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WO2005068420A1 - Composes d'uree et de thiouree et compositions pour la gestion de cholesterol et utilisations associees - Google Patents

Composes d'uree et de thiouree et compositions pour la gestion de cholesterol et utilisations associees Download PDF

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WO2005068420A1
WO2005068420A1 PCT/US2003/041789 US0341789W WO2005068420A1 WO 2005068420 A1 WO2005068420 A1 WO 2005068420A1 US 0341789 W US0341789 W US 0341789W WO 2005068420 A1 WO2005068420 A1 WO 2005068420A1
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Prior art keywords
thioureido
methyl
thiourea
hydroxy
bis
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Jean-Louis Henri Dasseux
Daniela Carmen Oniciu
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Esperion Therapeutics Inc
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Esperion Therapeutics Inc
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Priority to PCT/US2003/041789 priority Critical patent/WO2005068420A1/fr
Priority to AU2003300177A priority patent/AU2003300177A1/en
Publication of WO2005068420A1 publication Critical patent/WO2005068420A1/fr
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    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
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    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
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    • C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D261/10—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2408—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyalkyl compounds

Definitions

  • the invention encompasses urea and thiourea compounds and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof; compositions comprising urea and thiourea compounds and pharmaceutically acceptable salts, hydrates, solvates, and 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, 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, or enhancing bile production, or enhancing reverse lipid transport, which
  • 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
  • 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, intermediate-density lipoproteins (IDL), and LDL.
  • apo B-containing lipoproteins which include chylomicrons, CLDL, intermediate-density lipoproteins (IDL), and LDL.
  • the 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 Cholesterol Transport
  • 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.
  • 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.
  • VLDL very-low-density lipoprotein particle
  • 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 NLDL, apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E), although other apolipoproteins are present, such as apolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CH).
  • NLDL neoprotein
  • NLDL remnant a new kind of particle called intermediate-density lipoprotein (DDL) or NLDL remnant, decreased in size and enriched in cholesteryl esters relative to a VLDL, but retaining its two apoproteins.
  • DDL intermediate-density lipoprotein
  • IDL particles In human beings, about half of the IDL particles are removed from the circulation quickly, generally within two to six hours of their formation. This is because 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.
  • LDL receptors 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 DDL 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
  • 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 lecithinxholesterol acyltransferase
  • CETP Cholesterol ester transfer protein
  • PLTP phospholipid transfer protein
  • PLTP supplies lecithin to HDL
  • CETP can move cholesteryl esters made by LCAT to other lipoproteins, particularly apoB-containtng 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 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 (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 II-containing fraction is referred to herein as the AI/AH- HDL fraction of HDL.
  • Al HDL fraction the fraction of HDL containing only apo A I, referred to herein as the Al HDL fraction, appears to be more effective in RCT.
  • pre-beta-1 HDL lipid-poor complex
  • pre-beta-1 HDL is the preferred acceptor for cholesterol transferred from peripheral tissue involved in RCT.
  • 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 apolipoprotein such as 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 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 4:1127).
  • 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 ⁇ -oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol.1:489 530; Vamecq and Draye, 1989, Essays Biochem. 24:1115 225; and Nelali et al., 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 ⁇
  • PPRE peroxisome proliferator response elements
  • 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 90:21602164; Heyman et al, 1992, Cell 68:397 406, and Levin et al, 1992, Nature 355:359361). Since the discovery of PPAR ⁇ , additional isoforms of PPAR have been identified, e.g., PPAR/3, PPAR ⁇ and PPAR ⁇ , which have similar functions and are similarly regulated.
  • 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 ⁇ -oxidation of fatty acids; apolipoprotein A-I; medium chain acyl-CoA dehydrogenase, a key enzyme in mitochondrial 0-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:S1923).
  • 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 trans ferase reporter gene (Harris and Kletzien, 1994, Mol. Pharmacol. 45:439 445). Deletion analysis led to the identification of an approximately 30 bp region accounting for pioglitazone responsiveness.
  • 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 (PRAVACHOL, Bristol-Myers Squibb Co.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterol synthesis by inhibiting HMGCoA reductase, the key enzyme involved in the cholesterol biosynthetic pathway.
  • Lovastatin significantly reduces serum cholesterol and LDL-serum levels. 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.
  • 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. 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.
  • LOPID also increases HDL cholesterol, particularly the HDL2 and HDL3 subfractions, as well as both the AI/AII-HDL fractions.
  • the lipid response to LOPID is heterogeneous, especially among different patient populations.
  • 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; itemational Patent Publication WO 98/30530; U.S. Patent No.
  • 4,689,344 discloses /3,ft
  • Patent No.4,613,593, phosphates of dolichol, a polyprenol 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.
  • W 1 and W 2 are independently L, V, C(R 1 )(R 2 HCH 2 )c-C(R 3 )(R 4 HCH 2 ) deliberately-Y, or C(R')(R 2 )-(CH 2 ) c -V, wherein c is 1 or 2 and n is an independent integer ranging from 0 to 4;
  • each occurrence of R 1 and R 2 is independently (Ci-C ⁇ jalkyl, (C 2 -Ce)alkenyl, (C 2 - C 6 )al
  • R 3 is H, (C ⁇ -C 6 )alkyl, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, phenyl, benzyl, Cl, Br, CN, NO 2 , or CF 3 ;
  • R 4 is OH, (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 ;
  • L is C(R 1 )(R 2 )- ⁇ CH2)n-Y; where n is an independent integer ranging from 0 to 4; (i) V is
  • each occurrence of Y is independently (C 1 _C 6 )alkyl, OH, COOH, CHO, COOR 5 , SO 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 ⁇ )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
  • each occurrence of R 7 is independently H, (C ⁇ -C 6 )alkyl, (C 2 -
  • W l and W 2 are independently L, V, or C ' ⁇ MCH ⁇ -N, where c is 1 or 2;
  • R 1 and R 2 are independently (Ci-C ⁇ jalkyl, (C2-C6)alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl.
  • the invention encompasses compounds of formula la:
  • W 1 and W 2 are independently L, V, or C(R 1 )(R 2 HCH 2 ) C -V, where c is 1 or 2; (d) each occurrence of R 1 and R 2 is independently (C ⁇ -Ce)alkyl, (C 2 -C6)alkenyl, (C 2 - C 6 )alkynyl, phenyl, or benzyl;
  • L is CtR'XR ⁇ CH ⁇ n -Y, where n is an independent integer ranging from 0 to 4;
  • each occurrence of Y is independently (C ⁇ _C 6 )alkyl, OH, COOH, CHO, COOR 5 , SO 3 H,
  • R 3 is (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (Cr-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 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, Ci-C ⁇ alkoxy, or phenyl groups
  • each occurrence of R 5 is independently H, (Ci-C ⁇ jalkyl, (C 2 - C 6 )alkenyl, or (C ⁇ -CeJalkynyl.
  • formula la is independently H, (Ci-C ⁇ jalkyl,
  • the invention encompassses compounds of formula lb:
  • each occurrence of m is independently an integer ranging from 1 to 9;
  • each occurrence of n is an independent integer ranging from 0 to 4;
  • each occurrence of R 1 and R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl, benzyl, or R 1 , R 1 , and the carbon to which they are both attached are taken together to form a (C 3 -C )cycloalkyl group;
  • each occurrence of R 11 and R 12 is independently H, (C ⁇ -C6)alkyl, (C 2 -Ce)alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl or R 1 ', R 12 , and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group; and
  • each occurrence of Y is independently (C ⁇ -C 6 )alkyl, OH, COOH, CHO, COOR 5 ,
  • R 3 is (C ⁇ -O 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkvnyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C ⁇ -C ⁇ )alkoxy, or phenyl groups
  • each occurrence of R 4 is independently H, (Ci-C ⁇ jalkyl, (C 2 - C ⁇ jalkenyl, or (C 2 -C 6 ) lkynyl 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 ⁇ -C6)alkyl, (C 2 - C ⁇ jalkenyl, or (C 2 -C 6 )alkynyl.
  • each occurrence of Y is independently OH, COOR 3 , or COOH.
