WO1998051662A2 - Compounds and methods for the inhibition of the expression of vcam-1 - Google Patents

Compounds and methods for the inhibition of the expression of vcam-1 Download PDF

Info

Publication number
WO1998051662A2
WO1998051662A2 PCT/US1998/009781 US9809781W WO9851662A2 WO 1998051662 A2 WO1998051662 A2 WO 1998051662A2 US 9809781 W US9809781 W US 9809781W WO 9851662 A2 WO9851662 A2 WO 9851662A2
Authority
WO
WIPO (PCT)
Prior art keywords
butyl
substituted
alkyl
spacer
aryl
Prior art date
Application number
PCT/US1998/009781
Other languages
French (fr)
Other versions
WO1998051662A3 (en
Inventor
Patricia K. Somers
Lee K. Hoong
Charles Q. Meng
Original Assignee
Atherogenics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AT98922264T priority Critical patent/ATE294158T1/en
Priority to PL343904A priority patent/PL207885B1/en
Priority to HU0004592A priority patent/HUP0004592A3/en
Priority to EP98922264A priority patent/EP0994853B1/en
Priority to SI9830885T priority patent/SI1464639T1/en
Priority to IL15707798A priority patent/IL157077A/en
Priority to SK1532-99A priority patent/SK286392B6/en
Priority to IL13279798A priority patent/IL132797A0/en
Priority to DE69829966T priority patent/DE69829966T2/en
Priority to BR9809819-5A priority patent/BR9809819A/en
Priority to SK50038-2007A priority patent/SK286766B6/en
Priority to DK98922264T priority patent/DK0994853T3/en
Application filed by Atherogenics, Inc. filed Critical Atherogenics, Inc.
Priority to CA002289851A priority patent/CA2289851C/en
Priority to IL15707898A priority patent/IL157078A/en
Priority to EA199901026A priority patent/EA009370B1/en
Priority to KR1019997010458A priority patent/KR100882335B1/en
Priority to AU74851/98A priority patent/AU750041B2/en
Priority to IL16456898A priority patent/IL164568A0/en
Priority to JP54950298A priority patent/JP3930056B2/en
Publication of WO1998051662A2 publication Critical patent/WO1998051662A2/en
Priority to NO19995544A priority patent/NO316221B1/en
Publication of WO1998051662A3 publication Critical patent/WO1998051662A3/en
Priority to HK00105042A priority patent/HK1025947A1/en
Priority to NO20032254A priority patent/NO319855B1/en
Priority to IL164568A priority patent/IL164568A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/21—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/66—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfo, esterified sulfo or halosulfonyl groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton

Definitions

  • This invention is in the area of methods and compositions for the inhibition of the expression of NCAM-1 and, in particular, for the treatment of diseases mediated by VCAM- 1, including cardiovascular and inflammatory diseases.
  • Coronary heart disease remains the leading cause of death in the industrialized countries.
  • the primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system.
  • Atherosclerosis as manifested in its major clinical complication, ischemic heart disease, continues to be a major cause of death in industrialized countries. It is now well accepted that atherosclerosis can begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia or infarction. Therefore, it is desirable to provide methods of inhibiting the progression of atherosclerosis in patients in need thereof.
  • Cardiovascular disease has been linked to several causative factors, which include hypercholesterolemia, hyperlipidemia, and the expression of VCAM-l in vascular endothelial cells.
  • 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), intracellular adhesion molecule-1 (ICAM-1), and E-selectin.
  • VCAM-1 vascular cell adhesion molecule-1
  • IAM-1 intracellular adhesion molecule-1
  • E-selectin E-selectin.
  • 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 a mediator in chronic inflammatory disorders such as asthma, rheumatoid arthritis and autoimmune diabetes.
  • chronic inflammatory disorders such as asthma, rheumatoid arthritis and autoimmune diabetes.
  • VCAM-1 and ICAM-1 are increased in asthmatics.
  • 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, 11.
  • VCAM-1 is expressed by cells both as a membrane bound form and as a soluble form.
  • VCAM-1 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-oc). 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-oc).
  • linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin.
  • Saturated fatty acids such as stearic acid
  • monounsaturated fatty acids such as oleic acid
  • the induction of VCAM-1 by PUFAs and their fatty acid hydroperoxides is suppressed by dithiocarbamates, including pyrrolidine dithiocarbamate (PDTC).
  • the induction is mediated by an oxidized signal molecule, and that the induction is prevented when the oxidation of the molecule is blocked (i.e., the oxidation does not occur), reversed (i.e., the signal molecule is reduced), or when the redox modified signal is otherwise prevented from interacting with its regulatory target.
  • Cells that are chronically exposed to higher than normal levels of polyunsaturated fatty acids or their oxidized counterparts can initiate an immune response that is not normal and which is out of proportion to the threat presented, leading to a diseased state.
  • the oversensitization of vascular endothelial cells to PUFAs and ox-PUFAs can accelerate the formation, for example, of atherosclerotic plaque.
  • WO95/30415 that includes the removal, decrease in the concentration of, or prevention of the formation of oxidized polyunsaturated fatty acids including but not limited to oxidized linoleic (C 18 ⁇ 9,12 ), linolenic (C 18 ⁇ 6,9 ' 12 ), arachidonic (C 20 ⁇ 5 1 U4 ) and eicosatrienoic (C 20 ⁇ 8 ' 1 4 ) acids.
  • Nonlimiting examples of noncardiovascular inflammatory diseases that are mediated by VCAM-1 include rheumatoid and osteoarthritis, asthma, dermatitis, and multiple sclerosis.
  • 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 regulate endogenous cholesterol levels in those tissues. HDL transports cholesterol from peripheral tissues to the liver.
  • VLDL very low-density lipoproteins
  • LDL low density lipoproteins
  • HDL high-density lipoproteins
  • 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.
  • R 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.
  • Supplementation of saturated or monounsaturated fatty acids to cultured endothelial cells reduces their susceptibility to oxidant injury, whereas supplementation with polyunsaturated fatty acids (PUFA) enhances susceptibility to oxidant injury.
  • PUFA polyunsaturated fatty acids
  • 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.
  • LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood- vessel wall and that HDL functions in way that results in the HDL picking up cholesterol from the vessel wall and transporting it to the liver where it is metabolized
  • LDL cholesterol levels correlate well with the risk of coronary heart disease whereas the HDL cholesterol levels are inversely associated with coronary heart disease [Patton et al., Clin. Chem. 29, 1980 (1983)]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis.
  • 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.
  • monocyte/macrophages take up and degrade native LDL at relatively low rates and without marked accumulation of cholesterol.
  • 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.
  • HMG CoA reductase inhibitors have been termed statins or vastatins.
  • 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).
  • LDL low density lipoprotein
  • 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). Its full chemical name is 4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol).
  • 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. Unfortunately, probucol is almost insoluble in water and therefore cannot be injected intravenously. In fact, probucol is difficult for cells to absorb in vitro because of its poor miscibility in buffers and media for cell culture. Solid probucol is poorly absorbed into the blood, and is excreted in substantially unchanged form. Further, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients.
  • 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 that increase the water solubility of the compound.
  • the derivative is selected from the group consisting of a mono- or di- probucol ester of succinic acid, glutaric acid, adipic acid, seberic acid, sebacic acid, azelaic acid, or maleic acid.
  • the probucol derivative is a mono- or di- ester in which the ester contains an alkyl or alkenyl group that contains a functionality selected from the group consisting of a carboxylic acid group, amine group, salt of an amine group, amide groups, amide groups, and aldehyde groups.
  • probucol derivatives are hypocholesterolemic and hypohpemic agents: Fr 2168137 (bis 4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofiiryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3 -alky 1-5 -t-alky 1-4- thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4- nicotinoyloxyphenylthio)propanes; and Fr 2130975 (bis(4-(phenoxyalkanoyloxy)- phenylthio)alkanes).
  • 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 and to Shionogi Seiyaku Kabushiki Kaisha disclose phenolic thioethers for use in treating arteriosclerosis.
  • European Patent Application No. 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. disclose 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.
  • WO97/15546 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
  • 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.
  • a more general goal is to identify selective methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed.
  • a redox sensitive gene for example MCP-1, IL-6 and thrombin receptor.
  • the present invention provides a compound, composition and method for inhibiting the expression of VCAM-1, and thus can be used in the treatment of a disease mediated by VCAM-1, which includes administering a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • the compounds of formula (I) are
  • X is O, S, SO, SO 2 , CH 2 , or NH;
  • Spacer is a group selected from the group consisting of -(CH 2 ) n -, -(CH 2 ) n -CO-, -(CH 2 ) n - N-,
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH 2 , NHR, NR 2 , SO 2 -OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH 2 , C(O)NHR, C(O)NR 2 , SO 2 NH 2 ,
  • R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
  • R 1 and R 2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R 1 or R 2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
  • 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 .
  • the compound of formula (II) has the following structure
  • R a , R b , R,., and Rj are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R ⁇ , R b , R,.
  • R d groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH,)-! ⁇ , -C(O)-R g , and -C(O)-(CH 2 ) n -R h , wherein (a) when each of R ⁇ R b , R,., and Rj are t-butyl, Z cannot be hydrogen and (b) when each of R a , R b , R e , and R d are t-butyl, Z cannot be the residue of
  • R_. is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)R k , hydroxy, C(O)NH 2 , C(O)NHR, C(O)NR 2 ;
  • R g is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
  • R h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)R k , hydroxy, O-phosphate, C(O)NH 2 , C(O)NHR, C(O)NR 2 and pharmaceutically acceptable salts thereof;
  • R e , R g , and R h can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO 3 H, wherein spacer is as defined above, C(O)-spacer-SO 3 M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO 3 H 2 , C(O)-spacer-PO 3 M 2 , C(O)-spacer-PO 3 HM, C(O)-spacer-PO 4 H, C(O)-spacer-PO 4 M, SO 3 M, - PO 3 H 2 -PO 3 M 2 , -PO 3 HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)- spacer- [O(C,_ 3 alkyl) p ] n , wherein n is as defined above and p is 1, 2, or 3, -
  • the present invention further provides a method of inhibiting the peroxidation of LDL lipid in a patient in need thereof comprising administering to said patient an effective antioxidant amount of a compound of formula (I) or formula (II).
  • a method for suppressing the expression of a redox-sensitive gene or activating a gene that is suppressed through a redox-sensitive pathway that includes administering an effective amount to prevent the oxidation of the oxidized signal, and typically, the oxidation of a PUFA of a compound of formula (I) or formula (II).
  • Representative redox-sensitive genes that are involved in the presentation of an immune response include, but are not limited to, those expressing cytokines involved in initiating the immune response (e.g., IL-l ⁇ ), chemoattractants that promote the migration of inflammatory cells to a point of injury (e.g., MCP-1), growth factors (e.g., IL-6 and the thrombin receptor), and adhesion molecules (e.g., VCAM-1 and E-selectin).
  • cytokines involved in initiating the immune response e.g., IL-l ⁇
  • chemoattractants that promote the migration of inflammatory cells to a point of injury e.g., MCP-1
  • growth factors e.g., IL-6 and the thrombin receptor
  • adhesion molecules e.g., VCAM-1 and E-selectin
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of C, to C, 0 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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, hereby incorporated by reference.
  • lower alkyl refers to a C, to C 5 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.
  • alkylene refers to a saturated hydrocarbyldiyl radical of straight or branched configuration made up of from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1 ,2-propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like.
  • the alkylene group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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, hereby incorporated by reference.
  • -(CH 2 ) n - represents a saturated hydrocarbyldiyl radical of straight chain configuration.
  • n is defined as 0-10.
  • aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
  • 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 defind above linked to the molecule through an aryl group as defined above.
  • the alkyl group can be optionally substituted as describe above and the aryl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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.
  • aryl phenyl; naphthyl; phenylmethyl; phenylethyl; 3,4,5-trihydroxyphenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di- tertiarybutyl- 4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-l -naphthyl; 2-methyl-l- naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-tertiarybutylphenyl; 4- tertiarybutylphenylmethyl and the like.
  • halo as used herein, 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.
  • polyunsaturated fatty acid refers to a fatty acid (typically C 8 to C 2 ) that has at least two alkenyl bonds, and includes but is not limited to linoleic (C 18 ⁇ 9 - 12 ), linolenic (C 18 ⁇ 6 - 9 - 12 ), arachidonic (C 20 ⁇ 8 - 1 U4 ) acids.
  • oxidized polyunsaturated fatty acid refers to an unsaturated fatty acid in which at least on of the alkenyl bonds has been converted to a hydroperoxide.
  • Nonlimiting examples are 13-HPODE and 15-HPETE.
  • 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 " , wherien 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).
  • A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate,
  • VCAM-1 Diseases mediated by the VCAM-1 include, but are not limited to atherosclerosis, post- angioplasty restenosis, coronary artery disease, angina, small artery disease, and other cardiovascular diseases, as well as noncardiovascular inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis.
  • the invention is a method for treating a disease mediated by the expression of VCAM-1 comprising administering a compound of the formula
  • X is O, S, SO, SO 2 , CH 2 , or NH;
  • Spacer is a group selected from the group consisting of -(CH 2 ) n -, -(CH 2 ) n -CO-, -(CH 2 ) n - N-, -(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)-; n is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, orlO;
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, NH 2 , NHR, NR 2 , SO 2 -OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH 2 , C(O)NHR, C(O)NR 2 ;
  • R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
  • R 1 and R 2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R 1 or R 2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
  • 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 .
  • Preferred compounds of the present invention include compounds of formula (I) wherein
  • X is S, SO or SO 2 ;
  • Spacer is -(CH 2 ) n - or -(CH 2 ) n CO-; n is 0-10;
  • Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH 2 , NHR, NR 2 , alkyl, substituted alkyl, acyloxy, and substituted acyloxy;
  • R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
  • R 1 and R 2 are independently straight chained, branched or cyclic C,_ 10 alkyl;
  • R 3 and R 4 are independently hydrogen, halogen or R 1 .
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH 2 , NHR, NR 2 , alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently straight chained, branched or cyclic C,. 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0- 10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl- COOalkyl, alkyl-COO
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, aryl, heteroaryl or nitro-
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, aryl, heteroaryl or
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH 2 , CONHR, CONR 2 , -(CH 2 ) m -OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO 2 OH, SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 , or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, or nitro- substituted furanyl, or when attached to a nitrogen atom
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C ⁇ alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -CO-; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently Cj. 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is isoxazolyl or furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently Q.s alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is isoxazolyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C]_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH 2 NH 2 , CH 2 NHR, CH 2 NR 2 , COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C ⁇ alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is NH 2 , NHR or NR 2 ; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is NH 2 , NHR or NR 2 ; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) ⁇ -; n is 0-10; Y is NH 2 , NHR or NR 2 ; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -CO-; n is 0-10; Y is NH 2 , NHR or NR 2 ; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C ⁇ -5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO 2 OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, and aryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO 2 OH, COOH or COOR; and OCOR; R is alkyl or two adjacent R groups may combine to form a ring of 5 to 7 members; R 1 and R 2 are independently C ⁇ _ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO 2 OH, COOH; or COOR; R is alkyl; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR; R is alkyl; R 1 and R 2 are independently C 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n - or -(CH 2 ) n -CO-; n is 0-10; Y is OCOR; R is alkyl; R 1 and R 2 are independently C 1-5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -; n is 0-10; Y is OCOR; R is alkyl; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO 2 ; Spacer is -(CH 2 ) n -CO-; n is 0-10; Y is OCOR; R is alkyl; R 1 and R 2 are independently C,_ 5 alkyl; R 3 and R 4 are independently H.
  • Examples of the present invention include compounds of formula (I) defined as follows:
  • a compound of formula (II) and a method for treating a disease mediated by the expression of VCAM-1 comprising administering an effective amount of a compound of formula (II):
  • R a , R b , R,., and Rj are independently hydrogen, straight chained, branched (for example, tert-butyl), or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R ⁇ R,,, R j . and R ⁇ groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH ⁇ -R e , -C(O)-R g , and -C(O)-(CH 2 ) n -R h , wherein (a) when each of R a , R b , R ⁇ ., and Rj are t-butyl, Z cannot be hydrogen and (b) when each of R a , R b , R,., and Rj are t-butyl, Z cannot be the residue of succinic acid;
  • R e is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)R k , hydroxy, C(O)NH 2 , C(O)NHR, C(O)NR 2 ;
  • R g is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
  • R h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)R k , hydroxy, O-phosphate, C(O)NH 2 , C(O)NHR, C(O)NR 2 and pharmaceutically acceptable salts thereof; or, in an alternative embodiment, R e , R g , and R h can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO 3 H, wherein spacer is as defined above,
  • Substitutents on the groups defined above are selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino, alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH 2 , CONHR, CONR 2 , haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH 2 -OR, CH 2 -OH, OCOR, O- ⁇ hosphate, SO 2 -NH 2 , SO 2 -NHR, SO 2 -NR 2 .
  • a preferred embodiment of the present invention includes compounds of formula (II) wherein R ⁇ , R b , R,., and R ⁇ are independently hydrogen or straight chained, branched, or cyclic ., 0 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH 2 )- R e , -C(O)-R g , and -C(O)-(CH 2 ) n -R h , and pharmaceutically acceptable salts thereof.
  • R a , R b , R restroom and Rj are independently hydrogen or straight chained, branched, or cyclic C,_ 5 alkyl;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH 2 )-R e , -C(O)-R g , and -C(O)-(CH 2 ) n -R h , and pharmaceutically acceptable salts thereof.
  • R ⁇ , b , R c , and Rj are independently hydrogen or straight chained, branched, or cyclic C,_ 5 alkyl;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, -CH 2 -aryl substituted alkynyl, a carbohydrate group, -CH 2 -NR 2 , -CH 2 -alkoxy, -CH 2 -CHOH, -CH 2 -substituted aryl, -CH 2 - alkyl, -CH 2 -substituted alkyl, -CH 2 .-OCO-alkyl, -CH 2 -OCO-substituted alkyl, -CH 2 -COOR, - CH 2 -CH(OH)CH 2 NHCH 2 COOR, -CH 2 -CH
  • R ⁇ R b , R ⁇ ., and Rj are independently hydrogen or straight chained, branched, or cyclic C 5 alkyl;
  • Z is selected from the group consisting of hydrogen, alkyl, hydroxy alkyl, polyhydroxy alkyl, alkenyl, hydroxy alkenyl, acyl-substituted alkenyl, alkoxy alkyl, nitrophenylalkyl, aminophenylalkyl, alkylaminophenylalkyl, dialkylaminophenylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, acyloxyalkyl, oxiranyl- substituted hydroxyalkyl, hydroxyalkyl-substituted oxiranylmethylene, oxiranyl-substituted hydroxyalkoxyalkyl oxiranylmethylene,
  • Examples of the present invention include compounds of formula (II) wherein:
  • R a t-butyl
  • R b t-butyl
  • R d t-butyl
  • Z CO-(5-nitrofuran-2-yl)
  • R a t-butyl
  • R b t-butyl
  • Z 3-carboxypropyl
  • R a t-butyl
  • R b t-butyl
  • R c H
  • R d H
  • Z 4-aminobutyl
  • R a t-butyl
  • R b t-butyl
  • Z CO-(2-carboxyethyl)
  • R a t-butyl
  • R b t-butyl
  • R ⁇ . t-butyl
  • Z CO-(2-methoxycarbonylethyl)
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • Z 3-carboxypropyl
  • R a t-butyl
  • R b t-butyl
  • R d t-butyl
  • Z CO-2-carboxyethyl
  • R a t-butyl
  • R b t-butyl
  • R ⁇ -butyl and R ⁇ -butyl
  • Z CO-ammonium methyl (chloride)
  • R a t-butyl
  • R b t-butyl
  • Z 3-(2-hydroxy-2-oxiranyl)ethoxyoxiran-
  • R a t-butyl
  • R b t-butyl
  • R,. t-butyl
  • R d t-butyl
  • Z oxiranylmethyl
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • Z 2,3-dihydroxypropyl
  • R a t-butyl
  • R b t-butyl
  • Z ethyl
  • R a t-butyl
  • R b t-butyl
  • R ⁇ t-butyl and R ⁇ -butyl
  • Z CO-2-carboxyethyl
  • R a t-butyl
  • R b t-butyl
  • R d t-butyl
  • Z 3-methoxycarbonylpropyl
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • Z 3-(N-N-diethylamino)propyl
  • Z 2-ethoxycarbonylethenyl;
  • R a t-butyl
  • R b t-butyl
  • Z carboxymethylaminocarbonylmethyl
  • Z l,3- dicarboxypropylaminocarbonylmethyl;
  • R a t-butyl
  • R b t-butyl
  • R ⁇ . t-butyl
  • R d t-butyl
  • Z 2-hydroxy-3-(l,3- diethoxycarbonyl)propylaminopropyl
  • R a t-butyl
  • R b t-butyl
  • Z 3-hydroxypropenyl
  • R a t-butyl
  • R b t-butyl
  • R,. t-butyl
  • Z CH 2 CONH-(CH 2 )CH(NH 2 )COOH
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • Z CO-2,2-dimethyl-3-hydroxypro ⁇ yl
  • R a t-butyl
  • R b t-butyl
  • R c t-butyl
  • R d t-butyl
  • Z CH 2 CH(OH)CH 2 NH(2,3,4,5,6- pentahydroxyhexane.
  • the compounds of formula (I) can be prepared by utilizing known procedures and techniques, or routine modifications thereof.
  • a general synthetic scheme for preparing compounds of formula (I) is set forth in Scheme A, wherein all substituents, unless otherwise indicated, are previously defined.
  • a quantity of the 4-mercapto-2,6-di-t-butylphenol is dissolved in ethanol to make a
  • a phenol of structure (I) can be prepared by dissolving the appropriate 2,6- dialkyl-4-thiophenol (or suitably protected derivatives) in alcohol, preferably in ethanol, followed by addition of a halogenated aryl compound.
  • the starting material, a 2,6-dialkyl-substituted thiophenol may be protected by any of the many protecting groups known to one of ordinary skill in the art.
  • Suitable phenol protecting groups are ethers, such as methoxymethyl, 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 methoxymethyl, 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
  • sulfonates such as methane sulf
  • 2,6-di-t-butyl-4-thiophenol (238 mg, 1 mmol) was dissolved in ethanol (0.7 mL) and cooled to 0° C. 5 N NaOH (0.6 mL, 3 mmol) was added followed by addition of 4- (bromomethyl)phenyl acetic acid (229 mg, 1 mmol). The reaction was warmed to room temperature and after 0.5 h the reaction was complete. The reaction was quenched with 1 N HCl (3.5 mL) and diluted with ether (25 mL). The ether layer was separated and washed with water (1 x 5 mL) and brine (1 x 5 mL), dried over MgSO 4 , filtered and concentrated.
  • the aqueous layer was back-extracted with 2 x 2 mL of EtOAc; the combined organic layers were dried over anhydrous MgSO 4 .
  • the drying agent was removed by filtration; solvent was removed by rotary evaporation to give a crude oil.
  • the oil was purified by preparative thin-layer chromatography (pTLC) using 2 x 500 ⁇ plates and 1 : 1 hexanes- CH 2 C1 2 as eluant.
  • the desired product (2,6-di-tert-butyl-4-thio(4'-nitrobenzyl)phenol) was obtained in 86% yield (90 mg).
  • 2,6 di-t-butyl-4-thiophenol 180 mg, 0.755 mmol was dissolved in ethanol (1.5 mL) and then treated with 5 N NaOH (0.15 mL, 0.75 mmol). After 5 min, 4-(N,N- dimethylsulfonamide)benzyl bromide (210 mg, 0.755) in ethanol (1.5 mL) was added to the reaction. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with IN HCl to pH 7, diluted with water (3 mL), extracted with ether (10 mL), separated and dried over MgSO 4 .
  • 2,6-di-tert-butyl-4-thiophenol (0.84 mmol; 200 mg) was dissolved in 7.6 mL of DMF and treated with 1.1 mmol (46 mg) of NaH (60% dispersion in mineral oil) to give an orange mixture. After 15 min. , 0.76 mmol (0.12 mL) of 5-chloropentyl acetate was added. The mixture was stirred for 25 h then diluted with 20 mL of EtOAc and washed with H 2 O (25 mL). The organic layer was washed with brine then concentrated by rotary evaporation.
  • the crude material was purified by radial chromatography (2 mm SiO 2 plate; 85 : 15 hexanes-EtOAc as eluant) to give 2,6-di-tert-butyl-4-thio((r- (acetoxy))pentyl)phenol (93 mg; 30% yield) as a light yellow, amorphous solid.
  • a quantity of probucol (commercially available from Sigma Chemicals) in a 0.1 M solution of tetrahydrofuran is treated with 2 equivalents of sodium hydride and stirred at room temperature for 30 minutes.
  • To the reaction mixture is added 3 equivalents of a primary alkyl bromide or iodide and the reaction stirred at room temperature for 16 hours.
  • the reaction is quenched with 1 N aqueous HCl and diluted with ethyl acetate.
  • the aqueous layer is removed and the ehtyl acetate layer is washed with water and then with an aqueous saturated sodium chloride solution.
  • the ethyl acetate solution is dried over magnesium sulfate, gravity or vacuum filtered, and then concentrated.
  • a second alternative method for the preparation of compounds of formula (II) wherein Z forms an ether group is the treatment of probucol with a primary alkyl bromide or iodide in acetonitrile in the presence of potassium fluoride absorbed on alumina according to the method of Ando et al. ⁇ Bull. Chem. Soc. Jpn., 55, 1982, 2504-2507).
  • Phenol 4-[[l-[3,5-bis(l,l-dimethylethyl)4-[(4- nitrophenyl)methoxy]phenyl]thio]-l-methyIethyl]thio]2,6-bis(l,l- dimethylethyl)-
  • Butanedioic acid mono [4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]2,6-bis(l,l-dimethylethyl)phenyl]ester
  • Butanoic acid 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]2,6-dimethylphenoxy]-
  • Phenol 4-[[l-[[4-(4-aminobutoxy)-3,5-bis(l,l-dimethylethyl)phenyl]thio]- l-methylethyl]thio]2,6-bis(l , 1-dimethylethyl)-
  • Phenol 4-[[l-[[4-(4-aminobutoxy)-3,5-bis(l,l-dimethylethyl)phenyl]thio]-l- methylethyl]thio]2,6-bis(l,l-dimethylethyl)-
  • Example 28 Propanoic acid, 2,2-dimethyl-, [4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenoxy]methyl ester
  • acetonitrile 30 ml
  • chloromethyl pivalate 6.0 g, 40 mmol
  • potassium fluoride 8.0 g, 40% on alumina
  • Phenol 4-[[l-[[4-(4-aminobutoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)-
  • Butanoic acid 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]phenoxy]-
  • the resulting oil was chromatographed on silica gel eluting with 10% ethyl acetate/hexane followed by 20% ethyl acetate/hexane to yield 610 mg of the phthaloyl glycine ester.
  • the phthaloyl glycine ester was taken up in DMF(8.6 mL) and hydrazine hydrate was added (0.136 mL, 2.34 mmol) and the reaction stirred overnight.
  • IN HCl was added (5 mL) and the reaction stirred an additional 1 h.
  • the reaction was diluted with ethyl acetate (25 mL) and washed with NaHCO3 (aq) (1X10 mL).
  • Pentanedioic acid mono[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenyl] ester
  • Butanoic acid 4-[4-[[l-[[3,5-bis(l,l-dimethylethyI)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-
  • the ethyl acetate layer was dried over MgSO 4 , fileterd, concentrated and chromatographed on silia gel by elution with a concentration gradient of 10:90 methylene chloride/hexane to 60:40 methylene chloride hexane. The appropriate fractions were collected and concentrated to afford 442 mg of a white solid.
  • the methyl ester was taken up in THF:MeOH:H 2 0 (4:1:1)(5 mL) and lithium hydroxide (63 mg, 1.5 mmol) was added. After 2.5 h the reaction was complete and quenched with 1 N HCl (3 mL) and extracted with ethyl acetate (15 mL).
  • probucol 5.16 g, 10 mmol
  • acetonitrile 50 ml
  • potassium fluoride 2.9 g, 20 mmol
  • Phenol 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-(oxiranylmethoxy)phenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
  • Phenol 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-(3-ethoxy-2- hydroxypropoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-;
  • Phenol 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l , 1-dimethylethyl)-
  • Butanedioic acid mono[4-[[l-[[3,5-bis(l,l-dimethylethyI)-4- methoxyphenyl]thio]l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl] ester
  • Example 22 The compound of Example 22 (1.13 g, 1.83 mmol) was taken up in DMF (3.6 mL) and 60% sodium hydride (183 mg, 4.6 mmol) was added followed 0.25 h later by methyl iodide (0.342 mL, 5.5 mmol). The reaction was allowed to stir overnight. The reaction was quenched with water (2 mL), diluted with ether (50 mL). The ether layer was washed with water (2X10 mL) and saturated aqueous sodium chloride (1X10 mL), dried over MgSO 4 ,filtere, and concentrated.
  • Phenol 4-[[l-[[4-[2-[4-(dimethylamino)phenyl]ethoxy]-3,5-bis(l,l- dimethylethyl)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
  • Example 46 ⁇ -D-Galactopyranose, 6-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyI]thio]-2,6-bis(l,l-dimethylethyI)phenyl]- 1 ,2 :3,4-bis-O-(l -methylethylidene)
  • Phenol 4-[[l-[[4-[3-(dimethylamino)propoxy]-3,5-bis(l,l- dimethylethyl)phenyI]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
  • Example 48 Glycine, N-[ [4- [ [1 - [ [3,5-bis(l ,1 -dimethylethyl)-4-hydroxyphenyl] thio]- l,methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]acetyl]-
  • the reaction mixture was sti ⁇ ed overnight and the methylene chloride evaporated.
  • the reaction was diluted with ether (10 mL) and washed with water (2X3 mL), dried over MgSO 4 , filtered, and concentrated.
  • the crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane to give 50 mg of the ethyl ester of the product.
  • the ethyl ester dissolved in THF:H 2 0:MeOH (2:1:1)(1 mL) and LiOH-H20 (15 mg) was added and the reaction sti ⁇ ed for 1 h.
  • the reaction mixture was sti ⁇ ed overnight and the methylene chloride evaporated.
  • the reaction was diluted with ether(10 mL) and washed with water(2X3 mL), dried over MgSO , filtered, and concentrated.
  • the crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane to give 130 mg of the diethyl ester of the desired product.
  • the diethyl ester was dissolved in THF:H 2 0:MeOH(2:l:l)(3 mL) and LiOH-H 2 0 (100 mg) was added and the reaction sti ⁇ ed for 1 h.
  • Phenol 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-[[3-hydroxy-l- propenyl)oxy]phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
  • the reaction mixture was stirred overnight and the methylene chloride evaporated.
  • the reaction was diluted with ether(10 mL) and washed with water (2X3 mL), dried over MgSO 4 , filtered, and concentrated.
  • the crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane followed by 70:30 ether/hexane to give 128 mg of the methyl ester of product.
  • the methyl ester was dissolved in THF:H 2 0:MeOH(2: l:l)(3 mL) and LiOH-H 2 0 (50 mg) was added and the reaction stirred for 1 h.
  • Butanoic acid 4-hydroxy-3,3-dimethyl-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
  • the crude product mixture was dissolved in ether and chromatographed on silica gel with a concentration gradient of 70:30 hexane/ether to 0:100 hexane/ether. The appropriate fractions were combined and concentrated affording 700 mg of a white solid.
  • the white solid (214 mg, 0.332 mmol)) was taken up in THF (6 mL) and borane-dimethylsulfide (2M in THF, 0.665 mL, 0.664 mmol) was added and the reaction sti ⁇ ed for 6 h. The reaction was qenched with concentrated HCl (0.100 mL) and the reaction sti ⁇ ed overnight.
  • Butanoic acid 4-(suIfoxy)-, l-[4-[[3,5-bis(l,l-dimethylethyI)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl]ester
  • Butanoic acid, 4-hydorxy-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyljthio]- 1 -methylethyl]thio]-2,6-bis( 1 , 1 -dimethylethyl)phenyl ester (12.5 g, 20.75 mmol) was dissolved in DMF (150 ml) and sulfur trioxide trimethylamine complex (12.5 g, 87.5 mmol) was added. The mixture was sti ⁇ ed at room temperature overnight. It was evaporated and the residue was dissolved in dichloromethane (100 ml), washed with water (2 x 50 ml).
  • the present invention also includes the use of compounds of the formulas (I) and (II) in inhibiting the peroxidation of LDL lipid and in inhibiting the progression of atherosclerosis in patients in need thereof.
  • patient refers to warm-blooded animals or mammals, and in particular humans, who are in need of the therapy described herein.
  • 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, ImM Sodium Pyruvate and allowed to grow to about
  • 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.
  • the coated plate is washed 3 times with IXPBS, pH 7.4, -0.05% Tween 20.
  • IXPBS pH 7.4, -0.05% Tween 20
  • Boehringer Mannheim Incubate at room temperature for 1 hour, rocking gently. Wash the coated plate 3X with IXPBS, pH 7.4, -0.05% Tween 20
  • Example 63 VCAM-1 Assay Splitting the cells Two to four confluent PI 50 plates are trypsinized and the cells transfe ⁇ ed to a
  • Water soluble compounds Compounds are initially screened at 50 ⁇ M and 10 ⁇ M. A 50 mM stock solution for each compound is prepared in culture medium. The stock solution is diluted to 5 mM and 1 mM. When 10 ⁇ L of the 5 mM solution is added to the well (1 mL medium/well), the final concentration will be 50 ⁇ M. Adding 10 ⁇ L of the 1 mM solution to the well will give a final concentration of 10 ⁇ M. Water insoluble compounds
  • the compounds are added to the plate (each compound is done in duplicate). One plate is done for VCAM expression and one plate is done for ICAM expression.
  • TNF is added to each well. 100 units/mL TNF is usually added to each well. Since each lot of TNF varies in the number of units, each new lot is titrated to determine the optimum concentration. Therefore this concentration will change. If 100 units/mL is bing used, dilute the TNF to 10 units/ ⁇ L and add 10 ⁇ L to each well.
  • the plates are incubated at 37°C, 5% CO 2 overnight (approximately 16 hours). The next day the plates are checked under the microscope to see if there are any visual signs of toxicity. Records are made of any cell death, debris, or morphology changes, as well as insoluble compounds (particulate or turbity).
  • the media 500 ⁇ L is saved and frozenat -70°C. Wash cells once with roughly 1 ml/well of Hanks Balance Salt Solution (HBSS) or PBS. Gently empty the wash solution and then tap the plate onto paper towels. Add either 250 ⁇ L/well of HBSS +5% FCCS to the plank (no primary antibody wells) or 250 ⁇ L/well of primary antibody diluted in HBSS +5% FCS. Incubate for 30 minutes at 37°C. Wash the wells twice with .5 mL/well HBSS or PBS and gently tap the plates onto paper towels after the last wash.
  • HBSS Hanks Balance Salt Solution
  • Substrate solution is made immediately prior to use and contains: water 10 mL
  • TMB stock solution To 10 mg TMB, add 1 mL acetone. Store at 4°C protected from light.
  • VCAM-1 Ab stock .1 ⁇ g/ ⁇ L final concentration 0.25 ⁇ g/mL
  • ICAM-1 Ab stock .1 ⁇ g/ ⁇ L final concentration 0.25 ⁇ g/mL
  • Butanedioic acid mono 5 6 23 65% at 15
  • Butanedioic acid 40% at 100 mono[4-[[l-[[3,5- b ⁇ s( 1 , 1 -dimethylethyl)- 4- hydroxyphenyl]thio)- 1 -methylethyl ⁇ th ⁇ o-2,6- b ⁇ s(l ,l - d ⁇ methylethyl)phenyl methyl ester
  • Pentanedioic acid (1 - NE 25 methylethyhdene)b ⁇ s(th ⁇ o ⁇ 2,6-b ⁇ s(l,l- d ⁇ methylethyl)-4, 1 - phenylene)] ester
  • Pentanedioic acid 25 70% at 15 mono[4-[[l-[[3,5- b ⁇ s(l , l-d ⁇ methylethyl)-4- hydroxypheny 1] thio] - 1 - methylethyl]th ⁇ o]-2,6- b ⁇ s(l,l- d ⁇ methylethyl)phenyl] ester
  • Butanedioic acid (1- NE 25 methylethyl ⁇ d ⁇ ne)b ⁇ s[th ⁇ o[2,6-b ⁇ (l,l- d ⁇ methylethyl)-4, 1 - phenylene ⁇ ⁇ ester,
  • 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 administered; 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. Prefe ⁇ ed dosages for the described conditions range from 5-1500 mg per day. A more particularly prefe ⁇ ed 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 prefe ⁇ ed 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 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. 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.
  • prefe ⁇ ed carriers are 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
  • 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 Oagents, emollients, and stabilizers can be used to prepare topical compositions.
  • thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.

