Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1992-07-08
1993-09-28
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560104, 560 56, 560100, 560 9, 560 11, 560 11, 562498, 558179, C07C 6976
Patent
active
052488071
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to useful compounds in the field of medicament and the use thereof, in more detail, to endothelin-receptor antagonists comprising triterpene derivatives which are useful for preventing or treating diseases caused by excessive secretion of endothelin, and to novel triterpene derivatives.
BACKGROUND OF THE INVENTION
Endothelin, which has been disclosed by M. Yanagisawa et al. (Nature, 332, P411, 1988), is an endothelium-derived 21-residue vasoconstrictor peptide and supposed that excessive secretion of endothelin may be involved in various diseases, such as hypertention, coronary ischemia, encepholapathy, nephropathy, circulation failure of various organs, and asthma. In Kokai 2-273625, TXA.sub.2 -receptor antagonist and inhibitor of TXA.sub.2 -synthetic enzyme etc. are disclosed as substances capable of inhibiting the increase in intracellular calcium ion concentration, which is caused by excessive secretion of endothelin. However, nobody has reported on substance capable of specifically inhibiting actions caused by endothelin, and so development of such a new compound has been desired.
Some compounds similar to the present compounds in chemical structure have already been known, however, there has been no report on the activity of those compounds as endothelin antagonist. For example, though 27-(3,4-dihydroxycinnamoyl-oxy)-3.beta.-hydroxy-oleanolic acid which is analogous to the compounds of the present invention has been reported by J. M. Koekemore et al. in JOURNAL OF THE SOUTH AFRICAN CHEMICAL INSTITUTE (27, P131, 1974), however, which has no description about the endothelin antagonist activity.
DISCLOSURE OF THE INVENTION
After enormous research, the present inventors have found active substances capable of specifically inhibiting the binding of endothelin to endothelin-receptors, whereby they have completed the present invention. Namely, the present invention provides endothelin-receptor antagonists comprising triterpene derivatives represented by the formula (II): ##STR2## wherein, R.sup.1 is hydrogen or metabolic ester-residue; R.sup.3 is optionally substituted aryl or optionally substituted aromatic heterocycle; X is hydrogen and Y is hydroxy or X and Y may form together oxo; Z is an oxygen or two hydrogen atoms, or the salts thereof.
Triterpene derivatives represented by the formula (I): ##STR3## wherein, R.sup.1 is hydrogen or metabolic ester-residue; R.sup.2 is optionally substituted aryl or optionally substituted aromatic heterocycle; X is hydrogen and Y is hydroxy or X and Y may form together oxo; Z is an oxygen or two hydrogen atoms, provided that R.sup.2 is not 3,4-dihydroxyphenyl when R.sup.1 is hydrogen and Y is hydroxy, and the salts thereof are novel compounds and the present invention provides also these compounds.
In the present specification, "metabolic ester-residue" means ester-residue which decomposes to reproduce carboxylic acids in a living body. "Aryl" means phenyl or (.alpha.-or .beta.-) naphthyl. "Aromatic heterocycle" means aromatic 5-or 6-membered ring which contains one or more atoms selected from oxygen, sulfur, and/or nitrogen and may be condensed with carbon-cycle or another heterocycle, and N-or S-oxide of the aromatic heterocycle is included in this definition. The substituent meant in the phrase "optionally substituted" includes, for example, halogen (F, Cl, Br, I), hydroxy, amino, amino substituted by lower alkanoyl, amino substituted by mono-or di-lower alkyl, carboxy, cyano, nitro, lower alkyl, lower alkoxy, and lower alkanoyloxy. In the case either X or Y is hydroxy, the hydroxy may be in .alpha.-or .beta.-form.
Furthermore, in the case R.sup.1 is hydrogen, the present compounds may form salts with alkali metals (sodium, potassium etc.) alkaline earth metals (calcium, magnesium etc.) ammonia or an organic base (triethylammonium etc.).
The triterpene derivatives of the present invention are able to be extracted from Myrica cerifera L. by the following method for example. Namely, branches of the plant are s
REFERENCES:
Siddigui, S. et al., J. Chem. Soc. Pak. 13(2) 115-19, 1991.
Siddigui S. et al., J. Nat. Prod., 53(5) 1332-6, 1990.
Budzikiewicz, H. et al., Z. Naturforsch, B: Anorg. Chem., Org. Chem. 35B (2), 226-32 1980.
Fujimoto Masafumi
Konoike Toshiro
Mihara Shin'ichi
Nakamura Miharu
Sakurai Kensuke
Killos Paul J.
Shionogi & Co. Ltd.
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