Compounds and compositions as protein tyrosine kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula Ia

and its pharmaceutically acceptable salts, where
p is chosen from 0 and 1;
n means 1-3;
q is 1;
R5selected from hydrogen, -XNR7R8the pyrimidine-C0-4of alkyl, pyridine-C0-4of alkyl, phenyl, C3-10cycloalkyl-C0-4the alkyl and C3-6heteroseksualci-C0-4of alkyl, where C3-6heteroseksualci is a rich monocyclic the forge ring system, containing the specified number of atoms, provided that one or more of the carbon atoms replaced by O or NR, where R is hydrogen or C1-4alkyl; R7and R8represent1-4alkyl;
R6represents hydrogen; or R5and R6together with the nitrogen atom to which they are both attached, form a morpholine or piperidine;
where any pyrimidine-C0-4alkyl, pyridine-C0-4alkyl or C3-10cycloalkyl-C0-4the alkyl substituent R5,or a combination of the radicals R5and R6may be optionally substituted by 1-2 radicals, which are independently selected from-XNR7R8and-XOR7specified phenyl substituent R5substituted by a group-XR9,
specified With3-6heteroseksualci-C0-4the alkyl substituent R5optionally substituted by a group-XOR7where X represents a simple bond or a C1-4alkylen;
R7and R8independently selected from hydrogen and C1-4of alkyl; and
R9choose from C3-10geterotsiklicheskie, which is a saturated monocyclic ring system containing the specified number of atoms, provided that one or more of the carbon atoms replaced by O or NR, where R values specified above;
R10means hydrogen;
R15selected from halogen, C-6 the alkyl and C1-6alkoxy; and
R16selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12and-C(O)NR12R13where each R12selected from hydrogen and C1-6of alkyl;
R13selected from phenyl, teinila, pyrazolyl, pyridinyl or isoxazolyl where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl Deputy R13may be optionally substituted by 1-2 radicals, which are independently selected from halogen, C1-6of alkyl, halogen-substituted C1-6of alkyl, imidazol-C0-4of alkyl, C3-10cycloalkyl,3-10heteroseksualci-C0-4alkoxy and C3-10heteroseksualci-C0-4of alkyl; and specified With3-10heteroseksualci-C0-4alkoxy and C3-10heteroseksualci-C0-4alkyl, each represent a saturated monocyclic ring system containing the specified number of atoms, provided that one or more of the carbon atoms replaced by O or NR, where R has the above meanings; and specified With3-10heteroseksualci-C0-4alkoxy and C3-10heteroseksualci-C0-4the each alkyl may be optionally substituted 1 radical independently selected from C1-6of alkyl, hydroxylamino1-6the alkyl and NR7R8where R7and R8 are the above values.

2. The compound according to claim 1, where R5selected from hydrogen, diethylaminoethyl, morpholinomethyl, morpholinoethyl, morpholinopropan, cyclopropyl, 3-(2-oxo-pyrrolidin-1-yl)propyl, diethylaminoethyl; benzo[1,3]dioxol-5-yl, 3-(4-methylpiperazin-1-yl)propyl, morpholino, pyridinyl, methylpyridine, aminocyclohexane, piperidinyl, methylpiperidine, methylpiperazine, methylpiperazine, methylpiperazine, ethylpyrrolidin, dimethylpyridine, methylpyridine, dimethylaminoethyl, methylpyrrolidinyl, pyrrolidinyl, dimethylaminopropyl, morpholinopropan, methylpiperazine, benzo[1,3]dioxol-5-ylmethyl, methylpyrimidine, methoxypyridine, pyridinylmethyl, pyridinylmethyl, aminocyclohexane and dimethylaminomethyl.

