WO2009046371A1 - Procédés de traitement de maladies métaboliques - Google Patents

Procédés de traitement de maladies métaboliques Download PDF

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WO2009046371A1
WO2009046371A1 PCT/US2008/078845 US2008078845W WO2009046371A1 WO 2009046371 A1 WO2009046371 A1 WO 2009046371A1 US 2008078845 W US2008078845 W US 2008078845W WO 2009046371 A1 WO2009046371 A1 WO 2009046371A1
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compound
dose
human
acid
diabetes
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PCT/US2008/078845
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English (en)
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Francine Gregoire
Edward Clemens
Zuchun Zhao
Brian Lavan
Fang Zhang
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Metabolex, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Type I diabetes or insulin-dependent diabetes mellitus
  • pancreatic islet cells or “islet cells”
  • islet cells which produce insulin.
  • pancreatic islet cells or “islet cells”
  • hyperglycemia abnormally high level of glucose in the blood
  • euglycemia normal blood glucose level
  • Type II diabetes or non-insulin-dependent diabetes mellitus, develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond (called insulin resistance) may be due to reduced numbers of insulin receptors on these cells, or a dysfunction of signaling pathways within the cells, or both.
  • the beta cells initially compensate for this insulin resistance by increasing their insulin output. Over time, these cells become unable to produce enough insulin to maintain normal glucose levels, indicating progression to Type II diabetes (Kahn, S.E., Am. J. Med. (2000) 108 Suppl 6a, 2S-8S).
  • the fasting hyperglycemia that characterizes Type II diabetes occurs as a consequence of the combined effects of insulin resistance and beta cell dysfunction.
  • the beta cell defect has two components: the first component, an elevation of basal insulin release (occurring in the presence of low, non-stimulatory glucose concentrations), is observed in obese, insulin-resistant pre-diabetic stages as well as in Type II diabetes.
  • the second component is a failure to increase insulin release above the already elevated basal output in response to a hyperglycemic challenge. This lesion is absent in prediabetes and appears to define the transition from normo-glycemic insulin-resistant states to frank diabetes. There is currently no cure for diabetes.
  • Januvia is another recently approved drug that increases blood levels of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well characterized effects.
  • Januvia and other dipeptidyl peptidases IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated.
  • Hyperglycemia further accelerates the decline in ⁇ -cell function (UKPDS Group, J.A.M.A. 281 :2005-2012, 1999; Levy J, et al, Diabetes Med. 15:290-296, 1998; and Zhou YP, et ah, J Biol Chem 278:51316-23, 2003).
  • allelic variation is associated with an increased risk of Type II diabetes are expressed selectively in the beta cell (Bell GI and Polonsky KS, Nature 414:788-791 (2001); Saxena R, et al, Science (2007) Apr 26; [Epub ahead of print]; and Valgerdur Steinthorsdottir, et al, Nature Genetics (2007) Apr 26; [Epub ahead of print]).
  • Insulin secretion from the beta cells of pancreatic islets is elicited by increased levels of blood glucose.
  • Glucose is taken up into the beta cell primarily by the beta cell and liver selective transporter GLUT2 (Thorens B. MoI Membr Biol. 2001 Oct-Dec; 18(4):265- 73).
  • GLUT2 liver selective transporter GLUT2
  • glucose is phosphorylated by glucokinase, which is the primary glucose sensor in the beta cell since it catalyzes the irreversible rate limiting step for glucose metabolism (Matschinsky FM. Curr Diab Rep. 2005 Jun; 5(3): 171-6).
  • the rate of glucose- 6-phosphate production by glucokinase is dependent on the concentration of glucose around the beta cell, and therefore this enzyme allows for a direct relationship between level of glucose in the blood and the overall rate of glucose oxidation by the cell.
  • Mutations in glucokinase produce abnormalities in glucose dependent insulin secretion in humans giving further evidence that this hexokinase family member plays a key role in the islet response to glucose (Gloyn AL, et al, J Biol Chem. 2005 Apr 8; 280(14): 14105-13. Epub 2005 Jan 25).
  • Small molecule activators of glucokinase enhance insulin secretion and may provide a route for therapeutic exploitation of the role of this enzyme (Guertin KR and Grimsby J. Curr
  • VDCCs voltage dependent calcium channels
  • Potassium channel openers such as diazoxide, inhibit insulin secretion by preventing elevated ATP/ADP ratios from closing the Kir6.2 channel (Hansen JB. Curr Med Chem. 2006; 13(4):361-76).
  • Calcium channel blockers such as verapamil and nifedipine, can also inhibit insulin secretion (Henquin, J. C. (2004) Diabetes 53, S48-S58).
  • sulfonylureas and metaglitinides are effective glucose lowering agents in the clinic, they act independently of blood glucose levels. Because they act independently of glucose levels, these drugs may result in hypoglycemia.
  • Glucose dependent insulin secretion from the beta cell is dependent on numerous neurotransmitters and blood-borne hormones, as well as local, intra-islet factors.
  • CNS activation of the vagal innervation of the islet can lead to the release of small molecules such as acetylcholine and peptides such as vasoactive intestinal polypeptide (VIP), gastrin releasing peptide (GRP) and Pituitary Adenylate Cyclase Activating Peptide (PACAP).
  • VIP vasoactive intestinal polypeptide
  • GRP gastrin releasing peptide
  • PACAP Pituitary Adenylate Cyclase Activating Peptide
  • Elevation of beta cell cAMP has a substantial potentiating effect on insulin secretion in the presence of stimulatory levels of glucose (see below).
  • many potentiators of glucose-stimulated insulin secretion also have effects outside of the islet which limit their ability to be used as diabetes therapeutics.
  • the best available selective muscarinic agonists which stimulate insulin secretion also stimulate multiple undesirable responses in multiple tissues (Rhoades RA and Tanner GA, eds. (2003) Medical Physiology, 2nd ed. Lippincott, Williams and Wilkins. ISBN 0-7817-1936-4).
  • VIP and PACAP receptors are present in multiple organ systems and mediate effects on the reproductive, immune and other diverse systems that make them less attractive as specific enhancers of glucose dependent insulin secretion.
  • Incretin hormones such as Glucagon-Like Peptide 1 (GLP-I) and Glucose-dependent Insulinotropic Polypeptide (GIP, also known as Gastric Inhibitory Polypeptide) also bind to specific G ⁇ //?/z ⁇ s -coupled GPCRs receptors on the surface of islet cells, including beta cells, and raise intracellular cAMP (Drucker DJ. J Clin Invest. 2007 Jan; 117(l):24-32). Although the receptors for these hormones are present in other cells and tissues, the overall sum of effects of these peptides appear to be beneficial to control of glucose metabolism in the organism (Hansotia T, et al., JClin Invest.
  • GIP and GLP-I are produced and secreted from intestinal K and L cells, respectively, and these peptide hormones are released in response to meals by both direct action of nutrients in the gut lumen and neural stimulation resulting from food ingestion.
  • GIP and GLP-I have short half-lives in human circulation due to the action of the protease dipeptidyl-peptidase IV (DPP IV), and inhibitors of this protease can lower blood glucose due to their ability to raise the levels of active forms of the incretin peptides.
  • DPP IV protease dipeptidyl-peptidase IV
  • Peptides eg. exanatide (Byetta)
  • peptide-conjugates that bind to the GIP or GLP-I receptors but are resistant to serum protease cleavage can also lower blood glucose substantially (Gonzalez C, et al, Expert Opin Investig Drugs . 2006 Aug; 15(8):887-95), but these incretin mimetics must be injected and tend to induce a high rate of nausea and therefore are not ideal therapies for general use in the Type II diabetic population.
  • the clinical success of DPPIV inhibitors and incretin mimetics though far from ideal, do point to the potential utility of compounds that increase incretin activity in the blood or directly stimulate cAMP in the beta cell.
  • beta cell responsiveness to GIP is diminished in Type II diabetes (Nauck M.A., et al. J. Clin. Invest. 91:301-307 (1993); and Elahi D., et al. Regul. Pept. 51:63-74 (1994)).
  • Restoration of this responsiveness may be a promising way to improve beta cell function in vivo.
  • incretin activity has a positive effect on glucose dependent insulin secretion and perhaps other mechanisms that lead to lower blood glucose, it is also of interest to explore therapeutic approaches to increasing incretin release from intestinal K and L cells.
  • GLP-I secretion appears to be attenuated in Type II diabetes (Vilsboll T., et al, Diabetes. 50:609-613), so improving incretin release may ameliorate this component of metabolic dysregulation.
  • Nutrients such as glucose and fat in the gut lumen prompt incretin secretion by interaction with apical receptors (Vilsboll T., et al, Diabetes. 50:609-613).
  • GLP-I and GIP release can also result from neural stimulation; acetylcholine and GRP can enhance incretin release in a manner perhaps analogous to the effects of these neurotransmitters on the beta cell in regard to insulin secretion (Brubaker, P., Ann N Y Acad Sci. 2006 JuI; 1070:10-26; and Reimann, F. et al, Diabetes. 2006 Dec; 55 (Supplement_2):S78-S85). Somatostatin, leptin and free fatty acids also appear to modulate incretin secretion (Brubaker, P., Ann N Y Acad Sci. 2006 JuI; 1070: 10-26; and Reimann, F. et al, Diabetes.
  • Incretins can also increase the rate of beta cell proliferation and decrease the apoptotic rates of beta cells in animal models (Farilla L, et al, Endocrinology. 2002 Nov; 143(11):4397-408) and human islets in vitro (Farilla L, et al, Endocrinology. 2003 Dec; 144(12) :5149-58).
  • GLP-I has also been shown to protect islets from the destructive effects of agents such as streptozotocin by blocking apoptosis (Li Y, et al. , J Biol Chem. 2003 Jan 3; 278(l):471-8). Cyclin Dl, a key regulator of progression through the cell cycle, is up-regulated by GLP-I, and other agents that increase cAMP and PKA activity also have a similar effect (Friedrichsen BN, et al, J Endocrinol.
  • Beta cell cAMP levels may also be raised by inhibiting the degradation of this second messenger by phosphodiesterases to AMP (Furman B, and Pyne N.
