Imidazole 4-carboxamide compounds with adenosine deaminase inhibiting activity
View Patent ↗Imidazole compounds having adenosine deaminase inhibitory activity represented by the formula (I): wherein R 1 is optionally substituted aryl or optionally substituted heteroaryl, R 2 is lower alkyl; R 3 is hydroxy or protected hydroxy; X is O or S; and -A- is lower alkylene, its prodrug, or their salt. The compounds are useful for treating and/or preventing diseases for which adenosine is effective
1. A compound of the formula (I):
wherein R 1 is an optionally substituted phenyl, thienyl, or benzothienyl,
R 2 is lower alkyl;
R 3 is hydroxy or protected hydroxy;
X is O or S; and
-A- is ethylene;
or a salt thereof.
2. The compound according to claim 1 , wherein R 1 is thienyl.
3. The compound according to claim 1 , wherein R 1 is an optionally substituted phenyl with substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl.
4. The compound according to claim 1 , wherein A is ethylene and R 2 is methyl.
5. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
(1)1-{(3R,4S)-4-hydroxy-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride,
(2) 1-[(3R,4S)-4-Hydroxy-1-(2-phenyl-4-benzoxazolyl)-3-pentyl]-imidazole-4-carboxamide,
(3) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride,
(4) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-ethoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride;
(5) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-chlorophenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide,
(6) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methoxyphenyl)-7-benzoxazolyl]-3-pentyl}imidazole-4-carboxamide hydrochloride,
(7) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methylthiophenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide,
(8) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methylphenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide,
(9) 1-{(3R,4S)-4-Hydroxy-1-[2-(2-thienyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride,
(10) 1-{(3R,4S)-4-Hydroxy-1-[2-(2-benzothienyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride,
(11) 1-{(3R,4S)-4-Hydroxy-1-[2-(3-chlorophenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride,
(12) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-propoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride, and
(13) 1-{(3R,4S)-4-Hydroxy-1-[2-(4-chlorophenyl)-5-benzoxazolyl]-3-pentyl }-imidazole-4-carboxamide hydrochloride.
6. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
7. A process for producing the compound of claim 1 , comprising any of the following steps (1) to (2):
(1) reacting a compound of formula (III):
with a compound of formula (IV):
wherein R 1 , R 2 , R 3 , X and A are as defined above, and X 1 is hydroxy or a leaving group, provided that R 3 is not hydroxy; or
(2) reacting a compound of formula (I-1):
wherein R 1 , R 2 , X and A are as defined above, and R 1 is hydroxy protective group, with a deprotecting agent.
8. The compound according to claim 2 , wherein A is ethylene and R 2 is methyl.
9. A pharmaceutical composition comprising the compound of claim 5 as an active ingredient and a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
10. The compound according to claim 3 , wherein A is ethylene and R 2 is methyl.
11. The compound according to claim 1 , wherein R 1 is benzothienyl.
12. The compound according to claim 11 , wherein A is ethylene and R 2 is methyl.
13. The compound according to claim 1 , wherein R 1 is phenyl.
14. The compound according to claim 13 , wherein A is ethylene and R 2 is methyl.
15. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-hydroxy-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
16. The compound according to claim 5 , wherein the compound is 1-[(3R,4S)-4-Hydroxy-1-(2-phenyl-4-benzoxazolyl)-3-pentyl]-imidazole-4-carboxamide.
17. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
18. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-ethoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
19. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-chlorophenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide.
20. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methoxyphenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
21. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methylthiophenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide.
22. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-methylphenyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide.
23. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(2-thienyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamid hydrochloride.
24. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(2-benzothienyl)-7-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
25. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(3-chlorophenyl)-4-benzoxazolyl]-3-pentyl }-imidazole-4-carboxamide hydrochloride.
26. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-propoxyphenyl)-4-benzoxazolyl]-3-pentyl}-imidazole-4-carboxamide hydrochloride.
27. The compound according to claim 5 , wherein the compound is 1-{(3R,4S)-4-Hydroxy-1-[2-(4-chlorophenyl)-5 -benzoxazolyl]-3-pentyl }-imidazole-4-carboxamide hydrochloride.