Imidazolidinedione derivatives of cyclohexane or their salts

 

(57) Abstract:

The object of the invention is imidazolidinedione derivatives of cyclohexane General formula (I)

< / BR>
where A is a linear or branched alkyl or alkenyl with 1 to 8 carbon atoms each, or cycloalkyl with 3 to 8 carbon atoms; B is hydrogen, halogen or perfluoroalkyl from 1 to 5 carbon atoms; D is a group of formula-CH2OR3or-CO-R4where R3is hydrogen or a linear or branched alkyl with 1 to 8 carbon atoms, R4is hydrogen, the hydroxy-group or a linear or branched alkoxy with 1 to 8 carbon atoms, R1is hydrogen, halogen, the nitro-group, triptorelin group, a linear or branched alkyl, alkoxy or alkoxycarbonyl with 1 to 6 carbon atoms each, cyano or carboxyl, R2- the rest of the formula-CO-R5, -CO-NR6R7or

< / BR>
where R5is hydroxyl or linear or branched alkoxy with 1 to 8 carbon atoms, R6is hydrogen, a linear or branched alkyl with 1 to 6 carbon atoms, R7- the rest of the formulas-SO2R9or

< / BR>
where R9- linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by phenyl or tailam, or phenyl, which mogilany or branched alkyl with 1 to 6 carbon atoms or protecting hydroxylgroups, R8is hydrogen, a linear or branched alkyl with 1 to 4 carbon atoms or triphenylmethyl group,

and their salts. Other objects of the invention are a method of obtaining compounds of formula (I) and their salts, containing the drug and the method of its production, as well as the parent compound and the method of their derivation. 1 C.p. f-crystals, 5 PL.

The invention relates to new chemical compounds with valuable properties, in particular to compounds of General formula (I)

< / BR>
where

A linear alkyl with 1 to 8 carbon atoms,

B - halogen,

D is a group of formula-CH2OH or-CO-R1where R1means hydrogen or a hydroxy-group,

R is a residue of formula-CO-R2, -CO-OTHER3or

< / BR>
where

R2means a hydroxyl or linear or branched alkoxy with 1 to 8 carbon atoms, and R3- the remainder of the formula-SO2R5or

< / BR>
where

R5means phenyl which may be substituted with halogen or linear alkyl with 1 to 6 carbon atoms,

R4is hydrogen or triphenylmethyl group, or their salts.

In General refers to salts with organic or inorganic bases is
Physiologically tolerated salts imidazolidinedione derivatives of cyclohexane can be a salt of the proposed compounds 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.

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 triatomines, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or Ethylenediamine.

In the framework of the present invention proposed connection can idealnogo image (enantiomers), or not in the form of 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 (E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

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

< / BR>
where

E - the usual removable group, for example, chlorine, bromine, iodine, tosylate or mesilate, preferably bromine,

R6- linear or branched alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part or group triphenylmethyl-tetrazolyl-1-Il,

subjected to interaction with the compound of General formula (III)

< / BR>
where

A, B and D have the above meaning,

in inert solvents, optionally in the presence of a base or in inert gas, to obtain compounds of General formula (IV)

< / BR>
where

A, B, D, and R6have the above meaning,

in the case of the acids (R = CO2H) omelet esters, and in the case of amides and sulfonamides derived from the corresponding carboxylic acids, lidiruyut after PR is above the value,

optionally, in the presence of a base and/or auxiliary means, for example photodamage means, in inert solvents, in the case of free tetrazolo, otscheplaut trityloxy group acids, preferably triperoxonane acid or hydrochloric acid in dioxane, and if necessary, introduce the substituents A, B, and D in the usual ways, for example, recovery, oxidation, alkylation or hydrolysis, or transferred to other groups, if necessary, separate the isomers and in the case of obtaining salts is treated with the corresponding bases or acids.

The described method can be explained by the scheme presented in the end of the text.

As a solvent in the implementation of the above method 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, a simple 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 ether acetic kentril, acetone or nitromethane. In addition, it is also possible to use mixtures of these solvents. Particularly preferably used dimethylformamide and tetrahydrofuran.