  • 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:
  • R 1 and R 2 are independently (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl; or R 1 , R 2 , and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group;
  • R u and R 12 are independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl; or R 1 ', R 12 , and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group;
  • n is independently an integer ranging from 1 to 7;
  • each occurrence of m is independently an integer ranging from 0 to 4;
  • each occurrence of W 1 and W 2 is independently (d-C 6 )alkyl, CH 2 OH, COOH, CHO, 0C(0)R 3 , C(O)OR 3 , SO 3 H,
  • R 3 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 6 )alkoxy, or phenyl groups,
  • each occurrence of R 4 is independently H, (C ⁇ -C ⁇ )alkyl, (C 2 - C 6 )alkenyl, or (C 2 -C ⁇ )alkynyl and is unsubstituted or substituted with one or two halo, OH, C ⁇ -C 6 alkoxy, or phenyl groups;
  • each occurrence of R 5 is independently H, (C ⁇ -C6)alkyl, (C 2 -
  • each occurrence of n is independently an integer ranging from 0 to 4.
  • Preferred compounds of formula II are those wherein each occurrence of W is independently OH, COOR 3 , COOH,
  • R 1 and R 2 are independent (C ⁇ -C 6 )alkyl groups.
  • R 1 and R 2 are (d-CeJalkyl, CH 2 OH, COOH, CHO, OC(O)R 3 , C(O)OR 3 , SO 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, (C ⁇ -C 6 )alkoxy, or phenyl groups,
  • each occurrence of R 8 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 9 is independently H, (C ⁇ -C6)alkyl, (C 2 - C 6 )alkenyl, or (Cr-C ⁇ Jalkynyl;
  • R 3 and R 4 are (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (Cr-C6)alkynyl, phenyl, or benzyl;
  • R 5 and R 6 are hydrogen, halogen, (C 1 -C 4 )alkyl, (C ⁇ -C4)alkoxy, (C 6 )aryloxy, CN, or NO 2 , N(R 5 ) 2 where R 5 is H, (C ⁇ -C 4 ) alkyl, phenyl, or benzyl;
  • each occurrence of m is independently an integer ranging from 1 to 5;
  • each occurrence of n is independently an integer ranging from 0 to 4; and (g) C* 1 and C* 2 represent independent chiral-carbon centers, wherein each center may independently be R or S .
  • Preferred compounds of formula lla are those wherein each occurrence of R 1 and R 2 is independently OH, COOR 7 , or COOH.
  • compounds of formula lla are those wherein C* 2 is of the stereochemical configuration S or substantially S.
  • compounds of formula Ha are those wherein C* C* 2 are of the stereochemical configuration (S ! ,S 2 ) or substantially (S ,S ).
  • compounds of formula lla are those wherein C* C* 2 are of the stereochemical configuration (S ⁇ R 2 ) or substantially (S',R 2 ). In another particular embodiment, compounds of formula lla are those wherein C*
  • C* 2 are of the stereochemical configuration (R',R 2 ) or substantially (R ⁇ R 2 ).
  • compounds of formula lla are those wherein C* C* 2 are of the stereochemical configuration (R l ,S 2 ) or substantially (R ! ,S 2 ).
  • 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 (IBS), 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 pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, or mixures of stereoisomers thereof.
  • Compounds of formula I encompass subgroup formulas la, lb and lc.
  • Compounds of formula II encompass subgroup formula Ha.
  • “compound of the invention” collectively means compound of formulas I, la, lb, lc, II and Ha are pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, or mixures of stereoisomers 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 chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
  • the present invention provides novel compounds useful 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 urea or thiourea compound or composition of the invention.
  • a disease or disorder such as, but not limited to, aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy,
  • 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
  • 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 excipient, other than a compound of the invention. Accordingly, in one embodiment, 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, 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
  • 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; a phosphodiesterase-5-inhibitor; 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- IV and/or apolipoprotein genes.
  • compound A and “compound B” refer to the compounds l,3-bis-(6- hydroxy-5,5-dimethyl-hexyl)-urea and 1 ,3-bis-(5-hydroxy-4,4,-dimethyl-hexyl)-urea, having the respective structures:
  • 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 (Le., geometric isomers), enantiomers, or diastereomers.
  • stereoisomers such as double-bond isomers (Le., 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 (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 80% 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 80% de with respect to a particular chiral center.
  • a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding 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 lla.
  • 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 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 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 ether compound of the invention by weight of the isolate.
  • phrases "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. Compounds 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, glucaronate, saccharate, formate, benzoate, glutamate, mefhanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pa
  • 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.
  • 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.
  • spaces e.g., channels
  • guest molecule e.g., a solvent or water
  • “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.
  • Alcoholing 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, (Ci-C 6 )alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl,
  • alkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • 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-pro ⁇ yl-2-butenyl, 4-(2- methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • 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. Examples of 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. Preferably, 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, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, 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, referred to herein as "(C 2 - Cs)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 cycloalkyl groups include, but are not limited to, (C 3 -C )cycloaIkyl 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 ⁇ -C ⁇ )heterocycloalkyl.
  • 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 "(Ci-C ⁇ jalkoxy”.
  • 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 "(C 6 )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.
  • hydrocarbyl group means a monovalent group selected from (C ⁇ -Cg)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
  • 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 “HaF'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 ⁇ -C 8 )alkyl; (C l -C 8 )alkenyl; (C 6 )aryl; (C 2 -C 5 )heteroaryl; (C 3 - C 7 )cycloalkyl; (C ⁇ -C 8 )alkoxy; (C 6 )aryloxy; -CN; -OH; oxo; halo, -CO 2 H; -NH 2 ; -
  • the compounds of the invention can be obtained via the synthetic methodology illustrated in Schemes 1-13.
  • Starting materials useful for preparing the compounds of the invention and intermediates thereof, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • Amines V are commercially available (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin) or can be prepared by well-known synthetic methods.
  • Scheme 1 illustrates the synthesis of amines V from aldehydes III via the imine IV (see Wang et al. J. Org. Chem. 1995, 60, 7364, Tanaka et al. J. Med. Chem.
  • the temperature of the reaction mixture is raised to over 150 °C, preferably 180-200 °C, for 2 to 10 hours.
  • the reaction mixture is cooled at room temperature, treated with concentrated HC1 at 0 °C or higher for 2 to 6 hours, and the organic impurities extracted with an organic solvent such as diethyl ether, t-butyl methyl ether, benzene, toluene, hexane, preferably toluene.
  • the aqueous layer is made alkaline with an aqueous sodium hydroxide solution and the amine is extracted in an organic solvent and purified by methods commonly used in the field.
  • halide VI is treated with dibenzylamine neat at temperatures in the range of 100 to 150 °C, preferably 130 °C, or in diglyme in the presence of potassium carbonate at temperatures in the range of 120 to 180 °C, preferably at 140 °C, until no more change in the starting material is observed by an analytical method such as but not limited to HPLC or tic.
  • an analytical method such as but not limited to HPLC or tic.
  • the reaction is complete, the amine is converted into a hydrochloride salt and is precipitated as a hydrochloride salt in a dry solvent such as 2-propanol.
  • the dibenzylamine derivative VII is treated with 10% Pd/C and ammonium formate in methanol at reflux for 2 to 24 hours, then filtered through Celite and concentrated in vacuo to yield the crude amine V, which is purified by usual methods.
  • Pd/C 10% Pd/C and ammonium formate
  • methanol methanol
  • Celite a representative example see Purchase et al. J. Org. Chem. 1991, 56, 457-459.
  • Scheme 1 also illustrates the preparation of amines of formula V by Gabriel synthesis starting from halo-derivatives VI (for general references see Gibson et al. Angew. Chem. 1968, 80, 986, Smith and March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS AND STRUCTURES, 5 th Ed.; Wiley: New York, 2001 ; p 513, and references cited herein).
  • For an improved Gabriel synthesis see also Sheehan et al. J. Amer. Chem. Soc. 1950, 72, 2786-2788.
