Derivatives of tetrahydroisoquinoline and their salts and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

 

The technical FIELD

The present invention relates to new heterocyclic compound and its pharmaceutically acceptable salts, which possess hypoglycemic action, hypolipidemic effect in the bloodstream, the effect of increasing insulin resistance, or activating PPAR (receptor activated by means of the proliferation peroxisome) action. The present invention relates also to pharmaceutical compositions comprising the above-mentioned new heterocyclic compound or its pharmaceutically acceptable salt. In addition, the present invention relates to the hypoglycemic agent, a hypolipidemic the tool, the tool that improves insulin resistance, therapeutic tool for the treatment of diabetes, remedy complications in diabetes (i.e. therapeutic agent against diabetic complications), the tool that improves glucose tolerance, anti-atherosclerosis, anti-obesity, anti-inflammatory agent, the agent for the prophylaxis or treatment of PPAR-mediated diseases and the means for prevention or treatment of syndrome X, and all of them include the above new heterocyclic compound or its pharmaceutically acceptable salt.

BACKGROUND of INVENTION

As a therapeutic with whom estva for diabetes used connection biguanide, having as a primary action inhibitory effect on the absorption of glucose through the intestine and the release of glucose from the liver, joints sulfonylureas, has an accelerating effect on insulin secretion as a primary action, insulin and the like. However, the connection of biguanide cause lactic acidosis, and connection sulfonylureas sometimes cause serious hypoglycemia due to their strong hypoglycemic action. Therefore, should be taken due care when using these compounds. In recent years we have carried out active research and development of therapeutic tools for the treatment of diabetes, which does not have these disadvantages, have been found in various compounds with the effect of increasing insulin resistance.

Insulin resistance is important as causes of non-insulin dependent diabetes mellitus (NIDDM) along with a decrease in insulin secretion. Therefore, it was necessary to develop a pharmaceutical agent that increases insulin resistance. As a tool that can increase insulin resistance, various known compounds of thiazolidine. As such compounds, for example, 5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione (the conventional name: troglitazone) described in Japan patent JP-B-2-31079, 5-[[4-[2-(5-ethylpyridine-2-yl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (common name: pioglitazone) is described in the Japan patent JP-B-5-66956 and 5-[[4-[2-[N-methyl-N-(pyridine-2-ylamino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (common name: rosiglitazone) is described in the Japan patent JP-A-1-131169.

Thus, an object of the present invention is a compound which has a hypoglycemic action, hypolipidemic effect in the bloodstream, which increases insulin resistance effect and PAR-activating action, which have a structure different from the structure of the conventional compounds, in order to increase diversity and to expand the range of selection hypoglycemic agents, lipid-lowering means, means increasing insulin resistance, therapeutic agents for diabetes, therapeutic agents for the treatment of diabetic complications, tools, improve glucose tolerance, anti-atherosclerosis, anti-obesity, anti-inflammatory drugs, remedies for the prevention or treatment of PPAR-mediated diseases and resources for the prophylaxis or treatment of syndrome X.

Description of the INVENTION

The authors of the present invention conducted intensive studies to resolve the above problems and found that a heterocyclic compound that newaustralian formula [I]

where

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil, or monocyclic geterotsiklicheskikh, where the heterocycle include a 5 - or 6-membered ring containing a nitrogen atom, and optionally has a Deputy, selected from lower alkyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from oxygen atom and nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila, or its pharmaceutically acceptable salt has a hypoglycemic action, hypolipidemic effect in the bloodstream, the effect of increasing insulinresistant is here, and PPAR-activating action, which led to completion of the invention.

In accordance with this present invention relates to the following:

[1] derived tetrahydroisoquinoline formula [I]

where

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil, or monocyclic geterotsiklicheskikh, where the heterocycle include a 5 - or 6-membered ring containing a nitrogen atom, and optionally has a Deputy, selected from lower alkyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from oxygen atom and nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, al is Anila, cycloalkyl and tanila (hereinafter called heterocyclic compound [I]), and its pharmaceutically acceptable salt;

[2] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila, or its pharmaceutically acceptable salt;

[3] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

R1represents a hydrogen atom or lower alkyl,

R 2represents alkyl, cycloalkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil or a heterocycle-alkyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt;

[4] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, cycloalkyl and arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl,

R3represents a hydrogen atom,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents monatic is practical or condensed heterocyclyl, containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt;

[5] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

Y-A - is a

where RArepresents isopropyl or tert-butyl,

RBrepresents isopropyl or tert-butyl,

RCrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropanal, 3-butenyl, cyclopropyl, 1-butenyl or 2,2-dimethylpropyl,

and its pharmaceutically acceptable salt;

[6] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

Y-A - is a

where RAndrepresents isopropyl or tert-butyl,

Rinrepresents isopropyl or tert-butyl,

Rwithrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropyl or 3-butenyl,

and its pharmaceutically acceptable salt;

[7] derived tetrahydrothieno the ina by the above-mentioned [1], where in the formula [I]

Y-A - is a

and its pharmaceutically acceptable salt;

[8] derived tetrahydroisoquinoline on the above-mentioned [1], where in the formula [I]

Y-A - is a

and its pharmaceutically acceptable salt;

[9] derived tetrahydroisoquinoline on the above-mentioned [1], where the heterocyclic compound of the formula [1] is any of the following compounds (1) to (67):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(21) 2-(4-terbisil)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-ka is oil acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(47) 2-benzyl-7-(2-isopropylphenoxy-5-yl)IU the hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

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

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

(60) 7-[2-(5-ethylpyridine-2-yl)e is the hydroxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,

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

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

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

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

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

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

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

[10] derived tetrahydroisoquinoline according to the above [9], where the derivative of tetrahydroisoquinoline formula [I] is any of the above compounds (1)to(47) or its pharmaceutically acceptable salt;

[11] derived tetrahydroisoquinoline according to the above [9], where the derivative of tetrahydroisoquinoline formula [I] is any of the above compounds (1)to(21) and its pharmaceutically acceptable salt;

[12] the pharmaceutical composition having hypoglycemic and hypolipidemic is Kim action including derived tetrahydroisoquinoline according to any one of the above [1]to[11] or its pharmaceutically acceptable salt;

[13] a pharmaceutical agent comprising the derivative tetrahydroisoquinoline according to any one of the above [1]to[11] or its pharmaceutically acceptable salt, which is selected from the group comprising a hypoglycemic agent, a hypolipidemic agent, an agent that increases insulin resistance, terapevticheskii cure for diabetes, a therapeutic agent against diabetic complications, a tool that improves glucose tolerance, anti-atherosclerosis, anti-obesity, anti-inflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated diseases and an agent for the prophylaxis or treatment of syndrome X;

New derived tetrahydroisoquinoline formula [I]

where

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil, or anticline geterotsiklicheskikh, where the heterocycle include a 5 - or 6-membered ring containing a nitrogen atom, and optionally has a Deputy, selected from lower alkyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from oxygen atom and nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

and its pharmaceutically acceptable salt possess hypoglycemic action, hypolipidemic effect in the bloodstream, the effect of increasing insulin resistance, and PPAR-activating action.

Alkoxycarbonyl in the present invention preferably has from 2 to 5 carbon atoms. Examples include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl and the like.

Lower alkyl in R1, R3and R5represents, preferably, alkyl with an unbranched or branched chain, having from 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, preferably methyl, ethyl, propyl and isopropyl.

Lower alkoxy, R3represents, preferably, alkoxy with unbranched or branched chain, having from 1 to 6 carbon atoms, examples of which are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy and the like, preferably methoxy, ethoxy, propoxy, isopropoxy.

“Alkenyl” alkenyl, not necessarily with the Deputy, R2and R4represents, preferably, alkenyl with unbranched or branched chain, having from 2 to 6 carbon atoms, examples of which are vinyl, 1-propenyl, 2-propenyl, Isopropenyl, allyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, preferably, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 2-propenyl and 2-methyl-1-propenyl. Examples of the substituent is lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro and the Ino and the like. When alkenyl in R2or R4is substituted, the number of substituents, preferably 1 or 2.

“Quinil” quinil, not necessarily with the Deputy, R2represents, preferably, quinil with unbranched or branched chain, having from 2 to 4 carbon atoms, examples of which are ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-methyl-2-PROPYNYL and the like, preferably, ethinyl and 2-PROPYNYL. Examples of the substituent is lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When quinil in R2is substituted, the number of substituents, preferably 1 or 2.

“Alkyl” in the alkyl, optional with the Deputy, R2and R4represents, preferably, alkyl with an unbranched or branched chain, having from 1 to 8 carbon atoms, examples of which are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like, preferably methyl, ethyl, isobutyl, propyl, hexyl, pentyl and isopropyl. Examples of the substituent is lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, Ala xianbei, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When the alkyl in R2is substituted, the number of substituents, preferably 1 or 2.

Cycloalkyl in R2represents, preferably, cycloalkyl having from 3 to 8 carbon atoms, an example of which is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably, cyclopropyl, cyclopentyl and cyclohexyl.

Cycloalkenyl in R2is cycloalkylation, which cycloalkyl part is, preferably, cycloalkyl having from 3 to 8 carbon atoms, and the alkyl part is preferably alkyl with an unbranched or branched chain, having from 1 to 3 carbon atoms. Examples of it are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclooctylmethyl, 3-cyclopropylmethyl, 3-cyclobutylmethyl, 3-cyclopentylpropionyl, 3-cyclohexylprop, 3-cycloheptenyl, 3-cyclooctadiene, 1-cyclohexylethyl, 1-cyclohexylprop, 2-cyclohexylprop and the like, preferably, cyclohexylmethyl, 2-cyclohexylethyl, cyclopentylmethyl and 2-cyclopent later.

Examples of the aryl in the aryl, optionally with the Deputy, R2, R4and Y is phenyl, naphthyl and the like. Examples of the substituent is lower alkyl (as defined for the lower alkyl in R1, R3and R5), lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino, acyl (e.g. formyl, acetyl, propanol etc) and the like. When the aryl and Y is substituted, the number of substituents, preferably 1 or 2.

An example of arylalkyl, not necessarily with the Deputy, R2and R4is arylalkyl, in which the aryl part is preferably phenyl, naphthyl and the like, and the alkyl part is preferably alkyl with an unbranched or branched chain, having from 1 to 3 carbon atoms. Examples of arylalkyl are benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-(1-naphthyl) ethyl, 2-(2-naphthyl) ethyl, 3-phenylpropyl, 3-(1-naphthyl) propyl, 3-(2-naphthyl)propyl, 1-phenylethyl, 2-phenylpropyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 1-(1-naphthyl)propyl, 1-(2-naphthyl)propyl, 2-(1-naphthyl)propyl, 2-(2-naphthyl)propyl, and the like, preferably benzyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. Examples of the substituents are lower alkyl(as defined for the lower alkyl in R 1, R3and R5), lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino, acyl (e.g. formyl, acetyl, propanol etc) and the like, preferably, lower alkyl, lower alkoxy, halogen atom and acyl. When arylalkyl in Y is substituted, the number of substituents, preferably 1 or 2.

Aromatic heterocycle in the aromatic heterocyclic residue optionally having a substituent in Y, represents, preferably, a monocyclic heterocycle or a condensed heterocycle containing at least one heteroatom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. Condensed heterocycle in the present invention has two rings and includes a condensed heterocycle having heteroatom(s) in both rings. Monocyclic heterocycle, preferably, includes a 5 - or 6-membered ring. A heterocycle comprising the condensed heterocycle, preferably represents a 5 - or 6-membered ring. Ring without heteroatoms, which forms a condensed heterocycle, preferably a 5 - or 6-membered ring. Examples of the aromatic heterocyclic residue are monocyclic hetero Klionsky residue, such as furyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl or pyrazinyl and the like; condensed heterocyclic residue, such as indolyl, isoindolyl, indolinyl, isoindolyl, indazoles, benzofuranyl, benzothiophene, benzimidazole, benzoxazole, benzothiazole, hinely, ethanolic, benzoxazines, benzothiazines, furo[2,3-b]pyridyl, thieno[2,3-b]pyridyl, naphthyridine, imidazopyridine, oxazolopyridine, triazolopyridine and the like, with preference given to pyridyl, oxazolyl, indolinyl, benzoxazolyl, thiazolyl, benzothiazolyl, indolyl, Honolulu and benzofuranyl. Examples of the substituent is lower alkyl (as defined for the lower alkyl in R1, R3and R5), lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino, aryl (e.g. phenyl, naphthyl and the like), a heterocyclic residue (e.g., thienyl, pyridyl, furyl and the like), alkenyl (as defined for alkenyl in R2and R4), cycloalkyl (for example, cyclopropyl etc) and the like, preferably, aryl, lower alkyl, carboxy, heterocyclic residue, alkenyl and cycloalkyl. When the arene is political heterocyclic residue Y is substituted, the number of substituents, preferably 1 or 2.

Lowest alkylen in represents, preferably, alkylene with unbranched or branched chain, having from 1 to 6 carbon atoms, examples are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, METROTILE, 2,2-dimethyltrimethylene, 2-ethyltryptamine, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 3,3-dimethyltrimethylene, 3,3-dimethyltrimethylene and the like, preferably ethylene, trimethylene and tetramethylene.

Heterocyclic part in heterocyclic alkyl, optionally having the substituent in R2has the value specified for the “aromatic heterocyclic residue” in the “aromatic heterocyclic residue optionally having a Deputy, in Y. Example alkyl part is alkyl with an unbranched or branched chain, having from 1 to 3 carbon atoms. Specific examples of the heterocyclic alkyl are 1-pyridylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1- (1-pyridyl)ethyl, 1-(2-pyridyl)ethyl, 1-(3-pyridyl)ethyl, 1-(4-pyridyl)ethyl, 2-(1-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl; 1-(1-pyridyl)propyl, 1-(2-pyridyl)propyl, 1-(3-pyridyl)propyl, 1-(4-pyridyl)propyl, 2-(1-pyridyl)propyl, 2-(2-pyridyl)propyl, 2-(3-pyridyl)propyl, 2-(4-pyridyl)propyl, 3-(1-who iridis)propyl, 3-(2-pyridyl)propyl, 3-(3-pyridyl)propyl, 3-(4-pyridyl)propyl; 2-thienylmethyl, 3-thienylmethyl; 1-(2-thienyl)ethyl, 1-(3-thienyl)ethyl, 2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl; 1-(2-thienyl)propyl, 1-(3-thienyl)propyl, 2-(2-thienyl)propyl, 2-(3-thienyl)propyl, 3-(2-thienyl)propyl, 3-(3-thienyl)propyl, and the like. Heterocyclic alkyl may be substituted in the heterocyclic part. Examples of the substituents are lower alkyl (as defined for the lower alkyl in R1, R3and R5), lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, alkoxycarbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When the heterocyclic residue is substituted, the number of substituents, preferably 1 or 2.

As for the heterocyclic residue optionally having a Deputy, R4, heterocyclic residue is the same as the “aromatic heterocyclic residue” in the “aromatic heterocyclic residue optionally having a substitute in Y, which preferably represents pyridyl. Heterocyclic residue may be substituted. Examples of the substituents are lower alkyl (as defined for the lower alkyl in R1, R3and R5), lower alkoxy (as defined for the lower alkoxy, R3), hydroxy, carboxy, Alcock carbonyl, halogen atom (chlorine atom, bromine atom, iodine atom and fluorine atom), nitro, amino and the like. When the heterocyclic residue is substituted, the number of substituents, preferably 1 or 2.

Examples of heterocyclic compounds [I] and its pharmaceutically acceptable salts, preferred are the following compounds.

Heterocyclic compound of the above formula [I],

where

(1) R1represents a hydrogen atom or lower alkyl, R2represents a hydrogen atom, alkyl, optionally having a Deputy, cycloalkyl, cycloalkenyl, aryl, optionally with the Deputy, arylalkyl not necessarily have a Deputy, or-COR4where R4represents a hydrogen atom, alkyl, optionally having a Deputy, aryl, optionally having a Deputy, or arylalkyl, not necessarily with the Deputy,

R3represents a hydrogen atom, lower alkyl or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents a hydrogen atom or lower alkyl,

Represents a lower alkylene and

Y is aryl, optionally with the Deputy, or an aromatic heterocyclic residue optionally having a Deputy,

(2) R1represents a hydrogen atom ilinski alkyl,

R2represents a hydrogen atom, alkyl, cycloalkyl, arylalkyl, not necessarily with the Deputy, alkenyl, quinil, heterocyclic alkyl, or-COR4where R4represents alkyl, alkenyl or aryl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a simple bond or >N-R5where R5represents lower alkyl,

Represents a lower alkylene and

Y represents an aryl or aromatic heterocyclic residue optionally having a Deputy, or

(3) R1represents a hydrogen atom or lower alkyl,

R2represents a hydrogen atom, alkyl, cycloalkyl, arylalkyl not necessarily have a Deputy, or-COR4where R4represents alkyl or aryl,

R3represents a hydrogen atom,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene and

Y represents an aromatic heterocyclic residue optionally having a Deputy, and its pharmaceutically acceptable salt.

In the formula [I] Y-A - represents, preferably,

where RArepresents isopropyl or tert-butyl,

RBrepresents isopropyl or tert-butyl and

RCrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropyl or 3-butenyl or

where RArepresents isopropyl or tert-butyl,

RBrepresents isopropyl or tert-butyl and

RCrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropanal, 3-butenyl, cyclopropyl, 1-butenyl or 2,2-dimethylpropyl, with special preference given

Preferred examples of heterocyclic compounds [I] and its pharmaceutically acceptable salts are (1) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(21) 2-(4-terbisil)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid and its pharmaceutically acceptable salts. In addition to the above are preferred

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(43) 2-benzyl-7-(2-isopropylphenoxy-6-yl)methoxy-1,2,3,4-tetrahed ozkinay-(3S)-carboxylic acid,

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

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

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

acid and

(47) 2-benzyl-7-(2-isopropylphenoxy-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid and its pharmaceutically acceptable salts.

