JP2007525470A - Novel compounds and compositions comprising sterols and / or stanols and cholesterol biosynthesis inhibitors and their use in the treatment or prevention of various diseases and conditions - Google Patents

Abstract

Novel compounds and compositions containing sterols and / or stanols and cholesterol biosynthesis inhibitors, and their use in the treatment or prevention of various diseases and conditions. Novel compounds comprising sterols and / or stanols and cholesterol biosynthesis inhibitors (including salts of these compounds, and solvates and prodrugs of these compounds and / or salts) are provided. In another aspect, the present invention provides a composition comprising at least one sterol and / or stanol ester and at least one cholesterol biosynthesis inhibitor. Also provided are methods for treating and preventing various diseases, conditions and disorders by administering the compounds or compositions provided herein.
[Selection figure] None

Description

The present invention relates to the field of sterols, stanols and their novel derivatives and to their use in the treatment and prevention of cardiovascular and other diseases.

Recent advances in science and technology have helped to improve human life quality and prolong life, but the prevention of atherosclerosis, the root cause of cardiovascular disease (CVD), has not been adequately addressed . In fact, cardiovascular disease accounts for more deaths per year than other diseases including all forms of cancer (Non-Patent Document 1). Even in the United States, more than 1 million heart attacks occur every year, and more than 500,000 people die from it. This enormous victim needs ongoing research to determine the cause of CVD and the means to prevent and treat it.

The root cause of CVD is atherosclerosis, a disease characterized by the precipitation of lipids, such as cholesterol, into the arterial vessel wall that results in vascular narrowing and ultimately vascular stiffness. Atherosclerosis is a degenerative process resulting from the interaction of genetic factors and environmental factors such as diet and lifestyle. Studies to date have shown that cholesterol forms atherosclerotic plaques in blood vessels and ultimately cuts off blood supply to the myocardium or brain or extremities depending on the location of plaques in the arterial tree. This suggests that it may contribute to the disease (Non-Patent Documents 1 and 2). Total cholesterol levels above 225-250 mg / dl are associated with a significantly higher risk of CVD such as vascular disorders. An overview shows that a 1% reduction in human total serum cholesterol results in a 2% reduction in the risk of coronary events (3). Statistically, a 10% reduction in average serum cholesterol (eg, 6.0 mmol / L to 5.3 mmol / L) can result in the prevention of 100,000 deaths annually in the United States (4). .

Cholesteryl esters are a major cause of atheromatous lesions and the major storage form of cholesterol in arterial wall cells. Cholesteryl ester formation is also a step in the intestinal absorption of dietary cholesterol through a homeostatic control mechanism. These control mechanisms include interrelated regulation of dietary cholesterol, cholesterol biosynthesis and catabolism of cholesterol-containing plasma lipoproteins. Cholesterol biosynthesis and catabolism first occur in the liver and are therefore a major determinant of plasma cholesterol levels.

Lipoproteins are non-covalently bound lipid and protein complexes. Various lipoproteins have a unique mass, chemical composition, density and physiological role. Regardless of density or particle size, circulating lipids are composed of a core of cholesteryl esters and triglycerides, and a membrane of phospholipids, free cholesterol and apolipoprotein. Apolipoproteins are involved in lipoprotein assembly and secretion, impart structural integrity, activate lipoprotein denaturing enzymes, and are ligands for many types of receptors and membrane proteins. Lipoproteins found in plasma include HDL, LDL, intermediate density lipoprotein (IDL) and very low density lipoprotein (VLDL).

Each type of lipoprotein has a unique apolipoprotein composition or ratio. The most famous apolipoprotein in HDL is apolipoprotein-AI (apo-AI), which accounts for about 70% of the protein mass and another 20% is apo-AII. The ratio of ApoA-I to ApoA-II can determine HDL functional properties and anti-arteriosclerotic properties. The circulating HDL particles are composed of a heterogeneous mixture of disk-like and spherical particles having a mass of 200 to 400 kilodaltons and a diameter of 7 to 10 nm.

HDL is one of the major types of lipoproteins that function in the transport of lipids in plasma, and also reverse cholesterol transport, supply of cholesterol molecular substrates for bile acid synthesis, clusterin transport, paraoxanase transport, It has various functions in the body such as protein oxidation prevention and selective intake of cholesterol by adrenal cells. Major lipids associated with HDL include cholesterol, cholesteryl esters, triglycerides, phospholipids and fatty acids.

In order to fully understand how HDL is anti-atherosclerotic, a brief description of the arteriosclerosis process is necessary. The arteriosclerosis process begins with LDL being trapped inside the vessel wall. This oxidation of LDL causes binding to endothelial cells that line the blood vessel walls of mononuclear cells. These mononuclear cells are activated and enter the endothelial space where they are transformed into macrophages leading to further oxidation of LDL. Oxidized LDL is taken up by macrophages by the scavenger receptor, leading to foam cell formation. Fibrous capsules are generated by the proliferation and migration of arterial smooth muscle cells, thereby forming arteriosclerotic plaques.

HDL is essential for transporting cholesterol from tissues outside the liver to the liver and is excreted in the bile as free cholesterol or as a bile acid formed from cholesterol in the liver. The process requires several steps. The first process is the formation of newborn or pre-β HDL particles in the liver and intestine. Excess cholesterol moves through the cell membrane and into nascent HDL by the action of the ABC A1 transporter. Lecithin cholesterol acyltransferase (LCAT) converts cholesterol to cholesteryl ester, followed by conversion of nascent HDL to mature HDL. Esterified cholesterol is subsequently transferred from HDL to lipoproteins, including apolipoprotein-B, by cholesteryl ester transfer protein (CETP), which is taken up into the liver by a number of receptors (non-patent literature). 1). The nascent HDL is regenerated by liver triglyceride lipase and phospholipid transfer protein, and this cycle is repeated. In addition to cholesterol removed from peripheral cells, HDL receives cholesterol from LDL and erythrocyte membranes. Another mechanism for reverse cholesterol transport may involve passive diffusion of cholesterol between cholesterol-poor membranes and HDL or other receptor molecules.

HDL prevents the development of atherosclerosis both through its role in reverse cholesterol transport or possibly by preventing LDL oxidation. Several HDL related enzymes are involved in the process. Peroxonase (PON1), LCAT, and platelet activating factor acetylhydrolase (PAFAH) are all involved by hydrolyzing the phospholipid hydroperoxide produced during LDL oxidation, and of the oxidized lipids in LDL Work to prevent accumulation in cooperation. These enzymes are involved in the antioxidant and anti-inflammatory properties of HDL. Research papers show that low plasma concentrations of HDL cholesterol are an important risk factor for the development of atherosclerosis (Non-Patent Document 5), and its high level values prevent.

The liver is a major organ involved in the synthesis and secretion of VLDLs, and VLDLs are metabolized in the circulation to LDL as described above. LDLs are the major lipoproteins that transport cholesterol in plasma, and therefore their elevated levels are directly related to atherosclerosis. Simply put, less cholesterol absorption in the intestine will inevitably result in less cholesterol being delivered to the liver. As a result, VLDL production is reduced and at the same time hepatic clearance of plasma cholesterol, mostly in LDL form, is increased.

As a result, cholesterol acts in three different stages to regulate its own synthesis. First, it suppresses endogenous cholesterol synthesis by inhibiting the HMG CoA reductase enzyme. Second, activate LCAT. Third, the synthesis of the LDL-receptor is adjusted to ensure that cells that already have a sufficient amount of cholesterol do not take up additional cholesterol.

Sterols are naturally derived compounds that perform many important cellular functions. Sterols such as campesterol, stigmasterol and β-sitosterol in plants, ergosterol in fungi, and cholesterol in animals are the major components of the cell membrane and intracellular membrane, respectively, in each cell type. Human diet-derived phytosterols are derived from plant substances such as vegetables and vegetable oils. The estimated daily phytosterol content in a typical Western diet is about 60-80 milligrams, as opposed to a vegetarian dish that provides about 500 milligrams per day.

Phytosterol has received much attention due to its ability to lower serum cholesterol levels when supplied to many mammals such as humans. Although many of the exact mechanisms of action have not been elucidated, the relationship between cholesterol and phytosterols appears to be due in part to the similarity between their chemical structures (differences due to the side chains of the molecule). In the cholesterol absorption process, it is speculated that phytosterols replace micelle phase cholesterol, thereby reducing its absorption or competing with receptor and / or carrier sites.

Over 40 years ago, Eli Lilly found a sterol formulation derived from tall oil (later derived from soy oil) called Cytelin that was found to lower serum cholesterol by about 9% according to a paper. Was commercially available (Non-Patent Document 6). Various subsequent researchers have investigated the effects of cholesterol preparations on plasma lipid and lipoprotein concentrations (7) and the effects of sitosterol and campesterol from soy and tall oil sources on serum cholesterol. (Non-Patent Document 8). A composition of phytosterols that has been found to be very effective in lowering serum cholesterol is disclosed in US Pat. No. 5,770,749 to Katney et al., Which contains up to 70% by weight of β-sitosterol. , Containing at least 10% by weight campesterol and stigmasteranol (β-sitostanol). It is noted in this patent that some interaction exists between the constituent phytosterols, giving a cholesterol lowering result even better than previously obtained.

