Stereoselective synthesis of endothelin receptor antagonists

Details Stereoselective synthesis of endothelin receptor antagonists Stereoselective synthesis of endothelin receptor antagonists

1998-05-08

2000-06-27

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549434, 549435, 549448, C07D22104, C07D31748

Patent

active

060808624

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to the stereoselective synthesis of aryl and heteroaryl ring-fused cyclopentane derivatives useful as endothelin receptor antagonists and to the preparation of chiral intermediates in the process.


BACKGROUND OF THE INVENTION

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET- 1, ET-2 and ET-3 (unless otherwise stated, "endothelin" shall mean any or all of the isoforms of endothelin). Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
Many studies suggest that endothelin receptor antagonists would offer a unique approach toward the pharmacotheraphy of hypertension, renal failure, ischemia-induced renal failure, sepsis-endotoxin-induced-renal failure, prophylaxis and/or treatment of radio-contrast-induced renal failure, acute and chronic cyclosporin-induced renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, cyclosporin induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy.
Recent publications disclose that aryl and heteroaryl ring-fused cyclopentane derivatives have utility as endothelin receptor antagonists. See, e.g., International application Number PCT/US94/04603 (WO 94/25013) and U.S. Pat. No. 5,389,620. These particular publications also disclose synthetic approaches to the preparation of specific aryl and heteroaryl ring-fused cyclopentane derivatives, where those derivatives may function as endothelin receptor antagonists.
Unfortunately, the synthetic methods disclosed in the literature for making aryl and heteroaryl ring-fused cyclopentane derivatives do not provide for the desired products in high yield. Instead, the methods discussed in the literature require many steps, which are laborious and consequently expensive to conduct. Furthermore, when known methods provide for enantiomerically or diastereomerically pure products, they rely on chromatography to separate the various stereoisomers. Chromatography is far from a preferred approach in the preparation of isomerically pure materials on a commercial scale. Exemplary of this approach is the synthesis of (+) (1S,2R,3S) 3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop- 1-yloxy)indane-2-carboxylic acid and (+) (1S,2R,3S) 3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl-1-(3,4-methylenedioxyphenyl)-5 -(prop-1-yloxy)indane-2-carboxylic acid, which as set forth in WO 94/25013, is multi-step, low yielding and relies upon a chromatographic resolution of a racemic intermediate in order to prepare the named compounds in optically pure form.
A technique that needs to be developed in the synthetic art is the use of chiral aryl Grignard reagents. Chiral aryl Grignard reagents have seen some use as intermediates for the preparation of diastereomerically and enantiomerically pure compounds. Such chiral aryl Grignard reagents have been prepared, for example, from chiral oxazolidines derived from aryl aldehydes. See, e.g., Real, S. D. et al., U.S. Pat. No. 5,332,840 and Tet. Lett., 34, 8063-8066, 1993; Agami, C. et al.,

REFERENCES:
patent: 5389620 (1995-02-01), Ishikawa et al.

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