WO2001034570A1 - Nitrogenous heterocycle derivatives - Google Patents

Abstract

Nitrogenous heterocycle derivatives of general formula (I), pharmacologically acceptable salts of the same, or esters or other derivatives thereof, having an excellent inhibitory effect on ileal bile acid transporter. In said formula, R?1, R2, R3 and R4¿ are each hydrogen, hydroxyl, or lower alkoxy; R5 is aryl; and R6 is -CONR7R8 (wherein R7 is C¿1-10? alkyl or C2-10 alkenyl; and R?8¿ is aryl or an aromatic heterocyclic group), with the proviso that when R2 is hydrogen and R3 is lower alkoxy, R5 is aryl which is mono- to penta-substituted with hydroxyl and/or lower alkoxy groups.

Description

 Specification

Technical field

 The present invention provides a nitrogen-containing heterocyclic derivative having excellent ileal bile acid transporter inhibitory activity, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, a pharmaceutical composition containing them as an active ingredient, and a pharmaceutical composition. The invention relates to a method for preventing or treating hyperlipidemia and hyperlipidemia or arteriosclerosis, which comprises administering to a warm-blooded animal a use thereof for the manufacture of a product, or a pharmacologically effective amount thereof. Technology background

 Hyperlipidemia is one of the three major risk factors for ischemic heart disease, and it is widely accepted that lowering high cholesterol levels in blood is particularly useful for treating or preventing ischemic heart disease. I have. As currently available therapeutic agents for hyperlipidemia, for example, HMG-C0A reductase inhibitor Yin-ion exchange resin is known, and these agents are used for treating hyperlipidemia and arteriosclerosis. It has been used for preventive purposes [Am. J. Cardiol., 76, 899-905 (1995)].

 HMG-CoA reductase inhibitor has the effect of inhibiting cholesterol synthesis and increasing LDL (low density lipoprotein) receptor in the liver, thereby taking up cholesterol in the blood and promoting its excretion into bile. [Science, 232, 34 (1986)]. The usefulness and safety of these drugs are widely recognized and used by many patients.

In addition, anion exchange resins promote the conversion of cholesterol to bile acids in the liver by adsorbing bile acids and preventing the reabsorption of bile acids in the intestine, thereby increasing blood cholesterol levels. N. Engl. J. Med., 302, 1219-1222 (1980)] ₀ As such an anion exchange resin, for example, a method using cholestyramine has already been put into practical use, and it is difficult for the drug to be absorbed into the body. It is considered a first-line drug in the treatment of hyperlipidemia in children who require more safety. However, cholestyramine has the drawbacks that it is extremely difficult for patients to take because cholesterylamine is taken in an extremely large dose and the rough feel of the resin when taken is left in the mouth. In addition, anion exchange resins also adsorb and discharge certain vitamins, minerals, drugs, and the like. Therefore, it is necessary to consider replenishing vitamins and changing the administration method of concomitant drugs, which poses many problems. In recent years, a protein acting in the first step of bile acid reabsorption in the ileum, a ileal bile acid transporter, has been cloned [WongM. H. et al, J. Biol. Chem., 269, 1340-1347 ( 1994)]. It is thought that if the ileal bile acid transporter activity can be inhibited, a pharmacological effect similar to that of cholestyramine can be obtained. Against this background, ileal bile acid transporter inhibitors Have been attempted [Wess G. et al, J. Med. Chem. ', 37, 873-875 (1994)]. The following are compounds that are similar to the compounds of the present invention.

 (1) Japanese Patent Application Laid-Open No. H7-145152 (W094 / 1 1355)

 [In the above compound (a),

A is a carbonyl group, B is CR ³ R ⁴ , and R ³ and R ⁴ are the same or different A substitutable lower alkyl group, etc., W is an oxygen atom, X ¹ and X ² are a trifluoromethyl group, a hydroxy group, etc., Υ Υ ² , Υ ³ , Υ ⁴ and Ζ are a hydrogen atom, a halogen atom And alkyl. ] Has been disclosed.

 The compound (a) has the ability to have an oxo group as an essential substituent at the 2-position of the quinoline skeleton. The compound (I) of the present invention is characterized in that it has no oxo group at the 2-position of the quinoline skeleton. Different from compound (a).

 Furthermore, the above compound (a) has the ability to have a substituted lower alkyl group at the 3-position of the quinoline skeleton. The compound (I) of the present invention has a disubstituted rubamoyl group as an essential substituent. This is different from the above compound (a).

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, only the following compounds are disclosed in the exemplary compound table.

 Further, the above compound (a) is disclosed as a smooth muscle relaxant, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(2) JP-A-6-3 16522 (EP 614664 A)

In this publication, a 1,7-disubstituted 1-4-oxo-3-quinolinecarboxylic acid derivative represented by the following general formula (b)

[In the above compound (b),

R ¹ is a protecting group for hydrogen or a carboxyl group, R ² and R ³ are organic groups, and Z is CH. ] Has been disclosed.

 The compound (b) has a carboxyl group or a protected carboxyl group at the 3-position of the quinoline skeleton. The compound (I) of the present invention has a disubstituted carbamoyl group as an essential substituent. Different from compound (b).

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.o

また、 上記化合物 （b) は、 細胞接着阻害剤として開示されており、 回腸型胆汁 酸トランスポーター阻害作用としての用途は記載も示唆もされていない。

In addition, the above compound (b) is disclosed as a cell adhesion inhibitor, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(3) JP-A-4-226980 (EP458636A)

In this gazette, the following general formula (c)

 [In the above compound (C),

R ¹ is an aryl group, R ² is a hydroxy group, R ³ is hydrogen or the like, R ⁴ is a lower alkyl group, A is CH or the like, X is —NH—, n is 0 or 1. ] Has been disclosed.

 The compound (c) has a force s ′ having a force rubamoyl group mono-substituted with an azabicyclooctane ring or the like at the 3-position of the quinoline skeleton, and the compound (I) of the present invention has a force at the 3-position of the quinoline skeleton. They differ from alkyl or alkenyl groups in that they have a carbamoyl group disubstituted with a substituted aryl group.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.

 Further, the above compound (c) is disclosed as a 5-HT 3 antagonist and an antiemetic agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(4) JP-A-57-171975 (EP 59698A)

In this gazette, the following general formula (d)

 [In the above compound (d),

RR ² and R ³ are hydrogen and the like; R ⁴ is a lower alkyl, an optionally substituted phenyl group and the like; R ⁵ is an optionally substituted phenyl group; and R ¹³ is a lower alkyl group. A ¹ is a hydroxy group or the like, and A ² is an oxygen atom or the like. ] Has been disclosed.

 The compound (d) has an oxo group or the like as an essential substituent at the 2-position of the quinoline skeleton. The compound (I) of the present invention has an advantage in that it does not have a substituent at the 2-position of the quinoline skeleton. Wrong. Further, the compound (d) is a compound having a hydroxy group or the like as an essential substituent at the 4-position of the quinoline skeleton and having no oxo group, and the compound (I) of the present invention is a compound having an essential substituent. It also differs in having an oxo group.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.

 In addition, the above compound (d) is disclosed as a cell-mediated immunity enhancer, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(5) Japanese Unexamined Patent Publication No. 2-152992 In this gazette, the following general formula (e)

[In the above compound (e),

R ¹ is a phenyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a phenyl lower alkyl group which may have a substituent, or R ² and R ³ are nitrogen bonded to both. A heterocyclic ring may be formed together with the atom. ] Has been disclosed. The above compound (e), the force that having a Okiso group as a substituent essential to the 2-position of the half-hearted down ^skeleton?, Compound (I) of the present invention are that no substituent at the 2-position of the quinoline skeleton Is different. Further, the compound (e), the force having a hydrate port alkoxy group as essential substituents in the 4-position of the quinoline ^skeleton?, Compounds (I) of the present invention, in terms of having a Okiso groups as essential substituents Different. The compounds (I) of the present invention, the force having the requisite optionally substituted Ariru group as a substituent of the force Rubamoiru groups Yes at the 3-position of the half-hearted down ^skeleton?, The compound (e), the force Rubamoiru It is also different in that it has no aryl group which may be substituted as a substituent of the group.

 Further, this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed

Further, the above compound (e) is disclosed as a leukotriene antagonist, No use for Bile acid transporter inhibitory activity described or suggested

(6) US 5622967

 In this gazette, the following general formula (f)

[In the above compound (f),

X is a group having one CON (R) ₂ ; R is a lower alkyl group, a hydroxy-lower alkyl group, an aralkyl group and the like; Y is an aryl group; and Z is a hetero ring and the like. ] Has been disclosed.

 The compound (f) has the ability to have a ring such as a hetero ring as an essential substituent at the 7-position of the quinoline skeleton. The compound (I) of the present invention has a ring such as a hetero ring at the 7-position of the quinoline skeleton. They differ in that they do not. Further, the compound (I) of the present invention is a compound having an aryl group which may be substituted as an essential substituent of the rubamoyl group at position 3 of the quinoline skeleton. It is also different in that it does not have an aryl group which may be substituted as a substituent of the rubamoyl group. .

Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at least only the following compound is disclosed.

また、 上記化合物 （f ) は、 カルパイン阻害剤として開示されており、 回腸型胆 汁酸トランスポーター阻害作用としての用途は記載も示唆もされていない。

Further, the above compound (f) is disclosed as a calpain inhibitor, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(7) JP-A-6-271570 (EP 6 1273 1A)

 In this gazette, the following general formula (g)

 [In the above compound (g),

A is CH, and R ₂ is a hydrogen atom, halogen, etc., R ₃ is a heterocycle such as piperazine, etc., R ₄ is an amine residue, R ₅ is a hydrogen atom, R ₆ Is a group of one NR ₁₇ R ₁₈ , and R ₁₇ and R ₁₈ are a hydrogen atom and an alkyl group. ] And an intermediate of the above compound (g) are represented by the following formula (g ')

[上記化合物 （g') において、

[In the above compound (g '),

A, RR ₂ , R ₄ , R ₅ and R ₆ have the same meanings as described above, and E is a halogen atom. ] Has been disclosed.

 The compounds (g) and (g ′) are compounds having a hydrogen or alkyl group as a substituent of the rubamoyl group at the 3-position of the quinoline skeleton, and the compound (I) of the present invention is a compound having an essential substituent. This is different in that it has an aryl group which may be substituted.

Further, the above compound (g) has a ring such as piperazine as an essential substituent at the 7-position of the quinoline skeleton, but the compound (I) of the present invention has a ring at the 7-position of the quinoline skeleton as a substituent. It is also different in that it does not have it. Further, the compound (g '), the force having a halogen atom as essential substituents in the 7-position of the quinoline ^skeleton?, Compound (I) of the present invention has no halogen atom in the 7-position of the reluctant emissions backbone They are also different.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most only the following compound is disclosed.

また、 上記化合物 （g) は、 抗ウィルス剤として開示されており、 回腸型胆汁酸 トランスポーター阻害作用としての用途は記載も示唆もされていない。

Further, the above compound (g) is disclosed as an antiviral agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(8) WO 98/23608 In this gazette, the following general formula (h)

[In the above compound (h),

R ¹ is a heterocyclic ring such as pyridine, U is a single bond or alkylene, W is a group having one CON (R ¹⁰ ) .- (alkylene), and R ¹⁰ is hydrogen, alkyl, reels, a Ararukiru group, R "is phenyl (Ci- C ₄₎ alkyl group, Y is a force Rubamoiru groups substituted. a compound having is disclosed. the compounds of the invention (I) is a force having simultaneously an alkyl or alkenyl group and an optionally substituted aryl group as essential substituents of the force-rubamoyl group at position 3 of the quinoline skeleton, and the compound (h) is a force-rubamoyl The difference is that an alkyl or alkenyl group and an aryl group which may be substituted are not simultaneously present as a substituent of the group.

Further, the compound (h) has a heterocyclic ring such as pyridine as an essential substituent in the benzene ring portion of the quinoline skeleton, whereas the compound (I) of the present invention has a benzene ring of the quinoline skeleton. It is also different in that the ring portion does not have a hetero ring as a substituent. Further compounds (I) of the present invention, as an essential substituent at the 1-position of the quinoline skeleton, a force with an optionally substituted Ariru ^group?, The compound (h) is a Ariru group at the 1-position of the quinoline skeleton They differ in not having them.

Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (II) of the present invention. Even if the above compound is selected, at most only the following compound is disclosed.

 Further, the above compound (h) is disclosed as an anti-inflammatory agent and an anticancer agent, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(9) US P 4959363

 In this gazette, the following general formula (i)

[In the above compound (i),

R ¹ is a phenyl group; R ² and R ⁶ are a hydrogen atom, a halogen atom and the like; R ⁷ is a heterocycle such as a pyridyl group; and R is a hydrogen and an alkyl group. ] Are disclosed.

 The compound (i) is different in that it has a monosubstituted rubamoyl group at the 3-position of the quinoline skeleton, and the compound (I) of the present invention is different in that it has a di-substituted rubamoyl group.

 Further, the above compound (i) is a compound having a heterocyclic ring such as pyridine as an essential substituent at the 7-position of the quinoline skeleton, and the compound (I) of the present invention is a compound having a heterocyclic ring at the 7-position of the quinoline skeleton. There is also a difference in not having it.

In addition, this publication discloses a compound having a structure similar to that of the compound (I) of the present invention. No compounds are specifically disclosed, and even if a compound closest to the structure of the compound (I) of the present invention is selected, at most, only the following compounds are disclosed.

また、 上記化合物 （ i ) は、 ヘルぺスウィルス等の抗菌剤として開示されており- 回腸型胆汁酸トランスポーター阻害作用としての用途は記載も示唆もされていな い o

In addition, the above compound (i) is disclosed as an antibacterial agent for herpes virus and the like. No use as an ileal bile acid transporter inhibitory action is described or suggested.

 (10) JP-A-2-138260 (EP 3 1799 1 A)

 In this gazette, the following general formula (j)

 [In the above compound (j),

WXYZR is N—CH = C—C = 0, N—CH ₂ _CH—C = 0 or N—CH ₂ —C = C_OH, and R ¹ and R ² are a hydrogen atom and a lower alkoxy group R ³ is a heterocyclic ring such as phenyl or pyridyl, and m and n are integers of 0 or 1. ] Has been disclosed.

The compound (j) has a monosubstituted rubamoyl group at the 3-position of the quinoline skeleton. The compound (I) of the present invention has a disubstituted rubamoyl group in that it has a disubstituted rubamoyl group. Wrong.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.

 In addition, the above compound (j) is disclosed as an analgesic and an anti-inflammatory agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(1 1) US P 38 1 9637

 In this gazette, the following general formula (k)

 [In the above compound (k),

R ″ is hydrogen, alkyl, etc., 1 ^ ₂ ′ ″ and 1 ^ ₃ ′ ″ are hydrogen, R ₆ is hydrogen or an alkyl group, and m is 0 or 1. . ] Are disclosed.

The compound (k) has an ester group as an essential substituent at the 3-position of the quinoline skeleton. Force ⁵ 'to compounds (I) of the present invention differs in that a disubstituted force Rubamoiru group having no ester group.

 The compound (k) is also different in that the compound (I) of the present invention does not have a substituent at the 2-position of the quinoline skeleton.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.

 Further, the above compound (k) is disclosed as a contraceptive and a cholesterol lowering agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(12) JP-A-11-31463 (EP 343398A)

In this gazette, the following general formula (L)

[In the above compound (L), 007852

16

R ¹ represents a C _{6 to} C ₁₀ aryl which may be optionally substituted with 1 to 2 (or ₃ alkyl or halogen), and R ² represents (^ to (^ alkyl, C! C ^ an alkoxy etc., X ² is hydrogen, (广₍₃ an alkyl or halogen, X ³ is hydrogen, (^ - (- ₃ Al kills, indicates (广alkoxy or halogen, a is one CH- like Y represents an ester group, one CONR ⁴ R ⁵ , R ⁴ represents (^-(: ₃ alkyl, R ⁵ represents ~ C ₃ alkyl, optionally substituted phenyl) Are shown.] Is disclosed.

The compound (L) in 1-position of the quinoline skeleton, a force having a halogen or alkyl-substituted C ₆ which may be -C ₁₀ Ariru group with a group, the compounds (I) of the present invention, one quinoline bone rated When it has an aryl group substituted at the position, it is different in that it has a hydroxy group or a lower alkoxy group as a substituent.

アルコキシ基を有し、 キノリン骨格の 1位に無置換ァリール基を有する化合物を包含する力'、本発明の化 合物 （I) は、 キノリン骨格の 1位に、 無置換ァリール基を有するとき、 R²が水 素原子であり R³が低級アルコキシ基である化合物を除いている点でも上記化合物Further, the compound (L) is located at the 7-position of the quinoline skeleton.

The compound (I) of the present invention having an alkoxy group and a compound having an unsubstituted aryl group at the 1-position of the quinoline skeleton has an unsubstituted aryl group at the 1-position of the quinoline skeleton. And R ² is a hydrogen atom and R ³ is a lower alkoxy group.

(L) is different from the compound of the present invention. .

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.

Further, the above compound (L) is disclosed as an antibacterial agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested. (13) JP-A-1-254666 (EP 310971 A) In this publication, the following general formula (M)

 [In the above compound (M),

R ¹ represents an optionally substituted phenyl, R ² represents hydrogen, (: alkyl or the like, X ² represents hydrogen, nitro, or the like; X ³ represents hydrogen, halogen, or the like; Represents one CH—, etc., Y represents a carboxy group, an ester group, one C〇NR ⁴ R ⁵ , R ⁴ represents (^ 〜 (^ alkyl, R ⁵ represents Ci Cs alkyl, optionally substituted And Z ² represents hydrogen or a compound having the following formulas: (Hiroalkyl, etc.).

The above compound (M) has one CR ² ZiZ ² as an essential substituent at the 7-position of the quinoline ring, but the compound (I) of the present invention has a hydrogen atom, a hydroxyl group at the 7-position of the quinoline ring. In that it has a group or a lower alkoxy group.

 Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.

Also, the above compound (k) is disclosed as an antibacterial agent, and ileal bile No use as an acid transporter inhibitory action is described or suggested.

Disclosure of the invention

 The present inventors conducted a sharp study on a derivative having an ileal bile acid transporter inhibitory action, and found that a nitrogen-containing heterocyclic derivative, a pharmacologically acceptable salt thereof, an ester or other derivative thereof were excellent. The present inventors have found that they have an ileal bile acid transporter inhibitory action, and thus completed the present invention.

 Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned nitrogen-containing heterocyclic derivative, its pharmaceutically acceptable salt, its ester or other derivative as an active ingredient.

 Another object of the present invention is to use the above-mentioned nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof for producing a pharmaceutical composition. A method for preventing hyperlipidemia and Z or arteriosclerosis by administering a pharmacologically effective amount of a nitrogen-containing heterocyclic derivative, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof to a warm-blooded animal, or It is to provide a treatment method.

(1) The nitrogen-containing heterocyclic derivative, pharmacologically acceptable salt, ester or other derivative thereof of the present invention has the following general formula (I).

[Where,

R \ R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group;

R ⁵ is an aryl group, or a hydroxy group or a lower alkoxy group; Represents a substituted aryl group,

R ⁶ is a group having the formula: CONR ⁷ R ⁸ (wherein

R ⁷ represents a C “C _{1 ()} alkyl group or a C ₂ -C ₁₀ alkenyl group,

R ⁸ is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group. ),

However, when R ^{2 is a} hydrogen atom and R ^{3 is a} primary alkoxy group, R ⁵ represents an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups.

], Its pharmacologically acceptable salt, its ester or other derivatives. Substituent group a>

Halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino Group, carboxy group and lower alkoxycarbonyl group.

 Preferably,

 (2)! ^ And! ^ Is a hydrogen atom,

3) 1 ^ ² ', a compound that is a hydrogen atom,

(4) a compound wherein R ² is a hydroxy group or a lower alkoxy group,

(5) a compound wherein R ³ is a hydroxy group or a lower alkoxy group,

(6) R ⁵ is an aryl group compound,

(7) a compound wherein R ⁵ is an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups,

(8) a compound wherein R ⁵ is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups,

(9) R ⁵ forces, 3-arsenide Dorokishifueniru, 4-arsenide Dorokishifueniru, 3 main Toki Shifueniru, 4 main Tokishifue sulfonyl or 3, 4-dimethyl Tokishifueniru group compound object,

(10) a compound wherein R ⁷ is a C `` C ₁₀ alkyl group;

(1 1) a compound wherein R ⁷ is a C `` C ₆ alkyl group,

(1 2) a compound wherein R ⁷ is a C ₄ alkyl group,

(13) a compound wherein R ⁷ is a methyl group or an ethyl group,

(14) a compound wherein R ⁸ is an aromatic heterocyclic group or an aromatic heterocyclic group substituted with 1 to 5 groups selected from a substituent group a,

(15) a compound wherein R ⁸ is an aryl group or an aryl group substituted with 1 to 5 aryl groups or a group selected from substituent group a,

(16) a compound wherein R ⁸ is an aryl group or an aryl group substituted by 1 or 2 groups selected from a substituent group a,

(17) R ⁸ , aryl group, or one or two substituted aryl groups (the substituents may be the same or different and are each a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower An alkoxy group or a lower alkylthio group).

(18) a compound which is an R ⁸ aryl group or a substituted or unsubstituted aryl group (the substituents are the same or different and are a halogen atom, a hydroxy group or a lower alkoxy group);

(1 9) R ⁸ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, A compound which is a 3,5-difluorophenyl or 3,5-dichlorophenyl group,

 (20) Any one compound selected from the following or a pharmacologically acceptable salt thereof 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-1-4-oxo-1,4-dihydroquinoline-1 Carboxylic acid N-methyl-N-phenylamide,

1-1 (4-hydroxy) 1, 6, 7-dimethoxy 1-4-oxo 1, 4 1 Dihydroquinoline-1-carboxylate N-ethyl-1-N-phenylamide,

 1 _ (4-Hydroxyphenyl) -1,6,7-dimethoxy-14,4-year-old xo 1,4-Dihydroxyquinoline-1,3-carboxylate N-methyl-1-N- (3,5-difluorophenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1 4-oxo-1,4-Dihydroquinoline-3-3-Rubonic acid N-methyl-N-phenylamide,

 6,7-Dimethoxy 1- (4-Methoxyphenyl) -1-4-oxo-1,4-Dihydroquinoline 3-Ethyl carboxylate N-ethyl-N-phenylamide,

 1- (4-methoxyphenyl) 1-6,7-dimethoxy 4-oxo-1,4-dihydroquinoline 1-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide,

 11- (4-Methoxyphenyl) -1,6-dimethoxy-4-oxo-1,4-dihydroquinoline-13-Carboxylic acid N-methyl-N- (4-Methoxyphenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N— (3,5-difluorophenyl) amide Do

 1- (3,4-dimethoxyphenyl) 1.6-, 7-dimethoxy-4-oxo-1,4-dihydroxyquinoline-3-tetrafluorocarboxylic acid N-methyl-N— (4-fluorophenyl) amide,

 1- (3,4-Dimethoxyphenyl) 1-6,7-Dimethoxy-4-oxo-1,4-Dihydroxyquinoline 3-Carbonyl N-methyl-1-N— (4-Methoxyphenyl) amide ,.

1- (4-Methoxyphenyl) -16,7,8-Trimethoxy-14-Oxo-1,4-Dihydro-quinoline-13-N-Methyl-1-N- (4-fluorophenyl) amide 1— (4-Methoxyphenyl) _6,7,8—Trimethoxy-14-oxo-1,4-Dihydroxyquinoline-3-Carboxylic acid N-Methyl-1-N— (4-Methoxyphenyl) Do

 1- (3,4-dimethoxyphenyl) 1-6,7,8-trimethoxy-14-oxo—1,4-dihydroquinoline-1-3-carboxylate N-methyl-1-N— (4-fluorophenyl) Amid,

 1- (3,4-Dimethoxyphenyl) 1-6,7,8-Trimethoxy-1 4-oxo-1 1,4-Dihydro-quinoline-1-3-Carboxylic acid N-methyl-1-N— (4-Methoxy Sifenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N— (3-fluorophenyl) amite

 7-Methoxy 1- (4-Methoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) Mid,

 6,7-Dimethoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo_1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N- (3-fluorophenyl) amito, ,

7-Methoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide, 7-Methoxy-1- (4-methoxyphenyl) -1-oxo-1,4, -Dihydroquinoline-3-Carboxyl N-ethyl-N- (3,5-Difluorophenyl) amite ',

 1- (4-methoxyphenyl) -1 7-dimethoxy 4-oxo-1,4-dihydroxyl mouth quinoline 3-carboxylate N-ethyl-N-phenylamide,

 7-Dimethoxy-1- (4-methoxyphenyl) 1-14-oxo-1,4-dihydroquinoline-3 3-Capillonic acid N-methyl-N- (3-fluorophenyl) amide,

7—Methoxy 1— (4-Hydroxyphenyl) 1 4-oxo 1,4-dihydroquinoline Mouth quinoline 3-N-methyl-1-N-phenylamide

 7—Methoxy 1— (4-Hydroxyphenyl) 1 4-oxo 1,4-dihydroquinoline 1—3-Rubonic acid N-Ethyl-N— (3,5-Difluorophenyl) amide,

 1- (4-hydroxyphenyl) -1 7-dimethoxy-1 4-oxo-1,4-dihydroxyquinoline 3-carboxylate ェ -ethyl-l-phenylamide,

 7-Methoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-diethyl mouth quinoline-3-carboxylate Ν-methyl-1-phenylamine, and

 7-Dimethoxy-11- (4-hydroxyphenyl) 1-14-oxo-1,4-dihydroxyquinoline-3-3-Rubonic acid Ν-Methyl-1-Ν (3-fluorophenyl) amide Κ

Can be mentioned. Further, the ileal bile acid transporter inhibitor of the present invention contains, as an active ingredient, a compound having the general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof.

又は (2 1) — General formula (I) '

Or

General formula (I I)

[In the above formula,

RR ² and R \ R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group;

R ⁵ represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups;

R ⁶ is a group having the formula —CONR ⁷ R ⁸ , wherein

R ⁷ is one. An alkyl group or 1. Represents an alkenyl group,

R ⁸ is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group. ).

 ], Its pharmacologically acceptable salt, its ester or other derivatives. <Substituent group a>

Halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono lower alkylamino group, G lower alkylamino Group, carboxy group and lower alkoxycarbonyl group. JP00 / 07852

25 Preferably,

 (22) — a compound having the general formula (I),

 (23) — a compound having the general formula (II),

(24) the compound wherein R ¹ and R ⁴ are hydrogen atoms;

(25) the compound, wherein R ² is a hydrogen atom,

(26) a compound wherein R ² is a hydroxy group or a lower alkoxy group,

(27) a compound wherein R ³ is a hydroxy group or a lower alkoxy group,

(28) R ⁵ is a compound which is an aryl group,

(29) a compound wherein R ⁵ is an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups,

(30) a compound wherein R ⁵ is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups,

(31) a compound wherein R ⁵ is a 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl group;

(32) the compound, wherein R ⁷ is a d—C ₁₀ alkyl group,

(33) the compound, wherein R ⁷ is a d—C ₆ alkyl group,

(34) a compound wherein R ⁷ is a C `` C ₄ alkyl group;

(35) a compound wherein R ⁷ is a methyl group or an ethyl group,

(36) a compound wherein R ⁸ is an aromatic heterocyclic group substituted with 1 to 5 aromatic heterocyclic groups or a group selected from substituent group a,

(37) a compound wherein R ⁸ is an aryl group or an aryl group substituted with 1 to 5 groups selected from a substituent group a,

(38) a compound wherein R ⁸ is an aryl group or an aryl group substituted by 1 or 2 groups selected from a substituent group a,

(39) R ^{8 forces?,} Ariru group, or one or two substituted Ariru group (said substituent The groups are the same or different and are a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a lower alkylthio group. ) A compound,

(40) A compound which is R ⁸ , an aryl group, or a substituted or unsubstituted aryl group (the substituents are the same or different and are a halogen atom, a hydroxy group or a lower alkoxy group). ,

(4 1) R ⁸ forces phenyl, 3-fluorophenyl, 4-fluorophenyl, 3 - Black port phenyl, 4-black port phenyl, 3-main Tokishifueniru, 4 main Tokishifu Eniru, 3, 5-difluorophenyl or 3 A compound that is a, 5-dichlorophenyl group,

 (42) Any one compound selected from the following or a pharmacologically acceptable salt thereof: c 1- (4-hydroxyphenyl) -16,7-dimethoxy-14-oxo-1 1,4-dihydroquinoline _ 3-carboxylate N-methyl-N-phenylamide,

 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4, -dihydroxyquinoline-3-carboxylate N-ethyl-N-phenylamide,

 1- (4-Hydroxyphenyl) -6,7-Dimethoxy-1_4_oxo_1,4-Dihydroxyquinoline-3-Carbonyl N-methyl-1-N- (3,5-Difluorophenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-3-N-methyl-N-phenylamide

 6,7-dimethoxy_1- (4-methoxyphenyl) -1 4-oxo-1,4-dihydroxyquinoline 3-dicarboxylic acid N-ethyl-N-phenylamide

 1- (4-Methoxyethoxy) 1-6,7-Dimethoxy-1 4-oxo-1,4-Dihydroxyquinoline 3-Carbonyl N-methyl-N- (4-Fluorophenyl) amide, .

1- (4-methoxyphenyl) 1-6,7-dimethoxy-1 4-oxo-1 1,4 Hydroquinoline-l-3-Rubonic acid N-methyl-N- (4-methoxyphenyl) amide,

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1 4-oxo_1,4-dihydroxyquinoline-3-carboxylate N-methyl-N- (3,5-difluorophenyl) amide Do

 1- (3,4-dimethoxyphenyl) 1-6,7-dimethoxy-14 4-year-old xo 1,4-dihydroquinoline-1-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide,

 1- (3,4-dimethoxyphenyl) -16,7-dimethoxy-14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N- (4-methoxyphenyl) amide,

 11- (4-methoxyphenyl)-1,6,7,8-trimethoxy-4-oxo-1,4-dihydroquinoline-13-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, '

 11- (4-Methoxyphenyl) -16,7,8-Trimethoxy-14-oxo-1,4-Dihydroxyquinoline-3-Carboxylic acid N-methyl-N- (4-Methoxyphenyl) amide,

 1- (3,4-dimethoxyphenyl) 1-6,7,8-trimethoxy-1 4-oxo-1 1,4-dihydro-quinoline 1-3-carboxylate N-methyl-1-N— (4-fluorophenyl) amido Do

 1- (3,4-dimethoxyphenyl) 1-6,7,8-trimethoxy-4_oxo-1 1,4-dihydroxyquinoline _3-carboxylate N-methyl-N— (4-methoxyphenyl) Amid,

 7-Methoxy 1-phenyl 4-oxo-1,4-dihydroquinoline 3-force N-methyl-N-phenylamide

6, 7-Dimethoxy 1- (4-Methoxyethoxy) 1 4-oxo-1 1, 4 Hydroquinoline-3-carboxylate N-methyl-N- (3-fluorophenyl) amide ',

 7-Methoxy-1-1 (4-Methoxyphenyl) -14-Oxo-1,4-Dihydroquinoline-1-3-Rubonic acid N-methyl-N-phenylamide,

 6,7-Dimethoxy_1- (4-Methoxyphenyl) -1-4-oxo-1,4-Dihydroquinoline-3-3-Rubonate N-Ethyl-N— (3,5-Difluorophenyl) Mid,

 6,7-Dimethoxy-11- (4-hydroxyphenyl) -14-oxo-1,4-Dihydroxyquinoline_3-N-Ethyl-1-carboxylate N- (3,5-Difluorophenyl) amido Do

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline 3-Carbonyl N-methyl-1-N- (3-fluorophenyl) amido G

 7-Methoxy-1- (4-methoxyphenyl) _4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N-phenylamide,

 7-Methoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) amide ',

 1- (4-methoxyphenyl) -1 7-dimethoxy-1 4-oxo-1,4-dihydroxyquinoline 3-potassium N-ethyl-1N-phenylamide

 7-dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N- (3-fluorophenyl) amide,

7-Methoxy-1- (4-hydroxyphenyl) -1-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N-phenylamide,

7—Methoxy 1— (4-Hydroxyphenyl) 1-4-oxo-1,4-dihydroquinoline-1 3 _Carboxylic acid N-ethyl-N— (3,5-difluorophenyl) Amid,

 1- (4-hydroxyphenyl) -1 7-dimethoxy-1 4-oxo-1,4-dihydroxyquinoline 3-carboxylate N-ethyl-N-phenylamide,

 7-Methoxy 1- (4-Hydroxydiphenyl) 1-4-oxo_1,4-dihydroquinoline Mouth quinoline 3-Carbonic acid N-methyl-N-phenylamide,

 7-Dimethoxy-1-I- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid N-methyl-1-N- (3-fluorophenyl) amide ',

 1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1 2-oxo-1, 2-Dihydroxyquinoline-1-Carboxylic acid N-Methyl-1-N- (4-Fluorophenyl Amid,

 1— (4-Methoxyphenyl) —4-Hydroxy_6,7—Dimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-3-Carboxylic acid N-Methyl-1-N— (4-Methoxyphenyl) Ami Do

 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-1,6,7-Dimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-1 3 _Carboxylic acid N-methyl "-N— (4— Fluorophenyl) amide,

 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1-2-oxo-1; I, 2-Dihydroxyquinoline-1 3-Carboxylic acid N-methyl-1-N— (4—Methoxyphenyl Amid,

 1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7,8-Trimethoxy-1-2-Oxo-1,2-Dihydroxyquinoline-1-3-Carboxylic acid N-Methyl-1-N— (4-Fluoro Phenyl) amide,

1- (4-methoxyphenyl) 1-4-hydroxy-1,6,7,8-trimethoxy-1-2-oxo-1,2-dihydroxyquinoline-3-carboxylate N-methyl-1-N— (4-methyl Toxifenil) amide, 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy 6,7,8-Trimethoxy_2-Kizo 1,2-Dihydroxyquinoline-3-Carboxylic acid N-Methyl-1-N-Phenylami Do

 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-1,6,7,8-Trimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-1-3-Rubonic acid N-methyl-1- (4-fluorophenyl) amide,

 1- (3,4-Dimethoxyphenyl) 1-4 4-Hydroxy-6,7,8-Trimethoxy-1 2-oxo-1,2,2-Dihydroxyquinoline-3-carboxylate N-methyl-1-N-1 (4- Methoxy, amide,-

1- (4-Hydroxyphenyl) _4—Hydroxy-1 7-Methoxy-1 2-Oxo-1,2,2-Dihydroxyquinoline-1 3 _Carboxylic acid N-methyl-1-N-phenylamide,

1- (4-Hydroxyphenyl) 1-4-Hydroxy 7-Methoxy-1 2-Oxo-1,2,2-Dihydroxyquinoline 3-Carboxylic acid N-Ethyl-1-N-phenylamide

1- (4-Hydroxyphenyl) 1-4-Hydroxy 7-Methoxy-1 2-oxo—1,2-Dihydroxyquinoline 13-Carboxylic acid N-methyl-1-N— (3-Fluorophenyl) amide,

 1- (4-hydroxyphenyl) 1-4-hydroxy 7-methoxy-2-oxo-1,2, dihydroxyquinoline_3-carboxylate N-ethyl-N- (3-fluorophenyl) amide,

 1— (4-Hydroxyphenyl) 1-4—Hydroxy 7—Methoxy 2—Oxo—1,2-Dihydroxyquinoline 1-3—Carboxylic acid N-Methyl-1-N— (3,5-Difluorophenyl) amide,

 1- (4-Hydroxyphenyl) 1-4-Hydroxy 7-Methoxy-1 2-Oxo-1,2,2-dihydroxyquinoline 1-3-Carboxylic acid N-Ethyl-1-N— (3,5-Difluorophenyl) amide Do

1- (4-Methoxyphenyl) 1 4-Hydroxy 7-Methoxy 2-oxo 1,2-Dihydroxyquinoline _3-N-Methyl-1-N-phenylamide, rubonate, 1-1 (4-Methoxyphenyl) _4-Hydroxy-1 7-Methoxy 2-oxo-1

1, 2-Dihydroxyquinoline _ 3 -N-Ethyl-ruvonic acid N-phenylamide, 1- (4-Methoxyphenyl) 1-4-Hydroxy-1- 7-Methoxy 2-

1,2-dihydroquinoline-3-potassium N-methyl-1-N- (3-fluorophenyl) amide

 1- (4-Methoxyphenyl) _ 4—Hydroxy 7-Methoxy 2—Dioxo 1,2—Dihydroxyquinoline 3—N-Ethyl-1-N- (3-fluorophenyl) amide

 1- (4-Methoxyphenyl) 1-4-Hydroxy 7-Methoxy 2-oxo-1,2-Dihydroxyquinoline 1-3-Carbonyl N-methyl-1-N- (3,5-Difluorophenyl) Do

 1- (4-Methoxyphenyl) -1-hydroxy-7-Methoxy-2-oxo-1,2-Dihydroxyquinoline 3-Fe-Rubonate N-Ethyl-1-N- (3,5-Difluorophenyl) amide,

 1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1-2-oxo-1, 2-Dihydroxyquinoline_3-Carboxylic acid N-Methyl-1-N-phenylamide

 1- (4-Methoxyphenyl) 1-4-Hydroxy-1,6,7-Dimethoxy-2-oxo-1,2-Dihydroxyl-3-3-Carboxylic acid N-Ethyl-1-N-phenylamide ',.

 1- (4-Methoxyphenyl) 1-4 Hydroxy-6,7-Dimethoxy 1-2-Kiso 1,2-Dihydroxyquinoline 1-3 Carboxylic acid N-methyl-1-N— (3-Fluorophenyl) amide,

1- (4-Methoxyphenyl) 1-4 Hydroxy-6,7-Dimethoxy 1-2-year-old Kiso 1,2-Dihydroxyquinoline-3-Carboxylic acid N-Ethyl-1-N— (3-Full Orophenyl) amide,

 1- (4-Methoxyphenyl) 1-4-Hydroxy-1,6,7-Dimethoxy-1 2-Oxo-1,2—Dihydroxyquinoline-3,3-Rubonic acid N-Methyl-N— (3,5- Difluorophenyl) amide, and

 1- (4-Methoxyphenyl) _ 4-Hydroxy-I 6,7-Dimethoxy-2-Oxo 1,2-Dihydroxyquinoline-I 3-Carboxylic acid N-Ethyl-I N- (3,5-Difluorophenyl) amid Do

Can be mentioned. In the above formula, the “halogen atom” in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom. In the above formula, the “lower alkyl group” in the definition of the substituent group a includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1 A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl. the a d-C ₄ alkyl group, more preferably a C i-^ alkyl group, most preferably a methyl group ₀

In the above formula, "halogeno lower alkyl group" in the definition of substituent group a represents a halogen ^{nuclear?-Substituted} group in the "lower alkyl group", for example, triflates Ruo b Methyl , Trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,

2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-ethyl,

3—Clo-propyl propyl, 4-fluorobutyl, 6-hexohexyl, 2,2-dibu-c-C 1-6 halogeno lower alkyl group such as moethyl group, preferably halogeno d—C _{It is a 4-} alkyl group, more preferably a halogeno-C ₂ alkyl group, and most preferably a trifluoromethyl group. In the above formula, “lower alkoxy group” in the definition of RR ² , R ³ , R ⁴ , R ⁵ and the substituent group a represents a group bonded to the above “lower alkyl group” oxygen atom. Toxic, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy Such as methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably a d-C ^ alkoxy group, more preferably C i-C ₂ 7 Turkey A sheet group, most preferably main butoxy group. In the above formula, the “lower alkylthio group” in the definition of the substituent group “a” represents a group in which the above “lower alkyl group” is bonded to a sulfur atom, and is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl Thio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethyl Butylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-di A straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms, such as methylbutylthio, 2,3-dimethylbutylthio, preferably 1 C ₄ alkylthio, and more preferably d. —C is an alkylthio group, most preferably a methylthio group.

In the above formula, the term "lower aliphatic acyloxy group" in the definition of the substituent group a represents a group in which a hydrogen atom or a saturated or unsaturated chain hydrocarbon group is bonded to a dextrinoxy group, such as formyloxy or acetyloxy. Linear chain of 1 to 7 carbon atoms such as, propionyloxy, butyryloxy, isobutyryloxy, norrelyloxy, isonoleryloxy, vivaloyoxy, hexanoyloxy, acryloyloxy, methacryloyloxy, crotonyloxy Or a branched lower aliphatic acetyl group, preferably an acetyloxy or propionyloxy group, and most preferably an acetyloxy group. In the above formula, a group selected from “aryl group”, “aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups” in definition of R ⁵ and R ⁸ , and “substituent group a” Examples of the aryl moiety of the aryl group substituted with 1 to 5 include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl, and naphthyl, and a phenyl group is preferable. It is.