As grounds suitable known organic 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, methanolic or ethanolic or sodium or potassium tert.butyl potassium, or organic amines [trialkyl(C1-C6)amine], for example, 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, such as sodium hydrate. Preferred are sodium hydride, potassium carbonate, triethylamine, pyridine and tert.butyl potassium.

Usually the base is used in amounts of 0, is W ill result in temperatures from -30 to +100oC, preferably from -10 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 saponification of suitable conventional inorganic bases. To them, preferably belong hydroxide of 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, methanolic sodium, ethanolic sodium, methanolic potassium, ethanolate or potassium tert. butanolic potassium. Especially preferably using lithium hydroxide, sodium or grootes potassium.

As suitable solvents for the hydrolysis of water or commonly used for hydrolysis of organic solvents. To them, preferably belong alcohols, such as methanol, ethanol, propanol, isopropanol, butanol or tert.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 to t is given by acids, as, for example, triperoxonane acid, acetic acid, hydrochloric acid, a mixture of hydrochloric acid and dioxane, Hydrobromic acid, methanesulfonate, sulfuric acid or perchloric acid, preferably triperoxonane acid or hydrochloric acid in dioxane.

The hydrolysis is usually carried out at a temperature of 0 - 100oC, preferably at 20 to 80oC.

Typically, the hydrolysis is carried out at atmospheric pressure. However, it can also be carried out at reduced or elevated pressure (for example, at a pressure of 0.5 to 5 bar).

When carrying out the saponification of 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 reagents,

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 mineral acid, such as hydrochloric acid, Hydrobromic sour is appropriate were the acidification of alkaline saponification reaction mixture in the second stage without allocation of carboxylates. Then the acid can be distinguished by known techniques.

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 and sulfenamidovy can proceed, if necessary, through the stage of activation of the acid halides or mixed anhydrides, which can be obtained by reacting with thionyl chloride, trichloride phosphorus, pentachloride phosphorus, tribromide phosphorus, oxalylamino or methanesulfonamido.

The amidation and sulfenamidovy usually carried out at temperatures from -50 to +8-oC, preferably from -30 to +20oC and atmospheric pressure.

In addition to the above reason as the basis of a suitable preferably 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 amounts of 0.5 to 10 mol, preferably 1 to 5 mol, in terms of 1 mol of the compounds of General formula (IV).

As acid binding agent for the amidation can be used carbonates of alkaline or alkaline-earth is, as, for example, sodium hydroxide or potassium hydroxide, or organic bases, such as pyridine, triethylamine, N-methylpiperidine or a bicyclic amidine, as, for example, 1,5-diazabicyclo[3.4.0] -nonan-5 or 1,5-diazabicyclo[3.4.0]undecan-5. Preferably use triethylamine.

As the dehydration agent suitable carbodiimide, as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide, 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 chloranhydride methansulfonate, if necessary, in the presence of a base, such as, for example, triethylamine, N-ethylmorpholine, N-methylpiperidine, dicyclohexylcarbodiimide and N-oxysuccinimide (J. C. Sheehan, S. L. LEdis, J. Am. Chem. Soc. 95, 875 (1973); F. E. Frerman et al., J. Biol. Chem. 225, 507 (1982) and N. B. Benoton, K. Kluroda, Int. Pept. Prot. Res. 13, 403 (1979), 17, 187 (1981)).

Linking acid agents and agents of dehydration are usually used in amounts of 0.5 to 3 mol, preferably 1 indices A, B and D is usually known from the literature ways, and below explains the recovery of aldehydes or alkoxycarbonyl compounds to alcohols (a), oxidation of aldehydes to carboxylic acids (b) and alkylation (in):

a) Restoring alkoxycarbonyl compounds or aldehydes to the corresponding alcohols is usually carried out with hydrides, such as lithium aluminum hydride or sodium borohydride, preferably by alumaguard lithium, in an inert solvent, such as ethers, hydrocarbons or alcohols or their mixtures, preferably in environment, ethers, as for example diethyl ether, tetrahydrofurane or dioxane, or alcohols, such as ethanol, in the case of aldehydes, preferably with sodium borohydride in ethanol at a temperature of 0 to 150oC, preferably 20 - 100oC, at atmospheric pressure.

b) Oxidation of aldehydes to carboxylic acids is usually carried out in one of the abovementioned solvents, preferably tert.the butanol with potassium permanganate in the presence of sodium hydrogen phosphate and sodium sulfite at a temperature of from -30 to +20oC, preferably from -20 to +20oC and atmospheric pressure.

in) Alkyl is, for example, alkylhalogenide with 1 to 8 carbon atoms, esters of sulfonic acids, unsubstituted or substituted diallylsulfide with 1 to 6 carbon atoms or vallalat with 1 to 10 carbon atoms, preferably methyliodide, ester p-toluenesulfonic acid or dimethylsulfate.

