inhibition rate is the control group (25% dimethylacetamide, 25%
% Inhibition rate was calculated by comparison with a mixed solution of 40% polyethylene glycol 400 and 50% physiological saline solution intravenously).
The inhibition rates of the compounds of the present invention are shown in [Table 3].

[0115]

[Table 3]

[0116]

INDUSTRIAL APPLICABILITY The furoisoquinoline derivative of the present invention has an excellent PDE IV inhibitory action, and is effective for inflammatory diseases, asthma,
Chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease,
Depression, Alzheimer's dementia, memory impairment, diabetes,
It is useful as a prophylactic / therapeutic agent for arteriosclerosis.

[0117]

[Sequence list] <110> Takeda Chemical Industries, Ltd. <120> Furoisoquinoline Derivatives, Their Production and Use <130> B02186 <150> JP2001-190338 <151> 2001-06-22 <160> 4 <210> 1 <211> 24 <212> DNA <213> Artificial Sequence <400> 1 ccacgatagc tgctcaaaca agag 24 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <400> 2 atagaaaccc caagtccaat aaac 24 <210> 3 <211> 2435 <212> DNA <213> Human <222> (74) ... (2092) <400> 3 gaattcatct gtaaaaatca ctacatgtaa cgtaggagac aagaaaaata ttaatgacag 60 aagatctgcg aacatgatgc acgtgaataa ttttcccttt agaaggcatt cctggatatg 120 ttttgatgtg gacaatggca catctgcggg acggagtccc ttggatccca tgaccagccc 180 aggatccggg ctaattctcc aagcaaattt tgtccacagt caacgacggg agtccttcct 240 gtatcgatcc gacagcgatt atgacctctc tccaaagtct atgtcccgga actcctccat 300 tgccagtgat atacacggag atgacttgat tgtgactcca tttgctcagg tcttggccag 360 tctgcgaact gtacgaaaca actttgctgc attaactaat ttgcaagatc gagcacctag 420 caaaagatca cccatgtgca accaaccatc catcaacaaa gccaccataa cagaggaggc 480 ctaccagaaa ctggccagcg agaccctgga ggagctggac tggtgtctgg accagctaga 540 gaccctacag accaggcact ccgtcagtga gatggcctcc aacaagttta aaaggatgct 600 taatcgggag ctcacccatc tctctgaaat gagtcggtct ggaaatcaag tgtcagagtt 660 tatatcaaac acattcttag ataagcaaca tgaagtggaa attccttctc caactcagaa 720 ggaaaaggag aaaaagaaaa gaccaatgtc tcagatcagt ggagtcaaga aattgatgca 780 cagctctagt ctgactaatt caagtatccc aaggtttgga gttaaaactg aacaagaaga 840 tgtccttgcc aaggaactag aagatgtgaa caaatggggt cttcatgttt tcagaatagc 900 agagttgtct ggtaaccggc ccttgactgt tatcatgcac accatttttc aggaacggga 960 tttattaaaa acatttaaaa ttccagtaga tactttaatt acatatctta tgactctcga 1020 agaccattac catgctgatg tggcctatca caacaatatc catgctgcag atgttgtcca 1080 gtctactcat gtgctattat ctacacctgc tttggaggct gtgtttacag atttggagat 1140 tcttgcagca atttttgcca gtgcaataca tgatgtagat catcctggtg tgtccaatca 1200 atttctgatc aatacaaact ctgaacttgc cttgatgtac aatgattcct cagtcttaga 1260 gaaccatcat ttggctgtgg gctttaaatt gcttcaggaa gaaaactgtg acattttcca 1320 gaatttgacc aaaaaacaaa gacaatcttt aaggaaaatg gtcattgaca tcgtacttgc 1380 aacagatatg tcaaaacaca tgaatctact ggctgatttg aagactatgg ttgaaactaa 1440 gaaagtgaca agctctggag ttcttcttct tgataattat tccgatagga ttcaggttct 1500 tcagaatatg gtgcactgtg cagatctgag caacccaaca aagcctctcc agctgtaccg 1560 ccagtggacg gaccggataa tggaggagtt cttccgccaa ggagaccgag agagggaacg 1620 tggcatggag ataagcccca tgtgtgacaa gcacaatgct tccgtggaaa aatcacaggt 1680 gggcttcata gactatattg ttcatcccct ctgggagaca tgggcagacc tcgtccaccc 1740 tgacgcccag gatattttgg acactttgga ggacaatcgt gaatggtacc agagcacaat 1800 ccctcagagc ccctctcctg cacctgatga cccagaggag ggccggcagg gtcaaactga 1860 gaaattccag tttgaactaa ctttagagga agatggtgag tcagacacgg aaaaggacag 1920 tggcagtcaa gtggaagaag acactagctg cagtgactcc aagactcttt gtactcaaga 1980 ctcagagtct actgaaattc cccttgatga acaggttgaa gaggaggcag taggggaaga 2040 agaggaaagc cagcctgaag cctgtgtcat agatgatcgt tctcctgaca cgtaacagtg 2100 caaaaacttt catgcctttt ttttttttaa gtagaaaaat tgtttccaaa gtgcatgtca 2160 catgccacaa ccacggtcac acctcactgt catctgccag gacgtttgtt gaacaaaact 2220 gaccttgact actcagtcca gcgctcagga atatcgtaac cagttttttc acctccatgt 2280 tcatccgagc aaggtggaca tcttcacgaa cagcgttttt aacaagattt cagcttggta 2340 gagctgacaa agcagataaa atctactcca aattattttc aagagagtgt gactcatcag 2400 gcagcccaaa agtttattgg acttggggtt tctat 2435 <210> 