Pyperidin-4-ylamide derivatives and their application as antagonists of sst receptor subtupe 5

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: I, where R1 is selected from group, consisting of ethyl, 2-fluorethyl and isopropyl; R2 is selected from group, consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6, where R6 represents C1-7-alkyl, amino, phenyl, phenyl, substituted with 1-3 substituents, selected from group, consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl; R3 is selected from group, consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl and -o-tetrahydropyranyl; or R2 and R3 are bound to each other with formation of cycle together with carbon atoms to which they are bound, and R2 and R3 together represent -CH=CH-NH-; R4 is selected from group, consisting of hydrogen, halogen, pyridyl and pyrimidyl; R5 and R5' independently on each other are selected from hydrogen or methyl; A is selected from group, consisting of isphenyl; phenyl, substituted with 1-3 substituents, selected from group, consisting of C1-7-alkyl, C3-7-cycloalkyl, C1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylene-C(O)NR10R11, -C(O)OR10, -C1-7-alkylene-C(O)OR10, -O-C1-7-alkylene-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano- C1-7-alkoxy, fluorphenyl, pyridyl, tetrazolyl and tetrazolyl- C1-7-alkoxy; 1,3-benzodioxolyl; naphtyl; pyrimidinyl; pyridyl, substituted with one or two substituents, selected from group, consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino, C3-7-cycloalkylamino, halogen, cyano, morpholinyl, imidazolyl and -NH-C(O)-R9, where R9 represents C1-7-alkyl or C3-7-cycloalkyl, and indolyl; R10 and R11 independently on each other represent hydrogen or C1-7-alkyl; and to their pharmaceutically accdeptable salts. Invention also relates to pharmaceutical compositions.

EFFECT: obtaining novel biologically active compounds, which are antagonists of somatostatin receptor subtype 5 (SSTR5).

26 cl, 266 ex

 

The text descriptions are given in facsimile form.

1. The compounds of formula

where R1selected from the group consisting of ethyl, 2-veratile and isopropyl;
R2selected from the group consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy,
With3-7-cycloalkyl,
halogen,
-C(O)OR6where R6represents a C1-7-alkyl,
amino,
phenyl,
phenyl, substituted with 1-3 substituents selected from the group,
consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl;
R3selected from the group consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl-O-tetrahydropyranyl;
or R2and R3connected to each other to form a cycle together with the carbon atoms to which they are attached, and R2and R3together are-CH=CH-NH-;
R4selected from the group consisting of hydrogen, halogen, pyridyl and pyrimidyl;
R5and R5'independently from each other selected from hydrogen or methyl;
And selected from the group consisting the th of
phenyl;
phenyl, substituted with 1-3 substituents selected from the group consisting of C1-7-alkyl, C3-7-cycloalkyl,1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylen-C(O)NRl0Rll, -C(O)OR10- 1-7-alkylen-C(O)or SIG10, -O-C1-7-alkylen-C(O)OR-10, halogen, halogen-C1-7-alkoxy, cyano-C1-7-alkoxy, ftoheia, pyridyl, tetrazolyl and tetrazolyl-C1-7-alkoxy;
1,3-benzodioxolyl;
naphthyl;
pyrimidinyl;
pyridyl substituted by one or two substituents selected from the group consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino,3-7-cyclooctylamino, halogen, cyano, morpholinyl, imidazolyl and-NH-C(O)-R9where R9represents a C1-7-alkyl or C3-7-cycloalkyl,and indolyl;
R10and R11independently from each other represent hydrogen or C1-7-alkyl,
and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, where a represents phenyl or phenyl substituted by 1-3 substituents, in the abusive group, consisting of C1-7-alkyl, C3-7-cycloalkyl,1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylen-C(O)NR10R11, -C(O)OR10- 1-7-alkylen-C(O)OR10,
-O-C1-7-alkylen-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano-C1-7-alkoxy, ftoheia, pyridyl, tetrazolyl and tetrazolyl-C1-7-alkoxy.

