WO2005068418A1 - Composes sulfures et disulfures et compositions pour le controle de cholesterol et utilisations associees - Google Patents

Composes sulfures et disulfures et compositions pour le controle de cholesterol et utilisations associees Download PDF

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WO2005068418A1
WO2005068418A1 PCT/US2003/041612 US0341612W WO2005068418A1 WO 2005068418 A1 WO2005068418 A1 WO 2005068418A1 US 0341612 W US0341612 W US 0341612W WO 2005068418 A1 WO2005068418 A1 WO 2005068418A1
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compound
occunence
dimethyl
independently
phenyl
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PCT/US2003/041612
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Jean-Louis Basseux
Carmen Daniela Oniciu
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Esperion Therapeutics, Inc.
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Priority to PCT/US2003/041612 priority Critical patent/WO2005068418A1/fr
Priority to AU2003300439A priority patent/AU2003300439A1/en
Publication of WO2005068418A1 publication Critical patent/WO2005068418A1/fr

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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • 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
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    • 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
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Definitions

  • the present invention relates to sulfide and disulfide compounds and pharmaceutically acceptable salts, hydrates, solvates, or mixtures thereof; compositions comprising a sulfoxide or bis-sulfoxide compound or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof; and methods for treating or preventing a disease or disorder such as, but not limited to, aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease,
  • a disease or disorder such as, but not limited to, aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism
  • Synchron X glucose metabolism
  • elevated blood pressure hypertension
  • dyslipidemia blood lipid imbalance
  • LDL Low density lipoprotein
  • HDL high density lipoprotein
  • Reverse cholesterol transport describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol.
  • HDL is also responsible for the removal of non- cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream.
  • Atherosclerosis for example, is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the belief that lipids deposited in atherosclerotic lesions are derived primarily from plasma apolipoprotein B (apo B)-containing lipoproteins, which include chylomicrons, CLDL, LDL and LDL.
  • apo B-containing lipoprotein, and in particular LDL has popularly become known as the "bad" cholesterol.
  • HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDL are regarded as a negative risk factor.
  • HDL has popularly become known as the "good" cholesterol.
  • the fat-transport system can be divided into two pathways: an exogenous one for cholesterol and triglycerides absorbed from the intestine and an endogenous one for cholesterol and triglycerides entering the bloodstream from the liver and other non-hepatic tissue.
  • chylomicrons In the exogenous pathway, dietary fats are packaged into lipoprotein particles called chylomicrons, which enter the bloodstream and deliver their triglycerides to adipose tissue for storage and to muscle for oxidation to supply energy.
  • the remnant of the chylomicron, which contains cholesteryl esters, is removed from the circulation by a specific receptor found only on liver cells. This cholesterol then becomes available again for cellular metabolism or for recycling to extrahepatic tissues as plasma lipoproteins.
  • - 2 - DCl 360579.1
  • the liver secretes a large, very-low-density lipoprotein particle (VLDL) into the bloodstream.
  • VLDL very-low-density lipoprotein particle
  • VLDL The core of VLDL consists mostly of triglycerides synthesized in the liver, with a smaller amount of cholesteryl esters either synthesized in the liver or recycled from chylomicrons.
  • Two predominant proteins are displayed on the surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E), although other apolipoproteins are present, such as apolipoprotein CHI (apo CIII) and apolipoprotein CII (apo CH).
  • apolipoprotein CHI apo CIII
  • apolipoprotein CII apo CH
  • LDL intermediate-density lipoprotein
  • VLDL remnant VLDL remnant
  • IDL particles bind tightly to liver cells, which extract DDL cholesterol to make new VLDL and bile acids.
  • the IDL not taken up by the liver is catabolized by the hepatic lipase, an enzyme bound to the proteoglycan on liver cells.
  • Apo E dissociates from IDL as it is transformed to LDL.
  • Apo B-100 is the sole protein of LDL.
  • the liver takes up and degrades circulating cholesterol to bile acids, which are the end products of cholesterol metabolism.
  • the uptake of cholesterol-containing particles is mediated by LDL receptors, which are present in high concentrations on hepatocytes.
  • the LDL receptor binds both apo E and apo B-100 and is responsible for binding and removing both IDL and LDL from the circulation.
  • remnant receptors are responsible for clearing chylomicrons and VLDL remnants i.e., IDL).
  • the affinity of apo E for the LDL receptor is greater than that of apo B-100.
  • the LDL particles have a much longer circulating life span than LDL particles; LDL circulates for an average of two and a half days before binding to the LDL receptors in the liver and other tissues.
  • High serum levels of LDL, the "bad" cholesterol, are positively associated with coronary heart disease.
  • cholesterol derived from circulating LDL accumulates in the walls of arteries. This accumulation forms bulky plaques that inhibit the flow of blood until a clot eventually forms, obstructing an artery and causing a heart attack or stroke.
  • the amount of intracellular cholesterol liberated from the LDL controls cellular cholesterol metabolism.
  • the accumulation of cellular cholesterol derived from VLDL and LDL controls three processes. First, it reduces the cell's ability to make its own cholesterol by turning off the synthesis of HMGCoA reductase, a key enzyme in the
  • the incoming LDL-derived cholesterol promotes storage of cholesterol by the action of chlolesterol acyltransferase ("AC AT"), the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in storage droplets.
  • AC AT chlolesterol acyltransferase
  • the accumulation of cholesterol within the cell drives a feedback mechanism that inhibits cellular synthesis of new LDL receptors. Cells, therefore, adjust their complement of LDL receptors so that enough cholesterol is brought in to meet their metabolic needs, without overloading (for a review, see Brown & Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th Ed., Goodman & Gilman, Pergamon Press, New York, 1990, Ch. 36, pp.
  • apo B-containing lipoproteins can be trapped in the subendothelial space of an artery and undergo oxidation.
  • the oxidized lipoprotein is recognized by scavenger receptors on macrophages. Binding of oxidized lipoprotein to the scavenger receptors can enrich the macrophages with cholesterol and cholesteryl esters independently of the LDL receptor. Macrophages can also produce cholesteryl esters by the action of ACAT.
  • LDL can also be complexed to a high molecular weight glycoprotein called apolipoprotein(a), also known as apo(a), through a disulfide bridge.
  • LDL-apo(a) complex is known as Lipoprotein(a) or Lp(a). Elevated levels of Lp(a) are detrimental, having been associated with atherosclerosis, coronary heart disease, myocardial infarction, stroke, cerebral infarction, and restenosis following angioplasty.
  • 2.2 Reverse Cholesterol Transport Peripheral (non-hepatic) cells predominantly obtain their cholesterol from a combination of local synthesis and uptake of preformed sterol from VLDL and LDL. Cells expressing scavenger receptors, such as macrophages and smooth muscle cells, can also obtain cholesterol from oxidized apo B-containing lipoproteins. In contrast, reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the.
  • RCT reverse cholesterol transport
  • the RCT pathway represents the only means of eliminating cholesterol from most extrahepatic tissues and is crucial to maintenance of the structure and function of most cells in the body.
  • the enzyme in blood involved in the RCT pathway lecithhr.cholesterol acyltransferase (LCAT), converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL destined for removal.
  • LCAT is produced mainly in the liver and circulates in plasma associated with the HDL fraction.
  • Cholesterol ester transfer protein (CETP) and another lipid transfer protein, phospholipid transfer protein (PLTP), contribute - 4 - DCl: 360579.1 to further remodeling the circulating HDL population (see for example Bruce et al, 1998,
  • PLTP supplies lecithin to HDL
  • CETP can move cholesteryl ester made by LCAT to other lipoproteins, particularly apoB-containing lipoproteins, such as VLDL.
  • HDL triglyceride can be catabolized by the extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.
  • Each HDL particle contains at least one molecule, and usually two to four molecules, of apolipoprotein (apo A-I).
  • Apo A-I is synthesized by the liver and small intestine as prepro apolipoprotein which is secreted as a proprotein that is rapidly cleaved to generate a mature polypeptide having 243 amino acid residues.
  • Apo A-I consists mainly of a 22 amino acid repeating segment, spaced with helix-breaking proline residues.
  • Apo A-I forms three types of stable structures with lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL; flattened discoidal particles, referred to as pre-beta-2 HDL, which contain only polar lipids (e.g., phospholipid and cholesterol); and spherical particles containing both polar and nonpolar lipids, referred to as spherical or mature HDL (HDL 3 and HDL 2 ).
  • Most HDL in the circulating population contains both apo A-I and apo A-II, a second major HDL protein. This apo A-I- and apo A-II-containing fraction is referred to herein as the AI AII- HDL fraction of HDL.
