Inhibitors of NAAA and Methods Thereof

Abstract

Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effective to alleviate conditions associated with a reduced concentration of PEA. Among other uses, various NAAA inhibitors are especially contemplated as therapeutic agents in the treatment of inflammatory diseases.

1 . A pharmaceutical composition for treatment of a condition associated with a reduced level of palmitoylethanolamide, or in which elevation of palmitoylethanolamide levels is therapeutically desirable, comprising:
 a compound according to Formula I and a pharmaceutically acceptable carrier   
       
         
           
           
               
               
           
         
         wherein 
         A is O or S; B is O, S, or NR a ; R 1  and R 2  are independently H, halogen, or optionally substituted lower alkyl; n is an integer between 0 and 3; X is O, S, C(O), NR b , CHR b  or null; Y is C(O), C(S), or CHR c ; Z is O, S, NR d , or CHR d ; V is optionally substituted lower alkyl or optionally substituted lower alkenyl; wherein W is aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, or C(R 3 R 4 R 5 ); and wherein Y and V may optionally form a 5- or 6 membered ring; 
         wherein R a , R b , R c , and R d  are independently selected from the group consisting of H, optionally substituted lower alkyl, or optionally substituted lower thioalkyl; and 
         wherein R 3 , R 4  and R 5  are independently H, optionally substituted lower alkyl, optionally substituted lower aryl, optionally substituted lower cycloheteroalkyl, or optionally substituted lower heteroaryl. 
       
     
     
         2 . The pharmaceutical composition of  claim 1  wherein A and B are O. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein X is NR b  and Y is C(O) or C(S). 
     
     
         4 . The pharmaceutical composition of  claim 2  or  claim 3  wherein Z is O or CHR d , V is lower alkyl, and wherein W is aryl or lower alkyl. 
     
     
         5 . The pharmaceutical composition of  claim 2  or  claim 3  wherein n is 1, R 1  is H and R 2  is lower alkyl. 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein A is O, B is O or NR a , X is NR b  and Y is C(O) or C(S). 
     
     
         7 . The pharmaceutical composition of  claim 6  wherein W is aryl or lower alkyl. 
     
     
         8 . A method of treating a patient having a condition associated with reduced levels of palmitoylethanolamide or in which elevation of palmitoylethanolamide levels is therapeutically desirable, comprising administering a pharmaceutical composition comprising a compound according to Formula I according to  claim 1 . 
     
     
         9 . The method of  claim 8  wherein the condition associated with reduced levels of palmitoylethanolamide includes an inflammatory component, and wherein administration of the composition reduces inflammation in the patient. 
     
     
         10 . The method of  claim 8  wherein the condition is rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, psoriasis, an inflammatory bowel disease, or a spinal cord injury. 
     
     
         11 . The method of  claim 8  wherein A is O, B is O or NR a , X is NR b  and Y is C(O) or C(S). 
     
     
         12 . The method of  claim 11  wherein Z is O or CHR d , V is lower alkyl, and wherein W is aryl or lower alkyl. 
     
     
         13 . The method of  claim 11  wherein W is aryl or lower alkyl. 
     
     
         14 . A method of inhibiting of N-acylethanolamine-hydrolyzing acid amidase (NAAA), comprising contacting the NAAA with a compound according to Formula I 
       
         
           
           
               
               
           
         
         wherein 
         A is O or S; B is O, S, or NR a ; R 1  and R 2  are independently H, halogen, or optionally substituted lower alkyl; n is an integer between 0 and 3; X is O, S, C(O), NR b , CHR b  or null; Y is C(O), C(S), or CHR c ; Z is O, S, NR d , or CHR d ; V is optionally substituted lower alkyl or optionally substituted lower alkenyl; wherein W is aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, or C(R 3 R 4 R 5 ); and wherein Y and V may optionally form a 5- or 6 membered ring; 
         wherein R a , R b , R c , and R d  are independently selected from the group consisting of H, optionally substituted lower alkyl, or optionally substituted lower thioalkyl; and 
         wherein R 3 , R 4  and R 5  are independently H, optionally substituted lower alkyl, optionally substituted lower aryl, optionally substituted lower cycloheteroalkyl, or optionally substituted lower heteroaryl. 
       
     
     
         15 . The method of  claim 14  wherein A is O, B is O or NR a , X is NR b  and Y is C(O) or C(S). 
     
     
         16 . The method of  claim 15  wherein Z is O or CHR d , V is lower alkyl, and wherein W is aryl or lower alkyl. 
     
     
         17 . The method of  claim 14  wherein the step of contacting is performed in vivo using topical administration of the compound, aerosol administration of the compound, or intrathecal injection of the compound. 
     
     
         18 . The method of  claim 14  wherein the compound inhibits the NAAA at an 1050 of less than 20 microM.