3. The compounds of formula I according to claim 1, where a represents phenyl, substituted with 1-3 substituents selected from the group consisting of C1-7-alkyl, C1-7-alkylsulfonyl,1-7-alkoxy, hydroxy-C1-7-alkyl, C1-7-alkylamino, di-C1-7-alkylamino, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, -O-C1-7-alkylen-C(O)NRl0Rll, -C(O)OR10, halogen, halogen-C1-7-alkoxy and cyano-C1-7-alkoxy.

4. The compounds of formula I according to claim 1, where a represents phenyl, substituted C1-7-alkylsulfonyl or1-7-alkyl.

5. The compounds of formula I according to claim 1, where a is selected from the group consisting of 1,3-benzodioxolyl;
naphthyl;
pyrimidyl;
pyridyl, replaced by one who, or two substituents, selected from the group consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino,3-7-cyclooctylamino, halogen, cyano, morpholinyl, imidazolyl and-NH-C(O)-R9where R9represents a C1-7-alkyl or C3-7-cycloalkyl,and indolyl.

6. The compounds of formula I according to claim 1, where a is a pyridyl, substituted with one or two substituents selected from the group consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino,3-7-cyclooctylamino, halogen, cyano, morpholinyl, imidazolyl and-NH-C(O)-R9where R9represents a C1-7-alkyl or C3-7-cycloalkyl.

7. The compounds of formula I according to claim 1, where a is a pyridyl, substituted with one or two substituents selected from the group consisting of C1-7-alkyl, amino, C1-7-alkylamino, cyano and halogen.

8. The compounds of formula I according to claim 1, where R2selected from the group consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6where R6represents a C1-7-alkyl, amino, pyridyl, imidazolyl, triazolyl and pyrrolyl.

9. The compounds of formula I of claim 1, where R2selected from the group consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, -O-C3-7/sub> -cycloalkyl, halogen, -C(O)OR6where R6represents a C1-7-alkyl, amino and pyrrolyl.

10. The compounds of formula I according to claim 1, where R2selected from C1-7-alkyl, C1-7-alkoxy and halogen.

11. The compounds of formula I according to claim 1, where R2is imidazolyl or pyrrolyl.

12. The compounds of formula I according to claim 1, where R2represents phenyl or phenyl substituted by 1-3 substituents selected from the group consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy.

13. The compounds of formula I according to claim 1, where R2represents phenyl, substituted with 1-3 substituents selected from the group consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy.

14. The compounds of formula I according to claim 1, where R3and R4represent hydrogen.

15. The compounds of formula I according to claim 1, where R3represents a C1-7-alkoxy or-O-tetrahydropyranyl.

16. The compounds of formula I according to claim 1, where R4represents pyridyl or pyrimidyl.

17. The compounds of formula I according to clause 16, where R3represents hydrogen.

18. The compounds of formula I according to claim 1, where R5and R5'represent hydrogen.

19. The compounds of formula I according to claim 1, where R1represents ethyl.

20. The compounds of formula I according to claim 1, where
R1selected from the group consisting of ethyl and and the oprofile;
R2selected from the group consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy,
halogen,
-C(O)OR6where R6represents a C1-7-alkyl,
amino and pyrrolyl;
R3selected from the group consisting of hydrogen, C1-7-alkoxy, amino, and-O-tetrahydropyranyl;
R4selected from the group consisting of hydrogen, pyridyl and pyrimidyl;
R5and R5independently from each other selected from hydrogen or methyl;
And selected from the group consisting of phenyl;
phenyl, substituted with 1-3 substituents selected from the group consisting of C1-7-alkylsulfonyl,1-7-alkoxy, C1-7-alkyl, C1-7-alkylamino, di-C1-7-alkylamino, -C(O)NH2and halogen;
1,3-benzodioxolyl;
naphthyl;
pyridyl substituted by one or two substituents selected from the group consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di - C1-7-alkylamino, morpholinyl, imidazolyl and-NH-C(O)-R9where R9represents a C1-7-alkyl or C3-7-cycloalkyl; and indoline,
and their pharmaceutically acceptable salts.

