Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-09
1999-04-06
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31505
Patent
active
058918795
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/US95/11186 filed Aug. 29, 1995.
The present invention relates to compositions containing quinazolinones. More particularly, the present invention relates to a composition for the inhibition of restenosis, comprising a qunazolinone derivative as herein defined as active ingredient therein.
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 3,320,124, issued in 1967, there is described and claimed a method for treating coccdidiosis with quinazolinone derivatives.
Halogufinone, otherwise known as linone, was first described and claimed in said patent by American Cyanamid Company, and was the preferred compound taught by said patent and the one commercialized from among the derivatives described and claimed therein.
Subsequently, U.S. Reissue Pat. No. 26,833 and U.S. Pat. Nos. 4,824,847; 4,855,299; 4,861,758 and 5,215,993 all relate to the coccidiocidal properties of halofuginone, while U.S. Pat. No. 4,340,596 teaches that it can also be used for combatting theileriosis.
In U.S. Pat. No. 5,449,678, there is described and claimed an anti-fibrotic composition, comprising an amount of a compound of formula I: ##STR2## wherein: n 1 or 2 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; alkoxy, and alkenoxy-carbonyl; therein, and the physiologically acceptable salts thereof.
After further research and development, it has now been discovered that the above-identified compounds of formula I are effective in the inhibition of restenosis, which formally is not a fibrotic condition.
The pathogenesis of atherosclerosis involves abnormal migration and proliferation of smooth muscle cells (SMCs) infiltrated with macrophages and embedded in extracellular matrix (ECM) of adhesive glycoproteins, Coronary Artery Disease and the Acute Coronary Syndromes," New Eng. J. Med., Vol. 326, pp. 242-250 (1992); R. Ross, "The Pathogenesis of Atherosclerosis: A Perspective for the 1990's," Nature, Vol. 362, pp. 801-809 (1993)!. Under physiological conditions, the majority of arterial SMCs remains in the Go phase and cell growth is controlled by a balance between endogenous proliferation-stimulating and proliferation-inhibiting factors. Following endothelial cell perturbation due to atherogenic risk factors (i.e., hypertension, hyperlipoproteinemia, diabetes mellitus), platelets and non-platelet-derived growth factors and cytokines are released and stimulate monocyte and SMC migration as well as SMC proliferation (V. Fuster, et al., ibid.; R. Ross, ibid.). Among these et al., "Inhibition of Neoinitmal Smooth Muscle Accumulation after Angioplasty by an Antibody to PDGF," Science, Vol. 253, pp. 1129-1132 of Basic Fibroblast Growth Factor in Vascular Lesion Formation," Circ. and P. Libby, "Proliferating or Interleukin-1 Activated Human Vascular Smooth Muscle Cells Secrete Copious Interleukin 6, " J. Clin. Invest., Vol. 85, pp. 731-738 (1990)!. Macrophages and platelets also release enzymes, i.e., elastase, collagenase, heparanase) that digest various constituents of the ECM and release bFGF and possibly other growth factors al., "Extracellylar Matrix-bound Growth Factors, Enzymes and Plasma Proteins," in: Molecular and Cellular Aspects of Basement Membranes, Monographs in Cell Biology, D. H. Rohrbach and R. Timpl, Eds., Academic Press, New York, N.Y., U.S.A., pp. 327-346 (1993)!. A potent growth-promoting activity towards SMCs is also exerted by thrombin, which, Bar-Shavit, et al., "Thrombin Immobilized to Extracellular Matrix Is a Mitogen for Vascular Smooth Muscle Cells: Non-Enzymatic Mode of Action," Cell Reg., Vol. 1, pp. 453-463 (1990); S. M. Schwartz, "Serum-Derived Growth Factor is Thrombin?" J. Clin. Invest., Vol 91, p. 4 (1993)!. Molecules that interfere with the growth-promoting activity of these growth factors may attenuate the progression of the atherogenic process.
Proliferation of arterial smooth muscle cells (SMC) in response to endothelial injury is a basic event in the process of restenosis of coronary arteries after percutaneous translumina
REFERENCES:
patent: 5449678 (1995-09-01), Pines et al.
Granot et al, Biochimica et Biophysica Acta, vol. 1156 pp. 107-112 1993.
Lindner et al. Circulation Research, vol. 68 (1), pp. 106-113 1991.
Nagler Arnon
Pines Mark
Slavin Shimon
Vlodavsky Israel
Agricultural Organization Ministry of Agriculture State of Israe
Cook Rebecca
Hadasit Medical Research Services & Development Co., Inc.
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