The method of obtaining derivatives of piperidine-4(options) and derived lower alilovic esters of 3-[n-lower alkyl-n-[3- (2-karbassi alkoxy lower alkyl)]amino]-2,3-novyh acids

 

(57) Abstract:

In the invention the methods of obtaining derivatives of piperidine-4 by reductive cyclization of compounds of formula (II), followed by hydrolysis and decarboxylation in an acidic environment, as well as by hydrogenation of compounds of formula (II) with subsequent cyclization and treatment in an acidic environment, in addition the proposed new derivatives alilovic esters of 3-(N-lower alkyl-N - (3-(cerboneschi alkoxy lower alkyl))amino)-2,3 unsaturated carboxylic acids of General formula (II):

< / BR>
where R1-R7each independently denote hydrogen, phenyl, lower alkoxy, or lower alkyl, possibly substituted by phenyl or lower alkoxy. R8and R9is lower alkyl. 3 C.p. f-crystals, 2 tab.

The invention relates to a General organic chemistry, specifically, to methods for derivative piperidone-4 (I) containing substituents in different positions [1-6] as well as to new derived alilovic ethers of tri-(N-alkyl-N - (3-(2-carbalkoxy)-2,3-unsaturated carboxylic acid (II), which can be used for the synthesis of derivatives of piperidine-4. Derivatives piperidone-4 is widely used for the synthesis of pharmaceuticals in promyshlennovskogo replaced by finalom or lower alkoxy, R8, R9lower alkyl.

Known methods of synthesis piperidones.-4:

1. Condensation of aldehydes to esters aacondicionado acid in the presence of primary amines or ammonia [2,3]

< / BR>
where R, R1, R2and R6represent H, alkyl, aryl, etc.

The disadvantage of this method is the possibility to obtain only 1,2,6-substituted piperidone-4.

2. The interaction of diphenylmethane and primary amines [1,4,5,6]

< / BR>
The disadvantage of this method is the complexity of the synthesis source diphenylethanol and their instability (large amounts of waste, the use of explosive derivatives of acetylene).

The closest is a method for attaching a primary amine to the ester, unsaturated carboxylic acid and subsequent cyclization according to Dikman [8] according to the following scheme:

< / BR>
where R, R' represents H, alkyl, aryl, etc.

Cyclization of (IIIa) is carried out under the action of Alkonost alkali metal, subsequent hydrolysis and decarboxylation is carried out by heating (IVa) in an acidic environment.

This method is chosen as a prototype.

The disadvantage of this method is the possibility of the price obtained with a very low yield up to 10%

The aim of the invention is to develop a simple and feasible method of obtaining derivatives of piperidine-4 with high output, which may contain various substituents in the ring.

The method is reductive cyclization of derivatives alilovic esters of 3-(N-alkyl-N - (3-(2-carbalkoxy))amino)-2,3-unsaturated carboxylic acid (II) with subsequent treatment of the obtained compound (V) in an acidic environment. The process proceeds according to the following scheme:

< / BR>
where R1-R7represents hydrogen, phenyl, lower alkoxy, or lower alkyl, possibly substituted by phenyl or lower alkoxy; R8, R9lower alkyl.

The process of reductive cyclization is carried out in the processing of compounds of the formula (II) alkali metal in a solvent environment, which is a proton donor reactions, for example, lower alcohol, or mixtures thereof with inert in the reaction solvent. The output at this stage is 80-90% Hydrolysis and decarboxylation is conducted by heating in an acidic environment (yield 90-95% ). General method of synthesis of (I) options reductive cyclization shown in example 1.

The compounds of formula (I) in accordance with the invention can be polyh derivative III with subsequent processing of the obtained compounds (IV) in acidic medium according to the following scheme:

< / BR>
where R1-R7represent hydrogen, phenyl, lower alkoxy, or lower alkyl, possibly substituted by phenyl or lower alkoxy; R8, R9lower alkyl.

The hydrogenation process is carried out by catalytic hydrogenation, e.g. with hydrogen in the presence of palladium catalyst. Can be used and other hydrogenation catalysts.

General methods of synthesis (I) according to the variant of stepwise recovery and cyclization shown in example 2.

