HK1053657B

HK1053657B - Novel heterocyclic compounds and salts thereof and medicinal use of the same

Info

Publication number: HK1053657B
Application number: HK03106069.0A
Authority: HK
Inventors: 松井博; 小林英夫; 小豆泽智; 笠井正恭; 吉见彰久; 白波濑弘明
Original assignee: 京都药品工业株式会社
Priority date: 1999-12-03
Filing date: 2000-11-29
Publication date: 2006-03-17

Description

Novel heterocyclic compounds and salts thereof and their medicinal use

The technical field to which the invention belongs

The present invention relates to a novel heterocyclic compound having a hypoglycemic action, a hypolipidemic action, an insulin resistance-improving action and a PPAR (peroxisome proliferator-responsive receptor) activating action, and a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a pharmaceutical composition containing the above novel heterocyclic compound or a pharmaceutically acceptable salt thereof. The present invention also relates to an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance-improving agent, a therapeutic agent for diabetes, an agent for diabetic complication (i.e., a therapeutic agent for diabetic complication), an agent for improving glucose tolerance insufficiency, an agent for arteriosclerosis, an anti-obesity agent, an anti-inflammatory agent, an agent for preventing and treating PPAR-mediated diseases, and an agent for preventing and treating syndrome X, each containing the above novel heterocyclic compound or a pharmaceutically acceptable salt thereof.

Background

As a therapeutic agent for diabetes, biguanide compounds mainly having an action of inhibiting absorption of sugar from the intestinal tract and releasing sugar from the liver, sulfonylurea compounds mainly having an action of promoting insulin secretion, insulin, and the like have been used. However, since biguanide compounds cause lactic acidosis, sulfonylurea compounds have a strong hypoglycemic effect and often cause severe hypoglycemia, etc., great attention is required in the use process. In recent years, studies on diabetes therapeutic agents free from these drawbacks have been carried out, and various compounds having an insulin resistance-improving action have been found.

Insulin resistance is an important cause of non-insulin-dependent resistant diabetes mellitus (NIDDM) together with low insulin secretion, and therefore development of a drug for improving insulin resistance is desired. As these drugs for improving insulin resistance, various thiazolidine compounds are known. As these compounds, 5- [4- [ (6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl) methoxy ] benzyl ] -2, 4-thiazolidinedione (common name: troglitazone) is described in Japanese patent application No. 31079/1990, 5- [ [4- [2- (5-ethyl-pyridin-2-yl) ethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione (common name: pioglitazone) is described in Japanese patent application No. 66956/1993, and 5- [ [4- [2- [ N-methyl-N- (pyridin-2-yl) amino ] ethoxy ] phenyl ] methyl ] -2 is described in Japanese patent application No. 131169/1989, 4-thiazolidinedione (common name: Roselletone).

The present invention has an object to provide a compound having a structure completely different from those of the conventional compounds and having a hypoglycemic action, a hypolipidemic action, an insulin-resistance-improving action and a PPAR activating action, and to provide a wide selection range of anti-hyperglycemic agents, anti-hyperlipidemic agents, insulin-resistance-improving agents, diabetes-treating agents, diabetes-complication-treating agents, glucose-resistance-improving agents, anti-arteriosclerosis agents, anti-obesity agents, anti-inflammatory agents, PPAR-mediated disease preventing/treating agents and X syndrome preventing/treating agents.

Disclosure of the invention

The present inventors have conducted intensive studies to solve the above problems and as a result, have found a compound represented by the general formula [ I ] and a pharmaceutically acceptable salt thereof, having a novel structure:

(in the formula, R¹Represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, a cycloalkylalkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a heterocycloalkyl group which may have a substituent, or-COR⁴(in the formula, R⁴Represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, an alkenyl group which may have a substituent, an arylalkyl group which may have a substituent, or a heterocyclic residue which may have a substituent),

R³represents a hydrogen atom, a lower alkyl group or a lower alkoxy group,

a represents a single bond or > N-R⁵(in the formula, R⁵Represents a hydrogen atom or a lower alkyl group),

b represents a lower alkylene group, and B represents a lower alkylene group,

y represents an optionally substituted aryl group or an optionally substituted aromatic heterocyclic residue

Has hypoglycemic action, hypolipidemic action, insulin resistance-improving action and PPAR activating action, and has been completed.

That is, the present invention relates to the following.

[1] A heterocyclic compound represented by the general formula [ I ] (hereinafter also referred to as a heterocyclic compound [ I ]) or a pharmaceutically acceptable salt thereof:

(in the formula, R¹Represents a hydrogen atom or a lower alkyl group,

R³represents a hydrogen atom, a lower alkyl group or a lower alkoxy group,

b represents a lower alkylene group, and B represents a lower alkylene group,

y represents an aryl group which may have a substituent or an aromatic heterocyclic residue which may have a substituent).

[2] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, in the general formula [ I ],

R¹represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, a cycloalkylalkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent or-COR⁴(in the formula, R⁴Represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, an arylalkyl group which may have a substituent),

R³represents a hydrogen atom, a lower alkyl group or a lower alkoxy group,

b represents lower alkylene, and

y represents an aryl group which may have a substituent or an aromatic heterocyclic residue which may have a substituent.

[3] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, in the general formula [ I ],

R¹represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group which may have a substituent, an alkenyl group, an alkynyl group, a heterocycloalkyl group or-COR⁴(in the formula, R⁴Represents an alkyl group, an alkenyl group or an aryl group),

R³represents a hydrogen atom or a lower alkoxy group,

a represents a single bond or > N-R⁵(in the formula, R⁵Represents a lower alkyl group),

b represents lower alkylene, and

y represents an aryl group or an aromatic heterocyclic residue which may have a substituent.

[4] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, in the general formula [ I ],

R¹represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group which may have a substituent or-COR⁴(in the formula, R⁴Represents an alkyl group or an aryl group),

R³represents a hydrogen atom, and is represented by,

b represents lower alkylene, and

y represents an optionally substituted aromatic heterocyclic residue.

[5] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, wherein, in the general formula [ I ], Y-A-is:

or

(in the formula, R^ARepresents an isopropyl group or a tert-butyl group,

R^Brepresents an isopropyl group or a tert-butyl group,

R^Crepresents isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or 2, 2-dimethylpropyl).

[6] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, wherein, in the general formula [ I ], Y-A-is:

or

(in the formula, R^ARepresents an isopropyl group or a tert-butyl group,

R^Brepresents an isopropyl group or a tert-butyl group,

R^Crepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropenyl or 3-butenyl).

[7] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, wherein, in the general formula [ I ], Y-A-is:

or

[8] The heterocyclic compound of the above [1] or a pharmaceutically acceptable salt thereof, wherein, in the general formula [ I ], Y-A-is:

[9] the heterocyclic compound of the above [1], or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the following compounds (1) to (67):

(1)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(2) 2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(3) 2-acetyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(4) 2-methyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(5) 2-hexanoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(6) 2-hexyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(7) 2-isobutyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(8) 2-cyclohexylmethyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(9)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (3-phenylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(10) 2-benzoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(11) 2-benzyl-7- [2- (N-methyl-N- (pyridin-2-yl) amino) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(12) 2-benzyl-7- [2- (5-ethyl-pyridin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(13) 2-benzyl-7- [2- (indolin-1-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(14) 2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester,

(15)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester,

(16)2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(17)2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester,

(18)2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(19)2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester,

(20) 2-benzyl-7- [2- (6-carboxyindolin-1-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(21)2- (4-fluorobenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(22)2- (2, 2-dimethylpropionyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(23)2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(24) 2-benzyl-7- [2- (5-methyl-2-tert-butyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(25) 2-benzyl-7- [2- (5-methyl-2- (thiophen-2-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(26) 2-benzyl-7- [2- (5-methyl-2-isopropyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(27) 2-butyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(28) 2-benzyl-7- {2- [ 5-methyl-2- (2-methylpropenyl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(29) 2-benzyl-7- {2- [2- (3-butenyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(30) 2-allyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(31)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (2-propynyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(32)2- (2-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(33) 2-benzyl-7- [ (indolin-3-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(34)2- (3-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(35)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2-pentanoyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(36)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (4-pentenoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(37)2- (3-methyl-2-butenoyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(38)2- (3, 3-dimethylbutyryl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(39) 2-benzyl-7-methoxy-6- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3RS) -carboxylic acid,

(40)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (pyridin-2-ylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(41) 2-benzyl-7- (3-methyl-3-phenylbutoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(42) 2-benzyl-7- (3, 3-dimethyl-4-phenylbutoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(43) 2-benzyl-7- (2-isopropylbenzoxazol-6-yl) methoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(44) 2-benzyl-7- (2-tert-butylbenzooxazol-6-yl) methoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(45) 2-benzyl-7- (2-tert-butylbenzooxazol-5-yl) methoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(46)7- (2-tert-butylbenzooxazol-6-yl) methoxy-2- (2, 2-dimethylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(47) 2-benzyl-7- (2-isopropylbenzoxazol-5-yl) methoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(48)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (pyridin-4-ylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(49)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- [ (pyridin-2-yl) carbonyl ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(50) 2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester,

(51) 2-benzyl-7- [2- (2-cyclopropyl-5-methyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(52)2- (3-methyl-2-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(53)2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-tert-butyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(54) 2-benzyl-7- {2- [ (1-butenyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(55) 2-benzyl-7- {2- [ (2, 2-dimethylpropyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(56)2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester,

(57)7- (benzofuran-2-ylmethoxy) -2-benzyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(58) 2-isobutyryl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(59)7- [2- (benzofuran-2-yl) ethoxy ] -2-benzyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(60)7- [2- (5-ethylpyridin-2-yl) ethoxy ] -2-hexanoyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(61) 2-carboxymethyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(62)2- [3- (methoxycarbonyl) propionyl ] -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(63)2- [3- (ethoxycarbonyl) propyl ] -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(64) 2-benzyl-6- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3RS) -carboxylic acid,

(65)2- (3-acetylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(66)2- (2-acetylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid, and

(67) 2-benzyl-7- [ (5-methyl-2-phenyloxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[10] The heterocyclic compound of the above [9] or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the above-mentioned compounds (1) to (47).

[11] The heterocyclic compound of the above [9] or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the above-mentioned compounds (1) to (21).

[12] A pharmaceutical composition comprising the heterocyclic compound according to any one of the above [1] to [11] or a pharmaceutically acceptable salt thereof.

[13] A pharmaceutical agent selected from the group consisting of antihyperglycemic agents, antihyperlipidemic agents, insulin resistance improving agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, glucose tolerance improving agents, antiatherosclerotic agents, antiobesity agents, anti-inflammatory agents, preventive/therapeutic agents for PPAR-mediated diseases, and preventive/therapeutic agents for syndrome X, which comprises any one of the heterocyclic compounds of the above [1] to [11] or a pharmaceutically acceptable salt thereof.

[14] An antihyperglycemic agent comprising the heterocyclic compound according to any one of the above [1] to [11] or a pharmaceutically acceptable salt thereof.

[15] An antihyperlipidemic agent comprising any one of the heterocyclic compounds of [1] to [11] or a pharmaceutically acceptable salt thereof.

[16] An insulin resistance-improving agent comprising the heterocyclic compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof.

[17] A therapeutic agent for diabetic complications, which comprises any one of the heterocyclic compounds according to [1] to [11] or a pharmaceutically acceptable salt thereof. And

[18] a therapeutic agent for diabetes, which comprises any one of the heterocyclic compounds according to [1] to [11] or a pharmaceutically acceptable salt thereof.

Novel heterocyclic compounds of the general formula [ I ] and pharmaceutically acceptable salts thereof:

(in the formula, R¹Represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group which may have a substituent, or a cycloalkyl groupCycloalkylalkyl, aryl which may have a substituent, arylalkyl which may have a substituent, alkenyl which may have a substituent, alkynyl which may have a substituent, heterocycloalkyl which may have a substituent, or-COR⁴(in the formula, R⁴Represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, an alkenyl group which may have a substituent, an arylalkyl group which may have a substituent, or a heterocyclic residue which may have a substituent),

R³represents a hydrogen atom, a lower alkyl group or a lower alkoxy group,

b represents a lower alkylene group, and B represents a lower alkylene group,

Has effects in reducing blood sugar and blood lipid, improving insulin resistance, and activating PPAR.

The alkoxycarbonyl group in the present invention preferably includes an alkoxycarbonyl group having 2 to 5 carbon atoms, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, and the like.

As R¹、R³And R⁵The lower alkyl group in (3) preferably includes a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl, and preferably include methyl, ethyl, propyl, and isopropyl.

As R³The lower alkoxy in (3) is preferably a linear or branched alkoxy having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, pentyloxy, n-hexyloxy,Neopentyloxy, hexyloxy and the like, and preferably, methoxy, ethoxy, propoxy and isopropoxy are mentioned.

As R²And R⁴The "alkenyl group" in the alkenyl group which may have a substituent(s) in (1) is preferably a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, examples thereof include vinyl, 1-propenyl, 2-propenyl, isopropenyl, allyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, and preferred examples thereof include allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 2-propenyl, 2-methyl-1-propenyl and the like. As the substituent, there may be mentioned lower alkoxy (and R)³Lower alkoxy in (3) is the same as defined), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), a nitro group, an amino group or the like. R²Or R⁴The number of substitution in the case of an alkenyl group which may have a substituent is preferably 1 or 2, respectively.

As R²The "alkynyl group" in the alkynyl group which may have a substituent(s) in (b) is preferably a linear or branched alkynyl group having 2 to 4 carbon atoms, and examples thereof include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-methyl-2-propynyl group and the like, and preferred examples thereof include an ethynyl group and a 2-propynyl group. As the substituent, there may be mentioned lower alkoxy (and R)³Lower alkoxy in (3) is the same as defined), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), a nitro group, an amino group or the like. R²The number of substitution in the optionally substituted alkynyl group is preferably 1 or 2.

As R²And R⁴The "alkyl group" in the alkyl group which may have a substituent(s) in (b) is preferably a straight-chain or branched alkyl group having 1 to 8 carbon atoms, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like, and examples of which include methyl, ethyl, isobutyl and the likePropyl, hexyl, pentyl, isopropyl and the like. As the substituent, there may be mentioned lower alkoxy (and R)³Lower alkoxy in (3) is the same as defined), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), a nitro group, an amino group or the like. R²The number of substituents in the case of an alkyl group which may have a substituent is preferably 1 or 2.

As R²The cycloalkyl group in (3) preferably includes cycloalkyl groups having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, and preferred examples thereof include cyclopropyl, cyclopentyl, and cyclohexyl groups.

As R²The cycloalkylalkyl group in (1) includes cycloalkyl groups having preferably 3 to 8 carbon atoms in the cycloalkyl moiety, cycloalkylalkyl groups having preferably 1 to 3 carbon atoms in the alkyl moiety, which are preferably linear or branched alkyl groups, and examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 3-cyclooctylpropyl, 1-cyclohexylethyl, 1-cyclohexylpropyl, 2-cyclohexylpropyl, and the like, and preferably include, cyclohexylmethyl, 2-cyclohexylethyl, cyclopentylmethyl, 2-cyclopentylethyl.

At R²、R⁴Of the aryl groups which may have a substituent(s) in Y, examples of the aryl group include phenyl and naphthyl. As the substituent, there may be mentioned lower alkyl (and R)¹、R³And R⁵Lower alkyl in (1) is as defined), lower alkoxy (same as R)³Lower alkoxy in (3) is the same as defined), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), a nitro group, an amino group, an acyl group (for example, formyl group, acetyl group, propionyl group, etc.), etc. Y is the number of substitution of an optionally substituted aryl group, and is preferably 1 or 2.

As R²And R⁴Examples of the arylalkyl group which may have a substituent(s) in (1) include, for example, an arylalkyl group in which an aryl moiety is preferably a phenyl group or a naphthyl group, and an alkyl moiety is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Examples of the arylalkyl group include a benzyl group, a 1-naphthylmethyl group, a 2-phenylethyl group, a 2- (1-naphthyl) ethyl group, a 2- (2-naphthyl) ethyl group, a 3-phenylpropyl group, a 3- (1-naphthyl) propyl group, a 3- (2-naphthyl) propyl group, and a 1-phenylethyl group, 2-phenylpropyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 1- (1-naphthyl) propyl, 1- (2-naphthyl) propyl, 2- (1-naphthyl) propyl, 2- (2-naphthyl) propyl and the like, and preferred examples thereof include benzyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. As the substituent, there may be mentioned lower alkyl (and R)¹、R³And R⁵Lower alkyl in (1) is as defined), lower alkoxy (same as R)³Wherein the lower alkoxy group is the same as defined above), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom or a fluorine atom), a nitro group, an amino group, an acyl group (e.g., a formyl group, an acetyl group, a propionyl group, etc.), etc., and preferably a lower alkyl group, a lower alkoxy group, a halogen atom, an acyl group, etc. Y is the number of substitution in the case of an arylalkyl group which may have a substituent, and is preferably 1 or 2.

