Novel use of a peptide class of compound for treating non neuropathic inflammatory pain

Abstract

The present invention concerns the use of compounds of the Formula (I) for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain in mammals. The pain to be treated may be e.g. chronic inflammatory pain, rheumatoid arthritis pain and/or secondary inflammatory osteoarthritic pain. The compounds show an antinociceptive profile and differ from classical analgesics like opioids and non-steroidal anti-inflammatory drugs (NSAIDS) and are useful as specific analgesics.

1 - 35 . (canceled)  
     
     
         36 . A method of treating a mammal suffering from or susceptible to acute or chronic pain, comprising administering to the mammal an effective amount of a compound of the following Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group;  
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; and wherein heterocyclic in R 2  and R 3  is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl;  
 Z is O, S, S(O) 2 , NR 6 ′; or PR 4 ;  
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 ,  
                     
 R 6 ′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R 4  may be unsubstituted or substituted with an electron withdrawing group or electron donating group;  
 R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and  
 R 7 , is COOR 8 , COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R 7  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group;  
 R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and n is 1-4;  
 wherein each electron-withdrawing group is bromo, fluoro, chloro, iodo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl, or carbalkoxy;  
 wherein each electron-donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, or disulfide (lower alkyldithio);  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         37 . The method of  claim 36  wherein R is substituted with at least one electron-withdrawing group.  
     
     
         38 . The method of  claim 36  wherein R is substituted with at least one electron-donating group.  
     
     
         39 . The method of  claim 36  wherein R 2  and R 3  are each independently monocyclic heterocyclic moieties of formula:  
       
         
           
           
               
               
           
         
       
       where R 50  is H, an electron-donating group or an electron-withdrawing group; A, E, L. and J are independently CH, or a heteroatom selected from the group consisting of N, O, S; n is 0 or 1; and G is CH or a heteroatom selected from the group consisting of N, O, S.  
     
     
         40 . The method of  claim 36 , wherein n is 1, R 2  is H, R 3  is hydrogen, an alkyl group which is substituted by an electron withdrawing group or an electron donating group or ZY, R is aryl, aryl lower alkyl, wherein the aryl group is substituted or unsubstituted, and R 1  is lower alkyl.  
     
     
         41 . The method of  claim 36 , wherein the effective amount is between about 1 mg to about 100 mg per kilogram of body weight per day.  
     
     
         42 . The method of  claim 36 , wherein the compound is administered orally.  
     
     
         43 . The method of  claim 36 , wherein the compound is administered intravenously.  
     
     
         44 . The method of  claim 36 , wherein the compound is administered muscularly  
     
     
         45 . The method of  claim 36 , wherein the compound is administered subcutaneously.  
     
     
         46 . The method of  claim 36 , wherein the compound is the L-stereoisomer.  
     
     
         47 . The method of  claim 36 , wherein the compound is the D-stereoisomer.  
     
     
         48 . A method of treating a mammal suffering from or susceptible to acute or chronic pain, comprising administering to the mammal an effective amount of a composition comprising a compound of the following Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group;  
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; and wherein heterocyclic in R 2  and R 3  is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl;  
 Z is O, S, S(O) 2 , NR 6 ′; or PR 4 ;  
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 ,  
                     
 R 6 ′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R 4  may be unsubstituted or substituted with an electron withdrawing group or electron donating group;  
 R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and  
 R 7 , is COOR 8 , COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R 7  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and  
 R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and n is 1-4;  
 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.  
 
     
     
         49 . The method of  claim 48  wherein the composition further comprises a supplementary active ingredient.  
     
     
         50 . The method of  claim 48  wherein the active compound is present in from about 1 to about 750 mg/mL of carrier.  
     
     
         51 . The method of  claim 48  wherein R 2  and R 3  are each independently monocyclic heterocyclic moieties of formula:  
       
         
           
           
               
               
           
         
       
       where R 50  is H, an electron-donating group or an electron-withdrawing group; A, E, L. and J are independently CH, or a heteroatom selected from the group consisting of N, O, S; n is 0 or 1; and G is CH or a heteroatom selected from the group consisting of N, O, S.  
     
     
         52 . The method of  claim 48 , wherein n is 1, R 2  is H, R 3  is hydrogen, an alkyl group which is substituted by an electron withdrawing group or an electron donating group or ZY, R is aryl, aryl lower alkyl, wherein the aryl group is substituted or unsubstituted, and R, is lower alkyl.  
     
     
         53 . The method of  claim 48  wherein the compound is: 
 (R)-2-acetamide-N-benzyl-3-methoxy-propionamide;    O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;    O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;    N-acetyl-D-phenylglycinebenzylamide;    D-1,2=(N, O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; or    D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide; or a pharmaceutically acceptable salt thereof.