Novel histone deacetylase inhibitors

FIELD: chemistry.

SUBSTANCE: present invention describes novel compounds of formula (I), where substitutes R1, R2, R3, Ar and A are described in the formula of invention, having histone deacetylase inhibiting activity, use thereof and methods for synthesis of said compounds.

EFFECT: improved composition properties.

15 cl, 72 ex, 9 tbl, 6 dwg

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

where R3represents hydrogen;
Ar represents phenyl or naphthyl, optionally substituted by one or two groups selected from halogen, hydroxy, C1-4of alkyl, C1-4alkoxy, drifters1-4of alkyl, drifters1-4alkoxy, dis1-4elcamino-, morpholine, morpholine-4-yl-methyl, piperazinil, 4-methyl-piperazine-1-Il, methoxycarbonyl, monocyclic or bicyclic heterocyclic 5-9-membered unsaturated ring containing 1 heteroatom selected from N, O or S, optionally substituted by a halogen atom;
But a
and
where R2selected from hydrogen, C1-4of alkyl, halogen, C1-4alkoxy;
R1is:
or
and R1attached in the meta - or para-position to the N-hydroxyacetylamino group, and where Y represents Oh; provided that when a represents pyridyloxy group, R1located in the para-position to the N-hydroxyacetamido group and to the Yes R 1represents 1-oxo-prop-2-enyl, Ar represents phenyl.

2. The compound according to claim 1, in which R1group, and R3containing group, preferably bound in the para position relative to each other in the ring A.

3. The compound according to claim 1, having one of the following structures:

where Ar and R2have the above meanings and X represents a carbon atom or nitrogen.

4. The compound according to claim 3, in which in the formula (Ia-c) X represents a carbon atom, R2 represents hydrogen and Ar is chosen from: phenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 1-naphthyl, 5-dihydrobenzofuran, despite the fact that in the formula (Ic) Ar represents phenyl.

