Synthesis, structure, and antitumor activity of 5,6-dihydro-5-azacytidine
AssigneeThe United States of America as represented by the Department of Health, Education and Welfare
InventorsJohn A. Beisler, Mohamed M. Abbasi, John S. Driscoll
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Abstract
The compound 5,6-dihydro-5-azacytidine, 5AC[H], and non-toxic acid addition salts such as the hydrochloride, together with its preparation from 5-azacytidine (5-AC) by reduction of the 5,6-double bond of 5-AC with an alkali metal borohydride such as sodium borohydride. Additionally, 5,6-dihydro-5-azacytidine, 5AC[H], has antitumor activity for murine leukemia systems L1210 and P388 as an injectable. In comparison with the parent compound, 5-AC, the antitumor activity is comparable and 5AC[H] exhibits a more favorable therapeutic index. It also has better solution stability over a broad pH range. A structure for the HCl salt is given below. ##STR1##
Claims6
5,6dihydro-5 -azacytidine and a non-toxic acid addition salt thereof wherein such salt is selected from a group consisting of non-toxic mineral acid salts and salts of organic acids selected from one member of a group consisting of maleate, tartrate, citrate, acetate, benzoate, and borate.
A process of reducing 5-azacytidine utilizing an alkali metal borohydride in hexamethylphosphoramide solution to produce the compound 5,6-dihydro-5-azacytidine as a boron complex and subsequently hydrolyzing said boron complex with a mineral acid to produce 5,6-dihydro-5-azacytidine as the acid salt.
A method of inhibiting leukemia L1210 and P388 in mice which comprises utilizing an effective amount of 5,6-dihydro-5-azacytidine as an injectable in a dosage regimen of 6 mg/kg - 600 mg/kg of body weight of the compound 5,6-dihydro-5-azacytidine and a non-toxic acid addition salt thereof wherein such salt is selected from a group consisting of non-toxic mineral acid salts and salts of organic acids selected from one member of a group consisting of maleate, tartrate, citrate, acetate, benzoate, and borate.
Dependencies are inferred from the claim text.