Among the aromatic heterocyclic residues which may have a substituent(s) in Y, preferable examples of the aromatic heterocyclic group include monocyclic heterocyclic groups and fused heterocyclic groups each containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom. In the present invention, the fused heterocyclic ring is a 2-ring system, and includes a case where hetero atoms are present in both rings. Preferred monocyclic heterocycles are 5-or 6-membered rings. As the heterocyclic ring constituting the fused heterocyclic ring, a 5-or 6-membered ring is preferable, and as the ring not containing a hetero atom constituting the fused heterocyclic ring, a 5-or 6-membered ring is preferable. Examples of the aromatic heterocyclic residue include monocyclic heterocyclic residues such as furyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, or pyrazinyl; indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenylThienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazolyl, furo [2, 3-b ] o]Pyridyl, thieno [2, 3-b ]]Examples of the fused heterocyclic residue include pyridyl, naphthyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl and the like, and preferred examples thereof include pyridyl, oxazolyl, indolinyl, benzoxazolyl, thiazolyl, benzothiazolyl, indolyl, quinolyl and benzofuranyl. As the substituent, there may be mentioned lower alkyl (and R)¹、R³And R⁵Lower alkyl in (1) is as defined), lower alkoxy (same as R)³Lower alkoxy in (1) is as defined), hydroxy, carboxy, alkoxycarbonyl, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), nitro, amino, aryl (e.g., phenyl, naphthyl, etc.), a heterocyclic residue (e.g., thienyl, pyridyl, furyl, etc.), alkenyl (with R)²And R⁴The alkenyl group in (1) is the same as defined), cycloalkyl group (e.g., cyclopropyl group, etc.), etc., preferably aryl group, lower alkyl group, carboxyl group, heterocyclic residue, alkenyl group, cycloalkyl group. Y is the number of substitution of a heterocyclic residue which may have a substituent, and is preferably 1 or 2.

The lower alkylene group in B is preferably a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 2-dimethyltrimethylene, 2-ethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-dimethyltrimethylene and 3, 3-dimethyltetramethylene, and preferred examples thereof include ethylene, trimethylene and tetramethylene.

At R²In the optionally substituted heterocycloalkyl group in (1), the heterocyclic moiety is as defined as the "aromatic heterocyclic residue" of the "optionally substituted aromatic heterocyclic residue" in Y, and examples of the alkyl moiety include a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples of the heterocycloalkyl group include, for example, 1-pyridylmethyl, 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylA methyl group; 1- (1-pyridyl) ethyl group, 1- (2-pyridyl) ethyl group, 1- (3-pyridyl) ethyl group, 1- (4-pyridyl) ethyl group, 2- (1-pyridyl) ethyl group, 2- (2-pyridyl) ethyl group, 2- (3-pyridyl) ethyl group, 2- (4-pyridyl) ethyl group, 1- (1-pyridyl) propyl group, 1- (2-pyridyl) propyl group, 1- (3-pyridyl) propyl group, 1- (4-pyridyl) propyl group, 2- (1-pyridyl) propyl group, 2- (2-pyridyl) propyl group, 2- (3-pyridyl) propyl group, 2- (4-pyridyl) propyl group, 3- (1-pyridyl) propyl group, and mixtures thereof, 3- (2-pyridyl) propyl group, 3- (3-pyridyl) propyl group, 3- (4-pyridyl) propyl group; 2-thienylmethyl, 3-thienylmethyl; 1- (2-thienyl) ethyl, 1- (3-thienyl) ethyl, 2- (2-thienyl) ethyl, 2- (3-thienyl) ethyl; 1- (2-thienyl) propyl, 1- (3-thienyl) propyl, 2- (2-thienyl) propyl, 2- (3-thienyl) propyl, 3- (2-thienyl) propyl, 3- (3-thienyl) propyl, and the like. The heterocycloalkyl group, heterocyclic moiety may be substituted, and as the substituent, lower alkyl (and R) may be mentioned¹、R³And R⁵Lower alkyl in (1) is as defined), lower alkoxy (same as R)³Lower alkoxy in (3) is the same as defined), hydroxyl group, carboxyl group, alkoxycarbonyl group, halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), nitro group, amino group. The number of substitution when the heterocyclic moiety is substituted with the substituent is preferably 1 or 2.

At R⁴In the optionally substituted heterocyclic residue of (2), the heterocyclic moiety is as defined in the "aromatic heterocyclic residue" of the "optionally substituted aromatic heterocyclic residue" in Y, and preferably a pyridyl group is mentioned. The heterocyclic residue may be substituted, and as the substituent, lower alkyl (and R) may be mentioned¹、R³And R⁵Lower alkyl in (1) is as defined), lower alkoxy (same as R)³Lower alkoxy in (3) is the same as defined), a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom (chlorine atom, bromine atom, iodine atom or fluorine atom), a nitro group, an amino group or the like. The number of substitution when the heterocyclic moiety is substituted with the substituent is preferably 1 or 2.

As the heterocyclic compound [ I ] and pharmaceutically acceptable salts thereof, preference is given to

In the above-mentioned general formula [ I ],

①R¹represents a hydrogen atom or a lower alkyl group,

R²represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, a cycloalkylalkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent or-COR⁴(in the formula, R⁴Represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent or an arylalkyl group which may have a substituent),

R³represents a hydrogen atom, a lower alkyl group or a lower alkoxy group,

b represents lower alkylene, and

y represents an aryl group which may have a substituent or a heterocyclic compound of an aromatic heterocyclic residue which may have a substituent, and a pharmaceutically acceptable salt thereof;

②R¹represents a hydrogen atom or a lower alkyl group,

R³represents a hydrogen atom or a lower alkoxy group,

b represents lower alkylene, and

y represents an aryl group or a heterocyclic compound of an aromatic heterocyclic residue which may have a substituent, and a pharmaceutically acceptable salt thereof;

③R¹represents a hydrogen atom or a lower alkyl group,

R³represents a hydrogen atom, and is represented by,

b represents lower alkylene, and

y represents a heterocyclic compound having an aromatic heterocyclic residue which may have a substituent, and a pharmaceutically acceptable salt thereof.

In the formula [ I ], it is preferable that Y-A-is,

or

Or

(in the formula, R^ARepresents an isopropyl group or a tert-butyl group,

R^Brepresents an isopropyl group or a tert-butyl group,

R^Crepresents isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl or 3-butenyl) or

And

(in the formula, R^ARepresents an isopropyl group or a tert-butyl group,

R^Brepresents an isopropyl group or a tert-butyl group,

R^Ca group representing isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or 2, 2-dimethylpropyl), particularly preferably

As preferred examples of the heterocyclic compound [ I ] and pharmaceutically acceptable salts thereof, mention may be made of

(20) 2-benzyl-7- [2- (6-carboxyindolin-1-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid, and

(21)2- (4-fluorobenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid, and pharmaceutically acceptable salts thereof, in addition to which,

(47) 2-benzyl-7- (2-isopropylbenzoxazol-5-yl) methoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid, and pharmaceutically acceptable salts thereof, among others,

(67) 2-benzyl-7- [ (5-methyl-2-phenyloxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid, and pharmaceutically acceptable salts thereof.

In addition, the heterocyclic compound [ I ] has an asymmetric carbon atom at the 3-position of the 1, 2, 3, 4-tetrahydroisoquinoline ring, and thus has various stereoisomers. The most preferred spatial configuration is

(in the formula, R¹、R²、R³Y, A and B are as defined above. )

The heterocyclic compound [ I ] may form a pharmaceutically acceptable salt as required. The heterocyclic compound [ I ], which can form an acid addition salt when having a basic group, is not particularly limited as long as it is an acid which can form a salt with a basic moiety and is pharmaceutically acceptable. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.

When the heterocyclic compound [ I ] has an acidic group such as a carboxyl group, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an organic base salt (e.g., triethylamine salt, dicyclohexylamine salt, pyridine salt, etc.), and the like can be formed.

The heterocyclic compound [ I ] and a pharmaceutically acceptable salt thereof can be produced by any of the following production methods.

Preparation method 1

(in the formula, R¹、R³R A, B and Y are as defined above⁶Represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group, a cycloalkylalkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, an aryl group which may have a substituentAlkenyl, alkynyl which may have substituents, heterocycloalkyl which may have substituents, -COR⁴(in the formula, R⁴As defined above) or an amino-protecting group, X represents a leaving group such as a hydroxyl group, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) or an alkanesulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), an arylsulfonyloxy group (e.g., benzenesulfonyloxy, tolylsulfonyloxy, etc.), etc. )

The production method 1 is a production method for producing a compound of the general formula [ Ia ] (also referred to as a compound [ Ia ]) by reacting a compound of the general formula [ II ] (also referred to as a compound [ II ]) with a compound of the general formula [ III ] (also referred to as a compound [ III ]).

R⁶The definition of "alkyl group which may have substituents", "cycloalkyl group", "cycloalkylalkyl group", "aryl group which may have substituents", "arylalkyl group which may have substituents", "alkenyl group which may have substituents", "alkynyl group which may have substituents" and "heterocycloalkyl group which may have substituents" in (1) is defined as R²Are the same as defined above.

As R⁶Examples of the amino-protecting group in (b) include formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, trimethylsilyl, 2, 2, 2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, t-butoxycarbonyl (hereinafter referred to as Boc), and trityl.

Preparation method 1-a: in the case where X is a hydroxyl group, preparation 1 is carried out according to the mitsunobu reaction (Regenstfor Organic Synthesis, Fisher)&Fisher, vol.6, 645), etc. by a dehydration reaction. The reaction is usually carried out by using azo compounds and phosphines in the presence of a solvent. As the azo compounds, for example, azobis (C) azodicarboxylate₁～C₄Alkyl) esters (e.g., diethyl azodicarboxylate, etc.), azocarboxamides (e.g., 1, 1' - (azodicarbonyl) dipiperidine, etc.), and the like.As phosphines, for example, triarylphosphines (e.g., triphenylphosphine, etc.), tris (C), and the like can be used₁～C₄Alkyl) phosphines (e.g., tributylphosphine, etc.), and the like.

The solvent used in the production process 1-a is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide; and mixtures thereof, and the like.

The amount of the compound [ II ] used in the production process 1-a is not particularly limited, and is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ III ], and the amounts of the azo compound and the phosphine compound used are usually 1 to 3 moles, preferably 1 to 1.5 moles, based on 1 mole of the compound [ III ].

The reaction conditions such as the reaction temperature and the reaction time in the preparation method 1-a may vary depending on the reaction reagent and the reaction solvent used, and the reaction is usually carried out at-30 to 50 ℃ for 30 minutes to 10 hours.

Preparation method 1-b: when X is a halogen atom or a leaving group such as alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy, etc.), preparation 1-b is carried out in the presence of a base in a solvent in the same manner as preparation 1-a.

The base used in the production process 1-b is not particularly limited, and examples thereof include inorganic bases such as alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal hydride compounds (e.g., sodium hydride, potassium hydride, calcium hydride, etc.); and organic bases such as alkali metal alkoxides (for example, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) and amines (for example, triethylamine, diisopropylethylamine, etc.).

The amount of the compound [ II ] used in the production process 1-b is not particularly limited, and is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ III ], and the amount of the base used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ III ].

The reaction conditions such as the reaction temperature and the reaction time in the preparation method 1-b may vary depending on the reaction reagent and the reaction solvent used, and the reaction is usually carried out at-30 to 150 ℃ for 30 minutes to 10 hours.

In Process 1, the compound [ III ] is preferred]R of (A) to (B)¹In the case of lower alkyl. At this point R is obtained¹Compounds which are lower alkyl [ Ia]Which itself can be hydrolysed by known methods to give R¹Compound being hydrogen atom [ Ia]。

Further, in Process 1, the compound [ III]R of (A) to (B)⁶When is an amino protecting group, to give R⁶Compounds which are protecting groups for amino group [ Ia]Which may be deprotected by known methods to give R⁶Compound being hydrogen atom [ Ia]。

Preparation method 2

(in the formula, R¹、R³A, B and Y are as defined above, R⁷Represents an amino protecting group, R⁸Represents an alkyl group which may have a substituent, a cycloalkyl group, a cycloalkylalkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a heterocycloalkyl group which may have a substituent, and U represents a leaving group such as a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), or an alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), an arylsulfonyloxy (e.g., benzenesulfonyloxy, tolylsulfonyloxy, etc.), etc. )

Preparation 2 is that the general formula [ Ib]Compound (also referred to as Compound [ Ib ]]) Amino protecting group R of⁷Are removed by methods known per se to giveTo general formula [ Ic ]]Compound (also referred to as compound [ Ic ])]) By reacting it with a compound of the formula [ V ]]Compound (also referred to as Compound [ V ]]) Reaction to prepare the general formula [ Id]Compound (also referred to as Compound [ Id ]]) The preparation method of (1).

R⁸The definition of "alkyl group which may have substituents", "cycloalkyl group", "cycloalkylalkyl group", "aryl group which may have substituents", "arylalkyl group which may have substituents", "alkenyl group which may have substituents", "alkynyl group which may have substituents" and "heterocycloalkyl group which may have substituents" in (1) is defined as R²Are the same as defined above.

R⁷Amino protecting group of (1) with R⁶The amino protecting groups in (A) are defined identically.

In the preparation process 2, the reaction of the compound [ Ic ] with the compound [ V ] to obtain the compound [ Id ] is carried out in the presence of a base in a solvent which does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, etc., and a mixture thereof).

In the preparation method 2, the base used for the reaction of the compound [ Ic ] and the compound [ V ] is not particularly limited, and examples thereof include inorganic bases such as alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal hydride compounds (e.g., sodium hydride, potassium hydride, calcium hydride, etc.); and organic bases such as alkali metal alkoxides (for example, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) and amines (for example, triethylamine, diisopropylethylamine, etc.).

The amount of the compound [ V ] used in the preparation process 2 is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ], and the amount of the base used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ].

In the preparation method 2, the reaction conditions such as the temperature and the reaction time in the reaction of the compound [ Ic ] and the compound [ V ] may vary depending on the reaction reagent, the reaction solvent, and the like used, and the reaction is usually carried out at-30 to 150 ℃ for 30 minutes to 20 hours.

In Process 2, the compound [ Ib ] is preferred]R of (A) to (B)¹In the case of lower alkyl. At this point R is obtained¹Compounds which are lower alkyl [ Id]Which itself can be hydrolysed by known methods to give R¹Compound being hydrogen atom [ Id]。

Preparation method 3

(in the formula, R¹、R³、R⁴A, B and Y are as defined above)

Preparation method 3 is a method for producing a compound of the general formula [ Ie ] (also referred to as compound [ Ie ]) by reacting the compound [ Ic ] with a compound of the general formula [ VI ] (also referred to as compound [ VI ]).

In Process 3, the compound [ VI ] may be used not only in the form of a free acid but also in the form of a salt (e.g., sodium salt, potassium salt, calcium salt, triethylamine salt, pyridine salt, etc.) or a reactive derivative (e.g., acid halide such as acid chloride, acid bromide, etc., acid anhydride, mixed acid anhydride such as substituted phosphoric acid such as dialkylphosphoric acid, alkyl carbonate such as monoethyl carbonate, etc., activated amide of amide with imidazole, etc., ester such as cyanomethyl ester, 4-nitrophenyl ester, etc.), etc.

In addition, in the preparation method 3, when the compound [ VI ] is used in a free acid or salt state, the reaction is preferably carried out in the presence of a condensing agent, and as the condensing agent, for example, carbodiimide compounds such as N, N '-dicyclohexylcarbodiimide, 1-ethyl-3- (3' -dimethylaminopropyl) carbodiimide, N-cyclohexyl-N '-morpholinoethylcarbodiimide, and N-cyclohexyl-N' - (4-diethylaminocyclohexyl) carbodiimide; and dehydrating agents such as azo compounds such as N, N '-carbonyldiimidazole and N, N' -sulfinyldiimidazole. The amount of the condensing agent to be used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ]. When these condensing agents are used, it is considered that the compound [ VI ] forms a reactive derivative and reacts.

Process 3 is generally carried out in an inert solvent with respect to the reaction. Specific examples of the solvent include acetone, dioxane, acetonitrile, chloroform, benzene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, N-dimethylformamide, pyridine, water, and a mixed solvent thereof. In preparation method 3, a base such as triethylamine, pyridine, 4-dimethylaminopyridine or potassium carbonate can be used. When the base is used, it can be used in an amount of usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ].

The amount of the compound [ VI ] used in the preparation method 3 is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ].

In the preparation method 3, the reaction conditions such as the reaction temperature and the reaction time in the reaction of the compound [ VI ] and the compound [ Ic ] may vary depending on the reaction reagent, the reaction solvent, and the like used, and the reaction is usually carried out at-30 to 150 ℃ for 10 minutes to 10 hours.

In the preparation method 3, the compound [ Ie ] obtained by separating the compound [ VI ] after the reaction with the compound [ Ic ] can be further reduced to obtain the compound [ Ie' ]. The reduction reaction is carried out in the presence of a reducing agent in a solvent which does not inhibit the reaction (for example, water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or a mixture thereof).

The reducing agent used in the reduction reaction is not particularly limited as long as it is a reducing agent commonly used for reducing a carbonyl group to a methylene group, and examples thereof include metal hydrogen complexes (e.g., lithium aluminum hydride and sodium cyanoborohydride (NaBH)₃CN), sodium borohydride, etc.), borane, etc. The amount of the reducing agent used is based on1 mol of Compound [ Ie]Usually, the amount is 1 to 5 moles, preferably 1 to 3 moles.

The reaction conditions such as the reaction temperature and the reaction time in the reduction reaction may vary depending on the reaction reagent and the reaction solvent used, and the reaction is usually carried out at-30 to 150 ℃ for 30 minutes to 10 hours.

Preparation method 4

(in the formula, R¹、R²、R³、R⁵R B, X, Y and U are as defined above¹⁰Represents an amino protecting group. )

R¹⁰Amino protecting group of (1) with R⁶The amino protecting groups in (A) are defined identically.

