Use of dideoxy nucleoside analogues in the treatment of viral in

Details Use of dideoxy nucleoside analogues in the treatment of viral in Use of dideoxy nucleoside analogues in the treatment of viral in

1995-04-12

2000-12-05

Wilson, James O.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 50, 514885, 514894, 536 2714, 536 282, A61K 3170, A01N 4304, C07H 1900

Patent

active

06156737&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to nucleoside analogues and their use in medicine. More specifically the invention is concerned with dideoxy nucleoside analogues, pharmaceutical formulations thereof and the use thereof in the treatment of viral infections.
The only compounds currently approved for the treatment of conditions caused by HIV are D-3'-azido-3'-deoxythymidine (AZT, zidovudine, BW 509U) and .beta.-D-2',3'-dideoxyinosine (ddI, didanosine) which has been approved for use in patients who are intolerant to AZT. Also, .beta.-D-2',3'-dideoxycytidine (ddC) has received approval only in combination with AZT. The above compounds derived from physiologically important nucleosides have significant side-effect liability and dose-limiting toxicity. Additionally, resistance to AZT, ddC and ddI has emerged (K. J. Connolly and S. M. Hammer, Antimicrob. Agent. Chemother. 1992; 36, 245-254).
There is, in consequence, a continuing need to provide compounds which are effective against HIV but with a concommitant significantly better therapeutic index (i.e. more selective).
The compounds mentioned above are all used in the form of their natural enantiomers (D sugars). The corresponding unnatural enantiomers of AZT (L-AZT) and ddI (.beta.-L-ddI) have been found to be inactive against HIV (J. Wengel et al. J. Org. Chem, 1991; 56, 3591-3594; and M. M. Mansuri et al. BioMed. Chem. Lett. 1991; 1, 65-68) whereas the unnatural enantiomer of ddC (.beta.-L-ddC) was reported to be inactive or weakly active against HIV (M. Okabe & al. J. Org. Chem. 1988; 54, 4780-4786 and M. M. Mansuri & al. Bio Med. Chem. Lett. 1991; 1, 65-68) with no mention of selectivity. Furthermore, there has been no report in the literature about the activity of .beta.-L-ddC against the Hepatitis B virus (HBV).
We have now found that, surprisingly, .beta.-L-ddC, the unnatural (-)-enantiomer of ddC is active against HIV with unexpectedly high selectivity.
Furthermore, we have also found, unexpectedly, that .beta.-L-ddC possesses excellent activity against Hepatitis B virus.
Moreover, the 5-fluoro analogue of ddC (5F-ddC) has been described and tested in the form of its natural enantiomer (.beta.-D-5F-ddC) and found to be active against HIV (Kim et al., J. Med. Chem. 1987: 30, 862-866). However, its activity against HBV has not been reported.
We have found that the natural enantiomer of 5F-ddC (.beta.-D-5F-ddC) is active against against HBV.
In addition, there has been no reports of the activity of its corresponding unnatural enantiomer (.beta.-L-5F-ddC) against HIV or HBV.
We have also found, unexpectedly, that the unnatural enantiomer of 5F-ddC (.beta.-L-5F-ddC) possesses activity against HIV and HBV below its cytotoxic concentration.


SUMMARY OF THE INVENTION

There is thus provided, in a first aspect of the invention, the use of the (-)-enantiomer of ddC (.beta.-L-ddC) and pharmaceutically acceptable derivatives thereof in the treatment of HIV infection.
There is also provided, in a second aspect of the invention, the use of .beta.-L-ddC and pharmaceutically acceptable derivatives thereof in the treatment of HBV infections.
There is further provided, in a third aspect of the invention, the use of .beta.-D-5F-ddC and pharmaceutically acceptable derivatives thereof in the treatment of HBV infections.
Furthermore, there is provided, in a fourth aspect of the invention, the use of .beta.-L-5F-ddC and pharmaceutically acceptable derivatives thereof for the treatment of HIV infections.
There is also provided, in a fifth aspect of the invention, the use of .beta.-L-5F-ddC and pharmaceutically acceptable derivatives thereof for the treatment of HBV infections.
These compounds are represented by formula (I): ##STR1## wherein X is hydrogen or fluoro. The compounds of formula (I) are racemic mixtures of the two enantiomers of formulae (Ia) and (Ib): ##STR2##
The (-)-enantiomer of ddC has the absolute configuration of 1'S at the carbon bearing the base and 4'R at the carbon bearing the CH.sub.2 OH moiety. It has the absolute stereochemistry of the compound of form