  • the phthalimide of formula VIII thus obtained is treated in methanol with an 85% aqueous solution of hydrazine hydrate for 15 min to one hour. Addition of water and removal of the methanol is followed by addition of HC1 and heating under reflux for 1 hour, removal of crystalline phthalhydrazide by cooling to 0 °C, then workup of the amine V from the filtrate.
  • N-Alkylphthalimides of formula VIII are also prepared from an alcohol and phthalimide using Mitsunobu conditions (Mitsunobu et al. J. Amer. Chem. Soc. 1972, 94, 79-680).
  • the phthalimide in ethanol is treated with hydrazine hydrate at reflux for 15 min, then the suspension is cooled, acidified and filtered.
  • the amine of formula V is recovered from the filtrate either as a hydrochloride salt or as a free base by usual separation methods.
  • esters V are also prepared fromp-toluenesulfonic acid esters of formula IX, as illustrated in Scheme 2.
  • Esters IX can be obtained by various means, including treating the corresponding alcohols with j-toluenesulfonyl chloride as described in International Patent Application No. 01/31873 to Dasseux, et al. and by other methods well-known in the field (for a review, see Sandier and Karo, Organic Functional Group Preparations, 2d ed., vol. 3, Academic Press: New York, 1989, pp. 129-151), or via commercial sources (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin).
  • Scheme 3 illustrates the synthesis of isocyanates X via treatment of the corresponding amines V with phosgene or a phosgene substitute, such as trichloromethyl chloroformate, as shown in Scheme 3.
  • phosgene or a phosgene substitute such as trichloromethyl chloroformate
  • the amine of formula V in a solvent such as dichloromethane, chloroform, dichloroethane, preferably dichloromethane is treated with phosgene or a phosgene substitute at temperatures from —40 °C to ambient until disappearance of, or no more change in the starting material is observed by an analytical method such as but not limited to HPLC or tic.
  • the isocyanate is subsequently isolated and purified by usual chromatographic methods or recrystallization.
  • di-tert-butyldicarbonate is treated sequentially with equimolar amounts of 4-dimethylaminopyridine and amine in acetonitrile, then the mixture is stirred for 10 min to 1 hour at room temperature.
  • the mixture is treated with a solvent, preferably dichloromethane, and sulfuric acid is added afterwards as a 40% solution in acetonitrile.
  • Isocyanate X is extracted in an organic solvent, preferably a halogenated solvent, and afterwards is purified by methods well-known in the field.
  • the acyl halide XI is treated with sodium azide in an organic solvent, preferably acetone, at temperatures from ambient to reflux, then the product is separated by methods such as column chromatography, distillation or recrystallization to yield acyl azide XII, which is then taken up in an appropriate organic solvent, preferably toluene, and heated to temperatures ranging from 40 to 120 °C to yield the isocyanate X. XVI .
  • an isocyanate derivative XIV is treated with a diamine XV in conditions similar to the ones described above, and then intermediate XVI as a crude or purified product is further treated with a second mole of isocyanate XIV to yield a urea of formula I or la.
  • Aryl diamides of the general formula XVTI may be transformed into their corresponding isocyanates XVIII via a Hofmann rearrangement effected by treatment with lead tetraacetate (see March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS AND STRUCTURES, 1091, 4 th Ed., 1992, pp. 1090-1091 and references cited herein).
  • Isocyanates of formula XVIII may then be converted to aryl ureas of formulas I and la upon reaction with an appropriate amine as previously described.
  • Urea compounds of all general formulas (I, Ia-c, II and lla) may also be prepared from the corresponding thioureas (see Schemes 12 and 13 for general methodologies used to prepare thiourea compounds of the invention) by oxidation in the presence of various oxidizing agents, as illustrated in Scheme 7.
  • Typical oxidants employed for this transformation include manganese dioxide in dichloromethane, t-butyl hypochlorite in carbon tetrachloride, sodium nitrite in hydrochloric acid 4 , mercuric acetate in dichloromethane, and preferably hydrogen peroxide in sodium hydroxide (as reference see McKay et al. Can. J. Chem.
  • a thiourea (represented by structures XIX and XX) is dissolved in a mixture of an alcohol and aqueous sodium or potassium hydroxide, preferably ethanol and 30 % sodium hydroxide.
  • the solution is treated with a 50 % solution of hydrogen peroxide at temperatures of -20 to 0 °C, then the reaction is allowed to reach the ambient temperature or heated at up to 40 °C, until no more change in the starting material is detected by an analytical method, such as HPLC or tic.
  • the reaction is then quenched by adding water, and the product is extracted or recrystallized.
  • the crude urea is purified by known methods such as recrystallization, chromatography, etc.
  • Schemes 8-11 illustrate the syntheses of urea compounds of formula II and lla. Their preparation rely on methods well-known in the field that have been described and reviewed previously (Hegarty and Drennan, in COMPREHENSIVE ORGANIC FUNCTIONAL GROUP TRANSFORMATIONS, A. R. Katritzky, O. Meth-Cohn and C W. Rees, Eds.,
  • ureas of formula II and Ha are readily obtained by reacting an amine of formula V with an isocyanate of formula X.
  • an amine is treated with an isocyanate in an appropriate solvent, at temperatures varying from 0 °C to room temperature or higher (reflux of the solvent) for 2 hours to 4 days, or until no more change in or disappearance of the starting materials is evidenced by an analytical method such as but not limited to NMR, GC, HPLC, or tic.
  • Suitable solvents are dichloromethane, diethyl ether, absolute ethanol, acetonitrile, chloroform, diglyme, toluene, anhydrous dioxane, anhydrous methanol and aqueous sodium hydroxide 2N, or mixtures of the above solvents, preferably dichloromethane. Examples are found in Tanaka et al. J. Med. Chem. 1998, 41, 2390-2410, Mounetou et al. J. Med. Chem. 2001, 44, 694-702, Hirst et al. J. Med. Chem. 1996, 39, 5236-5245, Scheerder et al. J. Org. Chem.
  • Ureas of formulas II and lla are also obtained from amines of formula V via either the trichloro- or tribromo-acetamide XXI as described above, via an elimination reaction with a second mole of amine V at temperatures from ambient to 80 °C (Braverman et al. Tet. Lett. 1999, 40, 3235-3238).
  • Chloroformates are commercially available reagents (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin). Carbamates of the formula XXII may then be employed in the synthesis of ureas of formula II by treatment of an amine V with a phenyl, benzyl or thio N- substituted carbamate XXII most often in the presence of a base.
  • Triethylamine, pyridine or ⁇ , ⁇ -dimethylaniline are typically utilized bases, preferably triethylamine.
  • the reaction is performed in a solvent such as toluene, dimethylformamide, phenylmethanol, dioxane, chloroform or dichloromethane at temperatures between RT and reflux for 2 to 24 hours.
  • a solvent such as toluene, dimethylformamide, phenylmethanol, dioxane, chloroform or dichloromethane at temperatures between RT and reflux for 2 to 24 hours.
  • Procedures are described in Tanaka et al. J. Med. Chem. 1998, 41, 2390-2410, Tanaka et al. J. Med. Chem. 1998, 41, 4408-4420, Crosby et al. J. Amer. Chem. Soc. 1954, 76, 4458, 4462, Shawali et al. J. Org. Chem.
  • Scheme 10 illustrates the synthesis of ureas of formula II by treatment of an amine V with triphosgene (XVIIIa) at 0°C to RT or at reflux in dichloromethane for 0.5 to 2 hours, then, after cooling, treatment of the trichloromethyl amido derivative XXIVa with an equivalent of the second amine in a solvent, preferably dichloromethane, at room temperature or higher for 2 to 24 hours (Kozikowski et al. J. Med. Chem. 2001 , 44, 298- 301, Tanaka et al. J. Med. Chem. 1998, 41, 2390-2410).
  • a solvent preferably dichloromethane
  • reaction of amine with bis(2/J-imidazol-2-yl)-methanone or carbonyldiimidazole (XVIIIb) leads to intermediate XXIVb, which can then be further treated with a second mole of amine in equimolar amounts to afford asymmetric ureas of formula II.
  • the amine preferably in the presence of a base such as triethylamine, pyridine, or DMAP, dissolved in a solvent such as dichloromethane, chloroform, dimethylformamide, toluene, diglyme, preferably dichloromethane or dimethylformamide, is treated with carbonyldiimidazole for 24 to 48 h at 0°C to room temperature.
