MXPA99010404A - Monoesters of probucol for the treatment of cardiovascular and inflammatory disease - Google Patents

Abstract

This invention is a method and composition for the inhibition of VCAM-1, and in particular for the treatment of cardiovascular or inflammatory disease, including atherosclerosis, that includes the administration of an effective amount of an ester of probucol.

Description

PROBUCOL MONOESTERS FOR THE TREATMENT OF CARDIOVASCULAR AND INFLAMMATORY DISEASE This invention is a method and composition for the inhibition of VCAM-1 and in particular for the treatment of cardiovascular or inflammatory diseases, including atherosclerosis, including administration of a effective amount of a probucol ester.

BACKGROUND OF THE INVENTION [0002] Cardiovascular disease is currently the leading cause of death in the United States. Approximately ninety percent of cardiovascular disease is currently diagnosed as atherosclerosis. Cardiovascular disease has been linked to several causative factors, including hypercholesterolemia, hyperlipidemia and VCAM-1 expression in vascular endothelial cells.

Hypercholesterolemia and Hyperlipidemia Hypercholesterolemia is an important risk factor associated with cardiovascular disease. The serum lipoproteins are the carriers of the lipids in the circulation. Lipoproteins are classified according to their density: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL) and P1673 / 99MX high density lipoproteins (HDL). Chylomicrons are mainly involved in transporting dietary triglycerides and cholesterol from the intestine to adipose tissue and to the liver. VLDLs distribute triglycerides synthesized endogenously from the liver to adipose tissue and other tissues. LDL transport cholesterol to peripheral tissues and regulate the levels of endogenous cholesterol in those tissues. HDL carries cholesterol from peripheral tissues to the liver. The cholesterol of the arterial wall is derived almost exclusively from LDL. Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980). In patients with low LDL levels, the development of atherosclerosis is rare. Elevated cholesterol levels are associated with several disease states, including restenosis, angina, cerebral atherosclerosis, and xanthoma. It is desirable to provide a method for reducing plasma cholesterol in patients at risk or with restenosis, angina, cerebral atherosclerosis, xanthoma and other disease states associated with elevated cholesterol levels. It has been determined that hypercholesterolemia is due to elevated LDL (hyperlipidemia), the decrease in LDL levels is attempted by dietary therapy. There are several classes of drugs that P1673 / 99MX are commonly used to lower LDL levels, including bile acid sequestrants, nicotinic acid (niacin), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Probucol and fibrate derivatives are sometimes used as adjunctive therapy, usually in combination with another medication. HMG CoA reductase inhibitors have been called statins or vastatins. Statins are among the most effective agents currently marketed for hypercholesterolemia and include pravastatin (Pravchol, Bristol Myers Squibb), atrovastatin (Warner Lambert / Pfizer), simvastatin (Zocor, Merck), lovastatin (Mevacor, Merck) and fluvastatin ( Lescol). For many patients, the diet plus one of the hypolipidemic agents will suffice. However, for patients with an initial LDL cholesterol level greater than 200 mg / dL, therapy is needed to lower LDL levels by 50% or more. Although a single agent may occasionally achieve this degree of LDL decrease, it is much more common to see decreases of only 20 to 30%. Thus, for the patient heterozygous familial hypercholesterolemia with an LDL cholesterol of 200 to 400 mg / dl, a combination of two or occasionally three hypolipidemic drugs will be required to achieve an LDL cholesterol level of less than 100 mg / ml.

P1673 / 99MX The combinations of a bile sequestrant resin and nicotinic acid can lower LDL levels between 45% and 55%, a resin plus a statin, by approximately 50% to 60%, nicotinic acid plus a statin by approximately 50% and triple drug therapy, using a combination of a bile acid-binder resin, a statin and nicotinic acid as much as 70%. Evidence suggests that the atherogenic effects of low-density lipoprotein (LDL) may be partly mediated through its oxidative modification. Probucol has been shown to have potent antioxidant properties and block oxidative modification of LDL. Consistent with these findings, probucol has been shown to actually delay the progression of atherosclerosis in rabbits deficient in LDL receptors in Carew et al. Proc. Na ti. Acad. Sci. U. S. A. 84: 7725-7729 (1987). Most likely, probucol is effective because it is quite fat-soluble and is transported by lipoproteins, protecting them against oxidative damage. Probucol is chemically related to the widely used food additives 2, [3] -ter-butyl-4-hydroxyanisole (BHA) and 2, 6-di-tert-butyl-4-methyl phenol (BHT). Its full chemical name is 4, 4 '- (isopropylidendithium) bis (2,6-di-tert-butyl phenol).

P1673 / 99MX Currently, probucol is used primarily to lower serum cholesterol levels in hypercholesterolemic patients. Probucol is commonly administered in the form of tablets available under the trademark LorelcoRM. Unfortunately, probucol is almost insoluble in water and therefore can not be injected intravenously. In fact, probucol is difficult to absorb by in vitro cells because of its low miscibility in buffers and cell culture media. Solid probucol is poorly absorbed in the blood and is excreted in practically the same form. In addition, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients. In one study (Heeg et al., Plasma Levéis of Probucol in Man After Singl and Repea ted Oral Doses, La Nouvelle Presse Medícale, 9: 2990-2994 (1980)), it was found that the patient's maximum serum probucol levels The patient is distinct as much as a factor of 20. In another study, Kazuya et al., J. Lipid Res. 32; 197-204 (1991) a minor incorporation was observed at approximately 1 μg of probucol / 10 6 cells when endothelial cells are incubated for 24 hours with 50 μM of probucol. U.S. Patent No. 5,262,439 to Parthasarathy discloses soluble probucol analogues in which one or both groups P1673 / 99MX hydroxyl are substituted with ester groups which impart the compound with water solubility. In one embodiment, the soluble derivative is selected from the group consisting of a mono- or di-ester of succinic acid, glutaric acid ester, adipic acid ester, suberic acid ester, sebasic acid ester, azelaic acid or sodium ester. maleic acid of probucol. In another embodiment, the probucol derivative is a mono- or diester wherein the ester contains an alkyl or alkenyl group having functional groups selected from the group consisting of carboxylic acid group, amino group, salt of an amino group, amide groups and aldehyde groups. A series of French patents states that certain probucol derivatives are hypocholesterolemic and hypolipidemic agents: Fr 2168137 (bis-4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic probucol esters); Fr 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis- (3-alkyl-5-t-alkyl-4-thiazole-5-carboxy) phenylthio) alkanes; Fr 2133024 (bis- (4-nicoinoyloxyphenylthio) propanes and Fr 2130975 (bis (4- (phenoxyalkanoyloxy) -phenylthio) alkanes) U.S. Patent No. 5,155,250 discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents The same compounds are exposed as agents that lower serum cholesterol in PCT Publication No. WO P1673 / 99MX 95/15760, published June 1, 1995. U.S. Patent No. 5,608,095 discloses that alkylated 4-silylphenols inhibit LDL peroxidation, lower plasma cholesterol and inhibit the expression of VCAM- l and in this way, they are useful in the treatment of atherosclerosis.

