Claims for Patent: 4,966,891

Summary for Patent: 4,966,891

Title:	Fluorocytidine derivatives
Abstract:	The novel 5'-deoxy-5-fluorocytidine derivatives of formula ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are hydrogen or an easily hydrolyzable radical under physiological conditions, with the proviso that, at least one or R.sup.1, R.sup.2 and R.sup.3 is an easily hydrolyzable radical under physiological conditions, as well as hydrates of solvates of these compounds have antitumor properties. They can be prepared from compounds of formula I, wherein R.sup.1 is hydrogen or an amino-protecting radical and R.sup.2 and R.sup.3 are hydrogen or a hydroxy-protecting radical or taken together are a cyclic hydroxy-protecting radical.
Inventor(s):	Fujiu; Morio (Chigasaki, JP), Ishitsuka; Hideo (Yokohama, JP), Miwa; Masanori (Kamakura, JP), Umeda; Isao (Yokohama, JP), Yokose; Kazuteru (Urayasu, JP)
Assignee:	Hoffmann-La Roche Inc. (Nutley, NJ)
Application Number:	07/268,437
Patent Claims:	1. A compound of the formula: ##STR43## wherein R.sup.1, R.sup.2 and R.sup.3 are each independently hydrogen, or an easily hydrolyzable radical under physiological conditions, with the proviso that, at least one of R.sup.1, R.sup.2, or R.sup.3 is an easily hydrolyzable radical under physiological conditions; as well as hydrates or solvates of the compounds of the general formula (I). 2. The compound of claim 1 wherein the easily hydrolyzable radical is selected from the group consisting of wherein R.sup.4 represents hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl; R.sup.5 is alkyl or aralkyl radical; and R.sup.6 is alkyl or aralkyl. 3. A compound selected from the group consisting of: N.sup.4 -acetyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -propionylcytidine, N.sup.4 -butyryl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -isobutyrylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-methylbutyryl)cytidine, 5'-deoxy-N.sup.4 -(2-ethylbutyryl)-5-fluorocytidine, 5'-deoxy-N.sup.4 -(3,3-dimethylbutyryl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -pivaloylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -valerylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -isovalerylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -hexanoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -heptanoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -octanoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -nonanoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -hexadecanoylcytidine, N.sup.4 -benzoyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-methylbenzoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3-methylbenzoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-methylbenzoyl)cytidine, 5'-deoxy-N.sup.4 -(4-ethylbenzoyl)-5-fluorocytidine, 5'-deoxy-N.sup.4 -(3,4-dimethylbenzoyl)-5-fluorocytidine, 5'-deoxy-N.sup.4 -(3,5-dimethylbenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-methoxybezoyl)cytidine, 5'-deoxy-N.sup.4 -(3,4-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-N.sup.4 -(3,5-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3,4,5-trimethoxybenzoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3,4,5-triethoxybenzoyl)cytidine, 5'-deoxy-N.sup.4 -(4-ethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-propoxybenzoyl)cytidine, 5'-deoxy-N.sup.4 -(3,5-diethoxybenzoyl)-5-fluorocytidine, N.sup.4 -(4-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, ' -deoxy-N.sup.4 -(3,4-dichlorobenzoyl)-5-fluorocytidine, 5'-deoxy-N.sup.4 -(3,5-dichlorobenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-nitrobenzoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-methoxycarbonylbenzoyl)cytidine, N.sup.4 -(4-acetylbenzoyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(phenylacetyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-methoxyphenylacetyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -nicotinoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -isonicotinoylcytidine 5'-deoxy-5-fluoro-N.sup.4 -picolinoylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-furoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(5-nitro-2-furoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-thenoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(5-methyl-2-thenoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(1-methyl-2-pyrrolecarbonyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3-indolylacetyl)cytidine, N.sup.4 -(3-butenoyl)-5'-deoxy-5-fluorocytidine, 3'-0-benzoyl-5'-deoxy-5-fluorocytidine, N.sup.4,3'-0-dibenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-N.sup.4 -(ethylthio)carbonyl-5-fluorocytidine. 4. A compound of claim 2 selected from the group consisting of: 5'-deoxy-5-fluoro-N.sup.4 -octadecanoylcytidine, N.sup.4 -cyclopropanecarbonyl-5'-deoxy-5-fluorocytidine, N.sup.4 -cyclohexanecarbonyl-5'-deoxy-5-fluorocytidine, N.sup.4 -(1-adamantanecarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-methoxybenzoyl)cytidine, 5'-deoxy-N.sup.4 -(2,4-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -piperonyloylcytidine, 5'-deoxy-5-fluoro-N.sup.4 -(4-fluorobenzoyl)cytidine, N.sup.4 -(2-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, N.sup.4 -(3-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3-nitrobenzoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -[4-(methylthio)benzoyl]cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(2-naphthoyl)cytidine, ' -deoxy-5-fluoro-N.sup.4 -(3-furoyl)cytidine, 5'-deoxy-5-fluoro-N.sup.4 -(3-phenylpropionyl)cytidine, N.sup.4 -cinnamoyl-5'-deoxy-5-fluorocytidine, 2',3'-di-0-benzoyl-5'-deoxy-5-fluorocytidine, N.sup.4,2'-0,3'-0-tribenzoyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N.sup.4 -(octyloxycarbonyl)cytidine, N.sup.4 -(benzyloxycarbonyl)-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluoro-N.sup.4 -formylcytidine. 5. A method for inhibiting the growth of sarcoma, fibrosarcoma, or carcinoma in a subject comprising administering to the subject an antitumor effective amount of the compound of Formula I or the hydrates and solvates thereof. 6. A method for the manufacture of the compound of Formula I comprising reacting a compound of the formula ##STR44## wherein R.sup.7 represents hydrogen or an amino-protecting radical; R.sup.8 and R.sup.9 are each independently hydrogen, or a hydroxy-protecting group; or R.sup.8 and R.sup.9, taken together, form a cyclic hydroxy-protecting group, with a compound of the formula wherein X is a leaving radical and R.sup.4 is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl, or aryl; or with a compound of the formula wherein Y is halogen and R.sup.10 is a radical of the formula, wherein R.sup.5 is alkyl or aralkyl, and R.sup.6 is alkyl or aralkyl; followed, if necessary, by removal of a protecting radical. 7. A pharmaceutical composition with antisarcoma, antifibrosarcoma, or anticarinoma activity comprised of an therapeutically effective amount of a compound of Formula I as the active ingredient.