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Definitions

• the invention relates to hydroxyl compounds and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof; compositions comprising a hydroxyl compound or a pharmaceutically acceptable salt, hydrate, solvate, or mixtures 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 peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), and a thrombotic disorder, which method comprise administering a hydroxyl compound or
• the compounds of the invention can also treat or prevent inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g., systemic lupus erythematosus), scleroderma, ankylosing spondylitis, gout and pseudogout, muscle pain: polymyositis/polymyalgia rheumatica fibrositis; infection and arthritis, juvenile rheumatoid arthritis, tendonitis, bursitis and other soft tissue rheumatism.
• IBS irritable bowel syndrome
• IBS irritable bowel syndrome
• inflammatory bowel disease e.g., Crohn's Disease, ulcerative colitis
• arthritis e.g., rheumatoid arthritis, osteoarthritis
• LDL Low density lipoprotein
• HDL high density lipoprotein
• LDL Low density lipoprotein
• HDL high density lipoprotein
• the term "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, very low density lipoproteins (VLDL), intermediate-density lipoproteins (TDL), 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.
• 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 CIH (apo CUT) and apolipoprotein CH (apo CH).
• IDL intermediate-density lipoprotein
• VLDL remnant VLDL remnant
• IDL particles bind tightly to liver cells, which extract IDL 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 affimty 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 IDL 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 ability of the cell to make its own cholesterol by turning off the synthesis of HMGCoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Second, the incoming LDL-derived cholesterol promotes storage of cholesterol by the action of cholesterol acyltransferase (“ACAT”), the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in storage droplets. Third, the accumulation of cholesterol within the cell drives a feedback mechanism that inhibits cellular synthesis of new LDL receptors.
• ACAT cholesterol acyltransferase
• 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.
• the 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.
• 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.
• reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the liver for recycling to extrahepatic tissues, hepatic storage, or excretion into the intestine in bile.
• the RCT pathway represents the only means of eliminating cholesterol from most extrahepatic tissues and is crucial to the maintenance of the structure and function of most cells in the body.
• LCAT lecithin :cholesterol acyltransferase
• PLTP supplies lecithin to HDL
• CETP can move cholesteryl esters made by LCAT to other lipoproteins, particularly apoB-containing lipoproteins, such as VLDL.
• HDL triglycerides 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 A I (apo A I).
• Apo A I is synthesized by the liver and small intestine as preproapolipoprotein, 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 refe ⁇ ed 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, refe ⁇ ed to as spherical or mature HDL (HDL3 and HDL2).
• 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 Il-containing fraction is refe ⁇ ed to herein as the AI/AII- HDL fraction of HDL.
• pre-beta-1 HDL lipid-poor complex
• pre-beta-1 HDL the lipid-poor complex, pre-beta-1 HDL
• Cholesterol newly transfe ⁇ ed 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 apolipoprotein such as apo A I or apo A-IV as an activator.
• Apo A-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 ultimate removal of cellular cholesterol.
• Cholesteryl esters in the mature HDL particles of the AI-HDL fraction are removed by the liver and processed into bile more effectively than those derived from the AI/AH-HDL fraction. This may be due, in part, to the more effective binding of AI-HDL to the hepatocyte membrane.
• Several HDL receptors have been identified, the most well characterized of which is the scavenger receptor class B, type I (SR Bl) (Acton et al, 1996, Science 271 :518-520).
• the SR-BI is expressed most abundantly in steroidogenic tissues (e.g., the adrenals), and in the liver (Landshulz et al, 1996, J. Clin. Invest.
• 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).
• HDL is not only involved in the reverse transport of cholesterol, but also plays a role in the reverse transport of other lipids, i.e., the transport of lipids from cells, organs, and tissues to the liver for catabolism and excretion.
• lipids include sphingomyelin, oxidized lipids, and lysophophatidylcholine.
• Robins and Fasulo (1997, J. Clin. Invest. 99:380 384) have shown that HDL stimulates the transport of plant sterol by the liver into bile secretions.
• 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. Cell Biol 1:489 530; Vamecq and Draye, 1989, Essays Biochem. 24:1115 225; andNelali etal, 1988, Cancer Res. 48:5316 5324).
• Chemicals included in this group are the fibrate class of hypolipidemic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol 12:1 58). Peroxisome proliferation can also be elicited by dietary or physiological factors, such as a high fat diet and cold acclimatization.
• PPAR ⁇ peroxisome proliferator activated receptor
• PPARa 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.
• PPARs have been identified in the enhancers of a number of gene-encoding proteins that regulate lipid metabolism. These proteins include the three enzymes required for peroxisomal
• 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. 45:439445). Deletion analysis led to the identification of an approximately 30 bp region accounting 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). Taken together, these studies suggested the possibility that the thiazolidinediones modulate gene expression at the transcriptional level through interactions with a PPAR and reinforce the concept of the interrelatedness of glucose and lipid metabolism. 2.5 Current Cholesterol Management Therapies
• Bile-acid-binding resins are a class of drugs that interrupt the recycling of bile acids from the intestine to the liver.
