Method for preparing 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

 

The present invention relates to a method for producing 2,6-diamino-4,5,6,7-tetrahydroindazole, intermediate compounds used in the production of pramipexole (pramipexole). The present invention also relates to the synthesis of pramipexole.

(S)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazolinone (or (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole), more commonly known as pramipexol, take on the early and late stages of Parkinson's disease as a dopamine agonist to stimulate dopamine receptors in the brain. Such use is described in EP 0186087.

In EP 0186087 also describes the synthesis of various tetrahydroindazole, including pramipexol. In particular, describes the following sequence of reactions for the synthesis of pramipexole. The initial interaction between bromide and 4-acetylgalactosamine conducted in the environment of glacial acetic acid under stirring for several hours at room temperature. After that, add the thiourea while boiling under reflux. The reaction mixture is cooled and the resulting crystals precipitated 6-acetylamino-2-amino-4,5,6,7-tetrahydroprotoberberine. The precipitate is filtered off, then washed with water and acetone. Thereafter, the crystals are dissolved in Hydrobromic acid and the resulting solution was refluxed in t the value of a few hours. Then the solution is concentrated by evaporation and the residue is dissolved in methanol, which produce crystals of 2,6-diamino-4,5,6,7-tetrahydrobenzaldehyde. After that, 2,6-diamino-4,5,6,7-tetrahydrobenzaldehyde can be turned into pramipexol.

The synthesis is illustrated by the following reaction scheme:

The scheme of synthesis includes a separate reaction stages, each of which is conducted in various conditions, in various solvents at different temperatures, etc. For its implementation requires the use of a periodic process with more than one stage of selection, which leads to increased processing times, low yields of the target product (the reaction product is lost at each stage of selection), a large amount of waste and increased consumption of solvent compared to a continuous process.

The inventors have developed a method of synthesis of 2,6-diamino-4,5,6,7-tetrahydroindazole of 4-acetamidocinnamate, which excludes multiple stages of selection, which are used in the previously described processes.

In accordance with one aspect of the present invention proposes a method of synthesis of 2,6-diamino-4,5,6,7-tetrahydroindazole, including: (i) the interaction of bromine with water dissolve the Ohm 4-acetamidocinnamate to obtain 2-bromo-4-acetamidocinnamate; (ii) add the following stage (i) thiourea with obtaining 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzaldehyde; (iii) adding after stage (ii) aqueous solution of Hydrobromic acid to obtain 2,6-diamino-4,5,6,7-tetrahydroindazole; and (iv) selected after stage (iii) of 2.6.-diamino-4,5,6,7-tetrahydroindazole in the form of free base.

An important feature of the present invention is the fact that stage (iii) is carried out without isolating the 6-acetylamino-2-amino-4,5,6,7-tetrahydroindazole obtained in stage (ii). Thus, the entire synthesis can be carried out in one reaction vessel. Preferably, at least three successive stages (i)to(iv) is carried out in one reaction vessel.

Front of stage (i) of the method may include the stage of oxidation of 4-acetamidophenol with the formation of 4-acetamidocinnamate. This stage can be performed in the same reaction vessel in which is conducted the following stages (i)-(iv), resulting in extra stage of selection.

The oxidation reaction can be carried out with the use of oxidizing agents, including, for example, Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate.

At the stage of (i) a solution of 4-acetamidocinnamate and bromine are mixed in the reaction vessel is preferably at a temperature in the range of 5-75° S, more preferably 15-40°S, most preferably at room temperature (about 25°). Preferably bromine is added dropwise to a solution of 4-acetamidocinnamate. After adding bromine to a solution of 4-acetamidocinnamate the resulting mixture is preferably heated to a temperature of 30-80°S, more preferably 40-50°S, most preferably about 45°C and maintained at this or about this temperature until completion of the synthesized. On completion of the synthesized judged by disappearance of the characteristic brown color associated with the presence of molecular bromine.

At stage (ii) the temperature is preferably increased to 50-95°S, more preferably 70-90°S, most preferably up to 80°C.

At stage (iii), the reaction mixture is preferably refluxed.