In the above formula, the “aromatic acyloxy group” in the definition of the substituent group “a” indicates a group in which the aryl group is bonded to a carbonyloxy group, and examples thereof include benzoyl, 1-indenylcarbonyl, and 2-indenyl. Nylcarbonyl, 1-naphthoyl and 2-naphthoyl groups, preferably a benzoyl group. In the above formula, the “mono-lower alkylamino group” in the definition of the substituent group “a” has the same meaning as described above in which the above “lower alkyl group” is bonded to one amino group. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-amino Tylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutyl Monomers such as amino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, and 2-ethylbutylamino C -! a C ₆ alkylamino group, preferably a mono one C i-C ₄ alkylamino is A group, further preferably a mono one C, is an C ₂ alkylamino groups, most preferably Mechiruamino group. In the above formula, the “di-lower alkylamino group” in the definition of the substituent group “a” is the same as the “lower alkyl group”. A group bonded to two amino groups, for example, a di-C ₆ alkylamino group such as dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, or dihexylamino group. And preferably a di-C ₄ alkylamino group,

More preferably, it is a di-C ₂ alkylamino group, most preferably a dimethylamino group. In the above formula, the “lower alkoxycarbonyl group” in the definition of the substituent group a represents a group in which the above “lower alkoxy group” is bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl

, Butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl , 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2 A lower alkoxycarbonyl group having 2 to 7 carbon atoms such as —dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl group, and preferably, C ₂ _C ₅ alkoxy A carbonyl group, more preferably a C ₂ -C ₃ alkoxycarbonyl group, and most preferably a methoxycarbonyl group

In the above formula, the aromatic heterocyclic portion of the `` aromatic heterocyclic group '' and the `` aromatic heterocyclic group substituted with 1 to 5 hydroxy groups or lower alkoxy groups '' in the definition of R ⁸ is a sulfur atom, an oxygen atom Or a 5- to 7-membered heterocyclic group containing Z and 1 to 3 nitrogen atoms, for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, — Mention may be made of aromatic heterocyclic groups such as oxaziazolyl, triazolyl, tetrazolyl, thiadiazolyl, vilanyl, pyridyl, pyridazinyl, pyrimidinyl, vilazinyl. In such an aromatic heterocyclic group, a 5- to 6-membered aromatic heterocyclic group or a 5- to 6-membered aromatic heterocyclic group condensed with a benzene ring is preferable, and chenyl, furyl, and the like are more preferable. A pyrenyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, or chenyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group condensed with a benzene ring, more preferably a furyl, thienyl or pyridyl group. Most preferably, it is a 2-phenyl, 3-phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group. In the above formula, “I. alkyl group” in the definition of R ⁷ is, for example, the above “lower alkyl group”, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methyl Hexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, octyl, 1-methylheptyl, 2-methyl Heptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7- Straight or branched chain having 1 to 10 carbon atoms such as dimethyloctyl, 7,7-dimethyloctyl group An alkyl group, preferably is an C ₆ alkyl group, preferably a further a C i-C alkyl group, and most preferably is a methyl group or Echiru group

In the above formula, “C ₂ —C ,. alkenyl group” in the definition of R ⁷ includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1 1-Propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-1-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-2- Butenyl, 1—Methyl-1-butenyl, 3-Methyl-2-butenyl, 1-Ethyl-2-butenyl, 3—Butenyl, 1—Methyl-3-butenyl, 2-Methyl-3-butenyl, 1—Ethyl-3-butenyl, 1-Pentenyl , 2 —pentenyl, 1 —methyl-2-pentenyl, 2 —methyl 2-pentenyl, 3 —pentenyl, 1 —methyl-1-pentenyl, 2-methyl-3 —pentenyl, 4-pentenyl, 1 —methyl-4 —pent A straight chain having 2 to 10 carbon atoms, such as tetra, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; A branched alkenyl group may be mentioned, preferably C ₂ —C ₆ It is an alkenyl group, more preferably a C ₂ -C ₄ alkenyl group, most preferably a 2-propenyl group. In the above, specific examples of the “aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups” in the definition of R ⁵ include, for example, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2,3-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,4,5-triphenyl Droxyphenyl, 2,3-Dimethoxyphenyl, 3,4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 5-Methoxyindene — 2-Nyl, 5-Methyl Toxinaphthalene-12-yl and 5-methoxymethoxyl-11-yl groups can be mentioned, and preferably 1 or 2 substituted with a hydroxy group or a lower alkoxy group. The a Ariru group, and most preferably, 3 - hydroxyphenyl We sulfonyl, 4-arsenide Dorokishifueniru, 3 main Tokishifue sulfonyl, 4-main Tokishifueniru or 3, 4 Jime Tokishifueniru group. In the above, specific examples of the “aryl group substituted by 1 to 5 groups selected from the substituent group a” in the definition of R ⁸ include, for example, the above “1 to 5 hydroxy groups or lower alkoxy groups”. Substituted aryl group ", 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-phenylphenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methylthiophenyl , 2-, 3- or 4-ethylthiophenyl, 2-, 3- or 4-formyloxyphenyl, 2 _, 3-or 4-acetyloxyphenyl, 2-, 3- or 4-propioni Okishifueniru, 2, 3 - or 4 _ Benzoiruo 0 07852

39 Xyphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 3,4-difluorophenyl, 3,4-dichloromouth Phenyl, 3,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 3, 5-dimethylphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-12-methoxyphenyl, 6-fluoro-4-methyl-12-methoxyphenyl, 5-fluoroindene-3-yl, 5-fluoro Loindene 3-yl, 5-methylindene 3-yl, 5-methoxyindene 3-yl, 5-fluoroindene_2-yl, 5-cloin-indene-2-yl, 5-methyl Ruindene 2-yl, 5-fluoronaphthalene

2-yl, 5-fluoronaphthalene-1-yl, 5-methylnaphthalene-1-yl, 5-fluoronaphthalene-111, 5-fluoronaphthalene-1-1-yl , 5-methylylphthalene-1-yl group, preferably an aryl group substituted by 1 or 2 groups, more preferably an aryl group substituted by 1 to 2 groups The substituents are the same or different and each is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a lower alkylthio group.)

A substituted or unsubstituted aryl group (the substituents are the same or different and are a halogen atom, a hydroxy group or a lower alkoxy group), most preferably 3-fluorophenyl, Fluorophenyl, 3-chlorophenyl, 4-cyclophenyl,

It is 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5-difluorophenyl or 3,5-dichlorophenyl group. In the above, specific examples of the “aryl group substituted by 1 to 5 groups selected from the substituent group a” in the definition of R ⁸ include, for example, 3—, 4—, or 5 —fluorofuran 1— 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxy 3-fur, 3-, 4- or 5-methylfur-2-yl, 2-, 4- or 5-methylfuran 3-yl, 3-, 4- or 5-methoxyfuran 2-yl, 2-, 4- or 5-methoxythifur-3-yl, 3-, 4- or 5-methylthiofuran 2-yl, 2-, 4- or 5-methylthiofuran — 3-yl, 4- or 5-acetyloxyfuran-2-yl, 2-, 4- or 5-acetyloxyfuran-3-yl, 4- or 5-formyl 2-yl, 2-, 4- or 5-formyloxyfuran 3-yl, 4- or 5-benzoyloxyfuran 1-2-yl, 2-, 4 —Or 5—Benzo loxyfuran-3-yl, 3—, 4—or 5-Fluorothiophene 2-yl, 3—, 4—or 5—Pro Chiofen one 2-I le, 3-, 4- or 5 - hydroxycarboxylic Chio phen one 2-I le, 3-, 4- or 5-methylthiophene one

2-yl, 2-, 4- or 5-methylthiophene-3-yl, 3-, 4- or 5-ethylthiophene-2-yl, 2-, 4- or 5- Tylthiophene 1-3-yl, 3-, 4- or 5-methoxythiophene 1-2-yl, 2_, 4- or 5-methoxythiophene-3-yl, 3-, 4- or 5-methylthiothiophene 1-yl, 2-, 4- or 5-methylthiothiophene 3-yl,

3-, 4- or 5-acetyloxytoxyfen-1-yl, 2-, 4- or 5-acetyloxytoxyfen-1 3-yl, 3-, 4- or 5- Formyloxy-xityophene-1-yl, 2-, 4- or 5-formyloxyxityophene-1-yl, 3-, 4- or 5-benzoyloxyxityophene-1-yl, 2- 4- or 5-benzoyloxythiophene-3-yl, 3-, 4- or 5-carboxythiophene-2-yl, 2-, 4- or 5-carboxythiophene-3-y 2-, 4- or 5-methoxycarbonylthiophene 3-yl, 3-, 4- or 5-methoxycarbonylthiophene-1-yl, 3- or 4-fluorothiazole 5-yl, 3- or 4-hydroxythiazol 5-yl, 3- or 4-methyl Luciazo 1-ru 5—yl, 3 _, 4 1 or 5— Fluorobenzothiophene-2-yl, 2-, 4_ or 5-Fluorobenzobenzothiophene-3-yl, 3-, 4_ or 5-bromobenzothiophene-2-yl, 2-, 4- or 5-bromobenzothiophene_3_yl, 3-, 4- or 5-hydroxybenzothiophene 2-yl, 2-, 4- or 5-hydroxybenzothiophene 3-yl, 3-, 4- or 5-methylbenzothiophene-2-yl, 2-, 4- or 5-methylbenzothiophene-3-yl, 3-, 4-one or 5-methoxy Benzothiophene 1-yl, 2-, 4- or 5-methoxybenzothiophene 3-yl, 41-, 5-, 6- or 7-methylbenzothiazol 1-2-yl, 2 —Or 4-Fluoropyridine-1-3-yl, 2- or 3-Fluoropyridine-1 4— 2-, 4- or 4-hydroxypyridine-1-yl, 2- or 3-hydroxypyridine-1-yl, 2- or 4-methylpyridine-3-yl, 2- or 3 —Methylpyridine-14-yl, 2- or 4-Methoxypyridine-14-yl, 2- or 3-Methoxypyridine-14-yl, 2- or 4-Methylthiopyridine-14- 2-, 3- or 3-methylthioviridine-1-yl, 2- or 4-acetyloxypyridine-13-yl, 2- or 3-acetyloxypyridine-14-yl, 2_ or 4- Formyloxypyridine-1-yl, 2- or 3-formyloxypyridine-14-yl, 2- or 4-benzoyloxypyridine-1-3-yl, 2- or 3-benzoyloxypyridine-1 4-yl group, preferably, Is a 5- or 6-membered aromatic heterocyclic group substituted with 1 or 2 or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring, more preferably 1 or 2 substituted A 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring (the substituents may be the same or different and each may be a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group A lower alkoxy group, a lower alkylthio group, a carboxy group or a lower alkoxycarbonyl group. And more preferably a 1- or 2-substituted 5- or 6-membered aromatic heterocyclic group (the substituents may be the same or different and are a carboxy group or a lower alkoxycarbonyl group). It is a radical group. And still more preferably 1 to 2 substituted phenyl or pyridyl groups (the substituents being the same or different and being a carboxy group or a lower alkoxy group). Is a 2-carboxy-thiophene-3-yl or 2-methoxycarbonyl-thiophene-13-yl group.

"Pharmacologically acceptable salt thereof" means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group, and When the compound has an acidic group such as a xy group, it can be converted to a salt by reacting with a base. The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, and salts such as benzenesulfonate and p-toluenesulfonate. Organic acid salts such as monosulfonic acid, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate; and glycine salts; Examples include amino acid salts such as lysine salt, arginine salt, ordinine salt, glutamate, and aspartate, and most preferably include organic acid salts. On the other hand, the salt based on an acidic group is preferably an alkaline metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or aluminum. Metal salts such as salts and iron salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, Getylamine, triethylamine, dicyclohexyla Min salt, N, N, 1-dibenzylethylenediamine salt, black mouth proforce salt, proforce salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium Amine salts such as organic salts such as dimethyl salt and tris (hydroxymethyl) aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate. the compounds having the general formula (I) or (II) of can Ru o the present invention, or left in the air, also, by recrystallization, absorb moisture, or with the suction hydraulic ^?, water It may be a hydrate, and such a hydrate is also included in the salt of the present invention. The compound having the general formula (I) or (II) of the present invention may have various isomers since an asymmetric carbon atom may be present in the molecule. In the compound of the present invention, these isomers and a mixture of these isomers are all represented by a single formula, that is, a general formula (I) or (II). Thus, the present invention includes all these isomers and mixtures of these isomers in any proportion. The “ester” in the above refers to the ester of the compound (I) or (II) of the present invention because it can be converted into an ester, and such esters include “ester of a hydroxy group” and “ester”. "Ester of a carboxy group", and refers to an ester in which each ester residue is a "general protecting group" or a "protecting group which can be cleaved in vivo by a biological method such as hydrolysis".

“General protecting group” refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. As the “general protecting group” for the “ester of a hydroxy group”, preferably, holmil, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pinocyloyl, norrelyl, isovaleryl, octanoyl, nonanoyl, decanol , 3-methylnonanoyl, 8-methylnonanoyl, 3-ethylyloctanoyl, 3, '7-dimethyloctanoyl, nddecanol, dodecanoyl, tridecanol, tetradecanol, pentadecanol, hexadecanyl, 1-methylpentadecanol 14-Methylpentadecanoyl, 13,13-Dimethyltetradecanoyl, Heptadecanoyl, 15-Methylhexadecanoyl, Octadecanoyl, 1-Methylheptadecanoyl, Nonadecanoyl, Eicosanoyl, Henicosanoy Alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioyl, methacryloyl, crotonyl, and isocrotonyl. A "substituted lower aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as (E) _2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms; ); Arylcarbonyl groups such as benzoyl, α-naphthoyl and mono-naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; 2,4,6-trimethylbenzoyl; Lower alkylation Arylcarbonyl, lower alkoxylated arylcarbonyl such as 4-anisyl, 4-nitrobenzoyl, nitrated arylcarbonyl such as 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl "Substituted aromatic carbonyl groups" such as lower alkenylcarbonyl carbonyl groups such as lower alkenylcarbonyl groups such as .4-phenylbenzoyl; methoxycarbonyl Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, lower alkoxycarbonyl groups such as isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl Yo An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group; tetrahydrodropyran-2-yl, 3-bromotetrahydridopyryl-2-yl, 4-methoxytetrahyl "Tetrahydrodrobilanyl or tetrahydrodrathiopyranyl groups" such as 4-pyrroyl, te.trahi-drothiopyran_2-yl, 4-methoxytetrahydro-drothiopyran-14-yl; tetrahydrofurofuran-2-yl, tetrahydro-drothiofuran-12 — “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as triyl; trimethylsilyl, triethylsilyl, isopropylpropylsilyl, t-butyldimethylsilyl, methyldisoprovirsilyl, methyldi-tert-butylsilyl, triisoproyl Tri-lower alkylsilyl groups such as luciryl; tri-lower alkylsilyl groups substituted by one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl, etc. “Silyl group”; lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxy "Alkoxymethyl group" such as lower alkoxymethyl group such as ethoxymethyl, lower alkoxymethyl group, halogeno lower alkoxymethyl group such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; Ethoxyxyl, 1— (isopropoxy "Substituted ethyl groups", such as lower alkoxylated ethyl groups such as ethyl, and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, / 3-naphthylmethyl, diphthyl Lower alkyl groups substituted with one to three aryl groups such as phenylmethyl, triphenylmethyl, _β -naphthyldiphenylmethyl, 9_anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3 , 4,5_Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl Such as lower alkyl, lower alkoxy, nitro, halogen, shear An "aralkyl group" such as a lower alkyl group substituted with one to three aryl groups in which the aryl ring is substituted with a phenyl group; such as vinyloxycarbonyl and aryloxycarbonyl; “Alkenyloxycarbonyl group”; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzoylcarbonyl, 4-nitrobenzene Even when the aryl ring is substituted with one or two lower alkoxy or di-total groups such as carbonyl, an "aralkyloxycarbonyl group" can be mentioned.

“Protecting group that can be cleaved in vivo by a biological method such as hydrolysis” is a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. A compound is administered to an experimental animal such as a rat mouse by intravenous injection, and then the body fluid of the animal is examined to determine whether or not the original compound or its pharmacologically acceptable Can be determined by the ability to detect the salt,

 As the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxy group”, preferably, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyl Oxymethyl, butyryloxymethyl, piper'royloxymethyl, norrelyloxymethyl, isonoleryloxymethyl, hexanoyloxymethyl, 1-formyloxetyl, 1-acetoxyl, 1-propionyloxetil , 1-butyryloxyxetil, 1-Pinoroyloxexetil, 1-Norelyloxyxetil, 1-Isonorelyloxixyl, 1-Hexanoyloxixyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxyp Pill,

1-Bivaloyloxypropyl, 1-valeryloxypropyl, 1-isonoryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl , 1-bivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryl Such as oxypentyl, 1-pinoloyloxypentyl, and 1-pinoloyloxyhexyl (“lower aliphatic acyl” oxy) “lower alkyl group”, cyclopentyl carbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyl, 1-cyclohexylcarbonyloxyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarboxyloxypropyl, 1-cyclopentylcarbonyloxylbutyl, 1- 1-("cycloalkyl" carbonyloxy) "lower alkyl" such as cyclohexylcarbonyloxybutyl; 11-("aromatic acyl" oxy) "lower alkyl" such as benzoyloxymethyl 1- (Asiloxy) "lower alkyl group"; Toxicoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyl Xymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1— (ethoxycarbonyloxy) ethyl, 1 1- (isopropoxycarbonyloxy) ethyl, 1_ (butoxycarbonyloxy) ethyl, 1_ (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarboxy) ethyl Nyloxy) ethyl, 1— (pentyloxycarbonyloxy) ethyl, 1— (hexyloxycarbonylcarbonyl) ethyl, 1— (cyclopentyloxycarbonyloxy) ethyl, 1— (cyclopentyloxycarbonyloxy) ) Propyl, 1— (cyclohexyloxycarbonyloxy) propyl, 1— (cyclopentyloxycarbonyloxy) butyl, 1 _ (cyclohexyloxycarbonyloxy) butyl, 1 _ (cyclohexyloxy) Carbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl, 1_ (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl (Isopro PC translation 0/07852

48 Poxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) ) Propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) Xy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1 '-(methoxycarbonyloxy) hexyl, 1 I (Ethoxycarbonyloxy) (5-Carbonyloxy) alkyl group; (5-phenyl-2-oxo_1,3-dioxolen-14-yl) methyl, [5- (4-methylphenyl) -12-oxo-1,3-dioxolen-14 —Yl] methyl, [5- (4-methoxyphenyl) 1-2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -12-oxo1 , 3-Dioxolen-4-1yl) methyl, [5_ (4-chlorophenyl) _2-oxo-1,3-dioxolen-41-yl] methyl, (2-oxo-1-1,3-dioxolen) (4-yl) methyl, (5.-methyl-1-oxo-1,3-dioxolene-41-yl) methyl, (5-ethyl-12-oxo-1, 3-dioxolen-4-1) ) Methyl, (5-propyl-1-2-oxo-1,3-dioxolen-4-yl) methyl (5-Isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, oxodioxorenylmethyl such as (5-butyl-2-oxo-1,1,3-dioxolen-4-yl) methyl “Carbonyloxy lower alkyl group” such as: phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl, etc. “phthalidyl group”: the above “lower aliphatic acyl group”: the above “aromatic acyl group”: “succinic acid” Half ester salt residue ”:“ Phosphate salt residue ”:“ Ester-forming residue such as amino acid ”: Lubamoyl group: Lubamoyl group substituted with one or two lower alkyl groups: and Vivaloyl "One (oxy) alkoxy, such as oxymethyloxycarbonyl A "carbonyloxy group", preferably a "carbonyloxyalkyl group". On the other hand, as the “protecting group capable of being cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group”, preferably, methoxyxyl, 1-ethoxyxyl, 1-methyl_ 1-Methoxyxetyl, 1- (Isopropoxy) ethyl, 2-Methoxyxyl, 2-Ethoxytyl, 1,1—Dimethyl-1-Methoxyxyl, Ethoxymethyl, n_Propoxymethyl, Isopropoxymethyl, n-Butoxymethyl, t Lower alkoxy lower alkyl group such as 1-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxyethoxymethyl, “aryl” oxy “lower alkyl group” such as phenoxymethyl, 2, 2 Halogens, such as 2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl An “alkoxyalkyl group” such as a lower alkoxy lower alkyl group; a “lower alkoxy” carbonyl “lower alkyl group” such as methoxycarbonylmethyl; a “cyano“ lower alkyl group ”such as cyanomethyl and 2-cyanoethyl; "Lower alkyl" thiomethyl groups such as methylthiomethyl and ethylthiomethyl; "aryl" thiomethyl groups such as phenylthiomethyl and naphthylthiomethyl; like 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl "Lower alkyl" sulfonyl "lower alkyl group" which may be substituted with halogen; "" aryl "sulfonyl" lower alkyl group "such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl The above-mentioned "11 (Ascillo) Xy) “lower alkyl group”; the above “phthalidyl group”; the above “aryl group”; the above “lower alkyl group”; “carboxyalkyl group” such as carboxymethyl; and such as phenylalanine "Amide-forming residues of amino acids" can be mentioned.

“Other derivatives” refers to the compounds (I) or (II) of the present invention having an amino group. In this case, a derivative other than the above-mentioned "pharmacologically acceptable salt" and the above-mentioned "ester thereof" can be used. Examples of such a derivative include amide derivatives such as an acyl group. Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, compounds listed in Tables 1 to 3 below. It is not limited. The compounds in Tables 1 and 2 have the structural formulas () and (IΓ), respectively.

In Table 1 and Table 2, the substituents R ⁵ represents the following group.

The abbreviations in the table are as follows,

 A c acetyl group

B z benzyl group

E tethyl group

Me methyl group

P h phenyl group

Pyrd (2) pyridine-1-yl group Pyrd (3) pyridine-3-yl group Pyrd (4) pyridine-1-yl group O / AV εudvl Fiberofc o ϊ¾

Enter H

-16 1 H (R-1) -Bz

-17 1 H (R-1)-(CH ₂ ) ₂ Ph-18 1 H (R-1) -Me

-19 1 H (-1) -iPr

-20 1 H (R-1) -Bu

-21 1 H (-1) -iBu

-22 1 H (R-1) -sBu

-23 1 H (R-1) -tBu

-24 1 H (R-1) -iPn

-25 1 H (R- 1) -CH ₂ CH (Et) ₂ -26 1 H (R- 1)-(CH ₂ ) ₂ CH (Et) ₂ -27 1 H (R_ 1) -1-Et- Bu-28 1 H (R-1) -1-Et-Pn-29 1 H (R-1) -All

-30 1 H (R-3) -CON (e) Ph-31 1 H (R-3) -C0CH (Et) ₂ -32 1 H (R-3) -COCH ₂ CH (Et) ₂ -33 1 H (R-3) -iBu

-3 1 H (R-3)-CH ₂ CH (Et) ₂ -35 1 H (R-3)-Bz

-36 1 H (R-5) -CONHCH (Et) ₂ -37 1 H (R-5) -CONHtBu-38 1 H (R-5)-圆 (4-Cl-Bz) -39 1 H (R -5) -CON (Me) Ph-40 1 H (R-5) -C0CH (Et) ₂ -41 1 H (R-5) -C0CH ₂ CH (Et) ₂

Bird

JPOO / 07852

57 -120 1 6-OH (R-6)-Bz

-121 1 6-OH (R-6)-(CH ₂ ) ₂ Ph

-122 1 6-OH (R-6) -iPr

-123 1 6-OH (R-6) -Bu

-12 1 6-OH (R-6)-sBu

-125 1 6-OH (R-6) -tBu

-126 1 6-OH (R-6) -iPn

-127 1 6-OH (R-6) -CH ₂ CH (Et) ₂

-128 1 6-OH (R-6)-(CH ₂ ) ₂ CH (Et) ₂

-129 1 6-OH (R-6) -1-Et-Bu

-130 1 6-OH (R-6) -1-Et-Pn

-131 1 6-OH (R- 7)-CON (Me) Ph

-132 1 6-OH (R-8) -CON (Me) Ph

-133 1 6-OH (R-ll) -CON (Me) Ph

-134 1 6-OH (R-12)-CON (Me) Ph

-135 1 6-OH (R-14) -CONHPh

-136 1 6-OH (R-14) -CONHCHMePh

-137 1 6-OH (R-14) -C0NHCHMe (4-Me0-Ph) -138 1.6-OH (R-14) -C0NHCHMe (3, 5-diF-Ph) -139 16-OH ( R-14) -C0NH (CH ₂ ) ₂ Ph

-140 1 6-OH (R-14) -CON (Me) Ph

-141 1 6-OH (R-14) -CON (Et) Ph

-142 1 6-OH (R-14)-C0NMe (4- F- Ph)

-143 1 6-OH (R-14) -C0NMe (4-Me0-Ph)

-144 16-OH (R-14)-C0NMe (3,4-diF-Ph) -145 16-OH (R-14) -C0NMe (3, 5-diF-Ph) () e RM- n Oi ^ ■ ^ Ο ζοο * ι σ ^ αι c O oo <n oo oo oo OO oo oo 7> σι y¾ σ¾

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-198 1 6-MeO (R- 2)-C0CH ₂ CH (Et) ₂

-199 1 6-MeO (R- 2) -C0CH (Et) ₂

-200 1 6-MeO (R- 2) -CONHPh

-201 1 6-MeO (-2) -CONHCHMePh

-202 16-MeO (R- 2) -C0NHCHMe (4-Me0-Ph) -203 16-MeO (R-2) -C0NHCHMe (3,5-diF-Ph) -204 16-MeO (R -2)-Picture (CH ₂ ) ₂ Ph

-205 1 6-MeO (R- 2)-CON (Me) Ph

-206 16-MeO (R-2) -C0N (Et) Ph

-207 16-MeO (R-2) -C0NMe (4-F-Ph) -208 16-MeO (R- 2) -Image e (4-CI-Ph) -209 16-MeO (R- 2) -CONMe (4- eO-Ph) -210 16-MeO (R- 2) -C0NMe (3,4-diF-Ph) -211 16-MeO (R- 2) -C0NMe (3,5 -diF-Ph) -212 16-MeO (R-2)-C0NMe (3,4-diMeO-Ph) -213 16-MeO (R-2) -C0NMe (3,5-di e0-Ph) -21 1 6-MeO (R-2) -cPn

-215 1 6-MeO (R-2)-Ph

-216 1 6-MeO (R-2)-Bz

-217 1 6-MeO (R- 2)-(CH ₂ ) ₂ Ph

-218 1 6-MeO (R-2) -Me

-219 1 6-MeO (R-2) -iPr

-220 1 6-MeO (-2) .- Bu

-221 1 6-MeO (R-2) -iBu

-222 1 6-MeO (R-2) -sBu

-223 1 6-MeO (R-2) -tBu -224 6-MeO (R-2) -iPn

-225 6-MeO (R- 2) -CH ₂ CH (Et) ₂

-226 6-MeO (R-2)-(CH ₂ ) ₂ CH (Et) ₂

-227 6-MeO (R-2) -1-Et-Bu

-228 6-MeO (R- 2) -1-Et-Pn

-229 6-MeO (R- 3) -C0CH ₂ CH (Et) ₂

-230 6-MeO (R-3)-C0CH (Et) ₂

-231 6-MeO (R-3) -CONHPh

-232 6-MeO (R-3) -CONHCHMePh

-233 6-MeO (R-3) -C0NHCHMe (4-Me0-Ph) -234 6-MeO (R-3) -C0NHCHMe (3,5-diF-Ph) -235 6-MeO (R-3) -C0NH (CH ₂ ) ₂ Ph

-236 6-MeO (R-3) -C0N (e) Ph

-237 6-MeO (R-3)-C0N (Et) Ph

-238 6-MeO (R-3) -C0NMe (4-F-Ph) -239 6-MeO (R-3) -C0NMe (4-Cl-Ph) -240 6-MeO (R-3) -C0NMe (4-Me0-Ph) -241 6-MeO (R-3) -C0NMe (3,4-diF-Ph) -242 6-MeO (R-3) -C0NMe (3,5-diF-Ph)- 243 6-MeO (R-3) -C0NMe (3,4-diMe0-Ph) -244 6-MeO (R-3) -CONMe (3,5-diMeO-Ph) -245 6-MeO (R-3 ) -cPn

-246 6-MeO (R-3) -Ph

-247 6-MeO (R-3) -Bz

-248 6-MeO (R- 3)-(CH ₂ ) ₂ Ph

-249 6-MeO (R-3)-Me -250 1 6-MeO (R-3) -iPr

-251 1 6-MeO (R-3)-Bu

-252 1 6-MeO (R-3) -iBu

-253 1 6-MeO (R-3) -sBu

-254 1 6-MeO (R-3) -tBu

-255 1 6-MeO (R-3) -iPn

-256 16-MeO (R- 3) -CH ₂ CH (Et) ₂ -257 16-MeO (R- 3)-(CH ₂ ) ₂ CH (Et) ₂ -258 16-MeO (R- 3) -1-Et-Bu-259 16-MeO (R-3) -1-Et-Pn-260 16-MeO (R-4) -CONHCHMePh-261 16-MeO (R-4)- CON (Me) Ph-262 16-MeO (R-4) -cPn

-263 1 6-MeO (R-4) -iBu

-264 16-MeO (R-5)-C0CH ₂ CH (Et) ₂ -265 16-MeO (R-5) -COCH (Et) ₂ -266 16-MeO (R-5) -COPh

-267 16-MeO (R-5) -C0 (4-Cl-Ph) -268 16-MeO (R-5) -CONHBu-269 16-MeO (R-5) -C0N (Et) ₂ -270 16-MeO (R-5) -C0NHCH ₂ CH (Et) -271 16-MeO (R-5)-圆 CH (Et) ₂ -272 16 -MeO (R-5) -CONHcPn- 273 1 6-MeO (R-5) -CONHcHx-274 16-MeO (R-5) -CONHPh-275 16-MeO (R-5) -CONHBz 852

63 -276 1 6-MeO (R-5) -C0NH (3-F-Bz)

-277 1 6-MeO (R-5) -C0NH (4-Cl-Bz)

-278 1 6-MeO (R-5) -CONHCHMePh

-279 16-MeO (R-5) -C0NHCHMe (4-Me0-Ph) -280 16-MeO (R-5) -C0NHCHMe (3, 5-diF-Ph) -281 16-MeO (R -5) -C0NH (CH ₂ ) ₂ Ph

-282 1 6-MeO (R-5) -C0NHCH ₂ CH (Me) Ph

-283 1 6-MeO (R-5) -C0NHCH ₂ CH (0H) Ph

-284 1 6-MeO (R-5) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -285 1 6-MeO (R-5) -C0NHCH ₂ CH (Me) Np (2) -286 1 6-MeO (R-5) -C0NH (CH ₂ ) ₂ Mor (4)

-287 1 6-MeO (R-5) -C0NHCH ₂ Fur (2)

-288 1 6-MeO (R-5) -C0NHCH ₂ Fur (3)

-289 1 6-MeO (R-5) -C0NHCH ₂ Prd (2)

-290 1 6-MeO (R-5) -C0NHCH ₂ Prd (3)

-291 16-MeO (R-5) -C0NHCH (Me) Prd (3) -292 16-MeO (R-5) -COPrd (l)

-293 1 6-MeO (R-5) -C0Mor (4)

-294 1 6-MeO (R-5) -COPiz (l)

-295 1 6-MeO (R-5) -C0 [4-Me-Piz (l)]

-296 1 6-MeO (R-5) -C0 H (CH ₂ ) ₂ NH ₂

-297 1 6-MeO (R-5) -CONHCH ₂ C0 ₂ Et

-298 1 6-MeO (R-5)-CON (Me) Ph

-299 1 6-MeO (R-5) -C0N (Et) Ph

-300 1 6-MeO (R-5) -C0NMe (4-F-Ph)

-301 1 6-MeO (R-5) -C0NMe (4-Cl-Ph) Λ: Key Ι200 S

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66 -354 6-MeO (R-6 -CONHPh

-355 6-MeO (R-6 -CONHBz

-356 6-MeO (R-6-圆 (3-F-Bz)

-357 6-MeO (R-6 -C0NH (4-Cl-Bz)

-358 6-MeO (R- 6 -CONHCHMePh

-359 6-MeO (R- 6-圆 CHMe (4- MeO-Ph) -360 6-MeO (R-6 -C0NHCH e (3,5-diF-Ph) -361 6-MeO (R-6- C0NH (CH ₂ ) ₂ Ph

-362 6-MeO (R-6-Image CH ₂ CH (Me) Ph

-363 6-MeO (R-6-圆 CH ₂ CH (0H) Ph

-364 6-MeO (R-6 -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -365 6-MeO (R-6 -C0NHCH ₂ CH (Me) Np (2) -366 6-MeO (R -6 -C0NH (CH ₂ ) ₂ Mor (4)

-367 6-MeO (R-6 -C0NHCH ₂ Fur (2)

-368 6-MeO (R-6 -C0NHCH ₂ Fur (3)

-369 6-MeO (R- 6 -C0NHCH ₂ Prd (2)

-370 6-MeO (R-6-Image CH ₂ Prd (3)

-371 6-MeO (R-6-圆 CH (Me) Prd (3) -372 6-MeO (R-6 -COPrd (l)

-373 6-MeO (R- 6 -C0 or (4)

-374 6-MeO (R-6 -COPiz (l)

-375 6-MeO (R-6-C0 [4-Me-Piz (l)]

-376 6-MeO (R-6 -C0NH (CH ₂ ) ₂ NH ₂

-377 6-MeO (R- 6 -C0NH (CH ₂ ) ₂ N (Me) ₂

-378 6-MeO (R- 6-圆 CH ₂ C0 ₂ H

-379 6-MeO (R-6 -C0NHCH ₂ C0 ₂ Me -380 1 6-MeO (-6) -C0NHCH ₂ C0 ₂ Et

-381 1 6-MeO (R-6) -C0N (e) Ph

-382 1 6-MeO (R-6) -C0N (Et) Ph

-383 1 6-MeO (R-6) -C0NMe (4-F-Ph) -384 16-MeO (-6)-C0NMe (4- Cl-Ph) -385 16-MeO (R-6) -C0NMe (4-Me0-Ph) -386 16-MeO (R-6) -Picture e (3,4-diF-Ph) -387 16-MeO (R-6) -C0NMe (3,5- diF-Ph) -388 16-MeO (R-6) -C0NMe (3,4-diMe0-Ph) -389 16-MeO (R-6) -CONMe (3,5-diMeO-Ph) -390 1 6-MeO (R-6) -C0N (Me) Bz

-391 16-MeO (R-6) -C0NMe (4-F-Bz) -392 16-MeO (R-6) -C0NMe (4-Me0-Bz) -393 16-MeO (R-6 ) -cPn

-394 1 6-MeO (R-6) -cHx

-395 1 6-MeO (R- 6)-Ph

-396 1 6-MeO (R-6)-4- CI-Ph

-397 1 6-MeO (R-6) -Bz

-398 1 6-MeO (R-6)-(4- MeO-Bz)

-399 1 6-MeO (R-6)-(3,4-diMeO-Bz) -400 16-MeO (R-6)-(3,4,5-triMeO-Bz) -401 16-MeO (R-6)-(CH ₂ ) ₂ Ph

-402 1 6-MeO (R-6)-(CH ₂ ) ₃ Ph

-403 1 6-MeO (R-6) -Thi (2)

-404 1 6-MeO (R-6) -Thi (3)

-405 1 6-MeO (R-6) -Fur (3) -406 16-MeO (R-6)-Me-407 16-MeO (R-6) -Et

-408 1 6-MeO (R-6)-Pr

-409 1 6-MeO (R-6) -iPr

-410 1 6-MeO (R-6) -Bu

-411 1 6-MeO (R-6) -iBu

-412 1 6-MeO (R-6) -sBu

-413 1 6-MeO (R-6) -tBu

-414 1 6-MeO (R-6)-Pn

-415 1 6-MeO (R-6) -iPn

-416 1 6-MeO (R-6) -1-Me-Bu

-417 1 6-MeO (R-6) -CH (Et) ₂

-418 16-MeO (R- 6) -CH ₂ CH (Et) ₂ -419 16-MeO (R-6)-(CH ₂ ) ₂ CH (Et) ₂ -420 16-MeO (R- 6)-1- Et-Bu

-421 1 6-MeO (R-6)-1-Et-Pn

-422 1 6-MeO (R-6) -Vin

-423 1 6-MeO (R-6) -Bun

-42 1 6-MeO (R-6)-3- (3- Me-Bun) -425 1 6-MeO (R-7) -CONHPh

-426 1 6-MeO (R-7) -CONHCHMePh-427 1 6-MeO (R-7) -CON (Me) Ph-428 16-MeO (R-7)-C0N (Et) Ph-429 1 6-MeO (R-7) -C0N e (4-F-Ph) -430 1 6-MeO (R-7) -C0NMe (4-Cl-Ph) -431 1 6-MeO (R-7)- C0NMe (4-Me0-Ph) i OVA Fiber-

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Ώ -458 6-MeO (R-8 -Bz-459 6-MeO (R-8-(CH ₂ ) ₂ Ph

-460 6- MeO (R- 8 -iPr

-461 6-MeO (R- 8 -Bu

-462 6-MeO (R-8 -iBu

-463 6-MeO (R-8 -tBu

-464 6-MeO (R- 8 -iPn

-465 6-MeO (R-8-1-Et-Bu

-466 6- MeO (R-8 -1-Et-Pn

-467 6- MeO (R-9 -CONHCHMePh

-468 6- MeO (R- 9 -CON (e) Ph

-469 6-MeO (R-9 -cPn

-470 6-MeO (R-9 -iBu

-471 6- MeO (R-10 -CONHCHMePh-472 6-MeO (R-10 -CON (e) Ph

-473 6- MeO (R-10 -cPn

-474 6-MeO (R-10 -iBu

-475 6-MeO (R-ll -CONHPh

-476 6-MeO (R-ll -CONHCHMePh-477 6-MeO (R-ll -CON (Me) Ph

-478 6-MeO (R-ll -CON (Et) Ph

-479 6-MeO (R-ll-圆 e (4- F-Ph) -480 6-MeO (R-ll -C0NMe (4- Cl-Ph) -481 6- MeO (R-ll-圆 e ( 4-MeO- Ph) -482 6-MeO (R-ll -C0NMe (3,4-diF-Ph) -483 6- MeO (R-ll-圆 e (3,5-diF- Ph) 0 ⁹ W ~ 9 T 60S-ΐ tM R J ΐ-a) 0 ⁹ W-9 ΐ 80S-! FlLT one I one ^, — (iH) 0 ⁹ W ~ 9 ΐ zos-τ

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ZS8Z, 0 / 00df / X3d 0 0 ΟΛ \ -510 1 6-MeO (R-14) -C0NHCH ₂ CH (Et) ₂ -511 1 6-MeO (R-14) -C0NHCH (Et) ₂

-512 16-MeO (R-14) -CONHcPn

-513 1 6-MeO (R-14) -CONHcHx

-51 1 6-MeO (R-14) -CONHPh

-515 1 6-MeO (R-14) -CONHBz

-516 1 6-MeO (R-14)-C0NH (3-F-Bz)

-517 16-MeO (R-14) -C0NH (4-Cl-Bz) -518 16-MeO (R-14) -CONHCHMePh

-519 16-MeO (R-14) -CONHCHMe (4-MeO-Ph) -520 16-MeO (R-14) -CONHCHMe (3,5-diF-Ph) -521 16-MeO (R -14) -C0NH (CH ₂ ) ₂ Ph

-522 16-MeO (R-14) -C0NHCH ₂ CH (Me) Ph-523 16-MeO (R-14) -C0NHCH ₂ CH (0H) Ph-524 16-MeO (R-14)- C0NH (CH ₂ ) ₂ (4-Cl-Ph) -525 16-MeO (R-14) -C0NHCH ₂ CH (e) Np (2) -526 16-MeO (R-14) -C0NH (CH ₂ ) ₂ Mor (4) -527 1 6-MeO (R-14) -C0NHCH ₂ Fur (2)

-528 1 6-MeO (R-14) -C0NHCH ₂ Fur (3)

-529 1 6-MeO (R-14) -C0NHCH ₂ Prd (2)

-530 1 6-MeO (R-14) -C0NHCH ₂ Prd (3)

-531 16-MeO (R-14) -C0NHCH (Me) Prd (3) -532 1 6-MeO (R-14)-COPrd (l)

-533 1 6-MeO (R-14)-C0Mor (4)

-534 1 6-MeO (R-14) -COPiz (l)

-535 1 6-MeO (R-14) _C0 [4-Me-Piz (l)] -536 1 6-MeO (R-14) -C0NH (CH ₂ ) ₂ NH ₂ -537 1 6-MeO (R-14) -C0NHCH ₂ C0 ₂ Et

-538 1 6-MeO (R-14) -C0N (Me) Ph

-539 1 6-MeO (R-14) -C0N (Et) Ph

-540 16-MeO (R-14) -C0 Me (4-F-Ph) -541 16-MeO (R-14) -C0NMe (4-Cl-Ph) -542 16-MeO (R- 14) -CO Me (4-MeO-Ph) -543 1 6-MeO (R-14) -C0NMe (3,4-diF-Ph) -544 1 6-MeO (R-14)-圆 e (3 , 5-diF-Ph) -545 16-MeO (R-14) -CONMe (3,4-diMeO-Ph) -546 16-MeO (R-14) -C0NMe (3,5-diMe0-Ph ) -547 1 6-MeO (R-14)-CON (Me) Bz

-548 1 6-MeO (R-14) -cPn

-549 1 6-MeO (R-14) -cHx

-550 1 6-MeO (R-14)-Ph

-551 1 6-MeO (R-14) -4-Cl-Ph

-552 1 6-MeO (R-14)-Bz

-553 16-MeO (R-14)-(3,4,5-triMeO-Bz) -554 16-MeO (R-14)-(CH ₂ ) ₂ Ph

-555 1 6-MeO (R-14) -Thi (2)

-556 1 6-MeO (R-14) -Thi (3)

-557 1 6-MeO (R-14) -Me

-558 1 6-MeO (R-14)-Et

-559 1 6-MeO (R-14)-Pr

-560 1 6-MeO (R-14) -iPr

-561 1 6-MeO (R-14)-Bu T / JPOO / 07852

74 -562 1 6-MeO (R-14)-iBus

-563 1 6-MeO (R-14) -sBu

-564 1 6-MeO (R-14) -tBu

-565 1 6-MeO (R-14)-Pn

-566 1 6-MeO (R-14) -iPn

-567 1 6-MeO (R-14) -1-Me-Bu

-568 1 6-MeO (R-14) -CH (Et) ₂

-569 1 6-MeO (R-14)-CH ₂ CH (Et) ₂

-570 1 6-MeO (R-14)-(CH ₂ ) ₂ CH (Et) ₂

-571 1 6-MeO (R-14) -1-Et-Bu

-572 1 6-MeO (R-14) -1-Et-Pn

-573 1 6-MeO (R-15) -CONHPh

-57 1 6-MeO (R-15) -CONHCHMePh

-575 1 6-MeO (R-15) -C0N (Me) Ph

-576 1 6-MeO (R-15) -C0N (Et) Ph

-577 1 6-MeO (R-15) -C0NMe (4-F-Ph)

-578 1 6-MeO (R-15)-圆 e (4-Cl- Ph)

-579 1 6-MeO (R-15)-圆 e (4-MeO-Ph)

-580 1 6-MeO (R-15) -C0NMe (3, 4-diF-Ph) -581 16-MeO (R-15)-C0NMe (3,5-diF-Ph) -582 1 6-MeO (R-15)-C0NMe (3,4-diMeO-Ph) -583 16-MeO (R-15)-圆 e (3,5-diMeO-Ph) -584 16-MeO (R-15) -cPn

-585 1 6-MeO (R-15)-Bz

-586 1 6-MeO (R-15)-(CH ₂ ) ₂ Ph

-587 1 6-MeO (R-15)-iPr

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JS8.0 / 00df / X3d 0 0 -640 1 6-MeO (R-17) -tBu

-641 1 6-MeO (R-17) -iPn

-642 16-MeO (R-17) -CH ₂ CH (Et) ₂ -643 16-MeO (R-17)-(CH ₂ ) ₂ CH (Et) -644 16-MeO (R-17 ) -1-Et-Bu-645 16-MeO (R-17) -1-Et-Pn-646 17-MeO K-l) -C0N (Me) Ph-647 17-MeO (R-1) ) -C0CH (Et) ₂ -648 1 7-MeO (R-1) -C0CH ₂ CH (Et) ₂ -649 17-MeO (R-1) -COPh

