WO2009046371A1

WO2009046371A1 - Methods of treating metabolic diseases

Info

Publication number: WO2009046371A1
Application number: PCT/US2008/078845
Authority: WO
Inventors: Francine Gregoire; Edward Clemens; Zuchun Zhao; Brian Lavan; Fang Zhang
Original assignee: Metabolex, Inc.
Priority date: 2007-10-05
Filing date: 2008-10-03
Publication date: 2009-04-09

Abstract

This invention provides methods of treating metabolic disesases by administering a compound of Formula (I).

Description

METHODS OF TREATING METABOLIC DISEASES

BACKGROUND OF THE INVENTION

[0001] Diabetes mellitus can be divided into two clinical syndromes, Type I and Type II diabetes mellitus. Type I diabetes, or insulin-dependent diabetes mellitus, is a chronic autoimmune disease characterized by the extensive loss of beta cells in the pancreatic islets of Langerhans (hereinafter referred to as "pancreatic islet cells" or "islet cells"), which produce insulin. As these cells are progressively destroyed, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high level of glucose in the blood) when the amount secreted drops below the level required for euglycemia (normal blood glucose level). Although the exact trigger for this immune response is not known, patients with Type I diabetes have high levels of antibodies against pancreatic beta cells (hereinafter "beta cells"). However, not all patients with high levels of these antibodies develop Type I diabetes. [0002] 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).

[0003] 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. Conventional treatments for diabetes are very limited, and focus on attempting to control blood glucose levels in order to minimize or delay complications. Current treatments target either insulin resistance (metformin, thiazolidinediones ("TZDs")), or insulin release from the beta cell (sulphonylureas, exanatide). Sulphonylureas, and other compounds that act by depolarizing the beta cell, have the side effect of hypoglycemia since they cause insulin secretion independent of circulating glucose levels. One approve drug, Byetta (exanatide) stimulates insulin secretion only in the presence of high glucose, but is not orally available and must be injected. Januvia (sitagliptin) 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. However, 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. There is an unmet need for oral drugs that stimulate insulin secretion in a glucose dependent manner.

[0004] Progressive insulin resistance and loss of insulin secreting pancreatic β-cells are primary characteristics of Type II diabetes. Normally, a decline in the insulin sensitivity of muscle and fat is compensated for by increases in insulin secretion from the β-cell. However, loss of β-cell function and mass results in insulin insufficiency and diabetes (Kahn BB, Cell 92:593-596, 1998; Cavaghan MK, et al, J. Clin. Invest. 106:329-333. 2000; Saltiel AR, Cell 104:517-529, 2001; Prentki M and Nolan CJ. J Clin Invest. 116: 1802-1812 (2006); and Kahn SE. J. Clin. Endicrinol. Metab. 86:4047-4058, 2001). Hyperglycemia further accelerates the decline in β-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). Several of the genes in which 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]).

[0005] 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). Once inside the cell, 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

Med Chem. 2006; 13(15):1839-43; and Matschinsky FM, et al, Diabetes 2006 Jan; 55(1):1- 12) in diabetes. Glucose metabolism via glycolysis and mitochondrial oxidative phosphorylation ultimately results in ATP production, and the amount of ATP produced in a beta cell is directly related to the concentration of glucose to which the beta cell is exposed. [0006] Elevated ratios of ATP to ADP that occur in the presence of higher glucose result in the closure of the Kir6.2 channel via interaction with the SURl subunit of the channel complex. Closure of these channels on the plasma membrane of the beta cell results in depolarization of the membrane and subsequent activation of voltage dependent calcium channels (VDCCs) (Ashcroft FM, and Gribble FM, Diabetologia 42:903-919, 1999; and Seino S: Annu Rev Physiol. 61 :337-362, 1999). Calcium ion entry as well as release of calcium from intracellular stores triggers exocytosis of insulin granules, resulting is secretion of insulin into the blood stream. Agents which close the Kir6.2 channel such as sulphonylureas and metaglitinides (Rendell M. Drugs. 2004; 64(12):1339-58; and Buckle JF. Diabetes Metab. 2006 Apr; 32(2): 113-20) also cause membrane depolarization, and therefore these agents stimulate insulin secretion in a glucose independent fashion. 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). Although 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.

[0007] 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). Acetylcholine activation of phospho lipase C through the G_αq-coupled GPCR M3 muscarinic receptor leads to release of Ca++ from intracellular stores (Gilon P, and Henquin JC. EndocrRev. 2001 Oct; 22(5):565-604). Cholinergic agonists also lead to a subtle Na+ - dependent plasma membrane depolarization that can work in concert with glucose-initiated depolarization to enhance insulin release (Gilon P, and Henquin JC. Endocr Rev. 2001 Oct; 22(5):565-604). VIP and PACAP each bind to an overlapping set of G_α-coupled GPCRs (PACl, VIPRl, and VIPR2) on the beta cell that lead to stimulation of adenylate cyclase and an increase in intracellular cAMP (Filipsson K, et al, Diabetes, 2001 Sep; 50(9): 1959- 69; Yamada H, et al, Regul Pept. 2004 Dec 15; 123(l-3):147-53; and Qader SS, et al., Am J Physiol Endocrinol Metab. 2007 May; 292(5):E1447-55).

[0008] Elevation of beta cell cAMP has a substantial potentiating effect on insulin secretion in the presence of stimulatory levels of glucose (see below). Unfortunately, many potentiators of glucose-stimulated insulin secretion also have effects outside of the islet which limit their ability to be used as diabetes therapeutics. For example, 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). Likewise, 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.

[0009] 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 Gα//?/zα_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. 2007 Jan; 117(1): 143-52. Epub 2006 Dec 21). 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. The glucose lowering that can be obtained with DPPIV inhibitors, however, is somewhat limited since these drugs are dependent on the endogenous release of the incretin hormones. Peptides (eg. exanatide (Byetta)) and 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. Some studies have indicated that 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 (Meneilly GS, et al, Diabetes Care. 1993 Jan; 16(1): 110-4) may be a promising way to improve beta cell function in vivo.

[0010] Since increased 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. 2006 Dec; 55(Supplement_2):S78-S85). To date, however, there does not appear to be a way to selectively impact these pathways to promote incretin secretion for therapeutic benefit. There is a need for oral drugs that stimulate incretin secretion in the treatment of diabetes. [0011] 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). The net result of these changes is an increase in beta cell number and islet mass, and this should provide for increased insulin secretory capacity, which is another desired aim of anti-diabetic therapies. 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. 2006 Mar; 188(3):481-92; and Kim, MJ et al, J Endocrinol. 2006 Mar; 188(3):623-33). Increased transcription of the cyclin Dl gene occurs in response to PKA phosphorylation of CREB (cAMP -response element binding) transcription factors (Hussain, MA, et al, MoI Cell Biol. 2006 Oct; 26(20):7747-5950). There is a need for oral drugs that increase beta cell number and islet mass in the treatment of diabetes. [0012] 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. Curr Opin Investig Drugs. 2006 Oct; 7(10):898-905). 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. 2002 Oct 4; 277(40):37446-55; WaIz HA, et al, J Endocrinol. 2006 Jun; 189(3):629-41; Choi YH, et al, J CHn Invest. 2006 Dec; 116(12):3240-51; and Cantin LD, et al, BioorgMed Chem Lett. 2007 May 15; 17(10):2869-73), but so far, no PDEs have been found to have the cell type selectivity necessary to avoid undesirable effects. However, this remains an area of active investigation due to the potential for amplification of the effects of incretins and other agents that stimulate adenylate cyclase.

[0013] There appear to be multiple mechanisms by which cAMP elevation in the beta cell can enhance glucose dependent insulin secretion. Classically, many of the intracellular effects of cAMP are mediated by the cAMP-dependent protein kinase (protein kinase A, PKA) (Hatakeyama H, et al, J Physiol. 2006 Jan 15; 570(Pt 2):271-82). PKA consists of a complex of two regulatory and two catalytic domains; binding of cAMP to the catalytic domains releases the catalytic domains and results in increased protein phosphorylation activity. One of the downstream effects of this kinase activity is enhanced efficiency of insulin exocytosis (Gromada J, et al, Diabetes. 1998 Jan; 47(l):57-65). Another cAMP binding protein is Epac, a guanine nucleotide exchange factor (GEF) (Kashima Y, et al, J Biol Chem. 2001 Dec 7; 276(49):46046-53. Epub 2001 Oct 11; and Shibasaki T, et al, J Biol Chem. 2004 Feb 27; 279(9):7956-61), which mediates a cAMP-dependent, but PKA- independent, increase in insulin exocytosis. 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.

[0014] Agents that raise intracellular cAMP levels in the beta cell increase insulin secretion in a glucose dependent manner (Miura, Y. and Matsui, H., Am. J. Physiol Endocrinol. Metab (2003) 285, E1001-E1009). One mechanism for raising cAMP is by the action of G-protein coupled cell surface receptors, which stimulate the enzyme adenylate cyclase to produce more cAMP. The GLP-I receptor, which is the target of exanatide, is an example of such a receptor (Thorens, B. et al, Diabetes (1993) 42, 1678-1682). There is a need for oral drugs that increase intracellular levels of cAMP in the treatment of diabetes.

[0015] 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. For a review of 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. They are classified according to their density: chylomicrons; very low-density lipoproteins (VLDL); intermediate density lipoproteins (IDL); low density lipoproteins (LDL); and high density lipoproteins (HDL). 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.

[0016] 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). Several lipoprotein abnormalities have been described among diabetic subjects (Howard B., et al., Artherosclerosis (1978) 30:153-162). Premature development of atherosclerosis and increased rate of cardiovascular and peripheral vascular diseases are characteristic features of patients with diabetes, with dyslipedemia being an important precipitating factor for these diseases.

[0017] 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

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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. [0022] 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.

[0023] 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.

[0024] In another aspect, 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. [0025] 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.

BRIEF DESCRIPTION OF THE DRAWINGS [0026] Fig. 1 shows the effect of the binding of fenofibrate, compound 39, GW7647 to PPAR-α, PPAR-δ, and the binding of rosiglitazone and compound 39 to PPAR-γ. See Example 22.

[0027] Fig. 2 shows that compound 39 binds to PPAR-γ in a different manner than rosiglitazone. See Example 22. [0028] Fig. 3 shows that compound 39 induces full co-repressor displacement while inducing partial co-activator recruitement binds to PPAR-γ. See Example 23.

[0029] Fig. 4 shows that compound 39 induces less adipogenesis than rosiglitazone in primary human adipocytes. See Example 24.

[0030] Fig. 5 shows that compound 39 stimulates glucose transport in 3T3-L1 adipocytes. See Example 25.

[0031] Fig. 6 shows that compound 39 lowers plasma triglycerides and free fatty acids in db/db mice. See Example 26.

[0032] 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. [0033] Fig. 8 shows that compound 39 lowers glucose, insulin, triglycerides and free fatty acids in Zucker diabetic fatty rats. See Example 28.

[0034] Fig. 9 shows that compound 39 preserves islet of langerhans morphology in Zucker diabetic fatty rats. See Example 29.

[0035] 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.

[0036] Fig. 11 shows that compound 39 decreased body weight gain in zucker fatty rats. See Example 31. [0037] Fig. 12 shows that compound 39 decreased fasting insulin levels in zucker fatty rats. See Example 31.

[0038] 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.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

[0039] The abbreviations used herein are conventional, unless otherwise defined.

[0040] Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: [0041] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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".

[0042] 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.

[0044] "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:

[0045] (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, camphorsulfonic acid, 4 methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or

[0046] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, JV-methylglucamine, and the like. [0047] "Prodrugs" means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. 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.

[0048] Turning next to the compositions of the invention, 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.

[0049] With reference to the methods of the present invention, the following terms are used with the noted meanings:

[0050] The terms "treating" or "treatment" of a disease includes:

[0051] (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,

[0052] (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or

[0053] (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0054] The term "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.

[0055] The term "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.

[0056] The term "blood" includes, without limitation, whole blood or a component of blood including plasma and serum.

[0057] The term "plasma" is defined herein to refer to the liquid component of blood in which the cells have been removed. [0058] The term "serum" is defined herein to refer to plasm in which the components involved in blood clotting have been removed.

[0059] The term "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. Manifestations of insulin resistance include insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. 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. The association of insulin resistance with glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor- 1), has been referred to as "Syndrome X" {see, e.g., Reaven, G. M., Physiol. Rev. (1995) 75:473-486).

[0060] The term "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". Two major forms of diabetes are Type I diabetes and Type II diabetes. As described above, 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. Most 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. In addition, many 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.

