WO2001070757A2 - Thiocetals et thioethers permettant d'inhiber l'expression de la molecule-1 d'adhesion cellulaire vasculaire (vcam-1) - Google Patents

Thiocetals et thioethers permettant d'inhiber l'expression de la molecule-1 d'adhesion cellulaire vasculaire (vcam-1) Download PDF

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WO2001070757A2
WO2001070757A2 PCT/US2001/009049 US0109049W WO0170757A2 WO 2001070757 A2 WO2001070757 A2 WO 2001070757A2 US 0109049 W US0109049 W US 0109049W WO 0170757 A2 WO0170757 A2 WO 0170757A2
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compound
vcam
substituted
disease
alkyl
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PCT/US2001/009049
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WO2001070757A3 (fr
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Charles Q. Meng
Lee K. Hoong
Patricia K. Somers
James A. Sikorski
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Atherogenics, Inc.
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Priority to AU4765101A priority Critical patent/AU4765101A/xx
Priority to AU2001247651A priority patent/AU2001247651B2/en
Priority to EP01920617A priority patent/EP1289944A2/fr
Priority to JP2001568958A priority patent/JP2003528109A/ja
Priority to CA002403823A priority patent/CA2403823A1/fr
Publication of WO2001070757A2 publication Critical patent/WO2001070757A2/fr
Publication of WO2001070757A3 publication Critical patent/WO2001070757A3/fr

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Definitions

  • This invention is in the area of compounds, compositions and methods for inhibiting the expression of VCAM-1 and, in particular, for treating diseases mediated by VCAM-1, including inflammatory disorders, cardiovascular diseases, occular diseases, autoimmune diseases, neurological disorders, and cancer.
  • the invention is further in the area of compounds, compositions and for treating hypercholesterolemia and hyperlipidemia.
  • Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, including atherosclerosis, autoimmune disorders and bacterial and viral infections.
  • Leukocyte recruitment to the endothelium is started when inducible adhesion molecule receptors on the surface of endothelial cells interact with counterreceptors on immune cells.
  • Vascular endothelial cells determine which type of leukocytes (monocytes, lymphocytes, or neutrophils) are recruited, by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM- 1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin.
  • VCAM-1 vascular cell adhesion molecule-1
  • IAM-1 intercellular adhesion molecule-1
  • VCAM-1 In the earliest stage of the atherosclerotic lesion, there is a localized endothelial expression of VCAM-1 and selective recruitment of mononuclear leukocytes that express the integrin counterreceptor VLA-4. Because of the selective expression of VLA-4 on monocytes and lymphocytes, but not neutrophils, VCAM-1 is important in mediating the selective adhesion of mononuclear leukocytes.
  • VCAM-1 is also a mediator of chronic inflammatory disorders such as asthma, rheumatoid arthritis, autoimmune diabetes and multiple sclerosis.
  • chronic inflammatory disorders such as asthma, rheumatoid arthritis, autoimmune diabetes and multiple sclerosis.
  • 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)).
  • blocking the integrin receptors for VCAM-1 and ICAM-1 suppressed both early and late phase responses in an ovalbumin-sensitized rat model of allergic airway responses (Rabb, H.
  • VCAM-1 is expressed by cells both as a membrane bound form 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 angiogenic response in rat cornea (Koch, A.F. et al., Nature 376, 517-519 (1995)).
  • Inhibitors of the expression of soluble VCAM-1 have potential therapeutic value in treating 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 lipopolysaccharide (LPS) and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha). These factors are not selective for activation of cell adhesion molecule expression.
  • LPS lipopolysaccharide
  • cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha).
  • VCAM-1 is expressed on brain micro vessel endothelial cells in active lesions of multiple sclerosis brain.
  • Multiple sclerosis is a common demyelinating disorder for the central nervous system, causing patches of sclerosis (plaques) in the brain and spinal cord. It occurs in young adults and has protean clinical manifestations.
  • Experimental therapy using antibodies for VCAM-1 in autoimmune encephalomyelitis, which is an animal model for multiple sclerosis, has shown that adhesion molecules play a role in the pathogenesis of the disease (Benveniste et al., J.
  • mice treated with anti-VCAM-1 monoclonal antibodies or anti-VLA-4 monoclonal antibodies were greater than the survival rate of a control group (Isobe et al., J. Immunol. 153: 5810-5818, 1994; Orosz et al, J. Heart Lung Transplant 16: 889-904, 1997).
  • Serum lipoproteins are the carriers for lipids in the circulation. Lipoproteins are classified according to their density: chylomicrons, very low-density lipoproteins (VLDL), low density lipoproteins (LDL) and high-density lipoproteins (HDL). Chylomicrons primarily participate in transporting dietary triglycerides and cholesterol from the intestine to adipose tissue and liver. VLDL deliver endogenously synthesized triglycerides from liver to adipose and other tissues. LDL transports cholesterol to peripheral tissues and regulates endogenous cholesterol levels in those tissues. HDL transports cholesterol from peripheral tissues to the liver. Arterial wall cholesterol is derived almost exclusively from LDL. Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980).
  • Oxidized LDL is a complex structure consisting of at least several chemically distinct oxidized materials, each of which, alone or in combination, may modulate cytokine- activated adhesion molecule gene expression.
  • Fatty acid hydroperoxides such as linoleyl hydroperoxide (13-HPODE) are produced from free fatty acids by lipoxygenases and are an important component of oxidized LDL.
  • LDL endothelial, smooth muscle, and/or inflammatory cells then convert LDL to ox- LDL.
  • monocytes avidly take up ox-LDL through a "scavenger" receptor whose expression, unlike the LDL receptor, is not inhibited as the content of intracellular lipid rises.
  • monocytes continue to take up ox-LDL and become lipid-engorged macrophage-foam cells that form the fatty streak.
