MXPA99011872A - Alkyl-4-silylheterocyclic phenols and thiophenols as antioxidant agents - Google Patents

Abstract

The present invention provides compounds of formula (1) wherein:R is hydrogen or -C(O)-(CH2)m-Q, wherein Q is hydrogen or -COOH and m is an integer 1, 2, 3 or 4;R1, R5 and R6 are independently a C1-C6 alkyl group;R2, R3 and R4 are independently hydrogen or a C1-C6 alkyl group;Z is thio, oxy or a methylene group;A is a C1-C4 alkylene group;X is thio or oxy;and G1 and G2 are independently hydrogen, C1-C6 alkyl or -C(O)-(CH2)n-CH3 an n is an integer 0, 1, 2 or 3;or a pharmaceutically acceptable salt therof;useful for the treatment of atherosclerosis and chronic inflammatory disorders;for inhibiting cytokine-induced expression of VCAM-1 and/or ICAM-1;for inhibiting the peroxidation of LDL lipid;for lowering plasma cholesterol;and as anti-oxidant chemical additives useful for preventing oxidative deterioration in organic materials.

Description

HETEROCYCLIC PHENOLS AND THYOPHENOLS OF ALKYL-4-SILYLL AS ANTIOXIDANT AGENTS BACKGROUND OF THE INVENTION Heart coronary disease (CHD) remains the cause of death in industrialized countries. Despite the recent decrease in mortality from CHD, the ECC is still responsible for more than 500,00 deaths in the US annually. It is estimated that the ECC, directly and indirectly, costs the U.S.A. plus $ 100 billion dollars per year. The main cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the walls of the arterial vessels, resulting in a narrowing of the passages of the vessels and finally the hardening of the vascular system. Atherosclerosis, as manifested in its main clinical complication, ischemic heart disease, was thought to begin with local damage to the arterial endothelium followed by the proliferation of arterial smooth muscle cells from the middle to the intimal layer with lipid deposition and accumulation. of spongy cells in the lesion. As the atherosclerotic plaque develops, it progressively blocks the blood vessels and can eventually lead to ischemia or infarction. Therefore, it is desired to provide a method to inhibit the progression of atherosclerosis in patients who need it.

Hypercholesterolemia is an important risk factor with CHD. For example, in December 1984, the National Institute of Health Consensus Development Panel concluded that low plasma cholesterol levels (specifically low density lipoprotein blood cholesterol levels) will definitely reduce the risk of heart attacks due to to ECC. The serolipoproteins are the carriers for the lipids in the circulation. These are classified according to their density: chylomicra, very low density lipoprotein (LMBD), low density lipoprotein (LBD) and high density lipoprotein (LAD). The chylomicra mainly participate in the transport of the diet of triglycerides and coiesterol from the intestine to adipose tissue and to the liver. The LMBD supplies triglycerides synthesized endogenously from the liver to adipose tissue and other tissues. LBD transports cholesterol to peripheral tissues and regulates endogenous cholesterol levels in these tissues. The LAD transports cholesterol from peripheral tissues to the liver. The cholesterol from arterial walls are derived almost exclusively from LBD Brown and Goldstein, Ann. Rev. Biochem. 52, 233 (1983): Miller, Ann. Rev. Med. 31, 97 C1980)). Consequently, it is desired to provide a method for reducing plasma cholesterol in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.

Elevated cholesterol levels are also associated with a number of disease states, including restenosis, angina, cerebral arteriosclerosis, and xanthoma. It is desired to provide a method for reducing plasma cholesterol in patients with, or at risk of developing, restenosis, angina, cerebral atherosclerosis, xanthoma, and other conditions of diseases associated with elevated cholesterol levels. The vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule (ICAM-1) are adhesion molecules in the immunoglobulin superfamily that are up-regulated in vascular endothelial and smooth muscle cells by cytokines, such as , for example, interleukin-1 (IL-1), interleukin-4 (IL-4) and tumor necrosis factor-a (TNF). Through interaction with the anti-integrin receptor, VCAM-1 and ICAM-1 mediate adhesion and transendothelial migration of leukocytes in inflammatory responses. Inhibitors of VCAM-1 and / or ICAM-1 have therapeutic applications for many types of chronic inflammatory disorders including atherosclerosis, asthma, rheumatoid arthritis, and autoimmune diabetes. For example, in situ hybridization and immunohistochemical analysis of atherosclerotic plaques of patients demonstrate an increased level of adhesion molecules (VCAM-1 and ICAM-1) when compared to areas without disease. O'Brien, K.D. and others, J.Cin. Invest. 92,945-951 (1993); Davies, M.J. and others, J.Pathol. 171, 223-229 (1993); Poston, R.N. and others, Am. J. Pathol. 140, 665-673 (1992). An atherogenic diet induces the expression of VCAM-1 in the aortic endothelium of rabbits and vascular smooth muscle cells within atheromas. Poston, R.N. and others, Ibid.; Cybulsky, M.l. and others, Science 251, 788-791 (1991); Li, H, and others, Arterioscler. Thromb. 13, 197-204 (1993). Considering these previous studies, the expression of increased VCAM-1 is thought to be associated with the initiation and progression of atherosclerosis plaques through the recruitment of circulating monocytes to the area of the lesion. In addition, VCAM-1 can also be involved as a mediator in other chronic inflammatory disorders such as asthma, rheumatoid arthritis and autoimmune diabetes. For example, it is known that the expression of VCAM-1 and ICAM-1 is increased in asthmatics. Pilewski, J.M. and others, Am. J. Respir. Cell Mol Biol. 12, 1-3 (1995); Ohkawara, Y. and others, Am. J. Respir. Cell Mol. Biol. 12, 4-12 (1995). Additionally, blockade of integrin receptors for VCAM-1 and ICAM-1 (VLA-4 and LFA-1, respectively) suppressed both near and far responses in a rat model sensitive to egg albumin in the form of allergic responses to air. Rabb, H.A. and others, 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. and others, Lab. Invest. 64, 313-322 (1991); Morales-Ducret, J. and others, Immunol. 149, 1421-1431 (1992). Neutralization antibodies directed against VCAM-1 or its counter receptor, VLA-4, can delay the progression of diabetes in a mouse model (NOD mice) which spontaneously develop the disease. Yang, X.D. and others, Proc. Nati Acad. Sci. USA 90, 10494-10498 (1993); Burkly, L.C. and others, Diabetes 43, 523-534 (1994); Barón, J.L. and others, J. Clin. Invest. 93, 1700-1708 (1994). Monoclonal antibodies to VCAM-1 may also have a beneficial effect in animal models of graft rejection, which suggests that inhibitors of VCAM-1 expression may have utility in the prevention of transplant rejection. Orocz, C.G. and others, Immunol. Lett. 32, 7-12 (1992). VCAM-1 is expressed by cells both as a membrane binding and as a soluble form. The soluble form of VCAM-1 has been shown to induce chemotaxis of vascular endothelial cells in vitro and stimulate an angigogenic response in rat cornea. Koch, A.E. and others, Nature 376, 517-519 (1995). Inhibitors of the expression of soluble VCAM-1 have potential therapeutic value in the treatment of diseases with a strong angiogenic component, which includes tumor growth and metastasis. Folkman, J, and Shing, Y, J. Biol. Chem. 10931-10934 (1992). The promoters for both VCAM-1 and ICAM-1 have been cloned and characterized. For example, both promoters contain multiple sequences of DNA elements which can bind the transcription factor, NF-kB. lademarco, M.F. and others, J. Biol. Chem 267, 16323-16329 (1992); Voraberger, G. And others, J. Immunol. 147, 2777-2786 (1991). The NF-kB family of transcription factors is central in the regulation of several genes up-regulated within sites of inflammation. The activation of NF-kB as a transcription factor involves the dissociation of an inhibitory subunit, IkB, in the cytoplasm. The subunits of NF-kB translocate to the nucleus, bind specific DNA sequence elements, and activate the transcription of several genes, including VCAM-1 and ICAM-1. Collins T. and others, Lab. Invest. 68, 499-508. (1993). It has been postulated that the regulation of gene expression in VCAM-1 can be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive to transcriptional or post-transcriptional regulation factors. The antioxidants of pyrrolidine dithiocarbamate and N-acetylcysteine inhibits cytokine-induced expression by VCAM-1, but not ICAM-1 in vascular endothelial cells. Mauri, N., et al., J. Clin. Invest. 92, 1866-1874 (1993). This would indicate that the inhibition of VCAM-1 expression by antioxidants involves some additional factors not involved in the regulation of ICAM-1 expression. 2,6-Di-alkyl-4-silyl-phenols are described as agents by Parker and others. In the Pat. of E.U.A. No. 5,155,250, issued October 13, 1992. In addition, 2,6-Di-alkyl-4-silyl-phenols are described as serum cholesterol lowering agents of TCP International Publ. No. WO 95/15760, published June 15, 1995. It would be advantageous to control the release of VCAM-1 and / or ICAM-1, and to treat VCAM-1 and / or ICAM-1 mediated effects. It will also be advantageous to control or treat chronic inflammation, without producing concomitant side effects known to accompany the use of anti-inflammatory steroids and non-steroidal anti-inflammatory agents. COMPENDIUM OF THE INVENTION The present invention provides compounds of the formula wherein R is hydrogen or -C (O) - (CH2) m-Q wherein Q is hydrogen or -COOH and m is an integer 1, 2, 3 or 4; R-1, Rs and Re are independently an alkyl group of d-C6; R2, R3 and R4 are independently hydrogen or an alkyl group of C6-C6; Z is thio, oxy or a methylene group; "A is an alkylene group of C? -C; X is thio or oxy, and Gi and G2 are independently hydrogen, C-? - C6 alkyl or - C (O) - (CH2) n -CH3 and n is a number 0 , 1, 2 or 3, or a pharmaceutically acceptable salt thereof The present invention also provides a method of inhibiting the peroxidation of LDL lipids in a patient in need thereof comprising administering to said patient an effective amount of antioxidant. a compound of formula (1).

