Fluorinated arylalkylaminocarboxamide derivatives

Abstract

Fluorinated arylalkylaminocarboxamide derivatives of formula (I) are described wherein W, J, n, R 1 , R 2 , R 2′ , R 3 , R 4 , R 5 and R 6 have the meanings as defined in the specification and pharmaceutically salts thereof, pharmaceutical compositions containing them as active ingredients and their use as sodium and/or calcium channel modulators useful in preventing, alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urolological, and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.

1 . A compound of general formula I 
       
         
           
           
               
               
           
         
         wherein: 
         W is a group A-[(CH 2 ) m —O]— wherein: m is zero, 1, 2, or 3; A is (C 1 -C 4 )alkyl optionally substituted with one to three fluorine atoms; (C 3 -C 6 )cycloalkyl; phenyl optionally substituted with a group selected from halo, methyl, methoxy, trifluoromethyl, acetylamino, and dimethylaminomethyl; thienyl optionally substituted with a chloro group; furanyl; isoxazolyl, thiazolyl; piperidinyl; morpholinyl; pyridinyl or pyrimidinyl, the pyridinyl and pyrimidinyl ring being optionally substituted with one or two methoxy groups; 
         J independently is hydrogen, (C 1 -C 4 )alkyl; (C 1 -C 4 )alkoxy; or an halo group; 
         n is 1 or 2;
 R 1  is hydrogen; (C 1 -C 4 )alkyl optionally substituted with a hydroxy group or a (C 1 -C 4 )alkoxy group; or (C 3 -C 8 )cycloalkyl; 
 R 2  and R 2′  are independently hydrogen; (C 1 -C 4 )alkyl optionally substituted with a (C 1 -C 4 )alkoxy group; phenyl optionally substituted with a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy or an halo group; benzyl optionally substituted with a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy or an halo group on the benzene ring; or R 2  and R 2′  taken together with the adjacent carbon atom form a (C 3 -C 6 )cycloalkylidene group. 
 R 3  is hydrogen; or (C 1 -C 4 )alkyl; 
 R 4  is hydrogen; (C 1 -C 4 )alkyl; phenyl; cyclohexyl; or benzyl; or 
 R 3  and R 4 , taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl ring, the piperidinyl ring being optionally substituted with one or two (C 1 -C 2 )alkyl group(s), and the piperazinyl ring being optionally substituted on the other N-atom with a (C 1 -C 4 )alkyl, benzyl, or phenylsulfonyl group; or a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl ring fused with a benzene ring; 
 R 5  is hydrogen or fluoro; and 
 R 6  is fluoro; 
 
         if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt. 
       
     
     
         2 . A compound of  claim 1 , wherein:
 W is a group A-[(CH 2 ) m —O]— wherein: m is zero, 1, 2 or 3; A is (C 1 -C 4 )alkyl optionally substituted by one to three fluorine atoms; (C 3 -C 6 )cycloalkyl; phenyl optionally substituted with a halo group; or thiazolyl   J independently is hydrogen; C 1 -C 4  alkyl; chloro; or fluoro;   n is 1 or 2;
 R 1  is hydrogen; (C 1 -C 4 )alkyl optionally substituted with a hydroxy group or a (C 1 -C 4 )alkoxy group; or (C 3 -C 6 )cycloalkyl; 
 R 2  is hydrogen; or (C 1 -C 4 )alkyl; 
 R 2′  is hydrogen or (C 1 -C 4 )alkyl optionally substituted with a (C 1 -C 4 )alkoxy or a phenyl group, the phenyl group being optionally substituted with a (C 1 -C 4 )alkoxy group; 
 R 3  is hydrogen; or (C 1 -C 4 )alkyl; 
 R 4  is hydrogen; (C 1 -C 4 )alkyl; phenyl; or cyclohexyl; or 
 R 3  and R 4 , taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, the piperydinyl ring being optionally substituted with one or two (C 1 -C 2 )alkyl group(s) and the piperazinyl ring being optionally substituted on the other N-atom with a (C 1 -C 4 )alkyl, benzyl, or phenylsulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl or piperazinyl ring fused with a benzene ring; 
 R 5  is hydrogen or fluoro; and 
 R 6  is fluoro; 
   if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt.   
     
