MXPA06009381A - Alpha-(trifluoromethyl-substituted aryloxy, arylamino, arylthio or arylmethyl)-trifluoromethyl-substituted phenylacetic acids and derivatives as antidiabetic agents - Google Patents

Abstract

Compounds having a formula (1) or a pharmaceutically acceptable salt or prodrug thereof, are provided, and are useful for the treatment of metabolic disorders.

Description

ACIDS a- (TRIFLUOROMETHYL-ARILOXYL, ARILAMINO, ARILTIOL OR SUBSTITUTE ARILMETILE) -TRIFLUORO ETIL-PHENYLLACTIC SUBSTITUTES AND THEIR DERIVATIVES AS ANTIDIABETIC AGENTS BACKGROUND OF THE INVENTION Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, for example, LeRoith, D. Et al. , (editors), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, PA E.Ü.A. 1996) and all the references cited here. According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the population in the world. Uncontrolled hyperglycemia is associated with premature increase and mortality due to the increased risk of microvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease. Likewise, the control of glucose homeostasis is an important critical factor for the treatment of diabetes. There are two main types of diabetes: Type 1 diabetes (formerly referred to as insulin-dependent diabetes or IDDM) and Type 2 diabetes (formerly referred to as non-insulin-dependent diabetes or NIDDM).

Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone that regulates the use of glucose. This insuin deficiency is generally characterized by the destruction of β-cells within the Islets of Langerhans in the pancreas, which usually results in an absolute deficiency of insulin. Type 1 diabetes has two forms: Immuno-Mediated Diabetes Mellitus, which results from autoimmune cell destruction mediated by pancreatic β-cells; and Idiopathic Diabetes Mellitus, which refers to forms of the disease that have unknown etiologies. Type 2 diabetes is a disease characterized by insulin resistance accompanied by a relative, rather than absolute, deficiency of insulin. Type 2 diabetes can be in the range from predominant insulin resistance with a relative insulin deficiency to a predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished capacity of insulin to exert its biological action through a wide range of concentrations. In individuals with insulin resistance, the body abnormally secretes large amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and proper glucose control, the development of the glucose tolerance state worsens. In a significant number of individuals, insulin secretion also decreases and the plasma glucose level increases, resulting in the clinical state of diabetes. Type 2 diabetes can be due to a deep insulin resistance stimulating the regulating effects on the metabolism of glucose and lipids in the main insulin sensitive tissues: muscles, liver and adipose tissue. This resistance to insulin sensitivity results in insufficient activation of insulin for increased glucose, oxidation and storage in muscles and inadequate insulin recession of lipolysis in adipose tissue and production of glucose and secretion in the liver. In Type 2 diabetes, free fatty acid levels are often high in obese patients and certain non-obese patients, so lipid oxidation is increased. The premature development of atherosclerosis and the increased rate of cardiovascular and peripheral vascular diseases are characteristic types of patients with diabetes, where hyperlipidemia is an important factor that precipitates these diseases. Hyperlipidemia is a condition generally characterized by an abnormal increase in serum lipids and blood flow and as indicated above, is an important risk factor in the development of atherosclerosis and heart disease. For a review of lipid metabolism disorders, see for example, Wilson, J. Et al. , (editor), Disorders of Lipid metabolism, Chapter 23, Textbook of Endocrinology, 9th edition (W. B. Sanders Company, Philadelphia, PA E.U.A. 1998; this reference and all references cited here are incorporated by reference here). The serum lipoproteins are the carriers of lipids in the circulation. These 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 generally classified as primary or secondary hyperlipidemia. Primary hyperlipidemia is usually caused by genetic defects, while secondary hyperlipidemia is usually caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia may result from a combination of primary and secondary causes of hyperlipidemia. Elevated cholesterol levels are associated with a number of disease states, including coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis and xanthoma. Dyslipidemia or abnormal levels of lipoproteins in plasma saguinum is a frequent occurrence among diabetics and has been shown to be one of the main contributors to the incidence of disease in coronary events and deaths among diabetic individuals (see, for example, Joslin. Ann. Chim. Med. (1927) 5: 1061-1079). Epidemiological studies since the association has been confirmed and have shown a much greater increase in coronary death among diabetic individuals compared with non-diabetic individuals (see for example, García MJ 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 individuals (Howard B., et al., Artherosclerosis (1978) 30: 153-162). What is needed in the art are new components and methods useful for the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. The present invention meets this and other needs by providing these compounds, compositions and methods for improving insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides compounds having the formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein the letter X represents a member selected from the group comprising O, S, SO, S02, CHR and NR, where R is H, alkyl (CL-Cg), CORa, COORa and CONRaRb where Ra and Rb are each indistinctly selected from the group comprising H and alkyl (C? -C8); the letter Y represents a member selected from the group comprising CH2ORc, C02Rc, tetrazole, CHO, CONRcRm, CH (= NRC) and CH (= NORc), where Rc is a member selected from the group comprising H, alkyl (C? C8), alkenyl (C3-C8), alkynyl (C3-C8), cycloalkyl (C3-C7), cycloalkylalkyl (C4-C8), aryl, aryl (C? -8) alkyl and alkylene-Z (C? -C8 ), wherein Z is selected from the group comprising CORd, COORd, NRdRe, NRdCONReRf, NRdCORe, NRdCOORe and CONRdRe where Rd, Re and Rf are each indistinctly selected from the group comprising H, (C?-C8) alkyl and phenyl, or optionally two of R, Re and Rf are attached to the same nitrogen atom which combines to form a five or six membered ring; and wherein Rm is selected from the group comprising H, alkyl (C? ~ C8), aryl and OH and Rm and Rc are optionally combined with the nitrogen atom where each is attached to form a five or six membered ring; each of the symbols R1 and R3 represents a member selected indistinctly from the group comprising halogen, hydroxyl, alkyl (C? -C8), alkenyl (C2-C8), alkynyl (C2-C8), alkoxy (C? -8), cycloalkyl (C3_C7), cycloalkylalkyl (C4-C8), haloalkyl (C? ~ C8), heteroalkyl (C? -8), heterocyclyl (C2-C5), cycloalkyl (C3-C7) heterosubstituted, cycloalkyl (C3-C7) heteroalkylsubstituted , O-haloalkyl (C? -8), nitro, cyano, phenyl, O-phenyl, NRj-phenyl, S (O) r-phenyl, CORj, COORj, NRjRk, S (0) rRj, S02NRjRk, NR ^ ONR1 ^ 1, NRjCORk, NRjCOORk and CONRjRk, where the phenyl ring is optionally substituted and Rj, Rk and R1 are each indistinctly selected from the group comprising H and (C? -C8) alkyl, including haloalkyl (C? -8), or optionally two of Rj, Rk and R1 when grouped to the same nitrogen atom are combined to form a five or six member ring and the superindicate r is an integer from 0 to 2; the symbol R2 represents a member selected from the group comprising H and alkyl (C? -C8); the letter Q represents CH or N; the subscript m is an integer from 0 to 3; and the subscript p is an integer from 0 to 2. In other aspects, the present invention provides pharmaceutical compositions that confer one or more of the above compounds as well as methods for treating a variety of metabolic disorders and conditions using one or more of the compounds provided above.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions The abbreviations used herein are conventional, unless otherwise defined. Unless stated otherwise, the following terms used in the specification and claims have the meaning given below: The term "alkyl" refers to a linear saturated monovalent idrocarbon radical or a branched saturated monovalent hydrocarbon radical which has the number of carbon atoms indicated in the prefix. For example, alkyl (C? -C6) means to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl and the like. For each of the definitions herein (eg, alkyl, alkenyl, alkoxy, aralkyloxy), when a prefix is not included to indicate the number of carbon atoms of the main chain in an alkyl portion, the radical or portion of This will have six or fewer carbon atoms in the main chain ..

