Esters of cyclohexanol containing pharmaceutical preparation

 

(57) Abstract:

Describes the new esters of cyclohexanol of formula I, where the values of X, Y, Z, R1- R6specified in paragraph 1 of the formula. Compounds pharmacologically effective and can therefore be used as medicines, in particular for the treatment of diabetes and other diseases that are characterized by increased secretion of glucose by the liver or increased activity of glucose-6-phosphatase system. 2 S. and 4 C.p. f-crystals.

The clinical picture of diabetes is characterized by elevated blood sugar. The reason caused by lack of insulin diabetes, or type 1 diabetes, is the death of producing insulin - cells of the pancreas; therefore, treatment is carried out by injection of insulin (hormone replacement therapy). Non-insulin-dependent diabetes, or type II diabetes, in contrast, is characterized by a decreased effect of insulin on muscle and adipose tissue (insulin resistance) and increased production of glucose by the liver. The cause of these metabolic disorders is still unclear. When conventional treatment with sulfonylureas compensate for insulin resistance by increasing the body's own insulin secretion, otbelivanie; many type II diabetics, due to "exhaustion" - cells become insulin dependent and suffer later emerging diseases such as cataract, nephropathy and angiopathy.

Due to this desirable new approaches to the treatment of type II diabetes.

The concentration of blood glucose in the fasting state is determined by the production of glucose by the liver. It was shown that in the case of type II diabetes increase the sugar content in the blood correlate with proportionally increased allocation of glucose from the liver. Secreted by the liver in blood glucose can be formed as due to the destruction of liver glycogen (glycogenolysis), and by gluconeogenesis.

Glucose-6-phosphate represents the end product of gluconeogenesis and glycogenolysis. The final stage of selection the liver glucose from glucose-6-phosphate is catalyzed by glucose-6-phosphatase (EC 3.1.3.9). Glucose-6-phosphatase is a located in the endoplasmic grid (ER) mnogovershinny complex. This enzyme complex consists of in ER-mebrana glucose-6-phosphotransferase localized on luminale side of the endoplasmic grid glucose-6-phosphatase and phosphate-translocases (CM.:Ashmore J. and G. Weber,"The Role of dell I. D.,"The molecular basis of the hepatic microsoma glucose-6-phosphatase system, "Biochem. Biophys. Asta 1092, 129-137 (1990)). The existing extensive literature shows that under all investigated conditions, which in animal experiments lead to increased content of sugar in the blood, for example, in the case of streptozotocin, alloxan, cortisol, thyroid hormones and fasting, the activity of this mnogovershinnoe complex also increased. It is shown that observed in the case of type II diabetics increased production of glucose is associated with increased activity of glucose-6-phosphatase.

The importance of glucose-6-phosphatase system for normal glucose homeostasis, emphasizes hypoglycemic symptoms in patients with disease type 16 associated with the accumulation of glycogen, there is no translocase component of glucose-6-phosphatester.

The decreased activity of glucose-6-phosphatase by researching suitable biologically active substances (inhibitors) should lead to reduced secretion of glucose by the liver. These biologically active substances must ensure the production of glucose by the liver for effective peripheral consumption. Due to this, in the state of fasting in diabetics of type II reduced the concentration of glucose in the blood, moreover, the literature describes a number of nonspecific inhibitors of glucose-6-phosphatase, for example, phlorizin [(Soodsma J. Legler Century nHerdlie R. C., J. Biol. Chem. 242, 1955-1960 (1967)] ; 5,5'-dithio-bis-2-nitro-benzoic acid [(Wallin C. K., and Arion, W. J., Biochem. Biophys., Res.Commun., 48, 694-699 (1972)] ; 2,2'-di-isothiocyanato-stilbene and 2-isothiocyanato-2'-acetoxy-stilbene [(Zoccoli, M. A. and Karnowski, M. L., J. Bio. Chem., 255, 1113-1119 (1980)] . The first therapeutically applicable inhibitors of glucose-6-phosphatase system proposed in the European applications 93114260.8 and 93114261.6.

Described below more cyclohexane derivatives represent a new, hitherto not described in the literature connection.

The authors have shown that esters of certain derivatives of cyclohexanol, for example, the compound according to example 4, are very good inhibitors of glucose-6-phosphatase system.