Expression of VCAM-l-1 The adhesion of leukocytes to the endothelium represents a first event, fundamental in cardiovascular disease as well as in a variety of inflammatory states, including autoimmune disorders and bacterial and viral infections. Recruitment of leukocytes in the endothelium begins when receptors of inducible adhesion molecules on the surface of endothelial cells interact with counter-receptors in immune cells. Vascular endothelial cells determine which type of leukocytes (monocytes, lymphocytes or neutrophils) are recruited, selectively expressing specific adhesion molecules, for example, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM -1) and E-selectin (ELAM). In the early stage of the atherosclerotic lesion, there is a localized endothelial expression of VCAM-1 and selective recruitment of mononuclear leukocytes expressing the integrin receptor VLA-4. TO P1673 / 99MX causes selective expression of VLA-4 in monocytes and lymphocytes, but not neutrophils; VCAM-1 is important for mediating selective adhesion of mononuclear leukocytes. VCAM-1 is implicated as a mediator in chronic inflammatory disorders such as asthma, rheumatoid arthritis and autonomic diabetes. For example, it is known that the expression of VCAM-1 and ICAM-1 are increased in asthmatics. Pilewski, J.M., et al. Am. J. Respir. Cell Mol. Biol. 12, 1-3 (1995); Ohkawara, Y., et al.,. Am. J. Respir. Cell Mol. Biol. 12, 4-12 (1995). In addition, blocking the integrin receptors for VCAM-1 and ICAM-1 (VLA-4 and LFA-1, respectively) suppresses responses in both the early and late phases in a model of allergic air responses in rat sensitized with ovalbumin . Rabb, 11. A. et al., Am. J. Respir. Care Med. 149, 1186-1191 (1994). There is also increased expression of endothelial adhesion molecules, including VCAM-1, in the microvasculature of the rheumatoid synovium. Koch, A.E. et al., LaJb. Inves t. 64, 313-322 (1991); Morales-Ducret, J. et al., Immunol. 149, 1421-1431 (1992). Neutralizing antibodies directed against VCAM-1 or its counter-receptor, VI A-4, can delay the onset of diabetes in a mouse model (NOD mice) that spontaneously develop the disease. Yang, X.D. et al., Proc. Na ti. Acad. Sci. USES. 90, 10494-10498 (1993); P1673 / 99MX Burkly, L.C. et al., Diabe tes 43, 523-534 (1994); Barón, J.L. et al., J. Clin. Inves t. 93, 1700-1708 (1994). The VCAM-1 monoclonal antibodies may also have a beneficial effect in animal models of allograft rejection, suggesting that inhibitors of VCAM-1 expression may have utility in preventing rejection in transplants. Oroez, C.G. et al., Immunol. Let t. 32, 7-12 (1992). VCAM-1 is expressed by the cells both in the form of membrane binding and in soluble form.

The soluble form of VCAM-1 has been shown to induce chemotaxis of vascular endothelial cells in vitro and to stimulate an angiogenic response in rat cornea. Koch, A.F. et al., Na ture 376, 517-519 (1995). Inhibitors of soluble VCAM-l expression have potential therapeutic value in the treatment of diseases with a strong angiogenic component, including tumor growth and metastasis. Folkman, J. and Shing, Y. Biol. Chem. 10931-10934 (1992). VCAM-1 is expressed in cultured human vascular endothelial cells after activation by lipopolysaccharides (LPS) and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-a). These factors are not selective for activation of expression of cell adhesion molecules. The subsequent conversion of leukocytes to P1673 / 99MX foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors and chemoattractants that help propagate platelet and leukocyte recruitment, smooth muscle cell proliferation, endothelial cell activation and extracellular matrix synthesis characteristic of maturing atherosclerotic plaque. The molecular analysis of regulatory elements in the human VCAM-l gene that control their expression suggests an important role for the nuclear factor -kB (NF-kB), a transcriptional regulatory factor or a binding protein type NF-kB in the regulation sensitive to oxidation-reduction of VCAM-l gene expression. Transcriptional factors are proteins that activate (or repress) the genetic expression within the nucleus of the cell by linking to specific DNA sequences called "enhancer elements" that are usually close to the region of the gene, called the "promoter" from from which the synthesis of RNA begins. The promoters have been cloned and synthesized for both VCAM-1 and ICAM-1. For example, both promoters contain multiple DNA sequence elements that can bind to the transcription factor, NF-kB. Iademarco, M.F. et al., J. Biol. Chem. 267, 16323-16329 (1992).