The term "alkylene" refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, alkylene (C? -C6) means to include methylene, ethylene, propylene, 2-methylpropylene, pentylene and the like. The term "alkenyl" refers to a branched monovalent hodricarburo radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but not more than three double bonds . For example, (C2-C6) alkenyl means to include ethenyl, propenyl, 1,3-butadienyl and the like. The term "alkynyl" means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. The term "alkynyl" further means including those alkyl groups having a triple bond and a double bond. For example, (C2-C6) alkynyl means that it includes ethynyl, propynyl and the like. The terms "alkoxy", "aryloxy", "aralkyloxy" or "heteroaralkyloxy" refer to a radical -OR, where R is an alkyl, aryl, aralkyl or heteroaralkyl respectively, as defined herein, for example, methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy and the like. The term "aryl" refers to a monovalent monocyclic bicyclic or monocyclic hydrocarbon radical with a ring of 6 to 10 atoms which is unsubstituted with one to four substitutes, preferably one, two or three substitutes selected from alkyl, cycloalkyl, cycloalkylalkyl, halo , nitro, cyano, hydroxyl, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), - (CR 'R ") n-COOR (where n is an integer from 0 to 5, R 'and R "is indistinctly hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (CR' R") n-CONRxRy (where n is an integer from 0 to 5, R 'and R "are indistinctly hydrogen or alkyl and Rx and Ry are indistinctly selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl.) More specifically the term aryl includes but is not It limits to phenyl, biphenyl, 1-naphthyl and 2-naphthyl and the substituted forms of these The term "aralkyl" refers to the radical -RXRY where Rx is an alkylene group (having six or less carbon atoms in the main chain) ) and R is an aryl group as defined above Thus, the term "aralkyl" refers to groups such as, for example, benzyl, phenylethyl, 3- (4-nitrophenyl) -2-methylbutyl and the like. , the term "aralkenyl" means a radical -R x R y where R x is an alkylene group (a group alkylene having one or two double bonds) and R? is an aryl group as defined above, for example, styryl, 3-phenyl-2-propenyl and the like. The term "arylheteroalkyl" means a radical -R x R y where R x is a heteroalkylene group and R y is an aryl group as defined herein, for example, 2-hydroxy-2-phenyl-ethyl, 2-hydroxy-1-hydroxymethyl-2- phenyl-ethyl and the like. The term "cycloalkyl" refers to a monovalent cyclic hydrocarbon radical with a ring of three to seven carbons. The cycloalkyl group may have a double bond and may also be optionally substituted without distinction with one, two or three substitutes selected from alkyl, optionally substituted phenyl or -C (0) Rz (where Rz is hydrogen, alkyl, haloalkyl, amino, mono- optionally substituted alkylamino, diakyl amino, hydroxyl, alkoxy or phenyl). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamidocyclohexenyl, 2-dimethylaminocarbonyl-cyclohexyl and the like.

The term "cycloalkyl-alkyl" means a radical -R x R y where R x is an alkylene group and R y is a cycloalkyl group as defined herein, for example, cyclopropylmethyl, cyclohexenylpropyl, 3-cyclohexyl-2-methylpropyl and the like. The prefix indicates the number of carbon atoms (e.g., C-C? O) which refers to the total number of carbon atoms of both the cycloalkyl portion and the alkyl portion. The term "haloalkyl" refers to an alkyl group that is substituted with one or more same or different halo atoms, for example, -CH2C1, -CF3, -CH2CF3, -CH2CC13 and the like and further includes those groups such as perfluoroalkyl wherein all the hydrogen atoms are replaced by fluorine atoms. The prefix "halo" and the term "halogen" when used is to describe a substitute, referring to -F, -Cl, -Br and I. The term "heteroalkyl" means an alkyl radical as defined herein with one, two or three substitutes selected indistinctly from cyano, -0RW, -RXRY and -S (0) nRz (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroaryl radical is through a carbon atom of the heteroalkyl radical. Rw is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido or mono- or di-alkylcarbamoyl. R x is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl. Ry is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl. Rz is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-aryl, aryl, aralkyl, amino, mono-alkylamino, di-alkylamino or idroxyalkyl. Representative examples include for example, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl and 2-methylsulfonyl-ethyl. For each of the above Rw, Rx, Ry and Rz, they can also be substituted by amino, fluoro, alkylamino, di-alkylamino, OH or alkoxy. Additionally, the prefix indicates the number of carbon atoms (eg, Ci-Cio) which refers to the total number of carbon atoms in the portion of the heteroalkyl group exclusive of the cyano, -ORw, -NRxRy or -S ( 0) nRz. The term "heteroaryl" means a monovalent bicyclic or monocyclic radical with a ring of 5 to 12 atoms having at least one aromatic ring containing one, two or three heteroatoms in the ring selected from N, O or S, the remaining atoms in the ring may be C, with the understanding that the point of attachment of the heteroaryl radical may be on an aromatic ring. The heteroaryl ring is optionally substituted interchangeably with one to four substitutes, preferably one or two substitutes, selected from aryl, cycloalkyl, cycloalkyl-alkyl, nitro, cyano, hydroxyl, alkoxy, amino, acylamino, mono-alkylamino, di- alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl, - (CR 'R ") n-COOR (where n is an integer from 0 to 5, R' is hydrogen, alkyl , phenyl or phenylalkyl), - (CR 'R ") n-COOR (where n is an integer from 0 to 5, R' and R" are either hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl , phenyl or phenylalkyl) or - (CR'R ") n-CONRxR? (where n is n integer from 0 to 5, R 'and R" are either hydrogen or alkyl and Rx and Ry are indistinctly one from another, hydrogenated , alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl.) More specifically the term "heteroaryl" includes but is not limited to pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl and derived from these. The term "heteroaralkyl" means a radical -R x R y where R x is a heteroalkyl group as defined herein, for example, pyridin-3-ylmethyl, 3- (benzofuran-2-yl) propyl and the like. The term "heteroaralkenyl" means a radical -R x R y where R x is an alkenylene group and R? is a heteroaryl group as defined herein, for example, 3- (pyridin-3-yl) propen-2-yl and the like. The term "heterocyclyl" or "cycloheteroalkyl" means a non-aromatic cyclic radical saturated or unsaturated with a ring of 3 to 8 carbon atoms wherein one or two ring atoms are heteroatoms selected from O, NR (where R is indistinctly hydrogen or alkyl) or S (0) n (where n is an integer from 0 to 2), the remaining ring atoms are C, where one or two C atoms can be optionally substituted by a carbonyl group. The heterocyclic ring can optionally be substituted interchangeably with one, two or three substitutes selected from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, nitro, cyano, hydroxyl, alkoxy, amino, mono-alkylamino, dialkylamino, haloalkyl, haloalkoxy, -COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), - (CR 'R ") n-COOR (n is an integer from 0 to 5, R' and R" are either hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl) or - (CR 'R ") n-CONRxRy (where n is an integer from 0 to 5, R' and R" is either hydrogen or alkyl , Rx and Ry are indistinctly one of another, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More specifically, the term heterocyclic includes but is not limited to tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, 2-pyrrolidon-l-yl, morpholino, thiomorpholino, thiomorpholin-1-oxide, thiomorpholin-1,1-dioxide, pyrolidinyl and derivatives thereof. The prefix indicates the number of carbon atoms (eg, C3-C10) which refers to the total number of carbon atoms in the cycloheteroalkyl or heterocyclyl group portion exclusive of the number of heteroatoms. The term "heterocyclylalkyl" or "cycloheteroalkyl-alkyl" means a radical -R x R y where R x is an alkylene group and R y is a heterocyclyl group as defined herein, for example, tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3-piperidinylmethyl and the like. The term "heteroalkylene" refers to a linear saturated divalent hydrocarbon radical of one to six carbons or a branched saturated hydrocarbon radical of three to six carbon atoms with one, two, three substituents indistinctly selected from -0RW, -NRXRY and -S (0) nRz (where n is an integer from 0 to 2) where Rw, Ry, Rx and Rz are as defined herein for a heteroalkyl radical. Examples include 2-hydroxyethane-1,2-diyl, 2-hydroxypropan-1,3-diyl and the like. The term "substituted cycloalkyl" means a cycloalkyl group where one, two or