  • AI-HDL fraction the fraction of HDL containing only apo A-I, referred to herein as the AI-HDL fraction, appears to be more effective in RCT.
  • pre-beta-1 HDL lipid-poor complex
  • Cholesterol newly transferred to pre-beta-1 HDL from the cell surface rapidly appears in the discoidal pre- beta-2 HDL.
  • PLTP may increase the rate of disc formation (Lagrost et al., 1996, J. Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCT is lacking.
  • LCAT reacts preferentially with discoidal and spherical HDL, transferring the 2-acyl group of lecithin or phosphatidylethanolamine to the free hydroxyl residue of fatty alcohols, particularly cholesterol, to generate cholesteryl esters (retained in the HDL) and lysolecithin.
  • the LCAT reaction requires an apoliprotein such apo A-I or apo A-IV as an activator.
  • ApoA-I is one of the natural cofactors for LCAT.
  • the conversion of cholesterol to its HDL-sequestered ester prevents re-entry of cholesterol into the cell, resulting in the r - J - DC1 360579 1 ultimate removal of cellular cholesterol.
  • HDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J. 15_:161-7; Kurata et al, 1998, J. Atherosclerosis and Thrombosis 4:112-7). While there is a consensus that CETP is involved in the metabolism of VLDL- and LDL-derived lipids, its role in RCT remains controversial. However, changes in CETP activity or its acceptors, VLDL and LDL, play a role in "remodeling" the HDL population. For example, in the absence of CETP, the HDL becomes enlarged particles that are poorly removed from the circulation (for reviews on RCT and HDLs, see Fielding & Fielding,
  • Peroxisome Proliferator Activated Receptor Pathway Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the /3-oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev.
  • Peroxisome proliferation can also be elicited by dietary or physiological factors, such as a high-fat diet and cold acclimatization. Insight into the mechanism whereby peroxisome proliferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, 1990, Nature 347:645-650 . This receptor, termed peroxisome proliferator activated receptor (PPARQ), was subsequently shown to be activated by a variety of medium and long-chain fatty acids.
  • PPARQ peroxisome proliferator activated receptor
  • PPAR ⁇ activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), in the form of a heterodimer with the retinoid X receptor (RXR).
  • RXR is activated by 9-cis retinoic acid (see Kliewer et al, 1992, Nature 358:771-774; Gearing et al, 1993, Proc. Natl Acad. Sci. USA 90:1440-1444, Keller et al, 1993, Proc. Natl. Acad. Sci. USA 90:2160-2164; Heyman et al, 1992, Cell 68:397-406, and Levin et al, 1992, Nature 355:359-361).
  • PPRE peroxisome proliferator response elements
  • PPAR* Since the discovery of PPAR*, additional isoforms of PPAR have been identified, e.g., PPAR ⁇ , PPAR ⁇ and PPAR 5 , which have similar functions and are similarly regulated. PPREs have been identified in the enhancers of a number of gene-encoding proteins that regulate lipid metabolism.
  • proteins include the three enzymes required for peroxisomal ⁇ -oxidation of fatty acids; apolipoprotein A-I; medium-chain acyl-CoA dehydrogenase, a key enzyme in mitochondrial -oxidation; and aP2, a lipid binding protein expressed exclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM, 4:291-296; see also Staels and Auwerx, 1998, Atherosclerosis 137 Suppl:S19-23 .
  • the nature of the PPAR target genes coupled with the activation of PPARs by fatty acids and hypolipidemic drugs suggests a physiological role for the PPARs in lipid homeostasis.
  • Pioglitazone an antidiabetic compound of the thiazolidinedione class, was reported to stimulate expression of a chimeric gene containing the enhancer/promoter of the lipid-binding protein aP2 upstream of the chloroamphenicol acetyl transferase reporter gene (Harris and Kletzien, 1994, Mol. Pharmacol 45:439-445). Deletion analysis led to the identification of an approximately 30 bp region responsible for pioglitazone responsiveness. In an independent study, this 30 bp fragment was shown to contain a PPRE (Tontonoz et ⁇ /.,1994, Nucleic Acids Res. 22:5628-5634).
  • PPRE Tontonoz et ⁇ /.,1994, Nucleic Acids Res. 22:5628-5634.
  • bile-acid-binding resins examples include cholestyramine (QUESTRAN LIGHT, Bristol-Myers Squibb), and colestipol hydrochloride (COLESTLD, Pharmacia & Upjohn Company). When taken orally, these positively charged resins bind to negatively charged bile acids in the intestine. Because the resins cannot be absorbed from the intestine, they are excreted, carrying the bile acids with them. The use of such resins, however, at best only lowers serum cholesterol levels by about 20%. Moreover, their use is associated with gastrointestinal side-effects, including constipation and certain vitamin deficiencies.
  • statins are inhibitors of cholesterol synthesis.
  • statins are used in combination therapy with bile-acid-binding resins.
  • Lovastatin (MEVACOR, Merck & Co., Inc.), a natural product derived from a strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers Squibb Co.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterol synthesis by inhibiting HMGCoA, the key enzyme involved in the cholesterol biosynthetic pathway.
  • Lovastatin significantly reduces serum cholesterol and LDL-serum levels. It also slows progression of coronary atherosclerosis. However, serum HDL levels are only slightly increased following lovastatin administration. The mechanism of the LDL- lowering effect may involve both reduction of VLDL concentration and induction of cellular expression of LDL-receptor, leading to reduced production and/or increased catabolism of LDL. Side effects, including liver and kidney dysfunction are associated with the use of these drugs.
  • Niacin also known as nicotinic acid, is a water-soluble vitamin B-complex used as a dietary supplement and antihyperlipidemic agent. Niacin diminishes production of VLDL and is effective at lowering LDL. It is used in combination with bile-acid-binding resins. Niacin can increase HDL when administered at therapeutically effective doses; however, its usefulness is limited by serious side effects.
  • Fibrates are a class of lipid-lowering drugs used to treat various forms of hyperlipidemia, elevated serum triglycerides, which may also be associated with hypercholesterolemia. Fibrates appear to reduce the VLDL fraction and modestly increase HDL; however, the effects of these drugs on serum cholesterol is variable. In the United States, fibrates have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia agents. For example, clofibrate (ATROMID-S, Wyeth- Ayerst Laboratories) is an antilipidemic agent that acts to lower serum triglycerides by reducing the VLDL fraction.
  • ATROMID-S Wyeth- Ayerst Laboratories
  • ATROMID-S may reduce serum cholesterol levels in certain patient subpopulations, the biochemical response to the drug is variable, and is not always possible to predict which patients will obtain favorable results.
  • ATROMID-S has not been shown to be effective for prevention of coronary heart disease.
  • LOPED also increases HDL cholesterol, particularly the HDL 2 and HDL 3 subtractions, as well as both the AI/AII-HDL fraction.
  • LOPED is heterogeneous, especially among different patient populations. Moreover, while prevention of coronary heart disease was observed in male patients between the ages of 40 and 55 without history or symptoms of existing coronary heart disease, it is not clear to what extent these findings can be extrapolated to other patient populations (e.g., women, older and younger males). Indeed, no efficacy was observed in patients with established coronary heart disease. Serious side-effects are associated with the use of fibrates, including toxicity; malignancy, particularly malignancy of gastrointestinal cancer; gallbladder disease; and an increased incidence in non-coronary mortality. These drugs are not indicated for the treatment of patients with high LDL or low HDL as their only lipid abnormality.
  • Oral estrogen replacement therapy may be considered for moderate hypercholesterolemia in post-menopausal women.
  • increases in HDL may be accompanied with an increase in triglycerides.
  • Estrogen treatment is, of course, limited to a specific patient population, postmenopausal women, and is associated with serious side effects, including induction of malignant neoplasms; gall bladder disease; thromboembolic disease; hepatic adenoma; elevated blood pressure; glucose intolerance; and hypercalcemia.
  • 4,689,344 discloses j3, ⁇ ,j8%j8'-tetrasubstituted- ⁇ , ⁇ -alkanedioic acids that are optionally substituted at their a,a,ti! ,c£ -positions, and alleges that they are useful for treating obesity, hyperlipidemia, and diabetes. According to this reference, both triglycerides and cholesterol are lowered significantly by compounds such as 3 ,3 , 14, 14- tetramethylhexadecane-l,16-dioic acid.
  • U.S. Patent No. 4,689,344 further discloses that the (3,
  • 3,930,024 also are not useful for treating hypercholesterolemia or obesity.
  • Other compounds are disclosed in U.S. Patent No. 4,711,896.