3. The compound according to claim 1, where R16selected from halogen, methoxy, nitro, -NH2, -COOH, -NHC(O)R13and-C(O)other13in which R13selected from phenyl, pyridinyl, pyrazolyl, isoxazolyl and tanila; and R13optionally substituted by 1-2 radicals, which are independently selected from methyl, tert-butyl, cyclopropyl, halogen, trifloromethyl, piperidylamine, pyrrolidinyloxy, ethylpiperazine, morpholino, methylpiperazine, methylpiperazine, ethylpiperazine, methylimidazole, morpholinomethyl, piperazinylmethyl, piperazinil, Dimity is aminopyrrolidine and hydroxyethylpiperazine.

4. The compound according to claim 1, selected from the group consisting of the following compounds:
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]benzamide (1),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-morpholine-4-yl-5-cryptomelane (2),
N-(3-{1-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (3),
N-(3-{1-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-4-(2-Mei-1-yl)-3-cryptomelane (4),
N-(3-{1-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-(4-Mei-1-yl)-5-cryptomelane (5),
N-(3-{1-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-4-(4-ethylpiperazin-1-ylmethyl)-3-cryptomelane (6),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-cryptomelane (7),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-4-(2-Mei-1-yl)-3-cryptomelane (8),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-5-methoxy-N-(3-triptoreline)benzamide (9),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-N-[4-(4-ethylpiperazin-1-ylmethyl)-3-triptoreline]-4-methylbenzamide (10),
(3,5-acid)-{1-[6-(4-(morpholine-4-ylphenyl the Mino)pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine (12),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-N-(3-triptoreline)benzamide (13),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-benzoic acid (14),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]benzamide (15),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-(4-Mei-1-yl)-5-cryptomelane (16),
N-3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-4-methylbenzo-1,3-diamine (18),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2-methyl-5-nitro-phenyl)amine (19),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-morpholine-4-yl-5-cryptomelane (20),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-(4-ethylpiperazin-1-yl)-5-cryptomelane (21),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were)-3-(4-ethylpiperazin-1-ylmethyl)-5-cryptomelane(22),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-4-morpholine-4-yl-3-cryptomelane (23),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-methyl-N-[4-(2-Mei-1-yl)-3-triptoreline]benzamide (24),
2,5-dimethoxy-N-methyl-3-{1-[6-(4-(morpholine-4-ilfenomeno)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}benzamide(25),
N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-3-Tr is formatively (27),
4-methyl-N3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)benzene-1,3-diamine (28),
(3,5-dichlorophenyl)-(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)amine (32),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(3,5-dichlorophenyl)-amine (37),
N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-3-piperazine-1-yl-5-cryptomelane (39),
3-(4-methylpiperazin-1-yl)-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (40),
3-(4-ethylpiperazin-1-yl)-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (41),
3-[4-(2-hydroxyethyl)piperazine-1-yl]-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (42),
3-(4-Mei-1-yl)-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (43),
3-(3-dimethylaminopropan-1-yl)-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (47),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(3-bromo-2-were)amine (49),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(5-bromo-2-were)amine (50),
3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-2,5-dimethoxy-N-methylbenzamide (52),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-methylbenzamide (53),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-chlorobenzamide (54),
N-{3-[1-(6-aminopyrimidine-4-and the)-1H-benzoimidazol-2-ylamino]-4-were}-3-(4-methylpiperazin-1-yl)-5-cryptomelane (56),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were)-3-(4-ethylpiperazin-1-yl)-5-cryptomelane (57),
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-chloro-4-(4-ethylpiperazin-1-ylmethyl)benzamide (58),
{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}amide 5-tert-butylthiophene-2-carboxylic acid (61),
{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}amide 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (62),
{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}amide 5-cyclopropyl-2H-pyrazole-3-carboxylic acid (63),
{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}amide 1-tert-butyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrazole-3-carboxylic acid (64),
(2-chloro-5-methoxyphenyl)-{1-[6-(4-N,N-diethylaminoethylamine)-pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine,
N-{4-methyl-3-[1-(6-morpholine-4-Yeremey-4-yl)-1H-benzoimidazol-2-ylamino]phenyl}-3-cryptomelane (79),
N-(4-methyl-3-{1-[6-(1-methylpiperidin-4-ylamino)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}phenyl)-3-cryptomelane (81),
N-(4-methyl-3-{1-[6-(4-methylpiperazin-1 ylamino)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}phenyl)-3-cryptomelane (82),
N-(4-methyl-3-{1-[6-(2-pyrrolidin-1 ylethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}phenyl)-3-cryptomelane (83),
N-[4-methyl-3-(1-{6-[2-(4-Mei the piperazine-1-yl)ethylamino]pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)phenyl]-3-cryptomelane (84),
N-(3-{1-[6-(2-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (85),
N-[4-methyl-3-(1-{6-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)phenyl]-3-cryptomelane (86),
N-[3-(1-{6-[(1-ethylpyrrolidin-2-ylmethyl)amino]pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)-4-were]-3-cryptomelane (87 and 88),
N-[3-(1-{6-[4-(2-hydroxyethyl)piperazine-1-ylamino]pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)-4-were]-3-cryptomelane (89),
N-(4-methyl-3-{1-[6-(3-morpholine-4-ylpropionic)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}phenyl)-3-cryptomelane (90),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(4-bromo-2-were)amine (93),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(3-bromo-2,4,6-trimetilfenil)amine (98),
N-(4-methyl-3-{1-[6-(2-pyridin-2-ylethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}phenyl)-3-cryptomelane (108),
N-(3-{1-[6-(4-aminocyclohexane)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (109),
[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]amide 2,5-dimethyl-2H-pyrazole-3-carboxylic acid (111),
[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]amide 5-tert-butylthiophene-2-carboxylic acid (112),
2-tert-butyl-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]isonicotinamide (113),
[4-meth is l-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]amide 5-methylisoxazol-3-carboxylic acid (114),
N-(3-{1-[6-(4-dimethylaminomethylene)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (115),
,,
.