  • cholesterol is carried in the blood of warm-blooded animals in certain lipid-protein complexes such as chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL).
  • VLDL very low density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • LDL lipid such as the unsaturated fatty acid portions of LDL cholesteryl esters and phospholipids
  • peroxidation of LDL lipid facilitates the accumulation of cholesterol in monocyte/macrophages which eventually are transformed into foam cells and become deposited in the sub-endothelial space of the vessel wall.
  • the accumulation of foam cells in the vessel wall is recognized as an early event in the formation of an atherosclerotic plaque.
  • peroxidation of LDL lipid is an important prerequisite to the facilitated accumulation of cholesterol in the vessel wall and the subsequent formation of an atherosclerotic plaque. (Parthasarathy et al., J. Gin. Invest. 77,641 (1986)). It is therefore desirable to provide methods of inhibiting LDL lipid peroxidation in a patient in need thereof.
  • Elevated cholesterol levels are associated with a number of disease states, including restenosis, angina, cerebral atherosclerosis, and xanthoma. It is desirable to provide a method for reducing plasma cholesterol in patients with, or at risk of developing, restenosis, angina, cerebral arteriosclerosis, xanthoma, and other disease states associated with elevated cholesterol levels.
  • Statins are among the most effective agents currently on the market for hypercholesterolemia, and include pravastatin (Pravchol, Bristol Myers Squibb), atorvastatin (Warner Lambert/Pfizer), simvastatin (Zocor, Merck), lovastatin (Mevacor, Merck), and fluvastatin (Lescol). Probucol has been shown to possess potent antioxidant properties and to block oxidative modification of LDL.
  • Probucol is chemically related to the widely used food additives 2,(3)-tert-butyl-4- hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methyl phenol (BHT). It is a thioketal having a chemical name of 4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol) and has the following chemical structure:
  • 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 LorelcoTM.
  • U.S. Patent No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups.
  • probucol ester derivatives are hypocholesterolemic and hypolipemic agents: Fr 2168137 (bis 4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); 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- nicotinoyloxyphenylthio)propanes; and Fr 2130975 (bis(4-(phenoxyalkanoyloxy)- phenylthio)alkanes) .
  • De Meglio et al. have described several ethers of symmetrical molecules for the treatment of hyperlipidemia. These molecules contain two phenyl rings attached to each other through a -S-C(CH 3 ) -S- bridge. In contrast to probucol, the phenyl groups do not have t-butyl as substituents. (De Meglio et al., New Derivatives ofGofibrate and probucol: Preliminary Studies of Hypolipemic Activity; Farmaco, Ed. Sci (1985), 40 (11), 833-44).
  • WO 00/26184 disclosed a large genus of compounds with a general formula of phenyl-S-alkylene-S-phenyl, in which one or both phenyl rings can be substituted at any position. These compounds were disclosed as lubricants.
  • U.S. Patent No. 5,155,250 to Parker, et al. discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on June 15, 1995.
  • U.S. Patent No. 5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.
  • a series of European patent applications of Shionogi Seiyaku Kabushiki Kaisha disclose phenolic thioethers for use in treating arteriosclerosis.
  • 348 203 discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages.
  • the compounds are useful as anti- arteriosclerosis agents.
  • Hydroxamic acid derivatives of these compounds are disclosed in European Patent Application No. 405 788 and are useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy.
  • Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U. S. Patent No. 4,954,514 to Kita, et al.
  • U.S. Patent No. 4,752,616 to Hall, et al. discloses arylthioalkylphenylcarboxylic acids for the treatment of thrombotic disease.
  • the compounds disclosed are useful as platelet aggregation inhibitors for the treatment of coronary or cerebral thromboses and the inhibition of bronchoconstriction, among others.
  • a series of patents to Adir et Compagnie disclose substituted phenoxyisobutyric acids and esters useful as antioxidants and hypolipaemic agents. This series includes U. S. Patent Nos. 5,206,247 and 5,627,205 to Regnier, et al. (which corresponds to European Patent Application No. 621 255) and European Patent Application No. 763 527.
  • WO 97/15546 to Nippon Shinyaku Co. Ltd. discloses carboxylic acid derivatives for the treatment of arterial sclerosis, ischemic heart diseases, cerebral infarction and post PTCA restenosis.
  • the Dow Chemical Company is the assignee of patents to hypolipidemic 2-(3,5-di- tert-butyl-4-hydroxyphenyl)thio carboxamides.
  • U. S. Patent Nos. 4,029,812, 4,076,841 and 4,078,084 to Wagner, et al. disclose these compounds for reducing blood serum lipids, especially cholesterol and triglyceride levels.
  • cardiovascular disease is currently the leading cause of death in the United States, and ninety percent of cardiovascular disease is presently diagnosed as atherosclerosis, there is a strong need to identify new methods and pharmaceutical agents for its treatment.
  • cardiovascular disease is currently the leading cause of death in the United States, and ninety percent of cardiovascular disease is presently diagnosed as atherosclerosis, there is a strong need to identify new methods and pharmaceutical agents for its treatment.
  • inflammation and VCAM-1 expression in cardiovascular disease and other disease states such as rheumatoid arthritis, multiple sclerosis, and allograft rejection, there is also a need to identify methods and pharmaceutical agents for reducing inflammation and VCAM-1 expression.
  • VCAM-1 cardiovascular and inflammatory diseases. It is also an object to provide new classes of compounds and pharmaceutical compositions for the treatment of diseases and disorders mediated by the expression of VCAM-1.