Many other compounds and compositions have been developed in the last decade with the aim of lowering serum LDL cholesterol, increasing serum HDL cholesterol, and preventing other significant risk factors for CVD.
US Pat. No. 5,770,749 Levi RI Declining Mortality in Coronary Heart Diseases Aerosclerosis 1981; 1: 312-325 Law R. Waldo N. J. et al. Wu. Hacksaw ZA. Bailey A. Systematic of of Between serum cholesteric concentration and ischemic heart dissertation in observative studies: Data from BUP Med. J. et al. 1994; 308: 363-366 La Rosa J.H. C. Hanning Hake D. Bush D. The cholesterol facts: A summary of the evidence releasing to dietary fats, the ensemble and the heart energetate, the joint energetate and the heart. Circulation 1990; 81: 1721-1733 Havel R. J. et al. Lapaport E. Drug Therapy: Management of Primary Hyperlipidemia. New England Journal of Medicine, 1995; 332: 1491-1498. Barker and Rye; Atherosclerosis 1996; 121: 1-12 Effects of plant sterols on cholesterol metabolism. Atherosclerosis, 1976-23: 239-248 Leeds R. S. Leeds A. M.M. Effects of situterotherapy on plasma lipid and lipoprotein contents. in: Greten H (Ed) Lipoprotein Metabolism. Springer-Verlag, Berlin, Heidelberg, New York, 1976: 119-124. Leeds A. M.M. Moku H. Y. I. Leeds S. McClassy M. A. Grundi S. M.M. Plant sterols as cholesterol-lowering agents: clinical trials in patents with hypercholesteria and studies of sterol balance. Atherosclerosis 1977; 28: 325-338.

The object of the present invention is to provide novel compounds that can obviate or reduce the disadvantages of previously known compounds that have been used to treat CVD and its underlying disorders such as lipid disorders.

The object of the present invention is to provide a novel composition that can obviate or reduce the disadvantages of previously known compositions used to treat CVD and its underlying disorders such as lipid disorders. .

（式中、Ｒはステロール又はスタノール部分を表し、Ｒ₂は少なくとも一つの遊離性及び
反応性カルボキシル基を有するコレステロール生合成阻害剤を表し；Ｒ₃は少なくとも一
つの遊離性及び反応性水酸基を有するコレステロール生合成阻害剤を表し；Ｒ₄はアスコ
ルビン酸に由来し、Ｘは水素原子であるか、又は、金属、アルカリ土類金属及びアルカリ金属からなる群から選択され、並びに、ｎは１−５を表す。）の一つ以上を有する新規化合物（生物学的に許容される塩又は溶媒和物、又は少なくとも一つの前記化合物の又はそれらの塩の又はそれらの溶媒和物のプロドラッグを含む。）を提供する。 In one aspect, the present invention provides the following chemical formula:

Wherein R represents a sterol or stanol moiety, R ₂ represents a cholesterol biosynthesis inhibitor having at least one free and reactive carboxyl group; R ₃ has at least one free and reactive hydroxyl group Represents a cholesterol biosynthesis inhibitor; R ₄ is derived from ascorbic acid, X is a hydrogen atom, or is selected from the group consisting of metals, alkaline earth metals and alkali metals, and n is 1-5 A novel compound (a biologically acceptable salt or solvate, or a prodrug of at least one of the aforementioned compounds or of their salts or of their solvates). )I will provide a.

（式中、Ｒはステロール又はスタノール部分を表し、Ｒ₄はアスコルビン酸に由来し、並
びにｎは１−５を表す。）の一般式を有する化合物（あらゆる生物学的に許容される塩又は溶媒和物、又は少なくとも一つの前記化合物の又はそれらの塩の又はそれらの溶媒和物のプロドラッグを含む。）から選択される少なくとも一つのコレステロール吸収阻害剤
ｂ）少なくとも一つのコレステロール生合成阻害剤
を含む組成物を提供する。 In another aspect, the present invention provides:
a)

(Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5) (any biologically acceptable salt or solvent) Or at least one cholesterol absorption inhibitor b) at least one cholesterol biosynthesis inhibitor selected from the group, or a prodrug of at least one of the above compounds or their salts or solvates thereof. A composition comprising is provided.

In another aspect, the present invention provides the following therapeutic purposes;
a) preventing, treating or alleviating one or more symptoms generally related to CVD, such as arteriosclerosis, atherosclerosis, arteriole sclerosis, angina and thrombosis,
b) reducing and / or eliminating one or more of the risk factors associated with CVD;
c) preventing, treating or reducing atherosclerosis,
d) preventing, treating or reducing hypercholesterolemia,
e) prevent, treat or alleviate high lipid symptoms;
f) preventing, treating or reducing lipid metabolism disorders;
g) preventing, treating or reducing hypertension,
h) preventing, treating or reducing coronary artery disease;
i) preventing, treating or reducing the occurrence of coronary plaque,
j) preventing, treating or reducing coronary plaque inflammation;
k) lowering serum LDL cholesterol,
l) increasing serum HDL cholesterol,
m) reducing serum triglyceride levels,
n) reducing cholesterol biosynthesis,
o) preventing, reducing, eliminating or ameliorating abnormal lipid metabolism conditions or disorders;
p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or low alpha lipoproteinemia,
q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaques;
r) preventing, reducing, eliminating or ameliorating the occurrence of inflammation associated with the occurrence of cardiovascular and coronary artery disease;
s) Lack of serum HDL or LDL, VLDL, Lp (a), beta-BLDL, I
Preventing, reducing, eliminating or ameliorating any symptoms, diseases or disorders that have or are exacerbated by excess DL or residual lipoproteins,
t) reducing the risk of seizures,
u) inhibiting isoprenoid synthesis;
v) preventing, treating or reducing Alzheimer's disease;
w) prevent, treat or alleviate dementia;
x) preventing, treating or reducing osteoporosis,
y) prevent, reduce, eliminate or ameliorate oxidative stress damage;
z) enhance and / or maintain the stability of HDL from oxidation,
aa) enhancing and / or maintaining the stability of LDL, VLDL, or IDL from oxidation,
bb) enhancing and / or maintaining the stability of triglycerides (TG) from oxidation;
cc) exhibit anticoagulant properties;
dd) exhibit anti-proliferative properties;
ee) exhibiting immunomodulatory properties;
ff) exhibiting blood vessel-derived properties;
gg) preventing, treating or reducing tumor growth;
hh) increasing bone mass and / or bone metabolism; and
ii) enhance any of the non-lipid related pleiotropic effects obtained by administration of statins, especially at the cellular or molecular level;
A method is provided for accomplishing one or more of the following, comprising administering to an animal a non-toxic and therapeutically effective amount of a compound or composition described and claimed herein.

In yet another aspect, the present invention relates to cardiovascular diseases and underlying symptoms (atherosclerosis, hypercholesterolemia, hyperlipidemia, lipid metabolism abnormality, hypertension, thrombosis, coronary artery disease, etc.) Including, but not limited to, a method of treating or preventing, or a method of treating or reducing inflammation, such as coronary plaque inflammation, said method comprising the non-toxic and non-toxic properties of one or more of the compounds set forth above Administration of a therapeutically effective amount to the animal.

In yet another aspect, the present invention relates to cardiovascular diseases and underlying symptoms (atherosclerosis, hypercholesterolemia, hyperlipidemia, lipid metabolism abnormality, hypertension, thrombosis, coronary artery disease, etc.) Including, but not limited to, methods of treating or preventing, or methods of treating or reducing inflammation, such as coronary plaque inflammation, wherein the prior methods are non-toxic of one or more of the compositions set forth above And administering a therapeutically effective amount to the animal.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising an effective or therapeutic amount of one or more of the novel compounds presented herein, and a pharmaceutically acceptable carrier. In a further aspect, the present invention provides an effective amount or therapeutic amount of at least one cholesterol absorption inhibitor having one of formulas i) -iv) together with an effective amount or therapeutic amount of at least one cholesterol biosynthesis inhibitor, and And a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

In a final aspect, the present invention provides an effective amount of at least one cholesterol absorption inhibitor having one of formulas i) -iv) in one container and a pharmaceutically acceptable carrier, and in another container A kit comprising an effective amount of at least one cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier is provided.

The most important aspect of the present invention is the supply and co-administration of a sterol and / or stanol with a cholesterol biosynthesis inhibitor such as preferably a statin. This can be accomplished in two ways.
1) by formation of a novel compound in which sterols and / or stanols are chemically linked in a unitary structure with the selected cholesterol biosynthesis inhibitor; and
2) By formation of a novel composition in which the selected cholesterol absorption inhibitor (in the form of a sterol and / or stanol ester or derivative) is mixed with the selected cholesterol biosynthesis inhibitor.

If the cholesterol biosynthesis inhibitor is derivatized with a sterol / stanol component, as described herein, or simply co-administered with sterol / stanol in the composition, a low dosage is selected. It is believed that cholesterol biosynthesis inhibitors may be required to obtain the desired effect. This is important because of proven adverse side effects in certain cholesterol biosynthesis inhibitors such as certain statins. The reduction of potential side effects is also considered important from a patient compliance perspective.

Some compounds of the present invention (expressed in the above formulas (e) and (f) and i) to iv) contain an ascorbyl moiety. These particular compounds have many advantages. In particular, the solubility in aqueous solutions such as water is improved by the ascorbyl moiety, thus allowing its own oral administration. Similarly, other dosage forms are facilitated. Accordingly, these selected compounds of the present invention can be prepared and used as such or can be readily incorporated into the pharmaceutical formulation whether or not the pharmaceutical formulation to be incorporated is aqueous. This enhanced solubility is generally interpreted as requiring low doses of the compound to achieve the desired therapeutic effect.