The present invention further provides a method for lowering plasma cholesterol level in a patient in need thereof by administering a plasma lowering amount of a compound of formula (1). The present invention further provides a method for inhibiting the progression of atherosclerosis and / or a method for treating atherosclerosis in a patient in need thereof comprising administering to the patient an anti-atherosclerotic amount of a compound of formula (1). The present invention further provides a method of inhibiting cytokine-induced expression of vascular cell adhesion molecules-1 and / or intracellular adhesion molecule-1 in a patient in need thereof comprising administering to the patient an adhesion molecule of effective vascular cell-1 and / or intracellular adhesion molecule-1 which inhibits the amount of a compound of formula (1). The present invention further provides a method of treating a patient suffering from a chronic inflammatory disease comprising administering to the patient a therapeutically effective amount of a compound of formula (1). DETAILED DESCRIPTION OF THE INVENTION. As used in this application: - * - a) the designation "" - ~ "~" refers to a junction that protrudes forward out of the plane of the page; b) the designation "" refers to a junction that projects beyond the plane of the page; c) the designation "'" refers to a union between the chiral molecules or a binding between the chiral molecules for which the stereochemistry is not designated. d) the term "C? -C6 alkyl" refers to a saturated hydrocarbyl radical of straight or branched or cyclic configuration made from one to six carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, butyl tertiary, n-pentyl, n-hexyl, cyclohexyl, and the like. e) the term "C 1 -C 4 alkylene" refers to a saturated hydrocarbyl radical of straight or branched configuration made from one to four carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethanediyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl. , 1,4-butane-diyl, and the like. f) the designation it refers to a tienílo and it is understandable that the radical is united in either position 2 or position 3; it is also understandable that when the radical is attached to position 2 the substituent or substituents represented by Gi or G2 can be attached at any of the 3, 4 or 5 positions; and that when the radical is attached at position 3 the substituent or substituents represented by Gi or G2 can be attached at any of 2, 4 or 5 positions; g) the designation refers to a furyl, furanyl or furan and it is understandable that the radical is attached in either position 2 or position 3; it is also understandable that when the radical is attached to position 2, the substituent or substituents represented by G or G2 can be attached at any of positions 3, 4 or 5; and that when the radical is attached at position 3 the substituent or substituents represented by d or G2 can be attached from 2, 4 or 5; h) the designation "C (O)" refers to a carbonyl group of the formula. OR i) the term "pharmaceutically acceptable salt" refers to a basic addition salt. The term "pharmaceutically acceptable basic addition salts" is intended to be applied to any of the non-toxic organic or inorganic basic addition salts of the compounds represented by the formula (1) or any of its intermediates. Illustrative bases which form suitable salts include alkali metals or hydroxides of alkaline earth metals such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonium and aliphatic, cyclic, or aromatic organic amines such as methylamine, dimethylamine, triethylamine, and picoline. The compounds of formula (1) can be prepared using methods and techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing compounds of the formula (1) wherein Z is sulfur or oxygen that are exhibited in scheme A, wherein all substituents, unless otherwise indicated, are previously defined. SCHEME A Optional Acylation 1a Ib Z '= S or O Hal = chlorine, bromine or iodine R' = R but without hydrogen In general, a phenol of structure 1a can be prepared by reacting alkyne-4-mercaptophenol or alkylhydroquinone of structure 2 (or appropriately protected derivatives) with a non-nucleophilic base, such as sodium hydride, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and the like, the appropriate haloalkylenosilane of structure 3, such as the appropriate bromoalkane or iodoalkane, in a solvent suitable aprotic, such as acetonitrile, dimethylformamide or dimethylacetamide, or in an aqueous solvent, such as water / 2-butanone. A phenol ester of structure 1b can be prepared by acylating a phenol of structure 1a according to normal acylation techniques. For example, a phenol of structure 1a is dissolved in a suitable aprotic solvent such as acetonitrile, dimethylformamide or dimethylacetamide, or an ether solvent such as diethyl ether or dioxane, and treated with a suitable base, such as triethylamine, N-methylmorpholine, sodium hydroxide or sodium hydride. An excess of O-acylating agent is then added at room temperature and the reaction is stirred at room temperature for 1 to 24 hours. Examples of O-acylating agents are acetyl chloride, propionyl chloride, monoetiisuccinyl chloride, succinic anhydride, and the like. The product is then purified by techniques well known in the art, such as extractor methods and flash chromatography. Optionally, additional treatment with a suitable base, such as sodium hydroxide with subsequent acidification with a suitable acid, such as hydrochloric acid, followed by extraction and flash chromatography can be performed to provide the phenol ester of structure 1b. The starting materials for use in the general synthetic process described in Scheme a are readily available to one of ordinary skill in the art. For example, certain phenol starting materials for various compounds of formula (1) wherein Z is sulfide, such as 2,6-di-butyl tertiary-4-mercaptophenol and 2-butter-4-mercaptophenol are described in the following patents: from the USA 3,576,883, U.S. Patent. 3,952,064, patent of E. * U.A. 3,479,407. Patent of E.U.A. 4,975,467, U.S. Patent. 5,155,250 and in Japanese patent application 73-28425. Other phenol starting materials for compounds of the formula (1) include trimethylhydroquinone, butyl tertiary-1,4-hydroquinone, and 2,5-di-tert-butylhydroquinone which are commercially available. The haloalkylene silane starting materials of structure 3 can be prepared using procedures and techniques well known to one skilled in the art. A general synthetic scheme for preparing starting materials of structure 3, wherein the radical is attached at position 2 are shown in Scheme 1A, where all substituents, unless otherwise indicated, are previously defined. SCHEME A1 3a 3b 3d 3e Hal '= bromine or iodine In general, the heterocycle of Structure 3a can be lithiated in a suitable organic solvent, such as a diethyl ether, by means of the reaction with n-butyllithium. The lithium compound formed, structure 3b, is reacted with the chloroalkyl silane of structure 3c to give the chloroalkylsilyl heterocycle of structure 3d. The chloroalkylsilyl heterocycle can optionally be reacted with Na-Hal 'to form the compound of structure 3e. Preferably the sodium iodide is reacted with the chloroalkylsilyl heterocycle of the 3d structure to form the iodine derivative of the 3d structure which provides a better reagent with hydroquinone. Examples of heterocycles of structure 3a which are available include commercially, furan, thiophene, 2-methylfuran, methyl 2-furoate, 2-methylthiophene, 3-methylthiophene, ethyl 2-furoate, ethyl 3-furoate, 2-ethylthiophene, and eti 2-thiophenecarboxylate. Aldrich Chemical Co, Milwaukee, Wl (1992). A general synthetic scheme for preparing starting materials of structure 3, wherein the radical is attached at position 3 is shown in scheme A2, wherein all substituents, unless otherwise indicated, are previously defined. SCHEME A2 l 3h 3i Hal '= bromine or iodine In general, the 3-bromoheterocycle of structure 3f is reacted with magnesium metal via a Grignard reaction to form the Grignard reagent of structure 3g. The Grignard reagent of structure 3g is then reacted with the chlorodyalkyl chloroalkyl silane of structure 3c to give the chloroalkylsilyl heterocycle of structure 3h. The chloroalkisilyl heterocycle can optionally be reacted with Na-Hal 'to form the compound of structure 3i. Preferably the sodium iodide is reacted with the chloroalkisilyl heterocycle of the 3d structure to form the iodine derivative of the 3d structure which provides a better reactant with hydroquinone. The 3-bromoheterocycle of structure 3f, for example, 3-bromofuran and 3-bromothiophene are commercially available. In those instances where the 1-phenol functionality of a compound of structure 2 can react with the compounds of structure 3 under the reaction conditions, the 1-phenol functionality of the compound of structure 2 can be blocked with phenol blocking agents. normal which are well known and appreciated in the art. The selection and use of particular blocking groups are well known to one of ordinary skill in the art. In general, blocking groups should be selected which adequately protect the phenol in question during subsequent synthetic steps and which are easily removable under conditions which do not cause degradation of the desired product. Examples of protecting groups of suitable phenol are ethers, such as methoxymethyl, 2-methoxyethoxymethyl, tetrahydro-pyranyl, t-butyl and benzyl; silyl ethers, such as trimethylsyl and t-butyldimethylsilyl; esters, such as acetate and benzoate; carbonates, such as methyl carbonate and benzyl carbonate; as well as sulfonates, such as methanesulfonate and toluenesulfonate.

In these instances where Ri and R2 are each t-butyl, the reaction of scheme A can be conveniently carried out without blocking the functionality of 1-phenol. The following examples present syntheses as described in Scheme A. These examples are understandable to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mol" refers to moles; "mmol" refers to millimoles; "M" refers to molar; "L" refers to liters; "mL" refers to milliliters; "pb" refers to the boiling point; "° C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "pf" refers to the melting point; "mg" refers to milligrams; "μM" refers to micromolar; "μg" refers to micrograms; "h" or "hrs." It refers to hours; "min." refers to minutes; "THF" refers to tetrahydrofuran; "GC / MS" refers to capillary gas chromatography / mass spectrometer. EXAMPLE 1 2,6-bis (1,1-dimethylethyl) -4-r (2-furanyldimethylsilylo) methoxy-phenol, (DL 106,939).

