Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-12-22
1997-09-02
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, 530323, 530330, 530331, A61K 3807, A61K 3808, C07K 510
Patent
active
056631391
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to substances which inhibit the action of retroviral proteases, to a process for their preparation and to their use, and also to pharmaceuticals containing these substances.
The etiological cause of acquired immune deficiency syndrome (AIDS) is the so-called human immunodeficiency virus (HIV) (F. Barre-Sinoussi et al., Science 220, (1983), 868-870; R. C. Gallo et al., Science 224, (1984), 500-502; R. C. Gallo and L. Montagnier, Scient. Am. 259(4), (1988), 40-48). HIV is a retrovirus and is included in the lentivirus group (M. A. Gonda, F. Wong-Staal and R. C. Gallo, Science, 227, (1985), 173; P. Sonigo et al., Gell, 42, (1985), 369).
The AIDS epidemic has by now spread, to a greater or lesser extent, to virtually all countries. The World Health Organization (WHO) estimates the number of infected adults worldwide to be about 8-10 million (Weekly Epidemiological Record, World Health Organization, Geneva, 1991, 66, 353-357). Of these, more than 1 million already have AIDS and a further million have developed serious infection-related diseases. 1 million children have been born who have been infected by their mothers and, of these children, about half have already developed AIDS or have died. WHO calculates that in the year 2000 roughly 30-40 million people will be infected.
While the sole substance hitherto licensed for the indication AIDS, zidovudine (AZT), is able to prolong patient life in many cases, it possesses serious, toxic side effects which in many cases require therapy to be discontinued. Strains of HIV have already been discovered which exhibited significantly less sensitivity to AZT and thus gave rise to the development of resistance. Further approaches to HIV therapy are therefore urgently required.
In analogy with proteins of other retroviruses, HIV proteins are initially translated as long, precursor gag, pol and env polyproteins (C. Dickson et al., in RNA Tumor Viruses (Editors: R. Weiss, N. Teich, H. Varmus and J. Coffin) 2nd Ed., revised, pages 513-648, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.) and are only subsequently processed proteolytically to form the structural proteins (p17 (MA), p24 (CA), p7 (NC) and p6), the enzymes (protease (PR), reverse transcriptase (RT) and integrase (IN)), and the coat proteins (gp120 (SU) and gp41 (TM)) (Nomenclature: J. Leis et al., J. Virol, 62, (1988), (1808-1809)). It is assumed that the cleavage of the gag and pol polyproteins is brought about by a virally encoded protease. Mutations within the region encoding the protease give rise to non-infectious virus particles (N. E. Kohl et al. Proc. Natl. Acad. Sci. USA 85, (1988), (4686-4690)).
The HIV protease is composed of 99 amino acids and evidently excises itself out of the pol polyprotein by hydrolyzing the two Phe-Pro bonds in positions 68-69 and 167-168, respectively (M. C. Graves, J. J. Lim, E. P. Heimer and R. A. Kramer Proc. Natl. Acad. Sci. USA 85 (1988); 2449-2453; J. Hansen, S. Billich, T. Schulze, S. Sukrow and K. Molling, EMBO J. 7 (1988), 1785-1791; E. P. Lillehoj et al., J. Virology 62 (1988) 3053-3058; J. Schneider and S. B. H. Kent, Cell 54 (1988) 363-368).
Some inhibitors of the HIV protease are already known from the literature. The first representative was pepstatin A, which has an IC.sub.50 value of approximately 0.5 mmol/l (I. Katoh, T. Yasunaga, Y. Ikawa and Y. Yoshinaka, Nature, 329, (1987), 654-656). Since then, some other inhibitors have been described (see, for example, B. A. G. Tomaselli et al., Chim. Oggi 9(5), (1991), 6027, EP 0428849, EP 0435059).
A novel structural class has now been found which is highly active in inhibiting the HIV protease in an enzyme test.
The present invention relates to compounds of the formula ##STR2## c1.1) in which Q is a radical of the formula IIa or IIb ##STR3## Y is oxygen or sulfur, and A is a radical of the formula IV and A* is a radical of the formula IV*, unnatural amino acid, azaamino acid or imino acid; ##STR4## and in which R.sup.1 and R.sup.1 *, independently of each other, a1) are and which i
REFERENCES:
Fox, J.L., "No winners against AIDS", Bio/Technology, vol. 12, p. 128. Feb. 1994.
I. Katoh et al., Nature, "Inhibition Of Retroviral Protease Activity By An Aspartyl Proteinase Inhibitor", vol. 329, No. 6140, pp. 654-656, Oct., 1987.
Stowasser et al. Tetrahedron Lett. vol. 33 No. 44 pp. 6625-6628 (Oct. 27, 1992).
Budt Karl-Heinz
Li Jian-Qi
Peyman Anuschirwan
Stowasser Bernd
Gupta Anish
Hoechst Aktiengesellschaft
Tsang Cecilia J.
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