US2002193590A1PendingUtilityA1

Azepine derivatives having effects on serotonin related systems

47
Priority: Jun 30, 1998Filed: May 8, 2002Published: Dec 19, 2002
Est. expiryJun 30, 2018(expired)· nominal 20-yr term from priority
Inventors:Kenneth Lee HauserLarry W. HertelYao-Chang Xu
A61P 43/00C07D 405/04A61P 25/22A61P 25/30A61P 25/24C07D 409/14C07D 409/04C07D 405/14
47
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Claims

Abstract

The present invention provides compounds of formula I and a method of inhibiting the reuptake of serotonin, antagonizing the 5-HT 1A receptor and antagonizing the 5-HT 2A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.

Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, NR, S(═O), or S(═O) 2 ;  
 Y is —C(═O)—, —CH(OH)—, —CH 2 —, —C(═NOR), CHNR 7 R, S, SO, or SO 2 ;  
   represents a single or a double bond;  
 n is 1, 2, 3 or 4;  
 R is H or C 1 -C 6  alkyl;  
 R 1a , R 1b , R 1c  and R 2  are each independently H, F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , —NR 7 R 8 , —C(═O)NR 7 R 8 , —NR 7 C(═O)R 8 , CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 3  is H, OH, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or (C 1 -C 6 )alkylthio;  
 R 4  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or  
 heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 5  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl; (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 6a  and R 6b  are each independently H or C 1 -C 3  alkyl;  
 R 7  and R 8  are each independently H, C 1 -C 6  alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein X is O.  
     
     
         3 . A compound according to  claim 1  wherein X is S.  
     
     
         4 . A compound according to  claim 2  wherein R 2  is H.  
     
     
         5 . A compound according to  claim 3  wherein R 2  is H.  
     
     
         6 . A compound according to  claim 4  wherein n is 2.  
     
     
         7 . A compound according to  claim 5  wherein n is 2.  
     
     
         8 . A compound according to  claim 7  wherein R 6a  and R 6b  are H.  
     
     
         9 . A compound according to  claim 8  wherein Y is —C(═O)—.  
     
     
         10 . A compound according to  claim 9  wherein R 5  is cyclohexyl or phenyl.  
     
     
         11 . A compound according to  claim 10  wherein R 3  is H or C 1 -C 6  alkyl.  
     
     
         12 . A compound according to  claim 11  wherein R 4  is 2-pyridyl, 3-pyridyl, or phenyl.  
     
     
         13 . A compound according to  claim 12  wherein R 1a , R 1b  and R 1c  are H.  
     
     
         14 . A method of inhibiting the reuptake of serotonin and antagonizing the 5-HTIA receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, NR, S(═O), or S(═O) 2 ;  
 Y is —C(═O)—, —CH(OH)—, —CH 2 —, —C(═NOR), CHNR 7 R, S, SO, or SO 2 ;  
   represents a single or a double bond;  
 n is 1, 2, 3 or 4;  
 R is H or C 1 -C 6  alkyl;  
 R 1a , R 1b , R 1c  and R 2  are each independently H, F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , —NR 7 R 8 , —C(═O)NR 7 R 8 , —NR 7 C(═O)R 8 , CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, N0 2 , NH 2 , or CN;  
 R 3  is H, OH, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or (C 1 -C 6 )alkylthio;  
 R 4  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or  
 heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 5  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 6a  and R 6b  are each independently H or C 1 -C 3  alkyl;  
 R 7  and R 8  are each independently H, C 1 -C 6  alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         15 . A method of potentiating the action of a serotonin reuptake inhibitor comprising administering to a subject in of such treatment a compound formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, NR, S(═O), or S(═O) 2 ;  
 Y is —C(═O)—, —CH(OH)—, —CH 2 —, —C(═NOR), CHNR 7 R, S, SO, or SO 2 ;  
   represents a single or a double bond;  
 n is 1, 2, 3 or 4;  
 R is H or C 1 -C 6  alkyl;  
 R 1a , R 1b , R 1c  and R 2  are each independently H, F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , —NR 7 R 8 , —C(═O)NR 7 R 8 , —NR 7 C(═O)R 8 , CN or phenyl substituted with from 1 to 3 20 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 3  is H, OH, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or (C 1 -C 6 )alkylthio; R4 is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 5  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 6a  and R 6b  are each independently H or C 1 -C 3  alkyl;  
 R 7  and R 8  are each independently H, C 1 -C 6  alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         16 . A method of treating depression comprising administering to a subject in need thereof an effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, NR, S(═O), or S(═O) 2 ;  
 Y is —C(═O)—, —CH(OH)—, —CH 2 —, —C(═NOR), CHNR 7 R, S, SO, or SO 2 ;  
   represents a single or a double bond;  
 n is 1, 2, 3 or 4;  
 R is H or C 1 -C 6  alkyl;  
 R 1a , R 1b , R 1c  and R 2  are each independently H, F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , —NR 7 R 8 , —C(═O)NR 7 R 8 , —NR 7 C(═O)R 8 , CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 3  is H, OH, hydroxy(C 1 -C 6 )alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or (C 1 -C 6 )alkylthio;  
 R 4  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or  
 heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 5  is aryl, heterocycle, C 3 -C 8  cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 6a  and R 6b  are each independently H or C 1 -C 3  alkyl;  
 R 7  and R 8  are each independently H, C 1 -C 6  alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         17 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  in combination with a pharmaceutically acceptable carrier, diluent or excipient.  
     
     
         18 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is O, S, NR, S(═O), or S(═O) 2 ;  
   represents a single or a double bond;  
 R is H or C 1 -C 6  alkyl;  
 R 1a , R 1b , R 1c  and R 2  are each independently H, F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , —NR 7 R 8 , —C(═O)NR 7 R 8 , —NR 7 C(═O)R 8 , CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN;  
 R 6a  and R 6b  are each independently H or C 1 -C 3  alkyl; and  
 R 7  and R 8  are each independently H, C 1 -C 6  alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, NO 2 , NH 2 , or CN.  
 
     
     
         19 . A compound according to  claim 18  wherein X is S.  
     
     
         20 . A compound according to  claim 18  wherein X is O.  
     
     
         21 . A compound according to  claim 20  wherein R 2  is H.  
     
     
         22 . The use of a compound according to  claim 1  for the manufacture of a medicament for inhibiting the reuptake of serotonin, antagonizing the 5-HT 1A  receptor, and antagonizing the 5-HT 2A  receptor.  
     
     
         23 . The use of a compound according to  claim 1  for inhibiting the reuptake of serotonin, antagonizing the 5-HT 1A  receptor, and antagonizing the 5-HT 2A  receptor.

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