Derivatives substituted heterocycle phenyl-cyclohexane - carboxylic acid, mixture of isomers, or individual isomers and their salts

 

(57) Abstract:

The invention relates to new heterocyclic substances exhibiting antagonist against angiotensin II action. Derivatives of formula I, where a and b form a radical of formula (a-g), and D and E is a radical of formula (d-I); R1, R2and R3- H, halogen, C1-8-alkyl, L - H, halogen, C1-6-alkyl, T is a radical of the formula - COOR4, -CONR5SO2R6, -CONR7(R8R9; R4- H, C1-8-alkyl; R5and R7- H, C1-6-alkyl; R6- phenyl, possibly substituted C1-6-alkyl, R8aryl with 6 to 8 carbon atoms, possibly substituted WITH 1-21-6-alkilani; R9- CH2OH9-CO2R10, -CO-NR11R12; R10, R11, R12is hydrogen, C1-8-alkyl; T - tetrazolyl, possibly substituted by trifluoromethyl or1-4-alkyl, a mixture of their isomers or individual and their salts. The compounds I inhibit vasoconstrictor and stimulates the secretion of aldosterone effects of angiotensin II. 3 C.p. f-crystals, 4 PL.

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The invention relates to new heterocyclic substances, possessing valuable pharmacological properties, in particular to proizvodi the heterocycle phenyl-cyclohexane-carboxylic acid, which possess biological activity, in particular, are antagonistic against angiotensin II action (see application EP 0407102).

The objective of the invention is to expand the Arsenal of highly active derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid, showing, in particular, antagonist against angiotensin II action.

This task is solved proposed derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of General formula I

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where A and B together form a radical of the formula

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D and E together form a radical of the formula

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where R1, R2and R3the same or different and mean hydrogen, halogen, an unbranched or branched alkyl with 1-8 carbon atoms;

L is hydrogen, halogen, an unbranched or branched alkyl with 1 to 6 carbon atoms;

T is a radical of the formula

-CO2R4, -CO-NR5SO2R6,

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where R4is hydrogen, unbranched or branched alkyl with 1 to 8 carbon atoms;

R5and R7the same or different and mean hydrogen or an unbranched or branched alkyl with 1 to 6 atoms of the UP>8aryl with 6 to 10 carbon atoms, unsubstituted or substituted one or twice identical or different substituents from among unbranched or branched alkyl with 1 to 6 carbon atoms;

R9group of the formula-CH2-OH, -CO2R10, -CO-HR11R12where R10, R11and R12mean hydrogen or an unbranched or branched alkyl with 1 to 8 carbon atoms,

or T means tetrazolyl, unsubstituted or substituted by triphenylmethyl or unbranched or branched alkyl with 1 to 4 carbon atoms,

the mixture of their isomers or individual isomers and their salts.

In the framework of the present invention prefer physiologically tolerated salt.

Physiologically tolerated salts of the new substituted heterocycle derivatives of phenyl-cyclohexane-carboxylic acids are salts with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred are, for example, salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultation, toluensulfonate, benzosulfimide, naphthalenedisulfonate, uksosn, alienboy acid or benzoic acid.

Physiologically tolerated salts can be salts with metals or ammonium salts of proposed compounds which contain free carboxyl group. Particularly preferred are sodium, potassium, magnesium or calcium salts, and also ammonium salts which are formed with ammonia or organic amines, for example, ethylamine, di - or triethylamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or Ethylenediamine.

In the framework of the present invention proposed connection may exist in different stereoisomeric forms, which represent the direct and inverse forms (enantiomers) or are not (diastereomers). The invention relates both to the enantiomers and diastereomers and their respective mixtures. As the racemic form, and diastereomer can be divided by the known techniques for pure stereoisomeric forms (see E. L. Eliel, Stereochemistry of Gardon Compounds, ed. McGraw Hill, 1962).