P1673 / 99MX The nuclear factor -kB is a multisubunit transcription factor expressed everywhere that is activated in several cell types by a large and diverse group of inflammatory agents such as TNFa, IL-1B, bacterial endotoxin and RNA viruses. It plays a key role in mediating inflammatory signals and other stress signals in the nuclear regulatory apparatus. Although the precise biochemical signals that activate NF-kB are unknown, this transcriptional factor may integrate many of the risk factors and "causative" signs of atherosclerosis into a common molecular pathway, such as hyperlipidemia, smoking, hypertension, and diabetes mellitus. Activation of NF-kB in vascular endothelial cells by various signals can be specifically inhibited with antioxidants such as N-acetylcysteine and pyrrolidine dithiocarbamate. This has led to the hypothesis that oxygenated radicals play an important role in the activation of NF-kB through an indefinite oxidation-reduction mechanism. Because an NF-kB type reinforcer element also regulates the transcription of the VCAM-1 promoter in an oxidation-reduction sensitive form, the hypothesis was generated that oxidative stress in the atherosclerotic lesion could play a role in the regulation of the genetic expression of VCAM-l a P1673 / 99MX through this transcriptional regulatory protein sensitive to oxidation-reduction. U.S. Patent No. 5,380,747 (PCT / US93 / 10496) disclosed for the first time that the expression of VCAM-1 in vascular endothelial cells can be inhibited by the administration of a type of dithiocarbamates, including pyrrolidin dithiocarbamate. So these dithiocarbamates are useful in the treatment of cardiovascular disease and have now been shown to significantly reduce the presence of atherosclerotic lesions in hypercholesterolemic rabbits. It has been hypothesized that the modification of low density lipoprotein (LDL) to LDL oxidatively modified (ox-LDL) by reactive oxygen species is the central fact that initiates and spreads atherosclerosis. Steinberg, et al., N. Engl. J. Med. 1989; 320: 915-924. Oxidized LDL is a complex structure consisting of at least several chemically distinct oxidized materials, each of which, alone or in combination, may modulate the genetic expression of the cytokine activated adhesion molecule. Hydroperoxides of fatty acids such as linoleyl hydroperoxide (13-HPODE) are produced from free fatty acids by lipoxygenases and are an important component of oxidized LDL. It has been proposed that a generation of P1673 / 99MX Oxidized lipids are formed by the action of the cellular lipoxygenase system and oxidized lipids are subsequently transferred to LDL. Later there is a propagation reaction within the LDL in the medium catalyzed by the transition metals and / or sulfhydryl compounds. Previous research has shown that modification of fatty acids from cultured endothelial cells can alter their susceptibility to oxidative damage. PCT / US95 / 05880 discloses that polyunsaturated fatty acids and their hydroperoxides induce the expression of VCAM-1, but not that of ICAM-1 or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other non-cytochemical signals. This was a fundamental discovery of an important and previously unknown biological pathway in immune responses mediated by VCAM-1. It has also been reported in PCT / US95 / 05880 that the induction of VCAM-1 by polyunsaturated fatty acids and their hydroperoxides is suppressed by dithiocarbamates, including pyrrolidin dithiocarbamate. Since cardiovascular disease is currently the leading cause of death in the United States, there is a need to provide new therapies for its treatment. It is a goal to provide new agents that can simultaneously treat hypercholesterolemia, hyperlipidemia and P1673 / 99MX can inhibit the expression of VCAM-1 in vascular endothelial cells. Therefore, it is an object of the present invention to provide a method and composition for the suppression of VCAM-1 and in particular a method for the treatment of cardiovascular disease. It is another object of the present invention to provide a method and composition for the treatment of cardiovascular disease which simultaneously can treat hypercholesterolemia, hyperlipidemia and can the expression of VCAM-1 in vascular endothelial cells.

SUMMARY OF THE INVENTION It has been discovered that monoesters of probucol are effective to simultaneously reduce cholesterol, decrease LDL and inhibit the expression of VCAM-1 and thus these compounds are useful as composite cardiovascular agents. Since the compound simultaneously shows three important vascular protection activities, the patient can take a drug instead of several drugs to achieve the same effect. This should increase the consistency of the therapy and the obedience of the patient. It was surprising to learn that the monoester of probucol inhibits VCAM-l, since probucol itself, although it is a potent antioxidant, does not P1673 / 99MX significantly affects the expression of VCAM-1. Also the diesters of probucol do not significantly affect the expression of VCAM-1, nor the statins. It has also been found that the monosuccinic ester of probucol reduces HDL only to a small degree in rabbits and does not affect HDL in mice and monkeys. In contrast, probucol reduces LDL only to a small degree and reduces HDL significantly. Statins reduce LDL and may or may not have an effect on HDL. It has further been discovered that the monoesters of probucol and in particular the monosuccinic acid ester of probucol (referred to herein as "MSE"), selectively inhibit VCAM-1 induced by TNF and the genetic expression of MCP-1 but not of ICAM-1 in aortic endothelial cells. The MSE does not affect the activation of NF-kB. MSE is used herein as illustrative of probucol monoesters. The use of the MSE by way of illustration is solely for convenience in the disclosure and does not mean that the scope of the invention is limited. Given the discovery that the monoesters of probucol and in particular the monosuccinic acid ester of probucol, block the induced expression of the endothelial cell surface adhesion molecule VCAM-1, they are useful in P1673 / 99MX the treatment of any disease that is mediated by VCAM-1, which include atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina and other cardiovascular diseases as well as non-cardiovascular inflammatory diseases that are mediated by VCAM-1 . These compounds can also be used in the treatment of rejection in cardiac transplantation. These compounds described herein are useful both in the primary medical treatment and in the adjunct of cardiovascular disease. The compounds are used in primary treatment, for example, of coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery disease and angina. These compounds can be administered to treat small vessel diseases that can not be treated with surgery or angioplasty or other vessel disease in which surgery is not an option. These compounds can also be used to stabilize patients before revascularization therapy. The invention described herein when used appropriately provides the possibility of medically "healing" atherosclerosis by preventing new lesions from developing and setbacks to regress. In an alternative modality, the compounds P1673 / 99MX which are disclosed herein can be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1 and in particular, human endothelial disorders that are mediated by VCAM-1, which include, but not limited to, asthma. , psoriasis, dermatitis exematosa, Kaposi's sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells. In another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions mediated by mononuclear leukocytes.

BRIEF DESCRIPTION OF THE DRAWINGS OR FIGURES Figure 1 is a bar graph of the comparison of the effect of the monosuccinic acid ester of probucol and probucol at 2.5 μM, 5 μM, 10 μM and 100 μM on the expression of VCAM-1 in HAEC cells. Figure 2 is a bar graph of the comparison of the effect of the monosuccinic acid ester of probucol and probucol at 2.5 μM, 5 μM, 10 μM and 100 μM on the expression of ICAM-1 in HAEC cells. Figure 3 is a bar graph of the comparison of 10 μM of monosuccinic acid ester of probucol, 50 μM of probucol and TNF in the expression of MCP-1 in human aortic endothelial cells P1673 / 99MX (HAEC). Figure 4 illustrates the effect of the monosuccinic acid ester of probucol (10 and 25 μM) and of probucol (50 μM) on gene expression in HAEC. Figure 5 is a bar graph of the effect of monosuccinic acid ester of probucol and probucol on the plasma cholesterol level in rabbits fed with lipids. Figure 6 is a bar graph of the comparison of the concentration of the monosuccinic acid ester of probucol and probucol in rabbit plasma after three weeks of dosing. Figure 7 is a graph of the effect of monosuccinic acid ester of probucol on total serum cholesterol in the hypercholesterolemic rabbit model for six weeks. Figure 8 is a bar graph of the effect of monosuccinic acid ester of probucol on total cholesterol, LDLc, VLDLc, ILDLc, HDLc and TG in rabbits fed with lipids after six weeks. Figure 9 is a graph of the percentage of aortic surface area covered by lesions in untreated rabbits fed lipids and those treated with the monosuccinic acid ester of probucol. Figure 10 is a graph of the plasma level of the monosuccinic acid ester of the P1673 / 99MX probucol in micromoles as a function of the days of treatment. Figure 11 is a bar graph of total cholesterol, VLDL, IDL, LDL, HDL and triglycerides in the ApoE-KO mouse two weeks after oral administration of the monosuccinic acid ester of probucol against a control, in mg / ml. Figure 12 is a graph of the decrease in serum LDL level in hypercholesterolemic monkeys with respect to the days during and after administration of the monosuccinic acid ester of probucol. Figure 13 is a bar graph of the effect of monosuccinic acid ester of probucol on serum LDL of hypercholesterolemic monkeys. Figure 14 is a bar graph of the effect in rats of two weeks of oral administration of the monosuccinic acid ester of probucol at 1000 mg / kg / d against a control in total protein, calcium, phosphate, glucose, bun and cholesterol, in arbitrary units. Figure 15 is a bar graph of the effect in rats of two weeks of oral administration of the monosuccinic acid ester of probucol at 1000 mg / kg / d against a control in albumin, creatinine, uric acid and total bilirubin, in arbitrary units.

