Substituted oxindole derivatives and their use as vasopressin receptor ligands

Abstract

The present invention relates to novel oxindole derivatives of the general formula (I) to medicaments comprising them and to their use for the prophylaxis and/or treatment of diseases vasopressin dependent.

1 . Compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R1 is ethoxy; 
         R2 is hydrogen; 
         R3 is cyano; 
         R4 is hydrogen; 
         R5 is hydrogen, methoxy or ethoxy; 
         R6 is hydrogen or methoxy; 
         R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl; 
         X1 is —NH—; 
         X2 is N or CH; 
         X3 is N or CH; 
         where X2 and X3 are not simultaneously N; 
         and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
       
     
     
         2 . Compounds according to  claim 1 , in which R5 is hydrogen or methoxy. 
     
     
         3 . Compounds according to  claim 1 , in which R7 is hydrogen, methyl or ethyl. 
     
     
         4 . Compounds according to any of  claims 1  to  3 , in which
 R5 is hydrogen or methoxy; 
 R7 is hydrogen, methyl or ethyl; 
 X1 is —NH—; 
 X2 is N; and 
 X3 is CH. 
 
     
     
         5 . Compounds according to any of  claims 1  to  3 , in which
 R5 is hydrogen or methoxy; 
 R7 is hydrogen, methyl or ethyl; 
 X1 is —NH—; 
 X2 is CH; and 
 X3 is N. 
 
     
     
         6 . Compounds according to any of  claims 1  to  3 , in which
 R5 is methoxy; 
 R6 is methoxy 
 R7 is methyl or ethyl; 
 X1 is —NH—; 
 X2 is CH and X3 is Nor 
 X2 is N and X3 is CH. 
 
     
     
         7 . Compounds according to any of  claims 1  to  3 , in which
 R5 is methoxy; 
 R6 is methoxy; 
 R7 is methyl; 
 X1 is —NH—; 
 X2 is N; and 
 X3 is CH. 
 
     
     
         8 . Compounds according to any of  claims 1  to  3 , in which
 R5 is methoxy; 
 R6 is methoxy; 
 R7 is methyl; 
 X1 is —NH—; 
 X2 is CH; and 
 X3 is N. 
 
     
     
         9 . Compounds according to any of  claims 1  to  3 , in which
 R5 is methoxy; 
 R6 is methoxy; 
 R7 is ethyl; 
 X1 is —NH—; 
 X2 is CH; and 
 X3 is N. 
 
     
     
         10 . Compounds of the general formula (I) according to any of  claims 1  to  9 , characterized in that they are present in optically active form and that they are the (laevorotatory) (−)-enantiomer, which rotates the plane of polarization of linear polarized light to the left, of the compound of the general formula (I) in question in the form of the free base, and the pharmaceutically acceptable salts, tautomeric forms and/or prodrugs thereof. 
     
     
         11 . Compounds of the general formula (I) according to any of  claims 1  to  9 , characterized in that they are present in optically active form, where the absolute configuration of the chiral C-3 ring carbon atom corresponds to the absolute configuration at C-3 of the (laevorotatory) (−)-enantiomer, which rotates the plane of polarization of linear polarized light to the left, of the compound of the formula (Ia) in the form of the free base 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
     
     
         12 . Compounds of the general formula (I) according to  claim 10  in optically active form, characterized in that the corresponding laevorotatory (−)-enantiomer is present in an optical purity (enantiomeric excess, ee) of greater than 50%, and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
     
     
         13 . Compounds of the general formula (I) according to  claim 11  in optically active form, characterized in that the enantiomer having the preferred absolute configuration at the C-3 ring carbon atom is present in an optical purity (enantiomeric excess, ee) of greater than 50%, and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
     
     
         14 . Compounds of the general formula (I) according to  claim 10  in optically active form, characterized in that the corresponding laevorotatory (−)-enantiomer is present in an optical purity (enantiomeric excess, ee) of greater than 90%, and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
     
     
         15 . Compounds of the general formula (I) according to  claim 11  in optically active form, characterized in that the enantiomer having the preferred absolute configuration at the C-3 ring carbon atom is present in an optical purity (enantiomeric excess, ee) of greater than 90%, and the pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof. 
     