5. Pharmaceutical composition for the inhibition of c-Src, FGFR3, KDR and/or Lck, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable filler.

6. Pharmaceutical composition for the inhibition of c-Src, FGFR3, KDR and/or Lck, comprising a therapeutically effective amount of a compound according to claim 4 and a pharmaceutically acceptable filler.

7. The compound of the formula

and its pharmaceutically acceptable salts, where
p is chosen from 0 and 1;
n means 2-3;
q means 0-1;
R5selected from hydrogen, -XNR7R8, phenyl, pyrimidine, pyridine and C3-10heteroseksualci-C0-4of alkyl, where C3-10heteroseksualci represents a saturated monocyclic ring system containing the specified number of atoms, provided that one or more of the carbon atoms replaced by O or NR, where R is hydrogen or C1-4alkyl;
R7and R8represent1-4alkyl;
R6represents hydrogen; or R5and R6together with the nitrogen atom to which they are both attached, form a morpholine;
where the shown phenyl pyridine or any substituent R 5or a combination of the radicals R5and R6may be optionally substituted by 1-2 radicals, which are independently selected from C1-6the alkyl and -- XR9where X represents a simple bond or a C1-4alkylen;
R9choose from C3-10geterotsiklicheskie, which is a saturated monocyclic ring system containing the specified number of atoms, provided that one or more of the carbon atoms replaced by O or NR where R represents hydrogen or C1-4alkyl; and specified With3-10heteroseksualci Deputy R9may be optionally substituted-XOR7where the values of X and R7above;
R10means hydrogen;
R15selected from halogen, nitro, C1-6the alkyl and C1-6alkoxy; and
R16selected from a halogen, and-C(O)NR12R12where each R12independently selected from hydrogen and C1-6the alkyl.

