Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-29
1997-03-18
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514274, A61K 3155, A61K 31505
Patent
active
056123337
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01897 filed on Jul. 13, 1993.
The present invention relates to combinations of antiviral agents. More specifically it is concerned with combinations of 1,3-oxathiolane nucleoside analogues with other antiviral agents, in particular agents effective against HIV. Human immunodefidency virus (HIV) causes a variety of clinical conditions including the acquired immune deficiency syndrome (AIDS) and chronic neurological disorders. Nucleosides such as AZT, ddC and ddl inhibit HIV replication in vitro, and appear to exert their antiviral activity on the virus-encoded reverse transcriptase enzyme after metabolism by the cell to their 5'-triphosphate derivatives.
AZT reduces morbidity and mortality in patients with AIDS. However, HIV infection of cells results in integration of the virus genome into the host chromosome, and so it has been necessary to continue AZT treatment for long periods of time. The consequences of long-term AZT therapy are associated bone-marrow toxicity and the appearance of AZT-resistant variants of HIV-1. Similarly, some AIDS patients treated with ddC develop peripheral neuropathy and ddl has been shown to induce pancreatitis and peripheral neuropathy.
The use of combinations of compounds may give rise to an equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy if synergy between compounds occurs. Lower overall drug doses will possibly also reduce the frequency of occurrence of drug-resistant variants of HIV. Many different methods have been used to examine the effects of combinations of compounds acting together in different assay systems. All of these methods have limitations and for example, some methods have been applied to systems other than those for which they were derived. AZT demonstrates synergistic antiviral activity in vitro in combination with agents that act at HIV-1 replicative steps other than reverse transcription, including recombinant soluble CD4 castanospermine and recombinant interferon alpha. However, it must be noted that combinations of compounds can give rise to increased cytotoxicity. AZT and recombinant interferon alpha have an increased cytotoxic effect on normal human bone marrow progenitor cells.
The compound (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyridmidin-2-one , also known as 3TC is currently undergoing clinical trials for the treatment of conditions associated with infection by HIV.
We have now found that 3TC exhibits unexpected advantages when used in combination with certain non-nucleoside inhibitors of HIV.
There is thus provided in a first aspect of the invention a combination comprising 3TC or a pharmaceutically acceptable derivitive thereof and nevirapine or a pharmaceutically acceptable derivative thereof.
Nevirapine has the chemical name 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,3-b;2.sup.1,3.sup.1 -e][1,4]diazepin-6-one and is also known as BI-RG-587.
3TC will normally be provided substantially free of the corresponding (+)-enantiomer, that is to say no more than about 5% w/w of the (+)-enantiomer, preferably no more than about 2%, in particular less than about 1% w/w will be present.
By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a parent compound or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the parent compound or an antivirally active metabolite or residue thereof.
It will be appreciated by those skilled in the art that 3TC may be modified to provide pharmaceutically acceptable derivatives thereof at functional groups in both the base moiety and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups are included within the scope of the invention. However of particular interest are pharmaceutically acceptable derivatives obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of 3TC include the compounds in which the hydrog
REFERENCES:
Merluzzi et al 1990, Science vol. 250 pp. 1411-1413.
Goldman et al., Proc. Natl. Acad. Sci. USA, vol. 88, No. 15, Aug. 1991, 6863-6867.
Flexner, Curr. Opin. Infect. Dis., vol. 5/6, May 1992, 798-805.
Declercq, AIDS Res. Hum. Retrovirus, vol. 8, No. 2, Feb. 1992, 119-134.
Schinazi et al., AIDS Res. Hum. Retrovirus, vol. 8, No. 6, Jun. 1992, 963-990.
Tisdale et al., Proc. Natl. Acad. Sci. USA, vol. 90, Jun. 1993, 5653-5656.
Glaxo Group Limited
Travers Russell
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