5. Compounds according to claim 1, chosen from:
3-[3-fluoro-4-(3-oxo-3-phenylpropyl)phenyl]-N-hydroxyacetamido;
3-[3-chloro-4-(3-oxo-3-phenylpropyl)phenyl]-N-hydroxyacetamido;
3-[3-chloro-4-(3-oxo-3-o-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-chloro-4-[3-(2-methoxyphenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-chloro-4-[3-(2-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-chloro-4-[3-(2-chlorophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-[3-chloro-4-(3-oxo-3-m-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-chloro-4-[3-(3-methoxyphenyl)-3-oxopropyl]phenyl-N-hydroxyacetamido;
3-{3-chloro-4-[3-(3-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-chloro-4-[3-(3-chlorophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-[3-chloro-4-(3-oxo-3-p-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-chloro-4-[3-(4-methoxyphenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-chloro-4-[3-(4-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-chloro-4-[3-(4-chlorophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-[3-chloro-4-(3-oxo-3-thiophene-2-ylpropyl)phenyl]-N-hydroxyacetamido;
3-[3-fluoro-4-(3-oxo-3-o-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(2-methoxyphenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(2-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{4-[3-(2-chlorophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-[3-fluoro-4-(3-oxo-3-m-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(3-methoxyphenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(3-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{4-[3-(3-chlorophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-[3-fluoro-4-(3-oxo-3-p-tolylpropan)phenyl]-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(4-methoxyphenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(4-forfinal)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{4-[3-(4-chlorophenyl)-3-oxopropyl]-3-forfinal}-N-hydroxyacetamido;
3-[3-fluoro-4-(3-oxo-3-thio is EN-2-ylpropyl)phenyl]-N-hydroxyacetamido;
3-{3-fluoro-4-[3-(4-(morpholine-4-yl-phenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
N-hydroxy-3-{4-[3-(2-methoxyphenyl)-3-oxopropyl]phenyl}-acrylamide;
N-hydroxy-3-{4-[3-oxo-3-(2-triptoreline)propenyl]phenyl}-acrylamide;
N-hydroxy-3-{4-[3-oxo-3-(2-trifloromethyl)propenyl]phenyl}-acrylamide;
3-{4-[3-(2-bromophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
N-hydroxy-3-{4-[3-(3-methoxyphenyl)-3-oxopropyl]phenyl}-acrylamide;
3-{4-[3-(3-bromophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
N-hydroxy-3-{4-[3-(4-methoxyphenyl)-3-oxopropyl]phenyl}acrylamide
N-hydroxy-3-{4-[3-oxo-3-(4-triptoreline)propenyl]phenyl}acrylamide;
N-hydroxy-3-{4-[3-oxo-3-(4-trifloromethyl)propenyl]phenyl}-acrylamide;
3-{4-[3-(4-bromophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
3-{4-[3-(4-diethylaminophenyl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
N-hydroxy-3-{4-[3-4-morpholine-4-yl-phenyl)-3-oxopropyl]phenyl}acrylamide;
3-[4-(3-furan-2-yl-3-oxopropyl)phenyl]-N-hydroxyacetamido;
N-hydroxy-3-[4-(3-oxo-3-thiophene-2-ylpropyl)phenyl]acrylamide;
N-hydroxy-3-{4-[3-oxo-3-(1H-pyrrol-2-yl)propenyl]phenyl}acrylamide;
3-[4-(3-benzofuran-2-yl-3-oxopropyl)phenyl]-N-hydroxyacetamido;
3-[4-(3-benzo[b]thiophene-2-yl-3-oxopropyl)phenyl]-N-hydroxyacetamido;
N-hydroxy-3-[4-(3-oxo-3-thiophene-3-ylpropyl)phenyl]acrylamide;
N-hydroxy-3-{4-[3-3-methoxy-4-morph the Lin-4-yl-were)-3-oxopropyl]phenyl}acrylamide;
3-{4-[3-(3,4-differenl)-3-oxopropyl]-phenyl}-N-hydroxyacetamido;
3-{4-[3-(3,5-differenl)-3-oxopropyl]-phenyl}-N-hydroxyacetamido;
3-{4-[3-(2,5-differenl)-3-oxopropyl]-phenyl}-N-hydroxyacetamido;
3-{4-[3-(2,6-differenl)-3-oxopropyl]-phenyl}-N-hydroxyacetamido;
N-hydroxy-3-[3-methoxy-4-(3-oxo-3-thiophene-2-yl-propenyl)-phenyl]-acrylamide;
N-hydroxy-3-[3-methyl-4-(3-oxo-3-thiophene-2-yl-propenyl)-phenyl]-acrylamide;
difficult methyl ester 4-{3-[4-(2-hydroxycarbamoyl)phenyl]-acryloyl} benzoic acid;
difficult methyl ester 3-{3-[4-(2-hydroxycarbamoyl)-phenyl]-acryloyl}benzoic acid;
3-{4-[3-(5-chlorothiophene-2-yl)-3-oxopropyl]phenyl}-N-hydroxyacetamido;
N-hydroxy-3-{4-[3-(3-hydroxyphenyl)-3-oxopropyl]phenyl}acrylamide;
N-hydroxy-3-(4-{3-[3-(4-methylpiperazin-1-yl)phenyl]-3-oxopropyl} phenyl)acrylamide;
N-hydroxy-3-[2-methoxy-4-(3-oxo-3-phenylpropyl)phenyl]-acrylamide;
3-[2-fluoro-4-(3-oxo-3-phenylpropyl)phenyl]-N-hydroxyacetamido;
3-[2-chloro-4-(3-oxo-3-phenylpropyl)phenyl]-N-hydroxyacetamido;
N-hydroxy-3-[4-(3-oxo-3-pyridin-3-ylpropyl)phenyl]acrylamide;
N-hydroxy-3-[4-(3-oxo-3-pyridin-2-ylpropyl)phenyl]acrylamide;
N-hydroxy-3-[4-(3-oxo-3-pyridin-4-ylpropyl)phenyl]acrylamide;
N-hydroxy-3-[3-methyl-4-(3-oxo-3-phenylpropyl)phenyl]-acrylamide;
N-hydroxy-3-[3-methoxy-4-(3-oxo-3-phenylpropyl)phenyl-acrylamide;
3-[3-fluoro-4-(3-oxo-3-pyridin-3-ylpropyl)phenyl]-N-hydroxyacetamido;
N-hydroxy-3-[5-(3-oxo-3-phenylpropyl)pyridine-2-yl]acrylamide;
N-hydroxy-3-{5-[3-(2-methoxyphenyl)-3-oxopropyl]-pyridine-2-yl}acrylamide;
N-hydroxy-3-[5-(3-oxo-3-thiophene-2-ylpropyl)-pyridine-2-yl]acrylamide;
3-{5-[3-(3,4-differenl)-3-oxopropyl]pyridine-2-yl}-N-hydroxyacetamido;

