Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1982-05-21
1985-07-09
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D40504, A61K 31505
Patent
active
045283729
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to N-phthalidyl-5-fluorouracil derivatives, particularly N-phthalidyl-5-fluorouracil derivatives represented by the general formula (I) ##STR5## wherein one of R.sub.1 and R.sub.2 represents the phthalidyl group: ##STR6## (wherein R.sub.3 is a hydrogen atom, a halogen atom or a group selected from alkoxyl groups or alkyl groups) and the other represents a hydrogen atom, an acyl group or a cyclic ether group ##STR7## (wherein n is 1 or 2), or R.sub.1 and R.sub.2 represent the same phthalidyl group; ##STR8## (wherein R.sub.3 is the same as that defined above). The object of the present invention is to provide a substance which has an excellent antitumor activity and can be used as a cancerocidal agent.
BACKGROUND TECHNOLOGY
Heretofore, 5-fluorouracil and various derivatives thereof have been known as antitumor agents. However, all of these derivatives do not always show the effectiveness expected and it has been generally recognized that they cause immunosuppression when used. In addition, some of 5-fluorouracil derivatives are highly toxic and might have side effects.
Consequently, the present invention aims to provide compounds which have no defect shown by conventional 5-fluorouracil derivatives, have less toxicity, can be dissolved in an oily material in a stable state so that they can be easily absorbed in body and are useful as cancerocidal agents.
DISCLOSURE OF THE INVENTION
The present invention relates to N-phthalidyl-5-fluorouracil derivatives (compounds).
The compounds provided according to the general formula (I) in the present invention are N-phthalidyl-5-fluorouracil derivatives represented, for example, by the general formulae (II) and (III) ##STR9## wherein R.sub.4 represents a hydrogen atom, an acyl group, a cyclic ether group ##STR10## (wherein n is 1 or 2) or a phthalidyl group ##STR11## (wherein R.sub.3 is a hydrogen atom, a halogen atom or a group selected from alkoxyl groups or alkyl groups). In this case, the substitution position of R.sub.3 in the phthalidyl group; ##STR12## is not particularly limited and one or more of the same may be substituted at the position 4, 5, 6 or 7 of the group, respectively. The "acyl group" used in the present specification means lower alkanoyl group having 1-6 carbon atoms, benzoyl group or substituted benzoyl group, more concretely, formyl, acetyl, propionyl, butyryl, benzoyl, toluyl, methoxybenzoyl, chlorobenzoyl group or the like. The "alkyl group" means straight chain or branched alkyl group having 1-6 carbon atoms, for example, straight chain or branched alkyl group in such a group as methyl, ethyl, propyl, butyl, amyl or hexyl group, etc., respectively. Further, "alkoxyl group" means alkoxyl group corresponding to the alkyl group mentioned above.
N-phthalidyl-5-fluorouracil derivatives represented by the general formula (I) in the present invention can be prepared according to the process mentioned below.
A compound wherein R.sub.4 in the general formula (II) is a hydrogen atom can be obtained by allowing 5-fluorouracil to react with a halogenated phthalide compound represented by the general formula (IV) ##STR13## (wherein R.sub.3 is the same as that defined above and X represents a halogen atom) or by the hydrolysis of a compound having an acyl group as R.sub.4 in the general formula (II) obtained by allowing N.sub.1 -acyl-5-fluorouracil to react with a halogenated compound represented by the general formula (IV) mentioned above. This phthalidylation reaction is carried out in an appropriate solvent in the presence of a base. Such a solvent can be freely selected as far as it has no direct effect on the reaction, for instance, there can be illustrated dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like. As the base used, there can be illustrated sodium carbonate, potassium carbonate, sodium hydride, sodium amide, sodium alcoholate and the like. Further, the hydrolysis of the compound having an acyl group as R.sub.4 in the general formula (II) can be carried out with water or
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Hiiragi Mineharu
Ichikawa Keiko
Kigasawa Kazuo
Nakazato Kikuo
Okada Taiji
Daus Donald G.
Grelan Pharmaceutical Co. Ltd.
Kapner Stephen
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