These effects and other important advantages will become apparent hereinafter.

The invention is illustrated by the following non-limiting figures,
FIG. 1 is a schematic diagram showing a method for preparing ascorbyl sitostanyl or campestanyl atorvastatin phosphate and its sodium salt;
FIG. 2 is a schematic diagram illustrating a method for preparing ascorbyl sitostanyl or campestanil simvastatin phosphate and its sodium salt;
FIG. 3 is a schematic diagram showing a method for preparing cytostanyl or campestanyl simvastatin phosphate;
FIG. 4 is a schematic diagram showing a method for preparing cytostanyl or campestanyl atorvastatin carboxylic acid ester.

The following detailed description is provided to assist those skilled in the art in practicing the present invention. However, this detailed description should not be construed to unduly limit the scope of the present invention. Modifications and variations of the embodiments discussed herein can be made by those skilled in the art without departing from the spirit and scope of the invention.

As used herein, “animal” means any member of the animal kingdom, including all mammals, most preferably humans.

As used herein, the term “prodrug” is a compound that is a drug precursor that, after administration to a patient, results in some chemical or physiological process (eg, a physiological pH, or It refers to a compound in which the drug is released in the body via enzymatic reaction, which converts the prodrug into the desired drug form.

As used herein, the term “solvate” refers to a solvent molecule or ion and a solute (eg, a compound of formula a) to f) or a prodrug of compounds a) to f). ) Molecule or ion complex. Non-limiting useful solvents include polar, protic solvents such as water and / or alcohol (eg methanol).

In the present specification, the term “compound” can be replaced with the terms “derivative”, “structure” and “analog”.

As used herein, the term “effective” or “therapeutically effective” is used to develop a biological or medical response in a cellular tissue, system, animal or mammal sought by a person administering the compound (s) or composition. In addition, it is intended to limit the amount of the compound (s) or composition administered to an animal, particularly a human, that achieves one or more of the following objectives.
a) preventing, treating or alleviating one or more symptoms generally related to CVD, such as arteriosclerosis, atherosclerosis, arteriole sclerosis, angina and thrombosis,
b) reducing and / or eliminating one or more of the risk factors associated with CVD;
c) preventing, treating or reducing atherosclerosis,
d) preventing, treating or reducing hypercholesterolemia,
e) prevent, treat or alleviate high lipid symptoms;
f) preventing, treating or reducing lipid metabolism disorders;
g) preventing, treating or reducing hypertension,
h) preventing, treating or reducing coronary artery disease;
i) preventing, treating or reducing the occurrence of coronary plaque,
j) preventing, treating or reducing coronary plaque inflammation;
k) lowering serum LDL cholesterol,
l) increasing serum HDL cholesterol,
m) reducing serum triglyceride levels,
n) reducing cholesterol biosynthesis,
o) preventing, reducing, eliminating or ameliorating abnormal lipid metabolism conditions or disorders;
p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or low alpha lipoproteinemia,
q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaques;
r) preventing, reducing, eliminating or ameliorating the occurrence of inflammation associated with the occurrence of cardiovascular and coronary artery disease;
s) Prevent any symptoms, diseases or disorders that have or are exacerbated by a lack of serum HDL or LDL, VLDL, Lp (a), beta-BLDL, IDL or excess of residual lipoproteins Reduce, eliminate or improve,
t) reducing the risk of seizures,
u) inhibiting isoprenoid synthesis;
v) preventing, treating or reducing Alzheimer's disease;
w) prevent, treat or alleviate dementia;
x) preventing, treating or reducing osteoporosis,
y) prevent, reduce, eliminate or ameliorate oxidative stress damage;
z) enhance and / or maintain the stability of HDL from oxidation,
aa) enhancing and / or maintaining the stability of LDL, VLDL, or IDL from oxidation,
bb) enhancing and / or maintaining the stability of triglycerides (TG) from oxidation;
cc) exhibit anticoagulant properties;
dd) exhibit anti-proliferative properties;
ee) exhibiting immunomodulatory properties;
ff) exhibiting blood vessel-derived properties;
gg) preventing, treating or reducing tumor growth;
hh) increasing bone mass and / or bone metabolism; and
ii) enhance any of the non-lipid related pleiotropic effects obtained by administration of statins, especially at the cellular or molecular level.

As used herein, the term “statin” inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase by competing with 3-hydroxy-3-methylglutanic acid to obtain a substrate binding site on HMG CoA reductase. , Including any natural or synthetic compound.

As used herein, the term “sterol” includes, without limitation, all sterols, eg, sitosterol, campesterol, stigmasterol (from any source and in any form (α, β and γ)). , Brush castrol (including dihydrobrass castrol), desmosterol, carinosterol, polyferasterol, cryoasterol, ergosterol, coprosterol, kodisosterol, isofucosterol, fucostosterol, clerolosterol, nervisterol, latosterol, stella Sterols, spinasterols, chondrasterols, pepostols, abenasterols, isoavenasterols, fecostosterols, polynassterols, cholesterol and all natural or synthetic forms thereof And a derivative (including isomers).

The term “stanol” means, for example: saturated or hydrogenated sterols, including all natural or synthetic forms and derivatives and isomers thereof (from any source and in any form (α, β and γ)) For example, sitostanol, campestanol, stigmasteranol, brush castanol (including dihydrobrush castanol), desmostanol, carinostanol, polyferrastanol, cliostananol, ergostanol, coprostanol, codistanol, isofucostanol, fucostanol, crilo Refers to stanol, nervistanol, latostanol, stellastanol, spinastanol, chondrastanol, pepostanol, abenastanol, isoavenastanol, fecostanol and polynastanol.

It is understood that modifications of sterols and stanols, ie including side chains, are also within the scope of the present invention. Unless otherwise specified throughout the specification and unless otherwise specified, the term “sterol” encompasses both sterols and stanols. The terms “phytosterol” and “phytostanol” may also be used, referring to plant-derived sterols or stanols, respectively.

The sterols and stanols used to form the derivatives according to the invention can be obtained from a variety of natural sources or they can be artificially synthesized. For example, they include corn oil and other vegetable oils, wheat germ oil, soybean extract, rice extract, rice bran, rapeseed oil, sunflower oil, sesame oil and other vegetable oils (including aquatic plants) and fish (and other marine raw materials) oils Can be obtained from the following processing. They can also be derived from fungi such as yeast and ergosterol. Thus, the present invention is not limited to a particular sterol source. U.S. Pat. No. 4,420,427 teaches a method for producing sterols from vegetable oil sludge using a solvent such as methanol. Also, phytosterols and phytostanols are derived from tall oil pitch or soap, which is a by-product of forestry operations, as described in US Pat. No. 5,770,749, incorporated herein by reference. Can be obtained. A further method for extracting sterols and stanols from tall oil pitch is described in Canadian Patent Application No. 2,230,373 filed Feb. 20, 1998 (international application filed Feb. 19, 1999). No. 10 / 060,022 filed on Jan. 28, 2002, the entire contents of which are hereby incorporated herein by reference. Incorporated into.

Thus, free sterols and stanols, esterified sterols and stanols with fatty acids or aromatic acids (resulting in the formation of fatty acid esters or aromatic acid esters, respectively), phenolic acid esters, cinnamic acid esters, ferrate esters, phytosterols and It is understood that the maximum possible definitions, including but not limited to phytostanol glycosides and acylated glycosides or acyl glycosides, are given herein for the terms “sterol” and “stanol”. Thus, the terms “sterol” and “stanol” encompass all analogs, which may further have a double bond at the fifth position in the cyclic unit, like many natural sterols, or It may have one or more double bonds at other positions in the ring (eg 6, 7, 8 (9), 8 (14), 14 5/7, etc.), or two in a cyclic unit like stanol It is not necessary to have a double bond. In addition, further methyl groups can be present, for example α ₁ -sitosterol.

Cholesterol Biosynthesis Inhibitor Within the scope of the present invention, and herein, the term “cholesterol biosynthesis inhibitor” refers to any compound that has an adverse effect on body cholesterol production, whatever the mechanism. Non-limiting examples of such compounds include 1) 3-hydroxy-3-methylglutaryl coenzyme A reductase “HMG CoA reductase”, 2) 3-hydroxy-3-methylglutaryl coenzyme A synthase “HMG CoA synthase” 3) squalene synthase, and 4) competitive inhibitors of squalene epoxidase.

HMG CoA reductase inhibitors are more commonly known as “statins”. These drugs have been used for primary and secondary prevention of coronary artery disease. HMG CoA reductase is a key enzyme in the cholesterol biosynthesis pathway. Statins reduce plasma total cholesterol and LDL cholesterol by reducing hepatic cholesterol biosynthesis (about 50% of circulating cholesterol is synthesized primarily endogenously as LDL cholesterol) and instead increasing production of LDL receptors. Decrease. Depending on the drug and dose, statins can also decrease serum triglyceride levels and increase serum HDL. Statins have become the standard treatment for lowering LDL cholesterol.

Indigestion, abdominal pain and intestinal gas filling are the most common side effects of statin administration. The most serious side effects of statins are elevated serum transaminase levels and the development of myositis.

Myotoxicity is a common effect of all statins at high doses. The mechanism appears to be mitochondrial oxidative damage. Statins cause a drop in lactate / pyruvate levels. The lactate / pyruvate ratio is a sensitive indicator of mitochondrial dysfunction and oxidation status. Statins have been shown in clinical studies to drastically reduce the essential cofactor required for energy production, Coenzyme Q. The decrease in coenzyme Q is dose dependent.
Coenzyme Q is an integral part of the mitochondrial electron transport process that supplies energy from the oxidation process. Statins function by blocking cholesterol synthesis in the catalytic process of HMG CoA reductase.

