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

 

(57) Abstract:

The object of the invention are derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid of General formula (I), And which is unsubstituted phenyl, unbranched or branched alkyl, each with 1 to 8 carbon atoms, or cycloalkyl with 3 to 8 carbon atoms; and D together form a radical of the formula a, b or C, where R2and R3denotes unbranched or branched alkyl, each with 1 to 8 carbon atoms, or halogen, R2and R3the same or different; T - tetrazolyl, unsubstituted or substituted by trifluoromethyl, or a radical of the formula-CO2R4, -CO-NR5SO2R6or-CONR7-CHR8R9where R4is hydrogen, unbranched or branched alkyl, each with 1 to 8 carbon atoms; R5and R7identical and denote hydrogen; R6is phenyl, substituted non-branched alkyl with 1 to 6 carbon atoms; R8is phenyl, unsubstituted or once substituted by halogen; R9is a group of formula-CH2-OH, -CO-NH2or pyridyl; mixtures of their isomers or individual isomers and their salts, which possess biological activity, in particular an antagonistic effect in relation to AVI, possessing valuable pharmacological properties, in particular derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid.

Known derivatives substituted heterocycle phenyl-cyclohexane-carboxylic acid, which possess biological activity, in particular, are antagonistic against angiotensin II action (see application EP 0 407 102).

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 by a heterocycle phenylcyclohexane-carboxylic acid of General formula

< / BR>
where A is unsubstituted phenyl, unbranched or branched alkyl, each with 1 to 8 carbon atoms, or cycloalkyl with 3 to 8 carbon atoms,

B and D together form a radical of the formula

< / BR>
where R2and R3denote unbranched or branched alkyl, each with 1 to 8 carbon atoms, or halogen, R2and R3the same or different,

T is a radical of the formula

-CO2R4, -CO-NR5SO2R
R5and R7identical and denote hydrogen,

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

R8is phenyl, unsubstituted or once substituted by halogen,

R9is a group of formula-CH2-OH, -CO-NH2or pyridyl, or tetrazolyl, unsubstituted or substituted by triphenylmethyl,

mixtures of their isomers or individual isomers and their salts.

In the framework of the present invention prefer physiologically tolerated salts. Physiologically tolerated salts of the new substituted heterocycle phenyl-cyclohexanecarboxylic acids and their derivatives 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, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Tiziani, 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, with connections available or as image and mirror image (enantiomers) or are not as image and mirror image (diastereomers). The invention relates both to the enantiomers and diastereomers and their respective mixtures. As the racemic forms and the diastereomers can be divided by the known techniques for pure stereoisomeric forms (see E. L. Eliel, Stereochemistry of Carbon Compounds, ed. McGraw Hill, 1962). Preferred are compounds of General formula (I), where A is unsubstituted phenyl, unbranched or branched alkyl, each with 1 to 4 carbon atoms, or cyclopropyl;

E is a nitrogen atom;

B and D together denote a radical of the formula

< / BR>
where R2and R3means methyl, fluorine, chlorine rotorod or unbranched or branched alkyl, each with 1 to 4 carbon atoms;

R5and R7identical and denote hydrogen;

R6- p-tolyl;

R8is phenyl, unsubstituted or substituted by fluorine or chlorine;

R9has specified in paragraph (1 value, or tetrazol, unsubstituted or substituted by triphenylmethyl,

mixtures of their isomers or individual isomers and their salts.

The new compounds of the above General formula (I), in particular, exhibit blood pressure lowering and anti-atherosclerotic actions.

The new compounds of General formula (I) can, for example, to obtain due to the fact that compounds of General formula

< / BR>
where W is a typical removable group, for example 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

< / BR>
where A, B and D 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

< / BR>
where A, B, D and X have the abovementioned meanings, if necessary after prior hydrolysis and/or Akti is P>7, R8and R9have the abovementioned meaning, in inert solvents, if appropriate in the presence of a base and/or auxiliary agent, such as agent dehydration and in the case of free 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 scheme shown in the end of the description.