  • cAMP phosphodiesterases There are several different cAMP phosphodiesterases in the beta cell, and many of these have been shown to serve as a brake on glucose-dependent insulin secretion. Inhibitors of cAMP phosphodiesterases have been shown to increase insulin secretion in vitro and in vivo, including PDElC, PDE3B, PDElO (Han P, et al, J Biol Chem. 1999 Aug 6; 274(32):22337-44; Harndahl L, et al, JBiol Chem.
  • Epac guanine nucleotide exchange factor
  • GEF guanine nucleotide exchange factor
  • Epac activated by cAMP may also enhance of release of intracellular Ca++ (HoIz GG. Diabetes 2004 Jan; 53(1):5-13).
  • the effects of cAMP on insulin secretion are dependent on elevated glucose levels, so raising cAMP in the pancreatic beta cell is an important goal for therapeutics of Type II diabetes.
  • Dyslipidemia is a condition generally characterized by an abnormal increase in serum lipids in the bloodstream and, as noted above, is an important risk factor in developing atherosclerosis and heart disease.
  • disorders of lipid metabolism see, e.g., Wilson, J. et al., (ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W.B. Sanders Company, Philadelphia, PA U.S.A. 1998; this reference and all references cited therein are herein incorporated by reference).
  • Serum lipoproteins are the carriers for lipids in the circulation.
  • Hyperlipidemia is usually classified as primary or secondary hyperlipidemia.
  • Primary hyperlipidemia is generally caused by genetic defects, while secondary hyperlipidemia is generally caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia can result from both a combination of primary and secondary causes of hyperlipidemia. Elevated cholesterol levels are associated with a number of disease states, including coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.
  • Dyslipidemia is a frequent occurrence among diabetics, and has been shown to be one of the main contributors to the increased incidence of coronary events and deaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med. (1927) 5:1061-1079). Epidemiological studies since then have confirmed the association and have shown a several-fold increase in coronary deaths among diabetic subjects when compared with nondiabetic subjects (see, e.g., Garcia, M. J. et al, Diabetes (1974) 23:105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997) 5(4):294-315).
  • the present invention fulfills this and other needs by providing such compounds, compositions and methods for alleviating insulin resistance, Type II diabetes, dyslipidemia, hyperlipidemia and hyperuricemia. BRIEF SUMMARY OF THE INVENTION
  • This invention provides methods of lowering blood triglyceride levels in a mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • This invention also provides methods of lowering blood free fatty acid levels in a mammal, including by administering a therapeutically effective amount of a compound of Formula I.
  • Another aspect of this invention provides methods of increasing blood levels of Apolipoprotein Al (ApoAl) in a mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • Apolipoprotein Al Apolipoprotein Al
  • Yet another aspect of this invention provides methods of increasing high density lipoprotein (HDL) particle size in the blood of a mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • the invention provides methods of preserving islet of langerhans function in a diabetic mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • the invention also provides methods of preserving beta cell function in a diabetic mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • the invention provides methods of preserving islet of langerhans insulin production in a diabetic mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • the invention also provides methods of preserving islet of langerhans morphology in a diabetic mammal, including humans, by administering a therapeutically effective amount of a compound of Formula I.
  • Fig. 1 shows the effect of the binding of fenofibrate, compound 39, GW7647 to PPAR- ⁇ , PPAR- ⁇ , and the binding of rosiglitazone and compound 39 to PPAR- ⁇ . See Example 22.
  • Fig. 2 shows that compound 39 binds to PPAR- ⁇ in a different manner than rosiglitazone. See Example 22.
  • Fig. 3 shows that compound 39 induces full co-repressor displacement while inducing partial co-activator recruitement binds to PPAR- ⁇ . See Example 23.
  • Fig. 4 shows that compound 39 induces less adipogenesis than rosiglitazone in primary human adipocytes. See Example 24.
  • Fig. 5 shows that compound 39 stimulates glucose transport in 3T3-L1 adipocytes. See Example 25.
  • Fig. 6 shows that compound 39 lowers plasma triglycerides and free fatty acids in db/db mice. See Example 26.
  • Fig. 7 shows that compound 39 does not increase body weight gain, heart weight and intrascapular brown adipose tisse in db/db mice. See Example 27.
  • Fig. 8 shows that compound 39 lowers glucose, insulin, triglycerides and free fatty acids in Zucker diabetic fatty rats. See Example 28.
  • Fig. 9 shows that compound 39 preserves islet of langerhans morphology in Zucker diabetic fatty rats. See Example 29.
  • Fig. 10 shows that compound 39 preserves the morphology of the islets of langerhans and increases insulin content of islets of langerhans in db/db diabetic mice. See Example 30.
  • Fig. 11 shows that compound 39 decreased body weight gain in zucker fatty rats. See Example 31.
  • Fig. 12 shows that compound 39 decreased fasting insulin levels in zucker fatty rats. See Example 31.
  • Fig. 13 shows that compound 39 increased plasma apoAl levels and increased high density lipoprotein particle size in human apoAl transgenic mice. See Example 32.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and ⁇ -sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992). [0043] Compounds of Formula I include the compounds of Formula Ia. The compounds of Formula Ia include its various stereoisomeric forms (the asymmetric center is indicated by the asterisk). Unless otherwise specified, all of the examples described herein where applicable utilized a racemic mixture of the compound of Formula Ia.
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2 hydroxyethanesulfonic acid, benzenesulfonic acid, A- chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, cam
  • Prodrugs include compounds of Formula I wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters ⁇ e.g., acetate, formate, and benzoate derivatives), amides, carbamates ⁇ e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I, and the like.
  • the term "pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • treating or “treatment” of a disease includes:
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount includes the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • mammal includes, without limitation, humans, domestic animals ⁇ e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys, rabbits, mice, rats, guinea pigs, hamsters, and other laboratory animals.
  • blood includes, without limitation, whole blood or a component of blood including plasma and serum.
  • plasma is defined herein to refer to the liquid component of blood in which the cells have been removed.
  • serum is defined herein to refer to plasm in which the components involved in blood clotting have been removed.
  • insulin resistance can be defined generally as a disorder of glucose metabolism. More specifically, insulin resistance can be defined as the diminished ability of insulin to exert its biological action across a broad range of concentrations producing less than the expected biologic effect (see, e.g., Reaven, G. M., J. Basic & Clin. Phys. & Pharm. (1998) 9:387-406 and Flier, J. Ann Rev. Med. (1983) 34:145-60). Insulin resistant persons have a diminished ability to properly metabolize glucose and respond poorly, if at all, to insulin therapy.
  • Insulin resistance can cause or contribute to polycystic ovarian syndrome, Impaired Glucose Tolerance (IGT), gestational diabetes, hypertension, obesity, atherosclerosis and a variety of other disorders. Eventually, the insulin resistant individuals can progress to a point where a diabetic state is reached.
  • ITT Impaired Glucose Tolerance
  • diabetes mellitus or "diabetes” means a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels in the body. The result of these defects is elevated blood glucose, referred to as "hyperglycemia".
  • Type I diabetes is generally the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
  • Type II diabetes often occurs in the face of normal, or even elevated levels of insulin and can result from the inability of tissues to respond appropriately to insulin.
  • Type II diabetic patients are insulin resistant and have a relative deficiency of insulin, in that insulin secretion can not compensate for the resistance of peripheral tissues to respond to insulin.
  • Type II diabetics are obese.
  • Other types of disorders of glucose homeostasis include Impaired Glucose Tolerance, which is a metabolic stage intermediate between normal glucose homeostasis and diabetes, and Gestational Diabetes Mellitus, which is glucose intolerance in pregnancy in women with no previous history of Type I or Type II diabetes.
  • second diabetes is diabetes resulting from other identifiable etiologies which include: genetic defects of ⁇ cell function (e.g., maturity onset-type diabetes of youth, referred to as "MODY", which is an early-onset form of Type II diabetes with autosomal inheritance; see, e.g., Fajans S. et ah, Diabet. Med. (1996) (9 Suppl 6):S90- 5 and Bell, G. et al., Annu. Rev. Physiol.
  • MODY maturity onset-type diabetes of youth
  • hyperinsulinemia refers to the presence of an abnormally elevated level of insulin in the blood.
  • hypouricemia refers to the presence of an abnormally elevated level of uric acid in the blood.
  • hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood.
  • Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, i.e., an elevated cholesterol level; (2) hypertriglyceridemia, i.e., an elevated triglyceride level; and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia.
  • secretagogue means a substance or compound that stimulates secretion.
  • an insulin secretagogue is a substance or compound that stimulates secretion of insulin.
  • hemoglobin refers to a respiratory pigment present in erythrocytes, which is largely responsible for oxygen transport.
  • a hemoglobin molecule comprises four polypeptide subunits (two ⁇ chain systems and two ⁇ chain systems, respectively). Each subunit is formed by association of one globin protein and one heme molecule which is an iron-protoporphyrin complex.
  • the major class of hemoglobin found in normal adult hemolysate is adult hemoglobin (referred to as "HbA”; also referred to HbAO for distinguishing it from glycated hemoglobin, which is referred to as "HbAl,” described infra) having ⁇ 2 ⁇ 2 subunits. Trace components such as HbA 2 ( ⁇ 2 ⁇ 2 ) can also be found in normal adult hemolysate.
  • HbA 1 glycated hemoglobin
  • HbA lal glycated hemoglobin
  • HbA la2 HbA la2
  • HbAi b HbA lc
  • HbA lc HbA lc
  • All of these subclasses have the same primary structure, which is stabilized by formation of an aldimine (Schiff base) by the amino group of N-terminal valine in the ⁇ subunit chain of normal hemoglobin HbA and glucose (or, glucose-6-phosphate or fructose) followed by formation of ketoamine by Amadori rearrangement.
  • glycosylated hemoglobin refers to a stable product of the nonenzymatic glycosylation of the ⁇ -chain of hemoglobin by plasma glucose.
