MORPHIC FORMS OF 4-AMINO-7-(3,4-DIHYDROXY-5-(HYDROXYMETHYL)TETRAHYDROFURAN-2-YL)-2-METHYL-7H-PYRROLO[2,3-d]PYRIMIDINE-5-CARBOXAMIDE AND USES THEREOF

Abstract

The present disclosure relates to crystalline morphic forms of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. The morphic form can be a stable hemihydrate crystalline form.

1 .- 17 . (canceled) 
     
     
         18 . A crystalline Form (“Form B”) of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, wherein the Form has a powder X-ray diffraction pattern comprising a peak at a diffraction angle (2θ) of about 22.9, wherein said powder X-ray diffraction pattern is obtained using Cu Kα1 X-rays at a wavelength of 1.5406 Å. 
     
     
         19 - 25 . (canceled) 
     
     
         26 . A method of treating a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. 
     
     
         27 . The method of  claim 26 , wherein the crystalline form is a crystalline hemihydrate form. 
     
     
         28 . The method of  claim 26 , wherein the viral infection is selected from norovirus, human cytomegalovirus, BK virus, Epstein-Barr virus, adenovirus, JC virus, SV40, MC virus, KI virus, WU virus, vaccinia, herpes simplex virus 1, herpes simplex virus 2, human herpes virus 6, human herpes virus 8, hepatitis B virus, hepatitis C virus, varicella zoster virus, variola major, variola minor, smallpox, cowpox, camelpox, monkeypox, poliovirus, picornaviridae, paramyxoviridae, ebola virus, Marburg virus, influenza, enterovirus, papilloma virus, West Nile virus, yellow fever virus, foot-and-mouth disease virus, Rift Valley fever virus, and other flavivirus, arenavirus, bunyavirus, alphavirus, human immunodeficiency virus, and any combination thereof. 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . A method of preparing a crystalline hemihydrate form of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide comprising:
 recrystallizing the 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide from a solvent system comprising 1-propanol and 0.01 M aqueous NaOH.   
     
     
         34 . The method of  claim 33 , wherein the solvent system comprises 1-propanol and 0.01 M aqueous NaOH at a volume ratio of 1:2. 
     
     
         35 . The method of  claim 33 , wherein the 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is dissolved in the solvent system comprising 1-propanol and 0.01 M aqueous NaOH at a temperature of about 90° C. to produce a solution. 
     
     
         36 . The method of  claim 35 , wherein the solution is cooled to about 80° C. and stirred for about an hour. 
     
     
         37 . The method of  claim 35 , wherein the solution is seeded with the morphic form of claim  3 . 
     
     
         38 . The method of  claim 37 , wherein the seed comprises about 1% of the amount of Compound 1 in the solution. 
     
     
         39 . The method of  claim 36 , wherein the solution is further cooled to a temperature of about 5° C. 
     
     
         40 . The method of  claim 39 , wherein the solution is stirred at about 5° C. for about 4 hours. 
     
     
         41 . The method of  claim 39 , wherein the cooling rate is about 5K/hour. 
     
     
         42 . The method of  claim 33 , wherein the crystallized 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is further washed with water. 
     
     
         43 . The method of  claim 33 , wherein the crystallized 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is over 99% pure.