8. The connection according to claim 7, where the join is chosen from the group consisting of the following compounds:
(2-chloro-6-were)-(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)amine (30),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2-chloro-6-were)amine (35),
(2-chloro-6-were)-[1-(6-morpholine-4-Yeremey-4-yl)-1H-benzoimidazol-2-yl]amine (69),
(2-chloro-6-were)-{1-[6-(morpholine-4-ylamino)pyrimidine-4-yl]-1H-benzamid the evils-2-yl)amine (70),
(2-chloro-6-were)-(1-{6-[2-(4-methylpiperazin-1-yl)ethylamino] pyrimidine-4-yl}-1H-benzoimidazol-2-yl)amine (71),
(2-chloro-6-were)-{1-[6-(3-morpholine-4-ylpropionic)pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine (72),
(2-chloro-6-were)-{1-[6-(4-(morpholine-4-reparacin-1-
yl)pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine (73),
(2-chloro-6-were)-{1-[6-(4-N,N-diethylaminoethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine (74),
(2-chloro-6-were)-{1-[6-(4-(morpholine-4-iletileri-2-yl-amino)pyrimidine-4-yl]-1H-benzoimidazol-2-yl}amine (77),
(2-chloro-6-were)-(1-{6-[5-(2-morpholine-4-retil)pyridine-2-yl-amino]pyrimidine-4-yl}-1H-benzoimidazol-2-yl)amine (78),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2,4,6-trimethyl-phenyl)amine (94),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(4-bromo-2,6-dimetilfenil)amine (95),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2-bromo-4,6-dimetilfenil)amine (96),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(4-bromo-2-chloro-6-were)amine (97).

9. Pharmaceutical composition for the inhibition of c-Src, FGFR3, KDR and/or Lck, comprising a therapeutically effective amount of a compound according to claim 7 and a pharmaceutically acceptable filler.

10. Pharmaceutical composition for the inhibition of c-Src, FGFR3, KDR and/or Lck, comprising a therapeutically effective amount of a compound of claim 8 and a pharmaceutically acceptable filler.