  • Hemoglobin A lc comprises the main portion of glycated hemoglobins in the blood. The ratio of glycosylated hemoglobin is proportional to blood glucose level. Therefore, hemoglobin A lc rate of formation directly increases with increasing plasma glucose levels.
  • glycosylation occurs at a constant rate during the 120-day lifespan of an erythrocyte
  • measurement of glycosylated hemoglobin levels reflect the average blood glucose level for an individual during the preceding two to three months. Therefore determination of the amount of glycosylated hemoglobin HbA lc can be a good index for carbohydrate metabolism control. Accordingly, blood glucose levels of the last two months can be estimated on the basis of the ratio of HbA lc to total hemoglobin Hb.
  • hemoglobin A lc in blood is used as a measurement enabling long-term control of blood glucose level (see, e.g., Jain, S., et al, Diabetes (1989) 38:1539-1543; Peters A., et al., JAMA (1996) 276:1246-1252).
  • the term "symptom" of diabetes includes, but is not limited to, polyuria, polydipsia, and polyphagia, as used herein, incorporating their common usage.
  • polyuria means the passage of a large volume of urine during a given period
  • polydipsia means chronic, excessive thirst
  • polyphagia means excessive eating.
  • Other symptoms of diabetes include, e.g., increased susceptibility to certain infections (especially fungal and staphylococcal infections), nausea, and ketoacidosis (enhanced production of ketone bodies in the blood).
  • the term "complication" of diabetes includes, but is not limited to, microvascular complications and macro vascular complications.
  • Microvascular complications are those complications which generally result in small blood vessel damage. These complications include, e.g., retinopathy (the impairment or loss of vision due to blood vessel damage in the eyes); neuropathy (nerve damage and foot problems due to blood vessel damage to the nervous system); and nephropathy (kidney disease due to blood vessel damage in the kidneys). Macrovascular complications are those complications which generally result from large blood vessel damage. These complications include, e.g., cardiovascular disease and peripheral vascular disease. Cardiovascular disease refers to diseases of blood vessels of the heart (see. e.g., Kaplan, R. M., et al., "Cardiovascular diseases" in HEALTH AND HUMAN BEHAVIOR, pp.
  • Cardiovascular disease is generally one of several forms, including, e.g., hypertension (also referred to as high blood pressure), coronary heart disease, stroke, and rheumatic heart disease.
  • Peripheral vascular disease refers to diseases of any of the blood vessels outside of the heart. It is often a narrowing of the blood vessels that carry blood to leg and arm muscles.
  • the term "atherosclerosis” encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and "atherosclerotic disease”.
  • the term “antihyperlipidemic” refers to the lowering of excessive lipid concentrations in blood to desired levels.
  • antiuricemic refers to the lowering of excessive uric acid concentrations in blood to desired levels.
  • modulate refers to the treating, prevention, suppression, enhancement or induction of a function or condition.
  • the compounds of the present invention can modulate hyperlipidemia by lowering cholesterol in a human, thereby suppressing hyperlipidemia.
  • TGs triglyceride(s)
  • TGs consist of three fatty acid molecules esterified to a glycerol molecule and serve to store fatty acids which are used by muscle cells for energy production or are taken up and stored in adipose tissue.
  • free fatty acid(s) refers to a carboxylic acid attached to a long saturated or unsaturated unbranched aliphatic chain.
  • Lipoproteins are water insoluble, they must be packaged in special molecular complexes known as "lipoproteins" in order to be transported in the plasma. Lipoproteins can accumulate in the plasma due to overproduction and/or deficient removal. There are at least five distinct lipoproteins differing in size, composition, density, and function. In the cells of the small of the intestine, dietary lipids are packaged into large lipoprotein complexes called "chylomicrons", which have a high TG and low-cholesterol content.
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL High density lipoprotein
  • dislipidemia refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g., elevated levels of LDL, VLDL and depressed levels of HDL).
  • Exemplary Primary Hyperlipidemia include, but are not limited to, the following:
  • Familial Hyperchylomicronemia a rare genetic disorder which causes a deficiency in an enzyme, LP lipase, that breaks down fat molecules.
  • the LP lipase deficiency can cause the accumulation of large quantities of fat or lipoproteins in the blood;
  • Familial Combined Hyperlipidemia also known as multiple lipoprotein-type hyperlipidemia; an inherited disorder where patients and their affected first-degree relatives can at various times manifest high cholesterol and high triglycerides. Levels of HDL cholesterol are often moderately decreased;
  • Familial Defective Apo lipoprotein B-100 is a relatively common autosomal dominant genetic abnormality. The defect is caused by a single nucleotide mutation that produces a substitution of glutamine for arginine which can cause reduced affinity of LDL particles for the LDL receptor. Consequently, this can cause high plasma LDL and total cholesterol levels;
  • Familial Dysbetaliproteinemia also referred to as Type III
  • Hyperlipoproteinemia is an uncommon inherited disorder resulting in moderate to severe elevations of serum TG and cholesterol levels with abnormal apolipoprotein E function. HDL levels are usually normal; and [0083] (6) Familial Hypertriglyceridemia, is a common inherited disorder in which the concentration of plasma VLDL is elevated. This can cause mild to moderately elevated triglyceride levels (and usually not cholesterol levels) and can often be associated with low plasma HDL levels.
  • Risk factors in exemplary Secondary Hyperlipidemia include, but are not limited to, the following: (1) disease risk factors, such as a history of Type I diabetes, Type II diabetes, Cushing's syndrome, hypothroidism and certain types of renal failure; (2) drug risk factors, which include, birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various ⁇ blockers; (3) dietary risk factors include dietary fat intake per total calories greater than 40%; saturated fat intake per total calories greater than 10%; cholesterol intake greater than 300 mg per day; habitual and excessive alcohol use; and obesity.
  • disease risk factors such as a history of Type I diabetes, Type II diabetes, Cushing's syndrome, hypothroidism and certain types of renal failure
  • drug risk factors which include, birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various ⁇ blockers
  • dietary risk factors include dietary fat intake per total calories greater than 40%; saturated fat intake per total calories greater than 10%; cholesterol intake greater than 300 mg per day; habitual and
  • apolipoprotein refers to lipid binding proteins that bind to lipids and transport lipids in the bloodstream.
  • apoliproteins and subclasses within the five major types, including, but not limited to apoAl, apoAII, apoBlOO, apoCl, apoD, apoE, and others.
  • Various types and subtypes and varying amounts of the apoliproteins are found associated with various particles identified as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), los density lipoprotein (LDL), and high density lipoprotein (HDL).
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Apolipoprotein Al apoAl is the major apolipoprotein found in HDL.
  • islet(s) of langerhans [islet(s)] as used herein refers to the endocrine ⁇ i.e., hormone-producing) cells found in the pancreas that are grouped together in the shape of an island.
  • the islets of langerhans constitute approximately one to two percent of the mass of the pancreas.
  • the islets of langerhans comprise several types of cells including alpha cell, beta cells, delta cells, and others.
  • the different cellular types of the islets of langerhans group together within the pancreas to form "islets" or "clusters" of cells. See Figure 9 herein.
  • the islets produce certain hormones such as insulin, amylin, glucagon, somatostatin, ghrelin, and pancreatic polypeptide.
  • morphology of the islet of the langerhans refers to the clustering of the cells that comprise the islets of langerhans.
  • the right panel of Figure 9 shows the clustering of the cells of an islet of langerhans in a healthy morphology.
  • the left panel of Figure 9 shows the cells of an islet of langerhans in which the various cells types are no longer clustering together, indicating a destruction of the morphology of the islet.
  • beta cell refers to beta cells found in the islet of langerhans that produce insulin and amylin.
  • oval refers to, according to the World Health
  • BMI Body Mass Index
  • m weight (kg)/height (m ).
  • the BMI can be calculated be well known formulas.
  • Obesity is linked to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of Type II diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989) 11 :172-181; and Knowler, et ah, Am. J. Clin. Nutr. (1991) 53:1543-1551).
  • the compound of Formula I can be prepared by methods known to those of skill in the art.
  • the compound of Formula I was synthesized by the methods described in co-owned application WO 2005/080340, filed 17 February 2005.
  • the disclosure WO 2005/080340 is hereby incorporated by reference.
  • the present invention provides compounds having a Formula I:
  • the letter X represents a member selected from the group consisting of O, S, SO, SO 2 , CHR and NR, wherein R is H, (C 1 - C 8 )alkyl, C0R a , C00R a and CONR a R b wherein R a and R b are each independently selected from the group consisting of H and (Ci-C 8 )alkyl;
  • X is O.
  • X is NR, preferably wherein R is H or (C 1 -C 4 ⁇ IkVl.
  • Preferred groups for Y include CH 2 OR C , CO 2 R C , tetrazole, CHO and C0NR c R m ; with CH 2 OR 0 , CO 2 R 0 and tetrazole being further preferred. The most preferred embodiments are those in which Y is CH 2 OR 0 or CO 2 R 0 .
  • Preferred groups for R 1 and R 3 are halogen, (Ci-C 8 )alkyl, (Ci-C 8 )alkoxy, (C 3 -
  • R 1 and R 3 are halogen, (Ci-C 8 )alkyl, (C 1 -C 8 )haloalkyl, nitro, O-phenyl, NR J C0R k and S(O) r R J .
  • Still further preferred groups for R 1 and R 3 are F, Cl, (Ci-C 4 )alkyl, CF 3 , NHCOCF 3 , NO 2 , SCH 3 and OC 6 H 4 CF 3 .
  • the substituent R is preferably H or (C 1 -C 4 )alkyl, more preferably H or CH 3 . In the most preferred embodiments, R is H.
  • the letter Q is preferably CH.
  • m is preferably 0 to 2. In one group of embodiments, m is 0. In another group of embodiments, m is 1. In yet another group of embodiments, m is 2.
  • p is 0 to 2. In one group of embodiments, p is 0. In another group of embodiments, p is 1. In yet another group of embodiments, p is 2.
  • R will preferably represent halogen, nitro, (Q-C ⁇ alkyl, (Ci-C 8 )alkoxy, or (C 1 -Cg)haloalkyl.