4 <211> 673 <212> PRT <213> Human <400> 4 Met Met His Val Asn Asn Phe Pro Phe Arg Arg His Ser Trp Ile Cys 1 5 10 15 Phe Asp Val Asp Asn Gly Thr Ser Ala Gly Arg Ser Pro Leu Asp Pro              20 25 30 Met Thr Ser Pro Gly Ser Gly Leu Ile Leu Gln Ala Asn Phe Val His          35 40 45 Ser Gln Arg Arg Glu Ser Phe Leu Tyr Arg Ser Asp Ser Asp Tyr Asp      50 55 60 Leu Ser Pro Lys Ser Met Ser Arg Asn Ser Ser Ile Ala Ser Asp Ile  65 70 75 80 His Gly Asp Asp Leu Ile Val Thr Pro Phe Ala Gln Val Leu Ala Ser                  85 90 95 Leu Arg Thr Val Arg Asn Asn Phe Ala Ala Leu Thr Asn Leu Gln Asp             100 105 110 Arg Ala Pro Ser Lys Arg Ser Pro Met Cys Asn Gln Pro Ser Ile Asn         115 120 125 Lys Ala Thr Ile Thr Glu Glu Ala Tyr Gln Lys Leu Ala Ser Glu Thr     130 135 140 Leu Glu Glu Leu Asp Trp Cys Leu Asp Gln Leu Glu Thr Leu Gln Thr 145 150 155 160 Arg His Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu                 165 170 175 Asn Arg Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln             180 185 190 Val Ser Glu Phe Ile Ser Asn Thr Phe Leu Asp Lys Gln His Glu Val         195 200 205 Glu Ile Pro Ser Pro Thr Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro     210 215 220 Met Ser Gln Ile Ser Gly Val Lys Lys Leu Met His Ser Ser Ser Leu 225 230 235 240 Thr Asn Ser Ser Ile Pro Arg Phe Gly Val Lys Thr Glu Gln Glu Asp                 245 250 255 Val Leu Ala Lys Glu Leu Glu Asp Val Asn Lys Trp Gly Leu His Val             260 265 270 Phe Arg Ile Ala Glu Leu Ser Gly Asn Arg Pro Leu Thr Val Ile Met         275 280 285 His Thr Ile Phe Gln Glu Arg Asp Leu Leu Lys Thr Phe Lys Ile Pro     290 295 300 Val Asp Thr Leu Ile Thr Tyr Leu Met Thr Leu Glu Asp His Tyr His 305 310 315 320 Ala Asp Val Ala Tyr His Asn Asn Ile His Ala Ala Asp Val Val Gln                 325 330 335 Ser Thr His Val Leu Leu Ser Thr Pro Ala Leu Glu Ala Val Phe Thr             340 345 350 Asp Leu Glu Ile Leu Ala Ala Ile Phe Ala Ser Ala Ile His Asp Val         355 360 365 Asp His Pro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu     370 375 380 Leu Ala Leu Met Tyr Asn Asp Ser Ser Val Leu Glu Asn His His Leu 385 390 395 400 Ala Val Gly Phe Lys Leu Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln                 405 410 415 Asn Leu Thr Lys Lys Gln Arg Gln Ser Leu Arg Lys Met Val Ile Asp             420 425 430 Ile Val Leu Ala Thr Asp Met Ser Lys His Met Asn Leu Leu Ala Asp         435 440 445 Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser Gly Val Leu     450 455 460 Leu Leu Asp Asn Tyr Ser Asp Arg Ile Gln Val Leu Gln Asn Met Val 465 470 475 480 His Cys Ala Asp Leu Ser Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg                 485 490 495 Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe Arg Gln Gly Asp Arg             500 505 510 Glu Arg Glu Arg Gly Met Glu Ile Ser Pro Met Cys Asp Lys His Asn         515 520 525 Ala Ser Val Glu Lys Ser Gln Val Gly Phe Ile Asp Tyr Ile Val His     530 535 540 Pro Leu Trp Glu Thr Trp Ala Asp Leu Val His Pro Asp Ala Gln Asp 545 550 555 560 Ile Leu Asp Thr Leu Glu Asp Asn Arg Glu Trp Tyr Gln Ser Thr Ile                 565 570 575 Pro Gln Ser Pro Ser Pro Ala Pro Asp Asp Pro Glu Glu Gly Arg Gln             580 585 590 Gly Gln Thr Glu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Asp Gly         595 600 605 Glu Ser Asp Thr Glu Lys Asp Ser Gly Ser Gln Val Glu Glu Asp Thr     610 615 620 Ser Cys Ser Asp Ser Lys Thr Leu Cys Thr Gln Asp Ser Glu Ser Thr 625 630 635 640 Glu Ile Pro Leu Asp Glu Gln Val Glu Glu Glu Ala Val Gly Glu Glu                 645 650 655 Glu Glu Ser Gln Pro Glu Ala Cys Val Ile Asp Asp Arg Ser Pro Asp             660 665 670 Thr 673

[Brief description of drawings]

FIG. 1 shows the complete nucleotide sequence of cDNA encoding PDE IV (SEQ ID NO: 3) and the amino acid sequence encoded by it (SEQ ID NO: 4).

FIG. 2 shows the entire nucleotide sequence (SEQ ID NO: 3) of cDNA encoding PDE IV and the amino acid sequence (SEQ ID NO: 4) encoded by it, which is a continuation of FIG. 1.

