Deuterated benzo[d][1,3]-dioxol derivatives

Abstract

The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

1 .- 68 . (canceled) 
     
     
         69 . A method of inhibiting the uptake of serotonin in a subject comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein:
 D is deuterium; 
 Y 1  is deuterium; 
 each of Y 2  and Y 3  are independently selected from deuterium and hydrogen; and 
 each hydrogen is independently optionally replaced with deuterium; and 
 
         wherein at least 90% of the compound has a deuterium atom at each position designated as deuterium in formula I; and a pharmaceutically acceptable carrier. 
       
     
     
         70 . The method of  claim 69 , wherein up to 4 hydrogen atoms are replaced by deuterium. 
     
     
         71 . The method to  claim 69 , wherein at least one of Y 2  and Y 3  is independently deuterium. 
     
     
         72 . The method of  claim 69 , wherein both Y 2  and Y 3  are independently deuterium. 
     
     
         73 . The method of  claim 69 , wherein the compound is selected from any one of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         74 . The method of  claim 73 , wherein all hydrogen atoms are present at their natural isotopic abundance. 
     
     
         75 . A method of inhibiting the uptake of serotonin in a subject comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein greater than 90% of the compound has a deuterium atom at each position designated as deuterium in formula (A), and any atom not designated as deuterium in Formula (A) is present at its natural abundance; and a pharmaceutically acceptable carrier. 
       
     
     
         76 . A method of inhibiting the uptake of serotonin in a subject comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein greater than 90% of the compound has a deuterium atom at each position designated as deuterium in formula (B), and any atom not designated as deuterium in Formula (B) is present at its natural abundance; and a pharmaceutically acceptable carrier. 
       
     
     
         77 . A method of treating a human or non-human subject suffering from or susceptible to depression, obsessive-compulsive disorder, generalized anxiety, posttraumatic stress, major depression, panic disorder, social phobia, premenstrual syndrome, cardiac disorders, non-cardiac chest pain; smoking to cause cessation or prevent relapses; reducing platelet activation states, alcoholism and alcohol dependence; psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy; late luteal phase dysphoric disorder, premature ejaculation, senile dementia, obesity, Parkinson's disease, canine affective aggression, cancer cell growth, osteoporosis, dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases, or premature female orgasm; said method comprising the step of administering to said subject a composition comprising an effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein:
 D is deuterium; 
 Y 1  is deuterium; 
 each of Y 2  and Y 3  are independently selected from deuterium and hydrogen; and 
 each hydrogen is independently optionally replaced with deuterium; and 
 
         wherein at least 90% of the compound has a deuterium atom at each position designated as deuterium in formula I; and a pharmaceutically acceptable carrier. 
       
     
     
         78 . The method of  claim 77 , wherein up to 4 hydrogen atoms are replaced by deuterium. 
     
     
         79 . The method to  claim 77 , wherein at least one of Y 2  and Y 3  is independently deuterium. 
     
     
         80 . The method of  claim 77 , wherein both Y 2  and Y 3  are independently deuterium. 
     
     
         81 . The method of  claim 77 , wherein the compound is selected from any one of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         82 . The method of  claim 81 , wherein all hydrogen atoms are present at their natural isotopic abundance. 
     
     
         83 . A method of treating a human or non-human subject suffering from or susceptible to depression, obsessive-compulsive disorder, generalized anxiety, posttraumatic stress, major depression, panic disorder, social phobia, premenstrual syndrome, cardiac disorders, non-cardiac chest pain; smoking to cause cessation or prevent relapses; reducing platelet activation states, alcoholism and alcohol dependence; psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy; late luteal phase dysphoric disorder, premature ejaculation, senile dementia, obesity, Parkinson's disease, canine affective aggression, cancer cell growth, osteoporosis, dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases, or premature female orgasm; said method comprising the step of administering to said subject a composition comprising an effective amount of a compound formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein greater than 90% of the compound has a deuterium atom at each position designated as deuterium in formula (A), and any atom not designated as deuterium in Formula (A) is present at its natural abundance; and a pharmaceutically acceptable carrier. 
       
     
     
         84 . A method of treating a human or non-human subject suffering from or susceptible to depression, obsessive-compulsive disorder, generalized anxiety, posttraumatic stress, major depression, panic disorder, social phobia, premenstrual syndrome, cardiac disorders, non-cardiac chest pain; smoking to cause cessation or prevent relapses; reducing platelet activation states, alcoholism and alcohol dependence; psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy; late luteal phase dysphoric disorder, premature ejaculation, senile dementia, obesity, Parkinson's disease, canine affective aggression, cancer cell growth, osteoporosis, dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases, or premature female orgasm; said method comprising the step of administering to said subject a composition comprising an effective amount of a compound formula B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein greater than 90% of the compound has a deuterium atom at each position designated as deuterium in formula (B), and any atom not designated as deuterium in Formula (B) is present at its natural abundance; and a pharmaceutically acceptable carrier.