  • R c is preferably H, (C 1 -
  • R 2 is H or CH 3 .
  • Q is CH; X is selected from the group consisting of O and NR; Y is selected from the group consisting of CH 2 OR 0 and CO 2 R 0 ; the subscript m is 0 to 2 and the subscript p is 0 to 1; each R 1 is selected from the group consisting of halogen, nitro, (C 1 -Cs) alkyl and (C 1 -Cs) alkoxy; each R is selected from the group consisting of halogen, nitro, (C 1 -Cs) alkyl and (C 1 -Cs) alkoxy; and R is H or CH 3 .
  • Selected groups of embodiments within the above are those in which (i) X is O and Y is CO 2 R 0 ; (ii) X is O and Y is CH 2 OR 0 ; (iii) X is NH and Y is CO 2 R 0 ; (iv) X is NH and Y is CH 2 OR 0 . Still further preferred embodiments for each of these group are those in which R 1 and R 3 are selected from F, Cl, (C 1 -C 4 )alkyl, CF 3 , NHCOCF 3 , NO 2 , SCH 3 and OC 6 H 4 . CF 3 .
  • the bromoesters 2 are reacted with the phenols, amines or mercaptans 3, to afford the products I.
  • the reaction is conducted in a polar aprotic solvent such as tetrahydrofuran or, preferably, dimethylformamide, in the presence of a base such as diazabicyclononene or, preferably, potassium carbonate.
  • a polar aprotic solvent such as tetrahydrofuran or, preferably, dimethylformamide
  • a base such as diazabicyclononene or, preferably, potassium carbonate.
  • the products I in which X is NH can be converted into the products in which N is acylated by a conventional acylation reaction, for example by reaction with an acyl chloride or anhydride in a basic solvent such as pyridine.
  • Scheme Ib illustrates the synthesis of the products I by means of a fluorine displacement reaction.
  • the substrates 4 are first converted into an alkali metal salt, by treatment with a base such as sodium hydride or sodium hexamethyldisilazide.
  • the reaction is conducted in an aprotic polar solvent such as tetrahydrofuran or dimethylformamide.
  • Scheme Id illustrates the introduction of the alkyl substituents R by means of an alkylation reaction.
  • the esters I are first reacted with a base such as sodium hydride or sodium hexamethyldisilazide, in an aprotic solvent such as tetrahydrofuran or dimethylformamide.
  • An alkylating agent R Br or R I is then added, and the reaction proceeds to yield the ester products I, in which Y is carboxyl ester and R is alkyl.
  • Basic hydro lyis for example by the use of lithium hydroxide in aqueous tetrahydrofuran, affords the carboxylic acids I in which R 2 is alkyl.
  • Scheme Ie illustrates methods for preparing compounds I in which Y is CHO, CH 2 OH and CH 2 OCOalkyl.
  • the acid chlorides 9 can be converted into the corresponding aldehydes by reduction employing lithium tri-tertiarybutyl aluminum hydride, as described in Journal of the American Society, 79:252 (1956).
  • Scheme If illustrates methods for preparing compounds I in which Y is tetrazole.
  • the bromonitriles 10 are reacted with the phenols, amines or mercaptans 3, to afford the intermediate 11.
  • the reaction is conducted in a polar aprotic solvent such as tetrahydrofuran or, preferably, dimethylformamide, in the presence of a base such as diazabicyclononene or, preferably, potassium carbonate.
  • the intermediate 11 is then converted into the tetrazole with an azide or, preferably trimethyltin azide.
  • Scheme 2a illustrates the Arndt-Eistert reaction, as described in Journal of the American Chemical Society, 72:5163 (1950), whereby variously substituted benzoic acids can be transformed into the corresponding phenylacetic acids.
  • the benzoic acid is first transformed into the acid chloride by treatment with oxalyl chloride or thionyl chloride.
  • the acid chloride is then reacted with an excess of diazomethane, and the resulting diazoketone is rearranged by treatment with a silver salt, for example silver benzoate, at reflux in an alcohol such as methanol, to afford the corresponding ester of the product 13 .
  • the free acid 13 can then be obtained by basic hydrolysis.
  • the ester of 13 can be alkylated, for example by treatment with a strong base such as lithium diisopropylamide, followed by reaction with a halide R 2 X, to afford after basic hydrolysis the alkylated phenylacetic acids 14.
  • a strong base such as lithium diisopropylamide
  • Scheme 2b illustrates the conversion of various bromobenzenes into the corresponding phenylacetic, phenylpropionic acids, etc.
  • the substituted bromobenzene 15 is first reacted with magnesium in an ethereal solvent such as tetrahydrofuran, to form a Grignard reagent.
  • Scheme 2c illustrates the conversion of variously substituted benzaldehydes into the ⁇ -bromophenylacetic acid eaters.
  • the benzaldehyde is first reacted with trimethylsilylcyanide in the presence of potassium cyanide and a crown ether, to afford the correspondingly substituted ⁇ -(trimethylsilyloxy)phenylacetonitriles 17.
  • These products are then treated with an alcohol in the presence of an acid catalyst to produce the ⁇ - hydroxyphenylacetic esters 18.
  • Reaction of the latter compounds with a brominating agent such as triphenyl phosphine/carbon tetrabromide, as described in Tetrahedron Letters, 28:3225 (1987), affords the bromoesters 19.
  • the ⁇ -hydroxyphenylacetic esters 4 are first converted to the corresponding ⁇ -bromo esters, as described above.
  • the acids 14 are first treated with bromine and thionyl chloride, to afford the ⁇ -bromo acid chlorides 21.
  • these compounds are converted into the ⁇ -bromophenylacetic esters 23.
  • the phenylacetic acids 14 are first converted into the esters 22, using conventional esterification procedures.
  • the esters 22 are then reacted with a brominating agent such as bromine or N- bromosuccinimide, to afford the ⁇ -bromophenylacetic esters 23.
  • a brominating agent such as bromine or N- bromosuccinimide
  • Route A represents the synthesis of phenols from the corresponding bromo compounds 24.
  • the bromo compound is first converted into an organo lithium or organomagnesium derivative 25, respectively by reaction with an alkyllithium such as n- butyllithium, or with magnesium metal.
  • the compound 25 is then converted to the phenol 26 either by direct oxidation using, for example, molybdenum pentoxide, as described in Journal of Organic Chemistry, 42:1479 (1979), or by reaction first with a trialkylborate followed by oxidation with hydrogen peroxide, as described in Journal of Organic Chemistry, 24:1141 (1959).
  • Route B represents the conversion of the bromo compounds 24 directly to the phenols 26 or thiophenols 28.
  • the reaction can be effected by treatment of the bromopyridine with aqueous acid or base, as described in Rec. Trav. Chim., 59:202 (1940).
  • the thiols corresponding to 26 are produced by reaction of the reactive bromo compound with sodium sulfide in an alcoholic solvent such as ethanol, as described in Rec. Trav. Chim., 64:102 (1945).
  • Route C represents the conversion of a phenol 26 into the corresponding thiol 27.
  • the phenol is first reacted with dimethylthiocarbamoyl chloride, to afford the intermediate thiocarbamate 28, which upon thermal rearrangement followed by basic hydrolysis, affords the thiol 29.
  • Route D represents the preparation of phenols 26 and cyano compounds 31 from the corresponding amine by a diazotization procedure, as described in Organic Syntheses, Collective volume 3, 130, 1955.
  • the amine is reacted with nitrous acid to afford the diazonium salt, which upon acidic hydrolysis yields the phenol 26.
  • the diazonium salt can be reacted with cuprous cyanide or nickel cyanide, as described in Organic Functional Group Preparations, by S. R. Sandler and W. Kara, Academic press, New York, p 463 to afford the cyano compound 31.
  • the cyano compound is useful for the preparation of the corresponding aldehyde 7.
  • Route E represents the conversion of the fluoro compound 5 to either the phenols 26, the thiols 28 or the amines 29.
  • the fluoro compound is reacted with, for example, sodium methoxide, to afford the corresponding methoxyl-substituted product.
  • the methoxyl group is then removed, using, for example, boron tribromide or aluminum chloride, to afford the phenol 26.
  • the fluoro compound 5 is reacted with a nitrogen nucleophile, such as, for example, sodium azide, to afford the corresponding azidobenzene. Reduction of the azido group, for example by the use of lithium aluminum hydride, affords the amino compound 29.
  • the thiols 28 are obtained by reaction of the fluoro compounds 5 with a sulfur nucleophile, for example with ethanolic sodium sulfide.
  • Route F represents the conversion of the carboxylic acids 30 to the amines 29 via the Curtius rearrangement as described in Organic Syntheses, Collective Volume 4, 819, 1963.
  • the carboxylic acid is first converted into the acid chloride by reaction with thionyl chloride.
  • the acid chloride is treated with sodium azide to afford the acyl azide, which upon thermal rearrangement in aqueous solution affords the amines 29.
  • Route G represents the conversion of the carboxylic acids 30 into the aldehydes 7 via corresponding nitrile 31.
  • the conversion of the carboxylic acids 30 into the nitriles 31 can be effected in a number of ways, as described in Comprehensive Organic
  • the carboxylic acid can first be converted into the acid chloride, and the latter compound is then reacted with ammonia to afford the corresponding amide.
  • the nitrile can then be reduced to afford the aldehyde 7, for example by employing diisobutylaluminum hydride, as described in Journal of the American Chemical Society, 107:7524 (1985).
  • Route H represents the conversion of the carboxylic acids 30 into the corresponding aldehydes 7.
  • This conversion can be effected in a number of ways, as described in Comprehensive Organic Transformations, by R.C. Larock, VCH Publishers, 1989, p 619ff.
  • the carboxylic acid can be first converted into the acid chloride, as described above.
  • the latter compound can then be hydrogenated, using a catalyst of palladium on barium carbonate, as described in Journal of the American Chemical Society, 108:2608 (1986), or by reduction using lithium aluminum tri- tertiarybutoxy hydride, as described in Journal of the American Chemical Society, 79:252 (1956) to afford the aldehydes 7.