Preferred are compounds of General formula I,

where A and B together denote a radical of the formula

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D and E together denote a radical of the formula

6

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where R
L is hydrogen, fluorine, chlorine, bromine, or unbranched or branched alkyl with 1 to 4 carbon atoms;

T is a radical of the formula

-CO2R4, -CO-NR5SO2R6,

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where R4is hydrogen, unbranched or branched alkyl with 1 to 6 carbon atoms;

R5and R7identical or different denote hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms;

R6is phenyl, unsubstituted or substituted non-branched alkyl with 1 to 4 carbon atoms;

R8is phenyl, unsubstituted or substituted unbranched or branched alkyl with 1 to 4 carbon atoms;

R9group of the formula-CH2-OH, -CO2R10, -CO-NR11R12where R10, R11and R12mean hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms;

or T means tetrazolyl, unsubstituted or substituted stands or triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

Particularly preferred are compounds of General formula I, where A and B together denote a radical of the formula

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D and E together denote a radical of the formula

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where RFor, chlorine, bromine, methyl;

T is a radical of the formula

-CO2R4, - CO-NR5SO2R6,

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where R4is hydrogen, unbranched or branched alkyl with 1 to 4 carbon atoms;

R5and R7the same or different and mean hydrogen or methyl;

R6is phenyl;

R8is phenyl, unsubstituted or substituted unbranched or branched alkyl with 1 to 3 carbon atoms;

R9group of the formula-CH2-OH, -CO2R10, - CO-NR11R12where R10, R11and R12mean hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms,

or T means tetrazolyl, unsubstituted or substituted stands or triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

In addition, preferred compounds of General formula I, where A and B together denote a radical of the formula

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D and E together denote a radical of the formula

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where R1, R2and R3the same or different and mean hydrogen or methyl;

L is hydrogen;

T is a radical of the formula

-CO2R4, -CO-NR5SO2R6,

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where R4is hydrogen or an unbranched or SUP> is phenyl;

R9group of the formula-CH2OH,

or T means tetrazolyl, unsubstituted or substituted by triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

The new compounds of General formula I can be obtained, for example, due to the fact that the compounds of formula II

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where L is the above value;

W - typical removable group, such as chlorine, bromine, iodine, tosylate or mesilate, preferably bromine;

X - alkoxycarbonyl with 1 to 6 carbon atoms or triphenylmethyl-tetrazolyl-1-Il,

subjected to interaction with compounds of General formula III

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where A, B, D, and E have the above values,

in inert solvents, if appropriate in the presence of a base and in an atmosphere of protective gas, and the resulting compounds of General formula IV

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where A, B, D, E, L and X have the above values,

if necessary after pre-hydrolysis and/or activation is subjected to amidation by sulfonamide or amines of General formula V and Va

HNR6-SO1-R7or

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where R6, R7R8and R9have the above values,

in inert solvents, in the case neobhodimyh of tetrazolo available, if necessary, triphenylmethyl group is removed by known techniques acids, preferably triperoxonane acid or hydrochloric acid in the environment of dioxane, and, if necessary, the isomers are separated and in the case of salts obtained compound is subjected to interaction with the appropriate base or acid

The above method is illustrated by the following scheme

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As a solvent in the implementation of the method described above it is possible to use inert organic solvents which do not change in the conditions of the reactions. These include ethers such as, for example, diethyl ether, dioxane, tetrahydrofuran, dimethyl ether glycol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or complex ethyl ester acetic acid, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide triamide hexamethylphosphoric acid, acetonitrile, acetone or nitromethane. In addition, it is also possible to use mixtures of these solvents. Particularly preferably used dimethylformamide and tetrahed is practical and inorganic bases. Preferably use a hydroxide of alkali metals such as sodium hydroxide or potassium, alkaline earth metal hydroxide such as barium hydroxide, carbonates of alkali metals such as sodium carbonate or potassium hydroxide, or carbonates of alkaline earth metals such as calcium carbonate or alcoholate of an alkaline or alkaline earth metals such as, for example, methanolate or ethanolate or sodium or potassium tert.butyl potassium, or organic amines (trialkyl(C1-C6)amines) such as triethylamine, or heterocycles, for example, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, diaminopyridine, methylpiperidine or morpholine. Can be used as bases alkali metals, e.g. sodium, or their hydrides, e.g. sodium hydride. Preferred are sodium hydride, potassium carbonate, triethylamine, pyridine and tert.butyl potassium, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]octane.

Usually the base is used in amounts of from 0.05 mol to 10 mol, preferably 1 to 2 mol based on 1 mol of the compounds of formula III.

The above method is usually carried out at temperatures from -30oC to +100oC, preferably from the and reduced pressure (for example, 0.5 to 5 bar).

As grounds for the implementation of the hydrolysis of suitable conventional inorganic bases. To them, preferably belong to the hydroxides of the alkali or alkaline earth metals, such as, for example, a hydroxide of lithium, sodium, potassium or barium, or carbonates of alkali metals, such as, for example, carbonates of sodium, potassium, or sodium bicarbonate, or alkali metal alcoholate, such as, for example, methanolate sodium, ethanolate sodium, methanolate potassium, ethanolate or potassium tert.butanolic potassium. Especially preferably use a hydroxide of lithium, sodium and potassium.