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, 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 an ester of acetic acid, triethylamine, pyridine, dimatia, you can also use a mixture of these solvents. Particularly preferable to use dimethyl formamide and tetrahydrofuran.

As grounds for the above-described method is suitable known organic and inorganic bases. It is preferable to use the alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide of the alkaline earth metals, such as barium hydroxide, carbonates of alkali metals, for example 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 methanolate or ethanolate or sodium or potassium tert.butyl potassium, or organic amines (trialkyl(C1- C6)amines) such as triethylamine, or heterocycles such as 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 such as sodium, or their hydrides, for example 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.

The above method is usually carried out at a temperature of from -80oC to +100oC, preferably from -30oC to +60oC, and at atmospheric pressure. However, the method can also be carried out at elevated or reduced pressure (e.g. from 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 methanolate sodium, ethanolate sodium, methanolate potassium, ethanolate or potassium tert.butanolic potassium. Especially preferably using lithium hydroxide, sodium or potassium hydroxide.

As solvents suitable for the implementation of the hydrolysis water or commonly used for hydrolysis of organic solvents. To them, preferably belong alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, or ethers, for example tetrahydrofuran or dioxane, or dimethylformamide, or dimethylsulfoxide. Especially predpoletnoy mixture of the mentioned solvents.

The hydrolysis can also be aqueous acids, for example water triperoxonane acid, aqueous acetic acid, aqueous hydrochloric acid, aqueous Hydrobromic acid, 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, for example hydrochloric acid, Hydrobromic acid,EcoObraz was the acidification of alkaline saponification reaction mixture in the second stage without allocation of carboxylates. Then the acid can be distinguished by known techniques. In the case of basic heterocycles by processing solutions carboxylates of the above acids can also be obtained salts heterocyclic compounds with inorganic acids.

The amidation and sulfenamidovy 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, which can be obtained from the corresponding acids by reacting with thionyl chloride, trichloride phosphorus, pentachloride phosphorus, tribromide phosphorus or oxalylamino.

The amidation and sulfenamidovy usually carried out at temperatures from -20oC to +80oC, preferably from -10oC to +30oC and atmospheric pressure.

In addition to the above grounds, 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 to soedinenii carbonates of alkaline or alkaline earth metals, for example sodium carbonate, potassium carbonate, hydroxides of alkaline or alkaline earth metals such as sodium hydroxide or potassium hydroxide, or organic bases, for example pyridine, triethylamine, N-methylpiperidine, or a bicyclic amidine, 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, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, N-oxysuccinimide, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, carbonyl compounds, such as 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.

Bania General formula

< / BR>
first, by hydrogenation with hydrogen in the presence of palladium on coal in one of the above solvents, for example methanol, transferred to compounds of General formula

< / BR>
and in the second stage, if T = tetrazolyl, atrificial by conventional means, and if T = tetrazolyl, is subjected to the 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 carried out at a temperature of from 0oC to +40oC, preferably at +20oC and pressure 1 - 10 bar, preferably 1 to 3 bar.

The etherification is carried out in one of the abovementioned solvents, preferably toluene, and occhialino via the acid chloride, and subsequent interaction with the corresponding alcoholate at a temperature of 0oC - +60oC, preferably at 10oC - 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 the environment of one of the abovementioned solvents, preferably carbon tetrachloride, at a temperature of 40oC - 100oC, preferably 60oC - 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 mol to 0.1 mol, preferably 0.01 mol to 0.05 mol, calculated per 1 mol of the compounds of General formula (VII).

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

< / BR>
subjected to interaction with 1,3-butadiene in one - 230oC, preferably at 200oC and a pressure of approximately 20 bar.

Compounds of General formula (III), (V) and (VIII) are known or can be obtained by known methods.