-650 1 7-MeO (R-1) -cPn

-651 1 7-MeO (R-1) -Bz

-652 1 7-MeO (R-1) -iPr

-653 1 7-MeO (R-1)-iBu

-654 1 • 7-MeO. (R-1) -CH ₂ CH (Et) ₂ -655 1 7-MeO (R-1) -All

-656 1 8-MeO (R-6)-CON (Me) Ph-657 1 8-MeO (R-14) -C0N (Me) Ph-658 16-EtO (R-6) -C0N (Me) Ph-659 16-EtO (R-14)-CON (Me) Ph-660 17-EtO (R-1)-CON (Me) Ph-661 17-EtO (R-2) -C0N (Me ) Ph-662 1 7-EtO (R-3) -C0N (Me) Ph-663 17-EtO (R-4) -C0N (Me) Ph-664 17-EtO (-5)-CON (Me ) Ph-665 1 7-EtO (R-6) -C0N (Me) Ph ¾ (¾3) Ν03- (S-φ HO-8 HO- L HO-9 e 169-ΐ qd (9W) N0D- (S-> HO-8 HO- L HO-9 ε 069-ΐ d ^z (¾3 ) HN03- (9 -H) HO-8 HO- L HO-9 £ 689-1

(¾-i! P-9'C) 3WH3HN03- (S -¾) HO-8 HO- L HO-9 £ 889-1

(¾-0 ⁹ W-) 3WH3H 03- (S-a) HO-8 HO- L HO-9 ε 89-Τ

 ■ ：)-(s -y) HO-8 HO- L HO-9 c 989- Τ

 HO-8 HO- L HO-9 ε S89-I qj (3w) 03- (ε-HO-8 HO- L HO-9 ε

 (3 o- (z -¾) HO-8 HO- HO- 9 ε m ~ id (3W) N03- (T -H) HO-8 HO- L HO-9 ε 289- Τ

¾ (3W) N03- (n-) HO-Z 189-ΐ

¾ (3W) 03- (9 -¾) HO-Z 089- ΐ qd (3W) N03- (-HO- 9 6Ζ9-Τ qj (9W) N03- (9 -¾) HO-9 8Ζ9-Ϊ d ( 3W) N03- (8Ϊ-Η) mL Ζ- 9-Ϊ qj ( ⁹ W) N03- (Ζΐ-¾) 013- 9Ζ9-Ι qd ( ⁹ W) N03- (9ΐ-¾) SZ9-I (3 03 -(ST-H) L9-1 Okina:)-(I-¾) εζ9-ι () ΝΟ-(ετ-a) 2Ζ9-Ϊ qd (3W) N03- d ΪΖ9-Ϊ qd (3W) 03- ( ΐΐ-¾ 0Ζ9-Ϊ

¾ (3W) N03- (Οΐ-Η) 053- 699- ΐ qd (3W) N03- (6-899-ΐ qd (3W) 0D- (8 -¾) on-i 99-Ϊ qj (3W) 03 -(z -¾) 999-ΐ

ZS8Z.0 / 00df / X3J ¾ί (靡 03- HO-8 H0- L H0-9 ε ζτζ-ΐ ¾ (3W) N03- H0-8 H0- I H0-9 ε 9U-ΐ ¾ '(¾3) HN03- HO-8 H0- I H0-9 ε STZ-ΐ (¾-Jl -S '£) 3WH3HN03- HO-8 H0- L H0-9 ε -ΐ (0 „excitation :)-HO-8 H0- L H0-9 ε εα-ΐ

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 MdHNOO- HO-8 H0- L H0-9 ε πζ-ΐ

 HO-8 H0- L H0-9 ε o -ΐ

-30 HO-8 H0- L H0-9 ε 60 -Τ

 HO-8 H0- I H0- 9 ε 80Ζ-Ϊ

^Ζ (Ϊ3) Η3¾3- H0-8 H0- L H0-9 e ο -τ ud!-HO-8 H0- L H0-9 £ 90Ζ-Ϊ

 HO-8 H0- L H0-9 ε SO ΐ ngi- HO-8 H0- L H0-9 ε-ΐ ng-HO-8 H0- L H0-9 ε εοζ-τ

 H0-8 H0- L H0-9 £

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 HO-8 H0- L H0-9 ε 669- ΐ

U (-H0-8 H0- L H0-9 ε 869-1

(d-0 ⁹ WlP-S '£) 3WM03- HO-8 H0- L H0-9 £ 69-Ϊ

(qd-o ⁹ wi-^ 'e) ⁹ wN03- HO-8 H0- I H0-9 969-ΐ

(qd-J! P-S'8) 3WN03- HO-8 H0- I H0-9 369-ΐ

(-J! P- 'ε) 3 顺 03-HO-8 H0- L H0-9 £, 69- ΐ

(-0¾-nutrition)-HO-8 H0- L H0-9 c £ 69- ΐ (qd-d-^) 3WN03- HO-8 H0- L H0-9 ε Ζ69-1

6L

ZS8.0 / 00df / X3d (¾-J! P-S'C) 3WH0HN03- (n-a) HO-8 H0_ L HO-9 ε ΐ

(¾-0 ⁹ W- ^) ⁹ WH3H 03- (π -¾) HO-8 H0- L HO-9 ε ΐ

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MdHNOO- (π -¾) HO-8 HO- I HO-9 ε οη-ι qd (3W) NOD- (ζι-) HO-8 HO- L HO-9 ε 6 £ L- \

¾ (3W) N03- (π-HO-8 HO- L HO-9 ε 8ε -ΐ

¾ (3W) N03- (8 HO-8 HO- L HO-9 ε ζε -τ

¾ ( ⁹ W) N03--HO-8 HO- L HO-9 ε 92L-1

¾-ί3-ΐ- (9 -¾) HO-8 HO- L HO-9 ε ng-: 13-ΐ-(9 -H) HO-8 HO- L HO-9 ε KL-1

³ (^ 3) Η3 '(¾3)-(9 -¾) HO-8 H0- L HO-9 c εε -ΐ

^Ζ (¾3) Η3¾3- (9-HO-8 HO- L HO-9 ε

 ud!-(9 -¾) 'HO-8 HO- L HO-9 c TC -T ng;-(9 -¾) HO-8 HO- L HO-9 2 οε -ι ngs-(9 -¾) HO-8 HO- L HO-9 ε ng-(9 -a) HO-8 HO- L HO-9 ε 82Ζ-Τ

Jdl- (9 -¾) HO- 8 HO- L HO-9 ε L-\

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.za- (9-¾) HO-8 HO- ■ L HO-9 c

 ud- (9-) HO-8 HO- ■ I HO-9 ε

(qd-o ⁹ w? p-s's) 3W 03- (9 -a) HO-8 HO- ■ I HO-9 ε ε-ΐ

(qd-o ⁹ wiP-^ 'e) ⁹ WN03- (9 -a) HO-8 HO- -L HO-9 ε

 (¾-i! P-S '£) 3WN03- (9 HO-8 HO- ■ Z HO-9 c \ ZL- \

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(¾--^) 3WN03- (9 -¾) HO-8 HO- -L HO-9 ε 8 -T

08

ZS8Z, 0 / 00df / X3d 0 0 ΟΛ \ (ΐ-Z 69Ζ-Ϊ qdHNOO- (ΐ -Η) o -L 0 ⁹ W-9 Z 89 ΐ (NO _ ΐ-a) HO-8 HO-Z HO-9 £ Ζ9 -Τ

¾ (3W) N03- (9ΐ-¾ HO-8 HO-Z HO-9 99Ζ-Ϊ

¾ (3W) N03- (ST-¾) HO-1 8 HO-Z HO-1 9 £ S9 ΐ

¾-ί3-ΐ- (^ τ-Η) HO-8 HO-Z HO-9 m-i

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'(53) Η3¾3- HO-8 HO-Z HO-9 £ Τ9 -Ϊ

 HO-8 HO-Z HO-9 ε 09-ΐ ng-HO-8 HO-Z HO-9 ε 69Ζ-Τ ngs- HO-8 HO-Z HO-9 ε 89Ζ-Ϊ-(η-ϋ) HO One 8 HO-Z HO One 9 ε L L-1

-(Η-Η) HO-8 HO-Z HO-9 £ 99Ζ-Ϊ

¾ '(¾3)-(Η-Η) HO-8 HO-Z HO-9 ε S9Z-T

 (i-a) HO-8 m- HO-9 £-\

Uc-(Η-Η) HO-8 HO-Z HO-9 £

(qd-0 ⁹ N! P- 'e) 3W 03- HO-8 HO-Z HO-9 ε ζ-\

(qd-0 ⁹ WIP-^ '8) ⁹ MJ03- HO-8 HO-Z HO-9 ε Τ9Ζ-Τ

(d- lP-S'e) 3WNOO- (Η-Η) HO-8 HO-Z HO-9 ε 09Ζ-Ϊ

(¾-JiP- 'e) 3WN03- HO-8 HO-Z HO-9 ε

 (-0) 9 ranks-HO-8 HO-Z HO-9 ε-ι

 (η-ϋ) HO-8 HO-Z HO-1 9 ε

 ¾i 3) Ν03-(-a) HO-8 HO-Z HO-9 £ -i

¾ (3W) N03- (Η-Η) HO-8 HO-Z HO-9 (¾) Shima-HO-8 HO-Z HO-9

X8

ZS8Z, 0 / 00df / XDd H3) Image 3- (Z -a) (FW-9 Z 56Ζ-Ϊ

(¾-i! P-S'S) 3WH3HN03- (Z -¾) o ⁹ wz (PW- 9 Z-\-(PW-) 3 Touch 3- (Z-) o ⁹ wz (FW-9 Z -i

(Z -¾) o ⁹ wz 0 ⁹ W-9 Z Z6L-1

(Z -¾) O -9 Z -i

(Z -¾) o ⁹ w- 0 ⁹ W-9 Z 06Ζ-Ϊ

'(¾3) Η3¾303- (Z -¾) 0 ⁹ N- 0 ⁹ N-9 Z 68Ζ-Ϊ

(ΐ -¾) o ⁹ wz 0 ³ W-9 Z 88Ζ-Ϊ ng- ai- (I -Η) o ⁹ wz 0 ⁹ W-9 Z Ζ8Ζ-Ϊ!-(T -¾ o ⁹ wz 03W-9 Z 98-ΐ ng;-(T -¾) 03W- (PW-9 Z 98Ζ-Ϊ

n _a _ (T -¾) (W-9 Z -i

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(qd-0 ⁹ Wi -5'C) 3WN03- (ΐ o ⁹ wz 0 ⁹ W-9 z 8Ζ -Ϊ

(Ή- (FW! P- 1 '£) ³丽 0-(ΐ-• 0 ⁹ W-9 z LLL-l

(Md-J! P-S'S) 3i¾N03- (ΐ-) 0 ⁹ NZ 0 -9 z 9ZZ-T

(M-JI-'S) 3WN03- (ΐ -¾) (PW-9 z SZZ-T

(WPW), 03- (ΐ-Η) 0 ⁹ N- (PW- 9 z I

(¾-I0-^) 3WN03- (ΐ -¾) o ⁹ wz 0 ⁹ W-9 z εζζ-τ

() Nutrition :)-(τ-) o ⁹ wz 0 -9 z ZLL- \ (难 03- (ΐ-Η) 03W-9 z ΐΖΖ-ΐ qd (3W) N03- (ΐ (PW— 0 ⁹ W -9 z ο -ΐ

28

ZS8.0 / 00df / X3d -796 26-MeO 7-MeO (R- 2) -C0N (Me) Ph

-797 2 6-MeO 7-MeO (R-2) -C0N (Et) Ph

-798 26-MeO 7-MeO (R- 2) -C0NMe (4-F-Ph) -799 26-MeO 7-MeO (R- 2) -C0NMe (4-Cl-Ph) -800 26 -MeO 7-MeO (R- 2) -C0NMe (4-Me0-Ph) -801 26-MeO 7-MeO (R-2)-C0NMe (3,4-diF-Ph) -802 26-MeO 7-MeO (R-2) -C0 Me (3,5-diF-Ph) -803 26-MeO 7-MeO (R-2) -CONMe (3,4-diMeO-Ph) -804 2 6- MeO 7-MeO (R-2) -CONMe (3,5-diMeO-Ph) -805 6-MeO 7-MeO (-2)-cPn

-806 2 6-MeO 7-MeO (-2)-Ph

-807 2 6-MeO 7-MeO (R-2)-Bz

-808 2 6-MeO 7-MeO (R- 2)-(CH ₂ ) ₂ Ph

-809 2 6-MeO 7-MeO (R-2)-Me

-810 2 6-MeO 7-MeO (R-2) -iPr

-811 2 6-MeO 7-MeO (-2)-Bu

-812 2 6-MeO 7-MeO (R-2) -iBu

-813 2 6-MeO 7-MeO (R-2) -sBu

-814 2 6-MeO 7-MeO (R-2) -tBu

-815 2 6-MeO 7-MeO (-2) -iPn

-816 2 6-MeO 7-MeO (R- 2) -CH ₂ CH (Et) ₂

-817 26-MeO 7-MeO (R- 2)-(CH ₂ ) ₂ CH (Et) ₂ -818 26-MeO 7-MeO (-2) -1-Et-Bu

-819 2 6-MeO 7-MeO (R-2) -1-Et-Pn

-820 2 6-MeO 7-MeO (R-3) -COCH ₂ CH (Et) ₂

-821 2 6-MeO 7-MeO (-3) -C0CH (Et) ₂ -822 26-MeO 7-MeO (R-3) -CONHPh -823 26-MeO 7-MeO (R-3) -CONHCHMePh

-824 26-MeO 7-MeO (R-3) -C0NHCH e (4-Me0-Ph) -825 26-MeO 7-MeO (R-3) -C0NHCHMe (3,5-diF-Ph)- 826 2 6-MeO 7-MeO (R-3) -C0NH (CH ₂ ) ₂ Ph

-827 2 6-MeO 7-MeO (R-3)-C0N (Me) Ph

-828 2 6-MeO 7-MeO (R-3)-C0N (Et) Ph

-829 26-MeO 7-MeO (R-3) -C0NMe (4-F-Ph) -830 26-MeO 7-MeO (R-3) -C0NMe (4-Cl-Ph) -831 26 -MeO 7-MeO (R-3) -C0NMe (4-Me0-Ph) -832 26-MeO 7-MeO (R-3) -C0NMe (3,4-diF-Ph) -833 26-MeO 7-MeO (R-3)-C0N e (3,5-diF-Ph) -834 2 6-MeO 7-MeO (R-3) -CONMe (3,4-di eO-Ph) -835 2 6 -MeO 7-MeO (R-3) -C0NMe (3,5-diMe0-Ph) -836 26-MeO 7-MeO (R-3) -cPn

-837 2 6-MeO 7-MeO (R-3)-Ph

-838 2 6-MeO 7-MeO (R-3)-Bz

-839 2 6-MeO 7-MeO (R-3)-(CH ₂ ) ₂ Ph

-840 2 6-MeO 7-MeO (R-3) -Me

-841 2 6-MeO 7-MeO (-3)-iPr

-842 2 6-MeO 7-MeO (R-3) -Bu

-843 2 6-MeO 7-MeO (R-3) -iBu

-844 2 6-MeO 7-MeO (R-3) -sBu

-845 2 6-MeO 7-MeO (R-3) -tBu

-846 2 6-MeO 7-MeO (-3)-iPn

—847 2 6-MeO 7-MeO (R-3)-CH ₂ CH (Et) ₂ -848 2 6-MeO 7-MeO (R-3)-(CH ₂ ) ₂ CH (Et) ₂

-849 2 6-MeO 7-MeO (R-3) -1-Et-Bu

-850 2 6-MeO 7-MeO (R-3)-1-Et-Pn

-851 2 6-MeO 7-MeO (R-4) -CONHCHMePh

-852 2 6-MeO 7-MeO (R-4) -C0N (Me) Ph

-853 2 6-MeO 7-MeO (R-4)-cPn

-854 2 6-MeO 7-MeO (R-4)-iBus

-855 2 6-MeO 7-MeO (R-5)-C0CH ₂ CH (Et) ₂

-856 2 6-MeO 7-MeO (R-5) -C0CH (Et) ₂

-857 2 6-MeO 7-MeO (R-5) -COPh

-858 2 6-MeO 7-MeO (R-5)-C0 (4- CI- Ph)

-859 2 6-MeO 7-MeO (R-5) -CONHBu

-860 2 6-MeO 7-MeO (R-5) -C0N (Et) ₂

-861 26-MeO 7-Me0 (R-5) -CONHCH ₂ CH (Et) ₂ -862 26-MeO 7-MeO (R-5) -C0NHCH (Et) ₂

-863 2 6-MeO 7-MeO (R-5) -CONHcPn

-864 2 6-MeO 7-MeO (R-5) -CONHcHx

-865 2 6-MeO 7-MeO (R-5) -CONHPh

-866 2 6-MeO 7-MeO (R-5) -CONHBz

-867 2 6-MeO 7-MeO (R-5) -C0NH (3-F-Bz)

-868 26-MeO 7-MeO (R-5) -C0NH (4-Cl-Bz) -869 26-MeO 7 -MeO (R-5) -CONHCHMePh

-870 2 6-MeO 7-MeO (R-5) -C0NHCHMe (4-Me0-Ph) -871 26-MeO 7-MeO (R-5) -C0NHCHMe (3,5-diF-Ph) -872 2 6-MeO 7-MeO (R-5)-圆 (CH ₂ ) ₂ Ph

-873 2 6-MeO 7— MeO (R-5) -CONHCH ₂ CH (Me) Ph -874 2 6-MeO 7-MeO (R-5) -C0NHCH ₂ CH (0H) Ph-875 26-MeO 7-MeO (R-5) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -876 2 6-MeO 7-MeO (R-5) -C0NHCH ₂ CH (Me) Np (2) -877 26-MeO 7-MeO (R-5) -C0 H (CH ₂ ) ₂ Mor (4 ) -878 26-MeO 7-MeO (-5) -C0NHCH ₂ Fur (2) -879 26-MeO 7-MeO (R-5) • -C0NHCH ₂ Fur (3) -880 26-MeO 7 -MeO (R-5) -C0NHCH ₂ Prd (2) -881 26-MeO 7-MeO (R-5) -C0NHCH ₂ Prd (3) -882 26-MeO 7-MeO (R-5)- C0NHCH (Me) Prd (3) -883 26-MeO 7-MeO (R-5) -COPrd (l)

-884 2 6-MeO 7-MeO (R-5) -C0Mor (4)

-885 2 6-MeO 7-MeO (-5) -COPiz (l)

-886 2 6-MeO 7-MeO (R-5)-C0 [4-Me-Piz (l)]-887 26-MeO 7-MeO (-5) -C0NH (CH ₂ ) ₂ NH ₂ -888 2 6-MeO 7-MeO (R-5) -CONHCH ₂ C0 ₂ Et

-889 2 6-MeO 7-MeO (R-5) -C0N (Me) Ph

-890 2 6-MeO 7-MeO (R-5) -C0N (Et) Ph

-891 26-MeO 7-MeO (R-5) -C0NMe (4-F-Ph) -892 26-MeO 7-MeO (R-5) -C0NMe (4-Cl-Ph) -893 26 -MeO 7-MeO (R-5) -CONMe (4-MeO-Ph) -894 26-MeO 7-MeO (R-5)-C0NMe (3,4-diF-Ph) -895 26-MeO 7-MeO (R-5) -C0NMe (3,5-diF-Ph) -896 26-MeO 7-MeO (-5) -CONMe (3,4-diMeO-Ph) -897 26-MeO 7 -MeO (R-5)-C0NMe (3,5-diMeO-Ph) -898 2 6-MeO 7-MeO (-5) -C0N (Me) Bz

-899 2 6-MeO 7-MeO (R-5) -cPn -900 2 6-MeO 7-MeO (R-5)-cHx

-901 2 6-MeO 7-MeO (R-5) -Ph

-902 26-MeO 7-MeO (R-5) -4-Cl-Ph-903 26-MeO 7-MeO (R-5)-Bz

-904 2 6-MeO 7-MeO (R- 5) - (3, 4, 5-triMeO-905 2 6-MeO 7-MeO (R- 5) - (CH 2) 2 Ph-906 2 6-MeO 7-MeO (R-5)-Thi (2) -907 2 6-MeO 7-MeO (-5) -Thi (3) -908 26-MeO 7-MeO (R-5) -Me

-909 2 6-MeO 7-MeO (R-5) -Et

 1

-910 2 6-MeO 7-MeO (R-5)-Pr

-911 2 6-MeO 7-MeO (R-5)-iPr

-912 2 6-MeO 7-MeO (R-5) -Bu

-913 2 6-MeQ 7-MeO (R-5)-iBus

-914 2 6-MeO 7-MeO (-5)-sBu

-915 2 6-MeO 7-MeO (R-5) -tBu

-916 2 6-MeO 7-MeO (R-5) -Pn

-917 2 6-MeO 7-MeO (R-5)-iPn

-918 26-MeO 7-MeO (R-5) -1-Me-Bu-919 26-MeO 7-MeO (R-5)

-920 2 6-MeO 7-MeO (R-5) -CH ₂ CH (Et) ₂ -921 2 6-MeO 7-MeO (R-5)-(CH ₂ ) ₂ CH (Et) ₂ -922 2 6-MeO 7-MeO (R-5) -1-Et-Bu-923 2 6-MeO 7-MeO (R-5)-1-Et-Pn-924 26-MeO 7-MeO (R-6 ) -COiPr

-925 2 6-MeO 7-MeO (R-6) -COiBu : d>

CM M CM CS1 M M si

! -O OO oi o

 J M CM M

 T> i C i ~ s <3> ~> TI oi

Dimension

 6

 9 inch 6

Spirits: 8 9H 0%- -952 2 6-MeO 7- MeO (R-6) -CONHCHMePh

-953 26-MeO 7-MeO (R-6)-C0NHCHMe (4-MeO-Ph) -954 26-MeO 7-MeO (R-6) -C0NHCHMe (3,4-diF-Ph) -955 2 6-MeO 7- MeO (R- 6) -C0NHCHMe (3,5-diF-Ph) -956 2 6-MeO 7-MeO (R - 6) -C0NH (CH 2) 2 Ph

-957 26-MeO 7-MeO (R-6) -C0NHCH ₂ CH (Me) Ph-958 26-MeO 7-MeO (R-6) -C0NHCH ₂ CH (0H) Ph-959 26-MeO 7-MeO (R-6) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -960 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ CH (Me) Np (2) -961 2 6-MeO 7- MeO (R-6) -C0NH (CH ₂ ) ₂ or (4) -962 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Fur (2)

-963 2 6-MeO 7- MeO (R-6) -C0 HCH ₂ Fur (3)

-964 2 6-MeO 7- MeO (R-6) -C0NHCH ₂ Prd (2)

-965 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Prd (3)

-966 2 6-MeO 7-MeO (R-6) -C0NHCH (Me) Prd (3) -967 26-MeO 7-MeO (R-6) -C0NHCH (Me) Pyr (4) -968 26 -MeO 7 eO (R-6) -COPrd (l)

-969 2 6-MeO 7- MeO (R-6) -C0 or (4)

-970 2 6-MeO 7-MeO '(R-6) -COPiz (l)

-971 2 6-MeO 7- MeO ( R- 6) -C0 [4 - Me- Piz (l)] - 972 2 6- MeO 7 - MeO (R - 6) -CONH (CH 2) 2 NH 2

-973 2 6-MeO 7- MeO ( R- 6) -C0NH (CH 2) 2 N (Me) 2 -974 2 6- MeO 7-MeO (R- 6) -CONHCH 2 C0 2 H

-975 2 6-MeO 7- MeO (R-6) -C0NHCH ₂ C0 ₂ e

-976 2 6-MeO 7-MeO (R- 6)-圆 CH ₂ C0 ₂ Et

i— -977 2 6-MeO 7-MeO (R-6) -CON (Me) Ph .

i—

 Ο —

 << D t> 0 Ϊ

Ϊ koto

 琴 Koto painting

Painting TJPOO / 07852

91 -1004 2 6-MeO 7-MeO (R-6)-Pr

-1005 2 6-MeO 7-MeO (R-6) -iPr

-1006 2 6-MeO 7-MeO (-6) -Bu

-1007 2 6-MeO 7-MeO (R-6) -iBu

-1008 2 6-MeO 7-MeO (R-6) -sBu

-1009 2 6-MeO 7-MeO (-6) -tBu

-1010 2 6-MeO 7-MeO (R-6)-Pn

-1011 2 6-MeO 7-MeO (R-6) -iPn

-1012 2 6-MeO 7-MeO (R-6) -1-Me-Bu

-1013 2 6-MeO 7-MeO (R-6)-CH (Et) ₂

-1014 2 6-MeO 7-MeO (R-6) -CH ₂ CH (Et) ₂

-1015 2 6-MeO 7-MeO (R-6)-(CH ₂ ) ₂ CH (Et) ₂

-1016 2 6-MeO 7-MeO (R-6) -1-Et-Bu

-1017 2 6-MeO 7-MeO (R-6) -1-Et-Pn

-1018 2 6-MeO 7-MeO (R-6) -Vin

-1019 2 6-MeO 7-MeO (R-6) -Bun

-1020 2 6-MeO 7-MeO (R-6) _3- (3-Me- Bun)

-1021 2 6-MeO 7-MeO (R-7) -CONHPh

-1022 2 6-MeO 7-MeO (R-7) -CONHCHMePh

-1023 2 6-MeO 7-MeO (R-7)-CON (Me) Ph

-1024 2 6-MeO 7-MeO (R-7)-C0N (Et) Ph

-1025 2 6-MeO 7-MeO (R-7) -C0NMe (4-F-Ph)

-1026 2 6-MeO 7-MeO (R-7)-C0NMe (4- CI- Ph)

-1027 2 6-MeO 7-MeO (R-7) -CONMe (4-MeO-Ph)

-1028 2 6-MeO 7-MeO (R-7)-C0NMe (3,4-diF-P

-1029 2 6-MeO 7-MeO (R-7) -CONMe (3,5-diF-P Bird

1. -1056 26-MeO 7-MeO (R-8) -iPr-1057 26-MeO 7-MeO (R-8) -Bu

-1058 2 6-MeO 7-MeO (R-8) -iBu

-1059 2 6-MeO 7-MeO (R-8) -tBu

-1060 2 6-MeO 7-MeO (R-8) -iPn

-1061 2 6-MeO 7-MeO (R-8) -1-Et-Bu

-1062 2 6-MeO 7- MeO (R-8) -1-Et-Pn

-1063 2 6-MeO 7- MeO (R-9) -CONHCHMePh

-1064 2 6-MeO 7-MeO (R-9) -CON (Me) Ph

-1065 2 6-MeO 7-MeO (R-9) -cPn

-1066 2 6-MeO 7- MeO (R-9) -iBu

-1067 2 6-MeO 7- MeO (-10) '-CONHCHMePh

-1068 2 6-MeO 7- MeO (R-10)-CON (Me) Ph

-1069 2 6-MeO 7- MeO (R-10) -cPn

-1070 2 6-MeO 7-MeO (R-10) -iBu

-1071 2 6-MeO 7- MeO (R-ll) -CONHPh

-1072 2 6-MeO 7- MeO (R-ll) -CONHCHMePh

-1073 2 6-MeO 7- MeO (R-ll) -C0N (Me) Ph

-1074 2 6-MeO 7-MeO (R-ll) -C0N (Et) Ph

-1075 26-MeO 7-MeO (R-ll) -C0NMe (4-F-Ph) -1076 26-MeO 7-MeO (R-ll) -C0NMe (4-Cl-Ph) -1077 26 -MeO 7- MeO (R-ll)-圆 e (4- MeO- Ph) -1078 26-MeO 7-MeO (R-ll) -CONMe (3,4-diF-Ph) -1079 2 6- MeO 7-MeO (R-ll) -CONMe (3,5-diF-Ph) -1080 26-MeO 7-MeO (R-ll) -C0NMe (3,4-diMe0-Ph) -1081 2 6- MeO 7-MeO (R-ll)-圆 e (3,5-diMeO-Ph)

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 L-1109 2 6-MeO 7-MeO (R-14) -CONHcHx

 [-1110 2 6-MeO 7-MeO (R-14) -CONHPh

ί-1111 2 6-MeO 7-MeO (R-14) -CONHBz

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 L-1113 26-MeO 7-MeO (R-14) -C0NH (4-Cl-Bz)

 L-1114 2 6-MeO 7-MeO (R-14) -CONHCHMePh

L-1115 26-MeO 7-MeO (R-14) -CONHCHMe (4-MeO-Ph) ί-1116 26-MeO 7-MeO (R-14) -C0 HCHMe (3,5-diF-Ph ) 1117 2 6-MeO 7-MeO (R-14) -CONH (CH ₂ ) ₂ Ph

1118 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ CH (Me) Ph 1119 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ CH (0H) Ph 1120 2 6-MeO 7 -MeO (R-14) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) 112 1121 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ CH (e) Np (2) 112 1122 2 6 -MeO 7-MeO (R-14) -C0NH (CH ₂ ) ₂ Mor (4)

L-1123 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Fur (2)

1-1124 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Fur (3) 1125 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Prd (2)

1-1126 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Prd (3)

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1-1128 2 6-MeO 7-MeO (R-14) -COPrd (l)

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 1-1130 2 6-MeO 7-MeO (R-14) -COPiz (l)

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1-1132 2 6-MeO 7-MeO (R-14) -CONH (CH ₂ ) ₂ NH ₂

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-1345 2 6-MeO 7-OH (R-14)-CH ₂ CH (Et) ₂ -1346 2 6-OH 7-MeO (R-1) -C0N (Me) Ph-1347 26-OH 7- MeO (R-1) -C0CH (Et) ₂ -1348 2 6-OH 7-MeO (R-1) -C0CH ₂ CH (Et) ₂ -1349 2 6-OH 7-MeO (R-1) -iBu

-1350 2 6-OH 7-MeO (R- 1) -CH ₂ CH (Et) ₂ -1351 26-OH 7-MeO (-I) '-C0N (Me) Ph-1352 26-OH 7- MeO (R- 1) -C0CH (Et) ₂ -1353 26-OH 7-MeO (R-1) -C0CH ₂ CH (Et) ₂ -1354 26-OH 7-MeO (R-6) -C0N (e) Ph-1355 26-OH 7-MeO (R-6) -C0CH (Et) ₂ -1356 26-OH 7-MeO (R-6) -C0CH ₂ CH (Et) ₂ -1357 26 -OH 7-MeO (R-6) -iBu

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-97 1 6- OH (R-5) -iPr

-98 1 6-0H (R-5) -Bu

-99 1 6-OH (R-5) -iBu

-100 1 6- OH (R-5) -tBu

-101 1 6-OH (R-5) -iPn

-102 1 6-OH (R-5)-CH ₂ CH (Et) ₂ ,

-103 1 6- OH (R-5)-(CH ₂ ) ₂ CH (Et) ₂

-104 1 6-OH (R-5) -1-Et-Bu

-105 1 6-OH (R-5) -1-Et-Pn

-106 1 6-OH (-6) -CONHPh

-107 1 6-OH (R-6) -CONHCHMePh

-108 16-OH (R-6) -CONHCHMe (4-MeO-Ph) -109 16-OH (R-6) -C0NHCHMe (3,5-diF-Ph) -110 16-OH (R -6) -C0NH (CH ₂ ) ₂ Ph

-111 1 6-OH (R- 6)-CON (Me) Ph

-112 1 6-OH (R-6)-C0N (Et) Ph

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-120 1 6-OH (R-6)-Bz

-121 1 6-OH (R-6)-(CH ₂ ) ₂ Ph -122 1 6-OH (R-6) -iPr

-123 1 6- OH (R-6)-Bu

-124 1 6-OH (-6) .- sBu

-125 1 6-OH (-6) -tBu

-126 1 6-OH (R-6) -iPn

-127 1 6-OH (R-6)-CH ₂ CH (Et) ₂

-128 1 6-OH (R-6) _ (CH ₂ ) ₂ CH (Et) ₂

-129 1 6-OH (R-6) -1-Et-Bu

-130 1 6-OH (R-6) -1-Et-Pn

-131 1 6-OH (R-7) -CON (Me) Ph

-132 1 6-OH (R-8)-CON (Me) Ph

-133 1 6-OH (R-11) -CON (Me) Ph

-134 1 6-OH (R-12)-CON (Me) Ph

-135 1 6-OH (R-14) -CONHPh

-136 1 6-OH (R-14) -CONHCHMePh

-137 16-OH (R-14) -CONHCHMe (4-MeO-Ph) -138 16-OH (R-14) -C0NHCHMe (3,5-diF-Ph) -139 16-OH (R -14) -CONH (CH ₂ ) ₂ Ph

-140 1 6-OH (R-14) -CO Australia) Ph

-141 1 6-OH (R-14) -CON (Et) Ph

-142 16-OH (R-14) -C0NMe (4-F-Ph) -143 16-OH (R-14) -C0NMe (4-Me0-Ph) -14 1 6-OH (R-14 )-C0N e (3,4- diF-Ph) -145 1 6- OH (R-14) -C0NMe (3,5-diF-Ph) -146 16-OH (R-14) -C0NMe (3 , 4-diMeO-Ph) -147 16-OH (R-14)-C0NMe (3,5-diMeO-Ph) -148 6-OH (R-14) -cPn

-149 6-0H (R-14) -Bz

-150 6- OH (R-14)-(CH ₂ ) ₂ Ph-151 6- OH (R-14) -iPr

-152 6- OH (R-14) -Bu

-153 6- OH (R-14) -sBu

-154 6-OH (R-14) -tBu

-155 6-OH (R-14) -iPn

-156 6- OH (R-14) -CH ₂ CH (Et) ₂ -157 6-OH (R-14)-(CH ₂ ) ₂ CH (Et) ₂ -158 6-OH (R-14)- 1-Et-Bu-159 6-OH (R-14) -1-Et-Pn-160 6-OH (R-15) -C0N (Me) Ph-161 6-OH (R-16) -C0N ( (Me) Ph-162 6- OH (R-17) -C0N (Me) Ph-163 7- OH (R-1) -CH ₂ CH (Et) ₂ -164 7-OH (R-6) -C0N ( Me) Ph-165 7- OH (R-14) -C0N (e) Ph-166 8- OH (R-6) -C0N (Me) Ph-167 8-OH (R-14) -C0N (e) Ph-168 8- OH (R-1) -C0N (Me) Ph-169 8-OH (R-2) -C0N (Me) Ph-170 8-OH (R-3) -Bz

-171 8-OH (R-4) -C0N (Me) Ph-172 8-OH (R-5) -C0N (Me) Ph-173 8-OH (R-7) -C0N (e) Ph '(^ 3) Η303- (z-¾) 0 ³ W-9 ΐ 66T-Z

² (53) Η0¾303- (z -¾) 0 ⁹ W "9 ΐ 86

 (I-) 03W-9 ΐ L61-Z

-; 3-ΐ-(ΐ-) 0 ⁹ W-9 ΐ 961-2

-(ΐ -¾) 0 ^a W-9 ΐ mz ngi- (ΐ -¾) 0 ⁹ N-9

ng- (τ-a) 0 ⁹ W ~ 9

-(ΐ-) (PHI- 9 ι mz (¾)-(ΐ-) 0 ³ W-9 .ΐ Οβΐ-2 za- (I -Η) 0 ⁹ W-9 ΐ 681-2

(ΐ -¾) 0 ⁹ W- 9 ΐ mz

(qd-0 ³ W! p-S '£) 3WN03- (ΐ-Φ 0 ⁹ W "9 ΐ L 1-Z

(¾-03W! P- ^) 3WN03- (ΐ-) 0 ⁹ W-9 ΐ mz

(qd-JiP-S ^< S) 3WN03- (ΐ -Η) 0 ⁹ W-9

(Md-diP-^ 'O ^ WNOO- (ΐ -¾) 0 ⁹ N-9 ΐ mz

(qd-0 ⁹ W- ^) ⁹ 03- (ΐ-¾) 0 ⁹ W-9 ΐ ε8ΐ-2

(-D- 0-(ΐ -¾) 0 ⁹ W-9 ΐ 281-2

(qd- -l7) 3W 03- (ΐ -¾) 0 ⁹ W-9 ΐ -z

¾i (Cold 0-(ΐ-Η) (PW-9 ΐ 08

Md (9W) N03- (ΐ -¾) 0 ⁹ W-9 ΐ -z 3 strokes;)-(ΐ -¾) 0 ⁹ W "9 \ 2LI-Z

MdHNOO- (ΐ -¾) 03W-9 d (3W) N03- (0ΐ-¾) HO- 8 τ -z (3 00- (6 HO-8

¾ (3W) 03- (8 —a) HO— 8 ΐ u \ -z

ZS8.0 / 00df / X3d (Z -H) 0 ⁹ W ~ 9 ΐ ZZ-Z

(Z -a) 0 ⁹ W-9 ΐ zz-z m- (Z -¾) 03W-9 ΐ mz ngs- (Z -H) 0-9 τ τα-τ

 ng- (Z -¾) 0 -9 ΐ m-z

^{J d -! (Z - 0} 9 W-9 ΐ

~ (Z 0 ³ W-9

 HO)-(Z 0 -9 ΐ ί \ ζ-ζ

{Z 0¾- 9 ΐ 9 \ Ζ ~ Ζ

U (-(Z -a) 0 ⁹ W-9 τ m

¾HPW! P- S '£) 3WN (X) 1 (Z 0 ⁹ W-9 ΐ ειζ d-03WiP-^' £) 3WN03- (Z 0 -9 ΐ ζ \ ζ-ζ

(qd- ^ iP-S'OsWNOO- (Z-ΐ

(qd-03W-^) 3fVN03- (Z-) 0 ⁹ W-9

1) Nutrition :)-(Z 0 ⁹ W "9

(¾-J-) 3WN03- (Z-) 0 ⁹ W-9 ΐ L0Z-Z

Md (^ a) N03- (Z-) 0 ^s W-9 1 902-2

¾ (3W) 03- (Z-) 0 ⁹ W-9 I 90Ζ-Ζ () excited:)-(Z -Η) o -9 ΐ d- lp-g'OQWHDHNOO- (Z-Η) 0 ⁹ N -9

((PW) 3 strokes :)-(Z-¾) 0 ⁹ W-9 ΐ ZQZ-Z quake :)-(Z-Η)

Shelf 03— (Z —a) 0 ⁹ W-9 ΐ mz

SIT iS8Z, 0 / 00df / X3d 0 0 O

-252 1 6-MeO (R-3) -iBu

-253 1 6-MeO (R-3) -sBu

-254 1 6-MeO (R-3)-tBu

-255 1 6-MeO (R-3) -iPn

-256 16-MeO (R-3) -CH ₂ CH (Et) ₂ -257 16-MeO (R- 3)-(CH ₂ ) ₂ CH (Et) ₂ -258 16-MeO (R- 3) -1-Et-Bu-259 16-MeO (R-3) -1-Et-Pn-260 16-MeO (-4) -CONHCHMePh-261 16-MeO (R-4)-CON (Me) Ph-262 16-MeO (R-4) -cPn

-263 1 6-MeO (R-4) -iBu

-264 1 6-MeO (R- 5 ) -C0CH 2 CH (Et) 2 -265 1 6-MeO (- 5) -C0CH (Et) 2 -266 1 6-MeO (R- 5) -COPh

-267 16-MeO (R-5) -C0 (4-Cl-Ph) -268 16-MeO '(R-5) -CONHBu-269 16-MeO (R-5) -C0N (Et) ₂ -270 1 6-MeO (R-5) -C0NHCH ₂ CH (Et) -271 16-MeO (R-5) -C0NHCH (Et) ₂ -272 16-MeO (R-5) -CONHcPn- 273 1 6-MeO (R-5) -CONHcHx-274 16-MeO (R-5) -CONHPh-275 16-MeO (R-5) -CONHBz-276 16-MeO (R-5)-圆 (3-F-Bz) -277 16-MeO (R-5) -C0NH (4-Cl-Bz) -278 6-MeO (R-5) -CONHCHMePh

-279 6-MeO (R-5) -C0NHCHMe (4-Me0-Ph) -280 6-MeO (R-5) -C0NHCHMe (3,5-diF-Ph) -281 6-MeO (R-5) -C0NH (CH ₂ ) ₂ Ph

-282 6-MeO (R-5) -C0NHCH ₂ CH (Me) Ph-283 6-MeO (R-5) -C0NHCH ₂ CH (0H) Ph-284 6-MeO (R-5) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -285 6-MeO (R-5) -C0NHCH ₂ CH (Me) Np (2) -286 6-MeO (R-5) -C0NH (CH ₂ ) ₂ Mor ( 4) -287 6-MeO (R-5) -C0NHCH ₂ Fur (2)

-288 6-MeO (R-5) -C0NHCH ₂ Fur (3)

-289 6-MeO (R-5) -C0NHCH ₂ Prd (2)

-290 6-MeO (R-5) -C0NHCH ₂ Prd (3)

-291 6-MeO (R-5) -C0NHCH (Me) Prd (3) -292 6-MeO (R-5) -COPrd (l)

-293 6-MeO (R-5) -C0Mor (4)

-294 6-MeO (R-5) -COPiz (l)

-295 6-MeO (R- 5) -C0 [4- Me- Piz (l)] - 296 6-MeO (R- 5) -C0NH (CH 2) 2 NH 2

-297 6-MeO (R-5) -CONHCH ₂ C0 ₂ Et

-298 6-MeO (R-5) -C0N (Me) Ph

-299 6-MeO (R-5) -CON (Et) Ph

-300 6-MeO (R-5) -C0NMe (4-F-Ph) -301 6-MeO (R-5) -C0NMe (4-Cl-Ph) -302 6-MeO (R-5) -C0NMe (4-Me0-Ph) -303 6-MeO (R-5) -C0NMe (3,4-diF-Ph) LO

OO

CO CO C

CM

cm

: ¾ ^ — Snow: s¾— 0-9

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 CM OO Dimension Ln tD tT- OO Oi O — M Dimension L to OO CT> o

 C dimension LO

 CO CO CO CO CO O CO CO CO)-O CO

 I I M CM CM CM CM CM CM CM CM CM CM C3 M CM CM CS1 C 1

 ) ≤ waking-; waking 9H-

 i country 3 9-; Awakeri 9¾-—

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10 9.— -356 1 6-MeO (R-6) -C0NH (3-F-Bz)

-357 16-MeO (-6)-C0NH (4- Cl-Bz) -358 16-MeO (R-6) -CONHCHMePh

-359 16-MeO (R-6) -C0NHCHMe (4-Me0-Ph) -360 16-MeO (R-6) -C0NHCHMe (3,5-diF-Ph) -361 16-MeO (R -6) -C0NH (CH ₂ ) ₂ Ph