21. The compounds of formula I according to claim 1, selected from the group consisting of the following compounds:
N-[1-(4-chloro-3-ethoxybenzyl)piperidine-4-yl]-3-methysulfonylmethane,
N-[1-(4-chloro-3-ethoxybenzyl)piperidine-4-yl]-3-methylbenzamide,
N-[-(4-chloro-3-ethoxybenzyl)piperidine-4-yl]-6-nicotine amide,
6-amino-N-[1-(4-chloro-3-ethoxybenzyl)piperidine-4-yl]nicotinamide,
N-[1-(4-chloro-3-ethoxybenzyl)piperidine-4-yl]-5-nicotine amide,
N-{1-[3-ethoxy-5-(tetrahydropyran-4-yloxy)benzyl]piperidine-4-yl}-5-nicotine amide,
N-[1-(3-ethoxy-4-methylbenzyl)piperidine-4-yl]-5-nicotine amide,
N-[1-(3-ethoxy-4-methoxybenzyl)piperidine-4-yl]-5-nicotine amide,
N-[1-(3-ethoxy-4-methoxy-2-pyridin-4-yl-)piperidine-4-ylbenzyl]-5-nicotine amide,
N-[1-(3-ethoxy-4-methoxy-2-pyrimidine-5-ylbenzyl)piperidine-4-yl]-5-nicotine amide,
and their pharmaceutically acceptable salts.

22. The compounds of formula I according to claim 1, selected from the group consisting of the following compounds:
N-[1-(2-ethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-nicotine amide,
N-[1-(2-ethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-6-metilnikotinamid,
N-[1-(3,5-diethoxy-4-imidazol-1-ylbenzyl)piperidine-4-yl]-5-nicotine amide,
N-[1-(3,5-diethoxy-4-pyrrol-1-ylbenzyl)piperidine-4-yl]-2,6-dimethyltryptamine acid,
N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-6-metilnikotinamid,
N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-nicotine amide,
6-chloro-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]nicotinamide,
6-amino-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]nicotinamide,
N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-6-isopropylamino name,
N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-3-hydroxymethyl-5-methoxybenzamide,
N-[1-(4-chloro-3,5-diethoxybenzoic)piperidine-4-yl]-5-methoxyethylamine acid,
N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-methoxyethylamine acid,
N-[1-(2,6-diethoxy-3',5'-diferuloyl-4-ylmethyl)piperidine-4-yl]-5-nicotine amide,
3 cyanoethoxy-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-methoxybenzamide,
rat-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-3-(2,3-dihydroxypropane)-5-methoxybenzamide,
3 carbamoylphenoxy-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-methoxybenzamide,
6-cyano-N-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-yl]-5-nicotine amide,
{3-[1-(2,6-diethoxy-4'-forbiden-4-ylmethyl)piperidine-4-ylcarbonyl]-5-methoxyphenoxy} acetic acid,
and their pharmaceutically acceptable salts.

23. Pharmaceutical compositions containing a compound according to any one of claims 1 to 22, which is an antagonist of the somatostatin receptor subtype 5 (SSTR5), as well as pharmaceutically acceptable carrier and/or adjuvant.

24. The pharmaceutical composition according to item 23, intended for the treatment and/or prevention of diseases that are associated with the modulation of SST receptors subtype 5.

25. Compounds according to any one of claims 1 to 22, which are antagonists of the somatostatin receptor is adtype 5 (SSTR5).

26. Compounds according to any one of claims 1 to 22 for use as therapeutically active substances for the treatment and/or prevention of diseases that are associated with the modulation of SST receptors subtype 5.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention relates to 2,4-pyrimidindiamins, such as N4-(4-Chlorine-3-methoxyphenyl)-5-fluorine-N2-[3-(N-ethylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-(3-Chlorine-4-methjopxycarbonylmethylenoxyphenyl)-5-fluorine- N2-[3-(N-methylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-[3-Chlorine-4-(N-methylamino)carbonylmethylenoxyphenyl]-5-fluorine-N2-[3-(]N methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin, N4-[3-Chlorine-4-(2-hydroxyethylenoxy)phenyl]-5-fluorine-N2-[3-(N- methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin and other compounds given in item 1 of claimed invention as Syk-kinase inhibitors, as well as to based on them pharmaceutical composition and their application.