• bile-acid-binding resins are cholestyramine (QUESTRAN LIGHT, Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia & Upjohn Company).
• QUESTRAN LIGHT Bristol-Myers Squibb
• colestipol hydrochloride cholestyramine
• 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.
• other oral medications must be taken at least one hour before or four to six hours subsequent to ingestion of the resin, complicating heart patients' drug regimens.
• statins are inhibitors of cholesterol synthesis. Sometimes, the 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
• 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.
• Nicotinic acid also known as niacin, is a water-soluble vitamin B-complex used as a dietary supplement and antihyperlipidemic agent. Niacin diminishes the 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.
• ATROMID-S In the United States, fibrates have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia agents.
• clofibrate ATROMID-S, Wyeth- Ayerst Laboratories
• ATROMR -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.
• the chemically and pharmacologically related drug, gemfibrozil is a lipid regulating agent which moderately decreases serum triglycerides and VLDL cholesterol.
• LOPID also increases HDL cholesterol, particularly the HDL2 and HDL3 subtractions, as well as both the AI/AII-HDL fractions.
• the lipid response to LOPID is heterogeneous, especially among different patient populations.
• 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.
• Long chain carboxylic acids, particularly long chain ⁇ , ⁇ -dicarboxylic acids with distinctive substitution patterns, and their simple derivatives and salts, have been disclosed for treating atherosclerosis, obesity, and diabetes (See, e.g., Bisgaier et al, 1998, J. Lipid Res. 39:17-30, and references cited therein; International Patent Publication WO 98/30530; U.S. Patent No.
• U.S. Patent No. 4,689,344 discloses /3,/3,j8',3'-tetrasubstituted- ⁇ , ⁇ - alkanedioic acids that are optionally substituted at their ⁇ , ⁇ , ⁇ ', ⁇ !'-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,/3,3',j3'-tetramethyl-alkanediols of U.S. Patent No. 3,930,024 also are not useful for treating hypercholesterolemia or obesity.
• phosphates of dolichol, apolyprenol isolated from swine liver are stated to be useful in regenerating liver tissue, and in treating hyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.
• U.S. Patent No. 4,287,200 discloses azolidinedione derivatives with anti- diabetic, hypolipidemic, and anti-hypertensive properties. However, the administration of these compounds to patients can produce side effects such as bone marrow depression, and both liver and cardiac cytotoxicity. Further, the compounds disclosed by U.S. Patent No. 4,287,200 stimulate weight gain in obese patients.
• the invention encompasses hydroxyl compounds useful in treating various disorders.
• 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.
• the invention encompasses a method 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), and a thrombotic disorder, comprising administering to a patient in need of such treatment or prevention 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 for inhibiting 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 invention further encompasses a method for reducing the fat content of meat in livestock comprising administering to livestock in need of such fat-content reduction 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 provides a method for reducing the cholesterol content of a fowl egg comprising administering to a fowl species 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.
• FCH Familial combined hyperlipidemia
• GDM Gestational diabetes mellitus
• HDL High density lipoprotein
• IDL Intermediate density lipoprotein IDDM: Insulin dependent diabetes mellitus
• LDL Low density lipoprotein
• NIDDM Non-insulin dependent diabetes mellitus
• PPAR Peroxisome proliferator activated receptor
• RXR Retinoid X receptor
• VLDL Very low density lipoprotein
• the phrase "compounds of the invention” means compounds disclosed herein. Particular compounds of the invention are compounds of formulas I-XXII and pharmaceutically acceptable salts, hydrates, enantiomers, diastereomer, racemates or mixtures of stereoisomers thereof. Thus, “compound of the invention” collectively means compound of formulas I-XXII and pharmaceutically acceptable salts, hydrates, enantiomers, diastereomer, racemates or mixtures of stereoisomers thereof.
• the compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is refe ⁇ ed to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is to be accorded more weight.
• 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 co ⁇ esponding compounds' enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
• composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
• a reaction that is "substantially complete” means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
• a compound of the invention is considered optically active or enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 90% ee (enantiomeric excess) or greater, preferably, equal to or greater than 95% ee with respect to a particular chiral center.
• 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 about 50% of is co ⁇ esponding enantiomer relative to all chiral centers in the molecule.
• the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of compounds of Formulas I through XXII.
• Enantiomeric and diastereomeric 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 diastereomers can also be obtained from diastereomerically- 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 refe ⁇ ed 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 When administered to a patient, e.g., to an animal for veterinary use or for improvement of livestock, or to a human for clinical use, 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.