Step a: Preparation of chloromethyl (dimethyl) furanylsilane Cold Furan (29 mL, 0.4 moles) in THF at a temperature between -65 ° C to -60 ° C in a dry ice / acetone bath. Add a solution of 2.5 M n-butyl lithium (160 mL, 0.4 moles) in hexane while maintaining the reaction temperature between -65 ° C to -60 ° C. Heat the reaction mixture to about 0 ° C for about 2 h, then cool again from -55 ° C to -50 ° C and add pure chlorine (chloromethyl) dimethylsilane (52.7 mL, 0.4 moles), while maintaining the temperature below -40 ° C. Once the addition is complete, warm slowly to room temperature and let stand overnight. Extinguish a small aliquot with saturated NH4CI and extract with ethyl acetate. GC / MS shows that the reaction is essentially complete with only -10% difuranyl impurity. Cool the reaction mixture on ice and add saturated NH CI (-200 mL) with vigorous stirring. Add ethyl acetate (-200 mL) and separate the organic phase. Wash three times with water, then three times with saturated sodium chloride. Drying and evaporation yields the title compound (-72 g). Distil the chloromethyl (dimethyl) furyl silane obtained in Example 1, step a in a ball distillation tube. Collect a product of -2.6 g and discard it. Collect clear liquid (47.2 g) between 70-75 ° C, GC / MS shows essentially 100% pure chloromethyl (dimethyl) furyl silane. Step b: Preparation of vodomethyl (dimethyl) furyl silane. Refluxing distilled chloromethyl (dimethyl) furyl silane (20 g, 114.5 mmol) in butanone (200 mL) containing sodium iodide (17.35 g, 116 mmol) for 4 h. GC / MS shows that the reaction is complete. Cool to room temperature and filter the sodium chloride. Evaporate and redissolve in ethyl acetate. Wash with water (3X), then wash with saturated sodium chloride (3X). Dry and evaporate to obtain a yellow liquid. Distil the yellow liquid in a ball distillation tube and collect iodomethyl (dimethyl) furyl-silane between 90 ° C-95 ° C as a light pink oil (26.8 g). Step c: Preparation of phenol, 2,6-bis (1,1-dimethylethyl) -4-f (2-furanyldimethylsilyl) methoxy-1 The reflux of a solution of iodomethyl (dimethyl) furanylsilane (18.0 g) , 67.6 mmol), 2,6-di-t-butylhydroquinone (150 g, 67.5 mmol) in acetonitrile (150 mL, previously purged with N2 for -0.5 h) and potassium carbonate (9.3 g, 67.5 mmol) for 4 days . GC / MS shows that -11% of the hydroquinone starting material remains. Also see some impurity of -9% with an apparent molecular weight of 448. Observe the product at 11.00 to 155 ° C. Obtain 12 g of dark retention fluid. GC / MS shows this to contain < 3% of the product, which is downloaded. The 12.2 g of missing material in the container is shown to contain -42% product. Dissolve the missing portion in the container in hexane (-50 mL). The material begins to crystallize. Cool in dry ice / acetone bath and filter the solids. Obtain hydroquinone starting material (2.5 g). Evaporate the filtrate, get the reddish orange oil (10 g). GC / MS shows this oil to contain 56% of product. Chromatograph the oil with 20% CH2Cl2 / hexane and obtain pale yellow oil (6.3 g). GC / MS shows -62% purity and shows that the highest impurities still present at 11.89 and 12.45 min. An additional flash chromatography in CH2Cl2 / hexane yields small changes. Pre-crystallize the entire sample and refrigerate. Filter the resulting crystals cold and wash with methanol at -70 ° C. GC / MS shows -96% purity. Repeat recrystallization and filter cold as before. Anal. Cale, for C2? J32O3: C, 69.95; H, 8.95 Found: C, 70.10; H, 8.84 EXAMPLE 2 2,6-bis (1,1-dimethylethyl) -4-r (dimethyl-2-thienylsilyl) rnetoxy] -phenol (MDL 107, 965) Step a: Preparation of chloromethyl (dimethyl) furanylsilane Dissolve thiophene (4.76 g, 56.5 mmol) in dry diethyl ether.

Add n-butyl lithium (62.2 mmol) at room temperature and stir overnight under nitrogen. Cool the mixture to 0 ° C, add chloro (chloromethyl) dimethylsilane (8.1 g, 56.5 mmol, in 2.5 mL of diethyl ether) slowly and stir overnight under nitrogen.

Add saturated NH4CI solution to the reaction mixture. Drain the aqueous phase and wash the organic phase with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Distill the residue in a ball distillation tube to give chloromethyl (dimethyl) furyl silane (4.4 g). Step b: Preparation of vodomethyl (dimethyl) furanylsilane Combine chloromethyl (dimethyl) furyl silane (4.4 g, 23.1 mmol) obtained from Example 2, step (a) with acetonitrile (100 ml). Add sodium iodide (3.5 g, 23.1 mmol) and stir overnight under nitrogen. Filter the mixture and remove -40 ml of solvent via distillation. Step c: Preparation of 2,6-bis (1,1-dimethylethyl) -4-r (dimethyl-2-thienylsilyl-methoxyl-phenol) Spray the solution obtained in Example 2, step b with nitrogen. di-t-butylhydroquinone (5.5 g, 24.7 mmol) and K2CO3 (3.4 g, 24.7 mmol) and reflux with nitrogen nitrogen Cool the reaction to room temperature The GC / MS indicates that the reaction is -90% complete. Solvent in vacuo and dissolve in water (150 ml) and extract with CH 2 Cl 2 (2X 150 ml) Dry the organic phase with MgSO 4, filter and concentrate in vacuo Purify via flash chromatography (5: 1 EtOAc / hexane) to give the compound of crude title (2.1 g) Pre-crystallize from hexane to give the title compound (1.2 g) Anal Cale, for C21H32O2S: C, 66.97; H, 8.56 Found: C, 66.89; H, 8.56 EXAMPLE 3 2.6- bis (1,1-dimethylethyl) -4-rfdimethyl (5-methyl (5-methyl-2-furanyPsilylmethoxyl-phenol Step a: Preparation of coromethyl (dimethyl) (5-methyl-2-furaniPsilane) React 2-methylfuran (0.4 moles) in THF with a solution of 2.5 M n-but-lithium (0.4 moles) in hexane and subsequently add chlorine (chloromethyl) dimethylsilane (0.4 mole) pure according to the procedure described in Example 1, step a, to provide the title compound Step b: Preparation of vodometl (dimethyl) (3-methyl-2-furani-p-silane) to chloromethyl (dimethyl) (3-methyl-2-furyl) siAne (114.5 mmol) in butanone (200 ml) containing sodium iodide (116 mmol) for 4 h, according to the procedure described in example 1, step b, to provide the title compound Step c: Preparation of 2,6-bis (1,1-dimethylethyl) -4- [Tdimethyl (3-methyl-2-furanysilylmethoxy-phenol) _ Reflux a solution of iodomethyl (dimethyl) ) (3-methyl-2-furii) silane (67.6 mmole), 2,6-di-t-butylhydroquinone (67.5 mmole) in acetonitrile (150 ml, previously purged with N2 for -0.5 h) and carb. potassium onate (9.3 g, 67.5 mmol) for 4 days, according to the procedure set forth in Example 1, step c, to provide the title compound. EXAMPLE 4 2- (1,1-dimethylethyl) -4-f (2-furanylmethylmethylsilyl] methoxy-1-phenol Reflux with iodomethyl (dimethyl) furanylsilane (67.6 mmol, Example 1, step b), t-butylhydroquinone (67.5 mmol) in acetonitrile (150 ml, previously purged with N2 for -0.5 h) and potassium carbonate (67.5 mmol) ) for 4 days according to the procedure set forth in Example 1, step c to provide the title compound. EXAMPLE 5 R 2,6-bis (1,1-di-methylethyl-4-rr (2-furanyldimethylsilydimethoxyphenyl) acid ester of butanedioic acid Stir a mixture of 2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) -methoxy] phenol (13.5 mmol, Example 1) and sodium hydride (15 mmol) in dimethylacetamide (100 ml) at room temperature for 1 hour. Add monoethyl-succinylchloride chloride (15 mmol) to the reaction mixture with stirring. Stir the reaction at room temperature overnight, then heat to reflux for 2 hours and allow to cool. Dilute the mixture with water and extract it with water. Wash the ether layer with water and evaporate to dryness to give a residue. Combine the residue with methanol (100 mL) and heat to reflux. Add sodium hydroxide (1.0 g in 20 ml of water) and heat the reaction to reflux for 30 minutes, then dilute with water and let it cool. Acidify the aqueous suspension with concentrated hydrochloric acid and extract the mixture with ether and tetrahydrofuran. Separate the organic layer, evaporate to dryness and recrystallize the title compound. EXAMPLE 6 Mono-ester r2- (1,1-dimethylethyl) -4-f (2-furanyl-dimethyl-ti-isylmethoxyl) nyl-butanedioic acid Stir a mixture of 2- (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl)] - methoxy] -phenol (20 mmol, Example 4), succinic anhydride (22 mmol), triethylamine (22 mmol) and acetonitrile (100 ml) at room temperature overnight, then heat at reflux for two hours. Dilute the cooled mixture with water and extract it with ether. Evaporate the ether layer to give a residue which was recrystallized with acetonitrile to give the title compound. EXAMPLE 7 2,6-bisd, 1-dimethylethyl) -4-rr (2-furanyldimethylsilylmethylthiol-phenol Heat a mixture of 2,6-di-t-butyl-4-mercaptophenol (50 mmol), chloromethyl (dimethyl) furanylsilane (50 mmol, Example 1, step a), potassium bicarbonate (50 mmol), potassium iodide ( 2.0 g) and isopropanol (150 ml) at reflux with stirring overnight. Cool the mixture, dilute it with water and ether and separate the layers. Evaporate the organic layer to dryness to give a residue which was distilled and purified to give the title compound. EXAMPLE 8 2,6-bisd. 1-dimethylethyl) -4-rr (dimethyl-2-thienylsilyl) methylamine-phenol Heat a mixture of 2,6-d? -t-butyl-4-mercaptophenol 850 mmol), chloromethyl (dimethyl) ienylsilane (50 mmol, Example 2, step a), potassium bicarbonate (50 mmol), potassium iodide ( 2.0 g) and isopropanol (150 ml) was heated to reflux with stirring overnight according to the procedure set forth in Example 7 to give the title compound. EXAMPLE 9 2- (1,1-dimethylet-p-4-r (2-furanyldimethylsilyl) methoxy-phenol acetate Stir a mixture of 2- (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl)] - methoxy] phenol (15.3 mmol, Example 4), triethylamine (30 mmol) and ether (100 ml) at room temperature. Slowly add acetyl chloride (30 mmol) with stirring. Stir the mixture for 4 hours, then dilute it with water. Separate the layers and evaporate the organic layer to dryness to give the title compound. EXAMPLE 10 2,5-bis (1,1-dimethylethyl-4-rf2-furanyldimethylsilyl-p-methoxy-phenol) Shake a mixture of chloromethyl (dimethyl) furanylsilane (0.3 mole, Example 1, step a), 2,5-di-t-butylhydroquinone (0.3 mole, Aldrich Chemical Co, Milwaukee, Wis. 53233), lithium bromide (0M moles), potassium carbonate (0.3 moles) sodium iodide (2.0 g) and acetonitrile (600 ml) at reflux for 3 days. Cool the mixture, dilute it with water and extract it with ether. Wash the ether layer with water and evaporate to dryness to give a residue. Distil and chromatograph the residue on silica gel to give the title compound. EXAMPLE 11 4-f (dimethyl-2-t-ethylsilyl) methoxy-2,3,5-trimethyl-phenol Heat a mixture of trimethylhydroquinone (66 mmol, Aldrich Chemical Co, Milwaukee, Wis. 53233), chloromethyl (dimethyl) furanylsilane (66 mmol, Example 1, step a), potassium carbonate (66 mmol), sodium iodide (9.9 g) and acetonitrile (150 ml) were heated to reflux with stirring for 5 days. Cool the mixture, dilute it with water and ether and separate the layers. Evaporate the organic layer to dryness to give a residue. Distil the residue and chromatograph the residue distilled over silica gel to give the title compound. EXAMPLE 12 4-r (dimethyl-2-thienylsilyl) methoxy-2,3,5-trimethylene-phenol Chromatography of the reaction product of Example 11, followed by distillation, gives 4 - [(dimethyl-2-thienylsilyl) methoxy] -2,3,5-trimethyl-phenol. The following compounds can be prepared by methods analogous to those described above in Examples 1-12. 2,6-diethyl-4 - [(2-furanyldimethylsilyl) methoxy] -phenol; 2,6-diethyl-4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol; 2,6-diethyl-4 - [[(2-furanyldimethylsilyl) methyl] thio] -phenol; 2,6-diethyl-4 - [[(dimethyl-2-thienylsilyl) methyl] thio] -phenol; 2,5-diethyl-4 - [(2-furanyldimethylsilyl) methoxy] -phenol; 2,5-diethyl-4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol; 2,5-diethyl-4 - [[(2-furanyldimethylsilyl) methyl] thio] -phenol; 2,5-diethyl-4 - [[(dimethyl-2-thienylsilyl) methyl] thio] -phenol; 2,6-diisopropyl-4 - [(2-furanyldimethylsilyl) methoxy] -phenol; 2,6-diisopropyl-4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol; 2,6-diisopropyl-4 - [[(2-furanyldimethylsilyl) methyl] thio] -phenol; 2,6-diisopropyl-4 - [[(dimethyl-2-thienylsilyl) methyl] thio] -phenol; 2,5-diisopropyl-4 - [(2-furanyldimethylsilyl) methoxy] -phenol; 2,5-diisopropyl-4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol; 2,5-diisopropyl-4 - [[(2-furanyldimethylsilyl) methyl] thio] -phenol; 2,5-diisopropyl-4 - [[(dimethyl-2-thienylsilyl) methyl] thio] -phenol; 4 - [(2-furanild imethylsilyl) methoxy] -2,3,6-trimethyl-phenol; 4 - [(dimethyl-2-thienylsilyl) methoxy] -2,3,5-trimethyl-phenol; 4 - [[(2-furanylmethyl-silyl) methyl] thio] -2,3,6-trimethyl-phenoxy; 4 - [[(d i metN-2-tienMsNil) methyl] thio] -2, 3, 5-tri methy1-phenol; 2- (1,1-dimethylethyl) -4 - [[(2-furanylmethyl) silyl) methyl] thio] -phenol; 2- (1,1-dimethylethyl) -4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol; 2- (1I1-dimethylethyl) -4 - [[(dimethyl-2-thienylsilyl) methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-methyl-2-thienyl) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[[dimethyl (5-methyl-2-thienyl) -silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[[dimethyl (5-methyl-2-furanyl) silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-furanyl) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-thienyl) silyl] methoxy] -phenol; 2, β-bis (1,1-dimethylethyl) -4 - [[[dimethyl (4-methyl-2-thienyl) silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[[dimethyl (4-methyl-2-furanyl) siiyl] methyl] thio] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-methyl-2-thienyl) silyl] methoxy] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[[dimethyl (5-methyl-2-thienyl) silyl] methyljthio] -phenol; '- 2,5-bis (1,1-dimethylethyl) -4 - [[[dimethyl] (5-methyl-2-furanl) silyl] methyl] thio] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl] (4-methyl-2-furanyl) silyl] methoxy] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-thienyl) silyl] -methoxy] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[[dimethyl (4-methyl-2-thienyl) silyl] -methyl] -thio] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[[dimethyl (4-methyl-2-furanyl) silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-ethyl-2-thienyl) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxopropyl) -2-furanyl) silyl] methoxy] -phenol; 2,6-bis (1,11-dimethylethyl) -4 - [[dimethyl (5- (1-oxopropyl) -2-thienyl) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[[dimethyl (5- (1-oxopropyl) -2-furanyl) silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxopropyl) -2- tie nor l) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxobutyl) -2-furanyl) silyl] methoxy] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxobutyl) -2-thienyl) silyl] methoxy] -phenol; 2,6-bys (1,1-dimethylethyl) -4 - [[[dimethyl (5- (1-oxobutyl) -2-furanyl) silyl] methyl] thio] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxobutyl) -2-thienyl) silyl] methoxy] -phenol; Acetate 2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) methoxy] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) methoxy] -phenol acetate; 2,5-bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl) methoxy] -phenol acetate; 2,6-bis (1,1-dimethylethyl) -4 - [[(2-furanyldimethylsilyl) methyl] thio] -phenol acetate; 4 - [(Dimethyl-2-thienylsilyl) methoxy] -2,3,6-trimethyl-phenol acetate; 4 - [(Dimethyl-2-thienylsilyl) methoxy] -2,3,5-trimethy1-phenol acetate; [2,6-Bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl) methoxy] phenyl] ester of propionic acid; Mono ester [2,5-bis (1,1-di methyl ethyl) -4 - [(2-thienyldimethylsilyl) methoxy] phenyl] propionic acid; Ester mono [2,5-bis (1,1-di methyl ethyl) -4 - [(2-furanyldimethylsilyl) methoxy] phenyl] propionic acid; [2,6-Bis (1,1-dimethylethyl) -4 - [[(2-thienyldimethylsilyl) methyl] thio] phenyl] ester of propionic acid; Ester mono [2,6-bis (1,1-di methylethyl) -4- [[(2-furanyldimethylsilyl) methyl] thio] phenyl] propionic acid; Mono-2,6-bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl) methoxy] -phenyl] ester of butanediic acid; Ester mono [2,5-bis (1,1-di methyl ethyl) -4 - [(2-thienyldimethylsilyl) methoxy] phenyl] of butanediic acid; Ester mono [2,5-bis (1,1-di methylethyl) -4 - [(2-furanyldimethylsilyl) methoxy] phenyl] of butanediic acid; Ester mono [2,6-bis (1,1-dimethylethyl) -4 - [[(2-thienyldimethylsilyl) methyl] thio] phenyl] of butanediic acid; and Ester mono [2,6-bis (1,1-dimethylethyl) -4 - [[(2-furanyldimethylsilyl) methyl] thio] phenyl] butanediic acid. A general synthetic scheme for preparing the compounds of the formula (1) wherein Z is methylene, is shown in Scheme B, wherein all substituents, unless otherwise indicated as previously defined.