Abstract

This invention is in the area of methods and compositions for the inhibition of the expression of VCAM-1 and, in particular, for the treatment of diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.

Description

COMPOUNDS AND METHODS FOR THE INHIBITION OF THE EXPRESSION OF VCAM-1
This invention is in the area of methods and compositions for the inhibition of the expression of NCAM-1 and, in particular, for the treatment of diseases mediated by VCAM- 1, including cardiovascular and inflammatory diseases.
BACKGROUND OF THE INVENTION Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries. The primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system.
Atherosclerosis as manifested in its major clinical complication, ischemic heart disease, continues to be a major cause of death in industrialized countries. It is now well accepted that atherosclerosis can begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia or infarction. Therefore, it is desirable to provide methods of inhibiting the progression of atherosclerosis in patients in need thereof.
Cardiovascular disease has been linked to several causative factors, which include hypercholesterolemia, hyperlipidemia, and the expression of VCAM-l in vascular endothelial cells.
Expression of NCAM-1
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), intracellular adhesion molecule-1 (ICAM-1), and E-selectin. 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. Subsequent conversion of leucocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate the leukocyte and platelet recruitment, smooth muscle cell proliferation, endothelial cell activation, and extracellular matrix synthesis characteristic of maturing atherosclerotic plaque.
VCAM-1 is a mediator in 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 are increased in asthmatics. Pilewski, J.M., et al. Am. J. Respir. CellMol. Biol. 12, 1-3 (1995); Ohkawara, Y., et al., Am. J. Respir. CellMol. Biol. 12, 4-12 (1995). Additionally, blocking the integrin receptors for VCAM-1 and ICAM-1 (VLA-4 and LFA-1, respectively) suppressed both early and late phase responses in an ovalbumin-sensitized rat model of allergic airway responses. Rabb, 11. A., et a\., Am. J. Respir. Care Med. 149, 1186- 1191 (1994). There is also increased expression of endothelial adhesion molecules, including VCAM-1, in the micro vasculature of rheumatoid synovium. Koch, A.E. et al., Lab. Invest. 64, 313-322 (1991); Morales-Ducret, J. et al., Immunol. 149, 1421-1431 (1992). Neutralizing antibodies directed against VCAM-1 or its counter receptor, VLA-4, can delay the onset of diabetes in a mouse model (NOD mice) which spontaneously develop the disease. Yang, X.D. et al., Proc. Natl. Acad. Sci. U.S.A. 90, 10494-10498 (1993); Burkly, L.C. et al., Diabetes 43, 523-534 (1994); Baron, J.L. et al., J. Clin. Invest. 93, 1700-1708 (1994). Monoclonal antibodies to VCAM-1 can also have a beneficial effect in animal models of allograft rejection, suggesting that inhibitors of VCAM-1 expression may have utility in preventing transplant rejection. Oroez, C.G. et al., Immunol. Lett. 32, 7-12 (1992). 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-oc). These factors are not selective for activation of cell adhesion molecule expression.
U. S. Patent No. 5,380,747 to Medford, et al., teaches the use of dithiocarbamates such as pyrrolidine dithiocarbamate for the treatment of cardiovascular and other inflammatory diseases.
U. S. Patent No. 5,750,351 to Medford, et al., and WO95/30415 to Emory University describe the discovery that polyunsaturated fatty acids ("PUFAs") and their hydroperoxides ("ox-PUFAs"), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM- 1 , but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin. The induction of VCAM-1 by PUFAs and their fatty acid hydroperoxides is suppressed by dithiocarbamates, including pyrrolidine dithiocarbamate (PDTC). This indicates that the induction is mediated by an oxidized signal molecule, and that the induction is prevented when the oxidation of the molecule is blocked (i.e., the oxidation does not occur), reversed (i.e., the signal molecule is reduced), or when the redox modified signal is otherwise prevented from interacting with its regulatory target. Cells that are chronically exposed to higher than normal levels of polyunsaturated fatty acids or their oxidized counterparts can initiate an immune response that is not normal and which is out of proportion to the threat presented, leading to a diseased state. The oversensitization of vascular endothelial cells to PUFAs and ox-PUFAs can accelerate the formation, for example, of atherosclerotic plaque.
Based on these discoveries, a method for the treatment of atherosclerosis, post- angioplasty restenosis, coronary artery diseases, angina, small artery disease and other cardiovascular diseases, as well as noncardiovascular inflammatory diseases that are mediated by VCAM-1, was described in WO95/30415 that includes the removal, decrease in the concentration of, or prevention of the formation of oxidized polyunsaturated fatty acids including but not limited to oxidized linoleic (C18Δ9,12), linolenic (C18Δ6,9'12), arachidonic (C20Δ5 1 U4) and eicosatrienoic (C20Δ8'1 4) acids.
Nonlimiting examples of noncardiovascular inflammatory diseases that are mediated by VCAM-1 include rheumatoid and osteoarthritis, asthma, dermatitis, and multiple sclerosis.
Hypercholesterolemia and hyperlipidemia
Hypercholesterolemia is an important risk factor associated with cardiovascular disease. 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 regulate 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). In patients with low levels of LDL, the development of atherosclerosis is rare.
Steinberg, et al., (N. Eng. J. Med. 1989; 320:915-924) hypothesized that modification of low-density lipoprotein (LDL) into oxidatively modified LDL (ox-LDL) by reactive oxygen species is the central event that initiates and propagates atherosclerosis. 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. R 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. It has been proposed that a generation of oxidized lipids is formed by the action of the cell lipoxygenase system and that the oxidized lipids are subsequently transferred to LDL. There is thereafter a propagation reaction within the LDL in the medium catalyzed by transition metals and/or sulfhydryl compounds. Previous investigations have demonstrated that fatty acid modification of cultured endothelial cells can alter their susceptibility to oxidant injury, whereas supplementation with polyunsaturated fatty acids (PUFA) enhances susceptibility to oxidant injury. Supplementation of saturated or monounsaturated fatty acids to cultured endothelial cells reduces their susceptibility to oxidant injury, whereas supplementation with polyunsaturated fatty acids (PUFA) enhances susceptibility to oxidant injury. Using reverse-phase HPLC analysis of native and saponified liquid extracts of LDL, it has been demonstrated that 13-HPODE is the predominant oxidized fatty acid in LDL oxidized by activated human monocytes. Chronic exposure to oxidized LDL provides an oxidative signal to vascular endothelial cells, possible through a specific fatty acid hydroperoxide, that selectively augments cytokine-induced VCAM-1 gene expression. Through a mechanism that is not well defined, areas of vessel wall predisposed to atherosclerosis preferentially sequester circulating LDL. Through a poorly understood pathway, endothelial, smooth muscle, and/or inflammatory cells then convert LDL to ox- LDL. In contrast to LDL, which is taken up through the LDL receptor, 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. Thus, monocytes continue to take up ox-LDL and become lipid-engorged macrophage-foam cells that form the fatty streak.
There is now a large body of evidence demonstrating that hypercholesterolemia is an important risk factor associated with heart disease. For example, in December 1984, a National Institute of Health Consensus Development Conference Panel concluded that lowering definitely elevated blood cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will reduce the risk of heart attacks due to coronary heart disease. Typically, 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). It is widely accepted that LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood- vessel wall and that HDL functions in way that results in the HDL picking up cholesterol from the vessel wall and transporting it to the liver where it is metabolized [Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)]. For example, in various epidemiologic studies the LDL cholesterol levels correlate well with the risk of coronary heart disease whereas the HDL cholesterol levels are inversely associated with coronary heart disease [Patton et al., Clin. Chem. 29, 1980 (1983)]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis.
Furthermore, there is evidence based on animal and laboratory findings that peroxidation of LDL lipid, such as the unsaturated fatty acid portions of LDL cholesteryl esters and phospholipids, facilitate 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. Thus it is believed that 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. For example, it has been shown that monocyte/macrophages take up and degrade native LDL at relatively low rates and without marked accumulation of cholesterol. In contrast, oxidized LDL is taken up by these monocyte/macrophages at much higher rates and with marked accumulation of cholesterol [Parthasarathy et al., J. Clin. 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.
Since it has been determined that hypercholesterolemia is due to elevated LDL (hyperlipidemia), the lowering of LDL levels by dietary therapy is attempted. There are several drug classes that are commonly used to lower LDL levels, including bile acid sequestrants, nicotinic acid (niacin), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Probucol and the fibrate derivatives are sometimes used as adjunctive therapy, usually in combination with other medications. The HMG CoA reductase inhibitors have been termed statins or vastatins. 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).
Evidence suggests that the atherogenic effects of low density lipoprotein (LDL) may be in part mediated through its oxidative modification. Probucol has been shown to possess potent antioxidant properties and to block oxidative modification of LDL. Consistent with these findings, probucol has been shown to actually slow the progression of atherosclerosis in LDL receptor-deficient rabbits as discussed in Carew et al. Proc. Natl. Acad. Sci. U.S.A. 84:7725-7729 (1987). Most likely, probucol is effective because it is highly lipid soluble and is transported by lipoproteins, thus protecting them against oxidative damage. 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). Its full chemical name is 4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol).
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 Lorelco™. Unfortunately, probucol is almost insoluble in water and therefore cannot be injected intravenously. In fact, probucol is difficult for cells to absorb in vitro because of its poor miscibility in buffers and media for cell culture. Solid probucol is poorly absorbed into the blood, and is excreted in substantially unchanged form. Further, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients. In one study (Heeg et al, Plasma Levels ofProbucol in Man After Single and Repeated Oral Doses, La Nouvelle Presse Medicale, 9:2990-2994 (1980)), peak levels of probucol in sera were found to differ by as much as a factor of 20 from patient to patient. In another study, Kazuya et al. J. Lipid Res. 32; 197-204 (1991) observed an incorporation of less than about 1 μg of probucol/ 106 cells when endothelial cells are incubated for 24 h with 50 μM probucol. 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 that increase the water solubility of the compound. In one embodiment, the derivative is selected from the group consisting of a mono- or di- probucol ester of succinic acid, glutaric acid, adipic acid, seberic acid, sebacic acid, azelaic acid, or maleic acid. In another embodiment, the probucol derivative is a mono- or di- ester in which the ester contains an alkyl or alkenyl group that contains a functionality selected from the group consisting of a carboxylic acid group, amine group, salt of an amine group, amide groups, amide groups, and aldehyde groups.
A series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypohpemic agents: Fr 2168137 (bis 4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofiiryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3 -alky 1-5 -t-alky 1-4- thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4- nicotinoyloxyphenylthio)propanes; and Fr 2130975 (bis(4-(phenoxyalkanoyloxy)- phenylthio)alkanes).
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 and to Shionogi Seiyaku Kabushiki Kaisha disclose phenolic thioethers for use in treating arteriosclerosis. European Patent Application No. 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., disclose 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.
WO97/15546 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. For example, 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.
Given that 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.
Important to this goal is the identification and manipulation of the specific oxidized biological compounds that act as selective regulators of the expression of mediators of the inflammatory process, and in particular, VCAM-1. A more general goal is to identify selective methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed.
It is therefore an object of the present invention to provide new compounds, compositions and methods for the treatment of cardiovascular and inflammatory diseases. It is still another object of the present invention to provide new compounds and compositions which are useful as inhibitors of LDL lipid peroxidation. It is still another object of the present invention to provide new compounds and compositions which are useful as antiatherosclerotic agents.
It is still another object of the present invention to provide new compounds and compositions which are useful as LDL lipid lowering agents.
It is still another object of the present invention to provide new compounds, compositions and methods for selectively inhibiting the expression of VCAM-1.
It is still another object of the present invention to provide a method for the treatment of a disease that is mediated by the expression or suppression of a redox sensitive gene, for example MCP-1, IL-6 and thrombin receptor.
SUMMARY OF THE INVENTION
The present invention provides a compound, composition and method for inhibiting the expression of VCAM-1, and thus can be used in the treatment of a disease mediated by VCAM-1, which includes administering a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The compounds of formula (I) are
Figure imgf000012_0001
wherein
X is O, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of -(CH2)n-, -(CH2)n-CO-, -(CH2)n- N-,
-(CH2)n-O-, -(CH2)n-S-, -(CH2O)-, -(OCH2)-, -(SCH2)-, -(CH2S-), -(aryl-O)-, -(O-aryl)-, -(alkyl- O)-, -(O-alkyl)-; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH2, NHR, NR2, SO2-OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2, SO2NH2, SO2NHR, SO2NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1.
The compound of formula (II) has the following structure
Figure imgf000013_0001
(II)
wherein
Ra, Rb, R,., and Rj are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R^, Rb, R,. and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH,)-!^, -C(O)-Rg, and -C(O)-(CH2)n-Rh, wherein (a) when each of R^ Rb, R,., and Rj are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be the residue of succinic acid;
R_. is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof;
Or, in an alternative embodiment, Re, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, - PO3H2 -PO3M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)- spacer- [O(C,_3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, -[O(C,_3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl. The present invention generally provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an effective amount of a compound of formula (I) or formula (II).
The present invention further provides a method of inhibiting the peroxidation of LDL lipid in a patient in need thereof comprising administering to said patient an effective antioxidant amount of a compound of formula (I) or formula (II).
In an alternative embodiment, a method is provided for suppressing the expression of a redox-sensitive gene or activating a gene that is suppressed through a redox-sensitive pathway, that includes administering an effective amount to prevent the oxidation of the oxidized signal, and typically, the oxidation of a PUFA of a compound of formula (I) or formula (II).
Representative redox-sensitive genes that are involved in the presentation of an immune response include, but are not limited to, those expressing cytokines involved in initiating the immune response (e.g., IL-lβ), chemoattractants that promote the migration of inflammatory cells to a point of injury (e.g., MCP-1), growth factors (e.g., IL-6 and the thrombin receptor), and adhesion molecules (e.g., VCAM-1 and E-selectin).
DETAILED DESCRIPTION OF THE INVENTION
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of C, to C,0, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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, hereby incorporated by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C, to C5 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group. Likewise the term alkylene refers to a saturated hydrocarbyldiyl radical of straight or branched configuration made up of from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1 ,2-propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like. The alkylene group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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, hereby incorporated by reference.
The term "-(CH2)n-" represents a saturated hydrocarbyldiyl radical of straight chain configuration. The term "n" is defined as 0-10. The moiety "-(CH2)n-" thus represents a bond (i.e., when n=0), methylene, 1,2-ethanediyl or 1,3-propanediyl, etc.
The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The term aralkyl, as used herein, and unless otherwise specified, refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above. The term alkaryl, as used herein, and unless otherwise specified, refers to an alkyl group as defind above linked to the molecule through an aryl group as defined above. In each of these groups, the alkyl group can be optionally substituted as describe above and the aryl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, 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. Specifically included within the scope of the term aryl are phenyl; naphthyl; phenylmethyl; phenylethyl; 3,4,5-trihydroxyphenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di- tertiarybutyl- 4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-l -naphthyl; 2-methyl-l- naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-tertiarybutylphenyl; 4- tertiarybutylphenylmethyl and the like. The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. The term halo, as used herein, includes chloro, bromo, iodo, and fluoro.
The term alkoxy, as used herein, and unless otherwise specified, refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above.
The term acyl, as used herein, 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.
As used herein, the term polyunsaturated fatty acid (PUFA) refers to a fatty acid (typically C8 to C2 ) that has at least two alkenyl bonds, and includes but is not limited to linoleic (C18Δ9-12), linolenic (C18Δ6-9-12), arachidonic (C20Δ8-1 U4) acids.
The term oxidized polyunsaturated fatty acid (ox-PUFA) refers to an unsaturated fatty acid in which at least on of the alkenyl bonds has been converted to a hydroperoxide. Nonlimiting examples are 13-HPODE and 15-HPETE.
The term pharmaceutically acceptable 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 cation formed from ammonia, N,N- dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+A", wherien 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).
Diseases mediated by the VCAM-1 include, but are not limited to atherosclerosis, post- angioplasty restenosis, coronary artery disease, angina, small artery disease, and other cardiovascular diseases, as well as noncardiovascular inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis.
In one embodiment, the invention is a method for treating a disease mediated by the expression of VCAM-1 comprising administering a compound of the formula
Figure imgf000018_0001
wherein
X is O, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of -(CH2)n-, -(CH2)n-CO-, -(CH2)n- N-, -(CH2)n-O-, -(CH2)n-S-, -(CH2O)-, -(OCH2)-, -(SCH2)-, -(CH2S-), -(aryl-O)-, -(O-aryl)-, -(alkyl- O)-, -(O-alkyl)-; n is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, orlO;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, NH2, NHR, NR2, SO2-OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1. Preferred compounds of the present invention include compounds of formula (I) wherein
X is S, SO or SO2; Spacer is -(CH2)n- or -(CH2)nCO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C,_10 alkyl; R3 and R4 are independently hydrogen, halogen or R1.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C,.5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0- 10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; NH2; NHR; NR2; straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Cj_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Cι_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; the R group may be further substituted by alkyl, alkyl-COOH, alkyl-COOalkyl, or alkyl-COOaryl; R1 and R2 are independently C 5 alkyl; R3 and R4 are independently H. Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H. Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently CJ.J alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, -(CH2)m-OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, or nitro- substituted furanyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C 5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl- COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C^ alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-CO-; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Cj.5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is isoxazolyl or furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Q.s alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is isoxazolyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C]_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C^ alkyl; R3 and R4 are independently H. Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C 5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)π-; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-CO-; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Cι-5 alkyl; R3 and R4 are independently H. Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, and aryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C 5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl or two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently Cι_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH; or COOR; R is alkyl; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-CO-; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR; R is alkyl; R1 and R2 are independently C 5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H. Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is -(CH2)n-CO-; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C,_5 alkyl; R3 and R4 are independently H.
Examples of the present invention include compounds of formula (I) defined as follows:
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y= - carboxymethylphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Sρacer=-CH2-; Y=4-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)2-; Y=4-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y= 2-carboxyethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3,5-di-t-butyl-4- carboxypropanoyloxy;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-carboxyphenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R =H; Spacer=-CH2-; Y=l-acetyloxy-l- methylethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3-nitroρhenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2,4-dinitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- trifluoromethylpheny 1 ; X=S; R'=t-butyl; R2=t-butyl; R =H; R4=H; Spacer=-CH2-; Y=2-carboxyfuranyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R =H; Spacer=-CH2-; Y=4-(N,N- dimethyl)sulfonamidophenyl;
X=SO; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl; X=SO2; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl; X=S; R]=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-acetyloxyphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-methylphenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Sρacer=-CH2-; Y=4-fluorophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=ethylsulfonic acid; X=S; R'=t-butyl; R2=t-butyl; R3=H; R =H; Spacer=-CH2-; Y=2- dimethylaminomethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)3-; Y=dimethylamino; X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2) ; Y=acetyloxy;
X=S; R!=t-butyl; R2=t-butyl; R3-H; R4=H; Spacer=-CH2-; Y=4-(2- hydroxy)ethylphenyl.
In another embodiment of the invention, there is provided a compound of formula (II) and a method for treating a disease mediated by the expression of VCAM-1 comprising administering an effective amount of a compound of formula (II):
Figure imgf000026_0001
wherein
Ra, Rb, R,., and Rj are independently hydrogen, straight chained, branched (for example, tert-butyl), or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R^ R,,, Rj. and R^ groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH^-Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, wherein (a) when each of Ra, Rb, R^., and Rj are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, R,., and Rj are t-butyl, Z cannot be the residue of succinic acid;
Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof; or, in an alternative embodiment, Re, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, - PO3H2 -PO3M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)- spacer- [O(C,_3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, -[O(C,_3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl.
Substitutents on the groups defined above are selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino, alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH2, CONHR, CONR2, haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH2-OR, CH2-OH, OCOR, O-ρhosphate, SO2-NH2, SO2-NHR, SO2-NR2. A preferred embodiment of the present invention includes compounds of formula (II) wherein R^, Rb, R,., and R^ are independently hydrogen or straight chained, branched, or cyclic .,0 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH2)- Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, and pharmaceutically acceptable salts thereof. Another preferred embodiment of the present invention includes compounds of formula (II) wherein Ra, Rb, R„ and Rj are independently hydrogen or straight chained, branched, or cyclic C,_5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH2)-Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, and pharmaceutically acceptable salts thereof. Another preferred embodiment of the present invention includes compounds of formula (II) wherein R^, b, Rc, and Rj are independently hydrogen or straight chained, branched, or cyclic C,_5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, -CH2-aryl substituted alkynyl, a carbohydrate group, -CH2-NR2, -CH2-alkoxy, -CH2-CHOH, -CH2-substituted aryl, -CH2- alkyl, -CH2-substituted alkyl, -CH2.-OCO-alkyl, -CH2-OCO-substituted alkyl, -CH2-COOR, - CH2-CH(OH)CH2NHCH2COOR, -CH2-CH(OH)-substituted oxiranyl (wherein the substituent is selected from the group consisting of hydrogen, CH2OH, CH2OCHOH-oxiranyl), -CO-aryl, -CO-substituted aryl, -CO-heteroaryl, -CO-substituted heteroaryl, -CO-(CH2)n-COOR, -CO- (CH2)n-OH, -CO-(CH2)n-O-phosphate, -CO-(CH2)n-CO-NR2, -CO-(CH2)n-aryl, -CO-(CH2)n- substituted aryl, -CO-(CH2)n-heteroaryl, -CO-(CH2)n-substituted heteroaryl, -CO-(CH2)n- CONH(CH2)COOR, -CO-(CH2)n-CON((CH2)COOR)2, monosaccharides, and cyclic monosaccharides, and pharmaceutically acceptable salts thereof.
Another preferred embodiment of the present invention includes compounds of formula (II) wherein R^ Rb, R<., and Rj are independently hydrogen or straight chained, branched, or cyclic C 5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, hydroxy alkyl, polyhydroxy alkyl, alkenyl, hydroxy alkenyl, acyl-substituted alkenyl, alkoxy alkyl, nitrophenylalkyl, aminophenylalkyl, alkylaminophenylalkyl, dialkylaminophenylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, acyloxyalkyl, oxiranyl- substituted hydroxyalkyl, hydroxyalkyl-substituted oxiranylmethylene, oxiranyl-substituted hydroxyalkoxyalkyl oxiranylmethylene, oxiranylmethylene, carboxyalkylaminohydroxyalkyl, alkoxyhydroxyalkyl, glucopyranosyl, galactopyranosyl, N,N-diacylalkylaminohydroxyalkyl, carboxyalkylaminopolyhydroxyalkyl, (amino)(carboxy)alkylaminohydroxyalkyl, acyloxyhydroxyalkyl, polyhydroxyalkylaminohydroxyalkyl, CO-carboxyalkyl, CO- nitrofuranyl, CO-hydroxyalkyl, CO-polyhydroxyalkyl, CO-amidoalkyl, CO-aminoalkyl, CO- alkylaminoalkyl, CO-dialkylaminoalkyl, CO-acylalkyl, CO-alkoxycarbonylalkyl, CO- tetrazolylalkyl, CO-(acyl)(amino)alkylamino, dialkoxycarbonylalkylamidoalkyl, CO- hydroxyphenyloxyphosphonoxyalkyl, or pharmaceutically acceptable salts thereof.