EFFECT: claimed compounds can be applied for treatment of autoimmune diseases, systemic http://lingvo.yandex.ru/?text=lupus%20erythematosus, rheumatoid arthritis, etc.

12 cl, 27 dwg, 11 tbl, 1797 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds N-(2-furylalkyl)-NHR carbamides with formula 1: , exhibiting growth-regulating and immuno-modeling activity, and method of producing them. The method involves reacting furfuryl idenacetone with urea in hydroamination conditions in an autoclave, in the presence of skeletal nickel catalyst and an organic solvent at 70-90°C temperature, and ratio of substrate to reagent equal to 1:1 or 2:1.

EFFECT: invention can be used in agriculture.

2 cl, 9 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in novel tocopherol-modified therapeutic drug compounds of formula 1 T-L-D, T is tocopherol, L is succinate, and D is camptotecin or its derivative, where all three fragments are bound covalently. Invention also relates to emulsions based on said compounds, formulations of micelles, including said compounds, methods of treating cell proliferative disease using said compounds and formulations, as well as to said compounds application for production of medication for treatment of cell proliferative disease.

EFFECT: increase of composition and treatment method efficiency.

18 cl, 17 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which have inhibiting properties on activity of at least one kinase selected from veGFR2, EphB4, PDGFRβ and c-Kit, having general formula I , where R denotes 0-1 substitutes independently selected from halogen, (C1-C6)-alkyl, (C1-C6) -alkoxy; R7 and R8 together with carbon atoms with which they are bonded form a condensed 5-member heteroaryl ring substituted with a -(Z1)mR1 group, where the heteroaryl ring contains at least one nitrogen atom and optionally an extra nitrogen atom; R1 is pyridinyl which can be substituted, where the substitutes are independently selected from hydroxy, cyano, halogen, (C1-C6)-alkyl, (C1-C6) - alkoxy, morpholinyl, imidazolyl, tetrazolyl, aminocarbonyl and -NHR10, where R10 is selected from hydrogen; (C1-C6)-alkyl; allyl, phenyl or pyrimidinyl, which may be substituted with CN; thiazolyl, pyridinyl, sulphonyl which is substituted with (C1-C6)-alkyl, an acyl which may be substituted with (C1-C6)-alkoxy, imidazolyl, cyclopropyl, (C1-C6)-alkyl, possibly substituted with NH2, NH(C1-C4-alkyl), N((C1-C4)-alkyl (C1-C4-alkyl)), hydroxy, (C1-C4)alkoxy, morpholinyl, pyrrolidinyl; Z1 is - CR5R6-, where each of R5 and R6 is selected from hydrogen; and m equals 1; R2 is benzo[1,3]dioxo-5-lyl or phenyl, which may be substituted with (C1-C6)-alkyl, halogen(C1-C6)-alkyl, halogen, phenyl, (C1-C6)-alkylsulphonyl or (C1-C6)-alkoxy, whose alkyl part may be substituted with hydroxyl, halogen, dioxanyl; and each of R3 and R4 is selected from hydrogen; provided that the formula 1 compound is not 5-(phenylcarbamoylamino)-3-(2-(4-pyridyl)ethyl)indole, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(1-(pyridin-4-yl)-1H-indol-5-yl)urea and 1(2-methoxy-5-(trifluoromethyl)phenyl)-3-(1-pyridin-4-yl)-1H-indol-5-yl)urea, as well as their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition, an inhibiting method and a method of preparing a pharmaceutical composition.

EFFECT: more effective use of the compounds.

29 cl, 1 dwg, 6 ex

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