  • U.S. Patent No. 5,756,544 ⁇ -dicarboxylic acid-terminated dialkane ethers are disclosed to have activity in lowering certain plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL- cholesterol, in animals, and elevating others, such as HDL-cholesterol. The compounds are also stated to increase insulin sensitivity.
  • Lp(a) triglycerides
  • VLDL-cholesterol VLDL-cholesterol
  • LDL- cholesterol LDL- cholesterol
  • U.S. Patent No. 4,287,200 discloses azolidinedione derivatives with anti-diabetic, hypolipidemic, and anti-hypertensive properties.
  • the administration of these compounds to patients can produce side effects such as bone marrow depression, and both liver and cardiac cytotoxicity.
  • the compounds disclosed by U.S. Patent No. 4,287,200 stimulate weight gain in obese patients.
  • the invention relates to a compound of the formula 1: w ⁇ z m ⁇ s ⁇ G / s ⁇ z m A ⁇
  • W 1 and W 2 are independently L, V, C(R 1 )(R 2 HCH 2 ) c -C(R 3 )(R 4 )-(CH 2 ) n _Y, or C(R 1 )(R 2 )-(CH ) C _V where c is 1 or 2 and n is an integer ranging from 0 to 4;
  • each occurrence of R 1 or R 2 is independently (C _C 6 )alkyl, (C 2 _C 6 )alkenyl, (C 2 _ C 6 )alkynyl, phenyl, or benzyl or when one or both of W and W is C(R )(R )- (CH 2 ) C X(R 3 )(R 4 )-Y > then R 1 and R 2 can both be H to form a methylene group; or R and R and the carbon to which they are both attached are taken together to form a (C 3 -C )cycloakyl group;
  • each occurrence of R 3 or R 4 is independently H, (C ⁇ _C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C ⁇ _C 6 )alkoxy, phenyl, benzyl, Cl, Br, CN, NO 2 , or CF 3 , with the proviso that when R 1 and R 2 are both H, then one of R 3 and R 4 is not H;
  • L is C(R 1 )(R 2 HCH 2 ) n _Y; or R 3 and R 4 and the carbon to which they are both attached are taken together to form a (C 3 -C )cycloakyl group;
  • each occurrence of Y is independently (C ⁇ _C 6 )alkyl, OH, COOH, CHO, COOR 5 SO 3 H,
  • R 5 is (C ⁇ _C 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 _C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 _C 6 )alkoxy, or phenyl groups,
  • each occurrence of R 6 is independently H, (C ⁇ _C 6 )alkyl, (C 2 _ C 6 )alkenyl, or (C 2 _C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ _C 6 alkoxy, or phenyl groups; and
  • each occurrence of R 7 is independently H, (C ⁇ _C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 _C 6 )alkynyl.
  • the invention encompasses compounds of formula la: z m o z m la
  • W 1 and W 2 are independently L, V, or C(R 1 )(R 2 )-(CH 2 ) C -V, where c is 1 or 2;
  • each occurrence of R 1 and R 2 is independently (C ⁇ _C 6 )alkyl, (C _C 6 )alkenyl, (C 2 _ C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
  • L is C(R 1 )(R 2 )-(CH 2 ) n -Y, where n is an integer ranging from 0 to 4;
  • each occurrence of Y is independently (d_C 6 )alkyl, OH, COOH, CHO, COOR 3 , SO 3 H,
  • R 3 is (C ⁇ _C 6 )alkyl, (C 2 A 6 )alkenyl, (C 2 X 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ -C 6 )alkoxy, or phenyl groups,
  • each occurrence of R 4 is independently H, (C ⁇ _C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 _C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ _C 6 alkoxy, or phenyl groups; and
  • each occurrence of R 5 is independently H, (C 1 _C 6 )alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl.
  • each occurrence of Y is independently OH, COOR 3 , or COOH.
  • the invention encompasses compounds of formula lb
  • each occurrence of m is independently an integer ranging from 1 to 9;
  • n is independently an integer ranging from 0 to 4.
  • each occurrence of R 1 and R 2 is independently (QX ⁇ alkyl, (C 2 X 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
  • each occurrence of R u and R 12 is independently (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl, benzyl, or R n and R 12 and the carbon to which they are both attached are taken together to form a (C -C 7 )cycloakyl group;
  • each occurrence of Y is independently (C ⁇ X 6 )alkyl, OH, COOH, CHO, COOR 3 , SO 3 H,
  • R 3 is (C 1 X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ X 6 )alkoxy, or phenyl groups,
  • each occurrence of R 4 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ alkoxy, or phenyl groups; and
  • each occurrence of R 5 is independently H, ( X ⁇ alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl.
  • each occurrence of Y is independently OH, COOR 3 , or
  • the invention encompasses compounds of formula lc
  • each occurrence of m is an independent integer ranging from 1 to 9;
  • the invention encompasses compounds of formula II:
  • each occurrence of R 1 or R 2 is independently (C ⁇ _C 6 )alkyl, (C X 6 )alkenyl, (C 2 - C 6 )alkynyl, benzyl, phenyl, or R 1 or R 2 and the carbon to which they are both attached are taken together to form (C X 7 )cycloalkyl group;
  • each occurrence of R 11 or R 12 is independently (C ⁇ _C 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 _ C 6 )alkynyl, benzyly, phenyl, or R 11 and R 12 and the carbon to which they are both attached are taken together to form (C 3 X 7 )cycloalkyl group;
  • n is independently an integer ranging from 0 to 6;
  • each occurrence of m is independently an integer ranging from 1 to 8.
  • W 1 and W 2 are independently (dX 6 )alkyl, CH 2 OH, C(O)OH, CHO, OC(O)R 3 , C(O)OR 3 , SO 3 H,
  • R 3 is (C 1 X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (dX ⁇ alkoxy, or phenyl groups,
  • each occurrence of R 4 is independently H, (C ⁇ X 6 )alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, QX 6 alkoxy, or phenyl groups; and
  • each occurrence of R 5 is independently H, (C ⁇ X 6 )alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl.
  • the invention encompasses compounds of formula Ila:
  • R 1 and R 2 are (C ⁇ _C 6 )alkyl, OH, COOH, CHO, COOR 7 , SO 3 H,
  • R 7 is (C ⁇ X 6 )alkyl, (C 2 _C 6 )alkenyl, (C 2 _C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ X 6 )alkoxy, or phenyl groups,
  • each occurrence of R 8 is independently H, (C 1 X 6 )alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, CjX 6 alkoxy, or phenyl groups,
  • each occurrence of R 9 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl;
  • R 3 and R 4 are (C ⁇ _C 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X 6 )alkynyl, phenyl, or benzyl;
  • R 5 and R 6 are H, halogen, (C ⁇ X )alkyl, (QX ⁇ alkoxy, (C6)aryloxy, CN, or NO 2( N(R 5 ) 2 where R 5 is H, ( X 4 ) alkyl, phenyl, or benzyl;
  • each occurrence of m is independently an integer ranging from 1 to 5;
  • n is independently an integer ranging from 0 to 4.
  • (f) * 1 and * 2 represent independent chiral-carbon centers, wherein each center may independently be R or S.
  • Preferred compounds of formula Ila are those wherein each occurrence of R 1 and R 2 is independently OH, COOR 7 , or COOH.
  • Other preferred compounds of formula Ha are those wherein m is 0.
  • Other preferred compounds of formula Ila are those wherein m is 1. 1 ")
  • Other preferred compounds of formula Ila are those wherem R and or R is C(O)OH or CH 2 OH.
  • Other preferred compounds of formula Ila are those wherein R 3 and R 4 are each independently (CjX 6 ) alkyl.
  • Other preferred compounds of formula Ila are those wherein R 3 and R 4 are each methyl.
  • compounds of formula Ila are those wherein * 1 is of the stereochemical configuration R or substantially R.
  • Other preferred compounds of formula Ha are those wherein * l is of the stereochemical configuration S or substantially S.
  • Other preferred compounds of formula Ila are those wherein * 2 is of the stereochemical configuration R or substantially R.
  • Other preferred compounds of formula Ha are those wherem * is of the stereochemical configuration S or substantially S. stereochemical configuration S or substantially S. - 21 - DCl : 360579.1
  • compounds of formula Ha are those wherein * l * 2 are of the stereochemical configuration (S',S 2 ) or substantially (S ⁇ S 2 ).
  • compounds of formula Ha are those wherein * l * 2 are of the stereochemical configuration (S ⁇ R 2 ) or substantially (S',R 2 ). In another particular embodiment, compounds of formula Ha are those wherein * l * 2 are of the stereochemical configuration (R ! ,R 2 ) or substantially (R ⁇ R 2 ). In another particular embodiment, compounds of formula Ha are those wherein * l * 2 are of the stereochemical configuration (R ⁇ S 2 ) or substantially (R ⁇ S 2 ). In yet another embodiment, the invention encompasses compounds of formula III
  • W 1 and W 2 are independently C(R 1 )(R 2 )-(CH 2 ) n _Y;
  • n is independently an integer ranging from 0 to 4.