[0061] The term "secondary diabetes" is diabetes resulting from other identifiable etiologies which include: genetic defects of β 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. (1996) 58:171-86; genetic defects in insulin action; diseases of the exocrine pancreas (e.g., hemochromatosis, pancreatitis, and cystic fibrosis); certain endocrine diseases in which excess hormones interfere with insulin action (e.g., growth hormone in acromegaly and Cortisol in Cushing's syndrome); certain drugs that suppress insulin secretion (e.g., phenytoin) or inhibit insulin action (e.g., estrogens and glucocorticoids); and diabetes caused by infection (e.g., rubella, Coxsackie, and CMV); as well as other genetic syndromes. [0062] The guidelines for diagnosis for Type II diabetes, impaired glucose tolerance, and gestational diabetes have been outlined by the American Diabetes Association (see, e.g., The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care, (1999) VoI 2 (Suppl 1):S5-19).

[0063] The term "hyperinsulinemia" refers to the presence of an abnormally elevated level of insulin in the blood. Similarly, the term "hyperuricemia" refers to the presence of an abnormally elevated level of uric acid in the blood. The term "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. [0064] The term "secretagogue" means a substance or compound that stimulates secretion. For example, an insulin secretagogue is a substance or compound that stimulates secretion of insulin.

[0065] The term "hemoglobin" or "Hb" refers to a respiratory pigment present in erythrocytes, which is largely responsible for oxygen transport. A hemoglobin molecule comprises four polypeptide subunits (two α chain systems and two β 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 α₂β₂ subunits. Trace components such as HbA₂ (α₂δ₂) can also be found in normal adult hemolysate.

[0066] Among classes of adult hemoglobin HbAs, there is a glycated hemoglobin (referred to as "HbA₁", or "glycosylated hemoglobin"), which may be further fractionated into HbA_lal, HbA_la2, HbAi_b, and HbA_lc with an ion exchange resin fractionation. 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 β subunit chain of normal hemoglobin HbA and glucose (or, glucose-6-phosphate or fructose) followed by formation of ketoamine by Amadori rearrangement.

[0067] The term "glycosylated hemoglobin" (also referred to as "HbAi₀,", "GHb", "hemoglobin - glycosylated", "diabetic control index" and "glycohemoglobin"; hereinafter referred to as "hemoglobin AIc") refers to a stable product of the nonenzymatic glycosylation of the β-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. Since 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. The analysis of the 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).

[0068] The term "symptom" of diabetes, includes, but is not limited to, polyuria, polydipsia, and polyphagia, as used herein, incorporating their common usage. For example, "polyuria" means the passage of a large volume of urine during a given period; "polydipsia" means chronic, excessive thirst; and "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). [0069] 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. 206-242 (McGraw-Hill, New York 1993). 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. [0070] 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". [0071] The term "antihyperlipidemic" refers to the lowering of excessive lipid concentrations in blood to desired levels. Similarly, the term "antiuricemic" refers to the lowering of excessive uric acid concentrations in blood to desired levels.

[0072] The term "modulate" refers to the treating, prevention, suppression, enhancement or induction of a function or condition. For example, the compounds of the present invention can modulate hyperlipidemia by lowering cholesterol in a human, thereby suppressing hyperlipidemia.

[0073] The term "triglyceride(s)" ("TGs"), as used herein, incorporates its common usage. 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.

[0074] The term "free fatty acid(s)" as used herein refers to a carboxylic acid attached to a long saturated or unsaturated unbranched aliphatic chain.

[0075] Because cholesterol and TGs 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. In the liver, TG and cholesterol esters are packaged and released into plasma as TG-rich lipoprotein called very low density lipoprotein ("VLDL"), whose primary function is the endogenous transport of TGs made in the liver or released by adipose tissue. Through enzymatic action, VLDL can be either reduced and taken up by the liver, or transformed into intermediate density lipoprotein ("IDL"). IDL, is in turn, either taken up by the liver, or is further modified to form the low density lipoprotein ("LDL"). LDL is either taken up and broken down by the liver, or is taken up by extrahepatic tissue. High density lipoprotein ("HDL") helps remove cholesterol from peripheral tissues in a process called reverse cholesterol transport. The size of HDL particles range from about 8 nm to about 12 nm.

[0076] The term "dyslipidemia" 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).

[0077] Exemplary Primary Hyperlipidemia include, but are not limited to, the following:

[0078] (1) 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;

[0079] (2) Familial Hypercholesterolemia, a relatively common genetic disorder caused where the underlying defect is a series of mutations in the LDL receptor gene that result in malfunctioning LDL receptors and/or absence of the LDL receptors. This brings about ineffective clearance of LDL by the LDL receptors resulting in elevated LDL and total cholesterol levels in the plasma;

[0080] (3) 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; [0081] (4) 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; [0082] (5) 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. [0084] 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 β 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.

[0085] The term "apolipoprotein" as used herein refers to lipid binding proteins that bind to lipids and transport lipids in the bloodstream. There are five major types of 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). Apolipoprotein Al (apoAl) is the major apolipoprotein found in HDL.

[0086] The term "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.

The term "morphology of the islet of the langerhans" as used herein 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.

[0087] The term "beta" cell as used herein refers to beta cells found in the islet of langerhans that produce insulin and amylin. [0088] The terms "obese" and "obesity" refers to, according to the World Health

Organization, a Body Mass Index (BMI) greater than 27.8 kg/m² for men and 27.3 kg/m² for women (BMI equals 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).

[0089] The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, certain excipients used in formulating the compound of Formula I may be optionally used in creating particular formulations with desired properties.

Description of the Embodiments

[0090] 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.

[0091] In one aspect, the present invention provides compounds having a Formula I:

or a pharmaceutically acceptable salt thereof, wherein the letter X represents a member selected from the group consisting of O, S, SO, SO₂, CHR and NR, wherein R is H, (C₁- C₈)alkyl, C0R^a, C00R^a and CONR^aR^b wherein R^a and R^b are each independently selected from the group consisting of H and (Ci-C₈)alkyl; the letter Y represents a member selected from the group consisting of CH₂OR^C, CO₂R^C, tetrazole, CHO, C0NR^cR^m, CH(=NR^C) and CH(=NOR^C), wherein R^c is a member selected from the group consisting of H, (Q-C^alkyl, (C₃-C₈)alkenyl, (C₃-C₈)alkynyl, (C₃-C₇)cycloalkyl, (C₄-C₈)cycloalkyl-alkyl, aryl, MyI(C₁- C₈)alkyl and (Ci-C₈)alkylene-Z, wherein Z is selected from the group consisting of COR^d, COOR^d, NR^dR^e, NR^dC0NR^eR^f, NR^dC0R^e, NR^dC00R^e and CONR^dR^e wherein R^d, R^e and R^f are each independently selected from the group consisting of H, (Ci-C₈)alkyl and phenyl, or optionally two of R^d, R^e and R^f when attached to the same nitrogen atom are combined to form a five- or six-membered ring; and wherein R^m is selected from the group consisting of H, (Ci-C₈)alkyl, aryl and OH, and R^m and R^c are optionally combined with the nitrogen atom to which each is attached to form a five or six membered ring; each of the symbols R¹ and R represents a member independently selected from the group consisting of halogen, hydroxy, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (Ci-C₈)alkoxy, (C₃-C₇)cycloalkyl, (C₄-C₈)cycloalkyl-alkyl, (Ci-C₈)haloalkyl, (Ci-C₈)heteroalkyl, (C₂-C₅)heterocyclyl, heterosubstituted(C₃-C₇)cycloalkyl, heteroalkyl substituted (C₃-C₇)cycloalkyl, 0(C₁-

C₈)haloalkyl, nitro, cyano, phenyl, O-phenyl, NR^J -phenyl, S(O)_r-phenyl, COR^J, COOR^J, NR^JR^k, S(O)_rR^J, SO₂NR^JR^k, NRCONRV, NR^JC0R^k, NR^JC00R^k and CONR^JR^k wherein the phenyl ring is optionally substituted and R^J, R^k and R¹ are each independently selected from the group consisting of H and (Ci-C₈)alkyl, including (C₁-C₈)haloalkyl, or optionally two of R^J , R^k and R¹ when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript r is an integer of from 0 to 2; the symbol R² represents a member selected from the group consisting of H and (Q-C^alkyl; the letter Q represents CH or N; the subscript m is an integer of from 0 to 3; and the subscript p is an integer of from 0 to 2.

[0092] Turning first to the linkage provided in Formula I as X, preferred groups are O, S and NR. In one group of embodiments, X is O. In another group of embodiments, X is NR, preferably wherein R is H or (C₁-C₄^IkVl.

[0093] Preferred groups for Y include CH₂OR^C, CO₂R^C, tetrazole, CHO and C0NR^cR^m; with CH₂OR⁰, CO₂R⁰ and tetrazole being further preferred. The most preferred embodiments are those in which Y is CH₂OR⁰ or CO₂R⁰. [0094] Preferred groups for R¹ and R³ are halogen, (Ci-C₈)alkyl, (Ci-C₈)alkoxy, (C₃-

C₇)cycloalkyl, (C₄-C₈)cycloalkyl-alkyl, (Ci-C₈)haloalkyl, O(Ci-C₈)haloalkyl, nitro, phenyl, O-phenyl, NR^J -phenyl, NR^JC0R^k, S(O)_r-phenyl and S(O)_rR^J. Particularly preferred groups for R¹ and R³ are halogen, (Ci-C₈)alkyl, (C₁-C₈)haloalkyl, nitro, O-phenyl, NR^JC0R^k and S(O)_rR^J. Still further preferred groups for R¹ and R³ are F, Cl, (Ci-C₄)alkyl, CF₃, NHCOCF₃, NO₂, SCH₃ and OC₆H₄ CF₃.

[0095] The substituent R is preferably H or (C₁ -C₄)alkyl, more preferably H or CH₃. In the most preferred embodiments, R is H.

[0096] The letter Q is preferably CH.

[0097] The subscript 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.

[0098] The subscript 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.

[0099] Within the above groups of embodiments, certain combinations are also preferred. Turning first to the embodiments in which Q is CH, X is preferably O, S or NR. Still further preferred are those embodiments in which Y is CO₂R⁰. Even further preferred are those embodiments in which m is 0 to 2 and p is 0 to 1. Within the group of embodiments in which Q is CH, X is O, S or NR, Y is CO₂R⁰, m is 0 to 2 and p is 0 to 1 , the symbol R¹ will preferably represent halogen, nitro, (Ci-C₈)alkyl, (Ci-C₈)alkoxy, or (C₁-C₈)haloalkyl. Returning to the group of embodiments in which Q is CH, X is O, S or NR, Y is CO₂R⁰, m is 0 to 2 and p is 0 to 1, the symbol R will preferably represent halogen, nitro, (Q-C^alkyl, (Ci-C₈)alkoxy, or (C₁-Cg)haloalkyl. For those embodiments in which two R groups are present, it is understood that each R³ group is independently selected from the provided list. For each of these groups of embodiments, including those in which R¹ and R³ are provided with their full scope according to formula I above, the symbol R^c is preferably H, (C₁-

Cs)alkyl or (Q-Cs^lkylene Z. Further preferred are those embodiments in which R² is H or CH₃.

[0100] In one group are particularly preferred embodiments, Q is CH; X is selected from the group consisting of O and NR; Y is selected from the group consisting of CH₂OR⁰ and CO₂R⁰; the subscript m is 0 to 2 and the subscript p is 0 to 1; each R¹ is selected from the group consisting of halogen, nitro, (C₁-Cs) alkyl and (C₁-Cs) alkoxy; each R is selected from the group consisting of halogen, nitro, (C₁-Cs) alkyl and (C₁-Cs) alkoxy; and R is H or CH₃. Selected groups of embodiments within the above are those in which (i) X is O and Y is CO₂R⁰; (ii) X is O and Y is CH₂OR⁰; (iii) X is NH and Y is CO₂R⁰; (iv) X is NH and Y is CH₂OR⁰. Still further preferred embodiments for each of these group are those in which R¹ and R³ are selected from F, Cl, (C₁-C₄)alkyl, CF₃, NHCOCF₃, NO₂, SCH₃ and OC₆H₄. CF₃.

Preparation of the Compounds

[0101] Compounds I in which Y is CO₂R⁰ and X is O, S or NH are prepared as shown in Scheme Ia and Ib. Compounds I in which X is C are prepared as shown in Scheme Ic.

[0102] An alternative method for introducing the substituent R¹ is shown in Scheme Id, and routes for preparing the aldehydes (I, Y = CHO), carbinols (I, Y = CH₂OH) and carbinol esters (I, Y = CH₂OCOR⁰) are shown in Scheme Ie.

[0103] The preparation of Compound I in which Y is tetrazole is shown in Scheme If, Ig. [0104] Compounds I in which Y = COOR⁰ and R° is H can be converted into compounds I in which R° is alkyl or aralkyl using conventional esterification procedures, for example as described in Preparative Organic Chemistry, by R.B. Wagner and H. D. Zook, Wiley, p 479. Scheme 1 - Preparation of Compounds I

(1a)

(1b) 1, X = O, S, NH, Nalkyl; Y=CO₂R^C

4

I, Y=OCOR^C Scheme 1 - Preparation of Compounds I (cont'd)

1, Y = tθtrazolθ

Displacement ofbenzylic bromides with nucleophiles

[0105] As illustrated in Scheme Ia, 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. 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.

