Imidazopyrimidines and imidazopyridine, the pharmaceutical composition based on them, the method of treatment of neurological disorders

 

Describes the derived imidazopyrimidines or imidazopyridine General formula (I), where a denotes N or C-R7In denotes N or C-R8; D substituted phenyl, X represents CH-R9, O, S(O)nand communication, R1stands With1-10alkyl, C3-8cycloalkyl, replaced by the groups-CN, COR13With2-8alkenyl,1-4halogenated, R2selected from the group including1-4alkyl, C3-8cycloalkyl, substituted with halogen and C1-4alkoxy, R3denotes H, C1-4alkyl and / or pharmaceutical composition and a method of treatment of neurological disorders. The technical result consists in obtaining antagonist factor in the release of corticotropin (CRF) of the formula (I) used for the treatment in mammals of psychiatric disorders and neurological diseases, disorders caused by anxiety and post-traumatic stress. 3 S. and 3 C.p. f-crystals, 15 PL.

Description text in facsimile form (see graphic part).

Claims

1. Derived imidazopyrimidines or imidazopyridine formula (I)or article is provided at least one of the groups a and b is N; D is phenyl, substituted by 1-4 substituents, which are in each case independently selected from group C1-6alkyl, methylenedioxy, -OR17, Cl, F, C1-4halogenated, -CN, -S(O)nR18, -NR17R19, -COR17and up to 1 phenyl, each phenyl substituent of substituted 1,2 substituents selected from the group comprising C1-3alkyl or benzofuranyl, oxazolyl, imidazolyl, pyridyl, indolyl, substituted 2 substituents, which are in each case independently selected from the group including1-6alkyl, -OR17, Cl; X is chosen from the group including CH-R9, O, S(O)nand communications; n = 0, 1, or 2;
R1selected from the group including C1-10alkyl, C3-8cycloalkyl,3-6cycloalkyl-C1-6alkyl; R1replaced with 0-1 substituents selected from the group comprising-CN, -COR13a, CO2R13a, -CONR13aR16aand C3-8cycloalkyl, where 0-1 carbon atom in the C4-8cycloalkyl substituted by a group selected from-O-; R1replaced also 0-3 substituents, which are in each case independently selected from the group including1a, R1bC1-6alkyl, C2-8alkenyl, SL, which is substituted by 0-1 R9provided that R1is not: (a) cyclohexyl-(CH2)2group; (b) 3-cyclopropyl-3-methoxypropyl group; (C) unsubstituted (alkoxy)methyl group; (d) 1-hydroxyalkyl group, and provided that when R1denotes alkyl, replaced IT, then the carbon atom adjacent to the ring N is CH2;
R1adenotes phenyl, substituted 0-1-OR17and 1 to 3 substituents, which are in each case independently selected from the group including C1-6alkyl, Br, Cl, F, -CN;
R1bdenotes heteroaryl chosen from the group comprising a pyridyl, furanyl, thienyl, imidazolyl, indolyl, oxazolyl, triazolyl, tetrazolyl, each heteroaryl substituted by 0, 1 substituents selected from the group comprising C1-6alkyl;
R2selected from the group including C1-4alkyl, C3-8cycloalkyl, he substituted 1, 2 substituents selected from the group comprising halogen and C1-4alkoxy;
R3, R7and R8in each case independently selected from the group including H, C1-4alkyl;
provided that when R1denotes unsubstituted C1-10alkyl, then R3not avsey, including H, C1-4, alkyl;
R13aand R16ain each case independently selected from the group including H, C1-4alkyl;
R17in each case independently selected from the group including H, C1-6alkyl, C1-2alkoxy-C1-2alkyl, C1-4halogenated;
R18and R19in each case independently selected from C1-6of alkyl;
in part NR17R19the elements of R17and R19taken together, form 1-morpholinyl.

