Substituted oxindole derivatives, medicaments containing the latter and use thereof

Abstract

The invention relates to novel oxindole derivatives of general formula (I), in which the substituents A, B, R 1 , R 2 and R 3 are defined as cited in claim 1 , to medicaments containing said derivatives and to the use of the latter for the prophylaxis and/or treatment of vasopressin-dependent and/or oxytocin-dependent diseases.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 A can be phenyl or naphthalene, each of which can be substituted by one, two, three or four radicals R 4  which are selected independently of one another from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , CONH(C 1 -C 4 -alkyl), CON(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NHCHO, NHCONH 2 , NH(C 0 -C 4 -alkylene)CONH 2 , NH(C 0 -C 4 -alkylene)CONH(C 1 -C 4 -alkyl), NHCOCH 3 , NO 2 , (CH 2 ) 0-2 —OH, (CH 2 ) 1-2 —O—C 1 -C 4 -alkyl, O—C 0 -C 4 -alkylene-phenyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl, 
 B is an aromatic or partially aromatic monocyclic or bicyclic system which may be composed of 6, 7, 8, 9 or 10 C atom members and which may be substituted by one, two, three or four radicals selected from the group consisting of the radicals R 6 , R 7 , R 8  and R 9 , where R 6 , R 7 , R 8  and R 9  are selected, independently of one another and independently of their respective occurrence, from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , CONH(C 1 -C 4 -alkyl), CON(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NHCHO, NH(C 0-4 -alkylene)CONH(C 1 -C 4 -alkyl), NHCOCH 3 , NO 2 , OH, O—C 1 -C 4 -alkyl, (CH 2 ) 0-2 —O—(CH 2 ) 0-3 —CH 3 , O—C 0 -C 4 -alkylene-phenyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl; 
 R 1  is CN; 
 R 2  is hydrogen, C 1 -C 4 -alkyl, O—(C 1 -C 4 -alkyl), Cl or F; 
 R 3  is a radical (W)—(X)—(Y)—Z, where 
 W is C 1 -C 4 -alkylene, (C 0 -C 4 -alkylene)-O—(C 0 -C 4 -alkylene) or (C 0 -C 4 -alkylene)-NR 5 —(C 0 -C 4 -alkylene), in which R 5  is hydrogen or C 1 -C 4 -alkyl,
 X is CO, SO 2 , (C═NH) or (C═N—CN); 
 Y is a radical selected from the group consisting of the radicals 
 
 
       
         
           
           
               
               
           
         
       
       and where Y may additionally be substituted by the radicals R 10  and R 11 , where R 10  and R 11  may have independently of one another the following meanings, namely
 R 10  may be hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, OH, O—C 1 -C 4 -alkyl, O—C 0 -C 4 -alkylene-phenyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), 
 R 11  may be hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, OH, O—C 1 -C 4 -alkyl, O—C 0 -C 4 -alkylene-phenyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), and 
 Z is a mono-, bi- or tricyclic heteroaromatic ring system which may consist of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring members, where the ring members may, besides C atoms, also be one, two, three, four, five, six or seven identical or different heteroatoms selected from the group consisting of O, N and S, and the hetero members may be present in one, two or distributed in the rings, where the ring system can comprise not more than one S ring member, two O ring members and 4 N ring members, and where the ring system comprises at least one heteroatom selected from the group consisting of S, O and N as ring member 
 and where Z may additionally be substituted by the radicals R 12 , R 13  and R 14 , where R 12 , R 13  and R 14  may have independently of one another the meanings mentioned below, namely 
 R 12  may be hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , COOH, CONH(C 1 -C 4 -alkyl), CON(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NHCHO, NHCONH 2 , N(C 0 -C 4 -alkylene)CONH 2 , NH(C 0 -C 4 -alkylene)CONH(C 1 -C 4 -alkyl), NHCOCH 3 , NO 2 , (CH 2 ) 0-2 —OH, O—C 1 -C 6 -alkyl, (CH 2 ) 0-2 —O—C 1 -C 4 -alkyl, O—C 0 -C 4 -alkylene-phenyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), 
 R 13  may be hydrogen, chlorine, bromine, iodine, fluorine, (CH 2 ) 0-2 —CN, CF 3 , OCF 3 , CONH 2 , COOH, CONH(C 1 -C 4 -alkyl), CON(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), NHCHO, NHCONH 2 , N(C 0 -C 4 -alkylene)CONH 2 , NH(C 0 -C 4 -alkylene)CONH(C 1 -C 4 -alkyl), NHCOCH 3 , NO 2 , (CH 2 ) 0-2 —OH, O—C 1 -C 6 -alkyl, (CH 2 ) 0-2 —O—C 1 -C 4 -alkyl, O—C 0 -C 4 -alkylene-phenyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl); 
 R 14  may be hydrogen, chlorine, fluorine, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 0 -C 4 -alkylene-phenyl; 
 