Displacement of fluorine substituents with phenylacetic ester nucleophiles [0106] Scheme Ib illustrates the synthesis of the products I by means of a fluorine displacement reaction. The carbinols, mercaptans, or amines 4, X = O, S, NH or N-alkyl are reacted with a fluorine-substituted benzene or pyridine moiety 5. In this 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. The aryl fluoride 5 is then added, and the reaction proceeds to afford the products, X = O, S, NH or Nalkyl.

Condensation reactions of aldehydes 7 with phenylacetic esters 6 [0107] Scheme Ic illustrates the synthesis of compounds I in which X is C. In this procedure, the tert-butyl esters 6 are first reacted with a base such as sodium hydride, in an aprotic solvent such as dimethylformamide. The anion generated is reacted with the aldehydes 7. After dehydration, the unsaturated products 8 are obtained. These compounds are converted into the products 1, X = C, by means of catalytic hydrogenation, using, for example, 5% palladium on carbon as catalyst.

Alkylation reactions to introduce substituents R [0108] Scheme Id illustrates the introduction of the alkyl substituents R by means of an alkylation reaction. In this procedure, 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 R² is alkyl.

Preparation of aldehyde and carbinol derivatives I

[0109] Scheme Ie illustrates methods for preparing compounds I in which Y is CHO, CH₂OH and CH₂OCOalkyl. The compounds I, Y = COOH, are first converted into the acid chlorides 9, by reaction with oxalyl chloride or, preferably, thionyl chloride. The acid chlorides 9 are then hydrogenated in the presence of a 5% palladium on barium carbonate catalyst, as described in Journal of the American Chemical Society, 108:2608 (1986), to afford the aldehydes I, Y = CHO. Alternatively, 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). The latter compounds are converted into the corresponding carbinols I, Y = CH₂OH, by means of a reduction reaction, for example by treatment with sodium borohydride in ethanol or isopropanol. The products I, Y = CH₂OH are transformed into the esters I, Y = CH₂OCOalkyl, by means of acylation reactions, for example by reaction with acetyl chloride in a basic solvent such as pyridine.

Preparation oftetrazole derivatives I

[0110] 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. Alternatively, intermediate 11 can be prepared from compound I ( Y = COOH) by first transforming the acid into an amide and followed by dehydration (Scheme Ig).

Scheme 2 - Preparation of Phenylacetic Acid Intermediates

₍2b₎

F₃

Phenylacetic acid and phenyl acetonitrile starting materials for the preparation of compounds I

[0111] Many variously substituted phenylacetic acids, and precursors therefor, are commercially available or are described in the literature. In addition, a number of synthetic routes are available to prepare compounds not previously reported. Scheme 2 shows some synthetic routes to variously substituted phenylacetic acids and derivatives thereof.

[0112] 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. In this procedure 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. [0113] Alternatively, 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 R²X, to afford after basic hydrolysis the alkylated phenylacetic acids 14.

[0114] Scheme 2b illustrates the conversion of various bromobenzenes into the corresponding phenylacetic, phenylpropionic acids, etc. In this procedure, the substituted bromobenzene 15 is first reacted with magnesium in an ethereal solvent such as tetrahydrofuran, to form a Grignard reagent. An equimolar amount of anhydrous zinc chloride is then added, followed by addition of ethyl bromoacetate, to afford after basic hydrolysis the appropriately substituted phenylacetic acid 6, R² = H. Compounds 6 in which R² is methyl, ethyl etc can be obtained by employing ethyl 2-bromopropionate, or ethyl 2-bromobutyrate, etc, in place of ethyl bromoacetate.

[0115] Scheme 2c illustrates the conversion of variously substituted benzaldehydes into the α-bromophenylacetic acid eaters. In this procedure, which is described in Synthetic Communications, 12:763 (1982), the benzaldehyde is first reacted with trimethylsilylcyanide in the presence of potassium cyanide and a crown ether, to afford the correspondingly substituted α-(trimethylsilyloxy)phenylacetonitriles 17. These products are then treated with an alcohol in the presence of an acid catalyst to produce the α- 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.

[0116] Scheme 2d illustrates the conversion of variously substituted α- hydroxyphenylacetic esters into the corresponding α-bromo and α-mercaptophenylacetic esters 20 and 4, X = S. In this procedure, the α-hydroxyphenylacetic esters 4 are first converted to the corresponding α-bromo esters, as described above. The bromoesters 20 are then reacted with a sulfur nucleophile, such as sodium thiolacetate to afford the corresponding α-mercaptophenylacetic esters 4, X = S. [0117] Scheme 2e illustrates alternative methods to prepare the α-bromo and α- mercaptophenylacetic esters 23 and 4, X = S, from the corresponding phenylacetic acids 14. In this procedure, the acids 14 are first treated with bromine and thionyl chloride, to afford the α-bromo acid chlorides 21. Upon treatment with an alcohol, these compounds are converted into the α-bromophenylacetic esters 23. Alternatively, 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 α-bromophenylacetic esters 23. These compounds can be transformed into the α-mercaptophenylacetic esters 4, X = S, as described previously.

[0118] All phenyl acetic acids can be transformed the corresponding phenyl acetonitriles by standard transformations (see Scheme Ig).

Scheme 3 - Preparations and interconversions of phenols, amines, mercaptans and aldehydes

Phenol, thiol, amine and aldehyde starting materials for the preparation of compounds I

[0119] Many phenols, thiols, amines and aldehydes required for the preparation of the compounds of this invention are commercially available or have been described in the literature. In addition, a number of synthetic routes are available to prepare compounds not previously made. In Scheme 3 are shown some synthetic routes to, and interconversions among, the compounds.

[0120] Route A represents the synthesis of phenols from the corresponding bromo compounds 24. In this route, 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).

[0121] Route B represents the conversion of the bromo compounds 24 directly to the phenols 26 or thiophenols 28. This reaction proceeds in the case of particularly reactive bromo compounds, for example, 2- or 4-bromopyridines, (24, Y = N). 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).

[0122] Route C represents the conversion of a phenol 26 into the corresponding thiol 27. In this procedure, described in Journal of Organic Chemistry, 81:3980 (1966), 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.

[0123] 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. In this reaction, the amine is reacted with nitrous acid to afford the diazonium salt, which upon acidic hydrolysis yields the phenol 26. Alternatively, 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.

[0124] Route E represents the conversion of the fluoro compound 5 to either the phenols 26, the thiols 28 or the amines 29. In this procedure, 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. Alternatively, 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.

[0125] 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. In this procedure, 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.

[0126] 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

Transformations, by R.C. Larock, VCH Publishers, 1989, p 963ff. For example, 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. Treatment of the amide with, for example, p-toluenesulfonyl chloride in pyridine, then affords the nitrile 31. 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).

[0127] 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. For example, 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.

Scheme 4 - Examples of protection and deprotection

deprotect

Protection and deprotection of reactive groups during syntheses

[0128] The phenylacetic acid derivatives 2, 4 and 6 may contain reactive groups such as OH, SH and NH₂ 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. [0129] 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. After reaction, as described above, with the intermediate 3, to afford the protected product 34, 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.

[0130] 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. Deprotection, employing mercuric acetate in trifluoroacetic acid, then affords the final product I. 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.

[0131] 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. After condensation with the aldehyde 7, as described above, and subsequent dehydration/hydro genation steps, the intermediate 36 is obtained. Deprotection, using trifluoroacetic acid, then affords the final product I.

[0132] The silylation/desilylation procedures are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by T.W. Greene and P.G.M. Wuts, Wiley, 1991, p 327.

Preparation of individual enantiomers of compounds I.

[0133] Individual enantiomers of those compounds I can be separated by a number of methods well known to those skilled in the art. For example, 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. Alternatively, 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. Alternatively, racemic compounds I can be separated into individual enantiomers by chiral HPLC.

[0134] In addition, the 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.

Scheme 5 - Nomenclature

43 44 45

Nomenclature

[0135] 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.

[0136] The names of the representative structures of Scheme 5 are as follows: 39 (4- Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid; 40 (4-Trifluoromethyl- phenyl)-(2-trifluoromethyl-phenylamino)-acetic acid; 41 (4-Hydroxy-3-trifluoromethyl- phenyl)-(2-nitro-4-trifluoromethyl-phenylsulfanyl)-acetic acid; 42 2-(3-Fluoro-4- trifluoromethyl-phenyl)-3-(2-fluoro-5-trifluoromethyl-phenyl)-propionic acid; 43 2-(3- Methoxy-4-trifluoromethyl-phenoxy)-2-(3-trifluoromethyl-phenyl)-propionic acid; 44 N-[2- Hydroxy- 1 -(4-trifluoromethyl-phenyl)-ethyl] -N-(2-trifluoromethyl-phenyl)-acetamide; 45 (4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid ethyl ester. (Names generated by Autonom).

[0137] In one aspect, 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. Preferably, 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.

[0138] In another aspect, 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. Preferably, 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.

[0139] 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. 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.

[0140] 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. Preferably, 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

[0141] In another aspect, 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. Preferably, 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.

[0142] 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. A human with a BMI of greater than 25 is generally considered to be overweight.

[0143] 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. Preferably, 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.

[0144] In another aspect, 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. Preferably, 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. [0145] 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. A human with a BMI of greater than 25 is generally considered to be overweight. [0146] 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. Preferably, 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. [0147] In another aspect, 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. Preferably, 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.

[0148] 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.

[0149] 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. Preferably, the mammal is a human. The function of the islet of langerhans can be measured as described in Examples 29 and 30.

[0150] In another aspect, 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. Preferably, 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.

[0151] 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. A human with a BMI of greater than 25 is generally considered to be overweight.

[0152] 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. Preferably, 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. [0153] In another aspect, 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. Preferably, 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.

[0154] 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. A human with a BMI of greater than 25 is generally considered to be overweight.

[0155] 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. Preferably, the mammal is a human. Insulin production can be measured by the methods described in Examples 29 and 30.

[0156] In another aspect, 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. Preferably, 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.

[0157] 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. A human with a BMI of greater than 25 is generally considered to be overweight.

[0158] 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. Preferably, the mammal is a human. The morphology of the islet of langerhans can be determined by the methods described in Examples 29 and 30. [0159] In another aspect, 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. Preferably, 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.

[0160] 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. A human with a BMI of greater than 25 is generally considered to be overweight.

[0161] 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. Alternatively, 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.

[0162] In accordance with the present invention, 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.

[0163] The compositions of the invention can include compounds of Formula I, pharmaceutically acceptable salts thereof, or a hydrolyzable precursor thereof. In general, the compound is mixed with suitable carriers or excipient(s) in a therapeutically effective amount. 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.

[0164] 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. As such, administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal administration. Moreover, the compound can be administered in a local rather than systemic manner, in a depot or sustained release formulation. In addition, the compounds can be administered in a liposome.

[0165] 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). [0166] 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. Moreover, for a brief review of methods for drug delivery, see, Langer, Science (1990) 249:1527-1533, which is incorporated herein by reference. The pharmaceutical 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.

[0167] For injection, 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. Preferably, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0168] For oral administration, 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). If desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [0169] Dragee cores are provided with suitable coatings. For this purpose, 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.

[0170] Pharmaceutical preparations 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. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration. [0171] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0172] For administration by inhalation, 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. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0173] 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. [0174] 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. Optionally, 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. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.

[0175] 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.

[0176] In addition to the formulations described previously, 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. Thus, for example, 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.

[0177] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In a presently preferred embodiment, long-circulating, i.e., stealth liposomes can be employed. Such 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.

[0178] Certain organic solvents such as dimethylsulfoxide (DMSO) also can be employed. Additionally, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various types of 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.

[0179] The pharmaceutical compositions also can comprise suitable solid or gel phase carriers or excipients. Examples of such 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.

[0180] Pharmaceutical 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. [0181] For any compound used in the method of the present invention, a therapeutically effective dose can be estimated initially from cell culture assays or animal models.

[0182] Moreover, 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 LD₅O, (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 LD₅₀ and ED₅₀. 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 ED₅₀ 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. However, as a general guide, 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. It will be understood, however, that 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.

[0184] 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.

[0185] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.

Combination Therapy

[0186] As noted above, 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. (1999) 84:1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21 : 87-92; Bardin, C. W.,(ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6^th Edition (Mosby - Year Book, Inc., St. Louis, MO 1997); Chiasson, J. et al, Ann. Intern. Med. (1994) 121 :928-935; Coniff, R. et al, Clin. Ther. (1997) 19:16-26; Coniff, R. et al, Am. J. Med. (1995) 98:443-451; and Iwamoto, Y. et al, Diabet. Med. (1996) 13:365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82(12A):3U-17U). These studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to the therapeutic regimen. 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. For example, 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. Where separate dosage formulations are used, 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.

