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 .- 51 . (canceled) 
     
     
         52 . A method for the treatment of at least one disorder selected from the group consisting of diabetes, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, 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, travel sickness, affective disorders, memory impairments and/or Alzheimer's disease, psychoses and/or psychotic disorders, Cushing's syndrome, sleep disorders, vasomotor symptoms and/or thermoregulatory dysfunctions, drug dependencies, medicament dependencies and/or dependencies mediated by other factors, stress caused by the withdrawal of one or more factors mediating the dependency, stress-induced relapses in the drug dependencies, medicament dependencies and/or dependencies mediated by other factors, schizophrenia and/or psychosis, or for delaying micturition in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or at least one pharmaceutically acceptable salt, or one tautomeric form thereof, is administered to a patient in need thereof, 
       
         
           
           
               
               
           
         
         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; and 
         X3 is N or CH; 
         where X2 and X3 are not simultaneously N. 
       
     
     
         53 . The method according to  claim 52 , in which R5 is hydrogen or methoxy. 
     
     
         54 . The method according to  claim 52 , in which R7 is hydrogen, methyl or ethyl. 
     
     
         55 . The method according to  claim 52 , in which
 R5 is hydrogen or methoxy;   R7 is hydrogen, methyl or ethyl;   X1 is —NH—;   X2 is N; and   X3 is CH.   
     
     
         56 . The method according to  claim 52 , in which
 R5 is hydrogen or methoxy;   R7 is hydrogen, methyl or ethyl;   X1 is —NH—;   X2 is CH; and   X3 is N.   
     
     
         57 . The method according to  claim 52 , in which
 R5 is methoxy;   R6 is methoxy;   R7 is methyl or ethyl;   X1 is —NH—; and   X2 is CH and X3 is N or   X2 is N and X3 is CH.   
     
     
         58 . The method according to  claim 52 , in which
 R5 is methoxy;   R6 is methoxy;   R7 is methyl;   X1 is —NH—;   X2 is N; and   X3 is CH.   
     
     
         59 . The method according to  claim 52 , in which
 R5 is methoxy;   R6 is methoxy;   R7 is methyl;   X1 is —NH—;   X2 is CH; and   X3 is N.   
     
     
         60 . The method according to  claim 52 , in which
 R5 is methoxy;   R6 is methoxy;   R7 is ethyl;   X1 is —NH—;   X2 is CH; and   X3 is N.   
     
     
         61 . The method according to  claim 52 , wherein the compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or a tautomeric form thereof, is present in optically active form as the (laevorotatory) (−)-enantiomer, which rotates the plane of polarization of linear polarized light to the left. 
     
     
         62 . The method according to  claim 52 , wherein the compound of the general formula (I) has formula (Ia), 
       
         
           
           
               
               
           
         
         wherein 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, 
         a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
       
     
     
         63 . The method according to  claim 61 , characterized in that the corresponding laevorotatory (−)-enantiomer is present in an optical purity (enantiomeric excess, ee) of greater than 50%, a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
     
     
         64 . The method according to  claim 62 , 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%, a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
     
     
         65 . The method according to  claim 61 , characterized in that the corresponding laevorotatory (−)-enantiomer is present in an optical purity (enantiomeric excess, ee) of greater than 90%, a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
     
     
         66 . The method according to  claim 62 , 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%, a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
     
     
         67 . The method according to  claim 52 , wherein the compound of the general formula (I) is in the form of the racemate, a pharmaceutically acceptable salt thereof, or a tautomeric form thereof. 
     
     
         68 . The method according to  claim 52 , characterized in that an effective amount of at least one medicament comprising at least one compound of the general formula (I), or at least one pharmaceutically acceptable salt, or one tautomeric form thereof, is administered to the patient. 
     
     
         69 . The method according to  claim 52 , characterized in that the patient is a mammal.