• 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 hydroxy compound of the invention by weight of the isolate.
• phrases "pharmaceutically acceptable salt(s),” as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the invention.
• Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compoimds 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, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate
• Compounds of the invention that include an amino moiety also can form pharmaceutically acceptable salts with various amino 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.
• 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.
• hydrate includes solvates, which are stoichiometric or non-stoichiometric amounts of a solvent bound by non-covalent intermolecular forces. Prefe ⁇ ed solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
• altering lipid metabolism indicates an observable
• the term "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, (d-C ⁇ Jalkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2 methyl 2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2 methyl-3-butyl, 2,2 dimethyl 1- propyl, 2-methyl- 1 -pentyl, 3 methyl- 1 -pentyl, 4 methyl- 1 -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4 methyl 2 pentyl, 2,2 dimethyl 1 butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl groups
• 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.
• the triple bond of an 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.
• an "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, refe ⁇ ed to herein as "(C6)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, pyrimidinyl, pyrazyl, triazinyl, py ⁇ olyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, furyl, phenyl, 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, refe ⁇ ed to herein as "(C 2 -C 5 )heteroaryl".
• cycloalkyl group means a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon- carbon multiple bonds.
• 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, py ⁇ olidino, 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, refe ⁇ ed to herein as (C.- C 6 )heterocycloalkyl.
• heterocyclic radical or “heterocyclic ring” mean 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, refe ⁇ ed to herein as "(C ⁇ -C 6 )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 substiments.
• the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, refe ⁇ ed to herein as "(C 6 )aryloxy".
• the term "benzyl” means -CH 2 -phenyl.
• the term “phenyl” means -C ⁇ 5 .
• a phenyl group can be unsubstituted or substituted with one or two suitable substituents, wherein the subtituent replaces an H of the phenyl group.
• “Ph,” represents a phenyl group or a substituted phenyl group.
• hydrocarbyl group means a monovalent group selected from (C ⁇ -C 8 )alkyl, (C2-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, refe ⁇ ed to herein as "(C ⁇ -C 6 )hydrocarbyl”.
• a "carbonyl” group is a divalent group of the formula C(O) .
• alkoxycarbonyl means a monovalent group of the formula -C(0)-alkoxy.
• the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, refe ⁇ ed to herein as a "lower alkoxycarbonyl” group.
• a "carbamoyl” group means the radical -C(0)N(R') 2 , wherein R' is chosen from the group consisting of hydrogen, alkyl, and aryl.
• halogen means fluorine, chlorine, bromine, or iodine. Accordingly, the meaning of the terms “halo” and “Ha_”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.
• suitable substituents include, but are not limited to: (C 1 -C 8 )alkyl; (C 1 -C 8 )alkenyl; (C ⁇ -C 8 )a-kynyl; (C 6 )aryl; (C 2 -C 5 )heteroaryl; (C 3 -C 7 )cycloalkyl; (d-C ⁇ alkoxy; (C 6 )aryloxy; -CN; -OH; oxo; halo, -C0 2 H; -NH 2 ; - NH((C ⁇ -C 8 )alkyl); -N((C ⁇ -C 8 )alkyl) 2 ; -NH((C 6 )aryl); -N((C 6 )aryl) 2 ; -CHO; -
• compositions that is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound. 5.
• the compounds of the invention are useful in medical applications for treating or preventing a variety of diseases and disorders such as, but not limited to, cardiovascular disease, stroke, and peripheral vascular disease; dyslipidemia; dyslipoproteinemia; a disorder of glucose metabolism; Alzheimer's Disease; Parkinson's Disease, diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (e.g., 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 erythemato
• the compounds and compositions of the invention are useful for treatment or prevention of high levels of blood triglycerides, high levels of low density lipoprotein 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 levels of high density lipoprotein cholesterol.
• the compounds and compositions of the invention also have utility for treatment of NIDDM without increasing weight gain.
• the compounds of the invention may also be used to reduce the fat content of meat in livestock and reduce the cholesterol content of eggs.
• the invention provides novel compounds particularly useful for treating or preventing a variety of diseases and conditions, which include, but are not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, modulating C reactive protein, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, and a thrombotic disorder.
• diseases and conditions include, but are not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile production, hypertension, impotence, inflammation,
• the invention encompasses compounds of formula I:
• each occurrence of m is independently an integer ranging from 0 to 5 ;
• each occu ⁇ ence of n is independently an integer ranging from 3 to 7;
• X is (CH 2 ) Z or PH, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of R 1 , R 2 , R n , and R 12 is independently H, (C.- )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl, wherein R 1 , R 2 , R u , and R 12 are not each simultaneously H; and
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C ⁇ alkyl, OH, COOH, COOR 3 , SO 3 H,
• Y 1 and Y 2 are not each simultaneously (C 1 -C6)alkyl
• R 3 is (C 1 -C 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, (d-C ⁇ Jalkoxy, or phenyl groups,
• each occurrence of R 4 is independently H, (Ci-Cejalkyl, (C2- C 6 )alkenyl, or (C 2 -C 6 )al ynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ -C 6 alkoxy, or phenyl groups; and
• each occu ⁇ ence of R 5 is independently H, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
• each occurrence of Y 1 and Y 2 is independently OH, COOR 3 , or COOH.