  • VCAM-1 VCAM-1
  • thioketals and thioethers in the treatment of inflammatory disorders (including but not limited to rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, Crohn's disease, asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease (COPD), dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, vasculitis, and organ transplant rejection);
  • inflammatory disorders including but not limited to rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, Crohn's disease, asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease (COPD), dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, vasculitis, and organ transplant rejection
  • thioethers and thioketals in the treatment of cardiovascular diseases (including but not limited to atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy);
  • thioethers and thioketals in the treatment of neurological diseases (including but not limited to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS);
  • ALS amyotrophic lateral sclerosis
  • cancer including but not limited to tumor metastasis and angiogenesis
  • the compounds of the present invention are thioketals represented by formula (I), and pharmaceutically acceptable salts thereof:
  • R a , Rb, Re, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C 1-10 alkyl or substituted -ioalkyl, terminated by sulfonic acid, (iv) C H Qalkyl or substituted C 1-10 alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C 1- oalkyl-O-C(O)-C 1- 10 alkyl, (vi) straight chained polyhydroxylated C3-10 alkyl; (vii)
  • X is O, S, SO, SO , CH 2 , or NH;
  • R a , Rb, Re, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C M oalkyl or substituted C 1-10 alkyl, terminated by sulfonic acid, (iv) Cj-ioalkyl or substituted .ioalkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C 1-1 oalkyl-O-C(O)-C ⁇ - l oalkyl, (vi) straight chained polyhydroxylated C 3-10
  • R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) -(CR 2 ) 1-6 - X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
  • R a , Rb, Re, an Rd are in one embodiment selected independently from substituted and unsubstituted lower alkyl, in one embodiment branched lower alkyl.
  • R a , R b , R e , and R d are substituted, they are in one embodiment substituted by halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, or acyloxy.
  • R a , Rb, Re, and Rd are all t-butyl.
  • Z can be selected from any type of naturally occurring or synthetic carbohydrate as that term is conventionally used and understood.
  • carbohydrate generally refers to a compound of carbon, hydrogen, and oxygen that contains an aldehyde or ketone group in combination with at least two hydroxyl groups.
  • the carbohydrates of the present invention can also be optionally substituted or deoxygenated at one or more positions. Carbohydrates thus include substituted and unsubstituted monosaccharides, disaccharides, oligosaccharides, and polysaccharides.
  • the saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6, or 7 carbons.
  • the carbohydrates are monosaccharides.
  • the carbohydrates are pyranose and furanose sugars.
  • Non limiting examples of pyranose and furanose sugars within the scope of the present invention include threose, ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, glactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose, trehalose, ruranose, cellobios
  • the carbohydrate can be optionally deoxygenated at any corresponding C-position, and/or substituted with one or more moieties such as hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound.
  • moieties such as hydrogen, halo, haloalkyl, carb
  • substituents include amine and halo, particularly fluorine.
  • the substituent or carbohydrate can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • the monosaccharide is a furanose such as (L or D)-ribose.
  • Z is ribofuranose.
  • Z can also be selected from any type of naturally occurring or synthetic alditols as that term is conventionally used and understood.
  • alditol generally refers to a carbohydrate in which the aldehyde or ketone group has been reduced to an alcohol moiety.
  • the alditols of the present invention can also be optionally substituted or deoxygenated at one or more positions.
  • the alditol may comprise 3, 4, 5, 6, or 7 carbons. Examples of useful alditols are those derived from reduction of monosaccharides.
  • the carbohydrates are derived from reduction of pyranose and furanose sugars.
  • One particular alditol is the arabitol analog of the formula where Z is -CH 2 -(CHOH) 3 CH 2 OH.
  • Another particular alditol is represented by the formula -CH 2 -(CHOH) CH 2 OH.
  • Z examples include the carbohydrates presented below in Table I and the alditols presented below in Table II.
  • Z may also be alkyl or substituted alkyl that terminates in sulfonic acid.
  • Z terminates in sulfonic acid when the longest chain of carbon atoms in an alkyl moiety, beginning at the oxygen in formula (I), terminates in sulfonic acid.
  • the alkyl moiety is substituted, it is suitably substituted by halogen, hydroxy, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, or carboxy.
  • a particular sulfonic acid moiety Z is -(CR 2 V 6 -sulfonic acid, wherein R is independently hydrogen, halo, amino, or hydroxy.
  • Z is (CR 2 ) 1- -sulfonic acid, wherein R is independently hydrogen or hydroxy.
  • An even more particular sulfonic acid moiety Z is 2-hydroxypropyl- 3-sulfonic acid.
  • Z may also be alkyl or substituted alkyl that terminates in phosphonic acid. Z terminates in phosphonic acid when the longest chain of carbon atoms in an alkyl moiety, beginning at the oxygen in formula (I), terminates in phosphonic acid. When the alkyl moiety is substituted, it is in one embodiment substituted by halogen, hydroxy, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, or carboxy.
  • a particular phosphonic acid moiety Z is -(CR 2 ) ⁇ - -phosphonic acid, wherein R is independently hydrogen, halo, amino, or hydroxy. In an even more particular embodiment Z is (CR 2 ) 1-6 -phosphonic acid, wherein R is independently hydrogen, halo, or hydroxy.
  • Z may also be substituted or unsubstituted C 1 . 10 alkyl-O-C(O)-C ⁇ _ ⁇ oalkyl. Again, when either alkyl moiety is substituted, it is in one embodiment substituted by halogen, hydroxy, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, or acyloxy.
  • the Ci- ⁇ o alkyl substituents are in one embodiment straight chain alkylene moieties comprising one to five carbon atoms, mono-or polysubstituted by hydroxy.
  • Z is represented by -(CR 2 ) ⁇ -6 -O-C(O)-(CR ) 1-6 -CHR , wherein R is independently hydrogen, amino, halo, or hydroxy.
  • Z is -(CHR) 1- -O-C(O)-(CHR) 1- 6 -CRH 2 , wherein R is independently hydrogen or hydroxy.
