Substituted piperazines, (1,4) diazepines, and 2,5-diazabicyclo (2.2.1) heptanes as histamine h1 and/or h3 antagonists or histamine h3 reverse antagonists

Abstract

The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer's disease.

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  represents heteroaryl, optionally substituted by one or more: halogen; trifluoromethyl; —C 1-6 alkyl optionally substituted by COOR 15 ; —C 1-6 alkoxy optionally substituted by COOR 15 ; C 1-6  alkenyl; NR 15 R 16 ; or C 1-6 alkylthio groups, and in which 
 R 15  and R 16  independently represent hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl or together may be fused to form a 5- to 7-membered non-aromatic heterocyclic ring optionally interrupted by an O or S atom and optionally substituted by halogen, C 1-6 alkyl or —C 1-6 alkylC 1-6 alkoxy group; 
 wherein R 15  and R 16  independently represent hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl or together may be fused to form a 5- to 7-membered non-aromatic heterocyclic ring optionally interrupted by an O or S atom and optionally substituted by a halogen, C 1-6 alkyl or C 1-6 alkylC 1-6 alkoxy group; 
 Z is a bond or CO; 
 m is 0 or 2; 
 p is 1; 
 R 3  represents —(CH 2 ) q —NR 11 R 12  in which q represents 3 and 
 NR 11 R 12  represents pyrrolidinyl, piperidinyl, azepanyl or azocanyl optionally substituted by one or more C 1-6  alkyl groups; 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       2 . A compound according to  claim 1 , in which R 1  represents optionally substituted benzofuranyl, indolyl, or quinolinyl. 
   
   
       3 . A compound according to  claim 1 , wherein m is 0. 
   
   
       4 . A compound according to  claim 1 , wherein R 1  is optionally substituted by 1, 2 or 3 substituents selected from chlorine, fluorine, bromine, trifluoromethyl, methyl, ethyl, isopropyl, propyl or t-butyl (wherein the methyl, ethyl, isopropyl, propyl or t-butyl is optionally substituted by COOR 15 ), methoxy (optionally substituted by COOR 15 ), ethenyl, N(Me) 2  or —S-ethyl. 
   
   
       5 . A compound according to  claim 1 , wherein NR 11 R 12  represents pyrrolidinyl, piperidinyl, azepanyl or azocanyl optionally substituted by one or more methyl or ethyl groups. 
   
   
       6 . A compound according to  claim 1  in which NR 11 R 12  represents unsubstituted pyrrolidinyl, piperidinyl, azepanyl or azocanyl. 
   
   
       7 . A pharmaceutical composition which comprises a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
   
   
       8 . A method of treatment of diseases of the upper respiratory tract which comprises administering to a host in need thereof an effective amount of a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       9 . A method of treatment according to  claim 8  in which the disease is allergic rhinitis.