-362 1 6-MeO (R-6) -C0NHCH ₂ CH (Me) Ph-363 16-MeO (R-6) -C0NHCH ₂ CH (0H) Ph-364 16-MeO (R-6)- C0NH (CH ₂ ) ₂ (4-Cl-Ph) -365 16-MeO (R-6) -C0NHCH ₂ CH (Me) Np (2) -366 16-MeO (-6) -C0NH (CH ₂ ) ₂ Mor (4) -367 1 6-MeO (-6) -C0NHCH ₂ Fur (2)

-368 1 6-MeO (R-6) -C0NHCH ₂ Fur (3)

-369 1 6-MeO (R-6) -C0NHCH ₂ Prd (2)

-370 1 6-MeO (R-6) -C0NHCH ₂ Prd (3)

-371 1 6-MeO (R-6) -C0NHCH (Me) Prd (3) -372 16-MeO (R-6) -COPrd (l)

-373 1 6-MeO (R-6) -C0Mor (4)

-37 1 6-MeO (R-6) -COPiz (l)

-375 1 6-MeO (R - 6) -C0 [4-Me-Piz (l)] - 376 1 6-MeO (R- 6) -C0NH (CH 2) 2 NH 2

-377 1 6-MeO (R-6) -C0NH (CH ₂ ) ₂ N (Me) ₂ -378 1 6-MeO (R-6) -C0NHCH ₂ C0 ₂ H

-379 1 6-MeO (-6) -C0NHCH ₂ C0 ₂ Me

-380 1 6-MeO (R-6) -C0NHCH ₂ C0 ₂ Et

-381 1 6-MeO (R-6) -C0N (Me) Ph -382 1 6-MeO (R-6) -C0N (Et) Ph

-383 1 6-MeO (R-6) -C0NMe (4-F-Ph) -384 16-MeO (R-6) -C0NMe (4-Cl-Ph) -385 16-MeO (R-6 ) -C0NMe (4-Me0-Ph) -386 16-MeO (R-6) -C0NMe (3,4-diF-Ph) -387 16-MeO (R-6) -C0NMe (3,5- diF-Ph) -388 1 6-MeO (R-6)-C0NMe (3,4-diMeO-Ph) -389 1 6-MeO (R-6)-C0NMe (3,5-diMeO-Ph) -390 1 6-MeO (R-6) -CON (Me) Bz

-391 16-MeO (R-6) -C0NMe (4-F-Bz) -392 16-MeO (R-6) -CONMe (4-MeO-Bz) -393 16-MeO (R-6 ) -cPn

-394 1 6-MeO (-6) -cHx

-395 1 6-MeO (R-6) -Ph

-396 1 6-MeO (R-6)-4-CI-Ph

-397 1 6-MeO (R-6) -Bz

-398 1 6-MeO (R-6)-(4-MeO-Bz)

-399 16-MeO (R-6)-(3,4-diMeO-Bz) -400 16-MeO (R-6)-(3,4,5-triMeO-Bz) -401 16-MeO (R-6)-(CH ₂ ) ₂ Ph

-402 1 6-MeO (R-6)-(CH ₂ ) ₃ Ph

-403 1 6-MeO (R-6) -Thi (2)

-404 1 6-MeO (R-6)-Thi (3)

-405 1 6-MeO (R-6) -Fur (3)

-406 1 6-MeO (R-6) -Me

-407 1 6-MeO (R-6)-Et d-! P-S'e) 3WN03- (Z -¾) 0 ⁹ W ~ 9 ΐ mz d-'ε) ³ strokes-(I-H) 0 ⁹ W-9 s s

(Ή-0) ())-U -¾) 03W-9 ΐ ιε

(¾-13- ^) ⁹ WN03- a -¾) 0 ⁹ W- 9 ΐ 02 -Z

(¾!-) ³ vice-u-Φ 03W-9 ΐ 6 qd (? A) N03- u 03W-9 ΐ

 Tsu--03W-9 ΐ Ζ qdsWHOHNOQ- u -¾) ΐ S

^ ciHNO-a -¾) (PW_9 ΐ

 (img- 9j¾-ε)-ε- (9 -H) 03W-9 ΐ

 ung- (9-) 03W-9 ΐ m-z

 (9-a) τ s

(9 -¾) 03W-9 τ ΐ

'(ΐ3) Η3 ^ζ (¾3)-(9-) 0 ⁹ W-9 I 6ί z (^ a) H3¾3- (9 -¾) 0 ⁹ W-9 ΐ mz

 (9 -H) 03W-9 ΐ

(9 -¾) 0 ⁹ W- 9 ΐ 9

(9-0-9 ΐ UZ

(9 -¾) 0 ⁹ W-9

 ngs- (9 -¾) τ ζ \ -ζ

 (9 -¾) 0 -9 τ π ng- (9 -¾) τ -z

-(9-03W-9 ΐ 60 one (9 03N-9 ΐ 80

2ΖΙ

ZS8.0 / 00df / X3d 0 0 OAV (8 -¾) 0 ⁹ W-9

(8 0 ⁹ W-9 ΐ 8S 2 uj- (8 -¾) 0 ⁹ W-9 ΐ -Z

(qd-0 ⁹ W! P-S'C) 3WN03- (8 -a) 03W-9 ΐ vz

(qd-0 ⁹ WIP-^ 'S) 3W 03- (8 -¾) 0 ⁹ W-9

 (qd-d! P-5'S) 3WN03- (8-) 03W-9

(-'£) 9 hanging-(8 0 ⁹ W-9 ΐ ss ^ -z

( ^8-0a W-9

(D) ⁹ Kin- (8 03W-9 ΐ mz

(¾-d-) 3WN00- (8-0 ⁹ N-9 ΐ OS

¾I (Cold (X)-(8 -¾) 0 ⁹ W ~ 9 τ βη-ζ qd (9W) N03- (8 "¾) 0 ⁹ W-9 ΐ 8 ^ -2, .Image:)-(8 -¾) ΐ

^ dH OO- (8 "¾) 0 ⁹ W-9 ΐ

¾-ϊ3-ΐ- U -H) 0 ⁹ W-9 ΐ η-ζ a _¾) 03W-9 ΐ mz ud!-"¾) 0 ⁹ W-9 ΐ ngi- U-0 ⁹ W-9

ngi- U 0 ⁹ W-9 ΐ \ η-ζ ng-U -¾) 0 ⁹ W-9 ΐ ο

a "¾) 0 ³ W-9 τ -zu -H) (FW- 9 τ 8ε zg- a -¾) 0 ⁹ W-9 τ ζ-u -¾) 0 ⁹ W-9 ΐ

(¾-0 ⁹ W! P-S '£) 9WN03- a-¾) 0 ⁹ W-9 I

 (— (PW! P £) 3 encouraged:)-a "¾) 03W-9 ΐ -z

ΨΖΙ

ZS8.0 / 00df / X3d 0 0 OAV 852

125 -460 1 6- eO (R-8) -iPr

-461 1 6-MeO (R-8)-Bu

-462 1 6-MeO (R-8) -iBu

-463 1 6-MeO (R-8) -tBu

-464 1 6-MeO (R-8)-iPn

-465 1 6-MeO (R-8) -1-Et-Bu

-466 1 6-MeO (R-8)-1 Ki Pn

-467 1.6-MeO (R-9) -CONHCHMePh

-468 1 6-MeO (R-9) -C0N (Me) Ph

-469 1 6-MeO (R-9) -cPn

-470 1 6-MeO (R-9) -iBu

-471 1 6-MeO (R-10) -CONHCHMePh

-472 1 6-MeO (R-10) -C0N (Me) Ph

-473 1 6-MeO (R-10) -cPn

-474 1 6-MeO (R-10) -iBu

-475 1 6-MeO (R-11) -CONHPh

-476 1 6-MeO (R-11) -CONHCHMePh

-477 1 6-MeO (R-11) -C0N (e) Ph

-478 1 6-MeO (R-11) -C0N (Et) Ph

-479 1 6-MeO (R-11) -C0NMe (4-F-Ph)

-480 1 6-MeO (R-11) -C0NMe (4-Cl-Ph)

-481 1 6-MeO (R-11) -C0NMe (4-Me0-Ph)

-482 16-MeO (R-11) -C0NMe (3,4-diF-Ph) -483 16-MeO (R-11)-C0NMe (3 '5-diF-Ph) -484 16-MeO (R-11) -CONMe (3, 4-diMeO-Ph) -485 16-MeO (R-11) -C0NMe (3, 5-diMeO-Ph) Blockage 08;

M CM

M CM

Xinjiang 9—

Snow Thunder-鲁 -512 6-MeO (R-14 -CONHcPn

-513 6-MeO (R-14 -CONHcHx

-514 6-MeO (R-14 -CONHPh

-515 6-MeO (R-14 -GONHBz

-516 6-MeO (R-14 -C0NH (3-F-Bz)

-517 6-MeO (R-14 -C0NH (4-Cl-Bz) -518 6-MeO (R-1 -CONHCHMePh

-519 6-MeO (R-14 -C0NHCHMe (4-Me0-Ph) -520 6-MeO (R-14 -C0NHCHMe (3,5-diF-Ph) -521 6-MeO (R-14-圆 ( CH ₂ ) ₂ Ph

-522 6-MeO (R-14 -CONHCH ₂ CH (Me) Ph-523 6-MeO (R-14-圆 CH ₂ CH (0H) Ph-524 6-MeO (R-14 -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -525 6-MeO (R-14 -C0NHCH ₂ CH (Me) Np (2) -526 6-MeO (R-14 -C0NH (CH ₂ ) ₂ Mor (4) -527 6-MeO (R-14 -CONHCH ₂ Fur (2)

-528 6-MeO (R-14-圆 CH ₂ Fur (3) -529 6-MeO (R-14 -C0NHCH ₂ Prd (2)-530 6-MeO (R-14 -C0NHCH ₂ Prd (3)- 531 6-MeO (R-14 -C0NHCH (Me) Prd (3) -532 6-MeO (R-14 -COPrd (l)

-533 6-MeO (R-1 -C0Mor (4)

-534 6-MeO (R-14 -COPiz (l)

-535 6-MeO (R-14 -C0 [4-Me-Piz (l)]-536 6-MeO (R-14 -C0NH (CH ₂ ) ₂ NH ₂

-537 6-MeO (R-14 -CONHCH ₂ C0 ₂ Et

ngi- (si-¾) (PW-9 ΐ -z ng-(ST-¾) 03W-9

 (si-ii) 0 -9 ΐ L2 -Z

(ST-¾) 0 ⁹ W-9 ΐ -z zg- (ST-¾) 03W-9

(ST-¾) (PW-9 τ -z d-0 ⁹ W] P-S'C) 3W 03-0 ⁹ W-9 ΐ 2S -Z cHPW! P- ε) 3 顺 0-(ST-¾ ) 03W-9

(ϋ 'ε) ο:)-(SI- 0 ⁹ W-9 ΐ mz

(ST-¾) 0 ⁹ W "9 ΐ 08 -2

(¾-03W-) 3WN03- (ST-¾) 03W-9 ΐ

(d-I3-) 3WN03- (ST-¾) 0 ⁹ W-9 ΐ 8 9-2

(qd-i-) 3WN03- (si-a) (PW-9 ΐ

(Dr 03- (si-a) 03W-9 ΐ 9Ζ9-2 qd (3W) N03- (si-a) 0 ⁹ W "9 ΐ qj9WH3HN03- 0 ⁹ W-9 ΐ

qjH OO- 0 ⁹ W-9 ΐ

0 ⁹ W-9 ΐ

0 ⁹ W-9 ΐ

0 ⁹ W-9 ΐ 09-2

^Ζ (Ϊ3) Η3¾3- (I- 03W-9 ΐ 69S-2

0 ⁹ W-9 ΐ

 (PW- 9 ΐ

0 ⁹ l¾-9 ΐ 99 -Ζ-0 ⁹ W-9 ΐ

(Ha) 0 ⁹ W-9 ΐ -z

6ST

ZS8.0 / 00df / X3d 0 0 OAV OAV / 8 U 0: _

〇

 O

- 7852

131 -616 1 6- MeO (R-17) -COCH (Et) ₂

-617 1 6-MeO (R-17) -CONHPh

-618 1 6-MeO (R-17) -CONHCHMePh

-619 16-MeO (R-17) -C0NHCHMe (4-Me0-Ph) -620 16-MeO (R-17) -C0NHCHMe (3,5-diF-Ph) -621 16-MeO (R -17) -CONH (CH ₂ ) ₂ Ph

-622 1 6-MeO (R-17) -CON (Me) Ph

-623 1 6-MeO (R-17) -CON (Et) Ph

-624 1 6-MeO (R-17) -C0NMe (4-F-Ph)

-625 1 6- MeO (R-17)-C0NMe (4-Cl-Ph)

-626 1 6-MeO (R-17) -C0NMe (4-Me0-Ph)

-627 16-MeO (R-17) -C0NMe (3,4-diF-Ph) -628 16-MeO (R-17)-圆 e (3,5-diF-Ph) -629 16- MeO (R-17)-C0NMe (3,4-diMeO-Ph) -630 16-MeO (R-17) -C0NMe (3,5-diMe0-Ph) -631 16-MeO (R-17) -cPn

-632 1 6- MeO (R-17)-Ph

-633 1 6- MeO (R-17) -Bz

-634 1 6-MeO (R-17)-(CH ₂ ) ₂ Ph

-635 1 6- MeO (R-17)-Me

-636 1 6- MeO (R-17) -iPr

-637 1 6-MeO (R-17) -Bu

-638 1 6- MeO (R-17) -iBu

-639 1 6- MeO (R-17) -sBu

-640 16-MeO (R-17)-tBu, -641 16-MeO (R-17)-iPn -642 6-MeO (R-17) -CH ₂ CH (Et) ₂ -643 6-MeO (R-17)-(CH ₂ ) ₂ CH (Et) ₂ -644 6-MeO (R-17)- 1-Et-Bu-645 6-MeO (R-17) -1-Et-Pn-646 7-MeO (R-1) -C0N (Me) Ph-647 7-MeO (R-1) -C0CH ( Et) ₂ -648 7-MeO (R-1) -C0CH ₂ CH (Et) ₂ -649 7-MeO (R-1) -COPh

-650 7-MeO (R-1) -cPn

-651 7-MeO (R-1) -Ph

-652 7-MeO (R-1) -Bz

-653 7-MeO (R-1) -iPr

-654 7-MeO (R-1) -iBu

-655 7-MeO (R-1) -CH ₂ CH (Et) ₂ -656 7-MeO (R-1) -All

-657 7-MeO (R-5) -C0N (Me) Ph-658 7-MeO (R-5) -C0CH (Et) ₂ -659 7-MeO (R-5) -C0CH ₂ CH (Et) ₂ -660 7-MeO (R-5) -COPh

-661 7-MeO (R-5) -cPn

-662 7-MeO (R-5) -Ph

-663 7-MeO (R-5) -Bz

-664 7-MeO (R-5) -iPr '-665 7-MeO (R-5) -iBu

-666 7-MeO (R-5) -CH ₂ CH (Et) ₂ -667 7-MeO (R-5) -All -668 1 7-MeO (R-6)-CON (Me) Ph-669 1 7-MeO (R-6) -C0CH (Et) ₂ -670 1 7-MeO (R-6) -C0CH ₂ CH ( Et) -671 17-MeO (R-6) -COPh-672 17-MeO (R-6) -cPn

-673 1 7-MeO (R-6)-Ph

-674 1 7-MeO (R-6) -Bz

-675 1 7-MeO (R-6) -iPr

-676 1 7-MeO (R-6)-iBu

-677 1 7-MeO (R-6) -CH ₂ CH (Et) ₂ -678 17-MeO (R-6) -All

-679 1 8-MeO (R-6)-CON (Me) Ph-680 1 8-MeO (R-14) -C0N (Me) Ph-681 16-EtO (R-6)-CON (Me) Ph-682 16-EtO (R-14)-CON (Me) Ph-683 17-EtO (R-1)-CON (Me) Ph-684 17-EtO (R-2) -C0N (Me ) Ph-685 17-EtO (R-3) -C0N (Me) Ph-686 17-EtO (R-4) -C0N (Me) Ph-687 17-EtO (R-5)-CON ( Me) Ph-688 17-EtO (R-6) -C0N (Me) Ph-689 17-EtQ (R-7) -C0N (Me) Ph-690 17-EtO (R-8) -C0N (Me) Ph-691 17-EtO (R-9)-CON (Me) Ph-692 17-EtO (R-10)-CON (Me) Ph-693 17-EtO (R-ll)- CON (Me) Ph (¾-i! -9) 9W 03- (S-HO-8 HO-Z HO-9 ε 6ΤΖ-2

(-d! P- 'S WNO-(S -¾) HO-8 HO-Z HO-9 ε

(-0 ⁹ W-) ³ strokes :)-(S -¾) HO-8 HO-Z HO-1 9ε

(¾-d-) 3WN03- (S -¾) HO-8 HO-Z HO-9 ε -z

¾ί (咖 0-(S -¾) HO-8 HO-Z HO-9 ε U-Z

¾ (3W) N03- (s-HO-8 HO-Z HO-9 ε m-z (¾)) ■-(S -Η) HO-8 HO-Z HO-9 ε ZIL-Z

(qd-JIP-S

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¾ (3N) N03- (1-H) HO-9 ZQL-Z

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0 0 OAV (¾-iIP-9'S) ⁹ WN03- (9-Φ HO-8 HO-Z HO-9 £

(¾-ilP-^ 'S) ⁹ W 03- (9-HO-8 HO-Z HO-9

(-(FW-) ³ encouragement :)-(9 HO-8 HO-Z HO-1 9 £

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¾ί (靡 0-(9 -a) HO-8 HO-Z HO-1 9 ε ιη-ζ

 -(9 "¾) HO-1 8 HO-Z HO-9 ε 0VL-Z qd '(¾a) HN03- (9-HO-8 HO-Z HO-9 ε m-z

(¾-i? P-S'e) ⁹ WH3HN03- (9 HO-8 HO-Z HO-9 ε -z

(Md-0 ⁹ W-^) 3WH3H 03- (9 HO-8 HO-Z HO-9 c LZL-Z

 ¾d3WH0HN03- (9-) HO-8 HO-Z HO-9 ε

 (9 -¾) HO-8 HO-Z HO-9 ε 2L-Z

(S _a) HO-8 HO-Z HO-9 ε -z

(S -H) HO-8 HO-Z HO-9 ε ZZL-Z z (^ a) H3 '(¾3)-(S -¾) HO-8 HO-Z HO-9 ε ZZL-Z

'(a) H3¾3- (5 -¾) HO-8 HO-Z HO-9 ε m-z

 (S -a) HO-1 8 HO- A HO-9 ε -z ng-(9 -¾) HO-8 HO-Z HO-9 £ mz ngi- (S -¾) HO-1 8 HO-Z HO- 9 c% zi-z

-(S -¾) HO-8 HO-Z, HO-9 ε LZL-Z

(S -¾) HO-8 HO-Z HO-9 ε -z (¾)-(9 -¾) HO-8 HO-Z HO-9 ε

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U (-(S-) HO-8 HO-Z HO-9 ε ZZL-Z

(¾-0 ⁹ W! P-5) ⁹ WN03- (S -H) HO-8 HO-Z HO-9 ε mz

(qd-0 ³ WlP-^ '8) ⁹ W 03- (S —a) HO-8 HO-Z HO-9 ε OZL-Z

921

ZS8Z.0 / 00df / X3d 0 0 ΟΛ \ (¾-i-^) 3W 03- ΐ-¾) HO— 8 HO-Z HO-9 ε \ LL ~ Z

 ΐ- HO-8 HO-Z HO-9 ε -z

¾d (3W) N03- HO-1 8 HO-Z HO-9 ε

 (¾)) Picture-(ΐ- HO-8 HO-Z HO-9 c 29L-Z

(¾-dIP-5 '£) 3WH3HN03- ΐ-3) HO-1 8 HO-Z HO-9 ε L9L-Z

(¾1-0-) 9 鹏-(i-H) HO-1 8 HO-Z HO-9 ε 99L-Z

qd ⁹ WH3HN03- (ΐ- HO— 8 HO-Z HO-9 c -z dHNOO- Οΐ- a) HO-8 HO-Z HO-9 ε -z qd (3W) N03- HO-8 HO-Z HO -9 ε £ 9L-Z qd (3w) OO- (π-Η) HO- 8 HO-Z HO-9 ε Z9L-Z

Md (3W) N03- ίο a) HO-1 8 HO-Z HO-9 £ m-z

¾ (3W) N03- a) HO-8 HO-Z HO-9 ε 09L-Z a) HO-8 HO-Z HO-9 ε 6 -Z

(9 -¾) HO-8 HO-Z HO-9 c 2 L-Z

(9 -H) HO-8 HO-Z HO-9 ε L L-Z

² (Ϊ3) Η3¾3- (9 -¾) HO-8 HO-Z HO-9 £ LZ

(9 -a) HO-8 HO-Z HO-9 LZ-(9-H) HO-8 HO-Z HO-9 -z ngs- (9 -H) HO-8 HO-Z HO-9 £ LZ ng-(9-) HO-8 HO-Z HO-9 Z9L-Z (9-H) HO-8 HOr HO-9 \ LZ (¾)) _ (9 -¾) .. HO-8 HO- Z HO-9 £ 0 LZ

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(qd-03Wl -G'C) 3WN03- (9-HO-8 HO-Z HO-1 9 £ L L-Z

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¾ (3W) N03- (9T-H) HO-8 HO-Z HO-1 9 06Z-Z

Md (3W) N03- (ST-¾ HO-8 HO-Z HO-9 £ -z

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 (ΐ-) HO-8 HO-Z HO-9 2 ud!-(ΐ- HO-8 HO-Z HO-9 ε -z

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(¾-0 ⁹ WIP-S '£) 3WN0D- HO-8 HO-Z HO-9 ε 9 ZZ

(-o ⁹ w! p ε) ³ Hidden :)-(-HO-8 HO-Z HO-9 ε LL-Z

(¾-J! P-5'S) 3W 03--H) HO-8 HO-Z HO-9 £ ui-z

(¾-J! P-^ 'S) 3WN03- HO-8 HO-Z HO-1 9 ZLL-l

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CSI CSI SI 1 S] M M

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03 CM CM CM SI CM CM NJ SI CM CM CM I C CM CM CM M

-824 2 6-MeO 7-MeO (R- 2) -C0N e (4-F-Ph) -825 2 6-MeO 7-MeO (R-2) -C0NMe (4-Cl-Ph) -826 2 6-MeO 7-MeO (R- 2) -C0NMe (4- e0-Ph) -827 2 6-MeO 7-MeO (R- 2) -C0NMe (3,4-diF-Ph) -828 2 6- MeO 7-MeO (R-2) -C0NMe (3,5-diF-Ph) -829 26-MeO 7-MeO (R-2) -CONMe (3,4-diMeO-Ph) -830 26- MeO 7-MeO (R-2) -CONMe (3,5-diMeO-Ph) -831 2 6-MeO 7-MeO (R-2) -cPn

-832 2 6-MeO 7-MeO (R- 2)-Ph

-833 2 6-MeO 7-MeO (R-2)-Bz

-834 2 6-MeO 7-MeO (R-2)-(CH ₂ ) ₂ Ph

-835 2 6-MeO 7-MeO (R-2) -Me

-836 2 6-MeO 7-MeO (R-2) -iPr

-837 2 6-MeO 7-MeO (R- 2)-Bu

-838 2 6-MeO 7-MeO (R-2) -iBu

-839 2 6-MeO 7-MeO (-2)-sBu

-840 2 6-MeO 7-MeO (R-2) -tBu

-841 2 6-MeO 7-MeO (R-2) -iPn

-842 2 6-MeO 7-MeO (R- 2)-CH ₂ CH (Et) ₂

-843 26-MeO 7-MeO (R- 2)-(CH ₂ ) ₂ CH (Et) ₂ -844 26-MeO 7-MeO (R- 2) -1-Et-Bu

-845 2 6-MeO 7-MeO (R-2) -1-Et-Pn

-846 2 6-MeO 7-MeO (R-3) -COCH ₂ CH (Et) ₂

-847 2 6-MeO 7-MeO (R-3)-C0CH (Et) ₂

-848 2 6-MeO 7-MeO (R-3) -CONHPh

-849 2 6-MeO 7-MeO (R-3) -CONHCHMePh (ε o -9 Z L2-Z

'(Ϊ3) Η3' (¾0)---09W-9 Z

 z (ia) H3¾o- (ε-(PW-(PW-9 Z 2L2-Z

!-(ε -¾) o ⁹ wz 03W-9 ZZ 2-Z

(ε -¾) o ⁹ wz (PW- 9 Z IL -Z ngs- (ε o ⁹ wz 03W-9 Z OLS-Z

(£ 03W- 03W-9 Z 698-2 ng- (£ o ⁹ wz 0-9 Z 898-Z

 (£-0 -9 Z L9 -Z

(ε -¾) o ⁹ w- 0 ⁹ W-9 Z 998-2 (¾))-(ε-φ 03W- 03W-9 z 998-2 zg-(ε -¾) 0 ⁹ NZ 0 -9 z mz

(ε-o ⁹ wz 03W-9 z one-(ε-) 0 ⁹ NZ 0 ⁹ W-9 z

(¾-0 ⁹ WIP-S'C) 9W 03- (ε-Φ o ⁹ wz (PW-9 z -zo ⁹ w! P- 'ε) ³顺 03-(£-Φ o ⁹ wz z 098- Two

(-S '£) ■:)-(£ -¾) o ⁹ wz 0 ⁹ W-9 z

(¾-iIP- 'C) 3WN03- (£ "¾) o ⁹ wz 03W-9 z -z

(-0) 9 strokes:)-(£ -¾) o ⁹ w- 0 ⁹ W-9 z

(¾-I3-^) 3WN03- (£ -Η) o ³ wz o -9 z

OO- (£-) o ⁹ w- 03W-9 z

^ i (0:)-(ε -¾) o ⁹ wz o -9 z -z (3 levels 0--¾) 03W-9 z

(¾)) painting :)-(ε -¾) 0 ⁹ W-9 z

(-d! PS '(ε "¾) o ⁹ wz 03W-9 z

((PW-3 Orchid:)-(ε -¾) o ⁹ wz z

rS8Z.0 / 00df / X3d -876 26-MeO 7-MeO (R-3) -1-Et-Pn-877 26-MeO 7-MeO (R-4) -CONHCHMePh

-878 26-MeO 7-MeO (R-4) -C0N (Me) Ph

-879 2 6-MeO 7-MeO (R-4) -cPn

-880 2 6-MeO 7-MeO (R-4) -iBu

-881 2 6-MeO 7-MeO (-5) -C0CH ₂ CH (Et) ₂

-882 2 6-MeO 7-MeO (R-5)-C0CH (Et) ₂

-883 2 6-MeO 7-MeO (R-5)-COPh

-884 2 6-MeO 7-MeO (R-5) -C0 (4-Cl-Ph)

-885 2 6-MeO 7-MeO (R-5) -CONHBu

-886 2 6-MeO 7-MeO (R-5) -C0N (Et) ₂

-887 2 6-MeO 7-MeO (R-5) -CONHCH ₂ CH (Et) ₂ -888 26-MeO 7-MeO (R-5) -C0NHCH (Et) ₂

-889 2 6-MeO 7-MeO (R-5) -CONHcPn

-890 2 6-MeO 7-MeO (R-5) -CONHcHx

-891 2 6-MeO 7-MeO (R-5) -CONHPh

-892 2 6-MeO 7-MeO (R-5) -CONHBz

-893 2 6-MeO 7-MeO (R-5) -C0NH (3-F-Bz)

-894 2 6-MeO 7-MeO (R-5)-圆 (4- Cl-Bz) -895 26-MeO 7-MeO (R-5) -CONHCHMePh

-896 26-MeO 7-MeO (R-5) -CONHCHMe (4-MeO-Ph) -897 26-MeO 7-MeO (-5) -C0NHCH e (3,5-diF-Ph) -898 2 6-MeO 7-MeO (R-5)-Image (CH ₂ ) ₂ Ph

-899 2 6-MeO 7-MeO (-5) -C0NHCH ₂ CH (e) Ph-900 26 -MeO 7-MeO (R-5) -C0NHCH ₂ CH (0H) Ph-901 26-MeO 7 -MeO (R- 5) -C0NH (CH 2) 2 (4-Cl-Ph) -902 2 6-MeO 7-MeO (R-5) -C0NHCH ₂ CH (Me) Np (2) -903 26-MeO 7-MeO (R-5) -C0NH (CH ₂ ) ₂ Mor (4) -904 2 6-MeO 7- MeO (R-5) -C0NHCH ₂ Fur (2) -905 2 6-MeO 7- MeO (R-5) -C0NHCH ₂ Fur (3) -906 26-MeO 7- MeO (R-5) -C0NHCH ₂ Prd (2) -907 26-MeO 7-MeO (R-5) -C0NHCH ₂ Prd (3) -908 26-MeO 7-MeO (R-5) -C0NHCH (Me) Prd (3) -909 2 6- MeO 7- MeO (R-5) -COPrd (l)

-910 2 6-MeO 7- MeO (R-5) -C0Mor (4)

-911 2 6- MeO 7- MeO (R-5) -COPiz (l)

-912 2 6-MeO 7-MeO (R-5) -C0 [4-Me-Piz (l)]-913 26-MeO 7-MeO (-5) -CONH (CH ₂ ) ₂ NH ₂ -914 2 6- MeO 7-MeO (R-5) -C0NHCH ₂ C0 ₂ Et

-915 2 6-MeO 7-MeO (R-5)-CON (Me) Ph

-916 2 6- MeO 7- MeO (R-5) -CON (Et) Ph

-917 2 6- MeO 7- MeO (R-5) -C0NMe (4-F-Ph) -918 26-MeO 7-MeO (R-5) -C0NMe (4-Cl-Ph) -919 26 -MeO 7- MeO (-5) -C0NMe (4-Me0-Ph) -920 26-MeO 7-MeO (R-5) -C0NMe (3,4-diF-Ph) -921 26-MeO 7 -MeO (R-5) -C0NMe (3,5-diF-Ph) -922 26-MeO 7-MeO (R-5) -C0NMe (3,4-diMeO-Ph) -923 26-MeO 7 -MeO (R-5) -CONMe (3,5-diMeO-Ph) -924 26-MeO 7-MeO (-5) -CON (Me) Bz

-925 2 6- MeO 7-MeO (R-5) -cPn

-926 2 6-MeO 7-MeO (R-5) -cHx

-927 2 6-MeO 7- MeO (R-5)-Ph

979eOMeOM 7CONieH---t C t t

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() eeoO 7MMC0CNH41BZ -----() 976eOe 7MOCM03HFBZ----- 975eO 7eoMMcoiz------(97eO 7MeO4MC0NH4eM _---(, eO) eO 7M 97eeO 7Mo2M cage 34 ph .-----7eOeOMM--70eeO. 7MMCONHcHx--9eO 7eoMC MOcNHPn---(968eOeOM 7MC0 solid: E.

 965eO 7MeOMCONBUHi .-- I

 Ma O 4e 7eo MMC orchid Pr i--963 (OeOMe 7MC0NE.--9 (6O2e 7MeoMC0NM ■--

956OMe 7MeOCOBz--(5Oe 7MeO MC04--

95e. 7eo4MMCOPh ■-- -980 2 6-MeO 7-MeO (R-6) -C0NHCHMe (3,5-diF-Ph) -981 26-MeO 7-MeO (R-6) -Picture (CH ₂ ) ₂ Ph

-982 26-MeO 7-MeO (R-6) -C0NHCH ₂ CH (Me) Ph-983 26-MeO 7-MeO (R-6) -C0NHCH ₂ CH (0H) Ph-984 26-MeO 7-MeO (R-6) -C0NH (CH ₂ ) ₂ (4-Cl-Ph) -985 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ CH (Me) Np (2) -986 2 6-MeO 7-MeO (R-6) -C0NH (CH ₂ ) ₂ Mor (4) -987 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Fur (2)

-988 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Fur (3)

-989 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Prd (2)

-990 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ Prd (3)

-991 26-MeO 7-MeO (-6) -C0NHCH (Me) Prd (3) -992 26-MeO 7-MeO (R-6) -C0NHCH (e) Pyr (4) -993 2 6- MeO 7-MeO (R-6) -COPrd (l)

-994 2 6-MeO 7-MeO (R-6) -C0 or (4)

-995 2 6-MeO 7-MeO (R-6) -COPiz (l)

-996 26-MeO 7-MeO (R-6) -C0 [4- e-Piz (l)]-997 26-MeO 7-MeO (R-6) -C0NH (CH ₂ ) ₂ NH ₂

-998 2 6-MeO 7-MeO (R-6) -C0NH (CH ₂ ) ₂ N (Me) ₂ -999 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ C0 ₂ H

-1000 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ C0 ₂ Me

-1001 2 6-MeO 7-MeO (R-6) -C0NHCH ₂ C0 ₂ Et

-1002 2 6-MeO 7-MeO (R-6)-CON (Me) Ph

-1003 2 6-MeO 7-MeO (R-6) -C0N (Et) Ph

-1004 26-MeO 7-MeO (R-6)-C0NMe (4-F-Ph) -1005 26-MeO 7-MeO (R-6) -C0NMe (4-Cl-Ph)

CD Pi

o o o o o o o o o o o o o o o o o o o o o o o o o o

I I I I I I

Cs3 M σ¾ O

CM

O o

-1032 26-MeO 7-MeO (R-6) -iBu-1033 26-MeO 7-MeO (R-6) -sBu

-1034 2 6-MeO 7- MeO (R-6) -tBu

-1035 2 6-MeO 7-MeO (R-6)-Pn

-1036 2 6-MeO 7- MeO (R-6) -iPn

-1037 2 6-MeO 7- MeO (-6) -1-Me-Bu

-1038 2 6-MeO 7-MeO (R-6) -CH (Et) ₂

-1039 2 6-MeO 7- MeO (R-6) -CH ₂ CH (Et) ₂

-1040 2 6-MeO 7-MeO (R-6)-(CH ₂ ) ₂ CH (Et) ₂ -1041 26-MeO 7-MeO (R-6)-1-Et-Bu

-1042 2 6-MeO 7-MeO (R-6) -1-Et-Pn

-1043 2 6- MeO 7- MeO (R-6) -Vin

-1044 2 6-MeO 7-MeO (R-6) -Bun

-1045 2 6-MeO 7-MeO (R- 6) -3- (3- Me- Bun) -1046 2 6-MeO 7-MeO (R-7) -CONHPh

-1047 2 6- MeO 7-MeO (R-7) -CONHCHMePh

-1048 2 6-MeO 7-MeO (R-7) -CON (Me) Ph

-1049 2 6- MeO 7-MeO (R-7) -CON (Et) Ph

-1050 2 6-MeO 7-MeO (-7)-圆 e (4-F- Ph) -1051 2 6-MeO 7-MeO (R-7) -C0NMe (4-Cl-Ph) -1052 2 6 -MeO 7-MeO (R-7) -CONMe (4-MeO-Ph) -1053 26-MeO 7-MeO (R-7)-C0NMe (3,4-diF-Ph) -1054 26-MeO 7-MeO (R-7) -C0NMe (3,5-diF-Ph) -1055 26-MeO 7-MeO (R-7)-C0NMe (3,4-diMeO-P-1056 26-MeO 7 -MeO (R-7) -CONMe (3,5-diMeO-P-1057 26-MeO 7-MeO (R-7)-cPn

 o o o o o o o o o o o o o o o o o o o o o o o o o

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Dimension

Csl M C CSI CM NJ C J CM CM CM Nl

 L C ^ OO 7i O i "H l C LO OO ^ O ^ H ac LO OO 00 X3 00 00 C0 CX y¾ a¾ a ^ 0¾ ^ r> T5 Ti CT) 3 ^ O O O O O O O O O O

3 Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο ·-3

 I I I

 C 1 CM CM CM CSI NJ CNJ NI CM CM CSJ C I CM M CN1 J SJ CS1 M]

Respectful

One i3 _- O 07852

150 -1110 2 6-MeO 7-MeO (R-ll)-iPr

-1111 2 6-MeO 7-MeO (R-ll) -Bu

-1112 2 6-MeO 7-MeO (R-ll) -iBu

-1113 2 6-MeO 7-MeO (R-ll) -tBu

-1114 2 6-MeO 7-MeO (R-ll)-iPn

-1115 2 6-MeO 7-MeO (R-ll) -1-Et-Bu

-1116 2 6-MeO 7-MeO (R-ll) -1-Et-Pn

-1117 2 6-MeO 7-MeO (R-12) -CONHCHMePh

-1118 2 6-MeO 7-MeO (R-12) -C0N (Me) Ph

-1119 2 6-MeO 7-MeO (R-12) -cPn

-1120 2 6-MeO 7-MeO (R-12) -iBu

-1121 2 6-MeO 7-MeO (R-13) -CONHCHMePh

-1122 2 6-MeO 7-MeO (R-13) -C0N (e) Ph

-1123 2 6-MeO 7-MeO (R-13) -cPn

-1124 2 6-MeO 7-MeO (R-13)-iBus

-1125 2 6-MeO 7-MeO (R-14) -C0CH ₂ CH (Et) ₂

-1126 2 6-MeO 7-MeO (R-14) -C0CH (Et) ₂

-1127 2 6-MeO 7-MeO (R-14) -COPh

-1128 2 6-MeO 7-MeO (R-14) -C0 (4-Cl-Ph)

-1129 2 6-MeO 7-MeO (R-14) -CONHBu

-1130 2 6-MeO 7-MeO (R-14)-C0N (Et) ₂

-1131 2 6-MeO 7-MeO (R-14) -CONHCH ₂ CH (Et) ₂

-1132 2 6-MeO 7-MeO (R-14) -C0NHCH (Et) ₂

-1133 2 6-MeO 7-MeO (R-14) -CONHcPn

-1134 26-MeO 7-MeO (R-14) -CONHcHx

-1135 2 6-MeO 7-MeO (R-14) -CONHPh -1136 26-MeO 7-MeO (R-14) -CONHBz-1137 26-MeO 7-MeO (R-14) -C0NH (3-F-Bz)

-1138 26-MeO 7-MeO (R-14)-C0NH (4- Cl-Bz) -1139 26-MeO 7-MeO (R-14) -CONHCHMePh

-1140 2 6-MeO 7-MeO (R-14) -C0NHCHMe (4-Me0-Ph) -1141 2 6-MeO 7-MeO (R-14) -C0NHCHMe (3,5-diF-Ph) -1142 2 6-MeO 7-MeO (R-14) -C0NH (CH ₂ ) ₂ Ph

-1143 26-MeO 7-MeO (R-14) -CONHCH ₂ CH (Me) Ph-1144 26-MeO 7-MeO (R-14) -C0NHCH ₂ CH (0H) Ph-1145 26-MeO 7-MeO (R-14)-C0NH (CH ₂ ) ₂ (4-Cl-Ph) -1146 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ CH (Me) Np (2) -1147 2 6-MeO 7-MeO (R-14) -C0NH (CH ₂ ) ₂ Mor (4) -1148 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Fur (2)

-1149 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Fur (3)

-1150 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Prd (2)

-1151 2 6-MeO 7-MeO (R-14) -C0NHCH ₂ Prd (3)

-1152 26-MeO 7-MeO (R-14) -C0NHCH (Me) Prd (3) -1153 26-MeO 7-MeO (R-14) -COPrd (l)

-1154 2 6-MeO 7-MeO (R-14) -C0Mor (4)

-1155 2 6-MeO 7-MeO (R-14) -COPiz (l)

-1156 2 6-MeO 7-MeO (R-14)-C0 [4-Me-Piz (l)]-1157 26-MeO 7-MeO (R-14) -C0NH (CH ₂ ) ₂ NH ₂

-1158 2 6-MeO 7-MeO (R-14) -CONHCH ₂ C0 ₂ Et

-1159 2 6-MeO 7-MeO (R-14) -C0N (Me) Ph

-1160 2 6-MeO 7-MeO (R-14) -C0N (Et) Ph

-1161 2 6-MeO 7-MeO (R-14) -C0NMe (4-F-Ph) i ■

1 1 1

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-1214 2 6-MeO 7-MeO (R-15) -1-Et-Pn

-1215 2 6- eO 7-MeO (R-16) -CONHPh

-1216 2 6-MeO 7-MeO (R-16) -CONHCHMePh

-1217 2 6-MeO 7-MeO (R-16)-CON (Me) Ph

-1218 2 6-MeO 7-MeO (R-16) -CON (Et) Ph

-1219 2 6-MeO 7-MeO (R-16) -C0NMe (4-F-Ph) -1220 26-MeO 7-MeO (R-16) -C0NMe (4-Cl-Ph) -1221 2 6 -MeO 7-MeO (R-16)-C0NMe (4- MeO-Ph) -1222 26-MeO 7-MeO (R-16) -C0NMe (3, 4-diF-Ph) -1223 2 6-MeO 7-MeO (R-16) -C0NMe (3, 5-diF-Ph) -1224 2 6-MeO 7-MeO (R-16) -CONMe (3, 4-diMeO-Ph) -1225 2 6-MeO 7-MeO (R-16) -C0NMe (3,5-diMeO-Ph) -1226 2 6-MeO 7-MeO (R-16) -cPn

-1227 2 6-MeO 7-MeO (R-16) -Bz

-1228 2 6-MeO 7-MeO (R-16)-(CH ₂ ) ₂ Ph '-1229 2 6-MeO 7-MeO (R-16)-iPr

-1230 2 6-MeO 7-MeO (R-16) -Bu

-1231 2 6-MeO 7-MeO (R-16)-iBus

-1232 2 6-MeO 7-MeO (R-16) -tBu

-1233 2 6-MeO 7-MeO (R-16) -iPn

-1234 2 6-MeO 7-MeO (R-16) -1-Et-Bu

-1235 2 6-MeO 7-MeO (R-16) -1-Et-Pn

-1236 2 6-MeO 7- MeO (R-17) -C0CH ₂ CH (Et) ₂

-1237 2 6-MeO 7-MeO (-17) -C0CH (Et) ₂

-1238 2 6-MeO 7-MeO (R-17) -CONHPh

-1239 2 6-MeO 7-MeO (R-17) -CONHCHMePh Parent- "

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ZS8.0 / 00df / X3d OZ.St'C / IO OAV -1370 2 6-MeO 7-OH (R-14 -C0CH ₂ CH (Et) ₂ -1371 26 -MeO 7-OH (R-14 -iBu

-1372 26-MeO 7-OH (R-14 -CH ₂ CH (Et) ₂ -1373 26 -MeO 7-OH (R-14-(CH ₂ ) ₂ CH (Et) ₂ -1374 2 6- OH 7-MeO (R- 1-CON (Me) Ph-1375 26-OH 7-MeO (R-1 -COCH (Et) ₂ -1376 26-OH 7-MeO (-1 -C0CH ₂ CH ( Et) ₂ -1377 2 6-OH 7-MeO (R-1 -iBu