Mevalonate is used to synthesize cholesterol through a series of enzymatic steps. Mevalonate is also a precursor of coenzyme Q. Therefore, inhibition of cholesterol synthesis suppresses coenzyme Q synthesis. At the same time muscle cells with high energy requirements are most susceptible to damage by statins, hepatocytes are also susceptible to damage. The latter is probably the result of the relative hypoxic state of centrilobular hepatocytes, where the main blood supply is from the hepatic portal system. The most serious condition of muscle damage occurs when muscle cell contents are released into the systemic circulation (rhabdomyolysis). Serious complications include acute heart failure and heart abnormalities. Cardiotoxicity can be a direct effect of statins on myocardial coenzyme Q values.

These adverse effects often occur in combination with statins and other drugs that suppress the cytochrome P450 system, such as azole antifungals, cimetadine and methotrexate. The risk of statin-related myositis is increased in patients taking gemfibrozil, nicotinic acid or macrolides.

The literature reporting statin indications is widely known.

Even if there is no possibility of drug-drug interactions, the major side effects of statins in muscle are important inhibitors of continuing the drug treatment for patients. Since myotoxicity is dose dependent, any adjunct therapy that allows the use of small statin doses and still achieves target LDL cholesterol levels is highly desirable. Thus, there is a unique market for compounds and compositions within the scope of the present invention that can additionally work with statins to provide further reductions in LDL cholesterol without simultaneously increasing the risk of side effects.

The following list includes preferred statins according to the invention and their referenced patents, and as indicated herein, the references are hereby fully incorporated by reference.

The following list illustrates some preferred statin formulas.
Lovastatin: [1S [1a (R) 3alpha, 7beta, 8beta (2S, 4S), 8abeta]] 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [ 2- (Tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1-naphthalenyl-2-methylbutanoate.
Pravastatin sodium: 1-naphthalene-heptanoic acid, 1,2,6,7,8a-hexahydro-beta, δ, 6-trihydroxy-2-methyl-8- (2-ethyl-1-oxybutoxy) -1- Monosodium salt [1S- [1alpha (betas, δ, S), 2alpha, 6alpha, 8beta (R), 8aalpha.
Simvastatin: butanoic acid, 2,2dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl) ethyl] -1-naphthalenyl ester [1S- [1alpha, 3alpha, 7beta, 8beta, (2S, 4S),-8abeta.
Fluvastatin sodium: [R, S (E)]-(+/−)-7- [3 (4-fluorophenyl) -1- (1 methylethyl) -1H-indol-2-yl] -3,5 -Dihydroxy-6-heptenoic acid, monosodium salt.

The present invention should not be regarded as limited to the aforementioned statins alone. Naturally derived statins are fungal metabolites (ML) isolated from Psium Ultimum, Monax rubber, Penicillium citrinum, Penicillum brevicompactum and Aspergillus tereus
-236B / compactin / monocalin K), but as indicated above, they can also be produced synthetically. Statin derivatives are well known in the literature and can be prepared by the methods disclosed in US Pat. No. 4,397,786. Currently, other methods are well known in the art.

The most preferred statin structure for use in the present invention is as follows:

Squalene synthase inhibitors decrease the activity of squalene synthase and thus inhibit the conversion of farnesyl pyrophosphate to squalene. Squalene synthase inhibitors
1) reducing the activity of one or more enzymes or cofactors involved in the activation of squalene synthase 2) increasing the activity of one or more enzymes or cofactors involved in the down-regulation of squalene synthase, thereby increasing the activity of squalene synthase Can act directly or indirectly.

Suitable squalene synthase inhibitors include α-phosphono-sulfonates disclosed in US Pat. No. 5,712,396, such as isoprenoid (phosphinyl-methyl) phosphonates, and, for example, US Pat. No. 4,871,721. Other known squalene synthase inhibitors such as, but not limited to, terpenoid pyrophosphates, farnesyl diphosphate analog A and presqualene pyrophosphate analogs disclosed in US Pat.

Preferably, for use in the present invention, the cholesterol biosynthesis inhibitor is lovastatin (eg, Mevacor® available from Merck), pravastatin (eg, Pravacol available from Bristol-Myers Squibb) (Registered trademark: PRAVACHOL)), fluvastatin, simvastatin (for example, zocor (registered trademark: ZOCOL) available from Merck), atorvastatin, cerivastatin, CI-981 and pitavastatin (Negma Kowa of Japan NK- HMG CoA reductase inhibitor selected from the group consisting of: HMG CoA synthase inhibitors such as L-659,699 ((E, E) -11- [3R ′-(hydroxyl-methyl) -4′- Oxo-2 ' R-oxetanyl] -3,5,7R-trimethyl-2,4-undecadienoic acid) and the like; squalene synthesis inhibitors such as squalesatin 1; and squalene epoxidase inhibitors such as NB-598 ((E)- N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-[(3,3′-bithiophen5-yl) methoxy] benzene-methanamine hydrochloride) and the like Selected.

（式中、Ｒはステロール又はスタノール部分を表し、Ｒ₂は少なくとも一つの遊離性及び
反応性カルボキシル基を有するコレステロール生合成阻害剤を表し；Ｒ₃は少なくとも一
つの遊離性及び反応性水酸基を有するコレステロール生合成阻害剤を表し；Ｒ₄はアスコ
ルビン酸に由来し、Ｘは水素原子であるか、又は、金属、アルカリ土類金属及びアルカリ金属からなる群から選択され、並びに、ｎは１−５を表す。）本発明の範囲にある化合物は、全ての生物学的に許容される塩又は溶媒和物、又は少なくとも一つの前記化合物の又はそれらの塩の又はそれらの溶媒和物のプロドラッグを含む。 Compounds The compounds of the present invention comprise a sterol or stanol moiety and a cholesterol biosynthesis inhibitor moiety represented by one or more of the following formulae.

Wherein R represents a sterol or stanol moiety, R ₂ represents a cholesterol biosynthesis inhibitor having at least one free and reactive carboxyl group; R ₃ has at least one free and reactive hydroxyl group Represents a cholesterol biosynthesis inhibitor; R ₄ is derived from ascorbic acid, X is a hydrogen atom, or is selected from the group consisting of metals, alkaline earth metals and alkali metals, and n is 1-5 The compounds within the scope of the present invention are all biologically acceptable salts or solvates, or prodrugs of at least one of said compounds or of their salts or of their solvates. Including.

In a preferred form of the compound, the cholesterol biosynthesis inhibitor, R ₂ and R ₃ are selected from the group consisting of HMG CoA reductase antagonist, HMG CoA synthase antagonist, squalene synthase antagonist and squalene epoxidase antagonist. Selected. In a further preferred embodiment of the invention, R ₂ is either atorvastatin or pravastatin sodium. In a further preferred embodiment, R ₃ is either simvastatin or lovastatin.

It should be noted that the formation of compounds a), b), c) and e) can only be achieved by selecting cholesterol biosynthesis inhibitors having at least one free and reactive carboxyl group. It is. Similarly, the formation of compounds d) and f) can only be achieved by selecting cholesterol biosynthesis inhibitors having at least one free and reactive hydroxyl group. Based on this, appropriate cholesterol biosynthesis inhibitors need to be selected, but doing so is completely within the scope of its activity, even for chemistry students.

In the most preferred aspect of the invention, the compound formed between the sterol and / or stanol moiety and the selected cholesterol biosynthesis inhibitor is selected from the group consisting of:

Compound 1: Ascorbyl phytostanil atorvastatin sodium phosphate

Compound 2: Ascorbyl phytostanil pravastatin phosphate disodium

Compound 3: Ascorbyl phytostanil simvastatin sodium phosphate

Compound 4: Ascorbyl phytostanil lovastatin phosphate disodium

Compound 5: sitostanol-simvastatin phosphate

Compound 6: sitostanol (or campestanol) lovastatin phosphate sodium salt

Compound 7: sitostanol atorvastatin ester

Compound 8: sitostanol pravastatin ester

If desired, the compounds of the present invention are formed with naturally-occurring or artificially synthesized beta-sitosterol, campestanol, sitostanol and campesterol, and each of these so-formed compounds may be modified prior to delivery. Mixed in the pharmaceutical composition in a small proportion. In the most preferred form, the compound of the present invention comprises one or more ascorbyl phytoides comprising two major components: ascorbylcampestanyl disodium phosphate (“DACP”) and ascorbyl sitostanil disodium phosphate (“DASP”). A chemical bond is included between stannyl phosphate disodium (denoted herein as “FM-VP4”).

Salts As used herein, the term “biologically acceptable salt” refers to the desirable biological and / or physiological activity of the compounds described herein, with only minor undesirable toxic effects. Refers to any salt not shown. Thus, references to compounds of formula a) to f) include references to their acidic and / or basic salts formed with inorganic and / or organic acids and bases.

Typical acid addition salts include acetate (eg, formed with acetic acid or trihaloacetic acid such as trifluroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulphate, borate, butyrate Citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfonate, heptanoate, hexanoate, hydrochloride silobromide, hydroiodide, 2-hydroethanesulfonate, lactate, malate, methanesulfonate, 2-naphthalenesulfonate, Nicotinate, Nitrate, Oxalate, Pectinate, Persulfonate, 3-Phenylpropyronate, Phosphate, Piclay There pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, and the like undecanoate.