  • Z is -CH 2 -CH(OH)-CH 2 -O-C(O)-(CH(OH)) 4 -CH 2 OH.
  • Z is a straight chained C 3-10 polyhydroxylated alkyl.
  • Z is -CH 2 -(CHR') 1 . 8 -CH 2 R'; wherein R' is independently hydrogen or hydroxy, and at least two, three, four, or five of R' are hydroxy.
  • Z is -CH 2 -(CHR') 1-6 -CH 2 R'; wherein R' is independently hydrogen or hydroxy, and at least two, three, or four of R' are hydroxy.
  • Z is -CH 2 -(CH(OH)) 3 -CH 2 OH.
  • Z is -(CR 2 ) M0 -COOH, or -(CR 2 ) 1-6 -COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen.
  • Z is defined by -(CH )o -6 -CF 2 -COOH or -(CH 2 ) ⁇ -6 -CH(NR 1 R )-COOH, wherein R 1 and R 2 are independently hydrogen or lower alkyl, in one embodiment hydrogen.
  • Z is -(CR 2 ) ⁇ -6 -X, wherein X is substituted or unsubstituted aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
  • Z is -(CHR) 1-6 -X, wherein X is substituted or unsubstituted aryl, heteroaryl, or heterocycle, and R is independently hydrogen or hydroxy.
  • X in either of the foregoing embodiments can be selected from substituted or unsubstituted pyrolidine, imidazole, pyridine, and pyrimidine.
  • Substituents include hydroxy, amino (NR R wherein R 1 and R 2 are independently hydrogen or lower alkyl), lower alkoxy, halo, and carboxy.
  • X is O, S, SO, SO 2 , CH 2 , or NH;
  • spacer is -(CH 2 ) n -, -(CH 2 ) n -CO-, -(CH 2 ) n -NH-, -(CH 2 ) n -O-, -(CH 2 ) n -S-, - (CH 2 O)-, -(OCH 2 )-, -(SCH 2 , -(CH 2 S-), -(aryl-O)-, -(O-aryl)-, -(alkyl-O)-, - (O-alkyl)-;-O-C(O)-(CH 2 ) n , -(CH 2 ) n -C(O)-O- 5 S-C(S) ⁇ (CH 2 ) n , -(CH 2 ) n -C(S)- S-, -C(S)- 5 S-C(S
  • R and R are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; e) R 3 and R 4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R 1 ; and f) Y is aryl or heteroaryl monosubstituted by -C(O)NR5R 6 , wherein R 5 and R ⁇ are independently hydrogen or alkyl.
  • the compounds are optionally substituted by halogen, alkyl, nitro, amino, amido, cyano, haloalkyl, alkylamino, O-alkyl, S-alkyl, OH, SH, dialkylamino, acyl, or carboxy.
  • -X-spacer- is -S-CH 2 - ;
  • R 1 and R 2 are substituted or unsubstituted branched alkyl,
  • R 3 and R 4 are hydrogen or lower alkyl;
  • Y is aryl or heteroaryl monosubstituted by -C(O)NR5K_s, wherein R 5 and R$ are independently hydrogen or lower alkyl.
  • -X-spacer- is -S-CH 2 -, R and R are t-butyl, R and R 4 are hydrogen; and Y is aryl or heteroaryl monosubstituted by -C ⁇ NRsR ⁇ , wherein R 5 and Re are independently hydrogen or alkyl.
  • -X-spacer- is -S-CH 2 -
  • R and R are t-butyl
  • R 3 and R 4 are hydrogen
  • Y is 4'-(N,N-dimethylaminocarbonyl)benzyl or 4'-(N,N- diethylaminocarbonyl)benzyl.
  • the compounds of formulas (I) and (II) display VCAM-1 IC 50 inhibition concentrations of less than about 25, 15, 10, or 5 ⁇ M, or LD 50 concentrations greater than twice, thrice, five times, or ten times the VCAM-1 IC 50 concentration. In another embodiment the compounds of formulas (I) and (II) display ApoB/HepG2 IC 50 inhibition concentrations of less than about 25, 15, or 10 ⁇ M, or LD 50 concentrations greater than twice, thrice, five times, or ten times the ApoB/HepG2 IC 50 inhibition concentration.
  • compositions for the treatment of diseases or disorders mediated by VCAM-1 wherein such compositions comprise a thioketal or thioether of the formula (I) or (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • exemplary pharmaceutical compositions and pharmaceutically acceptable carriers are set forth below in "Pharmaceutical Compositions and Modes of Administration.”
  • Pharmaceutically Acceptable Salts are set forth below in "Pharmaceutical Compositions and Modes of Administration.”
  • salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ !-ketoglutarate, and ⁇ - glycerophosphate.
  • Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • optically active and racemic forms may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). Examples of methods to obtain optically active materials are known in the art, and include at least the following.
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kmetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non- chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, including but not limited to those of C ⁇ to C 10 , and preferably Ci-C ⁇ , including methyl, (cyclopropy ⁇ )mefhyl, (cyclobutyl)methyl, (cyclopentyl)methyl, ethyl, 1-cyclopropylethyl, 2-cyclopro ⁇ ylethyl, 1- cyclobutylethyl, 2-cyclobutylethyl, propyl, isopropyl, l-(cyclopropyl)propyl, 2- (cyclopropy propyl, 3-(cyclopro ⁇ yl)propyl, cyclopropyl, mefhylcyclopropyl, 2,2- dimethylcyclopropyl, 1,2-dimethylcyclopropyl, ethylcyclopropyl, propylcyclopropy
  • the alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound,
  • alditol refers to a carbohydrate in which the aldehyde or ketone group has been reduced to an alcohol moiety.
