The method of obtaining 1,3-disubstituted 4-oxocyclohexa ureas

 

(57) Abstract:

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and mixtures thereof, in prisutstsovat sodium and polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea. The technical result is to increase the output and improve product purity. 10 C.p. f-crystals.

The scope of the invention

The invention relates to chemical methods of producing compounds that are useful in the treatment of various disorders; such uses include, but are not limited to, use as antifibrillatory and antiarrhythmic agents. The methods of this invention suitable for the production of 1,3-disubstituted 4-oxocyclohexa ureas, especially 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(4-methyl-1-piperazinil) butyl]-2,4-imidazolidinedione and its salts.

Background of the invention

This invention relates to a method for producing a 1,3-disubstituted 4-oxocyclohexa ureas, especially 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione or its salts, where the final product is obtained in pure form and high yield.

The dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione (azimilide) is described in U.S. Pat the connection type in U.S. patent 5462940, issued to Yu et al. October 31, 1995, describes two General ways. In each of the ways described a number of reactions, which include the selection of three to five intermediate compounds. The drawback of both methods are the use of very inflammable and sensitive to moisture sodium hydride, potentially explosive mixtures of DMF/sodium hydride, excessive amounts of solvents, sodium iodide and multiple stages of selection. Additional disadvantages of one method are: the use of aminosidine group and the need of the hydrogenation reaction to remove it.

From the art it is known that safe, giving higher yields of product, more economical ways of getting azimilide should be beneficial. Particularly advantageous should be reducing the number of synthetic steps, high performance response (higher concentration in the reaction), with the exception of the hydrogenation reaction, elimination aminosidine group, higher overall output, the ability to carry out the reaction on a large scale and better extraction of the final product. Unexpectedly, it was found that the disadvantages described syntheses of these compounds can be overcome p is, is skluceni use of sodium iodide to facilitate the alkylation of the amino group and the use of solvents, such as methylsulfoxide (DMSO) and N-organic (NMP), to reach much higher concentrations in the reactions, increased product yield and purity.

The subject of this invention is a method for 1,3-disubstituted 4-oxocyclohexa urea, whereby 1,3-disubstituted 4-oxocyclohexa urea conveniently synthesized with high yields, without the isolation of intermediate products, first by alkylation of the corresponding 1-substituted 4-oxocyclohexa urea reagent with carbon chain containing up to two leaving groups, with the formation of the adduct, which is used without selection for alkylation of an amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea, which, finally, is subjected to reaction with acid with the formation of the target salt. This method enables to obtain a 1,3-disubstituted 4-oxocyclohexa urea in the reaction conditions, which eliminate the need stage hydrogenation and use aminosidine group. This method allows you to achieve higher yields and improved product purity, more Vyacheslav connections.

In particular, the preferred methods of this invention provide a new methodology, which is particularly suitable for scaling transition and production azimilide.

Summary of the invention

This invention provides a method of obtaining a 1,3-disubstituted 4-oxocyclohexa ureas of General formula:

< / BR>
where R1, R2and R3, independently, selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy;

R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and

A represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen;

where specified 1,3-disubstituted 4-oxocyclohexyl urea receive method without isolation of intermediate products, vepu, containing at least two leaving groups, in the presence of a weak base and solvent to form adduct containing at least one leaving group, and

(Ib) condensation with the amine adduct with the formation of 1,3-disubstituted 4-oxocyclohexa urea, and

(II) allocation specified 1,3-disubstituted 4-oxocyclohexa urea.

This method is especially preferred for obtaining azimilide. 1-substituted 4-oxocyclohexa urea used to obtain azimilide is 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione.

Definitions and use of terms

The following is a list of definitions for terms used here:

Used herein, "acid" means an organic or inorganic acid. The inorganic acid is a mineral acid, such as sulphuric, nitric, hydrochloric and phosphoric. The organic acid is an organic carboxylic acid, such as formic acid, acetic acid, Chloroacetic acid, dichloracetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid and tartaric acid.