Compounds of General formula (IV) and (VII) are new 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 arteriosclerosis. 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, bronhospasticescoe and vascular caused by diseases of the respiratory way is amok and male rabbits were killed by a blow to the head and bled, in some cases, narcotically with Nembutal (60 - 80 mg/kg intravenously) and was slaughtered by opening the thorax. The thoracic aorta was removed, the adjacent connective tissue was removed, the aorta was divided into ring sections with a width of 1.5 mm, each of which when the initial loading of about 3.5 g was applied to a 10 ml bath containing a temperature of 37oC aerated with Carbogen nutrient solution Krebs/Henselite of the following composition: 119 mmol/l NaCl; 2.5 mmol/l dihydrate calcium chloride; 1.2 mmol/l dihydrogenphosphate potassium; 10 mmol/l glucose; 4.8 mmol/l of KCl; 1.4 mmol/l semihydrate magnesium sulfate and 25 mmol/l of sodium bicarbonate.

Reduction was determined isometrically using cell brand statistics of the main character US through bridge amplifiers, the signals were converted into digital values using an analog-to-digital Converter and evaluated. Curves for doses of the agonist and the action was every hour. In this case, each curve was based on 3 - 4 separate concentrations of the compounds, which were introduced into the bath at intervals of 4 minutes. After making the curve and subsequent wash cycles (16 times for about 5 sec/min above is again reached its original value.

Every third curve was used as reference value for the evaluation of each investigated in further experiments the connection that in the preparation of further curves were presented in tubs in increasing doses, starting with the incubation period. Each ring segment of the aorta was stimulated by the same agonist.

Agonists and their standard concentrations (volume applications on a separate cottage = 100 ál)

KCl - 22,7; 32,7; 42,7; and 52.7 mmol/l

1-Norepinephrine - 3 10-9; 3 10-8; 3 10-7; 3 10-6g/ml

Serotonin - 10-8; 10-7; 10-6; 10-5g/ml

B-HT 920 - 10-7; 10-6; 10-5g/ml

Methoxamine - 10-7; 10-6; 10-5g/ml

Angiotensin II - 3 10-9; 10-8; 3 10-8; 10-7g/ml

To determine CT50(concentration at which the analyzed compound causing 50% inhibition) proceeded from the effect obtained when the 3rd submaximal concentrations of agonist.

The proposed compounds inhibit depending on the dose induced by angiotensin II contraction of the isolated rabbit aorta. Induced by potassium depolarization or other agonists reduction generally is not inhibited or only SL the operation of the proposed connection with the angiotensin II receptor on the membrane fractions of the adrenal cortex (bovine)

Fresh bark of adrenal cattle were thoroughly cleaned from the brain substance and a shell, then of 0.32 M sucrose solution using a stirrer-type Ultra-Turrax (Janke und Kunkel, ,Staufen, DE) were crushed to a large membrane homogenate, which at two stages of centrifugation was purified by obtaining membrane fractions. Studies to determine the receptor binding was carried out on partially purified membrane fractions using radioactive angiotensin II. Analyze the environment volume of 0.25 ml contained partially purified membranes (50 - 80 µg),3H-angiotensin II (3 - 5 nm), buffer solution (50 mm Tris, pH of 7.2), 5 mm MgCl2and the compounds. After 60-minute incubation at room temperature, unbound radioactivity of the samples was separated using a wet glass fiber filters, and the associated radioactivity was determined spectrophotometrically in the scintillation medium after washing the protein a cold buffer solution (50 mm Tris/HCl, pH 7,4, 5% polyethylene glycol with a molecular weight of 6000). The data were processed using computer programs to obtain values of Kior CT50(Ki: fixed for used radioactivities specific communication radioligand). The experimental results are summarized in table 2.

Studies of inhibition of proliferation of smooth muscle cells offer connections

To determine antiproliferative action of the compounds used smooth muscle cells derived from art rats or pigs with the help of technically Media Explant (see R. Ross. J. Cell. 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 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 1 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 KT50expected concentration of tested compound that with successive breeding islamonline serum.

The results of the experiment are summarized in table 3.

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 crazyace or intravenously.

In the case of parenteral use, you can use the solutions of the active substance with the use of suitable liquid nositelal active substance in an amount of about 0.001 to 1 mg/kg, preferably 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 10 mg/kg 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 application of a larger amount, it is recommended to divide it into multiple daily doses.

