Conformationally restrained, chiral (phenylisopropyl)amino-substituted pyrazolo[3,4-d]pyrimidines and purines with selectivity for adenosine A1 and A2 receptors.
Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5- propoxy-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A2 and A1 adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5- propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A1 receptors, and were nonselective.
Peet
N P
NP
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Lentz
N L
NL
Sunder
S
S
Dudley
M W
MW
Ogden
A M
AM
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011983:Receptors, Purinergic; C076209:2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-propoxy-3H-imidazo(1,2-c)pyrazolo(4,3-e)pyrimidine