Adenosine deaminase inhibitors. Synthesis and biological evaluation of (.+-.)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol and some selected C-5 homologs of pentostatin

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Abstract
The synthesis of several analogs of (8R)-3-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin) is described. Ring closure of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (3) with triethyl orthoacetate or triethyl orthopropionate gave the C-5 methyl and ethyl ketoaglycons, 6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (4b) and 5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4c), respectively. Stannic chloride catalyzed condensation of the pertrimethylsilyl derivatives of 4b and 4c with a protected glycosyl halide afforded anomeric mixtures of ketonucleosides 3-(2-deoxy-3,5-di-O-p-toluoyl)-.beta.- and -.alpha.-D-erythro-pentofuranosyl)-6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (5b and 6b) and 3-(2-deoxy-3,5-di-O-p-toluoyl)-.beta.- and -.alpha.-D-erythro-pentofuranosyl)-5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (5c and 6c), respectively. Subsequent separation of the anomers, followed by deprotection and reduction of 5b, 6b and 5c, afforded the respective 8R and 8S isomers. Stannic chloride catalyzed condensation of pertrimethylsilyl ketoaglycon 4a with 2-(chloromethoxy)-1-(p-toluoyloxy)ethane to give ketonucleoside 6,7-dihydro-3-[[2-(p-toluoyloxy)ethoxy]methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one was followed by deprotection to 6,7-dihydro-3[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one (9b) and then reduction to the racemic acyclic pentostatin analog (.+-.)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol (2). Ki values for the in vitro adenosine deaminase (EC 3.5.4.4; type I; calf intestinal mucosa) inhibitory activities of (8R)-3(2-deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydro-5-methylimidazo [4,5-d][1,3]-diazepin-8-ol, (8R)-3-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-5-ethyl-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]-diazepin-8-ol and 2 were determined to be 1.6 .times. 10-8, 1.5 .times. 10-6 and 9.8 .times. 10-8 M, respectively. When compounds 2 and 9b were tested in combination with vidarabine against herpes simplex virus, type 1, in an [human laryngeal carcinoma] HEp-2 plaque reduction assay, only compound 2 was able to potentiate the antiviral activity of vidarabine.