Process for preparing an A2A-adenosine receptor agonist and its polymorphs

Abstract

Disclosed is a synthesis suitable for large scale manufacture of an A2A-adenosine receptor agonist, and also relates to polymorphs of that compound, and to methods of isolating a specific polymorph.

We claim: 
     
       1. A pharmaceutical composition prepared from a crystalline monohydrate form of the compound (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide by adding at least one pharmaceutically acceptable carrier. 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the monohydrate is substantially free of 2-hydrazinoadenosine. 
     
     
       3. The pharmaceutical composition of  claim 2 , wherein the monohydrate is substantially free of other hydrates or amorphous form. 
     
     
       4. The pharmaceutical composition of  claim 3 , wherein the monohydrate has a purity of at least about 99.6%. 
     
     
       5. The pharmaceutical composition of  claim 4 , wherein the monohydrate exhibits an X-ray powder diffraction pattern having peaks at diffraction angle 2θ (°) of about 6, about 9, about 11, about 13, about 14.5, about 16.5, and about 18 as measured by Cu-Kα1 X-ray powder diffractometry. 
     
     
       6. A pharmaceutical composition of an A 2A -adenosine receptor agonist produced by a process comprising the following step:
 dissolving a crystalline monohydrate form of the compound (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide that is substantially free of 2-hydrazinoadenosine in a pharmaceutically acceptable carrier.   
     
     
       7. The pharmaceutical composition of claim 6, wherein the crystalline monohydrate is substantially free of other hydrates or amorphous forms. 
     
     
       8. The pharmaceutical composition of claim 6, wherein the crystalline monohydrate has a purity of at least about 99.6%. 
     
     
       9. The pharmaceutical composition of claim 6, wherein the crystalline monohydrate exhibits an X-ray powder diffraction pattern having peaks at diffraction angle 2θ (°) of about 6, about 9, about 11, about 13, about 14.5, about 16.5, and about 18 as measured by Cu-Kα1 X-ray powder diffractometry. 
     
     
       10. The pharmaceutical composition of claim 6, wherein the crystalline monohydrate has an X-ray diffraction pattern as shown in FIG. 3. 
     
     
       11. A pharmaceutical composition comprising a crystalline monohydrate form of the compound (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide that is substantially free of 2-hydrazinoadenosine; and a pharmaceutically acceptable carrier. 
     
     
       12. The pharmaceutical composition of claim 11, wherein the crystalline monohydrate is substantially free of other hydrates or amorphous forms. 
     
     
       13. The pharmaceutical composition of claim 11, wherein the crystalline monohydrate has a purity of at least about 99.6%. 
     
     
       14. The pharmaceutical composition of claim 11, wherein the crystalline monohydrate exhibits an X-ray powder diffraction pattern having peaks at diffraction angle 2θ (°) of about 6, about 9, about 11, about 13, about 14.5, about 16.5, and about 18 as measured by Cu-Kα1 X-ray powder diffractometry. 
     
     
       15. The pharmaceutical composition of claim 11, wherein the crystalline monohydrate has an X-ray diffraction pattern as shown in FIG. 3. 
     
     
       16. The pharmaceutical composition of claim 11, wherein the crystalline monohydrate is dissolved in the pharmaceutically acceptable carrier. 
     
     
       17. A pharmaceutical composition comprising 99.6% pure (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide dissolved in a pharmaceutically acceptable carrier.