-1378 26-OH 7-MeO (R- 1 -CH ₂ CH (Et) ₂ -1379 26-OH 7-MeO (R-1 -CON (Me) Ph-1380 26-OH 7-MeO ( R- 1 -C0CH (Et) ₂ -1381 26-OH 7-MeO (R- 1 -COCH ₂ CH (Et) ₂ -1382 26-OH 7-MeO (R- 6 -CON (Me) Ph- 1383 2 6-OH 7-MeO (R-6 -C0CH (Et) ₂ -1384 2 6-OH 7-MeO (R-6 -C0CH ₂ CH (Et) ₂ -1385 2 6-OH 7-MeO (R -6 -iBu

-1386 2 6-OH 7-MeO (R-6 -CH ₂ CH (Et) ₂ -1387 2 6-OH 7-MeO (R-6 -CH ₂ CH ₂ CH (Et) ₂ -1388 26-OH 7-MeO (R-14 -CON (e) Ph-1389 26-OH 7-MeO (R-14-C0CH ₂ CH (Et) ₂ -1390 26-OH 7-MeO (R-14 -iBu

-1391 26-OH 7-MeO (R-14 -CH ₂ CH (Et) ₂ -1392 26-OH 7-MeO (R-15-CON (Me) Ph-1393 26-OH 7-MeO ( R-16 -CON (Me) Ph-1394 26-AcO 7-AcO (R-6-CON (Me) Ph -1395 26-AcO 7-AcO (R-14 -CON (Me) Ph

In the above,

 Suitable compounds include

Exemplary compound numbers: 1-57, 1-179, 1-181, 1-183, 1-185, 1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1- 542, 1-544, 1-770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-977 ~; 1-981, 1-983, 1-1019 , 1-1134, 1-1136, 1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313, 1-1315, 1-1316, 1 -1318, 1-1351, 1-1354, 1-1359, 1-1364, 1-1365, 1-1368, 1-1372 ~ レ 1379, 1-1381 ~ 1-1383 and 1-1384 ~ 1-1395

Can be mentioned,

 Further preferred compounds include

Exemplary compound number: 1-57, 1-181, 1-183, 1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1-542, 1-544, 1- 770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-977 ~; 1-981, 1-983, 1-1019, 1-1134, 1-1136 , 1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1 -1354, 1-1359, 1-1364, 1-1365, 1-1368, 1-1137-1 to 1379, 1-1381 to 1-1383, and 1-1384 to 1-1395,

 More preferred compounds include

Exemplary compound numbers: 1-57, 1-381, 1-383, 1-385, 1-538, 1-540, 1-542, 1-770, 1-772, 1-774, 1-827, 1- 828, 1-833, 1-977 ~; 1-981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138, 1-1140, 1-1284, 1-1286, 1-1287 , 1-1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1-1354, 1-1359, 1-1368, 1-1372-1-1379, 1-1381-1 -1383 and 1-1384 to 1-1395

Can be mentioned,

 The most preferred compounds include

Compound No. 1-827: 1— (4-Hydroxyphenyl) -1,6,7-dimethoxy-14_oxo-1,4, -Dihydroxyquinoline-1,3-N-methyl-1-N-phenylcarboxylate Amid,

Compound No. 1-828: 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-potassium N-ethyl-1-N-phenyl amide,

Compound No. 1-833: 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N— (3,5-difluoro Phenyl) amide,

Compound No. 1-977: 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-3-Rubonate N-methyl-N-phenylamide,

Compound No. 1-978: 6,7-dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N-phenylamide

Compound No. 1-979: 1- (4-Methoxyphenyl) -16,7-Dimethoxy-14 41-year-old Kiso 1,4-dihydroquinoline-13-Carboxylic acid N-methyl-N- (4-Fluorophenyl) amide Do

Compound No. 1-981: 1- (4-Methoxyphenyl) -16,7-Dimethoxy-14-Kiso_1,4-Dihydro-quinoline-1-3-Carboxylic acid N-methyl-1-N- (4-Methoxyphenyl Amid,

Compound No. 1-1019: 6,7-Dimethoxy 1- (4-Methoxyphenyl) -14-year-old Kiso 1,4-Dihydroquinoline-13-Carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide ,

Compound No. 1-1136: 1— (3,4-dimethoxyphenyl) -1,6,7-dimethoxy_4-oxo-1,4,4-dihydroquinoline-3-carboxylate N-methyl-N— (4-fluorophenyl) amido Do

Compound No. 1-1138: 1- (3,4-dimethoxyphenyl) 1-6,7-dimethoxy Picture 0/07852

164

— 4-oxo-1,4-diquinoline-3-one-carboxylate N-methyl-1-N—

(4-methoxyphenyl) amide,

Compound No. 1-1286: 1— (4-methoxyphenyl) -1,6,7,8-trimethoxy-14-1,4-oxo-1,4-dihydroquinoline-1-3-carboxylate N-methyl-1-N—

(4-fluorophenyl) amide,

Compound No. 1-1287: 1- (4-methoxyphenyl) -1,6,7,8-trimethoxy-14-oxo-1,4, -dihydroquinoline-1-3-carboxylate N-methyl-1-N-

(4—methoxyphen) amide,

Compound No. 1-1315: 1- (3,4-dimethoxyphenyl) -1,6,7,8-trimethoxy-4-oxo-1,4,4-dihydroquinoline-3-nitrocarboxylate N-methyl-N- (4 —Fluorophenyl) amide,

Compound No. 1-1316: 1— (3,4-dimethoxyphenyl) _6,7,8-trimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N- (4-methyl Toxifenil) amide,

Compound No. 1-1373: 6,7-Dimethoxy-1_ (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline_3-3-Rubonic acid N-methyl-N— (3-Fluorophenyl Amid,

Compound No. 1-1375: 7-Methoxy 11- (4-methoxyphenyl) 1-4-oxo-1,4, -dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide, Compound No. 1-1384: 6, 7-Dimethoxy-1- (4-methoxyphenyl) -14-year-old xo 1,4-dihydroquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) amide,

Compound No. 1-1385: 6,7-Dimethoxy 1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline 3-carboxylate N-ethyl-N- (3,5-difluorophenyl) Amid,

Compound No. 1-1386: 6,7-Dimethoxy-1- (4-Methoxyphenyl) -1 41 T JP00 / 07852

 165 N-Methyl-N- (3-Fluorophenyl) amide oxo-1,4-dihydroquinoline-3-carboxylate,

Compound No. 1-1387: 7-Methoxy 1_ (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-N-phenylamide, Compound No. 1-1388: 7-Methoxy 11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline_3-carboxylate N-ethyl-1-N- (3,5-difluorophenyl) amide,

Compound No. 1-1389: 1- (4-methoxyphenyl) -1- 7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N-phenylamide, Compound No. 1-1390: 7— Dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-N— (3-fluorophenyl) amide,

Compound No. 1-1391: 7-Methoxy-1- (4-hydroxyphenyl) -1 4-oxo-1,4,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide, Compound No. 1- 1392: 7-Methoxy 1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) amide,

Compound No. 1-1393: 1— (4-Hydroxyphenyl) -1 7-Dimethoxy 4-oxo-1,4-Dihydroquinoline 1-3—Carbonic acid N-ethyl-N-phenylami h \

Compound No. 1-1394: 7-methoxy-11- (4-hydroxyphenyl) -14-oxo-1,4-dihydroquinoline-13-tetracarboxylic acid N-methyl-N-phenylamide, and

Compound No. 1-1395: 7-Dimethoxy-11- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N— (3-fluorophenyl Amid T JP00 / 07852

166.

 In Tables 1 and 2 above, compounds suitable as ileal bile acid transporter inhibitors include:

Exemplary compound numbers: 1-57, 1-179, 1-181, 1-183, 1-185, 1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1- 542, 1-544, 1-646, 1-770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313, 1-1315, 1- 1316, 1-1318, 1-1351, 1-1354, 1-1359, 1-1364, 1-1365, 1-1368, 1-1369, 1-1372-1-1379,

1-1381 to 1383, 1-1384 to 1-1395, 2-181, 2-183, 2-383, 2-385, 2-411, 2-418,

2-540, 2-542, 2-562, 2-572, 2-646, 2-668, 2-797, 2-799, 2-809, 2-812, 2- 1004, 2-1006, 2- 1032, 2-1041, 2-1161, 2-1163, 2-1183, 2-1190, 2-1192, 2-1193, 2-1274 to 2-1276, 2-1311, 2-1312, 2-1322, 2-1325, 2-1327, 2-1339, 2-1341, 2-1342, 2-1355, 2-1357, 2-1374, 2-1382, 2-1388 and 2-1396 to 2-1413 Can be

 Further preferred compounds include

Exemplary compound number: 1-57, 1-181, 1-183, 1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1-542, 1-544, 1- 770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1- 1354, 1-1359, 1-1364,

1-1365, 1-1368, 1-1369, 1-1372-1-1379, 1-1381-1-1383, 1-1384-1-1395,

2- 181, 2-183, 2-383, 2-385, 2-411, 2-418, 2-540, 2-542, 2-562, 2-572, 2-646, 2-668, 2- 797, 2-799, 2-809, 2-812, 2-1004, 2-1006, 2-1032, 2-1041, 2-1161, 2-1163, 2-1183, 2-1190, 2-1192, 2-1193, 2-1274, 2-1275, 2-1276, 2-1311, 2-1312, 2-1322, 2-1325, 2-1327, 2-1339, 2-1341, 2-1342, 2- 1355, 2-1357, 2-1374, 2-1382, 2-1388 and 2-1396 to 2-1413

Can be mentioned, 852

167 More preferred compounds include

Exemplary compound number: 1-57, 1-381, 1-383, 1-385, 1-538, 1-540, 1-542, 1-770, 1-772, 1-774, 1-827, 1- 828, 1-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138, 1-1140, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1-1354, 1-1359, 1-1368, 1-1369, 1-1372 to 1-1379, 1- 1381〜

1-1383, 1-1384-1-1395, 2-383, 2-385, 2-540, 2-542, 2-668, 2-797, 2-799,

2- 1004, 2-1006, 2-1032, 2-1161, 2-1163, 2-1183, 2-1190, 2-1276, 2-1311, 2-1312, 2-1322, 2-1325, 2- 1327, 2-1339, 2-1341, 2-1342, 2-1355 and 2-1396 to 2-1413

Can be mentioned,

 The most preferred compounds include

Compound No. 1-827: 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenyl amide,

Compound No. 1-828: 1— (4-hydroxyphenyl) -1,6,7-dimethoxyl-4-oxo-1,4-dihydroxyquinoline-1,3-dicarboxylic acid N-ethyl-N-phenylamide,

Compound No. 1-833: 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-1,3-dicarboxylic acid N-methyl-N— (3,5-difluorophenyl) amide ,

Compound No. 1-977: 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-41-year-old 1,4-dihydroxyquinoline-3-3-Rubonate N-methyl-N-phenylamide-,

Compound No. 1-978: 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinolin-13-carboxylate N-ethyl-N-phenylamide ', Compound No. 1-979: 1- (4-Methoxyphenyl) 1-6,7-Dimethoxy-1 41-year-old Kiso 1,4-Dihydroquinoline-3-Carboxylic acid N-Methyl-N— (4-Fluorophenyl) Amid,

Compound No. 1-981: 1— (4-Methoxyethoxy) 1,6,7-Dimethoxy-4-oxo-1,4-Dihydroxyquinoline 1-3—Rubonic acid N-methyl-1-N— (4-Methoxyethoxy) Nil) Amid,

Compound No. 1-1019: 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid N-methyl-N— (3,5-difluorophenyl) Amid,

Compound No. 1-1136: 1— (3,4-Dimethoxyphenyl) _6,7-Dimethoxy-14-oxo-1,4-Dihydro-1-quinoline-3-3-Rubonic acid N-Methyl-N—

(4-monofluorophenyl) amide,

Compound No. 1-1138: 1— (3,4 dimethoxyphenyl) -1,6,7-dimethoxy-1,4-oxo-1,1,4-dihydroquinoline-1,3-dicarboxylic acid N-methyl-1-N—

(4—methoxyphen) amide,

Compound No. 1-1286: 1— (4-methoxyphenyl) -1,6,7,8-trimethoxy-14-oxo-1,4,4-dihydro-quinoline-1—3-carboxylate N-methyl-1-N—

(4-monofluorophenyl) amide,

Compound No. 1-1287: 1- (4-Methoxyphenyl) -1,6,7,8-Trimethoxy-14-Oxo-1,4-Dihydroquinoline-13-N-Methyl-1-N-

(4—methoxyphen) amide,

Compound No. 1-1315: 1- (3,4-dimethoxyphenyl) _6,7,8-trimethoxy-1-4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N- (4-monofluorophenyl Amid,

Compound No. 1-1316: 1- (3,4-dimethoxyphenyl) -1,6,7,8-trimethoxy-4-oxo-1,4, dihydro-quinoline-1-3-n-methyl ribonate -N- (4-methoxyphenyl) amide,

Compound No. 1-1369: 7-Methoxy 11-phenyl 4-oxo-1,4-dihydroquinoline 3-capronic acid N-methyl-1-N-phenylamide,

Compound No. 1-1373: 6,7-dimethoxy-11- (4-methoxyphenyl) -14-year-old xo_1,4-dihydroquinoline-3-carboxylate N-methyl-1-N- (3-fluorophenyl) Amid,

Compound No. 1-1375: 7-Methoxy 11- (4-methoxyphenyl) 1,4-oxo-1,4-dihydroquinolin-3-carboxylate N-methyl-1-N-phenylamide, Compound No. 1-1384: 6,7-dimethoxy-1- (4-methoxyphenyl) -14-year-old xo-1,4-dihydroquinoline-3-potassium N-ethyl-N- (3,5-difluorophenyl) amide,

Compound No. 1-1385: 6,7-Dimethoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-dihydroxyquinoline_3-Carboxylic acid N-ethyl-1N— (3,5-difluorophenyl) amido Do

Compound No. 1-1386: 6,7-Dimethoxy-11- (4-methoxyphenyl) -1 41-year-old Kiso-1,4-Dihydroquinoline-1 3-Carbonic acid N-methyl-N- (3-full Orophenyl) amide,

Compound No. 1-1387: 7-Methoxy 1- (4-Methoxyphenyl) 1-4 1-year-old 1,4-dihydroxyquinoline 1-3-Rubonate N-methyl-N-phenylamide, Compound No. 1-1388 : 7-Methoxy 1- (4-Methoxyphenyl) -1 4-oxo-1,4-dihydroquinoline-3-3-Rubonate N-ethyl-N- (3,5-difluorophenyl) amide,

Compound No. 1-1389: 1— (4-methoxyphenyl) -1 7-dimethoxy-1-4-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-1-N-phenylamide. Compound No. 1- 1390: 7-Dimethoxy-1- 1- (4-methoxyphenyl) -14-oxo-1,4-Dihydroquinoline-3-carboxylate N-methyl-N— (3-fluoro T JP00 / 07852

170 phenyl) amide,

Compound No. 1-1391: 7-Methoxy-1- (4-hydroxyphenyl) -1-41-year-old oxo — 1,4-dihydroxyquinoline-3-3-Rubonic acid N-methyl-N-phenylamide, Compound No. 1- 1392: 7-Methoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-dihydroquinoline-13-carboxylate N-ethyl-1-N— (3,5-difluorophenyl) amide,

Compound No. 1-1393: 1- (4-Hydroxyphenyl) -1-7-dimethoxy-4-oxo-1,4-dihydroxyquinoline -3-3-Rubonic acid N-ethyl-N-phenylamine Compound No. 1-1394: 7 —Methoxy-1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N-phenylamino

Compound No. 1-1395: 7-Dimethoxy-1- (4-hydroxyl) -1-4-oxo-1,4-dihydroxyquinoline 3-3-Rubonic acid Ν-Methyl-Ν- (3-Fluoro mouth Phenyl) amide,

Compound No. 2- 1004: 1— (4-Methoxyphenyl) -14-Hydroxy-6,7-Dimethoxy-1-2-Oxo-1,2-Dihydroxyquinoline-1 3 _Carboxylic acid Ν—Methyl-1 Ν— (4 —Fluorophenyl) amide,

Compound No. 2-1006: 1— (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1 2-Hydroxy-1,2, -Dihydroquinoline-1—3-Rubonic acid Ν—Methylol Methoxyphenyl) amide,

Compound No. 2-1161: 1— (3,4-Dimethoxyphenyl) -14-Hydroxy-1,6,7-Dimethoxy-2—Oxo-1,2, -Dihydroxyquinoline-1-3-Rubonate Ν—Methyl-1-Ν (4-fluorophenyl) amide,

Compound No. 2-1163: 1-(3,4 dimethoxyphenyl)-4-hydroxy-1,6,7 -dimethoxy-2-sodium 1,2-dihydroxyquinoline-3-carboxylic acid Ν- 7852

171 Methyl-N— (4-methoxyphenyl) amide,

Compound No. 2-1311: 1- (4-methoxyphenyl) 1-4-hydroxy 6,7,8-trimethoxy 2-oxo-1,2, dihydroxyquinoline-3-carboxylate N-methyl-1-N— (4 —Fluorophenyl) amide,

Compound No. 2-1312: 1- (4-methoxyphenyl) 1-4-hydroxy 6,7,8-trimethoxy 2-oxo-1,2, -dihydroxyquinoline-3-carboxylate N—methyl-1-N— (4-methoxyphenyl) amide,

Compound No. 2-1339: 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-1,6,7,8-Trimethoxy 2-L-oxo-1,2-Dihydroquinoline-1-3-N-Methyl-1-N —Phenylamide,

Compound No. 2-1341: 1- (3,4-dimethoxyphenyl) 1-4-hydroxy-1,6,7,8-trimethoxy-1-2-oxo-1,2-dihydroxyquinoline-1-3-carboxylate N-methyl-N — (4-fluorophenyl) amide,

Compound No. 2-1342: 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-6,7,8-Trimethoxy_2-Oxo-1 1,2-Dihydroxyquinoline-13-Carboxylic acid

N-Methyl-N- (4-methoxyphenyl) amide, ·

Compound No. 2-1396: 1- (4-hydroxyphenyl) -1-4-hydroxy-7-methoxy-2-oxo-1,2-dihydroxyquinoline-3-potassium N-methylcarboxylate

N_phenylamide,

Compound No. 2-1397: 1- (4-hydroxyphenyl) -1-4-hydroxy-7-methoxy-2-oxo-1,2-dihydroxyquinoline-3-carboxylate N-ethyl-N-phenylamide,

Compound No. 2-1398: 1- (4-Hydroxyphenyl) 1-4-Hydroxy-1 7-Methoxy 2- 2-Hydroxy 1,2-dihydroxyquinoline _3-Luvonic acid N-methyl-N- (3-fluorophenyl Amid,

Compound No. 2-1399: 1- (4-hydroxyphenyl) -1-4-hydroxy-7- Toxic 2-1,2-dihydroquinoline 1-3-carboxylic acid N-ethyl-N- (3-fluorophenyl) amide,

Compound No. 2-1400: 1- (4-Hydroxyphenyl) 1-4-hydroxy-17-methoxy-2-oxo-1,2-dihydroquinoline-13-Rubonic acid N-methyl-N— (3,5- Difluorophenyl) amide,

Compound No. 2-1401: 1- (4-hydroxyphenyl) 1-4-hydroxy-1 7-methoxy-12-oxo1-1,2-dihydroquinoline-1-3-carboxylate N-ethyl-1N- (3, 5-difluorophenyl) amide,

Compound No. 2-1402: 1- (4-Methoxyphenyl) 1-4-Hydroxy-7-Methoxy 2-oxo-1,2-Dihydroxyquinoline 3-Carbonyl N-methyl-N-phenylamide,

Compound No. 2-1403: 1- (4-methoxyphenyl) 1-4-hydroxy 7-methoxy 2-oxo-1,2, -dihydroxyquinoline 3-nitrocarboxylate N-ethyl-1 N-phenylamide ,

Compound No. 2-1404: 1- (4-Methoxyphenyl) 1-4-hydroxy-1 7-methoxy 2-oxo-1,2-dihydroxyquinoline-3-carboxyl N-methyl-1-N- (3-fluorophenyl Amid,

Compound No. 2-1405: 1— (4-Methoxyphenyl) 1-4-Hydroxy 7—Methoxy 1-2-Oxo-1,2-Dihydroxyquinoline 3-Fe-Rubonic Acid N-Ethyl-N-1 (3-Fluorophenyl Amid,

Compound No. 2-1406: 1- (4-Methoxyphenyl) 1-4-Hydroxy_7-Methoxy-1-2-Oxo-1,2-Dihydroquinoline-3-Fe-Rubonic Acid N-Methyl-N-I (3,5 —Difluorophenyl) amide,

Compound No. 2-1407: 1— (4-Methoxyphenyl) 1-4—Hydroxy 1 7—Methoxy 2—Hydroxy 1,1,2-Dihydroxyquinoline 3—N-Ethyl-N-Ethyl-N- (3, 5-difluorophenyl) amide, Compound No. 2-1408: 1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1 2-Oxo-1,2-Dihydroxyquinoline-3-Portable N-methyl N-phenylamide,

Compound No. 2-1409: 1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-1-2-Oxo-1,2,2-dihydroquinoline-3- 3-Rubonic acid N-Ethyl N-Phenylamide ,

Compound No. 2-1410: 1 _ (4-methoxyphenyl) 1-4-hydroxy-1,6,7-dimethoxy-2-oxo-1,2-dihydroxyquinoline-3-carboxylic acid N-methyl N- (3-fluorophenyl) amide,

Compound No. 2-1411: 1— (4-Methoxyphenyl) -14-Hydroxy-1,6,7-dimethyl-2-oxo-1,1,2-Dihydroxyquinoline-13-Carboxylic acid N-Ethyl-1-N— ( 3-fluorophenyl) amide,

Compound No. 2-1412: 1- (4-Methoxyphenyl) 1-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate N-methyl-1-N— (3,5- Difluorophenyl) amide, and

Compound No. 2-1413: 1— (4-Methoxyphenyl) 1-4-hydroxy-1,6,7-dimethoxy-12-oxo-1,1,2-dihydroquinoline-3-carboxylate N-ethyl-1-N— (3, 5-difluorophenyl) amide

Can be mentioned.

 The compounds having the general formulas (I) and (II) of the present invention can be produced according to the methods described below.

Method A is a method for producing compound (II).

 (Π)

 (XV) (Π)

In the above ^{formula, RR 2, R 3, R} 4, R 5, and R ⁶ have the same meanings as described _{above, p la R2a, R 3a,} R 4a, R5 a and _R 6a is, _{Rl, R} 2, _R3 , _R4 , _R5 , and R6 groups 7852

175 The definition of the groups RR ² , R ³ , RR \ and R ^{6 in which} the amino, hydroxy and Z or carboxy groups contained as substituents may be protected amino, hydroxy and / or carboxy groups And R ⁹ and R ⁹ ′ are the same or different and represent a hydrogen atom, a hydroxy group, a lower alkoxy group or a halogen atom, and R ¹⁰ is a hydrogen atom or hydroxy protecting group. R ¹¹ represents a hydrogen atom, a hydroxy group or a lower alkoxy group, and W is usually an unlimited force as long as it is a group capable of leaving as a nucleophilic residue, preferably chlorine, bromine, Halogen atoms such as iodine; lower alkoxy groups such as methoxy and ethoxy; trihalogenomethyloxy groups such as trichloromethyloxy; methanesulfonyloxy and ethanesulfonyloxy Lower alkenyl sulfonyloxy groups, such as trifluoromethane sulfonyloxy, and pentafluorofluorosulfonyloxy; lower alkenyl sulfonyloxy groups; benzenesulfonyloxy, p-toluenesulfonyloxy; And an arylsulfonyloxy group such as p-nitrobenzenesulfonyloxy, and most preferably a halogen atom and a lower alkoxy group. In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^6a is not particularly limited as long as it is a protecting group for an amino group used in the field of synthetic organic chemistry. , Formyl, acetyl, propionyl, butyryl, isobutyryl, noreryl, isonoleryl, bivaloyl, hexanoyl, acryloyl, lower aliphatic acetyl groups such as methacryloyl, crotonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, "Aliphatic acyls" such as halogeno lower alkyl radicals such as trifluoroacetyl, lower alkyl radicals substituted with lower alkoxy such as methoxyacetyl, etc .; There bound C ₇ primary aromatic Ashiru group, 2-Buromobenzoiru, 4 one black port benzo Ha Rogeno C ₇ such as Le - C _u aromatic Ashiru group, 2, 4, 6-trimethylbenzoyl I le, 4- Toruo I C _7, such is substituted with a lower alkyl as Le - C _u aromatic Ashiru group , 4-Anisir C ₇ such substituted with a lower Arukokishi as - C "aromatic Ashiru group, 4-nitro downy emission zone I le, C ^ substituted with two Toro, such as 2-nitro port Benzoiru - C u aromatic Ashiru group, 2- (main butoxycarbonyl) C ₇ substituted by lower alkoxycarbonyl, such as Benzoiru - C "aromatic Ashiru group, § Li such as 4-safe We sulfonyl benzo I Le - C ₇ substituted by Le — “Aromatic acyls” such as C _n aromatic acyl groups; the above-mentioned lower alkoxycarbonyl groups, halogens such as 2,2,2-trichloromouth ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; “Alkoxycarbonyls” such as substituted lower alkoxycarbonyl groups; “alkenyloxycarbonyls” such as vinyloxycarbonyl and aryloxycarbonyl Such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethyloxybenzyloxycarbonyl, 2-nitrobenzoyloxycarbonyl, and 4-nitrobenzyloxycarbonyl "Aralkyloxycarbonyls optionally substituted with one or two lower alkoxy or two-membered aryl rings"; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyl Tri-lower alkylsilyl groups such as diisoprovirsilyl, methyldi-tert-butylsilyl, triisopropyl pyrsilyl, aryls such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl And 3 groups selected from lower alkyl "Silyls" such as silyl groups; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, / 9-naphthylmethyl, diphenylmethyl, triphenylmethyl, a-naphthyldiphenylmethyl, 9-anthryl Lower alkyl group substituted with one to three aryl groups such as methyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl , 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) Low levels such as methyl and piperonyl "Aralkyls" such as lower alkyl groups substituted with 1 to 3 aryl groups, wherein the aryl ring is substituted with alkyl, nitro, halogen, cyano, or N, N-dimethylaminomethylene, benzylidene, Forming "Schiff bases" such as 4-methoxybenzylidene, 4-12 benzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro1-2-hydroxyphenyl) phenylmethylene substituted methylene group "; a and, preferably, lower aliphatic Ashiru group, C ₇ - a C _n aromatic Ashiru or alkoxy force Lupo two group, more preferably a lower alkoxide aryloxycarbonyl group And most preferably t-butoxycarbonyl.

In the above, in the definition of R ^Ia , R ^2a , RR% R ^5a and R ^6a , the “protecting group” of the “optionally protected hydroxy group” refers to protection of a hydroxy group used in the field of synthetic organic chemistry. Although it is not particularly limited as long as it is a group, for example, it has the same meaning as described above, and is preferably a lower aliphatic acyl group, a C ₇ -C „aromatic acyl group, a lower alkoxy group, a luponyl group or a (lower An alkoxy) methyl group, more preferably a lower aliphatic acyl group or a (lower alkoxy) methyl group, most preferably an acetyl group or a methoxymethyl group.

In the above, the “protecting group” of the “optionally protected carboxy group” in the definition of R ^6a is not particularly limited as long as it is a carboxy protecting group used in the field of synthetic organic chemistry. It has the same meaning as that of a soda, and is preferably a lower alkyl group or a benzyl group. The step A1 is a step of producing the compound (II). The compound having the general formula (III) is reacted with the compound having the general formula (III) in the presence or absence (preferably in the absence of) After reacting with a compound having the formula (IV), if desired, the protecting groups for the amino, hydroxy and / or carboxy groups in R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a are removed. Is performed.

 When the compound (III) is reacted with the compound (IV) in the absence of an inert solvent, the reaction temperature varies depending on the starting compound. The reaction temperature is usually 150 ° C to 350 ° C (preferably 200 to 300 ° C). In).

 The reaction time for reacting the compound (III) with the compound (IV) in the absence of an inert solvent varies depending on the starting compound, the reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 to 24 hours). Hours to 12 hours).

 When reacting compound (III) with compound (IV) in the presence of an inert solvent, the inert solvent used is not particularly limited as long as it is inert to the reaction. Aliphatic hydrocarbons, such as hexane, heptane, rig-in, petroleum ether; aromatic hydrocarbons, such as benzene, toluene, xylene, and triisopropylbenzene; Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl citrate, butyl acetate and getyl carbonate; getyl ether, disopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol Lumpur, n--flops Lono,. Knoll, Isoprono ,. Alcohols such as ethanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellulose; nitriles such as acetonitrile and isobutyronitrile; Amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; water; or a mixed solvent of the above solvents; and preferably aromatic hydrocarbons (most Preferably, it is triisopropylbenzene.

 The reaction temperature when reacting compound (II) with compound (IV) in the presence of an inert solvent varies depending on the starting compound, the solvent, etc., but is usually from 150 ° C to 300 ° C.

(Preferably, 20 °: to 25 or).

Reacting compound (III) with compound (IV) in the presence of an inert solvent The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 12 hours). Removal of protecting groups for amino, hydroxy, and carboxy groups depends on the type of if method generally known in the art of organic synthetic chemistry, for example, TW Green, (Protective Groups in Organic synthesis), John Wiley & 5ons: JFW According to the method described in Mc0mis, (Productive Groups in Organic Chemistry), Plenum Press, it can be performed as follows. When the protecting group of the amino group is a silyl, a compound which generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, monopyridine hydrofluoride, or potassium fluoride is usually used. And removed by treating with.

 The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include solvents such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Monoliths are preferred.

 The reaction temperature and the reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C. to 50 for 10 minutes to 18 hours.

 When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, the amino group is treated with an acid or a base in the presence of an aqueous solvent. Can be removed.

 The acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, An inorganic acid such as nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect other parts of the compound. Preferably, alkali metal carbonates such as lithium carbonate, sodium carbonate, and lithium carbonate are used. ; Lithium hydroxide, sodium hydroxide, hydroxylating power Alkali metal hydroxides such as lime; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium-t-butoxide; ammonia such as aqueous ammonia, concentrated ammonia-methanol ; Is used o

The solvent used in the above reaction is not particularly limited as Re der those used in the conventional hydrolysis reaction ^force?, For example, methanol, ethanol, n- propanol, isopropanol, n- butanol Ichiru , Isobutanol, t-butanol, isoamyl alcohol, alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methylcellulose sorb; dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl Ethers such as ethers; water; a mixed solvent of water and the above organic solvent; preferably ethers (most preferably dioxane).

 The reaction temperature and reaction time vary depending on the starting compound, solvent and acid or base used, and are not particularly limited.In order to suppress the force and side reactions, the reaction is usually performed at 0 ° C to 150 ° C. Let react for 10 to 10 hours.

When the protecting group for the amino group is an aralkyl or aralkyloxycarbonyl, the protecting group is usually brought into contact with a reducing agent in an inert solvent (preferably, at room temperature in the presence of a catalyst at room temperature). Reduction) A method of removing or using an oxidizing agent is preferred. The solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as toxicethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol , Mechiruse opening cellosolve Organic solvents such as acetic acid; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers, organic acids or water (most preferably, alcohols or Organic acids).

 The catalyst used for the catalytic reduction is not particularly limited as long as it is usually used in the catalytic reduction reaction. Preferably, the catalyst is palladium monocarbon, Raney-nickel, or oxidized. Platinum, platinum black, rhodium aluminum monoxide, triphenylphosphine-rhodium chloride and palladium monosulfate are used.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually from 0 to 100, for 5 minutes to 24 hours.

The solvent used in the removal by oxidation, force ⁵ is not particularly limited as Re der as it does not participate in the reaction ', preferably a water-containing organic solvent.

 Such organic solvents include, for example, chloroform, dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; nitriles such as acetonitrile, getyl ether, diisopropyl ether, tetrahydrofuran Ethers such as orchids, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide And sulfoxides such as dimethyl sulfoxide; sulfolane; preferably, halogenated hydrocarbons, ethers or sulfoxides (most preferably, halogenated hydrocarbons or sulfoxides).

The oxidizing agent to be used is not particularly limited as long as it is a compound used for the oxidation, but is preferably, for example, potassium persulfate, sodium persulfate, ammonium cellium nitrate (CAN), 2, 3 ^{-?-dichloro-5,} 6-Jishiano one p- base Nzokinon (DDQ) force is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually 0 to 1501: 1 for 10 minutes to 24 hours. T / JP00 / 07852

182 When the protecting group for the amino group is an aralkyl, the protecting group can be removed using an acid.

 The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction.For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid Acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoroacetic acid, organic acids such as trifluoromethanesulfonic acid, etc .; brenstead acids; zinc chloride, tin tetrachloride, boron Lewis acids such as trichloride, pollon trifluoride and pollon tribromide; acidic ion exchange resins; preferably inorganic or organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid). .

 The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, and acetic acid Esters such as butyl and getyl carbonate; ethers such as getyl ether, disopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, Isso Prono ,. Alcohols such as phenol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbate; formamide, dimethylformamide, dimethylacetate Amides such as amides and hexamethyl phosphate triamide; water; or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (most preferably dioxane, Tetrahydrofuran, ethanol or water).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, and the like, but is usually from 120 ° C to the boiling point (preferably from 0 to 100 ° C). 852

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).

 When the protecting group of the amino group is an alkenyloxycarbonyl, the protecting group of the amino is usually the above-mentioned aliphatic acyl, aromatic acyl, alkoxycarbonyl or a substituted methylene group forming a Schiff base. It is carried out by treating with a base in the same manner as in the removal reaction in some cases.

 In the case of an aryloxycarbonyl group, in particular, a method of removing it using palladium, and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

 When a silyl is used as a protecting group for a hydroxy group, a compound that produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride is usually used. Or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid Can be removed by treatment with an organic acid such as trifluoromethanesulfonic acid.

 In addition, when removing with a fluorine anion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

 The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, but is preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl. Ethers such as ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and reaction time vary depending on the starting compound, the catalyst, the solvent, and the like, but are usually from 0 to 100 ° C (preferably from 10 to 50) for 1 hour to 24 hours. When the c-hydroxy group protecting group is an aralkyl or an aralkyloxycarbonyl, it is usually contacted with a reducing agent in an inert solvent (preferably, JP00 / 07852

184 Catalytic reduction at room temperature in a medium) or a method using an oxidizing agent.

 The solvent used for the removal by catalytic reduction is not particularly limited as long as it does not take part in the reaction. Aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as toluene, benzene and xylene; esters such as ethyl acetate and propyl acetate; such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane and diethylene glycol dimethyl ether. Ethers: methanol, ethanol, n-prono. Knoll, Isoprono ,. Alcohols such as phenol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, methylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; formamide, dimethylformamide, dimethylacetate Amides such as amides, N-methyl-2-pyrrolidone, and hexamethyl phosphate triamide; fatty acids such as formic acid and acetic acid; water; mixed solvents of the above solvents; Most preferred is methanol).

 The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.For example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum Black, rhodium aluminum monoxide, triphenyl phosphine-rhodium chloride, and palladium monosulfate, and preferably palladium carbon.

 The pressure is not particularly limited, but it is usually 1 to 10 atm.

 The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually 0: to 100 (preferably 20 to 70 ° 0, 5 minutes to 48 hours (preferably Is from 1 hour to 24 hours).

 The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

Preferred as such organic solvents are ketones such as acetone; methylene chloride. Halogenated hydrocarbons such as lid, black form, carbon tetrachloride; nitriles such as acetonitrile; ethers such as J. ethylether, tetrahydrofuran, dioxane; dimethylformamide, dimethyla Examples include amides such as cetamide and hexamethylphosphoric acid triamide; and sulfoxides such as dimethyl sulfoxide.

 The oxidizing agent used is not particularly limited as long as it is a compound used for the oxidation, but is preferably, for example, potassium persulfate, sodium persulfate, ammonium cellum nitrate (CAN), 2, 3 5,6-Dicyano p-benzoquinone (DDQ) is used.

 The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually 0 to 150, for 10 minutes to 24 hours.

 Also in liquid ammonia or methanol, ethanol, n-propanol, isoprono. In alcohols such as ethanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbate, at temperatures between 178 ° C and 0 It can also be removed by the action of alkali metals such as lithium and metallic sodium.

 Furthermore, it can be removed with an alkylsilyl halide such as aluminum chloride sodium monoiodide or trimethylsilyl iodide in a solvent.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; and acetonitrile. Nitriles; mixed solvent of the above solvents; power ⁵ 'The reaction temperature and reaction time vary depending on the starting compound, solvent, etc., but are usually 0 to 50 ° C for 5 minutes to 72 hours. Is done.

In the case where the reaction substrate has a sulfur atom, aluminum sodium iodide is preferably used. When the protecting group of the hydroxy group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the reaction, in particular but not exclusively the force ^s as long as it does not affect the other parts of the compound, for example, lithium carbonate, sodium carbonate, alkali metal carbonates, such as carbonate force potassium; Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, sodium Metal alkoxides such as methoxide and potassium hydroxide; ammonia such as ammonia water and concentrated ammonia-methanol; preferably, alkali metal hydroxides, metal alkoxides or metal alkoxides. Ammonia (most preferably, alkali metal hydroxides or metal The solvent used in (xoxides) is not particularly limited as long as it is used in a usual hydrolysis reaction. Examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether. Ethers such as methanol; ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and alcohols such as methyl cellosolve Preferred solvents are mixed solvents of the above solvents.

 The reaction temperature and reaction time vary depending on the starting compound, the base used, the solvent, and the like, and are not particularly limited. Conducted for 10 hours.

 When the protecting group for the hydroxy group is an alkoxymethyl, tetrahydrobiranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or substituted ethyl, it is usually treated with an acid in a solvent. To be removed.

As the acid to be used, it is usually used as Brenstead acid or Lewis acid. It is not particularly limited as long as it is an organic acid such as hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid. Brenstead acid: a Lewis acid such as boron trifluoride. A strongly acidic cation exchange resin such as Dowex 50 W can also be used. The solvent used in the above reaction is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate Esters such as butyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropyl pyrether, tetrahydrofuran, dioxane, dimethyloxetane, and dimethyl glycol dimethyl ether; methanol, ethanol, n-propanol, Isopropanol, n-butanol, isobu Alcohols such as tanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbent; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone Water; a mixed solvent of the above solvents; preferably ethers (most preferably, tetrahydrofuran) or alcohols (most preferably, methanol).

 The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent, etc., but are usually from −10 to 200 ° C. (preferably from 0 ° C. to 150 ° C.). Minutes to 48 hours (preferably 30 minutes to '10 hours).

 When the protecting group for the hydroxy group is an alkenyloxycarbonyl, the conditions for the removal reaction when the protecting group for the hydroxy group is the above-mentioned aliphatic acyls, aromatic acyls or alkoxyl propyls are usually Similarly, it is achieved by treating with a base.

In the case of an aryloxycarbonyl group, palladium and triphenylphospho are particularly preferred. It is simple to remove with sphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate, and it can be carried out with few side reactions. it can. When the protecting group for the carboxy group is a lower alkyl group or a lower alkyl group substituted with one to three aryls which may be substituted with lower alkyl, lower alkoxy, ditrono, logen or cyano, hydroxy is usually used. The protecting group ability ⁵ ′ of the group can be achieved by treating with a base in the same manner as the conditions for the removal reaction in the case of an aliphatic acyl, an aromatic acyl, or an alkoxy group. The removal of the protecting group for the amino, hydroxy and / or carboxy group can be carried out in any order and the desired removal reaction can be carried out sequentially. After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. The step A2 is a step of producing a compound having the general formula (VI), wherein the compound having the general formula (V) is prepared in the presence or absence (preferably in the absence) of an inert solvent. After the reaction with the compound (IV), if necessary, the hydroxy group at the 4-position of the quinoline ring is protected, and the reaction is carried out by reacting the compound (V) with the compound (IV). It is performed in the same manner as the process. Method, the force varies depending on the kind of the protecting group ^Y, methods well known in the general organic synthetic chemistry techniques to protect the 4-position of the hydroxy group of the quinoline ring, for example, TWGreen,

(Protective Groups in Organic Synthesis) .John Wiley & 5ons: J.F.W.Mc0mis,

(Protective Groups in Organic Chemistry), Plenum Press.

 For example, as a method for protecting the hydroxy group at the 4-position of the quinoline ring of the compound (VI), a method in an inert solvent (preferably ketones such as acetone) in the presence or absence of a base (preferably Is in the presence of an alkali metal carbonate such as potassium carbonate), a compound in which the 4-position of the quinoline ring in compound (VI) is a hydroxy group is represented by the following formula

R ¹⁰ — W (VII)

Or

^{R 10 - 0- R 10 (VIII} )

[In the above formula, W has the same meaning as described above, and R ¹⁰ represents a protecting group for a hydroxy group. And at a reflux temperature of the solvent (preferably 01 C to the reflux temperature of the solvent used) for 10 minutes to 3 days (preferably 1 hour to 6 hours). Is performed.

Further, 4-position hydroxy group the lower aliphatic § sill of the quinoline ring separately the compound (VI), C ₇ - is a method of protecting at C _u aromatic Ashiru group or a lower alkoxycarbonyl group, in an inert solvent (Preferably in the presence of a halogenated hydrocarbon, such as methylene chloride), in the presence or absence of a condensing agent and a base (preferably, a carbodiimide such as dicyclohexylcarbodiimide). Compounds), compounds

The compound in which the 4-position of the quinoline ring in (V) is a hydroxy group is represented by the following formula:

R ¹⁰ -OH (IX)

[In the above formula, R ¹¹⁵ has the same meaning as described above. ]

And — at 20 T: to 80 (preferably 0 ° C. to room temperature) for 10 minutes to 3 days (preferably 30 minutes to 1 day). . After completion of the reaction, the target compound (VI) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. Step A3 is a step of producing compound (II), which comprises compound (VI) and general formula (X) in an inert solvent in the presence or absence (preferably in the presence) of a base. After subjecting the compound to an Ulman reaction [Synth. Comm., 1996, 3877] in the presence of a transition metal such as copper, palladium or nickel, if desired, R ^la , R ^2a , R ^3a , R ^4a , Amino in R ^5a及Pi R ^{6 a,} is performed Ri by the removing the protecting group of the hydroxy and Z also carboxy groups.

