Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1998-06-29
2000-08-15
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514261, 514262, 514263, 544244, 544264, 544265, 544266, 544267, 544276, 544277, A61K 3152, A61K 31522, C07D47334, C07D47316
Patent
active
061037079
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivatives 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)).
Thus, both of these groups have made reports on pyrimidine nucleosides, but are quite silent on purine nucleosides. An object of the present invention is therefore to provide novel and useful 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivatives.
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 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl) purine derivatives, and found that the compounds obtainable by this new process have excellent antiviral activity. The present invention has been accomplished on the basis of this finding.
The present invention therefore relates to 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivatives represented by the following formula [I]: ##STR3## wherein B represents a base selected from the group consisting of purine, azapurine and deazapurine, which may be substituted with halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, amino, alkylamino, hydroxyl, hydroxyamino, aminoxy, alkoxy, mercapto, alkylmercapto, aryl, aryloxy or cyano; and R represents a hydrogen atom or a phosphoric acid residue, and to pharmaceutical compositions, especially antiviral agents, comprising these compounds as active ingredients. Further, the present invention also relates to a process for producing 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivatives represented by the above formula [I], comprising the following 1st to 3rd steps: 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 represented by B 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 sugar moiety of the compound, thereby obtaining a 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivative represented by formula [I]: ##STR6## wherein B, R, R.sub.1, R.sub.2 and R.sub.3 are as defined above.
Furthermore, the present invention relates to a process for producing 9-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)purine derivatives represented by the above formula [I], comprising the following 1st to 4th steps: represented by formula [V], and treating the compound with a nucleophilic reagent by which a fluorine atom can be introduced, thereby obtaining a compound represented by formula [VI]: ##STR7## 2nd Step: a step of selectively de
REFERENCES:
Yoshimura, Tet. Letters 40, 1937, 1999.
Machida Haruhiko
Watanabe Mikari
Yamada Kohei
Yoshimura Yuichi
Berch Mark L.
Yamasa Corporation
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