Examples of the present invention include compounds of formula (II) wherein:
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-nitrophenyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-(CH2)2-COOH;
Ra=t-butyl, Rb=t-butyl, JL -butyl, and Rd=t-butyl; Z=CO-(5-nitrofuran-2-yl);
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-carboxypropyl;
Ra=l-methylethyl, Rb=t-butyl, R^^methyl, and Rd=methyl; Z^-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-aminobutyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and
Figure imgf000029_0001
Z=3-hydroxypropanoyl;
R^-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=t-butylcarbonyloxymethyl;
Ra=t-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, R^H, and Rd=H; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and R^-butyl; Z=carboxymethyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-(CONH2)ethanoyl;
R^t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=CO-(2-carboxyethyl);
Ra=t-butyl, Rb=t-butyl, R<.=t-butyl, and R^-butyl; Z=CO-(2-methoxycarbonylethyl);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-aminomethyl; Ra=t-butyl, Rb= -butyl, R^-butyl, and R^t-butyl; Z=CO-3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=CO-ammonium methyl (chloride)
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-2-oxiranyl-ethyl; R^-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-hydroxymethyloxirany-2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-(2-hydroxy-2-oxiranyl)ethoxyoxiran-
2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and Rd=t-butyl; Z=oxiranylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3- carboxymethylaminopropyl;
Ra=t-butyl, Rb=t-butyl, R<.=t-butyl, and R^-butyl; Z=2,3,4-trihydroxybutyl; Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-ethoxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxypropyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=ethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-N,N-dimethylaminophenethyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and R^-butyl; Z=CO-2-carboxyethyl;
R^-butyl, R,.=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl (L-arginine ester);
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=3-methoxycarbonylpropyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=2-carboxyethenyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=galactopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-(N-N-diethylamino)propyl;
Ra-t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=carboxymethylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=l,3- dicarboxypropylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, R<.=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(l,3- diethoxycarbonyl)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxy-4- carboxymethylaminobutyl; Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(5-amino-5- carboxy)propylaminopropyl;
R^-butyl, Rb=t-butyl, R<.=t-butyl, and Rd=t-butyl; Z=4-ethylcarbonyloxybutyl;
R^-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-hydroxybutyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl; Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and Rd=t-butyl; Z=CO-3-tetrazolylρropyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-hydroxypropenyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and R^-butyl; Z=CH2CONH-(CH2)CH(NH2)COOH;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl;
Z=CH2CONHCH(COOet)CH2CH2(COOet); Ra=t-butyl, Rb= -butyl, R ^-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=2,3,4,5,6-pentahydroxyhexane; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3-(2- hydroxyphenyloxyphosphoxy)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2,2-dimethyl-3-hydroxyproρyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-acetoxypropyl; Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=2-acetoxy-3-hydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CH(OH)CH2NH(2,3,4,5,6- pentahydroxyhexane.
The compounds of formula (I) can be prepared by utilizing known procedures and techniques, or routine modifications thereof. A general synthetic scheme for preparing compounds of formula (I) is set forth in Scheme A, wherein all substituents, unless otherwise indicated, are previously defined.
Scheme A The synthesis of the starting thiol, 4-mercapto-2,6-di-t-butylphenol, is described in the literature (U. S. Patent No. 3,129,262 to Laufer, incorporated herein by reference in its entirety). The starting alkyl halides are commercially available or made from commercially available starting materials by methods known to one of ordinary skill in the art.
A quantity of the 4-mercapto-2,6-di-t-butylphenol 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 is added and the reaction mixture stirred at room temperature for 24 hours. The reaction is quenched with 1 N HCl to pH 7, diluted with water, extracted with ether and dried over magnesium sulfate. The product is purified by silica gel chromatography.
Starting materials for use in the general synthetic procedure outlined 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 (I), such as 2,6-di-tertiarybutyl-4- mercaptophenol, are described in U.S. Pat. No. 3,576,883, U.S. Pat. No. 3,952,064, U.S. Pat.
No. 3,479,407 and in Japanese Patent Application 73-28425.
In general, a phenol of structure (I) can be prepared by dissolving the appropriate 2,6- dialkyl-4-thiophenol (or suitably protected derivatives) in alcohol, preferably in ethanol, followed by addition of a halogenated aryl compound. The starting material, a 2,6-dialkyl-substituted thiophenol, may be protected by any of the many protecting groups known to one of ordinary skill in the art. Examples of suitable phenol protecting groups are ethers, such as methoxymethyl, 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.
The following examples present typical syntheses as described in Scheme A. These examples are understood 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; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "mp" refers to melting point; "mg" refers to milligrams; "μM" refers to micromolar; "μg" refers to micrograms.
Example 1
2,6-di-tert-butyl-4-thio(4'(methyl)phenylacetic acid))phenoI Reaction Description:
2,6-di-t-butyl-4-thiophenol (238 mg, 1 mmol) was dissolved in ethanol (0.7 mL) and cooled to 0° C. 5 N NaOH (0.6 mL, 3 mmol) was added followed by addition of 4- (bromomethyl)phenyl acetic acid (229 mg, 1 mmol). The reaction was warmed to room temperature and after 0.5 h the reaction was complete. The reaction was quenched with 1 N HCl (3.5 mL) and diluted with ether (25 mL). The ether layer was separated and washed with water (1 x 5 mL) and brine (1 x 5 mL), dried over MgSO4, filtered and concentrated. Chromatography over silica gel and eluting with 50:50 ether/hexane provided 170 mg of (2,6- di-tert-butyl-4-thio(4'(methyl)phenylacetic acid))phenol). Η NMR (CDC13, 400 MHZ): δ 7.24 (s, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 7.11 (d, / = 8.4 Hz, 2 H), 5.20 (s, 1 H), 3.91 (s, 2 H), 3.59 (s, 2 H), 1.33 (s, 18 H). Example 2 2,6-di-tert-butyl-4-thio(4'-nitrobenzyl)phenol Reaction Description:
A solution of 0.28 mmol (68 mg) of 2,6-di-tert-butyl-4-thiophenol in 0.5 mL of EtOH (denatured) was stirred and treated with 0.3 mmol (0.06 mL) of NaOH (5 N in de-ionized water) at 0°C. After stirring for 5 min., 0.29 mmol (62 mg) of 4-nitrobenzyl bromide was added to give an orange solution. The progress of the reaction was monitored by TLC (1 : 1 hexanes- hexanes-CH2Cl2; visualized by UV and PMA/char). The bromide was consumed over a 2 h period. The mixture was then quenched with sat. NaCl-EtOAc. The aqueous layer was back-extracted with 2 x 2 mL of EtOAc; the combined organic layers were dried over anhydrous MgSO4. The drying agent was removed by filtration; solvent was removed by rotary evaporation to give a crude oil. The oil was purified by preparative thin-layer chromatography (pTLC) using 2 x 500μ plates and 1 : 1 hexanes- CH2C12 as eluant. The desired product (2,6-di-tert-butyl-4-thio(4'-nitrobenzyl)phenol) was obtained in 86% yield (90 mg). 'H MR CCDCls, 400 MHZ): δ 8.10 (d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H), 7.04 (s, 2 H), 5.28 (s, 1 H), 3.98 (s, 2 H), 1.34 ( H).
Example 3 2,6-di-tert-butyl-4-thio(4'-nitrophenethyl)phenol Reaction Description:
0.48 mmol (115 mg) of 2,6-di-tert-butyl-4-thiophenol was taken up and stirred in 2 mL of dry THF. The mixture was treated with 0.67 mmol (27 mg) of sodium hydride (60% suspension in mineral oil) to give a clear, dark yellow solution. 4-Nitrophenethyl iodide (0.49 mmol; 135 mg) was added to give a dark brown mixture which was stirred overnight. The progress of the reaction was monitored by TLC (3 x 10 : 1 hexanes-CH2Cl2; visualized by UV and PMA/char), and the reaction was quenched (with sat. NaCl-EtOAc) when only traces of the starting iodide remained. The aqueous layer was back-extracted with 2 x 5 mL of EtOAc; the combined organic layers were dried over anhydrous MgSO4. Filtration to remove the drying agent followed by solvent removal by rotary evaporation gave a dark brown oil. Purification of the crude material using radial chromatography (10 : 1 hexanes- CH2C12; 4 mm plate) gave 93 mg (50% yield) of 2,6-di-tert-butyl-4-thio(4'-nitrophenethyl)phenol. !H NMR (CDCI3, 400 MHZ): δ 8.15 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.24 (s, 2 H), 5.26 (s, 1 H), 3.11 (t, J = 7.2 Hz, 2 H), 3.09 (t, J = 7.6 Hz, 2 H), 1.43 (s, 18 H).
Example 4
2,6-di-tert-butyl-4-thio(3'-nitrobenzyl)phenoI Reaction Description:
3-Nitrobenzyl chloride (0.42 mmol; 72 mg) and 2,6-di-tert-butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mL of EtOH and treated with 92 μL of NaOH (5 N solution). The reaction mixture was stirred for 19.5 h then quenched with sat. NaCl and extracted with EtOAc. The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The organic portions were collected, dried over Na2SO4, and concentrated in to a yellow oil. The crude material was placed under vacuum for 2 h. Purification was performed via radial chromatography using 2 mm (SiO2) plates and 4 : 1 hexanes-EtOAc. 2,6-di-tert- butyl-4-thio(3'-nitrobenzyl)phenol was obtained as a yellow oil (108 mg; 69% yield). 8.07 (app d, J = 7.6 Hz, 1 H), 7.87 (s, 1 H), 7.48 (AB d, J = 7.6 Hz, 1 H), 7.42 (AB m, J = 7.6, 8.0 Hz, 1 H), 7.05 (s, 2 H), 5.27 (s, 1 H), 3.99 (s, 2 H), 1.34 (s, 18 H).
Example 5
2,6-di-tert-butyl-4-thio(2' ,4'-dinitrobenzyl)phenol Reaction Description:
2,4-dinitrobenzyl chloride (0.42 mmol; 91 mg) and 2,6-di-tert-butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mL of EtOH and treated with 92 μL of NaOH (5 N solution). The reaction mixture was stirred for 19.5 h then quenched with sat. NaCl and extracted with EtOAc (25 mL). The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The organic layers were collected, dried over Na2SO4, and concentrated to a brown oil. Purification of the oil via radial chromatography using 2 mm plate (SiO2) and 4 : 1 hexanes-EtOAc as eluant gave 2,6-di-tert-butyl-4-thio(2',4'-dinitrobenzyl)phenol as a yellow oil (37 mg; 21% yield). 'H NMR (CDC13, 400 MHZ): δ 8.74 (app d, J = 2.4 Hz, 1 H), 8.24 (dd, J = 8.8, 2.4 Hz, 1 H), 7.29 (d, J = 8.8 Hz, 1 H), 6.98 (s, 2 H), 5.35 (s, 1 H), 4.36 (s, 2 H), 1.34 (s, 18 H).
Example 6
(2,6-di-tert-butyl-4-thio(4'-(trifluoromethyl)benzyl)phenol Reaction Description:
4-(Trifluoromethyl)benzyl bromide (0.42 mmol; 100 mg) and 2,6-di-tert- butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mL of EtOH and treated with 92 μL of NaOH (5 N solution). The reaction mixture turned brown within 30 min. , and precipitation was observed. The mixture was stirred for 22 h then quenched with sat. NaCl and EtOAc. The aqueous layers were back-extracted with 2 x 10 mL of EtOAc. The combined organic layers were dried over Na2SO4 then concentrated to give a brownish orange solid. Purification of the solid via radial chromatography using 4 mm plate (SiO2) and 4 : 1 hexanes-EtOAc as eluant gave (2,6-di-tert-butyl-4-thio(4'- (trifluoromethyl)benzyl)phenol as a yellow solid (140 mg; 84% yield). 'H NMR (CDC13, 400 MHZ): δ 7.48 (AB d, J- 8.0 Hz, 2 H), 7.20 (AB d, J= 8.0 Hz, 2 H), 7.01 (s, 2 H), 5.24 (s, 1 H), 3.93 (s, 2 H), 1.33 (s, 18 H).
Example 7 2,6-di-tert-butyl-4-thio((2'-furancarboxyIic acid)-5-methyI)phenoI Reaction Description:
2,6-di-tert-butyl-4-thiophenol (0.49 mmol; 116 mg) was dissolved in dry THF (2 mL), stirred, and treated with sodium hydride (0.58 mmol; 23 mg; 60% dispersion in mineral oil). The resulting yellow solution was treated with methyl 5-(chloromethyl)-2-furoate (0.54 mmol; 95 mg). The brown mixture was stirred for 22 h then quenched with brine. Extraction with EtOAc (3 x 3 mL), combination of the organic layers and drying over MgSO4 then solvent removal by rotary evaporation gave a crude oil. The crude product was eluted on 2 x 500μ preparative thin-layer chromatography plates (SiO2; 1 : 1 hexanes-CH2Cl2 as eluant) to give the expected intermediate (132 mg; 72% yield). The intermediate (0.35 mmol; 132 mg) was taken up in 4 : 1 : 1 MeOH-THF-H2O (3 mL), stirred, and treated with LiOH monohydrate (1.2 mmol; 50 mg). The mixture was stirred at room temperature for 18 h then solvent was removed to give 2,6-di-tert-butyl-4-thio((2'-furancarboxylic acid)-5- methyl)phenol (94 mg; 74% yield) as a tan solid. Η NMR (CDC13, 400 MHZ): δ 7.21 (d, J = 3.2 Hz, 1 H), 7.19 (s, 2 H), 6.17 (d, / = 3.2 Hz, 1 H), 5.30 (br s, 1 H), 4.00 (s, 2 H), 1.40 (s, 18 H). Example 8
2,6-di-tert-butyl-4-thio(4,-methyl-N,N-dimethylbenzenesuIfonamide)phenol
Reaction Description:
2,6 di-t-butyl-4-thiophenol (180 mg, 0.755 mmol) was dissolved in ethanol (1.5 mL) and then treated with 5 N NaOH (0.15 mL, 0.75 mmol). After 5 min, 4-(N,N- dimethylsulfonamide)benzyl bromide (210 mg, 0.755) in ethanol (1.5 mL) was added to the reaction. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with IN HCl to pH 7, diluted with water (3 mL), extracted with ether (10 mL), separated and dried over MgSO4. The crude reaction mixture was purified by column chromatography over silica gel and eluting with 30:70 ether/hexane followed by 40:60 ether/hexane. The appropriate fractions were collected to give 160 mg of the desired product. 'H NMR (CDC13, 400 MHz): δ 7.67 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.08 (s, 2 H), 5.27 (s, 1 H), 2.69 (s, 6 H), 1.36 (s, 18 H).
Example 9
2,6-di-tert-butyl-4-sulfinyl(4'-nitrobenzyl)phenoI Reaction Description:
2,6-di-tert-butyl-4-thio(3'-nitrobenzyl)phenol (157 mg, 0.42 mmol) was taken up in methylene chloride (4.2 mL) and mCPBA was added. After 15 min the reaction was diluted with ether (15 mL) and washed with saturated aqueous sodium bicarbonate (2X5 mL), followed by water (1X5 mL) and brine (1X5 mL). The ether layer was dried over MgSO4, filtered, and concentrated. The resulting oil was chromatographed by radial silica gel chrolmatography eluting with a concentration gradient of 30:70 ether/hexane to 80:20 ether/hexane. The appropriate fractions were collected (Rf=0.2, 80:20 ether/hexane) and concentrated to give 50 mg of 2,6-di-tert-butyl-4-thio(3'-nitrobenzyl)phenol sulfoxide. 'H NMR (CDC13, 400 MHz): δ 8.11 (d, J = 8.8 Hz, 2 H), 7.07 (br s, 4 H), 5.57 (br s, 1 H), 4.13 (d, J = 12.4 Hz, 2 H), 4.01 (d, J = 12.4 Hz, 2 H), 1.36 (s, 18 H). Example 10 2,6-di-tert-butyl-4-(sulfonyl-(4'-nitrobenzyl))phenol Reaction Description: 2,6-di-tert-butyl-4-thio(3'-nitrobenzyl)phenol (157 mg, 0.42 mmol) was taken up in methylene chloride (4.2 mL) and mCPBA was added. After 15 minutes, the reaction was diluted with ether (15 mL) and washed with saturated aqueous sodium bicarbonate (2 X 5 mL), followed by water (1 X 5 mL) and brine (1 X 5 mL). The ether layer was dried over MgSO4, filtered, and concentrated. The resulting oil was chromatographed by radial silica gel chromatography eluting with a concentration gradient of 30:70 ether/hexane to 80:20 ether/hexane. The appropriate fractions were collected (Rf=0.5, 80:20 ether/hexane) and concentrated to give 72 mg of product. 8.16 (d, J=8.4 Hz, 2 H), 7.38 (s, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 5,84 (s, 1 H), 4.35 (s, 18 H).
Example 11 2,6-di-tert-butyl-4-thio(4'-acetoxybenzyI)phenol Reaction Description:
A solution of 2,6-di-tert-butylthiophenol (0.46 mmol; 110 mg) in dry DMF (4.2 mL) was treated with sodium hydride (0.63 mmol; 25 mg; 60% dispersion in mineral oil) and allowed to stir at room temperature for 15 min. The orange mixture was treated with 4-(chloromethyl)phenyl acetate (0.42 mmol; 77 mg) resulting in a rust-brown color. The mixture was stirred for 6.5 h then diluted with EtOAc (20 mL) and washed with de-ionized H2O (25 mL). The organic layer was washed with sat. NaCl then concentrated to give a crude oil. Purification by column chromatography (SiO2) using 4 : 1 hexanes-EtOAc gave 2,6-di-tert-butyl-4-thio(4'-acetoxybenzyl)phenol as an oil (38 mg; 21% yield). Η NMR (CDC13, 400 MHz): δ 7.17 (AB d, J = 8.8 Hz, 2 H), 7.10 (s, 2 H), 6.97 (AB d, J = 8.8 Hz, 2 H), 5.23 (s, 1 H), 3.94 (s, 2 H), 2.29 (s, 3 H), 1.37 (s, 18 H).
Example 12 2,6-di-tert-butyl-4-thio(4'-methylbenzyl)phenol Reaction Description: A solution of 0.64 mmol (153 mg) of 2,6-di-tert-butylthiophenol in 1.6 mL of dry THF was stirred and treated with 0.85 mmol (34 mg) of sodium hydride (60% suspension in mineral oil) to give a dark orange-brown mixture. 4-Methylbenzyl bromide (0.66 mmol; 122 mg) was added. The mixture was stirred overnight. The progress of the reaction was monitored by TLC (hexanes; visualization by UV and PMA/char). After approx. 24 h, the appearance of product was detected by TLC (PMA staining gave a blue-black spot). The reaction was quenched using sat. NaCl-EtOAc. The aqueous layer was back-extracted with 2 x 5 mL of EtOAc; the combined organic layers were dried over anhydrous MgSO4 then filtered to remove the drying agent. Removal of solvent by rotary evaporation gave a crude oil that was eluted twice on 2 x 500μ preparative TLC (SiO2) plates using hexanes. The product (2,6-di-tert-butyl-4-thio(4'-methylbenzyl)phenol) was isolated as a yellow solid in 32% yield (70 mg). 'H NMR (CDC13, 400 MHz): δ 7.10 (s, 2 H), 7.07 (s, 4 H), 5.22 (s, 1 H), 3.94 (s, 2 H), 2.33 (s, 3 H), 1.38 (s, 18 H).
Example 13
2,6-di-tert-butyl-4-thio(4'-fluorobenzyl)phenol Reaction Description:
A solution of 2,6-di-tert-butylthiophenol (0.46 mmol; 110 mg) in 0.7 mL of EtOH was treated with 92 μL of NaOH (5 N solution). The brown mixture was then treated with 4-fluorobenzyl bromide (0.42 mmol; 52 μL) then stirred for 24 h. The mixture was quenched with sat. NaCl and extracted with EtOAc (20 mL). The aqueous layer was back extracted with 2 x 10 mL of EtOAc. The combined organic layers were dried over Na2SO4 then concentrated to give the crude product. Purification by MPLC (SiO2) using a solvent gradient of 100% hexanes to 19 : 1 hexanes-EtOAc gave 119 mg of product that was contaminated with starting thiol. Further purification via preparative thin-layer chromatography (pTLC) using 2 x 500μ SiO2 plates and 19 : 1 hexanes-EtOAc as eluant gave 2,6-di-tert-butyl-4-thio(4'-fluorobenzyl)phenol (34 mg; 34% yield). 'H NMR (CDC13, 400 MHz): δ 7.09 (AB t, J= 8.8 Hz, 2 H), 7.07 (s, 2 H), 6.92 (AB t, J= 8.8 Hz, 2 H), 5.23 (s, 1 H), 3.91 (s, 2 H), 1.36 (s, 18 H). Example 14 2,6-di-tert-butyl-4-thio(3'-propanesulfonic acid)phenol Reaction Description:
2,6-di-tert-butylthiophenol (0.84 mmol; 200 mg) and 3-bromopropanesulfonic acid (0.92 mmol; 207 mg) were taken up in EtOH and treated with 0.18 mL of NaOH (5 N solution). The reaction was allowed to stir for 90 h then quenched with 1 mL of 0.3 N HCl and extracted with 10 mL of EtOAc. The organic layer was dried over MgSO4, concentrated on SiO2 (rotary evaporation), and purified via MPLC using the following solvent gradient: 100% CH2C12 followed by 4 : 1 CH2Cl2-MeOH (100 mL) followed by 4 : 1 CH2Cl2-MeOH containing 0.4 mL AcOH. 2,6-di-tert-butyl-4-thio(3'-propanesulfonic acid)phenol was obtained as an off-white solid (126 mg; 42% yield). 'H NMR ((CD3)2SO, 400 MHz): δ 7.06 (s, 2 H), 2.88 (app t, J = 7.2, 7.6 Hz, 2 H), 2.52-2.48 (m, 2 H), 1.88 (s, 2 H), 1.80 (pent, J = 7.2, 7.6 Hz, 2 H), 1.35 (s, 18 H). LRMS: Neg. Ion ES 359 (M-H).
Example 15
2,6-di-tert-butyl-4-thio(5'-methyl-2'-((dimethyIamino)methyl)furan)phenoI Reaction Description:
A solution of 2,6-di-tert-butyl-4-thiophenol disulfide (0.24 mmol; 112 mg) and 2- ((dimethylamino)methyl)-5-(hydroxymethyl)furan (0.13 mmol; 25 mg) in 2.4 mL of dry THF was treated with 0.13 mmol (32 mg) of tributylphosphine. The reaction was stirred for over 60 h then solvent was removed by rotary evaporation to give a light yellow oil. The crude oil was purified by radial chromatography (2 mm SiO2 plate; 95 : 5 CH2Cl2-MeOH as eluant) to give 7.3 mg (7.5% yield) of the title compound as a light yellow amorphous solid. 'H NMR (CDC13, 400 MHz): δ 7.17 (s, 2 H), 6.22 (d, J = 3.2 Hz, 1 H), 5.97 (d, J = 3.2 Hz, 1 H), 5.22 (br s H), 3.95 (s, 2 H), 3.72 (s, 2 H), 2.37 (s, 6 H), 1.40 (s, 18 H).
Example 16
2,6-di-tert-butyl-4-thio(3'-(dimethylamino)propyl))phenol Reaction Description: A solution of 0.5 mmol (119 mg) of 2,6-di-tert-butylthiophenol in 1.5 mL of dry DMF was stirred and treated with 0.55 mmol (22 mg) of sodium hydride (60% dispersion in mineral oil). 3-(Dimethylamino)propyl chloride hydrochloride (0.5 mmol; 79 mg) was added, and the brown mixture was stirred for 2 days. TLC (1 : 1 hexanes-CH2Cl2; visualization by UV and PMA/char) showed mostly starting materials. The mixture was treated with 0.5 mmol NaOH (5 N solution) then stirred overnight. TLC analysis showed the appearance of a new UV-active material (low Rf; streaks). The reaction was quenched with sat. NaCl-EtOAc. The aqueous layer was back-extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4. Drying agent was removed by filtration. Solvent removal by rotary evaporation gave a brown oil. Purification by preparative thin-layer chromatography (pTLC) using 2 x 500μ plates (SiO2) and EtOH as eluant provided 2,6-di-tert-butyl-4-thio(3'-(dimethylamino)propyl))phenol as a pale yellow solid (61 mg; 37% yield) Η NMR (CDC13, 400 MHz): δ 7.24 (s, 2 H), 5.20 (s, 1 H), 2.85 (t, J = 7.6, 7.2 Hz, 2 H), 2.37 (t, J = 7.6, 7.2 Hz, 2 H), 2.20 (s, 6 H), 1.77 (q, J = 7.6, 7.0 Hz, 2 H), 1.42 (s, 18 H).
Example 17
2,6-di-tert-butyl-4-thio((l'-(acetoxy))pentyl)phenol Reaction Description:
2,6-di-tert-butyl-4-thiophenol (0.84 mmol; 200 mg) was dissolved in 7.6 mL of DMF and treated with 1.1 mmol (46 mg) of NaH (60% dispersion in mineral oil) to give an orange mixture. After 15 min. , 0.76 mmol (0.12 mL) of 5-chloropentyl acetate was added. The mixture was stirred for 25 h then diluted with 20 mL of EtOAc and washed with H2O (25 mL). The organic layer was washed with brine then concentrated by rotary evaporation. The crude material was purified by radial chromatography (2 mm SiO2 plate; 85 : 15 hexanes-EtOAc as eluant) to give 2,6-di-tert-butyl-4-thio((r- (acetoxy))pentyl)phenol (93 mg; 30% yield) as a light yellow, amorphous solid. 'H NMR (CDC13, 400 MHz): δ 7.23 (s, 2 H), 5.20 (s, 1 H), 4.05 (app t, J = 6.4, 7.2 Hz, 2 H), 2.83 (app t, J = 6.8, 7.2 Hz, 2 H), 2.04 (s, 3 H), 1.66-1.58 (br m, 4 H), 1.50-1.42 (br m, 2 H), 1.43 (s, 18 H).
Example 18
2,6-di-tert-butyl-l-methoxy-4-thio(4'-trifluoromethyI)benzyI)benzene Reaction Description:
(2,6-di-tert-butyl-4-thio(4'-(trifluoromethyl)benzyl)phenol (60 mg, 0.15 mmol) was taken up in dimethylformamide (0.75 mL), 60% sodium hydride in mineral oil (9 mg, 0.225 mmol) was added followed by methyl iodide (0.014 mL, 0.225 mmol). After 0.5 h the reaction was quenched with 1 N HCl (1 mL) and diluted with ether (10 mL). The ether layer was washed with water (1X3 mL) and brine (1X3 mL), dried over MgSO4, filtered, and concentrated. The resulting oil was purified by radial silica gel chromatography eluting with hexane followed by 1:99 ether/hexane to give 20 mg of the product. ]H NMR (CDC13, 400 MHz): δ 7.48 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.01 (s, 2 H), 3.93 (s, 2 H), 3.60 (s, 3 H), 1.33 (s, 18 H).
Example 19
2,6-di-tert-butyl-4-thio(4'-(methyl)phenylethyl alcohol))phenoI Reaction Description: The compound of Example 1 (300 mg, 0.86 mmol) was dissolved in THF (17.2 mL) and cooled to -78° C. Borane-dimethyl sulfide (2M in THF, 1.72 mL, 1.72 mmol) was added and stirred overnight under nitrogen while cooling bath was allowed to warm to room temperature. The reaction was cooled to 0° C, and concentrated HCl was added (0.5 mL) and stirred overnight. The solvents in the reaction mixture were removed in vaccuo and the residue dissolved in ethyl acetate (25 mL), washed with brine (IX 5 mL), IN
NaOH (IX 5 mL), and brine (IX 5 mL). The ethyl acetate layer was dried over MgSO4, filtered, concentrated and chromatographed over silica gel with 40:60 ether/hexanes to yield 198 mg of product. Η NMR (CDC13, 400 MHz): δ 7.12 (s, 4 H), 7.09 (s, 2 H), 5.21 (s, 1 H), 3.94 (s, 2 H), 3.84 (br s, 2 H), 2.84 (t, J = 6.8 Hz, 2 H), 1.36 (s, 18 H). The compounds of formula (II) wherein Z forms an ether group can be prepared by known procedures and techniques, or routine modifications thereof. A general synthetic scheme for preparing compounds of formula (II) wherein Z forms an ether group is set forth in Scheme B, wherein all substituents, unless otherwise indicated, are previously defined. Scheme B
A quantity of probucol (commercially available from Sigma Chemicals) in a 0.1 M solution of tetrahydrofuran is treated with 2 equivalents of sodium hydride and stirred at room temperature for 30 minutes. To the reaction mixture is added 3 equivalents of a primary alkyl bromide or iodide and the reaction stirred at room temperature for 16 hours. The reaction is quenched with 1 N aqueous HCl and diluted with ethyl acetate. The aqueous layer is removed and the ehtyl acetate layer is washed with water and then with an aqueous saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate, gravity or vacuum filtered, and then concentrated. The product is purified by silica gel chromatography. An alternative method for the preparation of compounds of formula (II) wherein Z forms an ether group is the treatment of probucol with a primary alcohol according to the method of Mitsunobu {Synthesis, 1981, 1).
A second alternative method for the preparation of compounds of formula (II) wherein Z forms an ether group is the treatment of probucol with a primary alkyl bromide or iodide in acetonitrile in the presence of potassium fluoride absorbed on alumina according to the method of Ando et al. {Bull. Chem. Soc. Jpn., 55, 1982, 2504-2507).
The compounds of formula (II) wherein Z forms an ester group can be prepared by utilizing procedures and techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing compounds of formula (II) wherein Z forms an ester group is set forth in Scheme C, wherein all substituents, unless otherwise indicated, are previously defined.
Scheme C A quantity of probucol in a 0.1 M solution of tetrahydrofuran is treated with 2 equivalents of sodium hydride and stirred at room temperature for 30 minutes. To the reaction mixture is added 3 equivalents of an acid chloride or acid anhydride and the reaction stirred at room temperature for 16 hours. The reaction is quenched with 1 N aqueous HCl and diluted with ethyl acetate. The aqueous layer is removed and the ethyl acetate layer is washed with water and then with an aqueous saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate, gravity or vacuum filtered, and then concentrated. The product is purified by silica gel chromatography. Starting materials for use in the general synthetic procedures outlined in the above reaction schemes are readily available or can readily be prepared according to standard techniques and procedures. Probucol is readily available from Sigma Chemicals.
The following examples present typical syntheses as described in Schemes B and 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 20
pentanedioic acid, 4-[[l-[[3,5-bis(l,l-dimethylethyI)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-,6-bis(l,l-dimethylethyl)phenyl methyl ester
Reaction Description:
Probucol (2.8 g, 5.5 mmol) was taken up in THF (25 mL), 60% sodium hydride in mineral oil (528 mg, 13.2 mmol) was added followed by the addition of methyl chloroformyl butyrate (0.751 mL, 6.6 mmol). After 2 h the reaction was quenched with methanol (3 mL), followed by water (10 mL). The reaction mixture was extracted with ether (50 mL), concentrated and chromatographed on silica gel eluting with a concentration gradient of 0: 100 ether/hexanes to 20:80 ether /hexanes. The reaction yielded 500 mg of the product. 7.63 (s, 2 H), 7.45 (s, 2 H), 5.82 (s, 1 H), 3.71 (s, 3 H), 2.73 (t, J = 7.6 Hz, 2 H), 2.50 (t, J = 7.2 Hz, 2 H), 2.07 (pent, J = 7.6 Hz, 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.34 (s, 18 H).
Example 21
Phenol, 4-[[l-[3,5-bis(l,l-dimethylethyl)4-[(4- nitrophenyl)methoxy]phenyl]thio]-l-methyIethyl]thio]2,6-bis(l,l- dimethylethyl)-
Reaction Description: A solution of probucol (0.19 mmol; 100 mg) in dry DMF (1 mL) was stirred and treated with sodium hydride (0.28 mmol; 11 mg; 60% dispersion in mineral oil) followed by 4-nitrobenzyl iodide (0.24 mmol; 63 mg). The mixture was stirred for 18 h during which it turned yellow-green. The mixture was quenched with brine then extracted with 3 x 2 mL of Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation to give a brown oil. Purification by radial chromatography (2 mm plate; 1:1 hexanes-CH2Cl2 as eluant) gave the product as a yellow solid (53 mg; 43 % yield). 'H NMR (CDC13, 400 MHz): δ 8.06 (d, J = 7.6 Hz, 2 H), 7.35 (s, 2 H), 7.14 (d, J = 7.2 Hz, 2 H), 6.79 (s, 2 H), 5.41 (s, 1 H), 3.13 (s, 2 H), 1.45-1.43 (overlapping s, 21 H), 1.14 (s, 21 H).
Example 22
Butanedioic acid, mono [4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]2,6-bis(l,l-dimethylethyl)phenyl]ester
Reaction Description:
