Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-21
2002-07-02
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000, C546S283400, C546S283700
Reexamination Certificate
active
06413979
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds having antagonism against three kinds of endothelin (endothelin-1, endothelin-2 and endothelin-3), which are physiologically highly active endogenous peptides in the field of medicines, processes for their preparation and their use as a drug.
BACKGROUND ART
Endothelin is a polypeptide compound of 21 amino acids, and it is produced by endothelial cells of human and pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 32, 411-415 (1988)). Three endothelin family peptides (endothelin-1, endothelin-2 and endothelin-3), which resemble one another in structure, exist in the bodies of animals including human, and these peptides are known to have vasoconstriction and pressor effects (Proc. Natl. Acad. Sci. USA, 86, 2863-2867 (1989)).
It is clinically reported that the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids from the respiratory tract or the blood of asthmatics as compared with normal levels (Japan. J. Hypertension, 12, 79, (1989), J. Vascular Medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lances, ii, 747-748 (1989) and ii, 1144-1147 (1990)).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)), an improved renal function by an endothelin antibody in an acute renal failure model (J. Clin. Invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of the 19th Meeting of Japanese Society of Experimental Gastric Ulcer, 50 (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, it is revealed that endothelin is secreted not only by vascular endothelin cells but also by tracheal epithelial cells and kidney cells (FEBS Letters, 249, 42-46 (1989), and ibid., 255, 129-132 (1989)).
Endothelin was also found to control the release of physiologically active endogenous peptides such as renin and atrial natriuretic hormone, and other physiologically active substances such as endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys. Res. Commun., 157, 1164-1168 (1988); ibid., 155, 167-172 (1989); Proc. Natl. Acad. SCi. USA, 85, 9797-9800 (1989); J. Cardiovasc. Pharmacol., 13, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184 (1989)). Further, endothelin causes contraction of the smooth muscle of the gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys. Res. Commun., 159, 317-323 (1989)).
Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since it is known that the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role in controlling nervous functions (Neuroscience Letters, 97, 276-279 (1989)). Particularly, endothelin is suggested as one of the mediators for pain (Life Science, 49, PL61-PL65 (1989))
Further, endothelin is reported to appreciably promote endarterial hypertrophy induced by injury to rat coronary arterial endothelial cells by ballooning (J. Cardiovasc. Pharmacol., 22, 355-359 (1993)). Thus, it is suggested that endothelin is likely to be involved in restenosis following percutaneous transluminal angioplasty.
In recent years, it has been revealed that the human prostate has endothelin receptors A and B and shows a potent vasoconstrictor effect of endothelin (J. Urology, 151, 763-766 (1994); and Molecular Pharmacology, 45, 306-311 (1994)), which indicates that endothelin is involved in pathology of prostatism as one of the important factors.
On the other hand, endotoxin is one of the potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the supernatant of cultured endothelial cells was observed when endotoxin was exogenously administered to animals or added to the cultured endothelial cells, respectively. These findings suggest that endothelin is one of the important mediators for endotoxin-induced diseases (Biochem. Biophys. Res. Commun., 161, 1220 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
Further, it was reported that cyclosporin remarkably increased endothelin secretion in a renal cell culture (LLC-PKI cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, cyclosporin-induced renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases. Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)).
It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7), S119-S121 (1993)). One of the endothelin receptors is ET
A
receptor selective to ET-1 rather than ET-3, and the other is ET
B
receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348, 730-735 (1990)).
These two subtypes of endothelin receptors, which are different in selectivity to endothelin family peptides, are differently distributed in tissues. It is known that the ET
A
receptor is present mainly in the cardiovascular tissues, whereas the ET
B
receptor is widely distributed in various tissues such as the brain, the lung, the kidney, the heart and the vascular tissues.
In summary, endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excessive production or excessive secretion is believed to be one of the pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, acute renal failure, heart failure, myocardial infarction, angina pectoris, cerebral infarction and cerebral vasospasm. Further, it is suggested that endothelin serves as an important mediator involved in diseases such as restenosis, prostatism, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension. Two endothelin receptors ET
A
and ET
B
are known so far. Not only an antagonist against both the ET
A
and ET
B
receptors but also a selective antagonist against the ET
A
receptor is promising as a drug.
The prior art representing general technical standards in this field includes, for example, EP526708A1 and W093088799A1, which already disclose some peptidic compounds antagonistic to endothelin receptors.
The closest prior art includes W09505374A1. WO9505374A1 discloses condensed aromatic heterocyclic cyclopentene derivatives having as Ar, a phenyl group having various substituents inclusive of a methylenedioxyphenyl group, but not a 2,2-difluoro-1,3-benzodioxole group.
While the compounds disclosed in WO9505374A1 are mostly antagonists against both the ET
A
and ET
B
receptors, the compounds of the present invention, which are structurally diff
Hayama Takashi
Nishikibe Masaru
Otake Norikazu
Aulakh Charanjit S.
Banyu Pharmaceutical Co. Ltd.
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