Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and/or premature ejaculation are described.

What is claimed is: 
     
         1 . A method of treating neuropathic pain in a mammal comprising administering to the subject a compound that is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein sites designated as D contain deuterium enrichment of at least 1%. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is a mixture of enantiomers. 
     
     
         3 . The method of  claim 1 , wherein the compound is the R-enantiomer. 
     
     
         4 . The method of  claim 1 , wherein the compound comprises about 10% or less by weight of the S-enantiomer. 
     
     
         5 . The method of  claim 1 , wherein the compound is the S-enantiomer. 
     
     
         6 . The method of  claim 1 , wherein the compound comprises about 10% or less by weight of the R-enantiomer. 
     
     
         7 . The method of  claim 1 , wherein the compound is the hydrochloride salt. 
     
     
         8 . The method of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 10%. 
     
     
         9 . The method of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 20%. 
     
     
         10 . The method of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 50%. 
     
     
         11 . The method of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 70%. 
     
     
         12 . The method of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 90%. 
     
     
         13 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method of  claim 1 , wherein the compound affects decreased inter-individual variation in plasma levels of said compound or a metabolite thereof, as compared to the non-isotopically enriched compound. 
     
     
         18 . The method of  claim 1 , wherein the compound affects increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         19 . The method of  claim 1 , wherein the compound affects decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         20 . The method of  claim 1 , wherein the compound affects a decreased metabolism by at least one polymorphically-expressed cytochrome P 450  isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         21 . The method of  claim 20 , wherein said cytochrome P 450  isoform is CYP2C8, CYP2C9, CYP2C19, or CYP2D6. 
     
     
         22 . The method of  claim 1 , wherein the compound affects a decreased inhibition of at least one cytochrome P 450  isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         23 . The method of  claim 22 , wherein said cytochrome P 450 isoform is CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4×1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, or CYP51. 
     
     
         24 . The method of  claim 1 , wherein the compound elicits an improved clinical effect during the treatment in said mammal per dosage unit thereof as compared to the non-isotopically enriched compound.