As solvents suitable for the implementation of the hydrolysis of water or commonly used for hydrolysis of organic solvents. To them, preferably belong alcohols as methanol, ethanol, propanol, isopropanol, butanol, or ethers, such as tetrahydrofuran or dioxane, or dimethylformamide, or dimethylsulfoxide. Particularly preferably used alcohols, such as methanol, ethanol, propanol or isopropanol. In addition, it is also possible to use mixtures of the mentioned solvents.

The hydrolysis can also be aqueous acids, such as, for example, water triperoxonane is Oh, water methansulfonate, aqueous sulfuric acid or aqueous perchloric acid, preferably water triperoxonane acid.

The hydrolysis is usually carried out at a temperature from 0oC to +100oC, preferably from +20oC to +80oC, and at atmospheric pressure. However, it can also be carried out at reduced or elevated pressure (for example, at a pressure of from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is usually used in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol based on 1 mol of ester. Particularly preferably, use molar quantities of the reactants.

If the reaction is first get the carboxylates of the proposed compounds as intermediates, which can be distinguished. The offered acid is produced by processing carboxylates usual inorganic acids. To them, preferably belong acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid or triperoxonane acid. When obtaining carboxylic acids suitable turned out to be the acidification of the alkaline saponification reaction mixture to the second stud is clov by processing solutions carboxylates of the above acids can also be obtained salts heterocyclic compounds with inorganic acids.

The amidation of the compounds of General formula IV is usually carried out in one of the abovementioned solvents, preferably in tetrahydrofuran or dichloromethane.

The amidation may be, if necessary, via the activated stage of golodnikov [(IV) Y = halogen], you can get their respective acids by reacting with thionyl chloride, trichloride phosphorus, pentachloride phosphorus, tribromide phosphorus or oxalylamino.

The amidation is usually carried out at a temperature of from -80oC to +80oC, preferably from -30oC to +30oC and atmospheric pressure.

In addition to the above reason as the Foundation of the preferably usable triethylamine and/or dimethylaminopyridine, 1,5-diazabicyclo[3.4.0]undecan-5 and 1,4-diazabicyclo[2.2.2]octane.

The base is used in an amount of from 0.5 mol to 10 mol, preferably from 1 mol to 5 mol based on 1 mol of the compounds of General formula IV and V

As acid binding agent for the amidation can be used carbonates of alkaline or alkaline earth metals, such as sodium carbonate, potassium carbonate, hydroxides of alkaline or alkaline earth metals, ka is reprein or a bicyclic amidine, as, for example, 1,5-diazabicyclo [3.4.0]-nonan-5 or 1,5-diazabicyclo[3.4.0]undecan-5. It is preferable to use potassium carbonate.

As the dehydration agent suitable carbodiimide, as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-oxysuccinimide, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, carbonyl compounds, such as, for example, carbonyldiimidazole, 1,2-oxazolium compounds, such as 3-sulfonate 2-ethyl-5-phenyl-1,2-oxazole, anhydride propriospinal acid, isobutylacetate, getserverport benzothiazolinone-Tris-(dimethylamino)-phosphonium, amide complex diphenyl ether phosphonic acid or acid chloride of methansulfonate, if necessary, in the presence of a base, such as triethylamine, N-ethylmorpholine, N-methylpiperidine.

Linking acid agents and agents dehydration is usually used in amounts of 0.5 to 3 mol, preferably 1 to 1.5 mol, per mole of the corresponding carboxylic acid.

Most of the cyclohexane derivatives of the General formula II is new. They can be obtained that compounds of General formula VI

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where L is the above value,

first, by hydrogenation with hydrogen in the singing of General formula VII

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where L is the above value,

and in the second stage, if T tetrazolyl, atrificial by conventional means, and if T = tetrazolyl, the compound of formula (VI) is subjected to interaction with chlorosulfonylisocyanate in dichloromethane, the resulting cenocoeliinae, enter tetrazolyl group by reacting a mixture of sodium azide and chloride of triethylamine in nitrogen atmosphere in the presence of one of the abovementioned bases, preferably N,N-dimethylformamide, through further interaction with triphenylmethylchloride in the presence of one of the abovementioned solvents and bases, preferably dichloromethane and triethylamine, enter triphenylmethyl group and at the last stage can be bromination of the methylene group, optionally, in the presence of a catalyst.