FIG. 3 shows the entire nucleotide sequence (SEQ ID NO: 3) of cDNA encoding PDE IV and the amino acid sequence (SEQ ID NO: 4) encoded by it, which is a continuation of FIG. 2.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 11/06 A61P 11/06 25/00 25/00 25/24 25/24 25/28 25/28 29 / 00 29/00 101 101 37/06 37/06 43/00 111 43/00 111 F term (reference) 4C050 AA01 AA08 BB07 CC16 DD10 EE01 FF02 FF05 GG03 HH04 4C086 AA01 AA02 AA03 CB22 MA01 MA04 NA14 ZA02 ZA12 ZA16 ZA45 ZA45 ZB08 ZB11 ZB15 ZC20 ZC35

Claims (28)

[Claims] 1. The formula: A compound having a partial structure represented by or a salt thereof. 2. The formula: [Wherein R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent] or a salt thereof. . 3. The formula: [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ² and R ³ represent a hydrogen atom and a substituent, respectively. Represents a hydrocarbon group or an acyl group which may have, R ² and R ³
Is optionally substituted with an adjacent carbon atom 3
To may form a 8-membered ring, the R ⁴ and R ⁵ are each a hydrogen atom or an optionally substituted hydrocarbon group, R ⁶ and R ⁷ are a hydrogen atom or a substituent R ⁶ and R ⁷ may form a 3- to 8-membered ring which may have a substituent with an adjacent carbon atom, and R ⁸ is (1) a hydrogen atom. , (2) a hydrocarbon group which may have a substituent, (3) an acyl group, (4) a heterocyclic group which may have a substituent, (5) a halogen atom, (6) -O.
R ¹⁰ (R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (7) -SR ¹¹ (R ¹¹ Represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent),
(8) -S (O) R ¹² (R ¹² represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent), (9) -S (O ) ₂ R ¹³ (R ¹³ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) or (10) -NR ^1
4 R ¹⁵ (R ¹⁴ and R ¹⁵ each represent a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), and R ⁹ represents A hydrogen atom, a cyano group, a hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent, and X represents a methylene group or a carbonyl group which may have a substituent. And n is 0 or 1] or a salt thereof. 4. R¹Is either (i) or (ii) below
Shows: (I) (1) halogen atom, (2) C_1-3Alkylenedi
Oxy group, (3) nitro group, (4) cyano group, (5) halo
C which may be genated_1-6Alkyl group, (6)
C which may be rogenated_2-6An alkenyl group,
(7) C which may be halogenated_2-6Alkynyl
Base, (8) C_3-6Cycloalkyl group, (9) C_{6 -14}
Aryl group, (10) optionally halogenated C
_1-6Alkoxy group, (11) may be halogenated
I C_1-6Alkylthio group, (12) hydroxy group, (1
3) Amino group, (14) Mono-C_1-6Alkylamino
Group, (15) Mono-C _6-14Arylamino group, (16)
The-C_1-6Alkylamino group, (17) di-C_6-14
Arylamino group, (18) formyl, carboxy, cal
Bamoiru, C _1-6Alkyl-carbonyl, C_3-6Shi
Chloroalkyl-carbonyl, C_1-6Alkoxy-Cal
Bonil, C_6-14Aryl-carbonyl, C_7-16
Aralkyl-carbonyl, C_6-14Aryloxy-
Carbonyl, C_7-16Aralkyloxy-Carbonii
Group, nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 containing 1 to 3 heteroatoms selected from
Or 6-membered heterocyclic carbonyl, mono-C_1-6Alkyl-
Carbamoyl, di-C_1-6Alkyl-carbamoyl,
C_6-14Aryl-carbamoyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic carba containing 3 heteroatoms
Moyle, C_1-6Alkyl-thiocarbonyl, C_3-6
Cycloalkyl-thiocarbonyl, C_1-6Alkoxy
-Thiocarbonyl, C_6-14Aryl-thiocarboni
Le, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_7-16
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C _1-6Alkylsulfinyl, C_6-14A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
Group, (19) formylamino, C_1-6Alkyl-carbo
Xamide, C_6-14Aryl-carboxamide, C
_1-6Alkoxy-carboxamide, C_1-6Alkyl
Sulfonylamino and C_6-14Arylsulfonyl
Acylamino group selected from amino, (20) C_1-6A
Rukyl-carbonyloxy, C_6-14Aryl-Cal
Bonyloxy, C_1-6Alkoxy-carbonyl
Si, Mono-C_1-6Alkyl-carbamoyloxy, di
-C_1-6Alkyl-carbamoyloxy, C_6-14
Aryl-carbamoyloxy and nicotinoyloxy
Acyloxy group selected from Si, other than (21) carbon atoms
1 selected from nitrogen atom, sulfur atom and oxygen atom
A 4- to 14-membered heterocycle containing 4 heteroatoms
Group, (22) phosphono group, (23) C_6-14Aryl Oki
Si group, (24) di-C_1-6An alkoxy-phosphoryl group,
(25) C_6-14Arylthio group, (26) hydrazino group,
(27) imino group, (28) oxo group, (29) ureido group,
(30) C_1-6Alkyl-ureido group, (31) di-C
_1-6Alkyl-ureido group, (32) oxide group and
(33) 2 to 3 selected from the groups (1) to (32)
A group consisting of groups formed by combining individual groups (hereinafter referred to as substituent A
1 to 5 substituents selected from the group
Each may have C_1-6Alkyl group, C_2-6A
Lucenyl group, C_2-6Alkynyl group, C_3-6Cycloa
Rukiru group, C _3-6Cycloalkenyl group, C_6-14A
Reel base or C_7-16An aralkyl group, (ii) the above
Having 1 to 5 substituents selected from the group A of substituents,