Therefore, the invention relates to esters of cyclohexanol of formula (1):

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where R1means CONHSO2R14where R14is C1-C10by alkyl; benzothiazolium, substituted C1-C4alkoxyl; phenyl, unsubstituted or substituted by fluorine and/or nitro group; naphthyl, unsubstituted or substituted NR8R9group; tetrazolyl; thiazolyl; or a group of the formula

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where R8and R9the seat is is C3-cycloalkyl or C1-C10the alkyl, which in turn may be substituted by phenyl or chlorophenyl, n = 0.1 or R1and R2form a ring

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where R16represents C1-C10the alkyl (R11);

R3means benzimidazolyl,

Z denotes CH=C(R13), where R13is phenyl, unsubstituted or substituted IT;

R4, R5, R6denotes hydrogen, HE, and R4, R5, R6are the same or different;

Y is-O-;

X represents (CH2)mwhere m = 0.

Proposed according to the invention the compounds of formula (I), if they contain a carboxy group can form salts with inorganic or organic bases.

Therefore, the invention also relates to physiologically acceptable salts of the compounds of formula (I).

Proposed according to the invention the compounds of formula (I) contain a number of stereocenters. The invention relates to all possible enantiomers and diastereomers corresponding to the formula (I). In the above text, the substituents have the following meanings:

The specified values for R1, R3, R8, R9, R11, R13and R16alkyl is>alkyl groups are linear, branched or cyclic, and is also only one part of the residue may form a ring.

Protective spirit groups are groups forming substituted ethers, as methoxymethyl, methylthiomethyl, tert-butylthioethyl, benzoyloxymethyl, p-methoxybenzyloxy, tert-butoxymethyl, cilexitil, 2-methoxyethoxymethyl, 1 ethoxy-ethyl, allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenmethyl, 2,6-dichloro-benzyl, p-tenbensel, p-phenyl-benzyl, 2 - and 4-picolyl.

Protective groups for amino acids are:

a) forming carbamates groups as methyl and ethyl; 9-fluorenylmethyl; 9-(2-sulfo)- fluorenylmethyl; 9-(2,7-di bromo) fluorenylmethyl; 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydromyrcenol) 7-methyl; 4-methoxybenzyl; 2,2,2-trichloroethyl; 2-trimethylsilylmethyl; 2-phenylethyl; 1-(1-substituted)-1-methylethyl; 1-dimethyl-2-halogenated; 1,1-dimethyl-2, 2-dibromoethyl; 1, 1-dimethyl-2,2,2-trichloroethyl; 1-methyl-1-(4-biphenyl)-ethyl; 1- (3,5-di-tert-butylphenyl)-1-methylethyl; 2-(2'- and 4'-pyridyl)-ethyl; 2-(N,N-dicyclohexylcarbodimide)-ethyl; tert-butyl; 1-substituted; vinyl; allyl; 1-isotropically; cinnamyl; 4-nitrocinnamyl; 8-chinolin; N-hydroxyphenylethyl; 9-antimetal; and diphenylmethyl, tert-amyl, S-benzyl-thio group; p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-dicyclopentyl, diisopropylate, 2,2-dimethoxyaniline, o-(N,N-dimethyl-carboxamido)-benzyl, 1,1-dimethyl-3-(N,N-dimethylcarbamate) propyl, 1,1-dimethylpropyl, di-(2-pyridyl) methyl, 2-furylmethyl, 2-codetel, isobornyl, isobutyl, isonicotinic, p-(p'-methoxyphenylazo) benzyl, 1-methylcyclobutene, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-acid)ethyl, 1-methyl-1-(p-phenylazophenyl)-ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)-ethyl, phenyl, p-(phenylazo) benzyl, 2,4,6-tri-tert-butylphenyl, 4-(ammonium) benzyl and 2,4,6-trimethylbenzyl;

b) forming derivatives of urea groups, as phenothiazinyl-(10)-carbonyl, N'-p-toluensulfonyl and N'-phenylaminopyrimidine derivative;

C) forming the amide groups as N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-TRIFLUOROACETYL, N-phenylacetyl, N-3-phenylpropionyl, N-Picolines, N-3-pyridylcarbonyl, N-benzylpenicillin, N-benzoyl and N-p-phenyl-benzoyl.

Preferred compounds of formula (I) in which:

R1means CONHSO2R14,

R2mean O-C1-C1 the place form a ring

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Proposed according to the invention preferred compounds of formula (I), if they contain a carboxyl group, may also form salts with inorganic or organic bases. The preferred salts with inorganic bases, particularly the physiologically acceptable salts of alkali metals, especially sodium and potassium salts.