       and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
     
     
         2 . A compound of the formula (I) according to  claim 1 , in which R 1 , R 2  and R 3  may have the meanings stated in  claim 1   
       and
 A is a phenyl ring which may be substituted by one or two radicals R 4 , where R 4  may independently of one another have the meanings stated in  claim 1 ; 
 B is a phenyl ring which may be substituted by one, two, three or four radicals selected from the group consisting of the radicals R 6 , R 7 , R 8  and R 9 , where R 6 , R 7 , R 8  and R 9  may independently of one another and independently of their respective occurrence have the meanings stated in  claim 1 ; 
 
       and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
     
     
         3 . A compound of the formula (I) according to  claim 1  or  2 , in which
 A is a phenyl ring which may be substituted by one or two radicals R 4  which are selected independently of one another from the group consisting of hydrogen, chlorine, O—C 1 -C 4 -alkyl, (CH 2 ) 1-2 —O—(CH 2 ) 0-2 —CH 3  and C 1 -C 6 -alkyl, 
 B is a phenyl ring which may be substituted by one, two, three or four radicals selected from the group consisting of the radicals R 6 , R 7 , R 8  and R 9 , where R 6 , R 7 , R 8  and R 9  are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, chlorine, CN, NO 2 , O—C 1 -C 4 -alkyl, (CH 2 ) 1-2 —O—(CH 2 ) 0-2 —CH 3  and C 1 -C 6 -alkyl, 
 R 1  is CN and is located in position 5 of the oxindole of the formula (I), 
 R 2  is hydrogen, 
 R 3  is a radical (W)—(X)—(Y)—Z, where 
 W is O, CH 2 NH, NHCH 2 , OCH 2 , CH 2 O or NH, 
 X is CO, (C═NH) or (C═N—CN), 
 Y is a radical selected from the group consisting of the respective radicals 
 
       
         
           
           
               
               
           
         
         Z is a radical selected from the group consisting of the radicals 
       
       
         
           
           
               
               
           
         
       
       or
 Z is a radical selected from the group consisting of the radicals benzimidazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, 5-azaindolyl, 6-azaindolyl, 7-azaindolyl, imidazo[1,5-a]pyridinyl and pyrazolo[1,5-a]pyridinyl, where 
 A 2  and A 3  may independently of one another be N or C; 
 A 1  may be N, C, O or S; 
 D 1 , D 2 , D 3 , D 4  and D 5  may independently of one another be C or N, but where at least one of the variables D 1 , D 2 , D 3 , D 4  or D 5  is N, 
 
       and where
 Z may in each case additionally be substituted by the radicals R 12 , R 13  and R 14 , where R 12 , R 13  and R 14  may independently of one another have the meanings stated below, namely 
 R 12  may be hydrogen, chlorine, fluorine, CN, CF 3 , OCF 3 , CONH 2 , NHCONH 2 , NHCOCH 3 , NO 2 , OH, O—C 1 -C 4 -alkyl, C 1 -C 6 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl); 
 R 13  may be hydrogen, chlorine, fluorine, CN, CF 3 , OCF 3 , CONH 2 , NHCONH 2 , NHCOCH 3 , NO 2 , OH, O—C 1 -C 4 -alkyl, C 1 -C 6 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl); 
 R 14  may be hydrogen, fluorine, chlorine or C 1 -C 4 -alkyl; 
 
