Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases

Abstract

The present invention relates to novel carbamate-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

1 . A compound of the formula I 
       
         
           
           
               
               
           
         
         in which 
         R 1  is hydrogen, methoxy or ethoxy; 
         R 2  is hydrogen or methoxy; 
         R 3  is hydrogen, methyl, ethyl, n-propyl or isopropyl; 
         X 1  and X 2  are N or CH, with the proviso that X 1  and X 2  are not simultaneously N; 
         and their pharmaceutically acceptable salts and prodrugs thereof. 
       
     
     
         2 . A compound as claimed in  claim 1 , in which R 1  is hydrogen or methoxy. 
     
     
         3 . A compound as claimed in any of the preceding claims, in which R 3  is hydrogen, methyl or ethyl. 
     
     
         4 . A compound as claimed in any of the preceding claims, in which X 1  is N and X 2  is CH. 
     
     
         5 . A compound as claimed in any of  claims 1  to  3 , in which X 1  is CH and X 2  is N. 
     
     
         6 . A compound as claimed in any of  claims 1  to  3 , in which X 1  is CH and X 2  is CH. 
     
     
         7 . A compound as claimed in any of  claims 1  to  3  and  5 , in which
 R 1  is methoxy; 
 R 2  is methoxy; 
 R 3  is methyl or ethyl; 
 X 1  is CH; and 
 X 2  is N. 
 
     
     
         8 . A compound as claimed in any of  claims 1  to  3  and  5 , in which
 R 1  is methoxy; 
 R 2  is H; 
 R 3  is methyl or ethyl; 
 X 1  is CH; and 
 X 2  is N. 
 
     
     
         9 . A compound as claimed in any of  claims 1  to  3  and  5 , in which
 R 1  is H; 
 R 2  is methoxy; 
 R 3  is methyl or ethyl; 
 X 1  is CH; and 
 X 2  is N. 
 
     
     
         10 . A compound as claimed in any of  claims 1  to  3  and  5 , in which
 R 1  is H; 
 R 2  is H; 
 R 3  is methyl or ethyl; 
 X 1  is CH; and 
 X 2  is N. 
 
     
     
         11 . A compound as claimed in any of  claims 1  to  4 , in which
 R 1  is methoxy; 
 R 2  is methoxy; 
 R 3  is methyl or ethyl; 
 X 1  is N; and 
 X 2  is CH. 
 
     
     
         12 . A compound as claimed in any of  claims 1  to  4 , in which
 R 1  is methoxy; 
 R 2  is H; 
 R 3  is methyl or ethyl; 
 X 1  is N; and 
 X 2  is CH. 
 
     
     
         13 . A compound as claimed in any of  claims 1  to  4 , in which
 R 1  is H; 
 R 2  is methoxy; 
 R 3  is methyl or ethyl; 
 X 1  is N; and 
 X 2  is CH. 
 
     
     
         14 . A compound as claimed in any of  claims 1  to  4 , in which
 R 1  is H; 
 R 2  is H; 
 R 3  is methyl or ethyl; 
 X 1  is N; and 
 X 2  is CH. 
 
     
     
         15 . A compound as claimed in any of the preceding claims, which is the (−) enantiomer in an enantiomeric purity of at least 50% ee. 
     
     
         16 . A compound as claimed in  claim 15 , where the (−) enantiomer has an enantiomeric purity of at least 90% ee. 
     
     
         17 . A compound as claimed in any of  claims 1  to  14 , which is the racemate. 
     
     
         18 . A pharmaceutical composition comprising at least one compound of the formula I as defined in any of the preceding claims and/or at least one pharmaceutically acceptable salt or prodrug thereof and at least one pharmaceutically acceptable carrier. 
     
     
         19 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-dependent diseases. 
     
     
         20 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition. 
     
     
         21 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, and travel sickness. 
     
     
         22 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from affective disorders. 
     
     
         23 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from anxiety disorders and stress-dependent anxiety disorders. 
     
     
         24 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from memory impairments and Alzheimer's disease. 
     
     
         25 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from psychoses and psychotic disorders. 
     
     
         26 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from Cushing's syndrome and other stress-dependent diseases. 
     
     
         27 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from sleep disorders. 
     
     
         28 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from depressive disorders. 
     
     
         29 . The use as claimed in  claim 28  for the treatment and/or prophylaxis of childhood onset mood disorders. 
     
     
         30 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions. 
     
     
         31 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors; of stress caused by withdrawal of one or more factors mediating the dependence; and/or of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors. 
     
     
         32 . The use of compounds of the formula I as defined in any of  claims 1  to  17  or of pharmaceutically acceptable salts or prodrugs thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from schizophrenia and psychosis. 
     
     
         33 . A method for treating disorders defined as in any of  claims 19  to  32 , in which an effective amount of at least one compound of the formula I as defined in any of  claims 1  to  17  or of at least one pharmaceutically acceptable salt or a prodrug thereof or of a pharmaceutical composition as claimed in  claim 18  is administered to a patient.