The following examples illustrate how to obtain the original compounds to obtain new derivatives substituted by a heterocycle phenylcyclohexane-carboxylic acid of the formula (I)

Example 1

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

< / BR>
In a known manner (see Eur. J. Med. Chem. 11, 493 (1976)) 275 g (1,695 mol) 3-(4-tolyl)acrylic acid is subjected to interaction is Kinana for 22 hours at about 200oC and 20 bar. The mixture is diluted with toluene and extracted with 0.5 M aqueous sodium alkali. 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 2

TRANS-2-(4-tolyl)-cyclohexane-1-carboxylic acid

< / BR>
155 g (717 mmol) of the compound from example 1 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 3

Tert.butyl ether TRANS-2-(4-tolyl)-cyclohexane-1-carrierroute interaction from 49.5 ml (387 mmol) of oxalicacid while boiling 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 firm Merck, 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 2 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 a closed autoclave 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 sodium sulfate and evaporated.

Output: 23.3 g (84,9 mmol)

Example 4

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

< / BR>
11,70 g (of 42.6 mmol) of the compound from example 3 are subjected to interaction 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 5

6-Cyclopropyl-imidazo[2,3-b]pyridine

< / BR>
of 3.27 g (30 mmol) of 2,3-diaminopyridine and of 2.72 g (30 mmol) cyclopropanecarbonyl acid is stirred with 30 ml tolylphosphino acid at a temperature of 120oC for 3 hours. The reaction mixture is poured into ice water, adjusted with sodium hydroxide to pH = 6 - 7 and sodium carbonate adjusted to pH 8 - 9. After repeated extraction of the complex ethyl ester, acetic acid combined organic phases are dried over sodium sulfate, filtered and evaporated at the final stage in a high vacuum. After chromatographic processing of the crude product (silica gel grade 60, the firm Merck, DE, eluent: dichloromethane and sosmetal in the ratio 10 : 1).

Example 6

TRANS-2-(4-tolyl)-cyclohexane-1-carbonitrile

< / BR>
100.0 g (458,0 mmol) of the compound from example 2 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= 0,81 (dichloromethane)

Example 7

5-[TRANS-2-(4-tolyl)-cyclohex-1-yl]tetrazole

< / BR>
15,34 g (69,6 mmol) of the compound from example 6 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 under 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 pH = 1.5 with 1 M hydrochloric acid and the precipitation is filtered off, washed with water and dried in high vacuum over pationately in a ratio of 20 : 1).

Example 8

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

< / BR>
11,0 g (of 45.7 mmol) of the compound from example 7 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 with 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 9

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

< / BR>
22.1 g (to 45.5 mmol) of the compound from example 8 in 300 ml of carbon tetrachloride is subjected to interaction from 8.1 g (to 45.5 mmol) of N-bromosuccinimide and 0.3 g of azobisisobutyronitrile boiling under reflux for 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 PoA-[6-cyclopropyl-imidazo[2,3-b]-pyridine)-7-yl-methyl]-phenyl}-cyclohexane-2-carboxylic acid

< / BR>
0,90 g (5.7 mmol) of the compound of example 5 in 15 ml of dimethylformamide is subjected to interaction with 0.17 g (5.7 mol) of sodium hydride (80%, stabilized by paraffin) at a temperature of 0oC. After hydrogen evolution is additionally stirred for 20 minutes and then add drops at a temperature of 0oWith 2.00 g (5.7 mmol) of the compound of example 4 in 20 ml of dimethylformamide. When heated to a temperature of 20oWith advanced stirred for 20 hours and then after adding water, extracted several times with diethyl ether. The organic phase is dried with sodium sulfate, evaporated and the residue purified by chromatography on silicagel 60 (firm Mepk, DE, eluent: mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 1 : 1).

Yield: 0.4 g (0.9 mmol).

Rf= 0,60 (a mixture of petroleum ether and ethyl acetate in the ratio 1 : 2).

Analogously to example 10 receive summarized in table 4 for the connection.