three hydrogen atoms are substituted by substitutes selected interchangeably from the group comprising cyano, hydroxyl, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino or -SOnR ( where n is an integer from 0 to 2 and when n is 0, R is hydrogen or alkyl and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, amino, acylamino, monoalkylamino , dialkylamino or hydroxyalkyl). Examples include 4-hydroxycyclohexyl, 2-aminocyclohexyl, etc. The term "cycloalkyl substituted by heteroalkyl" means a cycloalkyl group where one, two or three hydrogen atoms are unsubstituted by heteroalkyl groups, with the understanding that the heteroalkyl group is linked to the cycloalkyl group by means of a carbon-carbon bond. Examples include 1-hydroxymethyl-cyclopent-1-yl, 2-hydroxymethyl-cyclohex-2-yl and the like. The term "heterocyclyl substituted with heteroalkyl" means a heterocyclyl group wherein one, two or three hydrogen atoms are substituted without distinction by heteroalkyl groups with the understanding that the heteroalkyl group is attached to the heterocyclyl group or carbon-carbon bonding medium. Examples include 4-hydroxymethyl-piperidin-1-yl and the like. The term "optionally substituted phenyl" means a phenyl ring that is optionally substituted interchangeably with one to four substitutes, preferably one or two substitutes selected from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, nitro, cyano, hydroxyl, alkoxy, amino, acylamino , mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl, - (CR 'R ") n-COOR (where n is an integer from 0 to 5 , R 'and R "are indistinctly hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or - (CR' R") n-CONRxRy (where n is an integer from 0 to 5, R 'and R "are indistinctly hydrogen or alkyl and Rx and R are indistinctly one of another, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl. For each of the above definitions, the term" di-alkylamino "is refers to an amino portion that has two groups alkyl which may be the same or different. As used herein, the term "surrogate substitute acid" refers to those portions that are used as substitutes for a carboxylic acid moiety. These groups are generally known to the expert in the art (see for example, THE PRACTICE OF MEDICINAL CHEMISTRY; Wermuth, C. G., ed., Amic Press, New York, 1996, page 203). Suitable or substitute isoesters include -C (0) NHS02R where R can be alkyl, haloalkyl, heteroalkyl, aralkyl, aryl, heteroaryl, heterocyclyl, alkoxy, haloalkoxy, aryloxy, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, arylamino, diarylamino, diaralkylamino or other groups to jointly provide an acidic character to the portion; sulfonic acids; sulfinic acids; phosphonic acids; phosphinic acids; activated sulfonamides (eg, -S02NHX where X is an electron removed from the group relative to an alkyl group, such as an acyl group or an aryl group, activated carboxamides (eg, -C (O) NHCN), idroxamic acids (- C (O) NHOH), acid heterocycles or substituted heterocycles (for example, tetrazoles, triazoles, hydroxypyrazoles, hydroxyoxazoles, hydroxythiadiazoles) and acid alcohols (for example, C (CF3) 2OH or -CH (CF3) OH). They have the same molecular formula but differ in the nature or bonding sequence of their atoms or the arrangement of their atoms in space are called "isomers." The isomers that differ in the arrangement of their atoms in space are called " stereoisomers. "The stereoisomers that do not reflect the image of each other are called" diastereomers "and those that do not superimpose reflected images of each other are called" enantiomers. "When a compound has an asymmetric center, for example, which is linked 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 S- sequencing rules of Canh and Prelog or by the way in which the molecule rotates in the plane of polarized light and is designated as dextrogiratory or levogyratory (that is, as (+) or (-) -isomers, respectively). A chiral compound can exist either as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." The compounds of this invention can exist in stereoisomeric form if they have one or more asymmetric centers or a double bond with asymmetric substitution and can therefore be produced as individual stereoisomers or as mixtures. Unless indicated otherwise, the disclosure is intended to include individual stereoisomers as well as mixtures thereof. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. march, John Wilry and Sons, New York, 1992). The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and having the desired pharmacological activity of the parent compound, these salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4 toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-en-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the original compound is substituted by either a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, triethylamine, A7-methylglucamine and the like. The term "prodrugs" means any compound that releases an active parent compound according to Formula 1 in vivo when the prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula 1 are prepared by modifying the functional groups present in the compound of Formula 1 where a route allows the binding modifications in vivo to release the parent compound. Prodrugs include compounds of Formula 1 wherein a hydroxyl, amino or sulfhydryl group in a compound of Formula 1 is attached to any group that can be linked in vivo to regenerate the free, amino or sulfhydryl hydroxyl 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 hydroxyl functional groups in the compounds of Formula 1 and Similary. The term "protecting group" refers to a grouping of atoms that when they bind to a reactive group in a molecule masks, reduces or prevents this reactivity. Examples of protecting groups are found in T. W. Greene and P. G. Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY (Wiley 2nd edition, 1991) and Harrison and Harrison et al. , COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Volumes 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, alkyloxycarbonyl, 9- Fluorenylmethyloxycarbonyl (FMOC), nitro-veratriloxycarbonyl (NVOC) and the like. Representative hydroxyl protecting groups include those wherein the hydroxyl group is either acylated or alkylated such as the benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. Returning again to the compositions of the invention, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and biologically undesirable on the other hand, and it includes a carrier or excipient that is acceptable for veterinary use as well as pharmaceutical use in humans. A "pharmaceutically acceptable carrier or excipient" as used in the specification and claims includes both one and more than one carrier or excipient. With reference to the methods of the present invention, the following terms are used with the notorious meaning: The terms "treat" or "treatment" of a disease include: (1) preventing the disease, that is, causing the clinical symptoms of the disease does not develop in a mammal that may be willing or predisposed to the disease but that does not produce experiences or shows symptoms of disease, (2) inhibit the disease, that is, enclose or reduce the development of disease or its clinical symptoms, or (3) relieving the disease, that is, causing regression of the disease or its clinical symptoms. The term "therapeutically effective amount" means the amount of the compound of the subject that will release the medical or biological response from a tissue, system, animal or human that is sought by the researcher, veterinarian, doctor or other clinician. A "therapeutically effective amount" includes the amount of a compound that when administered to a mammal to treat a disease, is sufficient to effect such treatment for the disease. The "therapeutically active amount" may vary depending on the compound, the disease and its severity, as well as age, weight, etc., of the mammal to be treated. The term "mammal" includes without limitation, humans, domestic animals (for example, dogs or cats), farm animals (cows, horses or pigs), monkeys, rabbits, mice and laboratory animals. The term "insulin resistance" can be defined in general as a disorder in the metabolism of glucose. More specifically, insulin resistance can be defined as the diminished ability of insulin to exert its biological action over a wide range of concentrations producing less biological effect than expected. (See for example, Reaven, G. M., J. Basic &; Clin. Phys. & Pharm. (1998) 9: 387-406 and Flier, J. Am. Rev. Med. (1983) 34: 145-160). People with insulin resistance have a decreased ability to metabolize glucose properly and respond poorly, at all, to insulin therapy. Manifestations of insulin resistance include insufficient insulin activation due to increased glucose, oxidation and stored in muscles and inadequate insulin repression of lipolysis in adipose tissue and glucose production and secretion in the liver.