  • the alditols of the present invention can also be optionally substituted or deoxygenated at one or more positions.
  • substituents include hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound.
  • substituents include amine and halo, particularly fluorine.
  • the substituent or alditol can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • the alditol may comprise 3, 4, 5, 6, or 7 carbons. Examples of useful alditols are those derived from reduction of monosaccharides, including specifically those derived from the reduction of pyranose and furanose sugars.
  • carbohydrate refers to a compound of carbon, hydrogen, and oxygen that contains an aldehyde or ketone group in combination with at least two hydroxyl groups.
  • the carbohydrates of the present invention can also be optionally substituted or deoxygenated at one or more positions. Carbohydrates thus include substituted and unsubstituted monosaccharides, disaccharides, oligosaccharides, and polysaccharides.
  • the saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6, or 7 carbons.
  • the carbohydrates are monosaccharides.
  • the carbohydrates are pyranose and furanose sugars.
  • Non limiting examples of pyranose and furanose sugars include threose, ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, glactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose, trehalose, furanose, cellobiose, amylopectin
  • the carbohydrate can be optionally deoxygenated at any corresponding C-position, and/or substituted with one or more moieties such as hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound.
  • moieties such as hydrogen, halo, haloalkyl,
  • substituents include amine and halo, particularly fluorine.
  • the substituent or carbohydrate can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • lower alkyl refers to a to C 6 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.
  • -(CH 2 ) n - represents a saturated alkylidene radical of straight chain configuration.
  • n can be any whole integer, including 0, 1, 2, 3, 4, 5, 6, 1, 8, 9, or 10.
  • aryl refers to phenyl, biphenyl, or naphthyl, and in one embodiment phenyl.
  • the aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, halo, alkylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991.
  • heteroaryl or heteroaromatic refers to an aromatic or unsaturated cyclic moiety that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
  • Nonlimiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzofhiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrcolyl, quinazolinyl, pyridazinyl, pyrazinyl, cin
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t- butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acycl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.
  • the heteroaryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phophonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991. hereby incorporated by reference.
  • heterocyclic refers to a nonaromatic cyclic group that can include alkyl moieties which may be substituted, and wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • heteroatom such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • Nonlimiting examples are morpholine, piperidine, piperazine, pyrrolidine, azetidine, and tetrahydrofuran.
  • the heterocyclic group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phophonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • aralkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
  • alkaryl refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above.
  • the aralkyl or alkaryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phophonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. , "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • halo includes chloro, bromo, iodo, and fluoro.
  • alkoxy refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above.
  • acyl refers to a group of the formula C(O)R ⁇ wherein R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
  • amino includes primary, secondary, and tertiary amines.
  • An amino moiety can be represented generally by the formula NR ⁇ R 2 , wherein R 1 and R 2 are independently hydrogen or substituted or unsubstituted lower alkyl.
  • salts or complexes refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.
  • Nonlimiting examples of such salts 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 such 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, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cturonic
  • quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + A " , wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate
  • raft means the transfer of tissue between two genetically dissimilar individuals of the same species, such as a tissue transplant between two humans who are not identical twins.
  • allografted organs include lung, heart, kidney, liver, pancreas and bone marrow.
  • the invention provides a method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • exemplary effective amounts and modes of administration are set forth below in "Pharmaceutical Compositions and Modes of Administration.”
  • VCAM-1 is implicated in a number of disorders which can be treated using the compounds of the present invention, including inflammatory disorders, cardiovascular diseases, occular diseases, autoimmune diseases, neurological disorders, and cancer.
  • Exemplary inflammatory disorders include but are not limited to rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, Crohn's disease, asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease (COPD), dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, vasculitis, and organ transplant rejection (allograft rejection).
  • rheumatoid arthritis osteoarthritis
  • inflammatory bowel disease Crohn's disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • dermatitis psoriasis
  • cystic fibrosis cystic fibrosis
  • vasculitis vasculitis
  • organ transplant rejection allograft rejection
  • Exemplary cardiovascular diseases include but are not limited to atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy.
  • Exemplary occular diseases include but are not limited to uveitis and macular degeneration.
  • Exemplary autoimmune diseases include but are not limited to systemic lupus erythematosus, autoimmune type-1 diabetes, and graft versus host disease.
  • Systemic lupus erythematotus attacks multiple systems in the body including the skin, joints, lungs, blood, blood vessels, heart, kidneys, liver, brain and the nervous system.
  • the method can be practiced to treat any of the symptoms of SME, including achy joints (arthralgia), fever arthritis, prolonged or extreme fatigue, skin rashes, anemia, chest pains (pleurisy), butterfly-shaped rashes across the cheeks and nose, weight gain, high blood pressure, dark urine, swelling around the eyes, legs, ankles, or fingers, photosensitivity, hair loss, abnormal blood clotting problems, Raynaud's phenomenon (fingers turning white and/or blue in the cold), seizures and mouth or nose ulcers
  • achy joints arthralgia
  • fever arthritis prolonged or extreme fatigue
  • skin rashes anemia
  • chest pains pleurisy
  • butterfly-shaped rashes across the cheeks and nose weight gain, high blood pressure, dark urine, swelling around the eyes, legs, ankles, or fingers, photo
  • Type 1 autoimmune diabetes is another autoimmune disease that can be treated according to the methods of the present invention.
  • the methods of this invention can be used to treat any of the symptoms of type-1 diabetes including frequent urination, unusual thirst, extreme hunger, unusual weight loss, extreme fatigue and irritability.
  • Exemplary neurological diseases include but are not limited to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Exemplary cancers include but are not limited to tumor metastasis and angiogenesis.
  • the compounds of the present invention also treat hypercholesterolemia and hyperlipidemia.