  • R 1 and R 2 are independently (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X 6 )alkynyl, phenyl, or benzyl or R 1 and R 2 are both H;
  • Y is (dX 6 )alkyl, OH, COOH, CHO, COOR 3 , SO 3 H,
  • R 3 is (dX f alkyl, (C 2 X 6 )alkenyl, (C2-C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ X 6 )alkoxy, or phenyl groups,
  • each occurrence of R 4 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ X 6 alkoxy, or phenyl groups,
  • each occurrence of R 5 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl;
  • each occurrence of p is independently 2 or 3 where the broken line represents an optional presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
  • each occurrence of W 1 and W 2 is an independent C(R 1 )(R 2 )-(CH 2 ) n _Y group and each occurrence of Y is independently OH, COOR 3 , or COOH.
  • the compounds of the invention are of formula Ilia, wherein the dashed line of compound III is removed, and therefore the rings are saturated.
  • the compounds of the invention are useful in medical applications for treating or preventing aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor- associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (EBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g., systemic l
  • the phrase "compounds of the invention” means, collectively, the compounds of formulas I, II, and III and pharmaceutically acceptable salts, hydrates, solvates, and clathrates, enantiomers, diasteriomer, racemates or mixtures of steroisomers thereof.
  • Compounds of formula I encompass subgroup formulas la lb, and lc.
  • Compounds of formula II encompass the subgroup of formula Ila
  • compounds of formula HI encompass subgroup of formula Ilia.
  • compound of the invention collectively means compound of formulas I, la, lb, lc, II, Ha, III, and Ilia and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diasteriomers, racemates or mixtures of steroisomers thereof.
  • the compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is referred to by both a chemical structure and a
  • the present invention further provides pharmaceutical compositions comprising one or more compounds of the invention and a pharmaceutically acceptable vehicle, excipient, or diluent.
  • a pharmaceutically acceptable vehicle can comprise a carrier, excipient, diluent, or a mixture thereof.
  • compositions are useful for treating or preventing aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor- associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (LBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g., systemic lupus erythe
  • the present invention provides a method for treating or preventing a aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g., rheuma
  • the invention also encompasses a method for inhibited hepatic fatty acid and sterol synthesis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable vehicle, excipient, or diluent.
  • the invention also encompasses a method of treating or preventing a disease or disorder that is capable of being treated or prevented by increasing HDL levels, which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable vehicle, excipient, or diluent.
  • the invention also encompasses a method of treating or preventing a disease or disorder that is capable of being treated or prevented by lowering LDL levels, which comprises administering to such patient in need of such treatment or prevention a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable vehicle, excipient, or diluent.
  • the compounds of the invention favorably alter lipid metabolism in animal models of dyslipidemia at least in part by enhancing oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis and therefore the invention also encompasses methods of treatment or prevention of metabolic syndrome disorders.
  • the compounds of the present invention are useful for the treatment of vascular disease, such as cardiovascular disease, stroke, and peripheral vascular disease; dyslipidemia; dyslipoproteinemia; a disorder of glucose metabolism; Alzheimer's Disease; Syndrome X; a peroxisome proliferator activated receptor-associated disorder; septicemia; a thrombotic disorder; obesity; pancreatitis; hypertension; renal disease; cancer; inflammation; inflammatory muscle diseases, such as polymylagia rheumatica, polymyositis, and fibrositis; impotence; gastrointestinal disease; irritable bowel syndrome; inflammatory bowel disease; inflammatory disorders, such as asthma, vasculitis, ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis, (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and autoimmune chronic hepatitis; arthritis, such as rheumatoid arthritis, juvenile rheuma
  • osteoporosis soft tissue rheumatism, such as tendonitis; bursitis; autoimmune disease, such as systemic lupus and erythematosus; scleroderma; ankylosing spondylitis; gout; pseudogout; non-insulin dependent diabetes mellitus; polycystic ovarian disease; hyperlipidemias, such as familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH); lipoprotein lipase deficiencies, such as hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemia; lipoprotein abnormalities associated with diabetes; lipoprotein abnormalities associated with obesity; and lipoprotein abnormalities associated with Alzheimer's Disease.
  • FH familial hypercholesterolemia
  • FCH familial combined hyperlipidemia
  • lipoprotein lipase deficiencies such as hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemia
  • lipoprotein abnormalities associated with diabetes lipoprotein abnormal
  • the compounds and compositions of the invention are useful for treatment or prevention of high levels of blood triglycerides, high levels of low density lipopotein cholesterol, high levels of apolipoprotein B, high levels of lipoprotein Lp(a) cholesterol, high levels of very low density lipoprotein cholesterol, high levels of fibrinogen, high levels of insulin, high levels of glucose, and low
  • Ib-2 4-[3-(4-Hydroxy-3 ,3 -dimethyl-butylsulfanyl)-propylsulfanyl]-2,2-dimethyl-butan- 1 -ol
  • Ib-83 5-[2-(4-Carboxy-3,3-dimethyl-butylsulfanyl)-ethylsulfanyl]-3,3-dimethyl-pentanoic acid
  • Ib-84 5-[2-(3,3-Dimethyl-5-oxo-pentylsulfanyl)-ethylsulfanyl]-3,3-dimethyl-pentanal
  • Ib-162 6-[3-(5-Cyanocarbamoyl-4,4-dimethyl-pentane-l-sulfanyl)-propane-l-sulfanyl]-3,3- dimethyl-hexanoic acid cyanamide
  • Ib-163 Phosphoramidic acid mono-[ 16-(amino-hydroxy-phosphoryloxy)-4,4, 15 , 15-tetramethyl- 7,11-dioxo-hexadecyl] thioester
  • Ib-170 1 [3 -(5 - ⁇ 5 -Hydroxy-4-oxo-4H-pyran-2-yl ⁇ -4,4-dimethyl-pentane-5 l-sulfanyl)-propane-l-sulfanyl]-5-(5-hydroxy-4-oxo-4H-pyran-2-yl)-4,4-dimethyl-pentane
  • IIIa-7 (6- ⁇ 2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-tetrahydro-thiopyran-2-yl]-ethyl ⁇ -tetrahydro- thiopyran-2-yl)-2 ,2-d imethyl-hexan- 1 -o 1
  • FIG. 2 illustrates the Effect of One Week Daily Oral Gavage Treatment on Lipoprotein Total Cholesterol in Chow-Fed male Sprague-Dawly Rats.
  • FIG. 3 is a graph of Effect of One Week Daily Oral Gavage Treatment on Serum Lipids in Chow-Fed Male Sprague-Dawly Rats
  • FIG. 4 is a graph of the Effects of Two Weeks of Daily Oral Gavage Treatment on
  • FIG. 5 is a table of the Effects of Two Weeks of Daily Oral Gavage Treatment in Chow-Fed Obese Female Zucker Rats. 4.
  • the present invention provides novel compounds useful for treating or preventing aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory processes and diseases like gastrointestinal disease,
  • the compounds of the invention are particularly useful when incorporated in a pharmaceutical composition having a carrier, excipient, diluent, or a mixture thereof.
  • a composition of the invention need not contain additional ingredients, such as an exicpient, other than a compound of the invention. Accordingly, in one
  • the compositions of the invention can omit pharmaceutically acceptable excipients and diluents and can be delivered in a gel cap or drug delivery device.
  • the present invention provides methods for treating or preventing aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (e
  • IBS irritable bowel syndrome
  • a compound of the invention is administered in combination with another therapeutic agent.
  • the other therapeutic agent provides additive or synergistic value relative to the administration of a compound of the invention alone.
  • the therapeutic agent can be a lovastatin; a thiazolidinedione or fibrate; a bile-acid-binding-resin; a niacin; an anti-obesity drug; a hormone; a tyrophostine; a sulfonylurea-based drug; a biguanide; an ⁇ -glucosidase inhibitor; an apolipoprotein A-I agonist; apolipoprotein E; a phosphodiesterase type-5 inhibitor drug; a cardiovascular drug; an HDL-raising drug; an HDL enhancer; or a regulator of the apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein genes.