The initial compounds of General formula (II) to obtain the derivative piperidone by the way, versions of which are described above, are novel compounds and can easily be obtained by known methods.

Example 1. (+)-1,2,5-trimethylpyridine-4-one.

To a mixture of 122 g (0.5 mol) of ethyl ester of 3-(N-methyl-N - (3-(2-carbomethoxyamino))amino) crotonic acid and 400 ml of ethanol under stirring add to 25.3 g (1.1 mol) of metallic sodium, distilled alcohol, after which the reaction mixture was added 450 ml of 20% hydrochloric acid, and boil until a negative reaction to ketoester (IV) with ferric chloride. The reaction mixture is cooled, neutralized with a solution of alkali and mnogokratni 11 mm RT.article Yield 86%

IR spectrum (CHCl3, , cm-1); 1720(C=0), 2800(CH3-N).

Range PMR (GMDS, d, M. D.): 2,93 kV (1H, C2-C1H3, J 6 Hz), 2,46 kV(1H-C5-CH3, J 6 Hz), 2616 C(3H, CH3-N), 2.06 m (4H, CH2), and 1.00 (3H, -C2H= J 6 Hz), 0,80 d (3H, -C5H= J 6 Hz).

Found,C, 68.65; H, 10.02; N, 9.97. C8H15NO.

Calculated,C, 68.09; H 10,83; N, 9.93.

n2D01,4590. d2400,9437. GC: 1' 30" (Inerton 5% E301, T=220oC, l=2 m, d= 2 mm, 25 ml/min, helium).

Example 2. (+)-1,2,5-trimethylpyridine-4-one.

To a mixture of 122 g (0.5 mol) of ethyl ester of 3-(N-methyl-N - (3-(2-carbomethoxyamino))amino) crotonic acid and 400 ml of ethyl alcohol add 30 g of palladium on activated carbon obtained from 25 g of palladium chloride. Then through the reaction mass for several hours bubbled hydrogen at intensive stirring and filtered. The filter adds 12.68 g (0.55 mol) of metallic sodium. Further processing of the reaction mass are similar to example 1. Get to 103.5 g of (+)-1,2,5-trimethylpyridine-4-it. Exit 81% n2D01,4593.

Found,C, 68.50; H 10.10; N, 9.87. C8H15NO.

Calculated,C, 68.09; H 10.63; N, 9.93.

GC: 1' 30" (see chromatography was carried out in examples 1 and 2, the compounds, are given in table. 1.

The purity and structure of the substances listed in the table. 1, confirmed by the data of elemental analysis, GC, spectroscopic and mass spectrometry.

Example 12. Ethyl ester of 3-(N-methyl-N - (3-(2-carbomethoxyamino))amino) crotonic acid.

A mixture of 35.2 g (0.2 mol) of ethyl ester of 3,3-diethoxybutane acid and 28.8 g (0.2 mol) of ethyl ester of 3-(N-methyl)-2-methylpropanoic acid, 5 ml of epirate boron TRIFLUORIDE and 200 ml of absolute methanol is boiled for 10 hours Distilled methyl alcohol and distilled at 1 mm RT.article collecting the fraction 90-95oC.

Exit at 47.47 g (92.0% of theory), n2D01,4372, d2400,8763. Tthe melt.57-58oC.

IR spectrum (CHCT3, , cm-1): 1720, 1730(C=0):B B 3445 (CH3N); 1670, 3010(C=C).

Range PMR (GMDS, d, M. D.): 4.30 c(1H,CH), 3,82(2H, CH2-, J 7 Hz), 3.71 c(3H, CH3-C= ). 3.30 kV(2H. -CH2-CH3), 2,73 c(3H, CH3O), 2.31 c(3H, CH3-N), 1.10 (d(3H, CH3-CH2-, J 6 Hz), 1.10 kV (3H, CH3-CH, J 7 Hz).

Found, C, 55.70; H, 8.70; N, 6.39; C12H2NO4.

Calculated, C, 55.50; H, 8.72; N, 6.42.

GC: 6' 15" (Inerton 5% E301, E 220oC, l=2 m, d=2 mm, 25 ml/min, helium).

