Disclosed are methods for making novel A 2B adenosine receptor antagonists having the structure of formula I or Formula II: The compounds are particularly useful for treating asthma, inflammatory gastrointestinal tract disorders, cardiovascular diseases, neurological disorders, and diseases related to undesirable angiogenesis.
1. A process for the preparation of a compound of Formula I or Formula II:
wherein:
R 1 and R 2 are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, opltonally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;
R 3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
X is optionally substituted arylene or heteroarylene;
Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino;
with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and
Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or
Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond;
with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and,
with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl
comprising:
contacting a compound of the formula:
in which R 1 , R 2 and R 3 are as defined above;
with a compound of the formula Z—Y—X—CO 2 H, in which X, Y, and Z are as defined above in the presence of a carbodiimide.
2. The process of claim 1 , wherein R 1 is n-propyl, R 2 is ethyl, and R 3 is hydrogen.
3. The process of claim 2 , wherein Z is 3-fluorophenyl, Y is methylene, and X is 1,4-pyrazolene:
and the compound of the formula Z—Y—X—CO 2 H is 1-[(3-fluorophenyl)methyl]pyrazo le-4-carboxylic acid.
4. The process of claim 1 , wherein the reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethylformamide.
5. The process of claim 1 , wherein
R 1 and R 2 are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl,
R 3 is hydrogen;
X is optionally substituted heteroarylene; and
Y is a covalent bond or lower alkylene.
6. The process of claim 5 , wherein X is optionally substituted pyrazolene, Y is lower alkylene, and Z is optionally substituted phenyl or optionally substituted oxadiazole.
7. The process of claim 6 , wherein R 1 is lower alkyl optionally substituted by cycloalkyl and R 2 is hydrogen.
8. The process of claim 7 , wherein X is optionally substituted 1,4-pyrazolene.
9. The process of claim 8 , wherein Y is —CH 2 — or —CH(CH 3 )—, and Z is optionally substituted phenyl.
10. The process of claim 9 , wherein R 1 is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 3-trifluoromethylphenyl, namely 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
11. The process of claim 9 , wherein R 1 is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is phenyl, namely 1-propyl-8-]1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
12. The process of claim 9 , wherein R 1 is n-butyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 3-fluorophenyl, namely 1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
13. The process of claim 9 , wherein R 1 is n-propyl, X is 1,4-pyrazolene, Y is
—CH(CH 3 )—, and Z is phenyl, namely 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
14. The process of claim 8 , wherein Y is —CH 2 — or —CH(CH 3 )—, and Z is optionally substituted oxadiazole.
15. The process of claim 14 , wherein R 1 is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione.
16. The process of claim 14 , wherein R 1 is n-butyl, X is 1,4-pyrazolene, Y is
—CH 2 —, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione.
17. The process of claim 1 , wherein R 1 and R 2 are independently lower alkyl optionally substituted by cycloalkyl.
18. The process of claim 17 , wherein X is optionally substituted pyrazolene.
19. The process of claim 18 , wherein X is optionally substituted 1,4-pyrazolene, Y is —CH 2 —, —CH(CH 3 )— or a covalent bond, and Z is hydrogen or optionally substituted phenyl.
20. The process of claim 19 , wherein R 1 and R 2 are n-propyl, Y is a covalent bond, and Z is hydrogen, namely 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
21. The process of claim 19 , wherein R 1 is sec-butyl, R 2 is methyl, Y is a covalent bond, and Z is hydrogen, namely 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
22. The process of claim 19 , wherein R 1 and R 2 are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-trifluoromethylphenyl.
23. The process of claim 19 , wherein R 1 and R 2 are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-fluorophenyl.
24. The process of claim 19 , wherein R 1 and R 2 are n-propyl, Y is —CH(CH 3 )—, and Z is 3-trifluoromethylphenyl, namely 1,3-dipropyl-8-(1-{[3-(trifluromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
25. The process of claim 19 , wherein R 1 and R 2 are n-propyl, Y is methylene, and Z is 4-carboxyphenyl, namely 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7trihydropurine-2,6-dione.
26. The process of claim 19 , wherein R 1 and R 2 are n-propyl, Y is —CH(CO 2 H)—, and Z is phenyl, namely 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic acid.
27. The process of claim 1 , wherein:
R 1 and R 2 are hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl,
R 3 is hydrogen;
X is optionally substituted phenylene; and
Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—.
28. The process of claim 27 , wherein R 1 and R 2 are independently lower alkyl optionally substituted by cycloalkyl.
29. The process of claim 28 , wherein R 1 and R 2 are n-propyl and Y is —OCH 2 —.
30. The process of claim 29 , wherein Z is optionally substituted oxadiazole.
31. The process of claim 30 , wherein Z is 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
32. The process of claim 30 , wherein Z is 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.
33. The process of claim 30 , wherein Z is 5-(4-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.