Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases

Abstract

The present invention is directed to novel compounds of Formula (I), pharmaceutically acceptable salts or solvates thereof, and their use.

1 - 18 . (canceled) 
     
     
         19 . A method of treating and/or preventing a sigma-1 receptor related disease, comprising the step of administering an effective amount of a compound Formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, 
         wherein 
         X 1  and X 5  are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         X 2 , X 3 , X 4  are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         with the proviso that at least one of X 1 , X 2 , X 3 , X 4 , X 5  is not hydrogen and that at least one of X 2 , X 3 , X 4  is not C1-C4-alkoxy; 
         L is —C(O)NH—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, or —NH—; 
         n is 0, 1 or 2; 
         m is 1, 2, 3, 4 or 5; 
         R 1  is H or alkyl, and 
         R 2  is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or 
         R 1  and R 2  together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen. 
       
     
     
         20 . The method according to  claim 19 , wherein the compound is selected from the group consisting of:
 N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,   N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,   N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,   N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,   N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,   N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,   N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,   N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,   4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,   N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine,   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         21 . The method according to  claim 19 , wherein the sigma-1 receptor related disease is a neurodegenerative disease. 
     
     
         22 . The method according to  claim 21 , wherein the neurodegenerative disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. 
     
     
         23 . A method of diagnosing of a sigma-1 receptor related disease, comprising the step of administering an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, 
         wherein 
         X 1  and X 5  are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         X 2 , X 3 , X 4  are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         with the proviso that at least one of X 2 , X 3 , X 4 , X 5  is not hydrogen and that at least one of X 2 , X 3 , X 4  is not C1-C4-alkoxy; 
         L is —C(O)NH—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, or —NH—; 
         n is 0, 1 or 2; 
         m is 1, 2, 3, 4 or 5; 
         R 1  is H or alkyl, and 
         R 2  is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or 
         R 1  and R 2  together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen. 
       
     
     
         24 . The method according to  claim 23 , wherein the compound is selected from the group consisting of:
 N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,   N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,   N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,   N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,   N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,   N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,   N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,   N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,   4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,   N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine,   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         25 . A diagnostic imaging composition, comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, 
         wherein 
         X 1  and X 5  are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or ten-butyl; 
         X 2 , X 3 , X 4  are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         with the proviso that at least one of X 2 , X 3 , X 4 , X 5  is not hydrogen and that at least one of X 2 , X 3 , X 4  is not C1-C4-alkoxy; 
         L is —C(O)NH—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, or —NH—; 
         n is 0, 1 or 2; 
         m is 1, 2, 3, 4 or 5; 
         R 1  is H or alkyl, and 
         R 2  is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or 
         R 1  and R 2  together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen. 
       
     
     
         26 . The diagnostic imaging composition according to  claim 25 , wherein the compound is selected from the group consisting of:
 N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,   N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,   N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,   N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,   N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,   N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,   N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,   N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,   4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,   N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine,   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         27 . A method of modulating sigma-1 receptor activity, comprising the step of administering an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, 
         wherein 
         X 1  and X 5  are independently selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         X 2 , X 3 , X 4  are independently selected from the group consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, —NHCOOR′, and —COOR′, wherein R′ is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; 
         with the proviso that at least one of X 2 , X 3 , X 4 , X 5  is not hydrogen and that at least one of X 2 , X 3 , X 4  is not C1-C4-alkoxy; 
         L is —C(O)NH—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, or —NH—; 
         n is 0, 1 or 2; 
         m is 1, 2, 3, 4 or 5; 
         R 1  is H or alkyl, and 
         R 2  is 5- or 6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally substituted by one or more substituents independently selected from halogen; or 
         R 1  and R 2  together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl group, which is fused to a 5- or 6-membered aryl group and which is optionally substituted by one or more substituents independently selected from C1-C3 alkyl, and wherein the resulting heterocyclic moiety is optionally substituted by one or more substituents independently selected from halogen. 
       
     
     
         28 . The method according to  claim 27 , wherein the compound is selected from the group consisting of:
 N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,   N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,   N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,   N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,   N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,   N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,   N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,   N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,   N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,   N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,   N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,   N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,   N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,   4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,   N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,   N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,   N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and   N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine,   or a pharmaceutically acceptable salt or solvate thereof.