N-piperidinyl acetamide derivatives as calcium channel blockers

Abstract

Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted T-type calcium channel activity are disclosed. Specifically, a series of compounds containing N-piperidinyl acetamide derivatives as shown in formula (1).

1 . A pharmaceutical composition comprising a compound of formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or conjugate thereof in admixture with a pharmaceutically acceptable excipient, wherein 
         A is C(O)NR′ or NR′C(O) wherein R′ is H or methyl; 
         X is an optionally substituted C1-C4 alkylene, C2-C4 heteroalkylene, C2-C4 alkenylene, or C2-C4 heteroakenylene; 
         n is 0 or 1;
 Ar is substituted phenyl or optionally substituted pyrazolyl, imidazolyl, pyridinyl, isoxazolyl, thiazolyl, thiophenyl, benzothiazolyl, or indolyl; 
 
         B is OH or NY 2 , wherein each Y is independently H, SR″, SOR″, SO 2 R″, or each Y is an optionally substituted group selected from C1-C10 alkyl, C2-C10 alkenyl, 2-C10 alkynyl, C2-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl; or two Y may together form an optionally substituted heterocyclic ring having 4-6 ring members; 
         each R is independently H, halo, CN, NO 2 , CF 3 , OCF 3 , COOR″, CONR″ 2 , OR″, SR″, SOR″, SO 2 R″, NR″ 2 , NR″(CO)R″, and NR″SO 2 R″; or each R is independently optionally substituted groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl; or two R on the same carbon atom taken together ═O, ═NOR″ or ═NCN; or two R together form an optionally substituted cyclic or heterocyclic ring having 3-6 ring members; or if B is NY 2 , one R and one Y together form an optionally substituted heterocyclic ring having 4-6 ring members, or two Y together form an optionally substituted heterocyclic ring having 4-6 ring members; 
         each R″ is independently H or an optionally substituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, or C2-C6 heteroalkynyl, wherein the optional substituents on Y, R and R″ may be one or more halo, ═O, ═NOR″, CN, NO 2 , CF 3 , OCF 3 , COOR″, CONR″ 2 , OR″, SR″, SOR″, SO 2 R″, NR″ 2 , NR″(CO)R″, and NR″SO 2 R″, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, or C2-C6 heteroalkynyl; 
         wherein the optional substituents on X and Ar may be one or more halo, CN, CF 3 , OCF 3 , COOR″, CONR″ 2 , OR″, SR″, SOR″, SO 2 R″, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl, C6-C10 aryl, heteroaryl having 5-12 ring members, C6-C10 D-aryl, O-heteroaryl having 5-12 ring members, C6-C12 aryl-C1-C6-alkyl; and wherein optional substituents on X may be additionally selected from ═O, ═NOR″, NO 2 , NR″ 2 , NR″(CO)R″, and NR″ SO 2 1=1″; and 
         wherein two substituents on Ar may form a cyclic or heterocyclic ring having 4-7 ring members. 
       
     
     
         2 . The pharmaceutical composition of  claim 1  wherein Ar is substituted phenyl. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein n is 0. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the substituents on Ar are independently selected from fluoro, bromo, chloro, trifluoromethyl, methyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, t-butyl, t-butyloxy, methoxy, phenoxy, pyrrolidinyl, pyridinyloxy morpholinomethyl, hydroxy, (CH 3 ) 3 COC(O) or wherein two optional substituents together form a five membered heterocyclic ring with Ar wherein the two substituents together form —O—CH 2 —O—, —O—CF 2 —O— or —O—CH 2 CH 2 —. 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein B is NY 2 . 
     
     
         6 . The pharmaceutical composition of  claim 5  wherein at least one Y is H or methyl. 
     
     
         7 . The pharmaceutical composition of  claim 5  wherein at least one Y is an alkyl or heteroalkyl. 
     
     
         8 . The pharmaceutical composition of  claim 5  wherein a carbonyl is immediately adjacent to the N in B. 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein each R is H, or two R on the same carbon atom together form ═O. 
     
     
         10 . The pharmaceutical composition of  claim 1  wherein the compound is of formula (2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or conjugate thereof, wherein Y is as defined in claim  19 , L is C(O)CH 2  or CH 2 CH 2 , one R 3  is H, halo, CF 3 , CH 3 , OCH 3  or OCF 3 , and one R 3  is halo, CF 3 , CH 3 , OCH 3  or OCF 3 . 
       
     
     
         11 . The pharmaceutical composition of  claim 10  wherein one Y is H or methyl and one Y is an optionally substituted alkyl (1-6C) or SO 2 R 4  wherein R 4  is an optionally substituted C1-C5 alkyl.