Neurotrophin antagonist compositions

Abstract

A pharmaceutical composition comprising a compound of Formula I wherein R 1 is selected from, inter alia, alkyl, aryl-loweralkyl, heterocycle-loweralkyl, loweralkyl-carbonate; optionally substituted amino; benimidaz-2-yl; optionally substituted phenyl; loweralkyl-(R 5 )(R 6 ) wherein one of R 5 and R 6 is selected from H and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxycarbonyl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and R 2 and R 3 are independently selected from H, NO 2 , halo, di(loweralkyl)amino, cyano, C(O)OH, phenyl-S—, loweralkyl, and Z(O)OR 7 wherein Z is selected from C and S and R 7 is selected from H, loweralkylamino and arylamino; or pharmaceutically acceptable salts or certain in vivo hydrolyzable esters or amides thereof, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable carrier, is described. The compositions are useful to inhibit undesirable neurotrophin-mediated activity such as the neurite outgrowth that occurs in some neurodegenerative disease states.

1 - 13 . (canceled) 
   
   
       14 . A compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein: R 1  is selected from the group consisting of: amino optionally monosubstituted or disubstituted with C 1 -C 4  alkyl or hydroxy(C 1 -C 4  alkyl); and C 1 -C 4  alkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and C 1 -C 4  alkyl, and the other is selected from carboxy, carboxy-(C 1 -C 4  alkyl) and (C 1 -C 4  alkoxy)-carbonyl; and R 2  and R 3  are independently selected from H and NO 2 . 
   
   
       15 . The compound according to claim  1 , wherein the compound of Formula I is selected from the group consisting of: 
     N-{5-nitro-1H-benz[de]isoquinoline-1,3(2H)-dione}-2-aminoethanol; 
     N-dimethylamino-1,3-dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-(1,3-dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)acetic acid; 
     N-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol naphthalicacid-N-aminoimide; 
     3-nitro-1,8-(N-propioncarboxylate)succinamidonaphthalene; 
     3-methyl-3-(1,3-dioxo-5-nitro(1H,3H)benz[de]isoquinolyl)butyric acid methylester; and 
     ethyl-5-nitro-1,3-dioxo-1H-benz[de]isoquinoline-2-3H-acetate. 
   
   
       16 . A compound selected from the group consisting of: 
     N-acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-furfuryl-1,8-naphthalimide; 
     6-(N,N-dimethylamino)-2-(benzimidazol-2-yl)napthalimide; 
     N-(pyrid-2-ylethyl)-1,8-naphthalimide; 
     1,3-dioxo-6-phenylmercapto-N-(pyrid-2-ylethyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     2-{2-(4-methylphenylsulphonamido)phenyl}-6-(N,N-dimethylamino)naphthalimide; 
     1,3-dioxo-2-{2-(4-methylphenylsulphonamido)phenyl}-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-octyl-5-nitronaphthalimide; 
     5-bromo-1,3-dioxo-N-methylpyrid-3-yl-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-5-nitro-N-(pyrid-2-ylethyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(tetrahydrofuran-2-ylmethyl)naphthalimide; 
     2-{2-(4-methylbenzsulphonamido)-4,5-dichlorophenyl}naphthalimide; 
     1,3-dioxo-2-(2-aminophenyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(pyrid-3-methyl)naphthalimide; 
     3-amino-7,4-bis(ethyl-1,3-dioxo)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     2-(benzimidaz-2-yl)-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-2-{4,5-dimethyl-2-(4-methylphenylsulphonamido)phenyl}-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-N-methyltetrahydrofurfur-2-yl-5-nitro-1,2,3,4-tetrahydro[i]isoquinoline; 
     N-(4-ethoxyphenyl)-5-nitronaphthalimide; 
     6-nitro-2-(furfuryl)naphthalimide; 
     naphthalicacid-N,N′-diimide; 
     2-(2-hydroxyphenyl)naphthalimide; 
     5-amino-N-butylnaphthalimide; 
     1,3-dioxo-5-nitro-n-propylmorpholino-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(pyrid-2-ylethyl)naphthalimide; 
     N-methylnaphthalimide; 
     N-(pyrid-2-ylmethyl)naphthalimide; 
     N-(3,5-dimethylphenyl)-1,8-naphthalimide; 
     6-bromo-N-dimethylamino-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-(1,3-dioxo-6-phenylmercapto-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol; and 
     N-anilino-1,8-naphthalimide. 
   
