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 (I) wherein R1, R2 and R3 are hydrogen or an easily hydrolyzable radical under physiological conditions, with the proviso that, at least one or R1, R2 and R3 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 R1 is hydrogen or an amino-protecting radical and R2 and R3 are hydrogen or a hydroxy-protecting radical or taken together are a cyclic hydroxy-protecting radical.
Inventor(s):	Morio Fujiu, Hideo Ishitsuka, Masanori Miwa, Isao Umeda, Kazuteru Yokose
Assignee:	Hoffmann La Roche Inc
Application Number:	US07/268,437
Patent Claims:	1. A compound of the formula: ##STR43## wherein R1, R2 and R3 are each independently hydrogen, or an easily hydrolyzable radical under physiological conditions, with the proviso that, at least one of R1, R2, or R3 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 R.sup.4 CO--,R.sup.5 OCO--, or R.sup.6 SCO-- wherein R4 represents hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl; R5 is alkyl or aralkyl radical; and R6 is alkyl or aralkyl. 3. A compound selected from the group consisting of:N4 -acetyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -propionylcytidine, N4 -butyryl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -isobutyrylcytidine, 5'-deoxy-5-fluoro-N4 -(2-methylbutyryl)cytidine, 5'-deoxy-N4 -(2-ethylbutyryl)-5-fluorocytidine, 5'-deoxy-N4 -(3,3-dimethylbutyryl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -pivaloylcytidine, 5'-deoxy-5-fluoro-N4 -valerylcytidine, 5'-deoxy-5-fluoro-N4 -isovalerylcytidine, 5'-deoxy-5-fluoro-N4 -(2-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N4 -(3-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N4 -(4-methylvaleryl)cytidine, 5'-deoxy-5-fluoro-N4 -hexanoylcytidine, 5'-deoxy-5-fluoro-N4 -heptanoylcytidine, 5'-deoxy-5-fluoro-N4 -octanoylcytidine, 5'-deoxy-5-fluoro-N4 -nonanoylcytidine, 5'-deoxy-5-fluoro-N4 -hexadecanoylcytidine, N4 -benzoyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(4-methylbenzoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(3-methylbenzoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(2-methylbenzoyl)cytidine, 5'-deoxy-N4 -(4-ethylbenzoyl)-5-fluorocytidine, 5'-deoxy-N4 -(3,4-dimethylbenzoyl)-5-fluorocytidine, 5'-deoxy-N4 -(3,5-dimethylbenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(4-methoxybezoyl)cytidine, 5'-deoxy-N4 -(3,4-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-N4 -(3,5-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(3,4,5-trimethoxybenzoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(3,4,5-triethoxybenzoyl)cytidine, 5'-deoxy-N4 -(4-ethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(4-propoxybenzoyl)cytidine, 5'-deoxy-N4 -(3,5-diethoxybenzoyl)-5-fluorocytidine, N4 -(4-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, ' -deoxy-N4 -(3,4-dichlorobenzoyl)-5-fluorocytidine, 5'-deoxy-N4 -(3,5-dichlorobenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(4-nitrobenzoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(4-methoxycarbonylbenzoyl)cytidine, N4 -(4-acetylbenzoyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(phenylacetyl)cytidine, 5'-deoxy-5-fluoro-N4 -(4-methoxyphenylacetyl)cytidine, 5'-deoxy-5-fluoro-N4 -nicotinoylcytidine, 5'-deoxy-5-fluoro-N4 -isonicotinoylcytidine 5'-deoxy-5-fluoro-N4 -picolinoylcytidine, 5'-deoxy-5-fluoro-N4 -(2-furoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(5-nitro-2-furoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(2-thenoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(5-methyl-2-thenoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(1-methyl-2-pyrrolecarbonyl)cytidine, 5'-deoxy-5-fluoro-N4 -(3-indolylacetyl)cytidine, N4 -(3-butenoyl)-5'-deoxy-5-fluorocytidine, 3'-0-benzoyl-5'-deoxy-5-fluorocytidine, N4,3'-0-dibenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-N4 -(ethylthio)carbonyl-5-fluorocytidine. 4. A compound of claim 2 selected from the group consisting of:5'-deoxy-5-fluoro-N4 -octadecanoylcytidine, N4 -cyclopropanecarbonyl-5'-deoxy-5-fluorocytidine, N4 -cyclohexanecarbonyl-5'-deoxy-5-fluorocytidine, N4 -(1-adamantanecarbonyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(2-methoxybenzoyl)cytidine, 5'-deoxy-N4 -(2,4-dimethoxybenzoyl)-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -piperonyloylcytidine, 5'-deoxy-5-fluoro-N4 -(4-fluorobenzoyl)cytidine, N4 -(2-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, N4 -(3-chlorobenzoyl)-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(3-nitrobenzoyl)cytidine, 5'-deoxy-5-fluoro-N4 -[4-(methylthio)benzoyl]cytidine, 5'-deoxy-5-fluoro-N4 -(2-naphthoyl)cytidine, ' -deoxy-5-fluoro-N4 -(3-furoyl)cytidine, 5'-deoxy-5-fluoro-N4 -(3-phenylpropionyl)cytidine, N4 -cinnamoyl-5'-deoxy-5-fluorocytidine, 2',3'-di-0-benzoyl-5'-deoxy-5-fluorocytidine, N4,2'-0,3'-0-tribenzoyl-5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluoro-N4 -(octyloxycarbonyl)cytidine, N4 -(benzyloxycarbonyl)-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluoro-N4 -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 R7 represents hydrogen or an amino-protecting radical; R8 and R9 are each independently hydrogen, or a hydroxy-protecting group; or R8 and R9, taken together, form a cyclic hydroxy-protecting group,with a compound of the formula XCOR.sup.4 (III) wherein X is a leaving radical and R4 is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl, or aryl; or with a compound of the formula YCOR.sup.10 (IV) wherein Y is halogen and R10 is a radical of the formula, R.sup.5 ZO--, or R.sup.6 S-- wherein R5 is alkyl or aralkyl, and R6 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.