Used here "alkenyl" means hydrocarbon Deputy with one or more double bonds, an unbranched or branched chain, unsubstituted or substituted.

Used herein, "alkoxy" means the Deputy, having the structure Q-O-, where Q is alkyl or alkenyl.

Used herein, "alkyl" means a saturated hydrocarbon Deputy with unbranched or branched chain, unsubstituted or substituted.

Used herein, "base" means the basic reagent, which is added to the reaction mixture to facilitate the alkylation of nitrogen using an alkylating agent. The grounds include nitrogenous bases and inorganic bases, such as N, N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

Used herein, "halogen" means a radical chlorine atom, bromine, fluorine or iodine. The preferred Halogens are bromine and chlorine.

Used herein, "heterocyclic ring" means a radical of a saturated, unsaturated or aromatic ring, soderzhashchimi or condensed, bridge or spironolactone systems. Monocyclic ring containing from 3 to 9 atoms, preferably from 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic ring containing from 7 to 17 atoms, preferably from 7 to 14 atoms and most preferably 9 or 10 atoms.

Used herein, the term "leaving group" means a substituted or unsubstituted alkyl - or arylsulfonyl or substituted or unsubstituted alkylhalogenide. Preferred substituents are halogen-free.

Used herein, the term "methylene" means the radical-CH2-.

Used herein, "polar aprotic solvent" is a solvent which has the property of high polarity, but does not have the ability to give the proton. Preferred polar aprotic solvents include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-organic (NMP) and methylsulfoxide (dimethyl sulfoxide, DMSO).

Defined above and used herein substituting groups may themselves be substituted. Such substitution may be performed by one or more substituents. Such substituents include the substituents, pericycle is Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (for example, aminomethyl and so on), cyano, halogen, alkoxy, alkoxyaryl (for example, carboethoxy and so on), thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci (for example, piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

Used herein, "volume" refers to liters specified solvent per kilogram of starting material.

Detailed description of the invention

This invention relates to a method for producing a 1,3-disubstituted 4-oxocyclohexa ureas, including, but not limited to, azimilide and other pharmaceutically acceptable salts, which can be obtained with high yields, high purity, high performance and synthetic simplicity. The invention includes the sequential procedure of interaction of 1-substituted 4-oxocyclohexa urea reagent with carbon chain containing two leaving groups, in a polar aprotic solvent, in the presence of a weak base, further interaction with the amine, salt precipitation of the co-solvent, filtration and, finally, add acid and excretion of 1,3-disubstituted 4-exocyclic>C, preferably at a temperature of from about 60 to 75oC. Base that you can use, choose from bases which form an easily filterable or other receding salt. Particularly preferred bases include N, N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. More preferred bases are potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. The most preferred base is potassium carbonate, usually from 0.8 to 4.0 equivalents, preferably from 1.2 to 2 equivalents per mole of imidazolidinedione. Preferred reagents with carbon chain selected from the group of reagents containing group, halogen-free, including, but limited to, 1-bromo-4-chlorobutane, 1,4-dichloro - or 1,4-dibromobutane; more preferred is 1-bromo-4-chlorobutane. Professionals in this field should be known that as reagents with carbon chain can also be used butyl alcohol, butylsulfonyl and tetrahydrofuran. Usually use from 0.8 to 2.5 equivalents, preferably 1 to 1.2 equivalent NMP. Usually use from 2 to 20 volumes, preferably from 2.5 to 5 volumes of NMP.

Preferred 1-substituted 4-oxocyclohexa urea selected from the group consisting of: 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione; 1-[[[5-(4-methanesulfonamido)-2-furanyl]methylene]amino] -2,4-imidazolidinedione; 1-[[[5-(4-forfinal)-2-furanyl]methylene]amino]-2,4-imidazolidinedione; 1-[[[5-(4-nitrophenyl)-2-oxazolidinyl] methylene] amino]-2,4-imidazolidinedione; 1-[[[5-(4-were)-2-furanyl]methylene]amino]-2,4-imidazolidinedione; 1-[[[5-(3,4-acid)-2-furanyl] methylene] amino]-2,4-imidazolidinedione. Upon receipt azimilide using 1-substituted 4-oxocyclohexyl urea, which is a 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione.

