AR039562A1 - OXO-AZABICICLIC COMPOUNDS - Google Patents

Abstract

Oxo-azabicyclic compounds and their use for the preparation of a pharmaceutical composition to treat the inhibition of type 13 matrix metalloprotease, by administration to a living body of an effective amount of said compound. The pharmaceutical composition is useful for the treatment of a disease selected from arthritis, osteoarthritis and others according to memory. Pharmaceutical composition comprising an effective amount of said compound alone or in combination with one or more pharmaceutically acceptable excipients or carriers. Claim 1: A compound selected from those of formula (1), characterized in that: X1, X2, and X3, independently of one another, represent a nitrogen atom or a -CR3 group wherein R3 represents a selected group of hydrogen, alkyl C1-6, amino, C1-6 monoalkylamino, C1-6 dialkylamino, hydroxy, C1-6 alkoxy, and halogen, with the proviso that no more than two of the groups X1, X2, and X3 simultaneously represent a nitrogen atom ; G1 represents a group selected from formulas (2) and (3) in which: the carbon atom with the number 2 is attached to the N-R1 group of the ring, R4 and R5, identical or different, independently of each other, represents a group selected from hydrogen, C 1-6 alkyl, aryl, C 1-6 arylalkyl, cycloalkyl, C 1-6 cycloalkylalkyl, heteroaryl, C 1-6 heteroarylalkyl, heterocycloalkyl, and C 1-6 heterocycloalkylalkyl, R 6 represents a group selected from: hydrogen, trifluoromethyl , OR7, NR7R8, wherein R7 and R8, identical or different independently of each other, represent hydrogen or C1-6 alkyl; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, C 1-6 arylalkyl, C 1-6 cycloalkylalkyl, heteroaryl, C 1-6 heteroarylalkyl, heterocycloalkyl, and C 1-6 heterocycloalkylalkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, C1-6 monoalkylamino, C1-6 dialkylamino, each alkyl group is identical or different independently from each other, cyano, C1-6 trihalogenoalkyl, acyl C1-6, -C (-O) OR7, -OR7 and -SR7, where R7 is defined above, G2 represents a selected group of carbon-carbon triple bond, -CH = C = CH-, C = O, C = S, S (O) n1 where n1 represents an integer from 0 to 2 inclusive, and a group of formula (4), where the carbon atom with the number 1 is attached to the bicycles of the compound of formula (1 ), Y1 represents a group selected from oxygen, sulfur, -NH and -C 1-6 alkyl, and Y2 represents a group selected from oxygen or, sulfur, -NH and -C1-6alkyl, n represents an integer from 0 to 6 inclusive, Z1 represents -CR9R10, where R9 and R10, identical or different independently of each other, represent a group selected from hydrogen, alkyl C1-6, trihalogeno C1-6 alkyl, halogen, -OR7, -SR7, and -C (-O) OR7, where R7 is defined above, amino, C1-6 monoalkylamino, C1-6 dialkylamino where each alkyl group is identical or different independently of each other, and where when n is greater than or equal to 2, the hydrocarbon chain Z1 optionally contains one to two isolated or conjugated multiple bonds, and / or where when n is greater than or equal to 2, one of said -CR9R10 can optionally be replaced with a selected group of oxygen, S (O) n1 where n1 is as defined above, -NH and -C1-6alkyl, A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups are 5- or 6-membered monocycles or bicycles composed of two 5- or 6-membered monocycles, R 1 represents a group selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno C1-6 alkyl, cycloalkyl, -C (= O) NR7R8, -C (= O) OR8, OR8, SR8, where R7 and R8, which may be identical or different independently of each other, represents hydrogen or C1-6 alkyl, and the group of formula (5), where p is an integer from 0 to 8 inclusive, Z2 represents -CR11R12 wherein R11 and R12, identical or different independently one of the other represents a group selected from hydrogen, C1-6 alkyl, phenyl, trihalogenoalkyl C1-6 alkyl, halogen, amino, OR7, SR7 and -C (-O) OR7 wherein R7 represents hydrogen or C1-6 alkyl, and where when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one to two isolated multiple bonds or conjugates, and / or when n is greater than or equal to 2, one of said -CR11R12 may optionally be replaced with a selected group of oxygen, S (O) n1 