In addition to the above preferred are heterocyclic compounds [I] and their pharmaceutically acceptable salts.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

As the heterocyclic compound [I] has an asymmetric carbon at the 3-position of the ring 1,2,3,4-tetrahydroisoquinoline, it includes various stereoisomers.

The most preferred configuration is

where R1, R2, R3, Y, a and b have the values specified above.

If you heterocyclic compound [I] can be converted into a pharmaceutically acceptable salt.

When the heterocyclic compound [I] contains the main group, you can get an acid additive salt. The acid used for the formation of an acid additive salt, not subject to any particular limitation, if it forms a salt with the main part and is pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid and the like, and the like.

When the heterocyclic compound [I] has an acid group (for example, carboxyl group and the like), you can get a salt such as a salt of an alkali metal (for example, when l sodium, the potassium salt and the like), alkali earth metal salt (e.g. calcium salt, magnesium salt and the like) or a salt of organic bases (for example, salt of triethylamine, salt dicyclohexylamine, salt of pyridine, and the like) and the like.

Heterocyclic compound [I] or its pharmaceutically acceptable salt can be obtained by any of the following methods to retrieve.

The method of obtaining 1

where R1, R3, A, b and Y have the meanings stated above, R6represents a hydrogen atom, alkyl, optionally having a Deputy, cycloalkyl, cycloalkenyl, aryl, optionally with the Deputy, arylalkyl, not necessarily with the Deputy, alkenyl, not necessarily with the Deputy, quinil, not necessarily with the Deputy, heterocyclic alkyl, optionally having a Deputy, -COR4(R4has the above values) or aminosidine group and X represents a hydroxy, a halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom) or a group to delete, such as alkanesulfonyl (for example, methanesulfonate, econsultancy, propanesulfonate, tripterocalyx and the like), arylsulfonyl (for example, phenylsulfonyl, tolilsulfonil and the like) and the like.

the method of obtaining 1 compound of the formula [Ia] (also referred to as the compound [Ia]) synthesized by the coupling of compounds of formula [II] (also referred to as compound [II]with the compound of the formula [III] (also known as a connection [III]).

“Alkyl, optionally having a Deputy”, “cycloalkyl”, “cycloalkenyl”, “aryl, optionally with a Deputy”, “arylalkyl, not necessarily with the Deputy”, “alkenyl, not necessarily with the Deputy”, “quinil, not necessarily with the Deputy” and “heterocyclic alkyl, optionally having a Deputy”, R6have the meanings indicated for R2.

Examples aminosidine group in R6are formyl, monochloracetic, dichloracetyl, trichloroacetyl, TRIFLUOROACETYL, methoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, p-nitrobenzenesulfonyl, diphenylmethylsilane, methoxyethylamine, methoxyethoxymethyl, trimethylsilyl, 2,2,2-trichlorocyanuric, 2-methylsulfonylbenzoyl, tert-butoxycarbonyl (denoted hereinafter Vos), trityl and the like.

The method of obtaining 1: When X is a hydroxy, a method of obtaining 1 involves the reaction of dehydration, such as reaction Mitsunobu (Reagents for Organic Synthesis, Fisher and Fisher, Vol. 6, 645), and the like. The reaction is usually conducted in a solvent to uzasadnienie and phosphine. Examples of the azo compounds are di(C1-C4-alkyl)azodicarboxylate (for example, diethylazodicarboxylate and the like), azodicarboxamide (for example, 1,1' -(azodicarbon)dipiperidino and the like) and things like the OE. Examples of phosphine are triarylphosphine (for example, triphenylphosphine and the like), three(C1-C4-alkyl)phosphine (for example, tributylphosphine and the like) and the like.

Examples of the solvent used in the production method of 1-and are dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, telengard, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like and mixtures thereof and the like, but the solvent is not limited, while it has no adverse effect on the reaction.

The amount of compound [II]used in the method of obtaining the I-and not subject to any particular limitation. It is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III]. Uzasadnienie and phosphine respectively used in amounts of usually 1-3 moles, preferably 1-1 .5 mol, per 1 mol of compound [III].

Although the reaction conditions such as reaction temperature and reaction time and the like, in the production method of 1-and varies depending on the reagent, solvent and the like, which are used in this reaction, the reaction generally proceeds at a temperature of from -30°C to 50°C for from 30 minutes to about 12 hours.

The way to obtain 1-b: When X represents a halogen atom or deleted is to Rupp, such as alkanesulfonyl (for example, methanesulfonate, econsultancy, propanesulfonate, tripterocalyx and the like), arylsulfonyl (for example, phenylsulfonyl, tolilsulfonil and the like) and the like, the retrieval method 1-b is carried out in a solvent similar to the solvent used in the production method of 1-a, and in the presence of a base.

Examples of the base used in the method of obtaining 1-b, but the base is not limited to these examples are inorganic base such as a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide and the like), hydride compound of the metal (e.g. sodium hydride, potassium hydride, calcium hydride and the like) and the like; organic base such as alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, tert-piperonyl potassium and the like), amines (e.g. triethylamine, diisopropylethylamine and the like) and the like.

The amount of compound [II]used in production method of 1-b, is not subject to any particular limitation. It is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 m is l, the compound [III]. The base is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [III].

Although the reaction conditions such as reaction temperature and reaction time, and the like, a method of producing 1-b vary depending on the reagent, solvent and the like used in the reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 30 minutes to about 12 hours.

In the process for 1 R1the compounds [III], preferably represents lower alkyl. In that case, get the compound [Ia], where R1represents lower alkyl, this compound can be converted into the compound [Ia], where R1represents a hydrogen atom by hydrolysis according to the method known per se.

In the production method of 1, when R6compound [III] is aminosidine group gives the compound [Ia], where R6represents aminosidine group. This compound can be converted into the compound [Ia], where R1represents a hydrogen atom, removing protection according to the method known per se.

The method of obtaining 2

where R1, R3, A, b and Y have the above values, R7represents aminosidine group, R8represents alkyl, optionally with mixing Itel, cycloalkyl, cycloalkenyl, aryl, optionally with the Deputy, arylalkyl, not necessarily with the Deputy, alkenyl, not necessarily with the Deputy, quinil not necessarily have a Deputy, or heterocyclic alkyl, optionally having a Deputy, and U represents a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) or a group to delete, such as alkanesulfonyl (for example, methanesulfonate, econsultancy, propanesulfonate, tripterocalyx and the like), arylsulfonyl (for example, phenylsulfonyl, tolilsulfonil and the like) and the like.

In the method of obtaining 2 aminosidine group, R7the compounds of formula [Ib] (also referred to as the compound [Ib]) helps eliminate a manner known per se, to obtain the compounds of formula [IC] (also referred to as the compound [IC]), which is then subjected to interaction with the compound of the formula [V] (also referred to as the compound [V]), through which they receive a connection formula [Id] (also referred to as the compound [Id]).

“Alkyl, optionally having a Deputy”, “cycloalkyl”, “cycloalkenyl”, “aryl, optionally with a Deputy”, “arylalkyl, not necessarily with the Deputy”, “alkenyl, not necessarily with the Deputy”, “quinil, not necessarily with the Deputy” the “heterocyclic alkyl, optional with Deputy”, R8have the meanings indicated for R2.

Aminosidine group in R7matter listed for R6.

In the method of obtaining 2 compound [IC] is subjected to interaction with the compound [V] in a solvent that does not inhibit the interaction, such as dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, telengard, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like and mixtures thereof and the like, in the presence of a base, to obtain the compound [Id].

In the production method of example 2 of the base used for interaction between the compound [IC] with the compound [V], but the base is not limited to these examples is an inorganic base such as a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide and the like), hydride compound of the metal (e.g. sodium hydride, potassium hydride and calcium hydride, and the like) and the like; organic base such as an alkoxide of an alkaline metal (e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like), amines (e.g. triethylamine, disop operationin and the like) and the like.

The amount of compound [V]used in production method of 2, is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic]. The base is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].

Although the reaction conditions such as reaction temperature and reaction time and the like, for interacting compounds [Ic] with the compound [V] in the method of obtaining 2 varies depending on the reagent, solvent and the like, which are used in this reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 30 minutes to about 24 hours.

In the method of obtaining 2 R1the compound [Ib]preferably represents lower alkyl. In this case, get the connection [Id], where R1represents lower alkyl, and the join can be converted into the compound [Id], where R1represents a hydrogen atom by hydrolysis according to the method known per se.

The method of obtaining 3

where R1, R3, R4, A, b and Y have the above values.

In the method of obtaining 3 compound of the formula [I] (also referred to as compound [I]) synthesized by the interaction of the compound [IC] with the compound of the formula [VI] (also referred to as the compound [VI]).

In the method of obtaining 3 compound [VI] can IP alsowhat not only in the form of the free acid, but also in the form of a salt (e.g. sodium salt, potassium salts, calcium salts, salts of triethylamine, pyridine salts, and the like) or in the form of a reactive derivative (for example, gelegenheid acid such as the acid chloride acid, bromohydrin acid and the like; acid anhydride; a mixed acid anhydride with substituted phosphoric acid such as dialkylphosphate and the like, and alkalicarbonate, such as monoethylamine and the like; reactive amide, which is Amida with imidazole and the like; ether complex, such as cinematology ether and 4-nitrophenyloctyl ether and the like) and the like.

In the method of obtaining 3, when the compound [VI] is used in the form of free acid or salt, this reaction is preferably carried out in the presence of a condensing agent. As the condensing agent can be used dehydrating agent such as a carbodiimide compound (e.g. N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-cyclohexyl-N'-(4-diethylaminoethoxy)carbodiimide and the like), the connection of asolid (for example, N,N'-carbonyldiimidazole, N,N'-conidiomata and the like) and the like. The condensing agent is used in amounts of generally 1-5 mol, preferred is part 1-3 mol, on 1 mol of compound [Ic]. Whereas, when using condensing agent, the compound [VI] becomes reactive derivative and reacts.

The method of obtaining 3 is usually conducted in a solvent inert to the reaction. Examples of the solvent are acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and mixed solvents. In the method of obtaining 3 you can use a base, such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like. When using the base, it is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].

In the method of obtaining 3 compound [VI] is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].

Although the reaction conditions such as reaction temperature and reaction time and the like, for interacting compound [VI] with the compound [Ic] in the method of obtaining 3 varies depending on the reagent, solvent and the like, which are used in this reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 10 minutes to about 12 hours.

In the method of obtaining 3 compound [Ie'] is produced by interaction of the compound [VI] with the compound [IC],the allocation and recovery of the resulting compound [Ie]. This reduction is carried out in a solvent which does not adversely influence the reaction (for example, water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylthiourea, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, mixtures thereof and the like) in the presence of a reducing agent.

Examples of the reducing agent used in this reaction is a hydride complex of the metal (for example, alumoweld lithium, cyanoborohydride sodium (NaBH3CN), borohydride sodium and the like), borane, and the like. The agent is not subject to any particular limitation, as it is usually used for recovery of the carbonyl group into a methylene group. The reducing agent is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ie].

Although the reaction conditions such as reaction temperature and reaction time and the like, in the reaction of recovery varies depending on the reagent, solvent and the like, which are used in this reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 30 minutes to about several hours.

The method of obtaining 4

where R1, R2, R3, R5,, X, Y, and U have the above meanings and R10represents aminosidine group.

Aminosidine group in R10matter listed for R6.

The method of obtaining 4 is intended for heterocyclic compounds [I], where a represents >N-R5. In this way the compound of the formula [VII] (also referred to as the compound [VII]) is subjected to interaction with the compound of the formula [VIII] (also referred to as the compound [VIII]) in the same manner as in the production method of 1, thus obtaining the compound of the formula [IX] (also referred to as the compound [IX]), and aminosidine group in R10the compound [IX] helps eliminate a manner known per se, thus obtaining the compound of the formula [X] (also referred to as the compound [X]), which is then subjected to interaction with the compound of the formula [XI] (also referred to as the compound [XI], through which they receive a connection formula [If] (also referred to as the compound [If].

The interaction of the compound [X] with the compound [XI] in the method of obtaining 4 is carried out in a solvent which does not adversely influence the reaction in the presence of a base. Examples of the solvent are dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, telengard, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like and MESI. When the compound [XI] can be used as a solvent, it is used as a solvent.

Examples of the base used in the reaction of compound [X] with the compound [XI] in the process for 4, but the base is not limited to these examples are inorganic base such as a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide and the like), hydride compound of the metal (e.g. sodium hydride, potassium hydride, calcium hydride and the like) and the like; organic base such as an alkoxide of an alkaline metal (e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like) and amines (e.g. triethylamine, diisopropylethylamine and the like) and the like. The base is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [X].

In the method of obtaining 4 compound [XI] is used in a proportion of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [X].

Although the reaction conditions such as reaction temperature and reaction time and the like, in the reaction of compound [X] with the compound [XI] in the method of obtaining 4 varies depending on the reagent, solvent and such that the second, used in this reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 30 minutes to about several hours.

The method of obtaining 5

where R1, R3, A, b and Y have the above values, R9represents a group that makes a group of the formula-CH2-R9the alkyl, optional with the Deputy, cycloalkylation, arylalkyl, not necessarily with the Deputy, alkenyl, not necessarily with the Deputy, quinil not necessarily have a Deputy, or a heterocyclic alkyl, optionally having a Deputy.

In the method of obtaining 5 compound [IC] is subjected to interaction with the compound of the formula [XII] (also referred to as the compound [XII]), through which they receive a connection formula [Ig] (also referred to as the compound [Ig]).

In the group of the formula-CH2-R9“alkyl, optionally having a Deputy”, “cycloalkenyl”, “arylalkyl, not necessarily with the Deputy”, “alkenyl, not necessarily with the Deputy”, “quinil, not necessarily with the Deputy”, and “heterocyclic alkyl, optionally having a Deputy”have the meanings specified for R2.

In the method of obtaining 5 compound [IC] and the compound [XII] condense the solvent, which is e inhibits the reaction (for example, water, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylthiourea, benzene, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, mixtures thereof and the like) in the presence of a reducing agent.

The reducing agent used in the production method of 5, not subject to any particular limitation, and his example is a hydride complex of the metal (for example, alumoweld lithium, cyanoborohydride sodium (NaBH3CN), borohydride sodium and the like), borane, and the like.

In the method of obtaining 5 compound [XII] is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [IC]. The reducing agent is used in amounts of generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound [Ic].

Although the reaction conditions such as reaction temperature and reaction time and the like, in the way of getting 5 varies depending on the reagent, solvent and the like, which are used in this reaction, the reaction generally proceeds at a temperature of from -30°to 150°C for from 30 minutes to about several hours.

Heterocyclic compound [I]obtained by the above methods 1-5, you can select the conventional way and, when necessary, to clear the generally accepted method, such as precrystallization is, preparative thin layer chromatography, column chromatography and the like. If necessary, the connection can also be cleaned by turning into salt.

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

Pharmaceutical composition comprising a heterocyclic compound [I] or its pharmaceutically acceptable salt of the present invention may contain an additive and the like. Examples of the additive are excipient (for example, starch, lactose, sugar, calcium carbonate, calcium phosphate and the like), a binder (e.g. starch, gum Arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose and the like), grease (for example, magnesium stearate, talc and the like), baking powder (for example, calcixerollic, talc and the like) and the like.

The above components are mixed with a drug for oral administration, such as capsule, tablet, powder, granule, dry syrup and the like, or preparation for parenteral administration such as injection, suppository and the like, according to the method known per se.

Although the dose of heterocyclic compounds [I] or its pharmaceutically acceptable salt varies in accordance with individuum is, which a dose, symptom and other factors, when administered orally to an adult patient suffering from such as diabetes, diabetic complications or hyperlipidemia, single dose of about 1-500 mg/kg of body weight at introduction 1-3 times a day.

Heterocyclic compound [I] or its pharmaceutically acceptable salt of the present invention exhibit a superior hypoglycemic action, gipolipidemicheskoe action in the bloodstream, the effect of increasing insulin resistance, and PPAR-activating effect in mammals (human, cattle, horse, dog, cat, rat, mouse, hamster and the like), and can be used as hypoglycemic agents, hypolipidemic tools, tools that improve insulin resistance, a therapeutic agent for diabetes, a therapeutic agent against complications in diabetes, a means of improving glucose tolerance, anti-atherosclerosis, anti - obesity, anti-inflammatory agents, agents for prevention or treatment of PPAR-mediated diseases and the means for prevention or treatment of syndrome X. Heterocyclic compound [I] or pharmaceutically acceptable salt of the present invention particularly useful for the prevention or treatment of dia is ETA, diabetic complications, hyperlipidemia, atherosclerosis, hyperglycemia, the diseases caused insulinorezistentne, impaired glucose tolerance, diseases caused by insulin resistance, obesity, inflammation, PPAR-mediated disease and syndrome X.

EXAMPLES

The present invention is explained in detail by reference to the following examples. The present invention is in no way limited to the given examples.

Example 1

7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

(1) Ethyl-2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.50 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethylmethanesulfonate (2.50 g) was dissolved in N,N-dimethylformamide (20 ml). To the solution was added potassium carbonate (2.0 g) and the mixture was stirred at 80°C for 5 hours. To the reaction mixture are added ethyl acetate (100 ml) and the mixture washed with water (100 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,62 g). Ethyl-2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-ka who boxill:

IR ν (undiluted) cm-1; 2978, 2930, 1738, 1699, 1614, 1587.

