A definitive synthesis for the potent adenosine deaminase inhibitor (8fi)-3-(2-deoxy-/3-D-erythro-pentofuranosyl)- 3,6,7,8-tetrahydroimidazo[4,5-d][l,3]diazepin-8-ol (l)la and its 8S isomer 13 is described, beginning with imidazole precursors. Construction of the heterocyclic portion 11 was accomplished by ring closure of the diamine 10 using triethyl orthoformate; 10 was prepared in eight steps from 4-methyl-5-nitroimidazole (4).Glycosylation of 11 was effected by using a low-temperature, stannic chloride catalyzed condensation of the pertrimethylsilyl derivative of 11 with a protected glycosyl halide.lb Subsequent separation of the anomeric nucleosides 12a and 12b, followed by deprotection and reduction of each, afforded the respective 8R,8S isomers 1,13, and 14. Of these, only the naturally occurring (8R)-3 isomer 1 showed full inhibitory activity against adenosine deaminase.

A number of 5'-(O-acyl) derivatives of 9-beta-D-arabinofuranosyladenine (ara-A, VIRA-A) (2a-k) were prepared by direct acylation of the parent nucleoside 1 in pyridine-N,N-dimethyliformamide. These compounds, designed as prodrugs for 1, offer a range of solubilities and lipophilicities indicating for several examples improved solubility and the potential for improved membrane transport over 1. All are resistant to deactivation by adenosine deaminase. Of special interest is the 5'-(O-valeryl) derivative 2d that shows a marked increase in antiviral activity over 1.

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A number of 2',3'- and 3',5'-di-O-acyl derivatives of 9-beta-D-arabinofuranosyladenine (1) were prepared and evaluated as antivirals. These compounds, designed as prodrugs of 1, offer a range of solubilities and lipophilicities, as well as a resistance to adenosine deaminase, that render some as being attractive as possibly useful antiviral agents. Of particular note is 9-(2,3-di-O-acetyl-beta-D-arabinofuranosyl)adenine that was found to be effective as a topical agent in a guinea pig model of genital herpes.

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