Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-11
2000-03-07
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514266, 514274, 544243, 544244, 544264, 544265, 544276, 544277, 544309, 544313, 544317, 549 13, 549 21, 549274, 549378, 556437, A61K 3152, C07D47318, C07D47340, C07D47330
Patent
active
060340878
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel nucleoside derivatives represented by following general formula (I); ##STR3## wherein, R.sub.1 is hydrogen, phosphate or phosphonate group, R.sub.2 is substituted or unsubstituted pyrimidine or purine base, and Z is S, SO, SO.sub.2, O or C; showing excellent anti-HBV effect, and the process for preparing thereof.
Each compound represented by the general formula (I) has at least two chiral centers, and thus the optical isomers or mixtures thereof are also included in the present invention.
BACKGROUND ART
Hepatitis B Virus(HBV) is a lethal virus which causes acute/chronic Hepatitis in human body, and finally developes the disease into liver cancer. At present, a remedy for treating the viral disease does not exist though vaccines against the virus have been developed. Up to the present, Ara-A, interferon or the like has been used in treatment of Hepatitis B, however, there are many problems in view of effectiveness and safety.
Recently, various nucleoside compounds having anti-HBV activity have been reported. For example, 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-fluoro-cytidine[Biochem. Pharm., 47, 171(1994)), 2',3'-dideoxy-.beta.-L-cytidine[Biochem. Pharm., 47, 171(1994)], etc. are reported as showing anti-HBV activity.
However, these compounds reported up to the present have substantial need to be improved in view of effectiveness and safety. Therefore, it is required to develop novel compounds having excellent effectiveness with low toxicity.
DISCLOSURE OF INVENTION
The object of the present invention is to provide such novel compounds represented by the above general formula (I) showing excellent anti-HBV activity with low toxicity, and processes for preparing thereof.
The compounds of the present invention represented by general formula (I) are compounds of which R.sub.1 is hydrogen, phosphate or phosphonate group, R.sub.2 is pyrimidine or purine base of natural origin or slightly modified pyrimidine or purine base of natural origin, and Z is S, SO, SO.sub.2, O or C.
More desirable compounds among the compounds of general formula (I) are those of which R.sub.1 is hydrogen, phosphate or phosphonate, R.sub.2 is selected from the groups represented by following formula, and Z is S, O or C. ##STR4##
In the formula, R.sub.3 is hydrogen, methyl, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxymethyl or 2-bromovinyl group, R.sub.4 is hydrogen or acyl group, R.sub.5 is hydrogen, fluoro or methyl group, and R.sub.6 is hydroxy, chloro or amino group.
The compound represented by formula (I) of the present invention can be obtained by reacting the compound represented by following formula (II); ##STR5## wherein, R.sub.7 is hydrogen or hydroxyl-protecting group, preferably alkyl, acyl or substituted silyl group, more preferably benzyl, acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl group, L is aromatic or nonaromatic acyl, halo or alkoxy group, preferably acetyl group, and Z is S, SO, SO.sub.2, O or C, with appropriate base.
More specifically, the compound (I) is obtained by condensating the compound (II) with a base protected by silyl group in the presence of Lewis acid catalyst. Desirable solvents used in the reaction include methylene chloride, 1,2-dichloroethane and aceonitrile. Desirable Lewis acid catalyst includes tin chloride and trimethylsilyl triflate.
The 1,4-oxathiane compounds, kinds of compounds represented by general formula (II) used as starting material for the preparation of the compounds of general formula (I) also are novel compounds, and can be prepared according to the following reaction scheme. ##STR6##
According to a preferred embodiment of the present invention, compound (XII), a kind of compound (II), can be prepared as follows:
Epichlorohydrin (III) is reacted with, alcohol in the presence of base to provide epoxy compound (IV), which is hydrolyse
REFERENCES:
patent: 5736549 (1998-04-01), Beasley
Jung, Tet Letters 32(14)5717 1991.
Prisbe, J. Med. Chem 29, 2445 1986.
Vuilhorgne, Heterocycles 11, 495 1978.
Van Aerchot, Nucleoside Nucleotides 10, 591-2 1991.
Antiviral Activity of 2',3'--dideoxy-.beta.-L-5-fluorocytidine (.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, Tai-Shun Lin et al., Biochemcial Pharmacology, vol. 47, No. 2, pp. 171-174, 1994.
Inhibition of the replication of hepatitis .beta. virus in vitro by 2',3'-dideoxy-3'-thiacytidine and related analogues, Shin-Lian Doong et al., Proc. Natl. Acad. Sci. USA, vol. 88, pp. 8495-8499, Oct. 1991.
Ahn Soon Kil
Cha Kyung Hoi
Choi Sung Jo
Chung Koo Hun
Jeong Byeong Seon
Berch Mark L.
Chong Kun Dang Corp.
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