The second alkylation occurs at temperatures from 50oWith up to 120oC, preferably at temperatures from about 75oWith up to 95oC. the Preferred amines for this stage are selected from the group consisting of dimethylamine; diethylamine; N, N-bis-(2-hydroxyethyl)amine; Isopropylamine; N-benzyl-N-methylamine; N-(2-hydroxyethyl)-N-methylamine; N-methylpiperazine; research; 4-hydroxypiperidine; N-methyl-N-phenylamine. Amin, ispolzuemye from 1.2 to 3 equivalents of amine per mole of imidazolidinedione.

After the second alkylation reaction mixture is cooled typically to a temperature of from 10o50oWith, preferably from 5o35oC. the co-solvent used for the deposition of salts, is a simple ether, acetone, methanol, ethanol or a mixture of the above-mentioned co-solvents, preferably acetone. Usually use anywhere from 0 to 20 volumes, preferably from 6 to 10 volumes. The insoluble salt is collected by filtration and washed with a co-solvent.

Water added to the reaction mixture to prepare for the formation of salts. Usually used from 0 to 5 volumes, preferably from 0.5 to 2.8 volumes of water. Acid, which is used to retrieve the target salt is hydrochloric acid.

Usually regulate pH in the range pH 3 to 7, preferably pH from 4.5 to 5, for the formation of crystallization centers, followed by further addition of acid to a pH of 0-3 for the deposition of the specified azimilide, which is collected by filtration output from 80 to 90%.

Azimilide obtained by the method of this invention suitable for the treatment of various medical disorders, such uses include, but are not limited to, use as antifibrillatory is the procedure for the formation of various forms of salts, which may facilitate the selection and manipulation, you can add various acids. According to the method of the present invention can be obtained other pharmaceutically acceptable salts, such as sulfate and hydrobromide, these salts are included in the scope of this invention.

This method is illustrated by the General scheme 1 (see the end of the description), where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NN, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy;

R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl;

A represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen;

X and Y represent, independently, a leaving group, preferably of different leaving groups;

where specified 1,3-disamis is:

(Ia) the interaction of 1-substituted 4-oxocyclohexa urea reagent with carbon chain containing at least two leaving groups, in the presence of a weak base and solvent to form adduct containing at least one leaving group, and

(Ib) condensation with the amine adduct with the formation of 1,3-disubstituted 4-oxocyclohexa urea, and

(II) allocation specified 1,3-disubstituted 4-oxocyclohexa urea.

The following non-limiting examples illustrate the methods of this invention.

Example 1. The use of dimethylformamide (DMF) as solvent for the reaction of obtaining azimilide.

In a three-neck flask 12 l equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel, download DMF (4,77 l) and heated to 50oC. Add 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -2,4-imidazolidinedione (597 g) and continue heating. When the dissolution is completed in the flask is charged with potassium carbonate (276 g) and heating continued until 85oC. After 10 minutes, add 1-bromo-4-chlorobutane (370 g) and heating continued until approximately the 100oC. After 35 minutes, add N-methylpiperazine (the tion to 10oC and filtered to remove insoluble materials. DMF is removed under reduced pressure at 65-68oWith and replaced with absolute ethanol (3.6 l). The mixture is heated to dissolve the free base and filtered to remove insoluble materials. The product precipitated from ethanol (only 6.0 liters) by adding 418 g of concentrated hydrochloric acid and then filtered, getting 680 g of this compound.

Example 2. Using methylsulfoxide (DMSO) as solvent for the reaction of obtaining azimilide

In a three-neck flask of 500 ml equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel, download DMSO (200 ml) and 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione (20 g). Once dissolved, add potassium carbonate (15.5 g) and 1-bromo-4-chlorobutane (13,6 g) and the mixture is heated to 70oC for 30 minutes. To the mixture for 15 minutes, add N-methylpiperazine (19,8 g) by heating to 90oC. After, in General, 2 hours and 15 minutes the reaction mixture is cooled to about 30oWith and add methanol (200 ml). The mixture is cooled to room temperature and filtered to remove insoluble materials. The filtrate is getting a 30.4 g of this compound.