Insulin resistance can cause or contribute to polycystic ovary syndrome, impaired glucose tolerance (IGT), gestational diabetes, hypertension, obesity, atherosclerosis and a variety of other disorders. Eventually, individuals with insulin resistance can progress to a point where a diabetic state is reached. The association of insulin resistance with glucose intolerance, an increase in plasma triglycerides and a reduction in high density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, dense low density lipoprotein particles and high levels of inhibitor- 1 plasminogen activator in the circulation, have been referred to as "Syndrome X" (see for example, Reaven, GM, Physiol. Rev. (1995) 75: 473-486). The term "diabetes mellitus" or "diabetes" means a disease or condition that is generally characterized by metabolic defects in the production and utilization of glucose which results in failure to maintain adequate blood sugar levels in the body. The result of these defects is high blood sugar, referred to as "hyperglycemia". Two major forms of diabetes are Type 1 diabetes and Type 2 diabetes. As described above, Type 1 diabetes is generally the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 2 diabetes often occurs under normal conditions or with high insulin levels and may result in the inability of tissues to respond adequately to insulin. Many patients with Type 2 diabetes are insulin resistant and have a relative insulin deficiency, while insulin secretion can not compensate for the resistance of peripheral tissues to respond to insulin. In addition, many Type 2 diabetics are obese. Other types of glucose homeostasis disorders include Tolerance to Impaired Glucose, which is an intermediate metabolic state between normal glucose homeostasis and diabetes and gestational diabetes mellitus, which is glucose intolerance during pregnancy in women who have no prior history of Type 1 or Type 2 diabetes. The term "secondary diabetes" is diabetes that results from other identifiable etiologies that include: genetic defects in β-cell function (eg, maturity of diabetes attacks during youth, referred to as "MODY", which is an early form of attack of Type 2 diabetes with autosomal inheritance, see for example, Fajans S. et al., Diabet Med. (1996) (9 Supplement 6): S90-5 and Bell, G. Et al., Annu Rev. Physiol. (1996) 58: 171-86, genetic defects of insulin action, diseases of the exocrine pancreas (for example, hemochromatosis, pancreatitis and cystic fibrosis), certain diseases and ndocrines where excess hormones interfere with the action of insulin (eg, hormonal development in acromegaly and cortisol in Cushing's syndrome); certain drugs that suppress insulin secretion (eg, phenytoin) or inhibit the action of insulin (eg, estrogen and glucocorticoids) and diabetes caused by infection (eg, rubella, Coxsackie, and CMV); as well as other genetic syndromes. Guidelines for the diagnosis of type 2 diabetes, impaired glucose tolerance and gestational diabetes have been profiled by the American Diabetes Association (see, for example, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care (1999) Volume 2 (Supplement 1): S5-19). The term "hyperinsulinemia" refers to the presence of an abnormally high 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 high level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, that is, an elevated cholesterol level; (2) hypertriglyceridemia, that is, an elevated level of triglycerides and (3) combined hyperlipidemia, that is, a combination of hypercholesterolemia and hypertriglyceride, mia. The term "secretagogue" means a substance or compound that stimulates secretion. For example, an insulin secretagogue is a substance or compound that stimulates insulin secretion. The term "hemoglobin" or "Hb" refers to a respiratory pigment present in erythrocytes, which is primarily responsible for the transport of oxygen. A hemoglobin molecule comprises four polypeptide subunits (two a-chain systems and two β-chain systems, respectively). Each subunit is formed by the association of a globin protein and a heme molecule that is a complex of protoporphyrin-iron. The main class of hemoglobin appears in the normal adult hemolysed (referred to as "HbA", also referred to as HbAO to distinguish it from the glycated hemoglobin, which is referred to as "HbAl", described infra) which has subunits < 22? 2. Trace components such as HbA2 (a2d2) can also appear in the normal adult homoling. Among the hemoglobin classes of adult HbA, there is a glycated hemoglobin (referred to as "HbAi" or "glycosylated hemoglobin"), which can also be fractionated into HbA? Al, HbA? A2, H ib and HbAlc with a fractionation of ion exchange All these subclasses have the same primary structure, which is stabilized by the formation of an aldimine (Schiff base) by the amino group of the N-terminal valine in the ß-chain subunit of normal hemoglobin HbA and glucose (or glucose-6) -phosphate or fructose) followed by the formation of ketoamine by the Amadori rearrangement. The term "glycosylated hemoglobin" (also referred to as "HbA? C", "GHb", "hemoglobin-glycosylated", "Diabetic control index" and "glycohemoglobin", referred to herein as "hemoglobin Ale") refers to the stable product of the non-enzymatic glycosylation of the β chain of hemoglobin by plasma glucose. Hemoglobin A? C comprises the major portion of hemoglobins glycated in the blood. The proportion of glycosylated hemoglobin is proportional to the blood glucose level. Therefore, the proportion of hemoglobin Alc formation increases directly with the increase in plasma glucose levels. Since glycosylation occurs at a constant rate during the 120-day life cycle of an erythrocyte, the quantification of glycosylated hemoglobin levels reflects the average blood glucose level for an individual during the preceding two to three months. Therefore, the determination of the amount of glycosylated hemoglobin HbAlc can be a good index for the control of carbohydrate metabolism. Accordingly, the blood glucose levels of the last two months can be estimated based on the proportion of HbAlc for the total hemoglobin Hb. The analysis of hemoglobin A? C in blood is used as a quantification that enables long-term control of the blood glucose level (see for example, Jain, S., et al., Diabetes (1989) 38: 1539- 1543; Peters A., et al., JAMA (1996) 276: 1246-1252). The term "symptom" of diabetes, includes but is not limited to polyuria, polydipsia and polyphagia, as used herein, incorporating their common use. For example, "polyuria" means the passage of a large volume of urine during a given period; "polydipsia" means chronic and excessive thirst; and "polyphagia" • means excessive feeding. Other symptoms of diabetes include, for example, increasing susceptibility to certain infections (especially fungal and staphylococcal infections), nausea, and ketoacidosis (increased production of ketone bodies in the blood). The term "complication" of diabetes includes but is not limited to microvascular complications and macrovascular complications. Microvascular complications are those complications that usually result in small damage to blood vessels. These complications include, for example, retinopathy (worsening or loss of vision due to damage of blood vessels in the eyes); neuropathy (nerve damage and pems in the feet due to damage to the blood vessels of the nervous system); and nephropathy (kidney disease due to damage to blood vessels in the kidneys). Macrovascular complications are those complications that generally result in more damaging blood vessels. These complications include, for example, cardiovascular disease and peripheral vascular disease. Cardiovascular disease is redirected to diseases of blood vessels of the heart. See, for example, Kaplan, R. M. et al. , "Cardiovascular diseases" in HEALTH AND HUMAN BEHAVIOR, pp. 206-242 (McGraw-Hill, New York 1993). Cardiovascular disease is in general one of several forms including, for example, hypertension (also referred to as high blood pressure), coronary heart disease, blockage and rheumatic heart disease. Peripheral vascular disease refers to diseases of any of the outer blood vessels of the heart. It is in general a narrowing of the blood vessels that carry blood to the muscles of the legs and arms. The term "atherosclerosis" encompasses vascular diseases and conditions that are recognized and understood by practicing physicists 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 blood vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed in terms of "atherosclerosis" and "atherosclerotic disease". The term "antihyperipidemic" refers to the reduction of excessive concentrations of blood lipids to desired levels. Similarly, the term "antiuricemic" refers to the reduction of excessive levels of uric acid in blood to the desired levels. The term "modulated" refers to the treatment, prevention, suppression, enhancement or induction of a function or condition. For example, the compounds of the present invention can modulate hyperlipidemia by reducing cholesterol in a human, and thereby suppress hyperlipidemia. The term "triglyceride (s)" ("TG") as used herein, incorporates their common use. TG consists of three molecules of fatty acids esterified for a glycerol molecule and are used to store fatty acids that are used by muscle cells for the production of energy or are raised and stored in the adipose tissue. Because cholesterol and TG are insoluble in water, they can 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 poor withdrawal. There are at least five different lipoproteins that differ in size, composition, density and function. In the small cells of the intestine, the lipids of the diet are packaged in large lipoprotein complexes called "chylomicrons", which have a high TG content and low cholesterol content. In the liver, Tg and cholesterol esters are packaged and released into the plasma as TG rich in lipoproteins known as very low density lipoproteins ("VLDL"), whose primary function is the endogenous transport of TG carried out in the liver or released by adipose tissue. Through the enzymatic action, VLDL can either be reduced and taken by the liver, or transformed into intermediate density lipoproteins ("IDL"). The IDL is in turn either taken by the liver or is also modified to form low density lipoproteins ("LDL"). LDL are either taken and degraded by the liver or taken by extrahepatic tissue. High density lipoproteins ("HDL") help remove cholesterol from peripheral tissues known as reverse cholesterol transport. The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma that include both depressed and / or elevated lipoprotein levels (e.g., elevated levels of LDL, VLDL and depressed levels of HDL). Exemplary Primary Hyperlipidemis includes but is not limited to the following: (1) Familial Hyperchlomicronemia, a rare genetic disorder that causes deficiencies in an enzyme, LP lipase, which degrades fat molecules. LP lipase deficiency can cause the accumulation of large amounts of fat or lipoproteins in the blood; (2) Familial hypercholesterolemia, a relatively common genetic disorder caused where the underlying effect is a series of mutations in the LDL receptor gene that results in a malfunction of LDL receptors and / or absence of LDL receptors. This causes the ineffective performance of LDL by LDL receptors that result in high LDL and total cholesterol levels in the plasma; (3) Combined familial hyperlipidemia, also known as multiple lipoprotein hyperlipidemia; an inherited disorder where patients and their relatives affected in the first degree can manifest in several periods of time high levels of cholesterol and triglycerides. HDL cholesterol levels are generally moderately reduced; (4) Family Defective Apolipoprotein B-100 is a relatively common autosomal dominant genetic abnormality. The defect is caused by the mutation of a single nucleotide that produces a substitution of glutamine by arginine that can cause a reduced affinity of LDL particles for the LDL receptor. Consequently, this can cause high plasma LDL levels and total cholesterol levels. (5) Familial dysbetaliproteinaemia, also referred to as type III hyperlipoproteinemia, is a rare inherited disorder that results in moderate to severe increases in serum TG as well as cholesterol levels with abnormal functioning of apolipoprotein E. HDL levels are generally normalees; and (6) Familial Hypertriglyceridemia, is a common inherited disorder where the concentration of VLDL in plasma is high. This can cause medium to moderately elevated triglyceride levels (and usually without cholesterol levels) and can often be associated with low plasma HDL levels. The risk factors in Hyperlipidemia Secondary exemplified include but are not limited to the following: (1) disease risk factors, such as a history of Type 1 diabetes, Type 2 diabetes, Cushing's syndrome, hypothyroidism, and certain types of renal failure; (2) drug risk factors, which include pills to control breathing; hormones such as estrogen and corticosteroids; certain diuretics and several β-blockers; (3) risk factors in the diet that include the intake of fats in the diet by total calories greater than 40%; saturated fat intake by total calories greater than 10%; cholesterol intake greater than 300 mg per day; excessive and habitual use of alcohol; and obesity. The terms "obese" and "obesity" refer, according to the World Health Organization, to a Body Mass Index (BMI) greater than 27.8 kg / m2 for men and 27.3 kg / m2 for women (BMI is equivalent to weight (kg ) / height (m2)). Obesity is related to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of Type 2 diabetes (see, for example, Barrett-Conner, E., Epidemiol, Rev. (1989) 11: 172-181, and Knowler et al., Am. Clin Nutr. (1991) 53: 1543-1551). The terms "optional" or "optionally" as used throughout the specification mean that the subsequently described event or circnstacia may but not necessarily occur and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocycle group optionally mono- or di-substituted with an alkyl group" means that the alkyl may not necessarily be present and the description includes situations where the heterocycle group is mono- or di-substituted with an alkyl group and situations where the Heterocycle group is not substituted with the alkyl group.