1H-NMR (Dl3) δ (ppm);

of 1.29 (3H, t, J=7.0 Hz), 1,46, 1,50 (N, C, C), a 2.36 (3H, s), 2,95 (2H, t, J=6.8 Hz), 2,90-3,30 (2H, m), 4,00-and 4.40 (4H, m), 4,51, br4.61 (2H, s, ), 4,70-4,90, 5,00-5,20 (1H, m, m), 6,60-of 6.90 (2H, m), 7,12 (1H, d, J=8,4 Hz), 7,30-of 7.55 (3H, m), of 7.90-of 8.15 (2H, m).

(2) Compound (5.2 g)obtained in the above stage (1), dissolved in formic acid (20 ml). To the solution add 8,78 n solution of hydrogen chloride (6.0 ml) in 2-propanol under ice cooling and the mixture is stirred at room temperature for 10 minutes To the reaction mixture are added ethyl acetate (100 ml) and the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and separated into two layers. The obtained ethyl acetate layer was washed with saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure, thus obtaining the ethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (3.6 g). Ethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tet-rehydrogenation-(3S)-carboxylate:

IR ν (nujol) cm-1; 3476, 1742, 1639, 1611, 1553.

1H-NMR (Dl3) δ (ppm);

of 1.29 (3H, t, J=7.0 Hz), 2,02 (1H, s), a 2.36 (3H, s), 2,80-3,10 (4H, m), 3,50-of 3.80 (1H, m), 4,00-4,40 (6N, m), 6,50-to 6.80 (2H, m), 7,00 (1H, d, J=8,4 Hz), 7,30 is 7.50 (3H, m), of 7.90-8,10 (2H, m).

(3) Connection (1,11 g)obtained in the above stage (2), dissolved in methane is Le (20 ml). To the solution was added 1 N. aqueous sodium hydroxide solution (3.0 ml) and the mixture is stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure. To the obtained crystalline residue is added water (5 ml) and the crystals are collected by filtration, thus obtaining specified in the header connection (0,92 g).

IR ν (nujol) cm-1; 3427, 1589, 1504.

1H-NMR (DMSO-d6) δ (ppm);

of 2.35 (3H, s), 2,60-3,10 (6N, m), 3,86 (2H, users), 4,14 (2H, t, J=6.6 Hz), 6,50-to 6.80 (2H, m)6,94 (1H, d, J=8.1 Hz), 7,40-of 7.60 (3H, m), 7,75-with 8.05 (2H, m).

Example 2

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

(1) Compound (1.40 g)obtained in example 1(2), dissolved in N,N-dimethylformamide (20 ml). To the solution was added sodium hydride (160 mg, 60% dispersion in oil) under ice cooling and the mixture is stirred at room temperature for 20 minutes To the mixture are added dropwise benzylbromide (0,40 ml) and the mixture is further stirred at the same temperature for 1 hour. To the reaction mixture are added ethyl acetate (50 ml) and the mixture washed with water (50 ml) and saturated salt solution (30 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4 and is)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.38 in).

Ethyl-2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1728, 1639, 1614, 1551.

1H-NMR (Dl3) δ (ppm);

to 1.21 (3H, t, J=7.0 Hz), was 2.34 (3H, s), of 2.92 (2H, t, J=7.0 Hz), 3,05-3,20 (2H, m), 3,60-4,00 (5H, m), of 4.12 (2H, square, J=7,0 Hz)to 4.16 (2H, t, J=7.0 Hz), 6,51 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2.0 a, and 8.4 Hz), 6,99 (1H, d, J=8,4 Hz), 7,30 is 7.50 (8H, m), 7,80-8,10 (2H, m).

(2) Connection (8,20 g)obtained in the above stage (1), dissolved in 80 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (42 ml) and the mixture was stirred at 50°C for 2 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration. The resulting crude crystals (9.0 g) is recrystallized from methanol, thus obtaining specified in the header connection (6,33 g).

IR ν (nujol) cm-1; 1638, 1501.

1H-NMR (DMSO-d6) δ (ppm);

of 2.33 (3H, s), 2,65-3,30 (4H, m), 3,50-4,00 (5H, m), 4,00-of 6.20 (1H, usher.), of 4.13 (2H, t, J=7.0 Hz), 6,59 (1H, users), of 6.68 (1H, userd, J=8,4 Hz), 7,01 (1H, d, J=8,4 Hz), to 7.32 (5H, s), 7,35-of 7.70 (3H, m), a 7.85-8,10 (2H, m).

Example 3

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

(1) Compound (800 mg)obtained in example 1(2), dissolved in methylene chloride (8.0 ml). To dissolve the add acetic anhydride (0,23 ml) under ice cooling and the mixture is stirred at room temperature for 10 minutes To the reaction mixture are added ethyl acetate (30 ml) and the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and then two layers separated. The obtained organic layer was washed with saturated salt solution (10 ml) and dried over Na2SO4. The solvent is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (873 mg).

Ethyl-2-acetyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1732, 1651, 1555.

1H-NMR (CDCl3) δ (ppm);

of 1.12 (3H, t, J=7.0 Hz), 2,13, of 2.21 (3H, s), a 2.36 (3H, s), 2,95 (2H, t, J=6.6 Hz), 3,05-3,30 (2H, m), Android 4.04 (2H, square, J=7,0 Hz), 4,22 (2H, t, J=6.6 Hz), to 4.62 (2H, s), the 5.45 (1H, DD, J=4,0, 5.7 Hz), 6,55-6,85 (2H, m),? 7.04 baby mortality (1H, d, J=8,2 Hz), 7,30 is 7.50 (3H, m), a 7.85-8,10 (2H, m).

(2) Compound (800 mg)obtained in the above stage (1), dissolved in 5.0 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (3.0 ml) and the mixture is stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (68 mg).

IR ν (nujol) cm-1; 3400, 1732, 1641, 1612, 1555.

1H-NMR (Dl3) δ (ppm);

2,10, 2,17 (3H, s), 2,32 (3H, s), 2,70-3,30 (4H, m), 3,90-4,20 (2H, m), 4,30-of 4.90 (2H, m), 5,35-the ceiling of 5.60 (1H, m), 6,50-to 6.80 (2H, m), 7,03 (1H, d, J=8.1 Hz), 7,30-of 7.60 (3H, m), 7,80-8,10 (2H, m).

Example 4

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

(1) Compound (1.0 g)obtained in example 1 (2), dissolved in methanol (10 ml). To the solution was added formalin (0.4 ml) and cyanoborohydride sodium (310 mg) and the mixture is stirred at room temperature for 1 hour. The methanol is evaporated under reduced pressure. To the obtained residue is added ethyl acetate (20 ml) and the mixture washed with water (20 ml) and saturated salt solution (10 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.08 g).

Ethyl-2-methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (undiluted) cm-1;, 2926, 2874, 1732, 1641, 1614.

1H-NMR (Dl3) δ (ppm);

of 1.25 (3H, t, J=7,0 Hz)to 2.35 (3H, s)of 2.50 (3H, s)to 2.94 (2H, t, J=6.8 Hz), to 3.02 (2H, d, J=6.0 Hz), of 3.45 (1H, t, J=6.0 Hz), to 3.64 (1H, d, J=15.6 Hz), 3,98 (1H, d, J=15.6 Hz), 4,17 (2H, square, J=7,0 Hz), 4,20 (2H, t, J=6.6 Hz), 6,56 (1H, d, J=2.0 G is), 6,70 (1H, DD, J=2.0 a, and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,30 is 7.50 (3H, m), a 7.85-8,10 (2H, m).

(2) Compound (1.08 g)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (7.5 ml) and the solution stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.74 g).

IR ν (nujol) cm-1; 1616, 1555, 1541, 1506.

1H-NMR (DMSO-d6) δ (ppm);

of 2.36 (3H, s)to 2.55 (3H, s), 2,70-3,10 (4H, m), 3,40-of 3.60 (1H, m), 3,70-4,30 (4H, m), 6,60-to 6.80 (2H, m), 7,05 (1H, d, J=8.6 Hz), 7,35-the 7.65 (3H, m), 7,75-8,10 (2H, m).

Example 5

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

(1) Compound (1.0 g)obtained in example 1(2), dissolved in methylene chloride (10 ml). To the solution add hexanoate (0,41 ml) and triethylamine (0.51 g) under ice cooling and the mixture was stirred at the same temperature for 10 minutes To the reaction mixture are added ethyl acetate (70 ml) and the mixture washed with 10% aqueous citric acid solution (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and then with saturated salt solution (50 ml) and dried over Na2SO4. Dissolve the spruce is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,02 g).

Ethyl-2-hexanoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1736, 1653, 1587.

1H-NMR (CDCl3) δ (ppm);

0,70-1,90 (N, m), 2,20-2,60 (2H, m), a 2.36 (3H, s), 2,95 (2H, t, J=6.8 Hz), of 3.10-3.20 (2H, m), Android 4.04 (2H, square, J=7,0 Hz), 4,22 (2H, t, J=7.0 Hz), 4,63 (2H, s), the 5.45 (1H, DD, J=4.0 a, 5,4 Hz), 6,60-of 6.90 (2H, m), ? 7.04 baby mortality (1H, d, J=8.1 Hz), 7,30 is 7.50 (3H, m), 7,80-8,10 (2H, m).

(2) Connection (1,02 g)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (6.0 ml) and the mixture is stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.56 g).

IR ν (nujol) cm-1; 1742, 1641, 1612, 1572.

1H-NMR (CDCl3) δ (ppm);

to 0.88 (3H, ushort, J=6.0 Hz), 1,10-1,90 (6N, m), 2,32 (3H, s), 2,30-of 2.50 (2H, m), 2,70-3,30 (4H, m), 4,07 (2H, t, J=7.0 Hz), 4,60 (2H, s), 5.40 to-ceiling of 5.60 (1H, m), 6,60-to 6.80 (2H, m), 7,05 (1H, d, J=8.6 Hz), 7,35-the 7.65 (3H, m), 7,75-8,10 (2H, m).

Example 6

2-Hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ETH is XI]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

(1) Compound (1.20 g)obtained in example 1(2), dissolved in N,N-dimethylformamide (12 ml). To the solution add hexolite (0,65 ml) and potassium carbonate (0,82 g) and the mixture was stirred at 50°C for 15 hours. To the reaction mixture are added water (100 ml) and the mixture is extracted twice with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,05 g). Ethyl-2-hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1724, 1643, 1611.

1H-NMR (CDCl3) δ (ppm);

to 0.88 (3H, ushort, J=5.0 Hz), 1,10-1,75 (11N, m)to 2.35 (3H, s), 2,50 is 2.80 (2H, m)to 2.94 (2H, t, J=7.0 Hz), to 3.02 (2H, d, J=5.5 Hz), 3,68 (1H, t, J=5.5 Hz), 3,83 (1H, s), of 3.94 (1H, s), of 4.12 (2H, square, J=7,0 Hz), 4,20 (2H, t, J=7.0 Hz), 6,50-to 6.80 (2H, m), 6,97 (1H, d, J=8,4 Hz), 7,30-of 7.60 (3H, m), 7,80-8,10 (2H, m).

(2) the Compound (1.0 g)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (5,1 ml) and the mixture is stirred at room temperature for 11 hours. The solvent is evaporated under reduced pressure and extracting the hydrated residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the header connection (0,80 g).

IR ν (nujol) cm-1; 1620, 1555, 1506.

1H-NMR (CDCl3) δ (ppm);

to 0.89 (3H, ushort, J=6.0 Hz), 1.00 and-1,45 (6N, m), 1,50-1,90 (2H, m), a 2.36 (3H, s), 2,70-3,30 (2H, m), with 2.93 (2H, t, J=6.2 Hz)and 3.15 (2H, d, J=6,4 Hz in), 3.75 (1H, t, J=6.4 Hz), 4,00-and 4.40 (4H, m), 6,23 (1H, users), 6,60-6,85 (2H, m), 7,06 (1H, d, J=8,4 Hz), 7,30-of 7.60 (3H, m), 7,80-8,10 (2H, m).

Example 7

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

(1) Compound (1.40 g)obtained in example 1(2), dissolved in N,N-dimethylformamide (14 ml). To the solution add isobutylated (1.20 ml) and potassium carbonate (0.95 g) and the mixture was stirred at 50°C for 3 days. To the reaction mixture are added water (100 ml) and the mixture is extracted twice with ethyl acetate (50 ml). The obtained ethyl acetate layer was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,15 g).

Ethyl-2-isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1719, 1645, 1614, 1506.

1H-NMR (Dl3) δ (ppm);

0,89 (6N, d, J=6.6 Hz), 1,19 (3H, t, J=7.0 Hz), 1,70-1,90 (1H, m)to 2.35 (3H, s), 2,10-of 2.50 (2H, m)to 2.94 (2H, t, J=7.0 Hz), to 3.02 (2H, d, J=5,2 Hz), 3,66 (1H, t, J=5,2 Hz), 3,83 (1H, s), 3,92 (1H, s)to 4.16 (2H, square, J=7,0 Hz), 4,20 (2H, t, J=7.0 Hz), 6,45 to 6.75 (2H, m), 6,97 (1H, d, J=8,2 Hz), 7,25 is 7.50 (3H, m), a 7.85-8,10 (2H, m).

(2) Connection of 1.05 g)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (5.7 ml) and the mixture is stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the header connection (0,83 g).

IR ν (nujol) cm-1; 3339, 1620, 1553, 1508.

1H-NMR (Dl3) δ (ppm);

of 0.95 (3H, d, J=6,7 Hz), a 1.01 (3H, d, J=7,0 Hz), 1,95-2,15 (1H, m), a 2.36 (3H, s), 2,60 is 2.80 (2H, m)to 2.94 (2H, t, J=6,7 Hz), and 3.16 (2H, d, J=6.6 Hz), 3,70 (1H, t, J=6.6 Hz), 4,11 (2H, s), 4,18 (2H, t, J=and 6.6 Hz), 4,84 (1H, users), 6,60-of 6.90 (2H, m), 7,49 (1H, d, J=8.1 Hz), 7,25 is 7.50 (3H, m), a 7.85-8,10 (2H, m).

Example 8

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

(1) Compound (1.40 g)obtained in example 1(2), dissolved in N,N-dimethylformamide (14 ml). To the solution add cyclohexylethylamine (1,44 ml) and potassium carbonate (0.95 g) and the mixture was stirred at 50°C for 2 days. To the reaction mixture on billaut water (100 ml) and the mixture is extracted twice with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,1, 3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0 g).

Ethyl-2-cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1728, 1638, 1614, 1504.

1H-NMR (Dl3) δ (ppm);

0,80 is 2.00 (11H, m)to 1.19 (3H, t, J=7.0 Hz), a 2.36 (3H, s), 2.40 a is 2.55 (2H, m)to 2.94 (2H, t, J=7,1 Hz)of 3.00 (2H, d, J=5.3 Hz), the 3.65 (1H, t, J=5.3 Hz), 3,82 (1H, s), 3,92 (1H, s), of 4.05 (2H, t, J=7.0 Hz), 4.16 the (2H, square, J=7,0 Hz), 6,50-to 6.80 (2H, m), 6,97 (1H, d, J=8.1 Hz), 7,30 is 7.50 (3H, m), 7,80-8,10 (2H, m).

(2) Compound (0.95 g)obtained in the above stage (1), dissolved in 28 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (7,13 ml) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the header connection (0,76 g).

IR ν (nujol) cm-1; 3319, 1624, 1506.

1H-NMR (Dl3) δ (ppm);

0,70-2,10 (11N, m), a 2.36 (3H, s), 2,4-by 2.55 (2H, m), with 2.93 (2H, t, J=6.4 Hz), and 3.16 (2H, d, J=7,2 Hz), 3,70 (1H, t, J=7.2 Hz), 4,00-4,30 (4H, m), and 5.30 (1H, users), 6,60-of 6.90 (2H, m), was 7.08 (1H, d, J=8,4 Hz), 7,30 is 7.50 (3H, m), 7,80-8,10 (2H, m).

Example 9

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

(1) Compound (1.40 g)obtained in example 1(2), dissolved in N,N-dimethylformamide (14 ml). To the solution was added 3-phenylpropylamine (0,78 ml) and potassium carbonate (0.95 g) and the mixture was stirred at 50°C for 22 h. To the reaction mixture are added water (100 ml) and the mixture is extracted twice with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,05 g).

Ethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1720, 1647, 1612, 1504.

1H-NMR (Dl3) δ (ppm);

of 1.17 (3H, t, J=7.0 Hz), 1.60-to was 2.05 (2H, m)to 2.35 (3H, s), 2,50 is 2.80 (4H, m)to 2.94 (2H, t, J=7,1 Hz), 3.04 from (2H, d, J=5.7 Hz), to 3.67 (1H, t, J=5.7 Hz), 3,84 (1H, s), of 3.94 (1H, s), Android 4.04 (2H, t, J=7,1 Hz), 4.16 the (2H, square, J=7,0 Hz), 6,50-to 6.80 (2H, m), 7,07 (1H, d, J=9.0 Hz), 7,20 (5H, s), 7,10-to 7.50 (3H, m), 7,80-8,10 (2H, m).

(2) the Compound (1.0 g)obtained in the decree which authorized above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (4,77 ml) and the mixture is stirred at room temperature for 10 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.66 g).

IR ν (nujol) cm-1; 3346, 1616, 1556, 1506.

