Condensed azepines as vasopressin agonists

Abstract

This invention provides novel compounds according to general formula (1) wherein A is a bicyclic or tricyclic azepine derivative, V 1 and V 2 are both H, OMe or F, or one of V 1 and V 2 is Br, Cl, F, OH, OMe, OBn, OPh, O-acyl, N 3 , NH 2 , NHBn or NH-acyl and the other is H, or V 1 and V 2 together are ═O, —O(CH 2 ) p O— or —S(CH 2 )S—; W 1 is either O or S; X 1 and X 2 are both H, or together are ═O or ═S; Y is OR 5 or NR 6 R 7 ; R 1 , R 2 , R 3 and R 4 are independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br; R 5 is selected from H and lower alkyl; R 6 and R 7 are independently selected from H and lower alkyl, or together are —(CH 2 ) n —; n=3, 4, 5, 6; and p is 2 or 3. The compounds are agonists at the vasopressin V2 receptor and are useful as antidiuretics and procoagulants. The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.

1 . A compound according to general formula 1, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a bicyclic or tricyclic azepine derivative selected from general formulae 2 to 7 
 
       
         
           
           
               
               
           
         
         A 1 , A 4 , A 7  and A 10  are each independently selected from CH 2 , O and NR 8 ; 
         A 2 , A 3 , A 9 , A 11 , A 13 , A 14  and A 15  are each independently selected from CH and N; 
         either A 5  is a covalent bond and A 6  is S, or A 5  is N═CH and A 6  is a covalent bond; 
         A 8  and A 12  are each independently selected from NH and S; 
         A 18  and A 17  are both CH 2 , or one of A 16  and A 17  is CH 2  and the other is selected from CH(OH), CF 2 , O, So x , and NR 8 , 
         V 1  and V 2  are both H, OMe or F, or one of V 1  and V 2  is OH, OMe, OBn, OPh, O-acyl, Br, CI, F, N 3 , NH 2 , NHBn or NH-acyl and the other is H, or V 1  and V 2  together are ═O, —S(CH 2 )pS— or —O(CH 2 )pO—; 
         W 1  is either O or S; 
         X 1  and X 2  are both H, or together are ═O or ═S; 
         Y is OR 5  or NR 6 R 7 ; 
         Z is S or —CH═CH—; 
         R 1 , R 2 , R 3  and R 4  are independently selected from H, lower alkyl, lower alkyloxy, F, CI and Br; 
         R 5  is selected from H and lower alkyl; 
         R 6  and R 7  are independently selected from H and lower alkyl, or together are —(CH 2 )n-; 
         R 8  is H or lower alkyl; 
         N=3, 4, 5 or 6; 
         P=2 or 3; 
         and x is 0, 1 or 2. 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 2. 
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 3. 
     
     
         4 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 4. 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 5. 
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 6. 
     
     
         7 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 7. 
     
     
         8 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a group according to general formula 7, Z is —Ch═Ch— and both A 16  and A 17  are —CH 2 . 
     
     
         9 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1  and R 2  is CI or Me and the other is H, and both R 3  and R 4  are H. 
     
     
         10 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of V 1  and V 2  is OMe or OBn and the other is H. 
     
     
         11 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1  and X 2  together are ═O and Y is NR 6 R 7 . 
     
     
         12 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
       
       wherein
 W 1  is either O or S; 
 one of R a  and R b  is CI or methyl and the other is H; 
 R c  is methyl or benzyl; and 
 R 6  and R 7  are independently selected from H and lower alkyl, or together are —CH 2 )n-; 
 and 
 n is 3, 4, 5 or 6. 
 
     
     
         13 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
       
       wherein
 W 1  is either O or S; 
 one of R a  and R b  is CI or methyl and the other is H; 
 R c  is methyl or benzyl; and 
 R 6  and R 7  are independently selected from H and lower alkyl, or together are —(CH 2 )n-; 
 and 
 n is 3, 4, 5 or 6. 
 
     
     
         14 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein V 1  and V 2  are both H. 
     
     
         15 . A compound according to  claim 14 , or a pharmaceutically acceptable salt thereof, wherein X 1  and X 2  together are ═O and Y is NR 6 R 7 . 
     
     
         16 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
       
       wherein
 W 1  is either O or S; 
 one of R a  and R b  is CI or methyl and the other is H; 
 R 6  and R 7  are independently selected from H and lower alkyl, or together are —CH 2 )n-; 
 and 
 n is 3, 4, 5 or 6. 
 
     
     
         17 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
       
       wherein
 W 1  is either O or S; 
 one of R a  and R b  is CI or methyl and the other is H; 
 R 6  and R 7  are independently selected from H and lower alkyl, or together are —CH 2 )n-; 
 and 
 n is 3, 4, 5 or 6. 
 
     
     
         18 . A compound according to  claim 1  which is selected from 
       1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide, 
       (4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, 
       (4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide, 
       (4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N,dimethylamide, 
       (4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, 
       (4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, 
       (4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide, and 
       (4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-4-ylcarbonyl)benzyl-carbamoyl)-4-methoxy-L-proline-N,N-dimethylamide, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . A pharmaceutical composition which contains active agent selected from compounds and pharmaceutically acceptable salts according to  claim 1 . 
     
     
         22 . A method for the treatment of polyuria, which method comprises the administration to a person in need of such treatment of an effective amount of the composition according to  claim 21   
     
     
         23 .- 25 . (canceled) 
     
     
         26 . A method of treatment of nocturnal enuresis, nocturia and central diabetes insipidus, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to  claim 21 . 
     
     
         27 . A method for the control of urinary incontinence, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to  claim 21 . 
     
     
         28 . A method of treatment according to  claim 27 , wherein the treatment results in voiding postponement. 
     
     
         29 . A method of treatment of bleeding disorders, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to  claim 21 .