These compounds containing an acid moiety can form salts with various organic and inorganic bases.

Thus, the present invention not only encompasses the parent compound comprising a sterol and / or stanol and a cholesterol biosynthesis inhibitor, but if possible (ie, the parent compound includes a free hydroxyl group), the present invention is disclosed. Also included are biologically acceptable metals, alkaline earth metals or alkali metal salts of such compounds.

The salts described herein are much more water soluble than the corresponding parent compound, and therefore their effectiveness and evaluation both in vitro and in vivo can be enhanced.

Salt formation of the compounds of the present invention can be readily performed, for example, by treating any parent compound containing a free OH group with a series of bases such as sodium methoxide or other metal alkoxides. An alkali metal salt is formed. Other metal salts such as calcium, magnesium, manganese, copper, zinc, etc. can be generated by reacting the parent compound with a suitable metal alkoxide.

Compound Formation There are many processes by which new compounds consisting of sterols and / or stanols and selected cholesterol biosynthesis inhibitors can be formed. In some processes, where cholesterol biosynthesis inhibitors have at least one free and reactive carboxyl group, but are selected sterols or stanols (or their halophosphates, halocarbonates, or halo-oxalate derivatives) and Cholesterol biosynthesis inhibitors are mixed together under reaction conditions that allow condensation of the “acid” moiety with the “alcohol” (phytosterol). These conditions are such that the acid chloride formed from the acid component and the alcohol component can react directly or in the presence of a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, etc. This is the same as that used in other general esterification reactions. The organic solvent generally used in the esterification reaction is an ether such as diethyl ether or tetrahydrofuran, or benzene, toluene or a similar aromatic solvent, and the temperature is increased from room temperature to a high temperature depending on the reactivity of the reactant that causes the reaction. Can vary.

In another preferred embodiment, the process of forming the ester derivative comprises “protecting” the hydroxyl group of the cholesterol biosynthesis inhibitor as an ester (eg, acetate ester) or an ether (eg, methyl ether), and then protected cholesterol Condensing the biosynthesis inhibitor with a reactive sterol / stanol (or their halophosphate, halocarbonate or halo-oxalate) under appropriate reaction conditions. In general, the condensation reaction is carried out in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents. Depending on the type and reactivity of the reactants, the reaction temperature can vary from low temperature (-15 degrees) to high temperature.

As a non-limiting example, FIG. 1 shows the formation of alkorvir cytostanyl or campestanyl atovastatin phosphates and their sodium salts. Starting materials produced by previously developed methods are condensed with atorvastatin in the presence of sulfuric acid as a catalyst in a classic esterification process to form a linked product. The latter is then treated with sodium methoxide to give the sodium salt as the final product.

In another non-limiting alternative approach, illustrated in the diagram of FIG. 2, the process for producing ascorbyl sitostanyl or campestanyl simvastatin phosphate and their sodium salts is described. The starting material is obtained by treating the starting material already shown in FIG. 1 with phosphorus oxychloride to give the indicated dichlorophosphate. The latter is then treated with simvastatin, whereby the free hydroxyl group of the statin is replaced with a halogen atom of the more reactive chlorophosphate group to give a linked product. Following acidification with mineral acid, treatment with sodium methoxide yields the final product as the disodium salt.

In another non-limiting alternative approach illustrated in the diagram of FIG. 3, the process for producing sitostanyl or campestanyl simvastatin phosphate is described. Sitostanol or campestanol is treated with phosphorus oxychloride to give the corresponding chlorophosphate ester. This intermediate is then reacted with the statin in a pyridine / THF mixture in order to affect the chloride substitution by the hydroxyl group of simvastatin. The resulting linked product is treated with water to complete the synthesis of the final phosphate ester.

In another non-limiting alternative approach, illustrated in the diagram of FIG. 4, the process for producing sitostanyl or campestanyl atorvastatin carboxylate is described. Sitostanol or campestanol is treated with atorvastatin in the presence of sulfuric acid as a catalyst to give the ester through a classic esterification process.

Although selected synthetic processes have been described for the formation of these derivatives, it is understood that there are many other ways in which the various disclosed and claimed derivatives can be made. Once a particular derivative is selected, it is well within the scope of the skilled artisan to perform the synthesis using techniques generally available in the art. For this reason, the synthetic suite of all the claimed derivatives is not described.

If the compounds described herein and their salts can exist in their tautomeric form, all such tautomeric forms are considered as part of the invention herein.

All of the compounds of the present invention, such as stereoisomers that may exist with asymmetric carbon atoms in various components, including enantiomeric forms (which may exist in the absence of asymmetric carbon atoms) and diastereomeric forms Stereoisomers are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention can be mixed, for example, as a racemate, or can be mixed with all other or other selected stereoisomers. The chiral center of the compound has the S or R configuration as defined by the IUPAC 1974 recommendation. When diastereomeric or enantiomeric products are produced, they can be separated by conventional techniques such as chromatographic crystallization or fractional crystallization.

Compositions According to another aspect of the present invention, a novel comprising at least one sterol / stanol-based cholesterol absorption inhibitor mixed with at least one cholesterol biosynthesis inhibitor, as described herein. Compositions are provided, which include CVD and inflammation such as atherosclerosis, hypercholesterolemia, hyperlipidemia, dyslipidemia, hypertension, thrombosis, coronary artery disease and coronary plaque inflammation, etc. Is suitable for use in the treatment or prevention of the underlying symptoms, but not limited thereto.

（式中、Ｒはステロール又はスタノール部分を表し、Ｒ₄はアスコルビン酸に由来し、並
びにｎは１−５を表す。）を有する化合物（あらゆる生物学的に許容される塩又は溶媒和物、又は少なくとも一つの前記化合物の又はそれらの塩の又はそれらの溶媒和物のプロドラッグを含む。）から選択される少なくとも一つのコレステロール吸収阻害剤、及び
ｂ）少なくとも一つのコレステロール生合成阻害剤
を含む。 More specifically, the composition comprises a) a general formula

Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5. Any biologically acceptable salt or solvate, Or at least one cholesterol absorption inhibitor selected from at least one of the aforementioned compounds or their salts or solvates thereof, and b) at least one cholesterol biosynthesis inhibitor. .

The compounds of formulas i) to iv) can be prepared, for example, by the following method and international application PCT / CA00 / 00730 (filed June 20, 2000, U.S. patent application 09 / 339,903 (June 23, 1999)). Can be produced in a known manner as described in (claiming priority) from the application), the entire contents of which are hereby incorporated by reference.

In general, the compounds of formulas i) to iv) can be prepared as follows. The selected sterol or stanol (or their halophosphate, halocarbonate or halo-oxanate derivative) and ascorbic acid are mixed together under reaction conditions that allow condensation of the “acid” moiety with the “alcohol” (sterol). . These conditions include other conditions such as the Fischer esterification process where the acid and alcohol components can react directly or in the presence of a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid. These are the same as those used in the general esterification reaction. The organic solvent generally used for the esterification reaction is an ether such as diethyl ether or tetrahydrofuran, or benzene, toluene or a similar aromatic solvent, and the temperature varies from room temperature to a high temperature depending on the reactivity of the reactant causing the reaction. It can be.

In a preferred embodiment, the process of forming the ester comprises “protecting” the hydroxyl group of ascorbic acid or a derivative thereof as an ester (eg acetate ester) or ether (eg methyl ether) and then protecting the protected ascorbic acid. Condensing with sterol / stanol halophosphate, halocarbonate or halo-oxalate under appropriate reaction conditions. In general, the condensation reaction is carried out in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents. Depending on the type and reactivity of the reactants, the reaction temperature can vary from low temperature (-15 degrees) to high temperature.

More particularly, the following is one preferred method for preparing compounds of formulas i) to iv), in particular of formula i): First, ascorbic acid is degraded by formation of 5,6-isopropylidene-ascorbic acid. Protect from. This can be achieved by mixing acetone with ascorbic acid and an acidic catalyst such as sulfuric acid or hydrochloric acid under suitable reaction conditions. Phytostanol chlorophosphate forms a phytostanol solution in toluene and pyridine (although other nitrogen bases such as, for example, aliphatic or aromatic amines can be used instead) and this solution is converted to phosphorus oxychloride. It is manufactured by processing with phosphorus derivatives such as. The residue formed after filtration and concentration of the mother liquor is phytostanol chlorophosphate. The latter is then mixed with 5,6-isopropylidene-ascorbic acid and concentrated after adding an appropriate alcohol such as ethanol and HCl. Alternatively, pyridine / THF can be added to concentrate the product. After final washing and drying, the new product obtained is stanol-phosphate-alcolbate .

Another preferred form of the process for producing the compounds of formulas i) to iv) is that ascorbic acid is protected at the hydroxyl position as an ester (eg acetate, phosphate etc.) rather than as 5,6-isopropylidene-ascorbic acid. Is done. The latter can then be condensed with sterols or stanols derivatized as described above using known esterification techniques to ultimately produce the compound. The formation of monophosphate and diphosphate of ascorbic acid is fully described in the literature. For example, US Pat. No. 4,939,128 (Kato et al.), Incorporated herein by reference, teaches the formation of phosphate esters of ascorbic acid. Similarly, US Pat. No. 4,999,437 (Dobler et al.), Incorporated herein by reference, describes a process for producing ascorbic acid 2-phosphate. In Dobler et al., The core reaction of phosphorylation of ascorbic acid or an ascorbic acid derivative with POCl3 in the presence of a tertiary amine (disclosed in German Offenlegungsschrift 2,719,303) is carried out with magnesium in the reaction solution. Improvement is achieved by adding a compound, preferably an aqueous magnesium compound solution. Any known ascorbic acid derivative can be used.