In addition to carbon atom, nitrogen atom, sulfur atom and oxygen source
5 to 5 containing 1 to 4 heteroatoms selected from children
14-membered heterocyclic group; R^TwoAnd R^ThreeAre the following
Indicates any of (i) to (iii): (I) a hydrogen atom, (ii) a group selected from the above substituent group A
C optionally having 1 to 5 substituents each_1-6
Alkyl group, C_2-6Alkenyl group, C_2-6Alkini
Lu group, C_{Three -6}Cycloalkyl group, C_3-6Cycloal
Kenyl group, C_6-14Aryl group or C_7-16Ara
Alkyl group, (iii) Substituent selected from Substituent group A
Formyl, carboxy, which may have 1 to 5
Ci, carbamoyl, C_1-6Alkyl-carbonyl, C
_{3- 6}Cycloalkyl-carbonyl, C_1-6Arcoki
Si-carbonyl, C_6-14Aryl-carbonyl, C
_7-16Aralkyl-carbonyl, C_6-14Aryl
Oxy-carbonyl, C_7-16Aralkyl Oxy-ca
Rubonyl, nitrogen atom, sulfur atom and acid other than carbon atom
Contains 1 to 3 heteroatoms selected from elementary atoms
5- or 6-membered heterocyclic carbonyl, mono-C_1-6Al
Kill-carbamoyl, di-C_1-6Alkyl-carbamo
Il, C_6-14Aryl-carbamoyl, carbon atom or less
Besides, 1 selected from nitrogen atom, sulfur atom and oxygen atom
To 5 or 6 membered heterocycles containing 3 to 3 heteroatoms
Carbamoyl, C_1-6Alkyl-thiocarbonyl, C
_3-6Cycloalkyl-thiocarbonyl, C_1-6Al
Coxy-thiocarbonyl, C_6-14Aryl-Thioca
Lubonyl, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_{7- 16}
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_{6- 14}A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
Group; R²And R³Is C with adjacent carbon atoms_1-6Al
Kill, C_6-14Aryl, C_7-16Aralkyl, a
Mino, Mono-C_1-6Alkylamino, mono-C_6
-14Arylamino, di-C_1-6Alkylamino,
The-C_6-14Arylamino and 4 to 10 members
1 to 3 substituents each selected from an aromatic heterocyclic group
May have C_3-8Cycloalkane or 3
May form an 8-membered heterocycle; R^FourAnd R⁵Gazo
Each of (i) a hydrogen atom or (ii) the above substituent group A
Each may have 1 to 5 substituents selected
I C_1-6Alkyl group, C _2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C_Three
-6Cycloalkenyl group, C_6-14Aryl group or
C_7-16An aralkyl group; R⁶And R⁷Respectively
(I) hydrogen atom or (ii) selected from the above substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C _2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C_{Three -6}Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16Represents an aralkyl group, R⁶And R⁷Is adjacent charcoal
C along with elementary atoms_1-6Alkyl, C_6-14Ally
Le, C_7-16Aralkyl, Amino, Mono-C_1-6A
Ruquilamino, Mono-C _6-14Arylamino, di-
C_1-6Alkylamino, di-C_6-14Arylami
And a unit selected from a 4- to 10-membered aromatic heterocyclic group.
C optionally having 1 to 3 substituents_3-8
Forming a cycloalkane or a 3- to 8-membered heterocycle
Well; R⁸Indicates one of the following (i) to (x): (I) a hydrogen atom, (ii) a group selected from the above substituent group A
C optionally having 1 to 5 substituents each_1-6
Alkyl group, C_2-6Alkenyl group, C_2-6Alkini
Lu group, C_{Three -6}Cycloalkyl group, C_3-6Cycloal
Kenyl group, C_6-14Aryl group or C_7-16Ara
Alkyl group, (iii) Substituent selected from Substituent group A
Formyl, carboxy, which may have 1 to 5
Ci, carbamoyl, C_1-6Alkyl-carbonyl, C
_{3- 6}Cycloalkyl-carbonyl, C_1-6Arcoki
Si-carbonyl, C_6-14Aryl-carbonyl, C
_7-16Aralkyl-carbonyl, C_6-14Aryl
Oxy-carbonyl, C_7-16Aralkyl Oxy-ca
Rubonyl, nitrogen atom, sulfur atom and acid other than carbon atom
Contains 1 to 3 heteroatoms selected from elementary atoms
5- or 6-membered heterocyclic carbonyl, mono-C_1-6Al
Kill-carbamoyl, di-C_1-6Alkyl-carbamo
Il, C_6-14Aryl-carbamoyl, carbon atom or less
Besides, 1 selected from nitrogen atom, sulfur atom and oxygen atom
To 5 or 6 membered heterocycles containing 3 to 3 heteroatoms
Carbamoyl, C_1-6Alkyl-thiocarbonyl, C
_3-6Cycloalkyl-thiocarbonyl, C_1-6Al
Coxy-thiocarbonyl, C_6-14Aryl-Thioca
Lubonyl, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_{7- 16}
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_6-14Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_1-6Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_{6- 14}A
Reel sulfinyl, sulfino, sulfo, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
A group, (iv) no substituent selected from the above substituent group A
In addition to the carbon atoms which may be five, nitrogen atoms, sulfur
1 to 1 heteroatoms selected from atoms and oxygen atoms
A 5- to 14-membered heterocyclic ring containing 4, (v) a halogen atom,
(Vi) -OR¹⁰(R¹⁰Is (i ') hydrogen atom, (i
i ′) 1 to 5 substituents selected from the above-mentioned substituent group A
C which each may have_1-6Alkyl group, C
_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6
Cycloalkyl group, C _3-6Cycloalkenyl group, C
_6-14Aryl group or C_7-16Aralkyl group,
(Iii ') There is no 1 substituent selected from the above substituent group A.
