METHODS AND COMPOSITIONS FOR TREATING INFLAMMATORY RESPONSE
Compositions for oral administration of compounds having A 2A adenosine receptor antagonist activity are provided. These compositions are useful for treatment of inflammatory conditions.
1 - 17 . (canceled)
18 . A method for preparing a compound of the formula (I):
comprising:
(i) reacting a compound of formula II with a compound of formula III
wherein:
each R is individually hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or phenyl(C 1 -C 3 )-alkyl;
X is —CH 2 OH, —CO 2 R 2 , —OC(O)R 2 , or C(O)NR 3 R 4 ;
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;
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 nonperoxide O, or are absent, and n is 1-3; or
a pharmaceutically acceptable salt thereof.
19 . The method of claim 18 , wherein the compounds of formulas II and III are reacted in the presence of CuI and P(PPh 3 ) 4 .
20 . The method of claim 18 , wherein 5′-X is CH 2 OH or —C(O)NR 3 R 4 .
21 . The method of claim 20 , wherein 5′-X is —C(O)NR 3 R 4 .
22 . The method of claim 21 , wherein R 3 is H and R 4 is (C 1 -C 4 )alkyl.
23 . The method of claim 18 , wherein each R is H or (C 1 -C 4 )alkyl.
24 . The method of claim 18 , wherein Z′ is —CH 2 — or —CH 2 —CH 2 —.
25 . The method of claim 24 , wherein Z is —CH 2 — or —CH 2 —CH 2 —.
26 . The method of claim 18 , wherein C 3 -C 10 cycloalkyl is cyclohexyl or cyclopentyl.
27 . The method of claim 26 , wherein X-Z is HO 2 C-Z-.
28 . The method of claim 26 , wherein X-Z and Z′ are trans on C 3 -C 10 cycloalkyl.
29 . The method of claim 18 , wherein R is H, and R 1 —C≡C— is 2-(4-methoxycarbonyl-cyclohexylmethyl)ethynyl or 2-(4-carboxy-cyclohexylmethyl)ethynyl.
30 . The method of claim 18 , wherein R is H, and R 1 —C≡C— is 2-(4-acetoxymethyl-cyclohexylmethyl)ethynyl.