6. The compound according to claims 1-5 inhibition historiescrazy.

7. The method of obtaining compounds of formula (I),

where R3represents hydrogen;
Ar represents phenyl or naphthyl, optionally substituted by one or two groups selected from halogen, hydroxy, C1-4of alkyl, C1-4alkoxy, drifters1-4of alkyl, drifters1-4alkoxy, dis1-4alkylamino-, morpholine, morpholine-4-yl-methyl, piperazinil, 4-methyl-piperazine-1-Il, methoxycarbonyl, monocyclic or bicyclic heterocyclic 5-9-membered unsaturated ring containing 1 heteroatom selected from N, O or S, optionally substituted by a halogen atom;
But a

where R2selected from hydrogen, C1-4of alkyl, halogen, C1-4alkoxy;
R1is:

where Y represents O,
including the interaction of compounds of the formula (VII)

where the leaving group is a halogen, with a compound of formula (III)

where Z represents O-alkyl group selected from t-Bu groups in the conditions of the Heck reaction with obtaining the compounds of formula (IX)

removing the protective group to obtain the compounds of formula (VI)

the interaction of this compound with the compound of the formula (VII)

obtaining an intermediate product of the formula (V)

his interaction with protected hydroxylamine (NH2OPG1), where PG1represents a protective group,
removing protection from obtaining the compounds of formula (I).

8. The method of obtaining the compounds of formula (I):

where R3represents hydrogen;
Ar is an unsubstituted phenyl;
But a

where R2selected from halogen;
R1represents a

where Y is Oh, comprising the conversion of the aldehyde of formula (II)

where R4represents a halogen in the appropriate dimethylacetal formula (XII)

where In represents g the lågen
interaction with alkyllithium, with the subsequent addition of DMF) in an aprotic solvent to obtain compounds of formula (XI)

the interaction of the compound (XI) with compound (VII)

in the presence of inorganic bases in proton solvent to obtain compounds of formula (X)

the interaction of the compounds of formula (X) with tert-butyldiethanolamine in the presence of an inorganic base in an aprotic solvent, and after removing the protective group to obtain the compounds of formula (V)

his interaction with protected hydroxylamine (NH2OPG1), where PG1represents a protective group, removing the protecting obtaining the compounds of formula (I).

9. The method of obtaining the compounds of formula (I):

where R3represents hydrogen;
Ar is an unsubstituted phenyl or pyridinyl;
Rather it represents a phenyl,
R2selected from hydrogen, C1-4of alkyl, halogen, C1-4alkoxy;
R1is a structure

where Y represents Oh, including interaction of the compound (VIII)

where the leaving group is a halogen with soedinenieto (VII)

obtaining the compounds of formula (XIII)

the interaction of the compounds of formula (XIII) with tert-butyl acrylate in the conditions of the Heck reaction, and removing the protective group of ester, resulting in obtaining the compounds of formula (V)

his interaction with protected hydroxylamine (NH2OPG1), where PG1represents a protective group, removing the protecting obtaining the compounds of formula (I).

10. The method of obtaining the compounds of formula (I):

where R3represents hydrogen;
Ar represents a phenyl ring, optionally substituted by two halogen atoms or With1-4alkoxygroup or unsubstituted thiophene;
A represents a pyridine,
R2represents hydrogen;
R1is a structure

where Y represents Oh, including interaction of the compound (II)

where the leaving group R4represents a halogen
with alkyllithium with the subsequent addition of DMF) in an aprotic solvent to obtain compounds of formula (XVI)

with tert-butyldiethanolamine in the presence of an inorganic base in an aprotic solvent;
prevremeni is dimethylacetal in the appropriate aldehyde of the formula (XV):

interaction with the compound of the formula (VII)

obtaining after removal of the protective group of ester tert-butyl, compound of formula (XIV)

the interaction of the compounds of formula (XIV) with a protected hydroxyamino (NH2OPG1), where PG1represents a protective group,
removing protection from obtaining the compounds of formula (I).