Process for preparing heterocyclic compounds [ I ]]Wherein A is > N-R⁵The preparation method of (1). Is prepared by reacting a compound of the formula [ VII]Compound (also referred to as Compound [ VII ]]) And general formula [ VIII]Compound (also referred to as compound [ VIII ]]) The reaction was carried out in the same manner as in preparation Process 1 to obtain a compound of the formula [ IX]Compound (also referred to as Compound [ IX ])]) The amino protecting group R of the product¹⁰By removing according to known methods the compound of the formula [ X ] obtained]Compound (also referred to as Compound [ X ]]) And general formula [ XI ]]Compound (also referred to as Compound [ XI ]]) Reaction to prepare the general formula [ If]Compound (also referred to as Compound [ If ]]) The method of (1).

The reaction of the compound [ X ] and the compound [ XI ] in the process 4 can be carried out in a solvent which does not inhibit the reaction in the presence of a base. Examples of the solvent include dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide; and a mixture thereof, and when the compound [ XI ] can be used as a solvent, the compound [ XI ] can also be used as a solvent.

The base used in the reaction of the compound [ X ] and the compound [ XI ] in the preparation process 4 is not particularly limited, and examples thereof include inorganic bases such as alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal hydride compounds (e.g., sodium hydride, potassium hydride, calcium hydride, etc.); and organic bases such as alkali metal alkoxides (for example, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) and amines (for example, triethylamine, diisopropylethylamine, etc.). The amount of the base used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ X ].

The amount of the compound [ XI ] used in the process 4 is usually 1 to 5 mol, preferably 1 to 3 mol, based on 1 mol of the compound [ X ].

In the preparation method 4, the reaction conditions such as the reaction temperature and the reaction time in the reaction of the compound [ X ] and the compound [ XI ] may vary depending on the reaction reagent, the reaction solvent, and the like used, and the reaction is usually carried out at-30 to 150 ℃ for 30 minutes to 10 hours.

Preparation method 5

(in the formula, R¹、R³R A, B and Y are as defined above⁹represents-CH₂-R⁹The group represented by (a) represents an alkyl group which may have a substituent(s), a cycloalkylalkyl group, an arylalkyl group which may have a substituent(s), an alkenyl group which may have a substituent(s), an alkynyl group which may have a substituent(s), or a heterocycloalkyl group which may have a substituent(s). )

The production process 5 is a process for producing a compound of the general formula [ Ig ] (also referred to as a compound [ Ig ]) by reacting a compound of the general formula [ Ic ] with a compound of the general formula [ XII ] (also referred to as a compound [ XII ]).

Formula (II): -CH₂-R⁹The "alkyl group which may have a substituent", "cycloalkylalkyl group", "may have a substituent" in the groups shownDefinitions of "arylalkyl" which may have substituents "," alkenyl "which may have substituents", "alkynyl" which may have substituents and "heterocycloalkyl" which may have substituents are defined with R²Are the same as defined above.

Preparation 5 is a method in which condensation is carried out in the presence of a reducing agent in a solvent which does not inhibit the reaction of compound [ Ic ] and compound [ XII ] (for example, water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or the like, or a mixture thereof).

The reducing agent used in preparation method 5 is not particularly limited, and examples thereof include metal hydrogen complexes (e.g., lithium aluminum hydride, sodium cyanoborohydride (NaBH)₃CN), sodium borohydride, etc.), borane, etc.

The amount of the compound [ XII ] used in the preparation process 5 is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ], and the amount of the reducing agent used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound [ Ic ].

The reaction conditions such as the reaction temperature and the reaction time in the preparation method 5 may vary depending on the reaction reagent and the reaction solvent used, and the reaction is usually carried out at-30 to 150 ℃ for 30 minutes to 10 hours.

The heterocyclic compound [ I ] obtained by the above-mentioned production processes 1 to 5 can be isolated by a conventional method, and if necessary, can be purified by a conventional method, for example, recrystallization, separation thin layer chromatography, column chromatography, etc. Further, if necessary, it may be purified in the form of a salt.

The heterocyclic compound [ I ] can be converted into a pharmaceutically acceptable salt by a method known per se.

In the pharmaceutical composition containing the heterocyclic compound [ I ] or a pharmaceutically acceptable salt thereof of the present invention, additives and the like may be mixed. Examples of the additives include excipients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), and disintegrants (e.g., carboxymethyl cellulose calcium, talc, etc.).

After mixing the above components, the mixture can be prepared into oral preparations such as capsules, tablets, fine granules, and oral syrups, or non-oral preparations such as injections and suppositories by a method known in the art.

The dosage of the heterocyclic compound [ I ] or a pharmaceutically acceptable salt thereof varies depending on the subject to be administered, symptoms, and other factors, but for example, in the case of oral administration to an adult in a patient with diabetes, diabetic complications, or hyperlipidemia, the dosage is about 1 to 500mg/kg body weight 1 time and about 1 to 3 times per day.

The heterocyclic compound [ I ] of the present invention and a pharmaceutically acceptable salt thereof exhibit excellent hypoglycemic activity, hypolipidemic activity, insulin resistance-improving activity and PPAR-activating activity in mammals (humans, cows, horses, dogs, cats, rats, mice, hamsters and the like), and are useful as antihyperglycemic agents, antihyperlipidemic agents, insulin resistance-improving agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, glucose tolerance-improving agents, anti-arteriosclerosis agents, anti-obesity agents, anti-inflammatory agents, prophylactic/therapeutic agents for PPAR-mediated diseases and prophylactic/therapeutic agents for X syndrome. That is, the heterocyclic compound [ I ] and a pharmaceutically acceptable salt thereof of the present invention are effective in the prevention and treatment of diabetes, diabetic complications, hyperlipidemia, arteriosclerosis, hyperglycemia, diseases caused by insulin-resistant glucose-resistant insufficiency, diseases caused by insulin resistance, obesity, inflammation, PPAR-mediated diseases, and syndrome X.

Examples

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid sodium salt

(1) 2-tert-Butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 1.50g and 2- (5-methyl-2-phenyloxazol-4-yl) ethanol methanesulfonate 2.50g were dissolved in N, N-dimethylformamide 20ml, and thereto was added potassium carbonate 2.0g, followed by stirring at 80 ℃ for 5 hours. To the reaction mixture was added 100ml of ethyl acetate, washed with 100ml of water and 50ml of saturated saline, and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-tert-butyloxycarbonyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy ] ethyl]-1.62 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-tert-butoxycarbonyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1；2978，2930，1738，1699，1614，1587。

¹H-NMR(CDCl₃)δ(ppm)；

1.29(3H，t，J＝7.0Hz)，1.46，1.50(9H，s，s)，2.36(3H，s)，

2.95(2H，t，J＝6.8Hz)，2.90-3.30(2H，m)，4.00-4.40(4H，m)，

4.51，4.61(2H，s，s)，4.70-4.90，5.00-5.20(1H，m，m)，

6.60-6.90(2H，m)，7.12(1H，d，J＝8.4Hz)，

7.30-7.55(3H，m)，7.90-8.15(2H，m)。

(2) 5.2g of the compound obtained in the above (1) was dissolved in 20ml of formic acid, and 6.0ml of a solution of hydrogen chloride in 8.78N-2-propanol was added thereto under ice cooling, followed by stirring at room temperature for 10 minutes. To the direction ofTo the reaction mixture was added 100ml of ethyl acetate, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by separation of the two layers. The ethyl acetate layer was washed with 50ml of saturated saline and dried (Na)₂SO₄). Distilling off ethyl acetate under reduced pressure to obtain 7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy ] ethyl]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 3.6 g.

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；3476，1742，1639，1611，1553。

¹H-NMR(CDCl₃)δ(ppm)；

1.29(3H，t，J＝7.0Hz)，2.02(1H，s)，2.36(3H，s)，2.80-3.10(4H，m)，

3.50-3.80(1H，m)，4.00-4.40(6H，m)，6.50-6.80(2H，m)，

7.00(1H，d，J＝8.4Hz)，7.30-7.50(3H，m)，7.90-8.10(2H，m)。

(3) 1.11g of the compound obtained in the above (2) was dissolved in 20ml of methanol, and 3.0ml of a 1N aqueous solution of sodium hydroxide was added thereto, followed by stirring at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, 5ml of water was added to the resulting crystalline residue, and the crystals were filtered to obtain 0.92g of the title compound.

IR v (liquid Paraffin) cm^-1；3427，1589，1504。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.35(3H，s)，2.60-3.10(6H，m)，3.86(2H，br-s)，4.14(2H，t，J＝6.6Hz)，

6.50-6.80(2H，m)，6.94(1H，d，J＝8.1Hz)，7.40-7.60(3H，m)，

7.75-8.05(2H，m)。

Example 2

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.40g of the compound obtained in example 1(2) was dissolved in 20ml of N, N-dimethylformamide, and 160mg of sodium hydride (60% oil suspension) was added under ice-cooling. After stirring at room temperature for 20 minutes, 0.40ml of benzyl bromide was added dropwise thereto, and the mixture was further stirred at the same temperature for 1 hour. To the reaction mixture was added 50ml of ethyl acetate, which was washed with 50ml of water and 30ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1.38 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1728，1639，1614，1551。

¹H-NMR(CDCl₃)δ(ppm)；

1.21(3H，t，J＝7.0Hz)，2.34(3H，s)，2.92(2H，t，J＝7.0Hz)，

3.05-3.20(2H，m)，3.60-4.00(5H，m)，4.12(2H，q，J＝7.0Hz)，

4.16(2H，t，J＝7.0Hz)，6.51(1H，d，J＝2.0Hz)，

6.68(1H，dd，J＝2.0，8.4Hz)，6.99(1H，d，J＝8.4Hz)，

7.30-7.50(8H，m)，7.80-8.10(2H，m)。

(2) 8.20g of the compound obtained in the above (1) was dissolved in 80ml of a tetrahydrofuran-methanol (3: 1) mixed solution, 42ml of a 2N lithium hydroxide aqueous solution was added thereto, and the mixture was stirred at 50 ℃ for 2 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered. The resulting crude crystals 9.0g were recrystallized from methanol to obtain the title compound 6.33 g.

IR v (liquid Paraffin) cm^-1；1638，1501。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.33(3H，s)，2.65-3.30(4H，m)，3.50-4.00(5H，m)，4.00-6.20(1H，br)，

4.13(2H，t，J＝7.0Hz)，6.59(1H，br-s)，6.68(1H，br-d，J＝8.4Hz)，

7.01(1H，d，J＝8.4Hz)，7.32(5H，s)，7.35-7.70(3H，m)，

7.85-8.10(2H，m)。

Example 3

2-acetyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 800mg of the compound obtained in example 1(2) was dissolved in 8.0ml of methylene chloride, and 0.23ml of acetic anhydride was added thereto under ice cooling. Stir at room temperature for 10 minutes. To the reaction mixture was added 30ml of ethyl acetate, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by separation of the two layers. The resulting organic layer was washed with 10ml of saturated saline and dried (Na)₂SO₄) Thereafter, the solvent was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-acetyl-7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy ] ethyl]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 873 mg.

2-acetyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1732，1651，1555。

¹H-NMR(CDCl₃)δ(ppm)；

1.12(3H，t，J＝7.0Hz)，2.13，2.21(3H，s，s)，2.36(3H，s)，

2.95(2H，t，J＝6.6Hz)，3.05-3.30(2H，m)，4.04(2H，q，J＝7.0Hz)，

4.22(2H，t，J＝6.6Hz)，4.62(2H，s)，5.45(1H，dd，J＝4.0，5.7Hz)，

6.55-6.85(2H，m)，7.04(1H，d，J＝8.2Hz)，7.30-7.50(3H，m)，

7.85-8.10(2H，m)。

(2) 800mg of the compound obtained in the above (1) was dissolved in 5.0ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 3.0ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystal was filtered to obtain 668mg of the title compound.

IR v (liquid Paraffin) cm^-1；3400，1732，1641，1612，1555。

¹H-NMR(CDCl₃)δ(ppm)；

2.10，2.17(3H，s，s)，2.32(3H，s)，2.70-3.30(4H，m)，

3.90-4.20(2H，m)，4.30-4.90(2H，m)，5.35-5.60(1H，m)，

6.50-6.80(2H，m)，7.03(1H，d，J＝8.1Hz)，7.30-7.60(3H，m)，

7.80-8.10(2H，m)。

Example 4

2-methyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.0g of the compound obtained in example 1(2) was dissolved in 10ml of methanol, and 0.4ml of formalin and 310mg of sodium cyanoborohydride were added thereto, followed by stirring at room temperature for 1 hour. The methanol was evaporated under reduced pressure, and 20ml of ethyl acetate was added thereto, followed by washing with 20ml of water and 10ml of saturated saline and drying (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-methyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1.08 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-methyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；2926，2874，1732，1641，1614。

¹H-NMR(CDCl₃)δ(ppm)；

1.25(3H，t，J＝7.0Hz)，2.35(3H，s)，2.50(3H，s)，

2.94(2H，t，J＝6.8Hz)，3.02(2H，d，J＝6.0Hz)，3.45(1H，t，J＝6.0Hz)，

3.64(1H，d，J＝15.6Hz)，3.98(1H，d，J＝15.6Hz)，4.17(2H，q，J＝7.0Hz)，

4.20(2H，t，J＝6.6Hz)，6.56(1H，d，J＝2.0Hz)，

6.70(1H，dd，J＝2.0，8.4Hz)，6.98(1H，d，J＝8.4Hz)，

7.30-7.50(3H，m)，7.85-8.10(2H，m)。

(2) 1.08g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 7.5ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.74g of the title compound.

IR v (liquid Paraffin) cm^-1；1616，1555，1541，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.36(3H，s)，2.55(3H，s)，2.70-3.10(4H，m)，3.40-3.60(1H，m)，

3.70-4.30(4H，m)，6.60-6.80(2H，m)，7.05(1H，d，J＝8.6Hz)，

7.35-7.65(3H，m)，7.75-8.10(2H，m)。

Example 5

2-hexanoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.0g of the compound obtained in example 1(2) was dissolved in 10ml of methylene chloride, and 0.41ml of hexanoyl chloride and 0.51ml of triethylamine were added thereto under ice cooling, followed by stirring at the same temperature for 10 minutes. To the reaction mixture was added 70ml of ethyl acetate, followed by washing and drying (Na) with 50ml of a 10% citric acid aqueous solution, 50ml of a saturated sodium bicarbonate aqueous solution, and 50ml of a saturated saline solution in this order₂SO₄) Thereafter, the solvent was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-hexanoyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1.02 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-hexanoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1736，1653，1587。

¹H-NMR(CDCl₃)δ(ppm)；

0.70-1.90(12H，m)，2.20-2.60(2H，m)，2.36(3H，s)，

2.95(2H，t，J＝6.8Hz)，3.10-3.20(2H，m)，4.04(2H，q，J＝7.0Hz)，

4.22(2H，t，J＝7.0Hz)，4.63(2H，s)，5.45(1H，dd，J＝4.0，5.4Hz)，

6.60-6.90(2H，m)，7.04(1H，d，J＝8.1Hz)，7.30-7.50(3H，m)，

7.80-8.10(2H，m)。

(2) 1.02g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 6.0ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.56g of the title compound.

IR v (liquid Paraffin) cm^-1；1742，1641，1612，1572。

¹H-NMR(CDCl₃)δ(ppm)；

0.88(3H，br-t，J＝6.0Hz)，1.10-1.90(6H，m)，2.32(3H，s)，

2.30-2.50(2H，m)，2.70-3.30(4H，m)，4.07(2H，t，J＝7.0Hz)，

4.60(2H，s)，5.40-5.60(1H，m)，6.60-6.80(2H，m)，

7.05(1H，d，J＝8.6Hz)，7.35-7.65(3H，m)，7.75-8.10(2H，m)。

Example 6

2-hexyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.20g of the compound obtained in example 1(2) was dissolved in 12ml of N, N-dimethylformamide, and 0.65ml of hexyl iodide and 0.82g of potassium carbonate were added thereto, followed by stirring at 50 ℃ for 15 hours. 100ml of water was added to the reaction mixture, which was then extracted 2 times with 50ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-hexyl-7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy]-1.05 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-hexyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1724，1643，1611。

¹H-NMR(CDCl₃)δ(ppm)；

0.88(3H，br-t，J＝5.0Hz)，1.10-1.75(11H，m)，2.35(3H，s)，

2.50-2.80(2H，m)，2.94(2H，t，J＝7.0Hz)，3.02(2H，d，J＝5.5Hz)，

3.68(1H，t，J＝5.5Hz)，3.83(1H，s)，3.94(1H，s)，

4.12(2H，q，J＝7.0Hz)，4.20(2H，t，J＝7.0Hz)，6.50-6.80(2H，m)，

6.97(1H，d，J＝8.4Hz)，7.30-7.60(3H，m)，7.80-8.10(2H，m)。

(2) 1.0g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 5.1ml of a 2N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 11 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.80g of the title compound.