2. Connection on p. 1, where the compound has formula Ia

3. Connection on p. 1, where the compound has formula Ib

4. Connection on p. 1, where the compound has formula IC

5. The pharmaceutical composition inhibiting the release of corticotropin (CRF) containing a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds of formula (I), where a denotes N or C-R7; In denotes N or C-R8; provided that at least one of the groups a and b is N; D is phenyl, substituted by 1-4 substituents, which are in each case independently selected from group C1-6Ala>and up to 1 phenyl, each phenyl substituent of substituted 1,2 substituents selected from the group comprising C1-3alkyl or benzofuranyl, oxazolyl, imidazolyl, pyridyl, indolyl, substituted 2 substituents, which are in each case independently selected from the group including1-6alkyl, -OR17, Cl, X is chosen from the group including CH-R9, O, S(O)nand communications; n = 0, 1, or 2; R1selected from the group including C1-10alkyl, C3-8cycloalkyl,3-6cycloalkyl-C1-6alkyl; R1replaced with 0-1 substituents selected from the group comprising-CN, -COR13a, CO2R13a, -CONR13aR16aand C3-8cycloalkyl, where 0-1 carbon atom in the C4-8cycloalkyl substituted by a group selected from-O-; R1replaced also 0-3 substituents, which are in each case independently selected from the group including1a, R1bC1-6alkyl, C2-8alkenyl, C2-8quinil, C1-4halogenated, OR13aC1-4alkoxy-C1-4alkyl and C3-8cycloalkyl, which is substituted by 0-1 R9provided that R1is not: (a) cyclohexyl-(CH2)2group; (b) 3-cyclopropyl-3-methoxypropyl group; (c) unsubstituted (alkoxy)m is ewenny HE then the carbon atom adjacent to the ring N is CH2; R1adenotes phenyl, substituted 0-1-OR17and 1 to 3 substituents, which are in each case independently selected from the group including C1-6alkyl, Br, Cl, F, CN; R1bdenotes heteroaryl chosen from the group comprising a pyridyl, furanyl, thienyl, imidazolyl, indolyl, oxazolyl, triazolyl, tetrazolyl, each heteroaryl substituted by 0, 1 substituents selected from the group comprising C1-6alkyl; R2selected from the group including C1-4alkyl, C3-8cycloalkyl, he substituted 1, 2 substituents selected from the group comprising halogen and C1-4alkoxy; R3, R7and R8in each case independently selected from the group including H, C1-4alkyl; provided that when R1denotes unsubstituted C1-10alkyl, then R3is not substituted or unsubstituted phenyl; R9in each case independently selected from the group including H, C1-4, alkyl; R13aand R16ain each case independently selected from the group including H, C1-4alkyl; R17in each case independently selected from the group including the m case independently selected from C1-6of alkyl; NR17R19the elements of R17and R19taken together, form 1-morpholinyl.

6. A method of treating a mammal affective disorder, anxiety, depression, irritable bowel syndrome, supranuclear palsy, Alzheimer's disease, gastrointestinal diseases, neurotic anorexia, or other digestive disorders, cardiovascular and heart disease, stroke, side amiotroficheskogo sclerosis, which is that the mammal is administered a therapeutically effective amount of the compounds of formula (I)

or its stereoisomer or pharmaceutically acceptable salt,
where a denotes N or C-R7;
In denotes N or C-R8;
provided that at least one of the groups a and b is N;
D denotes phenyl, substituted by 1-4 substituents, which are in each case independently selected from group C1-6alkyl, methylenedioxy, -OR17, Cl, F, C1-4halogenated, -CN, -S (O)nR18, -NR17R19, -COR17and up to 1 phenyl, each phenyl substituent of substituted 1,2 substituents selected from the group comprising C1-3alkyl or benzofur is independently selected from the group include1-6alkyl, -OR17, Cl;
X is chosen from the group including CH-R9, O, S(O)nand communication;
n = 0, 1, or 2;
R1selected from the group including C1-10alkyl, C3-8cycloalkyl,3-6cycloalkyl-C1-6alkyl; R1replaced with 0-1 substituents selected from the group comprising-CN, -COR13a, CO2R13a, -CONR13aR16aand C3-8cycloalkyl, where 0-1 carbon atom in the C4-8cycloalkyl substituted by a group selected from-O-; R1replaced also 0-3 substituents, which are in each case independently selected from the group including1a, R1bC1-6alkyl, C2-8alkenyl,2-8quinil, C1-4halogenated, OR13aC1-4alkoxy-C1-4alkyl and C3-8cycloalkyl, which is substituted by 0-1 R9provided that R1is not: (a) cyclohexyl-(CH2)2group; (b) 3-cyclopropyl-3-methoxypropyl group; (c) unsubstituted (alkoxy)methyl group; (d) 1-hydroxyalkyl group, and provided that when R1denotes alkyl, replaced IT, then the carbon atom adjacent to the ring N is CH2;
R1adenotes phenyl, substituted 0-1-OR17and 1 to 3 substituents, which means heteroaryl, chosen from the group comprising a pyridyl, furanyl, thienyl, imidazolyl, indolyl, oxazolyl, triazolyl, tetrazolyl, each heteroaryl substituted by 0, 1 substituents selected from the group comprising From1-6alkyl;
R2selected from the group including C1-4alkyl, C3-8cycloalkyl, he substituted 1, 2 substituents selected from the group comprising halogen and C1-4alkoxy;
R3, R7and R8in each case independently selected from the group including H, C1-4alkyl;
provided that when R1denotes unsubstituted C1-10alkyl, then R3is not substituted or unsubstituted phenyl;
R9in each case independently selected from the group including H, C1-4alkyl;
R13aand R16ain each case independently selected from the group including H, C1-4alkyl;
R17in each case independently selected from the group including H, C1-6alkyl, C1-2alkoxy-C1-2alkyl, C1-4halogenated;
R18and R19in each case independently selected from C1-6of alkyl;
in part NR17R19the elements of R17and R19taken instead of the Sabbath.

 

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