SCHEME B Step to to the 1 C 1d Hal = chlorine, bromine or iodine In general, a phenol of structure 1c can be prepared according to Scheme B in a two-step process. In step a, the appropriate haloalkylenesilane of structure 3 is reacted with magnesium metal in a suitable aprotic solvent, such as ethyl ether, in order to form magnesium halide salt. The magnesium halide salt (Grignard reagent) is then reacted with the appropriate alkyl-4-hydroxy-benzaldehyde of structure 4) (or a suitably protected derivative) to give the alcohol of structure 5. In step b , the alcohol of structure 5 can be reduced to the desired phenol of structure 1b by a variety of reduction techniques and procedures as well as can be appreciated well in the art. For example, the alcohol of structure 5 can be reduced by means of a reduction of Birch by reacting it with sodium in liquid ammonia. A phenol ester of structure 1d can be prepared by acylating a phenol of structure 1c according to normal acylation techniques as previously described in Scheme A.

The starting materials for use in the general synthetic procedures described in Scheme B are readily available or can be easily prepared according to standard techniques and procedures. Where it is necessary to avoid unwanted side reactions, the 1-phenol functionality of the alkyl-4-hydroxy-benzaldehyde of structure 4 in Scheme B can be blocked prior to the Grignard reaction with a normal phenol blocking agent as it was previously described in Scheme A. The following example presents a normal synthesis as described in Scheme B. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way. EXAMPLE 13 2,6-bis (1,1-dimethylethyl) 4-r 2 - (2-furanyldimethylsilyl) ethyl-phenol Step a: Mix the versions of magnesium (240 mg, 10 mmol) and ethyl ether anhydride under an inert atmosphere. Add a solution of chloromethyl (dimethyl) furanylsilane (10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 2,6-di-t-butyl-4-hydroxybenzaldehyde 810 mmol) in ethyl ether anhydride. Stir until the reaction is complete. Cool the reaction mixture to 0 ° C and add saturated ammonium chloride solution. Separate the ether layer, wash with water and dry (MgSO). Evaporate the appropriate intermediate from structure 5 and purify by silica gel chromatography. Step b: Mix the sodium metal (520 mg, 22.6 mmol) and liquid ammonia (13 ml). To this solution, add by dropwise addition, a solution of the intermediate of Example 13, pass to 810 mmole) in ethyl alcohol (0.5 g) and ethyl ether (5 ml). After the blue color disappears, carefully add water (13 ml), extract with ethyl ether, dry (MgSO 4) and evaporate the solvent. Purify the residue by silica gel chromatography to give the title compound. Alternatively, the compounds of formula (1) wherein Z is methylene can be prepared according to the procedure shown in Scheme C, wherein all substituents, unless otherwise indicated, were previously written. SCHEME C 1 C 1d Hal = chlorine, bromine or iodine In general, a phenol of structure 1b can be prepared by first reacting the appropriate haloalkane or haloalkene of structure 3 with magnesium metal in a suitable aprotic solvent, such as ethyl ether, in order to form the magnesium halide salt. . The magnesium halide salt (Grignard reagent) is then reacted with the appropriate alkyl-4-hydroxy-benzylhalide of structure 6 (or a suitably protected derivative) to give the desired phenol of structure 1c. A phenolic ester of structure 1d can be prepared by acylating a phenol of structure 1c in accordance with normal acylation techniques as previously described in Scheme A. The starting materials for use in the general synthetic procedures described in Scheme C, they are readily available or can be easily prepared according to normal techniques and procedures. For example, the preparation of 3,5-dimethyl-4-acetoxy-benzyl bromide of structure 6 in Scheme C can be blocked prior to the Grignard reaction with a normal phenol blocking agent as previously described in the Scheme. A. The following examples present normal syntheses as described in Scheme C. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.