• prefe ⁇ ed compounds of formula I are those wherein m is 0.
• Other prefe ⁇ ed compounds of formula I are those wherein m is 1.
• prefe ⁇ ed compounds of formula I are those wherein n is 4.
• Other prefe ⁇ ed compounds of formula I are those wherein n is 5.
• Other prefe ⁇ ed compounds of formula I are those wherein z is 0.
• Other prefe ⁇ ed compounds of formula I are those wherein z is 1.
• Other prefe ⁇ ed compounds of formula I are those wherein Y 1 is (d-
• Y 2 is OH.
• the invention encompasses compounds of formula
• each occu ⁇ ence of m is independently an integer ranging from 3 to 7;
• each occu ⁇ ence of n is independently an integer ranging from 0 to 5;
• X is (CH 2 ) Z or PH, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of Y 1 and Y 2 independently (d-C 6 )alkyl, OH, COOH, COOR 7 , S0 3 H,
• R 7 is (C ⁇ -C 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, (Ci-C ⁇ jalkoxy, or phenyl groups,
• each occu ⁇ ence of R 8 is independently H, (Ci-C ⁇ jalkyl, (Qj- 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
• each occu ⁇ ence of R 9 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl;
• R 3 and R are (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl;
• R 5 and R 6 are H, halogen, (d-C 4 )alkyl, (d-C 4 )alkoxy, (C 6 )aryloxy, CN, or N0 2 , N(R 5 ) 2 where R 5 is H, (d-C 4 ) alkyl, phenyl, or benzyl;
• C* l and C* 2 represent independent chiral-carbon centers wherein each center may independently be R or S.
• Exemplary compounds of formula II are those wherein each occu ⁇ ence of Y 1 and Y 2 is independently OH, COOR 7 , or COOH.
• Other compounds of formula ⁇ are those wherein m is 4.
• Other compounds of formula H are those wherein m is 5.
• Other compounds of formula II are those wherein X is (CH 2 ) Z and z is 0.
• Other compounds of formula ⁇ are those wherein X is (CH 2 ) Z and z is 1.
• Other compounds of formula ⁇ are those wherein Y 1 and or Y 2 is C(0)OH or CH 2 OH.
• compounds of formula ⁇ are those wherein C* 1 C* 2 are of the stereochemical configuration (S 1 , S 2 ) or substantially (S 1 , S 2 ).
• compounds of formula II are those wherein C* 1 C* 2 are of the stereochemical configuration (S 1 , R 2 ) or substantially (S 1 , R 2 ).
• compounds of formula ⁇ are those wherein C* 1 C* 2 are of the stereochemical configuration (R 1 , R 2 ) or substantially (R 1 , R 2 ).
• compounds of formula II are those wherein C* 1 C* 2 are of the stereochemical configuration (R 1 , S 2 ) or substantially (R 1 , S 2 ).
• the invention encompasses compounds of formula IH:
• each occu ⁇ ence of R 1 , R 2 , R 6 , R 7 , R 11 , or R 12 is independently hydrogen, (d- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH z or PH, wherein z is an integer from 0 to 4;
• each occurrence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, CH 2 OH, C(0)OH, OC(0)R 3 , C(0)OR 3 , SO 3 H,
• R 3 is (d-C 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, (d-C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (C ⁇ -C6)alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, Cj-C ⁇ alkoxy, or phenyl groups;
• each occurrence of R 5 is independently H, (Ci— C-6)alkyl, (C 2 - C6)alkenyl, or (C2-C 6 )alkynyl;
• (f) b is 0 or 1 and optionally the ring contains the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds such that when b is 0 the maximum number of carbon-carbon bonds is two or when b is 1 the maximum number of carbon-carbon bonds is three.
• the invention encompasses compounds of formula
• each occu ⁇ ence of R 1 , R 2 , R 6 , R 7 , R 1 ', or R 12 is independently hydrogen, (d- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) Z or PH, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, CH 2 OH, C(0)OH, OC(O)R 3 , C(O)OR 3 , S0 3 H,
• R 3 is (d-C 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, (d-C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (Ci-C ⁇ jalkyl, (Cr- 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;
• each occu ⁇ ence of R 5 is independently H, (Ci-C ⁇ jalkyl, (C 2 - C 6 )alkenyl, or (C 2 -C6)alkynyl;
• each occu ⁇ ence of b is independently 0 or 1 and optionally each of the rings independently contains the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds such that when b is 0 the maximum number of carbon-carbon bonds is two or when b is 1 the maximum number of carbon-carbon bonds is three.
