Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1995-11-08
1998-06-16
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562466, 562471, 514569, 514570, 548253, C07C 5940
Patent
active
057673101
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
This invention is concerned with non-peptidic endothelin receptor antagonists represented by the compound of Formula I, pharmaceutical compositions containing these compounds, as well as combination therapies which include a compound of the present invention. The compounds of the present invention are therapeutic agents particularly useful for the treatment of asthma, hypertension, pulmonary hypertension, arteriosclerosis, congestive heart failure, renal failure, particularly post-ischemic renal failure, cyclosporin nephrotoxicity, vasospasm, vascular restenosis, cerebral and cardiac ischemia and other ischemic states, myocardial infarction, Raynaud's disease, benign prostatic hyperplasia, inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, as well as other inflammatory diseases, or endotoxic shock caused by or associated with endothelin.
This invention further constitutes a method for antagonizing endothelin receptors in a mammal, including humans, which comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I.
BACKGROUND OF THE INVENTION
Endothelin is a 21-amino acid peptide produced by endothelial cells. The peptide is secreted not only by endothelial cells but also by tracheal epithelial cells or from kidney cells. Endothelin (ET-1) has a potent vasoconstrictor effect. The vasoconstricting effect is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells..sup.1-3
Endothelin-1 (ET-1) is one of three recently identified potent vasoconstricting peptides which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3) whose sequences differ from ET-1 by two and six amino acids, respectively..sup.4
Increased levels of endothelin are found in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease or atherosclerosis or in the washing fluids of the respiratory tract of patients with asthma compared to normal levels..sup.5-8
An experimental model of cerebral vasospasm and a second model of acute renal failure have led to the conclusion that endothelin is one of the mediators causing cerebral vasospasm following a subarachnoid hemorrhage, and renal failure..sup.9-10
Endothelin was also found to control the release of many physiological substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A.sub.2,.sup.14, prostacyclin, norepinephrine, angiotensin II and substance P..sup.11-16 Further, endothelin causes contraction of the smooth muscle of the gastrointestinal tract and the uterine smooth muscle..sup.17-19 Endothelin has also been shown to promote the growth of rat vascular smooth muscle cells which would suggest a possible relevance to arterial hypertrophy..sup.20
Endothelin receptors are present in high concentration in the peripheral tissues and also in the central nervous system, and cerebral administration of endothelin has been shown to induce behavioral changes in animals, suggesting that endothelin may play an important role in controlling neural functions..sup.21
Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelin is an important mediator for endotoxin-induced diseases..sup.22-23
A study has shown that cyclosporin added to a renal cell culture-, increased endothelin secretion..sup.24 Another study has shown that administration of cyclosporin to rats, led to a decrease in the glomerular filtration rate and an increase in the blood pressure, in association with a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the administration of anti-endothelin antibody..sup.25 These studies suggest that endothelin is significantly involved in the pathogenesis of cyclosporin-induced renal disease.
A recent study in patients with congestive heart failure demonstrated a good correlation between the elevated levels of endothelin in the plasma and
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Bagley Scott W.
Broten Theodore P.
Chakravarty Prasun K.
Dhanoa Daljit S.
Fitch Kenneth J.
Camara Valerie J.
Daniel Mark R.
Killos Paul J.
Merck & Co. , Inc.
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