In table 4 the following notation:

A = a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 4 : 1

B = a mixture of petroleum ether and complex ethyl ester of acetic acid in autosenses dichloromethane and methanol in the ratio of 10 : 1

Example 19

TRANS-2-{4-[6-cyclopropyl-imidazo[2,3-b]-pyridine)-7-yl-methyl]-phenyl}-cyclohexane-1-carboxylic acid

< / BR>
0.39 g (0.9 mmol) of the compound of example 10 in 10 ml of dioxane is subjected to interaction with 10 ml of concentrated hydrochloric acid at a temperature of 20oC. after 18 hours, adjusted to pH = 13 2 M sodium lye and 1 time shake diethyl ether. After phase separation from aqueous solution is removed in vacuum residues of solvent and at a temperature of 0oWith the lead up to pH = 5 with concentrated hydrochloric acid. Dropped when this precipitate is sucked off, washed with water and dried in high vacuum over sodium hydroxide and pjatiokisi phosphorus.

Yield: 0.28 g (0.7 mmol)

Rf= 0,08 (a mixture of dichloromethane and methanol in the ratio 10 : 1).

Analogously to example 19 receive summarized in table 5 compounds

Examples 25 and 26

N[(S)-phenylglycinol] amide, TRANS-2-{4-[6-cyclopropyl-imidazo[2,3-b]-pyridine)-7-yl-methyl]-phenyl}-cyclohexane-1-carboxylic acid

< / BR>
0.12 g (0.32 mmol) of the compound of example 19 in 4 ml of tetrahydrofuran is subjected to interaction with 89,6 ml (6.5 mmol) of triethylamine and 26.6 μl (0.35 mmol) of the acid chloride of methansulfonate at a temperature of -30oC. after 30 minutes, and additionally stirred for 19 hours at temperatures of 20oC. Then the mixture is poured into aqueous sodium bicarbonate solution and repeatedly extracted with diethyl ether. The ether extracts are dried over sodium sulfate, evaporated and the residue purified by chromatography on silicagel 60 (firm Mepk, DE, eluent: a mixture of dichloromethane and methanol in the ratio of 50 : 1).

Output:

60 mg (0.12 mmol)/Rf= 0,63 (a) diastereoisomer a (example 25)

40 mg (0.08 mmol)/Rf= 0,59 (a) diastereoisomer B (example 26).

Analogously to examples 25 and 26 receive summarized in table 6 for the connection.

Example 45

N-(4-tamilselvan)amide, TRANS-2-{4-[6-cyclopropyl-imidazo[2,3-b]-pyridine)-7-yl-methyl]-phenyl}-cyclohexane-1-carboxylic acid

< / BR>
120 mg (0.32 mmol) of the compound of example 19 in 4 ml of tetrahydrofuran is subjected to interaction from 26.6 μl (0.35 mmol) of the acid chloride of methansulfonate and 194 μl (1.4 mmol) of triethylamine at -20oC. after two hours the reaction mixture is added to 66.0 mg (0,39 mmol) of amide 4-toluenesulfonic acid and 155 mg (1.28 mmol) of 4-(N,N-dimethylamino)pyridine and additionally stirred for 20 hours. Poured on an aqueous solution of sodium bicarbonate and extracted with diethyl ether. Then the organic phase is dried over sodium sulfate and evaporated is in the ratio of 50 : 1) to obtain 34 mg (0.06 mmol) of the product.

Rf= 0,45 (a mixture of petroleum ether and ethyl acetate in the ratio 1 : 8).

Example 46

5-[TRANS-2-(2-cyclopropyl-imidazo[2,3-b]pyridine-1-yl]tetrazole

< / BR>
0.64 g (1.0 mmol) of the compound of example 9 is subjected to interaction with 3 ml water and 3 ml triperoxonane acid in 7 ml of tetrahydrofuran at a temperature of 20oC. after two hours, diluted with diethyl ether and extracted with aqueous sodium lye (pH = 13). The alkaline aqueous phase is brought to pH = 4.5 1 M hydrochloric acid and the resulting precipitate is sucked off, washed with water and dried in high vacuum over sodium hydroxide and pjatiokisi phosphorus.