Derivatives cylcohexane General formula (II) are new and can be obtained that compounds of General formula (VI)

< / BR>
first translated by hydrogenation with palladium on coal in one of the above solvents such as methanol, in an environment of hydrogen in compounds of General formula (VII)

,

and in the second stage, if R tetrazolyl, atrificial by conventional means, and if R = tetrazolyl, is subjected to the interaction with chlorosulfonylisocyanate in dichloromethane to obtain the corresponding cyanocobalamine, then enter tetrazolyl group using a mixture of sodium azide and triethylammonium in the presence of one of the abovementioned bases, preferably N,N-dimethylformamide in a nitrogen atmosphere, further interaction with triphenylmethylchloride in the presence of one of the abovementioned solvents and bases, preferably dichloromethane and triethylamine, enter triphenylmethyl group and then pravlenie double bond is carried out at a temperature of 0 - 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 the anhydrides of carboxylic acids, and subsequent interaction with the corresponding alcoholate at a temperature of 0 - 60oC, preferably at 10 - 35oC and atmospheric pressure.

Turning to cyanoacetylene and tetrazolyl compounds are usually at the boiling temperature of the solvent and atmospheric pressure.

Introduction triphenylmethyl group in tetrazole 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 at 60 - 90oC and atmospheric pressure.

As a catalyst for the synthesized suitable, for example, azobisisobutyronitrile, peroxide Dibenzoyl, preferably azobisisobutyronitrile, and the catalyst is used in amounts of 0.01 - 0.1 mol formulas are also new and can be obtained, for example, the fact that compounds of General formula (VIII)

,

where

R1has the above value,

subject interaction in one of the abovementioned solvents, preferably toluene, with 1,3-butadiene in the presence of hydroquinone at a temperature of 180 to 230oC, preferably at 200oC and a pressure of about 20 bar (Eur. J. Med. Chem. 11, 493 (1976)).

Compounds of General formula (VIII) are known or can be obtained by known methods (Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1977, S. 572).

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 (III) are known (EP N 324377, Beilstein 25, 163; 23, 45; U.S. Pat. USA N 4355040) or can be obtained by known methods.

Amines of General formula (V) are known or can be obtained in a known manner (Beilstein 11/104, R. C. Wichert, USP 32, 3 (1963); RICH 32, 1 (1969); Beilstein 4, 87).

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 communication angiotens the ina 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 respiratory diseases, retention of sodium and swelling.

Research delays induced by agonists reduce.

Females 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 aerated with Carbogen nutrient solution Krebs/Henselite having a temperature of 37oC, of the following composition: 119 mmol/l NaCl; 2.5 mmol/l dihydrate of chlormerodrin 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 the compilation of the curve and subsequent wash cycles (16 times for about 5 C/min above nutrient solution) conducted a 28-minute resting phase or incubation, for which, as a rule, the reduction was 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 high doses, beginning with the period of incubation. Each ring segment of the aorta was stimulated by the same agonist.

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

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

1-noradrenalin 310-9; 310-8; 310-7; 310-6g/ml

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

angiotensin II 310-9; 10-8; 310-8; 10-7g/ml

To determine CT50(concentration at which the analyzed compound causing 50% inhibition) proceeded from the effect obtained by the third 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 weakly inhibited in the presence of high concentrations. The results of the experiment are given in table. 1.

Definition antihypertensives of activity generalizirovanny hypertensive rats.

