Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1988-01-29
1990-01-09
Rollins, John W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
530331, C07H 1906
Patent
active
048929395
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new 5-fluorouridine compounds useful as anti-malignant tumor agents, anti-viral agents or immunosuppressive agents and a process for the preparation thereof.
BACKGROUND ART
5-Fluorouridine is a compound first synthesized in 1959 (U.S. Pat. No. 2,885,396) know to have anti-malignant tumor activity. Despite its superb anti-malignant tumor activity, 5-fluorouridine has not been put to use in practice because of the disadvantage that strong side effects follow. A number of attempts to overcome such disadvantage by converting 5-fluorouridine into different derivatives (see, for example, Japanese Laid-open Patent Applns. Nos. 64280/75, 82079/75, 83378/75 and 52183/76) have been made, but useful compounds have not been obtained yet.
Although the present inventors have previously provided new 5-fluorouridine-5'-O-acyl compounds (Japanese Laid-open Patent Applns. Nos. 77298/81, 91996/82 and 91997/82), even these 5'-O-acyl compounds do not possess satisfactory properties from the practical point of view.
DISCLOSURE OF THE INVENTION
The present invention relates to new 5'-O-oligopeptidyl-5-fluorouridine compounds of the general formula: ##STR2## wherein n is an integer of 1 to 3, R' stands for a straight or branched chain alkyl group having 1 to 4 carbon atoms or a benzyl group, and R stands for an alanyl, phenylalanyl, valyl, tyrosyl, 3,4-dihydroxyphenylalanyl or lysyl group, and pharmacologically acceptable salts thereof, as well as a process for the preparation thereof.
The new 5'-O-oligopeptidyl-5-fluorouridine compounds of the invention and pharmacologically acceptable salts thereof have anti-malignant tumor, anti-viral and immunosuppressive activities and are therefore useful as pharmaceuticals, in particular, anti-malignant tumor agents, anti-viral agents and immunosuppressive agents.
In the 5'-O-oligopeptidyl-5-fluorouridine compounds of the general formula (I) according to the invention, the moiety represented by ##STR3## in the formula represents a peptide structure comprising 1 to 3 amino acids linked through peptide bond and selected from alanine, valine, leucine, isoleucine and phenylalanine.
Illustrative of the pharmacologically acceptable salts of these compounds are salts with mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, or with organic acids such as methanesulfonic acid and para-toluenesulfonic acid.
In the following will now be described a process for the preparation of the 5'-O-oligopeptidyl-5-fluorouridine compounds mentioned above.
The 5'-O-oligopeptidyl-5-fluorouridine compounds of the invention are obtainable by N-acylating a 5'-O-acyl-5-fluorouridine or 5'-O-oligopeptidyl-5-fluorouridine derivative of the general formula: ##STR4## wherein n is an integer of 1 to 3, R' stands for a straight or branched chain alkyl group having 1 to 4 carbon atoms or a benzyl group, with an amino acid selected from the group consisting of alanine, phenylalanine, valine, tyrosine and 3,4-dihydroxyphenylalanine, or an acid anhydride thereof.
This reaction is carried out in a solvent in the presence of a condensing agent and a basic substance. Illustrative of the solvent are dimethylformamide, dimethylacetamide, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile and pyridine. Illustrative of the condensing agent are diethyl cyanophosphate, dicyclohexylcarbodiimide, p-toluenesulfonyl chloride and methane sulfonyl chloride. Illustrative of the basic substance are triethylamine, tributylamine, pyridine and lutidine. The reaction is carried out usually at room temperature using an equimolar proportion of the reactants. After the reaction, the resultant product is purified by way of column chromatography or recrystallization. The above mentioned pharmacologically acceptable salts may be formed by allowing a pharmacologically acceptable acid to be present in steps for removal of different protecting groups mentioned below, although they may be converted, after purification, into other salts.
In the reaction mentioned above, un
REFERENCES:
patent: 3975367 (1976-08-01), Gish et al.
patent: 4340728 (1982-07-01), Endo et al.
Chou Kiyoaki
Endo Takeshi
Sakai Katsumi
Fuji Kagaku Kogyo Kabushiki Kaisha
Rollins John W.
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