The restoration of the double bond is brought at a temperature of from 0oC to +40oC, preferably at +20oC and a pressure of 1 bar.

The etherification is carried out in one of the abovementioned solvents, preferably toluene and tetrahydrofuran, after the above pre-activation of the corresponding carboxylic acid, preferably through haranged is but when 10 - 35oC and atmospheric pressure.

Turning to cyanocobalamine and tetrazolyl compounds are usually at the boiling point of the employed solvent and atmospheric pressure.

Introduction triphenylmethyl group in tetrazolyl ring is usually at 0oC.

Bromination is conducted preferably N-bromosuccinimide, in an environment of one of the abovementioned solvents, preferably carbon tetrachloride, at a temperature of 40 - 100oC, preferably 60 to 90oC and atmospheric pressure.

As a catalyst for the synthesized suitable, for example, azobisisobutyronitrile, peroxide Dibenzoyl, preferably azobisisobutyronitrile, and the catalyst is used in an amount of 0.01 - 0.1 mol, preferably 0.01 to 0.05 mol based on 1 mol of the compounds of General formula VII.

Compounds of General formula VI are also new and can be obtained, for example, that compounds of General formula VIII

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where L is the above value,

subjected to interaction with 1,3-butadiene in one of the abovementioned solvents, preferably toluene, in the presence of hydroquinone at a temperature of 180oC - 230General formula III, V and VIII are known or can be obtained by known methods.

Compounds of General formulas IV and VII are novel and can be obtained, for example, one of the methods mentioned above.

Compounds of General formula I according to the invention possess unexpected valuable pharmacological spectrum of action.

The proposed compounds have specific antagonistic activity against angiotensin II, as they inhibit the communication of angiotensin II receptors. They inhibit vasoconstrictor and stimulates the secretion of aldosterone effects of angiotensin II. In addition, they inhibit the proliferation of smooth muscle cells.

Therefore they can be used in medicines to treat high blood pressure and atherosclerosis. In addition, they can be used to treat coronary heart disease, heart failure, cerebral activity, ischemic cerebrovascular disease, peripheral circulatory disorders, disorders of the kidney and adrenal gland, bronchospasmolytic and vascular caused by respiratory diseases, retention of sodium and swelling.

Studies of inhibition of proliferation of smooth muscle cells comprises the camping smooth muscle cells, obtained from art rats or pigs with the help of technically Media Explant (see R. Ross. J. Cll. Biol. 50; page 172, 1971). Cells were cultivated in suitable cups containing, as a rule 96 of the recess, and cultured in medium 199 containing 7.5% of fetal calf serum, 7.5% newborn calf serum, 2 mm L-glutamine and 15 mm HEPES buffer, pH 7,4, in an atmosphere containing 5% CO2at a temperature of 37oC for 2 to 3 days. The cells are then synchronized by removing serum for 2 to 3 days and then cultured in the presence of angiotensin II, serum and other relevant factors. At the same time were added the compounds. After 16 to 20 hours was added 2 MX3H-thymidine and after a further 4 hours was determined by the inclusion of this substance in the cell DNA, precipitated by treatment with trichloroacetic acid. To determine the values for KT50(the concentration which provides 50% inhibition) was calculated concentration of tested compound, which when serial dilution of the compounds provides premaxillary the delay thymidine caused 10% fetal calf serum.

The results of the experiment are given in table. 1.

Connection examples o invention belong to the category of non-toxic substances.

New active substance can be transferred by known techniques in conventional drugs, such as, for example, tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable carriers or solvents. The active compound should be present in a therapeutically effective concentration, for example, at a concentration of about 0.5 to 90% by weight of the corresponding composition, i.e., in a quantity sufficient to provide the below mentioned dosage.

Medications get, for example, by mixing the active substances with solvents and/or carriers, if appropriate using emulsifiers and/or dispersing agents, whereby, for example, in the case of using water as a diluent, organic solvents can be used as auxiliary solvents.

Application carried out in the usual manner, preferably orally or parenterally, in particular creatice or intravenously.

In the case of parenteral use, you can use the solutions of the active substance with the use of suitable liquid carriers.

To achieve effective results, predpochtitelno about 0.01 - 0.5 mg/kg of body weight, and in case of oral application, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 0 mg/kg of body weight.

But if necessary it may be appropriate for application of active substances and other quantities, namely depending on the body weight or the type of applications, from individual behaviour to the medication, type of medication, time or period, when making his application. For example, in some cases it may be sufficient use of the active substance in a quantity smaller than the specified minimum amount, while in other cases the active substance should be used in an amount greater than a specified maximum number. In the case of applications more encouraged to distribute it to several daily doses.

