Substituted tetrahydro-2h-isoquinolin-1-one derivatives, and methods for the production and use thereof

Abstract

This invention relates to compounds according to the general formula (I), where the definitions of the substituents R1, R2, Ar and X are as specified in the description, and to their physiologically tolerated salts, methods for the preparation of these compounds and their use as medicaments. These compounds are poly(ADP-ribose) polymerase (PARP) inhibitors.

1 . A method for the treatment of a patient suffering from, or subject to, a condition which can be ameliorated by the administration of a PARP inhibitor comprising administering to said patient an effective amount of a compound according to formula (I) 
       
         
           
           
               
               
           
         
         in which the meanings are: 
         X is a single bond, O, S, NH or N(C 1 -C 3 -alkyl); 
         R1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF 3  or C 1 -C 3 -alkyl which is optionally substituted by hydroxy, chlorine, methoxy or one, two or three fluorine atoms; 
         R2 is hydrogen, fluorine, —CN, hydroxy,
 methoxy, —OCF 3 , —NH 2 , —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2  or C 1 -C 3 -alkyl which is optionally substituted by hydroxy, chlorine, methoxy or one, two or three fluorine atoms; 
 
         R3
 is —(C 1 -C 3 -alkyl)-NR4R5, —SO 2 NR4R5, —C(O)NR4R5, —C(H)═N—OR9, —C(O)R6, —NHC(O)R6, —(C 1 -C 3 -alkyl)-NHC(O)R6, —NHSO 2 R6, —(C 1 -C 3 -alkyl)-NHSO 2 R6 or —CH(OH)R7; 
 
         R4 and R5 are independently of one another selected from the group consisting of: hydrogen; unsubstituted or at least monosubstituted C 1 -C 10 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl and heterocyclyl,
 where the substituents are selected from the group consisting of: aryl, heteroaryl, heterocyclyl, —O-aryl, fluorine, chlorine, bromine, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NHC(O)(C 1 -C 3 -alkyl), —NH 2 , hydroxy, C 1 -C 6 -alkyl, C 1 -C 3 -alkoxy, —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2 , —NH-aryl, —NH-heteroaryl, —NH—C(O)-heteroaryl, —SO 2 NH 2 , —SO 2 (C 1 -C 3 -alkyl) and —NH—SO 2 (C 1 -C 3 -alkyl), 
 and the aryl, heteroaryl and heterocyclyl fragments of these substituents may in turn be at least monosubstituted by fluorine, chlorine, bromine, oxo, —CF 3 , —OCF 3 , —NO 2 , —CN, aryl, heteroaryl, —NHC(O)(C 1 -C 3 -alkyl), —COOH, hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 3 -alkyl), —SO 2 N(C 1 -C 3 -alkyl) 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 3 -alkyl), —C(O)N(C 1 -C 3 -alkyl) 2 , —SO 2 (C 1 -C 3 -alkyl), —NH 2 , —NH(C 1 -C 3 -alkyl) or —N(C 1 -C 3 -alkyl) 2 ; or 
 R4 and R5 form together with the nitrogen atom to which they are bonded unsubstituted or at least monosubstituted heterocyclyl, 
 where the substituents are selected from the group consisting of: aryl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, bromine, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NHC(O)(C 1 -C 3 -alkyl), —NH 2 , hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2 , —SO 2 NH 2 , —SO 2 (C 1 -C 3 -alkyl) and —NH—SO 2 (C 1 -C 3 -alkyl), 
 and, of these substituents, aryl, heterocyclyl and heteroaryl in turn may be at least monosubstituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy; 
 
         R6 is unsubstituted or at least monosubstituted C 1 -C 6 -alkyl, phenyl, heteroaryl or heterocyclyl,
 where the substituents are selected from the group consisting of: fluorine, chlorine, bromine, aryl, heterocyclyl, 
 heteroaryl, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NHC(O)(C 1 -C 3 -alkyl), —NH 2 , hydroxy, C 1 -C 3 -alkyl, 
 C 1 -C 3 -alkoxy, —O-heteroaryl, —O-aryl, —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2 , —SO 2 NH 2 , —SO 2 (C 1 -C 3 -alkyl) and —NH—SO 2 (C 1 -C 3 -alkyl), 
 and the aryl, heterocyclyl and heteroaryl fragments of these substituents may in turn be at least monosubstituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy; 
 
         R7 is selected from the group consisting of:
 hydrogen; unsubstituted or at least monosubstituted C 1 -C 6 -alkyl, phenyl and heteroaryl, 
 where the substituents are selected from the group consisting of: 
 fluorine, chlorine, bromine, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NHC(O)(C 1 -C 3 -alkyl), —NH 2 , hydroxy, C 1 -C 3 -alkyl, 
 C 1 -C 3 -alkoxy, —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2 , —SO 2 NH 2 , —SO 2 (C 1 -C 3 -alkyl) and —NH—SO 2 (C 1 -C 3 -alkyl); 
 