The compounds of formula (I) inhibit the enzyme glucose-6-phosphatase in the liver of mammals. Therefore, compounds suitable as a pharmaceutical preparation. The invention relates also to pharmaceutical drug on the basis of the compounds of formula (I), if necessary in the form of physiologically acceptable salts.

The invention also includes the use of compounds of formula (I) or their salts for the treatment of diseases that are associated with increased activity of the enzyme glucose-6-phosphatase.

The invention also includes the use of compounds of formula (I), respectively, their salts, for treating diseases that are associated with an increased production of glucose by the liver.

In addition, the invention includes the use of compounds of formula (I) and their salts, for the treatment of type II diabetes (non-insulin-dependent or Starkey salts, to obtain drugs for the treatment of diabetes and other diseases that are characterized by increased secretion of glucose from the liver or increased activity of the enzyme glucose-6-phosphatase.

The action proposed according to the invention compounds on the enzyme glucose-6-phosphatase studied in enzyme test liver microsomes.

For preparation containing glucose-6-phosphatase microsome fractions using fresh liver of male Wistar rats and treated as described in the literature [Canfield W. K. and Arion, W. J., J. Biol.Chem. 263, 7458-7460 (1988)] . This microsome fraction can be stored at -70 C, at least for 2 months without significant loss of activity.

The activity of glucose-6-phosphatase was determined according to Arion, W. J. (Methods buzymol 174, Academic Press, 1989, S. 58-67) by determination of the released phosphate from glucose-6-phosphate. The test mixture (0.1 ml) contains glucose-6-phosphate (1 mmol/l), the test substance, 0.1 mg microsome fraction and 100 mmol/l HEPES-buffer [4-(2-hydroxyethyl) piperazine-1-econsultation], pH 7.0. The reaction is initiated by adding enzyme. After 20 minutes at room temperature the reaction is stopped by adding 0.2 ml of phosphate reagent. The sample is incubated in the course is ebimage substance is determined by comparison with a control sample, which does not contain the analyte of interest, according to the formula:

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If necessary, the inhibitory activity of the analyte determined as a function of the concentration of the substance and from it calculate the concentration for 50% inhibition of enzyme activity (IC50).

For the following compounds defined by the following IC50-value:

Connection - IC50(MK mol)

4 - 0.02

9 - 0,3

19 - 0,8

The next object of the invention is a pharmaceutical preparation which contains an effective amount of one or more compounds of the formula (I) according to the invention, and/or their pharmacologically acceptable salts.

Drugs have been known to a person skilled ways. As medicines offered in the invention of pharmacologically active compounds are used either as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets, pills, capsules, suppositories, emulsions, suspensions, granules, powders, solutions or preparations with prolonged secretion of biologically active substance, and the content of biologically active verstandige means, specialist known. Along with solvents, geleobrazovanie, the basics of suppositories, excipients for tablets and other carriers of biologically active substances can be applied, for example, antioxidants, dispersants, emulsifiers, antispyware, improves the taste of the ingredients, preservatives, agents, dissolution or dyes.

Biologically active substances can be applied tapicerki, orally, parenterally or intravenously, and the preferred method of administration depends on treatable disease. Preferably oral administration.

For oral use, the active compounds are mixed with suitable for this purpose additives, as carriers, stabilizers or inert diluents, and conventional methods lead to a suitable form of administration, as tablets, coated tablets, detachable capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. While the drug can be obtained in the form of dry and wet granulate. In katestone oil or fish oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salt, in a desirable scenario, along with the usual for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, transferred into a solution, suspension or emulsion, as solvents take into account, for example, water, physiological sodium chloride solution or alcohols, such as ethanol, propanol, glycerin, along with them also solutions of sugar, as glucose or mannitol, or a mixture of different solvents.

As pharmaceutical preparations for topical or local use suitable eye drops that contain the active compound in aqueous or oily solution. For introduction into a suitable nose sprays and sprinklers, as well as coarse powder, which is administered by rapid inhalation into the nose, and above all nose drops that contain the active compound in aqueous or oily solution.

Dosage introduce biologically active substances of the formula (I) and the frequency of introduction depends on the intensity of action and duration of action used compounds according to the invention, chrome the disposition mammal treatable. The average recommended daily intake proposed according to the invention compound is about 1 to 500 mg for a mammal weighing 75 kg, primarily for person, preferably about 10 to 250 mg, and can be done if necessary, the introduction of several doses per day and, if necessary, the dose may be less or more.