[0187] An example of combination therapy that modulates (prevents the onset of the symptoms or complications associated) atherosclerosis, wherein 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), an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthetase 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 β-sitosterol; a bile acid sequestrant anion exchange resin, such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (low density lipoprotein) receptor inducer; vitamin Be (also known as pyridoxine) and the pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); vitamin B₃ (also known as nicotinic acid and niacinamide, supra); antioxidant vitamins, such as vitamin C and E and beta carotene; a beta-blocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; and a platelet aggregation inhibitor, such as fibrinogen receptor antagonists (i.e., glycoprotein Ilb/IIIa fibrinogen receptor antagonists) and aspirin. As noted above, 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 β blocker.

[0188] 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, β₃ adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other 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 D₂ receptors, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

[0189] 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- SO₄); antiglucocorticoids; TNFα inhibitors; α-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 nateglinide), insulin, as well as the active agents discussed above for treating atherosclerosis.

[0190] 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.

[0191] Additionally, an effective amount of a compound of Formula I and a therapeutically effective amount of one or more active agents selected from the group consisting of: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent, such as a cholesterol biosynthesis inhibitor, for example, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as squalene synthase inhibitor); an acyl-coenzyme A cholesterol acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof; niacinamide; a cholesterol absorption inhibitor; a bile acid sequestrant anion exchange resin; a low density lipoprotein receptor inducer; vitamin B₆ and the pharmaceutically acceptable salts thereof; vitamin B₁₂; an anti-oxidant vitamin; a β - blocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; a platelet aggregation inhibitor; a fibrinogen receptor antagonist; aspirin; phentiramines, β₃ adrenergic receptor agonists; sulfonylureas, biguanides, α-glucosidase inhibitors, other insulin secretogogues, and insulin can be used together for the preparation of a pharmaceutical composition useful for the above-described treatments.

Kits [0192] In addition, the present invention provides for kits with unit doses of the compounds of Formula I, either in oral or injectable doses. In addition to 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. [0193] For the compositions, methods and kits provided above, one of skill in the art will understand that preferred compounds for use in each are those compounds that are preferred above and particularly those compounds provided in the Examples below.

EXAMPLES

[0194] General Methods. All operations involving moisture and/or oxygen sensitive materials were conducted under an atmosphere of dry nitrogen in pre-dried glassware. Unless noted otherwise, materials were obtained from commercially available sources and used without further purification. [0195] Flash chromatography was performed on E. Merck silica gel 60 (240-400 mesh) according to the protocol of Still, Kahn, and Mitra (J. Org. Chem. 1978, 43, 2923). Thin layer chromatography was performed using precoated plates purchased from E. Merck (silica gel 60 PF₂₅₄, 0.25 mm) and spots were visualized with long- wave ultraviolet light followed by an appropriate staining reagent. [0196] Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Inova-400 resonance spectrometer. ¹H NMR chemical shifts are given in parts per million (δ) downfield from tetramethylsilane (TMS) using TMS or the residual solvent signal (CHCI₃ = δ 7.24, DMSO = δ 2.50) as internal standard. ¹H 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.

[0197] Combustion analyses were performed by Robertson Microlit Laboratories, Inc. (Madison, NJ, USA) and optical rotations were measured on Perkin-Elmer 241 MC polarimeter and reported as: [α]^τλ (c = (g/100 mL), solvent). Melting points were measured on a Fisher- Johns 12-144 apparatus and uncorrected. Preparation 1. Bromo-(2-chloro-5-trifluoromethyl-phenyl)-acetic acid ethyl ester 49.

[0198] 2-Chloro-5-trifluoromethyl benzoic acid 46 (0.1 mol) was dissolved in dichloromethane (100 rnL). To which was then added thionyl chloride (0.2 mol) and dimethylformamide (0.1 mL). After 1 hour the solvents were removed under vacuum. The residue was dissolved in ethyl acetate and ethereal diazomethane (0.2 mol) was added. After 1 hour the solvents were removed under reduced pressure to afford the diazo ketone 47. This compound (0.05 mol) was dissolved in ethanol (100 mL). The solution was brought to reflux and a solution of silver benzoate (0.02 mol) in triethylamine (5 mL) was added. After 10 minutes the solution was cooled, filtered and the filtrate was concentrated to afford a residue. The residue was chromatographed to obtain (2-chloro-5- trifluoromethyl-phenyl)-acetic acid. The above compound (0.02 mol) was dissolved in methanol (20 mL) and a solution of lithium hydroxide monohydrate (0.02 mol) in water (20 mL) was added. The progress of the reaction was monitored by TLC. When it was complete, the mixture was acidified with dilute hydrochloric acid, and extracted with ether. The extract was dried and concentrated to afford (2-chloro-5-trifluoromethyl-phenyl)-acetic acid 48. [0199] Using the above procedure, different benzoic acids can be converted into the corresponding phenylacetic acids.

[0200] The acid 48 (0.01 mol) was dissolved in 1 ,2-dichloroethane (50 mL). Thionyl chloride (0.011 mol) was added, and the mixture was heated at 55⁰C for 1 hour. Bromine (0.01 mol) was added. After another 18 hours, the mixture was cooled to O⁰C and ethanol (50 mL) was added. After 2 hours the mixture was added to water and extracted with ether. The extract was dried and concentrated to afford the title compound, 49. [0201] Using the above procedure, different phenylacetic acids can be transformed into the corresponding bromo esters analogous to 49.

Preparation 2. 2-Bromo-2-(3-trifluoromethyl-phenyl)-propionic acid ethyl ester, 52.

50 51 52

[0202] 3-Trifluoromethylbromobenzene 50 (0.2 mol) was dissolved in dry tetrahydrofuran

(10OmL). A small amount of magnesium metal was added and the mixture was warmed until reaction commenced. Additional magnesium (0.2 mol) was added. The mixture was maintained at reflux until the magnesium was consumed. A solution of anhydrous zinc chloride (0.2 mol) in tetrahydrofuran (50 mL) was added. The mixture was maintained at 55⁰C for 2 hours, and then ethyl 2-bromopropionate (0.2 mol) was added. The mixture was maintained at 55⁰C and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and added to water and ether. The organic layer was dried and concentrated, and the residue was chromato graphed to afford 2-(3- trifluoromethyl-phenyl)-propionic acid ethyl ester 51.

[0203] Using the above procedure, but employing differently substituted bromo trifluoromethyl benzenes in place of 50, and different bromoesters in place of ethyl 2- bromopropionate, the corresponding compounds analogous to 51 were obtained.

[0204] The ester 51 (0.05 mol) was dissolved in carbon tetrachloride (75 mL) and N- bromosuccinimide (0.05 mol) was added. The mixture was heated at reflux and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and filtered. The solution was concentrated to afford the title compound 52. [0205] Using the above procedure, but employing different esters in place of 51, prepared as described above, different bromo esters analogous to 52 were obtained.

Preparation 3. Bromo-(4-trifluoromethyl-phenyl)-acetic acid methyl ester, 56.

[0206] 4-Trifluoromethylbenzaldehyde 53 (0.1 mol) was dissolved in dichloromethane (150 mL) and a catalytic amount of potassium cyanide and 18-Crown-6 were added. The mixture was cooled in ice and trimethylsilyl cyanide (0.1 mol) was added. After 16 hours at 25⁰C the solution was washed with aqueous sodium bicarbonate, dried and concentrated, to afford the silyl cyanohydrin 54. This material was dissolved in methanol (100 mL) and hydrogen chloride was bubbled into the solution for several minutes at O⁰C. After 16 hours at 25⁰C, the mixture was neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried and concentrated, and the residue was chromato graphed to afford hydroxy-(4-trifluoromethyl-phenyl)-acetic acid methyl ester, 55.

[0207] Using the above procedures, differently substituted trifluoromethyl benzaldehydes were converted into the corresponding hydroxy esters.

[0208] The ester 55 (0.05 mol) and triphenylphosphine (0.05 mol) were dissolved in dichloromethane (250 mL) at O⁰C and carbon tetrabromide (0.05 mol) was added. After 16 hours at 25⁰C, the solvent was removed and 2:3 hexane:ethyl acetate (300 mL) were added. A precipitate was removed by filtration and the solvent was removed under vacuum. The residue was chromatographed to afford the title compound 56.

[0209] Using the above procedure, different hydroxyesters, prepared as described in B above, can be converted into the corresponding bromoesters. Preparation 4. 2,4-Bis-trifluoromethyl-benzenethiol, 60.

[0210] 2,4-Di(trifluoromethyl)phenol 57 (0.1 mol) was dissolved in pyridine (50 niL) and dimethylaminothiocarbamoyl chloride (0.1 mol) was added. The mixture was heated at 60° for 12 hours, then was cooled and added to water. The aqueous solution was extracted with ether, and the extract was washed with dilute hydrochloric acid, then dried and concentrated to afford dimethyl-thiocarbamic acid O-(2,4-bis-trifluoromethyl-phenyl) ester 58. This compound was dissolved in N-methyl pyrrolidinone (50 mL) and the solution was heated at reflux. The progress of the reaction was monitored by TLC. When it was complete, the cooled solution was added to water and extracted with ether. The extract was dried and concentrated and the residue was chromatographed to afford dimethyl-thiocarbamic acid S- (2,4-bis-trifluoromethyl-phenyl) ester 59. This compound (0.05 mol) was dissolved in methanol, and IN aqueous sodium hydroxide (0.05 mol) was added. The progress of the reaction was monitored by TLC. When it was complete, the solution was added to dilute hydrochloric acid and extracted with ether. The extract was dried and concentrated to afford the title compound 60.

[0211] Using the above procedures, but employing different trifluoromethyl substituted phenols, the corresponding thiophenols were obtained.

Preparation 5. Mercapto-(4-trifluoromethyl-phenyl)-acetic acid methyl ester 63.

[0212] Bromo-(4-trifluoromethyl-phenyl)-acetic acid methyl ester 61 (0.05 mol) was dissolved in tetrahydrofuran (25 mL ) and a solution of sodium thiolacetate (0.05 mol) in water (5 mL) was added. The progress of the reaction was monitored by TLC. When it was complete, the solution was added to dilute hydrochloric acid and extracted with ether. The extract was dried and concentrated to provide compound 62. The residue 62 was dissolved in methanol and 5% aqueous ammonia (10 mL) was added. After 2 hours, the mixture was acidified with dilute hydrochloric acid and extracted with ether. The organic phase was dried and concentrated and the residue was chromatographed to afford the title compound 63.

[0213] Using the above procedure, but employing different bromoesters, the corresponding mercapto esters can be obtained.

Preparation 6. 2,5-Bis-trifluoromethyl-benzaldehyde, 66.

[0214] 2,5-Di(trifluoromethyl)aniline 64 (0.1 mol) was dissolved in concentrated hydrochloric acid (20 mL) and water (150 mL). The solution was cooled to O⁰C and a solution of sodium nitrite (0.1 mol) in water (50 mL) was added with vigorous stirring. After 10 minutes, the above solution was added to a solution of nickel cyanide (0.1 mol) in water (100 rnL) at O⁰C. After 2 hours, the mixture was heated to 6O⁰C for 30 minutes, then cooled and extracted with ethyl acetate. The extract was dried and concentrated, and the residue was chromatographed to afford 2,5-bis-trifluoromethylbenzonitrile 65. This compound (0.05 mol) was dissolved in toluene (50 mL). The solution was cooled to -8O⁰C and a 1.5M solution of diisobutylaluminum hydride (0.05 mol) in toluene was added. After 2 hours, the mixture was warmed to 5O⁰C for 1 hour. Water was added, and the organic phase was dried and concentrated. The residue was chromatographed to afford the title compound 66.

[0215] Using the above procedures, different trifluoromethyl-substituted anilines can be converted into the corresponding benzaldehydes.

Preparation 7. 2-Trifluoromethyl-4-nitrophenol 69 and 2-trifluoromethyl-4-trifluoromethyl acetamino-phenol 71.

[0216] l-Fluoro-4-nitro-2-trifluoromethylbenzene 67 (0.1 mol), was dissolved in tetrahydrofuran (100 mL). The solution was cooled to O⁰C and sodium methoxide (0.1 mol) was added. The reaction was warmed to room temperature over 2 hours. Water and ethyl acetate were added. The organic phase was dried and concentrated to afford l-methoxy-4- nitro-2-trifluoromethylbenzene 68. This material was dissolved in methylene chloride (100 niL) and the solution was cooled to -78⁰C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography then afforded the title compound 69.