General Description The present invention derives from the initial disclosure that phenylacetic (phenoxy) and acid (pyridyloxy) phenylacetic acids and their analogs, have a trifluoromethyl substitute in each of the aromatic rings, are extremely effective for the treatment of Type II diabetes and related metabolic disorders.

Description of the Compound Modes In one aspect, the present invention provides compounds having the formula: 1 or a pharmaceutically salt thereof, wherein the letter X represents a member selected from the group comprising 0, S, SO, S02, CHR and NR, where R is H, alkyl (Ci-Cß), C0Ra, C00Ra and C0NRaRb where Ra and Rb are each indistinctly selected from the group comprising H and alkyl (C? -C8); the letter Y represents a member selected from the group comprising CH20Rc, C02Rc, tetrazole, CHO, C0NRcRra, CH (= NRC) and CH (= N0Rc), where Rc is a member selected from the group comprising H, alkyl (C? C8), (C3-C8) alkenyl, (C3-C8) alkynyl, (C3-Ct) cycloalkyl, (C-C8) cycloalkyl, aryl, arylalkyl (C? -8) and alkylene-Z (C? C8), wherein Z is selected from the group comprising C0Rd, COORd, NRdNe, NRdC0NReRf, NRdC0Re, NRdC00Re and C0NRdRe where Rd, Re and Rf are each indistinctly selected from the group comprising H, alkyl (C? ~ C8) and phenyl , or optionally two of Rd, Re and Rf when joined to the same nitrogen atom combine to form a five or six member ring; and wherein Rm is selected from the group comprising H, (C? -C8) alkyl, aryl and OH and Rm and Rc are optionally combined with the nitrogen atom such that each is linked to form a ring of five. or six members; each of the symbols R1 and R3 represents a member selected from the group consisting of halogen, hydroxyl, alkyl (C? -C8), alkenyl (C2-C8), alkynyl (C2-C8), alkoxy (Cx-Cs), (C3-C7) cycloalkyl, (C4-C8) cycloalkyl, (C? -C8) haloalkyl, (C? -C8) heteroalkyl, (C2-C5) heterocyclyl, (C3-C7) cycloalkyl, heterosubstituted, (C3) cycloalkyl -C7) heteroalkylsubstituted, O-haloalkyl (C? -8), nitro, cyano, phenyl, O-phenyl, NRj-phenyl, S (O) x-phenyl, CORj, COORj, NRjRk, S (0) rRj, S02NRjRk , NR ^ ONR ^ 1, NRjCORk, NRjCOORk and CONRjRk, where the phenyl ring is optionally substituted and R3, R and R1 are each indistinctly selected from the group comprising H and (C? -C8) alkyl, including haloalkyl (C? -C8), or optionally two of B? , Rk and R1 when grouped to the same nitrogen atom are combined to form a five or six member ring and the superscript r is an integer from 0 to 2; the symbol R2 represents a member selected from the group comprising H and alkyl (C? -C8); the letter Q represents CH or N; the subscript m is an integer from 0 to 3; and the subscript p is an integer from 0 to 2. Returning first to the link provided in Formula 1 as X, the preferred groups are O, S and NR. In a group of modalities, X is O. In another group of embodiments, X is NR, preferably R is H or alkyl (C? -C4). Preferred groups for Y include CH2ORc, C02Rc, tetrazole, CHO, CONRcRm; with CH2ORc, C02Rc and tetrazole as the most preferred. The most preferred modalities are those where Y is CH2ORc or C02Rc.

Preferred groups for R 1 and R 3 are halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 3 C 8) cycloalkyl, (C 4 -C 8) cycloalkyl, halo (C 1 -C 8), 0- haloalkyl (C? -C8), nitro, phenyl, O-phenyl, NR3-phenyl, NRjC0Rk, S (0) r-phenyl and S (0) rRj. Particularly preferred groups for R1 and R3 are halogen, (C? -C8) alkyl, haloalkyl (C? -C8), nitro, O-phenyl, NRjC0Rk and S (0) rRj. Even other preferred groups for R1 and R3 are F, Cl, alkyl (C? -C4), CF3, NHC0CF3, N02, SCH3 and OC6H4 CF3. The substitute R2 is preferably H or alkyl (C? ~ C4), more preferably H or CH3. In the most preferred embodiments, R2 is H. The letter Q is preferably CH. The subscript m is preferably 0 to 2. In a group of modalities, m is 0. In another group of modalities, m is 1. Even in another group of modalities, m is 2. The subscript p is from 0 to 2. in a group of modalities, p is 0. In another group of modalities, p is 1. Even in another group of modalities, p is 2. Within the groups of previous modalities, certain combinations are also preferred, returning first to the modalities where Q is CH, X is preferably 0, S or NR. Even those modalities where Y is C02Rc are also preferred. Even more preferred are those modalities where m is from 0 to 2 and p is from 0 to 1. Within the group of modalities where Q is CH, X is 0, S or NR, Y is C02Rc, m is from 0 to 2 and p is from 0 to 1, the symbol R1 will preferably represent halogen, nitro, alkyl (C? ~ C8), alkoxy (C? -8) or haloalkyl (C? -8). Returning to the group of modalities where Q is CH, X is 0, S or NR, Y is C02Rc, m is from 0 to 2 and p is from 0 to 1, the symbol R3 will represent preferably halogen, nitro, alkyl (CJ- CB), alkoxy (C? -C8) or haloalkyl (Ci-C?). For those modalities where two groups R3 are present, it is understood that each group R3 is indistinctly selected from the list provided. For each of these modality groups, including those where R1 and R3 are provided with full scope according to Formula I above, the symbol Rc is preferably H, alkyl (C? ~ C8) or alkylene Z (C? -C8 ). Other preferred are those embodiments where R2 is H or CH3. In a group modalities are particularly preferred, Q is CH; X is selected from the group comprising O and NR; Y is selected from the group comprising CH20Rc and C02Rc; the subscript is 0 to 2 and the subscript p is 0 to 1; each R1 is selected from the group comprising halogen, nitro, alkyl (C? -8) and alkoxy (C? -8); each R3 is selected from the group comprising halogen, nitro, alkyl (C? -8) and alkoxy (Ci-Cs); and R2 is H or CH3. The selected groups of modalities within the above are those where (i) X is O and Y is C02Rc; (ii) X is 0 and Y is CH20Rc;; (iii) X is NH and Y is C02Rc; (iv) X is NH and Y is CH2ORc. Even other preferred embodiments for each of these groups are those wherein R1 and R3 are selected from F, Cl, alkyl (Cx-C4), CF3, NHCOCF3, N02, SCH3 and OCsH4-CF3.

Preparation of Compounds Compounds 1 where Y is C02Rc and X is 0, S or NH are prepared as shown in Reaction Schemes la and Ib. Compounds 1 where X is C are prepared as shown in the Reaction Scheme le. An alternative method to introduce the substitute R1 is shown in Reaction Scheme ld, and the routes for preparing the aldehydes (1, Y = CHO), carbinoles (1, Y = CH20H) and carbinol esters (1, Y = CH20C0Rc) are shown in the Reaction Scheme le. The preparation of Compound 1 wherein Y is tetrazole is shown in Reaction Schemes lf, lg. Compounds 1 wherein Y = C00Rc and Rc is H can be converted to compounds 1 wherein Rc is alkyl or aralkyl using conventional esterification methods, for example as described in Organic Chemistry Preparatory for R. B. Wagner and H. D. Zook, Wiley, p. 479 Reaction Scheme 1 - Preparation of Compounds 1 - |, Y = OCORc Reaction Scheme 1 - preparation of Compounds 1 (continued) ol 1 Y = COOH 1, Y = tetrazole Displacement of benzylic bromides with nucleophilic acids As illustrated in Reaction Scheme 1, bromo-esters 2 are reacted with the phenols, amines or mercaptans 3, to provide the products 1. The reaction is carried out in a polar aprotic solvent as tetrahydrofuran or, preferably, dimethylformamide in the presence of a base such as diazabicyclononene or preferably potassium carbonate. The products 1 wherein X is NH can be converted into products where 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 substitutes with f-enylacetic ester ucleophiles Reaction Scheme Ib illustrates the synthesis of products 1 by the reaction displacement of a fluorine atom. The carbinoles, mercaptans or amines 4, X = 0, S, NH or N-alkyl are reacted with a portion of benzene or pyridine substituted with fluorine 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 carried out in an aprotic polar solvent such as tetrahydrofuran or dimethylformamide. The aryl fluoride 5 is then added and the reaction proceeds to provide the products, X = 0, S, NH or N-alkyl.

Condensation reactions of aldehydes 7 with phenylacetic esters 6 The reaction scheme illustrates the synthesis of compounds 1 wherein X is C. In this process, the tert-butyl esters 6 are first reacted with a base such as sodium hydride, in an aprotic solvent such as dimethylformamide. The generated anion is reacted with the aldehydes 7. After the dehydration, the unsaturated products are obtained 8. These compounds are converted into the products 1, X = C, by means of catalytic hydrogenation using for example 5% of palladium on carbon as a catalyst Alkylation reactions to introduce substitutes R2 Reaction Scheme ld illustrates the introduction of the alkyl substitutes R2 by means of an alkylation reaction. In this process, the esters 1 ase react first with a base such as sodium hydride or sodium hexamethyldisilazide in an aprotic solvent such as tetrahydrofuran or dimethylformamide. The alkylating agents R2Br or R2I are then added and the reaction proceeds to provide the ester products 1, where Y is carboxylic ester and R2 is alkyl. Basic hydrolysis, for example, by the use of lithium hydroxide in aqueous tetrahydrofuran, provides carboxylic acids 1 where R2 is alkyl.

Preparation of the aldehyde and carbinol derivatives 1 The Reaction Scheme illustrates the methods for preparing compounds 1 wherein Y is CHO, CH2OH and CH2OCO-alkyl. The compounds 1, Y = COOH are first converted to 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, 79: 252 (1956). The latter compounds are converted to the corresponding carbinols 1, Y = CH 2 OH, by means of a reduction reaction, for example by treatment with sodium borohydride in ethanol or isopropanol. The products 1 Y = CH 2 OH are converted to esters 1, Y = CH 2 OCO-alkyl, by means of acylation reactions, for example by reaction with acetyl chloride in a basic solvent such as pyridine.

Preparation of tetrazole derivatives 1 The Scheme. Reaction lf illustrates methods for preparing compounds 1 where Y is tetrazole. The bromonitriles 10 are reacted with phenols, amines or mercaptans 3m to provide intermediate 11. The reaction is carried out in a polar aprotic solvent such as tetrahydrofuran or preferably dimethylformamide in the presence of a base such as diazabicyclononene or preferably carbonate of potassium. The intermediate 11 is then converted to the tetrazole with an azide or preferably with trimethyltin azide. Alternatively, intermediate 11 can be prepared from compound 1 (Y = COOH) by first transforming the acid into an amide after dehydration (Reaction Scheme lg).