IR v (liquid Paraffin) cm^-1；1620，1555，1506。

¹H-NMR(CDCl₃)δ(ppm)；

0.89(3H，br-t，J＝6.0Hz)，1.00-1.45(6H，m)，1.50-1.90(2H，m)，

2.36(3H，s)，2.70-3.30(2H，m)，2.93(2H，t，J＝6.2Hz)，

3.15(2H，d，J＝6.4Hz)，3.75(1H，t，J＝6.4Hz)，4.00-4.40(4H，m)，

6.23(1H，br-s)，6.60-6.85(2H，m)，7.06(1H，d，J＝8.4Hz)，

7.30-7.60(3H，m)，7.80-8.10(2H，m)。

Example 7

2-isobutyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.40g of the compound obtained in example 1(2) was dissolved in 14ml of N, N-dimethylformamide, and 1.20ml of isobutyliodide and 0.95g of potassium carbonate were added thereto and the mixture was stirred at 50 ℃ for 3 days. 100ml of water was added to the reaction mixture, which was then extracted 2 times with 50ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-isobutyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy ] ethyl]-1.15 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-isobutyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1719，1645，1614，1506。

¹H-NMR(CDCl₃)δ(ppm)；

0.89(6H，d，J＝6.6Hz)，1.19(3H，t，J＝7.0Hz)，1.70-1.90(1H，m)，

2.35(3H，s)，2.10-2.50(2H，m)，2.94(2H，t，J＝7.0Hz)，

3.02(2H，d，J＝5.2Hz)，3.66(1H，t，J＝5.2Hz)，3.83(1H，s)，

3.92(1H，s)，4.16(2H，q，J＝7.0Hz)，4.20(2H，t，J＝7.0Hz)，

6.45-6.75(2H，m)，6.97(1H，d，J＝8.2Hz)，7.25-7.50(3H，m)，

7.85-8.10(2H，m)。

(2) 1.05g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 5.7ml of a 2N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, the acidity was adjusted with citric acid, and the precipitated crystals were filtered to obtain 0.83g of the title compound.

IR v (liquid Paraffin) cm^-1；3339，1620，1553，1508。

¹H-NMR(CDCl₃)δ(ppm)；

0.95(3H，d，J＝6.7Hz)，1.01(3H，d，J＝7.0Hz)，1.95-2.15(1H，m)，

2.36(3H，s)，2.60-2.80(2H，m)，2.94(2H，t，J＝6.7Hz)，

3.16(2H，d，J＝6.6Hz)，3.70(1H，t，J＝6.6Hz)，4.11(2H，s)，

4.18(2H，t，J＝6.6Hz)，4.84(1H，br-s)，6.60-6.90(2H，m)，

7.49(1H，d，J＝8.1Hz)，7.25-7.50(3H，m)，7.85-8.10(2H，m)。

Example 8

2-cyclohexylmethyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2， 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.40g of the compound obtained in example 1(2) was dissolved in 14ml of N, N-dimethylformamide, and 1.44ml of cyclohexylmethyl bromide and 0.95g of potassium carbonate were added thereto, followed by stirring at 50 ℃ for 2 days. 100ml of water was added to the reaction mixture, which was then extracted 2 times with 50ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-cyclohexylmethyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1.0 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-cyclohexylmethyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1728，1638，1614，1504。

¹H-NMR(CDCl₃)δ(ppm)；

0.80-2.00(11H，m)，1.19(3H，t，J＝7.0Hz)，2.36(3H，s)，

2.40-2.55(2H，m)，2.94(2H，t，J＝7.1Hz)，3.00(2H，d，J＝5.3Hz)，

3.65(1H，t，J＝5.3Hz)，3.82(1H，s)，3.92(1H，s)，

4.05(2H，t，J＝7.0Hz)，4.16(2H，q，J＝7.0Hz)，6.50-6.80(2H，m)，

6.97(1H，d，J＝8.1Hz)，7.30-7.50(3H，m)，7.80-8.10(2H，m)。

(2) 0.95g of the compound obtained in the above (1) was dissolved in 28ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 7.13ml of a 2N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 3 days. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.76g of the title compound.

IR v (liquid Paraffin) cm^-1；3319，1624，1506。

¹H-NMR(CDCl₃)δ(ppm)；

0.70-2.10(11H，m)，2.36(3H，s)，2.40-2.55(2H，m)，

2.93(2H，t，J＝6.4Hz)，3.16(2H，d，J＝7.2Hz)，3.70(1H，t，J＝7.2Hz)，

4.00-4.30(4H，m)，5.30(1H，br-s)，6.60-6.90(2H，m)，

7.08(1H，d，J＝8.4Hz)，7.30-7.50(3H，m)，7.80-8.10(2H，m)。

Example 9

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- (3-phenylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.40g of the compound obtained in example 1(2) was dissolved in 14ml of N, N-dimethylformamide, and 0.78ml of 3-phenylpropyl bromide and 0.95g of potassium carbonate were added thereto, followed by stirring at 50 ℃ for 22 hours. 100ml of water was added to the reaction mixture, which was then extracted 2 times with 50ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy ] ethyl]-2- (3-phenylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 1.05 g.

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (3-phenylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1720，1647，1612，1504。

¹H-NMR(CDCl₃)δ(ppm)；

1.17(3H，t，J＝7.0Hz)，1.60-2.05(2H，m)，2.35(3H，s)，

2.50-2.80(4H，m)，2.94(2H，t，J＝7.1Hz)，3.04(2H，d，J＝5.7Hz)，

3.67(1H，t，J＝5.7Hz)，3.84(1H，s)，3.94(1H，s)，

4.04(2H，t，J＝7.1Hz)，4.16(2H，q，J＝7.0Hz)，6.50-6.80(2H，m)，

7.07(1H，d，J＝9.0Hz)，7.20(5H，s)，7.10-7.50(3H，m)，

7.80-8.10(2H，m)。

(2) 1.0g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, 4.77ml of a 2N lithium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.66g of the title compound.

IR v (liquid Paraffin) cm^-1；3346，1616，1556，1506。

¹H-NMR(CDCl₃)δ(ppm)；

1.70-2.20(3H，m)，2.35(3H，s)，2.40-2.70(4H，m)，2.70-3.30(2H，m)，

2.92(2H，t，J＝6.3Hz)，3.10(2H，d，J＝7.0Hz)，3.65(1H，t，J＝7.0Hz)，

3.90-4.30(4H，m)，5.12(1H，br-s)，6.55-6.80(2H，m)，

6.90-7.25(6H，m)，7.25-7.55(3H，m)，7.80-8.10(2H，m)。

Example 10

2-benzoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.4g of the compound obtained in example 1(2) was dissolved in 14ml of methylene chloride, and 0.48ml of benzoyl chloride and 0.72ml of triethylamine were added thereto under ice cooling, followed by stirring at the same temperature for 15 minutes. To the reaction mixture was added 100ml of ethyl acetate, followed by washing and drying with 50ml of a 10% aqueous citric acid solution, 50ml of a saturated aqueous sodium bicarbonate solution and 50ml of a saturated saline solution in this order (Na)₂SO₄) Thereafter, the solvent was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzoyl-7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy]-1.16 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzoyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1734，1638，1612，1591。

¹H-NMR(CDCl₃)δ(ppm)；

0.75-1.15(3H，m)，2.35(3H，s)，2.93(2H，t，J＝6.6Hz)，

3.05-3.25(2H，m)，3.85-4.40(4H，m)，4.20-4.80(2H，m)，

5.00-5.60(1H，m)，6.47(1H，br-s)，6.72(1H，br-d，J＝8.4Hz)，

7.05(1H，br-d，J＝8.4Hz)，7.30-7.60(8H，m)，

7.80-8.10(2H，m)。

(2) 1.0g of the compound obtained in the above (1) was dissolved in 10ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 6.0ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and 20ml of water was added thereto, followed by washing with 10ml of ethyl acetate. The resulting aqueous layer was acidified with 6N hydrochloric acid and extracted with 20ml of diethyl ether 2 times. The ether layer was washed with 30ml of saturated brine and dried (Na)₂SO₄) Thereafter, diethyl ether was distilled off under reduced pressure. The resulting residue was recrystallized from methanol to obtain 0.75g of the title compound.

IR v (liquid Paraffin) cm^-1；1730，1636，1551。

¹H-NMR(CDCl₃)δ(ppm)；

2.32(3H，s)，2.87(2H，t，J＝6.4Hz)，3.00-3.35(2H，m)，

4.02(2H，t，J＝6.4Hz)，4.40-4.90(2H，m)，4.90-5.30(1H，br)，

5.00-5.65(1H，m)，6.40(1H，br-s)，6.50-6.80(1H，m)，

7.03(1H，d，J＝8.4Hz)，7.20-7.60(8H，m)，7.75-8.05(2H，m)。

Example 11

2-benzyl-7- [2- (N-methyl-N- (pyridin-2-yl) amino) ethoxy ] ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

(1) 2-benzyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 1.38g dissolved in N, N-dimethylformamide 10ml in iceWhile cooling, 210mg of sodium hydride (60% oil suspension) were added. After stirring at room temperature for 30 minutes, 1.30g of 2- (N-t-butoxycarbonyl-N-methylamino) ethanol methanesulfonate was added thereto, and the mixture was further stirred at the same temperature for 1 hour. To the reaction mixture was added 50ml of ethyl acetate, which was washed with 50ml of water and 30ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzyl-7- [2- (N-tert-butoxycarbonyl-N-methylamino) ethoxy ] ethanol]-1.44 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzyl-7- [2- (N-tert-butoxycarbonyl-N-methylamino) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1；2978，2932，1732，1695，1614。

¹H-NMR(CDCl₃)δ(ppm)；

1.23(3H，t，J＝7.0Hz)，1.44(9H，s)，2.95(3H，s)，

3.08(2H，d，J＝4.9Hz)，3.54(2H，t，J＝5.5Hz)，3.60-4.30(7H，m)，

6.50(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.1Hz)，

7.01(1H，d，J＝8.1Hz)，7.20-7.50(5H，m)。

(2) 1.44g of the compound obtained in the above (1) was dissolved in 7.0ml of formic acid, and 2.0ml of a solution of hydrogen chloride in 8.78N-2-propanol was added thereto, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 100ml of ethyl acetate, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by separation of the two layers. The ethyl acetate layer was washed with 50ml of saturated saline and dried (Na)₂SO₄). Ethyl acetate was distilled off under reduced pressure to give 1.08g of 2-benzyl-7- (2-methylaminoethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester.

2-benzyl-7- (2-methylaminoethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1 ；3332，1732，1612，1504。

¹H-NMR(CDCl₃)δ(ppm)；

1.22(3H，t，J＝7.0Hz)，2.41(1H，br-s)，2.49(3H，s)，

2.95(2H，t，J＝5.5Hz)，3.08(2H，d，J＝4.9Hz)，3.60-4.25(7H，m)，

6.52(1H，d，J＝2.0Hz)，6.70(1H，dd，J＝2.0，8.4Hz)，

7.00(1H，d，J＝8.4Hz)，7.20-7.50(5H，m)。

(3) 1.05g of the compound obtained in the above (2) was dissolved in 2.0ml of 2-chloropyridine, and the mixture was stirred at 140 ℃ for 16 hours. The reaction liquid was purified by silica gel column chromatography to obtain 0.5g of ethyl 2-benzyl-7- [2- (N-methyl-N- (pyridin-2-yl) amino) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzyl-7- [2- (N-methyl-N- (pyridin-2-yl) amino) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1；2932，2905，1732，1597，1560，1504。

¹H-NMR(CDCl₃)δ(ppm)；

1.22(3H，t，J＝7.0Hz)，3.06(2H，d，J＝6.2Hz)，3.11(3H，s)，

3.60-4.30(11H，m)，6.40-6.80(4H，m)，6.97(1H，d，J＝8.4Hz)，

7.20-7.50(6H，m)，8.00-8.20(1H，m)。

(4) 488mg of the compound obtained in the above (3) was dissolved in 5.0ml of a mixed solution of tetrahydrofuran-methanol (3: 1), 2.2ml of a 1N lithium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, 10ml of water was added thereto, the mixture was saturated with sodium chloride, and the mixture was extracted 3 times with 30ml of ethyl acetate. Ethyl acetateThe layer was washed with 10ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. To the resulting residue was added diethyl ether, and the solid was filtered to give the title compound 356 mg.

IR v (liquid Paraffin) cm^-1；1597，1497。

¹H-NMR(MeOH-d₄)δ(ppm)；

2.95-3.20(2H，m)，3.07(3H，s)，3.40-4.20(9H，m)，

6.40-6.70(4H，m)，6.92(1H，d，J＝8.4Hz)，7.20-7.50(3H，m)，

7.90-8.15(1H，m)。

Example 12

2-benzyl-7- [2- (5-ethyl-pyridin-2-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid sodium salt

(1) 2-benzyl-7-hydroxy-1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid ethyl ester 1.0g dissolved in N, N-two methyl formamide 10ml, under ice cooling conditions added sodium hydride (60% oil suspension) 200mg, at room temperature stirring for 30 minutes, solution (A). In another aspect, 1.5g of 5-ethyl-2-pyridineethanol and 1.68ml of triethylamine are dissolved in 40ml of dichloromethane. 2.0ml of trifluoromethanesulfonic anhydride was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with 30ml of water and dried (Na)₂SO₄) The methylene chloride was distilled off under reduced pressure. 2.81g of the obtained 2- (5-ethylpyridin-2-yl) ethyl trifluoromethanesulfonate was added to the foregoing solution (A), and stirred at room temperature for 30 minutes. To the reaction mixture was added 100ml of ethyl acetate, which was washed with 50ml of water and 50ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzyl-7- [2- (5-ethyl-pyridin-2-yl) ethoxy ] ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester 0.58 g.

2-benzyl-7- [2- (5-ethyl-pyridin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1732，1612，1504。

¹H-NMR(CDCl₃)δ(ppm)；

1.22(6H，t，J＝7.2Hz)，2.61(2H，q，J＝7.2Hz)，3.07(2H，d，J＝5.5Hz)，

3.18(2H，t，J＝6.6Hz)，3.72(1H，t，J＝5.5Hz)，3.81(1H，s)，

3.90(4H，s)，4.13(2H，q，J＝7.2Hz)，4.27(2H，t，J＝6.6Hz)，

6.51(1H，d，J＝2.0Hz)，6.69(1H，dd，J＝2.0，8.4Hz)，

6.98(1H，d，J＝8.4Hz)，7.10-7.50(7H，m)，8.00-8.20(1H，m)。

(2) 0.94g of the compound obtained in the above (1) was dissolved in 40ml of a tetrahydrofuran-methanol (3: 1) mixed solution, 6.0ml of a 2N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at 40 ℃ for 2 hours. The solvent was distilled off under reduced pressure, 10ml of water was added thereto, and the mixture was saturated with sodium chloride, followed by extraction with 30ml of ethyl acetate 3 times. The ethyl acetate layer was washed with 10ml of saturated saline (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. To the resulting residue was added isopropyl ether, and the solid was filtered to obtain 0.58g of the title compound.

IR v (liquid Paraffin) cm^-1；1576，1504。

¹H-NMR(MeOH-d₄)δ(ppm)；

1.22(6H，t，J＝7.5Hz)，2.63(2H，q，J＝7.5Hz)，2.90-3.20(4H，m)，

3.72(1H，s)，3.85(1H，s)，3.95-4.35(5H，m)，4.27(2H，t，J＝6.6Hz)，

6.40-6.75(2H，m)，6.91(1H，d，J＝8.4Hz)，7.20-7.65(7H，m)，

8.20-8.35(1H，m)。

Example 13

2-benzyl-7- [2- (indolin-1-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid

(1) 2-benzyl-7-hydroxy-1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid ethyl ester 1.0g dissolved in N, N-two methyl formamide 10ml, under ice cooling conditions to add sodium hydride (60% oil suspension) 154mg, at the same temperature stirring for 30 minutes, then added 1- (2-bromoethyl) indoline 1.09g, then stirred at room temperature for 2 hours. To the reaction mixture was added 100ml of ethyl acetate, washed with 100ml of water and 50ml of saturated saline solution and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzyl-7- [2- (indolin-1-yl) ethoxy ] ethanol]-1.18 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzyl-7- [2- (indolin-1-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1；2926，2843，1732，1609，1493。

¹H-NMR(CDCl₃)δ(ppm)；

1.22(3H，t，J＝7.2Hz)，2.95(2H，t，J＝8.3Hz)，3.08(2H，d，J＝5.3Hz)，

3.20-3.60(3H，m)，3.60-4.30(10H，m)，6.40-6.80(4H，m)，

6.80-7.20(3H，m)， 7.20-7.50(5H，m)。

(2) 1.17g of the compound obtained in the above (1) was dissolved in 24ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 7.69ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at 50 ℃ for 1 hour. The solvent was evaporated under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered to obtain 0.93g of the title compound.

IR v (liquid Paraffin) cm^-1；1634，1609，1491。

¹H-NMR(CDCl₃)δ(ppm)；

2.95(2H，br-t，J＝8.2Hz)，3.16(2H，br-d，J＝6.1Hz)，3.25-3.60(3H，m)，

3.60-4.40(8H，m)，4.07(2H，s)，4.10(2H，t，J＝5.5Hz)，

4.13(2H，q，J＝7.2Hz)，5.60-6.30(1H，br)，6.30-6.85(4H，m)，

6.85-7.20(3H，m)，7.32(5H，s)。

Example 14

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester

10.0g of ethyl 2-benzyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate and 18.01g of 2- (5-methyl-2-phenyl-oxazol-4-yl) ethanol methanesulfonate were dissolved in 200ml of N, N-dimethylformamide, and 13.3g of potassium carbonate was added to the solution, followed by stirring at 80 ℃ for 10 hours. 1L of water was added to the reaction mixture, which was extracted 2 times with 200ml of ethyl acetate. The ethyl acetate layer was washed with 500ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7.06g of the title compound.

The IR and NMR spectra were in accordance with example 2 (1).

