Conformationally restrained, chiral (phenylisopropyl)amino-substituted pyrazolo[3,4-d]pyrimidines and purines with selectivity for adenosine A1 and A2 receptors

Abstract

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.

Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells

“…In Scheme 1, the amino ester 1 36 was readily cyclized to the corresponding 6-thioxo-6,7-dihydro-1H-pyrazolo [3,4-d]pyrimidin-4(5H)-one 2 37 through reaction with methyl N-phenyldithiocarbamate in DMF containing 1 N NaOH adopting previously reported procedure. Stirring 2 with methyl iodide in dry DMF containing anhydrous potassium carbonate gave rise to the methylsulfanyl derivative 3.…”

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…In addition, the 9-Et derivatives (i.e., 45) gave a slight improvement over the 9-methyladenines, and 2-Cl substitution of the ring (i.e., 46) was not detrimental for affinity. In a paper by Peet et al in 1992, chiral substituents at the N 6 -position were investigated, the (R)-and the (S)-enantiomers of 1-(hydroxymethyl)-2-phenylethyl were tested, and it seems that the binding pocket of the adenosine receptor has a preference for the (S)-isomer (47) [89]. In 1998, further investigations into the adenines were undertaken by Camaioni et al, systematically placing large substituents at each of C(2), C(6), and C(8) of the ring [90].…”

“…The difference is at the 4-amino domain, a chiral substituent attaches this in a five-membered ring formation to N(1) of the purine ring (i.e., 108; Table 13) [89].…”

Synthesis, DNA-binding, and Antiviral Activity of Certain Pyrazolo[3,4-d]pyrimidine Derivatives

“…5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester 1 was prepared through the reaction of ethyl (ethoxymethylene) cyanoacetate with phenylhydrazine [3,12] . Treatment of 1 with phenyl isothiocyanate afforded ethyl 5-(phenylthiourido)-1-phenylpyrazole-4-carboxylate 2 [13] , which was then cyclized by refluxing in neat hydrazine hydrate to produce the target compound 3 in 47% yield.…”

“…In our laboratory considerable effort has recently been invested in the preparation and evaluation of heterocyclic compounds containing the pyrimidine nucleus, leading to numerous compounds with promising antiviral and antitumor activities [7][8][9][10] . Moreover, some substituted pyrazolopyrimidines have been documented as adenosine antagonists [1][2][3] . These facts, in addition to our previously obtained results about the remarkable activity of thiazolotriazolopyrimidines [11] (structure A), encouraged the synthesis of new derivatives of the pyrazolo- [3,4-d]pyrimidine nucleus as purine isosteres and the evaluation of their DNA-binding and antiviral activities.…”