At stage (iv), the reaction mixture is preferably cooled to 1-35°S, more preferably up to 5-20°S, and most preferably up to about 10°C, after which the mixture is neutralized. Typically, the neutralization is carried out using a solution of caustic soda (NaOH), although they may be used and other alkalis. After neutralization conduct the reaction product, 2,6-diamino-4,5,6,7-tetrahydroindazole. The selection can be performed by filtration, centrifugation, or l is favorite color other suitable way. After separation, the product is preferably washed with chilled water.

The original 4-acetamidocinnamate traditionally produced by oxidation of 4-acetamidophenol.

The above-described compound, 2,6-diamino-4,5,6,7-tetrahydroindazole, used as intermediate compounds for receiving pramipexole and related compounds.

In accordance with another aspect of the present invention proposes a method of synthesis of pramipexole, which includes stages: obtaining 2,6-diamino-4,5,6,7-tetrahydroindazole according to the method of the present invention and its transformation into pramipexol.

The transformation of 2,6-diamino-4,5,6,7-tetrahydroindazole in pramipexol is well known in the art and described, for example, in US 4731374. In the present invention can be any of the methods described in US 4731374.

In accordance with one of the embodiments of the 2,6-diamino-4,5,6,7-tetrahydroindazole turn in pramipexol by the reaction with such propionyl the halide, as propenylboronic, under appropriate reaction conditions.

As 2,6-diamino-4,5,6,7-tetrahydroindazole and pramipexol contain an asymmetric carbon atom and exists as two different enantiomers: S(-) isomer and R(+) isomer. However, the pharmacological activity of S(-) isomer pramipexole twice the activity of the R(+) isomer and the name pramipexol" usually refers to the optically pure S(-) form. In the present description, the term "2,6-diamino-4,5,6,7-tetrahydroindazole covers R(+) and S(-) enantiomers separately, as well as any mixture, including a racemic mixture, and the term "pramipexol covers R(+) and S(-) enantiomers separately, as well as racemic mixture.

The separation of the racemic mixture of 2,6-diamino-4,5,6,7-tetrahydroindazole may be conducted after the above stage (iv). Methods of separation of optical isomers are known from the prior art. On the other hand, the racemate of pramipexole can be obtained without separation, after which, if desired, carry out the separation of a mixture of optical isomers.

The separation of the racemate pramipexole described by Schneider and Mierau (J. Med. Chem. 30, 494 (1987)). In this way diaminopropane (±)-4,5,6,7-tetrahydro-N6-propyl-2,6 - benzothiazolinone used as a substrate, and L(+) tartaric acid as a separating agent. After the separation of optically active pramipexol receive a two-step profilirovanie individual enantiomer of diaminopentane, including reaction with propionic anhydride, followed by reduction propylaniline intermediate connection.

Synthesis method of the present invention eliminates the need for isolation of intermediate compounds, resulting in increased yield of the target compounds and decreases BP is me processing. In addition, due to the absence of an organic solvent (e.g. acetic acid) lowers the cost of production and used in a more mild conditions of the reaction such conditions have a positive effect on product purity.

Further, the present invention is described with reference to the following examples.

Example 1

At room temperature bromine (112) was added dropwise to a solution of 4-acetamidocinnamate (100 g) in 500 ml of water. The mixture was heated to about 45°C and kept at this temperature until the colour disappears bromine. To the mixture was added thiourea (125 g) and the mixture was heated to about 80°C. was Added an aqueous solution of Hydrobromic acid (100 ml) and the contents of the reaction vessel was heated under reflux. Then the contents were cooled to about 10°and neutralized with a solution of caustic soda. The reaction product, 2,6-diamino-4,5,6,7-tetrahydroindazole, were isolated by filtration, washed with chilled water and dried. The resulting product had a yellowish color and its output amounted to about 60g.