11. Connection using the data from the group consisting of the following compounds:
N-{3-[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-(1-methylpiperidin-4-yloxy)-5-cryptomelane (17),
(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)-o-tolylamino (26),
(4-tert-butylphenyl)-(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)amine (29),
(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)-(2-trifloromethyl)amine (31),
(4-phenoxyphenyl)-(1-pyrimidine-4-yl-1H-benzoimidazol-2-yl)amine (33),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(4-tert-butylphenyl)amine (34),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2-trifloromethyl)amine (36),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(4-phenoxyphenyl)-amine (38),
N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-3-(piperidine-4-yloxy)-5-cryptomelane (44),
3-(1-methylpiperidin-4-yloxy)-N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-5-cryptomelane (45),
N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-3-(piperidine-4-ylamino)-5-cryptomelane (46),
N-[4-methyl-3-(1-pyrimidine-4-yl-1H-benzoimidazol-2-ylamino)phenyl]-3-(pyrrolidin-2-yloxy)-5-cryptomelane (48),
[1-(6-aminopyridin-4-yl)-1H-benzoimidazol-2-yl]-(2,5-dimetilfenil)amine (51),
N-{3-[1-(6-chloropyrimidine-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-cryptomelane (59),
N-{4-methyl-3-[1-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-1H-benzoimidazol-2-the laminitis]phenyl}-3-cryptomelane (60),
N-{3-[1-(6-methoxypyridine-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-cryptomelane (65),
N-(3-{1-[6-(2-dimethylaminoethoxy)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (66),
(2-chloro-6-were)-[1-(6-chloropyrimidine-4-yl)-1H-benzoimidazol-2-yl]amine (67),
2-[4-(6-{6-[2-(2-chloro-6-methylphenylimino)benzoimidazol-1-yl]pyrimidine-4-ylamino}-2-methylpyrimidin-4-yl)piperazine-1-yl]ethanol (68),
N-(3-{1-[6-(2-hydroxyethylamino)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (80),
N-{6-[2-(2-chloro-6-methylphenylimino)benzoimidazol-1-yl]pyrimidine-4-yl}-2-methyl-N-(2-morpholine-4-retil)pyrimidine-4,6-diamine (91),
N-{6-[2-(2-chloro-6-methylphenylimino)benzoimidazol-1-yl]pyrimidine-4-yl}-5-methyl-N-(2-morpholine-4-retil)pyrimidine-4,6-diamine (92),
2-(4-{6-[6-(2-chlorobenzimidazole-1-yl)pyrimidine-4-ylamino]-2-methyl-pyrimidine-4-yl}piperazine-1-yl)ethanol (99),
2-[4-(6-{6-[2-(5-methoxy-2-methylphenylimino)benzoimidazol-1-yl]pyrimidine-4-ylamino}-2-methylpyrimidin-4-yl)piperazine-1-yl]ethanol (100),
2-[4-(6-{6-[2-(4-bromo-2-methylphenylimino)benzoimidazol-1-yl]pyrimidine-4-ylamino}-2-methylpyrimidin-4-yl)piperazine-1-yl]ethanol (101),
2-[4-(2-methyl-6-{6-[2-(2,4,6-trimethylaniline)benzoimidazol-1-yl]pyrimidine-4-ylamino}pyrimidine-4-yl)piperazine-1-yl]ethanol (102),
2-[4-(6-{6-[2-(3-chloro-2,6-dimethylphenylimino)benzoimidazol-1-yl]pyrimidine-4-ylamino}-2-methylpyrimidin-4-yl)piperazine--yl]ethanol (103),
N-(3-{3-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-3H-imidazo[4,5-b]pyridine-2-ylamino}-4-were)-3-cryptomelane (104),
N-(3-{1-[6-(1-hydroxymethyl-2-methylpropylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (105),
N-(3-{1-[6-(2,3-dihydroxy-propylamino)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (106),
N-(3-{1-[6-(2-methoxyethylamine)pyrimidine-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (107),
3-{3-[6-(4-diethylaminoethylamine)pyrimidine-4-yl]-3H-imidazo[4,5-b]pyridine-2-ylamino}-4-methyl-N-(3-triptoreline)benzamide (110),
N-{3-[1-(6-chloro-5-methylpyrimidin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-cryptomelane (116),
N-{3-[1-(6-amino-5-methylpyrimidin-4-yl)-1H-benzoimidazol-2-ylamino]-4-were}-3-cryptomelane (117),
N-[4-methyl-3-(1-{5-methyl-6-[2-(4-methylpiperazin-1-yl)ethylamino]-pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)phenyl]-3-cryptomelane (118),
N-[4-methyl-3-(1-{5-methyl-6-[3-(4-methylpiperazin-1-yl)propylamino] pyrimidine-4-yl}-1H-benzoimidazol-2-ylamino)phenyl]-3-cryptomelane (119),
N-(3-{1-[6-(4-diethylaminoethylamine)-5-methylpyrimidin-4-yl]-1H-benzoimidazol-2-ylamino}-4-were)-3-cryptomelane (120).

12. Pharmaceutical composition for the inhibition of c-Src, FGFR3, KDR and/or Lck, comprising a therapeutically effective amount is soedineniya according to claim 11 and a pharmaceutically acceptable excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide by reacting 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one-hydrochloride with 5-chlorothiophene-2-carbonyl chloride, distinguished by that the reaction is carried out in a solvent selected from ether, alcohol, ketone and water or a mixture thereof using an inorganic base.

EFFECT: design of a simple method for synthesis of said thiophenecarboxamide without use of toxic solvents.

13 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing new 3,4-dithienyl-substituted maleic anhydrides or maleimides of general formula I: , where X=O, or NR1; R1 and R2=alkyl C1-C4; R3=alkyl C1-C4, or nitrogen- and/or sulphur-containing heterocyclic substitute. The method involves reacting the corresponding 2,5-disubstituted 3-thienyl-acetic acid with the corresponding 2,5-disubstituted 3-halogen acetythiophenes while heating in the presence of a base in a medium of inert organic solvent in atmospheric oxygen with subsequent separation of the end product of general formula I, where X=O, or, if necessary, the latter is converted to a compound of general formula I, where X=NR1, where R1 assumes values given above, by treating it with the corresponding amine. These compounds can be used as photochromes, which are widely used as optical switches in high-capacity data carriers used for recording, processing and storing data.