The following examples illustrate how to obtain the original compounds.

Example 1. TRANS-6-(4-tolyl)-cyclohex-3-ene-1-carboxylic acid

the racemate

In a known manner (see Eur.J. Med. Chem. ll, 493 (1976)). 275 g (1,695 mol) 3-E-(4-tolyl) acrylic acid is subjected to interaction with 580 ml of 1,3-butadiene (number defined in condensed form) in 480 ml of toluene with the addition of 3 water with caustic soda. Then acidifying the aqueous phase of 1 m hydrochloric acid and extracted with diethyl ether. Ethereal solutions are dried over sodium sulfate, evaporated and again dissolved in toluene. After boiling for 15 minutes in the presence of 5 g of active carbon was filtered while hot and evaporated the solvent to about 120 - 160 ml; at 0 to 4oC distilled 124 g (573 mol) of the product. The filtrate is a little more concentrated and again cooled for further crystallization. By repeating this operation falls a total of 42 g (194 mmol) of the product.

Rf= 0,39 (a mixture of dichloromethane and methanol in the ratio 10:1).

Example II. TRANS-2-(4-tolyl)-cyclohexane-1-karanova acid

the racemate

155 g (717 mmol) of the compound from example I are dissolved in 1 l of methanol and treated with hydrogen to 10 g of palladium (10% on the animal angle) at a temperature of 20oC and a pressure of 1 bar. After 16 hours the catalyst is filtered off and the solvent evaporated in vacuum.

Output: 153 g (701 mmol).

Rf= 0,38 (a mixture of dichloromethane and methanol in the ratio 10:1).

Example III. Tert.butyl ether TRANS-2-(4-tolyl)-cyclohexane-1-carboxylic acid

the racemate

Method A. to 45.8 g (184 mmol) connect the ipacarai under reflux. After 2 hours the solvent is distilled off together with excess reagent, for which the crude acid chloride of the carboxylic acid, if necessary, must be mixed with toluene, and then distilled. Thus obtained product is dissolved in 500 ml of tetrahydrofuran, mixed with 24.8 g (221 mmol) of tert.the butyl potassium at 0oC and continue to stir for 20 hours at 20oC. Then added water and diethyl ether and extracted several times. The organic phase is dried over sodium sulfate, evaporated and the residue purified by chromatography on silicagel 60 (product of the company MCR, DE, eluent: mixture of petroleum ether and ethyl acetate in a ratio of 20:1).

Output: 39,6 g (130 mmol).

Rf= 0,47 (a mixture of petroleum ether and ethyl acetate in the ratio 10:1).

Method B. 20,0 g (of 91.6 mmol) of the compound from example II in 7 ml of concentrated sulfuric acid are suspended in 100 ml of diethyl ether and mixed at -30oC with 80 ml (713 mmol) isobutene in the autoclave. The mixture is heated in an autoclave to 20oC and the reaction is carried out for 20 hours. Then cooled again to -30oC, open the autoclave and stirring the reaction mixture is poured into a mixture of 300 ml of 3 m sodium alkali and 400 ml diethylam sodium and evaporated.

Output: 23.3 g (84,9 mmol).

Example IV. Tert.butyl ether TRANS-2-(4-bromomethylphenyl)-cyclohexane-1-carboxylic acid

the racemate

11,70 g (of 42.6 mmol) of the compound from example III are interacting with to 7.59 g (of 42.6 mmol) of N-bromosuccinimide and 1.4 g of azobisisobutyronitrile by boiling under reflux in 100 ml of carbon tetrachloride. After 4 hours the mixture is cooled, filtered loose succinimide and the filtrate evaporated.

Yield: 14.2 g (40,2 mmol).

Rf=0,48 (a mixture of petroleum ether and ethyl acetate in the ratio 10:1).

Example V. 4,6-dimethyl-2-hydrazino-pyridine

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37,0 g (260 mmol) of 2-chloro-4,6-dimethyl-pyridine (U.S. patent N 3632807) and 67 ml of hydrazine hydrate in 200 ml of diethylene glycol is refluxed for 15 hours. After cooling to room temperature, extracted with water and with a mixture of diethyl ether and dichloromethane, the organic phase is dried on sodium sulfate and evaporated. The crude product can be fed to further processing without pre-treatment.

Rf=0,18 (a mixture of dichloromethane and methanol in the ratio 10:1).