Reaction Scheme 2 - Preparation of Phenylacetic Acid Intermediates F-enylacetic acid and phenylacetonitrile raw materials for the preparation of compounds 1 Many differently substituted phenylacetic acids and precursors thereof are commercially available or are described in the literature. In addition, a number of synthetic routes are available to prepare compounds that have not been previously reported. Reaction Scheme 2 shows some synthetic routes for the variously substituted phenylacetic acids and derivatives thereof. Reaction Scheme 2a illustrates the reaction of Arndt-Eistert, as described in Journal of the American Chemical Society, 72: 5163 (1950), while variously substituted benzoic acids can be transformed into the corresponding phenylacetic acids. In this process, the benzoic acid is first converted to 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, under reflux in an alcohol such as methanol, to provide the corresponding ester of product 13. The Free acid 13 can also be obtained by basic hydrolysis. Alternatively, the ester of 13 can be alkylated, for example by treatment with a strong base such as lithium diisopropylamide, followed by a reaction with a halide R2X, to then provide by basic hydrolysis the alkylated phenylacetic acids 14. Reaction Scheme 2b illustrates the conversion of various bromobenzenes to the corresponding phenylacetic, phenylpropionic, etc., acids. In this process, the substituted bromobenzene is first reacted with magnesium in an ethereal solvent such as tetrahydrofuran, to form the Grignard reagent. An equimolar amount of anhydrous zinc chloride is then added, followed by the addition of ethyl bromoacetate to provide, after basic hydrolysis, the suitably substituted phenylacetic acid, R 2 = H. The compounds 6 wherein R 2 is methyl, ethyl, etc. , can be obtained by employing ethyl 2-bromopropionate or ethyl 2-bromobutyrate, etc., in place of ethyl bromoacetate. Reaction Scheme 2c illustrates the conversion of various substituted benzaldehydes into the a-bromophenylacetic acid feeders. In this procedure described in Synthetic Communications, 12: 763 (1982), benzaldehyde is first reacted with trimethylsilylcyanide in the presence of potassium cyanide and a crown ether to provide the corresponding substituted 17- (trimethylsilyloxy) phenylacetonitriles. These products are then subjected to treatment with an alcohol in the presence of an acid catalyst to produce the α-hydroxyphenylacetic esters 18. The reaction of the latter compounds is carried out with a brominating agent such as triphenylphosphine / carbon tetrabromide as described in US Pat. Tetrahedron Letters, 28: 3225 (1987), providing the bromoesters 19. Reaction Scheme 2d illustrates the conversion of various substituted a-hydroxyphenylacetic esters into the corresponding esters a-bromo and a-mercaptofenylacetic 20 and 4, X = S. In this process, the α-hydroxyphenylacetic esters 4 are converted first to the corresponding a-bromoesters, as described above. The bromo-esters 20 are then reacted with a sulfur nucleophile as sodium thiolacetate to provide the corresponding a-mercaptophenylacetic esters 4, X = S. Reaction Scheme 2e illustrates alternative methods for preparing the a-bromo and a-mercapto-phenylacetic esters 23 and 4, X = S, of the corresponding phenylacetic acids 14. In this process, the acids 14 are first treated with bromide and thionyl chloride to provide the acid chlorides of α-bromine 21. in the treatment with an alcohol, these compounds are converted to a-bromophenylacetic esters 23. Alternatively, phenylacetic acids 14 are first converted to esters 22, using conventional esterification methods. The esters 22 are then reacted with a brominating agent such as bromide or N-bromosuccinimide to provide the a-bromophenylacetic esters 23. These compounds can be transformed into the a-mercaptophenylacetic esters 4, X = S, as previously described. All phenylacetic acids can be converted to the corresponding phenyl acetonitriles by conventional transformations (see Reaction Scheme ig).

Reaction Scheme 3 - Preparations and interconversions of phenols, amines, mercaptans and aldehydes Raw materials of phenol, thiol, amine and aldehyde for the preparation of the compounds 1 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 that have not been previously made. In Reaction Scheme 3 some synthetic routes for, and interconversions between the compounds are shown. Route A represents the synthesis of phenols from the corresponding bromide compounds 24. In this route, the bromide compound is first converted into an organolithium or organomagnesium derivative, respectively, by reaction with an alkyl lithium as n- Butyl-lithium or with metallic magnesium. Compound 25 is then converted to phenol 26 either by direct oxidation using, for example, molybdenum pentoxide as described in Journal of Organic Chemistry, 42: 1479 (1979), or by reaction first with a trialkylborate followed by oxidation with hydrogen peroxide as described in Journal of Organic Chemistry, 24: 1141 (1959). Route B represents the conversion of bromide compounds 24 directly to phenols 26 or thiophenols 28. This reaction proceeds in the case of particularly reactive bromide compounds, for example 2- or 4-bromopyridines (24, Y = N). The reaction can be effected by treatment of the bromopyridine with an aqueous acid or base as described in Rec. Trav. Chim. , 59: 202 (1940). The thiols corresponding to 26 are produced by reacting the bromide reactive compound with sodium sulfide in an alcohol solvent such as ethanol, as described in Rec. Trav. Chim. , 64: 102 (1945). Route C represents the conversion of a phenol 26 into the corresponding thiol 27. In this procedure described in Journal of Organic Chemistry, 81: 3980 (1966), the phenol is first reacted with dimethylthiocarbamoyl chloride, to provide the intermediate thiocarbamate. , where the thermal rearrangement after basic hydrolysis provides thiol 29. Route D represents the preparation of phenols 26 and cyano 31 compounds from the corresponding amine by the diazotization procedure as described in Organic Syntheses, Collective volume 3 , 130, 1955. In this reaction, the amine is reacted with nitrous acid to provide the diazonium salt where the acid hydrolysis produces phenol 26. Alternatively, the diazonium salt can be reacted with cuprous cyanide or nickel cyanide as described above. describes in Organic Functional Group Preparations, by SR Sandler and W. Karo, Academic Press, New York, p. 463 to provide the cyano compound 31. The cyano compound is useful for the preparation of the corresponding aldehyde 7. The E route represents the conversion of the fluorine compound to either the phenols 26, the thiols 28 or the amines 29. In this process , the fluorine compound is reacted with for example, sodium methoxide to provide the corresponding substituted methoxyl product. The methoxyl group is then removed using for example boron tribromide or aluminum chloride to provide the phenol 26. Alternatively, the fluorine compound 5 is reacted with a nitrogen nucleophile such as, for example, sodium azide to provide the corresponding azidobenzene. The reduction of the azido group, for example, by the use of lithium aluminum hydride, provides the amino compound 29. The thiols 28 are obtained by the reaction of the fluorine compounds with a sulfur nucleophile, for example with ethanolic sulfide. sodium. Route F represents the conversion of carboxylic acids 30 to amines 29 by means of rearrangement of Curtius as described in Organic Syntheses, Collective Volume 4, 819, 1963. In this procedure, the carboxylic acid is first converted to the acid chloride by reaction with thionyl chloride. The acid chloride is subjected to treatment with sodium azide to provide the acylazide, where the term rearrangement is carried out in aqueous solution to provide the amines 29. The G route represents the conversion of the carboxylic acids 30 into aldehydes 7 by means of the corresponding nitrile 31. The conversion of carboxylic acids 30 into nitriles 31 can be carried out in a number of routes, as described in Comprehensive Organic Transformations, by RC Larock, VCH Publishers, 1989, p. 963ff. For example, the carboxylic acid can first be converted to the acid chloride and the latter compound is then reacted with ammonia to provide the corresponding amide. Treatment of the amide with, for example, p-toluenesulfonyl chloride in pyridine then produces the nitrile 31. The nitrile can then be reduced to produce the aldehyde 7, for example by using diisobutylaluminum hydride as described in Journal of the American Chemical Society , 107: 7524 (1985). Route H represents the conversion of carboxylic acids 30 to the corresponding aldehydes. This conversion can be carried out on a number of routes as described in Comprehensive Organic Transformations by R. C. Larock, VCH Publishers, 1989, p. 619ff. For example, the carboxylic acid can first be converted to the acid chloride as described above. The latter compound can then be hydrogenated using a palladium catalyst on barium carbonate as described in Journal of the American Chemical Society, 108: 2608 (1986), or by reduction using lithium aluminum tri-butoxy-tertiary hydride, as described in Journal of the American Chemical Society, 79: 252 (1956) to produce the aldehydes 7.