• the invention encompasses compounds of formula
• each occu ⁇ ence of R 1 , R 2 , R 6 , R 7 , R u , or R 12 is independently hydrogen, (C.- C 6 )alkyl, (Cr-C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benyl;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) Z or PH, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, CH 2 OH, C(0)OH, OC(0)R 3 , C(0)OR 3 , S0 3 H,
• R 3 is (C 1 -C 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 ⁇ -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence 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 ⁇ alkoxy, or phenyl groups;
• each occu ⁇ ence of R 5 is independently H, (C ⁇ -C6)alkyl, (C-r- C 6 )alkenyl, or (C2-C6)alkynyl;
• (f) b is 0 or 1 and optionally the ring contains one or more carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• the invention encompasses compounds of the formula VI: VI
• each occu ⁇ ence of R 1 , R 2 , R 6 , R 7 , R n , or R 12 is independently hydrogen, (d- C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C6)alkynyl, phenyl, or benzyl;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) Z or PH, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, CH 2 OH, C(0)OH, OC(O)R 3 , C(0)OR 3 , S0 3 H,
• R 3 is (d-C 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 1 -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstimted or substituted with one or two halo, OH, d-C 6 alkoxy, or phenyl groups; and
• each occurrence of R 5 is independently H, (C ⁇ -C6)- ⁇ lkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl;
• (f) b is 0 or 1 and optionally the ring contains one or more carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• the invention encompasses compounds of the formula VII:
• each occu ⁇ ence of Y 1 and Y 2 is independently L, V, (CH 2 )n-Y, or C(R 1 )(R 2 )-(CH 2 )c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH 2 ) X , where x is 1, 2, 3, or 4, W 2 is CH 3 ;
• each occu ⁇ ence of R 1 or R 2 is independently (d-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is CfJl ⁇ fR 2 )- (CH 2 )c-C(R 3 )(R 4 HCH 2 )n-W, then R 1 and R 2 can both be H to form a methylene group;
• R 3 is H, (d-Q alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• R 4 is OH, (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (Cr-Q alkynyl, (d-C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• each occu ⁇ ence of W is independently OH, COOH, CHO, COOR 5 , S0 3 H, wherein:
• R 5 is (d-C 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 ⁇ -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence 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, (d-C ⁇ ) alkoxy, or phenyl groups;
• each occu ⁇ ence of R 7 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C ⁇ jalkenyl, or (C2-C 6 )alkynyl; and
• (j) X is (CH 2 ) 2 or PH, wherein z is an integer from 0 to 4.
• the invention encompasses compounds of the formula VIII: VIII
• each occu ⁇ ence of Y 1 and Y 2 is independently L, V, CfR ⁇ fR ⁇ CH ⁇ c-CCR 3 ) ⁇ 4 )- (CH 2 )n-Y, or C( 1 )(R 2 )-(CH 2 )c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH 2 ) X , where x is 1 , 2, 3, or 4, W 2 is CH 3 ;
• each occu ⁇ ence of R 1 or R 2 is independently (Cj-C ⁇ jalkyl, (C 2 -C 6 )alkenyl, (C 2 - C6)alkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is CCR- 1 ) ⁇ )- (CH 2 )o-C(R 3 )(R 4 HCH 2 )n-W, then R 1 and R 2 can both be H to form a methylene group;
• R 3 is H, (d-C 6 )alkyl, (Cr-C 6 )alkenyl, (C2-C 6 )alkynyl, (C ⁇ -C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• R 4 is OH, (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• V is: each occu ⁇ ence of W is independently OH, COOH, CHO, COOR 5 , S0 3 H,
• R 5 is (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C6) l ynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ -C 6 )alkoxy, or phenyl groups
• each occu ⁇ ence of R 6 is independently H, (d-C ⁇ Jalkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, (C.-C ⁇ ) alkoxy, or phenyl groups; and
• each occu ⁇ ence of R 7 is independently H, (C ⁇ C6)alkyl, (C2- C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
• the invention encompasses compounds of formula IX:
• each occu ⁇ ence of Y 1 and Y 2 is independently L, V, C ⁇ HCH ⁇ c-C R ⁇ fR 4 )- (CH 2 )n-Y, or C(R')(R 2 )- ⁇ CH 2 )c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH 2 ) X , where x is 1, 2, 3, or 4, W 2 is CH 3 ;
• each occu ⁇ ence of R 1 or R 2 is independently (d-C 6 )alkyl, (C 2 -C6)alkenyl, (C 2 - C ⁇ jalkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is C 1 ) ⁇ 2 )- (CH 2 )c-C(R 3 )(R 4 HCH 2 )n-W, then R 1 and R 2 can both be H to form a methylene group;