Formyl, carbamoyl, C, which may have 5
_1-6Alkyl-carbonyl, C_3-6Cycloalkyl
-Carbonyl, C_1-6Alkoxy-carbonyl, C
_6-14Aryl-carbonyl, C_7-16Aralkyl
-Carbonyl, C_6-14Aryloxy-carboni
Le, C_7-16Aralkyloxy-carbonyl, carbon source
Selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring carbonyl, mono-C_1-6Alkyl-carbamoy
Le, the C_1-6Alkyl-carbamoyl, C_6-14
Aryl-carbamoyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hets selected from yellow atom and oxygen atom
5- or 6-membered heterocyclic carbamoyl containing a carbon atom, C
_1-6Alkyl-thiocarbonyl, C_3-6Cycloal
Kill-thiocarbonyl, C_1-6Alkoxy-thiocal
Bonil, C_6-14Aryl-thiocarbonyl, C
_7-16Aralkyl-thiocarbonyl, C_6-14Ants
Oxy-thiocarbonyl, C_7-16Aralkillo
Xy-thiocarbonyl, nitrogen atom in addition to carbon atom, sulfur
1 to 3 hetero atoms selected from atoms and oxygen atoms
5- or 6-membered heterocyclic thiocarbonyl containing atoms, thi
Ocarbamoyl, Mono-C_1-6Alkyl-thiocarba
Moyle, The-C_1-6Alkyl-thiocarbamoyl, C
_6-14Aryl-thiocarbamoyl, other than carbon atom
1 selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered heterocyclic thio containing 3 heteroatoms
Carbamoyl, sulfamoyl, mono-C_1-6Archi
Rusulfamoyl, Di-C_1-6Alkylsulfamoy
Le, C_6-14Arylsulfamoyl, C_1-6Al
Killsulfonyl, C_6-14Arylsulfonyl, C
_1-6Alkylsulfinyl, C_6-14Arylsul
Finil, C_1-6Alkoxysulfinyl, C
_6-14Aryloxysulfinyl, C_1-6Arco
Xysulfonyl and C_6-14Aryloxysulfo
Acyl group selected from nyl or (iv ') substituent A
It may have 1 to 5 substituents selected from the group
From nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 to 14 members containing 1 to 4 heteroatoms selected
A heterocycle), (vii) -SR¹¹(R¹¹Is
(I ') hydrogen atom, (ii') selected from the above substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C _3-6Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16An aralkyl group, (iii ') from the substituent group A
A group which may have 1 to 5 selected substituents,
Mill, carbamoyl, C_1-6Alkyl-carbonyl,
C_3-6Cycloalkyl-carbonyl, C_1-6Arco
Xy-carbonyl, C_6-14Aryl-carbonyl,
C_7-16Aralkyl-carbonyl, C_6-14Ally
Luoxy-carbonyl, C_7-16Aralkyloxy-
In addition to carbonyl and carbon atom, nitrogen atom, sulfur atom and
Contains 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic carbonyl, mono-C_1-6A
Ruquil-carbamoyl, di-C_1-6Alkyl-carb
Moyle, C_6-14Aryl-carbamoyl, carbon atom
Besides, selected from nitrogen atom, sulfur atom and oxygen atom
5- or 6-membered complex containing 1 to 3 heteroatoms
Carbamoyl ring, C_1-6Alkyl-thiocarbonyl,
C_3-6Cycloalkyl-thiocarbonyl, C_1-6A
Lucoxy-thiocarbonyl, C_6-14Aryl-thio
Carbonyl, C_7-16Aralkyl-thiocarbonyl,
C_6-14Aryloxy-thiocarbonyl, C
_7-16Aralkyloxy-thiocarbonyl, carbon atom
Besides, selected from nitrogen atom, sulfur atom and oxygen atom
5- or 6-membered complex containing 1 to 3 heteroatoms
Ring thiocarbonyl, thiocarbamoyl, mono-C_1-6
Alkyl-thiocarbamoyl, di-C_1-6Alkyl-
Thiocarbamoyl, C_6-14Aryl-thiocarbamo
In addition to carbon and carbon atoms, nitrogen, sulfur and oxygen sources
Containing 1 to 3 heteroatoms selected from the group 5
Or a 6-membered heterocyclic thiocarbamoyl, sulfamoyl,
Mono-C_1-6Alkylsulfamoyl, di-C_1-6
Alkylsulfamoyl, C_6-14Aryl sulfa
Moyle, C_1-6Alkylsulfonyl, C_6-14Ants
Sulfonyl, C_1-6Alkylsulfinyl, C
_6-14Arylsulfinyl, C_1-6Alkoxys
Rufinil, C_6-14Aryloxysulfinyl,
C_1-6Alkoxysulfonyl and C_6-14Ally
An acyl group selected from luoxysulfonyl or (i
v ′) 1 to 5 substituents selected from the above substituent group A
Nitrogen atom, sulfur atom in addition to carbon atoms which may have
And 1 to 4 heteroatoms selected from oxygen atoms
Including 5 to 14 membered heterocycles), (viii) -S (O)
R¹²(R¹²Is (i ′) selected from the above-mentioned substituent group A
C optionally having 1 to 5 substituents each
_1-6Alkyl group, C_2-6Alkenyl group, C_2-6A
Lucinyl group, C_3-6Cycloalkyl group, C_3-6Shiku
Alkenyl group, C_6-14Aryl group or C
_7-16An aralkyl group or (ii ') the substituent group A
