Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-06-29
2000-11-14
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 51, 536 553, 536 285, 536 261, A61K 3170, C07H 1909, C07H 1910, C07H 100
Patent
active
061470589
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosines and a process for the production and use thereof.
BACKGROUND ART
A research group of University of Birmingham makes reference to 1-(2-fluoro-4-thio-beta-D-arabinofuranosyl)-5-methyluracil and 1-(2-fluoro-4-thio-beta-D-arabinofuranosyl)-5-iodocytosine in International Patent Application PCT/GB90/01518 (International Publication Number: WO 91/04982).
Further, a research group of NIH has recently made a report on such compounds as 1-(2,3-dideoxy-2-fluoro-4-thio-beta-D-erythro-pentafuranosyl)uracil represented by the following formula: ##STR2## provided that B is uracil in series a, and cytosine in series b (Tetrahedron Letters, 35, 7569-7572 (1994); Tetrahedron Letters, 35, 7573-7576 (1994); Chemistry Letters, 301-302 (1995)).
However, the group of University of Birmingham describes the above two compounds as mere instances, and fails to show examples in which they were practically synthesized. Moreover, although a process for producing the compounds is explained in the specification for the aforementioned international patent application, the process is simply an application of those processes which are described in known references (J. Org. Chem., 50, 2597 (1985), J. Org. Chem., 50, 3644 (1985)). It is clear from the above-described reports made by the group of NIH that desired compounds can never be obtained by employing such a process. The specification for the foregoing international application slightly makes mention of the antiviral activity of the compounds, but is quite silent on specific data in terms of the activity.
Further, although the group of NIH makes reference to the anti-HIV activity of the compounds synthesized, the activity is not necessarily satisfactory.
Furthermore, both of the groups have made no report on other biological activities than antiviral activity.
DISCLOSURE OF THE INVENTION
We formerly developed a simple process for synthesizing 2'-deoxy-2'-substituted-4'-thionucleoside derivatives, using glucose as a starting material (WO 96/01834). After this, we continued our studies on the basis of knowledge acquired in the course of the development of this process. As a result, we have established a simple process for synthesizing 2'-deoxy-2'-fluoro-4'-thioarabinonucleosides, and synthesized various compounds by using this new process. In the process of testing the biological activities of the compounds synthesized, we have found that especially 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosines have excellent antitumor activity. The present invention has been accomplished on the basis of this finding.
The present invention therefore relates to 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosines represented by the following formula [I]: ##STR3## wherein R represents a hydrogen atom or a phosphoric acid residue, and to pharmaceutical compositions, especially antitumor agents, comprising these compounds as active ingredients.
Further, the present invention also relates to a process for producing 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosines represented by the above formula [I], comprising the following 1st to 3rd steps:
1st step: diethylaminosulfur trifluoride (DAST) after protecting the primary hydroxyl group of the compound [II], thereby obtaining a compound represented by formula [III]: ##STR4## wherein R.sub.1 and R.sub.2 represent an alkyl, silyl or acyl group;
2nd step: sulfoxide by reacting the compound [III] with an oxidizing agent, and subjecting the sulfoxide to Pummerer rearrangement reaction by treating it with an acid anhydride or acid chloride, thereby obtaining a compound represented by formula [IV]: ##STR5## wherein R.sub.1 and R.sub.2 are as defined above, and R.sub.3 represents an acyl group; and
3rd step: -acylcytosine or cytosine to glycosylation reaction in the presence of a Lewis acid catalyst to obtain a protected compound, removing the protecting groups, and, if desired, phosphorylating the 5'-position of the
REFERENCES:
Jeong et al., Chemistry Letters, pp. 301-302, 1995.
Jeong et al., Tetrahedron Letters, 35(41):7569-7572, 1994.
Jeong et al., Tetrahedron Letters, 35(41):7573-7576, 1994.
Y. Yoshimura et al., Nucleic Acids Symposium Series, No. 35, pp. 15-16 (1996).
Y. Yoshimura et al., Journal of Organic Chemistry, vol. 61, No. 3, pp. 822-823 (1996).
Kitano Kenji
Machida Haruhiko
Miura Shinji
Watanabe Mikari
Yoshimura Yuichi
Kunz Gary L.
Yamasa Corporation
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