• R 3 is H, (d-C 6 )alkyl, (Cr-C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C6)alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• R 4 is OH, (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• each occu ⁇ ence of W is independently OH, COOH, CHO, COOR 5 , S0 3 H,
• R 5 is (C ⁇ -C 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 ⁇ -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 6 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C6)alkenyl, or (C 2 -C 6 )a]kynyl and is unsubstituted or substituted with one or two halo, OH, (Ci-C ⁇ ) alkoxy, or phenyl groups; and
• each occu ⁇ ence of R 7 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
• the invention further encompasses compounds of formula X:
• 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 and n is an integer ranging from 0 to 7;
• each occu ⁇ ence of R 1 or R 2 is independently (d_C 6 )alkyl, (C 2 _C6)alkenyl, (C2_ C 6 )alkynyl, phenyl, or benzyl or when one or both of W 1 and W 2 is CtR 1 ) ⁇ 2 )-
• R 1 and R 2 can both be H to form a methylene group; 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;
• R 3 is H, (C ⁇ _C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 _C 6 )alkynyl, (d . -C 6 )alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ;
• R 4 is OH, (d_C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C.-C6)alkoxy, phenyl, benzyl, CI, Br, CN, N0 2 , or CF 3 ; (g) wherein n is an integer from 0 to 5;
• each occu ⁇ ence of Y is independently (d_C 6 )alkyl, OH, COOH, COOR 5 , S0 3 H,
• R 5 is (d-C a-kyl, (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 ⁇ --C6)alkoxy, or phenyl groups,
• each occu ⁇ ence of R 6 is independently H, (C 2 _
• each occu ⁇ ence 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 XI:
• W 1 and W 2 are independently L, V, or C( ⁇ )(Ei 2 )--(C 2 )XV, where c is 1 or 2;
• each occu ⁇ ence of R 1 and R 2 is independently (C.-C ⁇ jalkyl, (C 2 _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 )cycloakyl group;
• (e) L is where n is an integer ranging from 0 to 5;
• each occu ⁇ ence of Y is independently (C ⁇ -C 6 )alkyl, OH, COOH, COOR 3 , S0 3 H,
• R 3 is (C 1 -C 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,
• each occu ⁇ ence of R 4 is independently H, (C ⁇ _C6)alkyl, (C 2 _ C6)alkenyl, or (C 2 _C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, or phenyl groups; and
• each occu ⁇ ence of R 5 is independently H, (d_C6)alkyl, (C 2 - C 6 )alkenyl, or
• each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• the invention encompasses compounds of formula X ⁇
• each occu ⁇ ence of m is independently an integer ranging from 1 to 9;
• each occu ⁇ ence of n is independently an integer ranging from 0 to 7;
• each occu ⁇ ence of R l , R 2 , R 11 , and R 12 is independently (d-Q alkyl, (C 2 _
• each occu ⁇ ence of Y is independently (d-C 6 )alkyl, OH, COOH, COOR 3 , S0 3 H,
• R 3 is (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X 6 )alkynyl J 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, (CiX ⁇ Jalkyl, (C 2 _ C6)alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C.X ⁇ alkoxy, or phenyl groups;
• each occu ⁇ ence of R 5 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl; and (f) X is (CH 2 ) Z or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• the invention encompasses compounds of formula XIH
• each occu ⁇ ence of m is an independent integer ranging from 1 to 9;
• the invention encompasses compounds of formula XIV:
• W l and W 2 are independently C(R J )(R 2 )-(CH 2 )n Y, where n is an integer ranging from 0 to 7;
• each occu ⁇ ence of R 8 and R 9 is independently H, (dX ⁇ Jalkyl, (C 2 X6)alkenyl, (C 2 - C 6 )alkynyl, phenyl, or benzyl or R 8 and R 9 can be taken together to form a carbonyl group;
• each occu ⁇ ence of R 1 and R 2 is independently H, (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 _ C ⁇ jalkynyl, phenyl, or benzyl or R 1 and R 2 can be taken together to form a carbonyl group 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 occu ⁇ ence of R 6 and R 7 is independently H, (d-C 6 )alkyl, or R 6 and R 7 can be taken together to form a carbonyl group or R ⁇ and R 7 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
• Y is (dX 6 )alkyl, OH, COOH, COOR 3 , S0 3 H,
• R 3 is (C ⁇ 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 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (CiX ⁇ Jalkyl, (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 occu ⁇ ence of R 5 is independently H, (C ⁇ X 6 )alkyl, (C 2 - C 6 )alkenyl, or (C 2 X 6 )alkynyl;
• each occu ⁇ ence of b is independently 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds;
• X is (CH 2 ) Z or Ph, wherein z is an integer from 0 to 4.
• each occu ⁇ ence of W l and W 2 is an independent CCR ⁇ fR 2 HCH2) ⁇ -Y group and each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• the invention encompasses compounds of formula XV:
• each occu ⁇ ence of m is independently an integer ranging from 1 to 5;
• X is (CH 2 ) Z or Ph, wherein z is an integer from 0 to 4;
• W 1 and W 2 are independently C R ⁇ MCH n -Y, where n is an integer ranging
• each occu ⁇ ence of R 1 or R 2 is independently (C ⁇ _C 6 )alkyl- (C 2 6)alkenyl, (C 2 _ C 6 )alkynyl, 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
• Y is (dX 6 )alkyl, (CH 2 ) n OH, (CH 2 ) n COOH, (CH 2 ) ⁇ COOR 3 , S0 3 H,
• R 3 is (C ⁇ 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 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (d.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, d 6 alkoxy, or phenyl groups,
• each occu ⁇ ence of R 5 is independently H, (C 1 X 6 )alkyl, (d- C 6 )alkenyl, or (C 2 X 6 )alkynyl;
• each occu ⁇ ence of b is independently 0 or 1 ;
• X is (CH 2 )z or Ph, wherein z is an integer from 0 to 4.
• W 1 and W 2 are independent C(R 1 )(R 2 )-(CH2) t v-Y, groups and each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• the invention encompasses compounds of formula XVI:
• W 1 and W 2 are independently C(R 1 )(R 2 )-(CH 2 ) n -Y . where n is an integer ranging from 0 to 4;
• each occu ⁇ ence of R 1 and R 2 is independently (C.X 6 )alkyl, (C 2 _ Ce)alkynyl, phenyl, or benzyl or R 1 and R 2 are both H;
• each occu ⁇ ence of R 6 and R 7 is independently H, (d-C ⁇ ) alkyl, or R 6 and R 7 can be taken together to form a carbonyl group;
• Y is OH, COOH, COOR 3 , S0 3 H,
• R 3 is (C,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, (dX6)alkoxy, or phenyl groups,
• each occu ⁇ ence of R4 is independently H, (C ⁇ X6)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 ⁇ alkoxy, or phenyl groups;
• each occu ⁇ ence of RS is independently H, (CiX ⁇ Jalkyl, (C 2 _ Ce)alkenyl, or (C 2 X 6 )alkynyl;
• each occu ⁇ ence of p is independently 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• each occu ⁇ ence of W 1 and W 2 is an independent CfR'XR 2 HCH 2 ) n _Y group and each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• the invention encompasses compounds of formula xv ⁇ .
• W 1 and W 2 are independently L, V, or C(R 1 )(R 2 )-(CH2)c.N. where c is 1 or 2; when G is (CH 2 ) X , where x is 1, 2, 3, or 4, W 2 is CH 3 ;
• each occu ⁇ ence of R 1 and R 2 is independently (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 _ C 6 )alkynyl, phenyl, or benzyl;
• L is C(R 1 )(R 2 )-(CH2)n_Y. where n is an integer ranging from 0 to 4;
• each occu ⁇ ence ofY is independently OH, COOH, CHO, COOR 3 , SO 3 H,
• R 3 is (C ⁇ X 6 )alkyl, (C 2 X 6 )alkenyl, (C 2 X6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (dXe)alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (dX6)alkyl, (C 2 _ C 6 )alkenyl, or (C 2 X 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, (CiX ⁇ ) alkoxy, or phenyl groups;
• each occurrence of R 5 is independently H, (C,X6)alkyl, (C 2 _ C 6 )alkenyl, or (C 2 6 ) l ynyl;
• each X is independently PH or (CH 2 ) r , where r is 1 , 2, 3, or 4.
• the invention encompasses compounds of formula XV ⁇ i:
• each occu ⁇ ence of m is independently an integer ranging from 0 to 5;
• each occu ⁇ ence of n is independently an integer ranging from 3 to 7;
• X is (CH 2 ) Z or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of R 1 and R 2 is independently (Ci-C ⁇ jalkyl, (C2-C6)alkenyl, (C 2 - C 6 )a_kynyl, 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 )cycloakyl group; (e) each occu ⁇ ence of R 11 and R 12 and the carbon to which they are both attached are taken together to form a (C3-C 7 )cycloakyl group;
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, OH, COOH, COOR 3 , S0 3 H,
• R 3 is (C ⁇ X 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C6)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 ⁇ -C6)alkyl, (C 2 - Q alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, Ci-C ⁇ alkoxy, or phenyl groups; and (iii) each occurrence of R 5 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C6)alkenyl, or (C2-C 6 )al ynyl.
• each occu ⁇ ence of Y is independently OH, COOR 3 , or COOH.
