Substituted 2-Aminoacetamides and the Use Thereof

Abstract

The invention is directed to substituted 2-aminoacetamides represented by formula (II): and to pharmaceutically acceptable salts and prodrugs thereof, wherein the substituents are defined herein. The invention is also directed to the use of substituted 2-aminoacetamides in methods for the treatment of neuronal damage following global and focal ischemia, and for the treatment, prevention or amelioration of pain, anxiety, or manic depression, as anticonvulsants, as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

1 . A method of treating or ameliorating pain in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound having the Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1 , R 2 , R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; 
         R 5 , R 6  and R 7  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 5 , is defined as above, and R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocycle; 
         A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; 
         X is one or O, S, NR 8 , CH 2 , C(O), NR 8 C(O), C(O)NR 8 , SO, SO 2  or a covalent bond; 
         where 
         R 8  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and 
         n is 0, 1, 2 or 3. 
       
     
     
         2 . The method according to  claim 1 , wherein A1 and A2 are both optionally substituted aryl moieties. 
     
     
         3 . The method according to  claim 1 , wherein
 A 1  and A 2  are phenyl moieties, that A 2  is optionally substituted by one or two substituents independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, hydroxy, C 1-4  alkoxy or trifluoromethyl;   R 1  and R 2  are hydrogen;   R 3  and R 4  are methyl;   R 5 , R 6  and R 7  are independently hydrogen, C 1-6  alkyl, or C 3-7  cycloalkyl; and   X is O, S, CH 2 , or NH.   
     
     
         4 . The method according to  claim 1 , wherein said compound is selected from the group consisting of:
 2-(4-(2-fluorobenzyloxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide;   2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;   2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide,   2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;   2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;   2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;   2-(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;   2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;   2-(3-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;   2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;   2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and   2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.   
     
     
         5 . A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions: treating, preventing or ameliorating pain; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias, comprising administering to a mammal in need of such treatment an effective amount of a compound having the Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1 , R 2 , R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; 
         R 5 , R 6  and R 7  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 5 , is defined as above, and R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocycle; 
         A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; 
         X is one or O, S, NR 8 , CH 2 , C(O), NR 8 C(O), C(O)NR 8 , SO, SO 2  or a covalent bond; 
         where 
         R 8  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and 
         n is 0, 1, 2 or 3; 
         provided that when X is O, S, CH 2  or NH; R 1  and R 2  are hydrogen, R 3  and R 4  are methyl or ethyl, then A 1  and A 2  are not both phenyl. 
       
     
     
         6 . The method according to  claim 5 , wherein said method is for treating, preventing or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain. 
     
     
         7 . The method according to  claim 6 , wherein:
 A 1  and A 2  are phenyl moieties, wherein A 1  is substituted by one or two substituents independently selected from the group consisting of hydrogen, C 1-6  alkyl, halogen, hydroxy, C 1-4  alkoxy and trifluoromethyl;   R 1  and R 2  are hydrogen;   R 3  and R 4  are methyl;   R 5 , R 6  and R 7  are independently hydrogen, C 1-6  alkyl, or C 3-7  cycloalkyl; and   and   X is O, S, CH 2 , or NH.   
     
     
         8 . The method of  claim 5 , wherein:
 A 1  is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A 2  is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and quinoxalinyl.   
     
     
         9 . The method of  claim 5 , wherein
 A 1  is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl, and A 2  is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl.   
     
     
         10 . A compound having the Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1 , R 2 , R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; 
         R 5 , R 6  and R 7  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 5 , is defined as above, and R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocycle; 
         A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; 
         X is one or O, S, NR 8 , CH 2 , C(O), NR 8 , C(O), C(O)NR 8 , SO, SO 2  or a covalent bond; 
         where 
         R 8  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; 
         n is 0, 1, 2 or 3. 
         provided that: 
         when X is O, S, CH 2  or NH; R 1  and R 2  are hydrogen, R 3  and R 4  are methyl or ethyl, then A 1  and A 2  are not both phenyl. 
       