  • a base such as triethylamine, pyridine, or DMAP
  • a solvent such as dichloromethane, chloroform, dimethylformamide, toluene, diglyme, preferably dichloromethane or dimethylformamide
  • Amines V in the presence of DCC or other carbodiimides as condensing agents and triethylamine or pyridine as a base are treated with an excess amount of dry ice added gradually into a solution containing carbodiimide and triethylamine at -78 °C (Le., Ogura et al. Synthesis 1978, 3498-3501). Finally, carbon dioxide is passed through a mixture of equimolar amounts of diphenyl phosphite and amine V in pyridine at 40 °C for 4 hours (i.e. , Yamazaki et al. Tet. Lett. 1999, 40, 1191-1194).
  • an amine of formula V can be treated with urea to yield a symmetrically substituted urea of formula II (i.e., Lavrov et al. J. Org. Chem. 1986, 51, 3498-3501, Davis et al. Organic Syntheses Coll. Vol. 1, Wiley: New York 1941, 453-455).
  • Secondary amines of formula X will react with carbon monoxide in the presence of selenium or sulfur to provide symmetric ureas of formula x (see March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS AND STRUCTURES, 640, 4 th Ed., 1992 and references cited herein).
  • the halide VI in acetonitrile is treated with sodium cyanate and a catalytic amount of tetrabutylammonium bromide (0.2 eq) in acetonitrile at room temperature, then water is added (1.2 to 1.5 equiv) with or without a catalyst, such as potassium iodide (0.2 eq).
  • a catalyst such as potassium iodide (0.2 eq).
  • the mixture is heated at temperatures higher than 40 °C, for up to 48 hours for bromide to up to 62 hours for chloride.
  • analytical method preferably GC or tic
  • the mixture is cooled and the product is purified by standard purification methods, such as chromatography or recrystallization.
  • Scheme 12 illustrates various methodologies for the synthesis of symmetric thiourea compounds of the Invention.
  • An amine of formula V can be reacted with carbon disulfide or potassium isothiocyanate to form symmetric thioureas of formula II.
  • Scheme 12 Shown in Scheme 13 is a method useful for the synthesis of symmetric and assymetric thioureas of formulas II and lla, respectively.
  • An amine of formula V can be reacted with thiocarbonyldiimidazole (XXV) to provide intermediate XXVI, which can then be reacted with a second amine of formula V in order to provide thioureas of formulas II and Ha.
  • a compound of the invention or a composition of the invention comprising a compound of the invention and a pharmaceutically acceptable vehicle, is administered to a patient, preferably a human, with or at risk of 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, gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (e
  • treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
  • treatment refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • the compounds of the invention or the compositions of the invention are administered to a patient, preferably a human, as a preventative measure against such diseases.
  • prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
  • compositions of the present invention are administered as a preventative measure to a patient, preferably a human having a genetic predisposition to 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.
  • IBS irritable bowel
  • Examples of such genetic predispositions include but are not limited to the e4 allele of apolipoprotein E, which increases the likelihood of Alzheimer's Disease; a loss of function or null mutation in the lipoprotein lipase gene coding region or promoter (e.g., mutations in the coding regions resulting in the substitutions D9N and N291S; for a review of genetic mutations in the lipoprotein lipase gene that increase the risk of cardiovascular diseases, dyslipidemias and dyslipoproteinemias, see Hayden and Ma, 1992, Mol. Cell Biochem. H3: 171-176); and familial combined hyperlipidemia and familial hypercholesterolemia .
  • the compounds of the invention or compositions of the invention are administered as a preventative measure to a patient having a non-genetic predisposition to 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 ehmination 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 (
  • compositions of the invention may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of polycystic ovarian disease while treating diabetes; prevention of impotence while treating a cardiovascular disease).
  • the present invention provides methods for the treatment or prevention of a cardiovascular disease, comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • cardiovascular diseases refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and/or dyslipidemias.
  • Cardiovascular diseases which the compositions of the present invention are useful for preventing or treating include but are not limited to arteriosclerosis; atherosclerosis; stroke; ischemia; endothelium dysfunctions, in particular those dysfunctions affecting blood vessel elasticity; peripheral vascular disease; coronary heart disease; myocardial infarcation; cerebral infarction and restenosis.
  • the present invention provides methods for the treatment or prevention of a dyslipidemia comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • dvslipidemias refers to disorders that lead to or are manifested by aberrant levels of circulating lipids. To the extent that levels of lipids in the blood are too high, the compositions of the invention are administered to a patient to restore normal levels. Normal levels of lipids are reported in medical treatises known to those of skill in the art.
  • the recommended level of HDL cholesterol in the blood is above 35 mg/dL; the recommended level of LDL cholesterol in the blood is below 130 mg/dL; the recommended LDL:HDL cholesterol ratio in the blood is below 5:1, ideally 3.5:1; and the recommended level of free triglycerides in the blood is less than 200 mg/dL.
  • Dyslipidemias which the compositions of the present invention are useful for preventing or treating include but are not limited to hyperlipidemia and low blood levels of high density lipoprotein (HDL) cholesterol.
  • the hyperlipidemia for prevention or treatment by the compounds of the present invention is familial hypercholesterolemia; familial combined hyperlipidemia; reduced or deficient lipoprotein lipase levels or activity, including reductions or deficiencies resulting from lipoprotein lipase mutations; hypertriglyceridemia; hypercholesterolemia; high blood levels of urea bodies (e.g. jS-OH butyric acid); high blood levels of Lp(a) cholesterol; high blood levels of low density lipoprotein (LDL) cholesterol; high blood levels of very low density lipoprotein (VLDL) cholesterol and high blood levels of non-esterified fatty acids.
  • familial hypercholesterolemia familial hypercholesterolemia
  • familial combined hyperlipidemia e.g. jS-OH butyric acid
  • Lp(a) cholesterol e.g. jS-OH butyric acid
  • Lp(a) cholesterol high blood levels of low density lipoprotein (LDL) cholesterol
  • VLDL very low density lipoprotein
  • the present invention further provides methods for altering lipid metabolism in a patient, e.g., reducing LDL in the blood of a patient, reducing free triglycerides in the blood of a patient, increasing the ratio of HDL to LDL in the blood of a patient, and inhibiting saponified and/or non-saponified fatty acid synthesis, said methods comprising administering to the patient a compound or a composition comprising a compound of the invention in an amount effective alter lipid metabolism.
  • the present invention provides methods for the treatment or prevention of a dyslipoproteinemia comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • the term “dyslipoproteinemias” refers to disorders that lead to or are manifested by aberrant levels of circulating lipoproteins. To the extent that levels of lipoproteins in the blood are too high, the compositions of the invention are administered to a patient to restore normal levels. Conversely, to the extent that levels of lipoproteins in the blood are too low, the compositions of the invention are administered to a patient to restore normal levels. Normal levels of lipoproteins are reported in medical treatises known to those of skill in the art.
  • Dyslipoproteinemias which the compositions of the present invention are useful for preventing or treating include but are not limited to high blood levels of LDL; high blood levels of apolipoprotein B (apo B); high blood levels of Lp(a); high blood levels of a ⁇ o(a); high blood levels of VLDL; low blood levels of HDL; reduced or deficient lipoprotein lipase levels or activity, including reductions or deficiencies resulting from lipoprotein lipase mutations; hypoalphalipoproteinemia; lipoprotein abnormalities associated with diabetes; lipoprotein abnormalities associated with obesity; lipoprotein abnormalities associated with Alzheimer's Disease; and familial combined hyperlipidemia.
  • apo B apolipoprotein B
  • Lp(a) high blood levels of Lp(a)
  • high blood levels of a ⁇ o(a) high blood levels of VLDL
  • low blood levels of HDL low blood levels of HDL
  • reduced or deficient lipoprotein lipase levels or activity including reductions or deficiencies resulting from lipoprotein lip
  • the present invention further provides methods for reducing apo C-II levels in the blood of a patient; reducing apo C-III levels in the blood of a patient; elevating the levels of HDL associated proteins, including but not limited to apo A-I, apo A-II, apo A-IV and apo E in the blood of a patient; elevating the levels of apo E in the blood of a patient, and promoting clearance of triglycerides from the blood of a patient, said methods comprising administering to the patient a compound or a composition comprising a compound of the invention in an amount effective to bring about said reduction, elevation or promotion, respectively.