P1673 / 99MX DETAILED DESCRIPTION OF THE INVENTION I. Definitions The term "probucol monoester", in the sense in which it is used herein, includes (i) any monoester of probucol which is described in U.S. Pat. 5,262,439, for example, esters of carboxylic acids and esters of dicarboxylic acids and salts thereof; (ii) any monoester of probucol which has greater water solubility than probucol and which decreases plasma cholesterol, lowers LDL and inhibits the expression of VCAM-1, as described in detail herein. In one embodiment, the monoesters of probucol include dicarboxylic acid esters of probucol, including, but not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebasic acid, azelaic acid, and maleic acid esters. In another embodiment, the ester group includes a functional moiety that increases the solubility of the compound with respect to probucol, including, but not limited to, saturated and unsaturated dicarboxylic acids and salts thereof, amino carboxylic acids and salts thereof. same, carboxylic acids containing aldehydes and salts thereof, an amino group, a salt of an amino group, an amide group, aldehyde groups and salts thereof. In yet another embodiment, the ester has a portion Functional P1673 / 99MX selected from the group consisting of sulfonic acid, sulfonic acid esters, phosphoric acids, phosphoric acid esters, cyclic phosphates, polyhydroxyalkyl groups, carbohydrate groups, C (0) -spacer-S03H, where spacer is - ( CH2) n-, - (CH2) n -CO-, - (CH2) nN-, (CH2) n-0-, - (CH2) nS, - (CH20) -, - (0CH2) -, - (SCH2 ) -, - (CH2S) -, - (aryl-0) -, - (0-aryl) -, - (alkyl-0) -, - (0-alkyl) -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C (O) -Spacer-S03M, wherein M is a metal used to form a pharmaceutically acceptable salt, eg, sodium or potassium, C (0) -spacer-P03H2, C (0) -spacer-P03M2, C ( O) -spacer-P03HM, C (0) -spacer-P04H, C (0) -spacer-P0M, S03M, -P03H2, -P03M2, -P03HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C (0) -spacer [0 (C? -3 alkyl) p] n, wherein n is as defined above and p is 1, 2 or 3, - [0 (C? -3 alkyl) p] n, carboxyalkyl lower, alkylcarbonyl lower alkyl lower, N, N-dialkylamino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl hydroxyalkyl lower, N -pyrril, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl or P1673 / 99MX thiazolyl lower alkyl. The term "pharmaceutically acceptable derivative" refers to a derivative of the active compound that upon administration to the recipient, is capable of directly or indirectly providing the parent compound, or showing activity in itself. The term "physiologically unfolding leaving group" refers to a portion which in vivo can be split from the molecule to which it is attached and includes, in non-exclusive form, an organic or inorganic anion, a pharmaceutically acceptable cation, acyl (including but not limited to (alkyl) C (O), including acetyl, propionyl and butyryl), alkyl, phosphate, sulfate and sulfonate. To be used in the treatment of atherosclerosis and other cardiovascular inflammatory diseases, monoesters of probucol should be chosen that have the adequate lipophilicity to be located in the affected place. The compound should not be distributed in regions of low rotation as fat deposits. In a preferred embodiment for treatment of cardiovascular disease, the pharmacokinetics of the compound should not be dramatically affected by congestive heart failure or renal failure. The active compound or a mixture of P1673 / 99MX compounds are administered in any appropriate manner, including non-exclusively, systemically, including orally or intravenously or topically, including transdermally. A general dose range will be between 0.1 and 500 mg / kg of body weight with a dose scheme that varies from once every third day to twice or several times a day. The duration of the dosage will vary from a single dose administered only once to twice-daily doses administered over the course of two to six months. In cardiovascular therapy, the compounds can also be administered directly to the vascular wall using perfusion balloon catheters at once or in lieu of coronary angioplasty or other arterial angioplasty. As an example, from 2 to 5 mL of a physiologically acceptable solution containing approximately between 1 and 500 mM of the compound or of the mixture of the compound is administered at a pressure of 1-5 atmospheres. Then, over the course of the next six months during the period of maximum risk of restenosis, the active compounds are administered through other routes and suitable dosage schedules. Relatively short-term treatments with the active compound are used to cause the "contraction" of disease lesions P1673 / 99MX coronary artery that can not be treated either by angioplasty or surgery. A non-exclusive example of a short-term treatment is two to six months of a dose ranging between 0.5 and 500 mg / kg / body weight administered in periods ranging from once every third day to three times a day. Long-term treatments can be used to prevent the development of advanced lesions in high-risk patients. A long-term treatment can be prolonged for years with doses ranging from 0.5 to 500 mg / kg / body weight administered in intervals ranging from once every third day to three times a day. The active compounds can also be administered in the immediate period prior to coronary angioplasty or subsequent to it as a means to reduce or eliminate the abnormal and inflammatory proliferative response that currently leads to clinically significant restenosis. The active compounds can be administered together with other drugs used in the treatment of cardiovascular disease, including inhibitors of platelet aggregation such as aspirin; antithrombotic agents such as coumadin; calcium channel blockers such as varapamil, diltiazem and nifedipine; angiotensin-converting enzyme (ACE) inhibitors such as captopril and enalopril and ß-blockers such as P1673 / 99MX propanalol, terbutalol and labetalol. The compounds can also be administered in combination with non-steroidal anti-inflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered with corticosteroids. The MSE administered by pellets implanted subcutaneously (controlled release pellets 150 mg / kg / day) blocks the LPS-induced gene expression of VCAM-1 and MCP-1 in lungs in a mouse model. Oral administration of MSE (150 mg / kg / day) for six weeks decreases the levels of total plasma cholesterol containing ApO-B and HDL cholesterol in a New Zealand White rabbit model. The effects on plasma cholesterol are accompanied by a marked inhibition of atherosclerotic lesion formation, accumulation of macrophages and expression of VCAM-1. Oral administration of MSE for two weeks selectively decreases apoB-containing lipoproteins in models of black C57 mice fed with cholesterol and apoE-knockedout without affecting HDL. Oral administration of MSE for two weeks in a model of monocytogenic hypercholesterolemic cinomolgous decreases total plasma and LDL cholesterol without affecting HDL. The MSE is not a mutagen in the test Bacterial P1673 / 99MX Ames. Oral administration of MSE at 1000 mg / kg / day for two weeks in rats did not result in any mortality and had no effect on hematocrit and serum electrolyte values. Elevations in serum LDH, alkaline phosphatase, SGOT and SGTP were observed but were not statistically different from the untreated group and were not accompanied by changes in hepatic histopathology or morphology. For topical applications in the treatment of inflammatory skin disorders, the selected compound should be formulated to be absorbed by the skin in an amount sufficient to produce a therapeutic effect at the affected site. The monoester of probucol must be physiologically acceptable. In general, compounds with a therapeutic index of at least 2 and preferably at least 5 or 10 are acceptable. The therapeutic index is defined as the EC50 / IC50, where EC50 is the concentration of the compound that inhibits the expression of VCAM -l in 5% and IC50 is the concentration of the compound that is toxic to 50% of the target cells. Cellular toxicity can be measured by direct cell count, exclusion with trypan blue or various studies of metabolic activity such as incorporation of 3H-thymidine, as is known to those skilled in the art. The invention is further illustrated in the following Examples, which use MSE as a compound P1673 / 99MX model. This is for illustration only and is not intended to limit the scope of the invention. Any other probucol monoester as defined herein can be used to treat cardiovascular disease and inflammatory disorders in a substantially similar manner.