Example 2

To a solution of 4-acetamidophenol (100 g) in acetone (1 l) at 10-15°With added Jones reagent (obtained from 68,5 g of chromium oxide, 105 g of sulfuric acid and 400 ml of water). The excess reagent was suppressed by addition of isopropanol (400 ml) and the solvent prowess and under reduced pressure. To the system was added ethyl acetate (600 ml), the content was stirred for 10 minutes and the lower aqueous layer was decanted. The ethyl acetate was concentrated under reduced pressure and the residue was dissolved in water (500 ml). Was added dropwise bromine (112 g), and other reaction was carried out according to the procedures described in Example 1.

Example 3

To a suspension of 4-acetamidophenol (100 g) in water (300 ml) was added 10% sodium hypochlorite solution (500 ml) and the contents of the reaction vessel was stirred at room temperature for 12 hours. In the resulting system was added liquid bromine (112 g) and the subsequent reaction was carried out according to the procedures described in Example 1.

You should take into account that the above-described invention allows various modifications.

1. The method of obtaining 2,6-diamino-4,5,6,7-tetrahydroindazole, comprising the following successive stages: (i) the interaction of bromine with an aqueous solution of 4-acetamidocinnamate to obtain 2-bromo-4-acetamidocinnamate; (ii) adding thiourea to obtain 6-acetylamino-2-amino-4,5,6,7-tetrahydroindazole; (iii) adding an aqueous solution of Hydrobromic acid to obtain 2,6-diamino-4,5,6,7-tetrahydroindazole without allocation of 6-acetylamino-2-amino-4,5,6,7-tetrahydroindazole obtained in stage (ii); (iv) the allocation of 2,6-diamino-4,5,6,7-tetrahydroindazole;

and, when necessary, is Timoti, the separation of 2,6-diamino-4,5,6,7-tetrahydroindazole allocated to stage (iv), R (+) and S (-) enantiomers and the allocation of R (+) and/or S (-) enantiomer.

2. The method according to claim 1, characterized in that any three successive stages (i)to(iv) is carried out in one reaction vessel.

3. The method according to claim 1, characterized in that stage (i)to(iv) is carried out in one reaction vessel.

4. The method according to claim 1, further comprising prior to stage (i) stage of oxidation of 4-acetamidophenol obtaining 4-acetamidocinnamate.

5. The method according to claim 4, characterized in that the stage of oxidation of 4-acetamidophenol obtaining 4-acetamidocinnamate and at least three successive stages (i)to(iv) is carried out in one reaction vessel.

6. The method according to claim 1, characterized in that the mixed aqueous solution of 4-acetamidocinnamate and bromine is carried out at a temperature of 15-40°C.

7. The method according to claim 1, characterized in that after mixing of bromine to a solution of 4-acetamidocinnamate the mixture is heated to a temperature of 40-50°C and maintained at this or about this temperature until completion of the synthesized.

8. The method according to claim 1, characterized in that in stage (ii) the temperature was raised to 70 to 90°C.

9. The method according to claim 1, characterized in that stage (iii) is carried out at boiling under reflux.

10. The method according to claim 1, characterized in that paragraph the following stage (iii), but before stage (iv), the reaction mixture was cooled to 5-20°and then neutralized.

11. The method of synthesis pramipexole, including the stage of the formation of 2,6-diamino-4,5,6,7-tetrahydroindazole using the method according to any of the preceding paragraphs and its transformation into pramipexol and, if necessary, separation of pramipexole on its R (+) and S (-) enantiomers and the allocation of R (+) and/or S (-) enantiomer.

12. The method according to claim 11, wherein the 2,6-diamino-4,5,6,7-tetrahydroindazole turn in pramipexol by reaction with Propionaldehyde.

13. The method according to claim 11 or 12, characterized in that the 2,6-diamino-4,5,6,7-tetrahydroindazole represents the R(+) enantiomer.

14. The method according to claim 11 or 12, characterized in that the 2,6-diamino-4,5,6,7-tetrahydroindazole represents the S(-) enantiomer.

15. The method according to claim 11 or 12, characterized in that the 2,6-diamino-4,5,6,7-tetrahydroindazole is a racemic mixture.



 

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EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

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EFFECT: higher efficiency of therapy.

14 cl, 354 ex

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< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

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FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

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FIELD: organic chemistry, chemical technology.

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EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, pharmacy.

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EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

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6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

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