Water-soluble derivatives of ara-cytidine (cytarabine, Cytosar) were prepared and tested for antitumor, immunosuppressive, and antiarthritic activities in animals after oral administration. The compounds tested included the 5'-palmitate, 5'-benzoate, and 5'-adamantoate esters of ara-cytidine, made water soluble by use of their hydrochloride salts of peptidyl derivatives, and two basic 5' esters (5'-nicotinoate and 5'-quinuclidinate) as their hydrochloride salts. Five of the compounds had antitumor activity superior to that found with ara-cytidine itself after oral administration in the L1210 leukemic mouse assay. One of these, 5'-adamantoyl-ara-cytidine hydrochloride, had antitumor activity after oral administration approaching that achieved with parenterally administered ara-cytidine.
To a suspension of anthranilic acid (13.7 g) in dimethylacetamide (100 ml) 4a (20 g) was added, and the mixt was heated to 150-160°for 3 hr. After cooling the solvent was evapd in vacuo, and the residue was dissolved in CHCls. The soln was extd with 2 N XaOH and with H20.The org phase was dried (Xa2S04) and evapd, and the residue was chromatogd on silica gel (Merck AG, 0.05-0.2 mm). The product was eluted with CHC13. After evapn the residue was dissolved in EtOH (80 ml), and the soln was satd with anhyd HC1. On addn of Et20 (300 ml) the hydrochloride crystd, it was removed bv filtration (5.9 g, 20%) and dried in vacuo (0.1 mm) at 60°, mp 267-270°. Anal. (Ci:,H1sX3OC1) X, O, Cl.Analogously 1,2,3,4,13,13a-hexahydro-7-methyl-1 lk-pyrido-[1 ',2':3,4]imidazo[2,1-5]quinazolin-ll-one (7e) was prepd in Notes 10% vield bv the above procedure from 3a and 3-methylanthranilic acid, 129-130°. Anal. ( ,, ,, )C, , X.1,2,3,4,13,13a-Hexahydro-8-methoxy-l 1/7-pyrido [1 ',2': 3,4]imidazo [2,[1][2][3][4][5][6] quinazolin-ll-one (7f).-A mixt of 4-methoxyanthranilic acid (6.0 g) and 3a (6.0 g) in 25 ml of DMAC was heated for 4 hr at 150-160°. The solvent was evapd and the remaining solid dissolved in CH2C12. The soln was washed with 2 N XaOH (50 ml) twice with water (100 ml), dried (XaoSOi), and evapd in vacuo.The residue crvstd from ECO, 4.0 g (42%), mp 154-157°. Anal. (CuH,;NjOs) C, , X, O.Acknowledgment.-We wish to thank Mr. Urs Stoeckli and Mrs. Nancy Engstrom for running the ir and nmr spectra. NotesNucleic Acids. 12. Synthesis of the l Enantiomer of -ß-Arabinofuranosylcytosine and of 02,02,-Anhydro-l-/3-D-arabinofuranosylcytosine
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