HK1069385B

HK1069385B - Heterocyclic compound and medicinal use thereof

Info

Publication number: HK1069385B
Application number: HK05101815.6A
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: 2001-05-29
Filing date: 2002-05-27
Publication date: 2006-09-01

Description

Heterocyclic compounds and their medical use

Technical Field

The present invention relates to a novel heterocyclic compound having a blood glucose lowering effect, a blood lipid lowering effect, an insulin resistance improving effect, and a PPAR (peroxisome proliferator-responsive receptor) activating effect, or a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising 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, a therapeutic agent for diabetic complications, a glucose tolerance-improving agent, an antiatherosclerotic agent, an antiobesity agent, an anti-inflammatory agent, a prophylactic and therapeutic agent for PPAR-mediated diseases, and a prophylactic and therapeutic agent for syndrome X, each comprising the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt thereof.

Background

As a therapeutic agent for diabetes, a biguanide compound mainly acting to inhibit the absorption of sugar into the intestinal tract and the release of sugar from the liver, a sulfonylurea compound mainly acting to promote the secretion of insulin, and the like can be used. However, since biguanide compounds cause lactic acidosis, and sulfonylurea compounds have a potent hypoglycemic action and often cause severe hypoglycemia, care must be taken in use. In recent years, extensive research and development have been conducted on therapeutic agents for diabetes which do not have these disadvantages, and various compounds having an insulin resistance-improving effect have been gradually found.

Insulin resistance, together with the lack of insulin secretion, plays an important role as one of the etiologies of insulin independent diabetes mellitus (NIDDM). Various thiazolidine compounds are known as agents for improving such insulin resistance. Examples of such compounds include 5- [4- [ (6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl) methoxy ] benzyl ] -2, 4-thiazolidinedione (generic name トログリタゾン) described in Japanese patent application publication No. 31079/1990 (US4572912, EP0139421, B1), 5- [ [4- [2- [ N-ethyl-N-pyridin-2-yl ] amino ] ethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione (generic name ピオグリタゾン) described in Japanese patent application publication No. 66956/1993 (US4687777, EP0193256, B1), and 5- [ [4- [2- [ N-methyl-N-, (generic name ピオグリタゾン) described in Japanese patent application publication No. 131169/1989 (US5002953, EP0306228, B1) Pyridin-2-yl) amino ] ethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione (generic name ロジグリタゾン). However, these agents for improving insulin resistance also have side effects such as liver disorders, retention of body fluids, edema, cardiac hypertrophy, obesity, and the like, and development of an insulin resistance improving agent which is effective for NIDDM and has higher safety has been desired.

Disclosure of the invention

The present invention aims to expand the range of drug choices by providing a compound which has a completely different structure, has a hypoglycemic action, a hypolipidemic action, an insulin resistance-improving action, and a PPAR activating action, and is highly safe, and thereby diversifying the properties of antihyperglycemic agents, antihyperlipidemic agents, insulin resistance-improving agents, diabetes therapeutic agents, diabetic complication therapeutic agents, glucose tolerance-improving agents, anti-arteriosclerosis agents, anti-obesity agents, anti-inflammatory agents, PPAR-mediated disease preventive and therapeutic agents, and X-syndrome preventive and therapeutic agents.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a novel heterocyclic compound represented by the general formula (I) having a novel structure or a pharmaceutically acceptable salt thereof has a hypoglycemic action, a hypolipidemic action, an insulin resistance-improving action and a PPAR activating action, and have completed the present invention.

General formula (I)

{ formula (II) wherein R¹Represents a hydrogen atom or C_1-6Alkyl radical, R²Represents a hydrogen atom, -CO-R³(in the formula, R³Represents C which may be substituted by halogen_2-6Alkyl), -CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R⁵Is represented by C_1-8Alkyl radical, C_2-8Alkenyl, aryl or aromatic heterocycle), -CO-C ≡ C-R⁶(in the formula, R⁶Is represented by C_1-8Alkyl radicals),

(wherein m represents an integer of 2 to 7), an aryl group, an optionally substituted aryl group C_1-3Alkyl, C which may be substituted by halogen_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl or C_3-8Cycloalkyl radical C_1-3An alkyl group, a carboxyl group,

y represents

[ in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Is represented by C_5-8Alkyl radical, C_4-8Cycloalkyl radical, C_1-4Alkylthio of C_1-6Alkyl radical, R¹⁰-C(R⁹)＝C(R⁵) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Represents C which may be substituted by halogen atoms_1-6Alkyl radical, C_2-8Alkenyl, aryl or aromatic heterocyclic radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-4Alkylthio of C_1-6Alkyl or by (R)⁹)₂N- (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl) substituted C_1-6Alkyl), R¹²-CO-N(R¹¹) - (in the formula R)¹¹Represents a hydrogen atom or C_1-4Alkyl radical, R¹²Is represented by C_1-6Alkyl or aryl), R¹³-Z- (wherein R is¹³Is represented by C_1-8Alkyl or aryl, Z represents an oxygen atom or a sulfur atom), or

(wherein k represents an integer of 2 to 7) and X represents an oxygen atom or a sulfur atom]Or represents R¹⁵-C(R¹⁴) Is N-O- (wherein R is¹⁴Represents a hydrogen atom or C_1-4Alkyl radical, R¹⁵Represents an aryl group or an aromatic heterocyclic group),

Y-(CH₂)_n-O-is bound to the 6-or 7-position of the tetrahydroisoquinoline skeleton, and n represents an integer of 1 to 4. }

That is, the present invention is as follows:

[1] a novel heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

general formula (I)

{ formula (II) wherein R¹Represents a hydrogen atom or C_1-6Alkyl radical, R²Represents a hydrogen atom, -CO-R³(R³Represents C which may be substituted by halogen_2-6Alkyl radicals),

-CO-C(R⁴)＝C(R⁴)-R⁵(in the formula, R⁴May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R⁵Is represented by C_1-8Alkyl radical, C_2-8Alkenyl, aryl or aromatic heterocycle), -CO-C ≡ C-R⁶(in the formula, R⁶Is represented by C_1-8Alkyl radicals),

y represents

[ in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Is represented by C_5-8Alkyl radical, C_4-8Cycloalkyl radical, C_1-4Alkylthio of C_1-6Alkyl radical, R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Represents C which may be substituted by halogen atoms_1-6Alkyl radical, C_2-8Alkenyl, aryl, aromatic heterocyclic radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-4Alkylthio of C_1-6Alkyl or by (R)⁹)₂N- (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl) substituted C_1-6Alkyl), R¹²-CO-N(R¹¹) - (in the formula R)¹¹Represents a hydrogen atom or C_1-4Alkyl radical, R¹²Is represented by C_1-6Alkyl or aryl), R¹³-Z- (wherein R is¹³Is represented by C_1-8Alkyl or aryl, Z represents an oxygen atom or a sulfur atom), or

(wherein k represents an integer of 2 to 7), and X represents an oxygen atom or a sulfur atom]Or represents R¹⁵-C(R¹⁴) Is N-O- (wherein R is¹⁴Represents a hydrogen atom or C_1-4Alkyl radical, R¹⁵Represents an aryl group or an aromatic heterocyclic group),

[2]The novel heterocyclic compound described in the above-mentioned (1) wherein R is represented by the general formula (I)²Is aryl C which may be substituted_1-3Alkyl, C which may be substituted by halogen_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl, or

(wherein m is an integer of 2 to 7).

[3] The novel heterocyclic compound described in the above (1) wherein Y represents a group represented by the general formula (I)

[ in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Is represented by C_1-4Alkylthio of C_1-6Alkyl radical, R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Represents C which may be substituted by halogen atoms_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-4Alkylthio of C_1-6Alkyl, or is (R)⁹)₂N- (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl) substituted C_1-6Alkyl) or represents

(wherein k represents an integer of 2 to 7) and X represents an oxygen atom or a sulfur atom ].

[4]The novel heterocyclic compound described in the above (1) wherein R is represented by the general formula (I)²Represents a hydrogen atom, -CO-R³(R³Represents C which may be substituted by halogen_2-6Alkyl), -COCR⁴＝C(R⁴)-R⁵(in the formula, R⁴May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R⁵Is represented by C_1-8Alkyl radical, C_2-8Alkenyl, aryl or aromatic heterocycle), -CO-C ≡ C-R⁶(in the formula, R⁶Is represented by C_1-8Alkyl), or represents aryl, Y represents

[ in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Is represented by C_5-8Alkyl radical, C_4-8Cycloalkyl radical, R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_1-6Alkyl radical, C_2-8Alkenyl, aryl or aromatic heterocyclic group), R¹²-CO-N(R¹¹) - (in the formula R)¹¹Represents a hydrogen atom or C_1-4Alkyl radical, R¹²Is represented by C_1-6Alkyl or aryl), or R¹³-Z- (wherein R is¹³Is represented by C_1-8An alkyl group or an aryl group, Z represents an oxygen atom or a sulfur atom), X represents an oxygen atom or a sulfur atom]Or R¹⁵-C(R¹⁴) Is N-O- (wherein, R is¹⁴Represents a hydrogen atom or C_1-4Alkyl radical, R¹⁵Represents an aryl group or an aromatic heterocycle).

[5]The novel heterocyclic compound described in the above (2) or (3) wherein Y- (CH) in the general formula (I) or a pharmaceutically acceptable salt thereof₂)_n-O-is bound to the 7-position of the tetrahydroisoquinoline skeleton and n is 2.

[6]The novel heterocyclic compound of the above-mentioned (4) wherein Y- (CH) in the general formula (I) or a pharmaceutically acceptable salt thereof₂)_n-O-is bound to the 7-position of the tetrahydroisoquinoline skeleton and n is 2.

[7] The novel heterocyclic compound described in the above (6) wherein Y represents a group represented by the general formula (I)

(in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Represents R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different, watchRepresents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_1-6Alkyl radical, C_2-8Alkenyl or aryl).

[8] The novel heterocyclic compound described in the above (6) wherein Y represents a group represented by the general formula (I)

(in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Represents R¹³-Z- (wherein R is¹³Is represented by C_1-8Alkyl or aryl, Z represents a sulfur atom).

[9] The novel heterocyclic compound described in the above (6) wherein Y represents a group represented by the general formula (I)

(in the formula, R⁷Represents a hydrogen atom or C_1-4Alkyl radical, R⁸Is represented by C_5-8Alkyl or C_4-8Cycloalkyl groups).

[10] The novel heterocyclic compound described in the above (5) wherein Y represents a group represented by the general formula (I)

[ in the formula, R⁷Represents a hydrogen atom or C_1-4An alkyl group, a carboxyl group,

R⁸represents R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_3-8Cycloalkyl radicals]。

[11]Any of the above notes (7) to (10)The novel heterocyclic compound or a pharmaceutically acceptable salt thereof as described in the above, wherein in the formula (I), R²represents-CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴Represents a hydrogen atom, R⁵Is represented by C_1-8Alkyl or C_2-8Alkenyl).

[12]The novel heterocyclic compound according to any one of the above (7) to (10) wherein R is represented by the general formula (I)²represents-CO-C.ident.C-R⁶(in the formula, R⁶Is represented by C_1-8Alkyl groups).

[13] The novel heterocyclic compound described in the above (6) wherein Y represents a group represented by the general formula (I)

[ in the formula, R⁷Is represented by C_1-4Alkyl radical, R⁸Represents R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_1-6Alkyl group), X represents an oxygen atom]。

[14] The novel heterocyclic compound described in the above (6) wherein Y represents a group represented by the general formula (I)

[ in the formula, R⁷Is represented by C_1-4Alkyl radical, R⁸Represents R¹⁰-C(R⁹)＝C(R⁹) - (in the formula R)⁹Represents a hydrogen atom, R¹⁰Represents an aryl group), X represents an oxygen atom]。

[15] The novel heterocyclic compound according to the above (4) or (5) wherein Y in the general formula (I) is any one atom group selected from the following (a) to (n), or a pharmaceutically acceptable salt thereof.

[16] The novel heterocyclic compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is any one of the following compounds (1) to (16):

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

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

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

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

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

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

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

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

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

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

(11)7- [2- (2-cyclopentyl-5-methyloxazol-4-yl) ethoxy ] -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(12)7- [2- (2-cyclohexyl-5-methyloxazol-4-yl) ethoxy ] -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(13)7- [2- (2-benzoylaminothiazol-5-yl) ethoxy ] -2- (2-heptenoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(14)7- [2- (2-butyrylaminothiazol-5-yl) ethoxy ] -2- (2-heptenoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

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

(16)2- (2-heptenoyl) -7- [2- (1-phenylethylidene aminooxo) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[17] The novel heterocyclic compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is any one of the following compounds (1) to (3):

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

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

(3)2- (2-hexynoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[18] The novel heterocyclic compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is any one of the following compounds (1) to (17):

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

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

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

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

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

(6)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (1-methyl-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

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

(8)7- {2- [ 5-methyl-2- (1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (2, 2, 3, 3, 3-pentafluoropropionyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(9)7- {2- [2- (4, 4-dimethyl-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(10)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (3-methyl-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(11)2- (2, 4-hexadienoyl) -7- (2- { 5-methyl-2- [2- (1-methylcyclohexanoyl-1-yl) vinyl ] oxazol-4-yl } ethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(12)7- {2- [2- (3, 3-dimethyl-1-buten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(13)2- (2, 4-hexadienoyl) -7- {2- [2- (3-methoxy-1-propen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(14)7- {2- [2- (2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(15)7- {2- [2- (2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(16)2- (3-butenyl) -7- {2- [ 5-methyl-2- (4-methyl-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(17)7- {2- [ 5-methyl-2- (4-methyl-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (4-pentenyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[19] The novel heterocyclic compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is any one of the following compounds (1) to (8):

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

(2)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(3)2- (2-heptenoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(4)2- (2, 4-hexadienoyl) -7- {2- [2- (trans-1-hexen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(5)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(6)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(7)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(8)2- (2-hexenoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[20] The novel heterocyclic compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is any one of the following compounds (1) to (6):

(1)7- {2- [ 5-methyl-2- (trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -2- (2, 2, 3, 3, 3-pentafluoropropionyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(2)7- {2- [2- (4, 4-dimethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(3)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (3-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(4)2- (2, 4-hexadienoyl) -7- (2- { 5-methyl-2- [ 2-trans- (1-methylcyclohexanoyl) vinyl ] oxazol-4-yl } ethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(5)7- {2- [2- (3, 3-dimethyl-trans-1-buten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(6)2- (2, 4-hexadienoyl) -7- {2- [2- (3-methoxy-trans-1-propen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[21] The novel heterocyclic compound described in the above-mentioned (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is a compound of the following (1) or (2):

(1)7- {2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(2)7- {2- [2- (trans-2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[22] The novel heterocyclic compound described in the above-mentioned (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the general formula (I) is a compound of the following (1) or (2):

(1)2- (3-butenyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(2)7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (4-pentenyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

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

(1)2- (2, 4-hexadienoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(2)7- {2- [2- (trans-2-cyclopentylvinyl) oxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(3)7- {2- [2- (trans-2-cyclohexylvinyl) oxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(4)2- (2-heptenoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(5)2- (2-hexenoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(6)2- (2, 4-hexadienoyl) -7- {2- [2- (trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(7)2- (2, 4-hexadienoyl) -7- {2- [2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(8)2- (2, 4-hexadienoyl) -7- {2- [2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

(9)2- (2, 4-hexadienoyl) -7- {2- [ (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid.

[24] A pharmaceutical composition comprising the novel heterocyclic compound according to any one of the above (1) to (23) or a pharmaceutically acceptable salt thereof.

[25] A pharmaceutical agent comprising a novel heterocyclic compound selected from the group consisting of an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance-ameliorating agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a glucose tolerance-ameliorating agent, an anti-arteriosclerosis agent, an anti-obesity agent, an anti-inflammatory agent, a prophylactic and therapeutic agent for PPAR-mediated diseases, and a prophylactic and therapeutic agent for syndrome X, wherein the novel heterocyclic compound is described in any one of (1) to (23) above, or a pharmaceutically acceptable salt thereof.

[26] A method for preventing and treating hyperglycemia, hyperlipidemia, diseases caused by insulin resistance, diabetes mellitus, diabetic complications, glucose tolerance insufficiency, arteriosclerosis, obesity, inflammation, PPAR-mediated diseases, and syndrome X, which comprises administering a therapeutically effective amount of the novel heterocyclic compound described in any one of (1) to (23) above or a pharmaceutically acceptable salt thereof to a patient.

[27] Use of the novel heterocyclic compound according to any one of the above-mentioned items (1) to (23) or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for the treatment or prevention of hyperglycemia, hyperlipidemia, diseases caused by insulin resistance, diabetes, diabetic complications, glucose tolerance insufficiency, arteriosclerosis, obesity, inflammation, PPAR-mediated diseases and syndrome X.

Detailed description of the invention

The following describes various symbols used in the present specification.

R⁴、R⁷、R⁹、R¹¹And R¹⁴C in (1)_1-4The alkyl group is a linear or branched alkoxy group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, with methyl, ethyl, propyl and isopropyl being preferred.

R¹、R¹⁰And R¹²C in (1)_1-6Alkyl is a straight chain or branched chain alkyl of 1 to 6 carbon atomsExamples of the oxy group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl groups, and methyl, ethyl, propyl, tert-butyl, isobutyl, and isopentyl groups are preferable.

R⁵、R⁶And R¹³C in (1)_1-8The alkyl group is a linear or branched alkoxy group having 1 to 8 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, and an octyl group, and preferred are a methyl group, an ethyl group, a propyl group, a tert-butyl group, a pentyl group, and a hexyl group.

R⁸C in (1)_5-8The alkyl group is a linear or branched alkoxy group having 5 to 8 carbon atoms, and examples thereof include pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl groups, with pentyl, neopentyl, and hexyl groups being preferred.

R³C which may be substituted by halogen atoms_2-6In the alkyl group, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, C_2-6The alkyl group is a linear or branched alkoxy group having 2 to 6 carbon atoms, and examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a neopentyl group, and a hexyl group. C when substituted by halogen atoms_2-6Examples of the alkyl group include a 2-chloroethyl group, a 2-bromoethyl group, a 2-iodoethyl group, a 2-fluoroethyl group, a 2, 2-difluoroethyl group, a 2, 2, 2-trifluoroethyl group, a pentafluoroethyl group, a 2, 2, 3, 3-tetrafluoropropyl group, a 3, 3, 3-trifluoropropyl group, a 4, 4, 4-trifluorobutyl group, a 5, 5, 5-trifluoropentyl group, and a 6, 6, 6-trifluorohexyl group, and among them, a 2-fluoroethyl group, a 2, 2-difluoroethyl group, a 2, 2, 2-trifluoroethyl group, a pentafluoroethyl group, and a 2, 2, 3, 3-tetrafluoropropyl group are preferable.

R²、R¹⁰C which may be substituted by halogen atoms_1-6In the alkyl group, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, C_1-6The alkyl group is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include the above-mentioned methyl groupEthyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl and the like. C when substituted by halogen atoms_1-6Examples of the alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-iodoethyl group, a 2-fluoroethyl group, a 2, 2-difluoroethyl group, a 2, 2, 2-trifluoroethyl group, a pentafluoroethyl group, a 2, 2, 3, 3-tetrafluoropropyl group, a 3-fluoropropyl group, a 3, 3-difluoropropyl group, a 3, 3, 3, 2, 2-pentafluoropropyl group, a 3, 3, 3-trifluoropropyl group, a 4, 4, 4-trifluorobutyl group, a 5, 5, 5-trifluoropentyl group, and a 6, 6, 6-trifluorohexyl group, among which a 3-fluoropropyl group, a 3, 3-difluoropropyl group, a trifluoromethyl group, a 2, 2, 2-trifluoroethyl, 2, 2-difluoroethyl, 3, 3, 3-trifluoropropyl, 3, 3, 3, 2, 2-pentafluoropropyl, and the like.

R²、R¹⁰C in (1)_3-8The cycloalkyl group has 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and among them, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are preferable.