Oral antigipertenzivna the proposed activity of the compounds was investigated in generalizirovanny rats using surgically induced unilateral stenosis of the arteries of the kidneys. For this purpose, the right renal artery narrowed by using silver bracket width in the lumen of 0.18 mm In this type of hypertension renin activity in blood plasma increased during the first six weeks after the intervention. Arterial blood pressure of these animals Beskrovny is of high value. The compounds in the form of tylsnol suspension was given in different doses intragastrically (orally) with the appropriate probe. The proposed compounds were reduced arterial blood pressure hypertensive rats at clinically relevant doses.

In addition, depending on the concentration of the proposed compounds inhibited the specific communication radioactive angiotensin II.

The interaction 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 g),3H-angiotensin II (3 - 5 nm), buffer solution (50 mm Tristano radioactivity of the samples was separated using wet Steklovolokno filters, and 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 KT50(Ki: fixed used for radioactivity values KT50; KT50- the concentration at which the analyzed compound causing 50% inhibition of specific communication radioligand).

The results of the experiment are given 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 (R. Ross. J. Cell. Biol. 50, page 172, 1971). Cells were sown 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 Soroti and other relevant factors. At the same time were added the compounds. After 16 to 20 h was added 1 MK Ci3H-thymidine and after a further 4 h was determined by the integration 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 provides premaxillary the delay thymidine caused 1% fetal calf serum.

The results of the experiment are given 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 necessary PR is zbawiciela 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 carriers.

To achieve effective results in intravenous applications it is advisable to use the 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 applications more records definition Rf(thin layer chromatography) the following solvents:

A - dichloromethane : methanol = 5 : 1

B - dichloromethane : methanol = 3 : 1

In - dichloromethane : methanol = 20 : 1

Mr. dichloromethane : methanol = 10 : 1

D - petroleum ether : ethyl acetate - = 10 : 1

E - petroleum ether : ethyl acetate - = 5 : 1

W - petroleum ether : ethyl acetate - = 2 : 1

C - petroleum ether : ethyl acetate - = 1 : 1

And - dichloromethane : methanol = 50 : 1

The following examples illustrate how to obtain the original compounds.

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

.

The known method (Eur. J. Med. Chem. 11, 493, 1976) 275 g (1,695 mol) of 3-(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 addition of 3 g of hydroquinone for 22 h at about 200oC and 20 bar. The mixture is diluted with toluene and extracted with 0.5 m aqueous sodium lye. 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 min in the presence of 5 g of activated charcoal was filtered while hot and evaporated Rasi slightly thickened and again cooled for further crystallization. By repeating this operation falls a total of 42 g (194 mmol) of the product. Rf=0,39 (G).

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

.

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 h, the catalyst is filtered off and the solvent evaporated in high vacuum. Output: 153 g (701 mmol). Rf=0,38 (G).

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

.

Method A.

of 45.8 g (184 mmol) of the compound from example II are dissolved in 600 ml of toluene and subjected to interaction with a 49.5 ml (387 mmol) of oxalicacid while boiling under reflux. After 2 h 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. butanolate potassium at 0oC and continue to stir for 20 h at 20oC. Then added water and diethyl ether and l the th on silicagel 60 (product of the firm Merck, DE; eluent B). Output: 39,6 (130 mmol). Rf=0,47 (D).

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 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 of diethyl ether at 20oC. the Aqueous phase is extracted with diethyl ether, the organic solution is dried over sodium sulfate and evaporated. Output: 23.3 g (84,9 mmol).

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

< / BR>
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-brooklynite and 1.4 g of azobisisobutyronitrile by boiling under reflux in 100 ml of carbon tetrachloride. After 4 h the mixture is cooled, filtered loose succinimide and the filtrate evaporated. Yield: 14.2 g (40,2 mmol), Rf= 0,48 (D).

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

< / BR>
100.0 g (458,0 mmol) connection when the boiling for one hour (Organic Synthesis 50, 18 (1970)). Then to the cooled reaction mixture was added dropwise 72 ml (938,9 mmol) N, N-dimethylformamide and stirred for 18 hours then Poured onto 350 g of ice, after the melting of the ice divide phase and 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 VI. 5-[TRANS-2-(4-tolyl)-cyclohex-1-yl]tetrazole.

.

15,34 g (69,6 mmol) of the compound from example V 230 l of anhydrous formamide 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; after 20 h and 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 (B).

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

.