To a 50 mL recovery flask was added probucol (l.Og, 1.93 mmol) and tetrahydrofuran (16 mL). To the solution was added 60% sodium hydride in mineral oil (0.23g, 5.75 mmol). To the cloudy white mixture was added succinic anhydride (0.58g, 5.8 mmol) in THF(12 mL). The reaction dark purple and was stirred at room temperature for 3 h. The dark purple reaction mixture was made acidic with IN HCl (25 mL) and extracted twice with ethyl acetate (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated affording an orange solid. The orange solid was dissolved in ether and chromatographed on silica gel with a concentration gradient of 70:30 hexane/ether to 0: 100 hexane/ether. The appropriate fractions were combined and concentrated affording a white solid. (170 mgm 0.276 mmol, 14%). TLC (silica gel, 60:40 ether/hexane + 10 drops HOAc, R = 0.35); 'H NMR (CDC13, 400 MHz): δ 7.61 (s, 2 H), 7.43 (s, 2 H), 5.38 (s, 1 H), 2.97 (t, J = 6.8 Hz, 2 H), 2.76 (t, J = 6.8 Hz, 2 H), 1.45 (s, 8 H), 1.42 (s, 16 H), 1.32 (s, 18 H). Example 23
2-FurancarboxyIic acid, 5-nitro-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
Reaction Description:
A solution of 0.39 mmol (200 mg) of probucol in dry THF (3.9 mL) was treated with sodium hydride (0.58 mmol; 23 mg; 60% dispersion in mineral oil) and stirred for 10 min. at room temperature. The clear mixture turned purple upon the addition of 4-nitrofuroyl chloride (0.77 mmol; 136 mg). The mixture was stirred for 47 h during which it turned brown, and precipitation was observed. The reaction mixture was diluted with Et2O (40 mL), washed with H2O (15 mL) then dried over Na2SO4 and concentrated by rotary evaporation to give a crude, yellow-orange solid. Purification by radial chromatography (2 mm SiO2 plate; 1 : 1 hexanes-CH2Cl2 as eluant) gave 4,4'-(isopropylidenedithio)[O-(5"-nitro-2"-furoyl)-2',6'-di-tert- butylphenol]-[2,6-di-tert-butylphenol] (83 mg; 33% yield). Η NMR (CDC13, 400
MHz): δ 7.70 (s, 2 H), 7.50 (d, J = 4.0 Hz, 1 H), 7.45 (d, J = 3.6 Hz, 1 H), 7.45 (s, 2 H), 5.39 (s, 1 H), 1.50 (s, 6 H), 1.45 (s, 14 H), 1.35 (s, 22 H).
Example 24
Butanoic acid, 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]2,6-dimethylphenoxy]-
Reaction Description: 4,4 ' -(isopropylidenedithio) [2 ' ,6 ' -di-methylphenol] [2,6-di-tert-butylphenol]
(0.55 mmol; 0.24 g) was dissolved in dry DMF (5.5 mL). Sodium hydride (1.38 mmol; 33 mg) was added to the mixture followed by methyl 4-iodobutyrate (0.83 mmol; 188 mg). The resulting mixture was stirred at room temperature for 4.5 h during which it turned green. The reaction was quenched with 0.3 N HCl (ca. 6 mL) causing the mixture to turn yellow. Dilution with Et2O (25 mL) was followed by washing with H2O (10 mL) and brine (10 mL). The solution was dried over MgSO4 then concentrated by rotary evaporation. Purification by MPLC ((SiO2; solvent gradient: 100% hexanes then 95 : 5 hexanes-Et2O then 90 : 10 hexanes-Et2O then 80 : 20 hexanes-Et2O) gave the desired intermediate as a yellow oil (197 mg; 67% yield). The oil (.35 mmol; 187 mg) was taken up in 4 : 1 : 1 MeOH-THF- H2O (3.5 mL). LiOH monohydrate (1.05 mmol; 44 mg) was added, and the mixture was stirred for 1.75 h at room temperature. The reaction mixture was then acidified with 0.1 N HCl to pH 4. Extraction with 3 x 15 mL of EtOAc then drying the combined extracts over MgSO4 and concentration by rotary evaporation gave the crude product. Purification by MPLC (SiO2; solvent gradient: 100% hexanes to 60 : 40 Et2O-hexanes (acidified with trace of acetic acid)) gave 4,4'- (isopropylidenedithio) [O-(γ-butyric acid)-2 ' , 6 ' -di-methylphenol] [2 , 6-di-tert- butylphenol] as a yellow foam (100 mg; 55% yield). 'H NMR (CDC13, 400 MHz): δ 7.44 (s, 2 H), 7.25 (s, 2 H), 5.38 (s, 1 H), 3.83 (app t, J = 6.0 Hz, 2 H), 2.68 (app t, J = 8.0 Hz, 2 H), 2.25 (s, 6 H), 2.14 (m, 2 H), 1.47 (s, 6 H), 1.45 (s, 18 H).
Example 25
Phenol, 4-[[l-[[4-(4-aminobutoxy)-3,5-bis(l,l-dimethylethyl)phenyl]thio]- l-methylethyl]thio]2,6-bis(l , 1-dimethylethyl)-
Reaction Description:
4,4' -(isopropy lidenedithio) [2 ' , 6 ' -di-methylphenol] [2 , 6-di-tert-buty lphenol] (1.44 mmol; 622 mg) was dissolved in dry DMF (14.4 mL) and treated with sodium hydride (3.6 mmol; 144 mg). Tetrabutylammonium iodide (0.72 mmol; 266 mg) was added followed by (N-bromobutyl)phthalimide (2.2 mmol; 608 mg). The mixture was stirred at room temperature for 17 h during which it turned dark green. The mixture was quenched with 0.3 N HCl (6 mL) then diluted with Et2O (100 mL). Washing was done with H2O (50 mL) and brine (50 mL). The aqueous layer was treated with NaCl then back-extracted with Et2O. The combined organic layers were dried over MgSO4 then concentrated by rotary evaporation.
Purification by MPLC (SiO2; solvent gradient: 100% hexanes to 75 : 25 hexanes- Et2O) gave the desired intermediate as a yellow-brown oil (750 mg; 82% yield). The intermediate (0.89 mmol; 563 mg) was dissolved in dry DMF (8.9 mL) and treated with hydrazine hydrate ((27 mmol; 0.83 mL). The mixture was stirred at room temperature for 42 h. The reaction mixture was treated with 1 N HCl (8.9 mL) and stirred for 1.5 h; NaHCO3 was added to adjust to pH 7 then extracted with EtOAc (2 x 15 mL) and dried over MgSO4. Solvent removal by rotary evaporation followed by purification by MPLC (SiO2; solvent gradient: 50 : 50 MeOH-CH2Cl2 to 49.5: 49.5 : 1 MeOH-CH2Cl2-NH4OH) gave 4,4'-(isopropylidenedithio)[O- (aminobutyl)-2',6'-di-methylphenol][2,6-di-tert-butylphenol] (93 mg; 21% yield). 'H NMR (CDC13, 400 MHz): δ 7.42 (s, 2 H), 7.22 (s, 2 H), 5.55 (s, 1 H), 3.76 (app t, J = 6.8 Hz, 2 H), 2.78 (app t, J = 6.8 Hz, 2 H), 2.24 (s, 6 H), 1.83 (m, 2 H), 1.66 (m, 2 H), 1.45 (s, 6 H), 1.42 (s, 18 H).
Example 26
Phenol, 4-[[l-[[4-(4-aminobutoxy)-3,5-bis(l,l-dimethylethyl)phenyl]thio]-l- methylethyl]thio]2,6-bis(l,l-dimethylethyl)-
Reaction Description:
Probucol (9.7 mmol; 5 g) was dissolved in dry DMF (14.5 mL) and treated with (N-bromobutyl)phthalimide (13.6 mmol; 3.82 g) and KF on alumina (48.4 mmol; 7.03 g). The reaction mixture was stirred at room temperature for 18 h then at 80 °C for 4 h. The mixture was filtered through a fritted funnel, and the residue was washed with H2O (10 mL) and Et2O (10 mL). The filtrate was diluted with Et2O (200 mL) then washed with H2O (50 mL and brine (50 mL). The combined organic layers were dried over MgSO4 and concentrated by rotary evaporation. Purification by MPLC (SiO2; solvent gradient: 100% hexanes to 80 : 20 hexanes-Et2O) gave the desired intermediate as a brown foam (346 mg; 5% yield). The intermediate (0.44 mmol; 314 mg) was taken up in DMF (4.4 mL) and treated with hydrazine hydrate (13 mmol; 0.41 mL) to give a green color. The mixture was stirred at room temperature for 16 h then treated with 1 N HCl (4.7 mL) and stiπed for another 1.5 h. NaHCO3 was added to adjust the mixture to pH 7. Extraction with 2 x 30 mL of EtOAc followed by washing the organic extracts with brine (20 mL), drying over MgSO4, and solvent removal by rotary evaporation gave a green liquid. Purification by MPLC (SiO2; solvent gradient: 100% CH2C12 to 90 : 10 CH2Cl2-MeOH) gave 4,4'- (isopropylidenedithio)[O-(aminobutyl)-2',6'-di-tert-butylphenol][2,6-di-tert- butylphenol] as a yellow solid ( 182 mg; 71 % yield). !H NMR (CDC13 , 400 MHz) : δ 7.52 (s, 2 H), 7.44 (s, 2 H), 5.28 (s, 1 H), 5.25 (br s, 2 H), 3.72-3.69 (m, 2 H), 2.92-2.88 (m, 2 H), 1.94-1.90 (m, 2 H), 1.73-1.69 (m, 2 H), 1.43 (s, 22 H), 1.40 (s, 20 H).
Example 27
Butanoic acid, 4-hydorxy-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
Reaction Description: To a solution of the compound of example 22 (6.17 g, 10 mmol) in THF (200 ml) cooled to -78 °C was slowly added borane-methyl sulfide (10 ml, 2 M solution in THF). The resultant mixture was stiπed overnight under nitrogen while the cooling bath was allowed to warm to room temperature. Then it was cooled to 0°C, hydrogen chloride (37%, 4 ml) was added and the mixture was stiπed at room temperature overnight. The mixture was evaporated to a residue and distributed between ethyl acetate (100 ml) and brine (100 ml). The organic phase was washed with 1 N sodium hydroxide solution (100 ml) and then brine (100 ml), dried over magnesium sulfate and evaporated. Silica gel chromatography (dichloromethane) gave the title compound as a viscous residue. Crystalyzation from hexanes/dichloromethane gave white crystals (5.5 g). MP: 138-139°C. 'H-NMR (400 MHz, CDC13): 7.63 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H), 3.76 (t, 2 H), 2.79 (t, 2 H), 2.01 (m, 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.34 (s, 18 H).
Example 28 Propanoic acid, 2,2-dimethyl-, [4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenoxy]methyl ester To a suspension of probucol (5.17 g, 10 mmol) in acetonitrile (30 ml) were added chloromethyl pivalate (6.0 g, 40 mmol) and potassium fluoride (8.0 g, 40% on alumina). The resultant mixture was stirred under nitrogen at reflux for 18 hours. After cooled to room temperature it was filtered and rinsed with dichloromethane (100 ml). The filtrate was washed with brine (100 ml), dried over magnesium sulfate and evaporated. Silica gel chromatography (hexanes/dichloromethane 4: 1) gave the title compound as a yellow oil (0.39 g). 'H- NMR (400 MHz, CDC13): 7.59 (s, 2 H), 7.45 (s, 2 H), 5.49 (s, 2 H), 5.38 (s, 1H), 1.464 (s, 6 H), 1.457 (s, 18 H), 1.445 (s, 18 H), 1.28 (s, 9 H).
Example 29
Phenol, 4-[[l-[[4-(4-aminobutoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)-
Reaction Description:
A solution of : 4,4'-(isopropylidenedithio)[phenol][2,6-di-tert-butylphenol] (0.18 mmol; 75 mg) in 2 mL of dry DMF was stirred and treated with 0.23 mmol (9 mg ) of sodium hydride (60% dispersion in mineral oil) to give a yellow mixture. N-(4-bromobutyl)phthalimide (0.22 mmol; 63 mg) was added followed by 0.22 mmol (33 mg) of NaT The mixture was heated to 120 °C, turning a dark green color. After 24 h, TLC (SiO2; CH2C12 as eluant; visualization by UV, PMA/char) showed only traces of starting material present. The reaction mixture was cooled to room temperature then quenched with 3 mL each of Et2O and sat. NaCl. The aqueous layer was back-extracted with 3 mL of Et2O; the combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation to give a dark brown oil. Purification by column chromatography (SiO2; 20 x 170 mm column; CH2C12 as eluant) gave the desired intermediate in 69% yield (69 mg). The intermediate (0.11 mmol; 69 mg) was taken up in 1 mL of DMF and stirred. Hydrazine hydrate (0.16 mmol; 8 μL) was added, causing a color change from yellow to deep blue-green. The reaction mixture was stirred at room temperature for 1 week by which time it had turned a clear yellow. TLC showed the presence of starting material. Additional hydrazine hydrate (10.3 mmol; 0.5 mL) was added; the mixture was stirred for another 24 h, after which starting material was completely consumed. The mixture was quenched with 12 N HCl to adjust the pH to 3. After stirring for 5 min., sat. NaHCO3 was added to neutralize the acid (final pH = 7). EtOAC was added, and the aqueous layer was back-extracted with 2 x 2 mL of EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography (SiO2; 15 x 110 mm column; EtOH as eluant) to give 4,4'- (isopropylidenedithio)[O-(aminobutyl)phenol][2,6-di-tert-butylphenol] (25 mg; 48% yield) as a yellow solid. Η NMR (CDC13, 400 MHz): δ 7.50 (d, J = 8.4 Hz, 2 H), 7.42 (s, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.36 (br s, 1 H), 3.97 (br m, 2 H), 3.10 (br m, 2 H), 2.01-1.86 (overlapping m, 4 H), 1.43 (s, 24 H).
Example 30
Butanoic acid, 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]phenoxy]-
Reaction Description:
A solution of : 4,4'-(isopropylidenedithio)[phenol][2,6-di-tert-butylphenol] (0.6 mmol; 242 mg) in 6 mL of dry DMF was stiπed and treated with 1.3 mmol (53 mg) of sodium hydride (60% dispersion in mineral oil) to give a brown solution. The reaction mixture was treated with 0.9 mmol (131 μL) of methyl 4-iodobutyrate. The progress of the reaction was monitored by TLC using CH2C12 as eluant (visualization by UV, PMA/char). After 24 h, TLC of the dark green mixture showed predominantly product. The mixture was quenched with sat. NaCl and Et2O. The aqueous layer was back-extracted with 2 x 6 mL of Et2O; the combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation to give a crude oil. Column chromatography (SiO2; 20 x 185 mm column) using CH2C12 gave 232 mg (77% yield) of the desired intermediate which was taken up and stiπed in 3 mL of 4 : 1 : 1 MeOH-THF-H2O. The pale yellow solution was treated with 0.92 mmol (39 mg) of LiOH monohydrate to give a greenish-yellow solution. The mixture was stirred at room temperature until all starting material was consumed (ca. 18 h) then treated with 12 N HCl to adjust the pH to 2 (yellow mixture). Et2O (5 mL) was added; the aqueous layer was back-extracted with 2 x 5 mL of Et2O. The combined organic layers were dried over MgSO4, filtered then concentrated by rotary evaporation to give a crude solid. Purification by column chromatography (SiO2; 15 x 180 mm column; 3 : 1 hexanes-EtOH as eluant) gave 4,4'-(isopropylidenedithio)[O- (γ-butyric acid)phenol][2,6-di-tert-butylphenol] as an oil (62 mg; 40% yield). Η NMR (CDC13, 400 MHz): δ 7.47 (d, J = 8.0 Hz, 2 H), 7.40 (s, 2 H), 6.80 (d, J = 7.6 Hz, 2 H), 5.35 (s, 1 H), 3.93 (br m, 2 H), 2.51 (br m, 2 H), 2.07 (br m, 2 H), 1.42 (s, 18 H), 1.25 (s, 6 H).
Example 31
Acetic acid, [4- [ [1 - [ [3,5-bis(l ,l-dimethylethyl)-4-hydroxyphenyl] thio]-l - methylethyl]thio]2,6-bis(l,l-dimethylethyl)phenoxy]-
Reaction Description:
To dimethylformamide (1.5 mL) was added probucol(0.5g, 0.967 mmol) and ethyl-2- iodo acetate (0.3 lg, 1.45 mmol) and 40% potassium fluoride on alumina (0.7 g) and the reaction was stiπed for 24 hours. The reaction mixture was diluted with ether (25 mL), filtered and washed with water (2X5 mL). The ether layer was dried over MgSO , filtered and concentrated. The resulting oil was purified by radial silica gel chromatography by elution with 5:95 ether/hexanes to yield 160 mg of the ethyl ester of the product. The ethyl ester dissolved in THF:H20:MeOH(4: 1 :1)(4 mL) and LiOH-H20 (50 mg) was added and the reaction stiπed for 1 h. The reaction was neutralized with IN HCl and extracted wtih ether (2X10 mL), dried over MgSO4, filtered, and concentrated. Silica gel chromatography and elution with 50:50 ether/hexanes gave 90 mg of the product. »H NMR (CDC13, 400 MHz): δ 7.55 (s, 2 H), 7.40 (s, 2 H), 5.35 (s, 1 H), 4.40 (s, 2 H), 1.43 (s, 6 H), 1.41 (s, 9 H), 1.39 (s, 9 H).
Example 32
Glycine, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
Reaction Description: To a solution of probucol (3.0g, 5.8 mmol) in THF (58 mL) was added 60% sodium hydride (1.16 g, 29.0 mmol) and the reaction stirred for 0.5 h at room temperature. The acid chloride of phthaloyl glycine was added and the reaction stirred an additional 0.5 h. The reaction was then diluted with ethyl acetate (150 mL), quenched with water (5 mL), then washed with water (2X50 mL) and brine (1x50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The resulting oil was chromatographed on silica gel eluting with 10% ethyl acetate/hexane followed by 20% ethyl acetate/hexane to yield 610 mg of the phthaloyl glycine ester. The phthaloyl glycine ester was taken up in DMF(8.6 mL) and hydrazine hydrate was added (0.136 mL, 2.34 mmol) and the reaction stirred overnight. IN HCl was added (5 mL) and the reaction stirred an additional 1 h. The reaction was diluted with ethyl acetate (25 mL) and washed with NaHCO3 (aq) (1X10 mL). The ethyl acetate layer was dried over MgSO4, filtered, concentrated, and chromatographed on silica gel, eluting with 1 % methanol/methylene chloride followed by 1.5% methanol/methylene chloride to yield 334 mg of product. 7.64 (s, 2 H), 7.45 (s, 2 H), 5.39 (br s, 1 H), 3.76 (s, 2 H), 1.48 (s, 6 H), 1.44 (s, 18 H), 1.33 (s, 18 H).
Example 33
Pentanedioic acid, mono[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenyl] ester
Reaction Description:
To a 50 mL recovery flask was added probucol(1.0g, 1.93 mmol) and tetrahydrofuran (20 mL). To the solution was added 60% sodium hydride in mineral oil (0.16g, 4 mmol). To the cloudy white mixture was added glutaric anhydride (0.170g, 3 mmol) in THF(12 mL). The reaction was stirred at room temperature for 3 h. The reaction mixture was made acidic with IN HCl (25 mL) and extracted twice with ethyl acetate (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated affording a yellow oil. The yellow oil was dissolved in ether and chromatographed on silica gel with a concentration gradient of 70:30 hexane/ether to 0: 100 hexane/ether. The appropriate fractions were combined and concentrated affording a white solid. 7.62 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H), 2.75 (t, / = 7.2 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 2 H), 2.09 (m, 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.43 ( H).
Example 34
Butanoic acid, 4-[4-[[l-[[3,5-bis(l,l-dimethylethyI)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-
Reaction Description:
Probucol (5g, 9.7 mmol) was stirred together with methyl 4-iodobutyrate (3.1g, 13.6 mmol) in DMF (15 mL). To the reaction mixture was added 40% potassium flouride on alumina (7g, 48 mmol) and stirring continued at room temperature overnight. The green reaction mixture was filtered into a separatory funnel, diluted with ethyl acetate (50 mL) and washed with water (2x20 mL) and saturated aqueous sodium chloride (1X20 mL). The ethyl acetate layer was dried over MgSO4, fileterd, concentrated and chromatographed on silia gel by elution with a concentration gradient of 10:90 methylene chloride/hexane to 60:40 methylene chloride hexane. The appropriate fractions were collected and concentrated to afford 442 mg of a white solid. The methyl ester was taken up in THF:MeOH:H20 (4:1:1)(5 mL) and lithium hydroxide (63 mg, 1.5 mmol) was added. After 2.5 h the reaction was complete and quenched with 1 N HCl (3 mL) and extracted with ethyl acetate (15 mL). The ethyl acetate solution was washed with saturated aqueous sodium chloride (3 mL), dried over MgSO4, filtered and concentrated. Chromatography over silica gel, eluting with a solvent gradient of 10:90 ether/hexanes to 50:50 ether/hexanes afforded 308 mg of product. 7.53 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H), 3.77 (t, J = 6.8 Hz, 2 H), 2.55 (t, J = 7.6 Hz, 2 H), 2.16 (m, 2 H), 1.44 (s, 24 H), 1.41 (s, 18 H).
Example 35
Oxiranemethanol, α-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]methyl]-;
Oxiranemethanol, 3-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]methyl]-; Oxiranemethanol, α-[[[3-[[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1- dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]- To a solution of probucol (5.16 g, 10 mmol) in acetonitrile (50 ml) were added 1,3-butadiene diepoxide (1.6 ml, 20 mmol) and potassium fluoride (2.9 g, 20 mmol, 40% on alumina). The resultant mixture was stirred under nitrogen at reflux for 18 hours. After cooled to room temperature it was poured into dichloromethane (150 ml), washed with water (2 x 100 ml), dried over magnesium and evaporated. Silica gel chromatography (hexanes/dichloromethane 2:1, 1: 1, 1:2 and then dichloromethane) gave Oxiranemethanol, -[[4-[[l-[[3,5-bis(l,l- dimethy lethyl)-4-hydroxyphenyl] thio] - 1 -methy lethy 1] thio] -2 , 6-bis ( 1 , 1 - dimethylethyl)phenoxy]methyl]- (0.47 g), Oxiranemethanol, 3-[[4-[[l-[[3,5-bis(l,l- dimethylethyl)-4-hydroxyphenyl]thio] - 1 -methy lethy 1] thio] -2 , 6-bis( 1,1- dimethy lethy l)phenoxy]methyl]- (0.15 g) and Oxiranemethanol, α-[[[3-[[4-[[l-[[3,5- bis(l , l-dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1- dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]- (0.05 g). Oxiranemethanol, α-[[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenoxy]methyl]- : Η-NMR (400 MHz, CDC13): 7.56 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H), 4.10-4.17 (m, 1 H), 3.83-3.97 (m, 2 H), 3.27-3.32 (m, 1 H), 2.83-2.94 (m, 2 H), 2.18 (br. s, 1 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.44 (s, 18 H).
Oxiranemethanol, 3-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]methyl]-: Η-NMR (400 MHz, CDCI3): 7.56 (s, 2 H), 7.45 (s, 2 H), 5.39 (s, 1 H), 4.38 (m, 2 H), 4.00 (m, 2 H), 3.89 (m, 2 H), 1.34-1.41 (m, 42 H). Oxiranemethanol, α-[[[3-[[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1- dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]-: Η-NMR (400 MHz, CDC13): 7.54 (s, 2 H), 7.45 (s, 2 H), 5.39 (s, 1 H), 4.24 (br. m, 1 H), 3.93 (m, 1 H), 3.81 (m, 1 H), 3.77 (br. m, 1 H), 3.16 (m, 1 H), 3.06 (m, 1 H), 2.91 (m, 1 H), 2.85 (m, 2 H), 2.84 (m, 1 H), 2.75 (m, 2 H), 1.41-1.44 (m, 42 H). Example 36
Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-(oxiranylmethoxy)phenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
To a solution of probucol (2,58 g, 5 mmol) in THF (50 ml) cooled to 0°C were added glycidol (0.66 ml, 10 mmol), triphenyl phosphine (2.62 g, 10 mmol), and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirred under nitrogen at reflux for 48 hours and then evaporated. Silica gel chromatography (hexanes/dichloromethane 4: 1, 2: 1) gave the title compound as a viscous residue (1.01 g). Η-NMR (400 MHz, CDC13): 7.56 (s, 2 H), 7.44 (s, 2 H), 5.39 (s, 1 H), 4.40 (m, 1 H), 3.75 (m, 1 H), 3.39 (m, 1 H), 2.91 (m, 1 H), 2.77 (m, 1 H), 1.40-1.49 (m, 42 H).
Example 37 Glycine, N-[3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]2-hydroxypropyl]-
To suspension of Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- (oxiranylmethoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1-dimethy lethy 1)- (0.17 g, 0.28 mmol) in ethanol (10 ml) were added glycine (43 mg, 0.57 mmol) and triethylamine (1 ml). The resultant mixture was stirred under nitrogen at reflux overnight. The mixture became a solution upon heating. It was then evaporated. Silica gel chromatography (dichloromethane/methanol 10: 1 to 1: 1) give the title compound (99 mg). Η-NMR (400 MHz, CDC13): 7.52 (s, 2 H), 7.43 (s, 2 H), 5.37 (s, 1 H), 4.58 (br. s, 1 H), 3.79 (br. m, 2 H), 3.67 (m, 1 H), 3.30 (m, 1 H), 3.21 (m, 1 H), 3.13 (m, 1 H), 1.43 (s, 18 H), 1.41 (s, 6 H), 1.38 (s, 18 H).
Example 38
1,2,3-Butanetriol, 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio] = l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-2- hydroxypropyl]-
To a solution of Oxiranemethanol, α-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1- dimethy lethy l)phenoxy] methyl]- (0.15 g) in actonitrile (5 ml) were added water (1 ml) and concetrated sulfuric acid (10 drops). The resultant mixture was stirred at room temperature for 48 hours and then poured into brine (50 ml), extracted with dichloromethane (3 x 50 ml), dried over magnesium sulfate and evaporated. Silica gel chromatography (dichloromethane/ethyl acetate 3: 1) gave the title compound as a colorless viscous residue (26 mg). Η-NMR (400 MHz, CDC13): 7.54 (s, 2 H),
7.43 (s, 2 H), 5.36 (s, 1 H), 4.27 (m, 2 H), 3. 98 (m, 2 H), 3.75 (m, 2 H), 1.36-
1.44 (m, 42 H).
Example 39
Phenol, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-(3-ethoxy-2- hydroxypropoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-;
1,2-Propanediol, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyI]thio]-l- methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenoxy]-
To a suspension of Oxiranemethanol, α-[[[3-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio] - 1 -methylethyl]thio]-2 , 6-bis( 1 , 1 - dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]- (0.32 g) in ethanol (10 ml) was added 1 N sodium hydroxide solution (1.5 ml). The resultant mixture was stirred at reflux for three days and then evaporated. The residue was distributed between ethyl acetate (50 ml) and brine (50 ml). The organic phase was washed with brine (50 ml), dried over magnesium sulfate and evaporated. Silica gel chromatography (hexanes/dichloromethane 1: 1, dichloromethane and then dichloromethane/ethyl acetate 4: 1) afforded 1,2-Propanediol, 3-[4-[[l-[[3,5-bis(l,l- dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethy lethy l)phenoxy]- (58 mg) and a mixture that contained the Phenol, 4-[[l- [[3,5-bis(l,l-dimethylethyl)-4-(3-ethoxy-2-hydroxypropoxy)phenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-, which was re-columned (hexanes/ethyl acetate 5: 1) and Phenol, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-(3- ethoxy-2-hydroxypropoxy)phenyl] thio] - 1 -methylethy 1] thio] -2 , 6-bis( 1 , 1 - dimethylethyl)- was obtained in pure form (52 mg). Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-(3-ethoxy-2- hydroxypropoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-:
'H-NMR (400 MHz, CDC13): 7.55 (s, 2 H), 7.45 (s, 2H), 5.38 (s, 1 H), 4.35 (m, 1 H),
4.11 (m, 1 H), 3.83 (m, 2 H), 3.62 (m, 1 H), 3.57 (m, 2 H), 1.43-1.46 (m, 42 H), 1.22 (t, 3 H).
1,2-Propanediol, 3-[4-[[l-[[3,5-bis(l, l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-: 'H-NMR (400 MHz, CDC13):
7.56 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H), 4.32 (m, 1 H), 3.94 (dd, 1 H), 3.85 (m, 1 H),
3.77 (m, 1 H), 3.66 (m, 1 H), 1.40-1.44 (m, 42 H).
Example 40
Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l , 1-dimethylethyl)-
2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-, ethyl ester, (E)-
2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-, ethyl ester, (E)-
To a solution of probucol (5.16 g, 10 mmol) in THF (50 ml) were added ethyl propiolate (1.2 ml, 12 mmol) and triethylamine (7 ml, 50 mmol). The resultant mixture was stirred under nitrogen at reflux over weekend. After cooled to room temperature it was poured into brine (100 ml), extracted with dichloromethame (3 x 100 ml), dried over magnesium sulfate and evaporated. Silica gel chromatography (hexanes/dichloromethane 9:1 to straight dichloromethane) gave Phenol, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-; (0.51 g), 2-Propenoic acid, 3-[4-[[l- [[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenoxy]-, ethyl ester, (£)-; (0.37 g) and 2-Propenoic acid, 3-[4-[[l- [[3 , 5-bis( 1 , 1 -dimethy lethy l)-4-hydroxyphenyl]thio]- 1 -methylethyl]thio]-2 , 6-bis( 1,1- dimethylethyl)phenoxy]-, ethyl ester, {E)~ (0.54 g). Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-: 'H-NMR (400 MHz, CDC13): 7.52 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H), 3.76 (quad., 2 H), 1.39-1.45 (m, 45 H). 2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-, ethyl ester, (E)-: !H- NMR (400 MHz, CDC13): 7.62 (s, 2 H), 7.44 (s, 2 H), 6.40 (d, 1 H), 5.38 (s, 1 H), 5.02 (d, 1 H), 4.23 (quad., 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.42 (s, 18 H), 1.30 (t, 3 H). 2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-ethoxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-, ethyl ester, (£)-: 'H- NMR (400 MHz, CDC13): 7.62 (s, 2 H), 7.51 (s, 2 H), 6.40 (d, 1 H), 5.03 (d, 1 H), 4.23 (quad., 2 H), 3.76 (quad., 2 H), 1.25-1.48 (m, 48 H).
Example 41
Butanedioic acid, mono[4-[[l-[[3,5-bis(l,l-dimethylethyI)-4- methoxyphenyl]thio]l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl] ester
Reaction Description:
The compound of Example 22 (1.13 g, 1.83 mmol) was taken up in DMF (3.6 mL) and 60% sodium hydride (183 mg, 4.6 mmol) was added followed 0.25 h later by methyl iodide (0.342 mL, 5.5 mmol). The reaction was allowed to stir overnight. The reaction was quenched with water (2 mL), diluted with ether (50 mL). The ether layer was washed with water (2X10 mL) and saturated aqueous sodium chloride (1X10 mL), dried over MgSO4,filtere, and concentrated. Column chromatography over silica gel and elution with a concentration gradient of 0: 100 ether/hexane to 40:60 ether/hexane gave 556 mg of dimethylated product. The product was taken up in THF:MeOH:H20 (4:1:1)(5 mL) and lithium hydroxide (63 mg, 1.5 mmol) was added. After 2.5 h the reaction was complete and quenched with 1 N HCl (3 mL) and extracted with ethyl acetate (15 mL). The ethyl acetate solution was washed with saturated aqueous sodium chloride (3 mL), dried over MgSO4, filtered and concentrated. Chromatography over silica gel, eluting with a solvent gradient of 10:90 ether/hexanes to 50:50 ether/hexanes afforded 400 mg of product. Η NMR (CDC13, 400 MHz): δ 7.62 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H), 3.71 (s, 3 H), 2.75 (t, J = 7.2 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 2 H), 2.09 (m, 2 H), 1.46 (s, 6 H), 1.44 (s, 18 H), 1.42 (s, 18 H).
Example 42
Phenol, 4-[[l-[[4-[2-[4-(dimethylamino)phenyl]ethoxy]-3,5-bis(l,l- dimethylethyl)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
Reaction Description:
Probucol (1.16 mmol; 600 mg) was dissolved in THF (11.6 mL) and treated with triphenylphosphine (2.3 mmol; 608 mg), diethyl azodicarboxylate (2.3 mmol; 0.37 mL), and 4-(dimethylamino)phenethyl alcohol (2.3 mmol; 383 mg). The brown mixture was stirred under reflux for 41.5 h. Solvent was removed by rotary evaporation to give a brown oil. Purification by chromatography gave 4,4'- (isopropylidenedithio) [O-(4 ' ' -(dimethylamino)phenethyl)-2 ' , 6 ' -di-tert- butylphenol][2,6-di-tert-butylphenol] as an oil (256 mg; 33% yield) 'H NMR (CDC13, 400 MHz): δ 7.52 (s, 2 H), 7.45 (s, 2 H), 7.12 (d, J = 8.4 Hz, 2 H), 6.74 (br d, J = 8.0 Hz, 2 H), 5.38 (s, 1 H), 3.84 (app t, J = 8.0, 8.8 Hz, 2 H), 3.09 (app t, J = 7.6, 8.8 Hz, 2 H), 2.93 (s, 6 H), 1.45-1.44 (overlapping s, 42 H).
Example 43
Benzenamine, 4,4'-[(l-methylethyIidene)bis[thio[2,6-bis(l,l-dimethylethyl)-4,l- phenylene] oxy-2,1 -ethanediyl]] bis [N,N-dimethyI-
Reaction Description:
Probucol (1.16 mmol; 600 mg) was dissolved in THF (11.6 mL) and treated with triphenylphosphine (2.3 mmol; 608 mg), diethyl azodicarboxylate (2.3 mmol; 0.37 mL), and 4-(dimethylamino)phenethyl alcohol (2.3 mmol; 383 mg). The brown mixture was stiπed under reflux for 41.5 h. Solvent was removed by rotary evaporation to give a brown oil. Purification by chromatography gave 4,4'- (isopropylidenedithio)bis[(4"-(dimethylamino)phenethyl)-2,6-di-tert-butylphenol] as a light pink solid (155 mg; 16% yield) ]H NMR (CDC13, 400 MHz): δ 7.50 (s, 4 H), 7.12 (d, J = 8.8 Hz, 4 H), 6.74 (br d, J = 8.0 Hz, 4 H), 3.84 (app t, J = 7.6, 8.8 Hz, 4 H), 3.09 (app t, J = 8.0, 8.8 Hz, 4 H), 2.93 (s, 12 H), 1.43-1.42 (overlapping s, 42 H).