Reaction Scheme 4 - Examples of protection and deprotection Desprnteger Protection and deprotection of reactive groups during synthesis Derivatives of phenylacetic acid 2, 4 and 6 can contain reactive groups such as IH, SH and NH2 that can generate undesired reactions during synthetic procedures. These groups may, according to the judgment of the person skilled in the art, require protection before a given synthetic step and deprotection after the synthetic step. Reaction scheme 4 shows examples of protection and deprotection. The selection, binding and removal of protective groups are described, for example, in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by TW Greene and PGM Wuts, Wiley, 1991. Reaction Scheme 4a illustrates the protection of a derivative of phenylacetic acid substituted by a hydroxyl 32. The compound is reacted with tert-butylchlorodimethylsilane in the presence of imidazole to produce the silyl ether 33. After the reaction, as described above with intermediate 3, the protected product 34 is provided, the protecting group is removed by treatment with tetrabutylammonium fluoride to produce the final product 1. Silylation / desilylation processes are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by TW Greene and PGM Wuts, Wiley, 1991, p. 145 Reaction Scheme 4b illustrates the protection of a mercapto-substituted phenylacetic acid derivative. The compound is reacted with 4-methoxybenzyl chloride to produce the thioether 35. This compound is reacted as described above with the intermediate 5 to produce the coupled product 36. The deprotection is carried out using mercuric acetate in trifluoroacetic acid which then provides the final product 1. the benzylation / debenzylation procedures are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by TW Greene and PGM Wuts, Wiley, 1991, p. 281. Reaction Scheme 4c illustrates the protection of an amino-substituted phenylacetic acid derivative. The compound is reacted with tert-butoxycarbonyl chloriro to produce the carbamate 37. After condensation with the aldehyde 7 as described above and the subsequent dehydration / hydrogenation steps, intermediate 36 is obtained. The deprotection is carried out performed using trifluoroacetic acid which provides the final product 1. Silylation / desilylation processes are described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, by TW Greene and PGM Wuts, Wiley, 1991, p. 327 Preparation of individual enantiomers of the compounds 1 The individual enantiomers of those compounds 1 can be separated by a variety of methods well known to those skilled in the art, for example, the racemic carboxylic acids 1 can be converted into salts with a chiral amine, such as for example, quinine, cinchonidine and the like. Fractional crystallization of the resulting salt, followed by release of the redissolved acids then provides the chiral compound 1. Alternatively, the chiral carboxylic acids can be converted to amides from chiral amines such as, for example, (R) or (S) 1-phenylethylamine. The resulting diastereomeric amides can then be separated by chromatography and the chiral acids regenerated by idolysis. Alternatively, the racemic compounds 1 can be separated into individual enantiomers by chiral HPLC. In addition, the racemic phenylacetic acid precursors of compounds 1 can be separated into individual enantiomers by using, for example, the methods described above before the formation of compounds 1.

Reaction Scheme 5 - Nomenclature 43 44 45 Nomenclature The compounds of this invention are known as the derivatives of phenylacetic acids. Compounds 1 wherein X is O, S or NH are respectively known as phenoxyl, phenylsulfanyl or phenylamino phenylacetic acid. Reaction Scheme 5 shows the representative compounds of this invention. The numbering system for the substitutes is shown from compound 39. The names of the representative structures of Reaction Scheme 6 are as follows: 39 acid (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) - acetic; (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 acid - (3-trifluoromethyl-phenyl) -propionic; 44 N- [2-idroxy-1- (4-trifluoromethyl-phenyl) -ethyl] -N- (2-trifluoromethyl-phenyl) -acetamide; ethyl ester of the acid ( 4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic The names were generated by Autonom.

Pharmaceutical Compositions and Methods for the Treatment of Diseases and Conditions In accordance with the present invention, a therapeutically effective amount of a compound of Formula 1 can be used for the preparation of a pharmaceutical composition useful for the treatment of an inflammatory condition, diabetes treatment. , treatment of hyperlipidemia, treatment of hyperuricemia, treatment of obesity, reduce triglyceride levels, reduce cholesterol levels, increase the level of high density lipoproteins in plasma and for treatment, prevention or reduction of the risk of developing atherosclerosis.

The compositions of the invention may include the compounds of formula 1, pharmaceutically acceptable salts thereof or a hydrolysable precursor thereof. In general, the compounds are mixed with acceptable carriers or excipients in a therapeutically effective amount. By "therapeutically effective dose", "therapeutically effective amount" or interchangeably "pharmacologically acceptable dose" or "pharmacologically acceptable amount" is meant that a sufficient amount of the compound of the present invention and a pharmaceutically acceptable carrier may be present at In order to achieve the desired result, for example, improve a symptom or complication of Type 2 diabetes. The compounds of formula 1 which are used in the methods of the present invention can be incorporated into a variety of formulations for therapeutic administration. More pcularly, the compounds of formula 1 can be formulated into pharmaceutical compositions by combination with suitable pharmaceutically acceptable carriers or diluents and can be formulated as solid, semisolid, liquid or gaseous forms, such as tablets, capsules, lozenges, powders, granules. , gregeas, gels, emulsions, ointments, solutions, suppositories, injections, inhalants and aerosols. Thus, the administration of the compounds can be carried out in various routes including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal administration. Moreover, the compound can be administered rather locally as systemically in a depot or sustained release formulation. In addition, the compounds can be administered in a liposome. The compounds of formula 1 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 via intramuscular or intravenous routes. The compounds can be administered transdermally and can be formulated as a sustained release dosage form and the like. The compounds of Formula 1 can be administered alone, in combination with one another or can be used in combination with other known compounds (see Combination Therapy below). Formulations suitable for use in the present invention are found in Remington's Pharmaceutical Sciences (Mark Publishing Company (1985) Philadelphia, PA, 17th edition), which is incorporated herein by reference. Furthermore, for a brief review of drug delivery methods, see Langer, Science (1990) 249: 1527-1533, which is incorporated herein by reference. The pharmaceutical compositions described herein can be manufactured in a manner known to the person skilled in the that is, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The following methods and excipients are merely exemplary and do not limit the paths. For injection, the compounds may be formulated into preparations upon dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, higher aliphatic acid esters 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 Hank's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, appropriate penetrants are used to the barrier to make it permeable. These penetrants are generally known in the art. For oral administration, the compounds of formula 1 can be rapidly formulated by combining them with pharmaceutically acceptable carriers that are well known in the art. These carriers allow the compounds to be formulated as tablets, lozenges, lozenges, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, mixtures, suspensions and the like, for oral ingestion by a patient undergoing treatment. Pharmaceutical preparations for oral use can be obtained by mixing the compounds with a solid excipient, optionally grinding a resulting mixture and processing the granule mixture, after adding suitable auxiliaries, if desired, to obtain tablets or dragee centers. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydrocylpropylmethyl cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linking polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. Dragee centers are provided with adequate coatings. For this purpose, concentrated sugar solutions can be used, which optionally contain gum arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. The dyes or pigments can be coated onto the tablets or coated with dragees for identification or to characterize different combinations of doses of active compounds. Pharmaceutical preparations that can be used orally include push capsules made of gelatin as well as softly sealed capsules made of cgelatine and a plasticizer such as glycerol or sorbitol. The push capsules may contain the active ingredients in a mixture with filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally, stabilizers. In soft capsules, 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 oral administration formulations may be in doses suitable for administration. For buccal administration, the compositions may take the form of tablets or diamonds formulated in a conventional manner. For administration by inhalation, the compounds to be used according to the present invention are conveniently delivered in the form of an aerosol spray presentation of pressurized packets or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane , carbon dioxide or other suitable gas, or free of propellant, dry powder inhalers. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for the release of a measured quantity. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated by containing a mixture of powder and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by means of an injection bolus or continuous infusion. Formulations by injection may be presented as a dosage unit, for example, in ampules or in multi-dose containers, with an additional preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble forms. Additionally, suspensions of the active compounds can be prepared as oily injectable suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or suitable agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions, suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, carboceras, polyethylene glycols or other gylcerides, all with a melting point at body temperature, but which solidify at room temperature. In addition to the formulations described previously, the compounds can also be formulated as a depot preparation. Formulations that act for prolonged periods can be administered by implantation (for example, as an emulsion in an acceptable oil) or by ion exchange resins or as economical soluble derivatives, for example, a soluble and economical salt. Alternatively, other delivery systems of the pharmaceutically hydrophobic compounds can be used. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In a currently preferred embodiment, large circulants, i.e., discrete liposomes, may be employed. Liposomes are described generally in Woodle et al. , U.S. Patent No. 5,013,556. The compounds of the present invention may also be administered by controlled release means and / or delivery devices such as those described in US Pat. Nos. 3,845,770; 3,916,899: 3,536,809; 3,598,123 and 4,008,719. Certain organic solvents such as dimethylsulfoxide (DMSO) can also be used, although usually the cost is a great toxicity. Additionally, the compounds can be released using a sustained release system, such as semipermeable matrices of solid idrophobic polymers containing the therapeutic agent. Various types of sustained release materials have been established and are well known to the person skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few hours up to 100 days. The pharmaceutical compositions may further comprise suitable solid phase or gel carriers or excipients. Examples of these carriers or excipients include but are not limited to calcium carbonate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. 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, according to the weight of the subject, the severity of the affliction, the form of administration and the judgment of the prescribing physician. The determination of an effective amount is well within the ability of the person skilled in the art, especially by virtue of the detailed description provided herein. For any compound used in the method of the present invention, a therapeutically effective dose can be estimated initially from the analysis of cell cultures or animal models. Moreover, the toxicity and therapeutic efficacy of the compounds described herein can be determined by conventional pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the lethal dose of 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index that can be expressed as the ratio between LD50 and ED50. Compounds that show high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dose ratio that is non-toxic for human use. The dosage of these compounds is preferably supported within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this proportion depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dosage can be individually selected by the physician in view of the patient's condition. (See, for example, Fingí et al., 1975 In: The Pharmacological Basis of Therapeutics, Chapter 1). The amount of active compound that can be combined with the carrier material to produce a simple dosage form can vary depending on the disease being treated, the species of mammal and the particular form of administration. However, as a general guide, suitable dosage units 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 dosage unit is between 500 mg to about 1500 mg. A more preferred dosage unit is between 500 to about 1000 mg. These dosage units 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, such that the daily dosage for an adult of 70 kg is in the proportion of 0.1 to about 250 mg per kg of subject weight per administration. A preferred dosage is from 5 to about 250 mg per kg of subject weight per administration and this therapy may be extended for a number of weeks or months and in some cases, years. It will be understood, however, that the specific dosage 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 to be treated; the time and route of administration, the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease submitted to therapy, will be well understood by those experts in the area.