EXAMPLE 14 2,6-dibetyl-4-r 2 - (2-furanldimethylsilyl) etiphenol Mix the magnesium versions (240 mg, 10 mmol) and ethyl ether anhydride under an inert atmosphere. Add a solution of chloromethyl (dimethyl) furanylsilane (10 mmol) in ethyl ether anhydride. Stir until the magnesium metal dissolves. Add a solution of 4-bromomethyl-2,6-diethylphenol 810 mmol) in ethyl ether anhydride and reflux the mixture until the reaction is complete. Pour into a mixture of ice / hydrochloric acid and separate the layers. Wash the ether layer with water, dry (MgSO) and evaporate to give the title compound which was purified by silica gel chromatography. EXAMPLE 15 Acetate of 2,6-diethyl-4-r 2 - (2-furanyldimethyl-1-yl) etphenol Stir a mixture of the product of Example 14 (20 mmol), triethylamine (2.53 g, 25 mmol) in ether (150 ml) at room temperature. Add acetyl chloride (1.96 g, 25 mmol) and stir the mixture overnight. Add water and ether and separate the layers.

Evaporation of the organic layer gives an oil that was distilled in a ball distillation tube. Chromatography on silica gel gives the title compound. The following compounds can be prepared by methods analogous to those described in the Examples 13-15: 2,6-bis (1,1-dimethylethyl) -4- [2- (dimethyl-2-thienylsilyl) ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4- [2- (2-furanyldimethylsilyl) ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4- [2- (dimethyl-2-thienylsilyl) ethyl] -phenol; 2- (1,1-dimethylethyl) -4- [2- (2-furanyldimethylsilyl) ethyl] -phenol; 2- (1,1-dimethylethyl) -4- [2- (dimethyl-2-thienylsilyl) ethyl] -phenol; 2,6-diisopropyl-4- [2- (2-furanyldimethylsilyl) ethyl] -phenol; 2,6-diisopropyl-4- [2- (dimethyl-2-t-butyl) ethyl] -phenol; 2,6-diethyl-4- [2- (dimethyl-2-thienylsilyl) ethyl] -phenol; 4- [2- (2-furanyldimethylsilyl) ethyl] -2,3,6-trimethyl-phenol; 4- [2- (2-furanyldimethylsilyl) ethyl] -2,3,5-trimethyl-phenol; 4- [2- (dimethyl-2-thieniisilyl) ethyl] -2,3,6-trimethyl-phenol; 4- [2- (dimethyl-2-thienylsilyl) ethyl] -2,3,5-trimethyl-phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-furanyl) silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-thienyl) silyl] ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-methyl-2-thienyl) silyl] ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-methyl-2-furanyl) silyl] ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-thienyl) silyl] ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [[dimethyl (4-methyl-2-furanyl) silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5-methyl-2-t] enyl) silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxopropyl) -2-furanyl] silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl); l) -4 - [[dimethyl (5- (1-oxopropyl) -2-thienyl] silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- ( 1-oxobutyl) -2-furanyl] silyl] ethyl] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [[dimethyl (5- (1-oxobutyl) -2-thienyl] silyl] ethyl ] -phenol; 2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl] ethyl] -phenol acetate; 2,5-bis (1, 1-dimethylethyl) -4- acetate (2-furanyldimethylsilyl] ethyl] -phenol; 2,5-bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl] ethyl] -phenol acetate; 4 - [(dimethyl-2-thienylsilyl) acetate ethyl] -2,3,6-trimethyl-phenol; 4 - [(dimethyl-2-ylsilylsilyl) ethyl] -2,3,5-tri-methyl tert-phenol; mono ester [2,6-bis ( 1, 1-dimethylethyl) -4 - [(2-thieniidimethylsilyl) ethyl] phenyl] propionic acid; ester tnono [2,5-bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl) ethyl] phenyl] of propionic acid; mono-ester [2,5-bis (1,1-dimethylethyl) -4 - [(2-furan-1-dimethylsilyl) ethyl] phenyl] of pro-acid pionic; [2,6-Bis (1,1 -dimethylethyl) -4 - [(2-f uranyldimethylsilyl) ethyl] -frylic] ester of propionic acid; Ester mono [2,6-bis (1,1-di-ethyl-ethyl) -4 - [(2-thienyl-di-methyl-silyl) -ethyl] -phenyl] butanedioic acid; Mono [2,5-bis (1,1-dimethylethyl) -4 - [(2-thienyldimethylsilyl) ethyl] phenyl] ester of butanedioic acid; Ester mono [2,5-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) ethyl] phenyl] of butanedioic acid; and Ester mono [2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) -ethylphenyl] butanedioic acid. It should be understood that the compounds of the formula (I) can exist in various stereoisomeric forms. All stereoisomeric forms that accord with the above structural formulas, as interpreted in accordance with standard conventions for expressing the stereoisomeric structure, are intended to be included within the scope of the present invention. Preferred compounds of the formula (I) are those in which R is hydrogen, acetyl or succinyl, preferably hydrogen; Ri is methyl or tertiary butyl; R2, R3 and R are each independently hydrogen, methyl or tertiary butyl; R5 and Re, are each methyl; A is methylene and Gi and G2 are each independently hydrogen, methyl or ethyl. More preferred are the compounds: 2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) methoxy] -phenol; and 2,6-bis (1,1-dimethylethyl) -4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol.