  • the present invention provides methods for the treatment or prevention of a glucose metabolism disorder, comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • glucose metabolism disorders refers to disorders that lead to or are manifested by aberrant glucose storage and/or utilization.
  • indicia of glucose metabolism i.e., blood insulin, blood glucose
  • the compositions of the invention are administered to a patient to restore normal levels.
  • indicia of glucose metabolism are too low
  • the compositions of the invention are admimstered to a patient to restore normal levels.
  • Glucose metabolism disorders which the compositions of the present invention are useful for preventing or treating include but are not limited to impaired glucose tolerance; insulin resistance; insulin resistance related breast, colon or prostate cancer; diabetes, including but not limited to non-insulin dependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus (GDM), and maturity onset diabetes of the young (MODY); pancreatitis; hypertension; polycystic ovarian disease; and high levels of blood insulin and/or glucose.
  • NIDDM non-insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • GDM gestational diabetes mellitus
  • MODY maturity onset diabetes of the young
  • pancreatitis hypertension
  • polycystic ovarian disease and high levels of blood insulin and/or glucose.
  • the present invention further provides methods for altering glucose metabolism in a patient, for example to increase insulin sensitivity and/or oxygen consumption of a patient, said methods comprising administering to the patient a compound or a composition comprising a compound of the invention in an amount effective to alter glucose metabolism.
  • the present invention provides methods for the treatment or prevention of a PPAR- associated disorder, comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • treatment or prevention of PPAR associated disorders encompasses treatment or prevention of rheumatoid arthritis; multiple sclerosis; psoriasis; inflammatory bowel diseases; breast; colon or prostate cancer; low levels of blood HDL; low levels of blood, lymph and/or cerebrospinal fluid apo E; low blood, lymph and/or cerebrospinal fluid levels of apo A-I; high levels of blood VLDL; high levels of blood LDL; high levels of blood triglyceride; high levels of blood apo B; high levels of blood apo C-III and reduced ratio of post-heparin hepatic lipase to lipoprotein lipase activity.
  • HDL may be elevated in lymph and/or cerebral fluid.
  • Renal diseases that can be treated by the compounds of the present invention include glomerular diseases (including but not limited to acute and chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesions associated with systemic disease, such as systemic lupus erythematosus, Goodpasture's syndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease, and chronic inflammatory diseases), tubular diseases (including but not limited to acute tubular necrosis and acute renal failure, polycystic renal diseasemedullary sponge kidney, medullary cystic disease, nephrogenic diabetes, and renal tubular acidosis), tubulointerstitial diseases (including but not
  • renal diseases that are treated by the compounds of the present invention are vascular diseases, including but not limited to hypertension, nephrosclerosis, microangiopathic hemolytic anemia, atheroembohc renal disease, diffuse cortical necrosis, and renal infarcts.
  • the present invention provides methods for the treatment or prevention of cancer, comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising a compound of the invention and a pharmaceutically acceptable vehicle.
  • Types of cancer that can be treated using a Compound of the Invention include, but are not limited to, those listed in Table 2.
  • Solid tumors including but not limited to fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma
  • Cancer including, but not limited to, a tumor, metastasis, or any disease or disorder characterized by uncontrolled cejl growth, can be treated or prevented by administration of a Compound of the Invention. 4.3.8 Treatment of Other Diseases
  • the present invention provides methods for the treatment or prevention of Alzheimer's Disease, Syndrome
  • treatment or prevention of Alzheimer's Disease encompasses treatment or prevention of lipoprotein abnormalities associated with Alzheimer's Disease.
  • treatment or prevention of Syndrome X or Metabolic Syndrome encompasses treatment or prevention of a symptom thereof, including but not limited to impaired glucose tolerance, hypertension and dyslipidemia/dyslipoproteinemia.
  • treatment or prevention of septicemia encompasses treatment or prevention of septic shock.
  • treatment or prevention of thrombotic disorders encompasses treatment or prevention of high blood levels of fibrinogen and promotion of fibrinolysis.
  • the compositions of the invention can be administered to an individual to promote weight reduction of the individual.
  • treatment or prevention of diabetic nephropathy encompasses treating or preventing kidney disease that develops as a result of diabetes mellitus (DM).
  • Diabetes mellitus is a disorder in which the body is unable to metabolize carbohydrates (e.g., food starches, sugars, cellulose) properly.
  • carbohydrates e.g., food starches, sugars, cellulose
  • the disease is characterized by excessive amounts of sugar in the blood (hyperglycemia) and urine; inadequate production and/or utilization of insulin; and by thirst, hunger, and loss of weight.
  • the compounds of the invention can also be used to treat or prevent diabetes mellitus.
  • treatment or prevention of diabetic retinopathy encompasses treating or preventing complications of diabetes that lead to or cause blindness.
  • Diabetic retinopathy occurs when diabetes damages the tiny blood vessels inside the retina, the light- sensitive tissue at the back of the eye.
  • treatment or prevention of impotence includes treating or preventing erectile dysfunction, which encompasses the repeated inability to get or keep an erection firm enough for sexual intercourse.
  • impotence may also be used to describe other problems that interfere with sexual intercourse and reproduction, such as lack of sexual desire and problems with ejaculation or orgasm.
  • treatment or prevention of impotence includes, but is not limited to impotence that results as a result of damage to nerves, arteries, smooth muscles, and fibrous tissues, or as a result of disease, such as, but not limited to, diabetes, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, vascular disease, and neurologic disease.
  • treatment or prevention of hypertension encompasses treating or preventing blood flow through the vessels at a greater than normal force, which strains the heart; harms the arteries; and increases the risk of heart attack, stroke, and kidney problems.
  • hypertension includes, but is not limited to, cardiovascular disease, essential hypertension, hyperpiesia, hyperpiesis, malignant hypertension, secondary hypertension, or white-coat hypertension.
  • treatment or prevention of inflammation encompasses treating or preventing inflammation diseases including, but not limited to, chronic inflammatory disorders of the joints including arthritis, e.g., rheumatoid arthritis and osteoarthritis; respiratory distress syndrome, inflammatory bowel diseases such as ileitis, ulcerative colitis and Crohn's disease; and inflammatory lung disorders such as asthma and chronic obstructive airway disease, inflammatory disorders of the eye such as corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, and endophthalmitis; inflammatory disorders of the gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy, inflammatory diseases of the kidney including glomerulonephritis and nephrosis; inflammatory disorders of the skin including acne, sclerodermatitis, psoriasis, eczema, photoaging and wrinkles; inflammatory diseases of the central nervous system
  • the compounds and compositions of the invention can be used in combination therapy with at least one other therapeutic agent.
  • the compound of the invention and the therapeutic agent can act additively or, more preferably, synergistically.
  • a compound or a composition comprising a compound of the invention is administered concurrently with the administration of another therapeutic agent, which can be part of the same composition as the compound of the invention or a different composition.
  • a compound or a composition comprising a compound of the invention is administered prior or subsequent to administration of another therapeutic agent.
  • combination therapy involves alternating between administering a compound or a composition comprising a compound of the invention and a composition comprising another therapeutic agent, e.g., to minimize the toxicity associated with a particular drug.
  • the duration of administration of each drug or therapeutic agent can be, e.g., one month, three months, six months, or a year.
  • the therapeutic agent can advantageously be administered at a dose that falls below the threshold at which the adverse side is elicited.
  • the present compositions can be administered together with a statin.
  • Statins for use in combination with the compounds and compositions of the invention include but are not limited to atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin, and cerivastatin.
  • the present compositions can also be administered together with a PPAR agonist, for example a thiazolidinedione or a fibrate.
