Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-03-14
1996-06-18
Killos, Paul J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544359, 549 12, A61K 31495
Patent
active
055278019
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01173 Sep. 14, 1992.
TECHNICAL FIELD
The present invention relates to a useful and novel agent as a medicine. Particularly, the present invention relates to a novel use of a specific dibenzo[b,e]thiepine derivative. That is, the present invention relates to an ameliorant for blood lipid metabolism, which comprises as an active ingredient a dibenzob[b,e]thiepine derivative of the following structural formula (hereinafter, referred to as Compound A), or a pharmaceutically acceptable salt thereof, more particularly, the present invention relates to a hyperlipidemia inhibitor and an inhibitor of atherosclerosis in the aorta, and a method for ameliorating blood lipid metabolism. ##STR1##
It has been already disclosed in Japanese Patent Second Publication (Kokoku) No. 58341/1991 (U.S.Pat. No. 4,749,703) that Compound A of the present invention and salts thereof have a potent calcium antagonistic activity and are useful as a hypotensive agent. Besides, it has also been disclosed in Jpn. J. Pharmacol., 52 (suppl. 1), 212 (No. P067) (1990) that Compound A and salts thereof have .alpha..sub.1 -receptor blocking activity.
In Am. J. Cardiology 64, 129 l-134 l (1989), there is an introduction of many reports as to the hyperlipidemia inhibitory activity and the atherosclerosis inhibitory activity of various calcium antagonists, wherein it is described that the antagonists did not show any hyperlipidemia inhibitory activity in most of the reports and that as to atherosclerosis inhibitory activity the antagonists showed positive activity in some reports but did not in other reports.
Moreover, it is reported that diltiazem, which is a benzothiazepine derivative and a well known hypotensive agent having calcium antagonistic activity, shows the atherosclerosis inhibitory activity in rabbits [Lab. Invest., 49 (2), 154-158 (1983)], and on the contrary, there is a report of having no inhibitory activity [Atherosclerosis, 51, 343-344 (1984)].
Besides, it is reported that prazosin, which is a benzopyrimidine derivative being well known as a hypotensive agent having .alpha..sub.1 -receptor blocking activity, shows blood lipid decreasing activity in human being [Am. J. Medicine, 76 (suppl. 2A), 79-84 (1984)], and on the contrary, there is a report of having no blood lipid decreasing activity [Prog. Medicine 3, 1517-1525 (1983)].
DISCLOSURE OF INVENTION
The present inventors have found that the above Compound A shows the hyperlipidemia inhibitory activity as well as the atherosclerosis inhibitory activity at a dose effective for showing hypotensive activity, and that they are useful as an ameliorant for blood lipid metabolism, more particularly, as a hyperlipidemia inhibitor and atherosclerosis inhibitor, and have accomplished the present invention.
That is, an object of the present invention is to provide an ameliorant for blood lipid metabolism which comprises as an active ingredient Compound A or a pharmaceutically acceptable salt thereof. More particularly, the object of the present invention is to provide a hyperlipidemia inhibitor and atherosclerosis inhibitor.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows the appearances of lipid deposition at the aortic inner wall. Each figure shows the appearances of lipid deposition, i.e. the appearances of plaque formation in the following groups, (a): the normal control group (normally fed);(b): the positive control group (fed with high fat feed); (c): maleate of Compound A-treated group; (d): the prazosin-treated group; and (e): the diltiazem-treated group.
BEST MODE FOR CARRYING OUT INVENTION
The present inventors have firstly found that the above mentioned Compound A and a pharmaceutically acceptable salt thereof inhibit the increase in blood lipid at a dose effective for showing hypotensive activity (hyperlipidemia inhibitory activity) as well as inhibit the lipid deposition at the aortic inner wall (atherosclerosis inhibitory activity), by which they are useful as an ameliorant for blood lipid metabolism, and have accomplished the prese
REFERENCES:
patent: 4749703 (1988-06-01), Uno et al.
Triggle, D. J. et al., "Calcium Antagonists", Drug News Perspective, vol. 4, No. 10, Dec. 1991, pp. 643-646.
Minato, H. et al., "Inhibitory Effect of the New Calcium Antagonist AJ-2615 on Progression of Atherosclerosis in Cholesterol-fed Rabbits", Journal of Cardiovascular Pharmacology, vol. 21, No. 4, 1993, pp. 663-669.
Minato, H. et al., "Preventive Effect of AJ-2615; A Novel Calcium Entry Blocker, On the Development of Experimental Atherosclerosis in Rabbits", 5th International Symposium on Calcium Antagonists: Pharmacology and Clinical Research, 1991, p. 91.
Drugs of the Future, vol. 17, No. 4, 1992, pp. 314-315.
Cubeddu, L. X. et al., "Effect of Doxazosin Monotherapy on Blood Pressure and Plasma Lipids in Patients with Essential Hypertension", American Journal of Hypertension, vol. 1, No. 2, 1988, pp. 158-167.
Bernini et al. (1989) "Effects of Calcium Antagonists on Lipids and Antherosclerosis" Am. J. Cardiology., 64, 129-134.
Ginsburg et al. (1983) "Calcium Antagonists Suppress Atherogenesis in Aorta but Not in the Intramural Coronary Arteries of Cholesterol-Fed Rabbits", Laboratory Investigation, 49:154-158.
Handa et al. (1983) "Report of Use of Prazosin Hydrochloride--as to Hypotensive Activity and Effects on Blood Lipids", Prog. Medicine, 3:1517-1525.
Lowenstein et al. (1984) "Effects of Prazosin and Propranolol on Serum Lipids in Patients with Essential Hypertension", Am. J. Medicine, 76:79-84.
Naito et al. (1984) "Ineffectiveness of Ca.sup.2+ -Antagonists Nicardipine and Diltiazem on Experimental Atherosclerosis in Cholesterol-fed Rabbits", Atherosclerosis, 51:343-344.
Okamura et al. (1990) "Effect of a novel Ca.sup.2+ entry blocker, AJ-2615 in isolated vascular smooth muscles", Jpn. J. Pharmacol., 52, (Suppl. 1):212 (Abstract No. P067).
Hosoki Kanoo
Ikeno Akihisa
Masuda Yoshinobu
Minato Hisao
Takeyama Kunihiko
Dainippon Pharmaceutical Co., Ltd.
Killos Paul J.
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