A carbon which may have 1 to 5 substituents selected from
Other than atom, selected from nitrogen atom, sulfur atom and oxygen atom
5 to 14 membered complex containing 1 to 4 heteroatoms
A ring), (ix) -S (O)_TwoR^Thirteen(R^ThirteenIs
(I ') the substituent selected from Group A above is 1 to
C which each may have 5_1-6Alkyl group, C
_2-6Alkenyl group, C_2-6Alkynyl group, C_3-6
Cycloalkyl group, C_3-6Cycloalkenyl group, C
_6-14Aryl group or C_7-16Aralkyl group
(Ii ') does not have 1 substituent selected from the above-mentioned substituent group A
In addition to the carbon atoms which may be five, nitrogen atoms, sulfur
1 to 1 heteroatoms selected from atoms and oxygen atoms
5 to 14-membered heterocycle containing 4), (x) -NR
¹⁴R¹⁵(R¹⁴And R¹⁵Each is (i ') water
Elementary atom, (ii ') a substituent selected from the above-mentioned substituent group A
1 to 5 C each may have_1-6Archi
Lu group, C_2-6Alkenyl group, C_2-6An alkynyl group,
C_{3- 6}Cycloalkyl group, C_3-6Cycloalkenyl
Base, C_6-14Aryl group or C_7-16Aralkyl
Group, (iii ') is a substituent selected from Group A of the substituent
Formyl and carbamoy, which may have 5 to 5
Le, C_1-6Alkyl-carbonyl, C_3-6Cycloa
Rukiru-carbonyl, C_1-6Alkoxy-Carbonii
Le, C_6-14Aryl-carbonyl, C_7-16Ara
Rukiru-carbonyl, C_6-14Aryloxy-cal
Bonil, C_7-16Aralkyloxy-carbonyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic carbonyl, mono-C_1-6Alkyl-carb
Moyle, The-C_1-6Alkyl-carbamoyl, C
_6-14Aryl-carbamoyl, nitrogen in addition to carbon atom
1 to 3 selected from atom, sulfur atom and oxygen atom
5 or 6 membered heterocyclic carbamo containing 5 heteroatoms
Il, C_1-6Alkyl-thiocarbonyl, C_3-6Shi
Chloroalkyl-thiocarbonyl, C_1-6Alkoxy-
Thiocarbonyl, C_6-14Aryl-thiocarboni
Le, C_7-16Aralkyl-thiocarbonyl, C
_6-14Aryloxy-thiocarbonyl, C_7-16
Aralkyloxy-thiocarbonyl, nitrogen atoms other than carbon
1 to selected from an elementary atom, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thioca containing 3 heteroatoms
Lubonyl, thiocarbamoyl, mono-C_1-6Alkyl
-Thiocarbamoyl, di-C_1-6Alkyl-thiocal
Bamoiru, C_{6-1 Four}Aryl-thiocarbamoyl, charcoal
Select from nitrogen atom, sulfur atom and oxygen atom in addition to elementary atom.
5 or 6 containing 1 to 3 heteroatoms
Membered heterocyclic thiocarbamoyl, sulfamoyl, mono-C
_1-6Alkylsulfamoyl, di-C_1-6Alkyl
Sulfamoyl, C_6-14Arylsulfamoyl,
C_{1- 6}Alkylsulfonyl, C_6-14Arylsul
Honil, C_1-6Alkylsulfinyl, C_6-14A
Reel sulfinyl, C_1-6Alkoxy sulfini
Le, C_6-14Aryloxysulfinyl, C_1-6
Alkoxysulfonyl and C_6-14Aryloxy
An acyl group selected from sulfonyl or (iv ')
Having 1 to 5 substituents selected from the group A of substituents,
In addition to carbon atom, nitrogen atom, sulfur atom and oxygen source
5 to 5 containing 1 to 4 heteroatoms selected from children
Indicates a 14-membered heterocycle) R⁹Is (i) hydrogen atom, (ii) cyano group, (iii)
1 to 5 substituents each selected from the group A of substituents
C which may be_1-6Alkyl group, C_2-6Archeni
Lu group, C_2-6Alkynyl group, C _3-6Cycloalkyl
Base, C_3-6Cycloalkenyl group, C_6-14Aryl
Group or C_7-16An aralkyl group, (iv) the substituent A
May have 1 to 5 substituents selected from the group
I, formyl, carboxy, carbamoyl, C_1-6A
Rukiru-carbonyl, C_3-6Cycloalkyl-carbo
Nil, C_1-6Alkoxy-carbonyl, C_6-14A
Reel-carbonyl, C_7-16Aralkyl-Carboni
Le, C_6-14Aryloxy-carbonyl, C
_7-16Aralkyloxy-carbonyl, other than carbon atom
1 selected from nitrogen atom, sulfur atom and oxygen atom
5 or 6-membered heterocyclic ring containing 3 heteroatoms
Lubonyl, Mono-C_1-6Alkyl-carbamoyl, di
-C_1-6Alkyl-carbamoyl, C_6-14Ally
Ru-carbamoyl, nitrogen atom, sulfur atom in addition to carbon atom
And 1 to 3 heteroatoms selected from oxygen atom
A 5- or 6-membered heterocyclic carbamoyl containing, C_1-6
Alkyl-thiocarbonyl, C_3-6Cycloalkyl-
Thiocarbonyl, C_1-6Alkoxy-thiocarboni
Le, C_6-14Aryl-thiocarbonyl, C_7-16
Aralkyl-thiocarbonyl, C_6-14Aryl Oki
