Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-10
1999-11-02
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514339, 514418, 546113, 546256, 5462777, 548486, A61K 3140, A61K 3144
Patent
active
059771305
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to intimal hypertrophy inhibitors containing an oxindole derivative as the active ingredient.
BACKGROUND ART
Coronary arteriosclerosis is known to precede and be the major cause of the onset of various pathological conditions such as angina pectoris and myocardial infarction. Luminal narrowing caused by arteriosclerosis and loss of vascular elasticity bring about deficiency of nutrition and oxygen in cardiac muscular tissue, to thereby induce the aforementioned pathological conditions. Narrowing of vascular lumina is considered to be primarily caused by accumulation of foamy macrophages and cholesterol on the inner wall, and in addition, by cell-fibrous intimal hypertrophy caused by migration of smooth muscle cells of the media into the intima, and proliferation of the cells in the intima. In the treatment of angina pectoris and myocardial infarction, antithrombotic agents, vasodilator agents, etc. have been used for the principal purpose of ameliorating the symptoms. However, these agents have failed to serve as a radical remedy for the narrowing and loss of elasticity of vascular lumina caused by arteriosclerosis. Therefore, pharmaceuticals that are capable of preventing or treating intimal hypertrophy which causes angiostenosis are earnestly desired.
In recent years, angiostenosis has been surgically treated by percutaneous transluminal coronary angioplasty (hereinafter referred to as PTCA). PTCA is a therapy in which a balloon catheter is inserted by remote operation into the narrow segment through, for example, the femoral artery, without performance of thoracotomy, and the balloon is inflated in situ, to thereby physically achieve vasodilation. Due to advancement in manipulation technique of PTCA, more than 90% of PTCA cases show amelioration of symptoms immediately after PTCA. In addition, PTCA rarely involves death or signs of adverse side effects such as induction of myocardial infarction. Accordingly, PTCA is accepted as an excellent therapy. However, about 30-40% of the cases that undergo PTCA revert to restenosis at the same site, and if restenosis occurs, PTCA must be performed again, or alternatively, an aorta bypass-forming operation must be performed. This constitutes the most significant problem in the clinical field. Autopsy of cases in which death was caused by reblockage after PTCA revealed that intimal hypertrophy had occurred at the site at which the vascular cavity had been dilated, thus reblocking the site [see, for example, British Heart Journal, 58, 635-643 (1987), Human Pathology, 477-485 (1989)].
Therefore, it is considered that inhibition of intimal hypertrophy would be effective for the prevention of restenosis after PTCA and further for the treatment of arteriosclerosis.
The pharmaceuticals that were expected to open the way up to the remedy of the aforementioned diseases have been studied in both preclinical and clinical stages [American Heart Journal, 122, 171-187 (1991)]. The candidate pharmaceuticals were anticoagulants such as heparin; platelet aggregation inhibitors such as aspirin, dipyridamole, ticlopidine, prostacycline, and their derivatives; thromboxane A2 inhibitors such as trapidil; cell proliferation inhibitors such as ketanserin; calcium antagonists such as diltiazem and nifedipine; lipid decreasing agents such as fish oil, eicosapentaenoic acid and lovastatin; and anti-inflammatory agents such as steroids. However, after actual investigation in clinical situations, none of these drugs were found to have clear utility.
Tranilast is an intimal hypertrophy inhibitor considered to be developed to the most advanced level (Japanese Patent Application Laid-Open (kokai) No. 6-135829). However, due to its weak activity, this drug is not a satisfactory intimal hypertrophy inhibitor.
Thus, presently there are no effective drugs against intimal hypertrophy, and therefore, clinically useful pharmaceuticals are strongly called for.
The active ingredients of the present invention, oxindole derivatives, partially comprise know
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Epoxides by the action of diaryldiazomethanes on ketones, Alexander Schoenberg and Klaus Junghans, Ber. 96 (12), 3328-37 (1963), vol. 60;4086a.
Synthesis and cardiotonic activity of 2-indolinones, Aldo Andreani, et al., Eur. J. Med. Chem. (1990) 25, 187-190.
Synthesis and cardiotonic activity of pyridylmethylene-2-indolinones, A. Andreani, et al., Eur. J. Med. Chem (1992) 27, 167-170.
Asao Tetsuji
Hagiwara Yu-ichi
Kitade Makoto
Sato Atsushi
Yamazaki Yasundo
Raymond Richard L.
Taiho Pharmeutical Co., Ltd.
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