[0217] l-Methoxy-4-nitro-2-trifluoromethylbenzene 68 (0.1 mol) and SnCl₂ (1 mol) was mixed in EtOAc. The mixture was stirred at rt for 2 hrs and then refluxed for 3 hrs until TLC indicated the completion of the reaction. The reaction mixture was cooled and quenched with aqueous NaHCO₃. The solid was filtered through a celite pad and washed with EtOAc. The organic layer of the filtrate was collected, dried and concentrated to afford the corresponding aniline. To the aniline (0.05 mol) in methylene chloride (20OmL) was added Et₃N and (CF₃CO)₂O at 0⁰C. The reaction was allowed to warm to 25°C with stirring. The reaction was then worked up between EtOAc and water. The organic layer was dried and concentrated. The residue was purified on silica gel column to afford 70. This material is dissolved in methylene chloride (100 mL) and the solution was cooled to - 78⁰C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography afforded the title compound 71.

[0218] Using the above procedures, but employing differently substituted fluorobenzenes, the correspondingly substituted phenols were obtained.

Preparation 8. (2-Acetamidoethyl)-4-trifluoromethylphenylbromoacetate 73.

73

[0219] 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 55-60⁰C. Gas evolution was observed and the solids dissolved as the internal temperature rose to 55-60⁰C. The mixture was then stirred at 55-60⁰C for 45 min. Bromine (33.0 mL, 0.33 mole) was charged and the mixture was maintained at 55- 60⁰C for 18 h. The internal temperature was then raised to 80-85⁰C over 1.5 h and heating continued for 18h. The mixture was cooled to 20-25⁰C and anhydrous dichloromethane (250 mL) was added. In a separate flask was placed 2-acetylethanolamine (1.03 mole) and anhydrous dichloromethane (250 mL) under argon and the mixture cooled to 2-8°C. To this was added the acyl halide solution at such a rate as to keep the internal temperature below 21⁰C. After the addition was complete, 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. Sodium thiosulfate (0.06 mole) was added in portions and gas evolution was observed. The layers were then partitioned in a separatory funnel (100 mL dichloromethane used in transfer), and the organic phase was extracted with 125 mL of water, dried over magnesium sulfate (10 g), and filtered. The filter cake was washed with dichloromethane (150 mL). Rotary evaporation and pumping at high vacuum afforded an oil, which was slurried in 100 mL hexane: ethyl acetate (70:30). Additional hexane (150 mL) was added until a white color formed in the top layer of the biphasic mixture. Vigorous agitation afforded a solid, which was filtered away from the supernatant to yield (2-acetamidoethyl)-4-trifluoromethylphenylbromoacetate. [0220] Using the above procedure, but employing differently substituted phenylacetic acids, the corresponding α-bromo-phenylacetates were obtained.

Preparation 9. 5-Trifluoromethyl-2-(3-trifluoromethyl-phenoxy)-phenylamine 77.

[0221] Phenol 75 (0.5 mol) was stirred at 25°C with K₂CO₃ in DMF for 2 hrs. The mixture was then cooled to 0⁰C, 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.

[0222] A mixture of compound 76 (10Og) and and SnCl₂ H₂O (32Ig) in EtOAc (1000 mL) was stirred at room temperature overnight. The reaction mixture was basified by adding aqueous KOH solution. The organic layer was washed with brine, dried and concentrated to give compound 77 as a pale yellow oil, which was used for next reaction without purification. ¹HNMR (CDCl₃, 400 MHz) δ 7.49-6.90 (m,7H), 4.06 (s, 2H).

[0223] Using the above procedure, but employing differently substituted nitrofluorobenzene and phenols, the corresponding anilines were obtained.

Preparation 10. α-Bromo-(3-trifluoromethyl-phenyl)-acetic acid ethyl ester, 79.

78

[0224] To a solution of (α,α,α-trifluoro-m-tolyl)acetic acid 78 (202.36 g, 0.99 mol) in absolute ethanol (1.0 L) at 0 ⁰C was added thionyl chloride (79 mL, 1.05 mol), and then the resulting solution was refluxed for 3 h. Concentration in vacuo gave a residue which was partitioned between EtOAc and water. The organic layer was washed with sat. NaHCO₃ and brine, dried over Na₂SO₄ and concentrated in vacuo to afford 220.1 g of ethyl ester as a pale yellow liquid.

[0225] To a mixture of crude ethyl ester (119.15 g, 0.51 mol) and NBS (100.48 g, 0.56 mol) in CCl₄ (1.0 L) was added benzoyl peroxide (1.0 g). The resulting mixture was heated at 75 ⁰C for 20 min. and then refluxed at 90 ⁰C overnight (14 h) until the brown mixture was turned to a pale-color with white precipitate. The mixture was cooled to 0 ⁰C, filtered through a pad of celite, concentrated in vacuo to afford 151.27 g (95%) of bromide 79 as a pale brown liquid. This product was sufficiently pure to be used directly in subsequent substitute reaction. This product was also prepared by refluxing (α,α,α-trifluoro-m- tolyl)acetic acid 78 with bromine in the presence of SOCl₂, and then quenching with EtOH. ¹H NMR (400 MHz, CDCl₃): δ 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.

[0226] Using the above procedure, but employing differently substituted phenylacetic acids, corresponding α-bromo-phenylacetates are obtained.

Example 1

Preparation of (4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 39

[0227] 4-Trifluoromethylphenol (add synthesis of the intermediates?) (43.8g, 0.27 mol), bromo-(3-trifluoromethyl-phenyl)-acetic acid ethyl ester 79 (7Og, 0.225 mol) and potassium carbonate (56g, 0.405 mol) were stirred in dimethylformamide (200 mL) for 16 hours. Ethyl acetate and brine were added and the organic phase was dried and concentrated. The residue was chromatographed to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl- phenyl)-acetic acid ethyl ester, 80, as an oil. This material was dissolved in tetrahydrofuran/methanol (400mL/300mL) and IN lithium hydroxide (300 mL) was added. After 1 hour, IN hydrochloric acid (300 mL) was added. The mixture was extracted with ethyl acetate. The extract was dried and concentrated, to afford the title compound 39 as a white solid. ¹H NMR (d₆-DMSO) δ 7.88-7.85 (m, 2H), 7.62-7.55 (m, 4H), 7.09 (d, 2H), 5.52 (s, IH). Example 2

Preparation of (3-fluoro-5-trifluoromethyl-phenyl)-(5-methoxy-2-trifluoromethyl-phenoxy)- acetic acid, 94

91 92 93 94

[0228] (S-Fluoro-S-trifluoromethyl-pheny^-hydroxy-acetic acid methyl ester 91 (0.1 mol) was dissolved in dimethylformamide (100 mL) and sodium hydride (0.1 mol) was added. When hydrogen evolution stopped, a solution of 2-fluoro-4-chloro-l-trifluoromethyl- benzene 92 (0.1 mol) in dimethylformamide (25 mL) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ethyl acetate were added. The organic phase was dried and concentrated, and the residue was chromato graphed to afford (3-fluoro-5-trifluoromethyl-phenyl)-(5-chloro-2-trifluoromethyl- phenoxy)-acetic acid methyl ester 93. Basic hydrolysis of this compound, as described in Example 1, then afforded the title compound 94. [0229] Using the above procedures, but employing different hydroxy esters and fluorobenzenes, the corresponding compounds analogous to 94 can be obtained.

Example 3

Preparation of (2,4-bis-trifluoromethyl-phenoxy)-( 3-trifluoromethyl-phenyl)

-acetic acid ethyl ester 97

[0230] To a solution of 95 (25.0 g, 0.10 mol) in anhy. THF (150 niL) was added NaOCH₃ (7.0 g, 0.13 mol) at 0⁰C. The mixture was then heated at 50⁰C for 6 h. After cooling to 25°C, the reaction mixture was quenched with sat. NH₄Cl, diluted with EtOAc, washed with brine, and concentrated in vacuo to afford crude methyl ether 96 (17.93 g, 73%) as a colorless liquid. This product was sufficiently pure to be used directly in subsequent reaction. ¹H NMR (400 MHz, CDCl₃): δ 7.83 (IH, s), 7.77 (IH, d, J = 8.4 Hz), 7.09 (IH, d, J = 8.4 Hz), 3.97 (3H, s) ppm. A solution of methyl ether 96 (9.98 g, 0.04 mol) in anhyrous CH₂Cl₂ (150 mL) was cooled to -78°C and treated with BBr₃ (6.0 mL, 0.063 mol). The resultant brown mixture was stirred for 1 h at -78°C, and then warmed up to 25°C over 4 h, and then quenched with water. The organic layer was separated and washed with sat. NaHCO₃ and brine, dried over Na₂SO₄, concentrated to ~13 mL in vacuo below 0⁰C and used directly in the following substitution reaction. Take this solution (ca. 1.15 mL) and diluted with DMF (8 mL), and then treated with K₂CO₃ (1.27 g) and bromide 79 (1.72 g). The resultant mixture was stirred at room temperature for 1 h, diluted with EtOAc, washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography (5:95 EtOAc / hexanes) on silica gel and then recrystallized with 10 % EtOAc / hexanes to give pure ester 97 as a white solid. ¹H NMR (400 MHz, DMSO-^): δ 8.60 (IH, d, J= 2.2 Hz), 8.17 (IH, dd, J= 8.6, 2.2 Hz), 7.96 (IH, s), 7.91 (IH, d, J= 8.6 Hz), 7.84 (IH, d, J= 8.2 Hz), 7.74 (IH, t, J= 7.8 Hz), 7.38 (IH, d, J = 9.0 Hz), 6.40 (IH, s), 4.19 (2H, m), 1.11 (3H, t, J= 7.2 Hz) ppm.

Example 4

Preparation of (3 -trifluoromethyl-phenyl)- (5 -trifluoromethyl-pyridin-2-yloxy)- acetic acid, 100

79 98 99 100

[0231] To a solution of 5-(trifiuoromethyl)-2-pyridinol 98 (2.11 g, 12.9 mmol) in DMF (20 mL) was added K₂CO₃ (2.68 g, 19.4 mmol) followed by bromide 79 (4.68 g, 15.0 mol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc, and washed with water. The organic layer was washed with sat. NaHCO₃ and brine, dried over Na₂SO₄, concentrated in vacuo, and purified by flash chromatography on silica gel (5:95 EtOAc / hexanes) to afford ester 99 (0.61 g, 12%) as a pale-yellow liquid. To a solution of ester 99 (0.61 g, 1.55 mmol) in THF / H₂O (10 mL/3 mL) at room temperature was added 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. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to afford acid 100 (0.53 g, 94%) as a brown liquid. ¹H NMR (400 MHz, DMSO-^): δ 8.55 (IH, s), 8.08 (IH, dd, J= 8.8, 2.6 Hz), 7.89 (IH, s), 7.86 (IH, d, J= 8.0 Hz), 7.71 (IH, d, J= 8.0 Hz), 7.61 (IH, d, J= 7.6 Hz), 7.14 (IH, d, J = 8.0 Hz), 6.19 (1H, s) ppm.

[0232] Using the above procedures, but employing different bromo-phenylacetic esters and pyridinols, compounds analogous to 100 can be obtained.

Example 5

Preparation of 2-(4-trifluoromethyl-phenyl)-3 -(3 -trifluoromethyl -phenyl)- propenoic acid, 104 and 2-(4-trifluoromethyl-phenyl)-3-(3-trifluoromethyl-phenyl)-propionic acid 105

[0233] 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), (α,α,α-trifluoro-p-tolyl)acetic acid (2.97 g, 14.5 mmol), and α,α,α-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 106⁰C for 18.5 hours. The heat was removed and the reaction conversion checked by TLC. Deionized water (16 mL) was added to the reaction flask at a rate such that the solution temperature was maintained at 70-80⁰C. An additional 20 mL of deionized water was added after the solution had cooled to ambient temperature and this caused crystals to start to precipitate. Finally, an additional 20 mL deionized water was added and the solution was allowed to stir overnight at room temperature. The solution was vacuum filtered at room temperature and the crystals were washed twice with 20 mL deionized water. The crystals were dried under high vacuum to afford a beige powder of cώ-3-(3-trifluoromethylphenyl)- 2-(4-trifluoromethylphenyl)-propenoic acid (3.542 g, 9.8 mmol) 104.

[0234] A one neck, 100 mL round bottom flask equipped with addition funnel (filled with 3A molecular sieves), water condenser, oil bath, and nitrogen line was charged with Z-3-(3- trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-acrylic acid (1.2 g, 3.33 mmol), N- acetylethanolamine (7 mL), dry dimethoxyethane (36 mL), and concentrated sulfuric acid (0.05 mL). The reaction mixture was heated to reflux for 16.5 hours. After the solution was cooled to room temperature, it was partitioned between 100 mL ethyl acetate and 100 mL water. 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 fractions containing product were combined and washed with water (2x100 mL) saturated sodium bicarbonate solution (100 mL), dried over magnesium sulfate, and concentrated by rotovap to yield 2-acetamidoethanol-Z-3-(3- trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-acrylate 104 (855 mg, 1.9 mmol).