1H-NMR (Dl3) δ (ppm);

1,70-of 2.20 (3H, m)to 2.35 (3H, s), 2.40 a-2,70 (4H, m), 2,70-3,30 (2H, m), of 2.92 (2H, t, J=6.3 Hz), 3,10 (2H, d, J=7,0 Hz), the 3.65 (1H, t, J=7.0 Hz), 3,90-4,30 (4H, m), 5,12 (1H, users), 6,55-to 6.80 (2H, m), 6.90 to-7,25 (6N, m), 7,25-of 7.55 (3H, m), 7,80-8,10 (2H, m).

Example 10

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

(1) Compound (1.4 g)obtained in example 1(2), dissolved in methylene chloride (14 ml). To the solution add benzoyl chloride (0,48 ml) and triethylamine (0,72 ml) under ice cooling and the mixture was stirred at the same temperature for 15 minutes To the reaction mixture are added ethyl acetate (100 ml) and the mixture is washed successively with 10% aqueous citric acid solution (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and then with saturated salt solution (50 ml) and dried over Na2SO4. The solvent is evaporated under reduced pressure. Receive the config residue purified column chromatography on silica gel, while receiving ethyl-2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,16 g).

Ethyl-2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1734, 1638, 1612, 1591.

1H-NMR (Dl3) δ (ppm);

of 0.75 to 1.15 (3H, m)to 2.35 (3H, s), with 2.93 (2H, t, J=6.6 Hz), 3,05-of 3.25 (2H, m), 3,85-and 4.40 (4H, m), 4,20-4,80 (2H, m), 5,00-the ceiling of 5.60 (1H, m), 6,47 (1H, users), 6,72 (1H, userd, J=8,4 Hz), 7,05 (1H, userd, J=8,4 Hz), 7,30-of 7.60 (8H, m), 7,80-8,10 (2H, m).

(2) the Compound (1.0 g)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (6.0 ml) and the mixture is stirred at room temperature for 1.5 hour. The solvent is evaporated under reduced pressure. To the residue is added water (20 ml) and the mixture washed with ethyl acetate (10 ml). The resulting aqueous layer acidified with 6 N. hydrochloric acid and the mixture is extracted twice diethyl simple ether (20 ml). A layer of diethyl ether, washed with saturated salt solution (30 ml) and dried over Na2SO4. Diethyl ether is evaporated under reduced pressure. The obtained residue is recrystallized from methanol, thus obtaining specified in the title compound (0.75 g).

IR ν (nujol) cm-1; 1730, 1636, 1551.

1H-NMR (Dl3 ) δ (ppm);

2,32 (3H, s), 2,87 (2H, t, J=6.4 Hz), 3.00 and-to 3.35 (2H, m), was 4.02 (2H, t, J=6.4 Hz), 4,40-of 4.90 (2H, m), 4,90-and 5.30 (1H, usher.), 5,00-the 5.65 (1H, m), 6,40 (1H, users), 6,50-to 6.80 (1H, m), 7,03 (1H, d, J=8,4 Hz), 7,20-of 7.60 (8H, m), 7,75-with 8.05 (2H, m).

Example 11

2-Benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

(1) Ethyl-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,38 g) dissolved in N,N-dimethylformamide (10 ml). To the solution was added sodium hydride (210 mg, 60% suspension in oil) under ice cooling and the mixture is stirred at room temperature for 30 minutes To a mixture of 2-(N-tert-butoxycarbonyl-N-methylamino)ethylmethanesulfonate (1,30 g) and the mixture is additionally stirred at the same temperature for 1 hour. To the reaction mixture are added ethyl acetate (50 ml) and the mixture washed with water (50 ml) and saturated salt solution (30 ml) and dried over PA2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-benzyl-7-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.44 g).

Ethyl-2-benzyl-7-[2-(N-tert-butoxycarbonyl-N-methylamino)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (undiluted) cm-1; 2978, 2932, 1732, 1695, 1614.

1H-NMR (Dl3) δ (ppm);

of 1.23 (3H, t, J=70 Hz), 1.44MB (N, C)2,95 (3H, s), is 3.08 (2H, d, J=4.9 Hz), of 3.54 (2H, t, J=5.5 Hz), 3,60-4,30 (7H, m), 6,50 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2.0 a, 8,1 Hz), 7,01 (1H, d, J=8.1 Hz), 7,20 is 7.50 (5H, m).

(2) Compound (1.44 g)obtained in the above stage (1), dissolved in formic acid (7.0 ml). To the solution add 8,78 n solution of hydrogen chloride (2.0 ml) in 2-propanol and the mixture is stirred at room temperature for 15 minutes To the reaction mixture are added ethyl acetate (100 ml) and the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and then two layers separated. The obtained ethyl acetate layer was washed with saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure, thus obtaining the ethyl-2-benzyl-7-(2-methylaminorex)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.08 g).

Ethyl-2-benzyl-7-(2-methylaminorex)-1,2,3,4-tetrahydroisoquinoline- (3S)-carboxylate:

IR ν (undiluted) cm-1; 3332, 1732, 1612, 1504.

1H-NMR (Dl3) δ (ppm);

to 1.22 (3H, t, J=7.0 Hz), 2,41 (1H, users), 2,49 (3H, s), 2,95 (2H, t, J=5.5 Hz), is 3.08 (2H, d, J=4.9 Hz), of 3.60-4.25 in (7H, m), of 6.52 (1H, d, J=2.0 Hz), 6,70 (1H, DD, J=2.0 a, and 8.4 Hz), 7,00 (1H, d, J=8,4 Hz), 7,20-7,50 (5H, m).

(3) Connection of 1.05 g)obtained in the above stage (2), dissolved in 2-chloropyridine (2.0 ml) and the mixture was stirred at 140°C for 16 hours. The reaction mixture was purified column chromatography on silica gel, receiving p and this ethyl-2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (0.5 g). Ethyl-2-benzyl-7-[2-(N-methyl-N-(pyridin-2-yl)amino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (undiluted) cm-1; 2932, 2905, 1732, 1597, 1560, 1504.

1H-NMR (Dl3) δ (ppm);

to 1.22 (3H, t, J=7.0 Hz), 3,06 (2H, d, J=6.2 Hz), 3,11 (3H, s), 3,60-4,30 (11N, m), 6,40-to 6.80 (4H, m), 6,97 (1H, d, J=8,4 Hz), 7,20-7,50 (6N, m), 8,00-to 8.20 (1H, m).

(4) the Compound (488 mg)obtained in the above stage (3), dissolved in 5.0 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous sodium hydroxide solution (2.2 ml) and the mixture is stirred at room temperature for 6 hours. The solvent is evaporated under reduced pressure. Add water (10 ml) and then brine before saturation and the mixture is extracted three times with ethyl acetate (30 ml). The ethyl acetate layer was washed with saturated salt solution (10 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. To the obtained residue is added diethyl simple ether. The solid is collected by filtration, thus obtaining specified in the title compound (356 mg).

IR ν (nujol) cm-1; 1597, 1497.

1H-NMR (MeOH-d4) δ (ppm);

2,95-3,20 (2H, m), of 3.07 (3H, s), 3,40-4,20 (N, m), 6,40-6,70 (4H, m), 6,92 (1H, d, J=8,4 Hz), 7,20 is 7.50 (3H, m), of 7.90-of 8.15 (1H, m).

Example 12

2-Benzyl-7-[2-(5-ethylpyridine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

(1) Ethyl-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0 g) is dissolved in N,N-dimethylformamide (10 ml). To the solution was added sodium hydride (200 mg, 60% suspension in oil) under ice cooling and the mixture is stirred at room temperature for 30 min, thus obtaining the solution (A). Separately, 5-ethyl-2-pyridinethiol (1.5 g) and triethylamine (1,68 ml) dissolved in methylene chloride (40 ml). To the solution add triftormetilfullerenov anhydride (2.0 ml) under ice cooling and the mixture is stirred at room temperature for 30 minutes, the Reaction mixture was washed with water (30 ml) and dried over Na2SO4. The methylene chloride is evaporated under reduced pressure. Received 5-ethyl-2-pyridineacetonitrile (2,81 g) added to the above solution and the mixture is stirred at room temperature for 30 minutes To the reaction mixture are added ethyl acetate (100 ml) and the mixture washed with water (50 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-benzyl-7-[2-(5-ethylpyridine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (0,58 g).

Ethyl-2-benzyl-7-[2-(5-ethylpyridine-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1732, 1612, 1504.

1H-NMR (Dl3) δ (ppm);

1,22 (6N, t, J=7.2 Hz), 2,61 (2H, square, J=7,2 Hz), of 3.07 (2H, d, J=5.5 Hz), 3,18 (2H, t, J=6.6 Hz), 3.72 points 1H, t, J=5.5 Hz), 3,81 (1H, s), 3,90 (4H, s), of 4.13 (2H, square, J=7,2 Hz), 4,27 (2H, t, J=6.6 Hz), 6,51 (1H, d, J=2.0 Hz), 6,69 (1H, DD, J=2.0 a, and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,10-to 7.50 (7H, m), 8,00-to 8.20 (1H, m,).

(2) Connection (0,94 g)obtained in the above item (1), dissolved in 40 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 2 n aqueous sodium hydroxide solution (6.0 ml) and the mixture was stirred at 40°C for 2 hours. The solvent is evaporated under reduced pressure. Add water (10 ml) and then sodium chloride up to saturation and the mixture is extracted three times with ethyl acetate (30 ml). The ethyl acetate layer was washed with saturated salt solution (10 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. To the obtained residue, add diisopropyl simple ether. The solid is collected by filtration, thus obtaining specified in the header connection (0,58 g).

IR ν (nujol) cm-1; 1576, 1504.

1H-NMR (MeOH-d4) δ (ppm);

1,22 (6N, t, J=7.5 Hz), 2.63 in (2N, square, J=7.5 Hz), 2,90-3,20 (4H, m), and 3.72 (1H, s), 3,85 (1H, s), 3.95 to of 4.35 (5H, m), 4,27 (2H, t, J=6.6 Hz), 6,40 to 6.75 (2H, m)6,91 (1H, d, J=8,4 Hz), 7,20-the 7.65 (7H, m), 8,20-8,35 (1H, m).

Example 13

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

(1) Ethyl-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0 g) is dissolved in N,N-dimethylformamide (10 ml). To the solution add hydride soda is I (154 mg, 60% suspension in oil) under ice cooling and the mixture is stirred at room temperature for 30 minutes Add 1-(2-bromacil)indolin (1,09 g) and the mixture is further stirred at room temperature for 2 hours. To the reaction mixture are added ethyl acetate (100 ml) and the mixture washed with water (100 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.18 g).

Ethyl-2-benzyl-7-[2-(indolin-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (undiluted) cm-1; 2926, 2843, 1732, 1609, 1493.

1H-NMR (Dl3) δ (ppm);

to 1.22 (3H, t, J=7.2 Hz), 2,95 (2H, t, J=8,3 Hz), is 3.08 (2H, d, J=5.3 Hz), 3,20-of 3.60 (3H, m), 3,60-4,30 (10H, m), 6,40-to 6.80 (4H, m), 6,80-7,20 (3H, m), 7,20 is 7.50 (5H, m).

(2) Connection (1,17 g)obtained in the above stage (1), dissolved in 24 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (7,69 ml) and the mixture was stirred at 50°C for 1 hour. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the header link is (0,93 g).

IR ν (nujol) cm-1; 1634, 1609, 1491.

1H-NMR (Dl3) δ (ppm);

2,95 (2H, ushort, J=8,2 Hz), and 3.16 (2H, userd, J=6,1 Hz), 3.25 to of 3.60 (3H, m), 3,60-and 4.40 (8H, m), 4,07 (2H, s), 4,10 (2H, t, J=5.5 Hz), 4,13 (2H, square, J=7,2 Hz), the ceiling of 5.60-6,30 (1H, usher.), 6,30-6,85 (4H, m), 6,85-7,20 (3H, m), to 7.32 (5H, s).

Example 14

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

Ethyl-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (10.0 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethylmethanesulfonate (to 18.01 g) dissolved in N,N-dimethylformamide (200 ml). To the solution was added potassium carbonate (13.3 g) and the mixture was stirred at 80°C for 10 hours. To the reaction mixture are added water (1 l) and the mixture is extracted twice with ethyl acetate (200 ml). The ethyl acetate layer was washed with saturated salt solution (500 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining specified in the header connection (7,06 g).

The IR and NMR spectra correspond to the spectra obtained in example 2(1).

Example 15

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

(1) Methyl 2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (15,16 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethylmethanesulfonate (20,0 g) is dissolved in N,N-dimetil is mamide (300 ml). To the solution was added potassium carbonate (19.7 g) and the mixture was stirred at 80°C for 3.5 hours. To the reaction mixture are added water (1 l) and the mixture is extracted twice with ethyl acetate (300 ml). The ethyl acetate layer was washed with saturated salt solution (500 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining methyl-2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (14.0 g). Methyl-2-tert-butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

1H-NMR (Dl3) δ (ppm);

1,46, 1,50 (N, C, C), a 2.36 (3H, s), 2,95 (2H, t, J=6.8 Hz), 2,90-3,30 (2H, m), of 3.60 (3H, s), is 4.21 (2H, t, J=6.8 Hz), 4,50, 4,60 (2H, s, ), 4,70-4,90, 5,00-5,20 (1H, m, m), 6,60-of 6.90 (2H, m), 7,12 (1H, d, J=8,4 Hz), 7,30-of 7.55 (3H, m), of 7.90-of 8.15 (2H, m).

(2) Compound (14.0 g)obtained in the above stage (1), dissolved in formic acid (42 ml). To the solution add 8,78 n solution of hydrogen chloride (10,7 ml) in 2-propanol under ice cooling and the mixture is stirred at room temperature for 20 minutes To the reaction mixture are added ethyl acetate (300 ml) and water (500 ml) and the mixture is neutralized with sodium bicarbonate and the two layers separated.

The obtained ethyl acetate layer was washed with saturated salt solution (500 ml) and dried over a 2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining specified in the title compound (9.4 g).

IR ν (nujol) cm-1; 3560, 1744, 1643, 1612, 1578, 1553, 1504.

1H-NMR (Dl3) δ (ppm);

of 1.92 (1H, s), a 2.36 (3H, s), 2,80-3,20 (4H, m), 3,60-of 3.85 (1H, m), 3,76 (3H, s), Android 4.04 (2H, s), is 4.21 (2H, t, J=6.6 Hz), to 6.57 (1H, d, J=2.0 Hz), of 6.71 (1H, DD, J=2,0, 8.6 Hz), 7,00 (1H, d, J=8.6 Hz), 7,30-7,60 (3H, m), a 7.85-of 8.15 (2H, m).

Example 16

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

(1) Compound (800 mg) of example 15 was dissolved in N,N-dimethylformamide (8 ml). To the solution was added sodium hydride (96 mg, 60% suspension in oil) under ice cooling and the mixture is stirred at room temperature for 30 minutes To the mixture are added dropwise 4-methoxybenzylamine (0,41 ml) and the mixture is further stirred at 50°C for 3 hours. To the reaction mixture are added ethyl acetate (50 ml) and the mixture washed with water (50 ml) and saturated salt solution (30 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining methyl-2-(4-methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (0,82 g).

Methyl-2-(4-methoxybenzo the l)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1736, 1638, 1614, 1553, 1514.

1H-NMR (Dl3) δ (ppm);

of 2.35 (3H, s), with 2.93 (2H, t, J=6.6 Hz), 3,05 (2H, d, J=5.5 Hz), 3,66 (3H, s), 3,70-4,00 (8H, m), 4,17 (2H, t, J=6.6 Hz), 6,50 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2,0, 8.6 Hz), 6,85 (2H, d, J=8.6 Hz), 6,98 (1H, d, J=8.6 Hz), 7,28 (2H, d, J=8.6 Hz), 7,30 is 7.50 (3H, m), 7,80-8,10 (2H, m).

(2) Compound (450 mg)obtained in the above stage (1), dissolved in 10 ml of a mixed solvent of tetrahydrofuran-methanol (3:1). To the solution add 2 N. aqueous solution of lithium hydroxide (2.5 ml) and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (350 mg).

IR ν (nujol) cm-1; 3288, 1612, 1555, 1514.

1H-NMR (Dl3) δ (ppm);

of 2.35 (3H, s), with 2.93 (2H, t, J=6.4 Hz), 3,18 (2H, d, J=6.8 Hz), 3,70-4,10 (5H, m), of 3.77 (3H, s)to 4.17 (2H, t, J=6.4 Hz), 4,50 (1H, users), 6,60 (1H, d, J=2.0 Hz), 6,65-to 6.95 (3H, m), was 7.08 (2H, d, J=8,4 Hz), 7,20-of 7.60 (5H, m), 7,80-8,10 (2H, m).

Example 17

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

In the same way as in example 16(1), receive specified in the header of the connection.

1H-NMR (Dl3) δ (ppm);

to 1.21 (3H, t, J=7.0 Hz), was 2.34 (3H, s), only 2.91 (2H, t, J=7.0 Hz), 3.04 from (2H, d, J=5.5 Hz), 3,60-of 3.95 (8H, m), 4,12 (2 is, square, J=7,0 Hz)to 4.15 (2H, t, J=7.0 Hz), 6,51 (1H, d, J=2.0 Hz), to 6.67 (1H, DD, J=2.0 a, 8,8 Hz), 's 6.75 to 7.00 (3H, m), 7,15-to 7.50 (5H, m), a 7.85-8,10 (2H, m).

