Therapeutic agents useful for treating pain

Abstract

A compound of formula: wherein A, Ar, R 3 , R 6 , and m are disclosed herein, or a pharmaceutically acceptable salt thereof (a “Cyanoiminopiperazine Compound”), compositions comprising an effective amount of a Cyanoiminopiperazine Compound, and methods for treating or preventing pain, urinary incontinence, an ulcer, inflammatory-bowel disease, irritable-bowel syndrome, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression in an animal comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound are disclosed.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is —NR 4 —, —O—, or —S—; 
 R 1  is —H, -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, —(C 3 -C 7 )heterocycle, or —(C 7 -C 10 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or —(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7  groups; 
 
 R 4  is —H, —(C 1 -C 6 )alkyl, or —O—(C 1 -C 6 )alkyl; 
 each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 8 ) 2 , —CH═NR 8 , —NR 8 OH, —COR 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —SR 8 , —S(O)R 8 , or —S(O) 2 R 8 ; 
 R 6  is -phenyl, -naphthyl, —(C 3 -C 8 )cycloalkyl, —(C 14 )aryl, or —(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7  groups; 
 each R 7  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 3 -C 5 )heterocycle, —C(halo) 3 , —CH 2 (halo), —CH(halo) 2 , —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 8 ) 2 , —CH═NR 8 , —NR 8 OH, —OR 8 , —COR 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —SR 8 , —S(O)R 8 , or —S(O) 2 R 8 ; 
 each R 8  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 3 -C 5 )heterocycle, —C(halo) 3 , —CH 2 (halo), or —CH(halo) 2 ; 
 each halo is independently —F, —Cl, —Br, or —I; and 
 m is an integer ranging from 0 to 2. 
 
     
     
         2 . The compound of  claim 1 , wherein A is —NH—. 
     
     
         3 . The compound of  claim 2 , wherein:
 m is 0; and   R 6  is phenyl.   
     
     
         4 . The compound of  claim 3 , wherein the R 6  phenyl is unsubstituted. 
     
     
         5 . The compound of  claim 3 , wherein the R 6  phenyl is substituted at the 4-position. 
     
     
         6 . The compound of  claim 5 , wherein the R 6  phenyl is substituted with a —(C 1 -C 6 )alkyl R 7  group. 
     
     
         7 . The compound of  claim 6 , wherein the R 7 —(C 1 -C 6 )alkyl is tert-butyl or iso-propyl. 
     
     
         8 . The compound of  claim 5 , wherein the R 6  phenyl is substituted with a —CF 3  or —OCF 3  R 7  group. 
     
     
         9 . The compound of  claim 3 , wherein R 1  is —Cl or —CH 3 . 
     
     
         10 . The compound of  claim 9 , wherein the R 6  phenyl is unsubstituted. 
     
     
         11 . The compound of  claim 9 , wherein the R 6  phenyl is substituted at the 4-position. 
     
     
         12 . The compound of  claim 11 , wherein the R 6  phenyl is substituted with a —(C 1 -C 6 )alkyl R 7  group. 
     
     
         13 . The compound of  claim 12 , wherein the R 7 —(C 1 -C 6 )alkyl is tert-butyl or iso-propyl. 
     
     
         14 . The compound of  claim 11 , wherein the R 6  phenyl is substituted with a —CF 3  or —OCF 3  R 7  group. 
     
     
         15 . The compound of  claim 1 , wherein A is —O—. 
     
     
         16 . The compound of  claim 1 , wherein A is —S—. 
     
     
         17 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar 1  is 
 
       
         
           
           
               
               
           
         
         Ar 2  is 
       
       
         
           
           
               
               
           
         
         R 1  is —H, -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
         each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
         each R 4  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
         each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 8 ) 2 , —CH═NR 8 , —NR 8 OH, —OR 8 , —COR 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —SR 8 , —S(O)R 8 , or —S(O) 2 R 8 ; 
         each R 6  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
         each R 7  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
         each R 8  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
         each R 11  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
         each halo is independently —F, —Cl, —Br, or —I; 
         m is 0 or 1; 
         o is an integer ranging from 0 to 4; 
         q is an integer ranging from 0 to 6; 
         r is an integer ranging from 0 to 5; 
         s is an integer ranging from 0 to 4; 
         t is an integer ranging from 0 to 2; and 
         u is 0 or 1. 
       
     
     
         18 . The compound of  claim 17 , wherein m is 1, R 3  is —CH 3 , t is 0, and u is 0. 
     
     
         19 . The compound of  claim 17 , wherein m is 1, R 3  is —CH 3 , t is 0, and u is 1. 
     
     
         20 . The compound of  claim 17 , wherein m is 0, t is 0, and u is 0. 
     
     
         21 . The compound of  claim 17 , wherein m is 0, t is 0, and u is 1. 
     
     
         22 . The compound of  claim 20 , wherein Ar 2  is phenyl substituted at the 4-position with an R 8  group. 
     
     
         23 . The compound of  claim 22 , wherein R 8  is —(C 1 -C 6 )alkyl. 
     
     
         24 . The compound of  claim 23 , wherein the R 8 —(C 1 -C 6 )alkyl is tert-butyl or iso-butyl. 
     
     
         25 . The compound of  claim 22 , wherein R 8  is —CF 3  or —OCF 3 . 
     
     
         26 . The compound of  claim 22 , wherein R 1  is —Cl or —CH 3 . 
     
     
         27 . The compound of  claim 21 , wherein Ar 2  is phenyl substituted at the 4-position with an R 8  group. 
     
     
         28 . The compound of  claim 27 , wherein R 8  is —(C 1 -C 6 )alkyl. 
     
     
         29 . The compound of  claim 28 , wherein the R 8 —(C 1 -C 6 )alkyl is tert-butyl or iso-butyl. 
     
     
         30 . The compound of  claim 27 , wherein R 8  is —CF 3  or —OCF 3 . 
     
     
         31 . The compound of  claim 27 , wherein R 1  is —Cl or —CH 3 . 
     
     
         32 . A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         33 . A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 17  and a pharmaceutically acceptable carrier or excipient. 
     
     
         34 . A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         35 . A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 17  and a pharmaceutically acceptable carrier or excipient. 
     
     
         36 . A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1 . 
     
     
         37 . A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 17 . 
     
     
         38 . A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1 . 
     
     
         39 . A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 17 .