Example 15

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid methyl ester

(1) Dissolving 15.16g of methyl 2-tert-butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate and 20.0g of 2- (5-methyl-2-phenyloxazol-4-yl) ethanol methanesulfonate in 300ml of N, N-dimethylformamide, adding 19.7g of potassium carbonate, and dissolving the mixture in 80g of dimethylformamideStirring at deg.C for 3.5 hr. 1L of water was added to the reaction mixture, which was then extracted 2 times with 300ml of ethyl acetate. The ethyl acetate layer was washed with 500ml of saturated saline and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-tert-butyloxycarbonyl-7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy ] ethyl]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester 14.0 g.

2-tert-butoxycarbonyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester:

¹H-NMR(CDCl₃)δ(ppm)；

1.46，1.50(9H，s，s)，2.36(3H，s)，2.95(2H，t，J＝6.8Hz)，

2.90-3.30(2H，m)，3.60(3H，s)，4.21(2H，t，J＝6.8Hz)，

4.50，4.60(2H，s，s)，4.70-4.90，5.00-5.20(1H，m，m)，

6.60-6.90(2H，m)，7.12(1H，d，J＝8.4Hz)，7.30-7.55(3H，m)，

7.90-8.15(2H，m)。

(2) 14.0g of the compound obtained in the above (2) was dissolved in 42ml of formic acid, and 10.7ml of a solution of hydrogen chloride in 8.78N-2-propanol was added under ice cooling, followed by stirring at room temperature for 20 minutes. To the reaction mixture were added 300ml of ethyl acetate and 500ml of water, followed by neutralization with an aqueous sodium bicarbonate solution and separation of the two layers. The ethyl acetate layer was washed with 500ml of saturated saline and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 9.4g of the title compound.

IR v (liquid Paraffin) cm^-1；3560，1744，1643，1612，1578，1553，1504。

¹H-NMR(CDCl₃)δ(ppm)；

1.92(1H，s)，2.36(3H，s)，2.80-3.20(4H，m)，3.60-3.85(1H，m)，

3.76(3H，s)，4.04(2H，s)，4.21(2H，t，J＝6.6Hz)，

6.57(1H，d，J＝2.0Hz)，6.71(1H，dd，J＝2.0，8.6Hz)，

7.00(1H，d，J＝8.6Hz)，7.30-7.60(3H，m)，7.85-8.15(2H，m)。

Example 16

2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 800mg of the compound produced in example 15 was dissolved in 8ml of N, N-dimethylformamide, 96mg of sodium hydride (60% oil suspension) was added under ice cooling, and after stirring at room temperature for 30 minutes, 0.41ml of 4-methoxybenzyl chloride was added dropwise and further stirred at 50 ℃ for 3 hours. To the reaction mixture was added 50ml of ethyl acetate, which was washed with 50ml of water and 30ml of saturated saline solution, and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester 0.82 g.

2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester:

IR v (liquid Paraffin) cm^-1；1736，1638，1614，1553，1514

¹H-NMR(CDCl₃)δ(ppm)；

2.35(3H，s)，2.93(2H，t，J＝6.6Hz)，3.05(2H，d，J＝5.5Hz)，

3.66(3H，s)，3.70-4.00(8H，m)，4.17(2H，t，J＝6.6Hz)，

6,50(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.6Hz)，

6.85(2H，d，J＝8.6Hz)，6.98(1H，d，J＝8.6Hz)，7.28(2H，d，J＝8.6Hz)，

7.30-7.50(3H，m)，7.80-8.10(2H，m)。

(2) 450mg of the compound obtained in the above (1) was dissolved in 10ml of a mixed solution of tetrahydrofuran-methanol (3: 1), 2.5ml of a 2N aqueous lithium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered. The title compound was obtained in an amount of 350 mg.

IR v (liquid Paraffin) cm^-1；3288，1612，1555，1514。

¹H-NMR(CDCl₃)δ(ppm)；

2.35(3H，s)，2.93(2H，t，J＝6.4Hz)，3.18(2H，d，J＝6.8Hz)，

3.70-4.10(5H，m)，3.77(3H，s)，4.17(2H，t，J＝6.4Hz)，4.50(1H，br-s)，

6.60(1H，d，J＝2.0Hz)，6.65-6.95(3H，m)，7.08(2H，d，J＝8.4Hz)，

7.20-7.60(5H，m)，7.80-8.10(2H，m)。

Example 17

2- (4-methoxybenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester

The title compound was obtained in the same manner as in (1) in example 16.

¹H-NMR(CDCl₃)δ(ppm)；

1.21(3H，t，J＝7.0Hz)，2.34(3H，s)，2.91(2H，t，J＝7.0Hz)，

3.04(2H，d，J＝5.5Hz)，3.60-3.95(8H，m)，4.12(2H，q，J＝7.0Hz)，

4.15(2H，t，J＝7.0Hz)，6.51(1H，d，J＝2.0Hz)，

6.67(1H，dd，J＝2.0，8.8Hz)，6.75-7.00(3H，m)，7.15-7.50(5H，m)，

7.85-8.10(2H，m)。

Example 18

2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 800mg of the compound of example 15 was dissolved in 8.0ml of N, N-dimethylformamide, 96mg of sodium hydride (60% oil suspension) was added under ice-cooling, and after stirring at room temperature for 30 minutes, 0.40ml of α -chloro-p-xylene was added dropwise, and further stirred at 50 ℃ for 3 hours and further at room temperature for 15 hours. To the reaction mixture was added 50ml of ethyl acetate, which was washed with 50ml of water and 30ml of saturated saline and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester 0.90 g.

2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester:

IR v (liquid Paraffin) cm^-1；1736，1639，1614，1595，1551。

¹H-NMR(CDCl₃)δ(ppm)；

2.34(6H，s)，2.93(2H，t，J＝6.7Hz)，3.06(2H，d，J＝5.0Hz)，

3.50-4.00(5H，m)，3.65(3H，s)，4.17(2H，t，J＝6.7Hz)，

6.51(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.6Hz)，

6.98(2H，d，J＝8.6Hz)，7.11(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，

7.30-7.55(3H，m)，7.80-8.15(2H，m)。

(2) 608mg of the compound obtained in the above (1) was dissolved in 17ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 6.1ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystal was filtered to obtain 400mg of the title compound.

IR v (liquid Paraffin) cm^-1；1620，1555，1506。

¹H-NMR(CDCl₃)δ(ppm)；

2.32(3H，s)，2.35(3H，s)，2.93(2H，t，J＝7.0Hz)，

3.17(2H，d，J＝6.6Hz)，3.65-4.05(5H，m)，4.17(2H，t，J＝7.0Hz)，

4.73(1H，br-s)，6.60(1H，d，J＝2.0Hz)，6.77(1H，dd，J＝2.0，8.8Hz)，

6.95-7.60(8H，m)，7.85-8.10(2H，m)。

Example 19

2- (4-methylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester

The title compound was obtained in the same manner as in (1) of example 18.

¹H-NMR(CDCl₃)δ(ppm)；

1.21(3H，t，J＝7.0Hz)，2.34(3H，s)，2.92(2H，t，J＝7.0Hz)，

3.05(2H，d，J＝5.4Hz)，3.71(1H，t，J＝5.4Hz)，3.80(1H，s)，

3.92(1H，s)，4.12(2H，q，J＝7.0Hz)，4.16(2H，t，J＝7.0Hz)，

6.51(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.4Hz)，

6.98(1H，d，J＝8.4Hz)，7.00-7.60(7H，m)，7.80-8.10(2H，m)。

Example 20

2-benzyl-7- [2- (6-carboxyindolin-1-yl) ethoxy ] ethanol]-1, 2, 3, 4-tetrakis Hydroisoquinoline- (3S) -carboxylic acid

(1) 2-benzyl-7-hydroxy-1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid ethyl ester 1.0g dissolved in N, N-two methyl formamide 10ml, under ice cooling conditions to add sodium hydride (60% oil suspension) 154 mg. After stirring at the same temperature for 30 minutes, 1.36g of 1- (2-bromoethyl) -6-methoxycarbonylindoline was added, and the mixture was further stirred at room temperature for 4 hours. To the reaction mixture was added 100ml of ethyl acetate, which was washed with 100ml of water and 50ml of saturated saline and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2-benzyl-7- [2- (6-methoxycarbonyl indolin-1-yl) ethoxy ] ethoxy]-1.18 g of ethyl 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

2-benzyl-7- [2- (6-methoxycarbonylindolin-1-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (pure) cm^-1；2949，2841，1717，1611，1587，1497。

¹H-NMR(CDCl₃)δ(ppm)；

1.23(3H，t，J＝7.2Hz)，2.99(2H，t，J＝8.8Hz)，3.00-3.25(2H，m)，

3.35-4.35(13H，m)，3.87(3H，s)，6.52(1H，d，J＝2.4Hz)，

6.70(1H，dd，J＝2.4，8.3Hz)，6.90-7.20(3H，m)，7.20-7.55(6H，m)。

(2) 1.31g of the compound obtained in the above (1) was dissolved in 33ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 15.3ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at 50 ℃ for 2 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered. 1.0g of the title compound was obtained.

IR v (liquid Paraffin) cm^-1；3400，1693，1612，1497。

¹H-NMR(MeOH-d₄)δ(ppm)；

2.96(2H，br-t，J＝8.0Hz)，3.15-3.75(3H，m)，3.80-4.50(10H，m)，

6.65-7.70(11H，m)。

Example 21

2- (4-fluorobenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2， 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.00g of the compound obtained in example 15 was dissolved in 20ml of N, N-dimethylformamide, and 0.46ml of 4-fluorobenzyl chloride, 0.53g of potassium carbonate and 0.21g of potassium iodide were added thereto, followed by stirring at 50 ℃ for 1.5 hours. To the reaction mixture was added 50ml of ethyl acetate, which was washed with 100ml of water and 100ml of saturated saline solution and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. Purifying the obtained residue with silica gel column chromatography to obtain 2- (4-fluorobenzyl) -7- [2- (5-methyl-2-phenyloxazole-4-yl) ethoxy]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester 0.92 g.

2- (4-fluorobenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester:

IR v (liquid Paraffin) cm^-1；1738，1639，1616，1551，1510

¹H-NMR(CDCl₃)δ(ppm)；

2.35(3H，s)，2.93(2H，t，J＝6.8Hz)，3.07(2H，d，J＝5.0Hz)，

3.55-4.00(5H，m)，3.65(3H，s)，4.18(2H，t，J＝6.8Hz)，

6.51(1H，d，J＝2.0Hz)，6.70(1H，dd，J＝2.0，8.6Hz)，6.80-7.15(3H，m)，

7.15-7.50(5H，m)，7.80-8.15(2H，m)。

(2) 900mg of the compound (1) above was dissolved in 18ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 8.9ml of a 1N aqueous lithium hydroxide solution was added thereto, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, made acidic with citric acid, and the precipitated crystals were filtered. 0.68g of the title compound was obtained.

IR v (liquid Paraffin) cm^-1；3398，1614，1555，1510。

¹H-NMR(CDCl₃)δ(ppm)；

2.36(3H，s)，2.94(2H，t，J＝6.4Hz)，3.15(2H，d，J＝6.4Hz)，

3.45-4.00(5H，m)，4.19(2H，t，J＝6.4Hz)，6.60(1H，d，J＝2.0Hz)，

6.75(1H，dd，J＝2.0，8.6Hz)，6.90-7.55(8H，m)，7.90-8.10(2H，m)。

Example 22

2- (2, 2-dimethylpropionyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) Ethoxy radical]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

7- [2- (5-methyl-2-phenyl oxazole-4-yl) ethoxy]0.60g of methyl (E) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate was dissolved in 6ml of methylene chloride, and 0.22ml of pivaloyl chloride and 0.32ml of triethylamine were added thereto under ice cooling, followed by stirring at the same temperature for 15 minutes. To the reaction mixture was added 100ml of ethyl acetate, and the mixture was washed and dried (Na) with 50ml of 10% citric acid aqueous solution, 50ml of saturated sodium bicarbonate aqueous solution and 50ml of saturated brine in this order₂SO₄) Thereafter, the solvent was distilled off under reduced pressure. Dissolving the residue in tetrahydrofuranTo 18ml of a mixed solution of furan-methanol (3: 1), 4.6ml of a 1N aqueous lithium hydroxide solution was added, and the mixture was stirred at 50 ℃ for 30 minutes. The solvent was distilled off under reduced pressure, 20ml of water was added thereto, citric acid was added thereto to adjust the mixture to acidity, and the mixture was extracted with 50ml of ethyl acetate. The ethyl acetate layer was washed with 30ml of a saturated saline solution and dried (Na)₂SO₄) Thereafter, ethyl acetate was evaporated under reduced pressure to give 0.65g of the title compound.

IR v (liquid Paraffin) cm^-1；1734，1630，1612，1553。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.24(9H，s)，2.36(3H，s)，2.80-4.00(1H，br)，2.92(2H，t，J＝6.4Hz)，

2.95-3.15(2H，m)，4.18(2H，t，J＝6.4Hz)，

4.41，4.91(2H，ABq，J＝18.1Hz)，4.90-5.15(1H，m)，

6.77(1H，dd，J＝2.0，8.1Hz)，6.89(1H，d，J＝2.0Hz)，

7.09(1H，d，J＝8.1Hz)，7.30-7.65(3H，m)，7.80-8.10(2H，m)。

Example 23

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

1.66g of the title compound of example 22 was dissolved in 16.6ml of pyridine, and 1.36g of sodium borohydride was added thereto, followed by stirring at 100 ℃ for 4 hours. 10% citric acid was added thereto to adjust the mixture to acidic, followed by extraction with 100ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of a 10% citric acid aqueous solution and 50ml of a saturated saline solution in this order and dried (Na)₂SO₄) After that, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.84g of the title compound.

IR v (liquid Paraffin) cm^-1；3391，3279，1668，1645，1616，1597，1497。

¹H-NMR(CDCl₃)δ(ppm)；

0.96(9H，s)，2.35(3H，s)，2.46，2.73(2H，ABq，J＝13.9Hz)，

2.93(2H，t，J＝6.7Hz)，3.03-3.23(2H，m)，3.57-3.78(1H，m)，

3.91，4.18(1H，ABq，J＝15.4Hz)，4.17(2H，t，J＝6.7Hz)，

5.60-6.05(1H，br)，6.60(1H，d，J＝2.0Hz)，6.73(1H，dd，J＝2.0，8.4Hz)，

7.04(1H，d，J＝8.4Hz)，7.30-7.55(3H，m)，7.80-8.10(2H，m)。

Example 24

(1)2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

1.5g of methyl 2- (2, 2-dimethylpropyl) -7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate and 2.59g of 2- (5-methyl-2-phenyloxazol-4-yl) ethanol methanesulfonate were dissolved in 45ml of toluene, and 2.24g of potassium carbonate and 0.60g of tetraethylammonium fluoride were added thereto, followed by stirring at 80 ℃ for 3 hours. The reaction mixture was washed with 50ml of water and 50ml of saturated saline in this order and dried (Na)₂SO₄) Thereafter, toluene was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] ethanol]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester 2.77 g.

¹H-NMR(CDCl₃)δ(ppm)；

0.88(9H，s)，2.35，2.58(2H，ABq，J＝14.5Hz)，2.36(3H，s)，

2.46(2H，t，J＝6.8Hz)，2.95-3.20(2H，m)，3.60(3H，s)，

3.60-3.80(1H，m)，3.85-4.20(2H，m)，4.19(2H，t，J＝6，8Hz)，

6.54(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.4Hz)，

6.98(1H，d，J＝8.4Hz)，7.30-7.50(3H，m)，7.85-8.05(2H，m)。

(2) 5.0g of the compound (1) was dissolved in 130ml of a tetrahydrofuran-methanol (3: 1) mixed solution, and 54ml of a 1N lithium hydroxide aqueous solution was added thereto, followed by stirring at 50 ℃ for 3.5 hours. The mixture was acidified with 6N hydrochloric acid, and the solvent was distilled off under reduced pressure, followed by extraction with 200ml of ethyl acetate. The ethyl acetate layer was washed with 100ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was dissolved in 25ml of ethanol, and 150ml of water was added thereto, followed by precipitation of crystals under stirring at room temperature. The crystals were collected by filtration to obtain 4.52g of the title compound.

IR and¹the H-NMR spectrum corresponds to that of example 23.

Example 25

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid hydrochloride

675mg of the title compound in example 2 was dissolved in 10.1ml of 75% ethanol under heating, 2.23ml of 6N hydrochloric acid was added thereto, and the mixture was allowed to stand at room temperature for 2 hours to precipitate crystals. The precipitated crystals were collected by filtration to give the title compound (625 mg).

IR v (liquid Paraffin) cm^-1；3398，1734，1680，1641，1620，1587，1574，1551。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.36(3H，s)，2.92(2H，t，J＝6.0Hz)，3.00-3.70(2H，m)，

4.19(2H，t，J＝6.0Hz)，4.25-4.75(5H，m)，

4.80-6.70(2H，br)，6.70-7.05(2H，m)，

7.20(1H，d，J＝8.6Hz)，7.30-7.77(8H，m)，7.80-8.10(2H，m)。

Example 26

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

1.0g of the title compound of example 2 was suspended in 10ml of methanol, and 1.02ml of a 2.09N sodium hydroxide solution in methanol was added thereto and dissolved, and then the methanol was distilled off under reduced pressure. To the resulting residue was added diethyl ether, and the precipitated crystals were filtered to obtain 1.03g of the title compound.