Example 3. The use of N,N-dimethylacetamide (DMAC) as solvent for the reaction of obtaining azimilide

In a three-neck flask of 2 l equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel, download DMAC (200 ml) and 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione (100 g), 1-bromo-4-chlorobutane (59 g) and potassium carbonate (73 g). The mixture is stirred for approximately 100 minutes when heated to 70oC. Add N-methylpiperazine (59,5 g) and the mixture is stirred for additional 3 hours with heating to 86oC. the Reaction mixture is cooled to 20oWith and add acetone (900 ml). The mixture is filtered to remove insoluble materials. The filtrate is acidified with concentrated hydrochloric acid to pH 1-2, cooled to 15oWith and filter, receiving the 122.7 g of this compound.

Example 4. The use of N-methylpyrrolidone (NMP) as a solvent for the reaction of obtaining azimilide

In a three-neck flask of 5 l equipped with a thermometer, mechanical stirrer, heating jacket, reflux condenser and addition funnel, download NMP (1.2 l), 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione 70oC. Add N-methylpiperazine (149 g) and the mixture is stirred for about 150 minutes when heated to 90oC. the Reaction mixture is cooled to 20oWith and add acetone (2.4 l). The mixture is filtered to remove insoluble materials. To the filtrate add water (0,42 l) and the mixture is heated to a temperature between 30 and 35oC. the Mixture is acidified with concentrated hydrochloric acid to a pH of from 4.5 to 5, make a seed product, stirred for 1 hour and then acidified with concentrated hydrochloric acid to a pH of from 0 to 3. The mixture is cooled to 10oWith and filtered, obtaining 382,8 g of this compound (see diagram 2 at the end of the description).

1. The method of obtaining 1,3-disubstituted 4-oxocyclohexa ureas having the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, CL, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy;

R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl;

A represents a substituted or unsubstituted, saturated or unsaturated, nvsat substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen;

R4attached to the nitrogen;

incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea.

2. The method according to p. 1, where the specified base is potassium carbonate.

3. The method according to p. 1 or 2, where the specified polar aprotic solvent selected from the group comprising N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), N-organic (NMP).

4. The method according to any of paragraphs. 1-3, where the specified radix is from 0.8 to 4 equivalents of potassium carbonate.

5. The method according to any of paragraphs. 1-4, where the specified osnovannaopyte from 0.8 to 2.5 equivalents of 1-bromo-4-chlorobutane per mole of 1-substituted 4-accomodatin.

7. The method according to any of paragraphs. 1-6, where at stage (a) use 1 to 1.2 equivalents of 1-bromo-4-chlorobutane per mole of 1-substituted 4-accomodatin.

8. The method according to any of paragraphs. 1-7, where stage (a) is conducted at a temperature of from 40 to 120oC.

9. The method according to any of paragraphs. 1-8, where stage (a) is conducted at a temperature of from 60 to 75oC.

10. The method according to any of paragraphs. 1-9, further comprising the extraction of the specified 1,3-disubstituted 4-oxocyclohexa urea in the form of dihydrochloride salt, and specified the first stage involves adding hydrochloric acid to a pH of from 4.5 to 5, the second adding hydrochloric acid to a pH of from 0 to 3 and collecting the resulting solid dihydrochloride salt.

11. The method according to any of paragraphs. 1-10, further comprising the extraction of the specified 1,3-disubstituted 4-oxocyclohexa urea, and the specified stage includes adding a co-solvent selected from the group comprising methanol, ethanol, acetone and mixtures thereof, and collecting the formed solids.

 

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< / BR>
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< / BR>
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< / BR>
< / BR>
< / BR>
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EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmacology.

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

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

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: pharmaceutical industry, medicine.

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

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

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

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