The solvent used in the reaction, particularly limited as long as the present reaction inert no force, for example, hexane, heptane, rig port in, aliphatic hydrocarbons such as petroleum ^ether;? Benzene , Toluene, xylene; aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; halogenated hydrocarbons such as ethyl formate, ethyl acetate, acetic acid Esters such as propyl, butyl acetate, and getyl carbonate; ethers such as getyl ether, diisopropanol, ether such as tetrahydrofuran, dioxane, dimethoxetane, and dimethyl glycol dimethyl ether; methanol, ethanol, n-propanol, Isopropanol, n-butanol, iso Tano Ichiru, t-blanking evening Nord, isoamyl alcohol, diethylene glycol, glycerin, Okutano Le, cyclohexane hexanol, an alcohol such as Mechiruse port cellosolve; acetone, main Chiruechiruketon, the cyclohexanone methyl isobutyl ketone, isophorone, cyclohexylene Ketones; water; a mixed solvent of the above solvents; preferably, halogenated hydrocarbons (most preferably, dichlorobenzene).

 Examples of the base used in the above reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and lithium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide and sodium methoxide Metal alkoxides such as sodium chloride, sodium ethoxide, potassium t-butyl and toxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-ge Luanilin, 1,5-diazabicyclo [4.3.0] noner 5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] I-Organic amines such as 7-indene (DBU); preferably, alkali metal carbonates (most preferably potassium carbonate).

 The reaction temperature varies depending on the starting compound, base, catalyst, solvent and the like, but is usually from 100 ° C to 30 ° C (preferably from 15 ° C to 20 or).

 The reaction time varies depending on the starting compound, base, catalyst, solvent, reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably from 1 hour to 30 hours).

The method of removing the protecting group for the amino, hydroxy and / or carboxy group in R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a , which is optionally carried out, comprises the amino of the above-mentioned method A, step A1 step, It is carried out in the same manner as the method for removing the protecting group of the hydroxy and Z or carboxy groups.

After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After washing with water, etc., anhydrous magnesium sulfate, anhydrous sodium sulfate And dried over anhydrous sodium bicarbonate or the like, and then the solvent is distilled off. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified.

Step A4 is a process for producing a compound having the general formula (XIII), which has the general formula (XI) in an inert solvent in the presence or absence (preferably in the presence) of a base. This step is carried out by subjecting the compound having the general formula (XII) to an iman reaction in the presence of copper powder, and this step is carried out in the same manner as the above-mentioned Method A, Step A3.

Step A5 is a step of producing a compound having the general formula (XV), and converting the compound (XIII) into a compound represented by the general formula (XIII) in an inert solvent in the presence or absence (preferably in the presence) of a base. The reaction is performed by reacting with a compound having (XIV).

The inert solvent used in the above reaction is not particularly limited as long as the present reaction inert ^force?, E.g., hexane, heptane, rig port in aliphatic hydrocarbons such as petroleum E one ether Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; Methyl acetate, ethyl acetate, propyl acetate and acetic acid Esters such as butyl and diethyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ester

—Ter-like ethers; methanol, ethanol, n-propanol, isopronol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol Alcohols, such as methylacetosolve; ketones, such as acetone; amides, such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; nitriles, such as acetonitrile Water; or water or the above solution T JP00 / 07852

193 solvents; preferably ketones (most preferably acetone). As the base used in the above reaction, for example, those similar to the ones used in the above-mentioned Method A, Step A3 can be mentioned, and preferred are organic amines (most preferably pyridine). .

The reaction temperature, starting compound, base, different forces by solvents such ^as?, Is usually, one 2 0 ° C to 1 5 0, preferably from 0 a to 1 0 0 ° C.

 The reaction time varies depending on the starting compound, the base, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

After completion of the reaction, the target compound (XV) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. Step A6 is a process for producing the compound (II). The compound (XV) is subjected to a Dieckmann-type cyclization reaction in an inert solvent in the presence of a base [Chem. Hetrocycl. Compd., 1994, 829] After the reaction, if necessary, the protecting group for the amino, hydroxy, Z or carboxy group in R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a is removed.

The inert solvent used in the reaction, the force is not particularly limited as long as the present reaction ^inert?, E.g., hexane, heptane, rig port in fat aliphatic hydrocarbons such as petroleum ether Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; JP00 / 07852

194 knol, ethanol, _n -prono. Nord, Isopuroha ⁰ Nord, n- blanking evening Nord, I Sobutanoru, t chromatography butanol, isoamyl alcohol, Jechirenguriko Ichiru, glycerin, Okutanoru, hexanol cycloalkyl, alcohol, such as Mechiruse port cellosolve; formamide, dimethylformamide Amides, such as amide, dimethylacetamide, and hexamethyl phosphate triamide; or a mixed solvent of the above solvents; preferably alcohols (most preferably, ethanol).

 Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method A, Step A3, and are preferably alkali metal alkoxides (preferably sodium ethoxide). is there.

 The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, and is usually from 120 ° C to 100 ° C (preferably from 0 ° C to 50 ° C).

 The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 5 minutes to 50 hours (preferably 30 minutes to 24 hours).

The method of removing the protecting group for the amino, hydroxy and / or carboxy group in R ^la , R ^2a , R, R ^4a , R ^5a and R ^6a , which is carried out as desired, is described in the above-mentioned amino acid in Step A1 of Method A. O, and a method similar to the method for removing a protecting group for a hydroxy and / or carboxy group.o

 After completion of the reaction, the target compound (II) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the target compound obtained may be combined with a conventional method, for example, recrystallization, reprecipitation, etc., as appropriate, using a method commonly used for separation and purification of organic compounds. Can be separated and purified.

第 B 9工程 Method B is a method for producing compound (I).

Step B 9

(XXIV)

 (XXV)

 (ΙΠ) (XXIX)

Step B 12

In the above ^{formulas, R ', R 2, R} 3, R 4, R 5, R 6, R la, R 2a, R 3a, R 4a, R 5a, R 6a, R 7, RR 9, R 9' and W has the same meaning as described above, and R ^8a is an amino, hydroxy and / or carboxy group which may be protected by the amino, hydroxy and / or carboxy group contained as a substituent in the R ⁸ group. And a group similar to the group in the definition of R ⁸ , R ¹² represents a hydroxy group or a lower alkoxy group, and X represents a halogen atom. 852

197

Step Bl is a step for producing a compound having the general formula (XVII), and converting the compound (III) into a compound represented by the general formula (XVII) in the presence or absence (preferably, absence) of an inert solvent (XVI).

The reaction temperature at which Ru is reacted with a compound in the absence of an inert solvent (III) The compound (XV I) is different forces by starting ^compound?, Usually 1 50 a to 350 ° C (good suitable are 200 ° C to 300 ° C).

 The reaction time for reacting compound (III) with compound (XVI) in the absence of an inert solvent varies depending on the starting compound, reaction temperature, etc., but is usually 30 minutes to 24 hours (preferably, 1 hour to 12 hours).

 When reacting compound (III) with compound (XVI) in the presence of an inert solvent, the inert solvent used is not particularly limited as long as it is inert to the reaction. Aliphatic hydrocarbons such as hexane, heptane, heptane, lignin, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene, and triisopropylbenzene; chromate form, dichloromethane, 1,2-dichloroethane And halogenated hydrocarbons such as carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxetane. Ethers such as dimethyl alcohol and dimethyl ether; methanol, ethanol Alcohols, such as n-propanol, isopropanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellulose sorb; acetonitrile, isobutyro Nitriles such as nitriles; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; water; or a mixed solvent of the above solvents; Aromatic hydrocarbons (most preferably, triisopropylbenzene).

Reacting compound (III) with compound (XVI) in the presence of an inert solvent 007852

Reaction temperature for 198 the starting compound, different forces by solvents such ^as?, Typically, 1 00 ° C to 3 00V (preferably, 1 50 ° C to 250) is.

 The reaction time for reacting compound (III) with compound (XVI) in the presence of an inert solvent varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably, 1 hour to 12 hours).

After completion of the reaction, the target compound (XVII) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified. Step B2 is a step of producing compound (I). Compound (XVII) is reacted with polyphosphoric acid or concentrated sulfuric acid and acetic anhydride in the presence or absence (preferably without) of an inert solvent. After reacting with a dehydrating agent such as a mixture of the above, if necessary, the protecting groups for the amino, hydroxy and also carboxy groups in R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a are removed. Done.

 The reaction temperature for reacting compound (XVII) with a dehydrating agent in the absence of an inert solvent varies depending on the starting compound, but is usually 0 ° C to 200 ° C (preferably 5O to 1 ° C). 50).

 The reaction time when the compound (XVII) is reacted with the dehydrating agent in the absence of an inert solvent may vary depending on the starting compound, the reaction temperature, etc., and generally ranges from 5 minutes to 24 hours (preferably, 1 to 24 hours). 5 minutes to 12 hours).

When reacting compound (XVII) with a dehydrating agent in the presence of an inert solvent, the inert solvent used is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignoin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; chromate form, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as carbon tetrachloride and tetrachloroethylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxetane Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octa Alcohols such as alcohol, cyclohexanol, and methyl sorbitol; nitriles such as acetonitrile and isobutyritol; tolamides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide Amides; water; or a mixed solvent of the above solvents; preferably, halogenated hydrocarbons (most preferably, tetrachloroethylene).

 The reaction temperature when reacting the compound (XVII) with a dehydrating agent in the presence of an inert solvent varies depending on the starting compound, the solvent and the like, but is usually 0 to 200 (preferably 50 to 100). 150 ° C).

 The reaction time for reacting compound (XVII) with a dehydrating agent in the presence of an inert solvent varies depending on the starting compound, solvent, reaction temperature and the like, but is usually from 5 minutes to 24 hours (preferably 1 5 minutes to 12 hours).

The method for removing the protecting group for the amino, hydroxy and / or carboxy group in R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a , which is carried out as desired, is described in the above-mentioned amino acid in Step A1 of Method A. The method is carried out in the same manner as in the method for removing the protecting groups for the hydroxyl group and the hydroxy group.

After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl ester is added, and the target compound is added. The obtained organic layer is separated, washed with water or the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, or the like, which is usually used for the separation and purification of organic compounds, by applying chromatography and applying an appropriate eluent. Separation and purification can be achieved by elution. Step B3 is a step for producing a compound having the general formula (XIX), and is performed in an inert solvent in a reactive derivative of the compound (XVIII) (acid halides, active esters or mixed acid anhydrides). ) Is produced, and then reacted with compound (XIV) in the presence of a base in the presence of a typical metal salt such as magnesium chloride.

 The method for producing the reactive derivative of the compound (XVIII) is performed in the same manner as in the above-mentioned Method A, Step A3.

The inert solvent used when reacting the reactive derivative of the compound (XVIII) with the compound (XIV) is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, Aliphatic hydrocarbons such as rig-in, petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane and diethylene glycol dimethyl ether ; Methanol, ethanol, n-propanol, isopropano Alcohols such as toluene, n-butanol, isobutanol, t-butanol, isoamyl alcohol, ethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; Amides such as formamide, dimethylformamide, dimethylacetamide, and hexamyltriamide; water; or a mixed solvent of the above solvents; preferably a halogenated hydrocarbon, Amides or nitriles (most preferably, dichloromethane TJP00 / 07852

201 dichloromethane, dimethylformamide or acetonitrile).

 The base used for reacting the reactive derivative of the compound (XVIII) with the compound (XIV) includes, for example, the same bases as those used in the above-mentioned Method A, Step A3. Are organic amines (most preferably triethylamine).

 The reaction temperature for reacting the reactive derivative of the compound (XVIII) with the compound (XIV) varies depending on the starting compound, the base used, the solvent, etc., but it is usually from 20 to 100 (preferably from 100 to 100). , 0 to 50 ° 0.

 The reaction time when reacting the compound (XIV) with the reactive derivative of the compound (XVIII) depends on the raw material compound, the base used, the solvent, the reaction temperature, etc.

5 minutes to 50 hours (preferably 30 minutes to 24 hours).

 After completion of the reaction, the target compound (XIX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. After washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and then removing the solvent, the obtained target compound can be obtained by a conventional method, if necessary. Separation and purification can be achieved by appropriately combining commonly used methods for separation and purification of organic compounds, such as crystallization and reprecipitation, by applying chromatography and eluting with an appropriate eluent. Step B4 is a process for producing a compound having the general formula (XX), in an inert solvent, in the presence or absence (preferably in the presence) of a salt such as sodium chloride or the like. This is carried out by heating the product (XIX) to cause a decarboxylation reaction.

The inert solvent used in the reaction is not particularly limited as long as the present reaction inert force, for example, heptane, alicyclic aliphatic hydrocarbons such as rig port in or petroleum ^ether;? Benzene, Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide Amides; sulfoxides such as dimethylsulfoxide; sulfolane; and sulfoxides (most preferably dimethylsulfoxide).

 The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually from 50 ° C to 300 ° C (preferably from 100 ° C to 250 ° C).

 The reaction time varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

 Further, when performing this reaction, water may be added.

 After completion of the reaction, the target compound (XX) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water, etc., drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the desired compound obtained can be combined with conventional methods, such as recrystallization and reprecipitation, etc., as appropriate, using methods commonly used for the separation and purification of organic compounds. Can be separated and purified. Step B5 is a step of producing a compound having the general formula (XXII), and reacting the compound (XX) with a compound having the general formula (XXI) in an inert solvent in the presence of an acid. Done.

The inert solvent used in the above reaction, the force is not particularly limited as long as the present reaction ^inert?, E.g., hexane, heptane, rig port in aliphatic such as petroleum E Ichite Le Hydrocarbons; aromatic hydrocarbons such as benzene, toluene, and xylene; chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride 0 07852

Halogenated hydrocarbons such as 203; esters such as acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphate triamide; water; or a mixed solvent of the above solvents And preferably esters (most preferably acetic anhydride).

 The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction.For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid Brensted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids; zinc chloride, tin tetrachloride, boron Lewis acids such as trichloride, pollontrifluoride and pollontripromide; acidic ion exchange resins; preferably organic acids (most preferably acetic anhydride).

 The reaction temperature varies depending on the starting compound, solvent and the like, but is usually from 50 to 300 (preferably from 80 ° C. to 250).

 The reaction time varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

After completion of the reaction, the target compound (XXII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is removed. It is obtained by separating, washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the target compound obtained may be used in a conventional manner, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for the separation and purification of organic compounds, applying chromatography, and applying a suitable eluent. Can be separated and purified. Step B6 is a step for producing a compound having the general formula (XXIII), which is carried out by reacting the compound (XXII) with the compound (XII) in an inert solvent.

 The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate; Esters such as butyl acetate and getyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-prononol, and isoprono. Alcohols such as phenol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, dimethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; alcohols such as acetonitrile and isobutyronitrile Nitriles; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; and preferably alcohols ( Most preferably, ethanol).

 The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually from 100 to 100 (preferably from −50 ° C. to 50 ° C.).

 The reaction time varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually 5 minutes to 50 hours (preferably 15 minutes to 24 hours).

After completion of the reaction, the target compound (XXIII) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After washing with water, etc., drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. It is. If necessary, the target compound obtained is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, applying chromatography. Can be separated and purified.

Step B7 is a step of producing compound (I). After subjecting compound (XXIII) to the Ullman reaction, if desired, R ^la , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a The removal of amino, hydroxy and / or carboxy groups in the above is carried out.

Step B8 is a step for producing a compound having the general formula (XXV), and converting the compound (III) into a compound of the general formula (XXIV) in the presence or absence (preferably in the absence) of an inert solvent This step is performed in the same manner as in the above-mentioned Method B, Step B1.

Step B9 is a step for producing a compound having the general formula (XXVI), and in the presence or absence (preferably absence) of an inert solvent, converting the compound (XXV) to polyphosphoric acid or This step is carried out by reacting with a dehydrating agent such as a mixture of concentrated sulfuric acid and acetic anhydride. This step is carried out in the same manner as the above-mentioned Method B, Step B2.

Step B10 is a step of producing compound (I). After reacting compound (XXVI) with a compound having general formula (XXVII) in an inert solvent, if desired, R ^la , R ^{la 2a,} R ^3a, R ^4a, is performed by removing Amino, a protective group for hydroxy and Z also carboxy group in R ^5a and R ^6a.

When R ⁹ is a halogen atom in the compound (XXVI), the compound (XXVI) is converted to the compound (XXVI) in an inert solvent in the presence or absence (preferably in the presence) of a base group.

VII).

The inert solvent used in the above reaction, the force is not particularly limited as long as the present reaction ^inert?, For example, such as hexane, heptane, rig port-in oil E one ether to Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Methyl acetate, ethyl acetate, acetic acid Esters such as propyl, butyl acetate, and diethyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, and isoprene. Lono ,. Alcohols such as phenol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellulose; ketones such as acetone; formamide; dimethylform Amides such as amide, dimethylacetamide and hexamethylphosphoric triamide; nitriles such as acetonitrile; water; or water or a mixed solvent of the above-mentioned solvents; (Most preferably acetone). As the base used in the above reaction, for example, those similar to the ones used in the above-mentioned Method A, Step A3 can be mentioned, and preferred are organic amines (most preferably pyridine). .

 The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from 120 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

 The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, and is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

When R ⁹ is a hydrogen atom in compound (XXVI), the reaction is carried out by reacting compound (XXVI) with compound (XXVII) in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, for example, hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Methanol, ethanol, n-prono ,. Knoll, Isoprono ,. Alcohols such as ethanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, methylene glycol, glycerin, octanol, cyclohexanol, and methyl cellulose; formamide, dimethylformamide, Amides such as dimethylacetamide and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide; sulfolane; or a mixed solvent of the above solvents; Preferably, they are ethers (most preferably, tetrahydrofuran). The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually 0 to 200 t (preferably 10 to 120 ° 0).

 The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

When R ⁹ is a hydroxy group in the compound (XXVI), the compound (XXVI) or a reactive derivative thereof (acid halides, active esters or mixed acid anhydrides) is dissolved in an inert solvent. The reaction is carried out by reacting with compound (XXV II).

 In the acid halide method, compound (XXVI) is converted to a halogenating agent (eg, oxalyl chloride, thionyl chloride, thionyl bromide, oxalic acid chloride, dichloride oxalate, phosphorus oxychloride, trichloride) in an inert solvent. Reaction with phosphorus, phosphorus pentachloride, etc.) to produce acid halides, and the acid halides and compound (XXVII) are reacted in an inert solvent with or without a base (preferably in the presence or absence of a base). Bottom), by reacting.

 Examples of the base used in the above reaction include those similar to those used in the above-mentioned Method A, Step A3. Preferably, the base is an organic amine (most preferably, pyridin). is there.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; getyl ether, diisopropyl ether, and tetrahydrofura Ethers such as butane, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; dimethyl Sulfoxides; sulfolane; preferably, hydrogenated hydrocarbons, ethers or amides (most preferably dichloromethane, chloroform, tetrahydrofuran or dimethylformamide). .

 The reaction temperature varies depending on the starting compounds, reagents, etc., but the reaction between the halogenating agent and the compound (XXVI) and the reaction between the acid halides and the compound (XXVII) are usually from −20 ° C to 150 ° C. C. Preferably, the reaction between the halogenating agent and the compound (XXVI) is from −10 ° C. to 100 ° C., and the reaction between the acid halides and the compound (XXV II) is not more than 20 ° C. ° C to 100.

 The reaction time varies depending on the starting compounds, reagents, reaction temperature, etc., but the reaction between the halogenating agent and the compound (XXV I) and the reaction between the acid halides and the compound (XXV II) are usually from 30 minutes to 30 minutes. 80 hours (preferably 1 hour to 48 hours).

 In the active ester method, the compound (XXVI) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent in the presence or absence of a base (preferably In the presence), with compound (XXV II). The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-1,2,3-dicarboximidone. N-hydroxy compounds such as disulfides; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbenyldiimidazole; triphenylphosphine; and diphenylphosphoryl azide. It is suitably performed in the presence of such a condensing agent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, lignin or petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride Primers; ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoric acid triamide; sulfoxides such as dimethyl sulfoxide; sulfolane; and preferably ethers or amides (most preferably dioxane, tetrahydrofuran or dimethylformamide). C).

 Examples of the base used in the above reaction include the same bases as those used in the acid halide method.

 The reaction temperature varies depending on the starting compounds, reagents, and the like, but is usually 170 to 150 for active esterification. C (preferably from −10 to 100 C), and in the reaction of the active ester with the compound (XXVII), the reaction temperature is preferably from 120 ° C. to 100 ° C. (preferably 0 ° C. to 100 ° C.). 1: to 50 ° C).

 The reaction time varies depending on the starting compounds, reagents, reaction temperature, etc., but is usually 30 minutes to 80 hours (preferably, 30 minutes for the active esterification reaction and the reaction of the active ester with the compound (XXVII)). 1 hour to 48 hours).

 In the mixed acid anhydride method, compound (XXVI) was reacted with a mixed acid anhydride in an inert solvent in the presence or absence of a base (preferably in the presence of a base) to produce mixed acid anhydrides. Thereafter, the reaction is carried out by reacting the mixed acid anhydride with the compound (XXVII) in an inert solvent.

 Examples of the base used in the above reaction include the same bases as those used in the acid halide method, and are preferably organic amines (most preferably, pyridine).

Examples of mixed acid anhydride agents used in the above reaction include lower alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; lower alkanoyl halides such as pivaloyl chloride; getyl cyanophosphonate and diphenyl cyanophosphonate. Di-lower alkyl or diaryl cyanophosphoric acid such as It is a lower alkyl carbonate carbonate (most preferably, isoptyl chlorocarbonate).

 The inert solvent used in the production of mixed acid anhydrides is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.For example, hexane, heptane, rig Aliphatic hydrocarbons such as molybdenum or petroleum ether; Aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide Amides such as dimethyl sulfoxide; sulfides such as dimethyl sulfoxide Kishido acids; sul Horan; is, preferably halogenated hydrocarbons or amino earth (and most preferably, di- chloromethane or dimethylformamidine de) is.

At the reaction temperature for the reaction producing a mixed acid anhydrides on the starting material, different forces by reagents such as, usually ^-? 5 0 to 1 0 0 (preferably 0 ° C to 6 0 ° C) is .

 Does the reaction time in the reaction to produce mixed acid anhydrides vary depending on the starting compounds, reagents, reaction temperature, etc.? It is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours).

 The reaction between the mixed acid anhydrides and the compound (XXVII) is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base. The base and the inert solvent used are as follows. The same as those used in the reaction for producing the mixed acid anhydrides described above.

 The reaction temperature in the reaction of the mixed acid anhydrides with the compound (XXVII) may vary depending on the starting compounds, reagents, etc. Usually, -30 ° C to 100 ° C (preferably 0 to 8Ot) :).

The reaction time in the reaction between the mixed acid anhydrides and the compound (XXVII) varies depending on the starting compound, the reagent, the reaction temperature, and the like, but is usually 5 minutes to 24 hours (preferably 30 minutes to 1 hour). 6 hours). When di-lower alkylcyanophosphoric acid or diarylcyanophosphoric acid is used in this reaction, compound (XXVI) and compound (XXVII) can be directly reacted in the presence of a base.

When R ⁹ is a lower alkoxy group in the compound (XXVI), in the presence or absence (preferably not present) of an inert solvent, in the presence or absence of a base (preferably not present) ), By reacting the compound (XXV I) with the compound (XXV II).

 Examples of the base used in the reaction of the compound (XXVI) with the compound (XXVII) include the same bases as those used in the above-mentioned Method A, Step A3. Organic amines (most preferably pyridine).

 The inert solvent used in the reaction of the compound (XXVI) with the compound (XXVII) is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane, rig Aliphatic hydrocarbons such as ketones and petroleum ethers; Aromatic hydrocarbons such as benzene, toluene, and xylene; Ethyl ethers, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether One ters; methanol, ethanol, n-propanol, isoprono. Alcohols such as phenol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; formamide, dimethylformamide, dimethyl Amides such as acetoamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably ethers or amides (most preferably tetrahydrofuran, dioxane or dimethyl). Formamide).

 The reaction temperature varies depending on the starting compound, base used, solvent and the like, and is usually 0 to 200 (preferably 50 ° C to 150).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours). After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution. Step B11 is a step of producing a compound having the general formula (XXIX), and converting the compound (III) into a compound of the general formula (III) in the presence or absence (preferably in the absence) of an inert solvent. XXV III), and this step is carried out in the same manner as in the above-mentioned Method B, Step B1. Step B12 is a step of producing compound (I). Compound (XXV) is reacted with polyphosphoric acid or concentrated sulfuric acid and acetic anhydride in the presence or absence (preferably without) of an inert solvent. after such reacted with a dehydrating agent as a ^{mixture, R la, R 2a, R} 3a, R 4a, Amino in R ^5a and R ^6a, hydroxy and also line by Rukoto to remove the protecting group of the carboxy group if desired Will be Starting compounds (1 1 1), (IV), (V), (VII), (VIII), (IX), (X), (XI), (XII), (XIV), (XV 1), ( XX 1), (XX IV), (XXV II) and (XXV III) are known or are easily produced according to known methods or methods analogous thereto. [For example, J. Med. Chem. So, 120 (37), 9722 (1998); 0rg. Synth., 250 (1941)]. The invention's effect The compound of the present invention having the general formula (I) or (II), a pharmacologically acceptable salt thereof, an ester or other derivative thereof is an excellent ileal bile acid transporter.

— A pharmaceutical composition comprising an inhibitory compound having the general formula (I) or (II) of the present invention, a pharmacologically acceptable salt thereof, or an ester or other derivative thereof as an active ingredient, It is useful as a preventive or therapeutic agent for lipemia and arteriosclerosis. Industrial applicability

When the compound having the general formula (I) or (II) of the present invention, its pharmacologically acceptable salt or its ester is used as the above-mentioned therapeutic or prophylactic agent, it may be used as such or as appropriate pharmacology Mixed with excipients, diluents and the like, for example, administered orally with tablets, capsules, granules, powders or syrups, or parenterally with injections or suppositories be able to. These preparations may contain excipients (eg, lactose, sucrose, dextrose, saccharides such as mannitol, sorbitol; corn starch, starch, corn starch, starch derivatives such as α-starch, dextrin; cells such as crystalline cellulose). Oral derivatives; Arabic gum; Dextran; Organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium metasilicate aluminium; Phosphates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, stearic acid). Metal salts of stearic acid, such as magnesium; talc; Mosquitoes; waxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium lauryl sulfate; magnesium lauryl sulfate Lauryl sulfates; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.) Agents (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants ( For example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked carboxymethylcellulose sodium; chemically modified starches such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone. 'Cellulose can be mentioned.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol Phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, usually Examples thereof include a sweetener, an acidifier, a flavor, and the like, which are used.), And a known method using additives such as a diluent. The dosage varies depending on symptoms, age, etc.In the case of oral administration, the lower limit is 1 mg (preferably 10 mg) per day and the upper limit is 2000 mg (preferably 400 mg) per day. In this case, the lower limit of 0.1 mg (preferably l mg) per day and the upper limit of 500 mg (preferably 300 mg) per adult may be 1 to 6 times per day, depending on the symptoms. The power to administer is desirable.

7852

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, examples and test examples will be shown, and the power for explaining the present invention in more detail and the scope of the present invention are not limited to these. Example 1

 1- (3,4-dimethoxyphenyl) 1-4-hydroxy-1,6,7,8-trimethoxy-1-2-oxo-1,2-dihydroxyquinoline-3-carboxylic acid N-methyl-N-phenylamide ( Exemplified compound number 2—1339)

 (l a) 2-[(3,4-dimethoxyphenyl) amino] _3,4,5-trimethoxybenzoic acid methyl ester

 2-Promote 3,4,5-trimethoxyethoxy, 13.7 g of carboxylic acid, 3,4-Dimethoxyaniline 14.4 g, potassium carbonate 3.25 g, copper 0.3 g, A mixture of 2.06 g of pyridine and 25 ml of water was heated to reflux for 2 hours. After acidification with hydrochloric acid, the solid was collected by filtration and dissolved in methylene chloride. The filtrate was further extracted with methylene chloride, and the combined methylene chloride layer was separated and purified by silica gel column chromatography (eluent: ethyl acetate Z methylene chloride = 14). The obtained solid was washed with hexane isopropyl ether to obtain 12.3 g of 2-[(3,4-dimethoxyphenyl) amino] _3,4,5-trimethoxybenzoic acid. This was dissolved in 20 ml of N, N-dimethylformamide, and was dissolved in 0. 5.66 g of potassium carbonate and 3.2 ml of methyl iodide were added with C, and the mixture was stirred for 2 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the ethyl acetate layer is washed with water and saturated saline, the solvent dried over sodium sulfate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate). / Hexane = 1 3) to give 4.18 g of the title compound as yellow crystals.

NMR spectrum (CDC 1 ppm: 3.59 (3H, s), 3.81 (3H, s), 3.83 (3Η, s), 3.85 (3H, s) JP00 / 07852

216 s), 3.88 (3H, s), 3.96 (3H, s), 6.40 (1H, dd, J = 2.5, 8.5 Hz), 6.52 (1H, d, J = 2.5 Hz), 6.73 (1H, d, J = 8.6Hz), 7.28 (1H, s).

(l b) 2 — [(3,4-Dimethoxyphenyl) 1-[(N-methyl-1-N-phenylcaproluvamoyl) acetyl] amino] —3,4,5-trimethoxyethoxy, methyl perfume

 N-Methyl-N-phenylmonomalonic acid amide 72 Omg of methylene chloride in 1 Om1 solution, 0.65 ml of oxalic acid chloride and a few drops of N, N-dimethylformamide, at room temperature 1. Stir for 5 hours. The reaction solution was concentrated under reduced pressure and dissolved in 3 ml of methylene chloride. This acid chloride solution was treated with 342 mg of 2-[(3,4-dimethoxyphenyl) amino] -1,3,4,5-trimethoxybenzoic acid methyl ester obtained in Example (1a) and pyridine 0.4 m The solution was added at 0 to a solution of 15 ml of acetone at 0 and stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and then dried over sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography- (ethyl acetate / methylene chloride = 1/2) to give 216 mg of the title compound as a yellow oil.

NMR spectrum _{(CDC1 3) ppm: 3.01- 3.95} (23H, m), 6.50-6.75 (1H, m), 6.96- 7.38 (8H, m).

(1c) 11- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-1,6,7,8-Trimethoxy-2-oxo-1, 2-Dihydroxyquinoline-13-Carboxylic acid N-Methyl-N-phenylamino Do

2 _ [(3,4-Dimethoxyphenyl) 1-((N-methyl-1-N-phenylcarbamoyl) acetyl) amino] —3,4,5-trimethoxybenzoic acid methyl ester obtained in Example (lb) 2 15% ethanol in 15 ml solution 20% sodium chloride The methoxide ethanol solution (0.4 m 1) was charged and stirred at room temperature for 2 hours. After adding 1N hydrochloric acid to the reaction solution and concentrating under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and dried over sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate Z methylene chloride = 1/1) to obtain 82 mg of the title compound as a pale red solid.

NMR spectrum _{(CDC1 3) Sppm: 3.13and3.22 (} total 3H, s), 3.48 (3H, s), 3,75 (3H, s), 3.85 (3H, s), 3.87 (3H, s ), 3.96 (3H, s), 6.11-6.40 (2H, m), 6.77, and 7.03 (total 1H, d, J = 7.8Hz), 7.18-7.37 (5H, m), 7.39 (1H, s).

Melting point: 179-182. Example 2

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo_1,4-dihydroquinoline-13-Carboxylic acid N-methyl-1-N-phenylamide (Exemplary compound number 1-977)

 (2 a) 2— [(N- (3,4-dimethoxyphenyl) 1 N— (4 meth ^ cyphenidyl) amino) methylene] getyl malonate

 N- (3,4-Dimethoxyphenyl) 1 N— (4-Methoxyphenyl) amine 5.

A mixture of 74 g and 4.92 ml of ethoxymethylene malonate getyl was heated and stirred at 250 ° C. for 4 hours. After cooling the reaction solution, it was directly separated and purified by silica gel column chromatography (elution solvent: ethyl acetate Z hexane = 1/4) to obtain 8.78 g of the title compound as a red oily substance.

NMR spectrum _{(CDC1 3) Sppm: 1.07 (} 3H, t, J = 7.3Hz), 1.26 (3H, t, J = 7.2Hz), 3.55 (2H, q, J = 7.2Hz), 3.81 (6H, s ), 3.87 (3H, s), 4.2 (2H, q, J = 7.2Hz), 6.63-6.65 (2H, m), 6.80 (1H, d, J = 8.7Hz), 6.86 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.8Hz), 7.87 (1H, s). (2b) 6,7-Dimethoxy 1- (4-Methoxyphenyl) 1-4 4-oxo-1,4-Dihydroquinoline 1-3-Ethyl rubonate

 8.38 g of 2-([N- (3,4-dimethoxyphenyl) -1-N- (4-methoxyphenyl) amino) methylene] methylene] maleic acid obtained in Example (2a) 8.38 g and polyphosphorus The mixture of 60 g of the acid was heated and stirred at 100 for 2 hours. The reaction solution was poured on ice to dissolve the polyphosphoric acid in water, and the insoluble matter was collected by filtration. The solid collected by filtration was dissolved in methylene chloride, the methylene chloride layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluting solvent: acetone, methylene chloride = 1/9-1/4), and the title compound, 6, 7-dimethoxy 1- (4-methoxyphenyl) 1-4 —Oxo 1, 4—Dihydroquinoline 3 —Ethyl carboxylate as a white solid 1.5 1 £ £ 1 — (3,4 dimethyl phenyl) 1 6—Methoxy 1 4 —Oxo 1 There was obtained 1.16 g of 1,4-dihydroquinoline-13-ethyl ribonate as a gray solid.

 6,7-Dimethoxy 1- (4-methoxyphenyl) _4-oxo- 1,4-dihydroquinoline mono-3-ethyl ethyl ester

NMR spectrum _{(CDC1 3) Sppm: 1.41 (} 3H, t, J = 7.2Hz), 3.71 (3H, s), 3.93 (3H, s), 4.00 (3H, s), 4.39 (2H, q, J = 7.2Hz), 6.33 (1H, s), 7.10 (2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8.8Hz), 7.93 (1H, s), 8,41 (1H, s) .

Melting point: 194〜195

 1- (3,4 dimethoxyphenyl) 1-6-methoxy-1,4-oxo-1,4-dihydroxyquinoline-3-carboxylate

NMR spectrum _{(CDC1 3) Sppm: 1.42 (} 3H, t, J = 7.3Hz), 3.90 (3H, s), 3.92 (3H, s), 3.99 (3H, s), 4.40 (2H, q, J = 7.3Hz), 6.88 (1H, d, J = 2.2Hz), 6.95-7.04 (3H, m), 7.13 (1H, dd, J = 2.9, 9.4Hz), 7.96 (1H, d, J = 3.0Hz) , 8.45 (1H, s).

Melting point: 207-209 ° C. (2c) 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-13-carboxylic acid

 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-13-carboxylic acid ethyl ester obtained in Example (2b). 30 ml of a 30% aqueous hydroxide water solution was added, and the mixture was heated and stirred at 100 for 1 hour. After cooling, the reaction solution was neutralized with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. The solid collected by filtration was dissolved in methylene chloride, the methylene chloride layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The precipitated solid was suspended in ether and collected by filtration to obtain 1.12 g of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3.76 (} 3H, s), 3.94 (3H, s), 4.05 (3H, s), 6.46 (1H, s), 7.12 (2H, d, J = 9.0Hz) , 7.35 (2H, d, J = 9.0 Hz), 7.86 (1H, s), 8.69 (1H, s). Melting point: 238-241.

(2d) 6,7-Dimethoxy 1- (4-methoxyphenyl) _4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N-phenylamide In Example (2c) The resulting 6,7-dimethoxy-1- (4-methoxyphenyl) -1,4-oxo-1,4-dihydroxyquinoline-1,3-hydroxycarboxylic acid 2 50 mg and triethylamine 0.26 ml anhydrous chloride To 5 ml of the methylene solution was added 0.12 ml of isobutyl chloroformate at 0. After stirring at 0 for 15 minutes, N-methylaniline (0.06 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Silica force gel column chromatography scratch residue: separated (eluting solvent methanol Z methylene chloride = 1/1 9), c NMR spectrum (CDC1 ₃₎ the title compound was obtained 1 24 mg as a white solid SPPM: 3.49 (3H, s), 3.67 (3H, s), 3.91 (3H, s), 3.95 (3H, s), 6.25 (1H, br.s), 7.04 (2H, d, J = 8.8 Hz), 7.09- 7.36 (7H, m), 7.69 (2H, br.s). Melting point: 180-182. Example 3

 6,7-Dimethoxy-1- (4-methoxyphenyl) 1-1,4-Dioxo-1,4-dihydroquinoline-1 '3-carboxylate Ν-Methyl-1-Ν (3-cyclomouth phenyl) (Exemplary Compound No. 1 1 372)

 6,7-Dimethoxy-11- (4-methoxyphenyl) obtained in Example 2 (c) —4-oxo-1,4-dihydroquinoline-3-3-hydroxyrubonic acid 150 mg, triethylamine 0.15 m The reaction was carried out in the same manner as in Example (2d) using 0.007 ml of isobutyl formate and 0.06 ml of 3-chloro-1-N-methylaniline to obtain 99 mg of the title compound as a white solid.

 NMR spectrum (CDC) 5 ppm: 3.47 (3H, s), 3.69 (3H, s), 3.92 (3H, s), 3.96 (3H, s), 6.29 (1H, s), 7.06-7.37 (8H , ra), 7.69 (1H, s), 7.79 (1H, s).

Melting point: 1 65-1 68. Example 4

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-carboxylic acid Ν-methyl-Ν- (4-chlorophenyl) amide (Example compound) (Number 11-980)

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,1,4-dihydroquinoline-13 obtained in Example 2 (c) 3-Carboxylic acid 150 mg, Triethylamine 0.1 The reaction was carried out in the same manner as in Example (2d) using 0.07 ml of isobutyl formate and 0.06 ml of 4-chloro-1-N-methylaniline in 5 m to give 164 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3.46 (} 3H, s), 3.68 (3H, s), 3.92 (3H, s), 3.96 (3H, s), 6.28 (1H, s), 7.06 (2H, d, J = 9.1Hz), 7.08-7.38 (6H, m), 7.66 (1H, br), 7.79 (1H, Melting point: 146-149. Example 5

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1,4-oxo-1,4-dihydroquinoline-3-carboxylate ボ ン -ethyl-1-phenylamide (Exemplified Compound No. 1-978) )

 6,7-Dimethoxy-11- (4-methoxyphenyl) —4-oxo-1,4-dihydroquinoline-13-carboxylic acid obtained in Example 2 (c) 200 mg, triethylamine 0.19 m The reaction was carried out in the same manner as in Example (2d) using 0.09 ml of isobutyl chloroformate and 0.07 ml of N-ethylaniline to obtain 21 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 1.22 (} 3H, t, J = 7.1Hz), 3.66 (3H, s), 3.84- 4.00 (2H, m), 3.9K3H, s), 3.94 (3H, s), 6.22 (1H, br), 7.04 (2H, d, J = 8.8Hz), 7.09-7.37 (6H, m), 7.53-7.67 (2H, m).

Melting point: 150-1 52 ° Co Example 6

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N- (4-methoxyphenyl) amide (Exemplary compound number 1-98 1)

 6,7-Dimethoxy-1- (4-methoxyphenyl) obtained in Example 2 (c) —4-oxo-1,4-dihydroquinoline-13-carboxylic acid 200 mg, triethylamine 0 The reaction was carried out in the same manner as in Example (2d) using 0.19 ml, 0.009 ml of isobutyl chloroformate and 73 mg of N-methyl-p-anisidine, to obtain 377 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) 3ppm: 3.44 (} 3H, s), 3.67 (3H, s), 3.74 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 6.23 (1H, br.s), 6.72-6.92 (2H, br), 7.00-7.40 (6H, m), 7.52-7.72 (2H, m).

Melting point: 166-1 67t. Example 7

 7-Methoxy 1- (3-Methoxyphenyl) 1-4-oxo-1,4-dihydroxyquinoline-3-Carboxylic acid N-methyl-1-N-phenylamide (Exemplary Compound No. 1-1368)

 (7a) 2-Bisbis (3-methoxyphenyl) amino] Methylene i-Jethyl malonate

 The reaction was carried out in the same manner as in Example (2a) using 4.0 g of bis- (3-methoxyphenyl) amine and 4.15 g of ethoxymethylenemalonate getyl, and purified to give the title compound. 5.73 g as an orange oil.

NMR spectrum (CDCi ₃ ) Sppm: 1.06 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 3.5K2H, q, J = 7.2 Hz, 3.77 (6H, s) , 4.22 (2H, q, J = 7.3Hz), 6.65 (2H, s), 6.69 (2H, d, J-7.9Hz), 6.77 (2H, d, J = 8.5Hz), 7.22-7.26 (2H, m), 7.93 (1H, s).

(7b) 7-Methoxy-1- (3-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-ethyl carboxylate

2— obtained in Example (7a)! [Bis- (3-methoxyphenyl) -amino] methylene I The reaction was carried out in the same manner as in Example (2b) using 5.59 g of getyl malonate and 40 g of polyphosphoric acid, and purified to give the title compound. -Methoxy-11- (3-methoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-3-tetraethyl carboxylate 1.84 g as a white solid and 5-methoxy-1- (3- (Methoxyphenyl) 1,4-dioxo-1,4-dihydroquinoline-13-carboxylate ethyl ester was obtained as a yellow solid (350 mg). 7-Methoxy-1- (3-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline 3-ethyl ethyl ester

NMR spectrum _{(CDC1 3) Sppm: 1.40 (} 3H, t, J = 6.9Hz), 3.75 (3H, s), 3.88 (3H, s), 4.39 (2H, q, J = 6.9Hz), 6.39 (1H , d, J = 2.3Hz), 6.94 (1H, dd, J = 2.1, 2.2Hz), 6.99-7.02 (2H, m), 7.10-7.13 (1H, ra), 7.51 (1H, t, J = 8.2 Hz), 8.45-8.49 (2H, m). Melting point: 2 1 1 to 2 12 ° C

 5-Methoxy 11- (3-methoxyphenyl) _4-oxo-1,4-dihydroxyquinoline-3-ethyl carboxylate

NMR spectrum _{(CDC1 3) Sppm: 1.38 (} 3H, t, J = 7.3Hz), 3.86 (3H, s), 3.98 (3H, s), 4.37 (2H, q, J = 7.3Hz), 6.50 (1H , d, J = 7.8Hz), 6.81 (1H, d, J = 8.4Hz), 6.90 (1H, dd, J = 2.2, 2.3Hz), 6.97 (1H, dd, J = 2.2, 8.3Hz), 7.08 -7.11 (1H, m), 7.36 (1H, dd, J = 8.2, 8.7Hz), 7.49 (1H, dd, J = 8.0, 8.1Hz), 8.32 (1H, s).