Getting proposed according to the invention compounds of formula (I) is illustrated by examples. Room temperature means a temperature of 20 - 25oC.

Example 1.

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Getting connection 2 connection 1.

3.7 g (0,054 mol) of carboxylic acid 1 (receipt, see: European patent application N 93114261.6; the reaction scheme of A structural element 68B) is dissolved in 36 ml of anhydrous dimethylformamide and at room temperature in an argon atmosphere mixed with 1,81 g (to 0.011 mole) N,N'-carbonyl-di-(1,2,4-triazole) and heated for 1.5 hours at 50 - 60oC. After cooling, 0.15 M solution of compound 2 without further processing used in the next stage.

Getting connection 3 connection 2.

0,057 g (0,006 mole) of methanesulfonamide dissolved in 3 ml of anhydrous dimethylformamide and at room tpri 50 - 60oC. Then, at this temperature, was added dropwise with 3.1 ml (0,00047 mol) 0.15 M solution triazolide formula 2. The reaction mixture is stirred for 1 hour at 60oC. Then the reaction mixture is added to a saturated solution of ammonium chloride, and the product of formula 3 is deposited as amorphous solids. The precipitate is sucked off, washed with distilled water and dried thus obtained solid substance in the course of 3 hours at 40oC and a pressure of 10-2Torr over calcium chloride. Get 0,248 g of compound 3.

Getting connection 4 connection 3.

0.24 g (0,000316 mole) of cyclohexylidene formula 3 make 10 ml of dioxane and at room temperature and vigorous stirring add 1.6 ml (0,0032 mol) of 2M hydrochloric acid. A clear solution is stirred for 2 hours at 50 - 60oC. Then the reaction solution is cooled to 10 - 20oC and adjusted to pH 3 with 1 M sodium hydroxide solution, diluted with 20 ml of distilled water and the reaction mixture was concentrated in vacuo to until no longer Athanasia any dioxane. When mixed with water slowly distilled residue, which is sucked off and washed with water. After wyszukiwanie is Thus synthesize the following compounds of formula (I):

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The connection 14 of the connection 13.

5.0 g (0,012 mol) of the lactone of formula 13 (receipt, see European patent application N 93114261.6, the reaction scheme of A structural element 68B) is dissolved in 80 ml anhydrous toluene and at -78oC in argon atmosphere was added dropwise 10 ml of a 0.012 mol) 1.2 M solution of diisobutylaluminium in hexane. After 1 hour at -50oC, hydrolyzing with a saturated solution of ammonium chloride. Extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The organic phase was concentrated in vacuo and the thus obtained lactol formula 14 without further purification used in the next stage.

The connection 15 of the connection 14.

4.6 g (to 0.011 mol) lactol formula 14 and 0,761 g (to 0.011 mol) of hydroxylamine-hydrochloride are dissolved in 50 ml of methanol. Add 750 ml of 0.014 mol) of potassium hydroxide. This solution is stirred for 1 hour at room temperature. Then the solution is mixed with 300 ml of a simple methyl tert-butyl ether, washed with water and saturated sodium chloride solution and the organic phase con is barely (eluting agent: ethyl acetate/n-heptane = 1:2). Obtain 3.6 g of the oxime of formula 15 in the form of a colorless oil.

The connection 16 of the connection 15.

20,0 g (0,046 mole) of the oxime of formula 15 is introduced into 200 ml of anhydrous dichloromethane and add 23,0 g (of 0.14 mole) of N,N'-carbonyldiimidazole. There is a strong gas evolution. After 14 hours of storage at room temperature, to the reaction solution was added 100 ml of methanol and the next 4 hours and refluxed for processing the solution is evaporated to dryness on a rotary evaporator and treated with simple methyl tert-butyl ether. The organic phase is washed with a mixture of water with a 0.1 M solution of potassium hydrosulfate, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (grain size of silica gel 35 - 78 μm, eluting system: ethyl acetate/n-heptane = 1:5, by the end of the fraction of n-heptane to reduce the ratio 1:3). Gain of 12.9 g of the nitrile of formula 16 in the form of a colorless oil.

The connection 17 of the connection 16.