  • the phenylacetic acid derivatives 2, 4 and 6 may contain reactive groups such as OH, SH and NH 2 which could undergo unwanted reactions during synthetic procedures. Such groups may, according to the judgement of one skilled in the art, require protection before a given synthetic step, and deprotection after the synthetic step.
  • Scheme 4 shows examples of protection and deprotection. The choice, attachment and removal of protective groups is described, for example, in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by T.W. Greene and P.G.M. Wuts, Wiley, 1991.
  • Scheme 4a illustrates the protection of a hydroxyl substituted phenylacetic acid derivative 32.
  • the compound is reacted with tert-butylchlorodimethylsilane in the presence of imidazole to afford the silyl ether 33.
  • the protective group is removed by treatment with tetrabutyl ammonium fluoride, to afford the final product I.
  • the silylation/desilylation procedures are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by T.W. Greene and P.G.M. Wuts, Wiley, 1991, p 145.
  • Scheme 4b illustrates the protection of a mercapto-substituted phenylacetic acid derivative 4.
  • the compound is reacted with 4-methoxybenzyl chloride, to afford the thioether 35.
  • This compound is reacted, as described above, with the intermediate 5, to afford the coupled product 36.
  • the benzylation/debenzylation procedures are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by T.W. Greene and P.G.M. Wuts, Wiley, 1991, p 281.
  • Scheme 4c illustrates the protection of an amino-substituted phenylacetic acid derivative 6.
  • the compound is reacted with tert-butoxycarbonyl chloride, to afford the carbamate 37.
  • the intermediate 36 is obtained.
  • racemic carboxylic acids I can be converted into salts with a chiral amine, such as, for example quinine, cinchonidine and the like. Fractional crystallization of the resultant salt, followed by release of the resolved acids, then affords chiral I.
  • chiral carboxylic acids can be converted into amides with chiral amines, such as, for example, (R) or (S) 1-phenylethylamine. The resultant diastereomeric amides can then be separated by chromatography, and the chiral acids regenerated by hydrolysis.
  • racemic compounds I can be separated into individual enantiomers by chiral HPLC.
  • racemic phenylacetic acid precursors of the compounds I can be separated into individual enantiomers, using, for example, the methods described above, prior to the formation of the compounds I.
  • the compounds of this invention are named as derivatives of phenylacetic acids.
  • Compounds I in which X is O, S or NH are respectively named as phenoxy, phenylsulfanyl or phenylamino phenylacetic acids.
  • Compounds in which X is C are named as derivatives of phenylpropionic acid.
  • Scheme 5 shows representative compounds of this invention. The numbering system for substituents is shown on compound 39.
  • this invention provides methods of lowering triglyceride levels in the blood of a mammal by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the levels of triglycerides in blood or a blood component, such as plasma and serum, can be measured by commercially available methods or as described in Examples 26 and 28.
  • this invention provides methods of lowering triglyceride levels in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods of lowering triglyceride levels in the blood of a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • a human with a BMI of greater than 27.8 for men and 27.3 for women is considered to be obese.
  • Another aspect of this invention provides methods of lowering free fatty acid levels in the blood of a mammal by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the levels of free fatty acids in blood or a blood component, such as plasma and serum, can be measured by commercially available methods or as described in Examples 26 and 28
  • this invention provides methods of lowering free fatty acid levels in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes, in particular a human, by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods of lowering free fatty acid levels in the blood of a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods of increasing the blood levels of apolipoprotein Al (ApoAl) in the blood of a mammal by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the levels of ApoAl in blood or a blood component, such as plasma and serum, can be measured by commercially available methods or as described in Example 32.
  • this invention provides methods of increasing blood levels of apolipoprotein Al (ApoAl) in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods of increasing blood levels of apolipoprotein Al (ApoAl) in the blood of a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods of increasing high density lipoprotein (HDL) particle size in the blood of a mammal by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the density of HDL particles in blood or a blood component, such as plasma and serum, can be measured by commercially available methods or as described in Example 32.
  • this invention provides methods of increasing high density lipoprotein (HDL) particle size in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods of increasing high density lipoprotein (HDL) particle size in the blood of a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods preserving islet of langerhans function in a mammal by administering a therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the function of the islet of langerhans can be measured as described in Examples 29 and 30.
  • this invention provides methods of preserving islet of langerhans function in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods preserving islet of langerhans function in a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods preserving the function of the beta cells of the islet of langerhans in a mammal by administering a therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the function of the beta cells can be measured by well known methods or as described in Examples 29 and 30.
  • this invention provides methods of preserving the function of the beta cells of the islet of langerhans in the blood of a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods preserving the function of the beta cells of the islet of langerhans in a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods of preserving insulin production by the islet of langerhans in a mammal by administering a therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • Insulin production can be measured by the methods described in Examples 29 and 30.
  • this invention provides methods of preserving insulin production by the islet of langerhans in a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods preserving insulin production by the islet of langerhans in a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • Another aspect of this invention provides methods of preserving morphology of the islet of langerhans in a mammal by administering a therapeutically effective amount of a compound of Formula I.
  • the mammal is a human.
  • the morphology of the islet of langerhans can be determined by the methods described in Examples 29 and 30.
  • this invention provides methods of preserving morphology of the islet of langerhans in a mammal diagnosed with dyslipidemia and/or Type II diabetes by administering an therapeutically effective amount of a compound of Formula I.
  • the mammal is a human. It is well within the skill of a physician or health care worker to diagnose and identify patients as having dyslipidemia and/or Type II diabetes.
  • Yet another aspect of this invention provides methods preserving morphology of the islet of langerhans in a human with a body mass index (BMI) of greater than about 20, or greater than about 25, by administering an therapeutically effective amount of a compound of Formula I.
  • BMI body mass index
  • a human with a BMI of greater than 25 is generally considered to be overweight.
  • a therapeutically effective amount is from about 1 mg/kg to about 200 mg/kg, or from about 5 mg/kg to about 100 mg/kg. In one embodiment, the therapeutically effective amount is from about 10 mg/kg to about 100 mg/kg. In another embodiment, the therapeutically effective amount is from about 10 mg/kg to about 75 mg/kg or from about 1 mg/kg to about 50 mg/kg. Preferably, the therapeutically effective amount is from about 10 mg/kg to about 40 mg/kg, or from about 10 mg/kg to about 30 mg/kg. Alternatively, a therapeutically effective amount is from about 10 mg/day to about 2000 mg/day. In one embodiment, the therapeutically effective amount is from about 10 mg/day to about 1000 mg/day.
  • the therapeutically effective amount is from about 10 mg/day to about 750 mg/day, from about 10 mg/day to about 500 mg/day, from about 10 mg/day to about 300 mg/day. In another embodiment, the therapeutically effective amount is from from 20 mg/day to about 300 mg/day, from about 30 mg/day to about 200 mg/day, or from about 50 mg/day to about 200 mg/day.
  • the therapeutically effective amount may be given to the patient in one dosage per day or multiple dosages per day. Preferably, the therapeutically effective amount is administered in one dosage.
  • the compound of Formula I may be administered every day, every other day, once every three days, or two times a week.
  • a therapeutically effective amount of a compound of Formula I can be used for the preparation of a pharmaceutical composition useful for treating an inflammatory condition, treating diabetes, treating hyperlipidemia, treating hyperuricemia, treating obesity, lowering triglyceride levels, lowering cholesterol levels, raising the plasma level of high density lipoprotein, and for treating, preventing or reducing the risk of developing atherosclerosis.
  • compositions of the invention can include compounds of Formula I, pharmaceutically acceptable salts thereof, or a hydrolyzable precursor thereof.
  • the compound is mixed with suitable carriers or excipient(s) in a therapeutically effective amount.
  • a therapeutically effective dose By a “therapeutically effective dose”, “therapeutically effective amount”, or, interchangeably, “pharmacologically acceptable dose” or “pharmacologically acceptable amount”, it is meant that a sufficient amount of the compound of the present invention and a pharmaceutically acceptable carrier, will be present in order to achieve a desired result, e.g., alleviating a symptom or complication of Type II diabetes.
  • the compounds of Formula I that are used in the methods of the present invention can be incorporated into a variety of formulations for therapeutic administration. More particularly, the compounds of Formula I can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal administration.
  • the compound can be administered in a local rather than systemic manner, in a depot or sustained release formulation.
  • the compounds can be administered in a liposome.
  • the compounds of Formula I can be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes.
  • the compounds can be administered transdermally, and can be formulated as sustained release dosage forms and the like.
  • Compounds of Formula I can be administered alone, in combination with each other, or they can be used in combination with other known compounds (see Combination Therapy below).
  • Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th ed.), which is incorporated herein by reference.
  • compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the compounds can be formulated into preparations by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the compounds of the present invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds of Formula I can be formulated readily by combining with pharmaceutically acceptable carriers that are well known in the art.
  • Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing the compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions can take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from propellant-free, dry-powder inhalers.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from propellant-free, dry-powder inhalers.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • propellant-free, dry-powder inhalers e.g.
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulator agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, carbowaxes, polyethylene glycols or other glycerides, all of which melt at body temperature, yet are solidified at room temperature.
  • rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, carbowaxes, polyethylene glycols or other glycerides, all of which melt at body temperature, yet are solidified at room temperature.
  • the compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • long-circulating liposomes can be employed.
  • liposomes are generally described in Woodle, et ah, U.S. Patent No. 5,013,556.
  • the compounds of the present invention can also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.
  • DMSO dimethylsulfoxide
  • the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few hours up to over 100 days.
  • compositions also can comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in a therapeutically effective amount.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective dose can be estimated initially from cell culture assays or animal models.
  • toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 5 O, (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g., Fingl et al. 1975 In: The Pharmacological Basis of Therapeutics, Ch. 1). [0183]
  • the amount of active compound that can be combined with a carrier material to produce a single dosage form will vary depending upon the disease treated, the mammalian species, and the particular mode of administration.
  • suitable unit doses for the compounds of the present invention can, for example, preferably contain between 100 mg to about 3000 mg of the active compound.
  • a preferred unit dose is between 500 mg to about 1500 mg.