Similarly, the compounds obtained, printlogo analysis, GC and PMR spectroscopy.

Example 21. Obtaining methyl ester 3(-N-methyl-N-(3-(2-etoxycarbonyl-1-methylethyl))amino-2-methylpropionic acid.

The solution 24,30 g (0.1 mol) of ethyl ester of 3-(N-methyl-N - (3-(2-carbomethoxyamino))amino) crotonic acid in 100 ml of methyl alcohol hydronaut hydrogen at 50 MPa and room temperature for 4 hours the Solution is filtered, the liquid phase is separated, evaporated methanol and distilled at 1 mm RT.article collecting the fraction 110-125oC. Re-distillation gives the product with TKip.=115-117oC/1 mm RT.article the number 22,81, the Output 93.1% of

Range PMR (GMDS, d, M. D. ): 3.98 kV(2H, -OCH2-, 15 Hz), 3.53 c(3H, CH3N), 3.00 m (1H, -CH-), 2.2 m (5H, N-CH-, -CH-C), 2.10 c(3H, CH3O-), 1.0 m (9H, -CH3-C).

Found, C 58,92; H 9,15; N 5,85; C12H23NO4.

Calculated C 58,78; H To 9.32; N 5,7.

n2D01,4435, d2401,0831. GC: 4'45" (Inerton 5%E301, T=220oC, l=2 m, d=2 mm, 25 ml/min, helium).

Sources of information

1. M. C. Rubtsov, A., Belchikov "Synthetic chemical teravpevtichesky drugs) Medicine, 1971, S. 195-198.

2. Robinson r. Soc. v.111/112, p.762 (1917).

3. Hall, H. K. J. Am. Chem. v.79, No. 20, p.5444 (1957).

4. I. N. Nazarov, N. With. Simpletons, N. And. Shvetsov GOH, T. 26]. USSR VCN, 1949, No. 2, S. 493.

7. Ziering A. Berger, L. J. Org.Chem. v.12, p.895 (1947).

8. Mc Elvain S. M. Roring K. J. Am.Chem.Soc. v.70, Nj 5, p.1820 (1948).

1. The method of obtaining derivatives of piperidine-4 General formula I

< / BR>
where R1R7each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy,

including cyclization of derivatives of esters aminocarbonyl acids in the presence of an alcoholate of alkali metals with subsequent treatment of products of cyclization by heating in an acidic medium, characterized in that as derived esters aminocarbonyl acids use derivatives lowest alilovic esters of 3-[N-lower alkyl-N-[3-(2 cerboneschi alkoxy lower alkyl)]amino]-2,3-novyh acids of General formula II

< / BR>
where R1R7each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;

R8and R9denote lower alkyl.

2. The method according to p. 1, wherein the process is carried out in the presence of an inert solvent.

3. The method of obtaining derivatives of piperidine-4 General formula I

< / BR>
where R1R7each independently of the including cyclization of derivatives of esters of monocarboxylic acids in the presence of an alcoholate of alkali metals with subsequent treatment of products of cyclization by heating in an acidic medium, characterized in that, as derived esters aminocarbonyl acids use derivatives lowest alilovic esters of 3-[N-lower alkyl-N-[3-(2 cerboneschi alkoxy lower alkyl)]amino] carboxylic acids of General formula III

< / BR>
where R1R7each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;

R8and R9denotes lower alkyl, obtained by hydrogenation of derivatives of lower alilovic esters of 3-[N-lower alkyl-N-[3-(2-carbonize alkoxylate alkyl)]amino]-2, 3-novyh acids of General formula II

< / BR>
4. Derivatives lowest alilovic esters of 3-[N-lower alkyl-N-3-(2 carnisse alkoxylate alkyl)]amino]-2,3-novyh acids of General formula II

< / BR>
where R1R7each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;

R8and R9denote lower alkyl.