     
         16 . Compounds of the general formula (I) according to any of  claims 1  to  9  in the form of the racemate, and the pharmaceutically acceptable salts, tautomeric forms and prodrugs of the racemate of the compounds of the general formula (I). 
     
     
         17 . Medicament, comprising at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof. 
     
     
         18 . At least one compound of the general formula (I) according to any of  claims 1  to  16 , or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for use as a medicament. 
     
     
         19 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment and/or prophylaxis of at least one vasopressin-dependent disease. 
     
     
         20 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of diabetes, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, and/or for delaying micturition. 
     
     
         21 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof 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 angioplasty), ischemias of the heart, disorders of the renal system, 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/or travel sickness. 
     
     
         22 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of affective disorders. 
     
     
         23 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of anxiety disorders and/or stress-dependent anxiety disorders. 
     
     
         24 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of memory impairments and/or Alzheimer's disease. 
     
     
         25 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of psychoses and/or psychotic disorders. 
     
     
         26 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of Cushing's syndrome or other stress-dependent diseases. 
     
     
         27 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of sleep disorders. 
     
     
         28 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of depressive disorders 
     
     
         29 . Use according to  claim 28 , for the treatment and/or prophylaxis of childhood onset mood disorders. 
     
     
         30 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the “hot flush” symptom. 
     
     
         31 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment and/or prophylaxis of drug dependencies, medicament dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by the withdrawal of one or more factors mediating the dependency and/or for the treatment and/or prophylaxis of stress-induced relapses into the drug dependencies, medicament dependencies and/or dependencies mediated by other factors. 
     
     
         32 . Use of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the treatment and/or prophylaxis of schizophrenia and/or psychosis. 
     
     
         33 . Method for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of diabetes, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, and for delaying micturition in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         34 . Method 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 angioplasty), ischemias of the heart, disorders of the renal system, 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 in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         35 . Method for the treatment and/or prophylaxis of affective disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         36 . Method for the treatment of anxiety disorders and/or stress-dependent anxiety disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         37 . Method for the treatment of memory impairments and/or Alzheimer's disease in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         38 . Method for the treatment of psychoses and/or psychotic disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         39 . Method for the treatment of Cushing's syndrome in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         40 . Method for the treatment of sleep disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         41 . Method for the treatment of depressive disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         42 . Method according to  claim 41 , for the treatment and/or prophylaxis of childhood onset mood disorders. 
     
     
         43 . Method for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the “hot flush” symptom, in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         44 . Method for the treatment and/or prophylaxis of drug dependencies, medicament dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by the withdrawal of one or more factors mediating the dependency and/or for the treatment and/or prophylaxis of stress-induced relapses in the drug dependencies, medicament dependencies and/or dependencies mediated by other factors, in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         45 . Method for the treatment and/or prophylaxis of schizophrenia and/or psychosis in a patient, characterized in that an effective amount of at least one compound of the general formula (I) according to any of  claims 1  to  16  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof is administered to the patient. 
     
     
         46 . Method according to any of  claims 33  to  45 , characterized in that the patient is a mammal, preferably a human or a nonhuman or a nonhuman transgenic mammal. 
     
     
         47 . Process for preparing at least one compound of the general formula (I) according to any of  claims 1  to  16 , characterized in that it can be prepared by the relevant skilled worker with knowledge of the technical teaching of the invention in implementation and/or in analogous implementation of process steps known per se. 
     
     
         48 . A compound of the formula (I) according to any of  claims 1  to  7 , or a pharmaceutically acceptable salt, a tautomeric form or a prodrug thereof for use in treatment and/or prophylaxis of a disease or disorder. 
     
     
         49 . The compound as claimed in  claim 48  for use in treatment and/or prophylaxis of a disease or disorder as set forth in any of  claims 19  to  32 . 
     
     
         50 . Use of the compound of the formula (I) according to any of  claims 1  to  7  or at least one pharmaceutically acceptable salt, one tautomeric form or one prodrug thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or disorder. 
     
     
         51 . The use as claimed in  claim 50 , where the disease or disorder is as set forth in any of  claims 19  to  32 .