Yield: 0.27 g (0.7 mmol).

Rf= 0,35 (a mixture of dichloromethane and methanol in the ratio 10 : 1).

Analogously to example 46 can be obtained are summarized in table 7 compounds.

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

< / BR>
where A is unsubstituted phenyl, unbranched or branched alkyl, each with 1 to 8 carbon atoms, or cycloalkyl with 3 to 8 carbon atoms;

B and D together form a radical of the formula

< / BR>
where R2and R3denote unbranched or branched alkyl, each with 1 - 8 atomapiR4, -CO-NR5S O2R6or

< / BR>
where R4is hydrogen, unbranched or branched alkyl, each with 1 to 8 carbon atoms; R5and R7- identical and denote hydrogen; R6is phenyl, substituted non-branched alkyl with 1 to 6 carbon atoms; R8is phenyl, unsubstituted or odnoklassnitsy halogen; R9is a group of formula-CH2-OH, -CO-NH2or pyridyl, or tetrazolyl, unsubstituted or substituted by triphenylmethyl, mixtures of their isomers or individual isomers and their salts.

2. Derivatives substituted heterocycle phenyl-cyclohexanecarbonitrile acid of the formula (I) under item 1, where A is unsubstituted phenyl, unbranched or branched alkyl, each with 1 to 4 carbon atoms, or cyclopropyl; B and D together denote a radical of the formula

< / BR>
where R2and R3means methyl, fluorine, chlorine or bromine, R2and R3the same or different;

T is a radical of the formula

-CO2R4, -CO-NR5SO2R6or

< / BR>
where R4is hydrogen or an unbranched or branched alkyl, each with 1 to 4 carbon atoms;

R5and R7identical and denote hydrogen,

R6- p-tolyl;

R8is phenyl, unsubstituted or is th or substituted by triphenylmethyl, mixtures of their isomers or individual isomers and their salts.

 

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The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

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The invention relates to a new retailexe-carbolin-derivatives and to methods for their preparation

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The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

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R7a hydrogen atom or alkyl with 1-6 carbon atoms,

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R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to derivatives of 4,5,6,7-tetrahydroimidazo General formula I or their salts, which are useful as drugs:

RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;

R4, R5, R6represent a hydrogen atom or a lower alkyl group;

X represents an oxygen atom or a sulfur atom

The invention relates to new chemical compounds in a series of benzimidazole, namely periodical benzimidazole General formula 1

where R is H, CH3; R1= CH3H

provided that 1A R - H, R1- H (N 65 in the work log); 1B, R = CH3, R1= H (N 66 in the work log); 1B, R = CH3, R1= CH3(N 71 in the work log);

possessing antibacterial action

The invention relates to a new method for obtaining compounds of formula 1

,

where

R can be lower alkyl,

R1is hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkyl (lower) alkyl, lower bicycloalkyl, aryl or aryl(lower) alkyl;

R2is lower alkyl, lower cycloalkyl, lower cycloalkyl (lower) alkyl, lower bicycloalkyl, aryl or aryl (lower) alkyl; or

R1and R2taken together with the nitrogen atom to which they are attached, form a group, 3,4-dihydro-2(1H)-isoquinoline;

X is lower alkyl, lower alkoxy, halogen or trifluoromethyl;

m=0,1 or 2,

which includes

a) implementation of the interaction of the compounds of formula II

,

where

R, X and m have the above significance, and R3is lower alkyl, with aluminofluoride, and then with a wine acid to obtain the compounds of formula III

,

where

R, X and m have the previously indicated meanings,

C) contacting the reaction mixture containing aetsa hydrogen, or (2) with the compound of the formula IV

,

where

R4is hydrogen or lower alkyl in the presence of a carboxylic acid of formula R5COOH, where R5is lower alkyl, to obtain the compounds of formula V

,

where

R, R4, X and m have the previously indicated meanings;

contacting the reaction mixture containing the compound of formula V obtained at the stage of /b/ with a compound of formula R1R2NH, where R1and R2have these values, and the allocation of the product of formula I

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

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