Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-08-03
2000-10-17
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514464, 514465, 544148, 544377, 548526, 549313, A61K 31365, A61K 31535, C07D40702, C07D41314
Patent
active
061332631
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, angina, arrhythmias, asthma, atherosclerosis, benign prostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease, congenital heart disease, congestive heart failure (CHF) (mild), congestive heart failure (CHF) (severe), cerebral ischemia, cerebral infarction, cerebral vasospasm, cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosal damage, glaucoma, head injury, hemodialysis, hemorrhagic shock, hypertension (essential), hypertension (malignant), hypertension (pulmonary), hypertension (pulmonary, after bypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease, ischemic disease, male penile erectile dysfunction, malignant hemangioendothelioma, myocardial infarction, myocardial ischemia, prenatal asphyxia, postoperative cardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure (chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgical operations, status epilepticus, stroke (thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerative colitis, uremia after hemodialysis, and uremia before hemodialysis.
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include: ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs).
The distribution of the two cloned receptor subtypes, termed ET.sub.A and ET.sub.B, have been studied extensively (Arai H., et al., Nature, 1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ET.sub.A, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H. Y., et al., Proc. Natl. Acad. Sci., 1991;88:3185). The ET.sub.B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells. The human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., Biochem. Biphys. Res. Chem., 1991;178:656, Hosoda K., et al., FEBS Lett., 1991;287:23). The ET.sub.A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET.sub.B receptor in the initial vasodilatory response to ET (Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent data has shown that the ET.sub.B receptor can also mediate vasoconstriction in some tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun., 1992;183(2):566).
The involvement of endothelin has been proven in many human disease states.
Elevated levels of endothelin have been measured in patients suffering from ischemic heart disease (Yasuda M., et al., Amer. Heart J., 1990;119:801-806) and either stable or unstable angina (Stewart J. T., et al., Br. Heart J., 1991;66:7-9).
The degree of elevation of plasma ET levels in patients with heart failure varies from 2-fold to 5-fold (Stewart, et al., Circulation, 1992;85:510-517; Lerman, et al., J. Am. Coll. Cardiology, 1992;20: 849-853). The greatest elevation measured appears to be in congestive heart failure (CHF) patients with marked pulmonary hypertension. The increased level of circulating ET in human congestive heart failure patients also correlated with the severity of the disease observed (Rodeheffer, et al., Am. J. Hypertension, 1991:4:9A; Rodeheffer, et al., Mayo Clin. Prod., 1992;67:719-724).
Many studies have indicated increased plasma levels of ET-1 after acute myocardial infarction (MI) in both
REFERENCES:
patent: 5691373 (1997-11-01), Berryman et al.
Arai et al., "Cloning and expression of a cDNA encoding an endothelin receptor", Nature, 1990, 348, 730-732.
Sakurai et al., "Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor", Nature, 1990, 348, 732-735.
Lin et al., "Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor", Proc. Natl. Acad. Sci. USA, 1991, 88, 3185-3189.
Sakamoto et al., "Cloning and functional expression of human cDNA for the Et.sub.B endothelin receptor", Biochem. Biophys. Res. Comm., 1991, 178:2, 656-663.
Hosoda et al., "Cloning and expression of human endothelin-1 receptor cDNA", FEBS Letters, 1991, 287:1/2, 23-26.
Takayanagi et al., "Presence of non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation", FEBS Letters, 1991, 282:1, 103-106.
Panek et al., "Endothelin and structurally related analogs distinguish between endothelin receptor subtypes", Biochem. Biophys. Res. Comm., 1992, 183:2, 566-571.
Yasuda et al., "Circulating immunoreactive endothelin in ischemic heart disease", American Heart Journal, 1990, 119:4, 801-806.
Stewart et al., "Plasma endothelin in coronary venous blood from patients with either stable or unstable angina", Br. Heart J., 1991, 66, 7-9.
Stewart et al., "Elevated Endothelin-1 in Heart Failure and Loss of Normal Response to Postural Change", Circulation, 1992, 85, 510-517.
Lerman et al., "Plasma Endothelin Concentrations in Humans With End-Stage Heart Failure and After Heart Transplantation", JAAC, 1992, 20:4, 849-853.
Rodeheffer et al., "Circulating plasma endothelin correlates with the severity of congestive heart failure in humans", Am. J. Hypertension, 1991, 4:9A-10A.
Rodeheffer et al., "Increased Plasma Concentrations of Endothelin in Congestive Heart Failure in Humans", Mayo Clin. Proc., 1992, 67, 719-724.
Stewart et al., "Increased Plasma Endothelin-1 in the Early Hours of Acute Myocardial Infarction", JAAC, 1991, 18:1, 38-43.
Tomoda, "Plasma endothelin-1 in acute myocardial infarction with heart failure", American Heart Journal, 1993, 125, 667-672.
Ray et al., "Circulating endothelin in acute ischaemic syndromes", Br. Heart J., 1992, 67, 383-386.
Tsuji et al., "Plasma endothelin levels during myocardial ischemia and reperfusion", Life Sciences, 1991, 48, 1745-1749.
Liu et al., "Ischaemia causes externalization of endothelin-1 binding sites in rat cardiac membranes", Biochem. Biophys. Res. Comm., 1989, 164:3, 1220-1225.
Watanabe et al., "Endothelin in myocardial infarction", Nature, 1990, 344, 114.
Margulies et al., "Increased Endothelin in Experimental Heart Failure", Circulation, 1990, 82:6, 2226-2230.
Kiowski et al., "Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure", Lancet, 1995, 346, 732-736.
Kiowski et al., "Vasodilator Effects of the Endothelin-1 Receptor Antagonist Bosentan in Patients with Severe Chronic Heart Failure", JACC, 1995, special edition 296A, 779-1.
Lopez-Farre et al., "A role for endothelin in the maintenance of post-ischaemic renal failure in the rat", Journal of Physiology, 1991, 444, 513-522.
Stockenhuber et al., "Plasma levels of endothelin in chronic renal failure and after renal transplantation: impact on hypertension and cyclosporin A-associated nephrotoxicity", Clinical Science, 1992, 82, 255-258.
Kon et al., "Glomerular Actions of Endothelin In Vivo", J. Clin. Invest., 1989, 83, 1762-1767.
Ohno, "Effects of Endothelin-specific Antibodies and Endothelin in Spontaneously Hypertensive Rats", J. Tokyo Women's Medical College, 1991, 61:10-11, 951-959.
Mino et al., "Protective effect of a selective endothelin receptor antagonist, BQ-123, in ischemic acute renal failure in rats", Eur. J. Pharmacol., 1992, 221, 77-83.
Benigni et al., "A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression", Kidney International, 1993, 44, 440-444.
Pagotto et al., "Expression and Localization of End
Cheng Xue-Min
Doherty Annette Marian
Patt William Chester
Repine Joseph Thomas
Anderson Elizabeth M.
Ramsuer Robert W.
Warner-Lambert & Company
LandOfFree
Endothelin antagonists with ether-linked groups does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Endothelin antagonists with ether-linked groups, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Endothelin antagonists with ether-linked groups will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-469129