  • the invention provides a method and composition for treating hypercholesterolemia in a patient in need thereof comprising administering to said patient an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method and composition for treating hyperlipidemia in a patient in need thereof comprising administering to said patient an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • the active compound can be administered in conjunction with other medications used in the treatment of cardiovascular disease, including platelet aggregation inhibitors 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 ⁇ -blockers such as propanalol, terbutalol, and labetalol.
  • ACE angiotensin converting enzyme
  • the compound can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, and sulindac.
  • the compound can also be administered in combination with a COX-2 inhibitor, for example, celecoxib.
  • a COX-2 inhibitor for example, celecoxib.
  • the compound can also be administered with a corticosteriod.
  • the compound can also be administered in combination with a TNF- ⁇ modulating agent, for example, etanercept or infliximab.
  • the thioketal compounds of formula (I) wherein Z forms an ether group can be prepared by known procedures and techniques, or routine modifications thereof.
  • General procedures for preparing compounds of formula (I) wherein Z forms an ether group are set forth in General Procedures A and B, wherein all substituents, unless otherwise indicated, are previously defined.
  • triphenylphosphine reagent can replace the triphenylphosphine reagent with other suitable phosphine reagents, including but not limited to tributylphosphine and polymer-supported triphenylphosphine.
  • phosphine reagents including but not limited to tributylphosphine and polymer-supported triphenylphosphine.
  • Z may also contain one or more alcohol, amine, carboxylate, phosphonate or thiol substituents that may participate in the reaction, one normally skilled in the art may choose to protect these substituent groups prior to the reaction.
  • Compounds of the present invention include the resulting protected intermediates.
  • the alcohol group included in Z above is a primary alcohol.
  • compounds of the present invention can be readily prepared by someone skilled in the art of organic synthesis using a standard alkylation reaction of the phenol.
  • a suitable aprotic solvent such as tetrahydrofuran (THF) or dimethylformamide
  • a strong base such as sodium hydride or potassium hydroxide or a tertiary amine base such as triethylamine, dimethyl aminopyridine, pyridine or diisopropylethylamine.
  • an appropriate electrophile containing the Z-group attached to an appropriate leaving group, L is added.
  • L-leaving groups examples include halogens such as chloride, bromide or iodide and alcohol derivatives such as mesylates, tosylates and triflates.
  • the Z group may optionally contain additional substituents as described above for Z.
  • the resultant mixture is stirred under nitrogen at reflux for 2 to 8 hours and then evaporated. Chromatography on silica gel gives the desired ether product.
  • Z may also contain one or more alcohol, amine, carboxylate, phosphonate, or thiol substituents that may participate in the reaction, one normally skilled in the art may choose to protect these substituent groups prior to the reaction.
  • Compounds of the present invention include the resulting protected intermediates. Alternatively, one skilled in the art can selectively remove these protecting groups using well established and known procedures to give the desired ether products containing one or more deprotected alcohol, amine, carboxylate, phosphonate, or thiol substituents in Z.
  • triphenylphosphine reagent can replace the triphenylphosphine reagent with other suitable phosphine reagents, including but not limited to tributylphosphine and polymer-supported triphenylphosphine.
  • the carbohydrate may also contain one or more alcohol or amine substituents that may participate in the reaction, one normally skilled in the art may choose to protect these substituent groups prior to the reaction.
  • Preferable protecting groups include acetates or ketals to protect alcohols and amides to protect amines.
  • Compounds of the present invention include the resulting protected intermediates.
  • Preferable deprotection reagents for acetate groups include but are not limited to an inorganic base such as potassium carbonate in a protic organic solvent such as methanol or ethanol.
  • a protic organic solvent such as methanol or ethanol.
  • the product is dissolved in methanol and potassium carbonate is added.
  • the reaction mixture is stirred for up to 8 hours with or without heating.
  • the product is extracted with dichloromethane from brine and purified by chromatography on silica gel to give the desired deprotected probucol-carbohydrate derivatives, as shown in Table I.
  • Preferable deprotection reagents for ketal groups include but are not limited to inorganic acids such as aqueous hydrochloric acid in a suitable organic solvent such as methylene chloride.
  • the above deprotected probucol-carbohydrate ether compounds can also be dissolved in an organic solvent such as THF and a suitable reducing agent such as lithium aluminum hydride is added.
  • a suitable reducing agent such as lithium aluminum hydride is added.
  • the reaction mixture is stirred for up to 8 hours with or without heating.
  • the product is extracted with dichloromethane from brine and purified by chromatography on silica gel to give the reduced functionalized probucol-polyol derivatives, as shown in Table II.
  • D-arabitol 5-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl] and D-ribose, 5-O-[4-[[l-[[3,5- bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenyl]
  • Probucol (21 g, 40.4 mmol) was dissolved in THF (250 mL), and treated with the 2- 3-dimethylethyl acetal of D-ribolactone (33.8 mmol, 6.9 g), triphenylphosphine (10.6 g, 40.4 mmol), and diethylazo-dicarboxylate (6.4 mL, 40.4 mmol).
  • the reaction was refluxed for 3 h followed by evaporation of the solvent and chromatography (ether/hexane 20%- 40%) to give 3.2 g (13.5% ) of the intermediate lactone.
  • the organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to give 4.1 g of light green syrup.
  • the light green syrup was dissolved in 150 mL of THF and 20 mL of 1M lithium aluminum hydride in ether was added at RT and stirred for 4 hours. The reaction was quenched with 50 mL of sat. sodium sulfate and stirred overnight. The organics were extracted with ether, dried over sodium sulfate and concentrated to dryness. The reaction products were purified by column chromatography (50% ether/hex to 100% ether).