         R8 is C 1 -C 3 -alkoxy, —O-phenyl,
 C 1 -C 3 -alkyl, —NH 2 , —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2  or phenyl, 
 and the above phenyl fragments may in turn be at least monosubstituted by fluorine, chlorine, bromine, oxo, —CF 3 , —OCF 3 , —NO 2 , —CN, aryl, heteroaryl, —NHC(O)(C 1 -C 3 -alkyl), —COOH, hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, —SO 2 NH 2 , —SO 2 NH(C 1 -C 3 -alkyl), —SO 2 N(C 1 -C 3 -alkyl) 2 , —C(O)NH(C 1 -C 3 -alkyl), —C(O)N(C 1 -C 3 -alkyl) 2 , —SO 2 (C 1 -C 3 -alkyl), —NH 2 , —NH(C 1 -C 3 -alkyl) or —N(C 1 -C 3 -alkyl) 2 ; 
 
         R9 is selected from the group consisting of:
 hydrogen; unsubstituted or at least monosubstituted C 1 -C 6 -alkyl and phenyl, where the substituents are selected from the group consisting of: 
 fluorine, chlorine, bromine, aryl, heterocyclyl, 
 heteroaryl, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NHC(O)(C 1 -C 3 -alkyl), C 1 -C 3 -alkyl, 
 C 1 -C 3 -alkoxy, —NH(C 1 -C 3 -alkyl), —N(C 1 -C 3 -alkyl) 2 , —SO 2 NH 2 , —SO 2 (C 1 -C 3 -alkyl) and —NH—SO 2 (C 1 -C 3 -alkyl), 
 and, of these substituents, aryl, heterocyclyl and heteroaryl may in turn be at least monosubstituted by fluorine, chlorine, bromine, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy; 
 
         is unsubstituted or at least monosubstituted aryl or heteroaryl, where the substituents are selected from the group consisting of: fluorine, chlorine, bromine, —CF 3 , —OCF 3 , —NO 2 , —CN, —C(O)R8, —NH 2 , —NHC(O)(C 1 -C 6 -alkyl), hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, —CH 2 —CH 2 —CH 2 —, —CH 2 —O—C(O)—, —CH 2 —C(O)—O—, —CH 2 —NH—C(O)—, —CH 2 —N(CH 3 )—C(O)—, —CH 2 —C(O)—NH—, —N(C 1 -C 6 -alkyl) 2 , —N(C 1 -C 6 -alkyl) 2 , —SO 2 (C 1 -C 6 -alkyl), heterocyclyl, heteroaryl, aryl and R3,
 and, of these substituents, heterocyclyl, aryl and heteroaryl may in turn be at least monosubstituted by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or OH; 
 
         heteroaryl is a 5 to 10-membered, aromatic, mono- or bicyclic heterocycle which comprises one or more heteroatoms selected from N, O and S; 
         aryl is a 5 to 10-membered, aromatic, mono- or bicycle; and 
         heterocyclyl is a 5 to 10-membered, non-aromatic, mono- or bicyclic heterocycle which comprises one or more heteroatoms selected from N, O and S; 
         or a physiologically tolerated salt thereof; 
         provided that Ar is not unsubstituted phenyl when X is a single bond. 
       
     
     
         2 . A method for the treatment of a patient suffering from, or subject to, a disease which is selected from the group consisting of: tissue damage resulting from cell damage or cell death owing to necrosis or apoptosis, neuronally mediated tissue damage or disorders, cerebral ischemia, head trauma, stroke, reperfusion damage, neurological disturbances and neurodegenerative disorders, vascular stroke, cardiovascular impairments, myocardial infarction, myocardial ischemia, experimental allergic encephalomyelitis (EAE), multiple sclerosis (MS), ischemia related to heart surgery, age-related macular degeneration, arthritis, arteriosclerosis, cancer, degenerative disorders of the skeletal muscles with subsequent replicative senescence, diabetes and diabetic myocardial disorders, said method comprising administering to said patient an effective amount of a compound according to  claim 1 . 
     
     
         3 . The method as claimed in  claim 2 , wherein the disease is selected from the group consisting of: cerebral ischemia, reperfusion damage, cardiovascular disorders, myocardial infarction, myocardial ischemia and ischemia related to heart surgery. 
     
     
         4 . The method as claimed in  claim 3 , wherein the disease is myocardial infarction. 
     
     
         5 . A method for the treatment of a patient suffering from, or subject to, a condition which can be ameliorated by the administration of a PARP inhibitor comprising administering to said patient an effective amount of a compound selected from the group consisting of:
 4-(3-methanesulfonylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(3-acetylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(5-butylaminomethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   3-methyl-4-(5-pyrrolidin-1-ylmethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-[5-(3-hydroxypyrrolidin-1-ylmethyl)furan-2-yl]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(5-{[(4-pyrrolidin-1-ylpiperidin-1-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4-{5-[(2-dimethylaminoethylamino)methyl]-furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-{5-[(2-hydroxy-2-phenylethylamino)methyl]furan-2-yl}-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(5-{[(4-methylpiperazin-1-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(5-{[(1-methyl-1H-pyrazol-4-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,   4-(5-butylaminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one and   4-(5-hydroxymethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one;   or a physiologically tolerated salt thereof.