Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-04
2001-10-02
Mckane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S106000, C544S114000, C544S129000, C544S359000, C546S207000, C546S214000, C548S517000, C549S295000, C549S320000, C549S321000
Reexamination Certificate
active
06297274
ABSTRACT:
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, chronic obstructive pulmonary disease, cryptogenic fibrosing alveolitis, 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 penis 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
A
and ET
B
, have been studied extensively (Arai H., et al.,
Nature
, 1990;348:730, Sakurai T., et al.,
Nature
, 1990;348:732). The ET
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
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. Biophys. Res. Chem
., 1991;178:656, Hosoda K., et al.,
FEBS Lett
., 1991;287:23). The ET
A
receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET
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
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 animals and humans (Stewart, et al.,
J. Am. Coll. Cardiol
., 1991:18:38-43; Tomoda, et al.,
Am. Heart J
., 1993;125:667-672; Ray, et al.,
Br. Heart J
., 1992;67:383-386; Tsuji, et al.,
Life Sci
., 1991;48:1745-1749). It has also been reported that the action of ET-1 may be enhanced under the conditions of ischemia (Liu, et al.,
Biochem. Biophys. Res. Conmmun
., 1989;164:1220-1225).
Several in vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a 4- to 7-fold increase in endogenous endothelin levels. Administration of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe T., et al., “Endothelin in Myocardial Infarction,”
Nature
, (Lond.) 1990;344:114). Thus, ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies K. B., et al., “Increased Endothelin in Experimental Heart Failure,”
Circulation
, 1990;82:2226).
Patients with chronic heart failure were treated with the ET antagonist Bosentan, which was found to improve cardiac performance, concluding that ET is involved in the regulation of vascular tone and that inhibition of its effects may be beneficial in chronic heart failure (Kiowski W., et al.,
Lancet
, 1995;346:732-36, also
J. Am. Coll. Cardiol
., 1995; special edition 296A:779-1).
Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60 minute period of renal ischaemia resulted in changes in renal function versus control. In addition, an increase in glomerular platelet-activating factor was attributed to endothelin (Lopez-Farre A., et al.,
J. Physiology
, 1991;444: 513-522). In patients with chronic renal failure as well as in patients on regular hemodialysis treatment mean plasma endothelin levels were significantly increased (Stockenhuber F., et al.,
Clin. Sci
. (
Lond
.), 1992;82:255-258).
Studies by Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the peptide's involvement in acute renal ischemic injury (Kon V., et al., “Glomerular Actions of Endothelin In Vivo,”
J. Clin. Invest
., 1989;83:1762).
Other investigators have reported that infusion of ET-specific antibodies into spontaneously hypertensive rats (SHR) decreased mean arterial pressure (MAP), and increased glomerular filtration rate and renal blood flow. In the control study with normotensive Wistar-Kyoto rats (WKY) there were no significant changes in these parameters (Ohno A., Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats,”
J. Tokyo Women's Med. Coll
., 1991;61:951).
Other studies have demonstrated the usefulness of ET antagonists in maintaining beneficial parameters of renal performance following ischemia-induced injuries (Mino, et al.,
Eur. J. Pharmacol
., 1992;221:77-83; Benigni, et al.,
Kidney Int
, 1993;44:440-444).
ET
A
receptor mRNA has been detected in 82% of human meningiomas (
J. Clin. Invest
., 1995;66:2017-2025
Plasma endothelin-1 levels were dramatically increased in a cancer patient with malignant hemangioendothelioma (Nakagawa K., et al.,
Nippon Hifuka Gakkai Zasshi
, 1990;100:1453-1456).
Exogenous endothelin-1 is also a prostate cancer mitrogen in vitro. Endothelin levels are significantly elevated in men with metastatic prostate cancer. Every human prostate cancer cell line tested by Nelson et al., (
Nature Medicine
, 1995; Vol 1(9):944) produced ET-1 mRNA and secreted immunoreactive endothelin.
An ET antagonist, PD 155080 was found to mediate prostate smooth muscle function in vivo, which demonstrated that endothelin antagonists may be useful in the treatment of benign prostatic hyperplasia (Chleko I., et al., Annual Meeting of the American Urological Assn, Orlando, 1996).
The ET receptor antagonist BQ-123 has been shown to block ET-1 i
Cheng Xue-Min
Doherty Annette Marian
Patt William Chester
Repine Joseph Thomas
Anderson Elizabeth M.
Kurlandsky David R.
McKane Joseph K.
Murray Joseph
Warner-Lambert & Company
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