Example 18

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

(1) Compound (800 mg) of example 15 was dissolved in N,N-dimethylformamide (8.0 ml). To the solution was added sodium hydride (96 mg, 60% suspension in oil) under ice cooling and the mixture is stirred at room temperature for 30 minutes To the mixture are added dropwise α-chloro-p-xylene (0,40 ml) and the mixture is further stirred at 50°C for 3 h and then stirred at room temperature for 15 hours. To the reaction mixture are added ethyl acetate (50 ml) and the mixture washed with water (50 ml) and saturated salt solution (30 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining methyl-2-(4-methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (from 0.90 g).

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

IR ν (nujol) cm-1; 1736, 1639, 1614, 1595, 1551.

1H-NMR (Dl3) δ (ppm);

2,34 (6N, (C), of 2.93 (2H, t, J=6,7 Hz), 3,06 (2H, d, J=5.0 Hz), 3,50-4,00 (5H, m), the 3.65 (3H, s)to 4.17 (2H, t, J=6,7 Hz), 6,51 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2,0, 8.6 Hz),6,98 (2H, d, J=8.6 Hz), 7,11 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), 7,30-of 7.55 (3H, m), 7,80-of 8.15 (2H, m).

(2) Compound (608 mg)obtained in the above stage (1), dissolved in 17 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (6,1 ml) and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (400 mg).

IR ν (nujol) cm-1; 1620, 1555, 1506.

1H-NMR (Dl3) δ (ppm);

2,32 (3H, s)to 2.35 (3H, s), with 2.93 (2H, t, J=7.0 Hz), 3,17 (2H, d, J=6.6 Hz), 3,65-of 4.05 (5H, m), 4,17 (2H, t, J=7.0 Hz), to 4.73 (1H, users), 6,60 (1H, d, J=2.0 Hz), 6,77 (1H, DD, J=2.0 a, 8,8 Hz), 6,95-of 7.60 (8H, m), a 7.85-8,10 (2H, m).

Example 19

Ethyl-2-(4-methylbenzyl)-1-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

In the same way as in example 18(1), receive specified in the header of the connection.

1H-NMR (Dl3) δ (ppm);

to 1.21 (3H, t, J=7.0 Hz), was 2.34 (3H, s), of 2.92 (2H, t, J=7.0 Hz), 3,05 (2H, d, J=5.4 Hz), 3,71 (1H, t, J=5.4 Hz), 3,80 (1H, s), 3,92 (1H, s), of 4.12 (2H, square, J=7,0 Hz)to 4.16 (2H, t, J=7.0 Hz), 6,51 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2.0 a, and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,00-of 7.60 (7H, m), 7,80-8,10 (2H, m).

Example 20

2-Benzyl-7-[2-(6-carboxyaniline-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic to the slot

(1) Ethyl-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.0 g) is dissolved in N,N-dimethylformamide (10 ml). To the solution was added sodium hydride (154 mg, 60% suspension in oil) under ice cooling and the mixture was stirred at the same temperature for 30 minutes To the mixture was added 1-(2-bromacil)-6-methoxycarbonylethyl (1,36 g) and the mixture is further stirred at room temperature for 4 hours. To the reaction mixture are added ethyl acetate (100 ml) and the mixture washed with water (100 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining the ethyl-2-benzyl-7-[2-(6-methoxycarbonylmethyl-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.18 g). Ethyl-2-benzyl-7-[2-(6-methoxycarbonylmethyl-1-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (undiluted) cm-1; 2949, 2841, 1717, 1611, 1587, 1497.

1H-NMR (Dl3) δ (ppm);

of 1.23 (3H, t, J=7.2 Hz), 2,99 (2H, t, J=8,8 Hz), 3,00-3,25 (2H, m), 3,35-4,35 (13H, m), a 3.87 (3H, s), of 6.52 (1H, d, J=2.4 Hz), 6,70 (1H, DD, J=2,4, and 8.3 Hz), 6.90 to-7,20 (3H, m), 7,20-7,55 (6N, m).

(2) Compound (1.31 g)obtained in the above stage (1), dissolved in 33 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (15.3 ml) and the ect stirred at 50° C for 2 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (1.0 g).

IR ν (nujol) cm-1; 3400, 1693, 1612, 1497.

1H-NMR (MeOH-d4) δ (ppm);

2,96 (2H, ushort, J=8.0 Hz), 3.15 and of 3.75 (3H, m), 3,80-4,50 (10H, m), 6,65-7,70 (11N, m).

Example 21

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

(1) Connection of 1.00 g)obtained in example 15, was dissolved in N,N-dimethylformamide (20 ml). To the solution was added 4-tormentilla ones (0.46 ml), potassium carbonate (0,53 g) and potassium iodide (0.21 g) and the mixture was stirred at 50°C for 1.5 hours. To the reaction mixture are added ethyl acetate (50 ml) and the mixture washed with water (100 ml) and saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining methyl-2-(4-terbisil)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (0,92 g). Methyl-2-(4-terbisil)-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1738, 1639, 1616, 1551, 1510.

1H-NMR (Dl3) δ (ppm);

of 2.35 (3H, s), with 2.93 (2H, t, J=68 Hz), of 3.07 (2H, d, J=5.0 Hz), 3,55-4,00 (5H, m), the 3.65 (3H, s), 4,18 (2H, t, J=6.8 Hz), 6,51 (1H, d, J=2.0 Hz), 6,70 (1H, DD, J=2,0, 8.6 Hz), 6,80-to 7.15 (3H, m), 7,15-to 7.50 (5H, m), 7,80-of 8.15 (2H, m).

(2) Compound (900 mg) above the stage (1) is dissolved in 18 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (8,9 ml) and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure and the obtained residue acidified with citric acid. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.68 g).

IR ν (nujol) cm-1; 3398, 1614, 1555, 1510.

1H-NMR (Dl3) δ (ppm);

of 2.36 (3H, s)to 2.94 (2H, t, J=6.4 Hz)and 3.15 (2H, d, J=6.4 Hz), 3.45 points-of 4.00 (5H, m), 4,19 (2H, t, J=6.4 Hz), 6,60 (1H, d, J=2.0 Hz), to 6.75 (1H, DD, J=2,0, 8.6 Hz), 6.90 to-at 7.55 (8H, m), of 7.90-8,10 (2H, m).

Example 22

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

Methyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (0,60 g) dissolved in methylene chloride (6 ml). To the solution add pivaloate (0,22 ml) and triethylamine (0,32 ml) under ice cooling and the mixture was stirred at the same temperature for 15 minutes To the reaction mixture are added ethyl acetate (100 ml) and the mixture is successively washed with 10% aqueous solution of citric acid is (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The solvent is evaporated under reduced pressure. The resulting residue is dissolved in 18 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (4.6 ml) and the mixture was stirred at 50°C for 30 minutes the Solvent is evaporated under reduced pressure. To the residue is added water (20 ml) and the mixture is acidified with citric acid. The resulting mixture was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated salt solution (30 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure, thus obtaining specified in the title compound (0.65 g).

IR ν (nujol) cm-1; 1734, 1630, 1612, 1553.

1H-NMR (DMSO-d6) δ (ppm);

1,24 (N, C), a 2.36 (3H, s), 2,80-4,00 (1H, usher.), of 2.92 (2H, t, J=6.4 Hz), 2.95 and is 3.15 (2H, m), 4,18 (2H, t, J=6.4 Hz), to 4.41, 4,91 (2H, Awkw., J=18,1 Hz), 4,90-of 5.15 (1H, m), 6,77 (1H, DD, J=2,0, 8.1 Hz), 6.89 in (1H, d, J=2.0 Hz), to 7.09 (1H, d, J=8.1 Hz), 7,30-the 7.65 (3H, m), 7,80-8,10 (2H, m).

Example 23

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

Specified in the title compound (1.66 g) of example 22 was dissolved in pyridine (16.6 ml). To the solution add borohydride sodium (1,36 g) and the mixture was stirred at 100°C for 4 hours. The mixture is acidified with 10% aqueous citric acid solution and extracted with ethyl acetate (100 ml). The ethyl acetate layer is washed successively adding 10% aqueous citric acid solution (100 ml) and saturated salt solution (50 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining specified in the title compound (0.84 g).

IR ν (nujol) cm-1; 3391, 3279, 1668, 1645, 1616, 1597, 1497.

1H-NMR (Dl3) δ (ppm);

0,96 (N, C)to 2.35 (3H, s), 2,46, by 2.73 (2H, Awkw., J=a 13.9 Hz), with 2.93 (2H, t, J=6,7 Hz), 3,03 is 3.23 (2H, m), 3,57-of 3.78 (1H, m), 3,91, 4,18 (1H, Awkw., J=to 15.4 Hz), 4,17 (2H, t, J=6,7 Hz), the ceiling of 5.60-6,05 (1H, usher.), 6,60 (1H, d, J=2.0 Hz), was 6.73 (1H, DD, J=2.0 a, and 8.4 Hz),? 7.04 baby mortality (1H, d, J=8,4 Hz), 7,30-of 7.55 (3H, m), 7,80-8,10 (2H, m).

Example 24

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

(1) Methyl-2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

Methyl-2-(2,2-dimethylpropyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1.5 g) and 2-(5-methyl-2-phenyloxazol-4-yl)ethylmethanesulfonate (2,59 g) dissolved in toluene (45 ml). To the solution was added potassium carbonate (2.24 g) and fluoride of tetraethylammonium (0,60 g) and the mixture was stirred at 80°C for 3 hours. The reaction mixture is washed successively water is (50 ml) and saturated salt solution (50 ml) and dried over Na 2SO4. The toluene is evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel, thus obtaining methyl-2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (2,77 g).

1H-NMR (Dl3) δ (ppm);

0,88 (N, C), 2,35, of 2.58 (2H, Awkw., J=14,5 Hz), a 2.36 (3H, s)to 2.46 (2H, t, J=6.8 Hz), 2.95 and-3,20 (2H, m), of 3.60 (3H, s), 3,60-of 3.80 (1H, m), 3,85-4,20 (2H, m), 4,19 (2H, t, J=6.8 Hz), is 6.54 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2.0 a, and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,30 is 7.50 (3H, m), a 7.85-with 8.05 (2H, m).

(2) the Compound (5.0 g) above the stage (1) is dissolved in 130 ml of a mixed solvent of tetrahydrofuran - methanol (3:1). To the solution was added 1 N. aqueous solution of lithium hydroxide (54 ml) and the mixture was stirred at 50°With over 3.5 hours and acidified with 6 N. hydrochloric acid. The solvent is evaporated under reduced pressure. The resulting residue is extracted with ethyl acetate (200 ml). The ethyl acetate layer was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is dissolved in ethanol (25 ml). To the solution was added water (150 ml) and the mixture is stirred at room temperature, thereby causing crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (4.52 g).

IR and1H NMR spectra according to testout spectra, obtained in example 23.

Example 25

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

Specified in the title compound (675 mg) of example 2 are dissolved in 75% ethanol (10.1 ml) under heating. To the solution add 6 N. hydrochloric acid (2,23 ml) and the mixture was incubated at room temperature for 2 hours to induce crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (625 mg).

IR ν (nujol) cm-1; 3398, 1734, 1680, 1641, 1620, 1587, 1574, 1551.

1H-NMR (DMSO-d6) δ (ppm);

of 2.36 (3H, s), of 2.92 (2H, t, J=6.0 Hz), 3.00 and-3,70 (2H, m), 4,19 (2H, t, J=6.0 Hz), 4,25-4,75 (5H, m), 4.80 to 6,70 (2H, usher.), 6,70-7,05 (2H, m), 7,20 (1H, d, J=8.6 Hz), 7,30-to 7.77 (8H, m), 7,80-8,10 (2H, m).

Example 26

2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

Specified in the title compound (1.0 g) of example 2 is suspended in methanol (10 ml). To the solution add 2,09 n sodium hydroxide solution (of 1.02 ml) in methanol. After the dissolution of the methanol is evaporated under reduced pressure. To the obtained residue is added diethyl simple ether and the precipitated crystals are collected by filtration, thus obtaining specified in the header connection (1,03 g).

IR ν (nujol) cm-1; 1638, 1589, 1503.

1H-NMR (DMSO-d6) δ (d);

of 2.33 (3H, s), 2,55-3,60 (6N, m), 3,60-4,30 (5H, m), 6,47 (1H, s), 6,60 (1H, d, J=8.6 Hz), 6,92 (1H, d, J=8.6 Hz), 7,00-to 7.67 (8H, m), to 7.67-with 8.05 (2H, m).

Example 27

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

Specified in the title compound (2.1 g) of example 23 was dissolved in methanol (10.5 ml). To this mixture 8,78 n solution of hydrogen chloride (1.07 ml) in isopropanol and then ethyl acetate (50 ml) and the mixture is stirred at room temperature for crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the header connection (1,03 g).

IR ν (nujol) cm-1; 3362, 3206, 1740, 1672, 1612, 1576, 1553.

1H-NMR (DMSO-d6) δ (ppm);

1,12 (N, C), is 2.37 (3H, s), 2,65-3,50 (6N, m), is 4.21 (2H, t, J=6.5 Hz), 4,40-4,80 (3H, m), 4,85-6,50 (2H, usher.), make 6.90 (1H, d, J=8.1 Hz), 6,94 (1H, s), 7,21 (1H, d, J=8.1 Hz), 7,35-the 7.65 (3H, m), 7,80-with 8.05 (2H, m).

Example 28

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

Specified in the title compound (0.5 g) of example 23 was dissolved in methanol (1.25 ml). To the mixture is added sulfuric acid (0.3 ml) and then water (16,8 ml) and the mixture is stirred at room temperature for crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.25 g).

IR ν (nujol) cm-1; 3400, 1715, 1650, 1615, 150.

1H-NMR (DMSO-d6) δ (ppm);

0,93 (N, C), a 2.36 (3H, s), 2.40 a-3,30 (6N, m), 3.75 to of 4.45 (5H, m), 4,60-6,50 (2H, usher.), 6,70 (1H, users), 6,74 (1H, d, J=8.1 Hz), 7,06 (1H, d, J=8.1 Hz), 7,25-the 7.65 (3H, m), 7,75-8,10 (2H, m).

Example 29

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

Specified in the title compound (0.5 g) of example 23 and n-toluensulfonate acid (0.28 g) was dissolved in ethanol (10 ml) under heating. After crystallization at room temperature under stirring, the precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.3 g).

IR ν (nujol) cm-1; 3047, 1734, 1645, 1612, 1514.

1H-NMR (DMSO-d6) δ (ppm);

1,07 (N, C)of 2.28 (3H, s), a 2.36 (3H, s), 2,70-3,50 (6N, m), is 4.21 (2H, t, J=6.5 Hz), 4,40-4,80 (3H, m), 6,80-to 7.35 (5H, m), 7,35-the 7.65 (5H, m), 7,75-with 8.05 (2H, m), 8,40-12,00 (2H, usher.).

Example 30

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

Specified in the title compound (1.0 g) of example 23 and fumaric acid (0,23 g) dissolved in methanol (5 ml). To the mixture is added water (5 ml) and the mixture is stirred at room temperature for crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the header connection (0,94 g).

IR ν (nujol) cm-1; 3500, 3395, 1680, 1650, 1625, 1575, 1550.

1H-NMR (DMSO-d6) δ (ppm);

0,85 (N, s), 2.00 in 6,30 (2H, usher.), of 2.35 (3H, s), 2,32, 2,59 (2H, Awkw., J=14,9 Hz), 2,75-3,10 (2H, m), 2,85 (2H, t, J=6.6 Hz), 3,45-4,30 (3H, m), is 4.15 (2H, t, J=6.6 Hz), is 6.61 (1H, d, J=2.2 Hz), only 6.64 (1H, s), of 6.66 (1H, DD, J=2,2, 8,4 Hz), 7,00 (1H, d, J=8,4 Hz), 7,35-the 7.65 (3H, m), of 7.75-8,10 (2H, m).

Example 31

2-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate calcium

Specified in the title compound (0.9 g) of example 23 was dissolved in ethanol (9 ml). To the mixture of 0.04 N. aqueous solution of calcium hydroxide (54 ml) and the mixture is stirred at room temperature for crystallization. The precipitated crystals are collected by filtration, thus obtaining specified in the title compound (0.79 in).

IR ν (nujol) cm-1; 3396, 1638, 1611, 1556, 1504.

1H-NMR (MeOH-d4) δ (ppm);

0,87 (N, C)of 2.34 (3H, s), 2,36, of 2.58 (2H, Awkw., J=14,0 Hz), 2,80-3,10 (2H, m), 2,90 (2H, t, J=6.5 Hz), 3,30-of 3.80 (3H, m), is 4.15 (2H, t, J=6.5 Hz), 6,50 (1H, d, J=2.4 Hz), 6,60 (1H, DD, J=2,4, and 8.2 Hz), make 6.90 (1H, d, J=8,2 Hz), 7,30-of 7.60 (3H, m), 7,80-8,05 (2N, m).

The following compounds were synthesized in the same manner as in examples 1-24.

Example 32

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

IR ν (nujol) cm-1; 3458, 1682, 1618, 1587, 1510.

1H-NMR (DMSO-d6) δ (ppm);

1,32 (N, C)of 2.23 (3H, s), and 2.83 (2H, t, J=6.6 Hz), 3,18 (2H, d, J=5,9 Hz), 3,65-4,40 (7H, m), the ceiling of 5.60 (1H, users), 6,56 (1H, ush is RS), of 6.73 (1H, userd), 7,06 (1H, d, J=8,4 Hz), 7,20-of 7.55 (5H, m).

Example 33

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

IR ν (nujol) cm-1; 3423, 1616, 1578, 1510.

