Coumarin derivatives as retroviral inhibitors

Details Coumarin derivatives as retroviral inhibitors Coumarin derivatives as retroviral inhibitors

1995-06-22

1998-03-03

Dees, Jose C.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549289, 549384, C07D31178, C07D40700, C07D49312

Patent

active

057236313

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/US 93/12500 filed Dec. 22, 1993.


FIELD OF INVENTION

The present invention relates to compounds which inhibit retroviral infection. The present invention also relates to the synthesis of said compounds and the use of such compounds in clinical applications, such as antiviral therapy. More specifically, this invention relates to certain inophyllum, calanolide and other coumarin derivatives which have antiviral activity.


BACKGROUND OF THE INVENTION

The human immunodeficiency virus (HIV), a retrovirus, is generally accepted as the causative agent of AIDS. Like all retroviruses, a typical retroviral sequence encodes for three genes, gag-pol-env, which actually give rise to multiple proteins by processing reactions. The gag gene gives rise to the protein components of the nucleoprotein core of the virion. The env gene encodes for components of the viral envelope, which also sequesters components from the host cell's cytoplasmic membrane. The pol gene encodes the enzyme reverse transcriptase (RT). Because retroviruses encode their genetic information as RNA, they must undergo reverse transcription of their viral RNA into a DNA copy, which is then integrated into the genome of a host cell. Since mammalian cells do not need RT, this enzyme is an inviting target in a search for anti-viral compounds.
The current AIDS drugs, such as AZT and ddI, are nucleoside analogs which inhibit RT. Although useful, the utility of AZT and related drugs is limited by at least two occurences. The first is that biological resistance often develops to these nucleoside drugs when they are used continuously. The other is that long-term use can be complicated by toxic side effects (Richman et at., N Engl J Med, 317:192-197 (1987)). As a result, non-nucleoside inhibitors of RT have been identified, e.g. , (commonly referred to as TIBO), but RT resistance can develop against TIBO compounds as well.
It has been found that some natural products and organisms are potential sources for chemical molecules having biological activity of great diversity, e.g., anti-viral, anti-tumor and anti-fungal properties. The calanolides, a group of natural products from several tropical plants of the genus Calophyllum, are characterized by coumarin, chromane, and chromene ring systems assembled about a phloroglucinol core. Polonsky, J., Bull. Soc. Chim. Fr. 914 (1956); Polonsky, J. et al., Bull. Soc. Chim. Fr, 929 (1958); Stout, G. H., et al., J. Org. Chem. 29; 3604 (1964); Stout, G. H., et al. J. Org. Chem. 33:4191 (1968); Gunasekera, S. P., et al. J. Chem. Soc. Perkin I. 1505 (1977); Dahrmaratne, H. R. W., et al. Phytochemistry. 24:1553 (1984); Kawazu, K., et al. Bull Inst. Chem. Res. Kyoto Univ, 50:160 (1972); Calanolide A (20) was recently identified as a potent inhibitor of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). Kashman, Y., et al. J. Med. Chem. 35:2735 (1992); As with other non-nucleoside HIV-1 RT inhibitors such as TIBO and nevirapine, calanolide-resistant RT mutants have been found. Boyer, P. L., et al. J. Virology, 67:2412 (1993); However, the calanolides differ from the other non-nucleosides in the distinct pattern of amino acid changes in RT required to confer resistance, indicating that the RT binding sites for these compounds are overlapping but not identical. (Kohlstaedt, L. A., et al. Science 256:1783 (1992)). Further study of calanolide analogues and their RT binding site could therefore aid in identifying drugs or drug combinations less prone to eliciting viral resistance. It is thus an object of the present invention to identify and produce compounds which selectively inhibit retroviral replication presumably due to inhibition of reverse transcriptase.


SUMMARY OF INVENTION

In one aspect, the present invention is a compound represented by the structure: ##STR2## wherein R.sub.1 is H, acyl, COCHR.sub.5 NR.sub.6 R.sub.7,P(O)(OH).sub.2 or S(O)(OH).sub.2 ; R.sub.6 and R.sub.7 are independently selected from the group consisting of H and C.sub.1-6 alkyl; and R.sub.6 and R.sub.7 ca

REFERENCES:
patent: 5489697 (1996-02-01), Boulanger et al.
Journal of Medicinal Chemistry, vol. 35, No. 15, Jul. 24, 1992, Kashman et al., "The Calanolides, a Novel HIV-Inhibitory Class of Coumarin Derivatives from the Tropical Rainforest Tree, Calop;hyllum lanigerum", pp. 2735-2743.
J.C.S. Perkin I, 1977, G;unasekera et al., "Chemical Investigation of Ce;ylonese Plants, Part 27, Extractives of Calophyllum cuneifolium Thw. and Calophyllum soulattri Burm. f. (Guttiferae)", pp. 1505-1511 1977.
Tetrahedron Letters No. 27, 1972, Gautier et al., "Structure of Calophynic Acid, a Novel Constituent of Calophyllum inophyllum", pp. 2715-2718.
Phytochemistry, vol. 25, No. 2, 1986, Bandara et al., "Two Chemically Distinct Groups of Calophyllum Species from Sri Lanka", pp. 425-428.
Bull. Inst. Chem. Res., Kyoto Univ., vol. 50, No. 3, 1972, Kawazu et al., "Piscicidal Constituents of Calophyllum Inophyllum", pp. 160-167.

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