R⁸C in (1)_4-8The cycloalkyl group has 4 to 8 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and cyclopentyl and cyclohexyl are preferable.

R⁵And R¹⁰C in_2-8The alkenyl group is a straight-chain or branched alkenyl group having 2 to 8 carbon atoms, and examples thereof include a vinyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1-heptenyl group, a 2-heptenyl group, a 3-heptenyl group, a 4-heptenyl group, a 5-heptenyl group, a 6-heptenyl group, a 1-octenyl group, a 2-octenyl group, a 3-, 5-octenyl, 6-octenyl, 7-octenyl and the like. Preference is given to 1-propenyl, 1-butenyl, 1-pentenyl, 1-A hexenyl group.

R²C in_2-6The alkenyl group is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, and a 5-hexenyl group. Preference is given to 3-butenyl, 4-pentenyl, 5-hexenyl.

R²、R⁵、R¹⁰、R¹²、R¹³And R¹⁵Examples of the aryl group in (1) include phenyl and naphthyl, and phenyl is preferable.

R⁵、R¹⁰And R¹⁵The aromatic heterocyclic ring in (3) preferably includes a mono-heterocyclic ring or a condensed heterocyclic ring containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom. The fused heterocyclic ring in the present invention is a bicyclic heterocyclic ring, and includes a case where both rings contain a hetero atom. Preferred mono-heterocyclic rings include five-or six-membered heterocyclic rings. The heterocyclic ring constituting the preferred fused heterocyclic ring includes a five-membered or six-membered heterocyclic ring. The ring having no hetero atom constituting the preferred fused heterocyclic ring may be a five-or six-membered ring. Examples of the aromatic heterocycle include monocyclic heterocycles such as furyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl and pyrazinyl; indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzoxazinyl, benzothiazinyl, furo [2, 3-b ] o]Pyridyl, thieno [2, 3-b ]]Fused heterocycles such as pyridyl, naphthyridinyl, imidazopyridinyl, oxazolopyridine and thiazolopyridyl, with furyl, thienyl, pyridyl, oxazolyl, thiazolyl, indolyl, indolinyl, benzofuryl, benzothienyl, quinolyl and isoquinolyl。

R²And R¹⁰C in_3-8Cycloalkyl radical C_1-3The alkyl group is a linear or branched alkyl group having 3 to 8 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety, and examples thereof include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclopropylethyl group, cyclobutylethyl group, cyclopentylethyl group, cyclohexylethyl group, cycloheptylethyl group, cyclooctylethyl group, cyclopropylpropyl group, cyclobutylpropyl group, cyclopentylpropyl group, cyclohexylpropyl group, cycloheptylpropyl group, cyclooctylpropyl group, 1-methylcyclopent-1-yl group, 1-methylcyclohex-1-yl group and the like, with cyclopropylmethyl group, cyclopropylethyl group, 1-methylcyclopent-1-yl group, 1-methylcyclohex-1-yl group, cyclopentylmethyl group, cyclohexylmethyl group and the like being preferred.

R¹⁰C in (1)_1-4Alkoxy radical C_1-6The alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms in the alkoxy group part and 1 to 6 carbon atoms in the alkyl group part, and examples thereof include methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, methoxybutyl, ethoxybutyl, propoxybutyl, butoxybutyl, methoxypentyl, ethoxypentyl, propoxypentyl, butoxypentyl, methoxyhexyl, ethoxyhexyl, propoxyhexyl, and butoxyhexyl groups. Among them, methoxymethyl, methoxyethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, ethoxyethyl and the like are preferable.

R²Aryl group C which may be substituted in (1)_1-3The alkyl group is an aryl group substituted with at least one straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, and examples thereof include an aryl moiety such as phenyl and naphthyl, and an alkyl moiety is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms. When the substituent is not substituted by the substituent, examples thereof include benzyl, 1-naphthylmethyl, 2-phenylethyl, 2- (1-naphthylethyl) and 2- (naphthyl) ethyl2-naphthylethyl), 3-phenylpropyl, 3- (1-naphthylpropyl), 3- (2-naphthylpropyl), 1-phenylethyl, 2-propylpropyl, 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, with benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl being preferred. As said substituent, there may be mentioned C_1-4Alkyl radical, C_1-4Alkoxy group, hydroxyl group, halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), nitro group, amino group, etc. The number of substitution is preferably 1 or 2.

R⁸And R¹⁰C in (1)_1-4Alkylthio of C_1-6The alkyl refers to the alkyl of the alkylthio part is a straight chain or branched alkyl of 1-4 carbon atoms, and the alkyl part is a straight chain or branched alkyl of 1-6 carbon atoms. Examples thereof include methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, methylthiopentyl, methylthiohexyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl, ethylthiobutyl, ethylthiopentyl, ethylthiohexyl, propylthiomethyl, propylthioethyl, propylthiopropyl, propylthiobutyl, propylthiopentyl, propylthiohexyl, isopropylthiomethyl, butylthiomethyl, butylthioethyl, butylthiopropyl, butylthiobutyl, butylthiopentyl and butylthiohexyl, and methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthioethyl and isopropylthiomethyl and methylthiopropyl are preferred.

R¹⁰Is (R) of⁹)₂N- (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl) substituted C_1-6Alkyl) substituted C_1-6Alkyl group, the alkyl moiety of which is an alkyl group having 1 to 6 carbon atoms is represented by (R)⁹)₂N-substituted. Is covered with⁹)₂N-substituted C_1-6Examples of the alkyl group include aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, aminopropyl, dimethylaminopropyl, aminobutyl, aminopentyl, aminohexyl, and,Diethylaminomethyl, diethylaminoethyl, ethylaminoethyl, etc., and among them, aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, aminopropyl, and dimethylaminopropyl are preferable.

R¹Preferably a hydrogen atom.

Preferred R²May be mentioned-CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴Represents a hydrogen atom, R⁵Is represented by C_1-8Alkyl or C_2-8Alkenyl or aryl), -CO-C.ident.C-R⁶(in the formula, R⁶Is represented by C_1-8Alkyl group), C_2-6An alkenyl group.

In the general formula (I), Y- (CH)₂)_n-O-is preferably bound to the 7-position of the tetrahydroisoquinoline skeleton. And in Y- (CH)₂)_nin-O-, n preferably represents 2.

Y is preferably a group represented by the formula,

(the symbols in the formula are defined as the same as those in the above).

Further, more preferably Y is represented by the formula,

①R⁷is a hydrogen atom or C_1-4Alkyl radical, and R⁸Represents R¹⁰-C-(R⁹)＝C(R⁹) - (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_1-6Alkyl radical, C_2-8Alkenyl or aryl) or,

②R⁷Is a hydrogen atom or C_1-4Alkyl radical, and R⁸Represents R¹³-Z- (in the formula, R¹³Is represented by C_1-8Alkyl or aryl, Z represents a sulfur atom),

③R⁷Is a hydrogen atom or C_1-4Alkyl radical, and R⁸Represents R¹³Is represented by C_5-8Alkyl or C_4-8The case of cycloalkyl radicals, and

④R⁷is a hydrogen atom or C_1-4Alkyl radical, and R⁸Represents R¹⁰-C-(R⁹)＝C(R⁹) - (in the formula, R⁹Represents a hydrogen atom, R¹⁰Is represented by C_3-8Cycloalkyl) groups.

Particularly preferred examples of Y include those represented by the formula,

⑤R⁷is represented by C_1-4Alkyl radical, R⁸Represents R¹⁰-C-(R⁹)＝C(R⁹) - (in the formula, R⁹May be the same or different and represents a hydrogen atom or C_1-4Alkyl radical, R¹⁰Is represented by C_1-6Alkyl group), and X represents an oxygen atom,

⑥R⁷Is represented by C_1-4Alkyl radical, R⁸Represents R¹⁰-C(R⁹)＝C(R⁹) - (in the formula, R⁹Represents a hydrogen atom, R¹⁰Represents an aryl group), and X represents an oxygen atom.

X in Y is preferably an oxygen atom.

Particularly preferred examples of Y include those selected from the following (a) to (n).

Furthermore, the heterocyclic compound (I) has stereoisomers because the carbon atom at the 3-position of the 1, 2, 3, 4-tetrahydroisoquinoline ring is an asymmetric carbon atom. The most preferred configuration is

(in the formula, R¹、R²Y and n are the same as above).

In the general formula (I), R²is-CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴And R⁵Synonymous with the above), R⁸Is R¹⁰-C-(R⁹)＝C(R⁹) - (in the formula, R⁹And R¹⁰Synonymous with the above) or Y is R¹⁵-C(R¹⁴) Is N-O- (wherein R is¹⁴And R¹⁵Synonymous with the above), stereoisomers (Z isomer and E isomer) exist in the double bond moiety or the oxime moiety, but both isomers are included in the present invention.

The compound (I) of the present invention may also form a pharmaceutically acceptable salt.

When the compound (I) has a basic group, an acid addition salt can be formed, and the acid for forming such an acid addition salt is not particularly limited as long as it can form a salt with a basic moiety and is a pharmaceutically acceptable acid. Examples of such acids 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 toluenesulfonic acid.

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

As the novel heterocyclic compound of the general formula (I) or a pharmaceutically acceptable salt thereof, the following acids and pharmaceutically acceptable salts thereof may be mentioned as suitable examples:

Of the above-mentioned specific examples (1) to (16), the following compounds (1) to (3) and pharmaceutically acceptable salts thereof are particularly preferable because they exhibit excellent blood glucose lowering action, blood lipid lowering action, insulin resistance improving action and PPAR (peroxisome proliferator-responsive receptor) activating action.

The following compounds (1) to (17) can be cited as examples of the novel heterocyclic derivative of the present invention or a pharmaceutically acceptable salt thereof.

Further, the following compounds (1) to (8) and pharmaceutically acceptable salts thereof may be mentioned as preferable specific examples:

(7)2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-buten-yl) ] -oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

Further, any of the following compounds (1) to (6) and pharmaceutically acceptable salts thereof are preferable:

Preferred specific examples thereof include the following compounds (1) and (2):

Furthermore, as preferable specific examples, the following compounds (1) or (2) and pharmaceutically acceptable salts thereof can be given:

In addition, any of the following compounds (1) to (9) and pharmaceutically acceptable salts thereof are also preferable:

The compound (I) of the present invention and pharmaceutically acceptable salts thereof can be produced by any of the following methods.

(preparation method 1)

[ in the formula, R¹Y and n have the same meanings as above, R^2arepresents-CO-R³(in the formula, R³Synonymous with the above-mentioned), -CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴And R⁵Synonymous with the above-mentioned), -CO-C.ident.C-R⁶(R⁶Synonymous with the above), aryl group C which may be substituted_1-3Alkyl, C which may be substituted by halogen_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl, or C_3-8Cycloalkyl radical C_1-3Alkyl radical, U¹Represents a hydroxyl group and/or a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) or an alkanesulfonyloxy group (e.g. methanesulfonylOxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy (e.g., phenylsulfonyloxy, tolylsulfonyloxy, etc.) leaving groups.]

The production method 1 is a method for producing a compound having the general formula (Ia) (compound (Ia)) by reacting a compound having the general formula (II) (compound (II)) with a compound having the general formula (III) (compound (III)).

Preparation method 1-a: when U is turned¹In the case of hydroxyl groups, preparation 1 can be carried out by mitsunobu reaction (Fieser)&Fieser, vol.6, page 645 of organic Synthesis reagent) and the like. The reaction is usually carried out with azo compounds and phosphines in the presence of a solvent. As the azo compound, for example, azodicarboxylic acid di-C can be used_1-4Alkyl esters (e.g., dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), azodicarbonamide (e.g., 1 '-azobis (N, N-dimethylformamide), 1' - (azodicarbonyl) dipiperidine, etc.), and the like. As phosphines, triarylphosphines (e.g., triphenylphosphine), tris (C) and the like can be used_1-8Alkyl) phosphines (e.g., tri-n-butylphosphine, tri-n-hexylphosphine, tri-n-octylphosphine, etc.).

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

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); the azo compounds and the phosphines are used in an amount of 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 vary depending on the reaction reagent and the reaction solvent used, but are usually-30 to 50 ℃ for 30 minutes to more than ten hours.

Preparation method 1-b: when U is turned¹When it is a halogen atom or a leaving group such as an alkanesulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy group (e.g., benzenesulfonyloxy, toluenesulfonyloxy, etc.), etc., production process 1-b is carried out in the presence of a base in the same solvent as in production process 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, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., sodium hydride, potassium hydride, calcium hydride, etc.), organic bases such as alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amines (e.g., triethylamine, diisopropylethylamine, etc.), 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); the amount of the base to be used is usually 1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound (III).

In addition, in the process 1-b, a catalyst may be used in a solvent in the presence of a base. The solvent is preferably toluene, and examples of the catalyst include quaternary ammonium salts such as tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, tetraethylammonium chloride, tetraethylammonium fluoride and benzyltrimethylammonium bromide, and tris [2- (2-methoxyethoxy) ethyl ] amine. Tetraethylammonium fluoride and tris [2- (2-methoxyethoxy) ethyl ] amine are preferred. The amount of the catalyst to be used is usually 0.1 to 1 mol, preferably 0.1 to 0.5 mol, based on 1 mol of the compound (III).

The reaction conditions such as the reaction temperature and the reaction time in the production process 1-b vary depending on the reaction reagent and the reaction solvent used, but are usually-30 to 150 ℃ for 30 minutes to more than ten hours.

In preparation 1-a and preparation 1-b, R in Compound (III)¹Preferably C_1-6Alkyl, in which case R may be obtained¹Is C_1-6The alkyl compound (Ia) may be hydrolyzed by a method known per se to introduce R¹A compound (Ia) which is a hydrogen atom.

(preparation method 2)

[ in the formula, R¹Y, n and U¹As defined above, R^2bRepresents an amino protecting group, R^3aRepresents C which may be substituted by halogen_2-6Alkyl, -C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴And R⁵Synonymous with the above), -C.ident.C-R⁶(R⁶Synonymous with the above) or

(wherein m represents an integer of 2 to 7) ].

R^2bExamples of the amino-protecting group in (b) include formyl, monochloroacyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethylcarbonyl, methoxymethyloxycarbonyl, trimethylsilyl, 2, 2, 2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbonyl (hereinafter also referred to as Boc), and trityl.

Preparation method 2 is a method of producing a compound (Id)) having the general formula (Id) by leaving an amino-protecting group of a compound (Ib)) having the general formula (Ib) by a method known per se to obtain a compound (Ic)) having the general formula (Ic) and reacting the compound (IV)) having the general formula (IV) with the compound (Ic). The compound (Ib) can be produced by reacting the compound (II) with the compound (IIIa) in the same manner and under the same reaction conditions as those in the reaction of the compound (II) with the compound (III) in the production process 1.

In preparation method 2, compound (IV) can be supplied to the reaction not only in the form of a free acid but also in the form of a salt (e.g., a salt of sodium salt, potassium salt, calcium salt, triethylamine salt, pyridine salt, etc.) or a reactive derivative (e.g., an acid halide such as acid chloride or acid bromide, an acid anhydride, a substituted phosphoric acid such as dialkylphosphoric acid, a mixed acid anhydride with an alkyl carbonate such as monoethylcarbonic acid, etc., an activated amide with an amide such as imidazole, etc., an ester such as cyanomethyl ester, 4-nitrophenyl ester, etc.), etc.

In addition, in the case where the compound (IV) is used in the form of a free acid or salt in the production process 2, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include dehydrating agents such as 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 アゾリイド compounds such as N, N '-carbonyldiimidazole and N, N' -thienyldiimidazole. When these condensing agents are used, it is considered that the reaction proceeds via the active derivative of the compound (IV).

In the production process 2, the reaction of the compound (Ic) with the compound (IV) is usually carried out in an inert solvent. As the inert solvent, acetone, hexamethylenedioxyne, acetonitrile, chloroform, benzene, methylene chloride, dichloroethane, tetrahydrofuran, ethyl acetate, N-dimethylformamide, pyridine, water, etc., or a mixture thereof can be specifically exemplified. Further, bases such as triethylamine, pyridine, 4-dimethylaminopyridine and potassium carbonate can be used. When such a base is used, the base is 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 (IV) used in the preparation process 2 is usually 1 to 5 mol, preferably 1 to 3 mol, based on 1 mol of the compound (Ic).

The reaction conditions such as the reaction temperature and the reaction time in the reaction of the compound (Ic) with the compound (IV) in the production process 2 vary depending on the reaction reagent and the reaction solvent used, but are usually-30 to 150 ℃ for 30 minutes to more than ten hours.

(preparation method 3)

[ in the formula, R¹Y and n have the same meanings as above, R¹⁷Represents C which may be substituted by halogen_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl group, and aryl group C which may be substituted_1-3Alkyl radical, U²A halogen atom, or a leaving group such as an alkanesulfonyloxy group such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, or a trifluoromethanesulfonyloxy group, or an arylsulfonyloxy group such as a benzenesulfonyloxy group or a toluenesulfonyloxy group.]

Production method 3 is a method of producing a compound having general formula (Ie) (compound (Ie)) by reacting a compound having general formula (V) (compound (V)) with compound (Ic).

The reaction of the compound (V) with the compound (Ic) to produce the compound (Ie) is carried out in the presence of a base in a solvent which does not interfere with the reaction, for example, hexamethylenetetramine, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, etc., and a mixture thereof.

The ratio of the compound (Ic) to the compound (V) is not particularly limited, but is preferably 1 to 5 moles, more preferably 1 to 3 moles of the compound (V) based on 1 mole of the compound (Ic).

The base which can be used in the reaction is not particularly limited, and examples thereof include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, metal hydrides such as sodium hydride, potassium hydride and calcium hydride, and organic bases such as triethylamine and diisopropylethylamine.

The molar ratio of the compound (Ic) to the base is not particularly limited, and 1 to 5 moles, more preferably 1 to 3 moles of the base are preferable based on 1 mole of the compound (Ic).

The reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent and the reaction solvent used, but are usually-30 to 150 ℃ for 30 minutes to more than ten hours.

In this process, R of the compound (Ic)¹Preferably an alkyl group, in which case R is obtained¹Is an alkyl compound (Ie), but R can also be derived by hydrolysis by methods known per se¹A compound (Ie) which is a hydrogen atom.

(preparation method 4)

[ in the formula, R¹Y and n have the same meanings as above, R¹⁸Formula (II): -CH₂R¹⁸Represents C which may be substituted by halogen_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl and aryl C which may be substituted_1-3An alkyl group.]

Production process 4 is a process for producing compound (If) by reducing compound (Id) obtained by reacting compound (Ic)) with compound (IV) with an appropriate reducing agent.

R¹⁸C which may be substituted by halogen in (1)_1-6Alkyl group "," C_3-8Cycloalkyl group "," C_3-8Cycloalkyl radical C_1-3Alkyl "and" aryl C which may be substituted_1-3Definition of alkyl radicals "withR²The groups in (1) are as defined.

The reaction of the compound (Ic) with the compound (IV) to obtain the compound (Id) in production Process 4 can be carried out in the same reaction mode and under the same reaction conditions as those of the reaction of the compound (Ic) with the compound (IV) in production Process 2.

In the preparation method 4, the solvent for the reaction to obtain the compound (If) by reacting the compound (Id) with a reducing agent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include water, methanol, ethanol, hexamethylenetetramine, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and the like, and a mixture thereof.

The reducing agent that can be used in the present reaction is not particularly limited, and examples thereof include metal complexes such as lithium aluminum hydride, sodium cyanoborohydride and sodium borohydride, and boranes.

The molar ratio of the compound (Id) to the reducing agent is not particularly limited, and it is preferable to use 1 to 5 moles, and more preferably 1 to 3 moles of the reducing agent per 1 mole of the compound (Id).

(preparation method 5)

(in the formula, R¹Y, n and R¹⁸The same meanings as above are given. )

Process 5 is a process for producing compound (If) by reacting compound (VI) with compound (Ic) in the presence of an appropriate reducing agent.