Melting point: 189-191 ° C

(7 c) 7-Methoxy 11- (3-methoxyphenyl) 1 4-oxo 1,4-dihydroquinoline 1-3-Rubonic acid

50-mg of 7-methoxy-11- (3-methoxyphenyl) _4-oxo-1,4, -dihydroquinoline-3-carboxylate obtained in Example (7b) was suspended in 1 Oml of ethanol and water was added. 1 ml and 500 mg of sodium hydroxide were added, and the reaction solution was heated to reflux for 30 minutes. After the solvent of the reaction solution was concentrated under reduced pressure, the aqueous layer was acidified with dilute hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was suspended in diisopropyl ether and collected by filtration to obtain 486 mg of the title compound as a white solid. NMR spectrum (CDC) pm: 3.78 (3H, s), 3.88 (3H, s), 6.52 (1H, d, J = 2.4 Hz), 6.93-7.2 (4H, m), 7.54 (1H, t , J = 8.1Hz), 8.48 (1H, d, J = 8.9Hz), 8.74 (1H, s). Melting point: 1 65-1 68 ° C (7 d) 7-Methoxy 1— (3-Methoxyphenyl) 14 4-year-old xo 1,4-dihydroquinoline-3-carboxylate N-methyl-N-phenylamide

 7-Methoxy-1- (3-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylic acid obtained in Example (7c) 200 mg, triethylamine 0.2 m The reaction was carried out in the same manner as in Example (2d) using 0.09 ml of isobutyl formate and 0.06 ml of N-methylaniline to obtain 118 mg of the title compound as a white solid.

 NMR spectrum (CDC 1 ppm: 3.48 (3H, s), 3.69 (3H, s), 3.84 (3H, s), 6.31 (1H, s), 6.72-7.41 (9H, ra), 7.45 (1H, s) t, J = 8.1Hz), 7.61-7.76 (1H, br), 8.24-8.26 (1H, m).

Melting point: 150—15 2 ° (: Example 8

 6-Methoxy-1- (3-, 4-dimethoxyphenyl) -1-oxo-1,4-dihydroquinoline-3-potassium N-methyl-1-N-phenylamide (Exemplified Compound No. 1-5) 3 8)

 (8a) 6—Methoxy 11 (3,4-Dimethoxyphenyl) 1 4-oxo 1 1,

4-dihydroquinoline-3-carboxylic acid

 6-Methoxy: 1- (3,4-Dimethoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-3-ethyl carboxylate 500 mg and sodium hydroxide

The reaction and post-treatment were carried out in the same manner as in Example (2c) using 50 Omg, to obtain 391 mg of the title compound as a white solid.

 NMR spectrum (1 ppm of CDC: 3.90 (3H, s), 3.97 (3H, s), 4.00 (3H, s), 6.87 (1H, d, J = 2.5 Hz) 6.98-7.34 (6H, m), 7.90 (1H, d, J = 2.9Hz), 8.76 (1H, s).

Melting point: 16 5 _ 16 8 ° C (8b) 6-Methoxy 11- (3,4-dimethoxyphenyl) 1-4-oxo-1,4-dihydroquinoline 1-3-Carboxylic acid N-methyl-N-phenylamide

6-Methoxy 1- (3,4-Dimethoxyphenyl) -1 4-oxo-1,4-Dihydroxyquinoline 3-Caprolubonic acid 200 mg, Triethylamine 0.19 m a reaction was conducted in the same manner as in example (2 d) using isobutyl 0. 09 m 1 and N- Mechiruanirin 0. 06m l, c NMR spectrum (CDC1 ₃ the title compound was obtained 23 l mg as a white solid ) Sppm: 3.50 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 3.97 (3H, s), 6.61-7.37 (7H, m), 7.65-7.84 (2H, m).

Melting point: 193—195 ° (: Example 9

 7-Methoxy 1-phenyl-1-oxo-1,4-dihydroquinoline 3-force N-methyl-N-phenylamide ribonate (Exemplary Compound No. 11-1369)

 (9a) 2—1 [N— (3-methoxyphenyl) 1-N-phenylamino] methylene 1-Jethyl malonate

 A reaction was carried out in the same manner as in Example (2a) using 10 g of N- (3-methoxyphenyl) -1-N-phenylamine and 10.5 g of ethoxymethylene getyl malonate, and the title compound was purified. 16.6 g was obtained as an orange oil.

NMR spectrum _{(CDC1 3) Sppm: 1.05 (} 3H, t, J = 7.1Hz), 1 · 27 (3Η, t, J = 6.9Hz), 3,48 (2H, q, J = 7.2Hz), 3.77 (3H, s), 4.21 (2H, q, J = 7.1Hz), 6.62-6.68 (2H, m), 6.77 (1H, dd, J = 8.3, 2.4Hz), 7.12 (2H, d, J = 7.8 Hz), 7.20-7.30 (1H, m), 7.35 (2H, t, J = 7.9Hz), 7.93 (1H, s).

(9b) 7-Methoxy 1-phenyl-1 4-oxo-1,4-dihydroquinoline-3-ethyl carboxylate 2-| [N- (3-Methoxyphenyl) 1 N-phenylamino] methylene I A reaction was conducted in the same manner as in Example (2b) using 16.6 g of getyl malonate and 120 g of polyphosphoric acid, and purified. The title compound, 7-methoxy-1-phenyl-14-oxo-1,4-dihydroquinoline-13-carboxylate, was obtained as a white solid with 75 Omg and 1- (3-methoxyphenyl) -14-oxo. 4.0 g of 1,4-dihydroquinoline-13-carboxylic acid ethyl ester was obtained as a yellow solid.

7-Methoxy 1-phenyl-1 4-oxo-1,4-dihydroxyquinoline 3-ethyl carboxylate

 NMR spectrum (DMS0-d6) ppm: 1.25 (3H, t, J = 7.2 Hz), 3.69 (3H, s), 4.20 (2H, q, J = 7.2 Hz), 6.26 (1H, d, 1 = 2.5Hz), 7.12 (1H, dd, 1 = 2.2, 8.8Hz), 7.60-7.72 (5H, m), 8.22 (1H, d, J = 9.1Hz), 8.39 (1H, s).

Melting point: 1 50

 1- (3-Methoxyphenyl) 1-4-oxo 1,4-dihydroquinoline 1-3

 NMR spectrum (DMS0-d6) S ppm: 1.26 (3H, t, J = 7.2 Hz), 3.82 (3H, s), 4.22 (2H, q, 1 = 7.2 Hz), 7.02 (1H, d, J = 8.5Hz), 7.20-7.24 (2H, m), 7.31 (1H, t, J = 2.1Hz), 7.49 (1H, t, J = 7.1Hz), 7.58 (1H, t, J = 8.2Hz) , 7.66 (1H, dt,) = 1.4, 8.7Hz), 8.28 (1H, dd, J = 8.0, 1.2Hz), 8.45 (1H, s).

Melting point: 228 ° C

(9 c) 7-Methoxy 1-phenyl-1 4-oxo-1,4-dihydroquinoline 1-3-Rubonic acid

7-Methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-13-force The reaction was carried out in the same manner as in Example (2c) using 595 mg of ethyl ribonate and 50 Omg of sodium hydroxide. After work-up, 39 l mg of the title compound was obtained as a white solid. NMR spectrum (CDCl ₃ ; ppm: 3.77 (3H, s), 6.46 (1H, d, J = 2.3 Hz), 7.15 (1H, dd, J = 2.4, 9.1 Hz), 7.40-7.6 (2H, m), 7.62- 7.69 (3H, m), 8.49 (1H, d, J = 9.3Hz), 8.74 (1H, s).

Melting point: 1 65— 1 68 ° C

(9 d) 7-Methoxy-1-phenyl 4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide

 7-Methoxy 1-phenyl-1 4-oxo-1,4-dihydroquinoline 3-force 200 mg of rubonic acid, 0.2 ml of triethylamine, 0.9 ml of isobutyl formate 0.09 m1 and N-methylaniline 0. The same reaction as in Example (2d) was performed using 06 ml to obtain 118 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) ppm: 3.48 (} 3H, s), 3.68 (3H, s), 6.24 (1H, s), 6.90 (1H, d, J = 8.5Hz), 7.09-7.78 (llH, m), 8.25-8.27 (1H, m),

Melting point: 143—145 ° C Example 10

 6,7-Dimethoxy 1- (3,4-Dimethoxyphenyl) 1-4-oxo-1,4-Dihydroquinoline 3-Carbonyl N-methyl-1-N-phenylamide (Exemplified Compound No. 11 1 1 34)

 (10 a) 2 — [(bis- (3,4-dimethoxyphenyl) amino] methylene] malonic acid getyl ester

 Using 15.0 g of bis- (3,4-dimethoxyphenyl) amine and 12.3 g of ethylmethylene malonate, the reaction was carried out and purified in the same manner as in Example (2a). 23.6 g of the title compound were obtained as a yellow oil.

NMR spectrum _{(CDC1 3) 3ppm: 1 ·} 07 (3Η, t, J = 7.0Hz), 1.23-1.28 (3H, m), 3.57 (2H, q, J = 7.1Hz), 3.82 (6H, s) , 3.88 (6H, s), 4.21 (2H, q, J = 7.1Hz), 6.65 (2H, s) m), 6.67 (1H, d, J = 2.4Hz), 6.81 (2H, d, J = 8.3Hz), 7.87 (1H, s).

(1 0 b) 1-(3,4-Dimethoxy-1-phenyl) -1,6,7-Dimethoxy-4,1-oxo-1,4-Dihydroquinoline-1-3-Ethyl ribonate

 Example 2 Using 2-3.6 g of 2-[(bis (3,4-dimethoxyphenyl) amino) methylene] methyl ethyl malonate and 150 g of polyphosphoric acid obtained in Example (10a), The reaction was carried out and purified in the same manner as in 2b) to give 17.1 g of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 1.41 (} 3H, t, J = 7.2Hz), 3.72 (3H, s), 3.92 (3H, s), 4.000 (3H, s), 4.002 (3H, s), 4.39 (2H, q, 1 = 7.2Hz), 6.34 (1H, s), 6.91 (1H, d, J = 2.0Hz), 7.03 (1H, d, J = 2.1Hz), 7.04 (1Η, s) , 7.93 (1H, s), 8.43 (1H, s). Melting point: 243-247.

(10c) 11- (3,4-dimethoxyphenyl) 1-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-13-carboxylic acid

1_ (3,4 dimethoxyphenyl) -16,7-dimethoxy-1,4-oxo-1,1,4-dihydroquinoline-3_carboxylate obtained in Example (10b) 3.50 The reaction was carried out and purified in the same manner as in Example (2c) using g and 10 ml of a 10% aqueous hydroxide aqueous solution to give 2.38 g of the title compound as a white solid. NMR spectrum _{(CDC1 3) Sppm: 3.77 (} 3H, s), 3.92 (3H, s), 4.01 (3H, s), 4.04 (3H, s), 6.50 (1H, s), 6.9K1H, d , J = 2.2Hz), 7.00-7.14 (2H, m), 7.85 (1H, s), 8.71 (1H, s).

Melting point: 235-240 ° C.

(10d) 6,7-Dimethoxy-1- (3-, 4-dimethoxyphenyl) 14-year-old Kiso 1,4-Dihydroxyquinoline-3-Carboxylic acid N-methyl-N-phenyla Mito '

 6,7-Dimethoxy-1_ (3,4-dimethoxyphenyl) -14-oxo-1,4, -Dihydroxyquinoline-13-caprolubonic acid 200 mg, triethylamine 0 obtained in Example (10c) The reaction was carried out in the same manner as in Example (2d) using 1.8 ml, 0.008 ml of isobutyl chloroformate and 0.05 ml of N-methylaniline, and 118 mg of the title compound was obtained as a white solid. Obtained.

R spectrum (CDCl ₃ ; ppm: 3.49 (3H, s), 3 · 68 (3Η, s), 3.88 (3Η, s), 3.96 (3Η, s), 3.98 (3Η, s), 6.29 (1Η, s), 6.73-6.92 (2Η, m), 6.99 (1H, d, J = 8.6Hz), 7.11- 7.38 (5H, m), 7.69 (2H, br).

Melting point: 242-243 ° C.

Example 1 1

 1- (3,4-dimethoxyphenyl) -1 4-oxo-1,4-dihydroquinoline N-methyl-1-N-phenylamide 3,3-dicarboxylic acid (Exemplified Compound No. 1-57) (1 1a) 2 -[(N— (3,4-Dimethoxyphenyl) -1-N-phenylamino) methylene] getyl malonate

Using 5.0 g of N- (3,4-dimethylmethoxy) -1-N-phenylamine and 4.85 ml of getyl ethoxymethyllenmalonate The reaction was performed and purified in the same manner as in Example (2a) to obtain 8.10 g of the title compound as an orange oil.

NMR spectrum _{(CDC1 3) Sppm: 1 ·} 06 (3Η, t, J = 7.3Hz), 1.27 (3H, t, J = 7.2Hz), 3.53 (2H, q, J = 7.2Hz), 3.82 (3H , s), 3.89 (3H, s), 4.21 (2H, q, J = 7.3 Hz), 6.67-6.71 (2H, m), 6.83 (1H, d, J = 8.5 Hz), 7.07 (2H, d, J = 7.7Hz), 7.19 (1H, t, J = 7.7Hz), 7.31-7.35 (2H, m), 7.93 (1H, s).

(lib) 1— (3,4-dimethoxyphenyl) 1 4-oxo-1 1,4-dihydro Mouth quinoline 3-ethyl ethyl ester

 2-[(N- (3,4-Dimethoxyphenyl) -N-phenylamino) methylene] Jetyl malonate (7.9 g) and polyphosphoric acid (60 g) were reacted and purified in the same manner as in Example (2b). Thus, the title compound 6,7-dimethoxy_4-oxo1-1-phenyl-1,4-dihydroquinoline-13-hydroxyethyl ester was obtained as a white solid as 91 Omg and 1- (3,4 Toxiphenyl) 4-oxo- 1,1,4-dihydroquinoline-3-ethyl ethyl ester 195 mg was obtained as a yellow solid.

 6,7-Dimethoxy 4-oxo-1-1-fluoro-1,4-dihydroquinoline-3-carboxylate

NMR spectrum _{(CDC1 3) (Jppm: 1.41} (3H, t, J = 7.3Hz), 6.70 (3H, s), 4.01 (3H, s), 4.39 (2H, q, J = 7.3Hz), 6.33 ( 1H, s), 7.45 (2H, dd, J = 2.1, 8.0Hz), 7.61-7.67 (3H, m), 7.94 (1H, s), 8.43 (1H, s).

Melting point: 191-192

 1-(3,4 dimethoxyphenyl) 1 4 _ oxo 1, 4-dihydroquinoline 1-3-ethyl ethyl ester

NMR spectrum (CDCl ₃ ) <5 ppm: 1.41 (3H, t, J = 7.3 Hz), 3 · 91 (3Η, s), 4.00 (3Η, s),, 4.41 (2H, q, J = 7.3 Hz) , 6.90 (1H, d, J = 2.2Hz), 6.99-7.05 (3H, m), 7.43 (1H, t, J = 7.8Hz), 7.51-7.55 (1H, m), 8.53-8.56 (2H, m ).

Melting point: 207-209 ° C.

(1 1 c) 1- (3,4-dimethoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The same reaction as in Example (2c) was performed using 58-mg of 1- (3,4-dimethoxyphenyl) -1,4-oxo-1,4-dihydroquinoline-13-carboxylic acid ethyl ester and 3.0 g of sodium hydroxide. The title compound was converted to a white solid by 5 10 007852

231 mg were obtained.

NMR spectrum _{(CDC1 3) Sppm: 3.91 (} 3H, s), 4.01 (3H, s), 6.89 (1H, d, J = 2.3Hz), 6.99-7.07 (2H, m), 7.20 (1H, d, J = 8.6Hz), 7.58 (1H, t, J = 7.5Hz), 7.70 (1H, t, J = 8.0Hz), 8.57 (1H, dd, J = 1.3, 8.1Hz), 8.83 (1H, s).

(l id) 1- (3,4-dimethoxyphenyl) -4-oxo-1,4-dihydroquinoline-13-Carboxylic acid N-methyl-1-N-phenylamide

 1- (3,4-Dimethoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-13-Capillonic acid 30 Omg, Triethylamine 505 mg, Isobutyl chloroformate 20 Omg and N-methylaniline 32 1 mg The reaction was carried out in the same manner as in Example (2d), and 336 mg of the title compound was obtained as a white solid.

NMR spectrum _{(CDC1 3) ppm: 3.49 (} 3H, s), 3.87 (3H, s), 3.98 (3H, s), 6.72 (1H (s), 6.84 (1H, br), 6.90-7.00 ( 7H, m), 7.12-7.20 (1H, m), 7.21-7.35 (5H, m), 7.45 (1H, t, J = 7.5Hz), 7.79 (1H, br), 8.33 (1H, br).

Melting point: 1 99 ° C. Example 1 2

 6-Methoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-galvonic acid N-methyl-1-N-phenylamide (Exemplified Compound No. 1-381)

 (1 2a) 2-[(bis- (4-methoxyphenyl) amino] methylene] malonic acid getyl ester

 The reaction was carried out and purified using 10.6 g of bis (4-dimethoxyphenyl) amine and 11.0 g of ethoxymethylenemalonate getyl in the same manner as in Example (2a). g of the title compound were obtained as white crystals.

NMR spectrum _{(CDC1 3) Sppm: 1.07 (} 3H, t, J = 7.2Hz), 1.26 (3H, t, J = 7.2Hz), 3.53 (2H, q, J = 7.2Hz), 3.80 (6H, s), 4.21 (2H, q, J = 7.2Hz), 6.85 (4H, d, J = 8.9Hz), 7.03 (4H, d, J = 8.9Hz), 7.88 (1H, s).

Melting point: 1 99 _ 20 Ot :.

(1 2 b) 6-Methoxy 1 _ (4-Methoxyphenyl) 1 4-oxo-1,4—Dihydroquinoline-3-carboxylate

 2-[(bis- (4-methoxyphenyl) amino) methylene] The reaction was carried out using 12.7 g of getyl malonate and 120 g of polyphosphoric acid in the same manner as in Example (2b), followed by purification. .86 g of the title compound were obtained as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 1.41 (} 3H, t, J = 7.2Hz), 3.91 (3H, s), 3.92 (3H, s), 4.39 (2H, q, J = 7.2Hz), 6.94 (1H , d, J = 9.0Hz), 7.07-7.13 (3H, m), 7.27-7.35 (2H, m), 7.96 (1H, d, J = 3.0Hz), 8.45 (1H, s).

Melting point: 196—199.

(1 2 c) 6-Methoxy 11- (4-Methoxyphenyl) 1 4-oxo-1 1,4 Dihydroquinoline-1-3-Rubonic acid

 6-Methoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-ethyl ether ester 6. Using 20 g and 30 ml of a 10% aqueous solution of potassium hydroxide 30 ml The reaction was carried out and purified in the same manner as in Example (2c) to give 2.98 g of the title compound as a white solid.

NMR spectrum (CDCl ₃ ) Sppm: 3.93 (3H, s), 3.97 (3H, s), 7.07-7.14 (3H, m), 7.27 (1H, dd, J = 9.46, 2.9 Hz), 7.33 (2H, dd, J = 7.04- 1.98m), 7.90 (1H ₍ d, J = 3.0Hz), 8.74 (1H, s).

Melting point: 2 2 1—223.

(1 2 d) 6-Methoxy 11 (4-Methoxyphenyl) 1 4-oxo 1 1, 4 007852

233 N-Methyl-N-phenylamide

 6-Methoxy 1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline 1-3 obtained from Example (1 2c) 3-Carbonic acid 30 Omg, Triethylamine 505 mg, black mouth The reaction was carried out in the same manner as in Example (2d) using 20 Omg of isobutyl formate and 32 lmg of N-methylaniline to obtain 364 mg of the title compound as a white solid.

 NMR spectrum (1 ppm of CDC: 3 · 49 (3Η, s), 3.87 (3H, s), 3.90 (3H, s), 6.85 (1H, d, J = 9.1 Hz), 7.00–7.35 (10H, m), 7.65-7.85 (2H, m).

Melting point: 20 O :. Example 13

 6,7-Dimethoxy 11-Furou 4 1-oxo 1, 4-Dihydroquinoline 13-dicarboxylic acid Ν-methyl-Ν-phenylamide (Compound No. 1-770) (1 3a) 6,1 7-Dimethoxy 4-oxo-one 1,4-dihydro 1,4-dihydroquinoline 3-butyric acid

 6,7-Dimethoxy-1,4-diethoxy-1,4-dihydroxy-1,3-dihydroxyquinoline obtained in Example (lib) 3-Ethyl ester of rubonic acid 770 mg ethanol solution 3 N in 3 ml — 5 ml of hydrochloric acid was added, and the mixture was heated under reflux for 2 hours. After diluting the reaction solution with methylene chloride, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated solid was suspended in diisopropylpropyl ether and collected by filtration to obtain 62 Omg of the title compound.

NMR spectrum _{(CDC1 3) Sppm: 3 ·} 74 (3Η, s), 4.05 (3H, s), 6.44 (1H, s), 7. 4-7.47 (2H, m), 7.66-7.68 (3H, m ), 7.86 (1H, s), 8.70 (1H, s).

(1 3 b) 6,7-Dimethoxy-1-phenyl 4-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N-phenylamide 6,7-Dimethoxy-11-phenyl-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid obtained in Example (13a) 25-Omg, Triethylamine 404 mg, Isobutyl formate 137 The reaction was carried out in the same manner as in Example (2d) by using 32 mg of N-methylaniline and 29 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3 ·} 49 (3Η, s), 3.65 (3H, s), 3.96 (3H, s), 6.25 (1H, s), 7.14-7.35 (8H, m), 7.51-7.62 (4H, m), 7.69 (1H, br).

Melting point: 202. Example 14

 6,7-Dimethoxy-1- (4-methoxyphenyl) -1 4-oxo_1,4-dihydroquinoline-3-3-Rubonic acid N-methyl-1-N- (3-fluorophenyl) amide (Exemplary Compound No. 1-1373)

 (14a) 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylate N- (3-fluorophenyl) amide Example (2c 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-13-capillonic acid 30 Omg, triethylamine 404 mg, isobutyl formate 13-3 The same reaction as in Example (2d) was performed using 7 mg and 333 mg of 3-fluoroaniline to obtain 368 mg of the title compound as a white solid.

 NMR spectrum (DMS0-d6) Sppm: 3.65 (3H, s), 3.89 (3H, s), 3.92 (3H, s), 6.45 (1H, s), 6.92 (1H, dt, J = 1.9, 7.8 Hz) ), 7.23 (2H, d, J = 8.8Hz), 7.33-7.43 (2H, m), 7.65 (2H, d, 8.8Hz), 7.72-7.82 (2H, m), 8.56 (1H, s)

(14 b) 6,7-Dimethoxy-1- (4-Methoxyphenyl) -1 4-year-old 1,4-Dihydroquinoline-3-nitrocarboxylate N-methyl-N- (3-fluorophenyl) amide

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,1,4-dihydroquinoline_3-carboxylate N- (3-Fluorophenyl) amide obtained in Example (14a) 33 Omg (7) N, N-dimethylformamide Add 1 Oml solution of sodium hydride (55% content) 6 Omg at room temperature, stir at room temperature for 30 minutes, and calorie 426 mg of methyl iodide The mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / methylene chloride = 5%) to obtain 304 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3 ·} 48 (3Η, s), 3.69 (3H, s), 3.92 (3H, s), 3.96 (3H, s), 6.29 (1H, s), 6.87 ( 1H, dt, J = 2.1, 8.2Hz), 7.00-7.30 (7H, m), 7.68 (1H, s). Melting point: 152. Example 15

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-3-Rubonic acid N-methyl-N- (3,5-difluorophenyl) amide (Exemplary Compound No. 1-110)

 (1 5a) 6,7-Dimethoxy 1- (4-Methoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-13-Carboxylic acid N- (3,5-difluorophenyl) amide

6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline_3-carboxylic acid 300 mg, Triethylamine 404 mg, Cloguchiformic acid obtained in Example (2c) The reaction was carried out in the same manner as in Example (2d) using 137 mg of isobutyl and 387 mg of 3,5-difluoroaniline. PC translation 52

378 mg were obtained as 236 colored solids.

 NMR spectrum (CDC ") ppra: 3.67 (3H, s), 3.94 (3H, s), 4.05 (3H, s), 6.44 (1H, s), 6.50-6.57 (lH, m), 7.12 ( 2H, d, J = 9.0Hz), 7.34-7.42 (4H, m), 7.89 (1H, s), 8.76 (1H, s).

(1 5 b) 6,7-Dimethoxy-1- (4-methoxyphenyl) -1,4-oxo-1,4-dihydroxyquinoline-3-Carboxylic acid N-methyl-N— (3,5-Difluorophenyl Amid

 6,7-Dimethoxy 1 _ (4-methoxyphenyl) obtained in Example (15a) —4-oxo-1,4-dihydroquinoline-13-carboxylic acid N— (3,5-difluorophenyl) To a solution of 355 mg of amide in 1 Om1 of N, N-dimethylformamide was added 6 Omg of sodium hydride (containing 55%) at room temperature, the mixture was stirred at room temperature for 30 minutes, and then 426 mg of methyl iodide was added. For 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated by silica gel column chromatography- (methanol / methylene chloride = 5%) and purified to give 314 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3.47 (} 3H, s), 3.70 (3H, s), 3.92 (3H, s), 3.97 (3H, s), 6.32 (1H, s), 6.63 (1H, tt, J = 2.2, 8.9Hz), 6.90 (2H, dd, J = 1.9, 8.OHz), 7.08 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.69 (1H, s), 7.90 (1H, s). Melting point: 213. Example 16

6-Hydroxy 7-Methoxy-1- (4-Methoxyphenyl) _4-oxo-1,4-Dihydroxyquinoline 3-Carboxylic acid N-Methyl-1-N-phenylamide (Exemplified Compound No. 1 1 3 54 ) (1 6 a) 2-| [(3-Methoxy 4-methoxy methoxyphenyl) 1- (4-methoxyphenyl) amino] Methylene! Getyl malonate

 A mixture of 2.0 g of N- (3-methoxy-4-methoxyethoxyphenyl) -N- (4-methoxyphenyl) amine and 1.54 ml of ethoxymethylenemalonate getyl was stirred at 200 for 2.5 hours. . The reaction mixture was directly separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 5Z1-5 / 2) to give 2.57 g of the title compound as a red solid.

NMR spectrum _{(CDC1 3) Sppm: 1.07 (} 3H, t, J = 7.3Hz), 1.26 (3H, t, J = 7.3Hz), 3.51 (3H, s), 3.55 (2H, q, J = 7.2Hz ), 3.81 (6H, s), 4.21 (2H, q, J = 7.3Hz), 5.20 (2H, s), 6.59 (1H, dd, J = 2.5, 8.7Hz), 6.64 (1H, s), 6.86 (2H, d, J = 8.8Hz), 7.05-7.09 (3H, m), 7.87 (1H, s).

Melting point: 88 ~ 90 ° C

(16b) 6- (t-Butyldimethylsilyloxy) 1- 7-methoxy 1- (4-methoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-13-capronic acid Example (1 6 2_ | [(3-Methoxy 4- methoxy methoxy) 1- (4-methoxy phenyl) amino] methylene I obtained in a) 1 1 g of getyl malonate, 20 m 1 of acetic anhydride and concentrated sulfuric acid A mixed solution of 1 Om1 was added, and the mixture was stirred at 50 ° C for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in a mixed solvent of 100 ml of ethanol and 100 ml of water, added with 10 g of sodium hydroxide, and heated under reflux for 1 hour. Ethanol was distilled off under reduced pressure, the residue aqueous solution was adjusted to pH 1 with dilute hydrochloric acid, and the precipitated solid was collected by filtration and washed with water and water. The obtained solid was dissolved in 100 ml of anhydrous N, N-dimethylformamide, 17.6 g of imidazole and 17.38 of t-butyldimethylsilyl chloride were added, and the mixture was stirred at 50 for 2 hours. did. The reaction solution was diluted with aqueous citrate solution and extracted with ethyl acetate. Acetate The chill layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / l to 0Zl), and purified with the title compound (1- (t-butyldimethylsilyloxy) -13-methoxyphenol). 5.2) g of a mixture of 1-6-methoxy-14-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as a pale orange solid.

NMR spectrum _{(CDC1 3) Sppm: 0.21,} 0.23 and 0.25 (total 6H, each s), 1.02 and 1.04 (total 9H, each s), 3.69, 3.83, 3.94 and 3, 97 (total 6H, each s), 6.42-7.37 (5H, m), 7.88-7.90 (1H, m), 8.67 and 8.76 (total 1H, each s).

Melting point: 192 ~ 193

(16 c) 6— (t-butyldimethylsilyloxy) 17-methoxy-11- (4—methoxyphenyl) 14-year-old oxo-1,4-dihydroquinoline-1-3-potassium N-methyl _N —Phenylamide

 6- (t_butyldimethylsilyloxy) -17-methoxy-1- (4-methoxyphenyl) -1,4-oxo-1,1,4-dihydroxyquinoline-1,3-carbone obtained in Example (16b) Mixture of acid and 1- (4- (t-butyldimethylsilyloxy) -13-methoxyphenyl) -1 6-methoxy-14-oxo-1, 4-Dihydroquinoline-13-Carbonic acid 5 2 g, 2.47 ml of N-methylaniline, 3.18 ml of triethylamine and 1.80 ml of isobutyl chloroformate were reacted in the same manner as in Example (2d). The obtained crude product was purified using reverse phase HPLC (elution solvent: acetonitrile Z buffer S SZS SS OZS O (buffer: water / triethylamine acetate = 1 000 2 2)), and the title compound was converted to a white solid. As 1.87 g, 1- (4- (t-butyldimethylsilyloxy) -13-methoxyphenyl) 1-6-methoxy-4,1-oxo-1,4-dihydroquinoline-1-3-carboxylic acid 3.61 g of N-methyl-N-phenylamide was obtained as a yellow foam.

6- (t-butyldimethylsilyloxy) -1- 7-methoxy 1- (4-methoxy 4-N-methyl-1,4-dioxoquinone 1,4-dihydroquinoline-3-N-methyl-1-N-phenylamide

NMR spectrum _{(CDC1 3) Sppm: 0.15 (} 6H, s), 0 · 98 (9Η, s), 3.48 (3H, s), 3.60 (3H, s), 3.90 (3H, s), 6.21 ( 1H, br s), 7.04 (2H, d, J = 9.0Hz), 7.14-7.29 (7H, m), 7.60-7.80 (2H, br).

Melting point: 1 96-201 ° C

 1- (4- (tert-Butyldimethylsilyloxy) -1-3-methoxyphenyl) -16-methoxy-1-4-oxo-1,4-dihydroquinoline-1-3-carboxylic acid N-methyl-1-N-phenylamino Do

NMR spectrum (CDCl ₃ ) 3 ppm: 0.22 (6H, s), 1.03 (9H, s), 3.50 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 6.65-6.80 ( 2H, br), 6.90 (1H, d, J = 9.2Hz), 6.96 (1H, d, J = 8.1Hz), 7.06-7.09 (1H, m), 7.14-7.17 (1H, m), 7.23-7.30 (4H, m), 7.70-7.85 (2H, br).

(16 d) 6-hydroxy-7-methoxy 1- (4-methoxyphenyl) 1-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-N-phenylamide

 6- (t_Butyldimethylsilyloxy) -1- (4-methoxyphenyl) -1,4-oxo-1,1,4-dihydroxyquinoline obtained in Example (16c) -3-carboxy To a suspension of 90 Omg of the acid N-methyl-N-phenylamide in 90 mL of anhydrous tetrahydrofuran was added dropwise 4.96 mL of a 1.0 M tetrabutylammonium fluoride dote trahydrofuran solution under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The solid precipitated from the residue was suspended in ethyl acetate and collected by filtration to give 54 Omg of the title compound as a white solid.

NMR spectrum (CDCl ₃ ppm: 3.48 (3H, s), 3.70 (3H, s), 3.91 (3H, s), 6.23 (1H, s), 7.04 (2H, d, J = 8.8 Hz), 7.15-7.30 (7H, m), 7.67 (1H, br), 7.81 (1H, s). / 07852

240 melting point: 240 Example 17

 1- (4-Hydroxy-1-3-methoxyphenyl) 1-6-Methoxy-4 4-year-old oxo 1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N-phenylamide (Ex. Compound No. 1-137) )

 1-1 (4- (t-butyldimethylsilyloxy) -13-methoxyphenyl) _6-methoxy 4-oxo-1,4-dihydroquinoline-1,3-dicarboxylic acid obtained in Example (16c) The reaction and purification were carried out in the same manner as in Example (16d) using 5.5 ml of 1.0 g of N-methyl-N-phenylamide and 5.5 ml of 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution. This gave 647 mg of the title compound as a pale yellow solid.

NMR-spectrum le _{(CDC1 3) <5ppm: 3.50} (3H, s), 3.87 (3H, s), 3 · 88 (3Η, s), 6.69- 6.79 (2H, m), 6.90 (1H, d, J = 9.1Hz), 7.04-7.30 (7H, m), 7.70-7.85 (2H, br). Melting point: 235 ~ 23 7 ° C Example 18

 7-Methoxy 1- (4-Methoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-3-Carboxylic acid N-methyl-N-phenylamide (Exemplary compound No. 1-1375)

 (1 8 a) 2-| [(4-Methoxyphenyl) mono (3-methoxyphenyl) monoamino] methylene I Malonic acid getyl ester

 The reaction was carried out in the same manner as in Example (2a) by using 7.50 g of (4-methoxyphenyl) -1- (3-methoxyphenyl) amine and 7.78 g of getyl ethoxymethylenemalonate. This gave 12.6 g of the title compound as a colorless oil.

NMR spectrum _{(CDC1 3) 3ppm: 1 ·} 07 (3Η, t, J = 7.3Hz), 1.26 (3H, t, J = 7.3Hz), 007852

241

3.53 (2H, q, J = 7.3Hz), 3.76 (3H, s), 3.82 (3H, s), 4.21 (2H, q, J = 7.3Hz), 6.58 (1H ₍ s), 6.62 (1H, d , J = 8.1Hz), 6.70-6.74 (1H, m), 6.88 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 8.8Hz), 7.21 (1H, dd, J = 8.1, 8.8Hz), 7.92 (1H, s).

(1 8 b) 7-Methoxy 11- (4-methoxyphenyl) 1 4-oxo-1,4-dihydroxyquinoline 1-3-Carboxylic acid ethyl ester

 2— | [(4-Methoxyphenyl) -1- (3-methoxyphenyl) -amino] —methylene I malonic acid getyl ester obtained in Example (18a) 11.7 g and polyphosphoric acid 75 g The reaction was carried out in the same manner as in Example (2b) and purified to obtain 0.83 g of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 1.40 (} 3H, t, J = 7.3Hz), 3 · 73 (3Η, s), 3.92 (3H, s), 4.38 (2H, q, J = 7,3Hz), 6.34 (1H, d, J = 2.2Hz), 6.99 (1H, dd, J = 2.4, 8.8Hz), 7.09 (2H, d, J = 8.7Hz), 7.34 (2H, d, J = 8.4Hz), 8.43 (1H, s), 8.47 (1H, d, J = 8.8Hz). Melting point: 146

(1 8 c) 7-Methoxy 11- (4-Methoxyphenyl) 1-4-oxo-1,4-Dihydroquinoline 3-Caprolubonic acid

7-Methoxy 1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-13-hydroxyethyl ester 660 mg obtained in Example (18 d), 4.0 g of potassium hydroxide The reaction was carried out in the same manner as in Example (2c) using 10 ml of ethanol and 10 ml of water to obtain 504 mg of the title compound as a white solid. NMR-spectrum le _{(CDC1 3) «5ppm: 3.78} (3H, s), 3.93 (3H, s), 6.47 (1H, s), 7.09-7.16 (3H, m), 7.33 (2H, d, J = 8.8 Hz), 8.48 (1H, d, J = 8.8Hz), 8.73 (1H, s). Melting point: 220-223 ° C (decomposition)

(18 d) 7—Methoxy 11 (4-Methoxyethoxy) 14—Oxo 1,4 —Dihydroxyquinoline-3-carboxylate N-methyl-N-phenylamide 7-Methoxy-1- (4-Methoxyphenyl) obtained in Example (18c) 1 4-Oxo-1 1,4-Dihydroxyquinoline Example using 303 mg of 1-3-carboxylic acid, 0.33 ml of triethylamine, 5 ml of anhydrous methylene chloride, 0.15 ml of isobutyl chloroformate and 1.01 ml of N-methylaniline (2d) The reaction was performed in the same manner as in, and 337 mg of the title compound was obtained as a white solid.

NMR spectrum _{(DMS0-d 6) Sppm:} 3.32 (3H, s), 3.64 (3H, s), 3 · 86 (3Η, s), 6.21 (1H, s), 6.98 (1H, dd, J = 1.5 , 8.1Hz), 7.12-7.18 (3H, m), 7.22-7.34 (6H, m), 7.90 (1H, s), 8.03 (1H, d, J = 8.8Hz).

Melting point: 1 49-1 50 ° C

Example 19

 3-I [6, 7 — Dimethyl oxy 1 _ (4 — methoxy phenyl) 1 4 1 oxo 1, 4 — Dihydroquinoline 1 3 — Ka Rubonyl] — methylamino i-thiophene 12 — methyl butyl ester rubnate (Exemplified Compound No. 11; 1376)

 (1 9 a) 3-I [6, 7-Dimethoxy 1-(4-methoxyphenyl) 1-4-oxo 1, 4-Hydroquinoline 1 3 —Carbonyl] amino i —Chophen-1 2 —Methylester

 6,7-Dimethoxy_1- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-13-carboxylic acid obtained in Example (2c) 425 mg, triethylamine 0 The reaction was carried out in the same manner as in Example (2d) using 42 m 1, 0.19 m 1 of isobutyl chloroformate and 1.88 g of 3-aminothiophene-2-carboxylic acid methyl ester to give the title compound. 516 mg were obtained as a white solid.

NMR spectrum (CDCl ₃ ) 3ppra: 3.74 (3H, s), 3.93 (3H, s), 4.02 (3H, s), 4.04 (3H, s), 6.41 (1H, s), 7.11 (2H, d, J = 8.8Hz), 7.37 (2H, d, J = 8.8Hz), 7.47 (1H, d, J = 5.9Hz), 8.11 (1H, s), 8.38 (1H, d, J = 5.9Hz), 8.78 (1H, s).

Melting point: 263-264 ° C

(1 9 b) 3 — I [6, 7 — Dimethoxy 1 1 — (4-methoxyphenyl) 1 4 _oxo 1, 1, 4-Dihydroquinoline 1 3 — carbonyl] — methyl amide 2 — methyl carboxylate

 3-j [6,7-dimethoxy-1- (4-methoxyphenyl) -14-oxo_1,4-dihydroquinoline-1-3-carbonylyl] amino I obtained in Example (19a) 1-thiophene methyl ester 100 mg, DMF 2.5 ml, sodium hydride (containing 55%) 16 mg and methyl iodide 0.038 m 1, as in Example (14b) The reaction was carried out to obtain 92 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3 ·} 41 (3Η, s), 3.67 (3H, s), 3.75 (3H, s), 3.91 (3H, s), 3.94 (3H, s), 6.24 (1H, s), 7.00-7.42 (6H, m), 7.59 (1H, s), 7.77 (1H, s).

Melting point: 1 99-20 1 ° C Example 20

 3-! [6,7-Dimethoxy-1- (4-methoxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline 3-carbonyl] 1-Ethyl-1-amino i-thiophene 2- 2-Methyl rubonate Ester (Exemplary Compound No. 1-137)

3— | [6,7-Dimethoxy-1 1 _ (4-methoxyphenyl) -14-oxo-1, 4-dihydroquinoline-1-3-carbonyl] obtained in Example (19a) ! 1-thiophene 1-Rubonic acid methyl ester 1 55mg, DMF 4m The reaction was carried out in the same manner as in Example (14b) using 25 mg of sodium iodide (containing 55%) and 0.075 ml of iodide chill to obtain 124 mg of the title compound as a white solid. C NMR spectrum _{(CDC1 3) (5ppm: 1.21} and 1.27 (total 3H, each t, J = 7.3Hz), 3.51 and 3.63 (total 3H, each s), 3.78-4.24 (8H, m), 6.23 (1H, s), 7.00-7.16 (3H, m), 7.25-7.42 (3H, m), 7.56-7.62 (1H, m), 7.79 and 7.82 (total 1H, each s).

Melting point: 15 1-1 52 C Example 2 1

 6,7-Dimethoxy 1- (4-methoxyphenyl) 1,4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N- (pyridine-1-yl) amide (Example compound) (Number 1—1 3 78)

 (2 1 a) 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-Dihydroxyquinoline-13-Carboxylic acid N- (Pyridine-1-yl) amide 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,1,4-dihydroquinoline-3-carboxylic acid obtained in Example (2c) 414 mg, triethylamine 0.41 m1, The reaction was carried out in the same manner as in Example (2d) using 0.20 ml of isobutyl chloroformate and 1.10 g of 2-aminoviridine to obtain 313 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3.74 (} 3H, s), 3.94 (3H, s), 4.04 (3H, s), 6.42 (1H, s), 7.0K1H, dd, J = 5.1, 8.3Hz ), 7.09- 7.13 (2H, m), 7.35-7.39 (2H, m), 7.66- 7.7K1H, ra), 7.96 (1H, s), 8.31 (1H, d, J = 8.1Hz), 8.37-8.39 (1H, m), 8.76 (1H, s).

Melting point: 260-262 ° C

(2 1 b) 6,7-Dimethoxy-1- (4-methoxyphenyl) 1.4-oxo1.4-Dihydroquinoline-1-3-Rubonic acid N-methyl-N— (Pyridine-1— 52

245) Amide

 6,7-Dimethoxy-11- (4-methoxyphenyl) obtained in Example (21a) —4-oxo_1,4-dihydroxyquinoline-13-carboxylic acid N— (pyridine-12-yl) The reaction was carried out in the same manner as in Example (175b) using 120 mg of amide, 2 ml of DMF, 22 mg of sodium hydride (containing 55%) and 0.052 ml of methyl iodide, and the title compound was eluted. 4 l mg were obtained as a pale yellow solid.