  • a more preferred unit dose is between 500 to about 1000 mg.
  • Such unit doses can be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70 kg adult is in the range of 0.1 to about 250 mg per kg weight of subject per administration.
  • a preferred dosage is 5 to about 250 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 10 to about 1500 mg tablet taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the compounds of the present invention will, in some instances, be used in combination with other therapeutic agents to bring about a desired effect. Selection of additional agents will, in large part, depend on the desired target therapy ⁇ see, e.g., Turner, N. et al, Prog. Drug Res. (1998) 51 :33-94; Haffner, S. Diabetes Care (1998) 21 :160-178; and DeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). A number of studies have investigated the benefits of combination therapies with oral agents ⁇ see, e.g., Mahler, R., J. Clin. Endocrinol. Metab.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound having the general structure of Formula I and one or more additional active agents, as well as administration of a compound of Formula I and each active agent in its own separate pharmaceutical dosage formulation.
  • a compound of Formula I and an HMG-CoA reductase inhibitor can be administered to the human subject together in a single oral dosage composition, such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations.
  • a compound of Formula I and one or more additional active agents can be administered at essentially the same time ⁇ i.e., concurrently), or at separately staggered times ⁇ i.e., sequentially). Combination therapy is understood to include all these regimens.
  • a compound of Formula I is administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent, such as a cholesterol biosynthesis inhibitor, e.g.
  • an hydroxymethylglutaryl (HMG) CoA reductase inhibitor also referred to as statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin
  • statins such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin
  • HMG-CoA synthase inhibitor an HMG-CoA synthase inhibitor
  • a squalene epoxidase inhibitor also known as squalene synthase inhibitor
  • an acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitor such as melinamide; probucol; nicotinic acid and the salts thereof and niacinamide
  • a cholesterol absorption inhibitor such as ⁇ -sitosterol
  • a bile acid sequestrant anion exchange resin such as cholestyramine, colestipol or dialkylamin
  • the compounds of Formula I can be administered in combination with more than one additional active agent, for example, a combination of a compound of Formula I with an HMG-CoA reductase inhibitor (e.g., lovastatin, simvastatin and pravastatin) and aspirin, or a compound of Formula I with an HMG-CoA reductase inhibitor and a ⁇ blocker.
  • an HMG-CoA reductase inhibitor e.g., lovastatin, simvastatin and pravastatin
  • aspirin e.g., aspirin
  • a compound of Formula I with an HMG-CoA reductase inhibitor and a ⁇ blocker e.g., lovastatin, simvastatin and pravastatin
  • Another example of combination therapy can be seen in treating obesity or obesity-related disorders, wherein the compounds of Formula I can be effectively used in combination with, for example, phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine, phentiramine, ⁇ 3 adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins.
  • agents used in treating obesity or obesity-related disorders wherein the compounds of Formula I can be effectively used in combination with, for example, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D 2 receptors, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).
  • neuropeptide Y enterostatin
  • cholecytokinin bombesin
  • amylin histamine H3 receptors
  • dopamine D 2 receptors dopamine D 2 receptors
  • melanocyte stimulating hormone corticotrophin releasing factor
  • galanin gamma amino butyric acid
  • Still another example of combination therapy can be seen in modulating diabetes (or treating diabetes and its related symptoms, complications, and disorders), wherein the compounds of Formula I can be effectively used in combination with, for example, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA- SO 4 ); antiglucocorticoids; TNF ⁇ inhibitors; ⁇ -glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretogogues (such as repaglinide, gliquidone, and n
  • a further example of combination therapy can be seen in modulating hyperlipidemia (treating hyperlipidemia and its related complications), wherein the compounds of Formula I can be effectively used in combination with, for example, statins (such as fluvastatin, lovastatin, pravastatin or simvastatin), bile acid-binding resins (such as colestipol or cholestyramine), nicotinic acid, probucol, betacarotene, vitamin E, or vitamin C.
  • statins such as fluvastatin, lovastatin, pravastatin or simvastatin
  • bile acid-binding resins such as colestipol or cholestyramine
  • nicotinic acid probucol
  • betacarotene vitamin E
  • vitamin C vitamin C
  • kits with unit doses of the compounds of Formula I either in oral or injectable doses.
  • the containers containing the unit doses will be an informational package insert describing the use and attendant benefits of the drugs in alleviating symptoms and/or complications associated with Type II diabetes as well as in alleviating hyperlipidemia and hyperuricemia, or for alleviating conditions dependent on PPAR.
  • Preferred compounds and unit doses are those described herein above.
  • NMR nuclear magnetic resonance
  • 1 H NMR information is tabulated in the following format: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant(s) (J) in hertz, and, in selected cases, position assignment.
  • the prefix app is occasionally applied in cases where the true signal multiplicity was unresolved and br indicates the signal in question was broadened.
  • This compound (0.05 mol) was dissolved in toluene (50 mL). The solution was cooled to -8O 0 C and a 1.5M solution of diisobutylaluminum hydride (0.05 mol) in toluene was added. After 2 hours, the mixture was warmed to 5O 0 C for 1 hour. Water was added, and the organic phase was dried and concentrated. The residue was chromatographed to afford the title compound 66.
  • a 250 mL three neck roundbottom flask was equipped with an efficient condenser attached to an acid scrubber, a magnetic stir bar, and placed under argon.
  • 4- Trifluoromethylphenyl acetic acid 72 (0.25 mole) was charged, followed by thionyl chloride (0.34 mole).
  • the condenser was cooled with 4°C water. The mixture was heated to an internal temperature of 55-60 0 C. Gas evolution was observed and the solids dissolved as the internal temperature rose to 55-60 0 C. The mixture was then stirred at 55-60 0 C for 45 min. Bromine (33.0 mL, 0.33 mole) was charged and the mixture was maintained at 55- 60 0 C for 18 h.
  • the internal temperature was then raised to 80-85 0 C over 1.5 h and heating continued for 18h.
  • the mixture was cooled to 20-25 0 C and anhydrous dichloromethane (250 mL) was added.
  • the acyl halide solution was added at such a rate as to keep the internal temperature below 21 0 C.
  • the mixture was stirred for 0.5h. This mixture was carefully added to water (0.75 L) containing sodium bicarbonate (0.9 mole) at such a rate that frothing was moderate.
  • Phenol 75 (0.5 mol) was stirred at 25°C with K 2 CO 3 in DMF for 2 hrs. The mixture was then cooled to 0 0 C, to which was then added 74 in DMF slowly. The reaction mixture was stirred and allowed to warm to 25°C. The reaction was worked up between water and EtOAc after TLC indicated the completion of the reaction. The organic layer was dried and concentrated to afford compound 76.
  • This product was also prepared by refluxing ( ⁇ , ⁇ , ⁇ -trifluoro-m- tolyl)acetic acid 78 with bromine in the presence of SOCl 2 , and then quenching with EtOH.
  • 1 H NMR 400 MHz, CDCl 3 ): ⁇ 7.80 (IH, s), 7.77 (IH, d), 7.61 (IH, d,), 7.51 (IH, t), 5.35 (IH, s), 4.26 (2H, q), 1.30 (3H, t) ppm.
  • ester 99 (0.61 g, 12%) as a pale-yellow liquid.
  • THF / H 2 O 10 mL/3 mL
  • lithium hydroxide monohydrate (0.31 g, 7.39 mmol).
  • the resulting solution was stirred at room temperature for 2 h.
  • the reaction was quenched with IN aqueous HCl and the mixture was extracted with EtOAc.
  • a one neck roundbotton flask was equipped with a Claisen adapter, temperature probe, water condenser, and nitrogen line. The apparatus was flushed with nitrogen. The system was charged with potassium acetate (1.52 g, 15.5 mmol), acetic anhydride (69 mL), ( ⁇ , ⁇ , ⁇ -trifluoro-p-tolyl)acetic acid (2.97 g, 14.5 mmol), and ⁇ , ⁇ , ⁇ -trifluoro-m- tolualdehyde (2 niL, 2.6 g, 14.9 mmole) with stirring. As the solution was heated, all solid dissolved around 75°C and the solution became clear yellow. The mixture was heated to 106 0 C for 18.5 hours.
  • the layers were separated and the organic layer was washed with aqueous sodium bicarbonate solution.
  • the organic phase was dried over magnesium sulfate and concentrated by rotovap and high vacuum, yielding 1.55 g of a viscous brown oil.
  • the product was purified by flash chromatography using a solvent system consisting of 5% acetic acid in chloroform.
  • the trans adduct was synthesized by isomerizing the c ⁇ -carboxylic acid with a sun lamp.
  • ester 119 (1.03 g, 2.17 mmol) in THF / H 2 O (15 mL / 5 mL) at rt was added lithium hydroxide monohydrate (0.95 g, 0.022 mol). The resulting solution was refluxed at rt for 1 h, cooled to rt, quenched with IN aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to afford acid 120 (0.93 g, 96%) as a pale-yellow liquid.
  • Dimethylaluminum amide was prepared by adding anhydrous toluene (60 mL) to ammonium chloride (2.14 g). The mixture was cooled to 0 0 C and trimethylaluminum in toluene (2.0 M, 20 mL) was added dropwise. The reaction was allowed to stir at 0 0 C for 15 min before warming to room temperature and stirred for an additional 2 hours. To the freshly prepared dimethylaluminumamide was added the ester 80 (6.0 g) in toluene (20 mL). The reaction was then warmed to 100 0 C and allowed to stir overnight. The reaction was then cooled to room temperature and Na 2 SO 4 10H 2 O was added and stirred for an additional hour.
  • a mixture of racemic acid 83 (7.97 g), and (lR,2R)-(-)-2-amino-l-(4-nitrophenyl)- 1,3 -propanediol (CAF D BASE) (2.56 g, 0.55 eq.) was dissolved in 70 mL of 2-propanol by heating at 75°C for 30 min. The solution was cooled slowly to room temperature, and then was allowed to stand at 4°C overnight. The solid (3.4 g) was collected by filtration. The solid was dissolved in 50 mL of 2-propanol at 80 0 C. The solution was cooled to room temperature slowly. Crystals (2.4 g) were collected by filtration.