Example VI. 2,4-dimethyl-5,6,7,8-tetrahydro - carbolin

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1.08 g (7.7 mmol) of the compound of example V paramashiva the positive cleaning refluxed in 30 ml of diethylene glycol for 20 hours. When cooled to - 10oC precipitation, which is sucked off and washed with a small amount of cold methanol. After drying the substance in high vacuum over pjatiokisi phosphorus obtain 0.32 g (1.6 mmol) of the product.

Rf= 0,41 (a mixture of petroleum ether and ethyl acetate in the ratio 1:1).

Analogously to example VI receive the following connections:

Example VII

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Rf=0,31 (a mixture of petroleum ether and ethyl acetate in the ratio 1:1).

Example VIII

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Rf=0,35 (a mixture of petroleum ether and ethyl acetate in the ratio 1:1).

Example IX. TRANS-2-(4-tolyl)-cyclohexane-1-carbonitrile

the racemate

100.0 g (458,0 mmol) of the compound from example II in 1 l of dichloromethane is subjected to interaction from 84.3 g (595,5 g) chlorosulfonylisocyanate in 100 ml dichloromethane at boiling for hours. Then to the cooled reaction mixture was added dropwise 72 ml (938,9 mmol) N,N-dimethylformamide and stirred for 18 hours. Put in 350 g of ice, after the melting of the ice divide phase and extracted with dichloromethane. Dried potassium carbonate organic phases are evaporated and the residue is distilled. Get of 57.8 g (290,2 mmol) of the product.

So Kip.: 122 - 131oC (0.2 mbar).

Rf=ol) of the compound from example IX in 230 ml of anhydrous N,N-dimethylformamide is subjected to interaction 22.6 g (348 mmol) of sodium azide and 47.9 g (348 mmol) of the chloride of triethylamine boiling in a nitrogen atmosphere; later, 20 hours after cooling poured into diethyl ether and 1 m sulfuric acid and then extracted with 10% sodium lye. The aqueous phase is at 0oC adjusted to a pH of 1.5 with 1 m hydrochloric acid and the precipitation is filtered off, washed with water and dried in high vacuum over pjatiokisi phosphorus and sodium hydroxide.

Yield: 11.2 g (46.2 mmol).

Rf=0,23 (a mixture of dichloromethane and methanol in a ratio of 20:1).

Example XI. 5-[TRANS-2-(4-tolyl)-cyclohex-1-yl]-2-triphenylmethyl-tetrazol

the racemate

11,0 g (of 45.7 mmol) of the compound from example X is subjected to interaction with 13.4 g (48.2 mmol) of triphenylmethylchloride and EUR 7.57 ml (54,6 mmol) of triethylamine at 0oC in 170 ml of dichloromethane. Stirred for about 20 hours, the mixture is heated to room temperature. Extracted with diethyl ether and aqueous citric acid. The organic phase is dried over sodium sulfate and evaporated.

Output: 22.1 g (to 45.5 mmol).

Rf=0,67 (a mixture of petroleum ether and ethyl acetate in the ratio 5:1).

Example XII. 5-[TRANS-2-(4-bromomethylphenyl)-cyclohex-1-yl]-2-triphenylmethyl-tetrazol

the racemate

22.1 g (to 45.5 mmol) of the compound from example XI in 300 ml of carbon tetrachloride is subjected entries batch shall within 3 hours. Then cooled to room temperature and then to 0oC and the precipitate is filtered off. The filtrate is evaporated and get the crude product (26,2 g) that no further purification is subjected to further processing.

Rf=0,47 (a mixture of petroleum ether and ethyl acetate in the ratio 10:1).

The following examples illustrate how to obtain the desired product of formula I.

To determine the values of Rfuse the following solvents:

A = a mixture of petroleum ether and ethyl acetate in the ratio of 1:1.

B = a mixture of dichloromethane and methanol in the ratio of 50:1.

In = a mixture of petroleum ether and ethyl acetate in the ratio of 5:1.

G = dichloromethane.

D = mixture of petroleum ether and dichloromethane in the ratio of 3:1.

E = a mixture of dichloromethane and methanol in a ratio of 20:1.

W = a mixture of dichloromethane and methanol in the ratio of 10:1.

C = a mixture of dichloromethane and ethyl acetate in the ratio of 1:1.

And = a mixture of dichloromethane and ethyl acetate in the ratio of 2:1.

Th = a mixture of dichloromethane, methanol and conc. aqueous ammonia at a ratio of 200:20:1.

