Carbocyclic analogs of cytosine nucleosides exhibiting antiviral and antineoplasticactivity

#This invention relates to novel analogs of cytosine nucleosides and, more particularly, to carbocyclic analogs of cytosine nucleosides in which the pentose moiety of the nucleosides is replaced by a cyclopentane ring.

#Cytosine nucleosides and their 5'-phosphates are involved essentially in the biosynthesis of nucleic acids and in other biochemical processes. Cytidine and 2'-deoxycytidine are nucleoside moieties of ribonucleic acid and deoxyribonucleic acid respectively. Because of the essential and intimate involvement of cytosine nucleosides in vital biochemical processes, structural analogs of these compounds are potentially important as chemotherapeutic agents.

#Currently, the best known example of a therapeutically useful cytosine nucleoside is 1-.beta.-D-arabinofuranosylcytosine, frequently designated by the acronym Ara-C. This compound has demonstrated antiviral and antineoplastic activity, as reviewed by Cohen, "Introduction to the Biochemistry of D-Arabinosyl Nucleosides", in Progress in Nucleic Acid Research and Molecular Biology, Vol. 5, Davidson and Cohn, Editors, Academic Press, New York, N.Y., 1966; and by Creasey, "Arabinosylcytosine", in Antineoplastic and Immunosuppressive Agents, Part II, Chapter 42, Sartorelli and Johns, Editors, Springer-Verlag, New York, N.Y., 1975.

#The invention is further illustrated by way of the following examples, wherein all temperatures are in degrees centigrade.

#The Carbocyclic Analog of Cytidine (Formula IV, R.sub.1 =R.sub.2 =H; X=Y=OH).

#A solution of benzoyl chloride (3.07 g.) in anhydrous pyridine (12.5 ml.) was added dropwise to a solution of 1-[(1d, 2.beta., 3.beta., 4.alpha.)-(.+-.)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl]-2,4(1H, 3H)-pyrimidinedione (Formula VII, R=H, X=Y=OH; the carbocyclic analog of uridine) (1.203 g.) in anhydrous pyridine (25 ml.). The solutions of the reactants and the reaction mixture were protected from atmospheric moisture, and the reaction mixture was stirred. The reaction was mildly exothermic; and, after the addition of benzoyl chloride had been completed, the reaction solution was heated at 57.degree.-58.degree. for 48 hr. The reaction solution was then cooled to room temperature and poured slowly into a water-ice mixture (500 ml.). The reaction vessel was rinsed twice with 3-ml. portions of pyridine, and these rinsings were added to the cold mixture. After the ice had melted, the mixture was filtered to separate a white solid that was washed thoroughly with water and dried under reduced pressure at room temperature: weight 3.18 g. (99% yield, calculated as the tetrabenzoyl derivative of the carbocyclic analog of uridine. A field-desorption mass spectrum (molecular ion at m/e 658) and thin-layer chromatography of the white solid confirmed that it was such tetrabenzoyl derivative.