Example 44
L- Arginine, mono[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl butanedioate]
Reaction Description:
To a solution of the compound of Example 22 (1.67 g, 2.7 mmol) in methanol (30 ml) was added L-arginine (0.47 g, 2.7 mmol). The resultant mixture was stiπed at room temperature for 2 hours and then filtered. The filtrate was evaporated and the residue was dissolved in minimum amount of ether. Then hexanes was added to precipitate out the title compound. It was filtered and dried on vacuum to afford a off-white solid (1.75 g). MP: 185-190°C. Η-NMR (400 MHz, CDC13): 7.60 (s, 2 H), 7.42 (s, 2 H), 5.37 (s, 1 H), 3.64 (br. s, 1 H), 3.11 (br. s, 2 H), 2.96 (br. s, 2 H), 2.58 (br. s, 2 H), 1.41-1.44 (m, 26 H), 1.23-1.31 (m, 20 H).
Example 45
2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenoxy]-, (E)-
To a solution of 2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1-dimethy lethy l)phenoxy]-, ethyl ester, (£)- (0.16 g, 0.26 mmol) in THF (5 ml) were added water (2 ml) and lithium hydroxide monohydrate (42 mg, 1 mmol). The resultant mixture was stirred at reflux overnight. After cooled to room temperature it was poured into dichloromethane (50 ml), washed with brine, dried over magnesium sulfate and evaporated. Silica gel chromatography (hexanes/ethyl acetate 4: 1) gave the title compound as a viscous residue (22 mg). 'H-NMR (400 MHz, CDC13): 7.63 (s, 2 H), 7.44 (s, 2 H), 6.52 (d, 1 H), 5.39 (s, 1 H), 5.08 (d, 1 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.42 (s, 18 H).
Example 46 α-D-Galactopyranose, 6-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyI]thio]-2,6-bis(l,l-dimethylethyI)phenyl]- 1 ,2 :3,4-bis-O-(l -methylethylidene)
To a solution of probucol (2.58 g, 5 mmol) and 1,2,3,4-di-O-isopropylidene- D-galactopyranose (1.8 ml, 10 mmol) in THF (100 ML) were added triphenylphosphine (2.62 g, 10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stiπed under nitrogen at reflux 72 hours. It was evaporated. Silica gel chromatography (cyclohexane/ethyl acetate 30:1) gave the title compound (0.16 g). 'H-NMR (400 MHz, CDC13): 7.53 (s, 2 H), 7.45 (s, 2 H), 5.60 (s, 1 H), 4.65 (m, 2 H),4.35 (m, 4 H), 1.59 (s, 6 H), 1.44 (s, 18 H), 1.43 (s, 18 H), 1.37 (s, 6 H), 1.33 (s, 6 H).
Example 47
Phenol, 4-[[l-[[4-[3-(dimethylamino)propoxy]-3,5-bis(l,l- dimethylethyl)phenyI]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
Reaction Description:
Probucol (0.5 g, 0.97 mmol) was dissolved in THF, cooled to 0° C, and 3- hydroxypropyldiethyl amine (0.287 mL, 1.94 mmol) was added followed by the addition of triphenylphosphine (0.508g, 1.94 mmol) and diethyl azodicarboxylate
(0.31 mL, 1.94 mmol). The reaction was heated to reflux and reflux continued for 30 h. The reaction mixture was concentrated and purified by silica gel chromatography eluting with 20:80 methanol/ether to give the product. 'H NMR (CDC13, 400 MHz): δ 7.52 (s, 2 H), 7.27 (s, 2 H), 3.74 (t, J = 1.6 Hz, 2 H), 2.56 (q, J = 7.2 Hz, 2 H), 2.03 (pent, / = 7.6 Hz, 2 H), 1.44 (q, J = 3.2 Hz, 4 H), 1.42 (s, 24 H), 1.25 (t, J = 3.3 Hz, 6 H).
Example 48 Glycine, N-[ [4- [ [1 - [ [3,5-bis(l ,1 -dimethylethyl)-4-hydroxyphenyl] thio]- l,methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]acetyl]-
Reaction Description: To Acetic acid, [4-[[l-3,5-bis(l,l-dimethylethyl)-4-hydrocyphenyl]thio]-l- methylethyl]thio]2,6-bis-(l,l-dimethylethylphenoxy)- (50 mg, 0.087 mmol) in methylene chloride (0.87 mL) was added glycine ethyl ester hydrochloride (15.8 mg, 0.11 mmol), l-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(22 mg, 0.11 mmol) and dimethylaminopyridine (28 mg, 0.23 mmol). The reaction mixture was stiπed overnight and the methylene chloride evaporated. The reaction was diluted with ether (10 mL) and washed with water (2X3 mL), dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane to give 50 mg of the ethyl ester of the product. The ethyl ester dissolved in THF:H20:MeOH (2:1:1)(1 mL) and LiOH-H20 (15 mg) was added and the reaction stiπed for 1 h. The reaction was neutralized with IN HCl and extracted wtih ether (2X10 mL), dried over MgSO4, filtered, and concentrated to give 25 mg of product. Η NMR (CDC13, 400 MHz): δ 7.56 (s, 2 H), 7.42 (s, 2 H), 5.39 (br s, 1 H), 4.31 (s, 2 H), 4.22 (d, J = 5.2 Hz, 2 H), 1.44 (s, 6 H), 1.42 (s, 9 H), 1.39 (s, 9 H).
Example 49
Glutamic acid, N-[[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyI]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]acetyl]-
Reaction Description:
To Acetic acid, [4-[[l-3,5-bis(l,l-dimethylethyl)-4-hydrocyphenyl]thio]-l- methylethyl]thio]2,6-bis-(l,l-dimethylethylphenoxy)- (100 mg, 0.174 mmol) in methylene chloride (1.8 mL) was added glutamic acid diethylester hydrochloride (54 mg, 0.22 mmol), l-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(44 mg, 0.22 mmol) and dimethylaminopyridine(55 mg, 0.45 mmol). The reaction mixture was stiπed overnight and the methylene chloride evaporated. The reaction was diluted with ether(10 mL) and washed with water(2X3 mL), dried over MgSO , filtered, and concentrated. The crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane to give 130 mg of the diethyl ester of the desired product. The diethyl ester was dissolved in THF:H20:MeOH(2:l:l)(3 mL) and LiOH-H20 (100 mg) was added and the reaction stiπed for 1 h. The reaction was neutralized with IN HCl and extracted wtih ether (2X10 mL), dried over MgSO4, filtered, and concentrated to give 45 mg of product. 'H NMR (CDC13, 400 MHz): δ 7.57 (s, 2 H), 7.42 (s, 2 H), 5.37 (s, 1 H), 4.83 (m, 1 H), 4.28 (s, 2 H), 2.56 (m, 2 H), 1.44 (s, 6 H), 1.43 (s, 9 H), 1.41 (s, 9 H).
Example 50
L-Glutamic acid, N-[3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]-2-hydroxypropyl]-di-, diethyl ester
Reaction Description:
To a suspension of Phenol, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- (oxiranylmethoxy)phenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1-dimethylethyl)- (0.12 g, 0.20 mmol) and L-glutamic acid diethyl ester hydrochloride (0.24 g, 1 mmol) in ethanol (15 ml) was added triethylamine (2 ml). The resultant mixture was stirred under nitrogen at reflux for 18 hours. It was evaporated. Silica gel chromatography (dichloromethane/methanol 5: 1) gave a yellow oil which was re-columned (dichloromethane/methanol 10: 1) to give the title compound as a white viscous residue (16 mg). Η-NMR (400 MHz, CDC13): 7.53 (s, 2 H), 7.42 (s, 2 H), 5.36 (s, 1 H), 4.90 (m, 1 H), 3.85 (m, 2 H), 3.55-3.75 (m, 7 H), 2.01 (m, 2 H), 1.39- 1.42 (m, 48 H), 1.23 (m, 2 H).
Example 51
2-Propenoic acid, 4-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenoxy]butyl ester
To a solution of probucol (2.58 g, 5 mmol) in THF (50 ML) were added 4- hydroxybutyl aery late (1.0 ml, 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirred under nitrogen at reflux over weekend. It was evaporated. Silica gel chromatography (hexanes/dichloromethane 4: 1) gave the title compound as a brown oil (0.92 g). 'H-NMR (400 MHz, CDC13): 7.54 (s, 2 H), 7.46 (s, 2 H), 6.42 (dd, 1
H), 6.14 (dd, 1 H), 5.84 (dd, 1 H), 5.38 (s, 1 H), 4.23 (t, 2 H), 3.75 (t, 2 H), 1.97
(m, 2 H), 1.82 (m, 2 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.42 (s, 18 H).
Example 52
Phenol, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-(4-hydroxybutoxy)phenyl]thio]-l- methylethyl]thio]-2,6-bis(l , 1-dimethylethyl)-
To a suspension of 2-Propenoic acid, 4-[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4- hydroxyphenyl] thio]- 1 -methylethyl]thio] -2 , 6-bis( 1 , 1 -dimethylethyl)phenoxy]butyl ester (0.82 g) in methanol (20 ml) was added poatssium carbonate (0.5 g). The resultant mixture was stirred under nitrogen at room temperature overnight. It was poured into water (50 ml), extracted with dichloromethane (2 x 50 ml), dried over magnesium fulfate and evaporated. Silica gel chromatography (hexanes/ethyl acetate 4:1) gave the title compound as a colorless oil (0.52 g). Η-NMR (400 MHz, CDC13): 7.54 (s, 2 H), 7.46 (s, 2 H), 3.71-3.77 (m, 4 H), 1.96 (m, 2H), 1.72 (m, 2 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.43 (s, 18 H).
Example 53 β-D-Glucopyranose, 6-O-[4-[[l-[[3,5-bis(l , l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl]-
To a solution of probucol (1.8 g, 3.5 mmol) in THF (20 ML) were added 1,2,3,4-tetra-O-actyl-β-D-glucopyranose (1.0 g, 2.9 mmol), triphenylphosphine
(0.92 g, 3.5 mmol) and diethyl azodicarboxylate (0.55 ml, 3.5 mmol). The resultant mixture was stirred under nitrogen at reflux for two hours. It was evaporated. Silica gel chromatography (hexanes/ethyl acetate 4: 1) gave the title compound as an off- white solid (0.92 g). Η-NMR (400 MHz, CDC13): 7.53 (s, 2 H), 7.45 (s, 2 H), 5.80 (d, 1 H), 5.38 (s, 1 H), 5.33 (dd, 1 H), 5.16 (dd, 1 H), 4.90 (dd, 1 H), 4.19 (m, 1 H), 3.88 (m, 1 H), 3.74 (m, 1 H), 2.14 (s, 3 H), 2.06 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 1.45 (s, 18 + 6 H), 1.38 (s, 18 H). Example 54
1-H-Tetrazole-l-butanoic acid, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
To a solution of Butanoic acid, 4-hydorxy-, 4-[[l-[[3,5-bis(l,l- dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenyl ester (60 mg, 0.1 mmol) in THF (10 ML) were added 1H- tetrazole 14 mg, 0.2 mmol), triphenylphosphine (52 mg, 0.2 mmol) and diethyl azodicarboxylate (0.03 ml, 0.2 mmol). The resultant mixture was stirred under nitrogen at reflux for 2 hours. It was evaporated. Silica gel chromatography
(hexanes/ethyl acetate 4: 1) gave the title compound as an oil (57 mg). Η-NMR (400 MHz, CDC13): 8.56 (s, 1 H), 7.64 (s, 2 H), 7.45 (s, 2 H), 5.39 (s, 1 H), 4.84 (t, 2 H), 2.74 (t, 2 H), 2.47 (m, 2 H), 1.47 (s, 6 H), 1.45 (s, 18 H), 1.33 (s, 18 H).
Example 55
Phenol, 4-[[l-[[3,5-bis(l , l-dimethylethyl)-4-[[3-hydroxy-l- propenyl)oxy]phenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)-
To a solution of 2-Propenoic acid, 3-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1-dimethy lethy l)phenoxy]-, ethyl ester, (£)- (65 mg, 0.1 mmol) in THF (15 ml) was added lithium aluminum hydride (1 ml, 1 M solution in THF). The resultant mixture was stirred under nitrogen at room temperature overnight. Saturated ammonium chloride solution (20 ml) was added and the mixture was stirred for 0.5 hour. It was extracted with dichloromethane (3 x 50 ml) and the organic phase was dried over magnesium sulfate and evaporated. Silica gel chromatography (hexanes/ethyl acetate 4: 1) gave the title compound as an oil (46 mg). Η-NMR (400 MHz, CDC13): 7.61 (s, 2 H), 7.45 (s, 2 H), 5.99 (d, 1 H), 5.39 (s, 1 H), 4.84 (m, 1 H), 4.46 (m, 2 H), 1.47 (s, 6 H), 1.45 (s, 18 H), 1.42 Example 56 ethyl)-4-hydroxyphenyl]thio]-l- L-Lysine, N6-[[4-[[l-[[3,5-bis(l,l-dimethyl methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenoxy]acetyl]-
Reaction Description:
To Acetic acid, [4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]2,6-bis(l,l-dimethylethyl)phenoxy]- (150 mg, 0.26 mmol) in methylene chloride (1.8 mL) was added lysine methyl ester hydrochloride (79 mg, 0.34 mmol), l-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(130 mg, 0.67 mmol) and dimethylaminopyridine(82 mg, 0.67 mmol). The reaction mixture was stirred overnight and the methylene chloride evaporated. The reaction was diluted with ether(10 mL) and washed with water (2X3 mL), dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel chromatography and elution with 50:50 ether/hexane followed by 70:30 ether/hexane to give 128 mg of the methyl ester of product. The methyl ester was dissolved in THF:H20:MeOH(2: l:l)(3 mL) and LiOH-H20 (50 mg) was added and the reaction stirred for 1 h. The reaction was concentrated and purified over silica gel eluting with 20:80 methanol/hexane to give 67 mg of product. 7.58 (s, 2 H), 7.44 (s, 2 H), 6.86 (m, 1 H), 5.39 (s, 1 H), 4.75 (m, 1 H), 4.29 (d, J = 7.2 Hz, 2 H), 3.44 (m, 2 H), 2.10 (m, 2 H), 1.95 (m, 2 H), 1.82 (m, 2 H), 1.46 (s, 6 H), 1.44 (s, 9 H), 1.42 (s, 9 H).
Example 57
D-Glucopyranose, 6-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]- l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl]-
To a suspension of β-D-Glucopyranose, 6-O-[4-[[l-[[3,5-bis(l,l- dimethylethyl)-4-hydroxyphenyl]thio]- 1 -methy lethy l]thio] -2 ,6-bis( 1,1- dimethy lethy l)phenyl]- (0.68 g) in methanol (50 ml) was added potassium carbonate (1 g) and the mixture was stirred under nitrogen at room temperature overnight. It was poured into water (200 ml), extracted with ethyl acetate (3 x 150 ml), washed with brine (100 ml), dried over magnesium and evaporated. Silica gel chromatography (dichloromethane/methanol 10:1 to 5:1) gave the title compound as an off-white solid (0.26 g). Η-NMR (400 MHz, CDC13): 7.52 (s, 2 H), 7.44 (s, 2
H), 5.36 (s, 1 H), 5.31 (s) and 4.78 (br. s, 1 H), 3.30-4.38 (br. m, 6 H), 1.38-1.43
(m, 42 H).
Example 58
D-Glucitol, 6-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l , l-dimethylethyl)phenyl]-
To a solution of D-Glucopyranose, 6-O-[4-[[l-[[3,5-bis(l,l-dimethylethyl)-
4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l , 1-dimethy lethy l)phenyl]- (70 mg) in THF (5 ml) was added sodium borohydride and the mixture was stirred under nitrogen at room temperature for 2 hours. Then saturated ammonium chloride (2 ml) was added and the mixture stirred for another hour. It was poured into water (50 ml) and extracted with dichloromethane (3 x 50 ml). The organic phase was dried over magnesium and evaporated. Silica gel chromatography (dichloromethane/methanol 100:12) gave the title compound as a white solid (19 mg). 'H-NMR (400 MHz, CDC13): 7.54 (s, 2 H), 7.44 (s, 2 H), 5.36 (s, 1 H), 4.35 (m 1 H), 3.30-4.10 (m, 7 H), 1.40-1.44 (m, 42 H).
Example 59
Butanoic acid, 4-[[hydroxy(2-hydroxyphenoxy)phosphinyl]oxy]-4-[[l-[[3,5- bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimeth lethy 1) phenyl ester
To a solution of Butanoic acid, 4-hydorxy-, 4-[[l-[[3,5-bis(l,l- dimethylethyl)-4-hydroxyphenyl]thio]- 1 -methylethyl]thio]-2,6-bis(l , 1 - dimethylethyl)phenyl ester (60 mg, 0.1 mmol) in pyridine (1 ml) was added 1,2- phenylene phosphorochloridate (21 mg, 0.11 mmol) and the mixture was stirred under nitrogen at room temperature for 1 hour. It was evaporated and the residue was dissolved in dichloromethane (10 ml). Water (1 ml) amd acetic acid (0.5 ml) were added and the mixture was stirred for 0.5 hour. It was poured into water (50 ml) and extracted with dichloromethane (2 x 50 ml). The organic phase was dried over magnesium and evaporated. Silica gel chromatography (dichloromethane/methanol 5: 1) gave the title compound as a white solid (21 m g). Η-NMR (400 MHz, CDC13): 7.58 (s, 2 H), 7.44 (s, 2 H), 7.15 (br. s, 1 H), 6.87 (br. s, 2 H), 6.71 (br. s, 1 H), 5.37 (s, 1 H), 3.97 (br. s, 2 H), 2.48 (br. s, 2 H), 1.83 (br. s, 2 H), 1.45 (s, 6 H), 1.43 (s, 18 H), 1.24 (s, 18 H).
Example 60
Butanoic acid, 4-hydroxy-3,3-dimethyl-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl ester
Reaction Description:
To a flask was added probucol (2.3g, 4.46 mmol) and tetrahydrofuran (23 mL). To the solution was added 60% sodium hydride in mineral oil (0.23g, 5.75 mmol). to the cloudy white mixture was added 2,2 dimethyl succinic anhydride (lg, 7.6 mmol). The reaction was stiπed at room temperature for 3 h. The dark purple reaction mixture was made acidic with IN HCl (25 mL) and extracted twice with ethyl acetate (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated. The crude product mixture was dissolved in ether and chromatographed on silica gel with a concentration gradient of 70:30 hexane/ether to 0:100 hexane/ether. The appropriate fractions were combined and concentrated affording 700 mg of a white solid. The white solid (214 mg, 0.332 mmol)) was taken up in THF (6 mL) and borane-dimethylsulfide (2M in THF, 0.665 mL, 0.664 mmol) was added and the reaction stiπed for 6 h. The reaction was qenched with concentrated HCl (0.100 mL) and the reaction stiπed overnight. The reaction was diluted with ether (25 mL), washed with water(lX 5mL), NaHCO3 (1X5 mL), and brine (1X5 mL). The ether layer was dried over MgSO , filtered, and concentrated. Radial silica gel chromatography and elution with a concentration gradient from 100:0 hexane/ether to 50:50 hexane/ether gave 85 mg of product. !H NMR (CDC13, 400 MHz): δ 7.64 (s, 2 H), 7.46 (s, 2 H), 5.39 (s, 1 H), 3.48 (d, J = 6.8 Hz, 2 H), 2.73 (s, 2 H), 1.47 (s, 6 H), 1.45 (s, 9 H), 1.35 (s, 9 H), 1.11 (s, 6 H). Example 61
Butanoic acid, 4-(suIfoxy)-, l-[4-[[3,5-bis(l,l-dimethylethyI)-4- hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl]ester
Reaction:
Butanoic acid, 4-hydorxy-, 4-[[l-[[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyljthio]- 1 -methylethyl]thio]-2,6-bis( 1 , 1 -dimethylethyl)phenyl ester (12.5 g, 20.75 mmol) was dissolved in DMF (150 ml) and sulfur trioxide trimethylamine complex (12.5 g, 87.5 mmol) was added. The mixture was stiπed at room temperature overnight. It was evaporated and the residue was dissolved in dichloromethane (100 ml), washed with water (2 x 50 ml). The aqueous phase was extracted with dichloromethane (75 ml). The combined organic phase was dried over magnesium sulfate and evaporated. Silica gel chromatography (dichloromethane/methanol 10:1, 5:1) gave a residue which was used for the next step of reaction.
The above product was dissolved in THF (200 ml). NaOH (0.8 g, 20 mmol) in water (5 ml) was added. The mixture was stiπed at room temperature for 2 h and then evaporated. 1 N NaOH solution (200 ml) was added to the residue and stiπed for 0.5 h. It was filtered and a yellowish solid was collected, which was dried to a constant weight (9.23 g).
The present invention also includes the use of compounds of the formulas (I) and (II) in inhibiting the peroxidation of LDL lipid and in inhibiting the progression of atherosclerosis in patients in need thereof.
As used herein, the term "patient" refers to warm-blooded animals or mammals, and in particular humans, who are in need of the therapy described herein.
The following examples illustrate the use of compounds of formula (I) according to the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way. Example 62 LIPID SCREEN & IC50 DETERMINATION PROTOCOL Preparation of HEPG2:
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, ImM Sodium Pyruvate and allowed to grow to about
50% confluency and then removed.
Day 1 Treatment:
The cells were treated with the desired concentration of compounds in 100 μl DMEM, 1%) RSA for 24 hours. The compounds are dissolved in DMSO. For IC50, the range of concentration is lOuM - 40uM, with each concentration being done in triples.
On the same day, 4X96-wells NuncImmunoSorb plate is coated with 100 μl of mouse anti-human ApoB monoclonal 1D1 (1:1000 dilution in IXPBS, pH 7.4). The coating is allowed overnight.
Day 2 ApoB ELISA:
The coated plate is washed 3 times with IXPBS, pH 7.4, -0.05% Tween 20.
100 μl of the standards is added to the selected wells. ApoB standards are prepared at
6.25, 3.12, 1.56, 0.78, 0.39 ng, and each concentration is done in triplicates. For samples:
90 μl of IXPBS, pH 7.4, -0.05% Tween 20 is added to each well coπesponding to the sample. 10 μl of media is transfeπed from the treated HEPG2 plates to the ApoB ELISA plate. The plate is incubated at room temperature for 2 hours, rocking gently. Wash the coated plate 3X with IXPBS, pH 7.4, -0.05% Tween 20. Add 100 μl of sheep anti-human ApoB polyclonal from Boehringer Mannheim. (1 :2000 dilution in
IXPBS, pH 7.4, -0.05% Tween 20) from Boehringer Mannheim. Incubate at room temperature for 1 hour, rocking gently. Wash the coated plate 3X with IXPBS, pH
7.4, -0.05% Tween 20. Add 100 μl of rabbit anti-sheep IgG (1 :2000 dilution in IXPBS, pH 7.4, -0.05% Tween 20). Incubate at room temperature for 1 hour, rocking gently. Wash the coated plate 3X with IXPBS, pH 7.4, -0.05% Tween 20. Add 100 μl of substrate (10 ml of distilled water, 100 μl of TMB (lOmg/ml), and 1 μl of hydrogen peroxide). Allow color to emerge and stop reaction with 25ul of 8N sulfuric acid. Wells are read with MicroPlate Reader @ 450nM. Graph accumulation of ApoB in media as a percentage of control for each sample and their concentration. A determination of IC50 is obtained from the graph.
Example 63 VCAM-1 Assay Splitting the cells: Two to four confluent PI 50 plates are trypsinized and the cells transfeπed to a
50 mL conical centrifuge tube. The cells are pelleted, resuspended, and counted using thetrypan blue exclusion method.
Cells are resuspended at a concentration of 36,000 cells/mL and 1 mL is aliquoted per well. Cells are split into 24 well tissue culture plates. The cells in each well should be approximately 90-95% confluent by the following day. Cells should not be older than passage 8. Preparation of compounds: Water soluble compounds Compounds are initially screened at 50 μM and 10 μM. A 50 mM stock solution for each compound is prepared in culture medium. The stock solution is diluted to 5 mM and 1 mM. When 10 μL of the 5 mM solution is added to the well (1 mL medium/well), the final concentration will be 50 μM. Adding 10 μL of the 1 mM solution to the well will give a final concentration of 10 μM. Water insoluble compounds
Compounds which will not go into solution in culture medium are resuspended in DMSO at a concentration of 25 mM. The stock solution is then diluted to the final concentration in culture medium. The old medium is aspirated and 1 mL of the new medium with the compound is added. For example, if the final concentration is 50 μM, the 2 μL of the 25 mM stock is added per mL of culture medium. The 50 mM solution is diluted for lower concentrations. Adding the compounds
The compounds are added to the plate (each compound is done in duplicate). One plate is done for VCAM expression and one plate is done for ICAM expression.
Immediately after the compounds are added, TNF is added to each well. 100 units/mL TNF is usually added to each well. Since each lot of TNF varies in the number of units, each new lot is titrated to determine the optimum concentration. Therefore this concentration will change. If 100 units/mL is bing used, dilute the TNF to 10 units/μL and add 10 μL to each well.
The plates are incubated at 37°C, 5% CO2 overnight (approximately 16 hours). The next day the plates are checked under the microscope to see if there are any visual signs of toxicity. Records are made of any cell death, debris, or morphology changes, as well as insoluble compounds (particulate or turbity).
Example 64 ELISA Assay
In order to assess MCP-1, the media (500 μL) is saved and frozenat -70°C. Wash cells once with roughly 1 ml/well of Hanks Balance Salt Solution (HBSS) or PBS. Gently empty the wash solution and then tap the plate onto paper towels. Add either 250 μL/well of HBSS +5% FCCS to the plank (no primary antibody wells) or 250 μL/well of primary antibody diluted in HBSS +5% FCS. Incubate for 30 minutes at 37°C. Wash the wells twice with .5 mL/well HBSS or PBS and gently tap the plates onto paper towels after the last wash. Add 250μL/well of HRP-conjugated second antibody diluted in HBSS +5% FCS to every well including the blank wells (no primary antibody). Incubate at 37°C for 30 minutes. Wash the wells four times with .5 mL/well HBSS or PBS and gently tap the plates onto paper towels after the last wash. Add 250 μL/well of substrate solution. Incubate at room temperature in the dark until there is adequate color development (blue). Note the length of time incubation was performed (typically 15-30 minutes). Add 75 μL/well stopper solution (8N sulfuric acid), and read A450 nm. Antibodies and solutions
1. Substrate solution is made immediately prior to use and contains: water 10 mL
30%) hydrogen peroxide 1 μL
TMB (3,3',5,5'-tetramethylbenzidine) 100 μL
TMB stock solution: To 10 mg TMB, add 1 mL acetone. Store at 4°C protected from light.
2. VCAM-1 Ab: stock .1 μg/μL final concentration 0.25 μg/mL
mix 25 μL stock VCAM-1 (Southern Biotechnology) and 10 mL HBSS + 5% FCS
3. ICAM-1 Ab: stock .1 μg/μL final concentration 0.25 μg/mL
mix 25 μL stock ICAM-1 (Southern Biotechnology) and 10 mL HBSS + 5% FCS
4. Secondary Ab: HRP-conjugated goat antimouse IgG diluted 1 :500
mix 20 μL stock (Southern Biotechnology) and 10 mL HBSS + 5%
FCS
The degree of inhibition of the compounds of formulas (I) and (II) was determined by the assays described in Examples 62-64. The results are provided in Table 1.
TABLE 1
Figure imgf000074_0001
Figure imgf000075_0001
2,6-dι-tert-butyl-4- 30% at 50 100 thιo(3'-
(dιmethylamιno)propyl)) phenol
2,6-dι-tert-butyl-4- 40% at 50 100 30 thιo((l '-
(acetoxy))pentyl)phenol
2,6-dι-tert-butyl-l- NE <10 methoxy-4-th_o(4'- trιfluoromethyl)benzyl) benzene
2,6-dι-tert-butyl-4- 15 50 53% at 15 thιo(4'-
(methyl)phenylethyl alcohol))phenol
Phenol, 4-[[l-[3,5- 30% at 50 >100 17% at 15 bιs( 1 , 1 -dιmethylethyl)4-
[(4- mtrophenyl)methoxy]ph enyl]thιo]-l- methylethyl]thιo]2,6- bιs( 1 , 1 -dimethylethyl)-
Butanedioic acid, mono 5 6 23 65% at 15
[4-[[l-[[3,5-bιs(l,l- dιmethylethyl)-4- hydroxyphenyl]thιo]- 1 - methylethyl]thιo]2,6- bιs(l,l- dιmethylethyl)phenyl] ester
2-Furancarboxylιc acid, 25 400 17% at 15
5-mtro-, 4-[[l-[[3,5- bιs( 1 , 1 -dimethylethyl)- 4-hydroxyphenyl]thιo]- 1 -methylethyl]thιo]-2,6- bιs(l,l- dιmethylethyl)phenyl ester
Butanoic acid, 4-[4-[[l- 75 41% at 15
[[3.5-bιs(l, l- dιmethylethyl)-4- hydroxyphenyl]thιo]- 1 - methylethyl]thιo]2,6- dimethy lphenoxy] -
Phenol, 4-[[l-[[4-(4- 25 amιnobutoxy)-3,5- bιs(l, l- dιmethylethyl)phenyl]thι o]-l- methylethyl]thιo]2,6- bιs( 1 , 1 -dimethylethyl) -
Figure imgf000077_0001
Butanedioic acid, 20 mono[4-[[l-[[3,5- bιs( 1 , 1 -dimethylethyl)- 4-hydroxyphenyl]thιo)- l -methylethyl}-2,6- dimethylphenyl] ester
Butanedioic acid, 40% at 100 mono[4-[[l-[[3,5- bιs( 1 , 1 -dimethylethyl)- 4- hydroxyphenyl]thio)- 1 -methylethyl } thιo-2,6- bιs(l ,l - dιmethylethyl)phenyl methyl ester
Glycine, 4-[[l-[[3,5- 25 30% at 5 bιs( 1 , 1 -dιmethylethyl)-4- hydroxypheny 1] thio] - 1 - methylethyl]thιo]-2,6- bιs(l ,l- dιmethylethyl)phenyl ester
Pentanedioic acid, (1 - NE 25 methylethyhdene)bιs(thι o{2,6-bιs(l,l- dιmethylethyl)-4, 1 - phenylene)] ester
Pentanedioic acid, 25 70% at 15 mono[4-[[l-[[3,5- bιs(l , l-dιmethylethyl)-4- hydroxypheny 1] thio] - 1 - methylethyl]thιo]-2,6- bιs(l,l- dιmethylethyl)phenyl] ester
Butanoic acid, 4-[4-[[l- 25 77% at 15
[[3,5-bιs(l ,l- dιmethylethyl)-4- hydroxypheny 1] thio] - 1 - methylethyl]thιo]-2,6- bιs(l,l- dιmethylethyl)phenoxy]-
Butanedioic acid, (1- NE 25 methylethylιdιne)bιs[thι o[2,6-bι(l,l- dιmethylethyl)-4, 1 - phenylene} } ester,
Glycine, (1- NE methylethylιdene)bιs
[bιs [thιo2,6-bιs (l,l- dιmethylthyl)-4,l- phenylene]] ester, dihydrochloπde
Figure imgf000079_0001
Figure imgf000080_0001
pentanedioic acid, 4-[[l- 80 NE
[[3,5-bis(l,l- dιmethylethyl)-4- hy droxypheny 1] thio] - 1 - methy lethy 1] thio] - , 6- bis(l,l- dιmethylethyl)phenyl methyl ester
2-Propenoic acid, 3-[4- 30 NE
[[l-[[3,5-bis(l,l- dιmethylethyl)-4- hydroxyphenyl] thio] - 1 - methylethyl]thio]-2,6- bis(l, l- dimethylethyl.phenoxy]-
, (£)- α-D-Galactopyranose, 6- 45 0-[4-[[l-[[3,5-bιs(l,l- dιmethylethyl)-4- hydroxyphenyl]thιo]- 1 - methylethyl]thιo]-2,6- bιs(l ,l- dιmethylethyl)phenyl]- l ,2:3,4-bis-0-(l- methylethyhdene)
Phenol, 4-[[l-[[4-[3- 22% at 50 (dιmethylamιno)propoxy
]-3,5-bιs(l,l- dιmethylethyl)phenyl]thι o]- 1 -methylethyl]thιo]-
2,6-bis(l ,l- dimethylethyl)-
Glycine, N-[[4-[[l -[[3,5- 15 50 83% at 15 bιs( 1 , 1 -dimethylethyl)- 4-hydroxyphenyl]thιo]- 1 ,methylethyl]thio]-2,6- bιs(l,l- dιmethylethyl)phenoxy] acetyl]-
Glutamic acid, N-[[4- 75 100 94% at 15
[[l-[[3,5-bιs(l,l- dιmethylethyl)-4- hydroxyphenyl]thio]- 1 - methylethyl]thιo]-2,6- bιs(l,l- dιmethylethyl)phenoxy] acetyl]-
L-Glutamic acid, N-[3- 50
[4-[[l-[[3,5-bis(l,l- dimethylethyl)-4- hydroxyphenyl]thio]-l- methylethyl]thio]-2,6- bis(l, l- dιmethylethyl)phenoxy]-
2-hydroxypropy 1] -di- , diethyl ester
Figure imgf000082_0001
Figure imgf000083_0001
Pharmaceutical Compositions
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 administered; 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. Prefeπed dosages for the described conditions range from 5-1500 mg per day. A more particularly prefeπed 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 prefeπed 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. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials 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.
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. In addition, 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 β-blockers such as propanalol, terbutalol, and labetalol. The compounds can also be administered in combination with 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 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. 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.
If administered intravenously, prefeπed carriers are physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
In a prefeπed embodiment, 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. 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 prefeπed 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. Patent No.
4,522,811 (which is incorporated herein by reference in its entirety). For example, 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.
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. In addition to the other materials listed above for systemic administration, thickening Oagents, emollients, and stabilizers can be used to prepare topical compositions. Examples of thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
Modifications and variations of the present invention relating to compounds that inhibit the suppression of VCAM-1 and methods of treating diseases mediated by the expression of VCAM-1 will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come with the scope of the appended claims.