12.9 g (0,0286 mole) of the nitrile of formula 16 is dissolved in 250 ml of anhydrous toluene and heated at 110oC. After three days in the time interval of 24 hours, depending on the circumstances, type of 5.89 g (0,0286 mol) trimethylated tin. Then the reactions of sodium hydroxide and 20 ml of tetrahydrofuran. The resulting sodium salt of compound 17 is sucked off, and then suspended in distilled water and acidified with 2 M acetic acid. Extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and concentrated in vacuo. Get 7,7 g tetrazole formula 17.

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Getting the initial connection B of the connection A.

274 mg (0,001 mol) of carboxylic acid of the formula A (receipt, see: European patent application N 93114261.6, method I ), in an argon atmosphere and at room temperature, dissolved in 20 ml of dimethylformamide and add 180,4 mg (0,0011 mol) N,N'-carbonyl-di-(1,2,4-triazole). The reaction solution is stirred for 1 hour at 60oC. the resulting solution of compound B without further processing used in the next stage.

The connection 18 from compound 17.

3.0 g (0,00652 mol) of compound 17 in argon atmosphere was dissolved in 30 ml of anhydrous dimethylformamide and at room temperature add 0,70 g (is 0.023 mole) of sodium hydride (80% dispersion in oil). After 1 hour was added dropwise 157 ml (0,0078 mole) of 0.5 M solution of compound B in dimethylformamide and again stirred for 1 hour at room temperature. Then the reaction solution SHL washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified using chromatography (grain size of silica gel: 35-70 μm; an eluting system: ethyl acetate/n-heptane/methanol/glacial acetic acid= 30: 10: 2: 1). Receive an ester of formula 18 in the form of an amorphous solid.

The connection 19 of the connection 18.

3.8 g (0,0053 mole) of cyclohexylidene formula 18 is treated with 150 ml of dioxane and mixed under stirring with 10 ml (0.02 mole) of 2 M hydrochloric acid. This solution is heated 2 hours at 60oC, then set the pH value of the reaction solution is equal to 3 with 18 ml of 1 M sodium hydroxide solution and the solvent is removed on a rotary evaporator. The residue is treated with ethyl acetate and the residue is filtered off. The filtrate was concentrated in vacuo and the residue purified by chromatography on silica gel (grain size of silica gel: 35-70 μm; an eluting system: ethyl acetate/methanol/water/glacial acetic acid= 4:1:1:0,5 ). Receive 2.5 g of compound 19 as a colorless amorphous solid.

Thus synthesize the following compounds of formula (I):

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The connection 22 from the connection 21.

of 2.26 g (0,01 mol) investorid, in argon atmosphere, bring in 5 ml of methanol and 3 ml of distilled water. The mixture is cooled to 0oC and added dropwise a solution of 1.63 g (0,025 mol) of potassium cyanide in 4 ml of distilled water. The reaction mixture is stirred for 4 hours at 0oC and 1 hour at room temperature and then under stirring contribute in a mixture of ice water and extracted three times with ethyl acetate. The combined organic phases are washed three times with distilled water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Obtain 5.0 g of a crude product of the formula 22, which without further purification used in the next stage.

The connection 23 from the connection 22.

3.7 g (0,01 mol) of cyanocobalamine formula 22 was dissolved in 8 ml of glacial acetic acid under stirring and at room temperature is mixed with a solution of 1.62 g (0,02 mol) of potassium cyanate in 4 ml of distilled water. The reaction solution is stirred for 75 minutes at room temperature and then poured onto a mixture of ice water, extracted twice with ethyl acetate and the combined organic phases are washed once with distilled water and once with saturated solution of sodium chloride. After vysushila the residue is dissolved in 4 ml of dioxane and this solution is mixed under stirring with 10 ml of 2M hydrochloric acid. After stirring for 1 hour at 55oC, the reaction mixture was poured into a mixture of ice water and extracted three times with ethyl acetate. The organic phase is washed three times with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue is purified by chromatography on silica gel (grain size of silica gel 35-70 μm; eluting agent: ethyl acetate/n-heptane/methanol/glacial acetic acid = 20:10:2: 1) and obtain 0.36 g of product of formula 23.

The connection 24 of the connection 23.