EXAMPLE 1 Expression of VCAM-1 in Human Aortic Endothelial Cells Figure 1 is a bar graph of the comparison of the effect of the monosuccinic acid ester of probucol and probucol at 2.5 μM, 5 μM, 10 μM and 100 μM in the expression of VCAM-1 in human aortic endothelial cells in vitro as a percentage of VCAM-1 expression induced by TNF alone. The cells were incubated for sixteen hours in cell culture medium at 37 degrees Celcius in a cell culture incubator. After sixteen hours, the cells were washed and incubated with VCAM-I antibodies. The amount of antibody that binds to the cells was determined by a colorometric ELISA test using a horseradish peroxidase conjugated antibody of VCAM-1 antibody. As indicated, MSE inhibits the expression of VCAM-1 under these conditions while probucol has no appreciable effect on VCAM-1.

P1673 / 99MX Example 2 Expression of ICAM-1 in Human Aortic Endothelial Cells Figure 2 is a bar graph of the comparison of the effect of the monosuccinic acid ester of probucol with probucol at 2.5 μM, 5 μM, 10 μM and 100 μM in the expression of ICAM-1 induced by TNF alone. The cells were incubated for sixteen hours in cell culture medium at 37 degrees Celcius in a cell culture incubator. After sixteen hours, the cells were washed and incubated with ICAM-1 antibodies. The amount of antibody that binds to the cells was determined by a colorometric ELISA test using a horseradish peroxidase conjugated antibody of the ICAM-1 antibody. As indicated, MSE has only a slight effect on ICAM-1 expression that was not highly concentration dependent and probucol had no effect on ICAM expression.

Example 3_ Expression of MCP-1 in Human Aortic Endothelial Cells Figure 3 is a bar graph of the comparison of 10 μM of monosuccinic acid ester of probucol, 50 μM of probucol and TNF in expression of MCP-1 in aortic endothelial cells human beings (HAEC). The cells were treated either with TNF alone or together with 10 micromoles of the monosuccinic acid ester of probucol for four hours. He P1673 / 99MX cell culture medium was harvested and used to quantify the amount of MCP-1 using a color-based ELISA. As illustrated, the monoester of probucol inhibited the expression of MCP-1 to a greater extent than probucol by itself. MCP-1 is a chemoattractant protein that recruits monocytes in an atherosclerotic lesion.

Effect 4 Ester effect of monosuccinic acid of probucol on gene expression in Human Aortic Endothelial Cells in vitro Figure 4 is a Northern blot analysis of gene expression of VCAM-1 and MCP-1 from RNA isolated from the lungs of ApoE mice knocked out stimulated with LPS. The mice were administered MSE, probucol and placebo subcutaneously in a 40 mg pellet with a release time of 90 days. After one week they were stimulated intraperitoneally with 1 mg / kg of LPS. After two hours the animals were sacrificed and the lungs were frozen to isolate the RNA. The RNA was fractionated by size by denaturing 1.0% agarose gel electrophoresis, transferred to a nylon membrane and hybridized with a 32 P-labeled JE-specific cDNA probe. The membrane was subsequently removed and hybridized with mouse VCAM-1 specific cDNA and then with a specific β-actin cDNA probe.

P1673 / 99MX Example 5 ^ Effect of Ester of Monosuccinic Acid of Probucol in Cholesterol in Plasma of Rabbits fed with lipids. The Figure 5 is a bar graph of the effect of monosuccinic acid ester of probucol and probucol on total cholesterol and lipoprotein cholesterol levels in the plasma of rabbits fed with lipids. For three weeks the rabbits were fed high-fat croquettes (0.5% cholesterol and 3% coconut oil) containing 0.5% w / w of MSE or probucol. The control animals were fed the same croquettes without the addition of the drug. The lipoprotein fractions were separated from the total plasma by high-speed liquid chromatography and analyzed for cholesterol content. MSE resulted in a statistically significant reduction of all lipoprotein fractions and probucol only in HDL cholesterol (p <; 0.05).

Example 6 ^ Comparison of the effect of MSE drug level and Probucol in plasma of rabbits fed a diet high in cholesterol for three weeks. MSE or probucol was administered to rabbits fed high-fat croquettes (0.5% cholesterol and 3% coconut oil) at a time.