IR v (liquid Paraffin) cm^-1；1638，1589，1503。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.33(3H，s)，2.55-3.60(6H，m)，3.60-4.30(5H，m)，6.47(1H，s)，

6.60(1H，d，J＝8.6Hz)，6.92(1H，d，J＝8.6Hz)，7.00-7.67(8H，m)，

7.67-8.05(2H，m)。

Example 27

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid hydrochloride

2.1g of the title compound of example 23 was dissolved in 10.5ml of methanol, 1.07ml of an isopropanol solution of 8.78N hydrogen chloride was added, and then 50ml of ethyl acetate was added to precipitate crystals at room temperature with stirring. The precipitated crystals were collected by filtration to obtain 1.03g of the title compound.

IR v (liquid Paraffin) cm^-1；3362，3206，1740，1672，1612，1576，1553。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.12(9H，s)，2.37(3H，s)，2.65-3.50(6H，m)，4.21(2H，t，J＝6.5Hz)，

4.40-4.80(3H，m)，4.85-6.50(2H，br)，6.90(1H，d，J＝8.1Hz)，

6.94(1H，s)，7.21(1H，d，J＝8.1Hz)，7.35-7.65(3H，m)，

7.80-8.05(2H，m)。

Example 28

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sulfate

0.5g of the title compound of example 23 was dissolved in 1.25ml of methanol, 0.3ml of sulfuric acid was added, 16.8ml of water was then added, and crystals were precipitated under stirring at room temperature. The precipitated crystals were collected by filtration to obtain 0.25g of the title compound.

IR v (liquid Paraffin) cm^-1；3400，1715，1650，1615，1550。

¹H-NMR(DMSO-d₆)δ(ppm)；

0.93(9H，s)，2.36(3H，s)，2.40-3.30(6H，m)，3.75-4.45(5H，m)，

4.60-6.50(2H，br)，6.70(1H，br-s)，6.74(1H，d，J＝8.1Hz)，

7.06(1H，d，J＝8.1Hz)，7.25-7.65(3H，m)，7.75-8.10(2H，m)。

Example 29

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinolineQuinoline- (3S) -carboxylic acid p-toluenesulfonate salt

0.5g of the title compound of example 23 and 0.28g of p-toluenesulfonic acid were dissolved in 10ml of ethanol by heating. After precipitating crystals under stirring at room temperature, the precipitated crystals were filtered to obtain 0.3g of the title compound.

IR v (liquid Paraffin) cm^-1；3047，1734，1645，1612，1514。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.07(9H，s)，2.28(3H，s)，2.36(3H，s)，2.70-3.50(6H，m)，

4.21(2H，t，J＝6.5Hz)，4.40-4.80(3H，m)，6.80-7.35(5H，m)，

7.35-7.65(5H，m)，7.75-8.05(2H，m)，8.40-12.00(2H，br)。

Example 30

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid fumarate

1.0g of the title compound in example 23 and 0.23g of fumaric acid were dissolved in 5ml of methanol, and 5ml of water was added to precipitate crystals with stirring at room temperature. The precipitated crystals were collected by filtration to obtain 0.94g of the title compound.

IR v (liquid Paraffin) cm^-1；3500，3395，1680，1650，1625，1575，1550。

¹H-NMR(DMSO-d₆)δ(ppm)；

0.85(9H，s)，2.00-6.30(2H，br)，2.35(3H，s)，

2.32，2.59(2H，ABq，J＝14.9Hz)，2.75-3.10(2H，m)，

2.85(2H，t，J＝6.6Hz)，3.45-4.30(3H，m)，4.15(2H，t，J＝6.6Hz)，

6.61(1H，d，J＝2.2Hz)，6.64(1H，s)，6.66(1H，dd，J＝2.2，8.4Hz)，

7.00(1H，d，J＝8.4Hz)，7.35-7.65(3H，m)，7.75-8.10(2H，m)。

Example 31

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid calcium salt

0.9g of the title compound of example 23 was dissolved in 9ml of ethanol, and 54ml of a 0.04N aqueous solution of calcium hydroxide was added to precipitate crystals with stirring at room temperature. The precipitated crystals were collected by filtration to obtain 0.79g of the title compound.

IR v (liquid Paraffin) cm^-1；3396，1638，1611，1556，1504。

¹H-NMR(MeOH-d₄)δ(ppm)；

0.87(9H，s)，2.34(3H，s)，2.36，2.58(2H，ABq，J＝14.0Hz)，

2.80-3.10(2H，m)，2.90(2H，t，J＝6.5Hz)，3.30-3.80(3H，m)，

4.15(2H，t，J＝6.5Hz)，6.50(1H，d，J＝2.4Hz)，

6.60(1H，dd，J＝2.4，8.2Hz)，6.90(1H，d，J＝8.2Hz)，7.30-7.60(3H，m)，

7.80-8.05(2H，m)。

The following compounds were synthesized according to examples 1 to 24.

Example 32

2-benzyl-7- [2- (5-methyl-2-tert-butyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3458，1682，1618，1587，1510。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.32(9H，s)，2.23(3H，s)，2.83(2H，t，J＝6.6Hz)，

3.18(2H，d，J＝5.9Hz)，3.65-4.40(7H，m)，5.60(1H，br-s)，

6.56(1H，br-s)，6.73(1H，br-d)，7.06(1H，d，J＝8.4Hz)，

7.20-7.55(5H，m)。

Example 33

2-benzyl-7- [2- (5-methyl-2- (thiophen-2-yl) oxazol-4-yl) ethoxy ] ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3423，1616，1578，1510。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.31(3H，s)，2.70-3.10(4H，m)，3.40-4.00(4H，m)，3.39(2H，s)，

4.11(2H，d，J＝6.2Hz)，6.59(1H，br-s)，6.67(1H，d，J＝8.4Hz)，

7.01(1H，d，J＝8.4Hz)，7.05-7.80(3H，m)，7.32(5H，s)。

Example 34

2-benzyl-7- [2- (5-methyl-2-isopropyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3456，1684，1614，1576，1510。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.21(6H，m)，2.19(3H，s)，2.70-3.10(5H，m)，3.50-4.20(5H，m)，

6.40-6.85(2H，m)，7.01(1H，d，J＝8.1Hz)，7.34(5H，br-s)。

Example 35

2-butyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3382，17Z2，1614，1554，1506。

¹H-NMR(CDCl₃)δ(ppm)；

0.88(3H，t，J＝6.6Hz)，1.10-1.95(4H，m)，2.36(3H，s)，

2.75-3.40(6H，m)，3.71(2H，br-t)，3.95-4.25(4H，m)，

6.57-7.57(6H，m)，7.80-8.10(3H，m)。

Example 36

2-benzyl-7- {2- [ 5-methyl-2- (2-methylpropenyl) oxazol-4-yl]Ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3443，3300，1695，1655，1622，1543，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.89(3H，s)，2.11(3H，s)，2.27(3H，s)，2.79(2H，t，J＝6.1Hz)，

2.90-3.20(2H，m)，3.50-4.00(4H，m)，3.93(2H，s)，

4.07(2H，t，J＝6.1Hz)，5.99(1H，s)，6.58(1H，s)，

6.67(1H，d，J＝8.2Hz)，6.72(1H，d，J＝8.2Hz)，7.33(5H，s)。

Example 37

2-benzyl-7- {2- [2- (3-butenyl) -5-methyloxazol-4-yl]1 of ethoxy } -1 of ethylene glycol ether, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3442，1688，1614，1578，1508。

¹H-NMR(CDCl₃)δ(ppm)；

2.23(3H，s)，2.49(2H，t，J＝6.2Hz)，2.65-2.90(4H，m)，

3.05-3.30(2H，m)，3.75-4.50(8H，m)，4.90-5.20(2H，m)，

5.65-6.10(1H，m)，6.58(1H，d，J＝1.7Hz)，6.75(1H，dd，J＝1.7，8.2Hz)，

7.07(1H，d，J＝8.2Hz)，7.35(5H，s)。

Example 38

2-allyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3335，1690，1618，1553，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.35(3H，s)，2.70-3.15(4H，m)，3.38(2H，d，J＝6.2Hz)，

3.55-4.00(3H，m)，4.16(2H，t，J＝6.6Hz)，4.40-5.50(1H，br)，

5.00-5.40(2H，m)，5.60-6.10(1H，m)，6.65(1H，s)，

6.69(1H，d，J＝8.1Hz)，7.01(1H，d，J＝8.1Hz)，7.35-7.65(3H，m)，

7.75-8.10(2H，m)。

Example 39

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- (2-propynyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3383，3306，3221，1692，1622，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.00-6.40(1H，br)，2.35(3H，s)，2.70-3.10(4H，m)，3.10-3.25(1H，m)，

3.50-4.00(5H，m)，4.17(2H，t，J＝6.4Hz)，6.66(1H，s)，

6.70(1H，d，J＝8.6Hz)，7.01(1H，d，J＝8.6Hz)，7.30-7.70(3H，m)，

7.85-8.05(2H，m)。

Example 40

2- (2-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2， 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3447，3342，1684，1620，1556。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.67(3H，d，J＝4.9Hz)，2.35(3H，s)，2.70-3.10(4H，m)，

3.20-3.50(2H，m)，3.50-4.00(3H，m)，4.16(2H，t，J＝6.4Hz)，

4.35-5.20(1H，br)，5.25-5.90(2H，m)，6.55-6.90(2H，m)，

7.01(2H，d，J＝8.1Hz)，7.35-7.70(3H，m)，7.75-8.10(2H，m)。

EXAMPLE 41

2-benzyl-7- [ (indolin-3-yl) ethoxy]-1，2，3，4-tetrahydroisoquinoline - (3S) -carboxylic acids

IR v (liquid Paraffin) cm^-1；1611，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.60-2.30(2H，m)，2.80-4.20(10H，m)，3.91(2H，s)，4.20-6.00(1H，br)，

6.25-7.10(7H，m)，7.33(5H，s)。

Example 42

2- (3-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2， 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3425，1682，1612，1555。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.10-2.40(2H，m)，2.35(3H，s)，2.60-3.15(6H，m)，3.50-4.00(3H，m)，

4.17(2H，t，J＝6.3Hz)，4.40-5.40(1H，br)，4.85-5.25(2H，m)，

5.55-6.10(1H，m)，6.50-6.85(2H，m)，7.01(1H，d，J＝8.1Hz)，

7.35-7.70(3H，m)，7.75-8.05(2H，m)。

Example 43

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2-pentanoyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1742，1639，1611，1572，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

0.88(3H，br-t)，1.05-1.75(4H，m)，2.15-2.70(2H，m)，2.35(3H，s)，

2.70-3.30(4H，m)，4.18(2H，br-t)，4.30-4.90(2H，m)，

4.90-5.25(1H，m)，6.60-6.95(2H，m)，7.08(1H，d，J＝7.9Hz)，

7.35-7.70(3H，m)，7.75-8.10(2H，m)，11.00-13.00(1H，br)。

Example 44

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- (4-pentenoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1742，1641，1611，1570。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.15-2.70(2H，m)，2.35(3H，s)，2.70-3.30(4H，m)，4.18(2H，br-t)，

4.37-5.50(5H，m)，5.60-6.15(1H，m)，6.60-6.95(2H，m)，

7.09(1H，d，J＝7.7Hz)，7.30-7.75(3H，m)，7.75-8.15(2H，m)，

11.00-13.00(1H，br)。

Example 45

2- (3-methyl-2-butenoyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) Ethoxy radical]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1738，1641，1611，1555。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.87(6H，s)，2.35(3H，s)，2.70-3.30(4H，m)，4.18(2H，br-t)，

4.49(1H，d，J＝18.0Hz)，4.76(1H，d，J＝18.0Hz)，4.95-5.22(1H，m)，

5.75-6.10(1H，m)，6.50-6.90(2H，m)，7.08(1H，d，J＝7.5Hz)，

7.20-7.60(3H，m)，7.60-8.05(2H，m)，11.00-13.00(1H，br)。

Example 46

2- (3, 3-dimethylbutyryl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) Ethoxy radical]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1738，1639，1611，1583，1555。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.02(9H，s)，2.36(5H，s)，2.73-3.20(4H，m)，4.17(2H，t，J＝7.0Hz)，

4.50(1H，d，J＝9.0Hz)，4.83(1H，d，J＝9.0Hz)，5.12(1H，t，J＝6.0Hz)，

6.60-6.95(2H，m)，7.10(1H，d，J＝7.0Hz)，7.35-7.65(3H，m)，

7.80-8.05(2H，m)，11.00-13.00(1H，br)。

Example 47

2-benzyl-7-methoxy-6- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3RS) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1722，1628，1553，1520。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.36(3H，s)，3.00(2H，t，J＝6.8Hz)，3.10-3.35(2H，m)，

3.80-4.10(3H，m)，3.75(3H，s)，4.23(2H，t，J＝6.8Hz)，

5.80-6.20(1H，br)，6.50，6.72(2H，s，s)，7.20-7.60(8H，m)，

7.80-8.10(2H，m)。

Example 48

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- (pyridin-2-ylmethyl) 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

IR v (liquid Paraffin) cm^-1；1609，1575，1554，1502。

¹H-NMR(CDCl₃)δ(ppm)；

2.32(3H，s)，2.60-3.20(4H，m)，3.20-3.90(5H，m)，

4.08(2H，br-t，J＝6.5Hz)，6.15-6.40(1H，m)，6.40-6.70(1H，m)，

7.75-8.20(3H，m)，7.20-7.65(4H，m)，7.75-8.10(2H，m)，

8.25-8.60(1H，m)。

Example 49

2-benzyl-7- (3-methyl-3-phenylbutoxy) -1, 2, 3, 4-tetrahydroisoquinoline - (3S) -carboxylic acids

IR v (liquid Paraffin) cm^-1；1612，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.32(6H，s)，2.02(2H，t，J＝7.5Hz)，2.80-3.10(2H，m)，

3.40-4.00(5H，m)，3.88(2H，s)，4.10-6.00(1H，br)，

6.36(1H，d，J＝2.0Hz)，6.53(1H，dd，J＝2.0，8.6Hz)，

6.96(1H，d，J＝8.6Hz)，7.10-7.55(10H，m)。

Example 50

2-benzyl-7- (3, 3-dimethyl-4-phenylbutoxy) -1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1611，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

0.87(6H，s)，1.61(2H，t，J＝7.0Hz)，2.54(2H，s)，2.85-3.15(2H，m)，

3.50-4.20(5H，m)，3.91(2H，s)，4.20-6.00(1H，br)，6.60(1H，br-s)，

6.67(1H，d，J＝8.6Hz)，7.01(1H，d，J＝8.6Hz)，7.05-7.50(10H，m)。

Example 51

2-benzyl-7- (2-isopropylbenzoxazol-6-yl) methoxy-1, 2, 3, 4-tetrahydro

Isoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1632，1585，1572，1501。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.37(6H，d，J＝7.0Hz)，2.85-3.45(4H，m)，3.50-4.20(6H，m)，

5.12(2H，s)，6.69(1H，s)，6.77(1H，d，J＝8.6Hz)，

7.04(1H，d，J＝8.6Hz)，7.25-7.85(8H，m)。

Example 52

2-benzyl-7- (2-tert-butylbenzooxazol-6-yl) methoxy-1, 2, 3, 4-tetrahydro Isoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1611，1583，1562，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.42(9H，s)，2.85-3.10(2H，br)，3.50-4.20(6H，m)，

5.13(2H，s)，6.70(1H，s)，6.77(1H，d，J＝8.4Hz)，

7.04(1H，d，J＝8.4Hz)，7.20-7.50(6H，m)，7.55-7.65(1H，m)，

7.70(1H，s)。

Example 53

2-benzyl-7- (2-tert-butylbenzooxazol-5-yl) methoxy-1, 2, 3, 4-tetrahydro Isoquinoline- (3S) -carboxylic acid

1R v (liquid paraffin) cm^-1；1717，1645，1612，1553。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.43(9H，s)，2.85-3.15(2H，m)，3.50-4.15(3H，m)，3.90(2H，s)，

5.11(2H，s)，6.69(1H，br-s)，6.75(1H，d，J＝8.1Hz)，

7.03(1H，d，J＝8.1Hz)，7.10-7.50(6H，m)，7.65(1H，d，J＝9.0Hz)，

7.71(1H，br-s)。

Example 54

7- (2-tert-butylbenzooxazol-6-yl) methoxy-2- (2, 2-dimethylpropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1740，1612，1560，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.10(9H，s)，1.43(9H，s)，2.79，3.19(2H，ABq，J＝13.6Hz)，

3.20-3.45(3H，m)，4.25-4.55(4H，br)，5.20(2H，s)，

6.96(1H，d，J＝8.1Hz)，7.00(1H，s)，7.20(1H，d，J＝8.1Hz)，

7.40(1H，d，J＝8.1Hz)，7.68(1H，d，J＝8.1Hz)，7.73(1H，s)。

Example 55

2-benzyl-7- (2-isopropylbenzoxazol-5-yl) methoxy-1, 2, 3, 4-tetrahydro Isoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1634，1587，1570，1501。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.37(6H，d，J＝6.8Hz)，2.90-3.15(2H，m)，3.25(1H，quintet，J＝6.8Hz)，

3.50-4.30(7H，m)，5.11(2H，s)，6.69(1H，s)，6.76(1H，d，J＝8.1Hz)，

7.04(1H，d，J＝8.1Hz)，7.20-7.50(6H，m)，7.55-7.65(1H，m)，

7.70(1H，s)。

Example 56

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- (pyridin-4-ylmethyl) 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

IR v (liquid Paraffin) cm^-1；3420，3177，1639，1558，1504。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.34(3H，s)，2.70-3.05(4H，m)，3.10-3.60(3H，m)，

