Inhibitors of fatty acid amide hydrolase, methods of treatment and methods of preparing same

Abstract

The present invention provides compounds, and pharmaceutical compositions thereof, encompassed by the formulae (I), (II) or (III). Methods of preparing compounds encompassed by the formulae (I), (II) or (III) are also provided. The present invention also provides methods for treating an FAAH mediated disease, disorder or condition by administering a therapeutically effective amount of a provided compound of the formulae (I), (II) or (III), or a pharmaceutical composition thereof, to a patient in need thereof. Additionally, the present invention provides methods for inhibiting FAAH in a patient by administering a therapeutically effective amount of a compound of the formulae (I), (II) or (III), or a pharmaceutical composition thereof, to a patient in need thereof.

1 . A method of preparing Compound 1 (3,3′-difluorobiphenyl-4-ylboronic acid), 
       
         
           
           
               
               
           
         
       
       the method comprising:
 reacting 1,4-dibromo-2-fluoro-benzene and 3-fluorophenylboronic acid to produce 4-bromo-3,3′-difluorobiphenyl; 
 reacting 4-bromo-3,3′-difluorobiphenyl with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane to produce a boronate ester; and 
 hydrolyzing the boronate ester to produce Compound 1 (3,3′-difluorobiphenyl-4-ylboronic acid) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or anhydride thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein reacting 1,4-dibromo-2-fluoro-benzene and 3-fluorophenylboronic acid to produce 4-bromo-3,3′-difluorobiphenyl comprises reacting 1,4-dibromo-2-fluoro-benzene, 3-fluorophenylboronic acid, a palladium reagent, and sodium bicarbonate to produce 4-bromo-3,3′-difluorobiphenyl. 
     
     
         3 . The method according to  claim 1 , wherein the palladium reagent comprises Pd(PPh 3 ) 2 Cl 2 . 
     
     
         4 . The method according to  claim 1 , wherein reacting 4-bromo-3,3′-difluorobiphenyl with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane to produce a boronate ester comprises reacting 4-bromo-3,3′-difluorobiphenyl with a palladium reagent, tricyclohexylphosphine, and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane to produce the boronate ester. 
     
     
         5 . The method according to  claim 4 , wherein the palladium reagent comprises Pd 2 (DBA) 3 . 
     
     
         6 . The method according to  claim 1 , wherein hydrolyzing the boronate ester comprises reacting the boronate ester with sodium periodate and ammonium acetate to produce the Compound 1 (3,3′-difluorobiphenyl-4-ylboronic acid) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or anhydride thereof. 
     
     
         7 . The method according to  claim 1 , further comprising dehydrating Compound 1 to produce the anhydride of Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         8 . The method according to  claim 6 , further comprising hydrolyzing the anhydride of Compound 1 to produce the Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         9 . A method of preparing a compound of formula 
       
         
           
           
               
               
           
         
       
       the method comprising:
 reacting an aryl halide with a halogenated boronic acid to produce a halogenated biphenyl halide; 
 reacting the halogenated biphenyl halide with a boronation reagent to produce a halogenated boronate ester; and 
 hydrolyzing the halogenated boronate ester to produce a compound of formula 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate or solvate thereof, or anhydride thereof, wherein each of R 1  and R 2  is a halogen, m is an integer between 0 to 5, and n is an integer between 0 to 4. 
     
     
         10 . The method according to  claim 9 , wherein reacting an aryl halide with a halogenated boronic acid to produce a halogenated biphenyl halide comprises reacting an aryl trihalide with a halogenated phenylboronic acid to produce the halogenated biphenyl halide. 
     
     
         11 . The method according to  claim 9 , wherein reacting an aryl halide with a halogenated boronic acid to produce a halogenated biphenyl halide comprises reacting 1,4-dibromo-2-fluoro-benzene and 3-fluorophenylboronic acid to produce 4-bromo-3,3′-difluoro-biphenyl. 
     
     
         12 . The method according to  claim 9 , wherein reacting an aryl halide with a halogenated boronic acid to produce a halogenated biphenyl halide comprises reacting 1,4-dibromo-2-fluoro-benzene and 4-fluorophenylboronic acid to produce 4-bromo-3,4′-difluoro-biphenyl. 
     
     
         13 . The method according to  claim 9 , wherein reacting the halogenated biphenyl halide with a boronation reagent comprises reacting the halogenated biphenyl halide with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane to produce a pinacolboronate intermediate. 
     
     
         14 . The method according to  claim 9 , wherein hydrolyzing the halogenated boronate ester to produce a compound of formula 
       
         
           
           
               
               
           
         
       
       comprises hydrolyzing the halogenated boronate ester to produce 
       
         
           
           
               
               
           
         
       
     
     
         15 . A method of treating a fatty acid amide hydrolase (FAAH)-mediated disease, disorder, or condition comprising:
 administering to a subject having a FAAH-mediated disease, disorder, or condition a therapeutically effective amount of a compound having the following chemical structure:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, tautomer, or polymorph thereof, wherein the FAAH-mediated disease, disorder, or condition comprises an inflammatory disorder or an immune disorder. 
       
     
     
         16 . The method according to  claim 15 , wherein the FAAH-mediated disease,
 disorder, or condition comprises a gastrointestinal disorder.   
     
     
         17 . The method according to  claim 15 , wherein the FAAH-mediated disease, disorder, or condition comprises inflammatory bowel disease, peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, Crohn's disease, gastritis, diarrhea, irritable bowel syndrome, or ulcerative colitis. 
     
     
         18 . The method according to  claim 15 , wherein the FAAH-mediated disease, disorder, or condition comprises inflammatory bowel disease. 
     
     
         19 . The method according to  claim 15 , wherein the FAAH-mediated disease, disorder, or condition comprises Crohn's disease or ulcerative colitis. 
     
     
         20 . The method according to  claim 15 , wherein the FAAH-mediated disease, disorder, or condition comprises irritable bowel syndrome. 
     
     
         21 . The method according to  claim 15 , further comprising administering to the subject an additional therapeutically active agent.