       and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
     
     
         4 . A compound of the formula (I) according to any of  claims 1  to  3 , in which
 A is a phenyl ring which may be substituted by one radical R 4 , where R 4  may be chlorine, O—C 1 -C 4 -alkyl, or C 1 -C 6 -alkyl; 
 B is a phenyl ring which may be substituted by one or two radicals selected from the group consisting of the radicals R 6  and R 7 , where R 6  and R 7  are independently of one another and independently of their respective occurrence selected from the group consisting of hydrogen, fluorine, chlorine, CN, NO 2 , O—C 1 -C 4 -alkyl and C 1 -C 6 -alkyl; 
 R 1  is CN and is located in position 5 of the oxindole of the formula (I); 
 R 2  is hydrogen; 
 R 3  is a radical (W)—(X)—(Y)—Z, where 
 W is O, CH 2  or NH, 
 X is CO, (C═NH) or (C═N—CN), 
 Y is a radical selected from the respective radicals 
 
       
         
           
           
               
               
           
         
         Z is a radical selected from the group consisting of the radicals 
       
       
         
           
           
               
               
           
         
       
       where
 A 2  and A 3  may independently of one another be N or C; 
 A 1  may be N, C, O or S; 
 D 1 , D 2 , D 3 , D 4  and D 5  may independently of one another be C or N, but where at least one of the variables D 1 , D 2 , D 3 , D 4  and D 5  is N, 
 
       and where
 Z may in each case be substituted by the radicals R 12 , R 13  and R 14 , where R 12 , R 13  and R 14  may independently of one another have the meanings stated below, namely 
 R 12  may be hydrogen, chlorine, fluorine, CN, CF 3 , OCF 3 , CONH 2 , NHCOCH 3 , NO 2 , OH, OC—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl); 
 R 13  may be hydrogen, fluorine, chlorine, OCH 3  or C 1 -C 4 -alkyl; 
 R 14  is hydrogen; 
 
       and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
     
     
         5 . A compound of the formula (I) according to any of  claims 1  to  4 , in which
 A is a phenyl ring which may be substituted by R 4 , where R 4  may be chlorine, OCH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or CH 2 CH 2 CH 3 , 
 B is a phenyl ring which may be substituted by one or two radicals selected from the group consisting of the radicals R 6  and R 7 , where R 6  and R 7  are independently of one another and independently of their respective occurrence selected from the group consisting of hydrogen, fluorine, chlorine, CN, NO 2 , O—C 1 -C 4 -alkyl, and C 1 -C 6 -alkyl; 
 R 1  is CN and is located in position 5 of the oxindole of the formula (I); 
 R 2  is hydrogen; 
 R 3  is a radical (W)—(X)—(Y)—Z, where 
 W is CH 2 , O or NH, 
 X is CO or (C═NH), 
 Y is the radical 
 
       
         
           
           
               
               
           
         
         Z is a radical selected from the group consisting of the radicals pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, isoxazolyl, imidazolyl and phthalazinyl 
       
       and where
 Z may in each case be substituted by R 12  and R 13 , where R 12  and R 13  may independently of one another have the meanings stated below, namely 
 R 12  may be hydrogen, chlorine, fluorine, CN, CF 3 , OCF 3 , OH, OC 1 -C 4 -alkyl, C 1 -C 4 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) or N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl); 
 R 13  may be hydrogen, fluorine or C 1 -C 4 -alkyl; 
 
       and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
     
     
         6 . A compound of the formula (I) according to any of  claims 1  to  5 , in which
 A is a phenyl ring which is substituted by O—CH 2 CH 3  in ortho position, 
 B is a phenyl ring which is substituted by one or two radicals selected from the group consisting of the radicals R 6  and R 7 , where R 6  and R 7  are selected independently of one another and independently of their respective occurrence from the group consisting of hydrogen, fluorine, chlorine, CN, NO 2 , O—C 1 -C 4 -alkyl, and C 1 -C 6 -alkyl, 
 R 1  is CN and is located in position 5 of the oxindole of the formula (I), 
 R 2  is hydrogen, 
 R 3  is a radical (W)—(X)—(Y)—Z, where 
 W is CH 2 , O or NH, 
 X is CO or (C═NH), 
 Y is a radical 
 
       
         
           
           
               
               
           
         
         Z is a radical selected from the group consisting of the radicals 
       
       
         
           
           
               
               
           
         
       
       and where Z may in each case be substituted by the radicals R 12  and R 13 , where R 12  and R 13  may independently of one another have the meanings stated below, namely
 R 12  may be hydrogen, chlorine, fluorine, CN, CF 3 , OCF 3 , OH, OCH 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NHCH 3  or N(CH 3 ) 2 ; 
 R 13  may be hydrogen, chlorine, fluorine or CH 3 , CH 2 CH 3 ;
 and the tautomeric, enantiomeric and/or diastereomeric forms thereof, and prodrugs thereof, and the physiologically tolerated salts of said compound. 
 
