2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists

Patent metadata

Field	Value
Publication number	US-RE47351-E
Application number	US-200015635017-A
Country	US
Kind code	E1
Filing date	Jun 21, 2000
Priority date	Jun 22, 1999
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

N-pyrazole substituted 2-adenosine compounds and methods for using the compounds as A 2 A-adenosine receptor agonists useful to stimulate mammalian coronary vasodilation for therapeutic purposes and as adjuncts in cardiological imaging.

First claim

What we claim is:

1. A compound having the formula:

wherein R 1 =CH 2 OH;
R 3 is selected from the group consisting of CO 2 R 20 , —CONR 7 R 8 , 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 OR 20 ;
R 7 is selected from the group consisting of hydrogen, straight or branched C 1-15 alkyl and C 3-8 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of aryl and CO 2 R 20 , and wherein the optional aryl substituent is optionally substituted with halo;

R 8 is selected from the group consisting of hydrogen, straight or branched C 1-15 alkyl and C 3-8 cycloalkyl;
R 20 is selected from the group consisting of hydrogen and C 1-15 alkyl;
and wherein R 2 and R 4 are hydrogen.

2. The compound of claim 1 wherein R 3 is CO 2 R 20 ; and R 20 is selected from the group consisting of hydrogen and C 1-4 alkyl.

3. The compound of claim 1 wherein R 3 is CONR 7 R 8 ;
R 7 is selected from the group consisting of hydrogen, straight or branched C 1-10 alkyl and C 3-5 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of aryl and CO 2 R 20 ;
R 8 is selected from the group consisting of hydrogen, straight and branched C 1-3 alkyl and C 3-5 cycloalkyl; and
R 20 is selected from the group consisting of C 1-4 alkyl.

4. The compound of claim 1 wherein R 3 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 OR 20 ; and
R 20 is selected from and the group consisting of C 1-4 alkyl.

5. The compound of claim 2 wherein R 3 is CO 2 R 20 ; and
R 20 is selected from the group consisting of hydrogen and C 1-4 alkyl.

6. The compound of claim 3 wherein R 7 is selected from the group consisting of hydrogen, C 1-3 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 CO 2 R 20 and wherein each optional phenyl substituent is optionally substituted with halo;
R 8 is selected from hydrogen and methyl; and
R 20 is selected from hydrogen and ethyl.

7. The compound of claim 4 wherein
R 3 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 OR 20 ;
and R 20 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 .

Assignees

• Gilead Sciences Inc

Inventors

• Zablocki Jeff A
• Elzein Elfatih O
• Palle Venkata P
• Belardinelli Luiz

Classifications

• C07H19/16 Primary

  Purine radicals · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D473/16 Primary

  two nitrogen atoms · CPC title

• C07H19/00

  Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides ; Anhydro-derivatives thereof · CPC title