K = a mixture of petroleum ether and ethyl acetate in the ratio of 4:1.

L = a mixture of dichloromethane="ptx2">

N = a mixture of dichloromethane and methanol in the ratio of 7:1.

Example 1. Complex tert.butyl ether TRANS-2-{4-[2,4-dimethyl-5,6,7,8-tetrahydro--carboline-9-yl-methyl]phenyl}-cyclohexane-1-carboxylic acid

the racemate

1.98 g (9.9 mmol) of the compound of example VI in 70 ml of anhydrous dimethylformamide is subjected to interaction with 298 mg (9.9 mol) of sodium hydride (80%, stabilized by paraffin) at a temperature of 0oC. After the evolution of hydrogen mixed with 3.5 g (9.9 mmol) of the compound of example IV for 20 hours at 25oC. After adding water, extracted several times with diethyl ether, the combined organic phases are dried over sodium sulfate, evaporated and the residue purified by chromatography on silicagel 60 (Merck, DE, eluent: mixture of petroleum ether and ethyl acetate in a ratio of 20:1 to 10:1).

Output: 2,31 g (4.9 mmol).

Rf=0,49 (a mixture of petroleum ether and ethyl acetate in the ratio 10:1).

Analogously to example 1 are summarized in table. 2 connections:

Primer.TRANS-2-{4-[2,4-dimethyl-5,6,7,8-tetrahydro--carboline-9-yl-methyl]phenyl}-cyclohexane-1-carboxylic acid

the racemate

1.50 g (3.2 mmol) of the compound of example 14 in 10 ml of dioxane is subjected to interaction Ohm sodium carbonate adjusted to pH= 8. The precipitation is sucked off, washed with water and diethyl ether and after drying in high vacuum, purified by chromatography on silicagel 60 (Merck, DE, eluent: a mixture of dichloromethane and methanol in the ratio of 50:1).

Output: 0,44 g (1.1 mmol).

Rf=0,63 (a mixture of dichloromethane and methanol in the ratio 10:1).

Analogously to example 14 receive are shown in table. 3 connection:

Example 26. N - [4-tamilselvan] amide, TRANS-2-{4-[2,4-dimethyl-5,6,7,8-tetrahydro--carboline-9-yl-methyl]phenyl}-cyclohexane-1-carboxylic acid

the racemate

427 mg (1,03 mmol) of the compound of example 14 in 20 ml of anhydrous tetrahydrofuran is subjected to interaction with 622 μl (4,51 mmol) of triethylamine and 87,2 μl (1.13 mmol) of methylchloride at a temperature of 20oC. After 2 hours, add 500 mg (4.1 mmol) of 4-(N,N-dimethylamino)pyridine and 211 mg (1,23 mmol) of amide 4-toluenesulfonic acid and stirred for another 18 hours while warming to 20oC. the Mixture was poured into water and extracted several times with diethyl ether. The combined organic phases are dried over sodium sulfate, concentrated and purified by chromatography on silicagel 60 (Merck, DE, eluent: mixture of petroleum ether and ethyl acetate in the ratio of 2:1 to 1:1).

Output: 0,38 g (0S)-phenylglycinol)amide, TRANS-2-{4-[2,4-dimethyl-5,6,7,8-tetrahydro--carboline-9-yl-methyl] phenyl} -cyclohexane-1-carboxylic acid

*TRANS

427 mg (1,03 mmol) of the compound of example 14 in 20 ml of anhydrous tetrahydrofuran is subjected to interaction with 288 ml (2.10 mmol) of triethylamine and 87 μl (1.13 mmol) of methylchloride at a temperature of - 30oC. After 30 minutes, add 169 mg (1,23 mmol) of (S)-phenylglycinol and 126 mg (1,03 mmol) of 4-(N,N-dimethylamino)pyridine in 15 ml of anhydrous tetrahydrofuran and stirred for further 20 hours when heated to 20oC. Add water and repeatedly extracted with diethyl ether. The organic phase is dried over sodium sulfate and evaporated. Then the crude product is purified by chromatography on silicagel 60 (Merck, DE, eluent: mixture of petroleum ether and ethyl acetate in the ratio of 2:1 to 1:1).

Outputs:

110 mg (0.21 mmol) of diastereoisomer a (example 27); Rf=0,29 (A).

40 mg (0.07 mmol) of diastereoisomer B (example 28); Rf= 0,15(A).

