Pharmaceutical compositions having A
The present invention provides compositions for oral administration of compounds having A 2A adenosine receptor agonist activity. These compositions are useful for treatment of inflammatory conditions.
1. A pharmaceutical composition comprising a compound of the formula (I):
wherein (a) each R is individually hydrogen, C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl, phenyl or phenyl(C 1 –C 3 )-alkyl;
(b) X is —CH 2 OH, —CO 2 R 2 , —OC(O)R 2 , —CH 2 OC(O)R 2 or —C(O)NR 3 R 4 ;
(c) each of R 2 , R 3 and R 4 is individually H, C 1-6 -alkyl; C 1-6 -alkyl substituted with 1–3 C 1-6 -alkoxy, C 3 –C 7 cycloalkyl, C 1-6 -alkylthio, halogen, hydroxy, amino, mono(C 1-6 -alkyl)amino, di(C 1-6 -alkyl)amino, or C 6-10 -aryl, wherein aryl may be substituted with 1–3 halogen, C 1-6 -alkyl, hydroxy, amino, mono(C 1-6 -alkyl)amino, or di(C 1-6 -alkyl)amino; C 6-10 -aryl; or C 6-10 -aryl substituted with 1–3 halogen, hydroxy, amino, mono(C 1-6 -alkyl)amino, di(C 1-6 -alkyl)amino or C 1-6 -alkyl;
(d) R 1 is (X-(Z)-) n [(C 3 –C 10 )cycloalkyl]-(Z′)- wherein Z and Z′ are individually (C 1 –C 6 )alkyl, optionally interrupted by 1–3 S or non-peroxide O, or is absent, and n is 1–3; or a pharmaceutically acceptable salt thereof;
in combination with a carrier; wherein the composition is suitable for oral administration.
2. The composition of claim 1 wherein 5′-X is —CH 2 OH or —C(O)NR 3 R 4 .
3. The composition of claim 2 wherein 5′-X is —C(O)NR 3 R 4 .
4. The composition of claim 2 wherein R 3 is H and R 4 is (C 1 –C 4 )alkyl.
5. The composition of claim 1 wherein each R is H or (C 1 –C 4 )alkyl.
6. The composition of claim 1 wherein Z′ is —CH 2 — or —CH 2 —CH 2 —.
7. The composition of claim 6 wherein Z is —CH 2 — or —CH 2 —CH 2 —.
8. The composition of claim 1 wherein C 3 –C 10 cycloalkyl group of R 1 is cyclohexyl or cyclopentyl.
9. The composition of claim 8 wherein X is (C 1 –C 4 )alkoxycarbonyl, —C(O)NR 3 R 4 or acetoxymethyl.
10. The composition of claim 8 wherein X is carboxy.
11. The composition of claim 8 wherein X-Z and Z′ are trans.
12. The composition of claim 1 wherein R is H, X is ethylaminocarbonyl, and R 1 is 2-(4-methoxycarbonylcyclohexylmethyl).
13. The composition of claim 1 wherein R is H, X is ethylaminocarbonyl, and R 1 is 2-(4-acetoxymethylcyclohexylmethyl).
14. The composition of claim 1 wherein the compound is methyl 4-(3-{9-6-aminopurin-2-yl)}prop-2-ynyl)cyclohexane-carboxylate.
15. The composition of claim 1 further comprising a Type IV phosphodiesterase inhibitor.
16. The composition of claim 15 wherein the inhibitor is rolipram.
17. The composition of claim 1 wherein the composition is a powder, a gelatin capsule, or compressed into a tablet.
18. The composition of claim 1 wherein X is —CH 2 OH, —CO 2 R 2 , —OC(O)R 2 , or —C(O)NR 3 R 4 .