  • the glycidol mono-ether of probucol (0.61 mmol; 350.7 mg) was dissolved in 15 mL of DMF at room temperature. The resulting solution was treated with gluconic acid (1.5 mmol; 0.24 mL) then stirred at room temperature for 24 hours. The mixture was then diluted with ethyl acetate and washed with water. The organic phase was washed with brine. Solvent was removed by rotary evaporation to give an oil. Purification of the oil by radial chromatography (SiO 2 ) using CH 2 C1 2 followed by 4% MeOH-CH 2 Cl 2 then 9% MeOH-CH 2 Cl to give the product contaminated with DMF. DMF was removed by dissolving the product in Et O and washing with water (3 x 50 mL). The ether phase was dried over sodium sulfate. Filtration and solvent removal (rotary evaporation) gave 60.6 mg of a beige foam.
  • the thioethers of fonnula (II) can be prepared by utilizing known procedures and techniques, or routine modifications thereof. See, for example, the synthetic methods disclosed in PCT/US 98/09781 published as WO 98/51662.
  • a general synthetic method for preparing compounds of formula (II) is set forth in General Procedure C, wherein all substituents, unless otherwise indicated, are previously defined.
  • a quantity of the 4-mercapto-2,6-di-t-butyl ⁇ henol is dissolved in ethanol to make a 0.5 M solution and treated with 1.2 equivalents of sodium hydroxide (5 N aqueous solution). After 5 minutes 1.2 equivalents of alkyl halide are added and the reaction mixture stirred at room temperature for 24 hours. The reaction is quenched with 1 N HC1 to pH 7, diluted with water, extracted with ether and dried over magnesium sulfate. The product is purified by silica gel chromatography.
  • a phenol of structure (II) can be prepared by dissolving the appropriate 2,6-dialkyl-4-thiophenol (or suitably protected derivatives) in alcohol, in one embodiment in ethanol, followed by addition of a halogenated aryl compound.
  • the starting material a 2,6-dialkyl-substituted thiophenol
  • suitable phenol protecting groups are ethers, such as methoxymefhyl, 2- methoxyethoxymethyl, tetrahydropyranyl, t-butyl and benzyl; silyl ethers, such as trimethylsilyl and 1-butyldimethylsilyl; esters, such as acetate and benzoate; carbonates, such as methylcarbonate and benzyl carbonate; as well as sulfonates, such as methane sulfonate and toluene sulfonate.
  • ethers such as methoxymefhyl, 2- methoxyethoxymethyl, tetrahydropyranyl, t-butyl and benzyl
  • silyl ethers such as trimethylsilyl and 1-butyldi
  • HEPG2 cell was started in 10ml of MEM, 10% FBS, ImM Sodium Pyruvate. The cells were incubated in a tissue culture incubator. The cells were split into 4X96-wells plate in MEM, 10% FBS, lmM Sodium Pyruvate and allowed to grow to about 50% confluency and then removed.
  • the cells were treated with the desired concentration of compounds in 100 ⁇ l DMEM, 1 % RSA for 24 hours.
  • the compounds are dissolved in DMSO.
  • the range of concentration is lOuM - 40uM, with each concentration being done in triples.
  • 4X96-wells NuncImmunoSorb plate is coated with 100 ⁇ l of mouse anti-human ApoB monoclonal 1D1 (1:1000 dilution in IXPBS, pH 7.4). The coating is allowed to stand overnight.
  • Day 2 ApoB ELISA Day 2 ApoB ELISA:
  • the coated plate is washed 3 times with IXPBS, pH 7.4, -0.05% Tween 20. 100 ⁇ l of the standards is added to the selected wells. ApoB standards are prepared at 6.25, 3.12,
  • ELISA plate The plate is incubated at room temperature for 2 hours, rocking gently.
  • the VCAM-1 assay is an enzyme immunoassay to detect tumor necrosis factor alpha (TNF-alpha) induced Vascular Cell Adhesion Molecule (VCAM-1) expression in endothelial cells.
  • HAEC Human aortic endothelial cells
  • EGM media Clonetics
  • FBS fetal bovine serum
  • TNF-alpha lng/ml
  • DMSO dimethylsulphoxide
  • HBSS Hanks buffered saline solution
  • PBS phosphate buffered solution
  • TMB peroxidase substrate 3.3', 5, 5'-tetramethyl- benzidine
  • Animals, including mammals and specifically humans, suffering from any of the above-described conditions can be treated by the topical, systemic or transdermal administration of a composition comprising an effective amount of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.
  • the composition is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, orally, submucosally, by inhalation, transdermally via a slow release patch, or topically, in an effective dosage range to treat the target condition.
  • An effective dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; 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 admimstered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.
  • Typical systemic dosages for all of the herein described conditions are those ranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a single daily dose or divided daily doses. Dosages for the described conditions range from 5-1500 mg per day. A more particular dosage for the desired conditions ranges from 25-750 mg per day. Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
  • the compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • a particular mode of administration of the active compound for systemic delivery is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • 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 can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a 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 flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a 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
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • the compound or its salts can be 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, dyes and colorings and flavors.
  • the compound can also be mixed with other' active materials which do not impair the desired action, or with materials that supplement the desired action.
  • the active compounds can be administered in conjunction with other medications used in the treatment of cardiovascular disease, including lipid lowering agents such as probucol and nicotinic acid; platelet aggregation inhibitors 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 ⁇ - blockers such as propanalol, terbutalol, and labetalol.
  • lipid lowering agents such as probucol and nicotinic acid
  • platelet aggregation inhibitors 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
  • the compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
  • nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
  • the compound can also be administered with corticosteriods.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, N- ethyl-2-pyrrolidone 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 for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • exemplary carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • physiological saline bacteriostatic water
  • Cremophor ELTM BASF, Parsippany, NJ
  • PBS phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations 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 (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also exemplary as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa.
  • thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.