[0235] The trans adduct was synthesized by isomerizing the cώ-carboxylic acid with a sun lamp.

[0236] A three neck, one liter round bottom flask equipped with condenser, thermometer, nitrogen line and magnetic stirrer was charged with Z-3-(3-trifluoromethylphenyl)-2-(4- trifluoromethylphenyl)-acrylic acid (103, 2.28 g, 6.3 mmol), ethanol (104 mL), palladium black (101.1 mg) and ammonium formate (1.608 g, 25.5 mmol). The reaction mixture was heated to 80⁰C for 4 hours. An aliquot was taken and TLC (solvent system was 20% ethyl acetate in hexanes with an acetic acid spike) showed absence of starting material. The solution was cooled to room temperature and vacuum filtered using a glass frit funnel. The solution was concentrated by rotary evaporation and high vaccum, yielding 3-(3- trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (2.83 g) 105.

[0237] 3-(3-Trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (105, 2.43 g, crude) was dissolved in anhydrous THF (6 mL) at ambient temperature. CDI (1.64 g, 10.1 mmol) was charged as a solid, followed by EtOAc (4 mL), to rinse the vial. The internal temperature remained between 20-21⁰C during the addition. N-acetylethanolamine (3.6mL, 39 mmol) was added, whereupon the temperature rose to 24.5°C. The mixture was stirred overnight (16 h) at 23-24°C and then rotary evaporated to a gummy residue. This was chromatographed on silica gel using EtOAc: hexane (70:30 v/v) (Rf = 0.35-0.40) to afford 2-acetamidoethyl-3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)propionate 105A (1.85 g).

[0238] Using the above procedures, but employing different phenylacetic esters and benzaldehydes, compounds analogous to 104, 105 and 105A can be obtained.

Example 6

Preparation of (3 -Methylsulfanyl-5 -trifluoromethyl-phenyl)-(4-nitro- 2-trifluoromethyl-phenylsulfanyl)-acetic acid, 109

106 107 108 109

[0239] Using the procedures of Example 1, bromo-(3 -methylsulfanyl-5 -trifluoromethyl- phenyl)-acetic acid methyl ester 106 and 4-nitro-2-trifluoromethyl-benzenethiol 107, prepared as described in Preparation 7 were combined to form (3-methylsulfanyl-5- trifluoromethyl-phenyl)-(4-nitro-2-trifluoromethyl-phenylsulfanyl)-acetic acid methyl ester, 108, which was then hydrolyzed under basic conditions to afford the title compound 109.

[0240] Using the above procedure, different bromoesters and thiols can be reacted together to afford the corresponding compounds 1 in which X is S.

Example 7

Preparation of (3 -trifluoromethyl-phenyl)-(2-trifluoromethyl-phenylamino)- acetic acid, 112

THF/H₂O

117 118

[0241] (3-Trifluoromethyl-phenyl)-(2-trifluoromethyl-phenylamino)-acetic acid: A neat mixture of o-trifluoromethylaniline (1.63 g, 10.1 mmol), bromide 79 (1.1 Ig, 3.57 mmol) and diisopropylethyl amine (1.56 g, 12.1 mmol) was stirred in a capped flask at 105°C for 6 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was washed with brine, dried over Na₂SO₄, concentrated in vacuo, and purified by flash chromatography on silica gel (5 : 95 EtOAc / hexanes) to afford pure ester 111 (0.19 g, 14%) as a colorless liquid. ¹H NMR (400 MHz, DMSO-^): δ 7.86 (IH, s), 7.76 (IH, d), 7.69 (IH, d), 7.63 (IH, t), 7.49 (IH, dd), 7.33 (IH, t), 6.77(1H, t). 6.66 (IH, d), 5.88 (IH, d), 5.73 (IH, d), 4.18 (2H, m), 1.11 (3H, t) ppm. To a solution of ester 111 (0.19 g, 0.49 mmol) in THFZH₂O (4 mL/1.5 mL) at room temperature was added lithium hydroxide monohydrate (0.10 g, 2.38 mmol). The resulting solution was stirred at room temperature for 1 h, quenched with IN aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to afford acid 112 (0.13 g, 99%) as an off-white solid. ¹H NMR (400 MHz, DMSO-^): δ 13.84 (IH, br, COOH), 7.84 (1Η, s), 7.75 (1Η, d), 7.68 (1Η, d, J= 8.0 Hz), 7.62 (IH, t), 7.48 (IH, dd,), 7.30 (IH, t), 6.74(1H, t). 6.59 (IH, d), 5.96 (IH, d), 5.56 (IH, d) ppm. [0242] (3-Trifluoromethyl-phenyl)-(3-trifluoromethyl-phenylamino)-acetic acid 117: To a solution of 3-trifluoromethylaniline (1.62 g, 0.010 mol) in DMF (30 mL) was added K₂CO₃ (2.10 g, 0.015 mol) followed by bromide 79 (3.41 g, 0.011 mol). The resulting mixture was stirred at 55°C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was washed with water and brine, dried over Na₂SO₄, concentrated in vacuo, and purified by flash chromatography on silica gel (5:95 EtOAc/hexanes) to afford the ester (0.87 g, 22%) as a yellow liquid. ¹H NMR (400 MHz, DMSO-^): δ 8.21 (IH, s), 8.14 (IH, d), 8.05 (IH, d), 7.84 (IH, t), 7.65 (IH, t), 7.58 (IH, d), 7.28 (IH, S), 7.27 (Ih, d), 4.16 (2H, m), 0.91 (3H, t) ppm. To a solution of the above ester (0.82 g, 2.10 mmol) in THFZH₂O (15 mL/5 mL) at room temperature was added lithium hydroxide monohydrate (0.53 g, 12.6 mmol). The resulting solution was stirred at room temperature for 2 h, quenched with IN aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to afford acid 117 (0.69 g, 90%) as a solid. ¹H NMR (400 MHz, DMSO-^): δ 8.21 (IH, s), 8.14 (IH, d), 8.05 (IH, d), 7.84 (IH, t), 7.65 (IH, t), 7.58 (IH, d), 7.28 (IH, S), 7.27 (Ih, d). [0243] Using the above procedures, but substituting the appropriate anilines and bromoesters for 79 and 110, the following compounds were obtained: (3-Trifluoromethyl- phenyl)-[5-trifluoromethyl-2-(3-trifluoromethyl-phenoxy)-phenylamino]-acetic acid 113 ¹HNMR (CDCl₃, 400 MHz) δ 7.46 (s,lH), 7.38-7.28 (m, 4H), 7.11 (m, 2H), 6.97 (s, IH), 6.85 (d, IH), 6.66 (d, IH), 6.52 (s, IH); (3,5-Bis-trifluoromethyl-phenylamino)-(3- trifluoromethyl-phenyl)-acetic acid 114, ¹HNMR (CDCl₃, 400 MHz) δ 7.78 (s,lH), 7.71 (d,lH), 7.64 (d,lH), 7.56-7.53 (m,lH), 7.20 (s,lH), 6.89 (s,lH), 5.22 (s, IH); (3- Trifluoromethyl-phenyl)-(4-trifluoromethyl-phenylamino)-acetic acid 115, ¹H NMR (400 MHz, DMSCM_J): δ 7.87 (IH, s), 7.79 (IH, d), 7.66 (IH, d), 7.60 (IH, t), 7.34 (2H, d), 7.10 (IH, d), 6.78(2H, d). 5.39 (IH, d) ppm; (4-Isopropyl-2-trifluoromethyl-phenylamino)-(3- trifluoromethyl-phenyl)-acetic acid 116, ¹H NMR (400 MHz, OMSO-d₆): δ 8.17 (IH, d), 8.15 (IH, s), 8.04 (IH, d), 7.79 (IH, t), 7.17 (IH, d), 7.14 (IH, s), 6.77 (IH, d), 2.77 (IH, m), 1.13 (6H, d) ppm; (4-Trifluoromethyl-phenyl)-(2-trifluoromethyl-phenylamino)-acetic acid 118, ¹H-NMR (DMSO, 400MHz): δ 7.80 - 6.50 (m, 8H), 5.98 (d, IH), 5.52 (d, IH).

Example 8

Preparation of 2-(4-trifluoromethyl-phenoxy)-2-(3 -trifluoromethyl-phenyl)- propionic acid

[0244] To a solution of ester 80 (3.01 g, 7.69 mmol) in anhyrous THF (30 mL) was added NaH (60% in oil, 0.80 g, 0.020 mol). After the resulting solution was stirred at rt for 2 h, iodomethane (2.5 niL, 0.040 mol) was added. The resulting mixture was stirred at rt overnight. The reaction was quenched with sat. NH₄Cl, diluted with EtOAc, washed with diluted aqueous HCl and brine, dried over Na₂SO₄, concentrated in vacuo, and purified by flash chromatography on silica gel (5 : 95 EtOAc / hexanes) to afford ester 119 (3.18 g, 87%) as a colorless liquid. ¹H NMR (400 MHz, DMSO-^): δ 7.91 (IH, s), 7.88 (IH, d), 7.7 (IH, d), 7.69 (IH, d), 7.65 (2H, d), 7.02 (IH, d), 4.16 (2H, q), 2.48 (3H, s), 1.03 (3H, t) ppm. To a solution of ester 119 (1.03 g, 2.17 mmol) in THF / H₂O (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 Na₂SO₄ and concentrated in vacuo to afford acid 120 (0.93 g, 96%) as a pale-yellow liquid.

[0245] Using the above procedures, but substituting the appropriate α-phenoxy phenyl acetic esters for 80, there were obtained the following compounds: 2-(4-Trifluoromethyl- phenoxy)-2-(4-trifluoromethyl-phenyl)-propionic acid, 121; 2-(2-Trifluoromethyl- phenoxy)-2-(3-trifiuoromethyl-phenyl)-propionic acid, 122, ¹HNMR (d-DMSO, 400 MHz) δ 13.85 (s, IH), 8.04 (s, IH), 7.86 (d,lH), 7.74 (d,lH), 7.70-7.66 (m,3H), 7.56 (m,lH), 7.15 (m,lH), 6.89 (d, IH), 1.89 (s, 3H).

Example 9

Preparation of (4-trifluoromethyl-phenoxy)-(3 -trifluoromethyl-phenyl)- acetaldehvde, 124

[0246] (4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 39 (0.05 mol) was dissolved in dichloromethane (50 mL) and thionyl chloride (5 mL) and dimethylformamide (0.1 niL) were added. After 2 hours, the solvents were removed under vacuum to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetyl chloride, 123. This compound (0.01 mol) was dissolved in ether (25 mL) and the solution was cooled to -80⁰C and lithium aluminum tri-tertiarybutoxy hydride (0.01 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was warmed to room temperature and water was added. The organic phase was dried and concentrated and the residue was chromatographed to afford the title compound 124.

Example 10

Preparation of 2-(4-trifluoromethyl-phenoxy)-2-(3-trifluoromethyl-phenyl)-ethanol, 125

124 125

[0247] (4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetaldehyde, 124 (0.02 mol) was dissolved in isopropanol (20 mL) and sodium borohydride (0.02 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was dried and concentrated, and the residue was chromatographed to afford the title compound 125. ¹H-NMR (DMSO, 400MHz): δ 7.75 - 7.24 (m, 8H), 5.59 (μs, IH), 5.22 (m, IH), 3.70 (m, 2H).

126 127 [0248] To a solution of ester 126 (1.04 g, 2.65 mol, prepared as described for 80) in anhyrous THF (15 mL) at 0⁰C was added LiAlH₄ (0.10 g, 2.64 mmol). After stirring at 0⁰C for 0.5 h, the reaction mixture was quenched with 15% aqueous NaOH (0.15 mL), filtered through a pad of celite, rinsed with EtOAc, concentrated in vacuo, and the residue was chromato graphed on silica gel (2:8 EtOAc / hexanes) to afford 127 (0.71 g, 81%) as a colorless liquid. ¹H NMR (400 MHz, DMSO-^): δ 7.79 (IH, s), 7.71 (IH, d), 7.65 (IH, d), 7.587.62 (2H, m), 7.50 (IH, t), 7.22 (IH, d), 7.03 (IH, t), 5.71 (IH, t), 5.14 (IH, t), 3.80- 7.85 (IH, m), 3.77-3.72 (IH, m) ppm.

[0249] Using the above procedures, but employing different aldehydes and esters in place of 124 and 126, carbinols 128-134 were obtained.

Example 11

Preparation of propionic acid 2-(4-trifluoromethyl-phenoxy)-2- (3-trifluoromethyl-phenvO-ethvl ester, 135

[0250] 2-(4-Trifluoromethyl-phenoxy)-2-(3-trifluoromethyl-phenyl)-ethanol, 125, (0.01 mol) was dissolved in pyridine (20 rnL) and the solution was cooled to 0⁰C. Propionyl chloride (0.015 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was washed with dilute hydrochloric acid, dried and concentrated. The residue was chromatographed to afford the title compound 135.