wherein n1 is as defined above, -NH, -C1 -alkyl 6, and carbonyl, B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups are 5 or 6 member monocycles or bicycles composed of two 5 or 6 member monocycles, which is an integer from 0 to 7 inclusive , the group (s) G3, which may be identical or different independently from each other, is selected from C1-6 alkyl, halogen, CN, NO2, CF3, OCF3, - (CH2) kNR13R14, -N (R13 ) C (= O) R14, -N (R13) C (= O) OR14, -N (R13) SO2R14, -N (SO2R13) 2, -OR13, -S (O) k1R13, -SO2-N (R13 ) - (CH2) k2-NR14R15, - (CH2) kSO2NR13R14, -X4 (CH2) kC (= O) OR13, - (CH2) kC (= O) OR13, -C (= O) O- (CH2) k2 -NR13R14, -C (= O) O- (CH2) k2-C (= O) OR16, -X4 (CH2) kC (= O) NR13R14, - (CH2) kC (= O) NR13R14, -R17-C (= O) OR13, -X5-R18, and -C (= O) -R19-NR13R14 where: X4 represents a selected group of an atom d and oxygen, a sulfur atom optionally substituted by one or two oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a C1-6 alkyl group, k is an integer from 0 to 3 inclusive, k1 is an integer from 0 to 2 inclusive, k2 is an integer from 1 to 4 inclusive, R13, R14 and R15, which can be identical or different independently from each other, are selected from hydrogen and C1-6 alkyl, R16 represents a group selected from C1-alkyl -6, -R19-NR13R14, -R19-NR13-C (= O) -R19-NR14R15, and -C (= O) O-R19-NR13R14 where R19 represents a linear or branched C1-6 alkylene group, and R13, R14 and R15 are as defined above, R17 represents a C3-6 cycloalkyl group, X5 represents a group selected from a single bond, -CH2-, an oxygen atom, a sulfur atom optionally substituted by one or two atoms of oxygen, and a nitrogen atom substituted by a hydrogen atom or a C1-6 alkyl group, R18 represents a select group do of: 5 or 6-membered aryl, heteroaryl monocycle, which is optionally substituted by one or more groups, which may be identical or different, selected from C1-6 alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C (= O) OR7 wherein R7 represents hydrogen or C1-6 alkyl, and 5- or 6- membered cycloalkyl, heterocycloalkyl monocycle, which is optionally substituted by one or more groups, which may be identical or different, selected from C1 alkyl -6, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C (= O) OR7 wherein R7 represents hydrogen or C1-6 alkyl, m is an integer from 0 to 7 inclusive, the group (s) R2 , which may be identical or different independently of each other, are selected from C1-6 alkyl, halogen, -CN, NO2, SCF3, -CF3, -OCF3, -NR7R8, -OR8, -SR8, -SOR8, -SO2R8, - (CH2) kSO2NR7R8, -X7 (CH2) kC (= O) OR8, - (CH2) kC (= O) OR8, -X7 (CH2) kC (= O) NR7R8, - (CH2) kC (= O) NR7R8, and -X8-R20 where: X7 represents a selected group of oxygen, sulfur opc ionically substituted by one or two oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a C1-6 alkyl group, k is an integer from 0 to 3 inclusive, R7 and R8, which may be identical or different independently from each other, hydrogen and C1-6 alkyl are selected, X8 represents a group selected from a single bond, -CH2-, an oxygen atom, a sulfur atom optionally substituted by one or two oxygen atoms, and an atom of nitrogen substituted by a hydrogen atom or a C1-6 alkyl group, R20 represents a 5- or 6- membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl monocycle which is optionally substituted by one or more groups, which may be identical or different, selected from C1-6 alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally, the racemic forms thereof, isomers of them, their N-oxides and the pharmaceutically acceptable salts thereof, it being understood that when no specification is described: an aryl group indicates an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the rings is aromatic, and the other ring can be aromatic or partially hydrogenated, a heteroaryl group indicates an aryl group described above where 1 to 4 carbon atoms are replaced by 1 to 4 selected heteroatoms of oxygen, sulfur and nitrogen, a cycloalkyl group indicates a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system is saturated or partially unsaturated but without aromatic character, and a heterocycloalkyl group indicates a cycloalkyl group defined above where 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrog eno.