Endothelin, which has been disclosed by M. Yanagisawa et al., Nature, 332, pp. 411, 1988, is an endothelium-derived vasoconstrictor peptide composed of 21 amino acids and is considered to act on various organs and tissues including blood vessel, trachea and the like through activation of specific receptors on cell membrane. It has been supposed that this peptide can cause contradiction of smooth muscles and that an excessive secretion thereof may lead to various circulatory diseases such as hypertension, coronary ischemia, encephalopathy, nephropathy, circulation failure of various organs, and asthma.
It has been reported that TXA.sub.2 -receptor antagonists and inhibitors of TXA.sub.2 -synthetic enzyme and the like can prevent the increase in intracellular calcium-ion level following the excessive secretion of endothelin. However, there have been no reports about specific antagonists against endothelin so far and, therefore, the development of substances capable of inhibiting various actions of endothelin has been demanded. Under the conditions, the present inventors had made intensive study and found that certain triterpene derivatives extracted from Myrica cerifera L. can specifically compete with endothelin for its receptors (PCT/JP/91/01707, W092/12991, U.S. Pat. No. 5,248,807).
The present inventors have made continuous efforts with purposes of developing more endothelin antagonists with higher activity and now found that certain novel triterpene derivatives are useful to achieve said purposes.
Thus, the present invention provides a compound of the formula (I) ##STR2## wherein R.sup.1 is hydrogen or a metabolic ester residue; R.sup.2 is hydrogen or --R.sup.3 --R.sup.4 wherein R.sup.3 is --SO.sub.3 --, --CH.sub.2 COO--, --COCOO--, or --COR.sup.5 COO-- (R.sup.5 is lower alkylene or lower alkenylene), R.sup.4 is hydrogen or lower alkyl or a pharmaceutically acceptable salt thereof.
Although all compounds of formula (I) are highly active endothelin antagonists and useful for purposes of the present invention, those wherein R.sup.1 is hydrogen are preferable and those wherein R.sup.1 is hydrogen and R.sup.2 is --COCH.dbd.CHCO.sub.2 H are more preferable.
For purposes of the present invention, as disclosed and claimed herein, the following terms are defined below.
The term "metabolic ester-residue" in definition fox R.sup.1 means independently an ester-residue which decomposes to reproduce biologically active carboxylic acid in a living body. Examples of metabolic ester-residue include (1-acyloxy) lower alkyl such as picvaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl and the like; (1-alkoxycarbonyloxy) lower alkyl such as 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl and the like; and (5-methyl-1,3-dioxolene-4-yl)methyl and the like.
The term "lower alkylene" means C.sub.1 -C.sub.6 alkylene shown by the formula --(CH.sub.2).sub.n --(n=1-6), preferably C.sub.1 -C.sub.4 alkylene such as methylene, ethylene, trimethylene and the like.
The term "lower alkenylene" means C.sub.1 -C.sub.6 alkenylene such as vinylene, propenylen, butenylene and the like. Preferable groups are those shown by the formula --(CH.dbd.CH).sub.m --(m=1-3).
The term "lower alkyl" in definition for R.sup.4 means straight or branched C.sub.1 -C.sub.6 alkyl such as methyl, ethyl, propyl, t-Butyl. The compounds (I) of the present invention may form salts with alkali metals (sodium, potassium etc.), alkaline earth metals (calcium, magnesium etc.), ammonium or an organic base (triethylammonium, trimethylammonium etc.).
The compounds (I) of the present invention may form salts with inorganic acids (HCl, H.sub.2 SO.sub.4 etc.), organic acids (benzenesulfonic acid, p-toluene sulfonic acid etc.) and the like.
The compounds (I) of the present invention having endothelin receptor antagonistic activities are novel. Although the preparation of them can be carried out using methods known in the art, it can be done efficiently according to the following method.
Thus, the compounds (I) can be prepared by reacting a compound of the formula (V): ##STR3## which has been disclosed in WO92/12991 with a corresponding aldehyde under reaction conditions of Horner-Emmons reaction in the presence of an amine such as triethylamine together with cesium carbonate or lithium bromide. The starting compound (V) can be derived from a substance which is obtainable from Myrica cerifera by extraction in a similar manner to that described in WO92/12991. Briefly, twigs of the plant are extracted for several days at room temperature with a polar solvent (e.g., alcohol such as methanol, ethanol, isopropanol, n-butanol, sec-butanol, tert-butanol; acetone; or acetonitrile). The resultant solution is further extracted with a water-immiscible organic solvent (e.g., chlorinated hydrocarbon such as chloroform, dichloromethane; ethyl acetate; or n-butanol) and the extract is chromatographed on silica gel. The isolated substance is then subjected to chemical modification to obtain Myricerone of the formula (IV): ##STR4##
The compound (V) is obtained by reacting the compound (IV) with dimethylphosphonoacetic acid.
The compound (V) is then reacted with an aldehyde of the formula (III): ##STR5## wherein R.sup.2 is as defined above and R.sup.6 is t-butoxycarbonyl (hereinafter, referred to as Boc) or hydrogen under the reaction condition for Horner-Emmons reaction. The condensation product is deprotected and/or chemically modified to give the compound (I) of the present invention.
The Horner-Emmons reaction can be effected in either of following two methods.