Claims

We claim:
1. A compound of formula (I)
Figure imgf000088_0001
wherein
X is O, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of -(CH2)n-, -(CH2)n-CO-, - (CH2)n-N-, -(CH2)n-O-, -(CH2)n-S-, -(CH2O)-, -(OCH2)-, -(SCH2)-, -(CH2S-), -(aryl-O)-, - (O-aryl)-, -(alkyl-O)-, -(O-alkyl)-; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH2, NHR, NR2, SO2-OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2, SO2NH2, SO2NHR, SO2NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy; R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein X is S, SO, or SO2; Spacer is -(CH2)n- or - (CH2)n-CO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C1-5 alkyl; R3 and R4 are independently H, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (I) wherein
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- carboxymethylphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y= -nitrophenyl;
X=S; R^-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)2-; Y=4-nitrophenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4-H; Space╬╣=-CH2-; Y= 2-carboxyethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Space╬╣=-CH2-; Y=3,5-di-t-butyl-4- carboxypropanoyloxy;
X=S; R'=t-butyl; R2=t-butyl; R =H; R4=H; Spacer=-CH2-; Y=4-carboxyphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=l-acetyloxy-l- methylethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2,4-dinitrophenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4-H; Spacer=-CH2-; Y=4- trifluoromethylphenyl ;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2-carboxyfuranyl;
X=S; R'=t-butyl; R2=t-butyl; R3-H; R4=H; Spacer=-CH2-; Y=4-(N,N- dimethyl)sulfonamidophenyl;
X=SO; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl; X=SO2; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-acetyloxyphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-methylphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-fluorophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Space╬╣=-CH2-; Y-ethylsulfonic acid;
X=S; R!=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2- dimethylaminomethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R =H; Spacer=-(CH2)3-; Y-dimethylamino;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)5-; Y^acetyloxy; and X=S ; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Space╬╣--CH2-; Y=4-(2- hydroxy)ethylphenyl.
4. A pharmaceutical composition for the treatment of a disease mediated by the expression of VCAM-1, comprising an effective amount of a compound of any one of claims 1, 2 or 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
5. A method for the treatment of a disorder mediated by the expression of VC AM- 1 , comprising administering to a patient an effective amount of a compound of formula (I) as claimed in any one of claims 1, 2 or 3, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
6. The method of claim 5, wherein the disorder is a cardiovascular disorder.
7. The method of claim 6, wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, or small artery disease.
8. The method of claim 5, wherein the disorder is an inflammatory disease.
9. The method of claim 8, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis.
10. A compound of formula (II)
Figure imgf000091_0001
wherein
Ra, Rb, R,., and Rd are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R^ Rb, R<. and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH^-R,,, -C(O)-Rg, and -C(O)-(CH2)n-Rh, wherein
(a) when each of R^, Rb, R^ and Rj are t-butyl, Z cannot be hydrogen and (b) when each of
Ra, Rb, R(., and Rj are t-butyl, Z cannot be the residue of succinic acid;
Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH,
COOR, -CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof;
Or, in an alternative embodiment, R^ Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, -PO3H2 -PO3M2, -POjHM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C,_3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, -[O(C,_3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyπolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10, wherein R^, Rb, R,., and Rd are independently hydrogen or straight chained, branched, or cyclic C 0 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH^-R^ -C(O)-Rg, and -C(O)-(CH2)n-Rh, and a pharmaceutically acceptable salt thereof, provided that (a) when each of Ra, Rb, R^ and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be the residue of succinic acid.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (II) wherein Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=4-nitrophenyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=CO-(CH2)2-COOH;
Ra=t-butyl, Rb=t-butyl, R_,=t-butyl, and Rd=t-butyl; Z=CO-(5-nitrofuran-2-yl);
Ra=t-butyl, Rb=t-butyl, R<.=t-butyl, and R^-butyl; Z=3-carboxypropyl;
Ra=l-methylethyl, Rb=t-butyl, Rc=methyl, and Rd=methyl; Z=4-aminobutyl; Ra=t-butyl, R^-butyl, R^-butyl, and R^-butyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=3-hydroxypropanoyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=t-butylcarbonyloxymethyl; Ra=t-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z= -aminobutyl; Ra^-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=carboxymethy 1 ; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=2-(CONH2)ethanoyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^t-butyl Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=CO-(2-carboxyethyl);
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl Z=CO-(2-methoxycarbonylethyl);
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl Z=CO-aminomethyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=CO-3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and R^t-butyl Z=3 -carboxypropyl ;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=CO-ammonium methyl (chloride)
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^t-butyl Z=2-hydroxy-2-oxiranyl-ethyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=3 -hydroxymethyloxirany-2-ylmethyl ;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=3-(2-hydroxy-2- oxiranyl)ethoxyoxiran-2-ylmethyl;
Ra^-butyl, Rb=t-butyl, R,.=t-butyl, and R^-butyl; Z=oxiranylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3- carboxymethylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^t-butyl; Z=2,3,4-trihydroxybutyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and R^-butyl; Z=2-hydroxy-3-ethoxypropyl;
Ra=t-butyl, R^-butyl, Rc=t-butyl, and R^-butyl; Z=2,3-dihydroxypropyl;
Ra=t-butyl, Rb=t-butyl, R<.=t-butyl, and Rd=t-butyl; Z=ethyl; Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, R,,=t-butyl, R,.=t-butyl, and R^t-butyl; Z=4-N,N-dimethylaminophenethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, R,,=t-butyl, Rc=t-butyl, and R^-butyl; Z=CO-2-carboxyethyl (L-arginine ester); Ra=t-butyl, R^-butyl, R. -butyl, and R^-butyl; Z=3-methoxycarbonylpropyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and R^-butyl; Z=2-carboxyethenyl; Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=galactopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and R^t-butyl; Z=3-(N-N-diethylamino)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=carboxymethylaminocarbonylmethyl; Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=l ,3- dicarboxypropylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=2-hydroxy-3-(l,3- diethoxycarbonyl)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxy-4- carboxymethylaminobutyl;
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(5-amino-5- carboxy)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-ethylcarbonyloxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R<,=t-butyl; Z=4-hydroxybutyl; Ra=t-butyl, Rb=t-butyl, R^t-butyl, and R^-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^t-butyl; Z=CO-3-tetrazolylpropyl;
Ra^-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z^-hydroxypropenyl;
Ra-t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=CH2CONH-(CH2)CH(NH2)COOH;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=CH2CONHCH(COOet)CH2CH2(COOet);
Ra=t-butyl, Rb=t-butyl, R^t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^t-butyl; Z=2,3,4,5,6-pentahydroxyhexane;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^t-butyl; Z=CO-3-(2- hydroxyphenyloxyphosphoxy)propyl; Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=CO-2,2-dimethyl-3-hydroxypropyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=2-hydroxy-3-acetoxypropyl;
Ra^t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=2-acetoxy-3-hydroxypropyl; and
Ra-t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CH(OH)CH2NH(2,3, 4,5,6- pentahydroxyhexane.
13. A pharmaceutical composition for the treatment of a disorder mediated by the expression of VCAM-1 comprising an effective amount of a compound of any one of claims 10, 11 or 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for the treatment of a disorder mediated by the expression of VCAM- 1 comprising administering to a patient an effective amount of a compound of any one of claims 10, 11 or 12, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
15. The method of claim 14, wherein the disorder is a cardiovascular disorder.
16. The method of claim 15, wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, and small artery disease.
17. The method of claim 14, wherein the disorder is an inflammatory disease.
18. The method of claim 17, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis.
19. The method of claim 6, comprising administering the compound in combination with another cardiovascular drug selected from the group consisting of lipid lowering agents, platelet aggregation inhibitors, antithrombotic agents, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and ╬▓-blockers.
20. The method of claim 15, comprising administering the compound in combination with another cardiovascular drug selected from the group consisting of lipid lowering agents, platelet aggregation inhibitors, antithrombotic agents, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and ╬▓-blockers.
21. The method of claim 8, comprising administering the compound in combination with another antiinflammatory drug.
22. The method of claim 16, comprising administering the compound in combination with another antiinflammatory drug.
23. Use of a compound of formula (I) for the suppression of VCAM- 1 , wherein formula (I) has the structure
Figure imgf000096_0001
wherein
X is O, S, SO, SO2, CH2, or NH; Spacer is a group selected from the group consisting of -(CH2)n-, -(CH2)n-CO-, -
(CH2)n-N-, -(CH2)n-O-, -(CH2)n-S-, -(CH2O)-, -(OCH2)-, -(SCH2)-, -(CH2S-), -(aryl-O)-, - (O-aryl)-, -(alkyl-O)-, -(O-alkyl)-; n is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfmyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH2, NHR, NR2, SO2-OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2, SO2NH2, SO2NHR, SO2NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1; or a pharmaceutically acceptable salt thereof.
24. Use of a compound as claimed in claim 23, wherein X is S, SO, or SO2; Spacer is - (CH2)n- or -(CH2)n-CO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C,.5 alkyl; R3 and R4 are independently H, or a pharmaceutically acceptable salt thereof.
25. Use of a compound as claimed in claim 23, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (I) wherein
X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- carboxymethylphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl;
X=S; R'=t-butyl; R2=t-butyl; R =H; R4=H; Spacer=-(CH2)2-; Y-4-nitrophenyl; X=S; R!=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y= 2-carboxyethyl;
X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3,5-di-t-butyl-4- carboxypropanoyloxy;
X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-carboxyphenyl;
X-S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=l-acetyloxy-l- methylethyl;
X=S; R -butyl; R2-t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3-nitrophenyl;
X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2,4-dinitrophenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- trifluoromethylphenyl; X=S; R -butyl; R2=t-butyl; R3=H; R4=Η; Spacer=-CH2-; Y=2-carboxy furanyl;
X=S; R]=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-(N,N- dimethyl)sulfonamidophenyl;
X=SO; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl;
X=SO2; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-acetyloxyphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-methylphenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-fluorophenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=ethylsulfonic acid;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2- dimethylaminomethy 1 ;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)3-; Y=dimethylamino;
X=S; R]=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)5-; Y=acetyloxy; and
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-(2- hydroxy)ethylphenyl.
26. Use of a compound of formula (I) for the treatment of a disease mediated by VCAM-1, wherein formula (I) has the structure
Figure imgf000098_0001
wherein
X is O, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of -(CH2)n-, -(CH2)n-CO-, - (CH2)n-N-, -(CH2)n-O-, -(CH2)n-S-, -(CH2O)-, -(OCH2)-, -(SCH2)-, -(CH2S-), -(aryl-O)-, - (O-aryl)-, -(alkyl-O)-, -(O-alkyl)-; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH2, NHR, NR2, SO2-OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2, SO2NH2, SO2NHR, SO2NR2; R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1; or a pharmaceutically acceptable salt thereof.
27. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 26, wherein the disease is a cardiovascular disease.
28. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 26, wherein the disease is an inflammatory disease.
29. Use of the compound of formula (I) as claimed in claim 26, 27 or 28, wherein X is S, SO, or SO2; Spacer is -(CH2)n- or -(CH2)n-CO-; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl- COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C1-5 alkyl; R3 and R4 are independently H, or a pharmaceutically acceptable salt thereof.
30. Use of the compound of formula (I) as claimed in claim 26, 27, or 28 or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (I) wherein
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- carboxymethylphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Space╬╣=-CH2-; Y=4-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)2-; Y=4-nitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y= 2-carboxy ethyl; X=S; R]=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3,5-di-t-butyl-4- carboxypropanoyloxy;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-carboxyphenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=l-acetyloxy-l- methylethyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=3-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer==-CH2-; Y=2,4-dinitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4- trifluoromethylphenyl; X=S ; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2-carboxyfuranyl;
X=S; R]=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-(N,N- dimethyl)sulfonamidophenyl;
X=SO; R'=t-butyl; R2=t-butyl; R3=H; R =H; Spacer=-CH2-; Y=4-nitrophenyl; X=SO2; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-nitrophenyl; X=S; R'=t-butyl; R2=t-butyl; R3-H; R4=H; Spacer=-CH2-; Y=4-acetyloxyphenyl;
X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-methylphenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=4-fluorophenyl; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=ethylsulfonic acid; X=S; R>=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-CH2-; Y=2- dimethylaminomethyl;
X=S; R -butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)3-; Y=dimethylamino; X=S; R'=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=-(CH2)5-; Y=acetyloxy; and X=S; R'=t-butyl; R2=t-butyl; R =H; R4=H; Spacer=-CH2-; Y=4-(2- hydroxy)ethylphenyl.
31. Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the suppression of VCAM-1, wherein formula (II) has the structure
Figure imgf000100_0001
wherein
Ra, Rb, Re, and Rd are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R^, Rb, Rc and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH2)-Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, wherein (a) when each of Ra, R^, Rp, and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be the residue of succinic acid;
Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof; Or, in an alternative embodiment, R^,, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, -PO3H2 -PO3M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C,_3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, -[O(C,_3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyπolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl or a pharmaceutically acceptable salt thereof.
32. Use of the compound of formula (II) or a pharmaceutically acceptable salt thereof as claimed in claim 31 , wherein It,, Rb, R^, and Rd are independently hydrogen or straight chained, branched, or cyclic C^o alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH2)-Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, and a pharmaceutically acceptable salt thereof, provided that (a) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be the residue of succinic acid.
33. Use of the compound of formula (II) as claimed in claim 31 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (II) wherein Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-nitrophenyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-(CH2)2-COOH; Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^t-butyl; Z=CO-(5-nitrofuran-2-yl); Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-carboxypropyl; Ra=l-methylethyl, Rb=t-butyl, Re=methyl, and Rd=methyl; Z=4-aminobutyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R.,=t-butyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-hydroxypropanoyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=t-butylcarbonyloxymethyl;
R,=t-butyl, Rb=t-butyl, Re=H, and Rd=H; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Re=H, and R =H; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=carboxymethyl; Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and Rd=t-butyl; Z=2-(CONH2)ethanoyl;
Ra=t-butyl, Rb=t-butyl, R ^-butyl, and Rd=t-butyl; Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, R,.=t-butyl, and Rd=t-butyl; Z=CO-(2-carboxyethyl);
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-(2-methoxycarbonylethyl);
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-aminomethyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R^-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-ammonium methyl (chloride)
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-hydroxy-2-oxiranyl-ethyl; Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-hydroxymethyloxirany-2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-(2-hydroxy-2- oxiranyl)ethoxyoxiran-2-ylmethyl;
R^-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=oxiranylmethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3- carboxymethylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2,3,4-trihydroxybutyl;
Ra=t-butyl, Rb=t-butyl, Re^t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-ethoxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxypropyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and R^-butyl; Z=ethyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=4-N,N-dimethylaminophenethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl (L-arginine ester); Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-methoxycarbonylpropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-carboxyethenyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=galactopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-(N-N-diethylamino)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and R^-butyl; Z=carboxymethylaminocarbonylmethyl; Ra^t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=l ,3- dicarboxypropylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(l,3- diethoxycarbonyl)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxy-4- carboxymethylaminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(5-amino-5- carboxy)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=4-ethylcarbonyloxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-hydroxybutyl; R^-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-3-tetrazolylpropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-hydroxypropenyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CH2CONH-(CH2)CH(NH2)COOH;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CONHCH(COOet)CH2CH2(COOet);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3,4,5,6-pentahydroxyhexane;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-3-(2- hydroxyphenyloxyphosphoxy)propyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-2,2-dimethyl-3-hydroxypropyl;
Ra^-butyl, Rb=t-butyl, Re^ -butyl, and R^-butyl; Z=2-hydroxy-3-acetoxypropyl;
R^-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-acetoxy-3-hydroxypropyl; and
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CH(OH)CH2NH(2,3,4,5,6- pentahydroxyhexane.
34. Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by VCAM-1, wherein the compound of formula (II) has the structure
Figure imgf000105_0001
wherein
Ra, Rb, Re, and 1^ are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R^, Rb, Re and R,j groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, -(CH2)-Re, -C(O)-Rg, and -C(O)-(CH2)n-Rh, wherein (a) when each of Ra, Rb, RΓÇ₧ and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be the residue of succinic acid; Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2; Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof;
Or, in an alternative embodiment, Re, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)- spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, -PO3H2 -PO3M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C!_3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, -[O(C,_3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyπolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tefrazolylamino lower alkyl, or thiazolyl lower alkyl or a pharmaceutically acceptable salt thereof.
35. Use of the compound of formula (II) as claimed in claim 34, wherein the disease is a cardiovascular disease.
36. Use of the compound of formula (II) as claimed in claim 34, wherein the disease is an inflammatory disease.
37. Use of the compound of formula (II) as claimed in claim 34, 35, or 36, wherein Ra, Rb, Re, and 1^ are independently hydrogen or straight chained, branched, or cyclic C1-10 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, -(CH2)-Re, -C(O)- Rg, and -C(O)-(CH2)n-Rh, and a pharmaceutically acceptable salt thereof, provided that (a) when each of Ra, Rb, Re, and Rd are t-butyl, Z cannot be hydrogen and (b) when each of R,,,
Rb, Re, and Rd are t-butyl, Z cannot be the residue of succinic acid.
38. Use of the compound of formula (II) as claimed in claim 34, 35, or 36, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (II) wherein
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=4-nitrophenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-(CH2)2-COOH;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-(5-nitrofuran-2-yl);
Ra=t-butyl, Rb=t-butyl, Rc-t-butyl, and R^-butyl; Z=3-carboxypropyl;
Ra=l-methylethyl, Rb=t-butyl, Rc=methyl, and Rd=methyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-hydroxypropanoyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=t-butylcarbonyloxymethyl;
Ra=t-butyl, Rb=t-butyl, RC=H, and Rd=H; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl Z=carboxymethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=2-(CONH2)ethanoyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R^-butyl Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=CO-(2-carboxyethyl) ;
Ra=t-butyl, Rb=t-butyl, Re^t-butyl, and R^-butyl Z=CO-(2-methoxycarbonylethyl) ;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, Re^ -butyl, and Rd=t-butyl Z=CO-3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl: Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R^t-butyl Z=CO-ammonium methyl (chloride)
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R^-butyl Z=2-hydroxy-2-oxiranyl-ethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl Z=3 -hydroxymethy loxirany-2-ylmethy 1 ;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl Z=3-(2-hydroxy-2- oxiranyl)ethoxyoxiran-2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, Re^t-butyl, and R^-butyl; Z=oxiranylmethyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3- carboxymethy laminopropy 1 ;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3,4-trihydroxybutyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-ethoxypropyl; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=ethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-N,N-dimethylaminophenethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl; Ra=t-butyl, Rb-t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl (L-arginine ester);
Ra=t-butyl, Rb-t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3 -methoxy carbonylpropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-carboxyethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=galactopyranosylmethyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=3-(N-N-diethylamino)propyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd==t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and R^t-butyl; Z=carboxymethylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=l,3- dicarboxypropylaminocarbonylmethyl; Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-( 1 ,3- diethoxycarbonyl)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxy-4- carboxymethylaminobutyl;
Ra^t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(5-amino-5- carboxy )propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=4-ethylcarbonyloxybutyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=4-hydroxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CO-3-tetrazolylpropyl; Ra=t-butyl, Rb=t-butyl, R^-butyl, and Rd=t-butyl; Z=3-hydroxypropenyl;
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=CH2CONH-(CH2)CH(NH2)COOH; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl;
Z=CH2CONHCH(COOet)CH2CH2(COOet);
Ra=t-butyl, Rb=t-butyl, Re=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3,4,5,6-pentahydroxyhexane; Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3-(2- hydroxyphenyloxyphosphoxy)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2,2-dimethyl-3-hydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-acetoxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-acetoxy-3-hydroxypropyl; and Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd-t-butyl; Z=CH2CH(OH)CH2NH(2,3, 4,5,6- pentahydroxyhexane.
PCT/US1998/009781 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1 WO1998051662A2 (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
CA002289851A CA2289851C (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
PL343904A PL207885B1 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
IL15707898A IL157078A (en) 1997-05-14 1998-05-14 Compounds and pharmaceutical compositions for the inhibition of the expression of vcam-1
SI9830885T SI1464639T1 (en) 1997-05-14 1998-05-14 Succinic acid ester of probucol for the inhibition of the expression of VCAM-1
IL15707798A IL157077A (en) 1997-05-14 1998-05-14 Compounds and pharmaceutical compositions for the inhibition of the expression of vcam-1
SK1532-99A SK286392B6 (en) 1997-05-14 1998-05-14 Succinic acid ester of probucol for the inhibition of the expression of VCAM-1 and use for treatment cardiovascular and inflammatory diseases
IL13279798A IL132797A0 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
DE69829966T DE69829966T2 (en) 1997-05-14 1998-05-14 A MONOETHER OF PROBUCOL AND METHODS FOR INHIBITING THE VCAM-1 EXPRESSION
BR9809819-5A BR9809819A (en) 1997-05-14 1998-05-14 Compounds and methods for inhibiting vcam-1 expression
SK50038-2007A SK286766B6 (en) 1997-05-14 1998-05-14 Composition and their use for treatment cardiovascular and inflammatory diseases
DK98922264T DK0994853T3 (en) 1998-05-14 1998-05-14 Monoether of probucol and methods for inhibiting expression of VCAM-1
AT98922264T ATE294158T1 (en) 1997-05-14 1998-05-14 A MONOETHER OF PROBUCOL AND METHODS OF INHIBITING VCAM-1 EXPRESSION
HU0004592A HUP0004592A3 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
EP98922264A EP0994853B1 (en) 1997-05-14 1998-05-14 A monoether of probucol and methods for the inhibition of the expression of vcam-1
EA199901026A EA009370B1 (en) 1997-05-14 1998-05-14 Compound and pharmaceutical composition for the inhibition of the expression of vcam-1
KR1019997010458A KR100882335B1 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
AU74851/98A AU750041B2 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of VCAM-1
IL16456898A IL164568A0 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1
JP54950298A JP3930056B2 (en) 1997-05-14 1998-05-14 Compounds and methods for inhibiting VCAM-1 expression
NO19995544A NO316221B1 (en) 1997-05-14 1999-11-12 Compounds for Inhibition of Expression of VCAM-1, Pharmaceutical Composition Including Same and Use of Same for Preparation of the Drug
HK00105042A HK1025947A1 (en) 1997-05-14 2000-08-14 A monoether of probucol and methods for the inhibition of the expression of vcam-1.
NO20032254A NO319855B1 (en) 1997-05-14 2003-05-19 Use of Compounds for the Preparation of Drug for Inhibition of Expression of VCAM-1.
IL164568A IL164568A (en) 1997-05-14 2004-10-14 Compounds and pharmaceutical compositions for treating diseases mediated by vcam-1

