Pyridinoylpiperidines as 5-HT1F agonists

Abstract

The present invention relates to compounds of formula I: or pharmaceutically acceptable acid addition salts thereof, where; R 1 is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 3 alkyl, substituted C 3 -C 7 cycloalkyl-C 1 -C 3 alkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle; R 2 is hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl-C 1 -C 3 alkyl, or a group of formula II R 3 is hydrogen or C 1 -C 3 alkyl; R 4 is hydrogen, halo, or C 1 -C 3 alkyl; R 5 is hydrogen or C 1 -C 3 alkyl; R 6 is hydrogen or C 1 -C 6 alkyl; and n is an integer from 1 to 6 inclusively. The compounds of the present invention are useful for activating 5-HT 1F receptors, inhibiting neuronal protein extravasation, and for the treatment or prevention of migraine in a mammal. The present invention also relates to a process for the synthesis of intermediates in the synthesis of compounds of Formula I.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable acid addition salt thereof, where;
 R 1  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, substituted C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle; 
 R 2  is hydrogen, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl-C 1 -C 3  alkyl, or a group of formula II 
 
     
       
         
         
             
             
         
       
       R 3  is hydrogen or C 1 -C 3  alkyl; 
       R 4  is hydrogen, halo, or C 1 -C 3  alkyl; 
       R 5  is hydrogen or C 1 -C 3  alkyl; 
       R 6  is hydrogen or C 1 -C 6  alkyl; and 
       n is an integer from 1 to 6 inclusively. 
     
   
   
       2 . The compound  claim 1  wherein R 5  is hydrogen and R 4  is hydrogen or halogen. 
   
   
       3 . The compound of  claim 2  wherein R 4  is hydrogen. 
   
   
       4 . The Compound of  claim 1  wherein R 2  is hydrogen or C 1 -C 3  alkyl. 
   
   
       5 . The compound of  claim 1  wherein R 1  is phenyl, substituted phenyl, heterocycle, or substituted heterocycle. 
   
   
       6 . The compound of  claim 1  wherein R 1  is phenyl, substituted phenyl, heterocycle or substituted heterocycle, wherein the heterocycle moiety is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, and indolyl, and wherein substituted is taken to mean the ring moiety is substituted with one to three halo substituents; or substituted with one to two substituents independently selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, and C 1 -C 4  alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can be further substituted independently with C 1 -C 2  alkoxy or with one to five halo groups each independently selected from fluoro and chloro; or substituted with one substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, or pyrimidinyloxy moiety can be further substituted with one to two substituents selected from the group consisting of halo, C 1 -C 2  alkyl, and C 1 -C 2  alkoxy; or substituted with one substituent selected from the group consisting of C 1 -C 4  acyl and C 1 -C 4  alkoxycarbonyl, and further substituted with zero to one substituent selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, and C 1 -C 4  alkylthio. 
   
   
       7 . The compound of  claim 1  wherein R 1  is phenyl, substituted phenyl, heterocycle or substituted heterocycle, wherein the heterocycle moiety is selected from the group consisting of pyridinyl, indolyl, benzofuranyl, furanyl, thiophenyl, benzodioxolyl, and thiazolidinyl, and wherein substituted is taken to mean the ring moiety is substituted with one to three halo substituents; or substituted with one to two substituents independently selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, and C 1 -C 4  alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can be further substituted independently with C 1 -C 2  alkoxy or with one to five halo groups each independently selected from fluoro and chloro; or substituted with one substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, or pyrimidinyloxy moiety can be further substituted with one to two substituents selected from the group consisting of halo, C 1 -C 2  alkyl, and C 1 -C 2  alkoxy; or substituted with one substituent selected from the group consisting of C 1 -C 4  acyl and C 1 -C 4  alkoxycarbonyl, and further substituted with zero to one substituent selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, and C 1 -C 4  alkylthio. 
   
   
       8 . (canceled) 
   
   
       9 . (canceled) 
   
   
       10 . (canceled) 
   
   
       11 . (canceled) 
   
   
       12 . A method for the treatment or prevention of migraine in a mammal comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable acid addition salt thereof, where;
 R 1  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, substituted C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, phenyl, -substituted phenyl, heterocycle, or substituted heterocycle; 
 R 2  is hydrogen, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl-C 1 -C 3  alkyl, or a group of formula II 
 
     
       
         
         
             
             
         
       
       R 3  is hydrogen or C 1 -C 3  alkyl; 
       R 4  is hydrogen, halo, or C 1 -C 3  alkyl; 
       R 5  is hydrogen or C 1 -C 3  alkyl; 
       R 6  is hydrogen or C 1 -C 6  alkyl; and 
       n is an integer front 1 to 6 inclusively. 
     
   
   
       13 . The method according to  claim 12  wherein the mammal is a human. 
   
   
       14 . The compound of  claim 5  wherein R 5  is hydrogen and R 4  is hydrogen or halogen. 
   
   
       15 . The compound of  claim 14  wherein R 4  is hydrogen. 
   
   
       16 . The compound of  claim 15  wherein R 2  is hydrogen or C 1 -C 3  alkyl. 
   
   
       17 . The compound of  claim 6  wherein R 5  is hydrogen and R 4  is hydrogen or halogen. 
   
   
       18 . The compound of  claim 17  wherein R 4  is hydrogen. 
   
   
       19 . The compound of  claim 18 , wherein R 2  is hydrogen or C 1 -C 3  alkyl. 
   
   
       20 . The compound of  claim 7  wherein R 5  is hydrogen and R 4  is hydrogen or halogen. 
   
   
       21 . The compound of  claim 20  wherein R 4  is hydrogen. 
   
   
       22 . The compound of  claim 21  wherein R 2  is hydrogen or C 1 -C 3  alkyl. 
   
   
       23 . A pharmaceutical formulation comprising a compound of  claim 1  and a pharmaceutical carrier, diluent, or excipient. 
   
   
       24 . (canceled) 
   
   
       25 . (canceled) 
   
   
       26 . (canceled)