  • apolipoprotein(a) apolipoprotein(a)
  • Apo A-I apolipoprotein A-I
  • Apo B apolipoprotein B
  • Apo E apolipoprotein E
  • FH Familial hypercholesterolemia
  • FCH Familial combined hyperlipidemia
  • GDM Gestational diabetes mellitus
  • HDL High density lipoprotein
  • IDL Intermediate density lipoprotein
  • IDDM Insulin dependent diabetes mellitus
  • LDH Lactate dehdyrogenase
  • LDL Low density lipoprotein
  • Lp(a) Lipoprotein (a) MODY: Maturity onset diabetes of the young
  • NIDDM Non-insulin dependent diabetes mellitus
  • PPAR Peroxisome proliferator activated receptor
  • RXR Retinoid X receptor
  • VLDL Very low density lipoprotein
  • the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding compound's enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • a compound of the invention is considered optically active or enantiomerically pure
  • a compound of the invention is considered to be in enantiomerically-enriched form when the compound has an enantiomeric excess of greater than about 1% ee, preferably greater than about 5% ee, more preferably, greater than about 10% ee with respect to a particular chiral center.
  • a compound of the invention is considered diastereomerically pure with respect to multiple chiral centers when the compound is about 90% de (diastereomeric excess) or greater, preferably, equal to or greater than 95% de with respect to a particular chiral center.
  • a compound of the invention is considered to be in diastereomerically-enriched form when the compound has an diastereomeric excess of greater than about 1% de, preferably greater than about 5% de, more preferably, greater than about 10% de with respect to a particular chiral center.
  • a racemic mixture means about 50% of one enantiomer and
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of compounds of Formulas I through III.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition.
  • isolated means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture.
  • a natural source such as a plant or cell, preferably bacterial culture
  • a synthetic organic chemical reaction mixture Preferably, via conventional techniques, the compounds of the invention are purified.
  • purified means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a single ether compound of the invention by weight of the isolate.
  • pharmaceutically acceptable salt(s), as used herein includes, but are not limited to, salts of acidic or basic groups that may be present in the compounds of the invention.
  • acids that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, I 'M DCl : 360579.1 glucaronate, saccharate, formate, benzoate, glutamate, methan
  • Compounds of the invention that include an amino moiety also can form pharmaceutically acceptable salts with various arnino acids, in addition to the acids mentioned above.
  • Compounds of the invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium lithium, zinc, potassium, and iron salts.
  • the term "solvate” means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • hydrate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound of the invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • Altering lipid metabolism indicates an observable (measurable) change in at least one aspect of lipid metabolism, including but not limited to total blood lipid content, blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood triglyceride, blood Lp(a), blood apo A-I, blood apo E and blood non-esterified fatty acids.
  • Altering glucose metabolism indicates an observable (measurable) change in at least one aspect of glucose metabolism, including but not limited to total blood glucose content, blood insulin, the blood insulin to blood glucose ratio, insulin sensitivity, and oxygen consumption.
  • alkyl group means a saturated, monovalent, unbranched or branched hydrocarbon chain.
  • alkyl groups include, but are not limited to, ( -C ⁇ alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l - propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl
  • DCl 360579.1 groups, such as heptyl, and octyl.
  • An alkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • An "alkenyl group” means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to (C 2 _C 6 )alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2- methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • An "alkynyl group” means monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, (C 2 -C 6 )alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.
  • aryl group means a monocyclic or polycyclic-aromatic radical comprising carbon and hydrogen atoms.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo- fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aryl group can be unsubstituted or substituted with one or two suitable substituents.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryl".
  • heteroaryl group means a monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phienyl, isoxazolyl, and oxazolyl.
  • a heteroaryl group can be unsubstituted or substituted with one or two suitable substituents.
  • a heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "(C 2 - C 5 )heteroaryl".
  • a "cycloalkyl group” means a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds. Examples of
  • DC1 - 360579.1 cycloalkyl groups include, but are not limited to, (C 3 _C 7 )cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or substituted by one or two suitable substituents.
  • the cycloalkyl group is a monocyclic ring or bicyclic ring.
  • heterocycloalkyl group means a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as ( -C ⁇ heterocycloalkyl.
  • a "heterocyclic radical” or “heterocyclic ring” means a heterocycloalkyl group or a heteroaryl group.
  • alkoxy group means an -O-alkyl group, wherein alkyl is as defined above. An alkoxy group can be unsubstituted or substituted with one or two suitable substituents.
  • the alkyl chain of an alkyloxy group is from 1 to 6 carbon atoms in length, referred to herein as "( -C ⁇ alkoxy”.
  • aryloxy group means an -O-aryl group, wherein aryl is as defined, above.
  • An aryloxy group can be unsubstituted or substituted with one or two suitable substituents.
  • the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6)aryloxy”.
  • benzyl means -CH 2 _phenyl.
  • phenyl means -C 6 H 5 .
  • a phenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • a “hydrocarbyl” group means a monovalent group selected from (C ⁇ -C 8 )alkyl, (C 2 _ C 8 )alkenyl, and (C 2 _C 8 )alkynyl, optionally substituted with one or two suitable substituents.
  • the hydrocarbon chain of a hydrocarbyl group is from 1 to 6 carbon atoms in length, referred to herein as "(C 1 _C 6 )hydrocarbyl".
  • a “carbonyl” group is a divalent group of the formula -C(O)-.
  • alkoxycarbonyl means a monovalent group of the formula -C(O)- alkoxy.
  • the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred to herein as a "lower alkoxycarbonyl” group.
  • a "carbamoyl” group means the radical -C(O)N(R') 2 , wherein R' is chosen from the group consisting of hydrogen, alkyl, and aryl.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • halo and “Hal”encompass fluoro, chloro, bromo, and iodo.
  • a "suitable substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
  • substituents include, but are not limited to: (C 1 _C 8 )alkyl; (C ⁇ _C 8 )alkenyl; (C ⁇ X 8 )alkynyl; (C 6 )aryl; (C 2 _C 5 )heteroaryl; (C 3 _ C 7 )cycloalkyl; (d_C 8 )alkoxy; (C 6 )aryloxy; -CN; -OH; oxo; halo, -CO 2 H; -NH 2 ; -NH((Ci_ C 8 )alkyl); -N((C,_C 8 )al yl)2; -NH((C 6 )aryl); -N((C 6 )aryl) 2 ; -CHO; -CO((C 1 _C 8 )alkyl); - CO((C 6 )aryl); -CO 2 ((Ci_C 8 )alkyl); and -
  • n is an integer ranging from 2 to 5
  • Scheme 1 illustrates the synthesis of mono-protected diols of the formula X, wherein n is an integer ranging from 0 to 4 and R 1 and R 2 are as defined above.
  • Scheme 1 first outlines the synthesis of mono-protected diols X, wherein n is 0, where esters 7 are successively reacted with a first ((R ) p JVI) then a second ((R )p_M) organometalhc reagent providing ketones 8 and alcohols 9, respectively.
  • M is a metal and p is the metal's valency value (e.g., the valency of Li is 1 and that of Zn is 2).
  • Suitable metals include, but are not limited to, Zn, Na, Li, and -Mg-Hal, wherein Hal is a halide selected from iodo, bromo, or chloro.
  • M is -Mg-Hal, in which case the organometalhc reagents, (R ⁇ p JVIg- Hal and (R )p_Mg-Hal, are known in the art as Grignard reagents.
  • Esters 7 are available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or can be prepared by
  • the reaction can be performed by adding an organic solution of (R')p V[ (about 0.5 to about 1 equivalents) to a stirred, cooled (about 0°C to about -80°C) solution comprising esters 7, under an inert atmosphere (e.g., nitrogen) to give a reaction mixture comprising ketones 8.
  • (R ⁇ p JVI is added at a rate such that the reaction-mixture temperature remains within about one to two degrees of the initial reaction-mixture temperature.
  • the progress of the reaction can be followed by using an appropriate analytical method, such as thin-layer chromatography or high-performance-liquid chromatography.
  • Suitable solvents for obtaining alcohols 9 include, but are not limited to, dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene, xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane), and mixtures thereof.
  • the organic solvent is diethyl ether or tetrahydrofuran.
  • alcohols 9 are converted to mono-protected diols X, wherein n is 0, using the well-known Williamson ether synthesis. This involves reacting alcohols 9 with -O-PG, wherein -PG is a hydroxy- protecting group.
  • Williamson ether synthesis see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 386-387, and for a list of procedures and reagents useful in the Williamson ether synthesis see Larock Comprehensive Organic Transformations; VCH: New York, 1989, pp. 446-448,
  • a "hydroxy- protecting group” means a group that is reversibly attached to a hydroxy moiety that renders the hydroxy moiety unreactive during a subsequent reaction(s) and that can be selectively cleaved to regenerate the hydroxy moiety once its protecting purpose has been served.