     
     
         11 . A compound according to  claim 10 , wherein
 A 1  is phenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen;   A 2  is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, quinolinyl, quinoxalinyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen; and   X is O or S.   
     
     
         12 . A compound according to  claim 10 , wherein
 A 1  is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinolinyl, furanyl, thiophenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen, and   A 2  is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethyelendioxyphenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen.   
     
     
         13 . A compound of  claim 10 , having Formula III or Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1  R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, n, A 1  and A 2  are as defined previously with respect to  claim 10 ; and 
         R 9 , R 10 , R 11 , and R 12  independently are hydrogen, halo, haloalkyl, axyl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloakyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or 
         R 9  and R 10  or R 11  and R 12  are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle; 
         provided that when A 2  is an optionally substituted phenyl, then R 9  and R 10  or R 11  and R 12  are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle; 
         R 13 , R 14 , R 15 , R 16  and R 17  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or 
         one of R 13  and R 14 , or R 14  and R 15 , or R 15  and R 16 , or R 16  and R 17  are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle; 
         provided that when A 1  is an optionally substituted phenyl, then R 13  and R 14 , or R 14  and R 15 , or R 15  and R 16 , or R 16  and R 17  are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. 
       
     
     
         14 . A compound of  claim 13 , having Formula V or Formula VI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         R 1 -R 7 , R 9 -R 12 , R 13 -R 17 , n and X are as defined previously with respect to  claim 13 ; and 
         A, B, C, D and E are independently nitrogen or carbon, provided that no more than three of A, B, C, D and E are nitrogen, and there is no substituent, except for oxygen (when the nitrogen is present as a N-oxide), present on A, B, C, D or E when said A, B, C, D or E represents nitrogen. 
       
     
     
         15 . A compound of  claim 15 , having the Formula VII or Formula VIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         R 1 -R 7 , R 9 -R 12 , R 13 -R 17 , n and X are as defined previously with respect to  claim 13 ; and 
         B 1  is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle; and 
         B 2  is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle. 
       
     
     
         16 . A compound according to  claim 15 , wherein B1 is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. 
     
     
         17 . A compound according to  claim 15 , wherein B 2  is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. 
     
     
         18 . A compound according to  claim 10 , wherein said compound is
 2-(4-(4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-methylenedioxyphenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-methylenedioxybenzyloxy)benzylamino)-2-methyl-propanamide;   2-(4-cyclohexyloxybenzylamino)-2-methyl-propanamide;   2-(4-(5,6,7,8-tetrahydro-2-naphthoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2-adamantanoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-Chloro-2-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,4-difluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(6-bromo-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-nitrophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-tetrahydropyranoxy)benzylamino)-2-methyl-propanamide;   2-(4-(3,5-difluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-chlorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(4-methylphenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(2-chloro-4-fluorophenoxy)benzylamino)-2-methyl-propanamide;   2-(4-(5-indanoxy)benzylamino)-2-methyl-propanamide;   2-(4-cycloheptoxybenzylamino)-2-methyl-propanamide;   2-(4-(1-methyl-4-piperidinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(exo-2-norbornoxy)benzylamino)-2-methyl-propanamide;   2-(3-(4-fluorophenoxy)-5-pyridylmethylamino)-2-methyl-propanamide;   2-(4-(4-pyridinoxy)benzylamino)-2-methyl-propanamide;   2-(3-fluoro-4-(4-fluorophenyl)benzylamino)-2-methyl-propanamide;   2-(4-(2-pyrimidinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(6-quinolinoxy)benzylamino)-2-methyl-propanamide;   2-(4-(N,N-diphenylamino)benzylamino)-2-methyl-propanamide;   2-(4-diphenylmethoxy)benzylamino-2-methyl-propanamide; and   2-(4-triphenylmethoxy)benzylamino-2-methyl-propanamide.   
     
     
         19 . A pharmaceutical composition, comprising the compound of  claim 10 , and a pharmaceutically acceptable carrier or diluent.