     
         3 . A compound of  claim 2  wherein:
 W is a group A-[(CH 2 ) m —O]— wherein: m is 1 or 2; A is (C 1 -C 4 )alkyl optionally substituted by one to three fluorine atoms; phenyl optionally substituted with a chloro or fluoro group; or thiazolyl; 
 J independently is hydrogen; methyl; or fluoro; 
 n is 1-2
 R 1  is hydrogen; (C 1 -C 4 )alkyl optionally substituted with a hydroxy group or a (C 1 -C 4 )alkoxy group; 
 R 2  is hydrogen; or methyl; 
 R 2′  is hydrogen; or (C 1 -C 4 )alkyl optionally substituted with a methoxy or a phenyl group, the phenyl group being optionally substituted with a methoxy group; 
 R 3  is hydrogen; or (C 1 -C 4 )alkyl; 
 R 4  is hydrogen; (C 1 -C 4 )alkyl; phenyl; or cyclohexyl; or 
 R 3  and R 4 , taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl ring, the piperidinyl ring being optionally substituted with one or two methyl group(s) and the piperazinyl ring being optionally substituted on the other N-atom with a methyl, benzyl or phenylsulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring fused with a benzene ring; 
 R 5  is hydrogen or fluoro; and 
 R 6  is fluoro; 
 
 if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt. 
 
     
     
         4 . A compound of  claim 3 , selected from:
 2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-pentyloxyphenyl)-ethylamino]-N,N-dimethyl-acetamide   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dipropyl-acetamide   2-[2,2-Difluoro-2-(3-butoxy-4-methylphenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dibutyl-acetamide;   2-[2,2-Difluoro-2-(3-hexyloxyphenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-pentyloxyphenyl)-ethylamino]-N,N-dipropyl-acetamide;   2-{2,2-Difluoro-2-[3-(3-(3-fluorophenyl)-propoxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-{2,2-Difluoro-2-[3-(3-(3-chlorophenyl)-propoxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxy-2-fluorophenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-{2,2-Difluoro-2-[3-(3-thiazol-2-yl-propoxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-benzyloxyphenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(pyrrolidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N-methyl-N-phenyl-acetamide;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-1-(pyrrolidin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-1-(pyrrolidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-benzyloxyphenyl)-ethylamino]-1-(morpholin-4-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-1-(morpholin-4-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-1-(morpholin-4-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-ethanone;   2-[2,2-Difluoro-2-(3-benzyloxyphenyl)-ethylamino]-1-(pyrrolidin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-N-methyl-N-phenyl-acetamide;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-N-methyl-N-phenyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(4-methylpiperazin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-1-(4-methylpiperazin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-1-(4-methylpiperazin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(piperidin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(3-phenylpropoxy)-phenyl]-ethylamino}-1-(piperidin-1-yl)-ethanone;   2-{2,2-Difluoro-2-[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-1-(piperidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-diethyl-acetamide;   2-{2,2-Difluoro-2-[3-(2-fluorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(cis-3,5-dimethylpiperidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(3,4-dihydroisoquinolin-2(1H)-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-diisopropyl-acetamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N-cyclohexyl-N-methyl-acetamide;   2-[2,2-Difluoro-2-(3-benzyloxyphenyl)-ethylamino]-1-(piperidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-[4-(phenylsulfonyl)-piperazin-1-yl]-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(indolin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(4-benzylpiperazin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-1-(azetidin-1-yl)-ethanone;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-propanamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-3-methoxy-N,N-dimethyl-propanamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-3-(4-methoxyphenyl)-N,N-dimethyl-propanamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-2-N,N-trimethyl-propanamide;   2-[2,2-Difluoro-2-(3-butoxyphenyl)-ethylamino]-4-N,N-trimethyl-pentanamide;   2-{[2,2-Difluoro-2-(3-butoxyphenyl)-ethyl]-methylamino}-N,N-dimethyl-acetamide;   2-{[2,2-Difluoro-2-(3-butoxyphenyl)-ethyl]-(3-methoxypropyl)-amino}-N,N-dimethyl-acetamide;   2-{[2,2-Difluoro-2-(3-butoxyphenyl)-ethyl]-(2-methoxyethyl)-amino}-N,N-dimethyl-acetamide;   2-[2-Fluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide;   2-{2-Fluoro-2-[3-(3-chlorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   2-{2-Fluoro-2-[3-(3-fluorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide;   if the case, either as single optical isomer in the isolated form or a mixture thereof in any proportion, and its pharmaceutically acceptable salt.   
     
     
         5 . A compound of  claim 4  which is selected from 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, 2-[2-fluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, its single optical isomer in the isolated form or a mixture thereof in any proportion, and the pharmaceutically acceptable salts thereof. 
     
     
         6 . A compound of  claim 5  which is 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A compound as in  claim 1  wherein the pharmaceutically acceptable salt is the hydrochloride. 
     
     
         8 . A pharmaceutical composition containing a compound of  claim 1  as active ingredient together with a pharmaceutically acceptable excipient. 
     
     
         9 . A pharmaceutical composition of  claim 8  containing a further therapeutical agent. 
     
     
         10 . A method for the treatment of a disorder caused by dysfunctions of voltage gated sodium and/or calcium channels in a patient, said method comprising the administration to a patient in need thereof an effective amount of a sodium and/or calcium channel modulating amount of a compound of  claim 1 . 
     
     
         11 . A method as in  claim 10  wherein the disorder caused by dysfunctions of voltage gated sodium and/or calcium channels is selected from neuropathic pain, chronic pain, acute pain, headaches, neurological conditions, neurogenerative disorders, cognitive disorders, psychiatric disorders, vertigo, tinnitus, muscle spasm, cardiovascular diseases, endocrine disorders involving excessive or hypersecretory or otherwise inappropriate cellular secretion of an endogenous substance, liver diseases, inflammatory processes affecting all body systems, disorders of the gastrointestinal (GI) tract, disorders of the genito-urinary tract, ophthalmic diseases and eating disorders. 
     
     
         12 . A method as in  claim 11  wherein the disorder is a neuropathic pain, chronic pain and/or acute pain. 
     
     
         13 . A method as  claim 11  wherein the disorder is headache. 
     
     
         14 . A method as in  claim 11  wherein the disorder is a cognitive and/or psychiatric disorder. 
     
     
         15 . A method as in  claim 11  wherein the disorder is a neurological condition. 
     
     
         16 . A method as  claim 11  wherein the disorder is an inflammatory process affecting all body systems, a disorder of the gastrointestinal tract, a disorder of the genito-urinary tract, an ophthalmic disease, a liver disease, a cardiovascular, and/or neurodegenerative disorder caused by dysfunctions of voltage gated sodium and/or calcium channels. 
     
     
         17 . A method as in  claim 11  wherein the patient is a poor metabolizer, having very little or no CYP2D6 function, or is assuming drug(s) that is(are) CYP2D6 inhibitor(s). 
     
     
         18 . A method as in  claim 15 , wherein the neurological condition is epilepsy. 
     
     
         19 . A method as in  claim 11 , wherein the patient is administered a further therapeutical agent. 
     
     
         20 . A pharmaceutical composition of  claim 8 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         21 . A pharmaceutical composition of  claim 20 , wherein the pharmaceutically acceptable salt is hydrochloride. 
     
     
         22 . A method as in  claim 10 , wherein the compound is in the form of a pharmaceutical acceptable salt. 
     
     
         23 . A method as in  claim 22 , wherein the pharmaceutically acceptable salt is hydrochloride. 
     
     
         24 . A compound of  claim 7  which is the hydrochloride salt of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide. 
     
     
         25 . A pharmaceutical composition of  claim 21 , wherein the compound is the hydrochloride salt of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide. 
     
     
         26 . The method as in  claim 23 , wherein the pharmaceutically acceptable salt is they hydrochloride salt of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide.