Pain-relieving compositions and uses therefor

Abstract

Compositions and methods are for inducing, promoting or otherwise facilitating pain relief. More particularly, sub-normovasodilatory doses of nitric oxide donors are used in the therapeutic management of vertebrate animals including humans, for the prevention or alleviation of pain, especially neuropathic pain. In some applications of the method, nitric oxide donors can be administered by any suitable route so as to provide concentrations of NO that are about ½ to 10 −15 times those known to induce vasodilation in normal circulations.

1 - 25 . (canceled) 
     
     
         26 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein one of R 1  and R 2  is selected from alkyl, —C 0-6 alkylCO 2 R 3 , phenyl and —C 0-6 alkylC(O)NHR 4  and the other of R 1  and R 2  is selected from optionally substituted —C 1-6 alkylaryl, substituted alkyl, —C 0-6 alkylCO 2 R 3 , —C 0-6 alkylN(R 4 ) 2 , aryl substituted in the 4-position and —C 0-6 alkylC(O)haloalkyl; 
         or R 1  and R 2  taken together form —C(O)CH 2 CH 2 —; 
         R 3  is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, —C 0-6 alkylcycloalkyl, —C 0-6 alkylcycloalkenyl, —C 0-6 alkylaryl, —C 0-6 alkylheterocyclyl, —C 0-6 alkylheteroaryl, —C 1-6 alkylCO 2 R 7 , —C 0-6 alkylN(R 4 ) 2 , —C 1-6 alkylNR 4 C(═NR 4 )N(R 4 ,) 2 , —C 1-6 alkylOR 7  and —C 1-6 alkylSR 7 ; and 
         each R 4  is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, —C 0-6 alkylcycloalkyl, —C 0-6 alkylcycloalkenyl, —C 0-6 alkylaryl, —C 0-6 alkylheterocyclyl, —C 0-6 alkylheteroaryl, —C 0-6 alkylC(O)R 8 , —C 0-6 alkylC(S)R 8 , —C 0-6 alkylCO 2 R 7 , —C 0-6 alkylSO 2 R 8  and —C 0-6 alkylOR 7 ; 
         each R 7  is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, —C 0-6 alkylcycloalkyl, —C 0-6 alkylcycloalkenyl, —C 0-6 alkylaryl, —C 0-6 alkylheterocyclyl and —C 0-6 alkylheteroaryl; and 
         R 8  is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, —C 0-6 alkylcycloalkyl, —C 0-6 alkylcycloalkenyl, —C 0-6 alkylaryl, —C 0-6 alkylheterocyclyl, —C 0-6 alkylheteroaryl and —N(R 7 ) 2 ; 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group is optionally substituted; or a pharmaceutically compatible salt thereof. 
       
     
     
         27 . A compound according to claim  1  wherein one of R 1  and R 2  is —CO 2 H and the other is ethyl. 
     
     
         28 . A compound according to claim  1  wherein one of R 1  and R 2  is —C(O)NH 2  and the other is ethyl. 
     
     
         29 . A compound according to claim  1  wherein one of R 1  and R 2  is —CO 2 H and the other is isopropyl. 
     
     
         30 . A compound according to claim  1  wherein one of R 1  and R 2  is —CONH 2  and the other is isopropyl. 
     
     
         31 . A compound according to claim  1  wherein one of R 1  and R 2  is —CO 2 H and the other is 4-fluorophenyl. 
     
     
         32 . A compound according to claim  1  wherein one of R 1  and R 2  is —C(O)CF 3  and the other is phenyl. 
     
     
         33 . A compound according to claim  1  wherein one of R 1  and R 2  is —CO 2 H and the other is isopropyl. 
     
     
         34 . A compound according to claim  1  wherein one of R 1  and R 2  is —CONH 2  and the other is 4-fluorophenyl. 
     
     
         35 . A compound according to claim  1  wherein one of R 1  and R 2  is —CONH 2  and the other is 4-methoxyphenyl. 
     
     
         36 . A compound according to claim  1  wherein one of R 1  and R 2  is methyl and the other is C 1 alkylphenyl substituted with hydroxyl. 
     
     
         37 . A compound according to claim  11  wherein the hydroxyl is substituted on the alkyl group. 
     
     
         38 . A compound according to claim  1  wherein one of R 1  and R 2  is methyl and the other is ethyl substituted with a hydroxyl group. 
     
     
         39 . A compound according to claim  1  wherein one of R 1  and R 2  is methyl and the other is —CH 2 N(alkyl) 2 . 
     
     
         40 . A compound according to claim  14  wherein the —CH 2 N(alkyl) 2  is —CH 2 N(ethyl) 2 . 
     
     
         41 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl, -C0-6alkylCO2R3, -C0-6alkylC(O)R3, -C0-6alkylC(O)NHR4, -C0-6alkylN(R4)2, -C0-6alkylN+(R7)3, -C0-6alkylOR5, -C0-6alkylSR5, -C0-6alkylC(═NR6)R3, -C0-6alkylN═NR5, -C0-6alkylNR4N(R4,)2, -C0-6alkylNR4C(═NR4)N(R4,)2, -C0-6alkylhalo, -C0-6alkylS(O)R3, -C0-6alkylSO2R3, —CN and —NO2; or R1 and R2 taken together form an optionally substituted 5 to 8 membered saturated or unsaturated carbocyclic or heterocyclic ring, an aryl ring or a heteroaryl ring; 
         R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl, -C1-6alkylCO2R7, -C0-6alkylN(R4)2, -C1-6alkylNR4C(═NR4)N(R4,)2, -C1-6alkylOR7 and -C1-6alkylSR7; 
         each R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl, -C0-6alkylC(O)R8, -C0-6alkylC(S)R8, -C0-6alkylCO2R7, -C0-6alkylSO2R8 and -C0-6alkylOR7; 
         R5 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl, -C0-6alkylC(O)R7, -C0-6alkylCO2R8, -C0-6alkylN(R7)2, -C0-6alkylC(O)N(R7)2, -C0-6alkylNR4C(═NR4)N(R4,)2, -C1-6alkylOR7 and -C1-6alkylSR7; 
         R6 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl, -C0-6alkylNHC(O)N(R7)2, -C0-6alkylNHC(O)R7, -C0-6alkylNHSO2R7, -C0-6alkylNHCO2R7, -C0-6alkylOC(O)R7, -C0-6alkylC(O)R7, —CN and —OR7; 
         each R7 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl and -C0-6alkylheteroaryl; and 
         R8 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C0-6alkylcycloalkyl, -C0-6alkylcycloalkenyl, -C0-6alkylaryl, -C0-6alkylheterocyclyl, -C0-6alkylheteroaryl and —N(R7)2; 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group is optionally substituted; or a pharmaceutically compatible salt thereof; 
         wherein the compound is not 4-formyl-3-methyl-1,2,5-oxidiazole-2-oxide.