3.98(2H，br-t，J＝5.7Hz)，4.10-4.25(2H，m)，6.51(1H，br-s)，

6.61(1H，br-d，J＝8.7Hz)，6.94(1H，br-d，J＝8.7Hz)，

7.25-7.65(5H，m)，7.75-8.00(2H，m)，8.46(2H，d，J＝5.2Hz)。

Example 57

7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-2- [ (pyridin-2-yl) carbonyl Base of]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

IR v (liquid Paraffin) cm^-1；3385，1624，1566，1504。

¹H-NMR(MeOH-d₄)δ(ppm)；

2.31，2.36(3H，s，s)，2.75-3.05(2H，m)，3.05-3.30(2H，m)，

4.00-4.30(2H，m)，4.50-5.30(3H，m)，6.60-6.80(2H，m)

7.03(1H，dd，J＝2.0，8.5Hz)，7.30-7.75(5H，m)，

7.75-8.10(3H，m)，8.50-8.70(1H，m)。

Example 58

2-benzyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IR v (liquid Paraffin) cm^-1；1736，1639，1612，1504。

¹H-NMR(CDCl₃)δ(ppm)；

2.34(3H，s)，2.92(2H，t，J＝7.0Hz)，3.07(2H，d，J＝5.0Hz)，

3.64(3H，s)，3.64-4.00(5H，m)，4.17(2H，t，J＝7.0Hz)，

6.51(1H，d，J＝2.0Hz)，6.68(1H，dd，J＝2.0，8.4Hz)，

6.98(1H，d，J＝8.4Hz)，7.20-7.60(8H，m)，7.80-8.10(2H，m)。

Example 59

2-benzyl-7- [2- (2-cyclopropyl-5-methyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3470，1684，1618，1583，1510。

¹H-NMR(DMSO-d₆)δ(ppm)；

0.70-1.10(4H，m)，1.80-2.20(1H，m)，2.16(3H，s)，

2.60-2.85(2H，m)，2.90-3.15(2H，m)，3.50-4.20(5H，m)，

6.50-6.80(2H，m)，7.03(1H，d，J＝8.1Hz)，7.34(5H，s)。

Example 60

2- (3-methyl-2-butenyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3447，3335，1670，1668，1622，1556，1506。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.61(3H，s)，1.72(3H，s)，2.35(3H，s)，2.70-3.20(4H，m)

3.39(2H，d，J＝7.0Hz)，3.50-4.01(3H，m)，4.16(2H，t，J＝7.0Hz)，

4.35-5.60(1H，br)，5.25(1H，br-t)，6.67(1H，s)，

6.71(1H，d，J＝8.4Hz)，7.02(1H，d，J＝8.4Hz)，7.30-7.70(8H，m)，

7.75-8.10(2H，m)。

Example 61

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-tert-butyloxazol-4-yl) ethyl Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1717，1614，1566，1504。

¹H-NMR(CDCl₃)δ(ppm)；

0.97(9H，s)，1.33(9H，s)，2.24(3H，s)，

2.44，2.68(2H，ABq，J＝13.9Hz)，

2.84(2H，t，J＝6.7Hz)，3.00-3.22(2H，m)，3.65(3H，t，J＝6.1Hz)，

3.83，4.08(2H，ABq，J＝15.1Hz)，4.07(2H，t，J＝6.7Hz)，

6.58(1H，d，J＝1.7Hz)，6.72(1H，dd，J＝1.7，8.4Hz)，

7.05(1H，d，J＝8.4Hz)，7.50-8.20(1H，br)

Example 62

2-benzyl-7- {2- [2- (1-butenyl) -5-methyloxazol-4-yl]The ratio of ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3470，1682，1614，1585，1512。

¹H-NMR(CDCl₃)δ(ppm)；

1.07(3H，t，J＝7.5Hz)，2.05-2.20(1H，m)，2.26(3H，s)，

2.50-3.00(3H，m)，3.65-4.45(7H，m)，5.92(1H，br-s)，

6.17(1H，d，J＝16.3Hz)，6.45-6.85(3H，m)，

7.05(1H，d，J＝8.4Hz)，7.34(5H，s)。

Example 63

2-benzyl-7- {2- [2- (2, 2-dimethylpropyl) -5-methyloxazol-4-yl]1 of ethoxy } -1 of ethylene glycol ether, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1722，1614，1568，1506。

¹H-NMR(CDCl₃)δ(ppm)；

0.95(9H，s)，2.34(3H，s)，2.55(2H，s)，2.60-3.00(2H，m)，

3.00-3.30(2H，m)，3.80-4.40(7H，m)，6.64(1H，br-s)，

6.70(1H，d，J＝8.8Hz)，7.02(1H，d，J＝8.8Hz)，

7.32(5H，s)，7.80(1H，br-s)。

Example 64

2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] ethyl]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester hydrochloride

IR v (liquid Paraffin) cm^-1；3400，1744，1676，1614，1589，1574，1553，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.12(9H，s)，1.23(3H，t，J＝7.0Hz)，2.36(3H，s)，

2.60-3.60(6H，m)，4.00-4.40(4H，m)，4.40-6.00(4H，m)，

6.88(1H，d，J＝8.0Hz)，6.92(1H，s)，7.18(1H，d，J＝8.0Hz)，

7.35-7.70(8H，m)，7.75-8.10(2H，m)。

Example 65

7- (benzofuran-2-ylmethoxy) -2-benzyl-1, 2, 3, 4-tetrahydroisoquinoline - (3S) -carboxylic acids

IR v (liquid Paraffin) cm^-1；1632，1587，1501。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.00-6.50(1H，br)，2.85-3.15(2H，m)，3.50-4.10(3H，m)，

3.91(2H，s)，5.16(2H，s)，6.60-7.80(8H，m)，7.33(5H，s)。

Example 66

2-isobutyryl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1736，1639，1612，1504。

¹H-NMR(DMSO-d₆)δ(ppm)；

1.02(6H，br-d)，2.35(3H，s)，2.65-3.30(5H，m)，

4.00-5.30(6H，m)，6.60-6.95(2H，m)，7.09(1H，d，J＝8.0Hz)，

7.25-7.70(8H，m)，7.70-8.10(2H，m)。

Example 67

7- [2- (benzofuran-2-yl) ethoxy ] ethanol]-2-benzyl-1, 2, 3, 4-tetrahydroisoquinoline Quinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1634，1585，1501。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.80-3.10(2H，m)，3.19(2H，br-t)，3.45-4.10(3H，m)，

3.90(2H，s)，4.25(2H，br-t)，6.50-7.80(9H，m)，7.33(5H，s)。

Example 68

7- [2- (5-ethylpyridin-2-yl) ethoxy]-2-hexanoyl-1, 2, 3, 4-tetrahydro Isoquinoline- (3S) -carboxylic acid hydrochloride

¹H-NMR(CDCl₃)δ(ppm)；

0.87(3H，br-t)，1.05-1.85(9H，m)，2.15-2.55(4H，m)，

2.55-3.75(4H，m)，4.00-4.90(4H，m)，5.25-5.50(1H，m)，

6.40-7.10(4H，m)，7.75(1H，br-d)，8.15(1H，br-d)，8.52(1H，br-s)。

Example 69

2-carboxymethyl-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3， 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1620，1585，1556，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.35(3H，s)，2.70-3.15(4H，m)，3.41，3.65(2H，ABq，J＝17.5Hz)，

3.70-4.00(3H，m)，4.16(2H，t，J＝7.0Hz)，6.00-11.00(1H，br)，

6.64(1H，s)，6.69(1H，d，J＝8.2Hz)，7.01(1H，d，J＝8.2Hz)，

7.20-7.70(8H，m)，7.70-8.05(2H，m)。

Example 70

2- [3- (methoxycarbonyl) propanoyl]-7- [2- (5-methyl-2-phenyloxazol-4-yl) Ethoxy radical]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1732，1652，1554，1505。

¹H-NMR(CDCl₃)δ(ppm)；

2.33(3H，s)，2.50-3.40(7H，m)，3.65(3H，s)，4.07(2H，br-t)，

4.45-5.50(3H，m)，5.60-6.20(1H，br)，6.59(1H，br-s)，

6.67(1H，d，J＝8.0Hz)，7.03(1H，d，J＝8.0Hz)，7.20-7.60(3H，m)，

7.80-8.10(2H，m)。

Example 71

2- [3- (ethoxycarbonyl) propyl]-7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3375，1733，1620，1555，1505。

¹H-NMR(CDCl₃)δ(ppm)；

1.18(3H，t，J＝7.0Hz)，1.76-2.15(2H，m)，2.15-2.50(2H，m)，

2.35(3H，s)，2.70-3.35(6H，m)，3.60-4.40(7H，m)，

5.27(1H，br-s)，6.61(1H，br-s)，6.73(1H，d，J＝8.4Hz)，

7.03(1H，d，J＝8.4Hz)，7.25-7.55(3H，m)，7.80-8.10(2H，m)。

Example 72

2-benzyl-6- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1，2，3，4- Tetrahydroisoquinoline- (3RS) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1634，1614，1499。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.35(3H，s)，2.65-3.25(4H，m)，3.40-4.00(3H，m)，

3.90(2H，s)，4.17(2H，br-t)，6.20-10.00(1H，br)，

6.50-7.00(2H，m)，6.71(1H，s)，7.30-7.70(3H，m)，

7.32(5H，s)，7.75-8.15(2H，m)。

Example 73

2- (3-acetylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy]-1， 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；1682，1620，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.33(3H，s)，2.56(3H，s)，2.70-3.20(4H，m)，

3.50-4.30(5H，m)，3.97(2H，s)，6.50-6.90(2H，m)，

7.02(1H，d，J＝8.4Hz)，7.30-8.00(9H，m)。

Example 74

2- (2-acetylbenzyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethyl ester Oxygen gas]-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acids

IR v (liquid Paraffin) cm^-1；1668，1643，1614，1504。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.33(3H，s)，2.36(3H，s)，2.70-3.20(4H，m)，

3.30-4.30(5H，m)，6.57(1H，d，J＝2.0Hz)，

6.66(1H，dd，J＝2.0，8.4Hz)，7.00(1H，d，J＝8.4Hz)，

7.20-7.75(7H，m)，7.75-8.10(2H，m)。

Example 75

2-benzyl-7- [ (5-methyl-2-phenyloxazol-4-yl) methoxy]-1，2，3，4- Tetrahydroisoquinoline- (3S) -carboxylic acid

IR v (liquid Paraffin) cm^-1；3462，1680，1614，1556，1508。

¹H-NMR(DMSO-d₆)δ(ppm)；

2.41(3H，s)，2.83-3.20(2H，m)，3.44-4.20(5H，m)，

4.91(2H，s)，6.73(1H，br-s)，6.77(1H，d，J＝8.1Hz)，

7.34(1H，d，J＝8.1Hz)，7.34(5H，s)，

7.40-7.68(3H，m)，7.75-8.10(2H，m)。

Reference example 1

2-Boc-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester Esters

(1) 25.0g of 3, 5-diiodo-L-tyrosine.2hydrate is suspended in 250ml of concentrated hydrochloric acid, 18ml of 1, 2-dimethoxyethane and 20ml of 37% formalin are sequentially added, and the temperature is raised to 75 ℃ over 30 minutes. To the reaction mixture were added 120ml of concentrated hydrochloric acid, 9ml of 1, 2-dimethoxyethane and 10ml of 37% formalin, followed by stirring at 75 ℃ for 18 hours. The precipitated crystal was filtered and washed with 20ml of 1, 2-dimethoxyethane to give 12.8g of 7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid hydrochloride.

7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid hydrochloride salt:

IR v (liquid Paraffin) cm^-1；1751，1599，1578。

¹H-NMR(CDCl₃)δ(ppm)；

3.00-3.30(2H，m)，4.05(2H，s)，4.30(1H，dd，J＝5.9，9.5Hz)，

7.71(1H，s)。

(2) 12.8g of the compound obtained in the above (1) was suspended in 500ml of ethanol, 10ml of concentrated hydrochloric acid was added, and the mixture was refluxed for 15 hours. After ethanol was distilled off under reduced pressure, 300ml of ethyl acetate was added, and the mixture was washed with 100ml of a saturated aqueous solution of sodium hydrogencarbonate and 100ml of a saturated saline solution. Drying (Na)₂SO₄) Then, ethyl acetate was distilled off under reduced pressure to give 11.11g of ethyl 7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

¹H-NMR(CDCl₃)δ(ppm)；

1.29(3H，t，J＝7.0Hz)，2.80-3.00(2H，m)，3.30-4.10(5H，m)，

4.23(2H，q，J＝7.0Hz)，7.46(1H，s)。

(3) 10% Pd-C350mg was suspended in 60ml of methanol, and 2.0ml of triethylamine and 2.80g of the compound obtained in the above (2) were added thereto at room temperature at 29.4X 10⁴Pa(3.0kgf/cm²) Catalytic hydrogenation was carried out for 3 hours. Filtering to remove Pd-C, and steaming under reduced pressure to remove nailAn alcohol. To the resulting residue was added 100ml of ethyl acetate, and the mixture was washed with 100ml of saturated saline. Drying (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. To obtain 1.14g of ethyl 7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester:

IR v (liquid Paraffin) cm^-1；1732，1607，1516。

¹H-NMR(CDCl₃)δ(ppm)；

1.28(3H，t，J＝7.0Hz)，2.80-3.10(3H，m)，3.60-3.80(1H，m)，

3.97(2H，s)，4.05-4.20(4H，m)，6.43(1H，s)，6.50-6.80(1H，m)，

6.92(1H，d，J＝8.4Hz)。

(4) 1.13g of the compound obtained in the above (3) was dissolved in 20ml of tetrahydrofuran, and 1.50g of di-tert-butyl dicarbonate was added, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 30ml of ethyl acetate, which was washed with 20ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 1.51g of the title compound.

IR v (liquid Paraffin) cm^-1；3260，1756，1671，1615，1506。

¹H-NMR(CDCl₃)δ(ppm)；

1.29(3H，t，J＝7.0Hz)，1.47(9H，s)，3.08(2H，d，J＝5.2Hz)，

4.21(2H，q，J＝7.0Hz)，4.41(1H，d，J＝15.5Hz)，

4.60-5.25(1H，m)，4.65(1H，d，J＝15.5Hz)，5.00-6.00(1H，br)，

6.50-6.80(2H，m)，6.98(1H，d，J＝8.1Hz)。

Reference example 2

2-Boc-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester Esters

The title compound was obtained in the same manner as in reference example 1.

IR v (liquid Paraffin) cm^-1；3261，1755，1672，1614，1506。

¹H-NMR(CDCl₃)δ(ppm)；

1.47(9H，s)，3.08(2H，d，J＝5.2Hz)，3.63(3H，s)，

4.40(1H，d，J＝16.5Hz)，4.60-5.25(1H，m)，4.66(1H，d，J＝16.5Hz)，

5.60-6.60(1H，br)，6.50-6.80(2H，m)，6.99(1H，d，J＝8.1Hz)。

Reference example 3

2- (5-methyl-2-phenyl-oxazol-4-yl) ethanol mesylate

To 200ml of methylene chloride were added 20g of 2- (5-methyl-2-phenyl-oxazol-4-yl) ethanol and 19.2ml of triethylamine, and 9.52ml of methanesulfonyl chloride was added dropwise thereto at 0 ℃ and then stirred at the same temperature for 15 minutes. The mixture was washed with 200ml of a 10% citric acid aqueous solution, 100ml of a saturated sodium bicarbonate aqueous solution and 100ml of a saturated saline solution and dried (Na)₂SO₄) Thereafter, methylene chloride was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 21.45g of the title compound.

¹H-NMR(CDCl₃)δ(ppm)；

2.53(3H，s)，2.94(3H，s)，2.94(2H，t，J＝7.0Hz)，

4.52(2H，t，J＝7.0Hz)，7.30-7.50(3H，m)，7.80-8.10(2H，m)。

Reference example 4

2-benzyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester

8.1g of the compound obtained in (3) in referential example 1 was dissolved in 80ml of N, N-dimethylformamide, and 2.0ml of triethylamine and 4.57ml of benzyl bromide were added thereto, followed by stirring at room temperature for 3 hours. 500ml of water was added to the reaction mixture, which was then extracted 2 times with 200ml of ethyl acetate. The combined ethyl acetate layers were washed with 500ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 10.46g of the title compound.

IR v (liquid Paraffin) cm^-1；3410，1717，1624，1506。

¹H-NMR(CDCl₃)δ(ppm)；

1.22(3H，t，J＝7.0Hz)，3.06(2H，d，J＝5.0Hz)，3.66(1H，t，J＝5.0Hz)，

3.78(2H，s)，3.90(2H，s)，4.13(2H，q，J＝7.0Hz)，

6.37(1H，d，J＝2.0Hz)，6.56(1H，dd，J＝2.0，8.4Hz)，

6.92(1H，d，J＝8.4Hz)，7.20-7.50(5H，m)。

Reference example 5

2- (N-Boc-N-methylamino) ethanol methanesulfonate

(1) 3.5ml of 2- (methylamino) ethanol was dissolved in 150ml of tetrahydrofuran, and 12.5g of di-tert-butyl dicarbonate was added and the mixture was stirred at room temperature for 20 minutes. The tetrahydrofuran was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to give 6.35g of 2- (N-tert-butoxycarbonyl-N-methylamino) ethanol.