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Abstract

L'invention concerne des thiocétals et des thioéthers permettant d'inhiber l'expression de la molécule-1 d'adhésion cellulaire vasculaire (VCAM-1), et pouvant être utilisés pour traiter les maladies induites par la VCAM-1, y compris les troubles inflammatoires, les maladies cardio-vasculaires, les maladies oculaires, les maladies auto-immunes, les troubles neurologiques, et le cancer. En outre, ces composés peuvent être utilisés pour traiter l'hyperlipidémie et/ou l'hypercholestérolémie.
PCT/US2001/009049 2000-03-21 2001-03-21 Thiocetals et thioethers permettant d'inhiber l'expression de la molecule-1 d'adhesion cellulaire vasculaire (vcam-1) WO2001070757A2 (fr)

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AU4765101A AU4765101A (en) 2000-03-21 2001-03-21 Thioketals and thioethers for inhibiting the expression of vcam-1
AU2001247651A AU2001247651B2 (en) 2000-03-21 2001-03-21 Thioketals and thioethers for inhibiting the expression of vcam-1
EP01920617A EP1289944A2 (fr) 2000-03-21 2001-03-21 Thiocetals et thioethers permettant d'inhiber l'expression de la molecule-1 d'adhesion cellulaire vasculaire (vcam-1)
JP2001568958A JP2003528109A (ja) 2000-03-21 2001-03-21 Ｖｃａｍ−１の発現を阻害するためのチオケタール及びチオエーテル
CA002403823A CA2403823A1 (fr) 2000-03-21 2001-03-21 Thiocetals et thioethers permettant d'inhiber l'expression de la molecule-1 d'adhesion cellulaire vasculaire (vcam-1)

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US6828447B2 (en) * 1997-05-14 2004-12-07 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
JP2005514344A (ja) * 2001-10-25 2005-05-19 アセロジエニクス・インコーポレイテツド 移植拒絶治療のための化合物と方法
US6960683B2 (en) 2002-07-12 2005-11-01 Atherogenics, Inc. Salt forms of poorly soluble probucol esters and ethers
WO2006063408A1 (fr) * 2004-12-17 2006-06-22 Stocker Ronald O Préparations et méthodes pour le traitement de troubles cardio-vasculaires
US7166605B2 (en) 2002-03-22 2007-01-23 Nicox, S.A. Probucol nitro-derivatives
EP1768660A2 (fr) * 2004-07-01 2007-04-04 Atherogenics, Inc. Composes et methodes de traitement des maladies vasculaires diabetiques
US7294737B2 (en) 2004-04-20 2007-11-13 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
WO2008118948A1 (fr) 2007-03-26 2008-10-02 Atherogenics, Inc. Procédés et compositions de dérivés de probucol pour le traitement du diabète
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
CN110452877A (zh) * 2018-05-07 2019-11-15 北京吉尚立德生物科技有限公司 一种肺癌实体瘤原代细胞的培养方法
US10947311B2 (en) 2015-11-20 2021-03-16 The Board Of Trustees Of The Leland Stanford Junior University VCAM-1 mediated methods and compositions for treating aging-associated impairments
EP4169533A1 (fr) 2013-02-28 2023-04-26 President and Fellows of Harvard College Procédés et compositions pour mobiliser des cellules souches

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US6828447B2 (en) * 1997-05-14 2004-12-07 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US7189870B2 (en) 1997-05-14 2007-03-13 Atherogenic, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
JP2005514344A (ja) * 2001-10-25 2005-05-19 アセロジエニクス・インコーポレイテツド 移植拒絶治療のための化合物と方法
US7166605B2 (en) 2002-03-22 2007-01-23 Nicox, S.A. Probucol nitro-derivatives
US7371895B2 (en) 2002-07-12 2008-05-13 Atherogenics, Inc. Salt forms of poorly soluble probucol esters and ethers
US6960683B2 (en) 2002-07-12 2005-11-01 Atherogenics, Inc. Salt forms of poorly soluble probucol esters and ethers
US7273948B2 (en) 2003-01-13 2007-09-25 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
WO2004062622A2 (fr) 2003-01-13 2004-07-29 Atherogenics, Inc. Procede de preparation d'esters et d'ethers de probucol et ses derives
US7622604B2 (en) 2003-01-13 2009-11-24 Salutria Pharmaceuticals Llc Process of preparing esters and ethers of probucol and derivatives thereof
US7294737B2 (en) 2004-04-20 2007-11-13 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
AU2005262390B2 (en) * 2004-07-01 2011-09-22 Atherogenics, Inc. Compounds and methods for treating diabetic vascular diseases
EP1768660A2 (fr) * 2004-07-01 2007-04-04 Atherogenics, Inc. Composes et methodes de traitement des maladies vasculaires diabetiques
EP1768660A4 (fr) * 2004-07-01 2009-05-13 Atherogenics Inc Composes et methodes de traitement des maladies vasculaires diabetiques
WO2006063408A1 (fr) * 2004-12-17 2006-06-22 Stocker Ronald O Préparations et méthodes pour le traitement de troubles cardio-vasculaires
WO2008118948A1 (fr) 2007-03-26 2008-10-02 Atherogenics, Inc. Procédés et compositions de dérivés de probucol pour le traitement du diabète
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
EP4169533A1 (fr) 2013-02-28 2023-04-26 President and Fellows of Harvard College Procédés et compositions pour mobiliser des cellules souches
US10947311B2 (en) 2015-11-20 2021-03-16 The Board Of Trustees Of The Leland Stanford Junior University VCAM-1 mediated methods and compositions for treating aging-associated impairments
CN110452877A (zh) * 2018-05-07 2019-11-15 北京吉尚立德生物科技有限公司 一种肺癌实体瘤原代细胞的培养方法

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