Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-08-26
1997-12-30
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 111, C07H 1900
Patent
active
057032246
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 94/02059 filed Dec. 12, 1994.
TECHNICAL FIELD
The present invention relates to a novel nucleoside derivative having antiviral or antimalignant-tumoral activities.
BACKGROUND TECHNOLOGY
Being transmitters of genetic information in living matter, nucleic acids play a crucial role in the differentiation and growth of cells. Among natural and unnatural nucleoside derivatives, many derivatives are known to inhibit biosynthesis of nucleic acids and are, therefore, useful as antiviral or antimalignant-tumoral agents. As antiviral agents, for instance, vidarabine (Ara-A: C. R. Acad. Soc. D (Paris), 259, 2725 (1964)), acyclovir (Proc. Natl. Acad. Sci, USA, 74, 5716 (1977)), azidothymidine (Proc. Natl. Acad. Sci, USA, 82, 7096 (1985)), 2',3'-dideoxyinosine (DDI), 2',3'-dideoxycytidine (DDC: WO90/14079), among other nucleosides, are known. As antimalignant-tumoral agents, cytarabine (Ara-C), enocitabine, thioinosine, etc. are known.
However, none of the above-mentioned antiviral agents and antimalignant-tumoral agents are fully satisfactory from the standpoint of effects and adverse actions. It is guessed to be one of the causes for insufficient efficacy that the above-mentioned nucleoside derivatives have the chemical structure in which the nucleic acid base moiety is directly bound to the sugar one and, therefore, they are susceptible to hydrolysis by acid or alkali and the nucleoside derivatives with activity are ready to be metabolized in living body.
Meanwhile, as the compounds resembling the compound of the present invention, there are known several nucleosides having the chemical structure in which a methylene group is inserted between the nucleic acid base moiety and the sugar one. They are generally called homonucleosides. For example, 2,5-anhydro-1-doexy-1-(adenin-9-yl)-D-allitol (1-homoadenosine: Collection Czechoslov. Chem. Commun., 36, 3043 (1971) and J. Heterocycl. Chem., 7, 443 (1970)), 2,5-anhydro-1-deoxy-1-(uracil-1-yl)-D-allitol (1-homouridine: Collection Czechoslov. Chem. Commun., 34, 1684 (1969) and Collection Czechoslov. Chem. Commun., 35, 81 (1970)), 2,5-anhydro-1-deoxy-1-(cytosin-1-yl)-D-allitol (1-homocytidine: Collection Czechoslov. Chem. Commun., 34, 1684 (1969)), 2,5-anhydro-1,3,4-trideoxy-1-(6-mercaptopurin-9-yl)-D-allitol, and 2,5-anhydro-1,3,4-trideoxy-1-(6-methylthiopurin-9-yl)-D-allitol (J. Med. Chem., 15, 571 (1972)) are known. However, useful pharmacologic activities of these compounds are not disclosed at all. Quite recently, a nucleoside containing an oxetanocin ring suggested its possibility as an antiviral and anticancer agent has been reported (Japanese Laid-Open H. 5-271224).
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide, as a medicine, a homonucleoside derivative which is difficult to be subjected to acid and alkali hydrolysis, and is chemically and enzymologically stable by inserting a methylene group between the nucleic acid base moiety and the sugar one of a nucleoside derivative.
The inventors of the present invention have researched in earnest and have above-mentioned object and then have completed the present invention. ##STR2## wherein B represents adenin-9-ylmethyl, guanin-9-ylmethyl, hypoxanthin-9-ylmethyl, thymin-1-ylmethyl, uracil-1-ylmethyl, or cytosin-1-ylmethyl; X and Y may be the same or different and each represents hydrogen or hydroxy, with the exception of the case in which X is hydrogen and Y is hydroxy.
The feature of the present invention exists in the very structure of the a novel compound not heretofore described in the literature.
Moreover, as above-mentioned, owing to its enhanced stability, both chemically and enzymologically, the compound of the invention is difficult to be metabolized in living body, so that its pharmacologic effect is increased in both intensity and duration as compared with the conventional nucleosides.
The compound of the present invention has antiviral and antimalignant-tumoral activities and has good stability and safety in living body and, therefore,
REFERENCES:
patent: 5393879 (1995-02-01), Wang et al.
Farkas, Collection of Czechoslov. Chem. Commun., 1971, 36, 3043-46.
Montgomery et al., 1-(Adenin-9-yl)-2,5-anhydro-1-deoxy-D-allitol, A Homolog of Adenosine, J. Heterocycl. Chem., 1970, 7, 443-445.
Holy, Collection of Czechoslov. Chem. Commun., 1970, 35, 81-88.
Bobek et al., Collection of Czechoslov. Chem. Commun., 1969, 34, 1684-89.
Ohgi Tadaaki
Yano Junichi
Burnett Friedrich N.
Kight John
Nippon Shinyaku Co. Ltd.
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