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; benzimidaz-2-yl; optionally substituted phenyl; loweralkyl-(R 5 )(R 6 ) wherein one of R 5 and R 6 is selected from H and 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.

We claim:  
     
         1 . A pharmaceutical composition comprising a compound of Formula I,  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is selected from alkyl; aryl-loweralkyl; heterocycle-loweralkyl; loweralkyl-carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from loweralkyl, aryl and hydroxyloweralkyl; benzimidaz-2-yl;  
         
           
             
             
                 
                 
             
           
         
         wherein R 4  is phenyl optionally monosubstituted or disubstituted with a substituent selected from loweralkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, loweralkoxy, hydroxy and loweralkyl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and loweralkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxycarbonyl; 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; and pharmaceutically acceptable salts thereof, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable carrier.  
       
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein R 1  is selected from alkyl; aryl-loweralkyl; heterocycle-loweralkyl; loweralkyl-carbonate; amino optionally monosubstituted or disubstitutued with a substituent selected from loweralkyl and hydroxyloweralkyl; benzimidaz-2-yl;  
       
         
           
           
               
               
           
         
         wherein R 4  is phenyl optionally monosubstituted or disubstituted with a substituent selected from loweralkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, loweralkoxy, hydroxy and loweralkyl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and loweralkyl-R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxy-carbonyl; and  
         R 2  and R 3  are independently selected from H, NO 2 , halo, di(loweralkyl)amino, and phenyl-S—.  
       
     
     
         3 . A pharmaceutical composition according to  claim 2 , wherein R 1  is selected from aryl-loweralkyl; heterocycle-loweralkyl; loweralkyl-carbonate; amino optionally monosubstituted or disbstitutued with a substituent selected from loweralkyl and hydroxyloweralkyl; benzimidaz-2-yl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and loweralkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxy-carbonyl; and 
 R 2  and R 3  are independently selected from H, NO 2 , di(loweralkyl)amino, and phenyl-S—.    
     
     
         4 . A pharmaceutical composition according to  claim 3 , wherein R 1  is selected from amino optionally monosubstituted or disbstitutued with a substituent selected from loweralkyl and hydroxyloweralkyl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and loweralkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxy-carbonyl; and 
 R 2  and R 3  are independently selected from H and NO 2 .    
     
     
         5 . A pharmaceutical composition 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-Acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline;  
 N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;  
 N-Furfuryl-1,8-naphthalimide;  
 6-(N,N-Dimethylamino)-2-(benzimidazol-2-yl)naphthalimide;  
 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-tetrahydro[i]isoquinoline;  
 6-Nitro-2-(tetrahydrofuran-2-ylmethyl)naphthalimide;  
 N-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;  
 Naphthalicacid-N-aminoimide;  
 2-{2-(4-Methylbenzsulphonamido)-4,5-dichlorophenyl}naphthalimide;  
 3-Nitro-1,8-(N-propioncarboxylate)succinamidonapthalene;  
 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;  
 2-(2-Aminophenyl)naphthalimide;  
 1,3-Dioxo-2-{4,5-dimethyl-2-(4-methylphenylsulphonamido)phenyl}-1,2,3,4-tetrahydrobenzo[i]isoquinoline;  
 3-Methyl-3-(1,3-dioxo-5-nitro(1H,3H)benz[de]isoquinolyl)butyric acid methylester;  
 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;  
 Ethyl-5-nitro-1,3-dioxo-1H-benz[de]isoquinoline-2-3H-acetate;  
 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.  
 
     
     
         6 . A pharmaceutical composition according to  claim 2  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-Acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline;  
 N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;  
 N-Furfuryl-1,8-naphthalimide;  
 6-(N,N-Dimethylamino)-2-(benzimidazol-2-yl)naphthalimide;  
 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-tetrahydro[i]isoquinoline;  
 6-Nitro-2-(tetrahydrofuran-2-ylmethyl)naphthalimide;  
 N-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;  
 Naphthalicacid-N-aminoimide;  
 2-{2-(4-Methylbenzsulphonamido)-4,5-dichlorophenyl}naphthalimide;  
 3-Nitro-1,8-(N-propioncarboxylate)succinamidonapthalene;  
 1,3-Dioxo-2-(2-aminophenyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline;  
 6-Nitro-2-(pyrid-3-methyl)naphthalimide;  
 3-Amino-7,4bis(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; and  
 2-(2-Aminophenyl)naphthalimide.  
 
     
     
         7 . A pharmaceutical composition according to  claim 3  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-Acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline;  
 N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;  
 N-Furfuryl-1,8-naphthalimide;  
 6-(N,N-Dimethylamino)-2-(benzimidazol-2-yl)naphthalimide;  
 N-(Pyrid-2-ylethyl)-1,8-naphthalimide; and  
 1,3-Dioxo-6-phenylmercapto-N-(pyrid-2-ylethyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline.  
 
     
     
         8 . A pharmaceutical composition according to  claim 4  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-Acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline; and  
 N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol.  
 
     
     
         9 . A pharmaceutical composition as defined in  claim 1 , which inhibits NGF-mediated activity.  
     
     
         10 . A method for inhibiting a neurotrophin-mediated activity comprising the step of exposing neuron cells to an effective amount of a composition as defined in  claim 1 .  
     
     
         11 . A method for inhibiting a neurotrophin-mediated activity in a mammal comprising the step of administering to said mammal a therapeutically effective amount of a composition as defined in  claim 1 .  
     
     
         12 . A method as defined in  claim 11 , wherein said composition is administered intraventricularly.  
     
     
         13 . An in vivo hydrolyzable ester or amide of a compound selected from the group consisting of: 
 N-{5-Nitro-1H-benz[de]isoquinoline-1,3(2H)-dione}-2-aminoethanol;    N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)acetic acid;    N-(1,3-Dioxo-5-nitro-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;    N-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[i]isoquinoline)aminoethanol;    Naphthalicacid-N-aminoimide;    3-Nitro-1,8-(N-propioncarboxylate)succinamidonapthalene;    1,3-Dioxo-2-(2-aminophenyl)-1,2,3,4-tetrahydrobenzo[i]isoquinoline;    3-Amino-7,4-bis(ethyl-1,3-dioxo)-1,2,3,4-tetrahydrobenzo[i]isoquinoline;    2-(2-Aminophenyl)naphthalimide; and    2-(2-Hydroxyphenyl)naphthalimide.