0.36 g (0,00106 mol) of compound 23 was dissolved 1.09 ml (0,0106 mole) of dimethoxypropane and 20 ml of anhydrous dichloromethane. Added 26 mg (10 mol. %) pyridine-para-toluensulfonate. The mixture is heated for 45 minutes at 40oC. Then the reaction solution make a saturated solution of sodium hydrosulphate, extracted with ethyl acetate and dried the combined organic phases over magnesium sulfate. The residue is purified by chromatography on silica gel (grain size of silica gel: 35-70 μm, eluting system: ethyl acetate/n-heptane = 2:1) and obtain 0.24 g in the form of a colorless solid.

The connection 25 from the connection 24.

230 mg (0,0006 mole) hydrocare argon added 55 mg (0,00184 mole) of sodium hydride (80% dispersion in oil). After 30 minutes of incubation at room temperature was added dropwise 22 ml of 0.5 M solution of compound B in dimethylformamide. After following 30 minutes of incubation at this temperature get a clear solution, which is mixed with a saturated solution of ammonium chloride, and the precipitated product of the formula 25 in the form of amorphous solids. It is sucked off and dried in vacuum. Obtain 310 mg of compound 25.

The connection 26 of the connection 25.

290 mg (0,00047 mol) of compound 25 was dissolved in 30 ml of dioxane and at room temperature and vigorous stirring is mixed with 4 ml (0,008 mol) of 2M hydrochloric acid. After stirring for 2 hours at 50oC the reaction solution is cooled to 10 - 20oC and with 1 M sodium hydroxide solution set therein pH 3. The solution was concentrated in vacuo and the oily residue is treated with isopropanol, filtered off the precipitated salts and the filtrate is again concentrated in vacuo. The residue is stirred with a simple methyl tert-butyl ether and the amorphous precipitate is sucked off. After drying in vacuo get 140 mg of compound 26 (target product of the formula (I)).

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The connection 28 of the connection 27.

The connection 30 from the connection 28.

15.0 g (of 0.038 mole) of the alcohol of formula 28 are dissolved in 250 ml of anhydrous dimethylformamide and 0 to 10oC added to 1.5 g (0.05 mole) of sodium hydride. Stirred for 1.5 hours at 20oC, then cooled to 0oC and added dropwise to 13.2 g (0,057 mole) of CIS-3-(4-chlorophenyl)-propylbromide (29), dissolved in 30 ml of anhydrous dimethylformamide. The reaction solution allowed to warm to room theory of ammonium chloride, extracted with ethyl acetate and the combined organic phases are washed with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase was concentrated in vacuo and purified by chromatography on silica gel (eluting agent: ethyl acetate/n-heptane = 1:2; grain size: 35-70 μm). Get 19,0 g of thiazole of formula 30 in the form of a viscous oil.

The connection 31 of the connection 30.

56,6 ml of 1 M solution of diethylzinc in toluene at 0oC and in an atmosphere of argon was added dropwise to 250 ml of anhydrous dichloromethane and then at 0oC add 9.0 ml (0,125 mole) chlorine-iodine-methane. The reaction solution is stirred for 30 minutes at the same temperature and then added dropwise 17.0 g (0,031 mole) of the olefin of formula 30, dissolved in 30 ml of anhydrous dichloroethane. Leave to rise slowly to room temperature. After 2 hours the reaction solution make a saturated solution of ammonium chloride, extracted with ethyl acetate and the combined organic phases are washed with a saturated solution of sodium chloride. After drying the organic phase over sodium sulfate, concentrate it under vacuum and the residue is stirred with a simple methyl tert-butyl ether. The precipitate is filtered off (as p of 4.2 g (24%) of compound 31 in the form of a viscous oil.

The connection 32 of the connection 31.

of 4.2 g (0,008 mol) of compound 31 was dissolved in 100 ml of methanol and 150 ml of dichloromethane and at room temperature add 0.7 g (of 0.003 mole) of pyridine-p-toluensulfonate. A clear solution aged for 14 hours at room temperature, mixed with 20 ml of 1 n sodium hydrogen carbonate solution and the mixture is concentrated until only the water phase. It is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluting agent: ethyl acetate/n-heptane = 1:1; grain size: 35-70 μm). Get 1,82 g (51%) of compound 32 as a colourless oil.

The connection 33 of the connection 32.

Similar to that described in example 2 to obtain compound 19 from compound 17, compound 32 through stage 2 receives the connection 33, corresponding to the formula (I), in the form of amorphous solids. Mass spectrum (FAB): m/z = 542 (M + H+).