  • hydroxy-protecting groups are found in Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition 17-237 (1999), incorporated herein by reference.
  • the hydroxy-protecting group is stable in a basic reaction medium, but can be cleaved by acid.
  • Suitable base-stable acid-labile hydroxy-protecting groups suitable for use with the invention include, but are not limited to, ethers, such as methyl, methoxy methyl, methylthiomethyl, methoxyethoxymethyl, bw(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl, 1- ethoxyethyl, 1 -methyl- 1-methoxyethyl, t-butyl, allyl, benzyl, o-nitrobenzyl, triphenylmethyl, ⁇ -naphthyldiphenylmethyl, ?-methoxyphenyldiphenylmethyl, 9-(9-phenyl- 10-oxo)anthranyl, trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl
  • Ethers are preferred, particularly straight chain ethers, such as methyl ether, methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether, bw(2-chloroethoxy)methyl ether.
  • -PG is methoxymethyl (CH 3 OCH 2 ).
  • Reaction of alcohols 9 with -O-PG under the conditions of the Williamson ether synthesis require the protection of the hydroxy group. Alcohols 9 are protected with a base-labile protecting group, but stable in the presence of nucleophiles or NaH, NA or other metals used in the next step.
  • Protecting groups recommended for this step are: pivolate, 2,4,6-trimetylbenzoate (mesitoate), alkylmethyl carbonate, or other similar reagents described in Greene, T.W., Protective Groups in Organic Chemistry, p. 170-187.
  • the alcohol 9 is treated with an acid chloride or an anhydride in the presence of a suitable base preferably pyridine or dimethylamino-pyridine in a temperature range of -20°C to 100°C, preferably at 0 °C, for various periods of time, from a few hours to a few days.
  • the reaction may occur with or without the presence of a solvent, with the base catalyst acting as one, or if a solvent is required dichloromethane, thetrachloroethylene, and toluene are preferred.
  • the alcohol 9 is then subjected to the Williamson ether sythesis, which involves adding a base to a stirred organic solution comprising HO-PG (e.g., methoxymethanol), maintained at a constant temperature within the range of about 0°C to about 80°C, preferably at about room temperature.
  • HO-PG e.g., methoxymethanol
  • the base is added at a rate such that the reaction-mixture temperature remains within about one
  • the base can be added as an organic solution or in undiluted form.
  • the base will have a base strength sufficient to deprotonate a proton, wherein the proton has a pK a of greater than about 15, preferably greater than about 20.
  • the acidity of an acid H-A is proportional to the stability of its conjugate base -A.
  • Suitable bases include, but are not limited to, alkylmetal bases such as methyllithium, n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and hydride bases such as sodium hydride and potassium hydride.
  • the preferred base is sodium hydride.
  • Solvents suitable for reacting alcohols 9 with -OPG include, but are not limited, to dimethyl sulfoxide, dichloromethane, ethers, and mixtures thereof, preferably tetrahydrofuran.
  • the reaction mixture can be adjusted to within a temperature range of about 0°C to about room temperature and alcohols 9 can be added, preferably at a rate such that the reaction-mixture temperature remains within about one to two degrees of the initial reaction-mixture temperature.
  • Alcohols 9 can be diluted in an organic solvent or added in their undiluted form.
  • the resulting reaction mixture is stirred until the reaction is substantially complete as determined by using an appropriate analytical method, preferably by gas chromatography, then the mono-protected alcohols X can be isolated by workup and purification. Mono-protected alcohols X are further treated with a suitable base or nucleophile to remove the OPG protecting group.
  • the preferred reagent for this purpose is lithium aluminum hydride, using as solvent THF, diethyl ether, diisopropyl ether, t-butyl-methyl ether or mixtures of solvents, at temperatures ranging from -20°C to 50°C and reaction times from 1 hour to 24 hours. Such Procedures are extensively described in Greene, T. W., Protective Groups in Organic Chemistry, p.170- 187.
  • the workup of the resulting reaction mixture is performed when the deprotection is complete, which is determined by using the appropriate analytical method, such as thin- layer chromatography or HPLC. Alcohols X are isolated from the reaction mixture by methods well-known in the art
  • Scheme 1 outlines a method useful for synthesizing mono-protected diols X, wherein n is 1.
  • compounds 11, wherein E is a suitable leaving group are reacted with compounds 12, wherein R 1 and R 2 are as defined above and R 8 is H, (C ⁇ _C 6 )alkyl or (C 6 )aryl, providing compounds 13.
  • Suitable leaving groups are well known in the art, for example, but not limited to halides, such as chloride, bromide, and iodide; aryl- or alkylsulfonyloxy, substituted arylsulfonyloxy (e.g., tosyloxy or mesyloxy); substituted alkylsulfonyloxy (e.g., haloalkylsulfonyloxy); phenoxy or subsituted phenoxy; and acyloxy groups.
  • Compounds 11 are available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or can be prepared by well-known methods such as halogenation or sulfonation of butanediol.
  • a suitable base will have a pK a of greater than about 25, more preferably greater than about 30.
  • Suitable bases include, but are not limited to, alkylmetal bases such as methyllithium, n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, lithium dusopropylamide, lithium diethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide, and lithium hexamethyldisilazide; hydride bases such as sodium hydride and potassium hydride.
  • Metal amide bases such as lithium dusopropylamide are preferred.
  • a solution of about 1 to about 1.2 equivalents of a suitable base is added to a stirred solution comprising esters 12 and a suitable organic solvent, under an inert atmosphere, the solution maintained at a constant temperature within the range of about -95 °C to about room temperature, preferably at about -78 °C to about -20°C.
  • the base is diluted in a suitable organic solvent before addition.
  • the base is added at a rate of about 1.5 moles per hour.
  • Organic solvents suitable for the reaction of compounds 11 with the compounds 12 include, but are not limited to, diethyl ether, tetrahydrofuran, benzene, toluene, xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane), and mixtures thereof.
  • reaction mixture is allowed to stir for about 1 to about 4 hours, and a compound 11, preferably dissolved in a suitable organic solvent, is added, preferably at a rate such that the reaction-mixture temperature remains within about one to two degrees of the initial reaction-mixture temperature.
  • the reaction- mixture temperature can be adjusted to within a temperature range of about -20 °C to about room temperature, preferably to about room temperature, and the reaction mixture is allowed to stir until the reaction is substantially complete as determined by using an appropriated analytical method, preferably thin-layer chromatography or high-performance liquid chromatography. Then the reaction mixture is quenched and compounds 13, wherein n is 1 can be isolated by workup.
  • Compounds 14 are then synthesized by reacting compounds 13 with -O-PG according to the protocol described above for reacting alcohols 9 with -O-PG.
  • compounds 14 can be converted to mono-protected diols X, wherein n is 1, by reduction of the ester group of compounds 14 to an alcohol group with a suitable reducing agent.
  • a wide variety of reagents are available for reduction of such esters to alcohols, e.g., see M. Hudlicky, Reductions in Organic Chemistry, 2nd ed., 1996 pp. 212- 217, incorporated by reference herein.
  • the reduction is effected with a hydride type reducing agent, for example, lithium aluminum hydride, lithium borohydride, lithium triethyl borohydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride, or sodium bts(2-methoxy)aluminum hydride.
  • a hydride type reducing agent for example, lithium aluminum hydride, lithium borohydride, lithium triethyl borohydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride, or sodium bts(2-methoxy)aluminum hydride.
  • the reduction is conducted by adding an organic solution of compounds 14 to a stirred mixture comprising a reducing agent, preferably lithium aluminum hydride, and an organic solvent.
  • a reducing agent preferably lithium aluminum hydride, and an organic solvent.
  • reaction mixture is maintained at a constant temperature within the range of about -20 °C to about 80 °C, preferably at about room temperature.
  • Organic solvents suitable for reacting 13 with -OPG include, but are not limited to, dichloromethane, diethyl ether, tetrahydrofuran or mixtures thereof, preferably tetrahydrofuran.
  • the reaction mixture is stirred at a constant temperature within the range of about room temperature to about 60°C, until the reaction is substantially complete as determined by using an appropriate analytical method, preferably thin-layer
  • Scheme 1 next illustrates a three step synthetic sequence for homologating mono- protected diols X comprising: (a) halogenation ( converting -CH 2 OH to -CH 2 _Hal); (b) carbonylation (replacing -Hal with -CHO); and (c) reduction (converting -CHO to - CH 2 OH), wherein a reaction sequence of (a), (b), and (c) increases the value of n by 1.
