Anti-HIV agent

Details Anti-HIV agent Anti-HIV agent

1996-05-06

1998-06-02

Travers, Russell

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514375, A61K 3142

Patent

active

057600651

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel anti-human immunodeficiency virus (HIV) agent which has HIV proliferation inhibitory activity.


BACKGROUND ART

HIV is the causative virus of acquired immune deficiency syndrome (AIDS). The virus infects helper T cells and proliferates therein to rupture the cells. As a result, cell-mediated immune deficiency is induced, which leads to the manifestation of AIDS.
Azidothymidine (AZT) and some other substances are currently known as anti-HIV agents.
The life cycle of HIV comprises binding, entry, uncoating, reverse transcription, integration, transcription, protein synthesis, modification, assembly, trafficking, and budding. The action of AZT as an anti-HIV agent is attributed to inhibition of reverse transcription peculiar to viruses.
On the other hand, it is known that Mycalolide B represented by formula (Ia): ##STR2## 67th Annual Meeting of the Japanese Pharmacological Society (1994)!, and Meeting of the Japanese Society of Veterinary Science (1992)!.
It is desired to develop anti-HIV agents which are excellent in effectiveness and have little side effect.


DISCLOSURE OF THE INVENTION

The present inventors selected the step of intracellular transportation (trafficking) of virus particles in the life cycle of HIV as the step at which the metabolism of HIV can be inhibited without affecting the metabolism of host cells. As a result of search, it has been found that the compounds having the structure shown below inhibit the trafficking of HIV and thus inhibit the proliferation of HIV, and the present invention has been completed.
The present invention relates to an anti-human immunodeficiency virus (HIV) agent which comprises, as an active ingredient, a compound represented by formula (I): ##STR3## wherein R.sup.1 represents ##STR4## or carboxymethyl; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents lower alkanoyl or lower alkyl; R.sup.4a represents hydrogen, and R.sup.4b represents ##STR5## or R.sup.4a and R.sup.4b together represent oxygen; R.sup.5 represents hydrogen, hydroxy, or lower alkoxy; R.sup.6 represents hydrogen, carbamoyl, or lower alkanoyl; R.sup.7a represents hydrogen, and R.sup.7b represents hydroxy, or R.sup.7a and R.sup.7b together represent oxygen; R.sup.8 represents hydrogen, lower alkyl, or hydroxymethyl; R.sup.9 represents lower alkoxy or lower alkyl; X.sup.1 represents hydrogen or hydroxy, and X.sup.2 represents hydrogen, or X.sup.1 and X.sup.2 together represent a single bond; and Y.sup.1 represents lower alkoxycarbonyl, and Y.sup.2 represents carbamoyl, or Y.sup.1 and Y.sup.2 together represent, as --Y.sup.1 --Y.sup.2 --, ##STR6##
The present invention also relates to a method for treating AIDS by administering an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
Further, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the preparation of pharmaceutical compositions useful for treating AIDS.
In the definitions of the groups in formula (I), the lower alkyl and the lower alkyl moiety of the lower alkanoyl, the lower alkoxy and the lower alkoxycarbonyl mean a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
Representative examples of Compound (I) are shown in Table 1 with structural formulae.


TABLE 1 (1) __________________________________________________________________________ ##STR7## Compound R.sup.2 R.sup.3 R.sup.4a R.sup.4b R.sup.5 __________________________________________________________________________ Mycalolide A CH.sub.3 CH.sub.3 CO O OCH.sub.3 Mycalolide B CH.sub.3 CH.sub.3 CO H ##STR8## OCH.sub.3 Mycalolide C CH.sub.3 CH.sub.3 CO H ##STR9## OCH.sub.3 Halichondramide H CH.sub.3 O H Jaspisamide B H CH.sub.3 O OH Jaspisamide C CH.sub.3 CH.sub.3 O H _________________________________

REFERENCES:
The 67th Annual Meeting of the Japanese Pharmacological Society (1994) 263p pp. 3-65 Masahi et al.
The 67th Annual Meeting of the Japanese Pharmacological Society (1994) 205p pp. 2-157 Botkyung et al.
The 113th Meeting of the Japanese Society of Veterinary Science (1992) 94.
Tetrahedron Letters, vol. 30, No. 21 pp. 2809-2812 (1989) Fusetari et al.
J. Org. Chem, Vo. 54, pp. 1360-1363 (1989).
J. Am. Chem. vol. 108, pp. 847-849 (1986).
J. Am. Chem. Soc. vol. 108, pp. 846-847 (1986).
J. Org. Chem. vol. 53, pp. 5014-5020 (1988).
Journal of National Products, vol. 56, No. 5, pp. 787-791 (1993).
Tetrahedron Letters, vol. 28, No. 25, pp. 2809-2812 (1987).

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