  • Thiazolidinediones for use in combination with the compounds and compositions of the invention include but are not limited to 5-((4-(2-(methyl-2-pyridinylammo)ethoxy)phenyl)methyl)-2,4-thiazohdinedione, troglitazone, pioglitazone, ciglitazone, WAY- 120,744, englitazone, AD 5075, darglitazone, and rosiglitazone.
  • Fibrates for use in combination with the compounds and compositions of the invention include but are not limited to gemfibrozil, fenofibrate, clofibrate, or cipro fibrate.
  • a therapeutically effective amount of a fibrate or thiazolidinedione often has toxic side effects. Accordingly, in a preferred embodiment of the present invention, when a composition of the invention is administered in combination with a PPAR agonist, the dosage of the PPAR agonist is below that which is accompanied by toxic side effects.
  • the present compositions can also be administered together with a bile-acid-binding resin.
  • Bile-acid-binding resins for use in combination with the compounds and compositions of the invention include but are not limited to cholestyramine and colestipol hydrochloride.
  • the present compositions can also be administered together with niacin or nicotinic acid.
  • the present compositions can also be administered together with a RXR agonist.
  • RXR agonists for use in combination with the compounds of the invention include but are not limited to LG 100268, LGD 1069, 9-cis retinoic acid, 2-(l-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl)-pyridine-5- carboxylic acid, or 4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)2-carbonyl)- benzoic acid.
  • the present compositions can also be administered together with an anti- obesity drug.
  • Anti-obesity drugs for use in combination with the compounds of the invention include but are not limited to /3-adrenergic receptor agonists, preferably ⁇ -3 receptor agonists, fenfluramine, dexfenfluramine, sibutramine, bupropion, fluoxetine, and phentermine.
  • the present compositions can also be administered together with a hormone.
  • Hormones for use in combination with the compounds of the invention include but are not limited to thyroid hormone, estrogen and insulin.
  • Preferred insulins include but are not limited to injectable insulin, transdermal insulin, inhaled insulin, or any combination thereof.
  • an insulin derivative, secretagogue, sensitizer or mimetic may be used.
  • Insulin secretagogues for use in combination with the compounds of the invention include but are not limited to forskolin, dibutryl cAMP or isobutylmethylxanthine (IBMX).
  • compositions can also be administered together with a phosphodiesterase type 5 ("PDE5") inhibitor to treat or prevent disorders, such as but not limited to, impotence.
  • PDE5 phosphodiesterase type 5
  • the combination is a synergistic combination of a composition of the invention and a PDE5 inhibitor.
  • the present compositions can also be administered together with a tyrophostine or an analog thereof.
  • Tyrophostines for use in combination with the compounds of the invention include but are not limited to tryophostine 51.
  • the present compositions can also be administered together with sulfonylurea- based drugs.
  • Sulfonylurea-based drugs for use in combination with the compounds of the invention include, but are not limited to, glisoxepid, glyburide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, and tolcyclamide.
  • the present compositions can also be administered together with a biguanide. Biguanides for use in combination with the compounds of the invention include but are not limited to metformin, phenformin and buformin.
  • compositions can also be administered together with an ⁇ -glucosidase inhibitor, ⁇ -glucosidase inhibitors for use in combination with the compounds of the invention include but are not limited to acarbose and miglitol.
  • compositions can also be administered together with an apo A-I agonist.
  • the apo A-I agonist is the Milano form of apo A-I (apo A-IM).
  • the apo A-M for administration in conjunction with the compounds of the invention is produced by the method of U.S. Patent No. 5,721,114 to Abrahamsen.
  • the apo A-I agonist is a peptide agonist.
  • the apo A-I peptide agonist for administration in conjunction with the compounds of the invention is a peptide of U.S. Patent No. 6,004,925 or 6,037,323 to Dasseux.
  • the present compositions can also be administered together with apolipoprotein E (apo E).
  • apo E apolipoprotein E
  • the apoE for administration in conjunction with the compounds of the invention is produced by the method of U.S. Patent No. 5,834,596 to Ageland.
  • the present compositions can be administered together with an HDL-raising drug; an HDL enhancer; or a regulator of the apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein genes.
  • the other therapeutic agent can be an antiemetic agent.
  • Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulphide, tetrahydrocannabinols, thiethylperazine, thioproperazine and tropisetron.
  • the other therapeutic agent can be an hematopoietic colony stimulating factor.
  • Suitable hematopoietic colony stimulating factors include, but are not limited to, filgrastim, sargramostim, molgramostim and erythropoietin alfa.
  • the other therapeutic agent can be an opioid or non- opioid analgesic agent.
  • opioid analgesic agents include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apornorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • Suitable non-opioid analgesic agents include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • Cardiovascular drugs for use in combination with the compounds of the invention to prevent or treat cardiovascular diseases include but are not limited to peripheral antiadrenergic drugs, centrally acting antihypertensive drugs (e.g., methyldopa, methyldopa HC1), antihypertensive direct vasodilators (e.g., diazoxide, hydralazine HC1), drugs affecting renin-angiotensin system, peripheral vasodilators, phentolamine, antianginal drugs, cardiac glycosides, modilators (e.g., amrinone, milrinone, enoximone, fenoximone, imazodan, sulmazole), antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, and rezulin.
  • peripheral antiadrenergic drugs e.g., centrally acting antihypertensive drugs (e.g., methyldopa, methyldop
  • the present invention includes methods for treating cancer, comprising administering to an animal in need thereof an effective amount of a Compound of the Invention and another therapeutic agent that is an anti-cancer agent.
  • Suitable anticancer agents include, but are not limited to, those listed in Table 3.
  • Taxoids paclitaxel
  • Anti-metabolites Anti-folates DHFR inhibitors: METHOTREXATE Trimetrexate
  • LHRH agonists flutamide bicalutamide
  • Dopaminergic neurotoxins l-methyl-4-phenyIpyridinium ion
  • Bleomycins bleomycin A2
  • MDR inhibitors verapamil Ca z+ ATPase inhibitors: thapsigargin
  • a composition of the invention further comprises one or more chemotherapeutic agents and/or is administered concurrently with radiation therapy.
  • chemotherapy or radiation therapy is administered prior or subsequent to administration of a present composition, preferably at least an hour, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g., up to three months), subsequent to administration of a composition of the invention.
  • the invention provides methods for treating or preventing cancer, comprising administering to an animal in need thereof an effective amount of a Compound of the Invention and a chemotherapeutic agent.
  • a chemotherapeutic agent is that with which treatment of the cancer has not been found to be refractory.
  • the chemotherapeutic agent is that with which the treatment of cancer has been found to be refractory.
  • the Compounds of the Invention can be administered to an animal that has also undergone surgery as treatment for the cancer.
  • the additional method of treatment is radiation therapy.
  • the Compound of the Invention is administered concurrently with the chemotherapeutic agent or with radiation therapy.
  • the chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a Compound of the Invention, preferably at least an hour, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g., up to three months), prior or subsequent to administration of a Compound of the Invention.
  • a chemotherapeutic agent can be administered over a series of sessions, any one or a combination of the chemotherapeutic agents listed in Table 3 can be administered.
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
  • Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
  • the invention provides methods of treatment of cancer with a
  • Compound of the Invention as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated.
  • the animal being treated can, optionally, be treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable.
  • the Compounds of the Invention can also be used in an in vitro or ex vivo fashion, such as for the treatment of certain cancers, including, but not limited to Ieukemias and lymphomas, such treatment involving autologous stem cell transplants.
  • This can involve a multi-step process in which the animal's autologous hematopoietic stem cells are harvested and purged of all cancer cells, the patient's remaining bone-marrow cell population is then eradicated via the administration of a high dose of a Compound of the Invention with or without accompanying high dose radiation therapy, and the stem cell graft is infused back into the animal. Supportive care is then provided while bone marrow function is restored and the animal recovers.
  • Cardiovascular diseases such as atherosclerosis often require surgical procedures such as angioplasty.
  • Angioplasty is often accompanied by the placement of a reinforcing a metallic tube-shaped structure known as a "stent" into a damaged coronary artery.
  • open heart surgery such as coronary bypass surgery may be required.
  • These surgical procedures entail using invasive surgical devices and or implants, and are associated with a high risk of restenosis and thrombosis.
