Methods of treating a fatty acid amide hydrolase-mediated condition

Abstract

The present invention provides fatty acid amide hydrolase inhibitors, solid forms thereof, compositions thereof, and methods of making and using the same.

We claim: 
     
         1 . A method of preparing Compound 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof, or anhydride thereof; 
         comprising the steps of: 
         (a) coupling a compound of formula E-1: 
       
       
         
           
           
               
               
           
         
         wherein: 
         LG 1  and LG 2  are independently selected from a halogen or sulfonate; 
         with a compound of formula E-2: 
       
       
         
           
           
               
               
           
         
         wherein each R 1  and R 2  is independently selected from hydrogen or an C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-12  aryl or C 6-12  heteroaryl group, or R 1  and R 2  are joined to form a 5-8 membered ring; 
         in order to provide a compound of formula E-3: 
       
       
         
           
           
               
               
           
         
         wherein: 
         LG 2  is selected from a halogen or sulfonate; and 
         (b) reacting E-3 with a boronation reagent and a metal reagent in order to provide Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or anhydride thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the method further comprises crystallizing Compound 1 of step (b) to provide crystalline Compound 1. 
     
     
         3 . The method according to  claim 2 , wherein the crystallizing step comprises crystallizing Compound 1 from a polar solution comprising water, a polar apolar solvent or a mixture thereof. 
     
     
         4 . The method according to  claim 2 , wherein the crystallizing step comprises crystallizing Compound 1 from a mixture of water and acetone. 
     
     
         5 . The method according to  claim 2 , wherein the crystalline Compound 1 is further washed with a non-polar solution. 
     
     
         6 . The method according to  claim 5 , wherein the non-polar solution comprises hexanes, heptanes or a mixture thereof. 
     
     
         7 . The method according to  claim 1 , wherein E-1 is E-1b: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 1 , wherein E-2 is E-2a: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method according to  claim 1 , wherein E-3 is E-3a: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 1 , wherein the coupling step comprises a palladium catalyst. 
     
     
         11 . The method according to  claim 10 , wherein the palladium catalyst is selected from Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(dppf) 2 Cl 2 , and PdCl 2 (PPh 3 ) 2 . 
     
     
         12 . The method according to  claim 1 , wherein the coupling step comprises a base. 
     
     
         13 . The method according to  claim 12 , wherein the base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium acetate, sodium acetate, potassium phosphate, lithium hydroxide, sodium hydroxide and magnesium hydroxide. 
     
     
         14 . The method according to  claim 1 , wherein the boronation reagent is a boronate ester. 
     
     
         15 . The method according to  claim 14 , wherein the boronate ester is selected from trimethyl borate, triethyl borate, triallyl borate, triisopropyl borate, Tributyl borate, Tri-tert-butyl borate, Tripentyl borate, Trihexyl borate, Tritolyl borate, Tribenzyl borate, Triphenyl borate, Trimethylene borate, Triethanolamine borate, Trimethallyl borate, 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-Methoxy-4,4,6-trimethyl-1,3,2-dioxaborinane, 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-Isopropoxy-4,4,6-trimethyl-1,3,2-dioxaborinane, 2-(2-dimethylaminoethoxy)-4-methyl-1,3,2-dioxaborinane, 2-butoxy-4,4,6-trimethylL-1,3,2-dioxaborinane, tris (2,2,2-trifluoroethyl) borate, tris(1-isopropyl-2-methylpropyl) borate, and 2,2′-(2-methyl-2,4-pentanediyldioxy)bis(4,4,6-trimethyl-1,3,2-dioxaborinane). 
     
     
         16 . The method according to  claim 1 , wherein the metal reagent is an alkyl lithium reagent comprising n-butyllithium or hexyllithium. 
     
     
         17 . The method according to  claim 1 , wherein the method step (b) further comprises the steps of dehydrating Compound 1 in order to provide an anhydride of Compound 1 followed by hydrolyzing the anhydride of Compound 1 in order to provide Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         18 . The method according to  claim 17 , wherein the anhydride of Compound 1 is Compound 2: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
     
     
         19 . A method of treating an FAAH-mediated condition comprising administering to a subject in need thereof a therapeutically effective amount of a solid form of a crystalline compound of formula 1: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or anhydride thereof. 
     
     
         20 . The method according to  claim 19 , wherein the FAAH-mediated condition is selected from the group consisting of a painful condition, an inflammatory condition, an immune disorder, a disorder of the central nervous system, a metabolic disorder, a cardiac disorder and glaucoma.