1H-NMR (DMSO-d6) δ (ppm);

2,31 (3H, s), 2,70-3,10 (4H, m), 3,40-4,00 (4H, m), 3,39 (2H, s), 4,11 (2H, d, J=6.2 Hz), 6,59 (1H, users), to 6.67 (1H, d, J=8,4 Hz), 7,01 (1H, d, J=8,4 Hz), 7,05-7,80 (3H, m), to 7.32 (5H, s).

Example 34

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

IR ν (nujol) cm-1; 3456, 1684, 1614, 1576, 1510.

1H-NMR (DMSO-d6) δ (ppm);

1,21 (6N, m), are 2.19 (3H, s), 2,70-3,10 (5H, m), 3,50-4,20 (5H, m), 6,40-6,85 (2H, m), 7,01 (1H, d, J=8.1 Hz), 7,34 (5H, users).

Example 35

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

IR ν (nujol) cm-1; 3382, 1722, 1614, 1554, 1506.

1H-NMR (Dl3) δ (ppm);

to 0.88 (3H, t, J=6.6 Hz), 1,10-of 1.95 (4H, m), a 2.36 (3H, s), 2,75-3,40 (6N, m), 3,71 (2H, ushort), 3,95-of 4.25 (4H, m), 6,57-EUR 7.57 (6N, m), 7,80-8,10 (3H, m).

Example 36

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

IR ν (nujol) cm-1; 3443, 3300, 1695, 1655, 1622, 1543, 1508.

1H-NMR (DMSO-d6) δ (ppm);

1,89 (3H, s), 2,11 (3H, s), and 2.27 (3H, s), and 2.79 (2H, t, J=6,1 Hz), 2,90-3,20 (2H, m), 3,50-4,00 (4H, m), 3,93 (2H, s)4,07 (2H, t, J=6,1 Hz), of 5.99 (1H, s), to 6.58 (1H, s), to 6.67 (1H, d, J=8 Hz), 6,72 (1H, d, J=8,2 Hz), 7,33 (5H, s).

Example 37

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

IR ν (nujol) cm-1; 3442, 1688, 1614, 1578, 1508.

1H-NMR (Dl3) δ (ppm);

of 2.23 (3H, s), 2.49 USD (2H, t, J=6.2 Hz), 2,65-2,90 (4H, m), 3,05-3,30 (2H, m), 3.75 to 4,50 (8H, m), 4,90-5,20 (2H, m), 5,65-6,10 (1H, m), to 6.58 (1H, d, J=1.7 Hz), to 6.75 (1H, DD, J=1,7, 8,2 Hz), 7,07 (1H, d, J=8,2 Hz), to 7.35 (5H, s).

Example 38

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

IR ν (nujol) cm-1; 3335, 1690, 1618, 1553, 1506.

1H-NMR (DMSO-d6) δ (ppm);

of 2.35 (3H, s), 2,70-3,15 (4H, m)to 3.38 (2H, d, J=6.2 Hz), 3,55-4,00 (3H, m)to 4.16 (2H, t, J=6.6 Hz), 4,40-of 5.50 (1H, usher.), 5,00-of 5.40 (2H, m), the ceiling of 5.60-6,10 (1H, m), of 6.65 (1H, s), 6,69 (1H, d, J=8.1 Hz), 7,01 (1H, d, J=8.1 Hz), 7,35-the 7.65 (3H, m), 7,75-8,10 (2H, m).

Example 39

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

IR ν (nujol) cm-1; 3383, 3306, 3221, 1692, 1622, 1508.

1H-NMR (DMSO-d6) δ (ppm);

2,00-6,40 (1H, usher.), of 2.35 (3H, s), 2,70-3,10 (4H, m), 3,10-of 3.25 (1H, m), 3,50-4,00 (5H, m), 4,17 (2H, t, J=6.4 Hz), of 6.66 (1H, s)6,70 (1H, d, J=8.6 Hz), 7,01 (1H, d, J=8.6 Hz), 7,30-of 7.70 (3H, m), a 7.85-with 8.05 (2H, m).

Example 40

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

IR ν (nujol) cm-1; 3447, 3342, 1684, 1620, 1556.

1H-NMR (DMSO-d6) δ (ppm);

to 1.67 (3H, d, J=4,9 Hz)to 2.35 (3H, s), 2,70-3,10 (4H, m), 3,20-3,50 (2H, m), 3,50-4,00 (3H, m)to 4.16 (2H, t, J=6.4 Hz), 4,35-5,20 (1H, usher.), the 5.25-5,90 (2H, m), 6,55-of 6.90 (2H, m), 7,01 (2H, d, J=8.1 Hz), 7,35-of 7.70 (3H, m), 7,75-8,10 (2H, m).

Example 41

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

IR ν (nujol) cm-1; 1611, 1506.

1H-NMR (DMSO-d6) δ (ppm);

1,60-of 2.30 (2H, m), 2,80-4,20 (10H, m), 3,91 (2H, s), 4,20-6,00 (1H, usher.), 6,25-7,10 (7H, m), 7,33 (5H, s).

Example 42

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

IR ν (nujol) cm-1; 3425, 1682, 1612, 1555.

1H-NMR (DMSO-d6) δ (ppm);

2,10-to 2.40 (2H, m)to 2.35 (3H, s), 2,60-3,15 (6N, m), 3,50-4,00 (3H, m), 4,17 (2H, t, J=6.3 Hz), 4,40-of 5.40 (1H, usher.), 4,85-a 5.25 (2H, m), 5,55-6,10 (1H, m), 6,50-6,85 (2H, m), 7,01 (1H, d, J=8.1 Hz), 7,35-of 7.70 (3H, m), 7,75-with 8.05 (2H, m).

Example 43

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

IR ν (nujol) cm-1; 1742, 1639, 1611, 1572, 1506.

1H-NMR (DMSO-d6) δ (ppm);

to 0.88 (3H, ushort), of 1.05 to 1.75 (4H, m), 2,15-2,70 (2H, m)to 2.35 (3H, s), 2,70-3,30 (4H, m), 4,18 (2H, ushort), 4,30-of 4.90 (2H, m), 4,90-a 5.25 (1H, m), 6,60-to 6.95 (2H, m), was 7.08 (1H, d, J=7.9 Hz), 7,35-of 7.70 (3H, m), 7,75-8,10 (2H, m), 11,00-13,00 (1H, usher.).

Example 44

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

IR ν (nujol) cm-1; 1742, 1641, 1611, 1570.

1H-NMR (DMSO-d6/sub> ) δ (ppm);

2,15-2,70 (2H, m)to 2.35 (3H, s), 2,70-3,30 (4H, m), 4,18 (2H, ushort), 4,37-5,50 (5H, m), the ceiling of 5.60-x 6.15 (1H, m), 6,60-to 6.95 (2H, m), to 7.09 (1H, d, J=7,7 Hz), 7,30 to 7.75 (3H, m), 7,75-of 8.15 (2H, m), 11,00-13,00 (1H, usher.).

Example 45

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

IR ν (nujol) cm-1; 1738, 1641, 1611, 1555.

1H-NMR (DMSO-d6) δ (ppm);

1,87 (6N, C)to 2.35 (3H, s), 2,70-3,30 (4H, m), 4,18 (2H, ushort), of 4.49 (1H, d, J=18,0 Hz), was 4.76 (1H, d, J=18,0 Hz), 4.95 points with 5.22 (1H, m), 5,75-6,10 (1H, m), 6,50-of 6.90 (2H, m), was 7.08 (1H, d, J=7.5 Hz), 7,20-of 7.60 (3H, m), 7,60-with 8.05 (2H, m), 11,00-13,00 (1H, usher.).

Example 46

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

IR ν (nujol) cm-1; 1738, 1639, 1611, 1583, 1555.

1H-NMR (DMSO-d6) δ (ppm);

1,02 (N, C), a 2.36 (5H, s), 2,73-3,20 (4H, m), 4,17 (2H, t, J=7.0 Hz), 4,50 (1H, d, J=9.0 Hz), a 4.83 (1H, d, J=9.0 Hz), 5,12 (1H, t, J=6.0 Hz), 6,60-to 6.95 (2H, m), 7,10 (1H, d, J=7,0 Hz), 7,35-the 7.65 (3H, m), 7,80-with 8.05 (2H, m), 11,00-13,00 (1H, usher.).

Example 47

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

IR ν (nujol) cm-1; 1722, 1628, 1553, 1520.

1H-NMR (DMSO-d6) δ (ppm);

of 2.36 (3H, s)of 3.00 (2H, t, J=6.8 Hz), 3,10-to 3.35 (2H, m), 3,80-4,10 (3H, m in), 3.75 (3H, s)to 4.23 (2H, t, J=6.8 Hz), 5,80-of 6.20 (1H, usher.), 6,50, 6,72 (2H, s), 7,20-of 7.60 (8H, m), 7,80-8,10, (2H, m).

Example 48

7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridi the-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

IR ν (nujol) cm-1; 1609, 1575, 1554, 1502.

1H-NMR (CDCl3) δ (ppm);

2,32 (3H, s), 2,60-3,20 (4H, m), 3,20-3,90 (5H, m), 4,08 (2H, ushort, J=6.5 Hz), 6,15-6,40 (1H, m), 6,40-6,70 (1H, m), 7,75-to 8.20 (3H, m), 7,20-the 7.65 (4H, m), 7,75-8,10 (2H, m), 8,25 at 8.60 (1H, m).

Example 49

2-Benzyl-7-(3-methyl-3-phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1612, 1506.

1H-NMR (DMSO-d6) δ (ppm);

1,32 (6N, C)2,02 (2H, t, J=7.5 Hz), 2,80-3,10 (2H, m), 3,40-4,00 (5H, m), 3,88 (2H, s), 4,10-6,00 (1H, usher.), 6,36 (1H, d, J=2.0 Hz), 6,53 (1H, DD, J=2,0, 8.6 Hz), of 6.96 (1H, d, J=8.6 Hz), 7,10-of 7.55 (10H, m).

Example 50

2-Benzyl-7-(3,3-dimethyl-4-phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1611, 1506.

1H-NMR (DMSO-d6) δ (ppm);

0,87 (6N, C)to 1.61 (2H, t, J=7.0 Hz), of 2.54 (2H, s), 2,85 is 3.15 (2H, m), 3,50-4,20 (5H, m), 3,91 (2H, s), 4,20-6,00 (1H, usher.), 6,60 (1H, users), to 6.67 (1H, d, J=8.6 Hz), 7,01 (1H, d, J=8.6 Hz), 7,05 is 7.50 (10H, m).

Example 51

2-Benzyl-7-(2-isopropylphenoxy-6-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1632, 1585, 1572, 1501.

1H-NMR (DMSO-d6) δ (ppm);

1,37 (6N, d, J=7,0 Hz), 2,85 is-3.45 (4H, m), 3,50-4,20 (6N, m), 5,12 (2H, s), 6,69 (1H, s), 6,77 (1H, d, J=8.6 Hz),? 7.04 baby mortality (1H, d, J=8.6 Hz), 7,25-a 7.85 (8H, m).

Example 52

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

IR ν (nujol) cm-1; 1611, 1583, 162, 1506.

1H-NMR (DMSO-d6) δ (ppm);

1,42 (N, C), 2,85-3,10 (2H, usher.), 3,50-4,20 (6N, m)to 5.13 (2H, s)6,70 (1H, s), 6,77 (1H, d, J=8,4 Hz),? 7.04 baby mortality (1H, d, J=8,4 Hz), 7,20-7,50 (6N, m), 7,55-the 7.65 (1H, m), of 7.70 (1H, s).

Example 53

2-Benzyl-7-(2-tert-butylbenzothiazole-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1717, 1645, 1612, 1553.

1H-NMR (DMSO-d6) δ (ppm);

1,43 (N, C), 2,85 is 3.15 (2H, m), 3,50-to 4.15 (3H, m), 3,90 (2H, s), 5,11 (2H, s), 6,69 (1H, users), to 6.75 (1H, d, J=8.1 Hz), 7,03 (1H, d, J=8.1 Hz), 7,10-7,50 (6N, m), the 7.65 (1H, d, J=9,0), 7,71 (1H, users).

Example 54

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

IR ν (nujol) cm-1; 1740, 1612, 1560, 1508.

1H-NMR (DMSO-d6) δ (ppm);

1,10 (N, C)1,43 (N, C), 2,79, 3,19 (2H, Awkw., J=13,6 Hz), 3,20-of 3.45 (3H, m), 4,25-4,55 (4H, usher.), 5,20 (2H, s), of 6.96 (1H, d, J=8.1 Hz), 7,00 (1H, s), 7,20 (1H, d, J=8.1 Hz), 7,40 (1H, d, J=8.1 Hz), to 7.68 (1H, d, J=8.1 Hz), 7,73 (1H, s).

Example 55

2-Benzyl-7-(2-isopropylphenoxy-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1634, 1587, 1570, 1501.

1H-NMR (DMSO-d6) δ (ppm);

1,37 (6N, d, J=6.8 Hz), 2,90 is 3.15 (2H, m)of 3.25 (1H, quintet, J=6.8 Hz), 3,50-4,30 (7H, m), 5,11 (2H, s), 6,69 (1H, s)6,76 (1H, d, J=8.1 Hz),? 7.04 baby mortality (1H, d, J=8.1 Hz), 7,20-7,50 (6N, m), 7,55-the 7.65 (1H, m), 7,70 (1H, s).

Example 56

7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridine-4-ylmethyl)-1,2,3,4-tetrahydrothieno the Lin-(3S)-carboxylate sodium

IR ν (nujol) cm-1; 3420, 3177, 1639, 1558, 1504.

1H-NMR (DMSO-d6) δ (ppm);

of 2.34 (3H, s), 2,70 was 3.05 (4H, m), 3,10-of 3.60 (3H, m), 3,98 (2H, ushort, J=5.7 Hz), 4,10-of 4.25 (2H, m), 6,51 (1H, users), is 6.61 (1H, userd, J=8.7 Hz), 6,94 (1H, userd, J=8.7 Hz), 7,25-the 7.65 (5H, m), 7,75-of 8.00 (2H, m), 8,46 (2H, d, J=5,2 Hz).

Example 57

7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-[(pyridin-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate sodium

IR ν (nujol) cm-1; 3385, 1624, 1566, 1504.

1H-NMR (MeOH-d4) δ (ppm);

2,31, a 2.36 (3H, s), 2,75 was 3.05 (2H, m), 3,05-3,30 (2H, m), 4,00-4,30 (2H, m), 4,50-and 5.30 (3H, m), 6,60-to 6.80 (2H, m), 7,03 (1H, DD, J=2,0, 8.5 Hz), 7,30 to 7.75 (5H, m), 7,75-8,10 (3H, m), 8,50-to 8.70 (1H, m).

Example 58

Methyl-2-bemail-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

IR ν (nujol) cm-1; 1736, 1639, 1612, 1504.

1H-NMR (Dl3) δ (ppm);

of 2.34 (3H, s), of 2.92 (2H, t, J=7.0 Hz), of 3.07 (2H, d, J=5.0 Hz), to 3.64 (3H, s), 3,64-4,00 (5H, m), 4,17 (2H, t, J=7.0 Hz), 6,51 (1H, d, J=2.0 Hz), of 6.68 (1H, DD, J=2.0 a, and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,20-7,60 (8H, m), 7,80-8,10 (2H, m).

Example 59

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

IR ν (nujol) cm-1; 3470, 1684, 1618, 1583, 1510.

1H-NMR (DMSO-d6) δ (ppm);

0,70-1,10 (4H, m), 1,80-2,20 (1H, m)of 2.16 (3H, s), 2,60-to 2.85 (2H, m), 2,90 is 3.15 (2H, m), 3,50-4,20 (5H, m), 6,50-to 6.80 (2H, m), 7,03 (1H, d, J=8.1 Hz), 7,34 (5H, s).

Example 60

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

IR ν (nujol) cm-1; 3447, 3335, 1670, 1668, 1622, 1556, 1506.

1H-NMR (DMSO-d6) δ (ppm);

to 1.61 (3H, s), 1,72 (3H, s)to 2.35 (3H, s), 2,70-3,20 (4H, m), 3,39 (2H, d, J=7,0 Hz), 3,50-4,01 (3H, m)to 4.16 (2H, t, J=7.0 Hz), 4,35-the ceiling of 5.60 (1H, usher.), the 5.25 (1H, ushort), to 6.67 (1H, s)of 6.71 (1H, d, J=8,4 Hz), 7,02 (1H, d, J=8,4 Hz), 7,30-of 7.70 (8H, m), 7,75-8,10 (2H, m).

Example 61

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

IR ν (nujol) cm-1; 1717, 1614, 1566, 1504.

1H-NMR (CDCl3) δ (ppm);

0,97 (N, C), 1,33 (N, C), 2,24 (3H, s), 2,44, of 2.68 (2H, Awkw., J=a 13.9 Hz), 2,84 (2H, t, J=6,7 Hz), 3.00 and-up 3.22 (2H, m), the 3.65 (3H, t, J=6,1 Hz), 3,83, 4,08 (2H, Awkw., J=15.1 Hz), 4,07 (2H, t, J=6,7 Hz), to 6.58 (1H, d, J=1.7 Hz), 6,72 (1H, DD, J=1,7, and 8.4 Hz), 7,05 (1H, d, J=8,4 Hz), 7,50-to 8.20 (1H, usher.).

Example 62

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

IR ν (nujol) cm-1; 3470, 1682, 1614, 1585, 1512.

1H-NMR (Dl3) δ (ppm);

of 1.07 (3H, t, J=7.5 Hz), 2,05-of 2.20 (1H, m), and 2.26 (3H, s), 2,50-3,00 (3H, m), 3,65 is 4.45 (7H, m), of 5.92 (1H, users), 6,17 (1H, d, J=16,3 Hz), 6,45-6,85 (3H, m), 7,05 (1H, d, J=8,4 Hz), 7,34 (5H, s).

