Full clinical utility of the antileukemic drug, 5-azacytidine (1), is hampered by its facile hydrolysis in aqueous formulations. The present study sought to improve the stability of the parent drug while retaining the antitumor attributes through the synthesis of a reduced analogue of 1. Borohydride reduction of 1 gave 5,6-dihydro-5-azacytidine hydrochloride (5) after acid hydrolysis of a boron-containing intermediate. The structure proof and characterization of 5 was achieved primarily with UV, NMR, and GC-MS with the aid of a deuterated derivative (7) prepared by using borodeuteride in the initial reduction step. Vigorous treatment of 5 with acid gave the aglycon 9 which was independently synthesized from 5-azacytosine (11). The dihydro analogue 5 was completely stable at room temperature in aqueous solutions over a broad pH range for up to 3 weeks. In comparative antitumor assays 5 showed good activity in L1210 systems when administered intraperitoneally or orally. Although higher dose levels were necessary, 5 had approximately 80% of the antitumor efficacy shown by 1. Neither 5 nor 1 showed a dependency on administration schedule. Cross resistance between 5 and 1 was demonstrated using an L1210 subline resistant to 1. 5 was found to be superior to 1 in therapeutic index and in its ability to cross the blood-brain barrier in sufficient quantity to be therapeutic against intracranially implanted L1210 cells. Subjective evidence is given which suggests 5 is a prodrug of 1.

5-Azacytosine arabinoside (ara-AC) can be considered a combination of structural elements derived from the antitumor nucleosides cytosine arabinoside (ara-C) and 5-azacytidine (5-AC). The synthesis of ara-AC, for which standard methods were inadequate, was accomplished using the stable dihydro derivative as a synthetic intermediate. A novel dehydrogenation of the latter through the application of a trimethylsilylation-oxidation procedure gave ara-AC in good yield. Using murine L1210 leukemia as a test system, ara-AC was evaluated for antitumor properties in parallel determinations with 5-AC and ara-C. Although higher dose levels were necessary, ara-AC demonstrated a reproducibly greater efficacy in the L1210 system (% ILS = 144-148) than that shown by 5-AC (% ILS = 126-124) or ara-C (% ILS=127-121 ). Moreover, initial data suggest that ara-AC exhibits less host toxicity than either 5-AC or ARA-C. Although ara-AC can equally be considered an analogue of either 5-AC or ara-C, preliminary results indicate that ara-AC is chemically similar to 5-AC but biologically more closely related to ara-C.

Phosphorus trichloride and hexamethylphosphorus triamide react with N-t-butyl-2,2'-iminodiethanol (4) forming the 2 : 3 adduct N,N-bis[2-(6-t-butyl-l,3,6,2-dioxazaphosphoran-2-yloxy)ethyl-t-butylamine (5) which, on treatment with water (2 mol equiv.) is hydrolysed to give 6-t-butyl-1,3,6,2dioxazaphosphocane 2-oxide (8) and N-t-butyl-2,2'-iminodiethanol (4). Compound (8) reacts with ochloranil to produce a crystalline product which in solution gives an equilibrium mixture of six-coordinated phosphorus with a P-OH bond (9) and the phosphate ester (10). Phenylphosphonous dichloride and N,N,N',N'-tetramethyl-P-phenylphosphonous diamide react with (4) to give 2-phenyl-6t-butyl-l,3,6,2-dioxazaphosphocane (1 1 ) which adds to o-chloranil to form a tautomeric equilibrium mixture of the four-co-ordinate and six-co-ordinate phosphorus compounds (1 3) (1 4). Phenyl azide reacts with (1 1 ) to give 2-phenyl-2-phenylimino-6-t-butyl-l,3,6,2-dioxazaphosphocane (1 5). The structural assignments are based on analytical, chemical, and spectroscopic results.

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