1. Esters of cyclohexanol I

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where R1means CDNHSO2R14where R14is1- C10- alkyl, benzthiazole, the naphthyl, unsubstituted or substituted NR8R9group, tetrazolium, thiazolium,

or a group of the formula

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where R8and R9denote hydrogen or C1- C4- alkyl;

R2denotes O-C1-C10- alkyl(R11); R11is3- cycloalkyl,1- C10- alkyl, which in turn may be substituted by phenyl or chlorophenyl;

n = 0, 1, or R1and R2form a ring

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where R16represents C1-C10- alkyl (R11)n; R3means benzimidazolyl; Z denotes CH=C(R13), where R13is phenyl, unsubstituted or substituted by OH;

R4, R5, R6denotes hydrogen, HE, and R4, R5, R6are the same or different;

Y is-O-;

X represents (CH2)mwhere m = 0,

and their physiologically acceptable salts.

2. Esters of cyclohexanol and their physiologically acceptable salts under item 1, where R1means CONHSO2R14, R2mean O-C1-C10- alkyl (R11)nn = 1, and the alkyl part is linear or branched, or R1and R2together form a ring

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4. Pharmaceutical drug that has inhibitory activity against the enzyme glucose-6-phosphatase containing the target additive and an effective amount of pharmaceutically active agent, wherein as the active agent it contains one or more compounds according to paragraphs.1 and 2.

5. Pharmaceutical drug under item 4, characterized in that it contains compounds on p. 1.

6. Pharmaceutical drug under item 4, characterized in that it contains compounds on p. 2.

 

Same patents:

The invention relates to 2-/2-imidazolin-2-yl/benzoheterocycles compounds, which have the following structure:

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in which: R1is hydrogen, CI/C1-C4/ alkylamino,

C1-C12the alkyl may be substituted by one to three substituents: C1-C4alkoxy, C1-C4alkylthio, halogen, hydroxy, C1-C4cycloalkyl, benzoyloxy, fullam, phenyl, possibly substituted by nitro, one to three halogen, C1-C4alkyl groups or C1-C4alkoxy groups, carboxy, C1-C4alkoxycarbonyl, cyano or three/C1-C4/ alkylammonium a halide;

C3-C12alkenyl may be substituted by one to three substituents: C1-C4alkoxy, phenyl, halogen or C1-C4alkoxycarbonyl;

C3-C6cycloalkyl, can be substituted one to three C1-C4alkyl groups;

C3-C16the quinil may be substituted by one to three halogen or a cation;

R2is C1-C4by alkyl;

R3is C1-C4the alkyl or C3-C6cyclo is the best C1-C4cycloalkyl possibly replaced by stands;

B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

R4is C1-C11the alkyl, chlorochilon or phenyl, possibly substituted with halogen, nitro or C1-C4by alkyl;

R5is C1-C4the alkyl or phenyl, possibly substituted C1-C4by alkyl;

X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;

configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;

R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;

R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;

Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs with hypotensive and analepticheskih activity

The invention relates to the compounds and their pharmaceutically acceptable salts and methods for treating HIV infections and related viruses and/or treatment of acquired immunodeficiency syndrome (AIDS)

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to medicine, namely to homeopathic medicines and can be used for prevention of acute respiratory viral infections (ARVI)

The invention relates to the field of cosmetology and pharmacology relates to cosmetic or pharmaceutical compositions and method of reception

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

The invention relates to new derivatives of piperazinylmethyl formula I which inhibit the protease encoded by human immunodeficiency virus (HIV)
The invention relates to medicine, namely to experimental Oncology, and can be used to reduce toxicity and enhance the antitumor activity of cyclophosphamide

The invention relates to the field of pharmaceutical and organic chemistry and relates to new inclusion complexes and pharmaceutical compositions based on them, which are used for treatment of certain medical conditions in mammals
The invention relates to medicine, namely to surgery, and for the prevention of early recurrence of angina and consequences of respiratory distress syndrome in adult patients undergoing surgery coronary artery bypass surgery

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

The invention relates to the field of medicine and for the new drug treatment of hypertension, representing a N-acetyl-5-methoxytryptamine (melatonin), and a method of treatment of hypertension using the specified funds or in combination with other antihypertensive agents

The invention relates to the field of medicine and for the new drug treatment of hypertension, representing a N-acetyl-5-methoxytryptamine (melatonin), and a method of treatment of hypertension using the specified funds or in combination with other antihypertensive agents
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