In the preparation process 5, the reaction of the compound (Ic) with the compound (VI) to obtain the compound (If) can be carried out by condensing the compound (Ic) with the compound (VI) in a solvent which does not interfere with the reaction, for example, water, methanol, ethanol, hexamethylenedioxyne, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and the like, and a mixture thereof in the presence of an appropriate reducing agent.

The reducing agent to be used in the reaction is not particularly limited, and examples thereof include metal complexes such as lithium aluminum hydride, sodium cyanoborohydride and sodium borohydride, and borane.

The molar ratio of the compound (Ic) to the compound (VI) is not particularly limited, and it is preferable to use 1 to 5 moles, more preferably 1 to 3 moles of the compound (VI) per 1 mole of the compound (Ic).

The molar ratio of the compound (Ic) to the reducing agent is not particularly limited, and it is preferable to use 1 to 5 moles, and more preferably 1 to 3 moles of the reducing agent per 1 mole of the compound (Ic).

Furthermore, the compound (III) used in the preparation process 1, wherein R is represented by the formula (III)^2ais-CO-R³(in the formula, R³Synonymous with the above-mentioned), -CO-C (R)⁴)＝C(R⁴)-R⁵(in the formula, R⁴And R⁵Synonymous with the above-mentioned), -CO-C.ident.C-R⁶(in the formula, R⁶Synonymous with the above), C which may be substituted with halogen_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl and aryl C which may be substituted_1-3In the case of an alkyl group, a compound having the general formula (IIIa) (compound (IIIa)) may be used as a raw material,

(in the formula, R¹Synonymous with the above, R¹⁶Represents a hydrogen atom or a hydroxyl protecting group), the reaction of production process 1 can be carried out in the same reaction manner and under the same reaction conditions as the reaction of compound (Ic) with compound (IV) in production process 2, the reaction of compound (Ic) with compound (V) in production process 3, or the reaction of compound (If) obtained from compound (Ic) in production process 4.

And in the general formula (III) when R is^2aIn the case of an amino-protecting group, R can be produced by introducing the amino-protecting group by a method known per se^2aCompound (III) which is an amino protecting group.

Examples of the amino-protecting group that can be used in the present production method include ethers such as methyl ether, isopropyl ether, t-butyl ether, benzyl ether, allyl ether, methoxymethyl ether, tetrahydropyrrolyl ether, p-bromobenzoylmethyl ether and trimethylsilyl ether, and esters such as acetyl, monochloroacyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, benzoyl, methanesulfonyl, benzenesulfonyl and p-toluenesulfonyl.

In the production of Compound (III), R in Compound (IIIa)¹⁶Preferably a hydroxyl protecting group. The hydroxyl-protecting group can be removed by a method known per se, and the compound (III) can be easily produced.

The heterocyclic compound (I) obtained in 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, fractionation, column chromatography, etc.

The heterocyclic compound (I) can be prepared into a pharmaceutically acceptable salt thereof by a method known per se.

The pharmaceutical composition comprising the heterocyclic compound (I) of the present invention or a pharmaceutically acceptable salt thereof may contain additives and the like. Examples of the additives include excipients (e.g., starch, lactose, granulated sugar, 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 disintegrating agents (e.g., carboxymethyl cellulose calcium, talc, etc.).

After mixing the above components, the mixture is prepared into oral preparations such as capsules, troches, fine granules, granules and anhydrous syrups or parenteral preparations such as injections and suppositories by a known method.

The dosage of the heterocyclic compound (I) or a pharmaceutically acceptable salt thereof varies depending on the subject, symptoms and other factors, and may be 1 to 500 mg per administration 1 to 3 times a day for oral administration to an adult in the case of diabetes, diabetic complications or hyperlipidemia patients.

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

The present invention will be described in detail by way of examples and reference examples, but the present invention is not limited to these examples.

Examples

Example 1

2- (2-heptenoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

(1) 500 mg of methyl 2- (2-heptenoyl) -7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate and 650 mg of 2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate were dissolved in 15 ml of toluene, and 650 mg of potassium carbonate and 100 mg of tetraethylammonium fluoride hydrate were added thereto, followed by stirring at 80 ℃ for 10 hours. To the reaction solution, 50 ml of ethyl acetate was added, followed by washing successively with 30 ml of water and 30 ml of saturated brine, drying (with sodium sulfate), and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 620 mg of methyl 2- (2-heptenoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

¹H-NMR(CDCl₃)δ(ppm)；0.95(6H，br-t)，1.15-1.75(6H，m)，2.00-2.45(4H，m)，2.27(3H，s)，2.87(2H，t，J＝6.8Hz)，3.00-3.30(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.8Hz)，4.50-5.70(3H，m)，6.18(1H，d，J＝15.8Hz)，6.35-7.20(5H，m)，7.04(1H，d，J＝8.2Hz).

(2) 200 mg of the compound obtained in the above (1) was dissolved in 5 ml of a tetrahydrofuran-methanol mixture (3: 1), and 1.2 ml of a 1M aqueous lithium hydroxide solution was added thereto, followed by stirring at 50 ℃ for 30 minutes. Making into acid with 10% citric acid water, and concentrating under reduced pressure. The precipitated gum was extracted with 20 ml of ethyl acetate, and the ethyl acetate layer was washed with 10 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to give 170 mg of 2- (2-heptenoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid. After dissolving it in 2 ml of methanol, 0.62 ml of 0.586M sodium hydroxide solution in methanol was added, and the methanol was distilled off under reduced pressure. The resulting residue was dissolved in 1 ml of water and lyophilized to obtain 170 mg of the title compound.

IRν(KBr)cm^-1；1653，1595，1506.

¹H-NMR(DMSO-d₆)δ(ppm)；0.89(6H，br-t)，1.10-1.75(6H，m)，1.90-2.20(4H，m)，2.25(3H，s)，2.79(2H，br-t)，3.00-3.30(2H，br)，4.07(2H，br-t)，4.20-5.15(3H，m)，6.19(1H，d，J＝16.7Hz)，6.30-6.80(5H，m)，6.96(1H，d，J＝8.4Hz).

Example 2

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

(1) 0.5 g 2-tert-butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester and 0.67 g 2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate were dissolved in 5 ml toluene, 0.68 g potassium carbonate and 0.12 g tetraethylammonium fluoride hydrate were added, and the mixture was stirred at 80 ℃ for 18 hours. To the reaction solution, 20 ml of ethyl acetate was added, followed by washing successively with 20 ml of water and 20 ml of saturated brine, drying (with sodium sulfate), and then distilling off the solvent under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.57 g of methyl 2-tert-butoxycarbonyl-7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；1746，1698，1615，1533，1505.

¹H-NMR(CDCl₃)δ(ppm)；0.89(3H，t，J＝7.0Hz)，1.20-1.80(11H，m)，2.00-2.40(2H，m)，2.28(3H，s)，2.89(2H，t，J＝6.8Hz)，2.90-3.20(2H，m)，3.61(3H，s)，4.15(2H，t，J＝6.8Hz)，4.40-4.90(2H，m)，5.00-5.20(1H，m)，6.18(1H，d，J＝16.1Hz)，6.73(1H，dt，J＝16.1，6.8Hz)，6.50-6.80(2H，m)，7.01(1H，d，J＝8.4Hz).

(2) 0.55 g of the compound obtained in the above (1) was dissolved in 3 ml of carboxylic acid, and 0.39 ml of 8.78M hydrogen chloride 2-propanol solution was added under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction solution was added 20 ml of ethyl acetate, and after neutralization with saturated sodium bicarbonate, the two layers were separated. The obtained ethyl acetate layer was washed with 10 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to obtain 0.39 g of methyl 7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；1743，1505.

¹H-NMR(CDCl₃)δ(ppm)；0.94(3H，t，J＝7.0Hz)，1.20-1.70(2H，m)，2.00-2.40(3H，m)，2.27(3H，s)，2.50-3.20(2H，m)，2.86(2H，t，J＝6.7Hz)，3.60-3.90(1H，m)，3.76(3H，s)，4.05(2H，s)，4.14(2H，t，J＝6.7Hz)，6.17(1H，d，J＝l6.0Hz)，6.40-6.80(1H，m)，6.54(1H，d，J＝2.6Hz)，6.69(1H，dd，J＝8.3，2.6Hz)，6.99(1H，d，J＝8.3Hz).

(3) 0.36 g of the compound obtained in the above (2) was dissolved in 5 ml of methylene chloride, and 0.13 g of pyrroside chloride and 0.17 ml of triethylamine were added thereto, followed by stirring at room temperature for 30 minutes. 30 ml of ethyl acetate was added, and the mixture was washed with 15 ml of 10% citric acid water and 15 ml of saturated brine in this order, dried (with sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.4 g of methyl 2- (2, 4-hexadienoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；1740，1655，1628，1605，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝6.8Hz)，1.20-1.70(2H，m)，1.85(3H，d，J＝5,0Hz)，2.00-2.40(2H，m)，2.04(3H，s)，2.87(2H，t，J＝6.7Hz)，3.00-3.25(2H，m)，3.59(3H，s)，4.15(2H，t，J＝6.7Hz)，4.50-5.65(3H，m)，6.00-6.90(7H，m)，7.03(1H，d，J＝8.2Hz)，7.15-7.55(1H，m).

(4) 0.37 g of the compound obtained in (3) above was dissolved in 9.4 ml of a tetrahydrofuran-methanol (3: 1) mixture, and 2.35 ml of a 1M aqueous lithium hydroxide solution was added thereto and stirred at 50 ℃ for 30 minutes. Making into acid with 10% citric acid water, and concentrating under reduced pressure. The precipitated gum was extracted with 50 ml of ethyl acetate, and the ethyl acetate layer was washed with 30 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to obtain 0.28 g of the title compound.

IRν(nujol)cm^-1；1728，1651，1616，1531，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.92(3H，t，J＝6.8Hz)，1.20-1.75(2H，m)，1.84(3H，d，J＝4.8Hz)，2.14(2H，m)，2.22(3H，s)，2.65(2H，br-t)，2.80-3.50(2H，m)，3.95(2H，br-t)，4.60-5.10(3H，m)，5.40-5.65(1H，m)，6.00-6.80(5H，m)，7.02(1H，d，J＝8.4Hz)，7.15-7.55(1H，m)，9.80-10.50(1H，br).

Example 3

2- (2-heptenoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

210 mg of the compound of example 2(2) was dissolved in 2.1 ml of dichloromethane, and 105 mg of 2-heptanoic acid and 160 mg of 1-ethyl-3- (3' -dimethylaminopropanol) carbodiimide hydrochloride were added and stirred at room temperature for 1 hour. 30 ml of ethyl acetate was added, and the mixture was washed with 15 ml of 10% citric acid water and 15 ml of saturated brine, dried (with sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 200 mg of methyl 2- (2-heptenoyl) -7- [2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

¹The H-NMR data agree with those of the compound of example 1 (1).

The compounds of examples 4 to 15 were synthesized according to examples 1 to 3.

Example 4

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

IRν(nujol)cm^-1；2237，1717，1684，1616，1576，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.85-1.20(6H，m)，1.25-1.90(4H，m)，2.00-2.50(4H，m)，2.24(3H，s)，2.60-3.50(4H，m)，3.80-4.10(2H，m)，4.35-5.20(2H，m)，5.30-5.65(1H，m)，6.18(1H，d，J＝16.0Hz)6.45-6.85(3H，m)，7.02(1H，d，J＝7.9Hz)，8.80-9.40(1H，br).

Example 5

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

IRν(nujol)cm^-1；1729，1652，1615，1575.

¹H-NMR(CDCl₃)δ(ppm)；1.83(3H，br-d)，2.28(3H，s)，2.82(2H，br-t)，2.90-3.50(2H，m)，4.03(2H，br-t)，4.60-5.10(3H，m)，5.40-5.65(1H，m)，6.00-6.80(5H，m)，6.84(1H，d，J＝16.5Hz)，7.04(1H，d，J＝8.4Hz)，7.15-7.65(7H，m)，9.40-10.20(1H，br).

Example 6

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

IRν(nujol)cm^-1；1740，1653，1612，1553，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.70-1.00(3H，br)，1.10-1.75(4H，m)，1.90-2.40(2H，br)，2.29(3H，s)，2.60-3.40(4H，m)，3.75-4.20(2H，m)，4.55-5.10(2H，m)，5.40-5.70(1H，m)，6.33(1H，d，J＝15.7Hz)，6.55-7.25(5H，m)，7.30-7.70(6H，m)，8.00-8.80(1H，br).

Example 7

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

IRν(nujol)cm^-1；2235，1734，1630，1580，1528，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.96，1.04(3H，t，t，J＝6.7Hz)，1.35-1.80(2H，m)，2.20-2.50(2H，m)，2.29(3H，s)，2.70-3.50(4H，m)，3.80-4.15(2H，m)，4.55-5.20(2H，m)，5.30-5.60(2H，m)，6.45-6.70(2H，m)，7.85(1H，d，J＝16.5Hz)，7.25-7.65(6H，m)，7.90-8.60(1H，br).

Example 8

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

IRν(nujol)cm^-1；1732，1680，1647，1614，1578，1531，1506.

¹H-NMR(CDCl₃+DMSO-d₆)δ(ppm)；2.34(3H，s)，2.91(2H，t，J＝6.6Hz)，3.10-3.30(2H，m)，4.18(2H，t，J＝6.6Hz)，4.40-5.30(3H，m)，6.50-6.90(2H，m)，6.84(1H，d，J＝16.5Hz)，6.90-7.25(2H，m)，7.30-7.60(5H，m).

Example 9

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

IRν(nujol)cm^-1；1732，1657，1614，1585，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.05(3H，br)，1.10-1.75(4H，br)，2.00-2.50(4H，m)，2.38(3H，s)，2.70-3.40(4H，m)，3.90-4.30(2H，m)，4.50-5.10(2H，m)，5.35-5.70(1H，m)，6.10-7.70(13H，m).

Example 10

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

IRν(nujol)cm^-1；1730，1648，1616，1456，1377，990.

¹H-NMR(DMSO-d₆)δ(ppm)；1.83(6H，br-s)，2.27(3H，s)，2.6-3.4(4H，m)，4.12(2H，br-t)，4.2-5.0(2H，m)，5.18(1H，br-t)，5.9-7.4(11H，m).

Example 11

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

IRν(nujol)cm^-1；1728，1653，1616，1574，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.87(3H，t，J＝5.9Hz)，1.10-1.40(4H，m)，1.45-1.80(2H，m)，1.84(3H，d，J＝4.6Hz)，2.20(3H，s)，2.65(2H，t，J＝8.1Hz)，2.73(2H，br-t)，3.93(2H，br-t)，4.40-5.10(3H，m)，5.45-5.70(1H，m)，6.10-6.80(5H，m)，7.03(1H，d，J＝8.6Hz)，7.10-7.50(1H，m)，9.10-10.00(1H，br).

Example 12

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

IRν(nujol)cm^-1；1733，1652，1615，1568.

¹H-NMR(CDCl₃)δ(ppm)；1.0-2.0(11H，m)，2.20(3H，s)，2.77(2H，t，J＝6.0Hz)，2.8-3.4(3H，m)，3.93(2H，t，J＝6.4Hz)，4.6-5.0(2H，m)，5.54(1H，br-t)，6.0-6.8(5H，m)，7.02(1H，d，J＝8.4Hz)，7.1-7.6(1H，m)，8.8-9.6(1H，br).

Example 13

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

IRν(nujol)cm^-1；1733，1652，l61，1456，1377，1260，999.

¹H-NMR(DMSO-d₆)δ(ppm)；1.0-2.0(13H，m)，2.20(3H，s)，2.77(2H，t，J＝6.4Hz)，2.8-3.4(3H，m)，4.09(2H，t，J＝6.4Hz)，4.2-5.0(2H，m)，5.17(1H，br-t)，5.9-7.3(7H，m).

Example 14

2- (2-heptenoyl) -7- [2- (1-phenylethylideneaminooxo) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；1732，1716，1651，1574，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.05(3H，m)，1.10-1.70(4H，m)，2.00-2.40(2H，m)，2.21(3H，s)，2.80-3.30(2H，m)，4.10-4.30(2H，m)，4.40-5.10(4H，m)，5.30-5.60(1H，m)，6.15-7.15(6H，m)7.25-7.50(3H，m)，7.60-7.80(2H，m).

Example 15

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

IRν(nujol)cm^-1；1726，1612，1582，1502.

¹H-NMR(DMSO-d₆)δ(ppm)；0.70-1.10(3H，m)，1.20-1.70(4H，m)，2.00-2.30(2H，m)，2.29(3H，s)，2.90-3.60(5H，m)，4.04(2H，t，J＝5.9Hz)，4.35-4.95(2H，m)，5.00-5.30(1H，m)，6.35-6.90(4H，m)，7.09(1H，d，J＝7.9Hz)，7.35-7.70(5H，m).

Example 16

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

(1) 2.43 g 2- (2-aminothiazole-5-yl) ethyl methane sulfonate and 2.17 g 2-tert-butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester were dissolved in 50 ml N, N-dimethylformamide, and 5.20 g cerium carbonate was added and stirred at 55 ℃ for 15 hours. To the reaction solution was added 200 ml of water, and the mixture was extracted three times with 100 ml of ethyl acetate. The ethyl acetate was washed twice with 100 ml of water, washed with 100 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to obtain 2.20 g of methyl 7- (2-aminooxazol-5-yl) ethoxy-2-tert-butoxycarbonyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

¹H-NMR(CDCl₃)δ(ppm)；1.46，1.51(9H，s，s)，2.80-3.30(4H，m)，3.61(3H，s)，4.07(2H，t，J＝6.3Hz)，4.30-4.90(4H，m)，4.95-5.25(1H，m)，6.55-6.90(3H，m)，7.03(1H，d，J＝8.4Hz).

(2) 500 mg of the compound obtained in the above-mentioned (1) was dissolved in 5.0 ml of N, N-dimethylformamide, and 0.25 ml of triethylamine and 0.16 ml of benzoyl chloride were added thereto, followed by stirring at 55 ℃ for 15 hours. To the reaction solution, 20 ml of water was added, and the mixture was extracted three times with 10 ml of ethyl acetate. The ethyl acetate layer was washed twice with 20 ml of water and then with 20 ml of saturated brine, dried (with sodium sulfate), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 535 mg of methyl 7- (2-benzoylaminooxazol-5-yl) ethoxy-2-tert-butoxycarbonyl-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(nujol)cm^-1；1746，1684，1605，1582，1555，1535，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.46，1.51(9H，s，s)，2.90-3.30(5H，m)，3.61(3H，s)，4.11(2H，t，J＝6.1Hz)，4.20-4.90(2H，m)，4.95-5.25(1H，m)，6.55-6.90(3H，m)，7.04(1H，d，J＝7.9Hz)，7.30-7.70(3H，m)，7.90-8.20(2H，m).

(3) 535 mg of the compound obtained in the above (2) was dissolved in 2.0 ml of carboxylic acid, and 0.30 ml of 8.78M hydrogen chloride 2-propanol solution was added under ice cooling, and stirred at the same temperature for 15 minutes. The reaction solution was neutralized with saturated sodium bicarbonate solution, and extracted with 30 ml of chloroform. After drying (with sodium sulfate), chloroform was distilled off under reduced pressure to give 401 mg of methyl 7- (2-benzoylaminothiazol-5-yl) ethoxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(nujol)cm^-1；3161，1744，1659，1603，1582，1558，1535，1501.

¹H-NMR(CDCl₃)δ(ppm)；2.90-3.10(2H，m)，3.19(2H，t，J＝6.1Hz)，3.60-3.80(1H，m)，3.77(3H，s)，4.00-4.30(4H，m)，6.58(1H，d，J＝2.2Hz)，6.74(1H，dd，J＝2.2，8.4Hz)，6.95-7.10(2H，m)，7.30-7.60(3H，m)，7.85-8.10(2H，m).