 

Same patents:

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a method for preparing derivatives of benzoxazine and describes a method for preparing compound represented by the formula . Method involves of compound represented by the formula (I): with compound represented by the formula (II-1-a): in the presence of a base to form compound represented by the formula (III-1-a): followed by reduction of this compound to compound represented by the formula (IV-a): , interaction of this compound with compound represented by the following formula: to form compound represented by the formula (V-a): and the following treatment of this compound in the presence of a base to obtain compound represented by the formula (VI-a): , treatment of this compound with compound of boron trifluorine and its conversion by this manner to the boron chelate compound represented by the following formula: followed by reaction of this compound with 4-methylpiperazine to obtain compound represented by the following formula: followed by cleavage and elimination of boron chelate of this compound. In each of above given formulas X1, X2 and X3 represents independently halogen atom; R1 represents a leaving group; R3 represents hydrogen atom or carboxyl-protecting group; R4 represents hydroxyl-protecting group; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms; R7 represents carboxyl-protecting group; Y represents alkoxy-group comprising 1-6 carbon atoms, halogen atom or dialkylamino-group (wherein alkyl groups can be similar or different and each represents alkyl group comprising 1-6 carbon atoms). Also, invention describes variants above described method, methods for preparing intermediate compounds and intermediate compound. Invention provides industrially favorable methods for preparing intermediate compounds that are useful for preparing compounds with antibacterial properties.

EFFECT: improved preparing methods, valuable properties of compounds.

96 cl, 102 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of making compounds with formula , involving reaction of but-2-enoic acid with chlorotrimethylsilane, bromination of the obtained trimethylsilylcrotonate with N-bromosuccinimide, reaction of the obtained trimethylsilyl-4-bromocrotonate or methyl or ethyl 4-bromocrotonate with dimethylamine so as to obtain 4-dimethylaminocrotonic acid, its separation in form of hydrochloride and chlorination with oxalyl chloride. The method allows for obtaining 4-dimethylamino-2-butenoylchloride, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

EFFECT: obtaining the agent, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

1 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing enantiomeric excess of asymmetrically alkynylated α-aminoesters of formula (III) in which R1 and R2 independently denote C1-7-alkyl, optionally substituted with phenyl or trimethylsilyl, or C3-5-cycloalkyl; Y denotes H or a nitrogen atom protecting group. The method involves reaction of α-iminoester of formula (I), in which R1 and Y assume values given for formula III, with an alkyl containing a terminal triple bond, of formula (II), in which R2 assumes values given for formula III, in the presence of a catalyst. The catalyst used contains a transition metal complex CuPF6·4MeCN or CuOTf·0.5C6H6 and a chiral ligand selected from , enantiomers thereof and mixture of enantiomers thereof.

EFFECT: method provides high output of asymmetrically alkynylated α-aminoesters of formula (III), which can be used in synthesis as optically active derivatives of amino acids which do not occur naturally.

3 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing a fluorine-containing acylacetic acid derivative of formula (3) involving preparation of a mixture containing a base, a compound of formula (1) and a compound of formula (2) and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; where Rf, R1, R2, R3 and R4 represent the same as given above. The invention also relates to a method of producing a fluorine-containing pyrazolecarboxylic acid ester derivative of formula (5), involving the following steps: - obtaining a mixture containing a base, a compound of formula (1) and a compound of formula (2), and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; to obtain a fluorine-containing acylacetic acid derivative of formula (3), where Rf, R1, R2, R3 and R4 represent the same as given above; - reaction of the obtained compound of formula (3) with a compound of formula (4) where R5 is an alkyl group having 1-6 carbon atoms, to obtain a compound of formula (5) where Rf, R3, R4 and R5 represent the same as given above; and a method of producing a fluorine-containing pyrazolecarboxylic acid derivative of formula (6) involving the following steps: - obtaining a mixture containing a base, a compound of formula (1) and a compound of formula (2), and adding a halogenating agent to the mixture, where Rf is an alkyl group having 1-6 carbon atoms which is substituted by at least one fluorine atom; where R1 and R2 each independently represents an alkyl group having 1-6 carbon atoms; R3 is a hydrogen atom; and R4 is an alkyl group having 1-6 carbon atoms; to obtain a fluorine-containing acylacetic acid derivative of formula (3), where Rf, R1, R2, R3 and R4 represent the same as given above; - reaction of the obtained compound of formula (3) with a compound of formula (4), where R5 is an alkyl group having 1-6 carbon atoms, to obtain a compound of formula (5), where Rf, R3, R4 and R5 represent the same as given above; -hydrolysis of the compound of formula (5) to obtain a compound of formula (6), where Rf, R3 and R5 represent the same as given above. Addition of a halogenating agent at the last step facilitates the desired reaction with good output.