[0251] Using the above procedure, but employing different carbinols and/or different acyl chlorides, the corresponding esters analogous to 111 can be obtained.

Example 12

Preparation of (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 2- acetvlamino-ethvl ester, 136

39 136 [0252] To a slurry of acid 39 (25.8 g, 0.071 mol) in anhydrous 1 ,2-dichloroethane (380 rnL) was added thionyl chloride (16.0 rnL, 0.21 mol), and then the resulting mixture was refluxed for 2 h. The mixture was cooled to rt, diluted with dry THF (150 mL) until the cloudy mixture turned clear, and then N-acetylethanolamine (39.12 g, 0.38 mol) was added. The resulting solution was stirred at rt overnight. The reaction was quenched with sat. NaHCO₃ carefully, diluted with EtOAc, and washed with water. The organic layer was washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was recrystallized from zPrOH / hexanes (11 mL / 31.5 mL) to afford pure product 136 (22.78 g, 71%) as a off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (IH, s), 7.80 (IH, d), 7.69 (IH, d), 7.57-7.61 (3H, t), 7.06 (2H, t), 5.78 (IH, s), 5.27 (IH, br), 4.24 (2H, m), 3.45 (2H, dd), 1.81 (3H, s) ppm.

[0253] Using the above procedure, but employing different carboxylic acids and/or different alcohols, the corresponding esters analogous to 136 are obtained.

Example 13

Preparation of (3-trifluoromethyl-phenyl)-(6-trifluoromethyl-pyridin-3-yloxy)-acetic acid 2- morpholin-4-vl-ethvl ester, 137

100 ₁₃₇

[0254] (3-Trifluoromethyl-phenyl)-(5-trifluoromethyl-pyridin-2-yloxy)-acetic acid, 100, prepared as described in Example 4, (0.05 mol) was converted into the acid chloride, using the procedure of Example 6. The acid chloride (0.01 mol) was dissolved in tetrahydrofuran (25 mL) and N,N-dimethylaniline (2 mL) and morpholinoethanol (2 mL) were added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was washed with dilute hydrochloric acid, dried and concentrated. The residue was chromatographed to afford the title compound 137. [0255] Using the above procedure, but employing different carboxylic acids and/or different alcohols, the corresponding esters analogous to 137 can be obtained.

Example 14

Preparation of (5-r(4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-methyll- IH- tetrazole 140

MeO₂CNSO₂N(C₂H₅)₃

[0256] Dimethylaluminum amide was prepared by adding anhydrous toluene (60 mL) to ammonium chloride (2.14 g). The mixture was cooled to 0⁰C and trimethylaluminum in toluene (2.0 M, 20 mL) was added dropwise. The reaction was allowed to stir at 0⁰C 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 100⁰C and allowed to stir overnight. The reaction was then cooled to room temperature and Na₂SO₄ 10H₂O was added and stirred for an additional hour. Filtration followed by concentration of the solution gave a yellow liquid. Purification with flash column chromatography (hexanes/ethyl acetate 1 :4) gave the amide 138 (2.7 g, 49%) as light yellow solid. ¹H-NMR (CDCl₃, 400MHz): δ 7.81 - 7.51 (m, 6H), 7.02 (d, 2H), 6.60 (br. IH), 5.78 (br. IH), 5.63 (s, IH). [0257] The amide 138 (2.7 g) was dissolved in dichloromethane and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (1.3 g) was then added. The resulting mixture was stirred overnight, and concentrated. Purification with flash column chromatography (hexane/ethyl acetate 5:1) gave the nitrile 139 as a white solid. ¹H-NMR (CDCl₃, 400MHz) δ 7.87 - 7.64 (m, 6H), 7.19 (d, 2H), 5.96 (s, IH).

[0258] The nitrile 139 (1.05 g) was dissolved in anhydrous THF (40 mL). Trimethyltin azide (1.3 mL) was then added. The reaction mixture was refluxed overnight. The solution was then cooled to room temperature, diluted with HCl (0.5 N), and extracted with ethyl acetate. The organic solution was dried with sodium sulfate, and concentrated. Purification with flash column chromatography (ethyl acetate) gave 1.15 g of tetrazole 140 (98%) as a white solid. ¹H-NMR (CDCl₃, 400MHz): δ 7.85 - 7.51 (m, 6H), 7.04 (d, 2H), 6.85 (s, IH).

[0259] Using the above procedure, but employing different carboxylic acids, the corresponding tetrazoles analogous to 140 can be obtained.

Example 15

Preparation of (4-trifTuoromethyl-phenoxy)-(3 -trifTuoromethyl-phenyl)- acetic acid sodium salt 141

[0260] A solution of the acid 39 in EtOAc was treated with 1 eq. of IN NaOH, and the resultant product was recrystallized from EtOAc / hexanes to afford white solid Na salt 141.

[0261] Using the above procedure, but employing different carboxylic acids, the corresponding salts analogous to 141 can be obtained. Example 16

Preparation of Enantiomers of (4-trifluoromethyl-phenoxy)- (4-trifluoromethyl-phenyO- acetic acid 83

83 83- A (enantiomer 1)

[0262] 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 80⁰C. The solution was cooled to room temperature slowly. Crystals (2.4 g) were collected by filtration. The crystals were mixed with 1 N HCl (50 mL), extracted with ethyl acetate. The organic solution was dried over Na₂SO₄. The solvent was removed in vacuum to give 1.6 g of enatiomerically enriched 83- A (20%) as white solid. ¹H-NMR (DMSO, 400MHz): δ 7.80 - 7.18 (m, 8H), 6.20 (s, IH).

[0263] Using the same procedure as described above, 83-B was obtained by using (lS,2S)-(+)-2-amino-l-(4-nitrophenyl)-l,3-propanediol as the chiral base. ¹H-NMR (DMSO, 400MHz): δ 7.80 - 7.18 (m, 8H), 6.20 (s, IH).

[0264] Using the above procedure, but employing different carboxylic acids and chiral bases, the corresponding enantiomers analogous to 83 can be obtained. Example 17

Preparation of Enantiomers of (4-trifluoromethyl-phenoxy)-(3 -trifluoromethyl-phenyl)- acetic acid, 39

[0265] 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 ⁰C 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. (+)-39, [α]²⁵λ = + 74.6 (c = 0.55, CH₃OH), and (-)-39 [α]²⁵ λ = - 74.8 (c = 0.89, CH₃OH). Chiral HPLC analysis of enantiomers was carried out at λ = 220 nm by injecting 10 μL of an approximately a 0.5 mg/mL solution of the sample dissolved in mobile phase onto a 25 cm x 4.6 mm Regis Technologies (R,R) Whelk-0 1 5 μm column with a 1.5 mL/min flow of (1.5/98.5/0.05) zPrOH/hexanes/TFA. Under these conditions, (+)-enantiomer eluted at 6.6 min, (-) enantiomer at 8.8 min (approximate retention times).

Example 18

Separation of enantiomers of (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid. 39 by chiral HPLC

[0266] 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.

[0267] The above procedure can be applied to other racemic acids of the present invention to provide their separated enantiomers.

Example 19

Preparation of Esterified Compounds

[0268] Potassium hydroxide (2.6 g, 0.046 mole) was dissolved in isopropanol (40 mL) under argon by heating to 50-60 ⁰C. The solution was the cooled to 0-10⁰C in an ice bath. To this was added 3-trifluromethylphenol (6.5 mL (8.7 g), 0.053 mole), which raised the internal temperature to 10-20⁰C. (2-Acetamidoethyl)-4-trifluoromethylphenylbromoacetate 73 (16.2 g, 0.044 mole) was dissolved in 12 mL isopropanol and cooled to 0-10⁰C. The phenoxide solution was then added to the bromoester, which raised the internal temperature to 5-15°C. The resulting mixture was stirred for 4 h in the cold bath. Citric acid (1.6 g, 0.0084 mole) was added in 12 mL water. The mixture was filtered to remove white potassium bromide and the cake washed with isopropanol (20 mL). The isopropanol was rotary evaporated and the residue dissolved in ethyl acetate (72 mL) and extracted with water (24 mL). The ethyl acetate phase was dried over sodium sulfate and filtered and the filter cake washed with ethyl acetate. After rotary evaporation, crude product were obtained. This was dissolved in ethyl ether: hexane (1 :1) and diluted with hexane, whereupon some material oiled out. The mixture was cooled in an Ice bath to 2-5°C a white solid formed at once and was filtered and washed with ethyl ether: hexane (1 : 1) to afford 142, after drying under vacuum.

Using the above procedures, but substituting the appropriate phenols and bromoesters for 73, the following compounds were obtained: 143-147.

Example 20

In vivo Activities

[0269] The anti-diabetic activities of the compounds were evaluated in the C57BL/6J ob/ob Mice model. A. Materials and methods

[0270] 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 ± 3⁰C 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.

B. Results

[0271] 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

Example 21

Effects of Compound 39 on PPAR-α. PPAR-δ. and PPAR-γ

[0272] Sub-confluent HEK-293 cells were co-transfected with 50 ng of GAL4-human, mouse or rat PPAR-α, PPAR-δ or PPAR-γ 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. The following day the media was removed and replaced with fresh media containing a DMSO vehicle control or a dilution series of MBX-213 acid (1-100 μM), a dilution series of GW501516 (0.00041-30 μM), a dilution series of GW7647 (0.00014-0.1 μM) and a dilution series of rosiglitazone (0.04-30 μM) and allowed to incubate overnight. The following day luciferase activity (luminescence) 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-α reporter assay. GW501516, a potent and selective human PPARδ 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. Pereira et al, "Synthesis of the PPARbeta/delta-selective agonist GW501516 and C4-thiazole-substituted analogs". Bioorg Med Chem Lett. 2006 Jan 1 ; 16(l):49-54.]

[0273] Reporter gene assays were used to evaluate the ability of Compound 39 to activate human PPAR-α, PPAR-δ and PPAR-γ. This was done with a reporter assay system using the human GAL4- PPAR-α, GAL4-PPAR-5 orGAL4- PPAR-γ 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. The fully potent potent PPAR-α agonist GW7647, the weaker PPAR-α agonist fenofibrate, the potent PPAR-δ agonist GW501516 and the potent PPAR-γ agonist rosiglitazone were run as positive controls and for comparison. The degree of PPAR-γ activation by Compound 39 was a small percentage of the maximum activation by rosiglitazone. The degree of PPAR-α 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- δ (EC₅₀S of 0.009 μM, 0.081 μM and 1.027 μM respectively) but Compound 39 did not activate human PPAR-δ. [0274] The binding of Compound 39, GW7647, and fenofibrate to the human PPAR-γ ligand binding domain was measured using the PolarScreen™ PPAR-γ Competitor Assay, Green (InVitrogen, Cat. No. PV3355) using the manufacturer's recommended protocol. The binding between Compound 39 and the human PPAR-α ligand binding domain was measured using the LanthaScreen™ PPAR-α 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-α and right panel of figure 1 shows the binding of rosiglitazone and compound 39 to PPAR-γ. The IC₅₀ of Compound 39, GW7647, and fenofibrate to human PPAR-α were 20.1, .0014, and 35.4 μM, respectively. The IC₅₀ of Compound 39 and rosiglitazone to human PPAR-γ were 63.3, and 0.11 μM, respectively.

Example 22

Binding Mode of Compound 39 to human PPAR-γ Ligand Binding Domain

[0275] Sub-confluent HEK-293 cells were co-trans fected with 50 ng of wild type or

Y473A mutant GAL4-human PPAR-γ 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, 10% FBS) containing a DMSO vehicle control or dilution series of MBX- 102 acid (0.4-120 μM) or rosiglitazone (0.05-300 μM) and allowed to incubate overnight. The following day luciferase activity (luminescence) was measured using the Steady Go Luciferase System (as per manufacturer's instructions). [0276] The binding of Compound 39, GW7647, and fenofibrate to the human PPAR-γ ligand binding domain was measured using the PolarScreen™ PPAR-γ Competitor Assay, Green (InVitrogen, Cat. No. PV3355) using the manufacturer's recommended protocol. The binding between Compound 39 and the human PPAR-α ligand binding domain was measured using the LanthaScreen™ PPAR-α 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-α and right panel of figure 1 shows the binding of rosiglitazone and compound 39 to PPAR-γ The IC₅₀ of Compound 39, GW7647, and fenofibrate to human PPAR-α were 20.1, .0014, and 35.4 μM, respectively. The IC50 of Compound 39, and rosiglitazone to human PPAR-γ were 63.3, and 0.11 μM, respectively.