More specifically, the following is another preferred method for preparing compounds of formulas i) to iv), especially formula ii): “Protected” ascorbic acid is provided and described in detail above. A process similar to that follows; however, the replacement of phosphorus oxychloride with oxalyl chloride yields stanol-oxalate-ascorbate.

In a preferred form, the composition of the present invention, together with at least one statin, has two major components: ascorbylcampestanyl disodium phosphate ("DACP") and ascorbyl sitostanyl phosphate disodium ("DASP"). ) Including one or more ascorbyl phytostanil phosphate disodium salts (referred to as “FM-VP4”).

In another preferred embodiment, sterol and / or stanol moieties can be incorporated into micelles before or after coupling with selected cholesterol biosynthesis inhibitors. The micelles can be produced using lecithin or any other suitable emulsifier and using methods known and widely applied in the art.

The composition of the present invention is such that the cholesterol absorption inhibitor and the cholesterol biosynthesis inhibitor are co-administered in a substantially simultaneous manner, such as in a single tablet or capsule having a fixed ratio of active ingredient, or This allows for "combination therapy" in which multiple therapeutic agents are administered separately. This separate administration includes continuous dosage forms.

USES OF THE INVENTION The following therapeutic objectives a) are generally related to CVD and prevent or treat one or more symptoms such as arteriosclerosis, atherosclerosis, arteriole sclerosis, angina and thrombosis, or Mitigating,
b) reducing and / or eliminating one or more of the risk factors associated with CVD;
c) preventing, treating or reducing atherosclerosis,
d) preventing, treating or reducing hypercholesterolemia,
e) prevent, treat or alleviate high lipid symptoms;
f) preventing, treating or reducing lipid metabolism disorders;
g) preventing, treating or reducing hypertension,
h) preventing, treating or reducing coronary artery disease;
i) preventing, treating or reducing the occurrence of coronary plaque,
j) preventing, treating or reducing coronary plaque inflammation;
k) lowering serum LDL cholesterol,
l) increasing serum HDL cholesterol,
m) reducing serum triglyceride levels,
n) reducing cholesterol biosynthesis,
o) preventing, reducing, eliminating or ameliorating abnormal lipid metabolism conditions or disorders;
p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or low alpha lipoproteinemia,
q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaques;
r) preventing, reducing, eliminating or ameliorating the occurrence of inflammation associated with the occurrence of cardiovascular and coronary artery disease;
s) Prevent any symptoms, diseases or disorders that have or are exacerbated by a lack of serum HDL or LDL, VLDL, Lp (a), beta-BLDL, IDL or excess of residual lipoproteins Reduce, eliminate or improve,
t) reducing the risk of seizures,
u) inhibiting isoprenoid synthesis;
v) preventing, treating or reducing Alzheimer's disease;
w) prevent, treat or alleviate dementia;
x) preventing, treating or reducing osteoporosis,
y) prevent, reduce, eliminate or ameliorate oxidative stress damage;
z) enhance and / or maintain the stability of HDL from oxidation,
aa) enhancing and / or maintaining the stability of LDL, VLDL, or IDL from oxidation,
bb) enhancing and / or maintaining the stability of triglycerides (TG) from oxidation;
cc) exhibit anticoagulant properties;
dd) exhibit anti-proliferative properties;
ee) exhibiting immunomodulatory properties;
ff) exhibiting blood vessel-derived properties;
gg) preventing, treating or reducing tumor growth;
hh) increasing bone mass and / or bone metabolism; and
ii) enhance any of the non-lipid related pleiotropic effects obtained by administration of statins, especially at the cellular or molecular level;
A method is provided for accomplishing one or more of the above, comprising administering to an animal a non-toxic and therapeutically effective amount of a compound or composition described and claimed herein.
The present invention further relates to the disclosed compounds and compositions for use in achieving one or more of the therapeutic purposes defined above for the symptoms described herein. Including any use.

In particular, the compounds and compositions of the present invention have been shown to be particularly useful in addressing at least two important factors that contribute to the multifactorial symptoms of cardiovascular disease: intestinal cholesterol absorption and internal cholesterol biosynthesis. . Serum cholesterol levels are controlled primarily by two organs: the liver (which produces cholesterol and bile acids (used for digestion)) and the intestine (which absorbs cholesterol from both food and bile (produced in the liver)). Sterols lower LDL serum cholesterol levels by a unique mechanism of action by inhibiting cholesterol absorption in the intestine. This mechanism of action complements sterols with cholesterol biosynthesis inhibitors that work in the liver, such as statins. Thus, patients taking sterols with statins can achieve further reductions in LDL and total cholesterol.

Therefore, it is highly advantageous to administer a portion that simultaneously reduces cholesterol absorption (eg, sterol / stanol) and another portion that reduces cholesterol biosynthesis (eg, statin). This is due to the administration of at least one compound of the formulas a) to f) or of one of the cholesterol absorption inhibitors (formulas i) to iv)) and a cholesterol biosynthesis inhibitor This is achieved by administration.

Ultimately, the most important benefits arising from the use of the compounds and compositions described herein are a reduction in serum LDL cholesterol, along with the additional beneficial effects obtained by increasing serum HDL cholesterol and decreasing serum triglycerides. And a reduction in total serum cholesterol. These benefits are achieved without the side effects associated with statin administration.

In addition, the overall hydrophobicity of cholesterol biosynthesis inhibitors (such as statins) can be reduced by covalently modifying the compounds of the present invention with the sterol-based cholesterol absorption inhibitors described herein. There are significant biological effects (and benefits) of changing. Specifically, the compounds of the present invention are generally more hydrophobic than natural statins. This is important in at least two aspects. First, it can increase the pleotrophic effect of statins. Second, if the compound is absorbed as is, the ADME properties of statins can be different, which can reduce potential toxicity, among other advantages.

While not intending to be bound by any one theory about the mechanism of action, the structural change of the compound, compared to the free statin, results in a high proportional distribution to the serum lipoprotein pool, so that the drug is transported specifically by HDL A greater proportion of the active ingredient is transported to peripheral tissues. This can greatly increase the potential effects of the compounds of the invention on the many reported “statin” symptoms, such as Alzheimer's disease and osteoporosis.

Furthermore, some of the compounds of the present invention (represented by formulas (e) to (f) and i) to iv) contain an ascorbyl moiety. These particular compounds have a number of additional advantages. First and foremost, the solubility of the compound is greatly increased in both aqueous solutions and non-aqueous media such as oils and fats. This excellent solubility can also reduce effective food and dosage, and concomitant costs. Secondly, when combined in a single structure, not only cardiovascular disease but also the underlying symptoms such as atherosclerosis and hyperlipidemia can be treated with phytosterols and ascorbic acid. There can even be synergistic or even additional effects. Third, the formation of these compounds eliminates degradation and allows the full potential of ascorbic acid to be realized. Fourth, these derivatives are heat resistant (stable to oxidation and hydrolysis) essential for some processing mechanisms.

The desired effects described herein can be achieved in a variety of different ways. The compounds and compositions of the invention can be administered using any conventional technique available for use with pharmaceuticals. Accordingly, the present invention in one aspect relates to a pharmaceutical composition comprising one or more compounds of formulas a) to f) and a pharmaceutically acceptable carrier. In another aspect, the present invention provides an effective amount or therapeutic amount of at least one cholesterol absorption inhibitor having one of formulas i) -iv), an effective amount and a therapeutic amount of at least one cholesterol biosynthesis inhibitor and It relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier. These compounds and / or compositions can be administered in any common dosage form, preferably in oral dosage forms such as tablets, capsules, powders, cachets, suspensions or solutions. The pharmaceutical composition may comprise from about 1% to 99% “active” ingredients (cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors), preferably from about 5% to 95% active ingredients.

Formulations and pharmaceutical compositions can be prepared by conventional techniques using conventional, pharmaceutically acceptable excipients and additives. The pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavorings, thickeners, colorants. And emulsifiers.

The exact amount or dose of compound and composition required to achieve the desired effect will, of course, be determined by selection of the particular compound or composition, efficacy of the administered compound or composition, method of administration, and age, weight, Depends on many factors such as symptoms and patient response. In particular, all of these factors are considered for each individual or patient by the attending physician.

For pharmaceutical compositions comprising at least one cholesterol absorption inhibitor having one of the formulas i) -iv) together with at least one cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier, usually once or twice a day A typical daily dose of a cholesterol biosynthesis inhibitor administered in a single dose or multiple doses of can range from about 0.1 mg to 160 mg / kg of mammal body weight per day, preferably It can range from 2 mg to 80 mg. For example, for an HMG CoA reductase inhibitor, about 0.25 mg to 40 mg per dose is given once or twice per day, giving a total daily dose of about 0.5 mg to 80 mg per day. For other cholesterol biosynthesis inhibitors, about 1 mg to about 1000 mg per dose is given once or twice per day, giving a total daily dose of about 1 mg to about 2000 m per day.

In general, the total daily dose of a cholesterol absorption inhibitor having one of formulas i) -iv) and comprising sterols and / or stanols is 10 mg to about 20 g per day in a single dose or multiple doses, more preferably A daily dose range of 10 mg to 1.5 g may be administered.

When the components of the compound are administered separately, the number of administrations and the total amount of each dose given per day need not be the same. For example, cholesterol absorption inhibitors may require a larger number of doses per day and / or require larger doses than cholesterol biosynthesis inhibitors.