REFERENCES:
patent: 4724232 (1988-02-01), Rideout et al.
patent: 4788181 (1988-11-01), Driscoll et al.
patent: 5039667 (1991-08-01), Tyrrell et al.
patent: 5179104 (1993-01-01), Chu et al.
patent: 5409906 (1995-04-01), Datema et al.
patent: 5631239 (1997-05-01), Lin et al.
patent: 5744596 (1998-04-01), Masour et al.
patent: 5756706 (1998-05-01), Masour et al.
J. Balzarini et al., "Potent and Selective Anti-HTLV-III/LAV Activity of 2', 3'-Dideoxycytidinene, The 2', 3'-Unsaturated Derivative of 2', 3'-Unsaturated Derivative of 2', 3'-Dideoxycytine," Biochem. Biophys. Res. Commun., 140, pp. 735-742 (1986).
S. Doong et al., "Inhibition of the Replication of Hepatitis B Virus In Vitro By 2', 3'-Dideoxy-3'-Thiacytidine and Related Analogues," Proc. Natl. Acad. Sci., 88, pp. 8495-8499 (1991).
F.A. Farraye et al., "Preliminary Evidence That Azidothymidine Does Not Affect Hepatitis B Virus Replication in Acquired Immunodeficiency Syndrome (AIDS) Patients," J. Med. Virol., 29, pp. 266-267 (1989).
H. Haritani et al., "Effect of 3'-Azido-3'-Deoxythymidine On Replication of Duck Hepatitis B Virus In Vivo and In Vitro," J. Med. Virol., 29, pp. 244-248 (1989).
C. Kassianides et al., "Effects of 2', 3'-Dideoxycytidine On Duck Hepatitis B Virus," Gastroenterology, 94, Abstract A552 (1988).
C. Kassianides et al., "Inhibition of Duck Hepatitis B Virus Replication by 2', 3'-Dideoxycytidine: A Potent Inhibitor of Reverse Transcriptase," Gastroenterology, 97, pp. 1275-1280 (1989).
C. Kim et al., "Potential Anti-AIDS Drugs: 2', 3'-Dideoxycytidine Analogues," J. Med. Chem., 30, pp. 862-866 (1987).
M. Mansuri et al., "1-(2, 3-Dideoxy-.beta.-D-glycero-pent-2-enofuranosyl) thymine. A Highly Potent and Selective Anti-HIV Agent," J. Med. Chem., 32, pp. 461-466 (1989).
H. Mitusya et al., "Inhibition of The In Vitro Infectivity and Cytopathic Effect of Human T-Lymphotrophic Virus Type III/Lymphadenopathy-Associated Virus (HTLV-III/LAV) by 2', 3'-Dideoxynucleosides," Proc. Natl. Acad. Sci., 83, pp. 1911-1915 (1986).
Siddiqui et al., "Chemistry and Anti-HIV Properties of 2'-Fluoro-2', 3'-dideoxyarabinofuranosylpyrimidines," J. Med. Chem., 35, pp. 2195-2201 (1992).
S. Suzuki et al., "Inhibition of Duck Hepatitis B Virus Replication By Purine 2', 3'-Dideoxynucleosides," Biochem. Biophys. Res. Commun., 156, pp. 1144-1151 (1988).
T. Yokota et al., "Comparative Activities of Several Nucleoside Analogs Against Duck Hepatitis B Virus In Vitro," Antimicrob. Agents Chemotherap., 34, pp. 1326-1330 (1990).
M. Baba et al., "Both 2', 3'-Dideoxythymidine and its 2', 3'-Unsaturated Derivative (2', 3'-Dideoxythymidinene) are Potent and Selective Inhibitors of Human Immunodeficiency Virus Replication In Vitro", Biochem. Biophys. Res. Commun., 142, pp. 128-134 (1987).
J.W. Beach et al., "Synthesis of Enantiomerically Pure (2'R,5'S)-(-)-1-[2-(Hydroxymethyl)oxathiolan-5-yl]cytosine as a Potent Antiviral Agent Against Hepatitis B Virus (HBV) and Human Immunodeficiency Virus (HIV)", J. Org. Chem., 57, pp. 2217-2219 (1992).
J.M. Cameron et al., "Lamivudine", Drugs of the Future, 18, pp. 319-323 (1993).
C.-N. Chang et al., "Deoxycytidine Deaminase-resistant Steroisomer Is the Active Form of (+/-)-2', 3'-Dideoxy-3'-Thiacytidine in the Inhibition of Hepatitis B Virus Replication", J.Biol. Chem., 267, pp. 13938-13942 (1992).
K.J. Connolly and S.M. Hammer, "Antiretroviral Therapy: Reverse Transcriptase Inhibition", Antimicrob. Agent Chemother., 36, pp. 2686-2692 (1992).
P.A. Furman et al., "The Anti-Hepatitis B Virus Activities, Cytotoxicites, and anabolic Profiles of the (-) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine", Antimicrob. Agents Chemther., 36, pp. 2686-2692 (1992).
P. Herdewijn et al., "3'-Substituted 2', 3'-Dideoxynucleoside Analogues as Potential Anti-HIV (HTLV-III/LAV) Agents", J. Med. Chem., 30, pp. 1270-1278 (1987).
P. Herdewijn and E. De Clercq, "Dideoxynucleoside Analogues as Inhibitors of HIV Replication" Design of Anti-AIDS Drugs, E. De Clercq, Ed., pp. 1

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