[0277] Previously it was shown that tyrosine 473 in the AF-2 helix of the PPAR-γ ligand binding domain plays an important role in the activation of PPAR-γ by TZDs [R.T. Nolte, et ah, "Ligand Binding and Co-Activator Assembly of the Peroxisome Pro liferator- Activated Receptor-γ", Nature, vol. 395, no. 6698, pp. 137-143, 1998.]. In addition, published reports have shown that mutation of the tyrosine 473 residue reduces the ability of fully potent agonists, such as rosiglitazone, to bind to PPAR-γ [T. Tsukahara, et ah, "Different Residues Mediate Recognition of 1-0-Oleyl-lysophosphatidic Acid and Rosiglitazone in the Ligand Binding Doman of Peroxisome Proliferator-activated Receptor γ", Journal of Biological Chemistry, vol. 281, no. 6, pp. 3398-3407, 2006.]. The importance of the tyrosine 473 residue on Compound 39 activation of human PPAR-γ was evaluated by reporter assay using human wild type and mutant Y473A (tyrosine mutated to alanine) GAL4-PPAR-γ LBD fusion constructs.

[0278] The fully potent PPAR-γ agonist rosiglitazone was run as a positive control and for comparison. In these studies there was no significant difference in the compound 39 activation (EC50) of wild type and Y473A mutant PPAR-γ. In contrast, rosiglitazone activation of Y473A mutant PPAR-γ led to a significant (>25 fold) shift in EC₅₀ compared to activation of wild type PPAR-γ. These results confirmed that tyrosine 473 is a key residue for activation of human PPAR-γ by rosiglitazone, and demonstrated that this residue is not important for activation by compound 39. These findings suggest that compound 39 binds to and activates PPAR-γ in a manner distinct from fully potent agonists, such as rosiglitazone. Example 23

Effect of Compound 39 on PPAR-γ co-Repressor Displacement and co-Activator

Recruitment

[0279] The effect of compound 39, rosiglitazone and pioglitazone on co-regulator interaction with PPAR-γ was evaluated using a TR-FRET based biochemical assay

(Lanthascreen TR-FRET PPAR-γ Co-activator Assay). This is a homogeneous assay which contains a mixture of GST-fused PPAR-γ ligand binding domain (LBD), terbium anti-GST antibody, fluorescein labeled co-activator and co-repressor protein peptides (containing an LXXLL binding motif), and agonist (experimental compound).

[0280] As depicted in the above diagram, when combined, the terbium anti-GST antibody binds to the GST-PP AR-γ LBD. Binding of agonist (experimental compound) to the GST- PPAR-γ 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).

[0281] Co-repressor peptides bind to the PPAR-γ LBD in the native state. Binding of ligand (experimental compound) to the GST-PP AR-γ 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).

[0282] The TR-FRET based assay system which includes PPAR-γ 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-γ 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-γ ligand binding domain, to a lesser degree in comparison to rosiglitazone and with a higher EC₅₀. COMPOUND 39 acid fully displaced NCOR co-repressor peptide from the PPAR-γ ligand binding in a similar manner as rosiglitazone and with a higher IC50. The data is provided in figure 3 Example 24

Effects of Compound 39 on Adipogenesis [0283] Cultured primary human preadipocytes (Zen-Bio, Inc.) were incubated in Adipocyte Medium (Catalog # AM-I, containing 100 nM insulin and 1.0 μM dexamethasone) in the presence of 0.25 mM isobutyl-methylxanthine and either vehicle, rosiglitazone (1 μM) or COMPOUND 39 (10, 50, or 100 μM) for 3 days. Cells were then fed with Adipocyte Medium for additional 12 days in absence of compounds. PPAR-γ- mediated ligand-induced differentiation was assessed by Oil Red O staining and analysis of total triglyceride (Differentiation Assay: Total Triglyceride at Zen-Bio, Inc.).

[0284] As shown in Figure 4 compound 39 induces less adipogenesis than rosiglitazone, and as also shown in Figure 4, total triglycerides in the compound 39 treated cells was significantly less than in the rosiglitazone treated cells. Example 25

Effect of Compound 39 on glucose transport in Adipocytes

[0285] 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, 0.2μM sterile filtered) and incubated with FCB at 37 C for 30min. 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-[³H] glucose (0.083 μCi/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

CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega). Figure 5 shows that glucose uptake in 3T3-L1 adipocytes was stimulated by compound 39. Example 26

Effect of Compound 39 on Triglycerides, Free Fatty Acids in db/db Diabetic Mice [0286] db/db Mice (8-10 wk of age) were purchased from Jackson Laboratories (Bar

Harbor, ME). After a 2-wk acclimation period, the 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. At necropsy, plasma was collected 24 h post-last dose for measurement of plasma glucose, insulin, FFA and triglyceride levels. Tissues including heart and brown adipose tissue were dissected and weighted. Statistical significance was determined by one-way ANOVA followed by Tukey post hoc tests.

[0287] Plasma glucose and triglycerides levels were measured using the colorimetric methods described by ^Tπnderl (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. [0288] Figure 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

Effect of Compound 39 on Body Weight Gain, Heart Weight, and Brown Adipose Tissue in db/db Diabetic Mice

[0289] The body weight gain, heart weight, and intrascapular brown adipose tissue in mice of Example 25 were examined. Figure 7 shows that the body weight gain of mice treated with compound 39 did not increase as compared with mice treated with vehicle. Similarly, the heart weight of mice treated with compound 39 stayed constant when compared with vehicle treated animals. In addition, intrascapular brown adipose tissue

(IBAT) weight remained approximately constant as well. In contrast, the body weight gain, heart weight, and IBAT all increased significantly in rosiglitazone treated mice. The data are provided in figure 7.

Example 28

Effect of Compound 39 on Insulin, Triglycerides, and Free Fatty Acids in Zucker Diabetic Fatty Rats

[0290] 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. After centrifugation of blood samples, plasma was used for measurements of glucose, insulin, FFA and triglyceride levels. Statistical significance was determined by one-way ANOVA followed by Tukey post hoc analyses. [0291] As shown in Figure 8 glucose, triglycerides, free fatty acids, and insulin were all significantly lowered in the rats treated with compound 39. In contrast, rats treated with rosiglitazone had higher levels of insulin, and the reduction of triglycerides was not statistically significant. The p-value was less than 0.05. Example 29

Effect of Compound 39 on Islet of Langerhans Morphology in Zucker Diabetic Fatty Rats and db/db Mice

[0292] 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-μm intervals on at least three levels and stained with Methyl Green and insulin (DAKO).

[0293] Three low magnification (5X objective) fields were randomly chosen from one slide/animal. Islets in these fields (>50 islets per treatment group) were counted qualitatively assigned by eye. Islet disintegration was defined as the lack of cohesiveness, and lack of a defined border.

[0294] 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

Effect of Compound 39 on Insulin Content in the Islets of Langerhans in db/db Diabetec Mice

[0295] 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

Effect of Compound 39 on Body Weight Gain and Fasting Insulin in Zucker Fatty Rats

[0297] 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. After centrifugation of blood samples, plasma was used for measurements of glucose, insulin, FFA and triglyceride levels. Statistical significance was determined by one-way ANOVA followed by Tukey post hoc analyses. [0298] 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.

[0299] 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

Effect of Compound 39 on Apoliprotein Al and HDL Particle Size [0300] 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.

[0301] Human apoAl plasma levels were determined using the Luminex technology (human apoAl single plex assay, Linco Diagnostics, Millipore Bioscience). HDL particle size was determined using NMR by Liposcience, Inc. Raleigh, North Carolina.

[0302] 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.

[0303] 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. In contrst, mice treated with 10 mg/kg rosiglitazone, HDL particle size remained approximately the same size at approximately 9.4 nM.

[0304] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

What is Claimed:

1. A method of lowering blood triglyceride levels in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said compound is administered at a dose of from about 1 mg/kg to about 200 mg/kg.

3. The method of claim 2 wherein said dose is from about 1 mg/kg to about 100 mg/kg.

4. The method of claim 2 wherein said dose is from about 1 mg/kg to about 75 mg/kg.

5. The method of claim 2 wherein said dose is from about 1 mg/kg to about 50 mg/kg.

6. The method of claim 2 wherein said dose is from about 2mg/kg to about 40 mg/kg.

7. The method of claim 2 wherein said dose is from about 5 mg/kg to about 30 mg/kg.

8. The method of claim 1 wherein said mammal is a human.

9. The method of claim 8 wherein said human is diagnosed with dyslipidemia.

10. The method of claim 8 wherein said human has a body mass index (BMI) of greater than about 20.

11. The method of claim 8 wherein said BMI is greater than about 25.

12. The method of claim 8 wherein said human is diagnosed with Type II diabetes.

13. A method of lowering blood free fatty acid levels in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 wherein said compound is administered at a dose of from about 1 mg/kg to about 200 mg/kg.

15. The method of claim 13 wherein said dose is from about 1 mg/kg to about 100 mg/kg.

16. The method of claim 13 wherein said dose is from about 1 mg/kg to about 75 mg/kg.

17. The method of claim 13 wherein said dose is from about 1 mg/kg to about 50 mg/kg.

18. The method of claim 13 wherein said dose is from about 2 mg/kg to about 40 mg/kg.

19. The method of claim 13 wherein said dose is from about 5 mg/kg to about 30 mg/kg.

20. The method of claim 13 wherein said mammal is a human.

21. The method of claim 20 wherein said human is diagnosed with dyslipidemia.

22. The method of claim 20 wherein said human has a body mass index (BMI) of greater than about 20.

23. The method of claim 20 wherein said BMI is greater than about 25.

24. The method of claim 20 wherein said human is diagnosed with Type II diabetes.

25. A method of preserving islet of langerhans function in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

26. The method of claim 25 wherein the function of the beta cells of the islet of langerhans is preserved.

27. A method of preserving insulin production by the islet of langerhans in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

28. A method of preserving islet of langerhans morphology in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

29. The method of claims 25, 26, 27, and 28 wherein said compound is administered at a dose of from about 1 mg/kg to about 200 mg/kg.

30. The method of claims 25, 26, 27, and 28 wherein said dose is from about 1 mg/kg to about 100 mg/kg.

31. The method of claims 25, 26, 27, and 28 wherein said dose is from about 1 mg/kg to about 75 mg/kg.

32. The method of claims 25, 26, 27, and 28 wherein said dose is from about 1 mg/kg to about 50 mg/kg.

33. The method of claims 25, 26, 27, and 28 wherein said dose is from about 2 mg/kg to about 40 mg/kg.

34. The method of claims 25, 26, 27, and 28 wherein said dose is from about 5mg/kg to about 30 mg/kg.

35. The method of claim 25, 26, 27, and 28 wherein said mammal is a human.

36. The method claim 35 wherein said human is diagnosed with Type II diabetes.

37. The method of claim 35 wherein said human is diagnosed with dyslipidemia.

38. The method of claim 35 wherein said human has a body mass index (BMI) of greater than about 20.

39. The method of claim 35 wherein said BMI is greater than about 25.

40. A method of increasing blood levels of Apolipoprotein Al (ApoAl) in a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

41. The method of claim 40 wherein said compound is administered at a dose of from about 1 mg/kg to about 200 mg/kg.

42. The method of claim 40 wherein said dose is from about 1 mg/kg to about 100 mg/kg.

43. The method of claim 40 wherein said dose is from about 1 mg/kg to about 75 mg/kg.

44. The method of claim 40 wherein said dose is from about 1 mg/kg to about 50 mg/kg.

45. The method of claim 40 wherein said dose is from about 2 mg/kg to about 40 mg/kg.

46. The method of claim 40 wherein said dose is from about 5 mg/kg to about 30 mg/kg.

47. The method of claim 40 wherein said mammal is a human.

48. The method of claim 47 wherein said human is diagnosed with dyslipidemia.

49. The method of claim 47 wherein said human has a body mass index (BMI) of greater than about 20.

50. The method of claim 47 wherein said BMI is greater than about 25.

51. The method of claim 47 wherein said mammal is diagnosed with Type II diabetes.

52. A method of increasing high density lipoprotein (HDL) particle size in the blood of a mammal comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

53. The method of claim 52 wherein said compound is administered at a dose of from about 1 mg/kg to about 200 mg/kg.

54. The method of claim 52 wherein said dose is from about 1 mg/kg to about 100 mg/kg.

55. The method of claim 52 wherein said dose is from about 1 mg/kg to about 75 mg/kg.

56. The method of claim 52 wherein said dose is from about 1 mg/kg to about 50 mg/kg.

57. The method of claim 52 wherein said dose is from about 2 mg/kg to about 40 mg/kg.

58. The method of claim 52 wherein said dose is from about 5 mg/kg to about 30 mg/kg.

59. The method of claim 52 wherein said mammal is a human.

60. The method of claim 59 wherein said human is diagnosed with dyslipidemia.

61. The method of claim 59 wherein said human has a body mass index (BMI) of greater than about 20.

62. The method of claim 59 wherein said BMI is greater than about 25.

63. The method of claim 59 wherein said human is diagnosed with Type II diabetes.