Disubstituted beta-lactones as inhibitors of n-acylethanolamine acid amidase (naaa)

Abstract

The present invention provides compounds and pharmaceutical compositions for inhibiting N-acylethanolamine acid amidase (NAAA). Inhibition of NAAA is contemplated as a method to sustain the levels of palmitoylethanolamide (PEA) and oleylethanolamide (OEA), two substrates of NAAA, in conditions characterized by reduced concentrations of PEA and OEA. The invention also provides methods for treating inflammatory diseases and pain, and other disorders in which decreased levels of PEA and OEA are associated with the disorder.

1 . A method of treating a mammal suffering from a dermal disease, disorder or condition, the method comprising administering to the mammal a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 .- 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the dermal disease, disorder or condition is allergic contact dermatitis, atopic dermatitis, seborrhoic dermatitis, eczema, urticaria, rosacea, acne, psoriasis, pruritus, lichen, neurodermatitis, psoriatic arthritis acne, scarring, a skin burn, scleroderma, solar keratosis, squamous cell carcinoma, or melanoma. 
     
     
         8 .- 44 . (canceled) 
     
     
         45 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is atopic dermatitis. 
     
     
         46 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is allergic contact dermatitis. 
     
     
         47 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is psoriasis. 
     
     
         48 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is rosacea. 
     
     
         49 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is pruritus. 
     
     
         50 . The method of  claim 1 , wherein the dermal disease, disorder, or condition is an inflammatory skin condition selected from one or more of atopic dermatitis, seborrheic dermatitis, psoriasis, and allergic contact dermatitis. 
     
     
         51 . The method of  claim 1 , wherein the compound is administered topically. 
     
     
         52 . The method of  claim 1 , wherein the compound is administered transdermally. 
     
     
         53 . The method of  claim 1 , wherein the compound is formulated as an ointment, cream, lotion, paste, gel, stick, patch, or wound dressing. 
     
     
         54 . The method of  claim 1  wherein the mammal is a human. 
     
     
         55 . The method of  claim 1 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, diluent, or mixtures thereof. 
     
     
         56 . The method of  claim 1 , wherein the pharmaceutically acceptable amount of the compound is from about 0.001 mg to about 100 mg. 
     
     
         57 . A method of treating a mammal suffering from atopic dermatitis; the method comprising administering to the mammal a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 57 , wherein the compound is administered topically. 
     
     
         59 . The method of  claim 57 , wherein the compound is formulated as an ointment, cream, lotion, paste, gel, stick, patch, or wound dressing. 
     
     
         60 . The method of  claim 57 , wherein the mammal is a human. 
     
     
         61 . The method of  claim 57 , wherein the compound is administered as a component of a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier, excipient, diluent, or mixtures thereof.