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AssigneeWyeth
InventorsRobert J. Steffan, Amedeo A. Failli
Estimating the term…
Antiatherosclerotic agents are provided which are represented by Formulas I or II: wherein R is wherein R9, R10, R11, R12, R13, and R14 are each, independently, hydrogen or a lower alkyl of 1-6 carbon atoms; R6, and R7 are each, independently, hydrogen, lower alkyl of 1-6 carbon atoms, or CH2COOR8, where R8 is a lower alkyl of 1-6 carbon atoms; and X is O or S; R1 is hydrogen or a lower alkyl of 1-6 carbon atoms; R2, R3, and R4 are each, independently, hydrogen or halogen; and R5 is a lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
An antiatherosclerotic agent represented by Formulas I or II:
Dependencies are inferred from the claim text.
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Not condensed with other rings: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen,…
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
Nitrogen atoms: acylated on said nitrogen atom
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
Term ended 18 Dec 2018 (estimated)
This invention is directed to antiatherosclerotic agents and more specifically to compounds, compositions and methods useful for elevating HDL cholesterol concentration which may be useful in the treatment of atherosclerosis and related conditions, such as dyslipoproteinemias and coronary heart disease.
Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL—C) concentrations (Russ et al., Am. J. Med., 11 (1951) 480-483; Gofman et al. Circulation, 34 (1966), 679-697; Miller and Miller, Lancet, 1 (1975), 16-19; Gordon et al., Circulation, 79 (1989), 8-15; Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381; Badimon et al., Lab. Invest., 60 (1989), 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller et al., Br. Med. J., 282 (1981), 1741-1744).
There are several mechanisms by which HDL may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis, 6 (1986), 434-441). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipi Res., 9 (1968), 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., J. Biol. Chem., 258 (1983), 7161-7167; McKinnon et al., J. Biol. Chem., 261 (1986), 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem., 253, (1978), 1834-1841; Lagocki and Scanu, J. Biol. Chem., 255 (1980), 3701-3706; Schaefer et al., J. Lipid Res., 23 (1982), 1259-1273). More recently, as a possible mechanism for protection against the development of atherosclerosis, Cockerill et. al. (Arterioscler., Thromb., Vasc. Biol, 15, (1995), 1987-1994) have demonstrated that plasma HDL's inhibit the cytokine-induced expression of endothelial cell adhesion molecules (VCAM-1 and ICAM-1) in a concentration dependent and cell specific manner. Accordingly, it is believed that agents which increase HDL cholesterol concentration would be of utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
1-(5-Chloro-2-methyl-phenyl)-3-(thiazol-2-yl)-thiourea
Prepared using Method C from 3.0 g (16.3 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 1.7 g (16.3 mmol) of 2-amino-thiazole to give 3.58 g of title compound as a beige solid, m.p. 197-198° C. (77% yield).
NMR (DMSO-d6, 400 MHz): 2.19 (s, 3H, ArCH3), 7.04 (broad s, 1H, ArH), 7.19 (dd, 1H, ArH), 7.22 (d, 1H, ArH), 7.41 (d, 1H, ArH), 7.44 (broad, 1H, ArH), 10.4 (broad, 1H, NH), 12.25 (broad, 1H, NH).