Example 63

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

IR ν (nujol) cm-1; 1722, 1614, 1568, 1506.

1H-NMR (Dl3) δ (ppm);

0,95 (N, C)of 2.34 (3H, s)to 2.55 (2H, s), 2,60-of 3.00 (2H, m), 3.00 and-3,30 (2H, m), 3,80-4,40 (7H, m), only 6.64 (1H, users, 6,70 (1H, d, J=8,8 Hz), 7,02 (1H, d, J=8,8 Hz), to 7.32 (5H, s), 7,80 (1H, users).

Example 64

Hydrochloride ethyl-2-(2,2-dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

IR ν (nujol) cm-1; 340,0, 1744, 1676, 1614, 1589, 1574, 1553, 1508.

1H-NMR (DMSO-d6) δ (ppm);

1,12 (N, C)of 1.23 (3H, t, J=7.0 Hz), a 2.36 (3H, s), 2,60-3,60 (6N, m)4,00-and 4.40 (4H, m), 4,40-6,00 (4H, m), to 6.88 (1H, d, J=8.0 Hz), 6,92 (1H, s), 7,18 (1H, d, J=8.0 Hz), 7,35-of 7.70 (8H, m), 7,75-8,10 (2H, m,).

Example 65

7-(Benzofuran-2-ylethoxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

IR ν (nujol) cm-1; 1632, 1587, 1501.

1H-NMR (DMSO-d6) δ (ppm);

2,00-6,50 (1H, usher.), 2,85 is 3.15 (2H, m), 3,50-4,10 (3H, m), 3,91 (2H, s), 5,16 (2H, s), 6,60-7,80 (8H, m), 7,33 (5H, s).

Example 66

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

IR ν (nujol) cm-1; 1736, 1639, 1612, 1504.

1H-NMR (DMSO-d6) δ (ppm);

1,02 (6N, userd), to 2.35 (3H, s), 2,65-3,30 (5H, m), 4,00-5,30 (6N, m), 6,60-to 6.95 (2H, m), to 7.09 (1H, d, J=8.0 Hz), 7,25-of 7.70 (8H, m), 7,70-8,10 (2H, m).

Example 67

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

IR ν (nujol) cm-1; 1634, 1585, 1501.

1H-NMR (DMSO-d6) δ (ppm);

2,80-3,10 (2H, m), 3,19 (2H, ushort), 3,45-4,10 (3H, m), 3,90 (2H,s), 4,25 (2H, ushort), 6,50-7,80 (N, m), 7,33 (5H, s).

Example 68

The hydrochloride of 7-[2-(5-ethylpyridine--yl)ethoxy]-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid

1H-NMR (CDCl3) δ (ppm);

of 0.87 (3H, ushort), of 1.05 to 1.85 (N, m), 2,15-to 2.55 (4H, m), 2,55 of 3.75 (4H, m), 4,00-of 4.90 (4H, m), 5.25-in of 5.50 (1H, m), 6,40-7,10 (4H, m), of 7.75 (1H, userd), 8,15 (1H, userd), charged 8.52 (1H, users).

Example 69

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

IR ν (nujol) cm-1; 1620, 1585, 1556, 1508.

1H-NMR (DMSO-d6) δ (ppm);

of 2.35 (3H, s), 2,70-3,15 (4H, m), 3,41, the 3.65 (2H, Awkw., J=17.5 Hz), 3,70-4,00 (3H, m)to 4.16 (2H, t, J=7.0 Hz), 6,00-11,00 (1H, usher.), only 6.64 (1H, s), 6,69 (1H, d, J=8,2 Hz), 7,01 (1H, d, J=8,2 Hz), 7,20-of 7.70 (8H, m), 7,70-with 8.05 (2H, m).

Example 70

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

IR ν (nujol) cm-1; 1732, 1652, 1554, 1505.

1H-NMR (DMSO-d6) δ (ppm);

of 2.33 (3H, s), is 2.50-3.40 (7H, m), the 3.65 (3H, s)4,07 (2H, ushort), 4,45-5,50 (3H, m), the ceiling of 5.60-of 6.20 (1H, usher.), 6,59 (1H, users), to 6.67 (1H, d, J=8.0 Hz), 7,03 (1H, d, J=8.0 Hz), 7,20-of 7.60 (3H, m), 7,80-8,10 (2H, m).

Example 71

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

IR ν (nujol) cm-1; 3375, 1733, 1620, 1555, 1505.

1H-NMR (DMSO-d6) δ (ppm);

of 1.18 (3H, t, J=7.0 Hz), 1,76-of 2.15 (2H, m), 2,15-of 2.50 (2H, m)to 2.35 (3H, s), 2,70-3,35 (6N, m), 3,60-4,40 (7H, m), 5,27 (1H, users), is 6.61 (1H, users), was 6.73 (1H, d, J=8,4 Hz), 7,03 (1H, d, J=8,4 Hz), 7,25-of 7.55 (3H, m), 7,80-8,10 (2H, m).

Example 72

2-Benzyl-6-[2-(5-methyl-2-phenyl shall xazal-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3RS)-carboxylic acid

IR ν (nujol) cm-1; 1634, 1614, 1499.

1H-NMR (DMSO-d6) δ (ppm);

of 2.35 (3H, s), 2,65-of 3.25 (4H, m), 3,40-4,00 (3H, m), 3,90 (2H, s), 4,17 (2H, ushort), 6,20-10,00 (1H, usher.), 6,50-7,00 (2H, m), of 6.71 (1H, s), 7,30-of 7.70 (3H, m), to 7.32 (5H, s), 7,75-of 8.15 (2H, m).

Example 73

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

IR ν (nujol) cm-1; 1682, 1620, 1508,

1H-NMR (DMSO-d6) δ (ppm);

of 2.33 (3H, s), of 2.56 (3H, s), 2,70-3,20 (4H, m), 3,50-4,30 (5H, m), of 3.97 (2H, s), 6,50-of 6.90 (2H, m), 7,02 (1H, d, J=8,4 Hz), 7,30-8,00 (N, m).

Example 74

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

IR ν (nujol) cm-1; 1668, 1643, 1614, 1504.

1H-NMR (DMSO-d6) δ (ppm);

of 2.33 (3H, s), a 2.36 (3H, s), 2,70-3,20 (4H, m), 3,30-4,30 (5H, m), to 6.57 (1H, d, J=2.0 Hz), of 6.66 (1H, DD, J=2.0 a, and 8.4 Hz), 7,00 (1H, d, J=8,4 Hz), 7,20 to 7.75 (7H, m), 7,75-8,10 (2H, m).

Example 75

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

IR ν (nujol) cm-1; 3462, 1680, 1614, 1556, 1508.

1H-NMR (DMSO-d6) δ (ppm);

to 2.41 (3H, s), 2,83-3,20 (2H, m), 3,44-4,20 (5H, m), 4,91 (2H, s), of 6.73 (1H, users), 6,77 (1H, d, J=8.1 Hz), 7,34 (1H, d, J=8.1 Hz), 7,34 (5H, s), 7,40-to 7.68 (3H, m), 7,75-8,10 (2H, m).

Reference example 1

Ethyl-2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

(1) Dihydrate 3,5-diid-L-tyrosine (25,0 g) su is ponderous in concentrated hydrochloric acid (250 ml). To a suspension successively added 1,2-dimethoxyethane (18 ml) and 37% formalin (20 ml) and the mixture is heated to 75°C for 30 minutes To the reaction mixture then add concentrated hydrochloric acid (120 ml), 1,2-dimethoxyethane (9 ml) and 37% formalin (10 ml) and the mixture was stirred at 75°C for 18 hours. The precipitated crystals are collected by filtration and washed with 1,2-dimethoxyethane (20 ml)to give the hydrochloride of 7-hydroxy-6,8-diid-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid (12.8 g).

The hydrochloride of 7-hydroxy-6,8-diid-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid:

IR ν (nujol) cm-1; 1751, 1599, 1578.

1H-NMR (Dl3) δ (ppm);

3,00-3,30 (2H, m), of 4.05 (2H, s), 4,30 (1H, DD, J=5,9, 9.5 Hz), 7,71 (1H, s).

(2) Compound (12.8 g)obtained in the above stage (1), suspender in ethanol (500 ml). To the suspension is added concentrated hydrochloric acid (10 ml) and the mixture is refluxed for 15 hours. The ethanol is evaporated under reduced pressure. To the obtained residue is added ethyl acetate (300 ml) and compound was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure, thus obtaining the ethyl-7-hydroxy-6,8-diid-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxy is at (11.11 g).

Ethyl-7-hydroxy-6,8-diid-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

1H-NMR (Dl3) δ (ppm);

of 1.29 (3H, t, J=7.0 Hz), 2,80-3,00 (2H, m), 3,30-4,10 (5H, m)to 4.23 (2H, square, J=7,0 Hz), 7,46 (1H, s).

(3) 10% Pd-C (350 mg) suspender in methanol (60 ml). To the suspension is added triethylamine (2.0 ml) and the compound (2,80 g)obtained in the above stage (2)and the connection catalytic way hydronaut at room temperature, 29,4×104PA (3.0 kgf/cm2within 3 hours. Pd-C is filtered off and the methanol is evaporated under reduced pressure. To the obtained residue is added ethyl acetate (10 ml). The mixture was washed with saturated salt solution (100 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure, thus obtaining the ethyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate (1,14 g).

Ethyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate:

IR ν (nujol) cm-1; 1732, 1607, 1516.

1H-NMR (Dl3) δ (ppm);

of 1.28 (3H, t, J=7.0 Hz), 2,80-3,10 (3H, m), 3,60-of 3.80 (1H, m), of 3.97 (2H, s), 4,05-4,20 (4H, m), to 6.43 (1H, s), 6,50-to 6.80 (1H, m), 6,92 (1H, d, J=8,4 Hz).

(4) the Compound (1.13 g)obtained in the above stage (3), dissolved in tetrahydrofuran (20 ml). To the solution was added di-tert-BUTYLCARBAMATE (1.50 g) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added ethyl acetate (30 ml) and the mixture is washed us the seal salt solution (20 ml) and dried over Na 2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography, thus obtaining specified in the title compound (1.51 g).

IR ν (nujol) cm-1; 3260, 1756, 1671, 1615, 1506.

1H-NMR (Dl3) δ (ppm);

of 1.29 (3H, t, J=7.0 Hz), 1,47 (N, C)is 3.08 (2H, d, J=5,2 Hz), is 4.21 (2H, square, J=7,0 Hz)to 4.41 (1H, d, J=15,5 Hz), 4,60-a 5.25 (1H, m)and 4.65 (1H, d, J=15,5 Hz), 5,00-6,00 (1H, usher.), 6,50-to 6.80 (2H, m), 6,98 (1H, d, J=8,1 Hz).

Reference example 2

Methyl-2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

In the same manner as in reference example 1, receive specified in the header of the connection.

IR ν (nujol) cm-1; 3261, 1755, 1672, 1614, 1506.

1H-NMR (Dl3) δ (ppm);

1,47 (N, C)is 3.08 (2H, d, J=5,2 Hz), 3,63 (3H, s), and 4.40 (1H, d, J=16.5 Hz), 4,60-a 5.25 (1H, m), of 4.66 (1H, d, J=16.5 Hz), the ceiling of 5.60-6,60 (1H, usher.), 6,50-to 6.80 (2H, m), of 6.99 (1H, d, J=8,1 Hz).

Reference example 3

2-(5-Methyl-2-phenyloxazol-4-yl)ethylmethanesulfonate

To methylene chloride (200 ml) is added 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (20 g) and triethylamine (19.2 ml). To the mixture are added dropwise methanesulfonanilide (9,52 ml) at 0°and the mixture was stirred at the same temperature for 15 minutes the Mixture was washed with 10% aqueous citric acid solution (200 ml), saturated aqueous sodium bicarbonate (100 ml) and saturated salt solution (100 ml) and dried over Na2SO4The methylene chloride is evaporated under reduced pressure. The resulting residue is purified column chromatography, thus obtaining specified in the header connection (21,45 g).

1H-NMR (Dl3) δ (ppm);

of 2.53 (3H, s)to 2.94 (3H, s)to 2.94 (2H, t, J=7,0 Hz)to 4.52 (2H, t, J=7.0 Hz), 7,30 is 7.50 (3H, m), 7,80-8,10 (2H, m).

Reference example 4

Ethyl-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylate

The compound (8.1 g)obtained in reference example 1(3), dissolved in N,N-dimethylformamide (80 ml). To the solution is added triethylamine (2.0 ml) and benzylbromide (4,57 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added water (500 ml) and the mixture is extracted twice with ethyl acetate (200 ml). The combined ethyl acetate layer was washed with saturated salt solution (500 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography, thus obtaining specified in the header connection (10,46 g).

IR ν (nujol) cm-1; 3410, 1717, 1624, 1506.

1H-NMR (Dl3) δ (ppm);

to 1.22 (3H, t, J=7.0 Hz), 3,06 (2H, d, J=5.0 Hz), 3,66 (1H, t, J=5.0 Hz), of 3.78 (2H, s), 3,90 (2H, s), of 4.13 (2H, square, J=7,0 Hz), 6,37 (1H, d, J=2.0 Hz), 6,56 (1H, DD, J=2.0 a, and 8.4 Hz), 6,92 (1H, d, J=8,4 Hz), 7,20 is 7.50 (5H, m).

Reference example 5

2-(N-tert-Butoxycarbonyl-N-methylamino)ethylmethanesulfonate

(1) 2-(Methylamino)ethanol (3.5 ml) dissolved in tetrahydrofuran (150 ml). The solution is to relax the Ute di-tert-BUTYLCARBAMATE (12.5 g) and the mixture is stirred at room temperature for 20 minutes The tetrahydrofuran is evaporated under reduced pressure. The resulting residue is purified column chromatography, thus obtaining 2-(N-tert-butoxycarbonyl-N-methylamino)ethanol (6,35 g).

2-(N-tert-Butoxycarbonyl-N-methylamino)ethanol:

IR ν (undiluted) cm-1; 3423, 2976, 2934, 2882, 1674.

1H-NMR (Dl3) δ (ppm);

1,43 (N, C), 2,89 (3H, s)to 3.34 (2H, t, J=5.8 Hz), to 3.67 (2H, t, J=5.8 Hz), 4,00-6,00 (1H, usher.).

(2) Compound (505 mg)obtained in the above stage (1), dissolved in methylene chloride (20 ml). To the solution is added triethylamine (0.5 ml) and methanesulfonamide (0.25 ml) and the mixture is stirred at room temperature for 1 hour. To the mixture is added methylene chloride (30 ml) and the mixture is washed with saturated salt solution (20 ml) and dried over Na2SO4. The methylene chloride is evaporated under reduced pressure, thus obtaining specified in the title compound (720 mg).

1H-NMR (Dl3) δ (ppm);

1,46 (N, C)to 2.94 (3H, s), a 3.01 (3H, s), of 3.54 (2H, t, J=5,5 Hz)to 4.33 (2H, t, J=5,5 Hz).

Reference example 6

1-(2-Bromacil)indolin

To 1,2-dibromethane (58,0 ml) add indolin (5.0 g) and triethylamine (28,7 ml) and the mixture was stirred at 90°C for 2 hours. To the reaction mixture are added ethyl acetate (200 ml) and the mixture is washed with saturated salt solution (400 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The floor is built the residue purified column chromatography, while receiving specified in the title compound (4.09 g).

IR ν (undiluted) cm-1; 2924, 2845, 1607, 1489.

1H-NMR (Dl3) δ (ppm);

to 2.99 (1H, t, J=8,4 Hz), of 3.45 (1H, t, J=8,4 Hz), 3,49 (4H, s), 6,40 to 6.75 (2H, m), 6.90 to-7,20 (2H, m).

Reference example 7

1-(2-Bromacil)-6-methoxycarbonylethyl

To 1,2-dibromethane (15.7 ml) is added 6-methoxycarbonylethyl (2,41 g) and triethylamine (7.8 ml) and the mixture was stirred at 90°C for 2 hours. To the reaction mixture are added ethyl acetate (150 ml) and the mixture is washed with saturated salt solution (300 ml) and dried over Na2SO4. The ethyl acetate is evaporated under reduced pressure. The resulting residue is purified column chromatography, thus obtaining specified in the header connection (1,71 g).

IR ν (undiluted) cm-1; 1713, 1611, 1499.

1H-NMR (Dl3) δ (ppm);

3,03 (1H, t, J=8,4 Hz), 3,53 (1H, t, J=8,4 Hz), 3,53 (4H, s), 3,88 (3H, s), 6,00-of 6.20 (2H, m), 7,39 (1H, DD, J=1.5 and 7.8 Hz).

Experimental example 1 Hypoglycemic effect (method A)

The blood was collected from the tail vein of male mice KK-AYin negrodem state, who were models of spontaneous diabetes was detected diabetes due to insulin resistance and that showed hyperglycemia and hyperinsulinemia. The level of glucose in the plasma was measured using a commercially available kit for anal is for (glucose CII-test WAKO, Wako Pure Chemical Industries, Ltd.). The mice were divided into groups (5 mice per group)with a control group and the group introduction (test connection), so that the mean and standard deviation of the glucose level in the plasma of each group was almost the same. Each test compound suspended or dissolved in a 5% solution of gum Arabic was administered orally to the group introduction during 4 consecutive days from the next day. 5% solution of gum Arabic oral was administered to the control group. The blood was collected from the tail vein of mice in negrodem for about 24 hours after the last injection and measured the level of glucose in plasma. Reducing the level of glucose in plasma was calculated by the following formula. The results are given in table 1.