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4702097P 1997-05-14 1997-05-14
US60/047,020 1997-05-14

Publications (2)

Publication Number Publication Date
WO1998051662A2 true WO1998051662A2 (en) 1998-11-19
WO1998051662A3 WO1998051662A3 (en) 2000-03-02

Family

ID=21946634

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US1998/009773 WO1998051289A2 (en) 1997-05-14 1998-05-14 Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
PCT/US1998/009781 WO1998051662A2 (en) 1997-05-14 1998-05-14 Compounds and methods for the inhibition of the expression of vcam-1

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US1998/009773 WO1998051289A2 (en) 1997-05-14 1998-05-14 Monoesters of probucol for the treatment of cardiovascular and inflammatory disease

Country Status (26)

Country Link
US (9) US6147250A (en)
EP (2) EP0994853B1 (en)
JP (4) JP3930056B2 (en)
KR (5) KR100882335B1 (en)
CN (7) CN1977836A (en)
AT (3) ATE356113T1 (en)
AU (2) AU750041B2 (en)
BR (2) BR9809819A (en)
CA (3) CA2289851C (en)
CY (1) CY1107645T1 (en)
CZ (4) CZ301183B6 (en)
DE (3) DE69829966T2 (en)
DK (2) DK1464639T3 (en)
EA (5) EA010183B1 (en)
ES (3) ES2241139T3 (en)
HK (2) HK1024629A1 (en)
HU (2) HUP0004592A3 (en)
ID (2) ID23877A (en)
IL (7) IL164568A0 (en)
NO (3) NO316221B1 (en)
NZ (2) NZ501069A (en)
PL (2) PL194329B1 (en)
PT (1) PT1464639E (en)
SK (4) SK286392B6 (en)
TR (2) TR199902803T2 (en)
WO (2) WO1998051289A2 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6121319A (en) * 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
WO2001070757A2 (en) * 2000-03-21 2001-09-27 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of vcam-1
WO2001077072A2 (en) * 2000-04-11 2001-10-18 Atherogenics, Inc. Compounds and methods to increase plasma hdl cholesterol levels and improve hdl functionality
US6323359B1 (en) * 2000-05-02 2001-11-27 Salsbury Chemicals, Inc. Process for preparing probucol derivatives
WO2001098291A2 (en) * 2000-06-20 2001-12-27 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders
WO2002087556A2 (en) * 2001-04-11 2002-11-07 Atherogenics, Inc. Probucol monoesters and their use to increase plasma hdl cholesterol levels and improve hdl functionality
WO2003039352A2 (en) * 2001-11-09 2003-05-15 Atherogenics, Inc. Methods of reversing and preventing cardiovascular pathologies
US6852878B2 (en) 1998-05-14 2005-02-08 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of VCAM-1
WO2005011594A2 (en) * 2003-07-31 2005-02-10 Epigenesis Pharmaceuticals Llc Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or vcam inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US6887712B1 (en) 1998-11-09 2005-05-03 Atherogenics, Inc. Methods and compositions to lower plasma cholesterol levels
JP2005514344A (en) * 2001-10-25 2005-05-19 アセロジエニクス・インコーポレイテツド Compounds and methods for transplant rejection therapy
WO2005051900A1 (en) * 2003-11-25 2005-06-09 Novo Nordisk A/S Novel compounds for the treatment of obesity
WO2006063408A1 (en) * 2004-12-17 2006-06-22 Stocker Ronald O Compositions and methods for treating cardiovascular disorders
US7071158B2 (en) 1997-07-01 2006-07-04 Atherogenics, Inc. Antioxidant enhancement of therapy for hyperproliferative conditions
US7078431B2 (en) 2000-06-20 2006-07-18 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders
JP2006188525A (en) * 1999-05-28 2006-07-20 Abbott Lab Cell proliferation inhibitor
US7087645B2 (en) 1997-05-14 2006-08-08 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US7094801B2 (en) 2001-12-19 2006-08-22 Atherogenics, Inc. Chalcone derivatives and their use to treat diseases
US7166605B2 (en) * 2002-03-22 2007-01-23 Nicox, S.A. Probucol nitro-derivatives
US7173129B2 (en) 2003-06-06 2007-02-06 Athero Genics, Inc. Sulfonamide-substituted chalcone derivatives and their use to treat diseases
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7271274B2 (en) 2004-04-20 2007-09-18 Ahterogenics, Inc. Phenolic antioxidants for the treatment of disorders including arthritis, asthma and coronary artery disease
US7273948B2 (en) * 2003-01-13 2007-09-25 Atherogenics, Inc. 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
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
WO2008118948A1 (en) 2007-03-26 2008-10-02 Atherogenics, Inc. Methods and compositions of derivatives of probucol for the treatment of diabetes
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
US10882828B2 (en) 2009-03-18 2021-01-05 Resverlogix Corp. Anti-inflammatory agents
US11649220B2 (en) 2018-01-30 2023-05-16 Demotech.Inc. Probucol derivative, preparation method therefor and use thereof

Families Citing this family (104)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001517617A (en) * 1997-09-24 2001-10-09 ノヴァ モレキュラー インク． Methods for increasing APOE levels for the treatment of neurodegenerative diseases
US7361684B2 (en) * 1999-06-28 2008-04-22 Massachusetts Institute Of Technology Screening of compounds for treatment of atherosclerosis and heart attack
US6403637B1 (en) 1999-08-09 2002-06-11 Univ Saint Louis Methods of modulating matrix metalloproteinase activity and uses thereof
US6670355B2 (en) * 2000-06-16 2003-12-30 Wyeth Method of treating cardiovascular disease
AUPQ872800A0 (en) * 2000-07-12 2000-08-03 Heart Research Institute, The Compositions and methods for treating cardiovascular disorders
US6982251B2 (en) * 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
EP1911462A3 (en) 2001-01-26 2011-11-30 Schering Corporation Compositions comprising a sterol absorption inhibitor
US6939554B2 (en) * 2002-02-05 2005-09-06 Michigan Biotechnology Institute Antimicrobial polymer
US7208467B2 (en) 2002-06-07 2007-04-24 Monty Krieger Lipid-altering compositions for the treatment of infertility
US6960683B2 (en) * 2002-07-12 2005-11-01 Atherogenics, Inc. Salt forms of poorly soluble probucol esters and ethers
US20050163821A1 (en) * 2002-08-02 2005-07-28 Hsing-Wen Sung Drug-eluting Biodegradable Stent and Delivery Means
US20040110803A1 (en) * 2002-09-13 2004-06-10 Hossein Dovlatabadi Methods and compositions for the use of D-malic acid to decrease serum triglyceride, cholesterol and lipoprotein levels
AU2003288925A1 (en) * 2002-10-08 2004-05-04 Massachusetts Institute Of Technology Compounds for modulation of cholesterol transport
AU2002953533A0 (en) * 2002-12-24 2003-01-16 Arthron Limited Fc receptor modulating compounds and compositions
ATE406364T1 (en) 2003-03-07 2008-09-15 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA
DE602004018617D1 (en) 2003-03-07 2009-02-05 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE FOR THE TREATMENT OF HYPERCHOLESTEROLMIA
SI1603553T1 (en) * 2003-03-17 2012-03-30 Japan Tobacco Inc Pharmaceutical compositions of cetp inhibitors
WO2005025492A2 (en) * 2003-07-07 2005-03-24 Emory University Novel compositions, pharmaceutical compositions, and methods for the treatment and prevention of heart disease
US20050074443A1 (en) * 2003-10-03 2005-04-07 Treadwell Benjamin V. Methods of attenuating autoimmune disease and compositions useful therefor
JP2007509054A (en) * 2003-10-17 2007-04-12 アミリン・ファーマシューティカルズ，インコーポレイテッド Silylphenol promotes vascular health
EP1918000A2 (en) 2003-11-05 2008-05-07 Schering Corporation Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
US7744889B2 (en) * 2003-11-14 2010-06-29 Temple University - Of The Commonwealth System Of Higher Education Alpha, beta-unsaturated sulfoxides for treating proliferative disorders
US20060025481A1 (en) * 2004-02-09 2006-02-02 Strange Matthew L Process for preparation of probucol derivatives and polymorphic forms thereof
US7294736B2 (en) * 2004-04-09 2007-11-13 Cambrex Charles City, Inc. Process for preparation of probucol derivatives
US20050282883A1 (en) * 2004-04-29 2005-12-22 John Griffin Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
US7199126B2 (en) * 2004-04-29 2007-04-03 Pharmix Corporation Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
US7183285B2 (en) * 2004-04-29 2007-02-27 Pharmix Corp. Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
US20050272770A1 (en) * 2004-04-29 2005-12-08 John Griffin Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
US20060063828A1 (en) * 2004-06-28 2006-03-23 Weingarten M D 1,2-Bis-(substituted-phenyl)-2-propen-1-ones and pharmaceutical compositions thereof
EP1768660A4 (en) * 2004-07-01 2009-05-13 Atherogenics Inc Compounds and methods for treating diabetic vascular diseases
US20060069080A1 (en) * 2004-09-29 2006-03-30 Veltri Enrico P Combinations of substituted azetidinones and CB1 antagonists
US20060111436A1 (en) * 2004-11-23 2006-05-25 John Griffin Compositions and treatments for modulating kinase and/or HMG-CoA reductase
NZ555320A (en) 2004-12-03 2010-11-26 Schering Corp Substituted piperazines as CB1 antagonists
US7345191B2 (en) * 2005-02-26 2008-03-18 Cambrex Charles City, Inc. Process for preparation of probucol derivatives
KR20080007373A (en) 2005-04-21 2008-01-18 아테로제닉스, 인코포레이티드 Process for the separation of probucol derivatives
US20070015779A1 (en) * 2005-04-29 2007-01-18 John Griffin Compositions and treatments for inhibiting kinase and/or hmg-coa reductase
US7737155B2 (en) 2005-05-17 2010-06-15 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
US20060269579A1 (en) * 2005-05-25 2006-11-30 Musculoskeletal Research Llc Compositions for treating osteoarthritis
US7767710B2 (en) 2005-05-25 2010-08-03 Calosyn Pharma, Inc. Method for treating osteoarthritis
JP2009528266A (en) 2006-01-18 2009-08-06 シェーリング コーポレイション Cannabinoid receptor modifier
WO2007142581A1 (en) * 2006-06-07 2007-12-13 Astrazeneca Ab Combination product for the treatment or prevention of dyslipidaemia
WO2008118946A1 (en) * 2007-03-27 2008-10-02 Atherogenics, Inc. Methods and compositions using certain phenolic derivatives for the treatment of diabetes
WO2008130616A2 (en) * 2007-04-19 2008-10-30 Schering Corporation Diaryl morpholines as cb1 modulators
JP2010531354A (en) * 2007-06-26 2010-09-24 アストラゼネカ アクチボラグ Method for isolating a probucol derivative monosubstituted with a carboxy group
KR20100051625A (en) * 2007-06-28 2010-05-17 인터벳 인터내셔널 비.브이. Substituted piperazines as cb1 antagonists
CN101790521A (en) * 2007-06-28 2010-07-28 英特维特国际股份有限公司 Substituted-piperazinyl as the CB1 antagonist
WO2009042854A1 (en) * 2007-09-26 2009-04-02 Musculoskeletal Research Llc Ion-channel regulator compositions and methods of using same
BRPI0817907B8 (en) 2007-10-02 2021-06-22 Lamodel Ltd apparatus for administering a substance to an individual
US10420880B2 (en) 2007-10-02 2019-09-24 West Pharma. Services IL, Ltd. Key for securing components of a drug delivery system during assembly and/or transport and methods of using same
US9345836B2 (en) 2007-10-02 2016-05-24 Medimop Medical Projects Ltd. Disengagement resistant telescoping assembly and unidirectional method of assembly for such
US9656019B2 (en) 2007-10-02 2017-05-23 Medimop Medical Projects Ltd. Apparatuses for securing components of a drug delivery system during transport and methods of using same
US7967795B1 (en) 2010-01-19 2011-06-28 Lamodel Ltd. Cartridge interface assembly with driving plunger
AU2008317057B8 (en) 2007-10-22 2014-02-13 Merck Sharp & Dohme Corp. Bicyclic Heterocycle Derivatives and their use as modulators of the activity of GPR119
CN103251631A (en) * 2008-05-13 2013-08-21 根梅迪卡治疗公司 Salicylate conjugates useful for treating metabolic disorders
EP2297117B1 (en) 2008-05-19 2012-10-31 Merck Sharp & Dohme Corp. Bicyclic heterocycle derivatives and use thereof as gpr119 modulators
EP2318404B1 (en) 2008-07-16 2013-08-21 Merck Sharp & Dohme Corp. Bicyclic heterocycle derivatives and use thereof as gpr119 modulators
US9393369B2 (en) 2008-09-15 2016-07-19 Medimop Medical Projects Ltd. Stabilized pen injector
US20100145305A1 (en) * 2008-11-10 2010-06-10 Ruth Alon Low volume accurate injector
EP2379547A1 (en) 2008-12-16 2011-10-26 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
WO2010075069A1 (en) 2008-12-16 2010-07-01 Schering Corporation Bicyclic pyranone derivatives as nicotinic acid receptor agonists
WO2010075273A1 (en) 2008-12-23 2010-07-01 Schering Corporation Bicyclic heterocycle derivatives and methods of use thereof
US8722882B2 (en) 2008-12-23 2014-05-13 Merck Sharp & Dohme Corp. Pyrimidine derivatives as GPCR modulators for use in the treatment of obesity and diabetes
CA2747809A1 (en) 2008-12-23 2010-07-01 Joel M. Harris Bicyclic heterocycle derivatives and methods of use thereof
US8152779B2 (en) * 2008-12-30 2012-04-10 Medimop Medical Projects Ltd. Needle assembly for drug pump
WO2010106083A1 (en) * 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Combination therapies for treating metabolic disorders
JP2012520342A (en) * 2009-03-16 2012-09-06 ジェンメディカ・セラピューティックス・ソシエダッド・リミターダ Anti-inflammatory and antioxidant conjugates useful for treating metabolic disorders
WO2010114957A1 (en) 2009-04-03 2010-10-07 Schering Corporation Bicyclic piperidine and piperazine derivatives as gpcr modulators for the treatment of obesity, diabetes and other metabolic disorders
AR076024A1 (en) 2009-04-03 2011-05-11 Schering Corp DERIVATIVES OF BRIDGED BICYCLIC HETEROCICLES AND METHODS OF USE OF THE SAME
HUE030253T2 (en) 2009-05-18 2017-04-28 Telomerase Activation Sciences Inc Compositions and methods for increasing telomerase activity
US10071196B2 (en) 2012-05-15 2018-09-11 West Pharma. Services IL, Ltd. Method for selectively powering a battery-operated drug-delivery device and device therefor
US8157769B2 (en) 2009-09-15 2012-04-17 Medimop Medical Projects Ltd. Cartridge insertion assembly for drug delivery system
US10071198B2 (en) 2012-11-02 2018-09-11 West Pharma. Servicees IL, Ltd. Adhesive structure for medical device
EP2493307B1 (en) 2009-10-29 2016-04-27 Merck Sharp & Dohme Corp. Bridged bicyclic piperidine derivatives and methods of use thereof
US20120232073A1 (en) 2009-11-23 2012-09-13 Santhosh Francis Neelamkavil Fused bicyclic pyrimidine derivatives and methods of use thereof
EP2503891B1 (en) 2009-11-23 2016-08-03 Merck Sharp & Dohme Corp. Pyrimidine ether derivatives and methods of use thereof
EP2503887B1 (en) 2009-11-24 2016-01-06 Merck Sharp & Dohme Corp. Substituted biaryl derivatives and methods of use thereof
US8348898B2 (en) 2010-01-19 2013-01-08 Medimop Medical Projects Ltd. Automatic needle for drug pump
WO2011141907A1 (en) 2010-05-10 2011-11-17 Medimop Medical Projects Ltd. Low volume accurate injector
US20130156720A1 (en) 2010-08-27 2013-06-20 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US8466197B2 (en) 2010-12-14 2013-06-18 Genmedica Therapeutics Sl Thiocarbonates as anti-inflammatory and antioxidant compounds useful for treating metabolic disorders
USD702834S1 (en) 2011-03-22 2014-04-15 Medimop Medical Projects Ltd. Cartridge for use in injection device
US9072827B2 (en) 2012-03-26 2015-07-07 Medimop Medical Projects Ltd. Fail safe point protector for needle safety flap
US9421323B2 (en) 2013-01-03 2016-08-23 Medimop Medical Projects Ltd. Door and doorstop for portable one use drug delivery apparatus
KR20230050355A (en) 2013-02-28 2023-04-14 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 Methods and compositions for mobilizing stem cells
US9011164B2 (en) 2013-04-30 2015-04-21 Medimop Medical Projects Ltd. Clip contact for easy installation of printed circuit board PCB
US10293120B2 (en) 2015-04-10 2019-05-21 West Pharma. Services IL, Ltd. Redundant injection device status indication
US10149943B2 (en) 2015-05-29 2018-12-11 West Pharma. Services IL, Ltd. Linear rotation stabilizer for a telescoping syringe stopper driverdriving assembly
WO2016196934A1 (en) 2015-06-04 2016-12-08 Medimop Medical Projects Ltd. Cartridge insertion for drug delivery device
US10576207B2 (en) 2015-10-09 2020-03-03 West Pharma. Services IL, Ltd. Angled syringe patch injector
US9987432B2 (en) 2015-09-22 2018-06-05 West Pharma. Services IL, Ltd. Rotation resistant friction adapter for plunger driver of drug delivery device
US10086145B2 (en) 2015-09-22 2018-10-02 West Pharma Services Il, Ltd. Rotation resistant friction adapter for plunger driver of drug delivery device
CN112972833B (en) 2015-10-09 2024-01-09 西医药服务以色列分公司 Syringe needle cap remover
CN109219456B (en) 2016-01-21 2020-05-15 西医药服务以色列有限公司 Force containment in autoinjectors
CN109310816B (en) 2016-01-21 2020-04-21 西医药服务以色列有限公司 Needle insertion and retraction mechanism
JP6885960B2 (en) 2016-01-21 2021-06-16 ウェスト ファーマ サービシーズ イスラエル リミテッド Drug delivery device with visual indicators
WO2017161076A1 (en) 2016-03-16 2017-09-21 Medimop Medical Projects Ltd. Staged telescopic screw assembly having different visual indicators
US10376647B2 (en) 2016-03-18 2019-08-13 West Pharma. Services IL, Ltd. Anti-rotation mechanism for telescopic screw assembly
JP6957525B2 (en) 2016-06-02 2021-11-02 ウェスト ファーマ サービシーズ イスラエル リミテッド Needle evacuation by 3 positions
US9650332B1 (en) * 2016-06-16 2017-05-16 Yong Xu Prodrug of probucol and method for preparing the same
EP3490635B1 (en) 2016-08-01 2021-11-17 West Pharma. Services Il, Ltd. Partial door closure prevention spring
CN109562229B (en) 2016-08-01 2021-07-13 西医药服务以色列有限公司 Anti-rotation medicine barrel pin
CN106905208B (en) * 2017-02-27 2018-09-07 江西瑞雅药业有限公司 Probucol prodrug and preparation method thereof and pharmaceutical composition
CN110869072B (en) 2017-05-30 2021-12-10 西部制药服务有限公司(以色列) Modular drive mechanism for a wearable injector
US11857767B2 (en) 2017-12-22 2024-01-02 West Pharma. Services IL, Ltd. Injector usable with different dimension cartridges

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3179701A (en) * 1962-05-14 1965-04-20 Shell Oil Co (3, 5-dialkyl-4-hydroxyphenyl) (3, 5-dialkyl-4-hydroxybenzyl) sulfides
GB1136539A (en) * 1966-12-13 1968-12-11 Uniroyal Inc Phenolic sulphides
GB1148550A (en) * 1967-12-02 1969-04-16 Uniroyal Inc Substituted benzylphenyl sulfides and their use as antioxidants
GB1199871A (en) * 1967-05-11 1970-07-22 Consolidation Coal Co Improvements in or relating to Sulfur-Containing Bisphenols
DE2716125A1 (en) * 1976-04-12 1977-10-27 Yoshitomi Pharmaceutical 3,5-DI-TERT.-BUTYL-4-HYDROXYPHENYLPYRIDINE COMPOUNDS, METHOD FOR THEIR MANUFACTURING AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
US4115590A (en) * 1964-02-26 1978-09-19 Ethyl Corporation Binuclear phenols for reducing plasma lipid levels
EP0190682A2 (en) * 1985-02-04 1986-08-13 G.D. Searle & Co. Novel disubstituted 4-hydroxyphenylthio anilides
US4755524A (en) * 1986-01-31 1988-07-05 G. D. Searle & Co. Novel phenolic thioethers as inhibitors of 5-lipoxygenase
EP0292660A2 (en) * 1987-03-17 1988-11-30 Merrell Dow Pharmaceuticals Inc. Alkylidenedithiobis (substituted) phenols for inhibiting interleukin-1 release and for alleviating interleukin-1 mediated conditions
EP0317165A1 (en) * 1987-11-13 1989-05-24 Riker Laboratories, Inc. DI-t-butylphenols substituted by an alkoxy or benzyloxy group or a benzylthio group
EP0348203A1 (en) * 1988-06-24 1989-12-27 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI &amp; CO. LTD. Phenolic thioethers, their production and use
EP0405788A2 (en) * 1989-06-29 1991-01-02 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI &amp; CO. LTD. Di-tert-butyl(hydroxy)phenylthio substituted hydroxamic acid derivatives
US5262439A (en) * 1992-04-30 1993-11-16 The Regents Of The University Of California Soluble analogs of probucol
EP0621255A1 (en) * 1993-04-20 1994-10-26 Adir Et Compagnie Substituted phenoxy-isobutyric acids and esters
WO1995030415A1 (en) * 1994-05-10 1995-11-16 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
WO1996012703A1 (en) * 1994-10-25 1996-05-02 G.D. Searle & Co. Heteroalkyl and heteroarylthioalkyl thiophenolic compounds as 5-lipoxygenase inhibitors
WO1998022418A1 (en) * 1996-11-20 1998-05-28 Hoechst Marion Roussel, Inc. Substituted phenols and thiophenols useful as antioxidant agents