Ci-thiocarbonyl, C_{7-1 6}Aralkyl oxy-chi
O-carbonyl, carbon atom, nitrogen atom, sulfur atom and
And 1 to 3 heteroatoms selected from oxygen atoms
Having 5- or 6-membered heterocyclic thiocarbonyl, thiocarba
Moyle, Mono-C_1-6Alkyl-thiocarbamoyl,
The-C_1-6Alkyl-thiocarbamoyl, C_6-14
Aryl-thiocarbamoyl, nitrogen atom other than carbon atom
1 to 3 selected from a child, a sulfur atom and an oxygen atom
5- or 6-membered heterocyclic thiocarba containing heteroatoms of
Moyle, Sulfamoyl, Mono-C_1-6Alkylsul
Famoyl, The-C_1-6Alkylsulfamoyl, C
_6-14Arylsulfamoyl, C_1-6Alkyls
Lefonil, C_6-14Arylsulfonyl, C_1-6A
Ruquilsulfinyl, C_{6-1 Four}Arylsulfini
Le, sulfino, sulfo, C_1-6Alkoxy sulfi
Nil, C_6-14Aryloxysulfinyl, C
_1-6Alkoxysulfonyl and C_6-14Aryl
An acyl group selected from oxysulfonyl, or (v)
Expression-OR⁹’(R⁹′ Is a hydrogen atom, the substituent group A
Each having 1 to 5 substituents selected from
Good C_1-6Alkyl group, C_2-6Alkenyl group, C
_2-6Alkynyl group, C_3-6Cycloalkyl group, C
_3-6Cycloalkenyl group, C_6-14Aryl group
Is C_7-16Aralkyl group or the above-mentioned substituent group A
Optionally having 1 to 5 substituents selected from
Lumil, carbamoyl, C_1-6Alkyl-carboni
Le, C_3-6Cycloalkyl-carbonyl, C_1-6A
Lucoxy-carbonyl, C_6-14Aryl-Carbonii
Le, C_7-16Aralkyl-carbonyl, C_6-14A
Reel oxy-carbonyl, C_7-16Aralkyl Oki
In addition to carbonyl and carbon atoms, nitrogen and sulfur atoms
And 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic carbonyl containing, mono-C
_1-6Alkyl-carbamoyl, di-C_1-6Alkyl
-Carbamoyl, C_6-14Aryl-carbamoyl,
From nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom
5 or containing 1 to 3 heteroatoms selected
6-membered heterocyclic carbamoyl, C_1-6Alkyl-thiocal
Bonil, C_3-6Cycloalkyl-thiocarbonyl, C
_1-6Alkoxy-thiocarbonyl, C_6-14Ally
L-thiocarbonyl, C_7-16Aralkyl-Tiocal
Bonil, C_6-14Aryloxy-thiocarbonyl,
C_7-16Aralkyloxy-thiocarbonyl, carbon source
Selected from nitrogen atom, sulfur atom and oxygen atom
A 5- or 6-membered compound containing 1 to 3 heteroatoms
Elementary ring thiocarbonyl, thiocarbamoyl, mono-C
_1-6Alkyl-thiocarbamoyl, di-C_{1- 6}Al
Kill-thiocarbamoyl, C_6-14Aryl-Thioca
In addition to luvamoyl and carbon atoms, nitrogen atoms, sulfur atoms and
Contains 1 to 3 heteroatoms selected from oxygen atoms
5- or 6-membered heterocyclic thiocarbamoyl, sulfamo
Il, Mono-C_1-6Alkylsulfamoyl, di-C
_1-6Alkylsulfamoyl, C _6-14Aryls
Rufamoil, C_1-6Alkylsulfonyl, C
_6-14Arylsulfonyl, C_1-6Alkylsulf
Inyl, C_6-14Arylsulfinyl, C_1-6A
Lucoxysulfinyl, C_6-14Aryl oxysul
Finil, C_1-6Alkoxysulfonyl and C
_6-14Acyl selected from aryloxysulfonyl
A group represented by the formula:
A methylene group which may have a selected substituent or
A carbonyl group; n according to claim 0 or 1;
Compound. 5. The compound according to claim ^{3, wherein} R ² and R ³ each represent a C _1-6 alkyl group. 6. The compound according to claim 3, wherein R ⁴ and R ⁵ each represent a hydrogen atom. 7. The compound according to claim 3, wherein R ⁶ and R ⁷ each represent a C _1-6 alkyl group. 8. The compound according to claim 3, wherein R ⁹ represents a hydrogen atom. 9. The compound according to claim 3, wherein n is 0. 10. R¹Is the expression [Chemical 4] [In the formula, R¹⁶May have a hydrogen atom or a substituent
C_6-14Aryl group, an amino group which may have a substituent
Group, heterocyclic group which may have a substituent or halogen
Represents a hydrogen atom], R^TwoAnd R^ThreeIs C_1-6
An alkyl group, R ^FourAnd R⁵Are hydrogen atoms,
R⁶And R⁷Is C_1-6An alkyl group, R⁸
Is a hydrogen atom or -OR¹⁰(R¹⁰Is a hydrogen atom,
C which may have a substituent_1-6Alkyl group or reed
R group), R⁹Is a hydrogen atom and n is 0
Item 3. The compound according to Item 3. 11. R¹⁰Is (1) hydrogen atom, (2) pyridyl
C which may be substituted _1-6Alkyl group or (3)
C substituted with a rogen atom_1-6Alkylsulfonyl
To R¹⁶Are replaced by (1) hydrogen atom and (2) acetylamino group.