(4) 400 mg of the compound obtained in the above-mentioned (3) was dissolved in 5.0 ml of methylene chloride, and 0.19 ml of 2-heptenoic acid and 265 mg of 1-ethyl-3- (3' -dimethylaminopropyl) carbodiimide hydrochloride were added under ice cooling, and stirred at room temperature for 1 hour. The extract was washed with 10 ml of 10% citric acid water and 30 ml of saturated brine in this order, dried (with sodium sulfate), and then the dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 495 mg of methyl 7- (2-benzoylaminooxazol-5-yl) ethoxy-2- (2-heptenoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；3165，1740，1661，1616，1558，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.80-1.10(3H，m)，1.20-1.70(4H，m)，2.00-2.50(2H，m)，3.00-3.45(4H，m)，3.60(3H，s)，4.12(2H，t，J＝5.9Hz)，4.50-5.00(2H，m)，5.40-5.60(1H，m)，6.35(1H，d，J＝15.1Hz)，6.65-7.20(4H，m)，7.35-7.70(3H，m)，7.80-8.15(2H，m).

(5) 490 mg of the compound obtained in the above (4) was dissolved in 20 ml of a tetrahydrofuran-methanol (3: 1) mixture, and 3.0 ml of a 1M aqueous lithium hydroxide solution was added thereto, followed by stirring at 50 ℃ for 30 minutes. The mixture was acidified with 10% citric acid water, and the solvent was distilled off under reduced pressure. The precipitated crystals were filtered to give 342 mg of the title compound.

IRν(nujol)cm^-1；1734，1655，1603，1560，1541，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.80-1.10(3H，m)，1.20-1.70(4H，m)，2.00-2.50(2H，m)，2.80-3.40(4H，m)，3.80-4.20(2H，m)，4.50-5.05(2H，m)，5.50-5.80(1H，m)，6.05-7.20(6H，m)，7.30-7.70(3H，m)，7.80-8.15(2H，m)，9.60-11.20(1H，br).

The compound of example 17 was synthesized according to example 16.

Example 17

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

IRν(nujol)cm^-1；3172，1734，1692，1655，1612，1562，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，t，J＝7.0Hz)，1.10-1.90(6H，m)，2.10-2.60(2H，m)，2.80-3.50(4H，m)，3.80-4.30(2H，m)，4.40-5.10(2H，m)，5.55-5.80(1H，m)，6.10-7.30(6H，m)，9.60-11.20(2H，br).

Example 18

7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3RS) -carboxylic acid methyl ester

(1) 1.0 g 2-tert-butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester and 1.4 g 2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate were dissolved in 30 ml toluene, and 1.35 g potassium carbonate and 0.2 g tetraethylammonium fluoride hydrate were added and stirred at 80 ℃ for 13 hours. To the reaction solution was added 50 ml of ethyl acetate, and the mixture was washed successively with 50 ml of water and 30 ml of saturated brine, dried (over sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.6 g of methyl 2-tert-butoxycarbonyl-7- [2- (5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；2957，2928，2872，1746，1701，1614，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.3Hz)，1.46，1.50(9H，s，s)，1.50-2.00(1H，m)，2.11(2H，t，J＝6.8Hz)，2.28(3H，s)，2.87(2H，t，J＝6.6Hz)，3.00-3.25(2H，m)，3.61(3H，s)，4.15(2H，t，J＝6.6Hz)，4.45-5.25(3H，m)，6.15(1H，d，J＝15.8Hz)，6.45-6.80(3H，m)，7.01(1H，d，J＝8.8Hz).

(2) 1.6 g of the compound obtained in the above (1) was dissolved in 8 ml of formic acid, and 1.1 ml of 8.78M hydrogen chloride 2-propanol solution was added under ice cooling, followed by stirring at room temperature for 15 minutes. To the reaction solution were added 50 ml each of ethyl acetate and water, followed by neutralization with sodium hydrogencarbonate and separation of the two layers. The obtained ethyl acetate layer was washed with 30 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to obtain 1.17 g of the title compound.

IRν(neat)cm^-1；3344，2955，2926，2870，1738，1661，1641，1612，1533，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.3Hz)，1.50-1.95(1H，m)，2.11(2H，t，J＝6.6Hz)，2.12(1H，br-s)，2.28(3H，s)，2.87(2H，t，J＝6.8Hz)，2.90-3.10(2H，m)，3.55-3.90(1H，m)，3.77(3H，s)，4.06(2H，s)，4.14(2H，t，J＝6.8Hz)，6.16(1H，d，J＝15.8Hz)，6.40-6.80(3H，m)，7.00(1H，d，J＝8.4Hz).

Example 19

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.15 g of the compound obtained in example 18 was dissolved in 20 ml of methylene chloride, and 0.45 g of pyruvoyl chloride and 0.6 ml of triethylamine were added thereto and stirred at room temperature for 15 minutes. 30 ml of methylene chloride was added, and 30 ml of each of water and a saturated common salt solution was added and washed, and after drying (with sodium sulfate), methylene chloride was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.36 g of methyl 2- (2, 4-hexadienoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；1740，1655，1628，1533，1508.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.4Hz)，1.50-1.95(4H，m)，2.11(2H，t，J＝7.0Hz)，2.28(3H，s)，2.87(2H，t，J＝6.6Hz)，3.00-3.30(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.6Hz)，4.50-5.15(2H，m)，5.40-5.70(1H，m)，6.00-6.90(7H，m)，7.04(1H，d，J＝8.2Hz)，7.15-7.55(1H，m).

(2) 1.36 g of the compound obtained in (1) above was dissolved in 16 ml of a tetrahydrofuran-methanol mixture (3: 1), and 8.3 ml of a 1M aqueous lithium hydroxide solution was added thereto and stirred at room temperature for 30 minutes. Making into acid with 10% citric acid water, and concentrating under reduced pressure. The precipitated gum was extracted with 50 ml of ethyl acetate, and the ethyl acetate layer was washed with 30 ml of saturated brine and dried (over sodium sulfate). Ethyl acetate was distilled off under reduced pressure to give 1.26 g of the title compound.

IRν(neat)cm^-1；2959，2930，2872，1738，1651，1620，1583，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.92(6H，d，J＝6.4Hz)，1.45-2.00(1H，m)，1.84(3H，d，J＝4.9Hz)，2.09(2H，t，J＝7.0Hz)，2.23(3H，s)，2.78(2H，t，J＝6.4Hz)，2.95-3.40(2H，m)，4.00(2H，t，J＝6.4Hz)，4.30-5.65(3H，m)，5.95-7.55(9H，m).

Example 20

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

1.25 g of the compound obtained in example 19 was dissolved in 7.0 ml of methanol, 0.55 ml of tert-butylamine was added dropwise thereto, and 70 ml of diisobutyl ether was added thereto and stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration to obtain 1.15 g of the title compound.

IRν(neat)cm^-1；2741，2633，2544，1653，1628，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.6Hz)，0.99(9H，s)，1.60-2.00(4H，m)，2.10(2H，t，J＝6.8Hz)，2.28(3H，s)，2.86(2H，t，J＝6.8Hz)，2.90-3.40(2H，m)，4.11(2H，t，J＝6.8Hz)，4.30-5.25(3H，m)，6.00-7.50(12H，m).

Example 21

7- {2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

(1) 2.93 g 2-tert-butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester and 4.29 g 2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethyl methanesulfonate were dissolved in 90 ml of toluene, and 3.95 g of potassium carbonate and 0.75 g of tetraethylammonium fluoride hydrate were added thereto, followed by stirring at 90 ℃ for 16 hours. To the reaction solution was added 30 ml of ethyl acetate, and the mixture was washed successively with 50 ml of water and 50 ml of saturated brine, dried (over sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.9 g of methyl 2-tert-butoxycarbonyl-7- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] oxazol-4-ylethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline- (3RS) -carboxylate.

IRν(neat)cm^-1；2955，2970，1742，1699，1614，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.20-2.00(17H，m)，2.27(3H，s)，2.34-2.74(1H，m)，2.86(2H，t，J＝6.6Hz)，2.99-3.20(2H，m)，3.61(3H，s)，4.12(2H，t，J＝6.6Hz)，4.24-5.20(3H，m)，6.15(1H，d，J＝16.1Hz)，6.61(1H，dd，J＝16.1，7.5Hz)，6.53-6.80(2H，m)，7.01(1H，d，J＝8.3Hz).

(2) 3.89 g of the compound obtained in the above (1) was dissolved in 9.7 ml of formic acid, and 2.28 ml of a 10M solution was added under ice cooling, followed by stirring at room temperature for 35 minutes. The reaction mixture was poured into 200 ml of a mixture of diisopropyl ether and hexane (1: 1) under ice cooling, and the resultant oily substance was separated by decantation. The resulting oily substance was dissolved in 100 ml of ethyl acetate, 100 ml of water was added, and the two layers were separated after neutralization with sodium hydrogencarbonate. The ethyl acetate layer was washed successively with 50 ml of water and 50 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. 3.07 g of the title compound are obtained.

IRν(neat)cm^-1；3344，2951，2870，2777，2740，1659，1643，1612，1504.

¹H-NMR(CDCl₃)δ(ppm)；1.20-1.97(8H，m)，1.99(1H，s)，2.27(3H，s)，2.30-2.77(1H，m)，2.86(2H，t，J＝6.7Hz)，2.80-3.10(2H，m)，3.60-3.83(1H，m)，3.76(3H，s)，3.95-4.34(4H，m)，6.15(1H，d，J＝16.0Hz)，6.41-6.80(3H，m)，6.99(1H，d，J＝8.4Hz).

Example 22

7- {2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

(1) 3.05 g of the compound obtained in example 21 was dissolved in 30 ml of dichloroethane, and 1.12 g of sorbic acid chloride and 1.35 ml of triethylamine were added under ice cooling, followed by stirring at the same temperature for 20 minutes. The extract was washed with 10% citric acid water and 20 ml of saturated brine, dried (with sodium sulfate), and then the dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.49 g of methyl 7- {2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；3464，2953，2870，1740，1657，1628，1605，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.20-1.97(8H，m)，1.85(3H，d，J＝4.8Hz)，2.27(3H，s)，2.40-2.75(1H，m)，2.86(2H，t，J＝6.5Hz)，3.00-3.22(2H，m)，3.59(3H，s)，4.14(2H，t，J＝6.5Hz)，4.36-5.00(2H，m)，5.40-5.60(1H，m)，6.07-6.80(5H，m)，6.15(1H，d，J＝16.1Hz)，6.61(1H，dd，J＝16.1，7.2Hz)，7.03(1H，d，J＝8.4Hz)，7.13-7.50(1H，m).

(2) 2.48 g of the compound obtained in (1) above was dissolved in 60 ml of a tetrahydrofuran-methanol (3: 1) mixture, and 14.7 ml of a 1M aqueous lithium hydroxide solution was added thereto and stirred at room temperature for 50 minutes. The solution was made acidic with 6M hydrochloric acid and concentrated under reduced pressure. The precipitated gum was extracted with 30 ml of ethyl acetate, and the ethyl acetate layer was washed with 30 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was dissolved in 2.4 ml of methanol, 1.0 ml of tert-butylamine was added dropwise thereto, and 30 ml of diisopropyl ether was added thereto and stirred under ice cooling for 20 minutes. The precipitated crystals were filtered to obtain 2.41 g of the title compound.

IRν(nujol)cm^-1；2731，2631，2544，1653，1626，1553，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.20-2.05(11H，m)，2.27(3H，s)，2.38-2.73(1H，m)，2.85(2H，t，J＝6.5Hz)，2.90-3.40(2H，m)，4.10(2H，t，J＝6.5Hz)，4.26-5.203H，m)，5.86-7.38(12H，m).

Example 23

2- (2-heptenoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(nujol)cm^-1；2955，2928，2872，1740，1661，1622，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-2.15(3H，m)，0.94(6H，d，J＝6.4Hz)，1.20-2.00(5H，m)，2.20-2.45(2H，m)，2.11(2H，t，J＝6.6Hz)，2.28(3H，s)，2.87(2H，t，J＝6.8Hz)，3.00-3.325(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.8Hz)，4.40-5.60(3H，m)，6.16(1H，d，J＝16.0Hz)，6.35-7.20(6H，m).

Example 24

2- (2-heptenoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；1661，1616，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-2.20(3H，m)，0.93(6H，d，J＝6.4Hz)，1.02(9H，s)，1.20-1.60(4H，m)，1.60-1.95(1H，m)，1.95-2.30(2H，m)，2.10(2H，t，J＝6.6Hz)，2.28(3H，s)，2.86(2H，t，J＝6.8Hz)，3.00-3.40(2H，m)，4.10(2H，t，J＝6.8Hz)，4.40-5.20(3H，m)，6.15(1H，d，J＝16.1Hz)，6.10-7.20(9H，m).

Example 25

7- {2- [2- (trans-1-hexen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3346，2955，2928，2872，1742，1661，1612，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.72-1.06(3H，m)，1.06-1.65(4H，m)，1.96-2.40(3H，m)，2.27(3H，s)，2.80-3.02(2H，m)，2.86(2H，t，J＝6.7Hz)，3.57-3.74(1H，m)，3.76(3H，s)，3.91-4.10(2H，m)，4.14(2H，t，J＝6.7Hz)，6.16(1H，d，J＝16.0Hz)，6.39-6.79(3H，m)，6.99(1H，d，J＝7.5Hz).

Example 26

2- (2, 4-Hexanedienoyl) -7- {2- [2- (trans-1-hexen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3468，3020，2957，2930，2872，1740，1657，1629，1605，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.07(3H，m)，1.20-1.60(4H，m)，1.85(3H，d，J＝5.0Hz)，2.08-2.40(2H，m)，2.27(3H，s)，2.87(2H，t，J＝6.6Hz)，3.00-3.25(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.6Hz)，4.35-5.10(2H，m)，5.52(1H，br-t)，5.96-6.84(7H，m)，7.01(1H，d，J＝8.4Hz)，7.15-7.50(1H，m).

Example 27

2- (2, 4-Hexanadienoyl) -7- {2- [2- (trans-1-hexen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3400，2745，2637，2548，2220，1651，1626，1556，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.16(3H，m)，0.98(9H，s)，1.20-1.60(4H，m)，1.70-2.00(3H，m)，2.07-2.40(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.5Hz)，2.88-3.30(2H，m)，4.11(2H，t，J＝6.5Hz)，4.25-5.20(3H，m)，5.90-7.40(12H，m).

Example 28

7- {2- [ 5-methyl-2- (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3346，2953，2926，2870，2849，1742，1641，1612，1533，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.90(6H，d，J＝6.1Hz)，1.15-1.73(3H，m)，1.86(1H，br-s)，2.04-2.40(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.90-3.06(2H，m)，3.55-3.75(1H，m)，3.77(3H，s)，3.90-4.10(2H，m)，4.22(2H，t，J＝6.6Hz)，6.17(1H，d，J＝16.0Hz)，6.39-6.81(3H，m)，6.99(1H，d，J＝8.3Hz).

Example 29

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3462，2955，2928，2870，1740，1653，1630，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.90(6H，d，J＝6.2Hz)，1.14-1.72(3H，m)，1.86(3H，d，J＝5.0Hz)，2.05-2.40(2H，m)，2.27(3H，s)，2.87(2H，t，J＝6.6Hz)，3.00-3.25(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.6Hz)，4.39-5.20(2H，m)，5.42-5.65(1H，m)，6.00-6.87(7H，m)，7.04(1H，d，J＝8.1Hz)，7.18-7.51(1H，m).

Example 30

2- (2, 4-Hexanadienoyl) -7- {2- [ 5-methyl-2- (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3400，2735，2635，2550，1657，1634，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.90(6H，d，J＝6.3Hz)，0.97(9H，s)，1.20-1.70(3H，m)，1.70-1.98(3H，m)，2.06-2.40(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.4Hz)，2.90-3.25(2H，m)，4.10(2H，t，J＝6.4Hz)，4.25-5.20(3H，m)，5.72-7.38(12H，m).

Example 31

7- {2- [ 5-methyl-2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3344，2957，2930，2872，1742，1647，1612，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝7.2Hz)，1.20-1.72(2H，m)，2.02(3H，s)，2.03-2.30(3H，m)，2.27(3H，s)，2.88(2H，t，J＝6.8Hz)，2.90-3.10(2H，m)，3.60-3.80(1H，m)，3.76(3H，s)，4.05(2H，s)，4.14(2H，t，J＝6.8Hz)，6.30-6.80(3H，m)，6.99(1H，d，J＝8.4Hz).

Example 32

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3462，2957，2930，2872，1740，1655，1628，1612，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝7.0Hz)，1.20-1.75(2H，m)，1.86(3H，d，J＝5.0Hz)，2.00-2.30(2H，m)，2.04(3H，s)，2.28(3H，s)，2.89(2H，t，J＝6.5Hz)，3.02-3.25(2H，m)，3.60(3H，s)，4.15(2H，t，J＝6.5Hz)，4.36-5.00(2H，m)，5.50(1H，br-t)，5.92-6.85(6H，m)，7.03(1H，d，J＝8.1Hz)，7.15-7.53(1H，m).

Example 33

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2748，2637，2544，2220，1651，1624，1600，1553.

¹H-NMR(CDCl₃)δ(ppm)；0.80-1.08(3H，m)，0.97(9H，s)，1.11-1.70(2H，m)，1.70-1.93(3H，m)，1.93-2.35(2H，m)，2.01(3H，s)，2.27(3H，s)，2.87(2H，t，J＝6.7Hz)，2.90-3.40(2H，m)，4.10(2H，t，J＝6.7Hz)，4.24-5.20(3H，m)，5.92-7.38(11H，m).

Example 34

7- {2- [ 5-methyl-2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；2956，2932，2875，1739，1646，1611，1582，1533，1505.

¹H-NMR(CDCl₃)δ(ppm)；1.06(3H，t，J＝7.5Hz)，2.01(3H，s)，2.10-2.45(3H，m)，2.27(3H，s)，2.70-3.20(4H，m)，3.55-3.90(1H，m)，3.76(3H，s)，4.05(2H，s)，4.14(2H，t，J＝6.8Hz)，6.25-6.85(3H，m)，6.99(1H，d，J＝8.6Hz).

Example 35

2- (2, 4-Hexanadieneacyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；2961，2933，2875，1739，1652，1627，1606，1534，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.06(3H，t，J＝7.5Hz)，1.85(3H，d，J＝5.0Hz)，2.01(3H，s)，2.05-2.45(2H，m)，2.28(3H，s)，2.89(2H，t，J＝6.4Hz)，3.00-3.40(2H，m)，4.15(2H，t，J＝6.4Hz)，4.30-5.65(3H，m)，7.03(1H，d，J＝8.4Hz)，5.90-7.60(7H，m).

Example 36

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2733，2635，2550，1657，1634，1611，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.05(3H，t，J＝7.5Hz)，1.65-1.95(3H，m)，2.01(3H，s)，2.05-2.45(2H，m)，2.28(3H，s)，2.87(2H，t，J＝6.7Hz)，2.90-3.30(2H，m)，4.11(2H，t，J＝6.7Hz)，4.25-5.20(3H，m)，5.90-8.30(12H，m).

Example 37

7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (2, 2, 3, 3, 3-pentafluoropropionyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；2725，2509，1917，1732，1682，1614，1589，1531.

¹H-NMR(CDCl₃)δ(ppm)；0.93(3H，t，J＝7.1Hz)，1.20-1.70(2H，m)，2.00-2.38(2H，m)，2.23(3H，s)，2.59-2.87(2H，m)，2.91-3.52(2H，m)，3.64-4.00(2H，m)，4.21-5.03(2H，m)，5.03-5.47(1H，m)，6.18(1H，d，J＝16.3Hz)，6.42-6.85(3H，m)，7.05(1H，d，J＝8.4Hz)，7.14-7.68(1H，br).

Example 38

7- {2- [2- (trans-2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；2926，2851，1740，1641，1612，1582，1533，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.80-2.45(11H，m)，2.27(3H，s)，2.70-3.20(2H，m)，2.86(2H，t，J＝7.0Hz)，3.55-3.85(1H，m)，3.76(3H，s)，4.04(2H，s)，4.14(2H，t，J＝6.8Hz)，6.12(1H，d，J＝16.0Hz)，6.40-6.80(3H，m)，6.99(1H，d，J＝8.4Hz).

