Nucleoside derivatives and process for preparing the same

Details Nucleoside derivatives and process for preparing the same Nucleoside derivatives and process for preparing the same

1998-05-01

2000-06-06

Wilson, James O.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 2711, 536 2721, 536 2722, 536 284, 536 285, 544253, 544264, 544269, C07H 1906, C07H 1916, C07H 1967, C07H 1673, C07H 19167

Patent

active

060720514

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel nucleoside derivatives having anti-viral activity, in particular, anti-HBV (anti-Hepatitis-B Virus) activity, represented by the following general formula (I): ##STR2## wherein R.sub.1 represents hydrogen, phosphate, phosphonate, alkyl or acyl, R.sub.2 represents alkoxy or halogen, R.sub.3 represents substituted or non-substituted pyrimidine or purine base, and X represents O, S, SO or SO.sub.2 ; pharmaceutically acceptable salts thereof, and processes for preparation thereof.
As a compound represented by general formula (I) has two or more asymmetric carbon atoms, the compound of the present invention represented by general formula (I) exists as a cis isomer as general formula (II) or trans isomer as general formula (III), or a mixture thereof. ##STR3##
In the formula, R.sub.1, R.sub.2, R.sub.3 and X are defined as above.
Each cis or trans isomer may exist as an optically pure isomer or as a mixture, i.e. racemic mixture. All isomers and mixture thereof mentioned above are included in the compounds of the present invention.


BACKGROUND ART

HBV is a lethal virus which causes acute or chronic viral hepatitis in human body and finally makes progress to liver cancer. Though the vaccines against the virus have been developed, a therapeutic agent has been hardly developed yet. Up to the present, Ara-A or interferon has been partially used for the treatment of hepatitis B, but both agents have many problems in their activity and safety.
Recently, a variety of nucleoside compounds having anti HBV activity have been reported.
For example, it is reported that 2',3'-dideoxy-3'-thiacytidine [Proc. Natl. Acad. Sci. USA, 88, 8495 (1991)], 5-fluoro-2', 3'-dideoxy-3'-thiacytidine [Proc. Natl. Acad. Sci. USA, 88, 8495 (1991)], 2', 3'-dideoxy-.beta.-L-5-fluorocytidine [Biochem. Pharm., 47, 171 (1994)], and 2', 3'-dideoxy-.beta.-L-cytidine [Biochem. Pharm., 47, 171 (1994)] have anti-HBV activity.
However, these compounds leave much to be improved in view of their activity and safety, whereby development of novel compounds having more activity and less toxicity has still been required.


DICLOSURE OF THE INVENTION

The object of the present invention is to provide novel compounds having excellent anti-HBV activity with low toxicity, which are represented by general formula (I), and processes for preparation thereof.
In the compounds of the present invention, which are represented by general formula (I), R.sub.1 represents hydrogen, phosphate, phosphonate, alkyl or acyl, R.sub.2 represents alkoxy or halogen, R.sub.3 represents pyrimidine or purine base which have natural origin, or their derivatives in which some portions of the base have been modified, and X represents O, S, SO or SO.sub.2, as defined above.
Among the compounds represented by general formula (I), more preferable are the compounds in which R.sub.1 represents hydrogen, phosphate or phosphonate, R.sub.2 represents alkoxy or halogen, R.sub.3 represents groups represented by the following formulas, and X represents O or S. ##STR4##
In the above formulas, R.sub.4 represents hydrogen, saturated or unsaturated alkyl which may have (a) substituent(s), or halogen, R.sub.5 represents hydrogen, hydroxy, alkoxy, saturated or unsaturated alkyl which may have (a) substituent(s), or saturated or unsaturated acyl which may have (a) substituent(s), R.sub.6 represents hydrogen, cyano, carboxyl, alkoxycarbonyl, carbamoyl or thiocarbamoyl, and R.sub.7 and R.sub.8 each represents hydrogen, hydroxy, amino or halogen.
Among the compounds represented by general formula (I), the most preferable are the compounds in which R.sub.1 represents hydrogen, phosphate or phosphonate, R.sub.2 represents alkoxy or halogen, R.sub.3 represents groups represented by the following formulas, and X represents O or S. ##STR5##
In the above formulas, R.sub.9 represents hydrogen, methyl, hydroxymethyl, methoxymethyl, methylthiomethyl, trifluoromethyl, ethyl, propyl, cyclopropyl, vinyl, 2-bromovinyl, fluoro, chloro, bromo or iodo, R.sub.10 represe

REFERENCES:
Hammerschmidt, F., et al., "Convenient Route to D-apio-.beta.-D-furanosyl- and 2'-deoxyapio-.beta.-D-furanosyl Nucleosides," Chemical Abstracts, 123: 257236f (Nov. 6, 1995).
Doong, S.L., et al., "Inhibition of the Republican of Hepatitis B Virus In Vitro by 2', 3'-dideoxy-3'-thiacytidine and Related Analogues," Proc. Nat'l. Acad. Sci., vol. 88, pg/ 8495-8499 (Oct. 1991).
Lin, T.S., et al., "Antiviral Activity of 2', 3'-dideoxy-.beta.-L-5-Fluourcytidine (.beta.-L-FddC) and 2', 3'-dideoxy-.beta.-L-Cytidine (.beta.-L-ddC) Against Hepatitis B Virus and Human Immunodeficiency Virus Type 1 In Vitro," Biochemical Pharmacology, vol. 47, No. 2, pp. 171-174 (1984).

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