Claims for Patent: RE47351

Summary for Patent: RE47351

Title:	2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists
Abstract:	N-pyrazole substituted 2-adenosine compounds and methods for using the compounds as A2A-adenosine receptor agonists useful to stimulate mammalian coronary vasodilation for therapeutic purposes and as adjuncts in cardiological imaging.
Inventor(s):	Jeff A. Zablocki, Elfatih O. Elzein, Venkata P. Palle, Luiz Belardinelli
Assignee:	Gilead Sciences Inc
Application Number:	US15/635,017
Patent Claims:	1. A compound having the formula: wherein R1=CH2OH; R3 is selected from the group consisting of CO2R20, —CONR7R8, and aryl, wherein the aryl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, and OR20; R7 is selected from the group consisting of hydrogen, straight or branched C1-15 alkyl and C3-8 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of aryl and CO2R20, and wherein the optional aryl substituent is optionally substituted with halo; R8 is selected from the group consisting of hydrogen, straight or branched C1-15 alkyl and C3-8 cycloalkyl; R20 is selected from the group consisting of hydrogen and C1-15 alkyl; and wherein R2 and R4 are hydrogen. 2. The compound of claim 1 wherein R3 is CO2R20; and R20 is selected from the group consisting of hydrogen and C1-4 alkyl. 3. The compound of claim 1 wherein R3 is CONR7R8; R7 is selected from the group consisting of hydrogen, straight or branched C1-10 alkyl and C3-5 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of aryl and CO2R20; R8 is selected from the group consisting of hydrogen, straight and branched C1-3 alkyl and C3-5 cycloalkyl; and R20 is selected from the group consisting of C1-4 alkyl. 4. The compound of claim 1 wherein R3 is aryl, wherein the aryl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl and OR20; and R20 is selected from and the group consisting of C1-4 alkyl. 5. The compound of claim 2 wherein R3 is CO2R20; and R20 is selected from the group consisting of hydrogen and C1-4 alkyl. 6. The compound of claim 3 wherein R 7 is selected from the group consisting of hydrogen, C1-3 alkyl and cyclopentyl, wherein the alkyl substituent is optionally substituted with from 1 to 2 substituents, independently selected from the group consisting of phenyl and CO2R20 and wherein each optional phenyl substituent is optionally substituted with halo; R8 is selected from hydrogen and methyl; and R20 is selected from hydrogen and ethyl. 7. The compound of claim 4 wherein R3 is aryl, wherein the aryl substituent is phenyl optionally substituted with from 1 to 2 substituents independently selected from the group consisting of chloro, methyl and OR20; and R20 is methyl. 8. The compound of claim 1 selected from the group consisting of ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4- carboxylate; (4S,2R,3R,5R)-2-{6-amino-2-[4-(4-chlorophenyl)-pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol; (4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methoxyphenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol; (4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methylphenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)-oxolane-3,4-diol; (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide; 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylic acid; (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N,N- dimethylcarboxamide; (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- ethylcarboxamide; 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxamide; 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- (cyclopentyl)carboxamide; (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-[(4-chlorophenyl)methyl]carboxamide, and ethyl 2-[(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4- yl)carbonylamino]acetate. 9. A method for stimulating coronary vasodilation in a mammal comprising administering by intravenous bolus injection an amount of a compound of claim 1 that is sufficient to stress the heart and induce a coronary steal situation for the purpose of imaging the heart. 10. The method of claim 9 wherein the mammal is a human. 11. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutical excipients. 12. The pharmaceutical composition of claim 11 wherein the pharmaceutical composition is in the form of a solution. 13. The compound of claim 8 wherein the compound is (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide. 14. The compound of claim 8 wherein the compound is 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- (cyclopentyl)carboxamide. 15. The compound of claim 8 wherein the compound is (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- ethylcarboxamide. 16. A method of dilating the coronary vessels of a mammal, as an adjunct to angioplasty, with the pharmaceutical composition of claim 11. 17. A method for adjunctive therapy in conjunction with angioplasty in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1. 18. A method for inhibition of platelet aggregation in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.