2- (N-tert-butoxycarbonyl-N-methylamino) ethanol:

IR v (pure) cm^-1；3423，2976，2934，2882，1674。

¹H-NMR(CDCl₃)δ(ppm)；

1.43(9H，s)，2.89(3H，s)，3.34(2H，t，J＝5.8Hz)，

3.67(2H，t，J＝5.8Hz)，4.00-6.00(1H，br)。

(2) 505mg of the compound obtained in the above (1) was dissolved in 20ml of methylene chloride, and 0.5ml of triethylamine and 0.25ml of methanesulfonyl chloride were added thereto, followed by stirring at room temperature for 1 hour. 30ml of methylene chloride was added thereto, and the mixture was washed with 20ml of saturated brine and dried (Na)₂SO₄). Methylene chloride was distilled off under reduced pressure to obtain the title compound (720 mg).

¹H-NMR(CDCl₃)δ(ppm)；

1.46(9H，s)，2.94(3H，s)，3.01(3H，s)，3.54(2H，t，J＝5.5Hz)，

4.33(2H，t，J＝5.5Hz)。

Reference example 6

1- (2-bromoethyl) indoline

To 58.0ml of 1, 2-dibromoethane were added 5.0g of indoline and 28.7ml of triethylamine, and the mixture was stirred at 90 ℃ for 2 hours. To the reaction mixture was added 200ml of ethyl acetate, which was washed with 400ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 4.09g of the title compound.

IR v (pure) cm^-1；2924，2845，1607，1489。

¹H-NMR(CDCl₃)δ(ppm)；

2.99(1H，t，J＝8.4Hz)，3.45(1H，t，J＝8.4Hz)，3.49(4H，s)，

6.40-6.75(2H，m)，6.90-7.20(2H，m)。

Reference example 7

1- (2-bromoethyl) -6-methoxycarbonylindoline

To 15.7ml of 1, 2-dibromoethane were added 2.41g of 6-methoxycarbonylindoline and 7.8ml of triethylamine, and the mixture was stirred at 90 ℃ for 2 hours. To the reaction mixture was added 150ml of ethyl acetate, which was washed with 300ml of saturated saline and dried (Na)₂SO₄) Thereafter, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 1.71g of the title compound.

IR v (pure) cm^-1；1713，1611，1499。

¹H-NMR(CDCl₃)δ(ppm)；

3.03(1H，t，J＝8.4Hz)，3.53(1H，t，J＝8.4Hz)，3.53(4H，s)，

3.88(3H，s)，6.00-6.20(2H，m)，7.39(1H，dd，J＝1.5，7.8Hz)。

Test example 1 blood sugar lowering action (method A)

Blood was collected from the tail vein of a male KK-a' mouse, which is a natural diabetes model causing diabetes onset due to insulin resistance and showing hyperglycemia and hyperinsulinemia, under non-fasting conditions, and glucose in plasma was measured using a commercially available measurement kit (glucose CII-test, light, and pure drug). The control group and the administration group were divided into 5 groups per group so that the average value and the standard deviation of glucose in plasma of each group were substantially equal. Starting on the next day, each test compound was suspended or dissolved in a 5% gum arabic solution and administered orally to the administration group for 4 consecutive days. The control group was orally administered with a 5% gum arabic solution. About 24 hours after the final administration, blood was collected from the tail vein in a non-fasting state, and the glucose value in plasma was measured. The blood glucose lowering rate was determined by the following equation. The results are shown in Table 1.

Blood glucose reduction rate (%) [ (mean plasma glucose value of control group-mean plasma glucose value of test compound administration group)/mean plasma glucose value of control group ] × 100

TABLE 1 hypoglycemic Effect (method A)

Compounds to be tested	Dosage (mg/kg)	Blood glucose reduction Rate (%)	Compounds to be tested	Dosage (mg/kg)	Blood glucose reduction Rate (%)
Compounds to be tested	Dosage (mg/kg)	Blood glucose reduction Rate (%)	Compounds to be tested	Dosage (mg/kg)	Blood glucose reduction Rate (%)	Example 2	1030	38.360.6	Example 40	30	46.3
EXAMPLE 41	30	11.1							Example 40	30	46.3
EXAMPLE 41	30	11.1	Example 3	30	11.8				Example 42	1030	27.649.6
Example 5	1030	34.143.4	Example 3	30	11.8
			Example 43	30	27.5
			Example 43	30	27.5	Example 6	1030	10.712.2	Example 44	30	48.0
Example 45	30	12.6							Example 44	30	48.0
Example 45	30	12.6	Example 7	1030	11.417.4				Example 46	30	28.6
Example 48	30	16.1							Example 46	30	28.6
Example 48	30	16.1				Example 9	30	20.3	Example 49	30	11.1
Example 12	10	12.0	Example 50	30	11.4	Example 9	30	20.3	Example 49	30	11.1
Example 12	10	12.0	Example 50	30	11.4	Example 16	30	34.5	Example 51	30	20.0
Example 18	30	39.7	Example 52	30	26.3	Example 16	30	34.5	Example 51	30	20.0
Example 18	30	39.7	Example 52	30	26.3	Example 21	30	43.4	Example 53	30	13.6
Example 23	1030	24.342.9	Example 54	30	10.8	Example 21	30	43.4	Example 53	30	13.6
			Example 54	30	10.8	Example 55	30	13.9
			Example 32	30	36.4	Example 55	30	13.9	Example 58	30	19.1
Example 33	30	38.8	Example 32	30	36.4	Example 67	30	10.6	Example 58	30	19.1
Example 33	30	38.8	Example 34	30	23.5	Example 67	30	10.6	Example 69	30	12.5
Example 35	30	22.1	Example 34	30	23.5	Example 70	30	15.2	Example 69	30	12.5
Example 35	30	22.1	Example 36	30	28.4	Example 70	30	15.2	Example 71	30	10.5
Example 37	30	11.1	Example 36	30	28.4	Example 72	30	15.9	Example 71	30	10.5
Example 37	30	11.1	Example 38	30	28.0	Example 72	30	15.9	Example 73	30	14.8
Example 39	30	30.7	Example 38	30	28.0				Example 73	30	14.8

Test example 2 hypoglycemic Effect (method B)

Blood was collected from the tail vein of a male KK-a' mouse, which is a natural diabetes model causing diabetes onset due to insulin resistance and showing hyperglycemia and hyperinsulinemia, under non-fasting conditions, and glucose in plasma was measured using a commercially available measurement kit (glucose CII-test, light, and pure drug). The control group and the administration group were divided into 5 groups per group so that the average value and the standard deviation of glucose in plasma of each group were substantially equal. From the next day, each test compound was mixed in an amount of 0.1 (W/W)%, with the powdered feed (CE-2, クレア), and administered with the mixed feed for 4 days. The control group was fed with normal powdered feed. On the 5 th day, blood was collected from the tail vein in a non-fasting state, and the glucose value in the blood sample was measured. The blood glucose lowering rate was determined by the following equation. The results are shown in Table 2.

TABLE 2 hypoglycemic Effect (method B)

Compounds to be tested	Blood glucose reduction Rate (%)
Compounds to be tested	Blood glucose reduction Rate (%)	Example 2	69.2
Example 10	42.4	Example 2	69.2

Test example 3 triglyceride lowering action

Blood was collected from the tail vein of a male KK-a' mouse, which is a natural diabetes model causing diabetes onset due to insulin resistance and showing hyperglycemia and hyperinsulinemia, under non-fasting conditions, and triglyceride in plasma was measured using a commercially available measurement kit (triglyceride G-test, light, and pure drug). Each group was divided into 5 groups into a control group and a drug group, and the mean value and standard deviation of triglycerides in plasma of each group were made substantially equal. Starting on the next day, each test compound was suspended or dissolved in a 5% gum arabic solution and administered orally to the administration group for 4 consecutive days. The control group was orally administered with a 5% gum arabic solution. After about 24 hours from the final administration, blood was collected from the tail vein in a non-fasting state, and the triglyceride value in plasma was measured. The triglyceride reduction rate was determined by the following formula. The results are shown in Table 3.

Triglyceride reduction rate (%) [ (mean plasma triglyceride of control group-mean plasma triglyceride of test compound administration group)/mean plasma triglyceride of control group ] × 100

TABLE 3 triglyceride lowering Effect

Compounds to be tested	Dosage (mg/kg)	Triglyceride reduction ratio (%)	Compounds to be tested	Dosage (mg/kg)	Triglyceride reduction ratio (%)
Compounds to be tested	Dosage (mg/kg)	Triglyceride reduction ratio (%)	Compounds to be tested	Dosage (mg/kg)	Triglyceride reduction ratio (%)	Example 2	1030	39.554.3	Example 38	30	30.0
Example 39	30	15.6							Example 38	30	30.0
Example 39	30	15.6	Example 4	10	14.3				Example 40	30	36.1
Example 5	30	30.9	Example 4	10	14.3	Example 42	30	31.6	Example 40	30	36.1
Example 5	30	30.9	Example 11	10	11.2	Example 42	30	31.6	Example 43	30	20.9
Example 12	10	22.9	Example 11	10	11.2	Example 44	30	19.1	Example 43	30	20.9
Example 12	10	22.9	Example 16	30	19.8	Example 44	30	19.1	Example 49	30	17.0
Example 18	30	45.5	Example 16	30	19.8	Example 50	30	35.7	Example 49	30	17.0
Example 18	30	45.5	Example 21	30	24.4	Example 50	30	35.7	Example 51	30	10.7
Example 23	1030	30.450.4	Example 21	30	24.4	Example 52	30	26.6	Example 51	30	10.7
			Example 56	30	14.0	Example 52	30	26.6
			Example 56	30	14.0	Example 32	30	32.5	Example 58	30	24.7
Example 33	30	42.0	Example 59	30	13.7	Example 32	30	32.5	Example 58	30	24.7
Example 33	30	42.0	Example 59	30	13.7	Example 34	30	17.3	Example 69	30	15.2
Example 35	30	12.4	Example 72	30	24.0	Example 34	30	17.3	Example 69	30	15.2
Example 35	30	12.4	Example 72	30	24.0	Example 36	30	13.7	Example 73	30	15.4

Test example 4 blood sugar and insulin lowering action in insulin resistant diabetic mice

The insulin resistance-improving effect was investigated using male KK-a' mice, which are natural diabetes models causing diabetes onset and showing hyperglycemia and hyperinsulinemia, as insulin resistance. Blood was collected from the tail vein of 12-week-old male KK-a' mice under non-fasting conditions, and glucose in plasma was measured using a commercially available measurement kit (glucose CII-test and light, Wako pure chemical industries, Ltd.). The control group and the administration group were divided into 5 groups per group so that the mean value and standard deviation of glucose and body weight in each group were substantially equal. For the administration group, each test compound suspended in 5% gum arabic was administered at 10mg/kg 1 time for 1 day for 4 days from the next day. The control group was orally administered with a 5% gum arabic solution. About 24 hours after the final administration, blood was collected from the tail vein in a non-fasting state, and the glucose and insulin concentrations in the blood samples were measured. The results are shown in Table 4.

That is, 10mg/kg of each test compound reduced plasma glucose and simultaneously reduced plasma insulin concentration. The compound to be tested does not act by secreting insulin but lowers blood glucose by enhancing the action of sensitivity to insulin (insulin resistance improving action), and thus shows improvement in hyperinsulinemia.

TABLE 4 hypoglycemic and insulinogenic actions

Compounds to be tested	Dose of test compound (mg/kg)	Blood sugar (mg/dl)	Insulin (ng/ml)
Compounds to be tested	Dose of test compound (mg/kg)	Blood sugar (mg/dl)	Insulin (ng/ml)	Control group	0	507	43
Example 2	10	313	26	Control group	0	507	43
Example 2	10	313	26	Example 23	10	382	28
Example 32	10	402	30	Example 23	10	382	28
Example 32	10	402	30	Example 42	10	308	27

Test example 5 Effect of promoting accumulation of triglyceride in 3T3-L1 cells

The medium of 80% fused 3T3-L1 cells was removed and the cells were detached with 0.25% trypsin-EDTA solution. 5% FBS-DMEM (equivalent to the removed medium) was added, and the resulting cell suspension was centrifuged at 100 Xg for 1 minute at 25 ℃ to pellet the cells and remove the supernatant. The cells were resuspended in an appropriate amount of 5% FBS-DMEM medium, and the cell number was counted. Preparing into 1 × 10 with 5% FBS-DMEM medium⁵Cells/ml, 1ml per well in a 24-well plate. At 37 ℃ 5% CO₂Culturing under ventilation condition for 2 days to confirm postconfluent state, subjecting the culture supernatant to exchange culture with a medium containing 0.5mM-IBMX for 2 days, and adding insulin 10ng/ml and insulin 10ng/ml^-7M was exchanged with the test compound medium and cultured for another 4 days. After removing the culture supernatant, the cells were dissolved in 0.1% SDS solution, and the amount of triglyceride was measured. The accumulation rate (%) of triglyceride due to the insulin potentiating effect of the test compound was determined by the following formula. The results obtained are shown in Table 5.

[ (amount of triglyceride at addition of test compound-amount of control triglyceride)/amount of control triglyceride ]. times.100

TABLE 5 triglyceride accumulation-promoting action

Compounds to be tested	Triglyceride accumulation rate (%)	Compounds to be tested	Triglyceride accumulation rate (%)
Compounds to be tested	Triglyceride accumulation rate (%)	Compounds to be tested	Triglyceride accumulation rate (%)	Example 2	260.4	Example 33	222.5
Example 5	233.0	Example 37	277.3	Example 2	260.4	Example 33	222.5
Example 5	233.0	Example 37	277.3	Example 8	275.5	Example 39	258.0
Example 16	288.9	Example 40	231.0	Example 8	275.5	Example 39	258.0
Example 16	288.9	Example 40	231.0	Example 21	284.9	Example 42	193.6
Example 23	214.2	Example 62	327.8	Example 21	284.9	Example 42	193.6
Example 23	214.2	Example 62	327.8	Example 32	181.2

ADVANTAGEOUS EFFECTS OF INVENTION

The heterocyclic compound [ I ] of the present invention and a pharmaceutically acceptable salt thereof exhibit an excellent blood sugar and blood lipid lowering action, insulin resistance improving action and PPAR activation action, and are useful as an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance improving agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a glucose tolerance improving agent, an anti-arteriosclerosis agent, an anti-obesity agent, an anti-inflammatory agent, a prophylactic/therapeutic agent for PPAR-mediated diseases, and a prophylactic/therapeutic agent for X syndrome. That is, the present invention is useful for the treatment and prevention of diabetes, diabetic complications, hyperlipidemia, arteriosclerosis, hyperglycemia, diseases caused by insulin resistance, obesity, inflammation, PPAR-mediated diseases, and syndrome X. The heterocyclic compound [ I ] of the present invention has a completely different structure from the active ingredient compounds of currently used insulin resistance improvers, and by providing the compound, an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance improver, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an agent for improving glucose tolerance insufficiency, an antiatherosclerotic agent, an antiobesity agent, an anti-inflammatory agent, an agent for preventing and treating PPAR-mediated diseases, and an agent for preventing and treating X syndrome can be provided in a wide variety of forms and with a wide selection range.

The present application is based on the patent applications of inventions in Japanese patent Nos. 345543/1999 and 295108/2000, and the contents thereof are all included in the present specification.

Claims

1. A heterocyclic compound represented by the general formula [ I ] or a pharmaceutically acceptable salt thereof:

in the formula, R¹Represents a hydrogen atom or C_1～6An alkyl group, a carboxyl group,

R²represents unsubstituted or substituted by carboxyl or C_2～5C of alkoxycarbonyl_1～8Alkyl radical, C_3～8Cycloalkyl radical C_1～3Alkyl, unsubstituted or substituted by C_1～6Alkyl radical, C_1～6Phenyl group C of any of alkoxy, formyl, acetyl, propionyl or halogen atoms_1～3Alkyl radical, C_2～6Alkenyl radical, C_2～4Alkynyl, pyridyl C_1～3An alkyl group, a carboxyl group,

Y-A-B-O-is positioned at the 7-position or the 6-position of the tetrahydroquinoline ring,

when Y-A-B-O-is in the 7-position, R³Represents a hydrogen atom located at the 6-position,

when Y-A-B-O-is in the 6-position, R³Represents a hydrogen atom or C in the 7-position_1～6An alkoxy group,

Y-A-is:

or

In the formula, R^ARepresents an isopropyl group or a tert-butyl group,

R^Brepresents an isopropyl group or a tert-butyl group,

R^Crepresents isopropyl, tert-butyl, phenyl, thiophen-2-yl, 2-methylpropenyl, 3-butenyl, cyclopropyl, 1-butenyl or 2, 2-dimethylpropyl,

b represents C_1～6An alkylene group.

2. The heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y-a-is:

3. the heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the following compounds (2) to (67):

(48)7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -2- (pyridin-4-ylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt,

(54) 2-benzyl-7- {2- [2- (1-butenyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(55) 2-benzyl-7- {2- [2- (2, 2-dimethylpropyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(56)2- (2, 2-dimethylpropyl) -7- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester hydrochloride,

4. The heterocyclic compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the above-mentioned compounds (2) to (47).

5. The heterocyclic compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound of the general formula [ I ] is any one of the above-mentioned compounds (2) to (21).

6. A pharmaceutical composition comprising the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. An antihyperglycemic agent comprising the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. An antihyperlipidemic agent comprising the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

9. An insulin resistance-improving agent comprising the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. A therapeutic agent for diabetic complications, which comprises the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

11. A therapeutic agent for diabetes, which comprises the heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.