As used herein, the term "patient" refers to a warm-blooded animal or mammal that needs the treatment of a chronic inflammatory disease, atherosclerosis, hypercholesterolemia or that requires the inhibition of cytokine-induced expression of the molecule 1 of adhesion of vascular cells and / or molecule 1 of intercellular adhesion. It is understood that guinea pigs, dogs, cats, rats, mice, hamsters, rabbits and primates, including humans are examples of patients within the scope of the meaning of the term. Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or plaque. The identification of those patients who need such treatment for atherosclerosis is within the capacity and knowledge of an ordinary expert in the field. For example, individuals who suffer from clinically important atherosclerosis or who are at risk of developing clinically significant atherosclerosis are patients who need treatment for atherosclerosis. A physician with ordinary skill in the art can easily determine, through the use of clinical tests, the physical examination and the medical / family history, if an individual is a patient in need of treatment for atherosclerosis. An effective antiatherosclerotic amount of a compound of the formula (I) is an amount that is effective to inhibit the development or growth of atherosclerosis in a patient in need thereof. As such, the successful treatment of a patient for atherosclerosis is understood to include the decrease, interruption, suspension, or effective arrest of the atherosclerotic lesion or growth or plaque growth and does not necessarily indicate a total elimination of atherosclerosis. Furthermore, it is understood and appreciated by those skilled in the art that successful treatment for atherosclerosis may include prophylaxis to prevent atherosclerotic lesion or plaque formation. Lipid LDL peroxidation, such as the unsaturated fatty acid portions of LDL cholesterol esters and phospholipids, is known to facilitate the deposition of cholesterol in macrophages that were subsequently deposited in the vessel wall and transformed into foam cells . The identification of those patients who need inhibition of LDL lipid peroxidation is within the capacity and recognition of someone with experience in the field. For example, individuals who need atherosclerosis treatment were defined earlier and also patients who need inhibition of LDL lipid peroxidation. An effective antioxidant amount of a compound of the formula (I) is an amount that is effective to inhibit the peroxidation of LDL lipids in the blood of a particular patient. Hypercholesterolemia is a disease state characterized by serum cholesterol levels of LDL cholesterol that were elevated by a clinically significant amount over those considered normal by those of ordinary experience in the field. The identification of patients who need treatment for hypercholesterolemia is within the capacity and knowledge of someone skilled in the art. For example, individuals who have serum cholesterol levels or LDL cholesterol levels, as determined by clinical laboratory tests, that rise substantially and chronically over what is considered normal by those of ordinary experience in the art, are patients who need treatment for hypercholesterolemia. As an additional example, individuals who are at risk of developing hypercholesterolemia may also be patients who need treatment for hypercholesterolemia. An expert in the field can easily identify, through the use of clinical tests, physical examination and medical / family history, those patients who suffer from hypercholesterolemia and those who are at risk of developing hypercholesterolemia and therefore it is easily determined if an individual is a patient who needs hypercholesterolemia. The term "chronic inflammatory disease" refers to diseases or conditions characterized by persistent inflammation in the absence of an identifiable irritant or microbial pathogen. Inflammatory diseases for which treatment with a compound of formula (I) will be particularly useful, include: asthma, chronic inflammation, rheumatoid arthritis, autoimmune diabetes, transplant rejection and tumor angiogenesis. A "therapeutically effective amount of a compound of formula (1) is an amount that is effective, by the administration of a single dose or multiple doses to the patient, providing relief from symptoms associated with chronic inflammatory diseases." An "effective inhibitory amount. of vascular cell adhesion molecule and / or inhibitor of intercellular cell adhesion molecule 1"of a compound of formula (1) is an amount that is effective, by the administration of a single dose or multiple doses to the patient, providing relief of symptoms associated with conditions mediated by vascular cell adhesion molecule 1 and / or intercellular adhesion molecule 1. As used herein, "symptom relief" of a chronic inflammatory disease or conditions mediated by vascular cell adhesion molecule 1 refers to the decrease in severity over what is expected in the absence of trafficking and does not necessarily indicate a total elimination or cure of diseases. The relief of symptoms is also intended to include prophylaxis. To determine the therapeutically effective amount or dose, the effective amount or dose of antioxidant, the quantity or dose that decreases plasma cholesterol, the effective antiatherosclerotic amount or dose or the inhibitory amount of VCAM-1 and / or effective ICAM-1 of a compound of formula (1), a number of factors were considered by the physician, including, but not limited to: mammalian species; its size, age, and general health, the specific disease involved, the degree of involvement, or the severity of the disease; the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances. A therapeutically effective amount of an effective antioxidant amount, a decrease amount of plasma cholesterol, an effective anti-atherosclerotic amount or an amount that inhibits VCAM-1 and / or ICAM-1 of a compound of formula (1) will generally vary from about 1 milligram per kilogram of body weight per day (mg / kg / day) to about 5 grams per kilogram of body weight per day (mg / kg / day). A daily dose of about 1 mg / kg to about 500 mg / kg is preferred. The compounds of this invention are inhibitors of the expression VCAM-1 and / or ICAM-1. It is thought that the compounds of this invention exert their inhibitory effect through inhibition of upregulation of VCAM-1 and / or ICAM-1 by cytokines and thus prevent or provide relief of symptoms for chronic inflammatory diseases including asthma, chronic inflammation, rheumatoid arthritis, autoimmune diabetes and the like; atherosclerosis and hypercholesterolemia. However, it should be understood that the present invention is not limited by any particular theory or mechanism proposed to explain its effectiveness in an end-use application. To effect the treatment of a patient, a compound of the formula (1) can be administered in any form or mode that makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like. Oral administration is generally preferred. One skilled in the art to prepare formulations can easily select the appropriate form and mode of administration depending on the state of the disease to be treated, the stage of the disease and other relevant circumstances. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990). A compound of the formula (1) can be administered in the form of pharmaceutical compositions or drugs which are made by combining a compound of the formula (1) with pharmaceutically acceptable carriers or excipients, the proportion and nature of which was determined by the chosen route of administration and normal pharmaceutical practice. The pharmaceutical compositions or medicaments were prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be adapted to oral or parenteral use and can be administered to the patient in a form of tablets, capsules, suppositories, solution, suspensions or the like. The pharmaceutical compositions can be administered orally, for example, with an inert diluent or with an edible vehicle. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of therapeutic administration, a compound of formula (1) can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of a compound of the formula (1), the active ingredient, but may vary depending on the particular form and may conveniently be between 4% to about 70% by weight of the unit. The amount of the active ingredient present in the compositions in said unit dose form suitable for administration will be obtained. Tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants, binders, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants, such as magnesium stearate or Sterolex; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin, can be added, or flavoring agents, such as peppermint, methyl salicylate or orange flavoring. When the unit dose form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other forms of unit doses may contain other different materials that modify the physical form of the unit dose, for example, as coatings. Therefore, the tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes or colorants and flavorings. The materials used to prepare these different compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral administration, a compound of the formula (1) can be incorporated into a solution or suspension. These preparations must contain at least 0.1% of a compound of the invention, but may vary to be between 0.1 and about 50% of the weight thereof. The amount of the active ingredient present in said compositions is such that an adequate dose will be obtained. Solutions or suspensions that also include one or more of the following adjuvants depending on the solubility and other properties of a compound of the formula (1); sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diamine tetraacetic acid; pH regulating compositions such as acetates, citrates or phosphates and agents for adjusting toxicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. EXAMPLE 18 Percent Inhibition of Cytokine-Induced Expression VCAM-1 and ICAM-1 by Selected Phenolic Antioxidants in Human Aortic Smooth Muscle Cells or Proliferating Human Umbilical Vein Endothelial Cells Plaque Proliferation of Umbilical Vein Endothelial Cells Human (CEVUH) or human aortic smooth muscle cells (MHCL) from Clonetics (San Diego, CA) in 96-well plates in 100 μl of medium per well at 20,000 cells per cm2. Maintain the cultures in growth medium (EGM or SMGM2, Cloneticx, San Diego, CA) for two days before the addition of cytokines or drugs. Add more or less compound cytokines for 20 to 24 hours before analysis for the adhesion of molecular levels. Add tumor necrosis factor (Genzyme, Cambridge, MA) to cultures at 500-1000 units / ml to stimulate the expression of adhesion molecules. Add interleukin-4 (GIBCO-BRL, Gaithersburg, MD) to cultures at 100-200 pg / ml to stimulate the expression of VCAM-1. (Perform additions by transferring 100 μl of cytokines plus compounds serially diluted into a separate 96-well plate in the cell-containing plates, do not exchange the medium in the cultures before the addition of effectors). Remove the culture medium and wash the monolayers twice with Hanks regulated saline solution (SSRH) at room temperature. Add the primary antibody (anti-human VCAM-1 from Upstate Biotechnology, Inc., Lake Placid, NY or anti-human ICAM-1 from Immunotech, Inc., Westbrook, ME) to each well (1 μg / ml in SSRH plus 5% serum newborn calf, GIBCO-BRL, Gaithersburg, MD) and incubate at 37 ° C for 1 hr. Wash the wells twice with SSRH, then add 100 μl of a 1/1000 dilution of goat anti-mouse IgG conjugated to horse radish peroxidase (BioRad, Hercules, CA) in SSRH plus 5% newborn calf serum to each well and incubate for 1 hr at 37 ° C. Wash the wells three times with SSRH, then add 100 μl of TMB substrate (BioRad, Hercules, CA) to each well. Stop the reaction after the blue color develops by the addition of 50 μl of 1N H2SO4. Measure the absorbance at 450 nm with a plate reader. The IC 50 value was defined as the concentration of drug that inhibits the expression of adhesion molecule induced by cytokine by 50%. The maximum values for adhesion of molecular expression in cytokine-induced cultures were subtracted from the basal level of expression of adhesion molecules (minus cytokines) in the cultures to determine the level of induction. Each drug concentration was tested in wells in quadruplicate. Table 1 summarizes the ability of two compounds of this invention to selectively inhibit VCAM-1 or inhibit both VCAM-1 and ICAM-1 using human umbilical vein endothelial cells (CEVUH). In these experiments, the cells were co-incubated with the tumor necrosis factor alpha together with the indicated compounds for 20 hours before analyzing the expression of cell surface adhesion molecules. TABLE 1 Inhibition of VCAM-1 and / or ICAM-1 in Human Umbilical Vein Endothelial Cells (CEVUH) Comp. No. VCAM-1 ICAM-1 (MDL No.) ICso (μM) * IC50 (μM) * 106,963 13 33 107,695 35 72, >; 100 * Average of two operations, except for MDL 107,695 1CAM-1 where both values are shown. The in vivo activity of these compounds can also be evaluated in other models of inflammation envisioned by implicating elevated VCAM-1 levels. One such model for respiratory diseases, such as asthma, is a model sensitized with ovalbumin. King.T.T. and others, Int. Arch. Allergy Immunol. 105. 83-90 (1994). This model of pulmonary inflammation is mediated by IgE and involves eosinophilia (as does the asthmatic human being). The bronchial alveolar lavage fluid (LAB) obtained from experimental animals can be evaluated for a number of parameters, including the expression of soluble adhesion molecules and the accumulation of leukocytes. The expression of soluble adhesion molecules can be assessed by immunohistochemistry within tissues, especially the lung, of experimental animals. The effect of the claimed compounds should suppress upregulation of VCAM-1 expression and inhibit eosinophil accumulation in BAL fluid. The inhibitors could be tested in an adjuvant arthritis rat model, which was previously shown to respond to anti-ICAM-1 monoclonal antibodies. Ligo, Y, and others, J. Immunol. 147, 4167-4171 (1991). In this model, the expression of adhesion molecules could be evaluated in the extremities (joints) of experimental animals. For autoimmune diabetes, compounds can be tested for their ability to delay onset or prevent adoptive disease transfer in the NOD mouse model. Heinke, E.W. and others, Diabetes 42. 1721-1730 81993); Barón, J.L. and others, J. Clin. Invest. 93, 1700-1708 (1994). In addition, the level of VCAM-1 expression in tissues (v.gr, pancreas) can be monitored, as well as monitoring the development of diabetes in experimental animals. The therapeutic potential for rejection of transplants can be evaluated by monitoring the survival of cardiac allograft (Balb / c hearts transplanted in C3H / He receptors, Isobe, M., et al., J. Immunol 153, 5810-5818 (1994). In vivo administration of anti-VCAM and antiVLA-4 monoclonal antibodies induces immunosuppression to cardiac allografts and soluble antigens in this mouse model.The effects of the compound on tumor metastasis and angiogenesis can be evaluated in a number of models. Meianoma models of B 16 (murine) and M24met (human beings) for experimental metastasis Fidier, I.J. Cancer Rs. 35, 218-224 (1975); Meuller, B. M, et al., Cancer Res. 51 , 2193-2198 The activity of the compounds can be evaluated by their effect on the number of lung metastases that they developed, as well as their effect on the expression of VCAM-1 in the lung as described above for the mouse respiratory model. A model for evaluating the anti-angiogenic compounds that can be used to test the compounds involves monitoring the vascular response to a mixture of angiogenic factors mixed with base membrane proteins injected subcutaneously into mice. Pasaaniti, A. and others, Lab. I nvest. 67, 519-528 (1992). Angiogenesis was classified by the number of recipients enrolled in Matrigel and by the hemoglobin content of the gels. The expression of adhesion molecules and the accumulation of leukocytes can be determined by immunohistochemical methods as in all previous examples. EXAMPLE 17 5? Hypocholesterolemic Effects and Antioxidants of Compounds of the Formula (1) in New Zealand White Rabbits Females Fed with Cholesterol A. Experimental Protocol Perform five independent experiments in the following manner. Each study has a control group and 1-5 groups treated with the MDL compound (N = 5 per group). Feed the New Zealand White rabbits females (Hazelton, -2.0-2.3 kg), rabbit croquettes enriched with 0.2% cholesterol (Purina # 5322) with or without 0.4% MDL compound. Solubilize the MDL compounds in 100% ethanol. Spray the croquettes with the MDL blends and allow them to dry overnight in a chemical fume hood. Spray the control croquettes with ethanol. Feed the rabbits with 100 grams of feed per day for 7 days (0.6% MDL 103,491 were fed for 14 days); make water available at free demand. On day 7, draw blood from rabbits (about 2 ml) (having fasted at night) from a marginal ear vein. Kill the rabbits with an overdose of carbon dioxide. Record the total weights and the weight of the liver in grams. Record the food as grams "day" 1"rabbit" 1. Use aliquots of fresh serum for clinical chemistry, determination of lipoprotein cholesterol, thiobarbituric acid reactive substances (SRATB) and concentrations of the compound and metabolites in serum. Freeze the livers (aliquots of about 5 grams) at -20 ° C for a compound and determine the concentration of metabolites to the last. B. Clinical Chemistry Allow the blood to clot at room temperature for 30 minutes. Obtain serum after centrifugation for 10 minutes at 5 ° C at 3000 rpm in a Beckman GPKR centrifuge with a GH rotor. Analyze by a COBAS MIRA autoanalyzer (Roche Diagnostics) using Roche diagnostic reagents for total cholesterol (CHOL, equipment # 44334) and triglycerides (TG, equipment # 44120). Calculate cholesterol and triglycerides as mg / dl. C. Analysis of SRATB STRAB are a qualitative indication of the oxidation of lipids in a sample. In this analysis, initiate the oxidation of serum lipids with CuSO4, resulting in the formation of aldehydes, such as malodialdehyde (MDA). When incubated with thiobarbituric acid, the absorbance of the aldehydes can be detected at 530-540 nm. SRATB values that are lower than the control serum values indicate the relative ability of a compound to inhibit oxidation. Measure as follows: mix 50 μl of serum with 50 μl of 0.9% saline solution and 400 μl of a CuSO solution and incubate at 37 ° C for 5 hr. Stop the reactions by the addition of 1.0 ml of 20% trichloroacetic acid. Then add 1.0 ml of 0.67% thiobarbituric acid in 0.05N sodium hydroxide, mix and incubate the samples for 30 minutes at 90 ° C. Centrifuge the samples briefly for the material not dissolved in pellets and transfer the supernatants to a 96-well microtiter plate. Measure the absorbances at 540 nm using a Biotek model EL311 microplate reader. The nols of MDA produced were calculated from a normal curve of 0 to 10 nmoles of MDA prepared from bis (dimethylacetal) of malonaldehyde. Compare serum samples from treated rabbits to serum samples from control rabbits that did not receive CDM compound. D. Quantification of HPLC Concentration of Compounds and Metabolites in Serum and Liver Determine the concentrations of serum and liver to the parent compounds and the metabolites, bisphenol and diphenoquinone, by reverse phase HPLC using a Waters 990 Powerline system. Homogenize the livers (1 gram) with 5.0 my PBS, pH 7.4, using a Polytron tissue homogenizer graduated in 5 for 20-30 seconds. Extract serum or liver homogenates as follows: add 100 μl of serum or homogenate to 2.0 ml of diethyl ether: ethanol (3: 1) while stirring in the tube. Cap the sample tubes and centrifuge for 10 minutes at 5 ° C at 3500 rpm in a Beckman GPKR centrifuge with a GH 3.7 rotor. Transfer the supernatants to clean the tubes and dry under N2. Reconstitute samples with 200 μl of acetonitrile: hexane: 0.1M ammonium acetate (90: 6.5: 3.5 by volume). Inject 100 ml into a Waters Deltapak C18-300 column? and eluting with a mobile phase of 83% acetonitrile: 17% water at a flow rate of 1.5 ml / min. Record the absorbances at the wavelengths of 240, 254 and 420 nm. Calculate compound concentrations of known amounts of authentic parent compounds after correction for recovery. Calculate serum concentrations of μg / ml as μg / g of liver. E. Separation by CLAR and Quantification of Lipoprotein Subfraction Cholesterol Levels Separate lipoprotein fractions (very low density lipoprotein), LDMB, low density lipoproteins, LDB, and high density lipoproteins, LDA) on a Sepharose 6HR column (1x 30 cm, Pharmacia) attached to a Waters Powerline CLAR system. Inject serum (50 μl) into the column and elute with phosphate buffered saline, pH 7.4, at a flow rate of 0.5 ml (min) Add the cholesterol reagent (Roche Diagnostics, device # 44334, diluted with 20 ml of water and then with 20 ml of 0.9% saline) at 0.2 ml / min for the eluent after the column and incubate in a PFTE Kratos nodule reaction coil (Applied Biosystems) at 37 ° C for 5 min. absorbance at 500 nm The lipoprotein subfractions were quantified as follows: (total serum cholesterol) x (% area under the curve for each subfraction) EXAMPLE 18 Activity measurement Antioxidant and Bioavailability of Compounds of Formula (1) by In Vivo Screening in Sprague-Dawley Male Rats A. Expental Protocol _ A normal expent consists of 4-6 groups of rats (N = 5 per group) with 1 group being a control which does not receive a CDM compound and the other groups being treated with the MDL 0.3% compound. Some of the compounds were repeated at 0.3% or re-evaluated at the lower dose of 0.1%. The Sprague-Dawley Macho House rats, 50-100 g, (Harían Laboratories, Indianapolis, IN) in groups of 5, feeding freely with water and croquettes for Purine Rodents (# 5002) with or without the MDL compound as a mixture dietetic for 4 days. Form dietary mixes (0.3%) by mixing 1.2 grams of a MDL compound with 400 grams of rodent croquettes Purina (# 5002). Mix the MDL compound with approximately 50 grams of food using a mortar. This was added to the rest of the food and mixed for 3 hours in a rotary mixer. On the morning of day 5, anesthetize rats that are not fasting with carbon dioxide and collect blood by cardiac puncture. Sacrifice the rats by cervical dislocation. Record body weights and liver weights in grams. Record the consumption of food as grams "day" 1"rat" 1. Deaths were recorded as mortality. Use aliquots of fresh serum for clinical chemistries, thiobarbituric acid reactive substances (SRATB) and conjugated diene measurements. Freeze the aliquots of serum (approximately 0.5 ml) and the whole livers at -20 ° C for the determination of the concentration of compounds and metabolites at the end.