P1673 / __ 9MX concentration of 0.5% weight / weight for three weeks. The drugs were extracted from the plasma on ether and analyzed by high pressure liquid chromatography. As indicated, the levels of MSE and probucol were similar, as was shown in the examples above, the compounds had a significantly different effect on plasma cholesterol and lipoprotein levels.

Example 1_ Effect of the MSE on Activation of NF-kB. Aortic endothelial cells were treated with TNF alone or in combination with 25 micromoles of MSE or PDTC over a period of one hour, two hours or three hours. The cells were washed and nuclear extracts prepared to perform a gel displacement analysis using a VCAM-1 promoter probe. It was determined that the MSE does not affect the activation of NF-kB while the PDTC inhibits it.

Example 8_ Effect of MSE after Six Weeks on the Cholesterol Level in Rabbits Fed with Cholesterol New Zealand white rabbits were fed diets high in cholesterol (0.5%) alone or together with 0.5 by weight (approximately 150 mg / kg / day for either AGE-3 or probucol for six weeks) Figure 8 is a bar graph of the effect of the acid ester P1673 / 99MX monosuccinic probucol in total cholesterol, LDLc, VLDLc, ILDLc, HDLc and triglycerides (TG) in rabbits fed fat for six weeks. After six weeks, lipoprotein fractions were separated from the whole plasma by high-speed liquid chromatography and analyzed for cholesterol and triglyceride content. As indicated in Example 8, the total cholesterol, as well as the cholesterol in VLDL and IDL were reduced more with the treatment with AGE-3 than with that of probucol.

Example 9_ Effect of AGE-3 on the Progression of Atherosclerosis in Hypercholesterolemic Rabbits that were described in the Example 8 were sacrificed and the aortas were obtained. The aortas were stained with sudan-4 and the degree of staining was analyzed. Figure 9 is a graph of percent aortic surface covered by lesions in fat-fed rabbits treated and untreated with MSE. The aortas of the rabbits that received AGE-3 had much less staining, which indicated reduced atherosclerosis in those who were treated with the monosuccinic acid ester of probucol. Sections of the aortas were subjected to immunostaining to detect VCAM-1 expression or accumulation of macrophages using antibodies of VCAM-1 or Ram-11 antigen. Treatment with AGE-3 Pt615_ / lll.WV_ markedly reduced the expression of VCAM-1 and the accumulation of macrophages (for example, approximately more than 75%). In a similar experiment, probucol at the same dose was much less effective (less than 25% reduction in VCAM-1 expression and macrophage accumulation).

Example 10 AGE-3 decreases the reversibility of LDL in Hypercholesterolemic Monkeys Cinomolgus monkeys became hypercholesterolemic before dosing AGE-3 by feeding them with a high cholesterol diet. Then the monkeys were dosed orally with AGE-3 (100 mg / kg / day) for two weeks. The percentage of serum LDL cholesterol in monkeys decreased in a range of 4 to 60 percent during this time period. The administration of the drug was then terminated and the serum cholesterol was checked on day 29. The cholesterol level returned to the pretreatment level and remained there.

Example 10 Figure 10 is a graph of the plasma level of the monosuccinic acid ester of probucol in micromoles as a function of days. As indicated, the plasma MSE level remained very constant.

P1673 / 99MX Example 11 Figure 11 is a bar graph of total cholesterol, VLDL, IDL, LDL, HDL and triglycerides in the ApoE-KO mouse two weeks after oral administration of the monosuccinic acid ester of probucol (150 mg / kg / day) against a control, in mg / ml.

Example 12 Figure 12 is a bar graph of the reversible decrease of LDL in hypercholesterolemic monkeys with respect to the days during and after administration of the monosuccinic acid ester of probucol.

Example 13 Figure 13 is a bar graph of the effect of the monosuccinic acid ester of probucol on the serum LDL of hypercholesterolemic rabbits.

Example 14 Figure 14 is a bar graph of the effect in rats, of two weeks of oral administration of the monosuccinic acid ester of probucol at 1000 mg / kg / d against a control, in total protein, calcium, phosphate, glucose, and cholesterol, in arbitrary units.

P1673 / 99MX Example 15 Figure 15 is a bar graph of the effect in rats of oral administration of the monosuccinic acid ester of probucol at 1000 mg / kg / d against a control, in albumin, creatinine, uric acid and total bilirubin, in arbitrary units. It has been observed that there is a difference in the effect of MSE and probucol in mice with respect to rabbits and monkeys in terms of the effect on total cholesterol and LDL. MSE is significantly more effective in decreasing both cholesterol and LDL in rabbits and monkeys than in mice. MSE seems to have the same effect as probucol in mice, that is, a minimal effect, if any, on these two factors. The MSE, however, inhibits the expression of VCAM-l in all the species that were tested.

III. Human, equine, canine, bovine, and particularly mammalian pharmaceutic compositions that suffer from any of the disease states described herein, including cardiovascular disorders and inflammatory conditions mediated by VCAM-1, can be treated by administering to the patient an effective amount of one or more of the compounds identified above or a pharmaceutically acceptable derivative or a salt thereof in a carrier or P1673 / 99MX pharmaceutically acceptable diluent. The active materials can be administered by any suitable route, for example, oral, parenteral, intravenous, intradermal, subcutaneous or topically. As used herein, the term "pharmaceutically acceptable salts or complexes" refers to salts or complexes that maintain the desired biological activity of the compounds identified above and exhibit minimal undesirable toxicological effects. Non-exclusive examples of salts of this type are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like) and salts formed with organic acids as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium and the like with an organic cation formed from N, -dibencylethylene diamine, D-glucosamine, ammonium, tetraethylammonium or ethylenediamine; or (c) combinations of (a) and (b); for example, a zinc tannate salt P1673 / 99MX and the like. The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to supply a patient with a therapeutically effective amount without causing serious toxic effects in the treated patient. A preferred dose of the active compound for all the conditions mentioned above is in the range of between about 0.1 and 500 mg / kg, preferably between 1 and 100 mg / kg per day. The effective dose ranges of the pharmaceutically acceptable derivatives can be calculated based on the weight of the precursor compound to be delivered. If the derivative shows activity by itself, the effective dose can be estimated in the same way as above using the weight of the derivative or by other means known to those skilled in the art. For systemic administration, the compound is conveniently administered in any suitable unit dosage form, including non-exclusively, one containing between 1 and 3000 mg, preferably between 5 and 500 mg of active ingredient per form. of unit dose. In general, an oral dose of 25 to 250 mg is convenient. The active ingredient must be administered to achieve a maximum plasma concentration of the active compound of approximately 0.1 to 100.