NMR spectrum _{(CDC1 3) ppm: 3.78 (} 3H, s), 3.96 (3H, s), 4.10 (3H, s), 4.73 (3H, s), 6.47 (1H, s), 7,16 ( 2H, d, J = 8.8Hz), 7.40 (2H, d, J = 8.8Hz), 7.59 (1H, t, J = 6.6Hz), 7 · 90 (1Η, s), 8.23 (1H, dd, J = 8.1, 8.8Hz), 8.76 (1H, s), 9.03 (1H, d, J = 8.8Hz), 9.92 (1H, d, J = 6.6Hz).

Melting point: 1 75-1 77 Example 22

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-potassium N-ethyl-N- (pyridine-12-yl) amide (Example compound) (Number 1 1 1 379)

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,1,4-dihydroquinoline-13-potassic acid N- (pyridine-12-i) obtained in Example (21a) The reaction was carried out in the same manner as in Example (14b) using 100 mg of amide, 2.5 ml of DMF, 22 mg of sodium hydride (containing 55%) and 0.07 ml of iodide chill, 36 mg of the title compound were obtained as a white solid.

NMR spectrum _{(CDC1 3) 5ppm: 1.26 (} 3H, t, J = 7.3Hz), 3.67 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 4.12 (2H, q, J = 7.3Hz), 6.29 (1H, s), 7.03-7.06 (3H, m), 7.21-7.25 (2H, m), 7.41 (1H, d, J = 8.1Hz), 7.60-7.65 (2H, m), 7.91 (1H, d, J = 8.8Hz), 8.30 (1H, dd, J = 2.2, 5.9Hz).

Melting point: 1 53-1 56 ° C Example 23

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4, -Dihydroxyquinoline-3-carboxylate ェ -Ethyl-1-Ν (pyridine-13-yl) amide

(Exemplary Compound No. 1-138 1)

 (23a) 6,7-Dimethoxy-11- (4-methoxyphenyl) -1,4-oxo-1,4-dihydroxyquinoline-13-Rubonic acid N- (pyridine-13-yl) amide Example 6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylic acid obtained in (2c) 300 mg, Triethylamine 0.29 m The same reaction as in Example (2d) was carried out using 0.113 ml of isobutyl formate and 794 mg of 3-aminoviridine to obtain 123 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) Sppm: 3.76 (} 3H, s), 3.94 (3H, s), 4.06 (3H, s), 6.45 (1H, s), 7.12 (2H, d, J = 8.8Hz) , 7.27-7.30 (1H, m), 7.31-7.38 (2H, m), 7.91 (1H, s), 8.28-8.37 (2H, m), 8.79 (1H, m), 8.91 (1H, d, J = 2.2Hz).

Melting point: 249-250 ° C

(23 b) 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylate N-ethyl-N- (pyridine-13-yl) Amid

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,1,4-dihydroquinoline-13-carboxylic acid N- (pyridine-13-yl) obtained in Example (23a) The reaction was carried out in the same manner as in Example (175b) using 70 mg of amide, 2.5 mg of DMF, and 13 mg of sodium hydride (containing 55%) and 0.039 ml of thiol iodide. 25 mg was obtained as a pale yellow solid.

NMR spectrum _{(CDC1 3) Sppm: 1.22 (} 3H, t, J = 7.3Hz), 3.67 (3H, s), 3 · 91 (3Η, PC orchid 0/07852

247 s), 3.92 (3Η, s), 3.98 (2H, q, J = 7.3 Hz), 6.26 (1H, s), 6.70 (1H, s), 7.07 (2H, d, J = 8.8 Hz) , 7.26-7.32 (2H, m), 7.53 (1H, br), 7.83 (1H, dd, J = 1.5, 8.1Hz), 7.92 (1H, s), 8.37 (2H, br).

Melting point: 204—207 ° C Example 24

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N- (pyridine-14-yl) amide (Exemplary Compound No. 1) One 1 382)

 (24a) 6,7-Dimethoxy-11- (4-methoxyphenyl) -1,4-oxo-1,4-dihydroquinoline-1,3-dicarboxylic acid N- (pyridine-41-yl) amide 6,7-Dimethoxy-11- (4-methoxyphenyl) obtained in Example (2c) —4-oxo-1,4-dihydroquinoline-l-3-hydroxycarboxylic acid 300 mg, triethylamine 0.39 m The reaction was carried out in the same manner as in Example (2d) using 0.113 ml of isobutyl chloroformate and 794 mg of 4-aminoviridine to obtain 306 mg of the title compound as a white solid.

NMR spectrum _{(CDC1 3) ppm: 3 ·} 76 (3Η, s), 3.95 (3H, s), 4.06 (3H, s), 6.45 (1H, s), 7.10- 7.16 (2H, m), 7.34-7.40 (2H, m), 7.68-7.72 (2H, m), 7.90 (1H, s), 8.51-8.53 (2H, m), 8.78 (1H, s).

Melting point: 26 1-263 ° C

(24b) 6,7-Dimethoxy-11- (4-Methoxyphenyl) 1-41-year-old oxo-1,4-Dihydroquinoline-1-3-carboxylate N-methyl-1-N- (pyridine-14-yl) Amid

6,7-Dimethoxy-1_ (4-methoxyphenyl) -14 obtained in Example (24a) 4-year-old oxo-1,4-dihydroxyquinoline-1-carboxylic acid N— (pyridine-14 The reaction was carried out in the same manner as in Example (14b) using 70 mg of amide, 13 mg of DMF 1 m sodium hydride (containing 55%) and 0.030 ml of methyl iodide. 42 mg of the title compound were obtained as a white solid.

NMR spectrum _{(CD 3 0D) Sppm: 3.71} (3H, s), 3.94 (3H, s), 3.99 (3H, s), 4.23 (3H, s), 6.53 (1H, s), 7.24 (2H , d, J = 8.8Hz), 7.54 (2H, d, J = 8.8Hz), 7.87 (1H, s), 8.26 (2H, d, J = 7.3Hz), 8.63 (2H, d, J = 7.3Hz) ), 8.77 (1H, s).

Melting point: 2 14-2 17 ° C (decomposition) Example 25

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N- (pyridine-14-yl) amide (Exemplified Compound No. 11-1) 1 383)

 6,7-Dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-13-carboxyrvonic acid N- (pyridine-14-yl) obtained in Example (24a) The reaction was carried out in the same manner as in Example (14b) using 7 Omg of amide, 1 m of DMF, 13 mg of sodium hydride (containing 55%), and 13 mg of thiol iodide. 2 l mg were obtained as a white solid.

NMR spectrum (CD ₃ OD) Sppm: 1.22 (3H, t, J = 7.3 Hz), 3.66 (3H, s), 3.87 (3H, s), 3.9K3H, s), 4.04 (2H, q, J = 7.3Hz), 6.42 (1H, s), 7.19 (2H, d, J = 7.3Hz), 7.36-7.41 (4H, m), 7.55 (1H, s), 8.12 (1H, s), 8.41 (2H, d, J = 6.6Hz).

Melting point: 165-169 ° C Example 26

1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4,4-hydroxyquinoline-3-carboxylate N-methyl-N-phenylamide (Exemplary compound No. 1-827) (2 6 a) 2-| [(3,4 Dimethoxyphenyl) -1- (4-Methoxymethoxyphenyl) -amino] —Methylene I Getyl malonate

The reaction was carried out in the same manner as in Example (2a) using 5.79 g of (3,4 dimethoxyphenyl) -1- (4-methoxymethoxyphenyl) amine and 4.44 ml of ethoxymethylenemalonate. Purification gave 8.60 g of the title compound as a white solid. NMR spectrum _{(CDC1 3) Sppm: 1 ·} 07 (3Η, t, J = 7.1Hz), 1.26 (3H, t, J = 7.1Hz), 3.48 (3H, s), 3.55 (2H, q, J = 7.2Hz), 3.82 (3H, s), 3.88 (3H, s), 4.21 (2H, q, J = 7.1Hz), 5.16 (2H, s), 6.64-6.68 (2H, ra), 6.81 (1H, d, J = 9.4Hz), 6.95-7.06 (4H, m), 7.87 (1H, s).

Melting point: 94-96 ° C

(2 6 b) 1 _ (4-Acetoxyphenyl) -1,6,7-Dimethoxyl 4-oxo-1,1,4-Dihydroquinoline-1-3-Carboxylic acid ethyl ester

 2- (| 3,4-Dimethoxyphenyl)-(4-methoxyethoxyphenyl) -amino-methylene I obtained in Example (26a) -methylene I-Jethyl malonate 8.60 g and acetic anhydride A mixed solution of 20 m 1 and concentrated sulfuric acid 1 Om 1 was added, and the mixture was stirred at 50 for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: dichloromethane / methane / ethyl acetate = 1/1) to give the title compound, 11- (4-acetoxyphenyl) -16,7-dimethoxy-14- 4.69 g of oxo-1,4-dihydroquinoline-13-carboxylic acid ethyl ester as a white solid, and 6-acetoxy-1- (3,4-dimethoxyphenyl) -14-oxo-1,4-diphenyl There was obtained 32 Omg of droquinoline-1-ethyl ribonate as a red solid.

1- (4-Acetoxyphenyl) -1 6,7-Dimethoxy 4-Oxo-1,4 Dihydroquinoline-13-Carboxylic acid ethyl ester NMR spectrum _{(CDC1 3) Sppm: 1.41 (} 3H, t, J = 7.1Hz), 2.38 (3H, s), 3.72 (3H, s), 4.00 (3H, s), 4.39 (2H, q, J = 7.1Hz), 633 (1Η, s), 7.38 (2H, d, J = 8.8Hz), 7.48 (2H, d, J = 8.8Hz), 7.93 (1H, s), 8.42 (1H, s) .

Melting point: 1 88— 1 89 ° C

 6-acetoxy-1- (3,4-dimethoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-ethyl carboxylate

NMR spectrum _{((CDC1 3) Sppm: 1.40} (3H, t, J = 7.1Hz), 2.34 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 4.40 (2H, q , J = 7.1Hz), 6.87-7.35 (5H, m), 8.20 (1H, s), 8 · 52 (1Η, s).

Melting point: 72-75

(26 c) 1- (4-hydroxyphenyl) -1, 6,7-dimethoxy-1 4-oxo—1,4-dihydroxyquinoline-13-carboxylic acid ethyl ester

 1. 44 g of ethanol solution of 1.1- (4-acetoxyphenyl) _6,7-dimethoxy-14-oxo-1,4-dihydroquinoline-13-carboxylic acid ethyl ester obtained in Example (26b) To 20 ml was added sodium ethoxide (715 mg) at room temperature, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic layer was washed with dilute hydrochloric acid and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give 1.29 g of the title compound as a white solid.

 NMR spectrum (DMS0-d6) ppm: 1.25 (3H, t, J = 7.1 Hz), 3.62 (3H, s), 3.87 (3H, s), 4.20 (2H, q, J = 7.0 Hz), 6.37 (1H, s), 7.00 (2H, d, J = 8.7Hz), 7.43 (2H, d, J = 8.7Hz), 7.65 (1H, s), 8.30 (1H, s).

Melting point: 133-1 35 ° C

(26 d) 6,7-Dimethoxy 1- (4-Methoxymethoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-1 3-Carboxylic acid methyl ester 1.11 g of 4- (4-hydroxyphenyl) -1,6-dimethoxy_4-oxo-1,4-dihydroxyquinoline-13-ethylruvonate obtained in Example (26c) 1.29 g To a DMF solution (20 mi) of above, 168 mg of sodium hydride was added at 0, and the mixture was stirred for 10 min. After methanol was added to the reaction solution and stirred for a while, the solvent was concentrated under reduced pressure, and the residue was diluted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetone Z dichloromethane = 1 Z2) to obtain 845 mg of the title compound as a white solid.

NMR spectrum (CDU ₃ ; ppm: 3.55 (3H, s), 3.73 (3H, s), 3.92 (3Η, s), 4.0I (3H, s), 5.28 (2H, s), 6.36 (1H, s), 7.25 (2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8.8Hz), 7.93 (1H, s), 8.43 (1H, s).

Melting point: 205-208 ° C

(2 6 e) 6,7-Dimethoxy-1- 1- (4-Methoxymethoxyphenyl) -14-Oxo-1,4,4-Dihydroquinoline-1-Carboxylic acid

 6,7-Dimethoxy-1_ (4-methoxymethoxyphenyl) -1,4-dioxo-1,4-dihydroquinoline-1,3-dihydroxyquinone obtained in Example (26d) 84-Methylester 84 5 mg in ethanol solution 1 To 0 ml, 200 mg of an aqueous solution of 200 mg of sodium hydroxide was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was cooled to 0, hydrochloric acid was added until the pH reached 3, and this was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 815 mg of the title compound as a yellow solid.

NMR spectrum (CDCl ₃ ) Sppm: 3.56 (3H, s), 3.77 (3H, s), 4.05 (3H, s), 5.30 (2H, s), 6.48 (1H, s), 7.26 (2H, s) d, J = 8.8Hz), 7.35 (2H, d, J = 8, 8Hz), 7.86 (1H, s), 8.68 (1H, s).

Melting point: 1 74 _ 1 78 ° C 007852

252

(26 f) 6,7-Dimethoxy 11- (4-Methoxy-methoxyphenyl) 1 4-Oxo-1, 4-Dihydroquinoline-1-3-Rubonic acid N-methyl-1-N-phenyl monoamide

 6,7-Dimethoxy-11- (4-methoxyethoxyphenyl) -1,4-oxo-1,4-dihydroxyquinoline-13-carboxylic acid obtained in Example (26d) 81-4 mg, triethylamine 0 The reaction was carried out in the same manner as in Example (2d) using 0.33 ml of isobutyl chloroformate and 2.29 ml of N-methylaniline, to give the title compound as a yellow solid (1.00 g). Obtained.

 NMR spectrum (1 ppm of CDC: 3.49 (3H, s), 3.54 (3H, s), 3 · 68 (3Η, s), 3.96 (3H, s), 5.26 (2H, s), 6.27 (1H, s) s), 7.10-7.30 (9H, m), 7.60-7.73 (2H, m).

Melting point: 71-73 ° C

(26 g) 1- (4-Hydroxyphenyl) -6,7-dimethoxy-14-year-old oxo-1,4-dihydroxyquinoline-13-potassium N-methyl-N-phenylamide In Example (26f) The resulting 6,7-dimethoxy-11- (4-methoxymethoxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylic acid N-methyl N-phenylamide 1.00 g, concentrated hydrochloric acid Then, the mixture was stirred at 60 ° C for 30 minutes. The reaction solution was diluted with methylene chloride, and the organic layer was washed with water and saturated saline, and then dried over sodium sulfate. The solvent was concentrated under reduced pressure to obtain 789 mg of the title compound as a yellow solid.

Image R spectrum _{(CDC1 3) Sppm: 3.52 (} 3H, s), 3.68 (3H, s), 3.94 (3H, s), 6.34 (1H, s), 6.93-7.40 (9H, m), 7.60 -7.80 (2H, m).

Melting point: 1 49-1 1 52 0 07852

253 Test Example 1

Measurement of bile acid transporter inhibitory activity

 Male Syrian golden hamsters were used for the experiments. Animals were housed in metal cages and had free access to food and water. The compound of the present invention was orally administered (100 mg / 10 ml / kg) as a suspension in 0.5% carboxymethyl cellulose. 1.5 hours after administration, [¾] -taurocholic acid (37 KBq) in physiological saline was orally administered. Hamsters were dissected 24 hours after oral administration of [] -taurocholic acid. Gallbladder bile was collected, and radioactivity in the gallbladder bile was determined. The inhibition rate (%) was determined from the radioactivity of the control obtained without using the compound of the present invention and the radioactivity obtained when a certain concentration of the compound of the present invention was used. As a result, the compound of the present invention exhibited excellent ileal bile acid transporter inhibitory activity. Test example 2

 Measurement of ileal bile acid transporter inhibitory activity using hamster everted ileal rings

 Measurement of ileal bile acid transporter inhibitory activity in this test example,

 [Pharm. Res., 12, 693-699 (1995)], and was performed according to the method of Stewart et al.

That is, a hamster inverted intestinal ring was used as a material for the ileal bile acid transporter. A 5- to 7-week-old male Syrian hamster was anesthetized with ether, and the ileum was removed about 10 cm from the blind end and inverted. By cutting each mm, 15 rat inverted intestinal rings were obtained. In order to correct the difference in bile acid transporter expression levels depending on the site of the ileum, rings were appropriately selected from the top and bottom of the ileum, and three rings were considered as one group, for a total of five groups. One of the five groups was a control group to which no sample was added, and a group to which a 100-fold higher concentration of non-radiolabeled taurocholic acid was added in consideration of nonspecific incorporation of bile acids into rings. (Bag Round group). The remaining three groups were groups to which various samples were added. The ileal bile acid transporter incorporated the radiotaurocholic acid into the rings while shaking each ring in 1 ml radioactive cholic acid solution at 37 rpm for 5 minutes at 37 rpm. The composition of the radioactive taurocholic acid solution is composed of 1.0 Ci radioactive taurocholic acid, 0.037 mM non-radioactive taurocholic acid (however, the knocking ground group is 37 mM), various analytes at appropriate concentrations, and Ringer's buffer. After washing the ring three times with Ringer's buffer solution, measure the wet weight, place it in a vial, and add the tissue lysing agent NC S-II (1.81 ¥ 1 £ 1 ^ 511 811 ^) to 0.1%. 5 ml was added and left at 50 overnight to completely dissolve. 2. Add 5 ml of liquid scintillation force and measure the radioactivity on a liquid scintillation counter. The ileal bile acid transporter activity was calculated by correcting the radioactivity incorporated in each ring by wet weight, expressing it as dpm / mg (radioactivity per mg), and then calculating the background from the average value of each group. The activity was determined by subtracting the average value of the group, and the inhibition rate of ileal bile acid transporter activity when the concentration of the compound of the present invention was 30 μg / ml was determined. As a result, the compound of the present invention exhibited excellent ileal bile acid transporter inhibitory activity. Example compound number Inhibition rate (%)

5 48. 3

1 5 55. 3 Formulation Example 1

Tablets

 Example 15 Compound of 5 10 mg Lactose 6 8 5 Microcrystalline cellulose 20 Sodium carboxymethyl starch 5 Light citric anhydride 0

— Stearic acid _magnesium _ ― 1

 1 0 5 mg

Claims

The scope of the claims 1. General formula (I)

[Where, R \ R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group; R ⁵ represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups; R ⁶ is a group having the formula: CONR ⁷ R ⁸ (wherein R ⁷ represents a C ₁₀ alkyl group or a C ₂ _C ₁₀ alkenyl group, R ⁸ is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group. ), However, when R ² is a hydrogen atom and R ³ is a lower alkoxy group, R ⁵ represents a hydroxy group or an aryl group substituted with 1 to 5 lower alkoxy groups. ], A pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. Substituent group a> Halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono-lower alkylamino group, di-lower alkyl An amino group, a carboxy group and a lower alkoxy group. 2. In Claim 1, A compound or a pharmacologically acceptable salt thereof, wherein R ¹ and are hydrogen atoms. 3. In Claim 1 or 2, A compound which is an R ² hydrogen atom or a pharmacologically acceptable salt thereof. 4. In Claim 1 or 2, R ² , a compound that is a hydroxy group or a lower alkoxy group or a pharmacologically acceptable compound thereof. 5. In any one of claims 1 to 4, R ³ compound having a hydroxy group or lower alkoxy group or a pharmaceutically acceptable compound thereof 6. In any one of claims 1 to 5, R ⁵ is an aryl group compound or a pharmacologically acceptable salt thereof. 7. In any one of claims 1 to 5, R ⁵ is a compound or a pharmacologically acceptable salt thereof, wherein the compound is an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups. 8. In any one of claims 1 to 5, R ⁵ is a compound or a pharmacologically acceptable salt thereof, wherein the compound is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups. 9. In any one selected from claims 1 to 5, R ⁵ 3-arsenide Dorokishifueniru, 4-arsenide Dorokishifueniru, 3 main Tokishifue sulfonyl, 4-main Tokishifue sulfonyl or 3, 4 Jime Tokishifueniru compound or pharmacologically acceptable salt thereof is a group. 10. In any one selected from claims 1 to 9, A compound or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a C i —C _1Q alkyl group. 11 1. In any one selected from claims 1 to 9, A compound or a pharmacologically acceptable salt thereof, wherein R ⁷ is a d—C ₆ alkyl group. 1 2. In any one selected from claims 1 to 9, A compound or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a C 1, 1 C ₄ alkyl group. 13 3. In any one of claims 1 to 9, A compound or a pharmacologically acceptable salt thereof, wherein R ⁷ is a methyl group or an ethyl group. 14. In any one selected from claims 1 to 13, R ⁸ is a compound or a pharmacologically acceptable salt thereof, which is an aromatic heterocyclic group substituted with 1 to 5 aromatic heterocyclic groups or a group selected from substituent group a. 15. In any one of claims 1 to 13, R ⁸ is a compound or a pharmacologically acceptable salt thereof, wherein the compound is an aryl group or an aryl group substituted with 1 to 5 aryl groups or a group selected from substituent group a. 16. In any one selected from claims 1 to 13, R ⁸ is a compound or a pharmacologically acceptable salt thereof, wherein the compound is an aryl group or an aryl group substituted with one or two aryl groups or a group selected from substituent group a. 17. In any one of claims 1 to 13, R ⁸ aryl group or one or two substituted aryl groups (the substituents may be the same or different and are a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or Or a pharmacologically acceptable salt thereof. 18. In any one of claims 1 to 13, R ^{8 forces?,} Ariru group, or one or two substituted Ariru group (the substituent same or different, a halogen atom, a hydroxy group or a lower alkoxy group.), Compound or a pharmacologically Above acceptable salts. 1 9. In any one selected from claims 1 to 13, R ^{8 forces?,} Phenyl, 3-fluorophenyl, 4 one-fluorophenyl, 3-black port phenyl, 4-black port phenyl, 3- main Tokishifue sulfonyl, 4-main Tokishifue sulfonyl, 3, 4-difluorophenyl, A compound having 3,5-difluorophenyl or 3,5-dichlorophenyl group or a pharmacologically acceptable salt thereof. 20. In claim 1,  Any one compound selected from the following or a pharmacologically acceptable salt thereof.  1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4-dihydroxyquinoline-3-carboxylate N-methyl-1-N-phenylamide, 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N-phenylamide, 1- (4-Hydroxyphenyl) -1 6,7-Dimethoxy 4-oxo-1,4-Dihydroxyquinoline 3-Carbonyl N-methyl-1-N- (3,5-difluorophenyl) amide ,  6,7-dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N-phenylamide,  6,7-dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-3-carboxylic acid N-ethyl-N-phenylamide  1- (4-Methoxyphenyl) 1-6,7-Dimethoxy 4-oxo-1,4-Dihydroxyquinoline 3-Carboxylic acid N-methyl-1-N- (4-Fluorophenyl) amide,  11- (4-Methoxyphenyl) 1-6,7-Dimethoxy-1-4-oxo-1,4-Dihydroxyquinoline 3-Carbonyl N-methyl-1-N— (4-Methoxyphenyl) Amid,  6,7-Dimethoxy-1- (4-methoxyphenyl) -1 4-oxo_1,4-dihydroquinolin-1-carboxylic acid N-methyl-1-N— (3,5-difluorophenyl) Amid,  1- (3,4-Dimethoxyphenyl) 1-6,7-Dimethoxy 4-oxo-1,4-Dihydroxyquinoline 1-3-Rubonic acid N-methyl-N- (4-fluorophenyl) amide,  1- (3,4-Dimethoxyphenyl) -16,7-Dimethoxy-4-oxo-1,4-Dihydroxyquinoline-3-Carboxylic acid N-methyl-N— (4-Methoxyphenyl) amide,  1- (4-Methoxyphenyl) 1-6,7,8—Trimethoxy 4 1-year-old 1,4-dihydro-quinoline 1-3-Rubonic acid N-methyl-N- (4-fluorophenyl) amide , 1— (4-Methoxyethoxy) 1 6,7,8—Trimethoxyl 4-oxo-1, 4-dihydroquinoline-3-carboxylate N-methyl-N- (4-methoxyphenyl) amide,  1-(3,4-Dimethoxyphenyl) 1,6,7,8-Trimethoxy-4-oxo- 1,4-Dihydroxyquinoline 3-3-Rubonic acid N-methyl-1-N— (4-Fluoro mouth Phenyl) amide,  1 _ (3,4-Dimethoxyphenyl) 1,6,7,8-Trimethoxy 4-oxo- 1,4-Dihydro-quinoline 1-3-Carbonyl N-methyl-N— (4-Methoxy phenyl ) Amido,  6,7-Dimethoxy-11- (4-methoxyphenyl) 1-4-oxo-1,4-dihydroquinoline-3-3-Rubonic acid N-methyl-N- (3-fluorophenyl) amide ',  7-Methoxy 1- (4-Methoxyphenyl) 1-4-oxo 1,4-dihydroquinoline 1-3-Rubonic acid N-methyl-N-phenylamide,  6,7-dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) amide,  6,7-Dimethoxy-1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline-3-hydrocarboxylate N-ethyl-N- (3,5-difluorophenyl) amide ,  6,7-Dimethoxy-11- (4-methoxyphenyl) 1-41-oxo-1,4-dihydroquinoline-3-Carbonyl N-methyl-1-N- (3-fluorophenyl) amide, ,  7-Methoxy 1 _ (4-methoxyphenyl) 1-4 4-oxo 1, 4-dihydroquinoline 3- 3-carboxylic acid N-methyl-1-N-phenylamide, 7—Methoxy 1— (4-Methoxyphenyl) -1-4-oxo-1,4-Dihydroquinoline 3-N-ethyl ethyl N-ethyl-3N— (3,5-difluorophenyl) Mit  1- (4-methoxyphenyl) -1 7-dimethoxy-1 41-oxo-1,4-dihydroxyquinoline 3-dicarboxylic acid N-ethyl-N-phenylamide  7-Dimethoxy-1- (4-methoxyphenyl) 1-14-oxo-1,4-dihydroquinoline-1-3-N-Methyl-1-N- (3-fluorophenyl) amide 7-Methoxy-1- (4-hydroxyphenyl) -1-oxo-1,4-diethyl mouth quinoline-3-carboxylate N-methyl-1-N-phenylamide,  7-Methoxy-1- 1- (4-hydroxyphenyl) -1 4-oxo-1,4-dihydroquinoline 1-3-Carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide ,  1- (4-hydroxyphenyl) -1 7-dimethoxy-4,1-oxo-1,4-dihydroxyquinoline-3-carboxylate N-ethyl-N-phenylamide,  7-Methoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-dihydroquinoline-13-Carboxylic acid N-methyl-1-N-phenylamide, and  7-Dimethoxy-1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline_3-carboxylate N-methyl-N- (3-fluorophenyl) amido 21. A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 22. — An ileal bile acid transporter containing a nitrogen-containing heterocyclic derivative having the general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient Pharmaceutical composition for inhibiting lipase. General formula (I)

Or General formula (I I)

[In the above formula, R \ R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group; R ⁵ represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups; R ⁶ is a group having the formula —CONR ⁷ R ⁸ , wherein R ⁷ represents (^ —. An alkyl group or a ^ -alkenyl group; R ⁸ is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group. ). ]  <Substituent group a> Halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono-lower alkylamino group, di-lower alkyl Amino group, carboxy group and lower alkoxycarbonyl group. 2 3. In claim 22,  A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. 2 4. In claim 22,  A pharmaceutical composition for inhibiting ileal bile acid transporter, comprising a compound having the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient. 25. In any one selected from claims 22 to 24, A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising as an active ingredient a compound that is a R ¹ and R ⁴ atom or a hydrogen atom or a pharmacologically acceptable salt thereof. 26. In any one of claims 22 to 25, R ^{2 force?,} Represent hydrogen atoms or containing a pharmaceutical composition for inhibiting the ileal bile acid transponder one data scratch a pharmacologically acceptable salt thereof as an active ingredient. 27. In any one selected from claims 22 to 25, R ² force; ', a compound is a hydroxy group or a lower alkoxy group or containing a pharmacologically acceptable salt thereof as an active ingredient, a pharmaceutical composition for inhibiting the ileal bile acid transporter. 28. In any one selected from claims 22 to 27, A pharmaceutical composition for inhibiting an ileal bile acid transporter, which comprises, as an active ingredient, a compound having R ³ ′, a hydroxy group or a lower alkoxy group, or a pharmaceutically acceptable salt thereof. 29. In any one selected from claims 22 to 28, A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising a compound in which R ⁵ is an aryl group or a pharmacologically acceptable salt thereof as an active ingredient. 30. In any one of claims 22 to 28, R ⁵ contains a hydroxy group or a lower alkoxy group is 1 to 5-substituted Ari Le group compound or a pharmacologically acceptable salt thereof as an active ingredient, inhibits ileal bile acid transponder one data one Pharmaceutical compositions for 3 1. In any one of claims 22 to 28, R ⁵ is a compound for inhibiting an ileal bile acid transporter, which contains, as an active ingredient, a compound which is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups, or a pharmacologically acceptable salt thereof. Pharmaceutical composition. 3 2. In any one selected from claims 22 to 28, R ^{5 forces?,} 3 arsenide Dorokishifueniru, 4-arsenide Dorokishifueniru, 3 main Tokishifue sulfonyl, 4-main Tokishifue sulfonyl or 3, 4 Jime Tokishifue two Le compound or active ingredient a pharmacologically acceptable salt thereof is a group A pharmaceutical composition for inhibiting ileal bile acid transporter, comprising 33. In any one selected from claims 22 to 32, R ⁷ is one. A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising a compound which is an alkyl group or a pharmacologically acceptable salt thereof as an active ingredient. 34. In any one selected from claims 22 to 32, R ⁷ forces, C ^-?! C ₆ compound is an alkyl group or an active ingredient a pharmacologically acceptable salt thereof A pharmaceutical composition for inhibiting ileal bile acid transporter, which is contained as a component. 35. In any one selected from claims 22 to 32, ^? R ⁷ forces, C, - C ₄ compound is an alkyl group or contains a pharmacologically acceptable salt thereof as an active Ingredient The pharmaceutical composition for inhibiting the ileal bile acid transporter. 36. In any one selected from claims 22 to 32, R ^{7 forces?,} Compound a methyl group or Echiru group or containing a pharmacologically acceptable salt thereof as an active ingredient, a pharmaceutical composition for inhibiting the ileal bile acid transponder one data one 37. In any one selected from claims 22 to 36, With free R ⁸ force, an aromatic heterocyclic group, or a group selected from Substituent group a is 1 to 5-substituted aromatic heterocyclic group compound or a pharmacologically acceptable salt thereof as an active ingredient, A pharmaceutical composition for inhibiting an ileal bile acid transporter. 38. In any one selected from claims 22 to 36, An ileal bile acid containing as an active ingredient a compound or a pharmacologically acceptable salt thereof, wherein R ⁸ is an aryl group or an aryl group substituted by 1 to 5 groups selected from substituent group a, as an active ingredient. A pharmaceutical composition for inhibiting a transporter. 39. In any one selected from claims 22 to 36, R ^{8 forces?,} Containing § Li Ichiru group or with a group selected from Substituent group a 1 to a 2-substituted § aryl group compound or a pharmacologically acceptable salt thereof as an active ingredient, times A pharmaceutical composition for inhibiting intestinal bile acid transporter. 40. In any one of claims 22 to 36, R ⁸ , aryl group, or one or two substituted aryl groups (the substituents may be the same or different, and may be a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient. 41. In any one of claims 22 to 36, A compound which is R ⁸ , an aryl group or an aryl group substituted by 1 or 2 (the substituents are the same or different and are a halogen atom, a hydroxy group or a lower alkoxy group) or a pharmacologically thereof; A pharmaceutical composition for inhibiting ileal bile acid transporter, comprising an acceptable salt as an active ingredient. 42. In any one selected from claims 22 to 36, R ⁸ force s-, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl A pharmaceutical composition for inhibiting an ileal bile acid transporter, comprising a compound which is a 3,5-difluorophenyl or 3,5-dichlorophenyl group or a pharmacologically acceptable salt thereof as an active ingredient. 4 3. In claim 22, A pharmaceutical composition _c for inhibiting an ileal bile acid transporter, comprising as an active ingredient any one compound selected from the following or a pharmacologically acceptable salt thereof _: 1- (4-hydroxyphenyl) -1,6,7-dimethoxy_4-oxo-1,4, -dihydroquinoline_3-carboxylate N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-1,4-oxo-1,4-dihydroquinoline-3-butyric acid N-ethyl-N-phenylamide, 1- (4-hydroxyphenyl) -1,6,7-dimethoxy-1,4-oxo-1,4-dihydroquinoline _3, -N-methyl-1-N- (3,5-difluorophenyl) amide  6,7-Dimethoxy 1- (4-Methoxyphenyl) -1-4-oxo-1,4-dihydroquinoline-3-3-Rubonic acid N-methyl-N-phenylamide,  6,7-dimethoxy-11- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-ethyl-N-phenylamide,  11- (4-methoxyphenyl) -16,7-dimethoxy-14-oxo-1,4,4-dihydroxyquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide,  1- (4-methoxyphenyl) 1-6,7-dimethoxy-1 4-oxo-1,4-dihydro-quinoline 1-3-carboxylic acid N-methyl-1-N— (4-methoxyphenyl) Amid,  6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N— (3,5-difluorophenyl) Mid,  1- (3,4-dimethoxyphenyl) -1,6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-1,3-dicarboxylic acid N-methyl-N- (4-fluorophenyl) amide,  1- (3,4-Dimethoxyphenyl) 1-6,7-Dimethoxy-4-oxo-1,4-Dihydroquinoline 1-3-Carboxylic acid N-methyl-1-N- (4-Methoxyphenyl) Do  1- (4-Methoxyphenyl) 1-6,7,8-Trimethoxy-14-Oxo-1,4,4-Dihydro-quinoline-3-3-N-methyl-1-N_ (4-fluorophenyl) amide 1- (4-methoxyphenyl) 1-6,7,8-trimethoxy-1 4-oxo-1 4-dihydroxyquinoline-l-dicarboxylic acid N-methyl-l-N- (4-methoxyphenyl) amide,  1- (3,4-Dimethoxyphenyl) 1, 6,7,8-Trimethoxy 4-oxo-1 1,4-Dihydroxyquinoline 1-3-Carboxylic acid N-Methyl-N— (4-Fluoro-phenyl) Ami Do  1- (3,4-dimethoxyphenyl) -16,7,8-trimethoxy-14-oxo—1,4-dihydro-quinoline-13-carboxylate N-methyl-N— (4-methoxydiphenyl) Le) Amido,  7-Methoxy 1-phenyl 4-oxo-1,4-dihydroquinoline 3-nitrobenzene N-methyl-1-N-phenylamide  6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-1-N- (3-fluorophenyl) amite  7-Methoxy 11- (4-methoxyphenyl) _ 4-oxo-1,4-dihydroquinoline 3-potassium N-methyl-1-N-phenylamide  6,7-Dimethoxy 1- (4-Methoxyphenyl) 1- 4-oxo-1,4-Dihydroquinoline 3-Carbonyl N-ethyl-N- (3,5-Difluorophenyl) Do  6,7-dimethoxy-11- (4-hydroxyphenyl) -14-oxo-1,4-dihydroxyquinoline-3-carboxylate N-ethyl-N- (3,5-difluorophenyl) amide,  6,7-Dimethoxy-1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-3-carboxylate N-methyl-N- (3-fluorophenyl) amide, , 7-Methoxy 11- (4-methoxyphenyl) 1-4 4-oxo 1,4-dihydroquinoline 3-3-N-methyl-N-phenylamide 7-Methoxy 1- (4-Methoxyphenyl) -1 4-oxo-1,4-dihydroquinoline 3-Carboxyl N-ethyl-1 N- (3,5-Difluorophenyl) amite  1- (4-Methoxyphenyl) -1 7-Dimethoxy 4-oxo-1,4-Dihydroquinoline-1 3-N-Ethyl-1-N-phenylamide  7-Dimethoxy 1- (4-methoxyphenyl) -14-oxo-1,4-dihydroquinoline-1 3-Carboxylic acid N-methyl-1-N- (3-fluorophenyl) amide, 7-Methoxy 1 _ (4-hydroxyphenyl) 1-4-oxo 1, 4-dihydroquinoline 3- carboxylic acid N-methyl-N-phenylamide,  7-Methoxy 1- (4-hydroxyphenyl) 1- 4-oxo-1,4-dihydroquinoline 3- 3-N-ethyl-N-ethyl-N- (3,5-difluorophenyl) amide  1- (4-hydroxyphenyl) -1- 7-dimethoxy-4-oxo-1,4-dihydroxyquinoline 3-carboxylate N-ethyl-N-phenylamide,  7-Methoxy-1- (4-hydroxyphenyl) -14-oxo-1,4-dihydroxy mouth quinoline 3-carboxylate N-methyl-N-phenylamide,  7-Dimethoxy 1- (4-hydroxyphenyl) -1-4-oxo-1,4-dihydroxyquinoline 3-potassium N-methyl-1-N- (3-fluorophenyl) amine K,  1- (4-Methoxyphenyl) 1-4-Hydroxy-1,6,7-Dimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-3-Carboxylic acid N-Methyl-1-N— (4-Fluorophenyl Amid,  1- (4-Methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy-1-2-Kiso-1 1,2-Dihydroxyquinoline-3-Carbonyl N-methyl-1-N— (4-Methoxyphenyl) Amid, 1-(3,4 dimethoxyphenyl) 1-4-hydroxy-6, 7-dimethoxy-1 2-oxo-1,2-dihydroquinoline_3_carboxylate N-methyl-1-N— (4-fluorophenyl) amide,  1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy-1,6,7-Dimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-1-3-Rubonic acid N-methyl-N— (4-methyl Toxifenil) amide,  1- (4-Methoxyethoxy) 1 4-Hydroxy-6,7,8-Trimethyoxy 2-L-oxo-1,2-Dihydroquinoline-1-3-Rubonate N-Methyl-1-N— (4-I Fluorophenyl) amide,  1- (4-Methoxyethoxy) 1-4-Hydroxy-6,7,8-Trimethoxy-1-2-Hexane 1,2-Dihydroquinoline-3-Carboxylic acid N-Methyl-1-N— (4-Methyl Toxiphenyl) amide,  1- (3,4-dimethoxyphenyl) 1-4-hydroxy 6,7,8-trimethoxy_2-2-year-old 1,2-dihydroxyquinoline 3-dicarboxylic acid N-methyl-N-phenylamide,  1 1- (3,4-Dimethoxyphenyl) 1-4-Hydroxy_6,7,8-Trimethoxy-1-2-oxo-1,2-Dihydroxyquinoline-3-Carboxylic acid N-Methyl-N-1 (4 —Fluorophenyl) amide,  1- (3,4-Dimethoxyphenyl) 1-4 4-Hydroxy-1,6,7,8-Trimethoxy_2-Aged 1,2-Dihydroxyquinoline-1-3-Carboxylic acid N-methyl-1-N-1 4-methoxy amide, amide,  1- (4-Hydroxyphenyl) 1-4-Hydroxy 7-Methoxy-2-Oxo-1 1,2-Dihydroxyquinoline 1-3-Carboxylic acid N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) 1-4-hydroxy 7-methoxy-1-oxo-1,1,2-dihydroxyquinoline-3-carboxylate N-ethyl-N-phenylamide, 1- (4-hydroxyphenyl) 1-4-hydroxy 7-methoxy 2-oxo-1,1,2-dihydroxyquinoline 1-3-carboxylic acid N-methyl-N— (3_fluoro Phenyl) amide,  11- (4-Hydroxyphenyl) _ 4-Hydroxy-1- 7-Methoxy 2 _oxo — 1,2-Dihydroquinoline-1 —3-Rubonate N-Ethyl N- (3-Fluorophenyl) amide,  11- (4-Hydroxyphenyl) 1-4-Hydroxy-1 7-Methoxy 2-1,2-Dihydroxy-1,3-difluoroquinoline N-Methyl-1-N- (3,5-Difluorophenyl) Do  1- (4-hydroxydroxyphenyl) 1-4-hydroxy7-methoxy-2-oxo-1,2,2-dihydroxyquinoline-1,3-dicarboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide,  1- (4-Methoxyphenyl) 1-4-Hydroxy 7-Methoxy 2-oxo-1, 2-Dihydroxyquinoline-3-Carboxylic acid N-methyl-N-phenylamide 11- (4-methoxyphenyl) 1-4-hydroxy 7-methoxy 2-oxo-1,2-dihydroxyquinoline-3-carboxylate N-ethyl-N-phenylamide, 11- (4-methoxyphenyl) 1-4-hydroxy 7-methoxy-12-oxo-1,2-dihydroxyquinoline-3-carboxylate N-methyl-1-N- (3-fluorophenyl) amide,  11- (4-methoxyphenyl) 1-4-hydroxy 7-methoxy 2-oxo-1,2-dihydroxyquinoline 3-carboxylate N-ethyl-1-N- (3-fluorophenyl) amide,  1- (4-Methoxyphenyl) 1-4-Hydroxy 7-Methoxy-1 2-Oxo-1,2-Dihydroxyquinoline 1-3-Carbonyl N-methyl-1-N- (3,5-Difluorophenyl) amide ,- 1- (4-Methoxyphenyl) 1-4-Hydroxy 7-Methoxy_2-Oxo-1,1,2-Dihydroxyquinoline-3-Carboxylic acid N-Ethyl-1-N— (3,5-Difluorophenyl) Do 1- (4-Methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy-12-oxo 1,2-Dihydroxyquinoline 1-3-Carbonyl N-methyl-1-N-phenylamide,  1- (4-Methoxyphenyl) 1-4-Hydroxy-6,7-Dimethoxy-12-oxo-1,3-Dihydroxyquinoline-1-3-Rubonic acid N-Ethyl-N-Phenylamide  1- (4-Methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy 1-2-Year-old Kiso 1,2-Dihydroxyquinoline 1-3-Carbonyl N-methyl-N- (3-Fluorophenyl) Do  1- (4-Methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy-1-Oxo 1,2-Dihydroxyquinoline 1-3-Carbonyl N-ethyl-N- (3-Fluorophenyl) amide ,  1- (4-methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy 2-Kiso 1-, 2-Dihydroxyquinoline 3-Carbonyl N-methyl-N- (3,5-Difluorophenyl Amides, and  1- (4-Methoxyphenyl) 1-4-Hydroxy 6,7-Dimethoxy 2-oxo-1,3-Dihydroxyquinoline 1-3-Carbonic acid N-Ethyl N- (3,5-Difluorophenyl) Amid. 44. The pharmaceutical composition according to any one of claims 22 to 43 for prevention or treatment of hyperlipidemia. 45. The pharmaceutical composition according to any one of claims 22 to 43 for preventing or treating arteriosclerosis. 46. For producing a pharmaceutical composition for inhibiting an ileal bile acid transporter Use of the compound according to claims 22 to 43, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof.