Use of 1-Phenyl-3-Dimethylamino-propane Compounds for Treating Neuropathic Pain

Abstract

Use of 1-phenyl-3-dimethylaminopropane compounds for the production of medicaments for treating neuropathic pain, preferably polyneuropathic pain, also preferably diabetic neuropathic pain, more preferably diabetic peripheral neuropathic pain, and furthermore preferably for treating diabetic peripheral neuropathy.

1 . A method of treating pain in a subject in need thereof, said method comprising administering to the subject an effective pain inhibiting amount of a 1-phenyl-3-dimethylamino-propane compound corresponding to Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 X denotes OH, F, Cl, OC(O)CH 3  or H; 
 R 1  denotes saturated and unsubstituted, branched or unbranched C 1-4 -alkyl; 
 R 2  and R 3  independently denote H or saturated and unsubstituted, branched or unbranched C 1-4 -alkyl; or 
 R 2  and R 3  together with the carbon atom to which they are attached form a saturated or unsaturated, and unsubstituted, monosubstituted or polysubstituted C 5-6 -cycloalkyl group; and 
 at least 3 of R 9  to R 13  denote H and the remainder are independently selected from the group consisting of H, Cl, F, OH, CF 2 H, CF 3 , saturated and unsubstituted, branched or unbranched C 1-4 -alkyl, OR 14  and SR 14 ;
 wherein R 14  denotes saturated and unsubstituted, branched or unbranched C 1-3 -alkyl,; 
 or 
 R 12  and R 11  together form a 3,4-OCH═CH ring; 
 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A method according to  claim 1 , wherein in said compound of Formula I:
 X denotes OH, F, OC(O)CH 3  or H;   R 1  denotes CH 3 , C 2 H 5 , C 4 H 9  or t-butyl;   R 2  and R 3  independently denote H, CH 3 , C 2 H 5 , i-propyl or t-butyl;   or   R 2  and R 3  together with the carbon atom to which they are attached form a saturated and unsubstituted C 5-6 -cycloalkyl group; and   at least 3 of R 9  to R 13  denote H and the remainder are independently selected from the group consisting of H, Cl, F, OH, CF 2 H, CF 3 , OCH 3  and SCH 3 ;   
     
     
         3 . A method according to  claim 1 , wherein in said compound of Formula I,
 R 9 , R 11  and R 13  denote H, one of R 10  and R 12  also denotes H, and the other is selected from the group consisting of Cl, F, OH, CF 2 H, CF 3 , OR 14  and SR 14 .   
     
     
         4 . A method according to  claim 3 , wherein the other of R 10  and R 12  is selected from the group consisting of OH, CF 2 H, OCH 3  and SCH 3 . 
     
     
         5 . A method according to  claim 1 , wherein in said compound of Formula I,
 R 9  and R 13  each denote H;   R 11  denotes OH, OCH 3 , Cl or F; and   one of R 10  and R 12  denotes H, while the other denotes OH, OCH 3 , Cl or F.   
     
     
         6 . A method according to  claim 5 , wherein R 11  and the other of R 10  and R 12  each denote Cl. 
     
     
         7 . A method according to  claim 1 , wherein in said compound of Formula I,
 R 9 , R 10  ,R 12  and R 13  each denote H; and   R 11  denotes CF 3 , CF 2 H, Cl or F.   
     
     
         8 . A method according to  claim 1 , wherein in said compound of Formula I,
 R 10 , R 11  and R 12  each denote H; and   one of R 9  and R 13  denotes H, while the other denotes OH, OC 2 H 5  or OC 3 H 7 .   
     
     
         9 . A method according to  claim 1 , wherein said compound of Formula I is in the form of an isolated stereoisomer. 
     
     
         10 . A method according to  claim 1 , wherein said compound of Formula I is in the form of a mixture of stereoisomers. 
     
     
         11 . A method according to  claim 10 , wherein said mixture is a racemic mixture. 
     
     
         12 . A method according to  claim 1 , wherein said pain is neuropathic pain. 
     
     
         13 . A method according to  claim 12 , wherein said neuropathic pain is selected from the group consisting of mononeuropathic pain, polyneuropathic pain, and diabetic peripheral neuropathic pain. 
     
     
         14 . A method according to  claim 1 , wherein in said compound of Formula I,
 R 3  denotes H, and said compound is present in the form of an isolated diastereomer having the stereochemical configuration of Formula Ia   
       
         
           
           
               
               
           
         
       
       or a mixture of diastereomers containing more than 50% of the diastereomer having the stereochemical configuration of Formula Ia. 
     
     
         15 . A method according to  claim 1 , wherein said compound of Formula I is selected from the group consisting of:
 (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2methyl-pentan-3-ol,   (+)-(2R, 3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,   (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,   (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,   (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,   (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2methyl-pentan-3-ol,   (2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2methyl-pentan-3-ol,   (2RS, 3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-ol,   (3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol,   (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,   (1RS, 2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,   (+)-(1R, 2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,   (1R, 2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,   (−)-(1S, 2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,   (1S, 2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,   (RS, RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (+)-(1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (+)-(1R, 2R)-acetic acid-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl propyl ester,   (2RS, 3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol,   (+)-(2R, 3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,   (2RS, 3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3methylbutan-2-ol,   (+)-(2R, 3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol, and   
       pharmaceutically acceptable salts thereof. 
     
     
         16 . A method according to  claim 15 , wherein said compound of Formula I is selected from the group consisting of:
 (RS, RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol,   (−)-(1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,   (1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, and   
       pharmaceutically acceptable acid addition salts thereof. 
     
     
         17 . A method according to  claim 16 , wherein said compound of Formula I is (1RS, 2RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol or a hydrochloride salt thereof. 
     
     
         18 . A method according to  claim 16 , wherein said compound of Formula I is (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a hydrochloride salt thereof. 
     
     
         19 . A method according to  claim 1 , wherein said pain is diabetic neuropathic pain.