Substituted phenyl, (3) (i) C_1-6Alkylsulfonyl
A group, (ii) pyridylcarbonyl or (iii) sulfamoyl
R-C_1-6A substituent selected from an alkyl group
Is optionally substituted amino, (4) pyridyl or
(5) The compound according to claim 10, which represents a halogen atom. 12. A prodrug of the compound according to claim 3. 13. The formula: [Wherein, R ¹⁷ represents a vinyl group or an allyl group which may have a substituent] or a salt thereof and a formula R ¹ -CN [wherein R ¹ is Item 2
And a salt thereof, represented by the formula: A method for producing a compound having a partial structure represented by the formula: wherein R ¹ has the same meaning as defined above, or a salt thereof. 14. The formula: [Wherein each symbol has the same meaning as in claim 3] or a salt thereof and a compound of the formula R ¹ -CN [wherein R ¹
Has the same meaning as in claim 3], or a salt thereof. 15. The formula: Wherein - - - represents a single bond or a double bond The compound or pharmaceutical composition comprising a salt thereof having a partial structure represented by. 16. The formula: [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or an optionally substituted C _6-14 aryl group. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent or a halogen atom], or a salt thereof. Composition. 17. A pharmaceutical composition comprising the compound according to claim 3, a salt thereof or a prodrug thereof. 18. The formula: Wherein - - - represents a single bond or a double bond] The compound or a phosphodiesterase IV inhibitor comprising a salt thereof having a partial structure represented by. 19. The formula: Wherein - - - represents a single bond or a double bond The compound or inflammatory diseases containing a salt having a partial structure represented by, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, A prophylactic / therapeutic agent for autoimmune diseases, depression, Alzheimer's dementia, memory disorders, diabetes or arteriosclerosis. 20. The pharmaceutical composition according to claim 15, which is a phosphodiesterase IV inhibitor. 21. Inflammatory disease, asthma, chronic obstructive pulmonary disease,
The pharmaceutical composition according to claims 15 to 17, which is a prophylactic / therapeutic agent for rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis. 22. For mammals the formula: Wherein - - - represents a single bond or a double bond The compound or phosphodiesterase IV inhibitory method characterized by administering an effective amount of a salt having a partial structure represented by. 23. The formula for mammals: [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom] is administered, and an effective amount of the compound or salt thereof is administered. A method for inhibiting phosphodiesterase IV, which comprises: 24. The formula for mammals: Wherein - - - represents a single bond or a double bond] inflammatory disease, which comprises administering a compound or an effective amount of a salt thereof having a partial structure represented by, asthma, chronic obstructive Lung disease, rheumatoid arthritis, autoimmune disease, depression,
A method for preventing or treating Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis. 25. For mammals the formula: [In the formula, R ² ′, R ³ ′, R ⁶ ′, and R ⁷ ′ each represent a C _1-6 alkyl group, and R ¹⁶ ′ represents a hydrogen atom or a C _6-14 aryl which may have a substituent. Group, an amino group which may have a substituent, a heterocyclic group which may have a substituent, or a halogen atom] is administered, and an effective amount of the compound or salt thereof is administered. A method for preventing or treating inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis characterized by the following: 26. A formula for preparing a phosphodiesterase IV inhibitor Wherein - - - represents a single bond or a double bond] The compound or a salt thereof having a partial structure represented by. 27. An inflammatory disease, asthma, chronic obstructive pulmonary disease,
Formula for producing a prophylactic / therapeutic agent for rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis Wherein - - - represents a single bond or a double bond] The compound or a salt thereof having a partial structure represented by. 28. The formula: [In the formula, R ^2a and R ^3a each represent an aliphatic hydrocarbon group which may have a substituent, and R ^4a and R ^5a each represent a hydrogen atom or a hydrocarbon group which may have a substituent. , R ^6a and R ^7a each represent a hydrogen atom or a substituent hydrocarbon group which may have a 3- to may have a substituent group together with the carbon atoms R ^6a and R ^7a are adjacent 8-membered R ^8a may form a ring, and R ^8a may have (1) a hydrogen atom, (2) a hydrocarbon group optionally having a substituent, (3) an acyl group, or (4) a substituent. Good heterocyclic group, (5) halogen atom, (6)-
OR ^10a (R ^10a represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (7) -SR ^11a (R
^11a is a hydrogen atom, a substituted and may be a hydrocarbon group, acyl group or optionally substituted heterocyclic group), (8) -S (O ) R 1 2a ( R ^12a is
A hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent is shown), (9) -S (O) ₂
R ^13a (R ^13a represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) or (10) -NR ^14a R ^15a (R ^14a and R ^15a Each represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), and R ^9a has a hydrogen atom and a substituent. A hydrocarbon group, an acyl group or a hydroxyl group which may have a substituent], or a salt thereof.