Example 39

7- {2- [2- (trans-2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(nujol)cm^-1；1745，1614，1531，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.85-2.45(14H，m)，2.27(3H，s)，2.87(2H，t，J＝6.8Hz)，3.00-3.35(2H，m)，3.59(3H，s)，4.15(2H，t，J＝6.8Hz)，4.30-5.65(3H，m)，6.00-7.55(7H，m)，6.50(1H，d，J＝6.4Hz)，7.03(1H，d，J＝8.4Hz).

Example 40

7- {2- [2- (trans-2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2739，2635，2548，1655，1630，1560，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.98(9H，s)，1.00-2.40(14H，m)，2.27(3H，s)，2.85(2H，t，J＝6.8Hz)，2.90-3.30(2H，m)，4.10(2H，t，J＝6.8Hz)，4.20-5.20(3H，m)，5.80-7.45(12H，m).

EXAMPLE 41

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

IRν(nujol)cm^-1；1728，1647，1612，1578，1533，1506.

¹H-NMR(DMSO-d₆)δ(ppm)；0.89(3H，t，J＝7.3Hz)，1.20-1.70(2H，m)，1.95-2.25(2H，m)，2.26(3H，s)，2.65-2.95(2H，m)，2.95-3.15(2H，m)，3.60-5.80(1H，br)，3.95-4.35(2H，m)，4.40-5.60(3H，m)，6.19(1H，d，J＝16.5Hz)，6.33-6.90(3H，m)，7.11(1H，d，J＝8.4Hz)，7.30-7.95(7H，m).

Example 42

7- {2- [2- (3-ethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2735，2633，2544，1653，1624，1599，1551，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.87(6H，t，J＝7.2Hz)，0.96(9H，s)，1.20-1.63(4H，m)，1.63-2.10(4H，m)，2.28(3H，s)，2.86(2H，t，J＝6.8Hz)，2.90-3.30(2H，m)，4.11(2H，t，J＝6.8Hz)，4.40-5.30(3H，m)，5.80-7.60(12H，m).

Example 43

7- {2- [2- (3, 3-dimethyl-trans-1-butenyl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3568，2745，2637，2216，1653，1553.

¹H-NMR(CDCl₃)δ(ppm)；0.97(18H，s)，1.60-2.00(3H，m)，2.28(3H，s)，2.86(2H，t，J＝6.5Hz)，2.90-3.35(2H，m)，4.11(2H，t，J＝6.5Hz)，4.28-5.20(3H，m)，5.90-7.48(12H，m).

Example 44

7- {2- [2- (3, 3-dimethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3400，2745，2635，2544，2220，1651，1622，1553.

¹H-NMR(CDCl₃)δ(ppm)；0.82(3H，t，J＝7.3Hz)，0.98(9H，s)，1.05(6H，s)，1.41(2H，q，J＝7.3Hz)，1.63-1.94(3H，m)，2.28(3H，s)，2.86(2H，t，J＝6.8Hz)，2.90-3.37(2H，m)，4.11(2H，t，J＝6.8Hz)，4.23-5.20(3H，m)，6.09(1H，d，J＝16.3Hz)，6.00-7.39(11H，m).

Example 45

7- {2- [2- (4, 4-dimethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2733，2635，2550，1657，1634，1611，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.94(9H，s)，1.01(9H，s)，1.65-1.95(3H，m)，2.09(2H，d，J＝7.5Hz).2.28(3H，s)，2.86(2H，t，J＝6.6Hz)，2.90-3.30(2H，m)，4.11(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，5.90-7.35(12H，m).

Example 46

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (3-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2741，2633，2544，1651，1622，1553，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.01(9H，s)，1.08(6H，d，J＝6.7Hz)，1.65-1.95(3H，m)，2.28(3H，s)，2.35-2.70(1H，m)，2.86(2H，t，J＝6.6Hz)，2.85-3.30(2H，m)，4.11(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，5.85-8.00(12H，m).

Example 47

2- (5-methyl-2-hexenoyl) -7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3398，2741，2635，2548，1661，1614，1553.

¹H-NMR(CDCl₃)δ(ppm)；0.70-1.14(18H，m)，1.14-2.20(7H，m)，2.27(3H，s)，2.85(2H，br-t)，2.90-3.40(2H，m)，4.10(2H，br-t)，4.40-5.20(3H，m)，5.80-7.10(10H，m).

Example 48

2- (4, 4-dimethyl-2-pentenoyl) -7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2741，2633，1622，1556，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.94(3H，t，J＝7.5Hz)，1.05(9H，s)，1.10(9H，s)，1.20-1.70(2H，m)，2.05-2.45(2H，m)，2.28(3H，s)，2.86(2H，t，J＝6.3Hz)，2.95-3.30(2H，m)，4.11(2H，t，J＝6.3Hz)，4.30-5.20(3H，m)，5.00-6.00(3H，br)，6.00-7.20(7H，m).

Example 49

2- (2, 4-Hexanadieneacyl) -7- {2- [ 5-methyl-2- (trans-2-thiophen-2-ylvinyl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3420，2737，2633，2548，1651，1622，1558，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.97(9H，s)，1.83(3H，br-d)，2.31(3H，s)，2.89(2H，t，J＝6.3Hz)，2.90-3.23(2H，m)，4.13(2H，t，J＝6.3Hz)，4.30-5.20(3H，m)，6.00-6.78(10H，m)，6.85-7.37(2H，m)，7.49(1H，d，J＝16.4Hz).

Example 50

2- (2-heptenoyl) -7- {2- [ 5-methyl-2-thiophenyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；2571，1732，1657，16l4，1583，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.91(3H，br-t)，1.10-1.70(4H，m)，2.82(2H，t，J＝6.8Hz)，1.90-2.40(2H，m)，2.22(3H，s)，2.95-3.40(2H，m)，4.07(2H，t，J＝6.8Hz)，4.20-5.65(3H，m)，6.32(1H，d，J＝16.2Hz)，6.50-6.85(4H，m)，7.04(1H，d，J＝7.7Hz)，7.20-7.65(5H，m).

Example 51

2- (2, 4-Hexadienoyl) -7- {2- [2- (trans-1-penten-1-yl) -5-propyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2731，2633，2546，1630，1553，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.91(6H，t，J＝7.0Hz)，0.96(9H，s)，1.25-2.00(7H，m)，2.20(2H，q，J＝7.0Hz)，2.60(2H，t，J＝7.0Hz)，2.87(2H，t，J＝6.6Hz)，2.90-3.30(2H，m)，4.11(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，5.80-7.40(12H，m).

Example 52

2- (2, 2-difluorobutanoyl) -7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2745，2638，2552，1661，1614，1564，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-2.20(6H，m)，1.25-1.70(2H，m)，1.85-2.45(4H，m)，0.93(9H，s)，1.26-2.70(11H，m)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.95-3.25(2H，m)，4.11(2H，t，J＝6.6Hz)，4.30-5.15(3H，m)，6.17(1H，d，J＝16.3Hz)，6.35-7.50(7H，m).

Example 53

2- (4, 4-Difluoropentanoyl) -7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3398，2745，2637，2550，1645，1556.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝7.5Hz)，0.99(3H，s)，1.26-2.70(11H，m)，2.28(3H，s)，2.86(2H，br-t)，3.00-3.41(2H，m)，4.11(2H，br-t)，4.36-4.70(2H，m)，4.80-5.10(1H，m)，5.57-6.14(3H，br)，6.16(1H，d，J＝16.3Hz)，6.41-6.80(3H，m)，6.83-7.08(1H，m).

Example 54

7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (3, 3, 3-trifluoropropionyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；2723，2621，1732，1661，1614，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝7.5Hz)，1.20-1.75(2H，m)，2.23(2H，t，J＝6.8Hz)，2.34(3H，s)，2.94(2H，br-t)，3.00-3.60(4H，m)，4.09(2H，br-t)，4.30-5.50(3H，m)，6.36(1H，d，J＝16.0Hz)，7.04(1H，d，J＝7.7Hz)，6.50-6.95(3H，m)，8.93(1H，br-s).

Example 55

2- (2, 4-Hexanedienoyl) -7- {2- [ 5-methyl-2- (2-methylthioethyl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2745，2637，2548，1651，1624，1601，1553，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.97(9H，s)，1.65-2.00(3H，m)，2.11(3H，s)，2.25(3H，s)，2.70-5.40(6H，m)，2.85(2H，t，J＝6.8Hz)，4.10(2H，t，J＝6.8Hz)，4.25-5.20(3H，m)，5.80-7.40(12H，m).

Example 56

2- (2, 4-Hexanilido) -7- (2- { 5-methyl-2- [ 2-trans- (1-methylcyclohexen-1-yl) ethenyl ] oxazol-4-yl } ethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2739，2631，2548，1651，1622，1599，1585，1547，1508.

¹H-NMR(CDCl₃)δ(ppm)；0.97(9H，s)，1.05(3H，s)，1.15-2.00(13H，m)，2.28(3H，s)，2.86(2H，t，J＝6.6Hz)，2.90-3.40(2H，m)，4.11(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，5.85-7.50(12H，m).

Example 57

2- (2, 4-Hexanedienoyl) -7- (2- { 5-methyl-2- [ 2-trans- (1-methylcyclopenten-1-yl) vinyl ] oxazol-4-yl } ethoxy) -1, 2, 3, 4-tetrahydroisoquinolin- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2739，2633，2544，1634，1549，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.14(3H，s)，1.30-2.05(11H，m)，2.28(3H，s)，2.86(2H，t，J＝6.8Hz)，2.90-3.40(2H，m)，4.11(2H，t，J＝6.8Hz)，4.25-5.20(3H，m)，5.80-7.45(12H，m).

Example 58

7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (4-pentenyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

(1) 1.0 g 7- {2- [ 5-methyl-2- (4-methyl-trans-1-pentene-1-yl) oxazole-4-yl ] ethoxy } -1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid methyl ester dissolved in 10 ml N, N-two methyl formamide, added 1.4 ml three and 1.2 ml 5-bromo pentene-1-pentene, at room temperature under stirring for 40 hours, added 1.05 ml three and 0.89 ml 5-bromo pentene-1, stirring for another 26 hours. 20 ml of ethyl acetate was added, and the mixture was washed twice with 50 ml of water, then washed successively with 10 ml of 10% citric acid water and saturated brine, dried (with sodium sulfate), and then the ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.89 g of 7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (4-pentenyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester as an oily substance.

IRν(neat)cm^-1；3449，2953，2928，2870，1738，1641，1614，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.3Hz)，1.40-1.90(3H，m)，1.90-2.33(4H，m)，2.27(3H，s)，2.50-3.17(6H，m)，3.65(3H，s)，3.70-4.25(5H，m)，4.80-5.13(2H，m)，5.45-6.00(1H，m)，6.16(1H，d，J＝16.0Hz)，6.36-6.79(3H，m)，6.97(1H，d，J＝8.4Hz).

(2) 0.8 g of the compound obtained in (1) above was dissolved in 23 ml of a tetrahydrofuran-methanol (3: 1) mixture, and 5.66 ml of a 1M aqueous lithium hydroxide solution was added thereto and stirred at room temperature for 40 minutes. Adjusting to acidity with 10% citric acid water, and concentrating under reduced pressure. The precipitated gum was extracted with 20 ml of ethyl acetate, and the ethyl acetate layer was washed with 20 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. N-hexane was added to the residue, and the precipitated crystals were filtered to obtain 0.74 g of the title compound.

IRν(nujol)cm^-1；3400，3057，2725，2664，2565，2494，1626，1551，1508.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.48-2.30(7H，m)，2.28(3H，s)，2.60-3.33(6H，m)，3.72(1H，br-t)，3.82-4.46(4H，m)，4.80-5.20(2H，m)，5.42-5.97(1H，m)，6.15(1H，d，J＝16.1Hz)，6.40-6.90(3H，m)，7.08(1H，d，J＝8.4Hz)，8.55-9.05(1H，br).

Example 59

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

(1) 483 mg of methyl 2-benzyl alcohol-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate and 700 mg of 2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate were dissolved in 15 ml of N-toluene, followed by addition of 674 mg of potassium carbonate and 100 mg of tetraethylammonium fluoride hydrate and stirring at 90 ℃ for 18 hours. To the reaction mixture was added 10 ml of ethyl acetate, and the mixture was washed with 20 ml of water and 20 ml of saturated brine in this order, dried (with sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 590 mg of methyl 2-benzyl-7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

IRν(neat)cm^-1；3443，3027，2953，2926，2871，2841，1739，1613，1534，1505.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.48-2.00(1H，m)，2.10(2H，t，J＝6.8Hz)，2.26(3H，s)，2.84(2H，t，J＝6.8Hz)，3.08(2H，d，J＝4.6Hz)，3.66(3H，s)，3.70-4.30(5H，m)，3.90(2H，s)，6.15(1H，d，J＝16.1Hz)，6.38-6.78(3H，m)，6.98(1H，d，J＝8.2Hz)，7.16-7.50(5H，m).

(2) 570 mg of the compound obtained in the above (1) was dissolved in 14 ml of a tetrahydrofuran-methanol (3: 1) mixture, and 3.5 ml of a 1M aqueous lithium hydroxide solution was added thereto and stirred at 40 ℃ for 1.5 hours. The solution was made acidic with 6M hydrochloric acid and concentrated under reduced pressure. The precipitated gum was extracted with 15 ml of ethyl acetate, and the ethyl acetate layer was washed with 10 ml of saturated brine, dried (over sodium sulfate), and distilled under reduced pressure to remove ethyl acetate. N-hexane was added to the residue, and after stirring for 30 minutes under ice-cooling, the precipitated crystals were filtered to obtain 445 mg of the title compound.

IRν(nujol)cm^-1；3385，3047，1718，1636，1585，1549，1533，1501.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.46-1.99(1H，m)，2.10(2H，t，J＝6.7Hz)，2.27(3H，s)，2.85(2H，t，J＝6.8Hz)，3.19(2H，d，J＝6.1Hz)，3.63-4.40(5H，m)，4.03(2H，s)，6.15(1H，d，J＝15.8Hz)，6.36-6.85(3H，m)，7.06(1H，d，J＝8.6Hz)，7.20-7.60(5H，m)，9.37(1H，br-s).

Example 60

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

IRν(nujol)cm^-1；3420，1680，1614，1506.

¹H-NMR(DMSO-d₆)δ(ppm)；1.07(9H，s)，2.23(3H，s)，2.77(2H，t，J＝6.3Hz)，2.80-3.10(2H，m)，3.20-4.60(8H，m)，6.07(1H，d，J＝16.5Hz)，6.59(1H，d，J＝16.5Hz)，6.40-6.80(2H，m)，7.01(1H，J＝8.4Hz)，7.32(5H，br-s).

Example 61

2- (2, 2-dimethylpropyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3398，2746，2637，2554，1641，1612，1543.

¹H-NMR(CDCl₃)δ(ppm)；0.87(9H，s)，0.93(6H，d，J＝6.6Hz)，1.02(9H，s)，1.48-2.00(1H，m)，2.11(2H，t，J＝6.8Hz)，2.28(3H，s)，2.48(2H，d，J＝7.9Hz)，2.60-3.20(2H，m)，2.86(2H，t，J＝6.8Hz)，3.30-3.53(1H，m)，4.00(2H，dd，J＝16.6Hz，52.7Hz)，4.11(2H，t，J＝6.8Hz)，6.16(1H，d，J＝16.0Hz)，6.37-7.00(6H，m)，6.90(1H，d，J＝8.1Hz).

Example 62

7- {2- [ 5-methyl-2- (trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -2- (2, 2, 3, 3, 3-pentafluoropropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；1697，1610，1529，1508.

¹H-NMR(DMSO-d₆)δ(ppm)；0.89(3H，t，J＝7.3Hz)，1.20-1.70(2H，m)，1.95-2.25(2H，m)，2.25(3H，s)，2.00-4.40(1H，br)，2.79(2H，m)，2.95-3.15(2H，m)，3.30-4.40(7H，m)，6.19(1H，d，J＝16.5Hz)，6.33-6.90(3H，m)，7.02(1H，d，J＝8.1Hz).

Example 63

7- {2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (3, 3, 3-trifluoropropyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；1616，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.93(3H，t，J＝6.8Hz)，1.30-1.75(2H，m)，2.10-2.70(4H，m)，2.27(3H，s)，2.75-3.40(6H，m)，3.60-4.20(5H，m)，5.80-8.00(1H，br)，6.10-6.80(4H，m)，7.02(1H，d，J＝8.1Hz).

Example 64

2- (3-butenyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid

IRν(nujol)cm^-1；3385，3080，2725，2583，1717，1614，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.48-1.99(1H，m)，2.11(2H，t，J＝6.7Hz)，2.28(3H，s)，2.35-2.62(2H，m)，2.70-3.35(6H，m)，3.76(1H，br-t)，3.85-4.46(4H，m)，4.90-5.25(2H，m)，5.45-5.98(1H，m)，6.15(1H，d，J＝16.1Hz)，6.40-6.86(3H，m)，7.08(1H，d，J＝8.2Hz)，8.60-9.00(1H，br).

Example 65

2- (2, 4-Hexanedienoyl) -7- {2- [2- (3-methoxy-1-trans-1-propen-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2737，1652，1624，1599，1555，1587，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.00(9H，s)，1.85-2.00(3H，m)，2.29(3H，s)，2.87(2H，t，J＝6.8Hz)，2.90-3.25(2H，m)，3.38(3H，s)，3.95-4.20(2H，m)，4.11(2H，t，J＝6.8Hz)，4.30-5.20(3H，m)，5.90-8.40(12H，m).

Example 66

7- {2- [2- (5-fluoro-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2735，2631，2544，2432，2365，2212，16511624，1599，1553，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.50-2.10(5H，m)，2.15-2.55(2H，m)，2.28(3H，s)，2.80-3.40(2H，m)，2.86(2H，t，J＝6.6Hz)，4.11(2H，t，J＝6.6Hz)，4.47(2H，dt，J＝47.0，5.7Hz)，4.50-5.20(3H，m)，5.80-6.80(9H，m)，6.85-7.25(2H，m).

Example 67

7- [2- (2-cyclopentylidenemethyl-5-methyloxazol-4-yl) ethoxy ] -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2737，2631，2544，1653，1624，1587，1553，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.96(9H，s)，1.50-2.05(7H，m)，2.28(3H，s)，2.25-2.55(2H，m)，2.55-3.30(4H，m)，2.87(2H，t，J＝6.8Hz)，4.12(2H，t，J＝6.8Hz)，4.25-5.20(3H，m)，5.80-7.40(11H，m).

Example 68

7- [2- (2-cyclohexylidenemethyl-5-methyloxazol-4-yl) ethoxy ] -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2739，2631，2542，1653，1624，1549，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.01(9H，s)，1.40-2.00(9H，m)，2.10-2.40(2H，m)，2.27(3H，s)，2.65-3.40(6H，m)，2.86(2H，t，J＝6.6Hz)，4.12(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，5.80-7.40(11H，m)，5.93(1H，s).

Example 69

2-cyclopentylideneacetyl-7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2745，2638，2554，1655，1556，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.8Hz)，0.97(9H，s)，1.43-2.00(5H，m)，2.11(2H，t，J＝6.7Hz)，2.28(3H，s)，2.30-2.8(4H，m)，2.86(2H，t，J＝6.8Hz)，2.90-3.40(2H，m)，4.11(2H，t，J＝6.8Hz)，4.20-5.20(3H，m)，5.93-6.28(1H，m)，6.40-6.80(3H，m)，6.80-7.20(4H，m).

Example 70

2-cyclohexylidene acetyl-7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2743，2637，2554，2216，1636，1556，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.02(9H，s)，1.33-1.80(7H，m)，2.00-2.50(6H，m)，2.28(3H，s)，2.86(2H，t，J＝6.7Hz)，2.95-3.42(2H，m)，4.11(2H，t，J＝6.7Hz)，4.27-5.20(3H，m)，5.64(1H，d，J＝7.7Hz)，6.16(1H，d，J＝14.8Hz)，6.40-6.80(3H，m)，6.80-7.30(4H，m).