B. Clinical Chemistry. __ Allow the blood to clot at room temperature for 30 minutes. Obtain serum after centrifugation for 10 minutes at 4 ° C at 3000 rpm in a Beckman J-6M / E centrifuge with a JS-4.2 rotor. Analyze fresh serum by a COBAS MIRA S autoanalyzer (Roche Diagnostics) using Roche diagnostic reagents for the following clinical chemistry measurements: alkaline phosphatase (ALP, # 44553), alanine transaminase (ALT, # 42375), aspartate aminotransferase ( AST, equipment # 42381), total cholesterol (CHOL, equipment # 44334), triglyceride (TG, equipment # 44120), and glucose (GLU, equipment # 44558). Calculate ALP, ALT and AST as units / l. Calculate cholesterol, triglycerides and glucose as mg / dl. C. CLAR Quantification of Metabolite Compound Concentration in Serum and Liver Determine the serum and liver concentrations of the parent compound and the metabolites, bisphenol and diphenolquinone, by reverse phase HPLC using a Waters 990 Powerline system. Homogenize liver (1 gram samples) with 5.0 my PBS, pH 7.4 using a Polytron tissue homogenizer graduated at 5 for 20-30 seconds. Extract homogenates of serum or liver as follows: add 100 μl of serum or homogenate to 2.0 ml of diethyl ether: ethanol (3: 1) while stirring the tube. Cap the sample tubes and centrifuge for 10 min. At 5 ° C at 3500 rpm in a Beckman GPKR centrifuge with a GH 3.7 rotor. Transfer the supernatants to clean tubes and dry under N2. Reconstitute samples with 200 μl of acetonitrile: hexane: 0.1 M of ammonium acetate (90: 6.5: 3.5 by volume). Then, inject 100μl into a Waters Deltapak C18-300 Á column, and elute with a mobile phase of 83% acetonitrile: 17% water at a flow rate of 1.5 ml / min. Record the absorbances at the wavelengths of 240, 254 and 420 nm. Calculate compound concentrations of known amounts of authentic parent compounds after correction for recovery. Calculate concentrations as μg / ml. Calculate concentrations as μg / ml of serum and μg / g of liver. D. Analysis of Reactive Substances of Thiobarbituric Acid (SRATB) In this analysis, the oxidation of serum lipids was initiated with CuSO, resulting in the formation of aldehydes, such as malondialdehyde (MDA). When incubated with thiobarbituric acid, the absorbance of the aldehydes can be detected at 530-540 nm. As stated in the previous example, the SRATB values that are lower than the control serum values indicate the relative ability of a test compound to inhibit the oxidation of lipids in a sample. Measure SRATB as follows: mix 100 μl of serum with 400 μl of a 5 mM CuSO solution and incubate at 37 ° C for 3 hr. Deemer the reactions by adding 1.0 ml of 20% trichloroacetic acid. Then add 1.0 ml of 0.67% thiobarbituric acid in 0.05 N sodium hydroxide, mix and incubate the samples for 30 minutes at 90 ° C.

Centrifuge the samples briefly to obtain material not dissolved in pellets, and transfer the supernatants to a 96-well microtiter plate. Measure the absorbances at 540 nm using a Biotek model EL311 microplate reader. The nmoles of MDA produced were calculated from a normal burst of 0 to 10 nmoles of MDA prepared from malonaldehyde bis (dimethylacetal). Serum samples from treated rats were compared to serum samples from control rats that did not receive the MDL compound. E. Determination of Conjugate Diene The lag phase of conjugated diene is a gold indicator of lipid oxidation. Lipids exposed to CU + + form conjugated dienes that absorb ultraviolet light on the 230 to 235 nm scale. The lag phase of diene formation gives indications of the amount of oxidation of the lipids. A longer lag phase than the control samples indicate the inhibition of oxidation. Determine the phase and of conjugated dienes using a spectrophotometer Varian DMS200 (adapted with a sample exchanger of 5 buckets at constant temperature) at 30 ° C. Add twenty (20) μl of combined serum for cuvettes containing 3.0 ml of phosphate-buffered saline, pH 7.5 and mix. Record the absorbance of each cuvette at 2 minute intervals for a period of 840 min. Capture the data and transfer it to a Microsoft EXCEL® spreadsheet where the curves are standardized and the spreads are obtained. Mathematically determine lag times as minutes. Combine the serum samples (N = 5); the presented data are the average values of 2 determinations. Compare serum samples from treated rats to serum samples from control rats that did not receive CDM compound. Tables 2, 3, and 4 below present data summarizing the individual experiments of this test procedure. Table 2 presents measurements of serum chemistries in male Sprague-Dawley rats, Table 3 presents the parameters of animals and Table 4 provides the drug or concentrations of metabolites in serum and liver. TABLE 2 The Antioxidant Effects of the Compounds of Formula (1) in Male Sprague-Dawley Rats as a Percentage of Control MDL No. Diet ALP AST ALT COL GLUC TRIG SRATB DIENO% CONJ. (min.) 106,939 0.3 123% 106% 92% 120% 83% 108% 64% 391 107,965 0.3 137% 89% 96% 121% 86% 90% 57% 237 * ND: not determined N = 5 rats per group Diet% = (compound weight MDL / weight of food) x (IOO) Dieno Conj. = lag phase of conjugated diene in minutes (mean of 2 determinations of combined samples, N = 5); Control = 61 min. (average of 9 determinations, varying from 18 to 126 min).

