Phenylpiperidines and Phenylpyrrolidines

Abstract

Substituted phenylpiperidines and phenylpyrrolidines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

1 . A composition comprising a compound of formula (I):  
     
       
         
         
             
             
         
       
       Wherein  
       L is a direct bond, or an optionally C 1-4 alkyl substituted radical selected from the group consisting of C 1-4 alkylene or C 3-4 alkenylene wherein NR 1 R 2  is attached to an Sp 3  hybridized carbon, C 3-4 alkynylene wherein NR 1 R 2  is attached to an Sp 3  hybridized carbon, C 2-4 alkylidene wherein NR 1 R 2  is attached to an Sp 3  hybridized carbon, aryloxy wherein NR 1 R 2  is not attached to the oxygen, arylthio wherein NR 1 R 2  is not attached to the sulfur, C 2-4 alkoxy wherein NR 1 R 2  is not attached to the oxygen or a carbon attached to the oxygen, C 2-4 alkylthio wherein NR 1 R 2  is not attached to the sulfur or a carbon attached to the sulfur, and —C 2-3 alkyl-X—C 1-2 alkyl- wherein X is O, S or NH and wherein NR 1 R 2  is not attached to a carbon attached to X;  
       p is 0, 1 or 2;  
       q is 1 or 2; provided that 2≦p+q≦4;  
       R 1  is a substituent independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-6  alkenyl, C 3-9  carbocyclyl, pyridinyl, phenyl, pyridinylC 1-6  alkylene, and (phenyl)C 1-6  alkylene;  
       R 2  is a substituent independently selected from the group consisting of C 1-6  alkyl, C 3-6  alkenyl, C 3-9  membered carbocyclyl, pyridinyl, phenyl, pyridinylC 1-6  alkylene, and (phenyl)C 1-6  alkylene;  
       wherein R 1  and R 2  are optionally and independently substituted with 1-3 substituents selected from the group consisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide, C 1-6  alkyl, C 1-6  acyl, 5-9-membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, C 1-12 -hydroxyalkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl):-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O—; and wherein each of the preceding substituents of R 1  and R 2  may optionally have between 1 and 3 substituents independently selected from the group consisting of trifluoromethyl, halo, nitro, cyano, hydroxy, and C 1-3  alkyl;  
       one of R 3 , R 4  and R 5  is G and the other two independently are hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C 1-3  alkoxy;  
       G is L 2 Q;  
       L 2  is unbranched —(CH 2 ) n — wherein n is an integer from 1 to 7;  
       Q is a N:-linked heterocyclyl which is piperidinyl or pyrrolidinyl;  
       wherein Q is optionally substituted with 1-3 substituents selected (in addition to the preceding paragraph) from the group consisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide, C 1-6  alkyl, C 1-6  acyl, 5-9-membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C 1-3  alkylene, C 1-2 -hydroxyalkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl):-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O—; and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, hydroxy, and C 1-3  alkyl;  
       R a  are independently C 1-3  alkyl, trifluoromethyl;  
       m is 0, 1, 2 or 3; and  
       wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxy, and C 1-3  alkyl;  
       or a pharmaceutically acceptable acid addition alkali metal or alkaline earth metal salt, thereof.  
     
   
   
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       14 . A compound of  claim 1 , wherein one of R 3  and R 4  is G.  
   
   
       15 . A compound of  claim 14 , wherein R 4  is G.  
   
   
       16 . A compound of  claim 14 , wherein R 3  is G.  
   
   
       17 . A compound of  claim 1 , wherein q is 2 and p is 1.  
   
   
       18 . A compound of  claim 1 , wherein q is 1 and p is 1.  
   
   
       19 . A compound of  claim 1 , wherein q is 2 and p is 2.  
   
   
       20 . A compound of  claim 1 , wherein  1 , is —CH 2 —.  
   
   
       21 . A compound of  claim 1 , wherein  1 , is a direct bond.  
   
   
       22 . A compound of  claim 1 , wherein  1 , is —CH 2 CH 2 —.  
   
   
       23 . A compound of  claim 1 , wherein L 2  is —CH 2 —.  
   
   
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       29 . A compound of  claim 1 , wherein Q is optionally substituted with between 1 and 3 substituents selected from hydroxy, halo, carboxamide, C 1-6  alkyl, C 1-6  acyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C 1-3  alkylene, C 1-12 -hydroxyalkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl):-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, hydroxy, and C 1-3  alkyl.  
   
   
       30 . A compound of  claim 29 , wherein Q is substituted with a substituent comprising a 5-9 membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-16  alkylene, pyrrolidinyl, and pyrrolyl.  
   
   
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       46 . A compound of  claim 1 , wherein Q is piperidinyl or substituted piperidinyl.  
   
   
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       48 . A compound of  claim 1  wherein R a  is hydrogen.  
   
   
       49 . A compound of  claim 1  selected from the group consisting of 
 Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;    Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;    Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;    Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;    Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;    Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine; and    Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine.    
   
   
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       54 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically-acceptable excipient.  
   
   
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