 
     
     
         7 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than about 100 nM. 
     
     
         8 . A compound according to any of  claims 1  to  6 , having a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, the quotient of Ki(V1a)/Ki(V1b) being greater than 1. 
     
     
         9 . A compound according to any of  claims 1  to  6 , having a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype, the quotient of Ki(V2)/Ki(V1b) being greater than 1. 
     
     
         10 . A compound according to any of  claims 1  to  6 , having a selectivity for the vasopressin V1b receptor subtype vis-à-vis the oxytocin (OT) receptor, the quotient of Ki(OT)/Ki(V1b) being greater than 1. 
     
     
         11 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, the quotient of Ki(V1a)/Ki(V1b) being greater than 1. 
     
     
         12 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype, the quotient of Ki(V2)/Ki(V1b) being greater than 1. 
     
     
         13 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the oxytocin (OT) receptor, the quotient of Ki(OT)/Ki(V1b) being greater than 1. 
     
     
         14 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype and the vasopressin V2 receptor subtype, the quotients of Ki(V1a)/Ki(V1b) and Ki(V2)/Ki(V1b) being in each case greater than 1. 
     
     
         15 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM, preferably between about 10 nM and about 100 nM, and simultaneous selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype and the oxytocin (OT) receptor, the quotients of Ki(V1a)/Ki(V1b) and Ki(OT)/Ki(V1b) being in each case greater than 1. 
     
     
         16 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and simultaneous selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype and the oxytocin (OT) receptor, the quotients of Ki(V2)/Ki(V1b) and Ki(OT)/Ki(V1b) being in each case greater than 1. 
     
     
         17 . A compound according to any of  claims 1  to  6 , having a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and simultaneous selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, the vasopressin V2 receptor subtype and the oxytocin (OT) receptor, the quotients of Ki(V1a)/Ki(V1b), Ki(V2)/Ki(V1b) and Ki(OT)/Ki(V1b) being in each case greater than 1. 
     
     
         18 . A compound of the formula (I) according to any of  claims 1  to  17  for use as medicament. 
     
     
         19 . A medicament comprising at least one compound of the formula (I) according to any of  claims 1  to  17 . 
     
     
         20 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of vasopressin-dependent and/or oxytocin-dependent diseases. 
     
     
         21 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of diabetes insipidus, noctural enuresis, incontinence, diseases in which blood coagulation disorders occur, and for delaying micturition. 
     
     
         22 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasie), ischemias of the heart, disorders of the renal systems, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring during chemotherapy, and travel sickness. 
     
     
         23 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of affective disorders. 
     
     
         24 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of anxiety disorders and stress-dependent anxiety disorders. 
     
     
         25 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of memory impairments and/or Alzheimer's disease. 
     
     
         26 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of psychoses and/or psychotic disorders. 
     
     
         27 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of Cushing's syndrome. 
     
     
         28 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment of sleep disorders. 
     
     
         29 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of depressive disorders. 
     
     
         30 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of vasomotor disorders. 
     
     
         31 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment and/or prophylaxis of disorders associated with drug withdrawal. 
     
     
         32 . The use of at least one compound of the formula (I) according to any of  claims 1  to  17  for producing a medicament for the treatment of schizophrenia. 
     
     
         33 . A method for the therapeutic and/or prophylactic treatment of a mammal requiring a treatment by administering an effective amount of at least one compound of the formula (I) according to any of  claims 1  to  17  for the treatment of at least one disease or disorder according to any of  claims 20  to  32 . 
     
     
         34 . The method according to  claim 33 , where the mammal is a human, a nonhuman animal or a nonhuman transgenic animal. 
     
     
         35 . A process for preparing at least one compound of the formula (I) according to any of  claims 1  to  17 , wherein the preparation can take place by process steps known per se and/or with analogous application of process steps known per se to the relevant skilled worker with knowledge of the present invention.