11. The method according to claim 7, where the compound of formula (III) represents n-butyl acrylate.

12. The method according to claim 7, where the reaction of the accession of the compounds of formula (III) is conducted in the presence of potassium phosphate and acetate palladium.

13. The method of obtaining the compounds of formula (I)

where R3represents hydrogen;
Ar represents phenyl or naphthyl, optionally substituted by one or two groups selected from halogen, hydroxy, C1-4of alkyl, C1-4alkoxy, drifters1-4of alkyl, drifters1-4alkoxy, dis1-4elcamino-, morpholine, morpholine-4-yl-methyl, piperazinil, 4-methyl-piperazine-1-Il, methoxycarbonyl, monocyclic or bicyclic heterocyclic 5-9-membered unsaturated ring containing 1 heteroatom selected from N, O or S, optionally substituted by a halogen atom;
But a

where R2selected from hydrogen, C1-4of alkyl, halogen, C1-4alkoxy;
R1represents a

and R1attached in meta-position to N-hydroxyacetylamino group, and where Y represents O,
includes the following stages of the synthesis of

where X="C",
stage and perform in the presence of potassium phosphate and acetate, palladium, stage b perform the addition of an appropriate quantity of acetophenone to n-butyl-3-formicinae in alcohol-core environment, the stage to perform processing carboxylic acid derivative protected hydroxylamine (NHzOPG1), where PG1represents a protective group, under standard conditions of formation of peptide bonds.

14. The compound of formula (I)

where R3represents hydrogen;
Ar represents a phenyl, a is selected from

where R2selected from hydrogen, C1-4of alkyl, halogen, C1-4alkoxy;
R1is:

and R1attached in the para-position to the N-hydroxyacetylamino group, and where Y represents Oh, according to the following synthesis scheme

where the stage and perform in alcohol primary environment,
stage b is performed in the presence of the tvii phosphate and potassium acetate, palladium, stage - alcohol primary environment,
stage d - interaction ethylchloride and triethylamine, followed by treatment of 0-(2-methoxy-2-propyl)hydroxylamine and alyazia on ion-exchange resin.

15. The application of one or more compounds of the formula (I) according to claims 1 to 6 in the preparation of a medicine for inhibiting the deacetylation of histones.



 

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38 cl, 22 ex

FIELD: medicine, pharmaceutics.

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27 cl, 147 ex

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7 cl, 1 tbl, 53 ex

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7 cl, 179 ex

FIELD: chemistry.

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EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

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EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of new complexing analytical reagents which are suitable for doping nanoparticles and for use in luminescence-spectral analysis, biochip technology, as well as extractants of ions of heavy and rare-earth metals. Description is given of complexing benzo-containing heterocyclic compounds, which contain a β-dicarbonyl substitute with fluorinated radicals of formula: HetAr-C(O)CH2C(O)CF3, where HetAr= ,

which form luminescent complexes with Eu3+ ions. Proposed compounds are on the same level as compounds with closely resembling structure with regards to duration of luminescence and bonding efficiency, although they are easily accessible with respect technology of production and have high water solubility >10-4 mol/l, which enables their use in making conceptually new biochips with time, spatial and spectral signal selection.

EFFECT: high output of desired product.

1 cl, 5 dwg, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

The invention relates to new triaromatic the vitamin D analogues of General formula (I):

where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)

where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)

R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,

R3-

where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

FIELD: chemistry.

SUBSTANCE: present invention is related to thiophen amidines of general formula I or their solvate, hydrate or pharmaceutically acceptable salt, where Z stands for -S(O2)-; R1 - halogen, amino, C1-6alkylthio; Ar - phenyl, piridyl, thiazolyl, phuranyl, benzothiazolyl, benzimidazolyl, every of which is not necessarily substituted; R2, R3, R4 and R7- hydrogen Compounds may be used for inhibition of ferment Cls, protease of classical pathway of complement system. Pharmaceutical compositions are also described on the basis of formula I compounds.

EFFECT: compounds may find application for treatment of certain acute and chronic immunological diseases, some neurogenerative diseases.

24 cl, 1 tbl, 337 ex

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