• Other compounds of formula XVHI are those wherein m is 0.
• the invention encompasses compounds of the formula XIX:
• each occu ⁇ ence of R 1 and R 2 is independently (Cr-C ⁇ a-kyl, (C2-C6)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 )cycloakyl group;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) 2 or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d-C 6 )alkyl, CH 2 OH, C(0)OH, OC(0)R 3 , C(0)OR 3 . S0 3 H,
• R 3 is (d-C 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, (d-C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (d-C6)alkyl, (C2- C6)a]kenyl- or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C.-C ⁇ alkoxy, or phenyl groups;
• each occu ⁇ ence of R 5 is independently H, (C ⁇ -C6)alkyl, (Cr- C6)alkenyl, or (C 2 -C 6 )alkynyl;
• (g) b is 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• Exemplary compounds of formula XIX are those in which each occu ⁇ ence of R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C3-C 7 )cycloakyl group.
• the invention encompasses compounds of formula
• each occu ⁇ ence of R 1 and R 2 is independently (C.-C 6 )alkyl, (C 2 -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;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) Z or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence ofm is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (C ⁇ -C6)alkyl, CH 2 OH, C(0)OH, OC(0)R 3 , C(0)OR 3 , SO3H,
• R 3 is (d-C 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 ⁇ -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (C ⁇ -C 6 )alkyl, (C 2 - C 6 )alkenyl, or (CrX ⁇ alkynyl and is unsubstituted or substituted with one or two halo, OH, d-C 6 alkoxy, or phenyl groups;
• each occu ⁇ ence of R 5 is independently H, (C.-C6)alkyl, (C 2 - C ⁇ )alkenyl, or (C 2 -C 6 )a-kynyl;
• each occu ⁇ ence of b is independently 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• the invention encompasses compounds of formula
• each occu ⁇ ence of R 1 and R 2 is independently (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C6)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 occu ⁇ ence of R u and R 12 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (C ⁇ -C 6 )alkyl, CH 2 OH, C(0)OH, OC(0)R 3 , C(0)OR 3 , S0 3 H,
• R 3 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 ⁇ -C 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (C.-C6)alkyl, (C 2 - C 6 )alkenyl, or (C-X ⁇ jalkynyl and is unsubstituted or substituted with one or two halo, OH, Ci-C ⁇ alkoxy, or phenyl groups;
• each occu ⁇ ence of R 5 is independently H, (d-C6)alkyl, (C 2 - C 6 )alkenyl, or (d-C ⁇ Jalkynyl;
• (g) b is 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds.
• the invention encompasses compounds of formula
• each occu ⁇ ence of R 1 and R 2 is independently (C ⁇ -C 6 )alkyl, (C2-C6)alkenyl, (C ⁇ 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 occu ⁇ ence of R 1 and R 12 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
• each occu ⁇ ence of n is independently an integer ranging from 1 to 7;
• X is (CH2) Z or Ph, wherein z is an integer from 0 to 4;
• each occu ⁇ ence of m is independently an integer ranging from 0 to 4.
• each occu ⁇ ence of Y 1 and Y 2 is independently (d ⁇ alkyl, CH 2 OH, C(0)OH,
• R 3 is (d ⁇ C 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 1 X 6 )alkoxy, or phenyl groups,
• each occu ⁇ ence of R 4 is independently H, (d-C6)alkyl, (C 2 - C 6 )alkenyl, or (C 2 - - 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, d-C 6 alkoxy, or phenyl groups; and
• each occu ⁇ ence of R 5 is independently H, (C ⁇ -C6)alkyl, (C-r- C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
• compositions comprising one or more compounds of the invention.
• Particular pharmaceutical compositions further comprise pharmaceutically acceptable vehicle, which can comprise a carrier, excipient, diluent, or a mixture thereof.
• the present invention provides a method for treating or preventing aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabohsm, dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing reverse lipid transport, hypertension, impotence, inflammation, insulin resistance, hpid 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), and a thrombotic disorder, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of the invention.
• the present invention further provides a method for reducing the fat content of meat in livestock comprising administering to livestock in need of such fat-content reduction a therapeutically effective amount of a compound of the invention or a pharmaceutical composition.
• the present invention provides a method for reducing the cholesterol content of a fowl egg comprising administering to a fowl species a therapeutically effective amount of a compound of the invention.
• the compounds of the invention are particularly useful when incorporated in a pharmaceutical composition comprising a carrier, excipient, diluent, or a mixture thereof.
• a compound of the invention need not be administered with excipients or diluents and can be delivered in a gel cap or drug delivery device.
• 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.
• Examples of other therapeutic agents include, but are not limited to, 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 cardiovascular drug; an HDL- raising drug; an HDL enhancer; or a regulator of the apolipoprotein A-I, apolipoprotein A-

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