  • step (a) protected halo-alcohols 15, wherein Hal is a halide selected from the group of chloro, bromo, or iodo, preferably iodo, can be prepared by halogenating mono-protected diols X, by using well-known methods (for a discussion of various methods for conversion of alcohols to halides see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 431-433, incorporated herein by reference).
  • protected iodo-alcohols 15 can be synthesized starting from mono-protected diols X by treatment with Ph 3 /I 2 /imidazole (Garegg et al, 1980, J.C.S Perkin 72866 ; 1,2-dipheneylene phosphorochloridite/I 2 (Corey et al, 1967, J. Org. Chem. 82:4160); or preferably with Me 3 SiCl/NaI (Olah et al, 1979, J. Org. Chem. 44:8, 1247), all of which citations are incorporated by reference herein.
  • Protected halo-alcohols 15 can be carbonylated with Li(BF 3 .Et 2 O)/HCONMe 2 using the procedure described in Maddaford et /., 1993, J. Org. Chem. 58:4132; Becker et al, 1982, J. Org. Chem.
  • Reduction step (c) useful for synthesizing mono-protected diols X from aldehydes 16 can be accomplished by well-known methods in the art for reduction of aldehydes to the corresponding alcohols (for a discussion see M. Hudlicky, Reductions in Organic Chemistry, 2nd ed., 1996 pp 137-139), for example, by catalytic hydrogenation (see e.g., Carothers, 1949, J. Am. Chem .Soc.
  • aldehydes 16 preferably by reacting aldehydes 16 with a hydride reducing agent, such as lithium aluminum hydride, lithium borohydride, sodium borohydride (see e.g., the procedures described in Chaikin et al, 1949, J. Am. Chem. Soc. 71:3245; Nystrom et al, 1947, J. Am. Chem. Soc. 69:1197; and Nystrom et al, 1949, J.
  • a hydride reducing agent such as lithium aluminum hydride, lithium borohydride, sodium borohydride
  • Scheme 2 outlines methodology for the synthesis of protected alcohols 18a wherein Y, R 1 , R 2 , Z, and m are defined as above.
  • Protected alcohols 18a correspond to compounds of the formula W (1)(2 ⁇ Zm-OPG, wherein W (1)(2) is C(R 1 )(R 2 )-Y.
  • Protected alcohols 17, wherein Y comprises a-C(O)OH group can be synthesized by oxidizing mono-protected diols X with an agent suitable for oxidizing a primary alcohol to a carboxylic acid (for a discussion see M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, 1990, pp. 127-130, incorporated by reference herein).
  • Suitable oxidizing agents include, but are not limited to, pyridinium dichromate (Corey et al, 1979, Tetrahedron Lett. 399 ); manganese dioxide (Ahrens et al, 1967, J. Heterocycl Chem. 4:625); sodium permanganate monohydrate (Menger et al, 1981, Tetrahedron Lett.
  • protected alcohols 17, wherein Y comprises a -C(O)OH group can be synthesized by treatment of protected halo- alcohols 15, wherein X is iodo, with CO or CO 2 , as described in Bailey et al, 1990, J. Org. Chem. 55:5404 and Yanagisawa et al, 1994, J. Am. Chem. Soc.
  • protected alcohols 17, wherein Y comprises a -C(O)OR 5 group are synthesized from the corresponding carboxylic acid (i.e., 17, wherein Y comprises -C(O)OH) by esterification with R 5 OH (e.g., see March, J., Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p.
  • protected alcohols 17, wherein Y comprises -C(O)OR 5 can be prepared from protected halo-alcohols 15 by carbonylation with transition metal complexes (see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 484-486; Urata et /., 1991, Tetrahedron Lett. 32:36, 4733); and Ogata et al, 1969, J. Org. Chem. 3985, the three of which citations are incorporated by reference herein).
  • Protected alcohols 17, wherein Y comprises -OC(O)R 5 , wherein R 5 is as defined aboye can be prepared by acylation of mono-protected diols X with a carboxylate equivalent such as an acyl halide (i.e., R 5 C(O)-Hal, wherein Hal is iodo, bromo, or chloro, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 392 and Org. Synth. Coll. Vol. Ill, Wiley, NY, pp.
  • acyl halide i.e., R 5 C(O)-Hal, wherein Hal is iodo, bromo, or chloro
  • R 5 C(O)-O-(O)CR 5 see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 392-393 and Org. Synth. Coll. Vol. m, Wiley, NY, pp. 11, 127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955), all of which citations are incorporated herein by reference).
  • the reaction is conducted by adding a base to a solution comprising mono-protected diols X, a carboxylate equivalent, and an organic solvent, which solution is preferably maintained at a constant temperature within the range of 0°C to about room temperature.
  • Solvents suitable for reacting mono-protected diols X with a carboxylate equivalent include, but are not limited to, dichloromethane, toluene, and ether, preferably dichloromethane.
  • Suitable bases include, but are not limited to, hydroxide sources, such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate; or an amine such as triethylamine, pyridine, or dimethylaminopyridine.
  • R 6 is defined as above
  • R 6 can be prepared by phosphorylation of mono-protected diols X according to well-known methods (for a general reviews, see Corbridge Phosphorus: An Outline of its Chemistry, Biochemistry, and Uses, Studies in Inorganic Chemistry, 3rd ed., pp. 357-395 (1985); Ramirez et ⁇ /.,1978, Ace. Chem. Res. 11:239; and Kalckare Biological Phosphorylations, Prentice-Hall, New York (1969); J. B. Sweeny in
  • R 6 wherein R 6 is defined as above, can be prepared by treatment of mono-protected diol X with phosphorous oxychloride in a suitable solvent, such as xylene or toluene, at a constant temperature within the range of about 100°C to about 150°C for about 2 hours to about 24 hours. After the reaction is deemed substantially complete, by using an appropriate analytical method, the reaction mixture is hydrolyzed with RADH. Suitable procedures are referenced in Houben-Weyl, Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. 12/2, pp. 143-210 and 872-879, incorporated by reference herein.
  • both R 6 when both R 6 are hydrogen, can be synthesized by reacting mono-protected diols X with silyl polyphosphate (Okamoto et al, 1985, Bull Chem. Soc. Jpn. 58:3393, incorporated herein by reference) or by hydrogeno lysis of their benzyl or phenyl esters (Chen et al, 1998, J. Org. Chem. 63:6511, incorporated herein by reference).
  • the monophosphate esters can be prepared by reacting mono-protected diols X with appropriately substituted phophoramidites followed by oxidation of the intermediate with w-chloroperbenzoic acid (Yu et al, 1988, Tetrahedron Lett. 29:979, incorporated herein by - 1 - DC 1: 360579.1 reference) or by reacting mono-protected diols X with dialkyl or diaryl substituted phosphorochloridates (Pop, et ⁇ /, 1997, Org.
  • the phosphoramidites are commercially available (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or readily prepared according to literature procedures (see e.g. , Uhlmann et al.1986, Tetrahedron Lett. 27: 1023 and Tanaka et al, 1988, Tetrahedron Lett. 29:199, both of which are incorporated herein by reference).
  • the phosphorochloridates are also commercially available (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or prepared according to literature methods (e.g., Gajda et al, 1995, Synthesis 25:4099.
  • protected alcohols 17, wherein Y comprises a monophosphate group and R 6 is alkyl or aryl can be prepared by reacting
  • R 6 is defined as above, can be synthesized by reacting the above-discussed monophosphates of the formula:
  • protected alcohols 17 wherein Y comprises the triphosphate group can be prepared by reacting mono-protected diols X with salicyl phosphorochloridite and then pyrophosphate and subsequent cleavage of the adduct thus obtained with iodine in pyridine as described in Ludwig et al, 1989, J. Org. Chem. 54:631, incorporated herein by reference.
  • protected alcohols 17 can by synthesized by reacting protected halo-alcohols 15 with sodium sulfite as described in Gilbert Sulfonation and Related Reactions; Wiley: New York, 1965, pp. 136-148 and pp. 161-163; Org. Synth. Coll. Vol. II, Wiley, NY, 558, 564 (1943); and Org. Synth. Coll. Vol. IV, Wiley, NY, 529 (1963), all three of which are incorporated
  • protected alcohols 17 can be prepared by reacting protected halo-alcohols 15 with the corresponding heterocycle in the presence of a base.
  • the heterocycles are available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or prepared by well-known synthetic methods (see the procedures described in Ware, 1950, Chem. Rev. 46:403-470, incorporated herein by reference).
  • the reaction is conducted by stirring a mixture comprising 15, the heterocycle, and a solvent at a constant temperature within the range of about room temperature to about 100°C, preferably within the range of about 50°C to about 70°C for about 10 to about 48 hours.
  • Suitable bases include hydroxide bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.