Example 71

7- {2- [2- (5-tert-butylsulfanyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；2928，2864，1740，1638，1612，1578，1533，1504.

¹H-NMR(CDCl₃)δ(ppm)；1.32(9H，s)，1.60-2.00(2H，m)，1.98(1H，br-s)，2.15-2.40(2H，m)，2.27(3H，s)，2.56(2H，t，J＝7.2Hz)，2.80-3.05(2H，m)，2.86(2H，t，J＝6.7Hz)，3.55-3.80(1H，m)，3.76(3H，s)，4.04(2H，br-s)，4.16(2H，t，J＝6.7Hz)，6.17(1H，d，J＝16.0Hz)，6.40-6.80(3H，m)，6.99(1H，d，J＝8.3Hz)，

Example 72

7- {2- [2- (5-tert-butylsulfanyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；2957，2926，2862，1740，1655，1612，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.32(9H，s)，1.60-2.00(5H，m)，2.15-2.40(2H，m)，2.28(3H，s)，2.57(2H，t，J＝7.5Hz)，2.87(2H，t，J＝6.6Hz)，3.00-3.25(2H，m)，3.59(3H，s)，4.15(2H，t，J＝6.6Hz)，4.35-5.60(3H，m)，5.90-6.85(7H，m)，7.04(1H，d，J＝8.4Hz)，7.15-7.50(1H，m).

Example 73

7- {2- [2- (5-tert-butylsulfanyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；2743，2635，2548，1742，1655，1628，1601，1555，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.00(9H，s)，1.32(9H，s)，1.60-2.00(5H，m)，2.15-2.40(2H，m)，2.28(3H，s)，2.56(2H，t，J＝7.2Hz)，2.86(2H，t，J＝6.3Hz)，2.90-3.35(2H，m)，4.11(2H，t，J＝6.3Hz)，4.30-5.15(3H，m).5.90-7.35(12H，m).

Example 74

7- {2- [2- (5-dimethylamino-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

IRν(neat)cm^-1；3404，2949，2860，2818，2770，1743，1655，1626，1603，1533，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.40-1.95(5H，m)，2.10-2.40(4H，m)，2.23(6H，s)，2.28(3H，s)，2.87(2H，t，J＝6.6Hz)，3.05-3.25(2H，m)，3.59(3H，m)，4.14(2H，t，J＝6.6Hz)，4.60-5.00(2H，m)，5.40-5.70(1H，m)，6.00-6.80(7H，m)，6.90-7.35(2H，m).

Example 75

7- {2- [2- (5-dimethylamino-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid sodium salt

IRν(nujol)cm^-1；3381，2766，2725，1651，1595，1535，1504.

¹H-NMR(CDCl₃)δ(ppm)；1.40-1.95(5H，m)，2.05-2.60(4H，m)，2.25(9H，s)，2.65-3.10(4H，m)，3.90-4.10(2H，m)，4.40-4.80(2H，m)5.05-5.55(1H，m)，5.80-6.75(7H，m)，6.80-7.25(2H，m).

Example 76

2- (2-hexenoyl) -7- {2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；1661，1616，1558，1506.

¹H-NMR(CDCl₃)δ(ppm)；0.75-2.20(3H，m)，0.93(6H，d，J＝6.4Hz)，1.02(9H，s)，1.20-1.60(2H，m)，1.60-1.95(1H，m)，1.95-2.30(4H，m)，2.10(2H，t，J＝6.6Hz)，2.27(3H，s)，2.86(2H，t，J＝6.8Hz)，3.00-3.40(2H，m)，4.10(2H，t，J＝6.8Hz)，4.40-5.20(3H，m)，6.15(1H，d，J＝16.1Hz)，6.10-7.20(9H，m).

Example 77

2- (2, 4-Hexadienoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3435，2729，2633，2548，2214，1657，1630，1551，1504.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.6Hz)，0.97(9H，s)，1.60-1.90(4H，m)，2.13(2H，t，J＝6.8Hz)，2.80-3.20(2H，m)，3.03(2H，t，J＝6.6Hz)，4.15(2H，t，J＝6.6Hz)，4.25-5.20(3H，m)，6.00-7.30(12H，m)，7.38(1H，s).

Example 78

7- {2- [2- (trans-2-cyclopentylvinyl) oxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.20-2.05(11H，m)，2.38-2.73(1H，m)，2.90-3.40(2H，m)，2.94(2H，t，J＝6.5Hz)，4.14(2H，t，J＝6.5Hz)，4.26-5.20(3H，m)，5.86-7.38(12H，m)，7.50(1H，s).

Example 79

7- {2- [2- (trans-2-cyclohexylvinyl) oxazol-4-yl ] ethoxy } -2- (2, 4-hexadienoyl) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.98(9H，s)，1.00-2.40(14H，m)，2.90-3.30(2H，m)，2.94(2H，t，J＝6.8Hz)，4.14(2H，t，J＝6.8Hz)，4.20-5.20(3H，m)，5.80-7.47(12H，m)，7.49(1H，s).

Example 80

2- (2-heptenoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.75-2.20(3H，m)，0.93(6H，d，J＝6.4Hz)，1.02(9H，s)，1.20-1.60(4H，m)，1.60-1.95(1H，m)，1.95-2.30(2H，m)，2.10(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.8Hz)，3.00-3.40(2H，m)，4.15(2H，t，J＝6.8Hz)，4.40-5.20(3H，m)，6.15(1H，d，J＝16.1Hz)，6.10-7.20(9H，m)，7.48(1H，s).

Example 81

2- (2-hexenoyl) -7- {2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

IRν(nujol)cm^-1；3435，2729，2633，2548，2214，1661，1622，1553，1504.

¹H-NMR(DMSO-d₆)δ(ppm)；0.80-1.00(3H，m)，0.90(6H，d，J＝6.2Hz)，1.14(9H，s)，1.20-1.90(6H，m)，1.95-2.25(2H，m)，2.70-3.40(3H，m)，4.10-5.20(8H，m)，6.10-6.85(6H，m)，7.00(1H，d，J＝8.4Hz)，7.78(1H，s).

Example 82

2- (2, 4-Hexanadienoyl) -7- {2- [2- (trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.16(3H，m)，0.98(9H，s)，1.20-1.60(4H，m)，1.70-2.00(3H，m)，2.07-2.40(2H，m)，2.88-3.30(2H，m)，2.95(2H，t，J＝6.5Hz)，4.16(2H，t，J＝6.5Hz)，4.25-5.20(3H，m)，5.90-7.40(12H，m)，7.49(1H，s).

Example 83

2- (2, 4-Hexadienoyl) -7- {2- [2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.80-1.08(3H，m)，0.97(9H，s)，1.11-1.70(2H，m)，1.70-1.93(3H，m)，1.93-2.35(2H，m)，2.01(3H，s)，2.90-3.40(2H，m)，2.96(2H，t，J＝6.7Hz)，4.14(2H，t，J＝6.7Hz)，4.24-5.20(3H，m)，5.92-7.38(11H，m)，7.50(1H，s).

Example 84

2- (2, 4-Hexadienoyl) -7- {2- [2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.99(9H，s)，1.05(3H，t，J＝7.5Hz)，1.65-1.95(3H，m)，2.01(3H，s)，2.05-2.45(2H，m)，2.90-3.30(2H，m)，2.96(2H，t，J＝6.7Hz)，4.15(2H，t，J＝6.7Hz)，4.25-5.20(3H，m)，5.90-8.30(13H，m).

Example 85

2- (2, 4-Hexanadienoyl) -7- {2- [ (5-methyl-trans-1-hexen-1-yl) oxazol-4-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid tert-butylamine salt

¹H-NMR(CDCl₃)δ(ppm)；0.90(6H，d，J＝6.3Hz)，0.97(9H，s)，1.20-1.70(3H，m)，1.70-1.98(3H，m)，2.06-2.40(2H，m)，2.90-3.25(2H，m)，2.95(2H，t，J＝6.4Hz)，4.15(2H，t，J＝6.4Hz)，4.25-5.20(3H，m)，5.72-7.38(12H，m)，7.50(1H，s).

Reference example 1

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

(1) 25 g of 3, 5-diiodo-L-tyrosine dihydrate are suspended in 250 ml of concentrated hydrochloric acid, and 18 ml of 1, 2-dimethoxyethane and 20 ml of 37% formalin are added in this order. The temperature was raised to 75 ℃ in 30 minutes. Then, 120 ml of concentrated hydrochloric acid, 9 ml of 1, 2-dimethoxyethane and 10 ml of 37% formalin were added to the reaction mixture, and the mixture was stirred at 75 ℃ for 18 hours. The precipitated crystal was filtered and washed with 20 ml of 1, 2-dimethoxyethane to obtain 12.8 g of 7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid hydrochloride.

IRν(nujol)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) 12.8 g of the compound obtained in the above (1) was suspended in 500 ml of ethanol, and 10 ml of concentrated hydrochloric acid was added thereto and refluxed for 15 hours. The ethanol was distilled off under reduced pressure, and after adding 300 ml of ethyl acetate, the mixture was washed successively with 100 ml of sodium hydrogencarbonate water and 100 ml of saturated brine. After drying (with sodium sulfate), ethyl acetate was distilled off under reduced pressure to give 11.11 g of ethyl 7-hydroxy-6, 8-diiodo-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylate.

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) 350 mg of 10% palladium on charcoal was suspended in 60 ml of ethanol, and 2.0 ml of triethylamine and 2.8 g of the compound of (2) were added to the suspension, followed by hydrogenation contact at room temperature under a pressure of 3.0 kg-force/cm for 3 hours. The palladium-on-charcoal was filtered, the methanol was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue, which was then washed with 100 ml of saturated brine. After drying (with sodium sulfate), ethyl acetate was distilled off under reduced pressure to give 1.14 g of 7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid ethyl ester.

IRν(nujol)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) 1.13 g of the compound obtained in the above (3) was dissolved in 20 ml of tetrahydrofuran, and 1.5 g of di-t-butyldicarbonate was added and stirred at room temperature for 1 hour. To the reaction solution was added 30 ml of ethyl acetate, and the mixture was washed with 20 ml of saturated brine. After drying (with sodium sulfate), ethyl acetate was distilled off under reduced pressure, and the obtained residue was purified by column chromatography to obtain 1.51 g of the title compound.

IRν(nujol)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-tert-Butoxycarbonyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

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

IRν(nujol)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- (2, 4-Hexanedienoyl) -7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid methyl ester

1.24 g 7-hydroxy-1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid methyl ester dissolved in 25 ml dichloromethane, added 5.0 ml three ethylamine, ice-cold under the dropwise addition of 2.1 ml sorbic acid chloride. After stirring at the same temperature for 15 minutes, the reaction mixture was washed successively with 20 ml of 10% citric acid water, 20 ml of saturated sodium bicarbonate water and 20 ml of saturated brine, dried (with sodium sulfate), and then the dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography. The resulting 1.04 g of oil was dissolved in 20 ml of methanol, and 3.0 ml of 1M aqueous lithium hydroxide solution was added in portions over 1 hour at room temperature. After the acid solution was adjusted to an acid wash with 10% citric acid water, the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by silica gel column chromatography to obtain 0.65 g of the title compound.

IRν(neat)cm^-1；3184，1734，1576，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.84(3H，d，J＝5.0Hz)，2.80-3.40(2H，m)，3.59(3H，s)，4.30-5.10(2H，m)，5.30-5.60(1H，m)，5.70-6.50(4H，m)，6.64(1H，s)，6.68(1H，d，J＝7.9Hz)，6.99(1H，d，J＝7.9Hz)，7.15-7.50(1H，m).

Reference example 4

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

0.9 g 7-hydroxy-1, 2, 3, 4-four hydrogen isoquinoline- (3S) -carboxylic acid methyl ester dissolved in 10 ml dichloromethane, added 1.39 g 2-heptene and 2.08 g 1-ethyl-3- (3' -two methyl amino propyl) two carbodiimide hydrochloride, at room temperature stirring for 30 minutes. 20 ml of methylene chloride was added, and the mixture was successively washed with 20 ml of 10% citric acid water and 20 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove methylene chloride. The obtained residue was purified by silica gel column chromatography to obtain 1.15 g of the title compound.

IRν(neat)cm^-1；3265，1740，1655，1593，1508.

¹H-NMR(CDCl₃)δ(ppm)；0.90(3H，br-t)，1.10-1.70(4H，m)，1.90-2.40(2H，m)，3.00-3.40(2H，m)，3.59(3H，s)，4.35-5.65(4H，m)，6.36(1H，d，J＝15.2Hz)，6.55-6.80(1H，m)，6.64(1H，s)，6.80-7.20(1H，m)，6.99(1H，d，J＝7.9Hz).

Reference example 5

2- (5-methyl-2-phenethyloxazol-4-yl) ethanol

(1) 20 g of L-aspartic acid beta-methyl ester are suspended in 400 ml of dichloromethane, 18.14 g of cinnamoyl chloride are added, 53 ml of triethylamine are added dropwise at-5 ℃, and the mixture is stirred at the same temperature for 1.5 hours. The reaction solution was extracted five times with 300 ml of water, and the aqueous layer was made acidic with 6M hydrochloric acid and extracted with 500 ml of ethyl acetate. The ethyl acetate layer was then washed with 300 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The resulting 13.3 g residue was dissolved in 100 ml of toluene, 22.6 ml of acetic anhydride, 21.1 ml of N-methylmorpholine and 4-dimethylaminopyridine were added, and the mixture was stirred at 65 ℃ for 5 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution, and the two layers were separated. The toluene layer was washed with 100 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove toluene. The resulting 9.1 residue was dissolved in 90 ml of toluene, and 9.2 ml of phosphorus oxychloride was added thereto and refluxed for 6 hours. Ice water was poured into the reaction solution, neutralized with potassium carbonate, and the two layers were separated. The toluene layer was washed with 100 ml of saturated brine, dried (with sodium sulfate), and then toluene was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography to obtain 1.31 g of methyl (5-methyl-2-styryloxazol-4-ylacetate).

IRν(neat)cm^-1；1742，1641.

¹H-NMR(CDCl₃)δ(ppm)；2.33(3H，s)，3.52(2H，s)，3.73(3H，s)，6.85(1H，d，J＝16.2Hz)，7.15-7.60(6H，m).

(2) 1.31 g of the compound obtained in the above (1) was dissolved in 25 ml of diethyl ether, and 0.23 g of lithium aluminum hydrate was added in portions at 0 ℃ and stirred at the same temperature for 20 minutes. 5 ml of water were added, the insoluble matter was filtered, and the two layers were separated. The ether layer was washed with 15 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ether, and the obtained residue was purified by column chromatography to obtain 0.55 g of the title compound.

¹H-NMR(CDCl₃)δ(ppm)；2.31(3H，s)，2.61(2H，d，J＝6.0Hz)，3.20-3.50(1H，br)，3.84(2H，d，J＝6.0Hz)，6.84(1H，d，J＝16.2Hz)，7.20-7.60(6H，m).

Reference example 6

(5-methyl-2-styryloxazol-4-yl) acetic acid methyl ester

0.5 g of cinnamamide and 0.71 g of methyl 4-bromo-3-pentanoate were dissolved in 2.5 ml of N, N-dimethylformamide and stirred at 100 ℃ for 15 hours. 50 ml of ethyl acetate were added, and the mixture was washed with 100 ml of water and then 100 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by column chromatography to obtain 0.1 g of the title compound.

IR and¹H-NMR was in accordance with (1) in reference example 5.

The following compounds were synthesized according to reference examples 5 and 6.

Reference example 7

2- (5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl) ethanol

IRν(neat)cm^-1；3350，1664，1654，1641，1534.

¹H-NMR(CDCl₃)δ(ppm)；0.95(3H，t，J＝7.0Hz)，1.20-1.80(2H，m)，2.00-2.40(2H，m)，2.25(3H，s)，2.64(2H，t，J＝5.7Hz)，2.70-3.20(1H，br)，3.86(2H，t，J＝5.7Hz)，6.17(1H，d，J＝8.0Hz)，6.64(1H，dt，J＝6.6，8.0Hz).

Reference example 8

2- (5-methyl-2-pentyloxazol-4-yl) ethanol

IRν(neat)cm^-1；3341，1576.

¹H-NMR(CDCl₃)δ(ppm)；0.90(3H，br-t)，1.20-1.50(4H，m)，1.50-1.95(2H，m)，2.21(3H，s)，2.45-2.80(4H，m)，3.09(1H，br-s)，3.85(2H，t，J＝5.7Hz).

Reference example 9

2- (2-cyclopentyl-5-methyloxazol-4-yl) ethanol

IRν(neat)cm^-1；3341，1572.

¹H-NMR(CDCl₃)δ(ppm)；1.40-2.30(8H，m)，2.21(3H，s)，2.61(2H，t，J＝6.0Hz)，2.95-3.30(1H，m)，3.36(1H，br-s)，3.84(2H，t，J＝6.0Hz).

Reference example 10

2- (2-cyclohexyl-5-methyloxazol-4-yl) ethanol

IRν(neat)cm^-1；3360，1742，1570，1450.

¹H-NMR(CDCl₃)δ(ppm)；1.10-2.40(11H，m)，2.21(3H，s)，2.60-3.00(1H，m)，2.61(2H，t，J＝5.8Hz)，3.09(1H，br-s)，3.84(2H，t，J＝5.8Hz).

Reference example 11

2- [ 5-methyl-2- (trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate

1.03 g of 2- [ 5-methyl-2- (1-penten-1-yl) oxazol-4-yl ] ethanol was dissolved in 10 ml of dichloromethane, 1.03 ml of triethylamine was added, 0.41 ml of methanesulfonyl chloride was added dropwise at 0 ℃ and the mixture was stirred at room temperature for 30 minutes. 100 ml of ethyl acetate was added, and the mixture was washed successively with 100 ml of 10% citric acid water and 100 ml of saturated brine, dried (with sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain 1.1 g of the titled compound.

IRν(neat)cm^-1；1654，1643，1551，1534.

¹H-NMR(CDCl₃)δ(ppm)；0.90(3H，t，J＝7.2Hz)，1.20-1.80(2H，m)，2.00-2.40(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.7Hz)，2.94(3H，s)，4.45(2H，t，J＝6.7Hz)，6.16(1H，d，J＝16.0Hz)，6.69(1H，dt，J＝16.0，6.6Hz).

Reference example 12

2- (5-methyl-2-styryl oxazol-4-yl) ethyl methanesulfonate

(1) 3.27 g of cinnamamide was dissolved in 33 ml of tetrahydrofuran, 4.94 g of ロ - ソン reagent was added, and after refluxing for 3 hours, 6.97 g of methyl 4-bromo-3-pentanoate was added, and further refluxing was carried out for 11 hours. Tetrahydrofuran was distilled off under reduced pressure, and 300 ml of ethyl acetate was added to the resulting residue, which was then washed successively with 200 ml of water and 200 ml of saturated brine, dried (with sodium sulfate), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 2.9 g of methyl (5-methyl-2-styryloxazol-4-yl) acetate.

IRν(nujol)cm^-1；1732，1595，1573，1537.

¹H-NMR(CDCl₃)δ(ppm)；2.41(3H，s)，3.72(3H，s)，3.75(2H，s)，7.15-7.60(7H，m).

(2) 2.85 g of the compound obtained in the above (1) was dissolved in 16.7 ml of toluene, and 16.7 ml of a 1.5M toluene solution of diisobutylaluminum hydrate was added dropwise thereto at-10 ℃ and stirred at the same temperature for 1 hour. 5 ml of water were added, the insoluble matter was filtered, and the two layers were separated. The toluene layer was washed with 10 ml of saturated brine, dried (with sodium sulfate), and then the toluene was distilled off under reduced pressure. 2.8 g of the obtained crude 2- (5-methyl-2-styryloxazol-4-yl) ethanol was dissolved in 30 ml of dichloromethane, 1.89 ml of triethylamine was added, 0.97 ml of methanesulfonyl chloride was added dropwise at 0 ℃, and the mixture was stirred at room temperature for 20 minutes. 200 ml of ethyl acetate was added, and the mixture was washed successively with 200 ml of 10% citric acid water and 100 ml of saturated brine, dried (with sodium sulfate), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 1.1 g of the title compound.

