Manufacturing methods and polymorphs of a thiazoline anti-hyperalgesic agent

Abstract

Provided herein are methods of making a thiazoline anti-hyperalgesic, Compound 1, and polymorphs thereof. The methods described herein use inexpensive reagents and are capable of providing Compound 1 in commercial-scale quantities. Also provided are pharmaceutical compositions of Compound 1 suitable for human administration.

1 - 23 . (canceled) 
     
     
         24 . A method of treating post-surgical pain in a subject, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein the composition comprises about 0.0001% to about 0.004% w/w, relative to the weight of Compound 1 in the composition, of each of:
 2-Cl-BO (2-Chlorobenzoxazole), 
 BO-Imp-3 (2-Aminophenol), and 
 BO-Imp-4 (2-[Bis(1,3-benzoxazol-2-yl) amino]phenol). 
 
     
     
         25 . The method of  claim 24 , wherein the compound of Formula I is present at an enantiomeric purity of at least about 98% in the composition. 
     
     
         26 . The method of  claim 24 , wherein the composition further comprises at least one pharmaceutically acceptable carrier. 
     
     
         27 . The method of  claim 24 , wherein the post-surgical pain is a result of surgery at a site selected from the group consisting of thorax, upper abdomen, lower abdomen, and limb. 
     
     
         28 . A method of treating post-surgical pain in a subject, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a crystalline form of the compound of Formula I:   
       
         
           
           
               
               
           
         
         wherein the crystalline form is characterized by an X-ray powder diffraction (XPRD) pattern comprising approximate peak positions (degrees 2θ±0.2), when measured using Cu K α  radiation, of 9.6, 15.2, 18.0, 19.4, 23.0, and 31.4, when the XPRD is collected from about 2 to about 42 degrees 2θ. 
       
     
     
         29 . The method of  claim 28 , wherein the crystalline form is characterized by an XPRD pattern comprising approximate peak positions (degrees 2θ±0.2) of 9.6, 15.2, 15.8, 17.5, 18.0, 19.4, 21.9, 23.0, 24.5, 25.1, 26.4, and 31.4. 
     
     
         30 . The method of  claim 28 , wherein the composition further comprises at least one pharmaceutically acceptable carrier. 
     
     
         31 . The method of  claim 28 , wherein the post-surgical pain is a result of surgery at a site selected from the group consisting of thorax, upper abdomen, lower abdomen, and limb. 
     
     
         32 . A method of treating diabetic neuropathy in a subject, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a crystalline form of the compound of Formula I:   
       
         
           
           
               
               
           
         
         wherein the crystalline form is characterized by an X-ray powder diffraction (XPRD) pattern comprising approximate peak positions (degrees 2θ±0.2), when measured using Cu K α  radiation, of 9.6, 15.2, 18.0, 19.4, 23.0, and 31.4, when the XPRD is collected from about 2 to about 42 degrees 2θ. 
       
     
     
         33 . The method of  claim 32 , wherein the crystalline form is characterized by an XPRD pattern comprising approximate peak positions (degrees 2θ±0.2) of 9.6, 15.2, 15.8, 17.5, 18.0, 19.4, 21.9, 23.0, 24.5, 25.1, 26.4, and 31.4. 
     
     
         34 . The method of  claim 32 , wherein the composition further comprises at least one pharmaceutically acceptable carrier. 
     
     
         35 . The method of  claim 32 , wherein the post-surgical pain is a result of surgery at a site selected from the group consisting of thorax, upper abdomen, lower abdomen, and limb.