  • the solvent used in forming protected alcohols 17 is selected from dimethylformamide; formamide; dimethyl sulfoxide; alcohols, such as methanol or ethanol; and mixtures thereof.
  • heteroaryl rings can be prepared by metallating the suitable heteroaryl ring then reacting the resulting metallated heteroaryl ring with protected halo-alcohols 15 (for a review, see Katritzky Handbook of Heterocyclic Chemistry, Pergamon Press: Oxford 1985).
  • the heteroaryl rings are available commercially or prepared by well-known synthetic methods (see e.g., Joule et al, Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo et A/., 1971, J. Chem. Soc. (C) 86; Osier et fl/., 1983, J. Org. Chem. 48:4307; Iwai et al, 1966, Chem. Pharm. Bull.
  • the term "metallating" means the forming of a carbon-metal bond, which bond may be substantially ionic in character.
  • Metallation can be accomplished by adding about 2 equivalents of strong organometalhc base, preferably with a pK a of about 25 or more, more preferably with a pK a of greater than about 35, to a mixture comprising a suitable organic solvent and the heterocycle. Two equivalents of base are required: one equivalent of the base deprotonates the -OH group or the -NH group, and the second equivalent metallates the heteroaryl ring.
  • the hydroxy group of the heteroaryl - 148 - DCl: 360579.1 ring can be protected with a base-stable, acid-labile protecting group as described in Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition 17-237 (1999), incorporated herein by reference. Where the hydroxy group is protected, only one equivalent of base is required.
  • Suitable base-stable, acid-labile hydroxyl-protecting groups include but are not limited to, ethers, such as methyl, methoxy methyl, methylthiomethyl, methoxyethoxymethyl, b/s(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1 -methyl- 1- methoxyethyl, t-butyl, allyl, benzyl, o-nitrobenzyl, triphenylmethyl, - naphthyldiphenylmethyl, />-methoxyphenyldiphenylmethyl, 9-(9-phenyl- 10-oxo)anthranyl, trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyl
  • Ethers are preferred, particularly straight chain ethers, such as methyl ether, methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether, bis(2- chloroethoxy)methyl ether.
  • the pK a of the base is higher than the pK a of the proton of the heterocycle to be deprotonated.
  • Suitable bases include, but are not limited to, alkylmetal bases such as methyllithium, n- butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, lithium dusopropylamide, lithium diethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and hydride bases such as sodium hydride and potassium hydride.
  • alkylmetal bases such as methyllithium, n- butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium
  • metal amide bases such as lithium amide, sodium amide, potassium amide, lithium te
  • the organometalhc base can be activated with a complexing agent, such as NNN'.N - tetramethylethylenediamine or hexamethylphosphoramide (1970, J. Am. Chem. Soc. 92:4664, incorporated by reference herein).
  • Solvents suitable for synthesizing protected alcohols 17, wherein Y is a heteroaryl ring include, but are not limited to, diethyl ether; tetrahydrofuran; and hydrocarbons, such as pentane.
  • metallation occurs alpha to the heteroatom due to the inductive effect of the heteroatom, however, modification of conditions, such as the identity of the base and solvents, order of reagent addition, reagent addition times, and reaction and addition temperatures can be modified by one of skill in the art to achieve the desired metallation position (see e.g., Joule et al, Heterocyclic Chemistry, 3rd ed., 1995, pp. 30-42, incorporated by reference herein) Alternatively, the position of metallation can be controlled by use of a halogenated heteroaryl group, wherein the halogen is located on the position of the heteroaryl ring where metallation is desired (see e.g., Joule
  • Halogenated heteroaryl groups are available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or can be prepared by well-known synthetic methods (see e.g., Joule et al, Heterocyclic Chemistry, 3rd ed., 1995, pp. 78, 85, 122, 193, 234, 261, 280, 308, incorporated by reference herein).
  • the reaction mixture comprising the metallated heteroaryl ring is adjusted to within a temperature range of about 0°C to about room temperature and protected halo-alcohols 15 (diluted with a solvent or in undiluted form) are added, preferably at a rate such that the reaction-mixture temperature remains within about one to two degrees of the initial reaction-mixture temperature.
  • protected halo-alcohols 15 the reaction mixture is stirred at a constant temperature within the range of about room temperature and about the solvent's boiling temperature and the reaction's progress can be monitored by the appropriate analytical technique, preferably thin-layer chromatography or high-performance liquid chromatography.
  • protected alcohols 17 can be isolated by workup and purification.
  • protected alcohols 17 can be prepared from their corresponding carboxylic acid derivatives (17, wherein Y is -CO 2 H) as described in Belletire et al, 1988, Synthetic Commun. 18:2063 or from the corresponding acylchlorides (17, wherein Y is -CO-halo) as described in Skinner et al, 1995, J. Am. Chem. Soc. 77:5440, both citations are incorporated herein by reference.
  • the acylhalides can be prepared from the carboxylic acids by well known procedures such as those described in March, J., Advanced Organic Chemistry; Reactions
  • protected alcohols 17 can be prepared by first reacting protected halo-alcohols 15 with a trialkyl phosphite according to the procedure described in Kosolapoff, 1951, Org. React. 6:273 followed by reacting the derived phosphonic diester with ammonia according to the procedure described in Smith et al, 1957, J Org. Chem. 22:265, incorporated herein by reference.
  • Y is
  • protected alcohols 17 can be prepared by reacting their sulphonic acid derivatives (i.e., 17, wherein Y is -SO 3 H ) with ammonia as described in Sianesi et al, 1971, Chem. Ber. 104:1880 and Campagna et al, 1994, Farmaco, Ed. Sci. 49:653, both of which citations are incorporated herein by reference). As further illustrated in Scheme 2, protected alcohols 17 can be deprotected providing alcohols 18a.
  • the deprotection method depends on the identity of the alcohol- protecting group, see e.g., the procedures listed in Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition 17-237 (1999), particularly see pages 48-49, incorporated herein by reference.
  • One of skill in the art will readily be able to choose the appropriate deprotection procedure.
  • the alcohol is protected as an ether function (e.g. , methoxymethyl ether), the alcohol is preferably deprotected with aqueous or alcoholic acid.
  • Suitable deprotection reagents include, but are not limited to, aqueous hydrochloric acid, p- toluenesulfonic acid in methanol, pyridinium-p-toluenesulfonate in ethanol, Amberlyst H- 15 in methanol, boric acid in ethylene-glycol-monoethylether, acetic acid in a water- tetrahydrofuran mixture, aqueous hydrochloric acid is preferred. Examples of such procedures are described, respectively, in Bernady et al, 1979, J. Org. Chem. 44:1438;

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Abstract

La présente invention a trait à de nouveaux composés sulfurés et disulfurés, des compositions comportant des composés sulfurés et de disulfurés, et des procédés utiles pour le traitement et la prévention de maladies cardio-vasculaires, des dyslipidémies, des dysprotéinémies, et des troubles de métabolisme du glucose comprenant l'administration d'une composition comportant un composé d'éther. Les composés, compositions, et procédés de l'invention sont également utiles pour le traitement et la prévention de la maladie d'Alzheimer, du syndrome X, de troubles associés au récepteur activé de la prolifération des peroxysomes, de la septicémie, de troubles thrombotiques, de l'obésité, de la pancréatite, de l'hypertension, de la maladie rénale, du cancer, de l'inflammation, et de l'impuissance. Dans certains modes de réalisation, les composés, compositions, et procédés de l'invention sont utiles en thérapie de combinaison avec d'autres agents thérapeutiques, tels que des hypocholestérolémiants et hypoglycémiants.
PCT/US2003/041612 2003-12-24 2003-12-24 Composes sulfures et disulfures et compositions pour le controle de cholesterol et utilisations associees WO2005068418A1 (fr)

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JP2010053115A (ja) * 2008-08-28 2010-03-11 Korea Inst Of Science & Technology 新規フェニルアセテート誘導体またはその薬学的に許容可能な塩、その製造方法及びそれを有効成分として含むｔ−型カルシウムイオンチャンネルの活性によって誘発される疾患の予防または治療用組成物
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives

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Publication number Priority date Publication date Assignee Title
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives
US8962549B2 (en) 2008-08-22 2015-02-24 Baxter International Inc. Polymeric benzyl carbonate-derivatives
JP2010053115A (ja) * 2008-08-28 2010-03-11 Korea Inst Of Science & Technology 新規フェニルアセテート誘導体またはその薬学的に許容可能な塩、その製造方法及びそれを有効成分として含むｔ−型カルシウムイオンチャンネルの活性によって誘発される疾患の予防または治療用組成物

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