  • the compounds and compositions of the invention may be used as coatings on surgical devices (e.g., catheters) and implants (e.g., stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.
  • a composition of the invention can be administered to a non-human animal for a veterinary use for treating or preventing a disease or disorder disclosed herein.
  • the non-human animal is a household pet.
  • the non-human animal is a livestock animal.
  • the non-human animal is a mammal, most preferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit, or guinea pig.
  • the non-human animal is a fowl species, most preferably a chicken, turkey, duck, goose, or quail.
  • the compounds and compositions of the invention can be used to reduce the fat content of livestock to produce leaner meats.
  • the compounds and compositions of the invention can be used to reduce the cholesterol content of eggs by administering the compounds to a chicken, quail, or duck hen.
  • the compounds and compositions of the invention can be administered via the animals' feed or orally as a drench composition.
  • the compounds and compositions of the invention are useful for the treatment or prevention of aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, 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, enhancing bile production, enhancing reverse lipid transport, inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g.,
  • the invention provides methods of treatment and prophylaxis by administration to a patient of a therapeutically effective amount of a compound or a composition comprising a compound of the invention.
  • the patient is an animal, including, but not limited, to an animal such a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more preferably a mammal, and most preferably a human.
  • the compounds and compositions of the invention are preferably administered orally.
  • the compounds and compositions of the invention may also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with another biologically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer a compound of the invention.
  • more than one compound of the invention is administered to a patient.
  • Methods of administration include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
  • the preferred mode of administration is left to the discretion of the practitioner, and will depend in-part upon the site of the medical condition. In most instances, administration will result in the release of the compounds of the invention into the bloodstream.
  • This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • administration can be by direct injection at the site (or former site) of an atherosclerotic plaque tissue.
  • Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the compounds of the invention can be formulated as a suppository, with traditional binders and vehicles such as triglycerides.
  • the compounds and compositions of the invention can be delivered in a vesicle, in particular a Hposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
  • a vesicle in particular a Hposome
  • the compounds and compositions of the invention can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra; Sefton, 1987, CRCCrit. Ref. Biomed. Eng. .14:201; Buchwald et al, 1980, Surgery 88:507 Saudek et al., 1989, N. Engl. J. Med. 321:574).
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al, 1985, Science 228:190; During et al, 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).
  • a controlled-release system can be placed in proximity of the target area to be treated, e.g. , the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533 may be used.
  • compositions will contain a therapeutically effective amount of a compound of the invention, optionally more than one compound of the invention, preferably in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle so as to provide the form for proper administration to the patient.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • vehicle refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.
  • Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • the compounds and compositions of the invention and pharmaceutically acceptable vehicles are preferably sterile.
  • Water is a preferred vehicle when the compound of the invention is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the pharmaceutically acceptable vehicle is a capsule (see e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
  • the compounds and compositions of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • a pharmaceutical composition adapted for intravenous administration to human beings.
  • compounds and compositions of the invention for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the compositions may also include a solubilizing agent.
  • Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the compound of the invention is to be administered by intravenous infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Compounds and compositions of the invention for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs.
  • Compounds and compositions of the invention for oral delivery can also be formulated in foods and food mixes.
  • Orally administered compositions may contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds and compositions of the invention.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
  • the amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for oral administration are generally about 0.001 milligram to 2000 milligrams of a compound of the invention per kilogram body weight.
  • the oral dose is 0.01 milligram to 1000 milligrams per kilogram body weight, more preferably 0.1 milligram to 100 milligrams per kilogram body weight, more preferably 0.5 milligram to 25 milligrams per kilogram body weight, and yet more preferably 1 milligram to 10 milligrams per kilogram body weight. In a most preferred embodiment, the oral dose is 5 milligrams of a compound of the invention per kilogram body weight.
  • the dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the invention is administered, the preferred dosages correspond to the total amount of the compounds of the invention administered.
  • Oral compositions preferably contain 10% to 95% active ingredient by weight-
  • Suitable dosage ranges for intravenous (i.v.) administration are 0.01 milligram to 1000 milligrams per kilogram body weight, 0.1 milligram to 350 milligrams per kilogram body weight, and 1 milligram to 100 milligrams per kilogram body weight.
  • Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight.
  • Suppositories generally contain 0.01 milligram to 50 milligrams of a compound of the invention per kilogram body weight and comprise active ingredient in the range of 0.5% to 10% by weight.
  • Suitable dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration or administration by inhalation are in the range of 0.001 milligram to 200 milligrams per kilogram of body weight.
  • Suitable doses of the compounds of the invention for topical administration are in the range of 0.001 milligram to 1 milligram, depending on the area to which the compound is administered.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.
  • the invention also provides pharmaceutical packs or kits comprising one or more containers filled with one or more compounds of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the kit contains more than one compound of the invention.
  • the kit comprises a compound of the invention and another lipid- mediating compound, including but not limited to a statin, a thiazolidinedione, or a fibrate.
  • the compounds of the invention are preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans.
  • in vitro assays can be used to determine whether administration of a specific compound of the invention or a combination of compounds of the invention is preferred for lowering fatty acid synthesis.
  • the compounds and compositions of the invention may also be demonstrated to be effective and safe using animal model systems.
  • potassium phthalimide 49.1 g, 265.2 mmol was added to a stirred solution of 2-(6-bromo-2,2-dimethylhexyloxy)-tetrahydropyran (70.7 g, 241.1 mmol) in DMF (150 mL, dried over 4 A molecular sieves) at rt.
  • the suspension was heated to 80 - 95°C for 3 h.
  • the reaction mixture was cooled to rt, diluted with water (500 mL), and extracted with diethyl ether (2 x 250 mL, 1 x 100 mL).
  • the reaction mixture was cooled to rt after 18 h and a sample (2 mL of the solution) was taken for monitoring of the reaction progress by NMR spectroscopy (ratio product : starting material « 1 : 2). Additional triphenyl phosphite (10.2 g, 32.80 mmol) was added, CO 2 was introduced (for approximately 18 h), and the reaction mixture was heated to 55°C for 23 h (NMR analysis indicated a ratio product : starting material « 2 : 1). The solvent was removed in vacuo and the reaction mixture concentrated under high vacuum to give the THP-protected product (53 g) as a yellow oil. The crude, protected urea (53 g) was dissolved in methanol (200 mL), then coned.
  • Compound A may be synthesized via the oxidation of the analogous thiourea [Compound Al] as described below.
  • the organic layer was dried over MgSO 4 and concentrated in vacuo to yield the crude product as an orange oil.
  • the crude product (31.3 g, 40 % purity by NMR) was taken in methanol (100 mL) and coned. HCl (10 mL) was added. After refluxing for 3 hours, the mixture was cooled to rt and diluted with water (200 mL). The mixture was then extracted with methylene chloride (3 x 200 mL). The combined organic layers were washed with cold 10 % KOH solution (3 x 300 mL), then sat. KCl solution (200 mL).
  • Compound B may be synthesized via the oxidation of the analogous thiourea as described below.
  • N-2,6-Dimethylphenyl-N'-2-pyrimnylurea prepared by reacting 2,6-dimethylphenyl isocyanate with 2-amino ⁇ yridine in THF as described in Pavia, M., Lobbestael, S.J., Taylor, C.P., Hershenson, F.M., and Miskell, D.L. J. Med. Chem.
  • LiBEU (3.0 g, 138 mmol) was added carefully to anhydrous methylene chloride (100 mL) and heated to 30°C for 2 h, then cooled to rt.
  • Anhydrous methanol (4.4 mL, 101 mmol) was added dropwise to this solution, followed by dropwise addition of ethyl 5-bromo-2-methyl-2-phenyl- ⁇ entanoate (20.0 g, 67 mmol) in anhydrous methylene chloride (50 mL).
  • the mixture was heated to 40°C overnight, then cooled with an ice bath, and hydrolized by careful addition of deionized water (35 mL) and 2 N HCl (80 mL).