¹H-NMR(CDCl₃)δ(ppm)；2.42(3H，s)，2.91(3H，s)，3.11(2H，t，J＝6.6Hz)，4.57(2H，t，J＝6.6Hz)，7.00-7.65(7H，m).

Reference example 13

2- [ (1-Phenylethylidene) aminooxy ] ethanol

1.00 g of acetophenone oxime and 3.09 g of 2- (2-bromoethoxy) tetrahydropyran were dissolved in 30 ml of N, N-dimethylformamide, and 7.16 g of potassium carbonate was added and stirred at 80 ℃ for 19 hours. After the reaction mixture was allowed to cool, 100 ml of water was added to the reaction mixture, and the mixture was extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed successively with 50 ml of water and 50 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The obtained residue was purified by column chromatography to obtain 2.01 g of a colorless oil. The resulting 1.99 g of oil was dissolved in 30 ml of methanol, and 1.73 g of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring at room temperature for 1 hour. After methanol was distilled off under reduced pressure, 30 ml of saturated sodium bicarbonate was added, extraction was performed twice with 30 ml of ethyl acetate, and the ethyl acetate layers were combined, washed successively with 50 ml of saturated sodium bicarbonate water and 50 ml of saturated brine, dried (with sodium sulfate), and then ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 1.09 g of the title compound.

IRν(neat)cm^-1；3700-3100，1445，1369，1315，1043，762，694，559.

¹H-NMR(CDCl₃)δ(ppm)；2.27(3H，s)，3.8-4.1(2H，m)，4.2-4.5(2H，m)，7.2-7.5(3H，m)，7.5-7.8(2H，m).

The following compounds were synthesized according to reference example 11.

Reference example 14

2- [ (1-Phenylethanolamine) aminooxo ] ethyl methanesulfonate

IRν(nujol)cm^-1；1354，1177，1069，1018，924，804，764，696，529.

¹H-NMR(CDCl₃)δ(ppm)；2.26(3H，s)，3.02(3H，s)，4.3-4.7(4H，m)，7.2-7.5(3H，m)，7.5-7.8(2H，m).

Reference example 15

2- (4-methyl-2-phenylthiothiazol-5-yl) ethyl methanesulfonate

(1) 1.90 ml of thiophene was dissolved in 10 ml of N, N-dimethylformamide, and 740 mg of sodium hydride (60% oil suspension) was added in portions under ice cooling, and stirred at room temperature for 15 minutes. Then, a solution of 10 ml of 3.05 g of ethyl 2-chloro-4-methylthiazole-5-carboxylate in N, N-dimethylformamide was added dropwise thereto, and the mixture was stirred at the same temperature for another 20 minutes. 50 ml of water was added to the reaction solution, followed by extraction with 50 ml of ethyl acetate. The ethyl acetate layer was washed twice with 50 ml of water, then with 30 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. The resulting residue was purified by column chromatography to give 3.85 g of ethyl 4-methyl-2-phenylthiothiazol-5-ylcarboxylate.

IRν(neat)cm^-1；1713，1531.

¹H-NMR(CDCl₃)δ(ppm)；1.28(3H，t，J＝7.2Hz)，2.67(3H，s)，4.24(2H，t，J＝7.2Hz)，7.40-7.80(5H，m).

(2) 3.85 g of the compound obtained in the above (1) was dissolved in 80 ml of tetrahydrofuran, and 630 mg of lithium aluminum hydrate was added in portions and stirred at the same temperature for 15 minutes. 20 ml of water and 50 ml of ethyl acetate were added, and the insoluble matter was filtered, and the two layers were separated. The ethyl acetate layer was washed with 20 ml of saturated brine, dried (over sodium sulfate), and then ethyl acetate was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography to give 3.25 g of 4-methyl-2-phenylthiothiazol-5-ylmethanol.

IRν(neat)cm^-1；3265，1582，1555.

¹H-NMR(CDCl₃)δ(ppm)；2.31(3H，s)，2.50(1H，s)，4.65(2H，s)，7.30-7.70(5H，m).

(3) 7.30 g of the compound obtained in the above (2) was dissolved in 100 ml of dichloromethane, 6.40 ml of triethylamine was added, 2.90 ml of methanesulfonyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After washing with 20 ml of cold water and drying (over sodium sulfate), dichloromethane was distilled off under reduced pressure. The resulting residue was dissolved in 100 ml of acetonitrile, 2.26 g of sodium cyanide and 1.50 g of 18-crown-6 were added, and the mixture was stirred at 60 ℃ for 2 hours. Acetonitrile was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue, which was washed twice with 50 ml of water, then with 30 ml of saturated brine, and dried (with sodium sulfate). The ethyl acetate was distilled off under reduced pressure. The resulting residue was purified by column chromatography to give 2.80 g of (4-methyl-2-phenylthiothiazol-5-yl) acetonitrile.

IRν(neat)cm^-1；2254，1582，1555.

¹H-NMR(CDCl₃)δ(ppm)；2.36(3H，s)，3.68(2H，s)，7.40-7.70(5H，m).

(4) 2.80 g of the compound obtained in the above (3) was dissolved in 5.6 ml of concentrated hydrochloric acid and stirred at 100 ℃ for 20 minutes. Then, 120 ml of methanol was added to the reaction solution, and the mixture was refluxed for 1 hour. Methanol was distilled off under reduced pressure, and to the resulting residue were added 50 ml of ethyl acetate, washed successively with 50 ml of water, 30 ml of saturated sodium bicarbonate water and 30 ml of saturated brine, and dried (over sodium sulfate). The ethyl acetate was distilled off under reduced pressure. 2.77 g of methyl (4-methyl-2-phenylthiothiazol-5-yl) acetate are obtained.

IRν(neat)cm^-1；1740.

¹H-NMR(CDCl₃)δ(ppm)；2.33(3H，s)，3.64(2H，s)，3.69(3H，s)，6.30-6.70(5H，m).

(5) 2.77 g of the compound obtained in the above (4) was dissolved in 55 ml of tetrahydrofuran, and 376 mg of lithium aluminum hydrate was added in portions under ice cooling, and stirred at the same temperature for 15 minutes. 20 ml of water and 50 ml of ethyl acetate were added, and the insoluble matter was filtered, and the two layers were separated. The ethyl acetate layer was washed with 20 ml of saturated brine, dried (over sodium sulfate), and then ethyl acetate was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography to give 2.49 g of 2- (4-methyl-2-phenylthiothiazol-5-yl) ethanol.

IRν(neat)cm^-1；3302.

¹H-NMR(CDCl₃)δ(ppm)；1.60-2.00(1H，br)，2.33(3H，s)，2.89(2H，t，J＝6.1Hz)，3.75(2H，t，J＝6.1Hz)，7.30-7.70(5H，m).

(6) 2.49 g of the compound obtained in the above (5) was dissolved in 25 ml of dichloromethane, 2.0 ml of triethylamine was added, 0.93 ml of methanesulfonyl chloride was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed with 20 ml of 10% citric acid water, 20 ml of saturated sodium bicarbonate water and 20 ml of saturated brine, dried (with sodium sulfate), and then the dichloromethane was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain 1.82 g of the title compound.

IRν(neat)cm^-1；1582，1551.

¹H-NMR(CDCl₃)δ(ppm)；2.34(3H，s)，2.92(3H，s)，3.09(2H，t，J＝6.6Hz)，4.26(2H，t，J＝6.6Hz)，7.30-7.80(5H，m).

Reference example 16

2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] acetic acid methyl ester

5.7 g of 5-methyl-trans-2-hexenamide are suspended in 35 ml of toluene, 14.0 g of methyl 4-bromopropionylacetate are added and refluxed for 14 hours. 50 ml of ethyl acetate was added, and the mixture was washed successively with 50 ml of water and 50 ml of saturated brine, dried (over sodium sulfate), and then the solvent was distilled off. The obtained residue was purified by column chromatography to give 3.36 g of the title compound.

IRν(neat)cm^-1；2957，2928，2870，1746，1643，1551.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.3Hz)，1.50-2.10(1H，m)，2.11(2H，t，J＝6.9Hz)，2.27(3H，s)，3.48(2H，s)，3.71(3H，s)，6.17(1H，d，J＝16.0Hz)，6.61(1H，dt，J＝6.9Hz，16.0Hz).

Reference example 17

(1) 44.68 g of L-aspartic acid-beta-methyl ester were dissolved in 220 ml of water, and 42.54 g of sodium carbonate were added. 110 ml of tetrahydrofuran were added, 42.8 g of 5-methyl-trans-2-hexenoyl chloride were added dropwise and stirred at room temperature for 15 hours. 220 ml of water are added, the mixture is washed with 110 ml of ethyl acetate, and the aqueous layer is adjusted to pH 2 with concentrated hydrochloric acid and extracted with 400 ml of ethyl acetate. The ethyl acetate layer was washed with 150 ml each of water and saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove ethyl acetate. 59.7 g of oil are obtained. The resulting oil was dissolved in 220 ml of toluene, and 60 ml of acetic anhydride, 52 ml of pyridine and 5.2 g of 4-dimethylaminopyridine were added thereto, followed by stirring at 65 ℃ for 5 hours. 300 ml of water was added to the reaction solution, and the reaction solution was washed with 500 ml of 1M hydrochloric acid. 300 ml of water was added to the toluene layer, neutralized with sodium bicarbonate water, and the two layers were separated. The toluene layer was washed with 200 ml of saturated brine, dried (sodium sulfate), and then the toluene was distilled off under reduced pressure. N-hexane was added to the obtained residue, and the precipitated crystals were filtered to obtain 27, 42 g of methyl 3- (5-methyl-trans-2-hexenylamino) -4-pentanoate.

IRν(neat)cm^-1；3329，1747，1720，1666，1626，1531.

¹H-NMR(CDCl₃)δ(ppm)；0.93(6H，d，J＝6.4Hz)，1.50-2.00(1H，m)，2.09(2H，t，J＝7.0Hz)，2.25(3H，s)，2.78，3.06(2H，ABq，J＝4.4，17.2Hz)，3.69(3H，s)，4.70-4.95(1H，m)，5.83(1H，d，J＝15.1Hz)，6.45-7.00(1H，br)，6.88(1H，dt，J＝7.2Hz，15.1Hz).

(2) 0.8 g of the compound obtained in the above (1) was dissolved in 5.6 ml of toluene, and 0.58 ml of phosphorus oxychloride was added thereto and refluxed for 1 hour. The reaction solution was poured into 10 ml of ice water, neutralized with sodium hydrogencarbonate, and the two layers were separated. The toluene layer was washed with 10 ml of saturated brine, dried (with sodium sulfate), and then toluene was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography to obtain 0.9 g of the title compound.

IR and¹H-NMR was the same as in reference example 16.

Reference example 18

2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethanol

3.34 g of the compound of reference example 16 were dissolved in 30 ml of toluene and 37.5 ml of a 1.5M solution of diisobutylaluminum in toluene were added dropwise at-70 ℃ and stirred at-70 to-40 ℃ for 1 hour. 100 ml of water was added to the reaction solution, and after insoluble matter was filtered, the two layers were separated. The toluene layer was washed with 50 ml of saturated brine, dried (over sodium sulfate), and then distilled under reduced pressure to remove toluene. The obtained residue was purified by column chromatography to obtain 1.75 g of the title compound.

IRν(neat)cm^-1；3346，2957，2926，2870，1661，1641，1533.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.4Hz)，1.50-2.10(1H，m)，2.11(2H，t，J＝7.0Hz)，2.25(3H，s)，2.71(2H，t，J＝5.9Hz)，2.81(1H，br-s)，3.86(2H，t，J＝5.9Hz)，6.16(1H，d，J＝16.0Hz)，6.62(1H，dt，J＝7.0，16.0Hz).

Reference example 19

2- [ 5-methyl-2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate

1.73 g of the compound of reference example 18 was dissolved in 20 ml of dichloromethane, 2.3 ml of triethylamine was added, 0.77 ml of methanesulfonyl chloride was added dropwise at 0 ℃, and then stirred at room temperature for 20 minutes. 30 ml of methylene chloride was added, and the mixture was washed with 30 ml of 10% citric acid water and 30 ml of saturated brine, dried (with sodium sulfate), and then distilled under reduced pressure to remove methylene chloride. The obtained residue was purified by column chromatography to obtain 2.21 g of the title compound.

IRν(neat)cm^-1；2959，2928，2870，1643，1535.

¹H-NMR(CDCl₃)δ(ppm)；0.94(6H，d，J＝6.4Hz)，1.50-2.10(1H，m)，2.12(2H，t，J＝7.0Hz)，2.27(3H，s)，2.87(2H，t，J＝6.7Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.15(1H，d，J＝15.8Hz)，6.62(1H，dt，J＝7.0，15.8Hz).

The following compounds were synthesized according to reference example 19.

Reference example 20

2- [2- (trans-2-cyclohexylvinyl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2926，2853，1736，1643，1533.

¹H-NMR(CDCl₃)δ(ppm)；0.85-2.50(11H，m)，2.26(3H，s)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.44(2H，t，J＝6.6Hz)，6.11(1H，d，J＝16.1Hz)，6.46(1H，dd，J＝6.6，16.1Hz).

Reference example 21

2- [2- (trans-1-hepten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；3628，3420，2959，2930，2860，1738，1643，1576，1533.

¹H-NMR(CDCl₃)δ(ppm)；0.75-1.10(3H，m)，1.10-1.67(4H，m)，2.04-2.40(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.7Hz)，2.94(1H，s)，4.45(2H，t，J＝6.7Hz)，6.16(1H，d，J＝16.0Hz)，6.64(1H，dt，J＝16.0Hz，6.8Hz).

Reference example 22

2- [2- (5-methyl-trans-2-hexen-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；3632，3410，2957，2928，2870，1661，1643，1535.

¹H-NMR(CDCl₃)δ(ppm)；0.91(6H，d，J＝6.2Hz)，1.13-1.90(3H，m)，2.00-2.22(2H，m)，2.26(3H，s)，2.86(2H，t，J＝6.7Hz)，2.94(3H，s)，4.45(2H，t，J＝6.7Hz)，6.20(1H，d，J＝15.7Hz)，6.62(1H，dt，J＝15.7，6.2Hz).

Reference example 23

2- [ 5-methyl-2- (1-methyl-trans-1-buten-1-yl) oxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2966，2934，2876，1647，1572，1535.

¹H-NMR(CDCl₃)δ(ppm)；1.07(3H，t，J＝6.8Hz)，2.00(3H，s)，2.05-2.40(2H，m)，2.27(3H，s)，2.87(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.45(1H，br-t).

Reference example 24

2- [ 5-methyl-2- (1-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；3393，2961，2932，2872，1647，1535.

¹H-NMR(CDCl₃)δ(ppm)；0.96(3H，t，J＝7.0Hz)，1.20-1.73(2H，m)，2.00(3H，s)，2.00-2.40(2H，m)，2.27(3H，s)，2.87(2H，t，J＝6.6Hz)，2.94(1H，s)，4.45(2H，t，J＝6.6Hz)，6.46(1H，dt，J＝1.4，7.0Hz).

Reference example 25

2- [2- (trans-2-cyclopentylvinyl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2955，2870，1736，1645，1533.

¹H-NMR(CDCl₃)δ(ppm)；1.20-2.00(8H，m)，2.26(3H，s)，2.36-2.78(1H，m)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.44(2H，t，J＝6.6Hz)，6.14(1H，d，J＝15.8Hz)，6.62(1H，dd，J＝15.8，7.5Hz).

Reference example 26

2- { 5-methyl-2- [ 2-trans- (1-methylcyclohexyl) ethenyl ] oxazol-4-yl } ethyl methanesulfonate

IRν(neat)cm^-1；2928，2853，1645，1531，1508.

¹H-NMR(CDCl₃)δ(ppm)；1.06(3H，s)，1.20-1.80(10H，m)，2.28(3H，s)，2.87(2H，t，J＝6.6Hz)，2.95(3H，s)，4.45(2H，t，J＝6.6Hz)，6.12(1H，d，J＝16.5Hz)，6.63(1H，d，J＝16.3Hz).

Reference example 27

2- { 5-methyl-2- [ 2-trans- (1-methylcyclopentyl) vinyl ] oxazol-4-yl } ethyl methanesulfonate

IRν(neat)cm^-1；2957，2872，1645，1551，1533.

¹H-NMR(CDCl₃)δ(ppm)；1.15(3H，s)，1.40-1.90(8H，m)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.13(1H，d，J＝16.3Hz)，6.71(1H，d，J＝16.3Hz).

Reference example 28

2- [ 5-methyl-2- (2-methylsulfamoylethyl) oxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2922，1651，1576.

¹H-NMR(CDCl₃)δ(ppm)；2.12(3H，s)，2.24(3H，s)，2.60-3.20(4H，m)，2.85(2H，t，J＝7.0Hz)，2.94(3H，s)，4.43(2H，t，J＝7.0Hz).

Reference example 29

2- [2- (3, 3-dimethyl-trans-1-buten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2962，2907，2869，1660，1645，1532.

¹H-NMR(CDCl₃)δ(ppm)；1.11(9H，s)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.11(1H，d，J＝16.2Hz)，6.67(1H，d，J＝16.2Hz).

Reference example 30

2- [2- (4, 4-dimethyl-trans-1-buten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2957，2907，2868，1661，1643，1533.

¹H-NMR(CDCl₃)δ(ppm)；0.95(9H，s)，2.10(2H，d，J＝7.5Hz)，2.28(3H，s)，2.87(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.15(1H，d，J＝16.0Hz)，6.65(1H，dt，J＝7.5，16.0Hz).

Reference example 31

2- [2- (3-ethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2963，2928，2876，1643，1578，1551，1533.

¹H-NMR(CDCl₃)δ(ppm)；0.86(6H，t，J＝6.8Hz)，1.20-1.70(4H，m)，1.70-2.20(1H，m)，2.27(3H，s)，2.87(2H，t，J＝6.6Hz)，2.94(1H，s)，4.45(2H，t，J＝6.6Hz)，6.12(1H，d，J＝15.8Hz)，6.41(1H，dd，J＝15.8，7.9Hz).

Reference example 32

2- [2- (3, 3-dimethyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；3034，3005，1643，1545.

¹H-NMR(CDCl₃)δ(ppm)；0.83(3H，t，J＝7.4Hz)，1.06(6H，s)，1.43(2H，q，J＝7.4Hz)，2.27(3H，s)，2.87(2H，t，J＝6.7Hz)，2.94(1H，s)，4.45(2H，t，J＝6.7Hz)，6.09(1H，d，J＝16.5Hz)，6.59(1H，d，J＝16.5Hz).

Reference example 33

2- { 5-methyl-2- [ (trans-2-thiophen-2-yl) ethenyl ] oxazol-4-yl } ethyl methanesulfonate

IRν(neat)cm^-1；3628，3420，3107，3020，2924，1734，1636，1547.

¹H-NMR(CDCl₃)δ(ppm)；2.31(3H，s)，2.90(2H，t，J＝6.5Hz)，2.95(3H，s)，4.78(2H，t，J＝6.5Hz)，6.64(1H，d，J＝16.1Hz)，7.02(1H，dd，J＝4.6，3.2Hz)，7.16(1H，d，J＝3.2Hz)，7.29(1H，d，J＝4.6Hz)，7.52(1H，d，J＝16.1Hz).

Reference example 34

2- (5-methyl-2-thiophenyloxazol-4-yl) ethyl methanesulfonate

IRν(neat)cm^-1；2928，1507.

¹H-NMR(CDCl₃)δ(ppm)；2.25(3H，s)，2.86(2H，t，J＝6.5Hz)，2.90(3H，s)，4.44(2H，t，J＝6.5Hz)，7.30-7.75(5H，m).

Reference example 35

2- [2- (3-methoxy-trans-1-propen-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2930，1354.

¹H-NMR(CDCl₃)δ(ppm)；2.28(3H，s)，2.87(2H，t，J＝6.4Hz)，2.94(3H，s)，3.39(3H，s)，4.45(2H，t，J＝6.5Hz)，6.30-6.80(2H，m).