Daily doses of these compounds and compositions are administered to an individual as a single dose or multiple doses, as needed. Sustained release doses can be used.

The use of pharmaceutically acceptable carriers to formulate the compounds and compositions disclosed herein for the practice of the invention in dosages suitable for in vivo administration is within the scope of the invention. By selection of appropriate carriers and suitable manufacturing practices, the compounds and compositions of the present invention, especially those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds and compositions can be readily formulated into formulations suitable for oral administration using pharmaceutically acceptable carriers known to those skilled in the art. The carrier allows the compounds and compositions of the invention to be formulated as tablets, tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral consumption by the patient being treated. To do.

Pharmaceutical compositions containing one or more of the compounds of the present invention include those wherein the active ingredients are contained in an amount effective to achieve their originally intended purpose. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

In addition to the active ingredient, these pharmaceutical compositions can contain suitable pharmaceutically acceptable carriers that can be used pharmaceutically and include excipients and adjuvants that facilitate the processing of the active compound in the formulation. Formulations formulated for oral administration can be in the form of tablets, dragees, capsules or solutions.

The pharmaceutical composition of the present invention can be manufactured by a method known per se, for example, by a conventional method such as mixing, dissolution, granulation, sugar-coated tablet formation, starch syrup, emulsification, encapsulation, encapsulation or lyophilization process. .

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances such as sodium carboxymethyl cellulose, sorbitol or dextran that increase the viscosity of the suspension. If desired, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the production of highly concentrated solutions.

Oral pharmaceutical preparations can be obtained by combining the active compound with solid excipients, optionally milling the resulting mixture, adding appropriate adjuvants, and then processing the granule mixture. If necessary, obtain a tablet or dragee core. Suitable excipients include lactose, sucrose, mannitol, sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, carboxymethylcellulose sodium, and polyvinylpyrrolidone (PVP) There is. If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which are optionally gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Can be included. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-in capsules may contain the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
In addition, stabilizers can also be added.

Oral liquid formulations may be in the form of an emulsion, syrup or elixir, or presented as a dry product that is reconstituted with water or other suitable vehicle prior to use. The liquid formulation may be a suspending agent such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fat, etc .; emulsifier such as lecithin, sorbitan monooleate or acacia; Vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate, or sorbic acid; And, if necessary, conventional additives such as conventional flavors or colorants may be included.

Since the present invention relates to a composition having a combination of active ingredients that can be co-administered or separately administered, a kit for said purpose is also provided herein. The kit comprises two separate units: a pharmaceutical composition comprising at least one cholesterol biosynthesis inhibitor described herein, and another medicament comprising at least one cholesterol absorption inhibitor described herein. Composition: is intended to be combined. The kit preferably includes instructions for administration of the separate components. This kit type arrangement is particularly useful when the separate components must be administered in different dosage forms (eg, oral and parenteral) or are administered at different dosage intervals.

Without further elaboration, the foregoing description fully describes the present invention, so that others can apply their current or future knowledge under the various circumstances described and claimed herein. The present invention can be adapted for use in.

Reference 1. Levi RI Declining Mortality in Coronary Heart Diseases Aerosclerosis 1981; 1: 312-325
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FIG. 1 is a schematic diagram showing a method for preparing ascorbyl sitostanyl or campestanyl atorvastatin phosphate and its sodium salt. FIG. 2 is a schematic diagram showing a method for preparing ascorbyl sitostanyl or campestanyl simvastatin phosphate and its sodium salt. FIG. 3 is a schematic diagram showing a method for preparing cytostanyl or campestanyl simvastatin phosphate. FIG. 4 is a schematic diagram showing a method for preparing cytostanyl or campestanyl atorvastatin carboxylic acid ester.

Claims (43)

Including sterols or stanols (including biologically acceptable salts thereof)

Wherein R represents a sterol or stanol moiety, R ₂ represents a cholesterol biosynthesis inhibitor having at least one free and reactive carboxyl group; R ₃ has at least one free and reactive hydroxyl group Represents a cholesterol biosynthesis inhibitor; R ₄ is derived from ascorbic acid, X is a hydrogen atom, or is selected from the group consisting of biologically acceptable metals or alkaline earth metals, and n Represents one or more of the following: (a biologically acceptable salt or solvate, or at least one of the compounds or their salts or their solvents) Including Japanese prodrugs). The sterols are sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrass castrol), desmosterol, carinosterol, polyferasterol, cryonasterol, ergosterol, coprosterol, kodisosterol, isofucosterol, fuco It is selected from the group consisting of sterols, clerolosterols, nerbisterols, latosterols, stellaterols, spinasterols, chondirasterols, pepostolols, abenasterols, isoabenasterols, fecosterols and polynassterols. The compound of claim 1. The stanol is sitostanol, campestanol, stigmasteranol, brush castanol (including dihydrobrush castanol), desmostanol, carinostanol, polyferastanol, cliostananol, ergostanol, coprostanol, codystanol, isofcostanol, Characterized in that it is selected from the group consisting of fucostanol, clerostanol, nervistanol, latostanol, stellastanol, spinastanol, chondrastanol, pepostanol, abenastanol, isoavenastanol, fecostanol and polynastanol, The compound of claim 1. The compound according to claim 1, wherein the sterol and stanol are in a natural or artificially synthesized form. The compound of claim 1, wherein the sterol and stanol are in any one of their isomeric forms. The R ₂ and R ₃ are selected from the group consisting of an HMG CoA reductase antagonist, an HMG CoA synthase antagonist, a squalene synthase antagonist, and a squalene epoxidase antagonist. The described compound. _2. A compound according to claim 1, characterized in that R2 represents atorvastatin or pravastatin. Wherein R ₃ is equal to or representing the simvastatin or lovastatin, a compound according to claim 1. The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein The following chemical formula

The compound according to claim 1, wherein a) General formula

Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5. Any biologically acceptable salt or solvate, Or at least one cholesterol absorption inhibitor selected from at least one of the above-mentioned compounds or their salts or solvates thereof; and b) at least one cholesterol biosynthesis inhibitor. Composition. The sterols are sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrass castrol), desmosterol, carinosterol, polyferasterol, cryonasterol, ergosterol, coprosterol, kodisosterol, isofucosterol, fuco Characterized in that it is selected from the group consisting of sterols, clerolosterols, nerbosterols, latosterols, stellaterols, spinasterols, chondirasterols, pepostosterols, abenasterols, isoavenasterols, fecostosterols and polynassterols. 18. A composition according to claim 17. The stanol is sitostanol, campestanol, stigmasteranol, brush castanol (including dihydrobrush castanol), desmostanol, carinostanol, polyferastanol, cliostananol, ergostanol, coprostanol, codystanol, isofcostanol, Characterized in that it is selected from the group consisting of fucostanol, clerostanol, nervistanol, latostanol, stellastanol, spinastanol, chondrastanol, pepostanol, abenastanol, isoavenastanol, fecostanol and polynastanol, The composition of claim 17. 18. The composition of claim 17, wherein the sterol and stanol are in a natural or artificially synthesized form. 18. A composition according to claim 17, characterized in that the sterol and stanol are in any one of their isomeric forms. The cholesterol biosynthesis inhibitor is selected from the group consisting of an HMG CoA reductase antagonist, an HMG CoA synthase antagonist, a squalene synthase antagonist, and a squalene epoxidase antagonist. The composition as described. 18. The composition according to claim 17, wherein the cholesterol biosynthesis inhibitor is a statin. The cholesterol biosynthesis inhibitor is lovastatin, pravastatin, pravastatin sodium, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 and pitavastatin, L-659,699 ((E, E) -11- [3'R- ( Hydroxylmethyl) -4′-oxo-2′R-oxetanyl] -3,5,7R-trimethyl-2,4-undecadienoic acid), mevastatin, verostatin, compactin, dalvastatin, fluindostatin, dihydrocompactin, itavastatin , Squalesstatin 1, NB-598 ((E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-[(3,3′-bithiophen-5-yl) ) Methoxy] benzene-methanamine hydrochloride) It is characterized in that it is selected from the group consisting of mixtures, 18. The composition of claim 17. The following chemical formula

Wherein R represents a sterol or stanol moiety, R ₂ represents a cholesterol biosynthesis inhibitor having at least one free and reactive carboxyl group; R ₃ has at least one free and reactive hydroxyl group Represents a cholesterol biosynthesis inhibitor; R ₄ is derived from ascorbic acid, X is a hydrogen atom, or is selected from the group consisting of metals, alkaline earth metals and alkali metals, and n is 1-5 At least one compound (a biologically acceptable salt or solvate, or a prodrug of at least one of said compounds or of their salts or of their solvates) And a pharmaceutically acceptable carrier therefor. 26. The R ₂ and R ₃ are selected from the group consisting of HMG CoA reductase antagonist, HMG CoA synthase antagonist, squalene synthase antagonist, and squalene epoxidase antagonist. The composition as described. Wherein R ₂ is equal to or representative of the atorvastatin or pravastatin (provastatin), 25. A composition according. Wherein R ₃ is equal to or representing the simvastatin or lovastatin, 25. A composition according. a) General formula

Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5. Any biologically acceptable salt or solvate, Or at least one cholesterol absorption inhibitor selected from at least one prodrug of said compound or a salt thereof or a solvate thereof;
A pharmaceutical composition comprising b) at least one cholesterol biosynthesis inhibitor; and c) a pharmaceutically acceptable carrier therefor. 30. The cholesterol biosynthesis inhibitor is selected from the group consisting of an HMG CoA reductase antagonist, an HMG CoA synthase antagonist, a squalene synthase antagonist, and a squalene epoxidase antagonist. The composition as described. 30. The composition of claim 29, wherein the cholesterol biosynthesis inhibitor is a statin. The cholesterol biosynthesis inhibitor is lovastatin, pravastatin, pravastatin sodium, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 and pitavastatin, L-659,699 ((E, E) -11- [3'R- ( Hydroxylmethyl) -4′-oxo-2′R-oxetanyl] -3,5,7R-trimethyl-2,4-undecadienoic acid), mevastatin, verostatin, compactin, dalvastatin, fluindostatin, dihydrocompactin, itavastatin , Squalesstatin 1, NB-598 ((E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-[(3,3′-bithiophen-5-yl) ) Methoxy] benzene-methanamine hydrochloride) It is characterized in that it is selected from the group consisting of mixtures according to claim 29 composition. The sterols are sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrass castrol), desmosterol, carinosterol, polyferasterol, cryonasterol, ergosterol, coprosterol, kodisosterol, isofucosterol, fuco It is selected from the group consisting of sterols, clerolosterols, nerbisterols, latosterols, stellaterols, spinasterols, chondirasterols, pepostolols, abenasterols, isoabenasterols, fecosterols and polynassterols 30. A composition according to claim 25 or claim 29. The stanol is sitostanol, campestanol, stigmasteranol, brush castanol (including dihydrobrush castanol), desmostanol, carinostanol, polyferastanol, cliostananol, ergostanol, coprostanol, codystanol, isofcostanol, Characterized in that it is selected from the group consisting of fucostanol, clerostanol, nervistanol, latostanol, stellastanol, spinastanol, chondrastanol, pepostanol, abenastanol, isoavenastanol, fecostanol and polynastanol, 30. A composition according to claim 25 or claim 29. The following therapeutic purposes:
a) preventing, treating or alleviating one or more symptoms generally related to CVD, such as arteriosclerosis, atherosclerosis, arteriole sclerosis, angina and thrombosis,
b) reducing and / or eliminating one or more of the risk factors associated with CVD;
c) preventing, treating or reducing atherosclerosis,
d) preventing, treating or reducing hypercholesterolemia,
e) prevent, treat or alleviate high lipid symptoms;
f) preventing, treating or reducing lipid metabolism disorders;
g) preventing, treating or reducing hypertension,
h) preventing, treating or reducing coronary artery disease;
i) preventing, treating or reducing the occurrence of coronary plaque,
j) preventing, treating or reducing coronary plaque inflammation;
k) lowering serum LDL cholesterol,
l) increasing serum HDL cholesterol,
m) reducing serum triglyceride levels,
n) reducing cholesterol biosynthesis,
o) preventing, reducing, eliminating or ameliorating abnormal lipid metabolism conditions or disorders;
p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or low alpha lipoproteinemia,
q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaques;
r) preventing, reducing, eliminating or ameliorating the occurrence of inflammation associated with the occurrence of cardiovascular and coronary artery disease;
s) Prevent any symptoms, diseases or disorders that have or are exacerbated by a lack of serum HDL or LDL, VLDL, Lp (a), beta-BLDL, IDL or excess of residual lipoproteins Reduce, eliminate or improve,
t) reducing the risk of seizures,
u) inhibiting isoprenoid synthesis;
v) preventing, treating or reducing Alzheimer's disease;
w) prevent, treat or alleviate dementia;
x) preventing, treating or reducing osteoporosis,
y) prevent, reduce, eliminate or ameliorate oxidative stress damage;
z) enhance and / or maintain the stability of HDL from oxidation,
aa) enhancing and / or maintaining the stability of LDL, VLDL, or IDL from oxidation,
bb) enhancing and / or maintaining the stability of triglycerides (TG) from oxidation;
cc) exhibit anticoagulant properties;
dd) exhibit anti-proliferative properties;
ee) exhibiting immunomodulatory properties;
ff) exhibiting blood vessel-derived properties;
gg) preventing, treating or reducing tumor growth;
hh) increasing bone mass and / or bone metabolism; and
ii) enhance any of the non-lipid related pleiotropic effects obtained by administration of statins, especially at the cellular or molecular level;
A method for achieving one or more of the following chemical formulas:

Wherein R represents a sterol or stanol moiety, R ₂ represents a cholesterol biosynthesis inhibitor having at least one free and reactive carboxyl group; R ₃ has at least one free and reactive hydroxyl group Represents a cholesterol biosynthesis inhibitor; R ₄ is derived from ascorbic acid, X is a hydrogen atom, or is selected from the group consisting of metals, alkaline earth metals and alkali metals, and n is 1-5 (Including biologically acceptable salts or solvates, or prodrugs of at least one of the compounds or of their salts or of their solvates). Administering a non-toxic and therapeutically effective amount of to an animal. Wherein R ₂ and R ₃ are HMG CoA reductase competitive inhibitors, HMG CoA synthase competitive inhibitor, a squalene synthetase competitive inhibitor, and characterized in that it is selected from the group consisting of squalene epoxidase competitive inhibitor of claim 35 The method described. Wherein R ₂ is equal to or representative of the atorvastatin or pravastatin (provastatin), The method of claim 35. Wherein R ₃ is equal to or representing the simvastatin or lovastatin method of claim 35, wherein. The following therapeutic purposes:
a) preventing, treating or alleviating one or more symptoms generally related to CVD, such as arteriosclerosis, atherosclerosis, arteriole sclerosis, angina and thrombosis,
b) reducing and / or eliminating one or more of the risk factors associated with CVD;
c) preventing, treating or reducing atherosclerosis,
d) preventing, treating or reducing hypercholesterolemia,
e) prevent, treat or alleviate high lipid symptoms;
f) preventing, treating or reducing lipid metabolism disorders;
g) preventing, treating or reducing hypertension,
h) preventing, treating or reducing coronary artery disease;
i) preventing, treating or reducing the occurrence of coronary plaque,
j) preventing, treating or reducing coronary plaque inflammation;
k) lowering serum LDL cholesterol,
l) increasing serum HDL cholesterol,
m) reducing serum triglyceride levels;
n) reducing cholesterol biosynthesis,
o) preventing, reducing, eliminating or ameliorating abnormal lipid metabolism conditions or disorders;
p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or low alpha lipoproteinemia,
q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaques;
r) preventing, reducing, eliminating or ameliorating the occurrence of inflammation associated with the occurrence of cardiovascular and coronary artery disease;
s) Prevent any symptoms, diseases or disorders that have or are exacerbated by a lack of serum HDL or LDL, VLDL, Lp (a), beta-BLDL, IDL or excess of residual lipoproteins Reduce, eliminate or improve,
t) reducing the risk of seizures,
u) inhibiting isoprenoid synthesis;
v) preventing, treating or reducing Alzheimer's disease;
w) prevent, treat or alleviate dementia;
x) preventing, treating or reducing osteoporosis,
y) prevent, reduce, eliminate or ameliorate oxidative stress damage;
z) enhance and / or maintain the stability of HDL from oxidation,
aa) enhancing and / or maintaining the stability of LDL, VLDL, or IDL from oxidation,
bb) enhancing and / or maintaining the stability of triglycerides (TG) from oxidation;
cc) exhibit anticoagulant properties;
dd) exhibit anti-proliferative properties;
ee) exhibiting immunomodulatory properties;
ff) exhibiting blood vessel-derived properties;
gg) preventing, treating or reducing tumor growth;
hh) increasing bone mass and / or bone metabolism; and
ii) enhance any of the non-lipid related pleiotropic effects obtained by administration of statins, especially at the cellular or molecular level;
A method of achieving one or more of the following:
a) General formula

Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5. Any biologically acceptable salt or solvate, Or at least one cholesterol absorption inhibitor selected from at least one of the aforementioned compounds or their salts or solvates thereof; and b) the non-toxicity of at least one cholesterol biosynthesis inhibitor. And administering a therapeutically effective amount to the animal. 40. The cholesterol biosynthesis inhibitor is selected from the group consisting of an HMG CoA reductase antagonist, an HMG CoA synthase antagonist, a squalene synthase antagonist, and a squalene epoxidase antagonist. The method described. 40. The method of claim 39, wherein the cholesterol biosynthesis inhibitor is a statin. The cholesterol biosynthesis inhibitor is lovastatin, pravastatin, pravastatin sodium, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 and pitavastatin, L-659,699 ((E, E) -11- [3'R- ( Hydroxylmethyl) -4′-oxo-2′R-oxetanyl] -3,5,7R-trimethyl-2,4-undecadienoic acid), mevastatin, verostatin, compactin, dalvastatin, fluindostatin, dihydrocompactin, itavastatin , Squalesstatin 1, NB-598 ((E) -N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl) -3-[(3,3′-bithiophen-5-yl) ) Methoxy] benzene-methanamine hydrochloride) The method of of being selected from the group consisting of mixtures according to claim 39, wherein. At least two other ingredients:
a) General formula

Wherein R represents a sterol or stanol moiety, R ₄ is derived from ascorbic acid, and n represents 1-5. Any biologically acceptable salt or solvate, Or a composition comprising at least one cholesterol absorption inhibitor selected from at least one of the aforementioned compounds or their salts or solvates thereof; and b) at least one cholesterol biosynthesis. A composition comprising an inhibitor;
In combination with instructions describing the administration of each composition.

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