EFFECT: improved method of producing a fluorine-containing acylacetic acid derivative.

6 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing N,N-diallylaminoethanoic acid which is used in synthesis of water-soluble polyelectrolytes. The method involves reaction of allyl chloride with a reaction mixture cooled to 0-5°C consisting of α-aminoacetic acid and sodium hydroxide in a water-alcohol solution for 15-30 minutes. Further, the reaction temperature is raised to 60-75°C and the reaction mixture is held for 3-5 hours. After the reaction, the reaction mixture gradually poured into dry acetone in portions. N,N-diallylaminoethanoic acid in form of flakes gathers on the surface of acetone and salts precipitate.

EFFECT: novel method of producing N,N-diallylaminoethanoic acid.

1 cl, 4 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry and specifically to N,N-diallyl aspartic acid of formula , which can be used as a starting compound (monomer) for producing novel polyelectrolytes with a controlled acid-base and hydrophilic-hydrophobic balance, which are used as flocculants, coagulants, etc.

EFFECT: invention also relates to a method of producing N,N-diallyl aspartic acid by reacting a sodium salt of α-aspartic acid in a water-alcohol solution with allyl chloride.

2 cl, 1 dwg, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of enantioselective allylic amination of derivatives of α,β-unsaturated carboxylic acids with obtaining enantiomerically enriched derivatives, described by formulae II , III , VII and VIII . Method is performed by interaction of racemic mixture of carboxylic acid derivative with chiral ligand on catalyst [Pd(allyl)Cl]2 in presence of nucleophilic reagent, selected from potassium phthalimide or amine of formula R1R2NH, where R1 represents benzyl, n-butyl or cyclohexyl group, R2 represents hydrogen or benzyl group.

EFFECT: enantioselective palladium-catalysed ally lamination of derivatives of α,β-unsaturated carboxylic acids with obtaining products with increased enantionmeric excess.

10 cl, 6 dwg, 3 tbl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I: cis-COOR-XCH-(CH2)a-CH=CH-(CH2)b-CH3, wherein (a) and (b) can take any value from 0 to 14, (X) is specified in: OH, NH2, CH3, F, F3C, HS, O-CH3, PO4(CH2-CH3)2 and CH3COO, and (R) represents sodium (Na) applicable for preventing and/or treating obesity, hypertension and/or cancer. Also, the invention refers to using the compounds of formula I for preparing a pharmaceutical and/or nutrient composition, to the pharmaceutical and/or nutrient composition based on the compounds of formula I, to a cosmetic, non-therapeutic method for improving skin manifestations and to a method for preventing and/or treating the diseases in humans and animals with using the compounds of formula I.

EFFECT: preparing the new compounds.

18 cl, 22 dwg, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic and medical chemistry, more specifically to bis{2-[(2E)-4-hydroxy-4-oxobut-2-enoyloxy]-N,N-diethylethanaminium} butan-dioate of formula I. Invention also relates to a method of producing the compound of formula I.

EFFECT: invention can be used as a neuroprotective agent.

3 cl, 2 tbl, 3 ex

I

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing formula I compounds and their salts, , where R1 is H or F; and Boc is tert-butoxycarbonyl. These compounds are useful as intermediate products during production of tryptase inhibitors.

EFFECT: invention also relates to intermediate products, which can be used when producing said compounds, as well as to methods of producing such intermediate products and their use in production of said compounds.

20 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

Phenyl derivative // 2639875

FIELD: pharmacology.

SUBSTANCE: invention relates to a compound of the general formula (I) having a high antagonistic activity with respect to human S1P2, and can be used to prepare a drug for treatment of a disease mediated by S1P2, such as a disease caused by vasoconstriction, fibrosis and respiratory disease.

EFFECT: compound application efficiency increase.

14 cl, 2 tbl, 9 ex

Up!