Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-05-20
2000-12-19
Barts, Samuel
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514510, 514114, 514311, 514533, 514562, 560 41, 560 24, 546169, A61K 31195
Patent
active
06162828&
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a compound that inhibits cysteine proteases such as interleukin-1.beta. converting enzyme (ICE), cathepsin B and cathepsin L, and more specifically to a therapeutic drug for various infectious diseases, immune diseases, bone diseases, neurologic diseases, tumors, inflammatory diseases etc.
BACKGROUND ART
In mammals, interleukin-1.beta. (IL-1.beta.) is produced and released mainly by peripheral monocytes, such as macro-phages; interleukin-1.beta. converting enzyme (ICE), an enzyme that converts IL-1.beta. precursor protein (33 KD) to mature IL-1.beta. (17 KD), cleaves the Asp.sup.116 -Ala.sup.117 site in the precursor protein [N. A. Thornberry et al., Nature, Vol. 356, p. 768 (1992)]. IL-1.beta. is a cytokine having various functions, especially in the cells involved in inflammation or bone diseases. For example, it stimulates polynuclear leukocyte infiltration into inflammatory sites, increases the chemotaxis of macrophages etc., attracts them to the inflammatory sites, and induces their production of various prostaglandins etc., thereby changing the pathologic state. IL-1.beta. also exhibits potent action on bone-associated cells. In particular, it stimulates osteoclasts to considerably accentuate bone resorption. This cytokine is also profoundly involved in rheumatoid arthritis.
Recent evidence suggests the involvement of ICE in nerve cell apotosis [V. Gazliadni et al., Science, Vol. 264, pp. 820-828 (1994)].
On the other hand, cathepsin B is assumed to play a role in antigen processing in antigen-presenting cells [Y. Matsunaga, FEBS Letters, Vol. 324, pp. 325-330 (1994)]. In addition, cathepsin L is reportedly an important enzyme that decomposes bone substrate during bone resorption by osteoclasts [E. Kakegawa et al., FEBS Letters, Vol. 321, pp. 247-250 (1994)].
These enzymes are cysteine proteases especially associated with infectious diseases, immune diseases, bone diseases etc.; research has been undertaken on inhibitors for respective enzymes. With regard to ICE inhibitors, for example, since publication of the first report of Ac-Tyr-Val-Ala-Asp-H [N. A. Thornberry et al., Nature, Vol. 356, p. 768 (1992)], a peptide-derived inhibitor containing 3-amino-4-oxobutanoic acid at its C-terminal, peptide type inhibitors containing various aspartic acid derivatives, such as Ac-Tyr-Val-Ala-Asp-CH.sub.2 OC(O)Ar [N. A. Thornberry et al., Biochemistry, Vol. 33, pp. 3934-3940 (1994)], .gamma.-pyron-3-acetic acid [M. J. Salvatore et al., Journal of Natural Products, Vol. 57, pp. 755-760 (1994)] etc. have been reported. As concerns cathepsin B or L inhibitors, peptidyl (acyloxy) methyl ketones are reported by D. Bromme et al. in Biological Chemistry Hoppe-Seyler, Vol. 375, pp. 343-347 (1994) and by B. M. Wazner et al. in the Journal of Medicinal Chemistry, Vol. 37, pp. 1833-1840 (1994); norleucinal-containing peptide-derived inhibitors are reported in Japanese Patent Unexamined Publication No. 155764/1993; peptidyl phenoxymethyl ketones are reported in WO-9404172; leucinal-containing peptide-derived inhibitors are reported in Japanese published unexamined patent application No. 202170/1992; epoxysuccinic acid derivatives are reported in Japanese published unexamained patent application No. 304075/1990; and norleucinal-containing peptide-derived inhibitors effective against bone diseases are reported in Japanese published unexamined patent application No. 268145/1990. Also, Japanese publication of translations of International patent application 510986/1994 reports on a peptide compound having a glutamic acid derivative at its C-terminal as a picornavirus protease inhibitor; actually synthesized compounds as such include the following: ##STR5##
DISCLOSURE OF INVENTION
However, even these investigators have failed to provide a practically applicable therapeutic agent.
The object of the present invention is to provide a therapeutic drug that acts against various infectious diseases, immune diseases, bone diseases, neurologic diseases, inflammatory diseases and t
REFERENCES:
patent: 4178371 (1979-12-01), Morgan
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Fujisawa Yukio
Fukuda Tsunehiko
Watanabe Hiroyuki
Barts Samuel
Takeda Chemical Industries Ltd.
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