11,0 g (of 45.7 mmol) of the compound from example VI in 170 ml of dichloromethane is subjected to interaction with 13.4 g (48.2 mmol) of triphenylmethylchloride and EUR 7.57 g (54,6 mmol) of triethylamine at 0oC. Displacement is citric acid. The organic phase is dried with sodium sulfate and evaporated. Output: 22.1 g (to 45.5 mmol). Rf= 0,67 (E).

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

.

22.1 g (to 45.5 mmol) of the compound from example VII in 300 ml of dichloromethane 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 (D).

The following examples illustrate how to obtain imidazolylidene cyclohexane derivatives of the formula (I).

Example 1. Tert.butyl ether TRANS-2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]- cyclohexane-1-carboxylic acid.

.

8,16 g (43,7 mmol) of 2-butyl-4-chloro-5-formyl-imidazole (EP N 324377) is stirred in 10 ml of dimethylformamide from 1.32 g (43,7 mmol) of sodium hydride (80%, stabilized by paraffin) until the evolution of hydrogen at a temperature of about 0oC. Then was added dropwise a solution of 18.4 g (437 mmol) of the compound from example VI 100 ml DIMET the e phase is dried over sodium sulfate and evaporated. The resulting residue is purified by chromatography on silica gel 60 (Merck, solvent (D)). Output: 7,81 g (17,0 mmol), Rf= 0,67 (E).

Example 2. TRANS-2-[4-(2-butyl-4-chloro-5-formyl-imidazol - 1-yl-methyl)phenyl]-cyclohexane-1-carboxylic acid.

< / BR>
2.7 g (5.2 mmol) of the compound of example 1 is subjected to interaction in 40 ml of dioxane with 16 ml of concentrated hydrochloric acid. After the reaction for 18 h at 20oC is diluted with ether, mixed with 1 m aqueous sodium lye and extracted in a long funnel with shaking. The aqueous alkaline phase (pH 13 - 14) freed in vacuo from the organic solvent and establish pH 2 at 0oC using 2 M hydrochloric acid. The precipitation is filtered off, washed with water and dried in high vacuum over sodium hydroxide and pjatiokisi phosphorus. Yield: 2.0 g (5.0 mmol), Rf= 0,28 (B).

Analogously to example 2 will receive are shown in table.4 connections.

Example 5. N-(4-tamilselvan)amide, TRANS-2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]- cyclohexane-1-carboxylic acid.

.

0.7 g (1.5 mmol) of the compound from example 2 are subjected to interaction in 30 ml of tetrahydrofuran at -20oC to 0.127 ml of 1.65 mmol) harang the ol and 4-(N,N-dimethylamino)pyridine and 0.31 g (1.8 mmol) of 4-toluensulfonate and stirred for 24 h at 20oC. Then the reaction mixture was poured into 1 M hydrochloric acid and repeatedly extracted with ether. The organic phase is dried with sodium sulfate, evaporated and the resulting residue purified on silica gel 60 (Merck, solvent W). Output: 0,72 g (1.3 mmol), Rf= 0,72 (B).

Examples 6 and 7. (S)-phenylglycinol[1,2-TRANS]-2-[4-(2- butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)-phenyl]-cyclohexane-1 - carboxylic acid.

.

1,3 (2.8 mmol) of the compound from example 2 are subjected to interaction with -30oC in 30 ml of tetrahydrofuran with 0,78 ml (5.6 mmol) of triethylamine and 0,235 ml (3.1 mmol) of acid chloride of methansulfonate. After 30 min at -30oC was added dropwise a solution of 459 mg (3.3 mmol) of (S)-phenylglycinol and 0.34 g (2.8 mmol) of 4-(N, N-dimethylamino) pyridine in 10 ml of tetrahydrofuran and the mixture is stirred while heating to 20oC for 24 h then Poured into 1 M hydrochloric acid and extracted repeatedly with ether. The organic phase is dried with sodium sulfate, evaporated and the residue is separated by chromatography (silica gel 60, Merck).

Yield: 186 mg (0.36 mmol) of example 6 (diastereoisomer A); 591 mg example 6/7 (mixture of diastereomers A + B); 230 mg (0.44 mmol) of example 7 (diastereoisomer B); Rf= 0,32 (3) example 6; Rf= 0,17 (3) example 7.