P1673 / 99MX mM, preferably between about 1 and 10 mM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or in an aqueous medium or administered as a bolus of the active ingredient. The concentration of active compound in the composition of the drug will depend on the rates of absorption, distribution, inactivation and excretion of the drugs, as well as other factors known to those skilled in the art. It is noted that the dose values will also vary with the severity of the drug. the conditions that are going to be alleviated. It should further be understood that for any particular subject, the specific dose regimens must be adjusted with respect to time according to individual needs and the professional judgment of the person administering or supervising the administration of the compositions and that the established concentration intervals. in the present they are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at the same time or may be divided into several small doses that are administered at varying time intervals. Oral compositions generally include an inert diluent or an edible vehicle. These can be contained in capsules P1673 / 99 X of gelatin or tablets in tablets. For the purposes of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, pills and the like can contain any of the following ingredients or compound of a similar nature: binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose or disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavor: When the unit dose form is a capsule, it may contain, in addition to the above materials, a liquid vehicle such as a fatty oil. In addition, unit dosage forms may contain other miscellaneous materials that modify the physical form of dosage unit, for example, sugar coatings, shellac or other enteric agents. The active compound or the pharmaceutically acceptable salt or derivative thereof can be P1673 / 99MX administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, colorants and flavorings. The active compound or the pharmaceutically acceptable derivatives or salts thereof can also be administered with other active materials that do not impair the desired action or with materials that complement the desired action, such as antibiotic, antifungal, anti-inflammatory or antiviral compounds. The active compounds can be administered with lipid lowering agents such as probucol and nicotinic acid; inhibitors of platelet aggregation such as aspirin; antithrombotic agents such as coumadin; calcium channel blockers such as varapamil, diltiazem and nifedipine; angiotensin-converting enzyme (ACE) inhibitors such as captopril and enalopril and ß-blockers such as propanalol, terbutalol and labetalol. The compounds can also be administered in combination with non-steroidal anti-inflammatories such as ibuprofen, indomethacin, aspirin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered with corticosteroids. Solutions or suspensions used for parenteral, intradermal, subcutaneous application P1673 / 99MX or topical may include the following components: a sterile diluent such as injectable water, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents to regulate tonicity such as sodium chloride or dextrose. The parenteral preparation can be included in ampoules, disposable syringes or multiple dose vials of glass or plastic. Suitable vehicles for topical application are those known and include lotions, suspensions, ointments, creams, gels, dyes, sprays, powders, pastes, slow release transdermal patches, asthma sprays and suppositories for rectal, vaginal, nasal or buccal mucosa. Thickening agents can be used to prepare topical compositions. Examples of thickening agents include petrolatum, beeswax, xanthan gum or polyethylene glycol, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives or squalene. Several solutions and ointments are commercially available. Sweeteners can be added or P1673 / 99MX natural or artificial flavors to improve the flavor of topical preparations applied for local effect on mucosal surfaces. Inert colorants can be added, particularly in the case of preparations designed for application on the surfaces of the buccal mucosa. The active compounds can be prepared with vehicles that protect the compound from rapid release, for example, a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biodegradable polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Many methods for the preparation of formulations of this type are patented or are generally known to those skilled in the art. If administered intravenously, the preferred vehicles are physiological saline or phosphate buffered saline (PBS). The active compound can also be administered through a transdermal patch. Methods for preparing transdermal patches are known to those skilled in the art. For example, see Brown, L., and Langer, R., Transdermal Delivery of Drugs, Annual Review of Medicine, 39: 221-229 (1988), which is considered part of the P1673 / 99MX present, as reference. In another embodiment, the active compounds are prepared with carriers that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biodegradable polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods of preparing formulations of this type will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions may also be pharmaceutically acceptable carriers. These can be prepared according to the methods known to those skilled in the art, for example, in the same manner as described in U.S. Patent 4,522,811 (which in its entirety is considered part of the present, as a reference). ). For example, liposomal formulations can be prepared by dissolving suitable lipid (s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidoyl phosphatidyl choline and cholesterol) in an inorganic solvent which is then evaporated, leaving a thin film of dry lipid on the surface P1673 / 99MX of the container. An aqueous solution of the active compound or its monophosphate, diphosphate and / or triphosphate derivatives are then introduced into the container. Then with the hand the container is turned to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming the liposome suspension. Modifications and variations of the present invention will be apparent to those skilled in the art from the foregoing. All these modalities are considered within the scope of this invention.

