Substituted indan derivatives

Abstract

The present invention relates to new piperidyl- or piperazinyl-substituted indan derivatives having the formula I wherein X is N or CH; Y is NR 2 CH 2 , CH 2 NR 2 , NR 2 CO, CONR 2 or NR 2 SO 2 wherein R 2 is H or C 1 -C 6 alkyl; R 1 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (CH 2 ) n -aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted; n is 0-4; R 9 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OCF 3 , OCHF 2 , OCH 2 F, halogen, CN, CF 3 , OH, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, NR 6 R 7 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C 1 -C 6 alkyl; or COR 8 ; wherein R 6 , R 7 and R 8 are as defined above, as (R)- enantiomers, (S)-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts or solvates thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.

1 . A compound having the formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 X is N or CH;  
 Y is NR 2 CH 2 , CH 2 NR 2 , NR 2 CO, CONR 2  or NR 2 SO 2  wherein R 2  is H or C 1 -C 6  alkyl;  
 R 1  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl;  
 R 3  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl or (CH 2 ) n -aryl,  
 wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substitited with R 4  and/or R 5 ;  
 wherein R 4  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, halogen, CN, CF 3 , OH, C 1 -C 6  alkoxy, NR 6 R 7 , OCF 3 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , phenyl, phenyl-C 1 -C 6  alkyl, phenoxy, C 1 -C 6  alkylphenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO 2  wherein the substituent(s) is(are) selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl and phenyl-C 1 -C 6  alkyl, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl and phenyl-C 1 -C 6  alkyl, or COR 8 ;  
 wherein R 6  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl;  
 R 7  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; and  
 R 8  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, CF 3 , NR 6 R 7 , phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO 2 ;  
 wherein R 5  is H, OH, CF 3 , OCF 3 , halogen, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;  
 n is 0-4;  
 R 9  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl OCF 3 , OCHF 2 , OCH 2 F, halogen, CN, CF 3 , OH, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy-C 1 -C 6  alkyl, NR 6 R 7 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O and S, wherein the substituent(s) is(are) C 1 -C 6  alkyl; or COR 8 ; wherein R 6 , R 7  and R 8  are as defined above,  
 as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein Y is NR 2 CO or CONR 2 .  
     
     
         3 . A compound according to any one of claims  1 - 2  wherein X is N.  
     
     
         4 . A compound according to any one of claims  1 - 3  wherein R 1  is H or C 1 -C 6  alkyl.  
     
     
         5 . A compound according to any one of claims  1 - 4  wherein R 3  is (CH 2 ) n -aryl.  
     
     
         6 . A compound according to any one of claims  1 - 4  wherein R 3  is (CH 2 ) n -aryl which is substituted with R 4 , which is an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O and S, or COR 8 .  
     
     
         7 . A compound according to any one of claims  5  and  6  wherein n is 0.  
     
     
         8 . A compound according to  claim 6  wherein R 8  is NR 6 R 7  or a heterocyclic ring containing two heteroatoms selected from N and O.  
     
     
         9 . A compound according to any one of claims  1 - 8  wherein R 9  is H, C 1 -C 6  alkyl, OCHF 2 , halogen or C 1 -C 6  alkoxy.  
     
     
         10 . A compound according to any one of claims  1 - 9  wherein X is N, Y is NR 2 CO and R 9  is C 1 -C 6  alkoxy.  
     
     
         11 . A compound according to  claim 10  wherein X is N, Y is NR 2 CO, R 4  is morpholino or COR 8  and R 9  is C 1 -C 6  alkoxy.  
     
     
         12 . A compound according to any one of claims  1 - 9  wherein X is N, Y is NR 2 CO and R 9  is C 1 -C 6  alkyl.  
     
     
         13 . A compound according to  claim 12  wherein X is N, Y is NR 2 CO, R 4  is morpholino or COR 8  and R 9  is C 1 -C 6  alkyl.  
     
     
         14 . A compound according to any one of claims  1 - 9  wherein X is N, Y is NR 2 CO and R 9  is H.  
     
     
         15 . A compound according to  claim 14  wherein X is N, Y is NR 2 CO, R 4  is morpholino or COR 8  and R 9  is H.  
     