  • Optically pure (-)-39 salt was obtained via classical resolution by serial recrystallization of the salt of the racemic acid 39 with (lR,2R)-(-)-2-amino-l-(4- nitrophenyl)-l,3-propandiol (0.55 eq.) in EtOAc / hexanes at 75 0 C to rt.
  • the first crystal collected afforded (-)-39 salt.
  • Serial recrystallization of the remaining mother liquid afforded another optically pure (+)-39 salt. After acidification of both salts with IN HCl in EtOAc, optically pure (-)-39 and (+)-39 were obtained as white solids respectively.
  • Racemic 39 was resolved into the enantiomers using chiral HPLC.
  • a 25cm x 2.1 mm Regis Technologies (R,R) WHELK-O 2 10/100 column was employed at room temperature.
  • Injection samples contained 5.0 mL of 12 mg/mL of racemic 39 in isopropanohhexane, 2:3.
  • the column was eluted with isopropanol:hexanes:trifluoroacetic acid 2:98:0.1, with detection at 220 nm.
  • the separately eluted enantiomers were collected and the fractions were concentrated to afford the individual enantiomers (+)-39 and (-)-39.
  • mice Male, 7-9 weeks old, C57BL/6J ob/ob mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Animals were housed (4-5 mice/cage) under standard laboratory conditions at 22 ⁇ 3 0 C temperature and 50 ⁇ 20% relative humidity, and were maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood was collected from the tail vein of each animal. Mice that had non- fasting plasma glucose levels between 250 and 500 mg/dl were used. Each treatment group consisted of 8-10 mice that were distributed so that the mean glucose levels were equivalent in each group at the start of the study.
  • mice were dosed orally by gavage once a day for 1-4 days with vehicle and one or more dose of test compound at a dose ranging from 5 to 125 mg/kg.
  • Compounds were delivered in a liquid formulation containing 5% (v/v) dimethyl sulfoxide (DMSO), 1% (v/v) Tween 80® and 0.9% (w/v) methylcellulose. The gavage volume was 10 ml/kg.
  • Blood samples were taken at 6 hours after the each dose and analyzed for plasma glucose. Food intake and body weight were measured daily. Plasma glucose concentrations were determined colorimetrically using a commercial glucose oxidase method (Sigma Chemical Co, St. Louis, MO, USA). Significant difference between groups (comparing drug-treated to vehicle -treated) was evaluated using the Student unpaired t-test.
  • Table 1 provides the relative potency of some selected compounds of the invention. Compounds that are effective for glucose lowering at the dose of ⁇ 125 mg/kg are assigned a potency of ++; compounds that are less effective for glucose lowering, typically exhibiting activity at a multiple dose or elevated dose of > 125 mg/kg is assigned the potency of +. Table 1. Potency of Invention Compounds
  • Sub-confluent HEK-293 cells were co-transfected with 50 ng of GAL4-human, mouse or rat PPAR- ⁇ , PPAR- ⁇ or PPAR- ⁇ expression plasmid, and 50 ng of pFR-luciferase reporter plasmid using Lipofectamine 2000 (as per manufacturer's instructions), plated into 96 well plates and incubated for 4 hours. The media was then removed, replaced with fresh media (DMEM, 10% FBS) and incubated overnight.
  • DMEM fetal bovine serum
  • luciferase activity was measured using the Steady Go Luciferase System (as per manufacturer's instructions).
  • GW7647 a potent and selective human PP ARa agonist was obtained from Sigma (cat number G6793) and was used as reference compound in the human GAL4-PPAR- ⁇ reporter assay.
  • GW501516 a potent and selective human PPAR ⁇ agonist was synthesized according to a published synthetic route [Sznaidman et ah, "Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PP ARdelta)— synthesis and biological activity”. Bioorg Med Chem Lett. 2003 May 5; 13(9):1517-21.
  • Reporter gene assays were used to evaluate the ability of Compound 39 to activate human PPAR- ⁇ , PPAR- ⁇ and PPAR- ⁇ . This was done with a reporter assay system using the human GAL4- PPAR- ⁇ , GAL4-PPAR-5 orGAL4- PPAR- ⁇ LBD fusion constructs. In this system compounds bind to and activate the GAL4-PP AR-LBD (ligand binding domain) leading to activation of luciferase expression. Luciferase activity was then measured using a commercially availiable substrate (Steady GIo) that is cleaved by the luciferase enzyme leading to a measurable luminescent signal.
  • a commercially availiable substrate (Steady GIo) that is cleaved by the luciferase enzyme leading to a measurable luminescent signal.
  • the fully potent potent PPAR- ⁇ agonist GW7647, the weaker PPAR- ⁇ agonist fenofibrate, the potent PPAR- ⁇ agonist GW501516 and the potent PPAR- ⁇ agonist rosiglitazone were run as positive controls and for comparison.
  • the degree of PPAR- ⁇ activation by Compound 39 was a small percentage of the maximum activation by rosiglitazone.
  • the degree of PPAR- ⁇ activation by Compound 39 was also much lower than the maximum activation observed with GW7647 but similar to that seen with fenofibrate.
  • the positive control GW501516 activated human PPAR- ⁇ (EC 50 S of 0.009 ⁇ M, 0.081 ⁇ M and 1.027 ⁇ M respectively) but Compound 39 did not activate human PPAR- ⁇ .
  • the binding of Compound 39, GW7647, and fenofibrate to the human PPAR- ⁇ ligand binding domain was measured using the PolarScreenTM PPAR- ⁇ Competitor Assay, Green (InVitrogen, Cat. No. PV3355) using the manufacturer's recommended protocol.
  • the binding between Compound 39 and the human PPAR- ⁇ ligand binding domain was measured using the LanthaScreenTM PPAR- ⁇ Competitor Asstay, Green (InVitrogen, beta testing kit) using the manufacturer's recommended protocol.
  • the left panel of figure 1 shows the binding of fenofibrate, compound 39, and GW7647 to PPAR- ⁇ and right panel of figure 1 shows the binding of rosiglitazone and compound 39 to PPAR- ⁇ .
  • the IC 50 of Compound 39, GW7647, and fenofibrate to human PPAR- ⁇ were 20.1, .0014, and 35.4 ⁇ M, respectively.
  • the IC 50 of Compound 39 and rosiglitazone to human PPAR- ⁇ were 63.3, and 0.11 ⁇ M, respectively.
  • Sub-confluent HEK-293 cells were co-trans fected with 50 ng of wild type or
  • Y473A mutant GAL4-human PPAR- ⁇ LBD expression plasmid 50 ng of pFR-lucif erase reporter plasmid and 5 ng of LacZ normalization plasmid using Lipofectamine 2000 diluted in Optimem media (as per manufacturer's instructions), plated into 96 well plates and incubated for 4 hours. The media was then removed and replaced with fresh media
  • DMEM fetal bovine serum
  • MBX- 102 acid 0.4-120 ⁇ M
  • rosiglitazone 0.05-300 ⁇ M
  • luciferase activity was measured using the Steady Go Luciferase System (as per manufacturer's instructions).
  • the binding of Compound 39, GW7647, and fenofibrate to the human PPAR- ⁇ ligand binding domain was measured using the PolarScreenTM PPAR- ⁇ Competitor Assay, Green (InVitrogen, Cat. No. PV3355) using the manufacturer's recommended protocol.
  • the binding between Compound 39 and the human PPAR- ⁇ ligand binding domain was measured using the LanthaScreenTM PPAR- ⁇ Competitor Asstay, Green (InVitrogen, beta testing kit) using the manufacturer's recommended protocol.
  • the left panel of figure 1 shows the binding of fenofibrate, compound 39, and GW7647 to PPAR- ⁇ and right panel of figure 1 shows the binding of rosiglitazone and compound 39 to PPAR- ⁇
  • the IC 50 of Compound 39, GW7647, and fenofibrate to human PPAR- ⁇ were 20.1, .0014, and 35.4 ⁇ M, respectively.
  • the IC50 of Compound 39, and rosiglitazone to human PPAR- ⁇ were 63.3, and 0.11 ⁇ M, respectively.
  • tyrosine 473 in the AF-2 helix of the PPAR- ⁇ ligand binding domain plays an important role in the activation of PPAR- ⁇ by TZDs [R.T. Nolte, et ah, "Ligand Binding and Co-Activator Assembly of the Peroxisome Pro liferator- Activated Receptor- ⁇ ", Nature, vol. 395, no. 6698, pp. 137-143, 1998.].
  • mutation of the tyrosine 473 residue reduces the ability of fully potent agonists, such as rosiglitazone, to bind to PPAR- ⁇ [T.
  • LBD GST-fused PPAR- ⁇ ligand binding domain
  • FRET fluorescein labeled co-activator and co-repressor protein peptides
  • agonist experimental compound
  • the terbium anti-GST antibody binds to the GST-PP AR- ⁇ LBD. Binding of agonist (experimental compound) to the GST- PPAR- ⁇ LBD causes a conformational change, resulting in a higher affinity for and binding of co-activator peptides. Due to the close proximity of the terbium on the anti-GST antibody and fluorescein on the co-activator peptide, stimulation of the terbium (excitation at 340 nm) leads to energy transfer to the fluorescein resulting in an increased TR-FRET signal (emission at 520 nm).
  • Co-repressor peptides bind to the PPAR- ⁇ LBD in the native state. Binding of ligand (experimental compound) to the GST-PP AR- ⁇ LBD causes a conformational change resulting in the displacement of the co-repressor peptide. Due to the increased distance between the terbium on the anti-GST antibody and fluorescein on the co-repressor peptide, stimulated terbium (excitation at 340 nm) is unable to transfer energy to the fluorescein resulting in a decreased TR-FRET signal (emission at 520 nm).
  • the TR-FRET based assay system which includes PPAR- ⁇ ligand binding domain and coregulator peptides (containing an LXXLL binding motif) was used to determine the effect of COMPOUND 39 on coregulator interaction with PPAR- ⁇ and to compare these results with rosiglitazone.