Analogously to examples 27 and 28 receive are shown in table. 4 connections:

Example 54. 5-[TRANS-2-{4-[2,4-dimethyl-5,6,7,8-tetrahydro-- carboline-9-yl-methyl]phenyl}-cyclohex-1-yl]tetrazole

the racemate

0.12 g (0.2 mmol) of the compound of example 8 in 3 ml of tetrahydrofuran is subjected to interaction with 0.5 ml water and 0.5 ml triperoxonane acid for 2 hours at 20oC. Then add dietit to pH 3-4. The precipitation is sucked off, washed with water and dried in high vacuum over pjatiokisi phosphorus and sodium hydroxide.

Yield: 0.05 g (0.1 mmol).

Rf= 0,38 (a mixture of dichloromethane and methanol in a ratio of 20:1).

1. Derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of General formula I

< / BR>
where A and B together form a radical of the formula

< / BR>
< / BR>
D and E together form a radical of the formula

< / BR>
< / BR>
where R1, R2and R3the same or different and mean hydrogen, halogen, unbranched to branched alkyl with 1 to 8 carbon atoms;

L is hydrogen, halogen, an unbranched or branched alkyl with 1 to 6 carbon atoms;

T is a radical of the formula

-CO2R4-CO-NR5SO2R6< / BR>
< / BR>
where R4is hydrogen, unbranched or branched alkyl with 1 to 8 carbon atoms;

R5and R7- same or different and mean hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms;

R6is phenyl, unsubstituted or substituted non-branched alkyl with 1 to 6 carbon atoms;

R8aryl with 6 to 10 carbon atoms, unsubstituted or substituted one or twice adineta;

R9group of the formula-CH2-OH, -CO2R10, -CO-NR11R12where R10, R11and R12mean hydrogen or an unbranched or branched alkyl with 1 to 8 carbon atoms,

or T means tetrazolyl, unsubstituted or substituted by triphenylmethyl or unbranched or branched alkyl with 1 to 4 carbon atoms,

the mixture of isomers or individual isomers and their salts.

2. Derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of the formula I on p. 1, where A and B together denote a radical of the formula

< / BR>
< / BR>
D and E together denote a radical of the formula

< / BR>
< / BR>
< / BR>
where R1, R2and R3the same or different and mean hydrogen, fluorine, chlorine, bromine, unbranched or branched alkyl with 1 to 6 carbon atoms;

L is hydrogen, fluorine, chlorine, bromine, or unbranched or branched alkyl with 1 to 4 carbon atoms;

T is a radical of the formula

-CO2R4-CONR5SO2R6< / BR>
< / BR>
where R4is hydrogen, unbranched or branched alkyl with 1 to 6 carbon atoms;

R5and R7- same or different and mean hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms; is phenyl, unsubstituted or substituted unbranched or branched alkyl with 1 to 4 carbon atoms;

R9group of the formula CH2-OH, -CO2R10, -CO-NR11R12where R10, R11and R12mean hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms,

or T means tetrazolyl, unsubstituted or substituted stands or triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

3. Derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of the formula I on p. 1, where A and B together form a radical of the formula

< / BR>
< / BR>
D and E together form a radical of the formula

< / BR>
< / BR>
< / BR>
where R1, R2and R3the same or different and mean hydrogen, fluorine, chlorine, bromine, methyl;

L is hydrogen, fluorine, chlorine, bromine, methyl;

T is a radical of the formula

CO2R4-CONR5SO2R6< / BR>
< / BR>
where R4is hydrogen, unbranched or branched alkyl with 1 to 4 carbon atoms;

R5and R7- same or different and mean hydrogen or methyl;

R6is phenyl;

R8is phenyl, unsubstituted or substituted unbranched or branched alkyl with 1 to 3 atoms in the 1
and R12mean hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms,

or T means tetrazolyl, unsubstituted or substituted stands or triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

4. Derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of the formula I on p. 1, where A and B together denote a radical of the formula

< / BR>
< / BR>
D and E together denote a radical of the formula

< / BR>
< / BR>
< / BR>
where R1, R2and R3the same or different and mean hydrogen or methyl;

L is hydrogen;

T is a radical of the formula

CO2R4-CONR5SO2R6< / BR>
< / BR>
where R4is hydrogen or an unbranched or branched alkyl with 1 to 4 carbon atoms;

R5and R7- mean hydrogen;

R6- n-stoked;

R8is phenyl;

R9group of the formula-CH2OH,

or T and means tetrazolyl, unsubstituted or substituted by triphenylmethyl,

the mixture of isomers or individual isomers and their salts.

 

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