Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-30
2001-10-02
Moezie, J.D., Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S396000
Reexamination Certificate
active
06297268
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to lowering of total serum cholesterol and to treating of diseases associated with high cholesterol in a patient in need thereof, by administering a therapeutically effective cholesterol lowering amounts of herein-disclosed imidazoles.
BACKGROUND OF THE INVENTION
Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Despite recent declines in coronary heart disease (“CHD”) mortality, CHD is still responsible for more than 500,000 deaths in the U.S. annually. It is estimated that CHD, directly or indirectly, causes the U.S. more than $100 billion a year. Risk factors for atherosclerotic coronary heart disease include, among several factors, hypertension, diabetes mellitus, family history, male gender, cigarette smoking and high serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is generally associated with a significant elevation of risk. Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Lowering of plasma cholesterol in patients with hypercholesterolemia has been of intense focus in pharmaceutical research in recent years.
Typically, cholesterol is carried in the blood of warm-blooded animals in certain lipid-protein complexes such as, for example, chylomicrons, very low density lipoprotein (“VLDL”), low density lipoprotein (“LDL”), and high density lipoprotein (“HDL”). It is widely accepted that LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood-vessel wall and that HDL functions in a way that results in the HDL picking up cholesterol from the vessel wall and transporting it to the liver where it is metabolized [M. S. Brown and J. L. Goldstein,
Ann. Rev. Biochem.,
52 (1983), 223; G. L. Miller,
Ann. Rev. Med.,
31 (1980), 97]. For example, in various epidemiological studies, the LDL cholesterol levels correlate well with the risk of coronary heart disease whereas the HDL cholesterol levels are inversely associated with coronary heart disease [J. G. Patton et al,
Clin. Chem.,
29 (1983), 1890]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis. Accordingly, it is desirable to provide a method for reducing LDL cholesterol in patients with hypercholesterolemia.
Several products are commercially available from drug manufacturers for the lowering of cholesterol. Some illustrative types and commercial products are: resins (for example, QUESTRAN® which is cholestyramine ion exchange resin from Bristol-Myers Squibb Corporation, Princeton, N.J.; and COLESTID® which is the hydrochloride of the polymer of N-(2-aminoethyl)-N′-[2-[(2-aminoethyl)amino]ethyl]-1,2-ethanediamine with (chloromethyl)oxirane) available from Pharmacia-Upjohn Company, Peapack, N.J.); fibrates (for example, LOPID® which is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid available from Warner-Lambert Company, Morris Plains, N.J.; and TRICOR® which is a fenofibrate available from Abbott Laboratories, Chicago, Ill.); and statins (for example, lovastatin as MEVACOR® available from Merck & Company, Whitehouse Station, N.J.; fluvastatin as LESCOL® from Novartis Corporation, East Hanover, N.J.; simvastatin as ZOCOR® from Merck & Company; pravastatin as PRAVACHOL® from Bristol Myers Squibb Corporation; atorvastatin as LIPITOR® from Warner-Lambert Company; and cerivastatin as BAYCOL® from Bayer Corporation, West Haven, Conn.).
U.S. Pat. Nos. 5,767,115; 5,744,467; 5,698,548; 5,688,787; 5,656,624; 5,633,246; 5,631,365; and 5,624,920 (all assigned to Schering Corporation, Kenilworth, N.J.) disclose various azetidinones and substituted p-lactam compounds as cholesterol lowering agents.
There is a continuing interest in finding novel cholesterol lowering agents.
It is an objective of this invention to find useful cholesterol lowering agents.
It is a farther objective of this invention to find methods of lowering cholesterol and treating diseases associated with high cholesterol, using novel compounds.
Other objectives and advantages of the present invention will be apparent to those skilled in the art from the accompanying description and claims.
SUMMARY AND DESCRIPTION OF THE INVENTION
This invention arises from a series of studies on the utility of imidazoles in lowering of serum cholesterol. It has now been found that certain imidazole compounds surprisingly exhibit desirable and therapeutically effective cholesterol lowering properties. Thus, one embodiment of the present invention comprises the use of therapeutically effective amounts of an imidazole compound (or an enantiomer, stereoisomer, tautomer, pharmaceutically acceptable salt or derivative of said imidazole) in the lowering of serum cholesterol, as well as in the treatment of hyperlipidemia or hypercholesterolemia, atherosclerosis, and other cardiovascular diseases associated with high cholesterol. Imidazole compositions are provided herein for use alone by themselves, as well as in combination with other suitable agents, said agents including, but not limited to, statins, resins, fibrates, azetidinones and the like, for the lowering of serum cholesterol as well as for the treatment of the above-mentioned diseases as well as other related diseases.
In another embodiment, the invention discloses a method to lower total serum cholesterol and lower LDL cholesterol in a patient in need thereof. The method comprises administering to said patient a composition comprising a therapeutically effective cholesterol lowering amount of a suitable imidazole or an enantiomer, stereoisomer, tautomer, pharmaceutically acceptable salt or derivative of said imidazole.
Yet another embodiment of the present invention discloses a method to inhibit the progression of atherosclerosis in a patient in need thereof, by administering to said patient a pharmaceutical composition comprising a therapeutically effective antiatherosclerotic amount of a suitable imidazole or an enantiomer, stereoisomer, tautomer, pharmaceutically acceptable salt or derivative of said imidazole.
Still another embodiment of the present invention discloses a general method of treating cardiovascular diseases in a patient in need of such treatment by administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a suitable imidazole (or an enantiomer, stereoisomer, tautomer, pharmaceutically acceptable salt or derivative of said imidazole) and a pharmaceutically acceptable carrier.
As used herein, the term “patient” refers to warm-blooded animals or mammals, including humans, who are in need of the specified treatment.
The term “hypercholesterolemia” refers to a disease state characterized by levels of total serum cholesterol or of LDL cholesterol which are elevated by a clinically significant amount over that considered normal by those of ordinary skill in the art. The identification of those patients who are in need of treatment for hypercholesterolemia is well within the knowledge and ability of one skilled in the art. For example, individuals who have serum cholesterol levels or LDL cholesterol levels, as determined by clinical laboratory tests, which are substantially and chronically elevated over that considered normal by those of ordinary skill in the art, are patients in need of treatment for hypercholesterolemia. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those patients who are suffering from hypercholesterolemia and those who are at risk of developing hypercholesterolemia and thus readily determine if an individual is a patient in need of treatment for hypercholesterolemia.
A therapeutically effective cholesterol lowering amount or amounts of a suitable imidazole refers to a
Evans Ellen W.
Merrill Carol
Mirro Elmer J.
Snyder Eileen A.
Bahar Mojdeh
Kalyanaraman Palaiyur S.
Moezie, J.D. Minna
Schering Corporation
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