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 compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  are independently hydrogen or deuterium; 
         R 19 , R 20 , and R 21  are independently —CH 3  or —CD 3 ; 
         wherein the compound contains at least one deuterium atom; and has deuterium enrichment that is at least about 1%. 
       
     
     
         2 . The compound as recited in  claim 1 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein said compound is a mixture of enantiomers. 
     
     
         4 . The compound of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 10%. 
     
     
         5 . The compound of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 20%. 
     
     
         6 . The compound of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 50%. 
     
     
         7 . The compound of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 70%. 
     
     
         8 . The compound of  claim 1 , wherein sites designated as D contain deuterium enrichment of greater than 90%. 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9 , formulated for oral, parenteral, or intravenous infusion administration. 
     
     
         11 . The pharmaceutical composition of  claim 9 , formulated as a tablet or a capsule. 
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein said therapeutically effective amount is about 0.5 milligram to about 400 milligram total daily. 
     
     
         13 . A method of treating a mammal suffering from a disease or condition involving monoamine reuptake or monoamine receptor related disorder comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1 of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein said monoamine disease or condition is selected from the group consisting of a psychotropic disorder, an anxiety disorder, a generalized anxiety disorder, depression, a post-traumatic stress disorder, an obsessive-compulsive disorder, a panic disorder, a hot flash, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, a psychiatric disorder, a premenstrual dysphoric disorder, a social phobia, a social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and premature ejaculation. 
     
     
         15 . A method of treating a mammal for a drug addiction comprising administering a therapeutically effective amount of a compound of Formula 1 of  claim 1  and an opioid antagonist. 
     
     
         16 . The method of  claim 15 , wherein said opioid antagonist is nalmefene, naltrexone, or naloxone. 
     
     
         17 . The method of  claim 15 , wherein said drug addiction is tobacco addiction, alcohol addiction, marijuana addiction, or cocaine addiction. 
     
     
         18 . The method of  claim 15 , wherein said compound of formula I is administered subsequent to said opioid antagonist. 
     
     
         19 . The method of  claim 15 , wherein said compound of formula I is administered substantially simultaneously with said opioid antagonist. 
     
     
         20 . The method of  claim 15 , wherein said compound of formula I is administered prior to said opioid antagonist.