Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-08-13
1998-06-09
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 46, 514 47, 514 48, 514 49, 514 50, 514 51, 536 2711, 536 2623, 536 2626, 536 267, 536 2671, 536 2674, 536 268, 536 276, 536 2762, 536 2763, 536 278, 536 2781, 536 285, 536 2851, 536 2852, 536 2853, 536 2854, 536 2855, A61K 3170
Patent
active
057634181
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a new nucleic acid derivative, and more particularly to a 3'-substituted nucleoside derivative or a pharmaceutically acceptable salt thereof, which has excellent antitumor activities and is useful as a medicine such as an antitumor agent, and use of such a compound for a medicine.
BACKGROUND ART
Pyrimidine compounds such as 5-fluorouracil, tegafur, UFT, doxifluridine, carmofur, cytarabine and enocitabine have heretofore been known as antitumor agents which are nucleic acid antimetabolites.
On the other hand, 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-.beta.-D-ribofuranosyl)thymin e has been known as a pyrimidine or purine nucleoside having an alkynyl group at a 3-position of a sugar moiety from Tetrahedron, 47, 1727-1736 (1991). There is however no description as to the medicinal utility of this compound, in particular, antitumor action. 1-(3-C-Ethynyl-.beta.-D-xylofuranosyl)thymine and 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-.beta.-D-xylofuranosyl)thymin e are also described ibid. The sugar moieties of these two compounds are both composed of xylose and differ in the configuration at a 3-position from the ribose in the compounds according to the present invention. Besides, the literature does not describe anything about antitumor action. compounds having an alkyl group at a 3-position of a sugar moiety are described in Japanese Patent Publication Nos. 11908/1970 and 4376/1971. However, their antitumor effects are extremely little, and they are hence of no utility value as anticancer agents under circumstances.
Accordingly, it is an object of the present invention to provide a new nucleic acid derivative which has excellent antitumor activities and is useful as a medicine, and a medicine comprising such a compound.
In view of the foregoing circumstances, the present inventor has carried out an extensive investigation. As a result, it has been found that a nucleic acid derivative at a 3-position of the sugar moiety of which a substituent has been introduced has excellent antitumor activities and is useful as an antitumor agent, thus leading to completion of the present invention.
DISCLOSURE OF THE INVENTION
The present invention provides a 3'-substituted nucleoside derivative represented by the following general formula (1): ##STR3## wherein B means a nucleic acid base which may have a substituent, Z represents a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the general formula (2): ##STR4## in which R.sup.a, R.sup.b and R.sup.c may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or an oxiranyl group which may be substituted by at least one lower alkyl group, R.sup.1 and R.sup.2 individually represent a hydrogen atom or an ester-forming residue capable of easily leaving in a living body, and R.sup.3 is a hydrogen atom, a mono- or polyphosphoric acid residue, or an ester-forming residue capable of easily leaving in a living body, with the proviso that the sugar moiety is ribose, or a pharmaceutically acceptable salt thereof.
The compound of the present invention represented by the general formula (1) has excellent antitumor activities and is useful as a medicine such as a remedy for various tumors.
Accordingly, the present invention also provides a medicinal composition comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
The present invention further provides a medicine, in particular, an antitumor agent, comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention further provides use of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof for a medicine.
The present invention still further provides a method of treating or preventing a cancer of a mammal, which comprises administering an effective amount of the compound of the general formula (1) or a pharma
REFERENCES:
Alvarez et al., "Novel TSAO Derivatives, Synthesis and Anti-HIV-1 Activity of Allofuranosyl-TSAO-T Analogues," Nucleosides & Nucleotides, 15(1-3), 349-359 (Jan.-Mar., 1996).
Matsuda et al. (I), "Nucleosides and Nucleotides. 152. 1-(3-C-Ethynl-.beta.-D-Ribo-pentofuranosy)uracil as a Broad Spectrum Antitumor Nucleoside," Bioorganic Medical Chem. Letters, 6(16), 1887, 1892 (Aug. 20, 1996).
Johnson et al., "3'-C-Trifluoromethy Ribonucleosides," Nucleosides & Nucleotides, 14(1 & 2), 185-194 (Feb.-Apr., 1995).
Ichikawa et al., "Nucleosides and Nucleotides. 163. Synthesis of 3'-.beta.-Branched Uridine Derivatives via Intramolecular Reformatsky-Type Reaction Promoted by Samarium Diiodide," J. Organic Chem., 62(5), 1368-1375 (Mar. 7, 1997).
Nielson et al., "Stereoselective Synthesis of 3'-Allyluridines and 3'-Spiro-.gamma.-lactone Uridine Analogues," Acta Chemica Scandinavica, 30(11), 1030-1035 (Nov. 1996).
Jung et al., "Rapid and Efficient Stereocontrolled Synthesis of C-3'-Ethynyl Ribo and Xylonucleosides by Organocerium Additions to 3'-Ketonucleosides," Tetrahedron Letters, 36(7), 1031-1034 (Feb. 13, 1995).
Beigelman et al., "Efficient Epimerization in the Acetolysis of 3-O-Acetyl-5-o-benzoyl-1-1,2-O-isopropylidene-3-C-methylnucleosides wtih .beta.-D-Ribo-and .alpha.-D-Arabino-Configurations," Doklady Chemistry(English Translation), 296(4-6), 458-461 (Apr. 1988); Doklady Akademii Nauk SSSR Chem. Sec., (Russian), 296(4-6), 1379-1382 (Oct. 1987).
Sophie Huss et al., "Synthesis of 3'-C-Ethynylnucleosides of Thymine", Tetrahedron, (1991) vol. 47, No. 9, pp.1727-1736 Month of publication date is unavailable.
Matsuda Akira
Takuma Sasaki
Crane L. Eric
Kight John
Matsuda Akira
Taiho Pharmaceutical Co. Ltd.
Takuma Sasaki
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