  • the data shows that COMPOUND 39 acid recruited TRAP220, CBP, SRCl and TIF2 co-activator peptides to the PPAR- ⁇ ligand binding domain, to a lesser degree in comparison to rosiglitazone and with a higher EC 50 .
  • COMPOUND 39 acid fully displaced NCOR co-repressor peptide from the PPAR- ⁇ ligand binding in a similar manner as rosiglitazone and with a higher IC50.
  • the data is provided in figure 3
  • Example 24 Example 24
  • Glucose uptake activity was analyzed by measuring the uptake of 2-deoxy-d-[ H] glucose essentially as described previously [Sakoda, et al, Diabetes 48 (1999)]. Briefly, confluent 3T3-L1 adipocytes grown in 96-well plates were treated overnight with compounds at the indicated concentrations. Cells were washed once with PBS, two times with Fat Cell Buffer (FCB: 125mM NaCl, 5mM KCl, 1.8mM CaC12, 2.6mM MgSO4, 25mM Hepes, 2mM pyruvate and 2% BSA, 0.2 ⁇ M sterile filtered) and incubated with FCB at 37 C for 30min.
  • FCB Fat Cell Buffer
  • Insulin were then added to adipocytes at indicated concentration for 20 minutes.
  • Glucose uptake was initiated by the addition of FCB with 2-deoxy-d-[ 3 H] glucose (0.083 ⁇ Ci/mL) and 1.1 mM glucose as final concentrations.
  • Glucose uptake was terminated by washing the cells three times with cold PBS. The cells were lysed with scintillation solution. The radioactivity retained by the cell lysates was determined by PHERAstar (BMG LABTECH) and normalized to cell number as measured with a
  • mice were pre-bled and assigned to three groups (vehicle, rosiglitazone, and compound 39; eight animals per group) based on starting plasma glucose and body weight.
  • the dosing vehicle for all studies was 1% (wt/vol) carboxymethylcellulose, 0.2% Tween 80. Rosiglitazone and compound39 were administered once daily by oral gavage at a dose of 10 mg/kg for rosiglitazone and 30 mg/kg for compound 39 for 10 weeks.
  • Body weight was measured every 2 to 3 days and was expressed as cumulative body weight gain (BWG) at the end of the study.
  • BWG body weight gain
  • Plasma glucose and triglycerides levels were measured using the colorimetric methods described by T ⁇ nderl (Glucose Oxidase G7016, Peroxidase P8125, and Triglyceride Diagnostic Kit No.344, Sigma Chemical Co., St. Louis, MO).
  • Plasma free fatty acid (FFA) levels were measured using the HR Series NEFA-HR (2) (Wako, Richmond, VA. The tests were modified for analysis in 96 well plates and were run according to the instructions provided by the manufacturer.
  • Plasma insulin levels were determined using either a rat or mouse Insulin EIA kit (Catalog No. 80-INSRTU-E10 and 80-INSMSU-E10, ALPCO Chem. Windham, NH), according to the instructions provided by the manufacturer.
  • FIG. 6 shows the results obtained, db/db mice treated with vehicle had triglyceride levels of approximately 210 mg/dl. In contrast db/db mice treated with compound 39 had triglyceride levels of approximately 60 mg/dl. In addition, the triglyceride levels of db/db (homozygous) mice treated with compound 39 was lower than heterozygous dbl mice treated with vehicle (approximately 100 mg/dl). db/db mice treated with vehicle had free fatty acid levels of approximately 1.75 mg/dl. In contrast db/db mice treated with compound 39 had lowered free fatty acid levels of approximately 1.25 mg/dl.
  • Example 27 shows the results obtained, db/db mice treated with vehicle had triglyceride levels of approximately 210 mg/dl. In contrast db/db mice treated with compound 39 had triglyceride levels of approximately 60 mg/dl. In addition, the triglyceride levels of
  • mice Male ZDF rats were obtained from Genetic Models (Indianapolis, IN) at 9 wk of age. After a 1-wk acclimation period, rats were pre-bled and assigned to four groups (nine animals per group; vehicle, rosiglitazone at 4 mg/kg per day; COMPOUND 39 at 25mg/kg per day) based on starting plasma glucose levels and body weight. Rats were administered compound daily by oral gavage for 4 days. The dosing vehicle was 1% (wt/vol) carboxymethylcellulose, 0.2% Tween 80. Blood samples were obtained 5 h postdose on day 4 from the tail vein of conscious animals by gentle massage after tail snip. Blood was collected in EDTA tubes and kept chilled on ice.
  • the islets of rats as described in Example 27 were morphometrically evaluated. Morphometric evaluation was performed by scoring insulin-stained islets derived from 3 animals from each treatment group. Pancreatic tissue was fixed for 24 h in 4% paraformaldehyde in 0.1 M phosphate -buffered saline (pH 7.4). Samples were dehydrated and prepared as paraffin blocks. Seven-micrometer-thick sections were obtained at 100-to- 150- ⁇ m intervals on at least three levels and stained with Methyl Green and insulin (DAKO).
  • DAKO Methyl Green and insulin
  • Islets in these fields were counted qualitatively assigned by eye. Islet disintegration was defined as the lack of cohesiveness, and lack of a defined border.
  • Figure 9 shows an example of of micrograph of two islets, one from a rat treated with compound 39, and one from a rat treated with vehicle.
  • the panel on the left shows a vehicle treated islet wherein the lack of cohesiveness and defined border are clearly visible.
  • the panel on the right shows a compound 39 treated islet wherein there is a clearly defined border and the insulin stained beta cells cluster together in a cohesive "islet”. Similar experiments performed in db/db mice demonstrated that compound 39 preserved the morphology of the islets in db/db mice.
  • Example 30
  • Diabetic db/db mice as described in Example 25 were treated with compound 39 for six weeks to determine the impact on the morphology and insulin content of the islets. Morphometric evaluations were performed according to Example 29 as disclosed herein. Pancreatic insulin content was determined by acid ethanol extraction using a commercially available insulin radioimmunoassay kit (Linco). [0296] The top panel of figure 10 shows a graph of the percent of islets in the pancreas that have disintegrated. Approximately 60% of the islets in mice treated with vehicle disintegrated, meaning that these islets had lost their cohesiveness and defined border. In contrast, mice treated with 30 mg/kg compound 39 had only approximately 20% of its islets disintegrated.
  • the bottom panel of figure 10 shows the pancreatic insulin content of mice treated with vehicle and compound 39.
  • the insulin content of the pancreas of mice treated with 30 mg/kg compound 39 was approximately three times higher than the vehicle treated mice, approximately 6,000 ng insulin per mg protein in compound treated mice versus approximately 2,000 ng insulin per mg proteint in vehicle treated mice.
  • Example 31
  • mice Male ZF rats were obtained from Charles River (Indianapolis, IN) at 7-8 wk of age. After a 1-wk acclimation period, rats were prebled and assigned to five groups (eight animals per group; vehicle, rosiglitazone at 30 mg/kg per day; COMPOUND 39 at 3, 10 and 30mg/kg per day), based on starting plasma insulin levels and body weight. Rats were administered compound daily by oral gavage for 43 days. The dosing vehicle was 1% (wt/vol) carboxymethylcellulose, 0.2% Tween 80. Blood samples were obtained 4 h postdose on day 3 from the tail vein of conscious animals by gentle massage after tail snip. Blood was collected in EDTA tubes and kept chilled on ice.
  • Figure 11 shows that statistically significant decreases in body weight gain in ZF rats treated with compound 39 when compared to the body weight gain in ZF rats treated with vehicle.
  • Figure 11 also shows that in ZF rats treated with rosiglitazone, the weight gain rate was greater than the rate of weight gain observed when treated with vehicle.
  • Figure 12 shows the fasting insulin levels in ZF rats treated with compound 39 and rosiglitazone. At 5, 9, 34, and 43 days, treatment with compound 39 decreased fasting insulin levels.
  • Example 32
  • mice Human ApoAl transgenic micewere purchased from Jackson Laboratories. After a 1-wk acclimation period, the mice were assigned (based on weight) to individual groups with six animals per group. The mice were administered compound daily by oral gavage between 0600 and 0700 h for 11 days. Fenofibrate was administered at 75, 150, 300 and 450 mg/kg per day, whereas compound 39 and rosiglitazone were each given at lOmg/kg per day. The dosing vehicle was 1% (wt/vol) carboxymethylcellulose, 0.2% Tween-80 with control animals receiving dosing vehicle only. Blood was collected by heart draw for analysis 3 h after the final dose.
  • Figure 13 shows the effect of compound 39 on plasma levels of apoAl and HDL particle size.
  • the plasma levels of transgenic mice expressing human apoAl are shown in the left panel of Figure 3.
  • Treatment with 10 mg/kg with Compound 39 approximately doubled the plasma levels of apoAl .
  • the increase in apoAl levels at 10 mg/kg was approximately equivalent to the increase obtained with300 mg/kg of fenofibrate.
  • the right panel of Figure 13 shows the increase in HDL particle size.
  • the particle size of vehicle treated mice was approximately 9.4 nM.
  • the HDL particle size of mice treated with 10 mg/kg was increased to approximately 12 nM.

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Abstract

Cette invention a pour objet des procédés de traitement de maladies métaboliques par l'administration d'un composé de formule (I).
PCT/US2008/078845 2007-10-05 2008-10-03 Procédés de traitement de maladies métaboliques WO2009046371A1 (fr)

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US8399685B2 (en) 2008-02-29 2013-03-19 Nissan Chemical Industries, Ltd. Process for producing thiophene compound and intermediate thereof
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US8598374B2 (en) 2008-12-18 2013-12-03 Metabolex, Inc. GPR120 receptor agonists and uses thereof
US8299117B2 (en) 2010-06-16 2012-10-30 Metabolex Inc. GPR120 receptor agonists and uses thereof
US8476308B2 (en) 2010-06-16 2013-07-02 Metabolex, Inc. GPR120 receptor agonists and uses thereof
CN104603090A (zh) * 2012-05-10 2015-05-06 塞利克斯比奥私人有限公司 治疗代谢综合征的组合物和方法

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