  • N,N'-bis(4,4-dimethyl-5-hydroxypentyI)urea Under argon, 5-amino-2,2- dimethyl-l-(tetrahydropyranyloxy) ⁇ entane (18.54 g, 77.5 mmol) was dissolved in pyridine (80 g, 1 mol). To this was added triphenylphosphite (26.53 g, 82.9 mmol). Finally, dry CO 2 was bubbled through the reaction mixture as it was heated to 40-60 °C for six hours. Gas flow was stopped and the mixture cooled to rt.
  • reaction mixture was cooled to rt, diluted with water (500 ml), and extracted with diethyl ether (2 x 250 ml, 1 x 100 ml).
  • diethyl ether 2 x 250 ml, 1 x 100 ml.
  • the combined organic layers were washed with saturated NaCI solution (100 ml), dried over MgSO 4 , concentrated in vacuo, and dried in high vacuo to furnish the expected product (78.4 g, 90 %) as a yellow oil.
  • the reaction mixture was cooled to rt after 18 h and a sample (2 ml of the solution) was taken for monitoring of the reaction progress by NMR spectroscopy (ratio P/SM « V%). Additional triphenyl phosphite (10.2 g, 32.80 mmol) was added, CO 2 was introduced (for approximately 18 h), and the reaction mixture was heated to 55 °C for 23 h (NMR analysis indicated a ratio P/SM « 2/1). The solvent was removed in vacuo and the reaction mixture concentrated in high vacuo to give the THP-protected product (53 g) as a yellow oil. The crude, protected urea (53 g) was dissolved in methanol (200ml) and coned.
  • ⁇ NMR (CDC13), ⁇ (ppm): 3.26 (s, 4 H); 3.11 (t, 4 H, J 6.8); 1.51 - 1.38 (m, 4 H); 1.36 - 1.18 (m, 8 H); 0.85 (s, 12 H).
  • N,/V'-bis(5-hydroxy-4,4-dimethyIpentyl)urea was dissolved in ethanol (100 mL), and a solution of NaOH (1.10g, 27.5 mmol) in H 2 O (3.3 mL) was added. To this mixture was added slowly 50% hydrogen peroxide solution (3.7 mL, 54 mmol). A vigorous reaction began; this mixture was stirred for 3 h, then diluted with 700 mL H 2 O and extracted with chloroform (3 x 500 mL).
  • N-2,6-Dimethylphenyl-N'-2-pyridinylurea (prepared by reacting 2,6- dimethylphenyl isocyanate with 2-aminopyridine in THF as described in Pavia, M., Lobbestael, S.J., Taylor, C.P., Hershenson, F.M., and Miskell, D.L. J. Med. Chem. 1990, 33, 854) (Tmmol) was dissolved in 5 mL 1,2-dichloroethane and added over 15 min, after which the cooling bath was removed and the mixture was stirred for 5 h. The completion of the conversion was checked by TLC (hexanes/EtOAc 8:2).
  • BIOLOGICAL ASSAYS 6.1 Effects of Illustrative Compounds A and Al on NonHDL-Chotesterol. HDL- CholesteroL Triglycer.de Levels. Glvcemic Control indicators and Body Weight Control in Obese Female Zucker Rats
  • illustrative compounds A and Al of the invention were administered daily at a dose of up to 100 mg kg to chow- fed obese female Zucker rats for fourteen days in the morning by oral gavage in 1.5% carboxymethylcellulose/0.2% Tween-20 or 20% ethanol/80% polyethylene glycol (dosing vehicles). Animals were weighed daily. Animals were allowed free access to rodent chow and water throughout the study except on days of blood sampling where food was restricted for six hours prior to blood sampling. Blood glucose was determined after the 6-hour fast in the afternoon without anesthesia from a tail vein.
  • Serum was also prepared from pretreatment blood samples subsequently obtained from the orbital venous plexus (with O 2 /CO 2 anesthesia) and following the fourteenth dose at sacrifice from the heart following O 2 /CO 2 anesthesia. Serums were assayed for lipoprotein cholesterol profiles, triglycerides, total cholesterol, NonHDL cholesterol, HDL cholesterol, the ratio of HDL cholesterol to that of Non-HDL cholesterol, insulin, non-esterified fatty acids, and beta hydroxy butyric acid. The percent body weight gain and the ratio of liver to body weight was also determined. These are shown as absolute values or as a percent change of the pretreatment values in Table 4.
  • illustrative compounds improved the ratio of non-HDL cholesterol to
  • Illustrative compounds reduced serum levels of harmful triglycerides, reduced serum levels of harmful non-esterified fatty acids, and elevated levels of the beneficial /3-hydroxy butyrate.
  • the compounds of the present invention or pharmaceutically acceptable salts, solvates, hydrates, clathrates, or prodrugs thereof are useful for improving the ratio of HDL:non-HDL cholesterol in the blood, reducing serum triglycerides, acting as insulin sensitizers, and/or elevating HDL-cholesterol, without the adverse side effect of promoting weight gain in a patient to whom the compound is administered.

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Abstract

La présente invention a trait à de nouveaux composés d'urée et de thiourée, des compositions comportant des composés d'urée et de thiourée, et des procédés utiles pour le traitement et la prévention du vieillissement, de la maladie d'Alzheimer, du cancer, de maladie cardio-vasculaire, de la néphropathie diabétique, de la rétinopathie diabétique, d'un trouble de métabolisme du glucose, de la dyslipidémie, de la dyslipoprotéinémie, l'amélioration de production biliaire, l'amélioration de transport lipidique inverse, de l'hypertension, de l'impuissance, de l'inflammation, de la résistance à l'insuline, l'élimination des lipides dans la bile, la modulation de la protéine C réactive, de l'obésité, l'élimination de l'oxystérol dans la bile, de la pancréatite, de la maladie de Parkinson, du trouble associé au récepteur activé de la prolifération des peroxysomes, l'élimination de phospholipides dans la bile, de la maladie rénale, de la septicémie, de troubles de syndrome métabolique, (par exemple, le syndrome X), d'un trouble thrombotique, d'un trouble gastro-intestinal, du syndrome du colon irritable, de la maladie intestinale inflammatoire (par exemple, la maladie de Crohn, la recto-colite ulcéro-hémorragique), de l'arthrite (par exemple, la polyarthrite rhumatoïde, l'ostéoarthrite), de la maladie auto-immune (par exemple, le lupus érythémateux systémique), de scléroderme, de la spondylite ankylosante, de la goutte et la pseudogoutte, de la douleur musculaire : de la polymyosite/polymogia rheumatica/bifrositis ; de l'infection et de l'arthrite, de la polyarthrite rhumatoïde juvénile, de la tendinite, de la bursite et autre rhumatisme du tissu mou. Dans certains modes de réalisation, les composés, les compositions, et le procédés de l'invention sont utilisés dans une thérapie de combinaison avec d'autres agents thérapeutiques, tels que des hypocholestérolémiants et des hypoglycémiants.
PCT/US2003/041789 2003-12-23 2003-12-23 Composes d'uree et de thiouree et compositions pour la gestion de cholesterol et utilisations associees Ceased WO2005068420A1 (fr)

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PCT/US2003/041789 WO2005068420A1 (fr) 2003-12-23 2003-12-23 Composes d'uree et de thiouree et compositions pour la gestion de cholesterol et utilisations associees
AU2003300177A AU2003300177A1 (en) 2003-12-23 2003-12-23 Urea and thiourea compounds and compositions for cholesterol management and related uses

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PCT/US2003/041789 WO2005068420A1 (fr) 2003-12-23 2003-12-23 Composes d'uree et de thiouree et compositions pour la gestion de cholesterol et utilisations associees

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US7875734B2 (en) 2006-03-10 2011-01-25 Cornell Research Foundation, Inc. Low pressure carbonylation of heterocycles
EP3214075B1 (fr) * 2016-03-02 2019-08-21 NerPharMa Srl Un procede secure et efficient pour la preparation de carmustine

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7875734B2 (en) 2006-03-10 2011-01-25 Cornell Research Foundation, Inc. Low pressure carbonylation of heterocycles
EP3214075B1 (fr) * 2016-03-02 2019-08-21 NerPharMa Srl Un procede secure et efficient pour la preparation de carmustine

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