US2009149442A1PendingUtilityA1

Atypical antipsychotic agents having low affinity for the D2 receptor

Assignee: KAPUR SHITIJPriority: Jun 26, 2001Filed: Jan 25, 2007Published: Jun 11, 2009
Est. expiryJun 26, 2021(expired)· nominal 20-yr term from priority
C07D 281/16A61P 25/18C07D 267/20
51
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Claims

Abstract

The present invention provides novel compounds of Formula I: The invention further relates to pharmaceutical compositions comprising compounds of Formula I and to methods of using compounds of Formula I to treat neuropsychiatric disorders (e.g., psychosis, depression, schizophrenia).

Claims

exact text as granted — not AI-modified
1 . A compound of Formula I or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein said Formula I is represented by: 
     
       
         
         
             
             
         
       
     
     and wherein
 R 1  is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3  and CH 3 O; 
 R 2  is selected from the group consisting of C 2-5  alkyl and (CH 2 ) n OH; 
 X is selected from the group consisting of O and S; and 
 n is an integer selected from 2, 3, 4 and 5. 
 
   
   
       2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is O. 
   
   
       3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is S. 
   
   
       4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2  is C 2-4  alkyl. 
   
   
       5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2  is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl and (CH 2 ) 2 OH. 
   
   
       6 . The compound of  claim 5 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2  is selected from the group consisting of ethyl and (CH 2 ) 2 OH. 
   
   
       7 . The compound of  claim 6 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1  is selected from the group consisting of halo and CF 3 . 
   
   
       8 . The compound of  claim 7 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1  is selected from the group consisting of F, Cl, Br and I. 
   
   
       9 . The compound of  claim 7 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1  is selected from the group consisting of Cl and CF 3 . 
   
   
       10 . The compound of  claim 1 , wherein said compound of Formula (I) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     (A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-2)=8-Trifluoromethyl-11-(4-(2′-hydroxyethyl)piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-3)=8-Trifluoromethyl-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-4)=8-Trifluoromethyl-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-5)=8-Trifluoromethyl-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-9)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-10)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-11)=8-Fluoro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-14)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and 
     
       
         
         
             
             
         
       
     
     (A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)dibenzo[b,f][1,4]thiazepine. 
   
   
       11 - 19 . (canceled) 
   
   
       20 . A method for the treatment of psychosis, said method comprising the step of administering, to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3  and CH 3 O; 
 R 2  is selected from the group consisting of C 2-5  alkyl and (CH 2 ) n OH; 
 X is selected from the group consisting of O and S; and 
 n is an integer selected from 2, 3, 4, and 5. 
 
   
   
       21 . The method of  claim 20 , wherein said compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, of Formula I is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     (A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-2)=8-Trifluoromethyl-11-(4-(2′-hydroxyethyl)piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-3)=8-Trifluoromethyl-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-4)=8-Trifluoromethyl-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-5)=8-Trifluoromethyl-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-9)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-10)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-11)=8-Fluoro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-14)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and 
     
       
         
         
             
             
         
       
     
     (A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine. 
   
   
       22 . A pharmaceutical composition comprising a compound of Formula I, or its pharmaceutical salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, said Formula I represented by: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from the group consisting of halo, CF 3 , CF 3 O, cyano, CH 3  and CH 3 O; 
 R 2  is selected from the group consisting of C 2-5  alkyl and (CH 2 ) n OH; 
 X is selected from the group consisting of O and S; and 
 n is an integer selected from 2, 3, 4, and 5. 
 
   
   
       23 . The method of  claim 20 , wherein said subject is a human. 
   
   
       24 . The compound of  claim 1 , wherein said Formula I represents an atypical antipsychotic drug in a human. 
   
   
       25 . The compound of  claim 10 , wherein said compound of Formula (I) is represented by a formula selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     (A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and 
     
       
         
         
             
             
         
       
     
     (A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine. 
   
   
       26 . The method of  claim 20 , wherein the compound of Formula I is an atypical antipsychotic drug in a human and said subject is a human. 
   
   
       27 . The method of  claim 26 , wherein the compound of Formula I is represented by a formula selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     (A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and 
     
       
         
         
             
             
         
       
     
     (A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine. 
   
   
       28 . The pharmaceutical composition of  claim 22 , wherein the compound of Formula (I) is represented by a formula selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     (A-1)=8-Trifluoromethyl-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-8)=8-Chloro-11-(4-propylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine; 
     
       
         
         
             
             
         
       
     
     (A-12)=8-Chloro-11-(4-ethylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; 
     
       
         
         
             
             
         
       
     
     (A-15)=8-Chloro-11-(4-isopropylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine; and 
     
       
         
         
             
             
         
       
     
     (A-16)=8-Chloro-11-(4-butylpiperazin-1-yl)-dibenzo[b,f][1,4]thiazepine. 
   
   
       29 . The pharmaceutical composition of  claim 28 , wherein the compound of Formula (I) is an atypical antipsychotic in a human.

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