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3485843A (en) * 1967-05-11 1969-12-23 Dow Chemical Co Piperazine adducts of ketone mercaptoles
US3479407A (en) * 1968-11-06 1969-11-18 Consolidation Coal Co Sulfurization of 2,6-di-tert-butylphenol
US3576883A (en) * 1969-06-30 1971-04-27 Consolidation Coal Co Alkylidenedithiobisphenols
DE2104524C3 (en) 1970-09-16 1980-08-07 Veb Kombinat Umformtechnik Herbert Warnke Erfurt, Ddr 5000 Erfurt Hydraulic overload protection
FR2130975A5 (en) * 1971-03-29 1972-11-10 Aries Robert Bis(4-(phenoxyalkanoyloxy)-phenylthio)alkanes - hypolipemics hypocholesterolemics
FR2133024A5 (en) * 1971-04-06 1972-11-24 Aries Robert Bis-(4-nicotinoyloxyphenylthio) propanes - with hypocholesterolaemic and hypolipaemic activity
FR2134810A5 (en) * 1971-04-21 1972-12-08 Aries Robert Bis-(3-alkyl-5-t-alkyl-4-(thiazole-5-carboxy)phenylthio) alcanes - - with hypocholesterolaemic and hypolipaemic activity
FR2140769A5 (en) * 1971-06-07 1973-01-19 Aries Robert Benzofuryloxy alkanoic derivs of probucol - hypocholesterolemic and hypolipemic agents
FR2140771A5 (en) * 1971-06-07 1973-01-19 Aries Robert Tetralinyl phenoxy alkanoic esters - of bis hydroxyphenylthio alkanes, hypolipemics etc
FR2168137A1 (en) * 1972-01-17 1973-08-31 Dynachim Sarl Bis 4-hydroxyphenylthioalkane esters - with hypocholesterolaemic and hypolipaemic activities
JPS4975552A (en) * 1972-11-20 1974-07-20
US3952064A (en) * 1973-03-12 1976-04-20 Crown Zellerbach Corporation Process for producing mercaptophenols
US4029812A (en) * 1976-02-18 1977-06-14 The Dow Chemical Company Novel hypolipidemic 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thio carboxamides
US4968514A (en) * 1984-12-11 1990-11-06 Forbes Polytech, Inc. Beer bottle with fully reacted thermoplastic polyurethane crown capliner
US4679520A (en) 1985-06-10 1987-07-14 Harken Olaf T Mainsail reefing and furling device and method
DE3530256A1 (en) 1985-08-23 1987-02-26 Merrell Dow Pharma USE OF PROBUCOL IN THE TREATMENT OF HEART ARRYTHMY
DE3625279A1 (en) 1986-07-25 1988-02-04 Merrell Dow Pharma USE OF PROBUCOL FOR THE PREVENTION AND TREATMENT OF HEART DISEASES
US4975467A (en) 1987-03-17 1990-12-04 Merrell Dow Pharmaceuticals Inc. Method of inhibiting interleukin-1 release and alleviating interleukin-1 mediated conditions
US4752616A (en) * 1987-06-29 1988-06-21 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, compositions containing same and method of use
US4968710A (en) 1987-11-13 1990-11-06 Riker Laboratories, Inc. Substituted di-t-butylphenols and anti-allergic use thereof
US5066822A (en) 1987-11-13 1991-11-19 Riker Laboratories, Inc Di-t-butylphenols substituted by an alkoxy or benzyloxy group or a benzylthio group
CH675422A5 (en) 1988-03-31 1990-09-28 Symphar Sa
JP2627003B2 (en) * 1989-01-25 1997-07-02 塩野義製薬株式会社 G-tert-butylhydroxyphenylthio derivative
US5527945A (en) 1989-02-10 1996-06-18 Basf Aktiengesellschaft Diphenylheteroalkyl derivatives, the preparation thereof and drugs and cosmetics prepared therefrom
CA2017956A1 (en) * 1989-07-06 1991-01-06 Werner Bollag Use of retinoids
DE3929913A1 (en) 1989-09-08 1991-04-04 Hoechst Ag 4-HYDROXYTETRAHYDROPYRAN-2-ONE AND THE CORRESPONDING DIHYDROXYCARBONSAEUREDERIVATES, SALTS AND ESTERS, PROCESS FOR THEIR PREPARATION, THEIR USE AS A MEDICAMENT, PHARMACEUTICAL PREPARATES AND PREPARED PRODUCTS
US5115250A (en) * 1990-01-12 1992-05-19 Hewlett-Packard Company Wiper for ink-jet printhead
US5112870A (en) 1990-05-09 1992-05-12 Merrell Dow Pharmaceuticals Inc. Bis(alkyl-substituted-4-hydroxyphenylthio)alkane analogs as inhibitors of cataractogenesis
US5061734A (en) 1990-05-09 1991-10-29 Merrell Dow Pharmaceuticals Inc. Bis(alkyl-substituted-4-hydroxyphenylthio)alkane analogs as inhibitors of cataractogenesis
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
US5155250A (en) * 1990-07-05 1992-10-13 Merrell Dow Pharmaceuticals Inc. 2,6-di-alkyl-4-silyl-phenols as antiatheroscerotic agents
US5085777A (en) * 1990-08-31 1992-02-04 E. I. Du Pont De Nemours And Company Reverse osmosis membranes of polyamideurethane
FR2666583B1 (en) * 1990-09-06 1994-09-09 Adir NOVEL DERIVATIVES OF SPIRO [4.5] DECANE, THEIR PREPARATION PROCESS AND THEIR PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
RU2024509C1 (en) * 1991-05-07 1994-12-15 Всероссийский научный центр по безопасности биологически активных веществ Derivatives of 9-aminoacridine or their salts with organic or inorganic acids showing psychotropic, antiamnestic and lipid-regulating activity
GB9115951D0 (en) 1991-07-24 1991-09-11 Pfizer Ltd Indoles
SK281016B6 (en) 1992-02-05 2000-10-09 Boehringer Ingelheim Kg Amidine derivatives, method of their preparation, their use and pharmaceuticals them containing
US5310949A (en) 1992-09-02 1994-05-10 Merck & Co., Inc. Cholesterol lowering compounds
GB9220571D0 (en) 1992-09-30 1992-11-11 Ici Plc Quinazoline derivatives
US5821260A (en) * 1992-10-30 1998-10-13 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5380747A (en) * 1992-10-30 1995-01-10 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5662934A (en) * 1993-01-05 1997-09-02 Najarian; Thomas Compositions and methods for lowering cholesterol while maintaining antioxidant levels
US5585235A (en) 1993-04-13 1996-12-17 Diagnescent Technologies, Inc. Fluorescent assay and method that corrects for spectral interference
JPH06312978A (en) * 1993-04-30 1994-11-08 Japan Tobacco Inc New phthalimide derivative having inhibiting activity against phospholipase a2
US5411741A (en) 1993-07-29 1995-05-02 Zaias; Nardo Method and composition for skin depigmentation
GB9320113D0 (en) 1993-09-29 1993-11-17 Zeneca Ltd Tricyclic derivatives
ES2263094T3 (en) * 1993-12-10 2006-12-01 Aventis Inc. USE OF 2,6-DIALQUIL-4-SILIL-PHENOLS TO TREAT XANTOMA.
US5426196A (en) 1993-12-22 1995-06-20 Glaxo Inc. Synthesis of diaryl methanes
JPH07328425A (en) * 1994-06-03 1995-12-19 Toshiba Corp Plasma chemical reaction device
CA2153553A1 (en) 1994-07-13 1996-01-14 Hidekazu Suzuki Stable lipid emulsion
US5792787A (en) * 1995-06-07 1998-08-11 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
JPH0959258A (en) * 1995-08-11 1997-03-04 Ono Pharmaceut Co Ltd Guanidyl derivative
FR2738817B1 (en) * 1995-09-14 1997-10-17 Adir NOVEL SUBSTITUTED ALKANOIC 2,2-DIMETHYL-OMEGA-PHENOXY ACIDS AND ESTERS, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO1997015546A1 (en) * 1995-10-26 1997-05-01 Nippon Shinyaku Co., Ltd. Carboxylic acid derivatives and pharmaceutical compositions
KR100443893B1 (en) 1996-01-15 2004-10-15 얀센 파마슈티카 엔.브이. Angiogenesis inhibitor pyridazine amine
US5608095A (en) * 1996-04-30 1997-03-04 Hoechst Marion Roussel, Inc. Alkyl-4-silyl-phenols and esters thereof as antiatherosclerotic agents
HUP9904567A3 (en) 1996-06-20 2001-10-29 Univ Texas Use of azo, thioalkyl, thiocarbonyl derivatives substituted by fused heterocycles and/or phenyl group for the preparation of pharmaceutical compositions stimulating bone growth
WO1998030255A2 (en) 1997-01-09 1998-07-16 Localmed, Inc. Localized intravascular delivery of antioxidant substances for inhibition of restenosis in recanalized blood vessels
GB9705502D0 (en) 1997-03-17 1997-05-07 Univ Wales Swansea The Chlorination or aromatic compounds and catalysts therefor
AU6715098A (en) 1997-03-24 1998-10-20 Gilles Cote Vascular remodeling agent
US6852878B2 (en) * 1998-05-14 2005-02-08 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of VCAM-1
US6670398B2 (en) * 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
AU750041B2 (en) * 1997-05-14 2002-07-11 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
KR20010020611A (en) * 1997-07-01 2001-03-15 아테로제닉스, 인코포레이티드 Antioxidant enhancement of therapy for hyperproliferative conditions
JP2001517617A (en) 1997-09-24 2001-10-09 ノヴァ モレキュラー インク． Methods for increasing APOE levels for the treatment of neurodegenerative diseases
WO1999024400A1 (en) 1997-11-10 1999-05-20 Vyrex Corporation Probucol esters and uses thereof
FR2785284B1 (en) 1998-11-02 2000-12-01 Galderma Res & Dev VITAMIN D ANALOGS
DE19850532A1 (en) 1998-11-03 2000-05-04 Nematel Dr Rudolf Eidenschink Bisphenylthio compounds
WO2000028332A1 (en) * 1998-11-09 2000-05-18 Atherogenics, Inc. Methods and compositions to lower plasma cholesterol levels
EP1133483B1 (en) 1998-11-23 2003-04-23 Janssen Pharmaceutica N.V. Il-5 inhibiting 6-azauracil derivatives
KR100979664B1 (en) 1999-03-10 2010-09-02 유니버시티 오브 피츠버그 오브 더 커먼웰쓰 시스템 오브 하이어 에듀케이션 Adipose-derived stem cells and lattices
BR0009507A (en) 1999-03-30 2002-01-15 Novartis Ag Phthalazine derivatives for the treatment of inflammatory diseases
CA2403490A1 (en) 2000-03-21 2001-10-25 Atherogenics, Inc. N-substituted dithiocarbamates for the treatment of biological disorders
EP1289944A2 (en) * 2000-03-21 2003-03-12 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of vcam-1
US6323359B1 (en) 2000-05-02 2001-11-27 Salsbury Chemicals, Inc. Process for preparing probucol derivatives
US20030064967A1 (en) * 2001-04-11 2003-04-03 Jayraz Luchoomun Methods to increase plasma HDL cholesterol levels and improve HDL functionality with probucol monoesters
JP4017988B2 (en) 2001-05-14 2007-12-05 オムノバ ソリューソンズ インコーポレーティッド Polymer surfactant derived from cyclic monomer having pendant fluorinated carbon group
US7187870B2 (en) * 2003-10-15 2007-03-06 Oewaves, Inc. Tunable balanced opto-electronic filters and applications in opto-electronic oscillators

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3179701A (en) * 1962-05-14 1965-04-20 Shell Oil Co (3, 5-dialkyl-4-hydroxyphenyl) (3, 5-dialkyl-4-hydroxybenzyl) sulfides
US4115590A (en) * 1964-02-26 1978-09-19 Ethyl Corporation Binuclear phenols for reducing plasma lipid levels
GB1136539A (en) * 1966-12-13 1968-12-11 Uniroyal Inc Phenolic sulphides
GB1199871A (en) * 1967-05-11 1970-07-22 Consolidation Coal Co Improvements in or relating to Sulfur-Containing Bisphenols
GB1148550A (en) * 1967-12-02 1969-04-16 Uniroyal Inc Substituted benzylphenyl sulfides and their use as antioxidants
DE2716125A1 (en) * 1976-04-12 1977-10-27 Yoshitomi Pharmaceutical 3,5-DI-TERT.-BUTYL-4-HYDROXYPHENYLPYRIDINE COMPOUNDS, METHOD FOR THEIR MANUFACTURING AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
EP0190682A2 (en) * 1985-02-04 1986-08-13 G.D. Searle & Co. Novel disubstituted 4-hydroxyphenylthio anilides
US4755524A (en) * 1986-01-31 1988-07-05 G. D. Searle & Co. Novel phenolic thioethers as inhibitors of 5-lipoxygenase
EP0292660A2 (en) * 1987-03-17 1988-11-30 Merrell Dow Pharmaceuticals Inc. Alkylidenedithiobis (substituted) phenols for inhibiting interleukin-1 release and for alleviating interleukin-1 mediated conditions
EP0317165A1 (en) * 1987-11-13 1989-05-24 Riker Laboratories, Inc. DI-t-butylphenols substituted by an alkoxy or benzyloxy group or a benzylthio group
EP0348203A1 (en) * 1988-06-24 1989-12-27 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI &amp; CO. LTD. Phenolic thioethers, their production and use
EP0405788A2 (en) * 1989-06-29 1991-01-02 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI &amp; CO. LTD. Di-tert-butyl(hydroxy)phenylthio substituted hydroxamic acid derivatives
US5262439A (en) * 1992-04-30 1993-11-16 The Regents Of The University Of California Soluble analogs of probucol
EP0621255A1 (en) * 1993-04-20 1994-10-26 Adir Et Compagnie Substituted phenoxy-isobutyric acids and esters
WO1995030415A1 (en) * 1994-05-10 1995-11-16 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
WO1996012703A1 (en) * 1994-10-25 1996-05-02 G.D. Searle & Co. Heteroalkyl and heteroarylthioalkyl thiophenolic compounds as 5-lipoxygenase inhibitors
WO1998022418A1 (en) * 1996-11-20 1998-05-28 Hoechst Marion Roussel, Inc. Substituted phenols and thiophenols useful as antioxidant agents

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 110:212254, XP002115683 -& CHEMICAL ABSTRACTS, vol. 110, no. 23, 5 June 1989 (1989-06-05) Columbus, Ohio, US; abstract no. 212254a, XP002115682 & S.D. PASTOR ET AL: PHOSPHOROUS SULFUR, vol. 37, no. 3-4, 1988, pages 117-123, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 122:187387, XP002115602 -& CHEMICAL ABSTRACTS, vol. 122, no. 15, 10 April 1995 (1995-04-10) Columbus, Ohio, US; abstract no. 187387, XP002115595 & JP 06 312978 A (NIPPON TOBACCO SANGYO ET AL) 8 November 1994 (1994-11-08) *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 124:146082, XP002115604 & V.I. KELAREV ET AL: KHIM. GETEROTSIKL. SOEDIN, no. 5, 1995, pages 667-673, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 124:8690, XP002115603 -& CHEMICAL ABSTRACTS, vol. 124, no. 1, 1 January 1996 (1996-01-01) Columbus, Ohio, US; abstract no. 8690, XP002115596 & V.I. KELAREV ET AL: KHIM. GETEROTSIKL. SOEDIN, no. 4, 1995, pages 514-517, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 126:277465, XP002115599 -& CHEMICAL ABSTRACTS, vol. 126, no. 21, 26 May 1997 (1997-05-26) Columbus, Ohio, US; abstract no. 277465, XP002115593 & JP 09 059258 A (ONO PHARMACEUTICAL CO) 4 March 1997 (1997-03-04) *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 127:75973, XP002115597 & V.Z. LANKIN ET AL: DOKL. AKAD. NAUK, vol. 351, no. 4, 1996, pages 554-557, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 82:86196, XP002115598 -& CHEMICAL ABSTRACTS, vol. 82, no. 13, 31 March 1975 (1975-03-31) Columbus, Ohio, US; abstract no. 86196, XP002115592 & JP 49 075552 A (SAGAMI CHEMICAL RESEARCH CENTER) 20 July 1974 (1974-07-20) *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 86:5066, XP002115601 -& CHEMICAL ABSTRACTS, vol. 86, no. 1, 3 January 1977 (1977-01-03) Columbus, Ohio, US; abstract no. 5066, XP002115594 & A.I. MEDVEDEV ET AL: TEZISY DOKL. NAUCHN. SESS. KHIM. TEKHNOL. ORG. SOEDIN. SERY SERNISTYKH NEFTEI, 13TH,1974, pages 123-124, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, accession no. 94:30290, XP002115600 & CH.I. MAMEDOV: MATER. NAUCHN. KONF. ASPIR. AKAD. NAUK AZ. SSR, vol. 1, 1980, pages 127-131, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, CAPLUS accession no. 1970:445047, XP002124423 & M.B. NEUWORTH ET AL: J. MED. CHEM., vol. 13, no. 4, 1970, pages 722-725, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US STN, CAPLUS accession no. 1986:28675, XP002124424 & CHEMICAL ABSTRACTS, vol. 104, no. 5, 3 February 1986 (1986-02-03) Columbus, Ohio, US; abstract no. 28675, & P. DE MEGLIO ET AL: FARMACO, ED. SCI., vol. 40, no. 11, 1985, pages 833-844, *
L. COMINACINI ET AL: FREE RADICAL BIOLOGY AND MEDICINE, vol. 22, no. 1-2, 1996, pages 117-127, XP002095164 *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087645B2 (en) 1997-05-14 2006-08-08 Atherogenics, Inc. Compounds and methods for treating transplant rejection
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
US6121319A (en) * 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
US7071158B2 (en) 1997-07-01 2006-07-04 Atherogenics, Inc. Antioxidant enhancement of therapy for hyperproliferative conditions
US6852878B2 (en) 1998-05-14 2005-02-08 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of VCAM-1
US6887712B1 (en) 1998-11-09 2005-05-03 Atherogenics, Inc. Methods and compositions to lower plasma cholesterol levels
JP2006188525A (en) * 1999-05-28 2006-07-20 Abbott Lab Cell proliferation inhibitor
AU2001247651B2 (en) * 2000-03-21 2007-01-04 Atherogenics, Inc Thioketals and thioethers for inhibiting the expression of vcam-1
WO2001070757A3 (en) * 2000-03-21 2002-03-14 Atherogenics Inc Thioketals and thioethers for inhibiting the expression of vcam-1
WO2001070757A2 (en) * 2000-03-21 2001-09-27 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of vcam-1
WO2001077072A3 (en) * 2000-04-11 2002-07-18 Atherogenics Inc Compounds and methods to increase plasma hdl cholesterol levels and improve hdl functionality
WO2001077072A2 (en) * 2000-04-11 2001-10-18 Atherogenics, Inc. Compounds and methods to increase plasma hdl cholesterol levels and improve hdl functionality
US7183317B2 (en) 2000-04-11 2007-02-27 Atherogenics, Inc. Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality
US6881860B2 (en) 2000-04-11 2005-04-19 Atherogenics, Inc. Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality
US6323359B1 (en) * 2000-05-02 2001-11-27 Salsbury Chemicals, Inc. Process for preparing probucol derivatives
WO2001098291A3 (en) * 2000-06-20 2002-05-16 Atherogenics Inc 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders
WO2001098291A2 (en) * 2000-06-20 2001-12-27 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat vcam-1 mediated disorders
US7078431B2 (en) 2000-06-20 2006-07-18 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders
WO2002087556A2 (en) * 2001-04-11 2002-11-07 Atherogenics, Inc. Probucol monoesters and their use to increase plasma hdl cholesterol levels and improve hdl functionality
WO2002087556A3 (en) * 2001-04-11 2003-02-06 Atherogenics Inc Probucol monoesters and their use to increase plasma hdl cholesterol levels and improve hdl functionality
JP2005514344A (en) * 2001-10-25 2005-05-19 アセロジエニクス・インコーポレイテツド Compounds and methods for transplant rejection therapy
EP1451138A4 (en) * 2001-11-09 2005-06-15 Atherogenics Inc Methods of reversing and preventing cardiovascular pathologies
WO2003039352A3 (en) * 2001-11-09 2003-10-23 Atherogenics Inc Methods of reversing and preventing cardiovascular pathologies
WO2003039352A2 (en) * 2001-11-09 2003-05-15 Atherogenics, Inc. Methods of reversing and preventing cardiovascular pathologies
US7094801B2 (en) 2001-12-19 2006-08-22 Atherogenics, Inc. Chalcone derivatives and their use to treat diseases
US7166605B2 (en) * 2002-03-22 2007-01-23 Nicox, S.A. Probucol nitro-derivatives
US7273948B2 (en) * 2003-01-13 2007-09-25 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
US7622604B2 (en) 2003-01-13 2009-11-24 Salutria Pharmaceuticals Llc Process of preparing esters and ethers of probucol and derivatives thereof
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7173129B2 (en) 2003-06-06 2007-02-06 Athero Genics, Inc. Sulfonamide-substituted chalcone derivatives and their use to treat diseases
WO2005011594A3 (en) * 2003-07-31 2007-04-12 Epigenesis Pharmaceuticals Llc Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or vcam inhibitor for treatment of asthma or chronic obstructive pulmonary disease
WO2005011594A2 (en) * 2003-07-31 2005-02-10 Epigenesis Pharmaceuticals Llc Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a tyrosine kinase inhibitor, delta opioid receptor antagonist, neurokinin receptor antagonist, or vcam inhibitor for treatment of asthma or chronic obstructive pulmonary disease
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
WO2005051900A1 (en) * 2003-11-25 2005-06-09 Novo Nordisk A/S Novel compounds for the treatment of obesity
US7271274B2 (en) 2004-04-20 2007-09-18 Ahterogenics, Inc. Phenolic antioxidants for the treatment of disorders including arthritis, asthma and coronary artery disease
US7294737B2 (en) 2004-04-20 2007-11-13 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
WO2006063408A1 (en) * 2004-12-17 2006-06-22 Stocker Ronald O Compositions and methods for treating cardiovascular disorders
WO2008118948A1 (en) 2007-03-26 2008-10-02 Atherogenics, Inc. Methods and compositions of derivatives of probucol for the treatment of diabetes
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
US10882828B2 (en) 2009-03-18 2021-01-05 Resverlogix Corp. Anti-inflammatory agents
US11407719B2 (en) 2009-03-18 2022-08-09 Resverlogix Corp. Anti-inflammatory agents
US11649220B2 (en) 2018-01-30 2023-05-16 Demotech.Inc. Probucol derivative, preparation method therefor and use thereof

Also Published As

Publication number Publication date
DE69831566T2 (en) 2006-06-14
HU226611B1 (en) 2009-04-28
KR100882335B1 (en) 2009-02-11
CN1977837B (en) 2010-12-08
CA2289851A1 (en) 1998-11-19
ATE294158T1 (en) 2005-05-15
US6147250A (en) 2000-11-14
JP2001524986A (en) 2001-12-04
US6828447B2 (en) 2004-12-07
PL343904A1 (en) 2001-09-10
KR20010012504A (en) 2001-02-15
HK1025947A1 (en) 2000-12-01
DK0981343T3 (en) 2006-01-30
ES2248901T3 (en) 2006-03-16
AU750041B2 (en) 2002-07-11
CN1977836A (en) 2007-06-13
PL336788A1 (en) 2000-07-17
BR9809793A (en) 2000-06-27
CZ301183B6 (en) 2009-12-02
DE69831566D1 (en) 2006-01-26
CN1287783C (en) 2006-12-06
CA2292388C (en) 2004-07-20
EA012847B1 (en) 2009-12-30
CN1200704C (en) 2005-05-11
SK153299A3 (en) 2000-05-16
CN101284808A (en) 2008-10-15
DK1464639T3 (en) 2007-07-09
CZ9904024A3 (en) 2001-10-17
US6548699B1 (en) 2003-04-15
NO20032254D0 (en) 2003-05-19
WO1998051289A3 (en) 1999-05-14
DE69837295T2 (en) 2007-11-15
PL194329B1 (en) 2007-05-31
IL132798A (en) 2006-12-31
HUP0004230A3 (en) 2001-12-28
KR20070008725A (en) 2007-01-17
ATE356113T1 (en) 2007-03-15
NO995543D0 (en) 1999-11-12
ATE304350T1 (en) 2005-09-15
AU747801C (en) 2003-01-30
DE69829966D1 (en) 2005-06-02
KR100919883B1 (en) 2009-09-30
KR20070007207A (en) 2007-01-12
SK286392B6 (en) 2008-09-05
CN1496740A (en) 2004-05-19
PL207885B1 (en) 2011-02-28
TR199902803T2 (en) 2000-07-21
WO1998051289A2 (en) 1998-11-19
CA2292388A1 (en) 1998-11-19
TR199902802T2 (en) 2000-04-21
US20020193446A1 (en) 2002-12-19
ES2283933T3 (en) 2007-11-01
IL132797A0 (en) 2001-03-19
AU747801B2 (en) 2002-05-23
EA199901027A1 (en) 2000-06-26
ID29158A (en) 2001-08-02
US20020177717A1 (en) 2002-11-28
EP0981343A2 (en) 2000-03-01
CN1496739A (en) 2004-05-19
ID23877A (en) 2000-05-25
EA200800375A1 (en) 2008-06-30
JP2002503227A (en) 2002-01-29
KR20080066885A (en) 2008-07-16
US7189870B2 (en) 2007-03-13
IL178072A0 (en) 2006-12-31
CN1263462A (en) 2000-08-16
US7375252B2 (en) 2008-05-20
NO995544L (en) 2000-01-10
NO319855B1 (en) 2005-09-26
CN100453530C (en) 2009-01-21
IL164568A0 (en) 2005-12-18
EA199901026A1 (en) 2000-08-28
EA009987B1 (en) 2008-04-28
EA009370B1 (en) 2007-12-28
US6617352B2 (en) 2003-09-09
PT1464639E (en) 2007-06-15
EA200601059A1 (en) 2007-02-27
CN1275596C (en) 2006-09-20
US20020188118A1 (en) 2002-12-12
IL178072A (en) 2010-12-30
HUP0004592A3 (en) 2001-12-28
CN1263522A (en) 2000-08-16
SK285695B6 (en) 2007-06-07
JP2006232848A (en) 2006-09-07
US20080214660A1 (en) 2008-09-04
IL175130A (en) 2009-02-11
EP0994853A2 (en) 2000-04-26
EP0981343B1 (en) 2005-09-14
US20020169215A1 (en) 2002-11-14
AU7485198A (en) 1998-12-08
SK286674B6 (en) 2009-03-05
HUP0004592A2 (en) 2001-06-28
ES2241139T3 (en) 2005-10-16
US6602914B2 (en) 2003-08-05
CA2428130A1 (en) 1998-11-19
NO316221B1 (en) 2003-12-29
EA200500249A1 (en) 2005-06-30
NZ501069A (en) 2000-07-28
NO327603B1 (en) 2009-08-31
CZ9904023A3 (en) 2001-07-11
EA010183B1 (en) 2008-06-30
JP2006265257A (en) 2006-10-05
DE69829966T2 (en) 2006-02-09
IL164568A (en) 2010-05-31
NO995543L (en) 2000-01-10
CZ301302B6 (en) 2010-01-06
DE69837295D1 (en) 2007-04-19
IL132798A0 (en) 2001-03-19
BR9809819A (en) 2001-09-18
CA2289851C (en) 2009-03-10
SK153199A3 (en) 2000-05-16
CZ301313B6 (en) 2010-01-13
JP3930056B2 (en) 2007-06-13
NO995544D0 (en) 1999-11-12
NZ528906A (en) 2005-06-24
KR100953990B1 (en) 2010-04-21
KR20010012503A (en) 2001-02-15
WO1998051662A3 (en) 2000-03-02
SK286766B6 (en) 2009-05-07
CZ301985B6 (en) 2010-08-25
CY1107645T1 (en) 2013-04-18
HUP0004230A2 (en) 2001-06-28
NO20032254L (en) 2000-01-10
AU7571198A (en) 1998-12-08
US6121319A (en) 2000-09-19
HK1024629A1 (en) 2000-10-20
US20050090487A1 (en) 2005-04-28
CN1977837A (en) 2007-06-13
EP0994853B1 (en) 2005-04-27

Similar Documents

Publication Publication Date Title
US6602914B2 (en) Compounds and methods for the inhibition of the expression of VCAM-1
CA2562992C (en) Probucol analogues, and use thereof as anti-inflammatory inhibitors of vcam-1
AU2006202461B2 (en) Compositions and methods for the inhibition of the expression of VCAM-1
AU2002300328B2 (en) Compounds and methods for the inhibition of the expression of VCAM-1
EP1468989A2 (en) Compounds and methods for the inhibition of the expression of VCAM-1
EP1726582A2 (en) Compounds and methods for the inhibition of the expression of vcam-1
EP1695959A1 (en) Compouds and methods for the inhibition of the expression of VCAM-1
MXPA99010402A (en) Compounds and methods for the inhibition of the expression of vcam-1

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 132797

Country of ref document: IL

Ref document number: 98807169.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 500841

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 153299

Country of ref document: SK

ENP Entry into the national phase

Ref document number: 2289851

Country of ref document: CA

Ref document number: 2289851

Country of ref document: CA

Kind code of ref document: A

Ref document number: 1998 549502

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/010402

Country of ref document: MX

Ref document number: PV1999-4023

Country of ref document: CZ

Ref document number: 1019997010458

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1999/02803

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 1998922264

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 74851/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 199901026

Country of ref document: EA

AK Designated states

Kind code of ref document: A3

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998922264

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019997010458

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV1999-4023

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 74851/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 157077

Country of ref document: IL

Ref document number: 157078

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 164568

Country of ref document: IL

WWG Wipo information: grant in national office

Ref document number: 1998922264

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV2006-375

Country of ref document: CZ

ENP Entry into the national phase

Ref country code: SK

Ref document number: SK A