Several 8-substituted derivatives of guanosine 3 ',5'-cyclic phosphate (cGMP), inosine 3'.5 '-cyclic phosphate (cIMP), and xanthosine 3 ',5 '-cyclic phosphate (cXMP) were synthesized and their biochemical properties compared to corresponding 8-substituted adenosine 3 ',5 '-cyclic phosphate (CAMP) derivatives. cGMP was brominated to give 8bromo-cGMP which was subsequently used to synthesize ciri nucleophilic reactions, %hydroxy-, 8-dimethylamino-, 8methylamino-, 8-benzylamino-, 8-p-chlorophenylthio-, 8benzylthio-, and 8-methylthio-cGMP. Deamination of cGMP and 8-bromo-cGMP gave cXMP and 8-bromo-cXMPj respectively. were prepared by deamination of the respective 8-substituted CAMP. Hydrogenation of 8-azido-cIMP gave 8-amino-cIMP. Thiation of 8-bromo-cIMP gave 8-thio-cIMP.The substituted cGMP derivatives were specific for lobster rnuscle cGMP-dependent protein kinase whereas the 8-substituted cAMP derivatives were specific for bovine brain

1-beta-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide 5'-phosphate (2) was prepared and converted into the following derivatives: the 5'-phosphoramidate 3, the 5'-diphosphate 4, the 5'-triphosphate 5, and the cyclic 3',5'-phosphate 6. The cyclic 2',3'-phosphate 7 was prepared from the parent nucleoside, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (1), and was opened to the 2'(3')-phosphate 8. These compounds were found to exhibit significant antiviral activity against several viruses in cell culture. Ribavirin 5'-phosphate (2) was shown to be effective when tested against lethal infections in mice caused by influenza A2, influenza B, and murine hepatitis viruses.

Derivatives of adenosine 3',5'-cyclic phosphate (cAMP) with modifications in both the 2' and the 8 positions were synthesized and their enzymic activities as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterases were determined. Three types of derivatives were investigated: 8-substituted derivatives of O2'-Bt-cAMP, 8-substituted derivatives of 9-beta-D-arabinofuranosyladenine 3',5'-cyclic phosphate (ara-cAMP), and 8-substituted derivatives of 8,2'-anhydro-9-beta-D-arabinofuranosyladenine 3,'5'-cyclic phosphate (8,2'-anhydro-cAMP). The 8-substituted O2'-Bt-cAMP derivatives were synthesized by acylation of the preformed 8-substituted cAMP (8-HS-cAMP, 8-MeS-cAMP, and 8-PhCH2S-cAMP). 8-Br-O2'-tosyl-cAMP was sued as an intermediate for the preparation of 8,2'-anhydro-cAMP derivatives (8-HO-, 8-SH-, 8-H2N-, and 8-H3 CHN derivatives of 8,2'-anhydro-cAMP). 8-Substituted ara-cAMP derivatives were obtained by ring opening of 8-HO-8,2'-anhydro-cAMP with H+/H2O, NH3/MeOH, or MeONa/MeOH (to yield the 8-HO-, 8-H2N-, and 8-MeO-ara-cAMP derivatives). All of these doubly modified derivatives of cAMP are less than one-hundredth as active as cAMP at activating protein kinase and did not serve as substrates for the phosphodiesterase. These data show that the general inactivity of 2' derivatives of cAMP with kinase was not overcome by addition of an 8-substituent, even though many 8-substituted derivatives of cAMP activate the kinase more efficiently than does cAMP itself. In addition they show that while 2'-modification were tolerated by the phosphodiesterase, addition of an 8-substituent countermanded the allowable 2'-modification. The 8-substituted derivates of 02'-Bt-cAMP were found in general to be slightly better inhibitors of phosphodiesterase than the parent compounds containing no o2'-Bt substitution. As a group, the 8-substituted ara-cAMP derivatives were poorer inhibitors of phosphodiesterase than 8-substituted cAMP derivatives while the 8,2'-anhydro-cAMP derivatives were much poorer inhibitors than the 8-substituted ara-cAMP derivatives.

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Acetylation of 8‐amino‐9‐β‐D‐ribofuranosylpurin‐6‐one (III), followed by chlorination of the tetraacetyl derivative 8‐acetamido‐9‐(2,3,5‐tri‐O‐aeetyl‐β‐D‐ribofuranosyl)purin‐6‐one (IV) with phosphorus oxychloride yielded 8‐aeetamido‐6‐ehloro‐9‐(2,3,5‐tri‐O‐acetyl‐β‐D‐ribofuranosyl)‐purine (V). The 6‐chloro substitutent of V was readily displaced with thiourea to give, after treatment with sodium methoxide 8‐acetamido‐9‐β‐D‐ribofuranosylpurine‐6‐thione (VIII). Chlorination of 8‐bromo‐9‐(2,3,5‐tri‐O‐acetyl‐β‐D‐ribofuranosyl)purin‐6‐one (IX) yielded 6,8‐dichloro‐9‐(2,3,5‐tri‐O‐acetyl‐β‐D‐ribofuranosyl)purine (X), which underwent nucleophilic displacement with ethanolic ammonia selectively in the 8 position. The resulting 8‐amino‐6‐chloro‐9‐β‐D‐ribofuranosylpurine (VII) was converted to 8‐amino‐9‐β‐D‐ribofuranosylpurine‐6‐thione (I), 8‐amino‐6‐methylthio‐9‐β‐D‐ribofuranosylpurine (II), and to 8‐amino‐6‐hydrazino‐9‐β‐D‐ribofuranosylpurine (XI).