     
         16 . A compound which is 4-(4-methylpiperazin-1-yl)-N-(4-morpholinophenyl)indan-2-carboxamide in the form of a free base or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         17 . A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims  1 - 16  as an enantiomer or racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof optionally in association with diluents, excipients or inert carriers.  
     
     
         18 . A pharmaceutical formulation according to  claim 17  for use in the treatment of 5-hydroxytryptamine mediated disorders.  
     
     
         19 . A pharmaceutical formulation according to any one of claims  17  or  18  for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension, urinary incontinence orvasospasm; or for growth control of tumors.  
     
     
         20 . A compound as defined in any of claims  1 - 16  for use in therapy.  
     
     
         21  A compound as defined in  claim 20  for use in the treatment of disorders in the central nervous system.  
     
     
         22 . A compound as defined in  claim 21  for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.  
     
     
         23 . A compound as defined in  claim 22  for use in the treatment of urinary incontinence or vasospasm or for growth control of tumors.  
     
     
         24 . A compound as defined in  claim 20  for use in the treatment of 5-hydroxytryptamine mediated disorders.  
     
     
         25 . A compound as defined in  claim 24  for use as a h5-HT 1B  antagonist.  
     
     
         26 . The use of a compound defined in any of claims  1 - 16  in the manufacture of a medicament for the treatment of disorders in the central nervous system and/or urinary incontinence or vasospasm; or for growth control of tumors.  
     
     
         27 . The use according to  claim 26  in the manufacture of a medicament for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.  
     
     
         28 . The use of a compound defined in any of claims  1 - 16  in the manufacture of a medicament for the treatment of 5-hydroxytryptamine mediated disorders  
     
     
         29 . The use according to  claim 28  wherein the compound according to any one of claims  1 - 16  is used as a h5-HT 1B  antagonist.  
     
     
         30 . A method for the treatment of disorders in the central nervous system and/or urinary incontinence or vasospasm or for growth control of tumors by administering to a mammal including man in need of such a treatment a therapeutically effective amount of a compound defined in any of claims  1 - 16 .  
     
     
         31 . A method according to  claim 30  for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain or hypertension.  
     
     
         32 . A method for the treatment of 5-hydroxytryptamine mediated disorders by administering to a mammal including man in need of such a treatment a therapeutically effective amount of a compound defined in any of claims  1 - 16 .  
     
     
         33  A method according to  claim 32  wherein the compound according to any one of claims  1 - 16  is used as a h5-HT 1B  antagonist.  
     
     
         34 . A process for the preparation of the compound of formula I according to  claim 1  by reacting, in the case where Y is CONR 2 , R 1 , R 2 , R 3  and R 9  is as defined in general formula I in  claim 1 , a compound of formula A  
       
         
           
           
               
               
           
         
       
       with a compound of formula VII, wherein X is a leaving group.  
     
     
         35 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is CONR 2  wherein R 2  is H or C 1 -C 6  alkyl  
 R 3  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl or (CH 2 ) n -aryl,  
 wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R 4  and/or R 5 ;  
 wherein R 4  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, halogen, CN, CF 3 , OH, C 1 -C 6  alkoxy, NR 6 R 7 , OCF 3 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , phenyl, phenyl-C 1 -C 6  alkyl, phenoxy, C 1 -C 6  alkylphenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO 2  wherein the substituent(s) is(are) selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl and phenyl-C 1 -C 6  alkyl, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl and phenyl-C 1 -C 6  alkyl, or COR 8 ;  
 wherein R 6  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl;  
 R 7  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; and  
 R 8  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, CF 3 , NR 6 R 7 , phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO 2  wherein R 6  and R 7  are as defined above;  
 wherein R 5  is H, OH, CF 3 , OCF 3 , halogen, C 1 -C 6  alkyl or C 1 -C 6  alkoxy;  
 n is 0-4; and  
 R 9  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, OCF 3 , OCHF 2 , OCH 2 F, halogen, CN, CF 3 , OH, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy-C 1 -C 6  alkyl, NR 6 R 7 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C 1 -C 6  alkyl; or COR 8 ; wherein R 6 , R 7  and R 8  are as defined above.