Example 8. Tert. bout the P CLASS="ptx2">

.

1 g (1.9 mmol) of the compound of example 1 dissolved in 10 ml of ethanol and subjected to interact with the 20oC from 74.2 mg (2.0 mmol) boronate sodium. After 1 h, add water and extracted with ether. The organic phase is dried with sodium sulfate and evaporated. Yield: 0.97 g (of 1.85 mmol), Rf= 0,53 (3).

Analogously to example 8 receive are shown in table. 5 connection.

Example 12. Tert.butyl ether TRANS-2-[4-(2-butyl-4-chloro - 5-carboxy-imidazol-1-yl-methyl)phenyl]-cyclohexane-1-carboxylic acid.

.

11,0 g (1.9 mmol) of the compound from example 1 are dissolved in 9 ml of tert. butanol and subjected to interact with the 20oC from 7.7 ml of 1.25 m aqueous solution of sodium hydrogen phosphate and 11.5 ml of 1 m aqueous solution of potassium permanganate. After 10 min, stop the reaction by adding saturated aqueous solution of sodium sulfate, set pH 3,51 M hydrochloric acid and extracted with ethyl acetate. After removal of the solvent contribute in diethyl ether and extracted with 2 M aqueous sodium lye. The aqueous phase is freed in vacuo from the remnants of the solvent and at 0oC set pH 11 by the addition of hydrochloric acid, the precipitated precipitate is filtered off, washed with water and dried in high vacuum over CME is straccia alkali 81% of the original product.

Example 13. N-(4-trisulfonic)amide, TRANS-2-[4-(2 - butyl-4-chloro-5-carboxy-imidazol-1-yl-methyl)phenyl]-cyclohexane - 1-carboxylic acid

.

Analogously to example 12 to obtain the target compound. Rf= 0,11 (B).

Example 14. 5-[TRANS-2-(4-{2-butyl-4-chloro-5-formyl-imidazol-1 - yl-methyl} -phenyl]-cyclohex-1-yl]-2-triphenylmethyl-tetrazol.

Analogously to example 1 get the target connection

.

Rf= 0,72 (W).

Example 15. 5[TRANS-2-(4{2-butyl-4-chloro-5-hydroxymethyl - imidazol-1-yl-methyl}phenyl)-cyclohex-1-yl]-2-triphenylmethyl - tetrazol.

Analogously to example 8 get the target connection

.

Rf= 0,23 (W).

Example 16. 5-{ TRANS-2[4-(2-butyl-4-chloro-5-formyl-imidazol - 1-yl-methyl)-phenyl]-cyclohex-1-yl}-tetrazol.

.

0.2 g (0.3 mmol) of the compound from example 14 is subjected to interaction in 2 ml of tetrahydrofuran with 1 ml water and 1 ml triperoxonane acid. After 2 h at room temperature then poured into a mixture of diethyl ether with water and set to pH 13 by addition of 10% sodium lye. The aqueous phase is acidified at 0oC 1 M hydrochloric acid to pH 2, in this fall product. Filtered off and dried in high vacuum over pjatiokisi is[2-butyl-4-chloro-5-hydroxymethyl - imidazol-1-yl-methyl)phenyl]-cyclohex-1-yl}-tetrazol.

Analogously to example 16 receive the target connection

.

Rf= 0,41 (G).

1. Imidazolidinedione derivatives of cyclohexane General formula I

< / BR>
where a is linear WITH1- C8-alkyl;

In - halogen; D is a group of formula-CH2HE or-CO - R1where R1is hydrogen or a hydroxy-group;

R is a residue of formula-CO - R2- - OTHER3or

< / BR>
where R2is hydroxyl or linear or branched C1- C8-alkoxyl;

R3- residue formula

- SO2R5< / BR>
or

< / BR>
where R5is phenyl which may be substituted with halogen or linear C1- C6-alkyl;

R4is hydrogen or triphenylmethyl group,

or their salts.

2. Imidazolidinedione derivatives of cyclohexane under item 1 and their salts, possessing antagonistic against angiotensin - II and inhibiting the proliferation of smooth muscle cell activity.

 

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FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

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EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

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EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

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

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

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2 ex, 7 tbl

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