P1673 / 99MX

Claims (20)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A method of inhibiting VCAM-1 comprising administering to a patient an amount effective of a probucol monoester or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the monoester is selected from the group consisting of dicarboxylic acids and salts thereof, amino carboxylic acids and salts thereof, carboxylic acids containing aldehydes and salts thereof, a group amino, a salt of an amino group, an amide group, a salt of an amide group, aldehyde groups and salts thereof wherein the ester may optionally be substituted with a portion selected from the group consisting of sulfonic acids, acid esters sulfonic acid, phosphoric acids, phosphoric acid esters, cyclic phosphates, polyhydroxyalkyl groups, carbohydrate groups, C (O) -spacer-S03H, where spacer is - (CH2) n-, - (CH2) n -CO-, - ( CH2) nN-, (CH2) n-0-, - (CH2) nS, - (CH20) -, - (OCH2) -, - (SCH2) -, - (CH2S) -, - (aryl-O) - , - (O-aryl) -, - (alkyl-O) -, - (0-alkyl) -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C (O) -spacer-S03M, where M is a metal used P1673 / 99MX to form a pharmaceutically acceptable salt, C (0) -spacer-P03H2, C (0) -spacer-P03M2, C (0) -spacer-P03HM, C (0) -spacer-P04H, C (0) -spacer-P04M, S03M, -P03H2, - P03M2, -P03HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C (0) -spacer [0 (C1-3 alkyl) p] n. wherein n is as defined above and p is 1, 2 or 3, - [0 (C? _3 alkyl) p] n, lower carboxyalkyl, lower alkylcarbonyl lower alkyl, N, N-dialkylamino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl hydroxyalkyl lower, N-pyrril, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl or thiazolyl lower alkyl. 3. The method according to claim 1, wherein the monoester is monosuccinic acid ester or a pharmaceutically acceptable salt thereof. 4. A method for the treatment of a VCAM-1 mediated disease comprising administering to a patient an effective amount of a probucol monoester or a pharmaceutically acceptable salt thereof. 5. The method according to claim 4, wherein the monoester is selected from the group P1673 / 99MX consists of dicarboxylic acids and salts thereof, amino carboxylic acids and salts thereof, carboxylic acids containing aldehydes and salts thereof, an amino group, a salt of an amino group, an amide group, aldehyde groups and salts thereof wherein the ester optionally may be substituted with a portion selected from the group consisting of sulfonic acids, sulfonic acid esters, phosphoric acids, phosphoric acid esters, cyclic phosphates, polyhydroxyalkyl groups, carbohydrate groups, C (O ) -spaciador-SOsH, where spacer is - (CH2) n-, (CH2) n-CO-, - (CH2) n-N-, - (CH2) n-0-, - (CH2) n-S, - (CH20) -, - (OCH2) -, - (SCH2) -, - (CH2S) -, - (aryl-O) -, - (O-aryl) -, - (alkyl-O) -, - (O-alkyl) -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C (O) -Spacer-S03M, wherein M is a metal used to form a pharmaceutically acceptable salt, C (O) -spacer-P03H2, C (O) -spacer-P03M2, C (O) -spacer-P03HM, C (O) - spacer-P04H, C (O) -spacer-P04M, S03M, -P03H2, - P03M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C (O) -spacer [O (C? _3 alkyl ) p] n, where n is as defined above and p is 1, 2 or 3, - [0 (C? _3 alkyl) p] n, lower carboxyalkyl, lower alkylcarbonyl lower alkyl, N, N-dialkylamino lower alkyl , pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, P1673 / 99MX thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl hydroxyalkyl lower, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl or thiazolyl lower alkyl. 6. The method according to claim 4, wherein the monoester is monosuccinic acid ester or a pharmaceutically acceptable salt thereof. The method according to claim 4, wherein the disease is cardiovascular disease. The method according to claim 7, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, and small artery disease. The method according to claim 4, wherein the disease is an inflammatory disease. The method according to claim 9, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis. The method according to claim 7, further comprising administering the monoester of probucol in combination with another cardiovascular agent selected from the group consisting of agent that P1673 / 99MX decreases lipids, platelet aggregation inhibitors, antithrombotic agents, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and β-blockers. The method according to claim 9, further comprising administering the monoester of probucol in combination with another anti-inflammatory agent. 13. Use of a monoester of probucol for the suppression of VCAM-1 in a patient, wherein the monoester is selected from the group consisting of dicarboxylic acids and salts thereof, amino carboxylic acids and salts thereof, carboxylic acids which they contain aldehydes and salts thereof, an amino group, a salt of an amino group, an amide group, a salt of an amide group, aldehyde groups and salts thereof, wherein the ester may optionally be substituted with a portion selected from the group consisting of sulfonic acids, sulfonic acid esters, phosphoric acids, phosphoric acid esters, cyclic phosphates, polyhydroxyalkyl groups, carbohydrate groups, C (0) -spacer-S03H, wherein spacer is - (CH2) n- , - (CH2) n-C0-, - (CH2) nN-, (CH2) n-0-, - (CH2) nS, - (CH20) -, - (0CH2) -, - (SCH2) -, - (CH2S) -, - (aryl-0) -, - (0-aryl) -, - (alkyl-O) -, - (0-alkyl) -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C (0) -spacer-S03M, wherein M is a metal used to form a pharmaceutically acceptable salt, P1673 / 99MX C (O) -spacer-P03H2, C (O) -spacer-P03M2, C (O) -spacer-P03HM, C (O) -spacer-P04H, C (O) -spacer-P04M, S03M, -P03H2, - P03M2, -P03HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C (O) - spacer [O (C? _3 alkyl) p] n, where n is as defined above and p is 1, 2 or 3, - [0 (C? _. 3 alkyl) p] n, lower carboxyalkyl, lower alkylcarbonyl lower alkyl, N, N-dialkylamino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl or thiazolyl lower alkyl. 14. Use of a monoester of probucol for the suppression of VCAM-1 in a patient, wherein the monoester is ester of monosuccinic acid. 15. Use of a monoester of probucol for the treatment of a disorder mediated by VCAM-1 wherein the monoester is selected from the group consisting of dicarboxylic acids and salts thereof, amino carboxylic acids and salts thereof, carboxylic acids which they contain aldehydes and salts thereof, an amino group, a salt of an amino group, an amide group, a salt of a group P1673 / 99MX amide, aldehyde groups and salts thereof, wherein the ester optionally may be substituted with a portion selected from the group consisting of sulfonic acids, sulfonic acid esters, phosphoric acids, phosphoric acid esters, cyclic phosphates, polyhydroxyalkyl groups, carbohydrate groups, C (0) -spacimer-S03H, wherein spacer is - (CH2) n- / - (CH2) n -CO-, - (CH2) nN-, (CH2) n-0-, - (CH2) nS, - (CH20) -, - (0CH2) -, - (SCH2) -, - (CH2S) -, - (aryl-0) -, - (0-aryl) -, - (alkyl- 0) -, - (0-alkyl) -; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C (O) -Spacer-S03M, wherein M is a metal used to form a pharmaceutically acceptable salt, C (0) -spacer-P03H2, C (0) -spacer-P03M2, C (0) -spacer-P03HM, C (0) -spacer-P04H, C (0) -spacer-P04M, S03M, -P03H2, -P03M2, -P03HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C (0) -spacer [0 (C? -3 alkyl) p] n, wherein n is as defined above and p is 1, 2 or 3, - [0 (C? -3 alkyl) p] n, lower carboxyalkyl, lower alkylcarbonyl lower alkyl, N, N-dialkylamino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl hydroxyalkyl lower, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl P1673 / 99MX lower alkyl, tetrazolylamino lower alkyl or thiazolyl lower alkyl. 16. Use of a monoester of probucol for the treatment of a disorder mediated by VCAM-1, wherein the monoester is monosuccinic acid ester. 17. Use of a probucol monoester according to claim 15 or 16, wherein the disorder is a cardiovascular disease. 18. Use of a probucol monoester according to claim 17, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina or small artery disease. 19. Use of a probucol monoester according to claim 15 or 16, wherein the disorder is an inflammatory disease. 20. Use of a probucol monoester according to claim 19, wherein the inflammatory disease is rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis or psoriasis. P1673 / 99MX