The data in Table 2, except for the conjugated dienes and percentage of diets, have been normalized as follows:% Controi = (Mean, treated group / Mean, control group) x (100) ALP = alkaline phosphatase, U / ml AST = aspartate aminotransferase, U / ml ALT = alanine aminotransferase, U / ml COL = total cholesterol, mg / dl TG = triglycerides, mg / dl GLU = glucose, mg / dl SRAT = reactive substances of thiobarbituric acid, expressed in nmoles of MDA TABLE 3 Parameters of Animals as a Percentage of CDM Control No. Diet Food P. Body PH / PC mortality 106, 939 0.3 88% 92% 130% 0% 107, 965 0.3 84% 84% 1 18% 0% N = 5 rats / group Diet% = (composite weight MDL / food weight) x (100) The data in Table 3 have been normalized according to the formula presented in Table 2. Food = grams eaten per day per rat Weight body weight = weight in grams PH / PC = (weight of liver / body weight in grams) Mortality = deaths per group TABLE 4 Concentration of Drugs and Metabolites in Rats and Liver MDL No. Diet Serum H i gado% Mother Bis Quin. Mother Bis Quin 106,939 0.3 3.3 0 0 97.7 0 0 107,965 0.3 12.6 0 0 82 0 0 The data in Table 4 were presented as means (N = 5) and have not been normalized for control values. Serum mother = concentration of mother compound as μg / ml serum Serum Bis = concentration of bisphenol as μ / ml serum Serum Quin = concentration of phenoquinone as μg / g serum Liver Mother = concentration of parent compound as μg / g liver Liver Bis = concentration of bisphenol as μg / g of liver Liver Quin = concentation of diphenoquinone as μg / g of liver EXAMPLE 19 Antisclerotic Effects of Compounds of Formula (1) in New Zealand White Rabbits Female Fed with Cholesterol A. Experimental Protocol __ Carry out four independent experiments. Each experiment has a control group and 1-5 groups treated with MDL compound (N = 5 per group). Feed the New Zealand White Rabbits Females (Hazelton, approx 2.0-2.3 kg) with rabbit croquettes enriched with 1% cholesterol (Purina # 5322) with or without 0.4% MDL compound. Solubilize the MDL compounds in 100% ethanol. Spray the croquettes with the MDL blends and allow them to dry overnight in a chemical fume hood. Spray the control croquettes with ethanol. Feed rabbits with 100 grams of feed per day for 70 days and make water available at free demand. Periodically draw blood from rabbits (about 2 mi) (having fasted during the night) from a marginal ear vein. Kill the rabbits on day 70 with an overdose of carbon dioxide. Record the total weights and the weight of the liver in grams. Record the food as grams »day" 1 »rabbit" 1. Use aliquots of fresh serum for clinical chemistry, determination of lipoprotein cholesterol, thiobarbituric acid reactive substances (SRATB) and concentrations of the compound and metabolites in serum. Freeze the livers (aliquots of about 5 grams) at -20 ° C for a compound and determine the concentration of metabolites to the last. Cut the aortas immediately after the rabbit dies. Remove the aorta from the ascending arch to the iliac bifurcation after removing the foreign adipose tissue. Store the aortas overnight in phosphate buffered saline, pH 7.4, at 4 ° C until final decomposition. Coar open the aortas longitudinally and stain with Sudan IV. After dyeing, place the aortas flat and quantify the areas of sudanophilic lesions after capturing an image electronically. B. Clinical Chemistry Allow the blood to clot at room temperature for 30 minutes. Obtain serum after centrifugation for 10 minutes at 5 ° C at 3000 rpm in a Beckman GPKR centrifuge with a GH rotor. Analyze by a COBAS MIRA autoanalyzer (Roche Diagnostics) using Roche diagnostic reagents for total cholesterol (CHOL, equipment # 44334) and triglycerides (TG, equipment # 44120). Calculate cholesterol and triglycerides as mg / dl. C. SRATB SRATB analysis is a qualitative indication of lipid oxidation in a sample. In this analysis, initiate the oxidation of serum lipids with CuSO, resulting in the formation of aldehydes, such as malodialdehyde (MDA). When incubated with thiobarbituric acid, the absorbance of the aldehydes can be detected at 530-540 nm. SRATB values that are lower than the control serum values indicate the relative ability of a compound to inhibit oxidation. Measure as follows: mix 50 μl of serum with 50 μl of 0.9% saline solution and 400 μl of a CuS04 solution and incubate at 37 ° C for 5 hr. Stop the reactions by the addition of 1.0 ml of 20% trichloroacetic acid. Then add 1.0 ml of 0.67% thiobarbituric acid in 0.05N sodium hydroxide, mix and incubate the samples for 30 minutes at 90 ° C. Centrifuge the samples briefly for the material not dissolved in pellets and transfer the supernatants to a 96-well microtiter plate. Measure the absorbances at 540 nm using a Biotek model EL311 microplate reader. The nols of MDA produced were calculated from a normal curve of 0 to 10 nmoles of MDA prepared from bis (dimethylacetal) of malonaldehyde. Compare serum samples from treated rabbits to serum samples from control rabbits that did not receive CDM compound. D. Quantification of HPLC Concentration of Compounds and Metabolites in Serum and Liver Determine the concentrations of serum and liver to the parent compounds and the metabolites, bisphenoi and diphenoquinone, by reverse phase HPLC using a Waters 990 Powerline system. Homogenize the livers (1 gram) with 5.0 my PBS, pH 7.4, using a Polytron tissue homogenizer graduated in 5 for 20-30 seconds. Extract serum or liver homogenates as follows: add 100 μl of serum or homogenate to 2.0 ml of diethyl ether: ethanol (3: 1) while stirring in the tube. Cap the sample tubes and centrifuge for 10 minutes at 5 ° C at 3500 rpm in a Beckman GPKR centrifuge with a GH 3.7 rotor. Transfer the supernatants to clean the tubes and dry under N2. Reconstitute samples with 200 μl of acetonitrile: hexane: 0.1M ammonium acetate (90: 6.5: 3.5 by volume). Inject 100 ml into a Waters Deltapak C18-300 Á column and elute with a mobile phase of 83% acetonitrile: 17% water at a flow rate of 1.5 ml / min. Record the absorbances at the wavelengths of 240, 254 and 420 nm. Calculate compound concentrations of known amounts of authentic parent compounds after correction for recovery. Calculate serum concentrations of μg / ml as μg / g of liver. E. Separation by CLAR and Quantification of Lipoprotein Subfraction Cholesterol Levels Separate the lipoprotein fractions (very low density lipoprotein, LDMB, low density lipoprotein, LDB, and high density lipoprotein, LDA) on a Sepharose 6HR column (1x 30 cm, Pharmacia) linked to a Waters Powerline CLAR system. Inject serum (50 μl) into the column and elute with phosphate buffered saline, pH 7.4, at a flow rate of 0.5 ml (min) Add the cholesterol reagent (Roche Diagnostics, device # 44334, diluted with 20 ml of water and then with 20 ml of 0.9% saline) at 0.2 ml / min for the eluent after the column and incubate in a PFTE Kratos nodule reaction coil (Applied Biosystems) at 37 ° C for 5 min. Absorbance at 500 nm The lipoprotein subfractions were quantified as follows: (total serum cholesterol) x (% area under the curve for each subfraction), the compounds of the formula (1) can be used as chemical antioxidant additives in organic materials normally subjected to oxidative deterioration, such as, for example, rubber, plastics, fats, petroleum products and the like. In general, a conservative amount of a compound of the formula (1), which is sufficient in concentration to inhibit oxidative deterioration of the material to be protected, is mixed with the material subject to oxidation. The conservative amount of a compound of the formula (1) will normally vary from about 0.01% to about 1.0% by weight.

Claims (27)

1. CLAIMS 1. A compound of the formula wherein R is hydrogen or -C (O) - (CH2) m-Q wherein Q is hydrogen or -COOH and m is an integer 1, 2, 3 or 4; Ri, 5 and e are independently an alkyl group of C? -C6; R2, R3 and R are independently hydrogen or an alkyl group of Ct-Ce; Z is thio, oxy or a methylene group; A is an alkylene group of C? -C4; X is thio or oxy; and Gi and G2 are independently hydrogen, d-C6 alkyl or -C (O) - (CH2) n -CH3 and n is a number 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
2. 2. A compound of claim 1, wherein R is hydrogen.
3. 3. A compound of claim 2, wherein Ri is methyl or tertiary butyl; R2, R3 and R4 are each independently hydrogen, methyl or tertiary butyl; and R5 and Re are each methyl.
4. 4. A compound of claim 3, wherein A is methylene.
5. 5. A compound of claim 3, wherein A is methylene. 5. a compound of claim 4, wherein d and G2 are each independently hydrogen, methyl or ethyl.
6. 6. A compound of claim 5, wherein X is oxy.
7. 7. A compound of claim 5, wherein X is a thio.
8. 8. A compound of claim 1, wherein R is -C (O) - (CH2) mQ wherein Q is hydrogen or -COOH and m is an integer of 1, 2, 3 or 4.
9. 9. A compound of Claim 8, wherein R is methyl or tertiary butyl; R2, R3 and R are each independently hydrogen, methyl or tertiary butyl; and Rs and Re are each methyl.
10. 10. A compound of claim 9 wherein A is methylene.
11. 11. A compound of claim 10, wherein d and G2 are each independently hydrogen, methyl or ethyl.
12. 12. A compound of claim 11, wherein X is oxy.
13. 13. A compound of claim 12, wherein X is a thio.
14. 14. A compound of claim 1, wherein the compound is 2,6-bis (1,1-dimethylethyl) -4 - [(2-furanyldimethylsilyl) methoxy)] phenol.
15. 15. A compound of claim 1, wherein the compound is 2,6-bis (1,1-dimethylethyl) -4 - [(dimethyl-2-thienylsilyl) methoxy] -phenol.
16. 16. A method for inhibiting the progression of atherosclerosis in a patient in need thereof, comprising administering to the patient an effective anti-atherosclerotic amount of a compound of claim 1.
17. 17. A method for treating a patient for atherosclerosis comprising administering to the patient an effective antiatherosclerotic amount of a compound of claim 1.
18. 18. A method for inhibiting LDL cholesterol peroxidation in a patient in need thereof comprising administering to the patient an effective antioxidant amount of a compound of claim 1.
19. A method for lowering the plasma cholesterol level in a patient in need thereof comprising administering to the patient a plasma cholesterol lowering amount of a compound of claim 1.
20. 20. A method for inhibiting cytokine-induced expression of vascular cell adhesion molecule-1 and / or molecule-1 of a intercellular adhesion in a patient in need thereof comprising administering to the patient an amount that inhibits vascular cell adhesion molecule-1 and / or effective intercellular adhesion molecule-1 of a compound of claim 1.
21. 21. A method for treating a patient suffering from chronic inflammatory disease comprising administering to the patient a therapeutically effective amount of a compound of claim 1.
22. 22. A method according to claim 21, wherein the inflammatory disease is asthma.
23. 23. A method according to claim 21, wherein the inflammatory disease is chronic inflammation.
24. 24. A method according to claim 21, wherein the inflammatory disease is rheumatoid arthritis.
25. 25. A method according to claim 21, wherein the inflammatory disease is autoimmune diabetes.
26. 26. A method according to claim 21, wherein the inflammatory disease is rejection of transplants.
27. 27. A method according to claim 21, wherein the inflammatory disease is tumor angiogenesis.