   
       17 . The compound according to claim  1 , wherein R 1  is C 1 -C 4  alkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H, and the other is selected from carboxy. 
   
   
       18 . A method of treating pain in a mammal comprising the step of administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound of  claim 15 . 
   
   
       19 . A method of treating pain in a mammal comprising the step of administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound of  claim 16 . 
   
   
       20 . A pharmaceutical composition comprising a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein: R 1  is selected from the group consisting of: amino optionally monosubstituted or disubstituted with C 1 -C 4  alkyl or hydroxy(C 1 -C 4  alkyl); and C 1 -C 4  alkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and C 1 -C 4  alkyl, and the other is selected from carboxy, carboxy-(C 1 -C 4  alkyl) and (C 1 -C 4  alkoxy)-carbonyl; and R 2  and R 3  are independently selected from H and NO 2 . 
   
   
       21 . The pharmaceutical composition according to  claim 20 , wherein the compound of Formula I is selected from the group consisting of: 
     N-{5-nitro-1H-benz[de]isoquinoline-1,3(2H)-dione}-2-aminoethanol; 
     N-dimethylamino-1,3-dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-(1,3-dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)acetic acid; 
     N-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol naphthalicacid-N-aminoimide; 
     3-nitro-1,8-(N-propioncarboxylate)succinamidonaphthalene; 
     3-methyl-3-(1,3-dioxo-5-nitro(1H,3H)benz[de]isoquinolyl)butyric acid methylester; and 
     ethyl-5-nitro-1,3-dioxo-1H-benz[de]isoquinoline-2-3H-acetate. 
   
   
       22 . A pharmaceutical composition, wherein the compound is selected from the group consisting of: 
     N-acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-furfuryl-1,8-naphthalimide; 
     6-(N,N-dimethylamino)-2-(benzimidazol-2-yl)napthalimide; 
     N-(pyrid-2-ylethyl)-1,8-naphthalimide; 
     1,3-dioxo-6-phenylmercapto-N-(pyrid-2-ylethyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     2-{2-(4-methylphenylsulphonamido)phenyl}-6-(N,N-dimethylamino)naphthalimide; 
     1,3-dioxo-2-{2-(4-methylphenylsulphonamido)phenyl}-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-octyl-5-nitronaphthalimide; 
     5-bromo-1,3-dioxo-N-methylpyrid-3-yl-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-5-nitro-N-(pyrid-2-ylethyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(tetrahydrofuran-2-ylmethyl)naphthalimide; 
     2-{2-(4-methylbenzsulphonamido)-4,5-dichlorophenyl}naphthalimide; 
     1,3-dioxo-2-(2-aminophenyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(pyrid-3-methyl)naphthalimide; 
     3-amino-7,4-bis(ethyl-1,3-dioxo)-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     2-(benzimidaz-2-yl)-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-2-{4,5-dimethyl-2-(4-methylphenylsulphonamido)phenyl}-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     1,3-dioxo-N-methyltetrahydrofurfur-2-yl-5-nitro-1,2,3,4-tetrahydro[i]isoquinoline; 
     N-(4-ethoxyphenyl)-5-nitronaphthalimide; 
     6-nitro-2-(furfuryl)naphthalimide; 
     naphthalicacid-N,N′-diimide; 
     2-(2-hydroxyphenyl)naphthalimide; 
     5-amino-N-butylnaphthalimide; 
     1,3-dioxo-5-nitro-n-propylmorpholino-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     6-nitro-2-(pyrid-2-ylethyl)naphthalimide; 
     N-methylnaphthalimide; 
     N-(pyrid-2-ylmethyl)naphthalimide; 
     N-(3,5-dimethylphenyl)-1,8-naphthalimide; 
     6-bromo-N-dimethylamino-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; 
     N-(1,3-dioxo-6-phenylmercapto-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol; and 
     N-anilino-1,8-naphthalimide. 
   
   
       23 . The pharmaceutical composition according to  claim 18 , wherein R 1  is C 1 -C 4  alkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H, and the other is selected from carboxy.