Substituted spirobenzazepines

Abstract

The invention is directed to nonpeptide substituted benzazepines of Formula I, which are useful as vasopressin receptor antagonists for treating conditions associated with vasopressin receptor activity such as those involving increased vascular resistance and cardiac insufficiency, including congestive heart failure, hyponatremia, and hypertension, among others disclosed. Pharmaceutical compositions comprising a compound of Formula I and methods of treating conditions such as hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, hyponatremia, renal vasospasm, renal failure, diabetic nephropathy, cerebral edema, cerebral ischemia, stroke, thrombosis, or water retention are also disclosed.

What is claimed is:  
     
         1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 one of R 1  and R 2  is H and the other is H, NR 5 R 6 , C 1-6  alkoxy, hydroxy, or halo; wherein each of R 5  and R 6  is independently H or C 1-3  alkyl;  
 R 3  is chloro;  
 R 4  is chloro, fluoro, methoxy, or methyl;  
 or a pharmaceutically acceptable C 1-6  ester, C 1-6  amide, or di (C 1-6  alkyl)amide or salt thereof.  
 
     
     
         2 . A compound of  claim 1 , wherein R 2  is amino.  
     
     
         3 . A compound of  claim 1 , wherein R 2  is C 1-4  alkoxy.  
     
     
         4 . A compound of  claim 1 , wherein R 2  is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or t-butoxy.  
     
     
         5 . A compound of  claim 4 , wherein R 2  is methoxy or ethoxy.  
     
     
         6 . A compound of  claim 1 , wherein R 4  is fluoro, chloro, or methyl.  
     
     
         7 . A compound of  claim 1 , wherein R 4  is fluoro or chloro.  
     
     
         8 . A compound of  claim 1  wherein R 4  is fluoro.  
     
     
         9 . A compound of  claim 6  wherein R 2  is methoxy, ethoxy, or isopropoxy.  
     
     
         10 . A compound of  claim 6  wherein R 1  is methoxy or ethoxy.  
     
     
         11 . A compound of  claim 7 , wherein R 2  is methoxy or ethoxy.  
     
     
         12 . A compound of  claim 1 , selected from: 
 (R)-4-(2-Chloro-5-fluorobenzoyl-3-methoxy4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-3-ethoxy4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-3-isopropoxy -4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-3-hydroxy-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-3-amino-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-3-chloro-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-2-chloro-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-2-amino-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-fluorobenzoyl-2-hydroxy-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2-Chloro-5-fluorobenzoyl-2-methoxy-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methylbenzoyl-3-methoxy4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methylbenzoyl-3-hydroxy-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methylbenzoyl-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methylbenzoyl-3-amino-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methylbenzoyl-3-chloro-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methoxybenzoyl-3-methoxy-4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methoxybenzoyl-3-hydroxy-4-am i nobenzoyl )-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methoxybenzoyl-4-aminobenzoyl )-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2-Chloro-5-methoxybenzoyl-3-amino4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)-4-(2-Chloro-5-methoxybenzoyl-3-chloro-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2,5-Dichlorobenzoyl-3-methoxy-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2,5-Dichlorobenzoyl-3-hydroxy-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2,5-Dichlorobenzoyl4-aminobenzoyl)-4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene    (R)4-(2,5-Dichlorobenzoyl-3-amino-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene; and    (R)4-(2,5-Dichlorobenzoyl-3-chloro-4-aminobenzoyl)4-aza-3′-(carboxy)-[6,4]-spiro-[5,6]-benzoundec-2′-ene.    
     
     
         13 . A compound of  claim 1 , selected from compound 6 and compound 7.  
     
     
         14 . A compound of  claim 1 , having the formula of compound 7.  
     
     
         15 . A compound of  claim 1 , having the formula of compound 6.  
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         17 . A pharmaceutical composition of  claim 16 , wherein said compound is selected from  claim 5 ,  8 ,  9 ,  10 ,  13 ,  14 , or  15 .  
     
     
         18 . A method of treating a subject suffering from a condition associated with vasopressin receptor activity, which comprises administering to the subject a therapeutically effective amount of the compound of Formula I as defined in  claim 1 .  
     
     
         19 . A method of inhibiting in a subject the onset or progression of a condition associated with vasopressin receptor activity, which comprises administering to the subject a prophylactically effective dose of a compound of Formula I as defined in  claim 1 .  
     
     
         20 . The method of  claim 18  or  19 , wherein said condition is selected from inner ear disorders, hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, diabetic nephropathy, hyponatremia, cerebral edema, cerebral ischemia, stroke, thrombosis, water retention, aggression, obsessive-compulsive disorders, dysmenorrhea, nephrotic syndrome, anxiety and central nervous injuries.  
     
     
         21 . The method of  claim 20  wherein said condition is congestive heart failure, or cardiac insufficiency.  
     
     
         22 . The method of  claim 20 , wherein said condition is hyponatremia.  
     
     
         23 . The method of  claim 20  wherein said condition is hypertension.  
     
     
         24 . The method of  claim 20  wherein said compound is selected from  claim 5 ,  8 ,  9 ,  10 ,  13 ,  14 , or  15 .  
     
     
         25 . A process for making a pharmaceutical composition comprising mixing any of the compounds according to  claim 1  and a pharmaceutically acceptable carrier.