N-pyrazole A2A receptor agonists
View Patent ↗The present disclosure provides a process for the preparation of 2-adenosine N-pyrazole compounds exemplified by the structure shown below that are potent and selective agonists for A 2A adenosine receptor, compositions comprising these compounds, and methods for using these compounds to stimulate mammalian coronary vasodilation for imaging the heart.
1. A method for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide:
comprising heating a compound of formula 10:
in excess methylamine to provide (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide.
2. The method of claim 1 , wherein the method comprises an aqueous solution of methylamine.
3. The method of claim 1 , wherein the method comprises heating at a temperature of about 65° C.
4. The method of claim 1 , wherein the method comprises an aqueous solution of methylamine and heating at a temperature of about 65° C.
5. The method of claim 1 , wherein the method further comprises preparing the compound of formula 10:
by reacting a compound of formula 1:
with ethoxycarbonylmalondialdehyde.
6. The method of claim 5 , wherein preparing the compound of formula 10 comprises a temperature of about 80° C.
7. The method of claim 5 , wherein preparing the compound of formula 10 comprises a mixture of CH 3 OH and CH 3 COOH as a solvent.
8. The method of claim 7 , wherein the mixture of CH 3 OH and CH 3 COOH is in a 1:1 ratio.
9. The method of claim 5 , wherein preparing the compound of formula 10 comprises a temperature of about 80° C. and a 1:1 mixture of CH 3 OH and CH 3 COOH as a solvent.
10. The method of claim 5 , wherein the method further comprises preparing the compound of formula 1:
by reacting a compound of formula 9:
with hydrazine hydrate.
11. The method of claim 10 , wherein the method further comprises preparing the compound of formula 9:
by reacting a compound of formula 8:
with NH 3 .
12. The method of claim 11 , wherein the method further comprises preparing the compound of formula 8:
by reacting a compound of formula 7:
with CH 3 (CH 2 ) 4 ONO and CH 2 I 2 .
13. The method of claim 12 , wherein the method further comprises preparing the compound of formula 7:
by reacting a compound of formula 6:
with POCl 3 .
14. The method of claim 13 , wherein the method further comprises preparing the compound of formula 6:
by reacting guanosine:
with acetic anhydride.