Reduction (%) level of plasma glucose = [(average glucose level in the plasma of control group - average level of glucose in the plasma group the introduction of the test compound)/the average level of glucose in the plasma of the control group] × 100.

Table 1

Hypoglycemic effect (method A)
Test connectionDose (mg/kg)Reduction (%) level of plasma glucoseTest connectionDose (mg/kg)Reduction (%) level the plasma glucose
Example 210

30
38,3

60,6
Example 403046,3
Example 413011,1
Example 33011,8Example 4210

30
27,6

49,6
Example 510

30
34,1

43,4
Example 433027,5
Example 610

30
10,7

12,2
Example 443048,0
Example 453012,6
Example 710

30
11,4

17,4
Example 463028,6
Example 483016,1
Example 93020,3Example 493011,1
Example 1210to 12.0Example 503011,4
Example 163034,5Example 513020,0
Example 18 3039,7Example 523026,3
Example 213043,4Example 533013,6
Example 2310

30
24,3

42,9
Example 543010,8
Example 553013,9
Example 323036,4Example 583019,1
Example 333038,8Example 673010,6
Example 343023,5Example 693012,5
Example 353022,1Example 703015,2
Example 363028,4Example 713010,5
Example 373011,1Example 723015,9
Example 383028,0Example 733014,8
Example 393030,7 

Expertise is mental example 2 Hypoglycemic action (method)

The blood was collected from the tail vein of male mice QC-Yin negrodem state, who were models of spontaneous diabetes was detected diabetes due to insulin resistance and that showed hyperglycemia and hyperinsulinemia. The level of glucose in the plasma was measured using a commercially available test kit (glucose CII-test WAKO, Wako Pure Chemical Industries, Ltd.). The mice were divided into groups (5 mice per group)with a control group and the group introduction (test connection), so that the mean and standard deviation of the glucose level in the plasma of each group was almost the same. Each test compound was mixed in a proportion of 0.1 wt./wt.% with powdered feed (CE-2, Clea) and the feed mixture was introduced to the group injection within 4 days from the next day. The control group was regularly introduced powdered food. On day 5 the blood was collected from the tail vein of mice in negrodem condition and measured the level of glucose in plasma. Reducing the level of glucose in plasma was calculated by the following formula. The results are given in table 2.

Reduction (%) level of plasma glucose = [(average glucose level in the plasma of control group - average level of glucose in the plasma group the introduction of the test compound)/the average level of glucose in the plasma of the control group] × 100.

Table 2

The hypoglycemic action (method)
Test connectionReduction (%) level of plasma glucose
Example 269,2
Example 1042,4

Experimental example 3 Hypotriglyceridemic action

The blood was collected from the tail vein of male mice KK-AYin negrodem state, who were models of spontaneous diabetes was detected diabetes due to insulin resistance and that showed hyperglycemia and hyperinsulinemia. The level of triglycerides in plasma were measured using commercially available test kit (triglyceride G-test WAKO, Wako Pure Chemical Industries, Ltd.). Mice were divided into groups (5 mice per group)with a control group and the group introduction (test connection), so that the mean and standard deviation of the level of triglyceride in the plasma of each group was almost the same. Each test compound suspended or dissolved in a 5% solution of gum Arabic was administered orally to the group introduction during 4 consecutive days from the next day. 5% solution of gum Arabic oral was administered to the control group. The blood was collected from the tail vein of mice in negrodem for about 24 hours after the placenta is introduced and measured the level of triglycerides in the plasma. Reducing the level of triglycerides in the plasma was calculated by the following formula.

The results are given in table 3.

Reduction (%) level of triglyceride in plasma = [(average level of triglyceride in plasma of control group - average level of triglyceride in the plasma group the introduction of the test compound)/average level of triglyceride in the plasma of the control group] ν 100.

Table 3

Hypotriglyceridemic action
Test connectionDose (mg/kg)Reduction (%) level of triglyceride in plasmaTest connectionDose (mg/kg)Reduction (%) level of triglyceride in plasma
Example 210

30
39,5

54,3
Example 383030,0
Example 3930the 15.6
Example 41014,3Example 403036,1
Example 53030,9Example 423031,6
Example 111011,2Example 433020,9
Example 12 1022,9Example 443019,1
Example 163019,8Example 4930of 17.0
Example 183045,5Example 503035,7
Example 213024,4Example 513010,7
Example 2310

30
30,4

50,4
Example 523026,6
Example 563014,0
Example 323032,5Example 583024,7
Example 333042,0Example 593013,7
Example 3430the 17.3Example 693015,2
Example 353012,4Example 723024,0
Example 363013,7Example 733015,4

Experimental example 4 Hypoglycemic effect and hypoinsulinemia action insulin is resistant diabetic mouse

The effect of increasing insulin resistance, was investigated in mice QC-Ywho were the models with spontaneous diabetes was detected diabetes due to insulin resistance and that showed hyperglycemia and hyperinsulinemia. The blood was collected from the tail vein in 12-week-old male mice (KK-AYin negrodem condition and the level of glucose in the plasma was measured using a commercially available test kit (glucose CII-test WAKO, Wako Pure Chemical Industries, Ltd.). Mice were divided into groups (5 mice per group)with a control group and the group introduction (test connection), so that the average level of glucose in the plasma and the average body weight of each group, as well as the standard deviation of the level were almost the same. The test compound (10 mg/kg) suspended in 5% aqueous solution of gum Arabic was administered orally once daily group injection within 4 days from the next day. 5% solution of gum Arabic oral was administered to the control group. The blood was collected from the tail vein of mice in negrodem condition 24 hours after the last injection. Measured concentrations of plasma glucose and insulin plasma. The results are given in table 4.

The result of each test compound (10 mg/kg) reduced the level of glucose in the plasma, and decreased concentration of insulin in plasma. This is means, that the test compound reduces the level of glucose in the plasma through the secretion of insulin, but by actions, potentiating insulin sensitivity (action, which increases insulin resistance), thereby improving the condition of hyperinsulinemia.

Table 4

Hypoglycemic effect and hypoinsulinemia action
Test connectionThe dose of the test compound (mg/kg)Plasma glucose (mg/DL)Insulin (ng/ml)
Control050743
Example 21031326
Example 231038228
Example 321040230
Example 421030827

Experimental example 5 Effect of stimulating the accumulation of triglyceride in the cells 3T3-L1

Culture medium 80% confluent cells 3T3-L1 was removed and cells dissociatively solution of 0.25% trypsin-EDTU. Added 5% FBS(fetal bovine serum)-DMEM(modified by way of Dulbecco Wednesday Needle), the same number as the number of the remote environment) poluchennuyu cell suspension was centrifuged at 25° With 100×g for 1 min to obtain the cell sediment and supernatant was removed. Cells are again suspended in an appropriate amount of medium with 5% FBS-DMEM and the cells counted. Added Wednesday, 5% FBS-DMEM to establish a concentration of 1×105cells/ml and the mixture was divided into 1 ml in 24-well plate. Cells were cultured with aeration 5% CO2at 37°C for 2 days. After confirmation postconfluent state of the culture supernatant was replaced with medium containing 0.5 mm IBMX, cells were cultured for 2 days. Then the medium was replaced with medium containing 10 ng/ml insulin and 10-7M of the test compound, and the cells were then cultured for 4 days. After removal of the supernatant of the cell culture was literally in 0.1% solution of SDS (sodium dodecyl sulphate) and measured the amount of triglyceride. The accumulation of triglyceride (%) due to potentiation of the activity of insulin test compound was calculated from the following formula. The results are given in table 5 [(the amount of the triglyceride with the addition of the test compound - amount of triglyceride control)/amount of triglyceride control] × 100.

Table 5

Action, stimulating the accumulation of triglycerides
Test connection Test connectionThe accumulation of triglyceride (%)
Example 2260,4Example 33222,5
Example 5233,0Example 37making up 277.3
Example 8275,5Example 39258,0
Example 16288,9Example 40231,0
Example 21284,9Example 42193,6
Example 23214,2Example 62327,8
Example 32181,2 

The patent

Heterocyclic compound [I] or pharmaceutically acceptable salt of the present invention exhibit a superior hypoglycemic action, gipolipidemicheskoe action in the bloodstream, the effect of increasing insulin resistance, and PPAR-activating effect, they can be used as hypoglycemic agents, hypolipidemic funds, funds that increase insulin resistance, therapeutic agents for diabetes, therapeutic agents against complications of diabetes, tools, improve glucose tolerance, anti-atherosclerosis, anti-obesity, protivoop the calculating means, means for the prevention or treatment of PPAR-mediated disease and funds for the prevention or treatment of syndrome X. Therefore, the heterocyclic compound [I] or pharmaceutically acceptable salt of the present invention are useful for prevention or treatment of diabetes, diabetic complications, hyperlipidemia, atherosclerosis, hyperglycemia, the diseases caused insulinorezistentne, impaired glucose tolerance, and diseases caused by insulin resistance, obesity, inflammation, PPAR-mediated disease and syndrome X. Heterocyclic compound [I] of the present invention has a structure completely different from the structures of the compounds are still used as an active ingredient conventional means, increasing insulin resistance. By providing this connection it is possible to obtain a large number of hypoglycemic agents, lipid-lowering means, means increasing insulin resistance, therapeutic agents for diabetes, therapeutic agents against complications of diabetes, tools, improve glucose tolerance, anti-atherosclerosis, anti-obesity, anti-inflammatory drugs, remedies for the prevention or treatment of PPAR-mediated disease and funds for the prevention or treatment is syndrome X, from which it is possible to freely select the desired tool.

This application is based on patent applications No. 345543/1999 and 295108/2000 registered in Japan, the contents of which, therefore, is included as a reference.

The study of toxicity after a single dose to mice and rats

Method

Male ICR mice and SD rats (aged 6 weeks) were divided into groups: the group that was administered the test compound and a control group (5 animals per group) so that the average body weight and standard deviation were almost the same in animals in the group. A single dose of suspension (1000 mg/20 ml/kg of the compound from example 2 in a 0.5% aqueous solution of methylcellulose) oral introduced the group selected for the introduction of test compounds, and a single dose of 0.5% aqueous methylcellulose oral was administered to the control group and observed the General condition of the animals. Starting from the next day for 14 days were regularly measured body weight and food consumption and watched the General condition of the animals, and then made the autopsy of animals for visual inspection of the appearance and condition of the major organs.

Results

The results are presented in tables 6 and 7.

The group, which injected the compound showed no abnormalities in behavior or condition of the animals in ECENA 6 hours after administration of the compound. This group also showed no abnormalities in behavior or condition of the animal under observation for 14 days after administration of the compound. At necropsy, there were no deviations appearance in sections and cavities of the heart, liver, kidney, spleen, lung, adrenal, pancreas, testes, stomach, small intestine and colon in all animals.

Table 6.

Toxicity induced by a single administration to mice of ICR
The analyzed connectionDose (ml/kg)Clinical signsWeightFood consumptionGeneral pathologyMortality
Example 21000N.E.N.E.N.E.N.E.0/5
N.E.: no effect
Table 2.

Toxicity caused by a single dose in rats SD
The analyzed connectionDose (ml/kg)Clinical signsWeightP the consumption of food General pathologyMortality
Example 21000N.E.N.E.N.E.N.E.0/5
N.E.: no effect

Examples of pharmaceutical compositions.

Example composition 1: tablet

A tablet containing the following ingredients, get the regular way. If necessary, a tablet can cause sugar or film coating.

Connection example 210 mg
Lactose80 mg
Corn starch33 mg
Crystal20 mg
cellulose 
Magnesium stearate2 mg
 145 mg

Example composition 2: capsule

The capsule containing the following ingredients, get the usual method of filling capsules.

Connection example 210 mg
Lactose100 mg
Corn starch58 mg
Magnesium stearate2 mg
 170 mg

1. Derivatives tetrahydroisoquinoline formula [I]

where

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil, or monocyclic geterotsiklicheskikh where the heterocycle include a 5 - or 6-membered ring containing a nitrogen atom, and optionally has a Deputy, selected from lower alkyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from oxygen atom and nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, the Rila, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt.

2. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, optionally having a Deputy selected from alkoxycarbonyl and carboxy, cycloalkyl, cycloalkenyl, aryl, optionally having a Deputy selected from lower alkyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt.

3. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

R1represents a hydrogen atom or lower alkyl,

R2presented yet an alkyl, cycloalkenyl, arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl, alkenyl, quinil or heterocyclyl,

R3represents a hydrogen atom or lower alkoxy,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents an aryl or monocyclic or condensed heterocyclyl containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt.

4. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

R1represents a hydrogen atom or lower alkyl,

R2represents alkyl, cycloalkyl and arylalkyl, not necessarily with the Deputy, selected from lower alkyl, lower alkoxy, halogen atom and acyl,

R3represents a hydrogen atom,

Rather it represents a direct link or >N-R5where R5represents lower alkyl,

Represents a lower alkylene, and

Y represents from the battle monocyclic or condensed heterocyclyl, containing at least one heteroatom selected from the group comprising an oxygen atom and a nitrogen atom, and optionally having a Deputy selected from lower alkyl, carboxy, aryl, alkenyl, cycloalkyl and tanila,

or its pharmaceutically acceptable salt.

5. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

Y-represents A

where RArepresents isopropyl or tert-butyl,

RBrepresents isopropyl or tert-butyl,

RCrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropanal, 3-butenyl, cyclopropyl, 1-butenyl or 2,2-dimethylpropyl,

or its pharmaceutically acceptable salt.

6. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

Y-represents A

where RArepresents isopropyl or tert-butyl,

RBrepresents isopropyl or tert-butyl,

RCrepresents isopropyl, tert-butyl, phenyl, thiophene-2-yl, 2-methylpropyl or 3-butenyl,

or farm citiesi acceptable salt.

7. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

Y-A - is a

or its pharmaceutically acceptable salt.

8. Derived tetrahydroisoquinoline according to claim 1, where in formula [I]

Y-A - is a

or its pharmaceutically acceptable salt.

9. Derived tetrahydroisoquinoline according to claim 1, where the heterocyclic compound of the formula [I] is any of the following compounds(2)-(14) (16)-(67):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

< num="1037"> (22) 2-(2,2-dimethylpropanoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-(3S)-carboxylic acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(40) 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridine-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-(33)-carboxylic acid,

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

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

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

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

(45) 2-benzyl-7-(2-tert-butylbenzothiazole-5-yl)methoxy-1,2,3,4-tetrahydroisoquinoline-(3S)-CT is about acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

or its pharmaceutically acceptable salt.

10. Derived tetrahydroisoquinoline according to claim 9, where the derivative of tetrahydroisoquinoline formula [I] is any of Visayas is the R compounds(2)-(14) (16)-(47) or its pharmaceutically acceptable salt.

11. Derived tetrahydroisoquinoline according to claim 9, where the derivative of tetrahydroisoquinoline formula [I] is any of the above compounds (2)to(14) and (16)-(21) and its pharmaceutically acceptable salt.

12. Pharmaceutical composition having hypoglycemic and hypolipidemic action, including derived tetrahydroisoquinoline according to any one of claims 1 to 11, or its pharmaceutically acceptable salt.

13. A pharmaceutical agent comprising the derivative tetrahydroisoquinoline according to any one of claims 1 to 11, or its pharmaceutically acceptable salt, which is selected from the group comprising a hypoglycemic agent, a hypolipidemic agent, an agent that increases insulin resistance, a therapeutic agent for diabetes, a therapeutic agent against diabetic complications, a tool that improves glucose tolerance, anti-atherosclerosis, anti-obesity, anti-inflammatory agent, an agent for the prophylaxis or treatment of PPAR-mediated diseases and an agent for the prophylaxis or treatment of syndrome X.

Priority:

03.12.1999 - according to claim 2, 4 and 11;

27.09.2000 - PP and 10;

29.11.2000 - PP. 1, 5-9 and 12-18.



 

Same patents:

FIELD: organic chemistry, chemical technology, explosive substances.

SUBSTANCE: invention relates to a method for preparing 4,4'-bis-[4-aminofurazan-3-yl-N(O)N-azoxy]-3,3'-azofurazane of the general formula (1):

that is a new thermostable explosive substance with improved exploitation indices. Method for preparing compound of the formula (1) involves treatment of 4,4'-diaminoazoxyfurazane with potassium bromate solution (KBrO3) in hydrochloric acid medium or its mixture with organic acid. Proposed compound can be used as a component of explosive compositions, solid rocket fuels and power-consuming compositions of different designations exploited at elevated temperatures (for example, in blast-hole drilling in depth mines).

EFFECT: improved preparing method, valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to chemistry and medicine, in particular relates to new chemical compounds - derivatives of 3,4-bis(furazan-3-yl)furoxan General formula I:

where R = R1= HE, NH2N3lowest alkoxy or a group of the General formula NR2R3where R2= R3= N or R2and R3together with the nitrogen atom form piperidinyl cycle, or R = NH2and R1- (lower alkanoyl)amino group, provided that R and R1not represent methoxy, possessing pharmacological activity

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry or heterocyclic compounds, chemical technology.

SUBSTANCE: invention relates to technology for manufacturing heterocyclic compounds, in particular, to technology for manufacturing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that is known as a substance for pharmaceutical designation "thiotriazoline". Invention describes a method for preparing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that involves reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in liquid medium wherein methylene chloride is used as a liquid medium. Method provides significant elevating the yield percent of the end product, enhances its quality and significant reducing industrial consumptions.

EFFECT: improved preparing method.

4 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

The invention relates to organic chemistry and can find application in medicine

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

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