EFFECT: versatility of the method, ie possibility of obtaining compounds with and without equivalent heterocyclic substitutes using readily available thienyl-acetic acid and halogen ketones of the thiophene family, which considerably widens the assortment of organic photochromic dithienylethenes.

4 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound represented by formula (1) , in formula A represents nitrogen-containing saturated ring; m represents integer number, equal to 0, 1 or 2; n represents integer number, equal to 1, 2, 3 or 4; G1 represents atom of hydrogen, hydroxyl group or alkoxygroup; G2 represents atom of halogen, hydroxyl group, cyanogroup, alkyl group, alkenyl group, alkinyl group, which may be substituted with hydroxyalkyl group, alkoxygroup, alkyl thiogroup, aminogroup or aryl group; G3 represents atom of hydrogen; G4 represents hydroxyl group or -N(R1)(R2) (R1 and R2 may be identical or different, and independently represent atom of hydrogen, alkyl group, aralkyl group, alkenyl group or saturated heterocyclic group); and G5 represents substituent at carbonic atom, which constitutes nitrogen-containing saturated ring, represented with A, and represents atom of hydrogen, to medicinal agent on the basis of this compound for treatment and prophylaxis of glaucoma, to inhibitor of phosphorylation of regulatory light chain of myosin and inhibitor of kinase Rho/Rho path, and also to method of therapeutical and/or prophylactic treatment of glaucoma.

EFFECT: new compounds have been produced and described, which efficiently inhibit phosphorylation of regulatory light chain of myosin.

32 cl, 42 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I) , where

R1 -C1-8alkyl; R2 - pyridynyl, unnecessarily substituted with C1-8alkyl, quinolyl or isoquinolyl; R3 - hydrogen or C1-8alkylcarbonyl; R4 means group of formula G-L1-(CRR')n-, in which n is integer number from 0 to 3; R and R' are independently selected from group that includes atoms of hydrogen and lower alkyl groups; L1 means connection group, selected from group, which includes direct connection, groups -O-, -CO-, -NR"-, -O(CO)O-, -O-(CO)-, -(CO)O- and -NR"-(CO)-, where R" is lower alkyl; G is selected from group, including atoms of hydrogen, C1-8alkyl, C2-8alkenyl, C3-7dicloalkyl, phenylC1-8alkyl, pyridinyl, thiophenyl or residue of indan, and also phenyl, unnecessarily substituted with atom of halogen, C1-8alkoxy, cyano- or C1-8alkyl, which, in its turn, unnecessarily contains one or more atoms of halogen. Specified compounds are active and selective inhibitors of phosphodiesterase 4 (FDE4), therefore, they are applicable for treatment, prevention or suppression of pathological conditions, diseases or disorders, for which it is known that their behavior is relieved by inhibition of FDE4, such as asthma, chronic obstructive lung disease, rheumatoid arthritis, atopic dermatitis, psoriasis or syndrome of sore large gut. Invention is related also to pharmaceutical compositions on the basis of mentioned compounds, application of compounds, method for treatment of subject, when efficient amount of specified compounds is introduced to them. Besides invention is related to combined product for treatment or prevention of pathological condition or disease, behavior of which is relieved by inhibition of phosphodiesterase 4, including specified compound and another compound, selected from the group that includes (a) steroids, (b) immunosuppressive agents, (c) blockers of T-cells receptors, (d) anti-inflammatory medicinal agents, (e) β2-adrenergic agonists and (f) antagonists of muscarine receptors M3, for single-time, separate or serial use.

EFFECT: improved efficiency of compounds use.

11 cl, 2 tbl, 77 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

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