Reference example 36

2- [2- (5-fluoro-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2964，2928，2860，1663，1643，1578，1535.

¹H-NMR(CDCl₃)δ(ppm)；1.60-2.15(2H，m)，2.20-2.50(2H，m)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，4.49(2H，dt，J＝5.8，47.2Hz)，6.21(1H，d，J＝16.0Hz)，6.63(1H，dt，J＝16.0，6.4Hz).

Reference example 37

2- [2- (2-cyclohexylidenemethyl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(nujol)cm^-1；1651，1545，1506.

¹H-NMR(CDCl₃)δ(ppm)；1.45-1.85(6H，br)，2.10-2.45(2H，br)，2.26(3H，s)，2.65-3.00(2H，br)，2.86(2H，t，J＝6.6Hz)，2.93(3H，s)，4.46(2H，t，J＝6.6Hz)，5.92(1H，s).

Reference example 38

2- [2- (2-cyclopentylidenemethyl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2957，2870，1659，1645，1576，1545，1526.

¹H-NMR(CDCl₃)δ(ppm)；1.50-2.00(4H，m)，2.27(3H，s)，2.30-3.00(4H，m)，2.87(2H，t，J＝6.6Hz)，2.93(3H，s)，4.46(2H，t，J＝6.6Hz)，6.10-6.25(1H，m).

Reference example 39

2- [2- (5-tert-butylsulfanyl-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2961，2928，2862，1641，1578，1535.

¹H-NMR(CDCl₃)δ(ppm)；1.32(9H，s)，1.55-1.95(2H，m)，2.15-2.40(2H，m)，2.27(3H，s)，2.57(2H，t，J＝7.0Hz)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.44(2H，t，J＝6.6Hz)，6.18(1H，d，J＝16.0Hz)，6.61(1H，dt，J＝16.0，6.4Hz)

Reference example 40

2- [2- (5-dimethylamino-trans-1-penten-1-yl) -5-methyloxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2941，2862，2818，2775，1643，1533.

¹H-NMR(CDCl₃)δ(ppm)；1.40-1.90(2H，m)，2.10-2.50(4H，m)，2.22(6H，s)，2.27(3H，s)，2.86(2H，t，J＝6.6Hz)，2.94(3H，s)，4.45(2H，t，J＝6.6Hz)，6.18(1H，d，J＝16.1Hz)，6.63(1H，dt，J＝16.1，6.4Hz).

Reference example 41

2- [2- (4-methyl-trans-1-penten-1-yl) oxazol-4-yl ] ethyl methanesulfonate

IRν(neat)cm^-1；2959，2930，2872，1661，1597，1549.

¹H-NMR(CDCl₃)δ(ppm)；0.95(6H，d，J＝6.4Hz)，1.50-2.00(1H，m)，2.14(2H，t，J＝6.8Hz)，2.96(3H，s)，2.96(2H，t，J＝6.7Hz)，4.48(2H，t，J＝6.7Hz)，6.21(1H，d，J＝16.0Hz)，6.70(1H，dt，J＝16.0，7.2Hz)，7.40(1H，s).

Test example 1

The pharmacological effects of the compounds tested were tested using male KKAy mice that developed spontaneous diabetic models of hyperglycemia, hypertriglyceridemia and hyperinsulinemia due to insulin resistance induced diabetes.

(test method)

Blood was collected from the tail artery of KKAy mice without fasting, and the glucose value and the triglyceride value in plasma were measured using commercially available measurement kits (glucose CII-test grade and triglyceride G-test grade, manufactured by Wako pure chemical industries, Ltd.). Five groups were divided into control and test compound groups, and the mean values of body weight, plasma glucose and triglyceride were made approximately equal to the standard deviation for each group. Starting on the next day, each test compound (the compounds of examples 1, 2, 4, 8, 20, 22, 24, 27, 30, 33, 36, 37, 40, 45, 47, 52, 56, 58 and 64) was suspended in a 5% gum arabic solution and orally administered to the test compound group for four consecutive days (10 mg/kg/day). The control group was orally administered a 5% gum arabic solution. 24 hours after the final administration, blood was collected from the tail vein without fasting, and the glucose value and the triglyceride value in the plasma were measured. The lowering rate of glucose and triglyceride in plasma was determined by the following formula. The results are shown in Table 1.

Percent reduction (%) (mean of control group-mean of test compound administration group)

Average of control group ]. times.100

(results)

TABLE 1

Test compound	Glucose reduction Rate (%)	Triglyceride reduction ratio (%)
Test compound	Glucose reduction Rate (%)	Triglyceride reduction ratio (%)	Example 1	46.1	45.3
Example 2	40.3	40.5	Example 1	46.1	45.3
Example 2	40.3	40.5	Example 4	40.3	40.5
Example 8	57.2	71.1	Example 4	40.3	40.5
Example 8	57.2	71.1	Example 20	57.7	65.6
Example 22	45.3	51.4	Example 20	57.7	65.6
Example 22	45.3	51.4	Example 24	52.8	50.7
Example 27	53.4	36.5	Example 24	52.8	50.7
Example 27	53.4	36.5	Example 30	55.4	57.0
Example 33	58.2	68.3	Example 30	55.4	57.0
Example 33	58.2	68.3	Example 36	39.8	27.5
Example 37	53.2	50.1	Example 36	39.8	27.5
Example 37	53.2	50.1	Example 40	54.3	37.0
Example 45	38.7	32.6	Example 40	54.3	37.0
Example 45	38.7	32.6	Example 47	29.9	10.9
Example 52	26.6	19.1	Example 47	29.9	10.9
Example 52	26.6	19.1	Example 56	21.0	11.9
Example 58	25.1	23.2	Example 56	21.0	11.9
Example 58	25.1	23.2	Example 64	29.4	25.1

Test example 2

The pharmacological actions of the compounds of examples 1, 2 and 20 were studied using db/db mice displaying hereditary hyperglycemia, hypertriglyceridemia, insulin resistance and obesity.

(test method)

Blood was collected from the caudal artery of male db/db mice without fasting, and the glucose value and the triglyceride value in plasma were measured using commercially available measurement kits (CII-glucose test grade and G-triglyceride test grade, manufactured by Wako pure chemical industries, Ltd.). Six groups were administered, and the group of control group and test compound (compounds in examples 1, 2 and 20) was divided into 3 mg/kg/day group so that the average values of body weight, glucose in plasma and triglyceride in each group were approximately equal to the standard deviation. Starting on the next day, the test compound was suspended in a 0.5% methylcellulose solution and orally administered for two consecutive weeks. The control group was orally administered a 0.5% methylcellulose solution. 24 hours after the final administration, blood was collected from the tail vein without fasting, and the glucose value and the triglyceride value in the plasma were measured. The lowering rate of glucose and triglyceride in plasma was determined by the following formula. The results are shown in Table 2.

Average of control group ]. times.100

(results)

TABLE 2

Test compound	Glucose reduction Rate (%)	Triglyceride reduction ratio (%)
Test compound	Glucose reduction Rate (%)	Triglyceride reduction ratio (%)	Example 1	21.3	62.7
Example 2	57.2	78.1	Example 1	21.3	62.7
Example 2	57.2	78.1	Example 20	54.0	72.0

Test example 3

Repeated drug toxicity studies using seven week old male ICR mice

(test method)

Seven mice were collected and the body weight average and standard deviation of the mice were made substantially equal, and the 30 mg/kg/day administration group and the 100 mg/kg/day administration group of the control group and the test compound (the compounds of examples 2 and 20) group were separated. Starting on the next day, the test compound (the compounds of examples 2 and 20) was suspended in a 0.5% methylcellulose solution and orally administered for two consecutive weeks. The control group was orally administered a 0.5% methylcellulose solution. 24 hours after the final administration, 100 micrograms of Evans blue/mouse was administered into the tail vein, and blood was collected from the orbital venous bundle under ether anesthesia 5 minutes later. The hematocrit value and the number of red blood cells were measured using blood to which EDTA was added, Evans blue was measured using plasma, and the plasma amount was calculated. The liver and heart were also extirpated and the wet weight was measured.

(results)

No significant difference was found between the test compound (compound of examples 2 and 20) administered at 30 mg/kg/day and the test compound administered at 100 mg/kg/day in body weight, hematocrit value, number of erythrocytes, plasma amount, liver and heart weight, and the control group.

Test example 4

Repeated drug toxicity was studied using six week old female Wistar rats

(test method)

A group of six rats was taken so that the weight average and standard deviation of the rats were approximately equal, and a 30 mg/kg/day administration group and a 100 mg/kg/day administration group of the control group and the test compound (the compounds of examples 2 and 20) were separated. Starting on the next day, the test compound was suspended in a 0.5% methylcellulose solution and orally administered for two consecutive weeks. The control group was orally administered a 0.5% methylcellulose solution. The patient is fasted for 16 hours from the final administration day, and 24 hours after the final administration, 50 mg/kg of pentobarbital sodium pentabarbital sodium is administered into the abdominal cavity for anesthesia and blood collection. Hematocrit and red blood cell counts were determined using blood with EDTA added, AST (GOT) and ALT (GPT) were determined using serum. White fat around the liver, heart and uterus was also extracted, and wet weight was measured.

(results)

No significant difference was found between the 30 mg/kg/day group and the 100 mg/kg/day group of the test compound (compounds of examples 2 and 20) in the hematocrit value, the number of red blood cells, the weight of white fat around the liver, heart and uterus, and ast (got) and alt (gpt), and the control group.

Test example 5

In order to confirm the water solubility of the compound of the present invention, the solubility in water was determined.

(test method)

To a buffer solution of pH7.0, 25 mg of the pulverized test compound (compounds of examples 2, 20, 22, 24, 27, 30, 40 and 65) was added, and after shaking at 25 ℃ for 1 hour, the mixture was filtered through a filtration membrane, and the concentration of the test compound in the filtrate was measured by a high performance liquid chromatography apparatus. The results are shown in Table 3.

TABLE 3

Test compound	Solubility (mg/ml)
Test compound	Solubility (mg/ml)	Example 2	10.0
Example 20	Over 25	Example 2	10.0
Example 20	Over 25	Example 22	Over 25
Example 24	18.7	Example 22	Over 25
Example 24	18.7	Example 27	Over 25
Example 30	17.3	Example 27	Over 25
Example 30	17.3	Example 40	18.7
Example 65	20.5	Example 40	18.7

Possibility of industrial utilization

The novel heterocyclic compound of the present invention represented by the general formula (I) and pharmaceutically acceptable salts thereof have a hypoglycemic action, a hypolipidemic action, an insulin resistance-improving action and a PPAR-activating 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, an agent for ameliorating glucose tolerance insufficiency, an anti-arteriosclerosis agent, an anti-obesity agent, an anti-inflammatory agent, a prophylactic and therapeutic agent for PPAR-mediated diseases and a prophylactic and therapeutic agent for syndrome X.

The present application is based on the japanese patent application No. 161489/2001, and the contents thereof are incorporated in their entirety in the present specification.

Claims

1. A novel heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

general formula (I)

In the formula (I), the compound is shown in the specification,

R¹represents a hydrogen atom or C_1-6An alkyl group;

R²represents a hydrogen atom, -CO-R³、-CO-C(R⁴)＝C(R⁴)-R⁵、-CO-C≡C-R⁶、

Phenyl radical C_1-3Alkyl, C which may be substituted by halogen_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl or C_3-8Cycloalkyl radical C_1-3An alkyl group;

wherein the content of the first and second substances,

R³represents C which may be substituted by halogen_2-6An alkyl group;

R⁴may be the same or different and represents a hydrogen atom or C_1-4An alkyl group;

R⁵is represented by C_1-8Alkyl radical, C_2-8Alkenyl or phenyl;

R⁶is represented by C_1-8An alkyl group;

m represents an integer of 2 to 7;

y represents

Or R¹⁵-C(R¹⁴)＝N-O-，

Wherein the content of the first and second substances,

R⁷represents a hydrogen atom or C_1-4An alkyl group;

R⁸is represented by C_5-8Alkyl radical, C_4-8Cycloalkyl radical, C_1-4Alkylthio of C_1-6Alkyl radical, R¹⁰-C(R⁹)＝C(R⁹)-、R¹²-CO-N(R¹¹)-、R¹³-Z-or

Wherein k represents an integer of 2 to 7;

x represents an oxygen atom or a sulfur atom,

wherein the content of the first and second substances,

R⁹may be the same or different and represents a hydrogen atom or C_1-4An alkyl group;

R¹⁰represents C which may be substituted by halogen atoms_1-6Alkyl radical, C_2-8Alkenyl, phenyl, phenylthio, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-4Alkylthio of C_1-6Alkyl or by (R)⁹)₂N-substituted C_1-6Alkyl radical, wherein R⁹Have the same meanings as described above;

R¹¹represents a hydrogen atom or C_1-4An alkyl group;

R¹²is represented by C_1-6Alkyl or phenyl;

R¹³is represented by C_1-8Alkyl or phenyl;

z represents an oxygen atom or a sulfur atom;

R¹⁴represents a hydrogen atom or C_1-4An alkyl group;

R¹⁵represents a phenyl group, and is represented by,

Y-(CH₂)_n-O-is bound to the 6-or 7-position of the tetrahydroisoquinoline skeleton, and n represents an integer of 1 to 4.

2. The novel heterocyclic compound according to claim 1, wherein in the general formula (I), R is²Is phenyl C_1-3Alkyl, C which may be substituted by halogen_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl or

Wherein m is an integer of 2 to 7.

3. The novel heterocyclic compound according to claim 1, wherein in the general formula (I), Y represents

In the formula (I), the compound is shown in the specification,

R⁷represents a hydrogen atom or C_1-4An alkyl group;

R⁸is represented by C_1-4Alkylthio of C_1-6Alkyl radical, R¹⁰-C(R⁹)＝C(R⁵) -or

Wherein

R¹⁰represents C which may be substituted by halogen atoms_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-4Alkylthio of C_1-6Alkyl or by (R)⁹)₂N-substituted C_1-6Alkyl radical, wherein R⁹Have the same meanings as described above;

k represents an integer of 2 to 7,

x represents an oxygen atom or a sulfur atom.

4. The novel heterocyclic compound according to claim 1, wherein in the general formula (I),

R²represents a hydrogen atom, -CO-R³、-COC(R⁴)＝C(R⁴)-R⁵or-CO-C.ident.C-R⁶；

Wherein the content of the first and second substances,

R³represents C which may be substituted by halogen_2-6An alkyl group;

R⁵is represented by C_1-8Alkyl radical, C_2-8Alkenyl or phenyl;

R⁶is represented by C_1-8An alkyl group, a carboxyl group,

y represents

Or R¹⁵-C(R¹⁴)＝N-O-，

Wherein the content of the first and second substances,

R⁷represents a hydrogen atom or C_1-4An alkyl group;

R⁸is represented by C_5-8Alkyl radical, C_4-8Cycloalkyl radical, R¹⁰-C(R⁹)＝C(R⁹)-、R¹²-CO-N(R¹¹) -or R¹³-Z-；

Wherein the content of the first and second substances,

R¹⁰is represented by C_1-6Alkyl radical, C_2-8Alkenyl, phenyl or thiophenyl;

R¹¹represents a hydrogen atom or C_1-4An alkyl group;

R¹²is represented by C_1-6Alkyl or phenyl;

R¹³is represented by C_1-8Alkyl or phenyl;

z represents an oxygen atom or a sulfur atom;

R¹⁴represents a hydrogen atom or C_1-4An alkyl group;

R¹⁵represents a phenyl group, and is represented by,

x represents an oxygen atom or a sulfur atom.

5. The novel heterocyclic compound or pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein in the formula (I), Y- (CH)₂)_n-O-is bound to the 7-position of the tetrahydroisoquinoline skeleton and n is 2.

6. The novel heterocyclic compound according to claim 4, wherein in the general formula (I), Y- (CH)₂)_n-O-is bound to the 7-position of the tetrahydroisoquinoline skeleton and n is 2.

7. The novel heterocyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y represents

In the formula, R⁷Represents a hydrogen atom or C_1-4An alkyl group; r⁸Represents R¹⁰-C(R⁹)＝C(R⁹) -, in which R⁹May be the same or different and represents a hydrogen atom or C_1-4An alkyl group; r¹⁰Is represented by C_1-6Alkyl radical, C_2-8Alkenyl or phenyl.

8. The novel heterocyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y represents

In the formula (I), the compound is shown in the specification,

R⁷represents a hydrogen atom or C_1-4An alkyl group;

R⁸represents R¹³-Z-，

Wherein the content of the first and second substances,

R¹³is represented by C_1-8Alkyl or phenyl;

z represents a sulfur atom.

9. The novel heterocyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y represents

In the formula, R⁷Represents a hydrogen atom or C_1-4An alkyl group; r⁸Is represented by C_5-8Alkyl or C_4-8A cycloalkyl group.

10. The novel heterocyclic compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein in the formula (I), Y represents

In the formula, R⁷Represents a hydrogen atom or C_1-4An alkyl group; r⁸Represents R¹⁰-C(R⁹)＝C(R⁹) -, in which R⁹May be the same or different and represents a hydrogen atom or C_1-4An alkyl group; r¹⁰Is represented by C_3-8A cycloalkyl group.

11. The novel heterocyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 7 to 10, wherein in the formula (I), R²represents-CO-C (R)⁴)＝C(R⁴)-R⁵Wherein R is⁴Represents a hydrogen atom, R⁵Is represented by C_1-8Alkyl or C_2-8An alkenyl group.

12. The novel heterocyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 7 to 10, wherein in the formula (I), R²represents-CO-C.ident.C-R⁶Wherein R is⁶Is represented by C_1-8An alkyl group.

13. The novel heterocyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y represents

In the formula (I), the compound is shown in the specification,

R⁷is represented by C_1-4An alkyl group;

R⁸represents R¹⁰-C(R⁹)＝C(R⁹)-，

Wherein the content of the first and second substances,

R¹⁰is represented by C_1-6An alkyl group, a carboxyl group,

x represents an oxygen atom.

14. The novel heterocyclic compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Y represents

In the formula (I), the compound is shown in the specification,

R⁷is represented by C_1-4An alkyl group;

R⁸represents R¹⁰-C(R⁹)＝C(R⁹)-，

Wherein the content of the first and second substances,

R⁹represents a hydrogen atom;

R¹⁰represents a phenyl group, and is represented by,

x represents an oxygen atom.

15. The novel heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 4 or 5, wherein in the general formula (I), Y is any one atom group selected from the following (a) to (n).

16. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following compounds (1) to (16):

17. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following compounds (1) to (3):

18. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following compounds (1) to (17):

(8)7- {2- [ 5-methyl-2- (1-penten-1-yl) oxazol-4-yl ] ethoxy } -2- (2, 2, 3, 3, 3-pentafluoropropionyl) 1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

19. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following (1) to (8):

20. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following compounds (1) to (6):

(4)2- (2, 4-hexadienoyl) -7- (2- { 5-methyl-2- [ 2-trans- (1-methylcyclohexanoyl-1-yl) vinyl ] oxazol-4-yl } ethoxy) -1, 2, 3, 4-tetrahydroisoquinoline- (3S) -carboxylic acid,

21. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is a compound of the following (1) or (2):

22. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is a compound of the following (1) or (2):

23. The novel heterocyclic compound according to claim 1, wherein the compound of the general formula (I) is any one of the following compounds (1) to (9):

24. A pharmaceutical composition comprising the novel heterocyclic compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical agent comprising the novel heterocyclic compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance-improving agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an agent for ameliorating glucose tolerance dysfunction, an anti-arteriosclerosis agent, an anti-obesity agent, an anti-inflammatory agent, an agent for the prevention and treatment of PPAR-mediated diseases, and an agent for the prevention and treatment of syndrome X.

26. The use of the novel heterocyclic compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treating or preventing hyperglycemia, hyperlipidemia, diseases caused by insulin resistance, diabetes, diabetic complications, glucose tolerance insufficiency, arteriosclerosis, obesity, inflammation, PPAR-mediated diseases, or X syndrome.