A typical dosage may be a tablet of 10 to about 1500 mg taken once a day or multiple times a day, or a time-release capsule taken once a day containing a highly proportional content of the active ingredient. The effect of release time can be obtained by capsule materials that dissolve at different pH values, by capsules that are released slowly by osmotic pressure, or by other known means of controlled release. It may be necessary to use dosages outside these proportions which in some cases will be apparent to the person skilled in the art. In addition, it will be noted that the clinician or attending physician will know how and when to interrupt, adjust or terminate the therapy in conjunction with the patient's individual response.

Combination Therapy As noted above, the compounds of the present invention may in some instances be used in combination with other therapeutic agents to achieve the desired effect. The selection of additional agents will be largely dependent on the desired target therapy (see, for example, Turner N. et al. Prog. Drug Res. (198) 51: 33-94; Haffner, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. Et al. (Editors), Diabetes Reviews (1997) Vol. 5 No. 4).

A number of studies have investigated the benefits of combination therapies with oral agents (see for example, Mahler, R., J. Clin, Endocrinol, Metab. (1999) 84: 1165-71, Prospective Study Group of Diabetes. from the United Kingdom: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, CW, (editor), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOL1SM, 6th 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; Keroerovich, P. Am. J. Cardiol. 1998) 82 (12A): 3U-17U). These studies indicate that the regulation of diabetes and hyperlipidemia can also be improved by the addition of a second agent to the therapeutic regimen. The combination therapy includes the administration of a simple pharmaceutical dosage containing a compound having the general structure of formula 1 and one or more additional active agents as well as the administration of a compound of formula 1 and each active agent in this formulation own of separate pharmaceutical dosage. For example, a compound of formula 1 and a HMG-CoA reductase inhibitor can be administered to the human subject together with a simple oral dosage composition, such as a tablet or capsule, or caga agent can be administered separately in oral dosage formulations. While the dosage formulations are used separately, a compound of formula 1 and one or more additional active agents can be administered at essentially the same time (ie, concurrently), or at staggered times separately (ie, sequentially) . The combination therapy is understood to include all of these regimens. An example of a combination therapy that regulates atherosclerosis (prevents attack of symptoms or associated complications), wherein a compound of formula 1 is administered in combination with one or more of the active compounds: an antihyperlipidemic agent; an agent that increases HDL in plasma; an antihypercholesterolemic agent, such as the cholesterol biosynthesis inhibitor, for example, a hydroxymethylglutaryl (HMG) CoA reductase inhibitor (also referred to as statins, such as loastatin, sinvastatin, pravastatin, fluvastatin and atrovastatin), an HMG-CoA synthase inhibitor, an squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as an squalene synthase inhibitor); an inhibitor acyl-coenzyme A cholesterol acyltransferase (ACAT), such as melinamide; probucol; nicotinic acid and the salts of these and niacinamide; a cholesterol absorption inhibitor, such as β-sitosterol; an anionic exchange resin bile acid sequester, such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a cross-linking dextran; an inducer of LDL (low density lipoprotein); fibrates such as clofibrate, bezafibrate, fenofibrate and genfibrizol; vitamin Be (also known as pyridoxine) and pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin Bi2 (also known as cyanocobalamin); vitamin B3 (also known as nicotinic acid and niacinamide, supra); antioxidant vitamins such as vitamins C and E and beta carotenes; a beta-blocker; an angiotensin II antagonist; an enzyme inhibitor that converts angiontensin; and a platelet aggregation inhibitor such as fibrinogen receptor antagonists (i.e., glycoprotein receptor IIb / fibrinogen Illa antagonists) and aspirin. As noted above, the compounds of formula 1 can be administered in combination with more than one additional active agent, for example, a combination of a compound of formula 1 with an HMG-CoA reductase inhibitor (for example, lovastatin, sinvastatin and prevastatin) and aspirin, or a compound of formula 1 with an HMG-CoA reductase inhibitor and a β-blocker. Another example of combination therapy can be seen in the treatment of obesity or in disorders related to obesity, where the compounds of formula 1 can be used effectively in combination with for example, phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine, fentiramine, β3-adrenoceptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat) and leptins. Other agents used in the treatment of obesity or in disorders related to obesity where the compounds of formula 1 can be used effectively in combination with for example neuropeptide Y, enterostatin, colecitoquinine, bombesin, amylin, histamine H3 receptors, receptors of dopamine D2, melanocyte stimulating hormone, corticotrophin release factor, amino gamma butyric acid and galanin (GABA). Even another example of combination therapy can be seen in the regulation of diabetes (or treating diabetes and its related symptoms, complications and disorders), where the compounds of formula 1 can be used effectively in combination with for example, sulfonylureas (such as chlorpropamide) , tolbutamide, acetohexamide, tolazamide, glyburide, glyzazoda, glinease, glimepiride and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone and rosiglitazone); dehydroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-S04); antiglucocorticoids; TNFa inhibitors; a-glucosidase inhibitors (such as acarbose, miglitol and voglibose), pramlintide (a synthetic analogue of the human hormone amylin), other insulin secregogues (such as repaglinide, gliquidone and nateglinide), insulin, as well as the active agents discussed above for the treatment of atherosclerosis. A further example of combination therapy may be in the regulation of hyperlipidemia (treatment of hyperlipidemia and its related complications), wherein the compounds of formula 1 can be effectively used in combination with for example, statins (such as fluvastatin, lovastatin, pravastatin or sinvastatin), resins that bind to bile acid (such as colestipol or cholestyramine), nicotinic acid, probicol, beta-carotene, vitamin E or vitamin C. Additionally, an effective amount of a compound of formula 1 and a therapeutically effective of one or more active agents selected from the group consisting of: an antihyperlipidemic agent; an agent that increases HDL in plasma; an anti-hypercholesterolemic agent, such as a cholesterol biosynthesis inhibitor, for example, a HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthase inhibitor (also known as an squalene synthase inhibitor); an acyl-coenzyme A cholesterol acyltransferase inhibitor; probucol; nicotinic acid and salts thereof; niacinamide; a cholesterol absorption inhibitor; an anion exchange resin bile acid sequestrant; a low density lipoprotein receptor inducer; clofibrate; fenofibrate and genfibrozil; vitamin B6 and pharmaceutically acceptable salts thereof; vitamin B? 2; an antioxidant vitamin; a β-blocker; an angiotensin II antagonist; an angiotensin-converting enzyme inhibitor; an inhibitor of platelet aggregation; a fibrinogen receptor antagonist; aspirin; Fentiramines; ß3 adrenergic receptor agonists; sulfonylureas, biguanides, a-glucosidase inhibitors, other insulin secretes and insulin can be used together for the preparation of a pharmaceutical composition useful for the treatments described above.

Equipment In addition, the present invention provides equipment with dosage unit of the compounds of formula 1, either in oral or injectable dose. In addition to the containers that contain the unit doses, there is an information package insert that describes the use and benefits of functioning of the drugs in the improvement of symptoms and / or complications associated with Type 2 diabetes, as well as in the improvement of hyperlipidemia and hyperuricemia, or to improve PPAR-dependent conditions. Preferred compounds and dosage unit are those described herein above. For the compositions, methods and compounds provided herein, one skilled in the art will understand that the preferred compounds to be used in each are those compounds that are preferred above and particularly those compounds provided in the Examples below.

EXAMPLES Experimental Section General Methods. All operations involve moisture and / or oxygen sensitive materials that are conducted under a dry nitrogen atmosphere in a previously dry glass container, unless noted otherwise, the materials were obtained from commercially available sources and used without further purification. The rapid chromatography on silica gel of E. Merck 60 (240-400 mesh) was carried out according to the protocol of Still, Kahn and Mitra [J. org. Chem. 1978, 43, 2923). Thin layer chromatography was carried out using previously purchased coated plates from E. Merck (silica gel 60 PF254, 0.25 mm) and the tips were visualized with long wave ultraviolet light followed by a suitable staining reagent.

A nuclear magnetic resonance (NMR) spectrum was recorded on a Varian Inova-400 resonance spectrometer. The chemical increase of the RMN was provided in parts per million (d) diluted tetramethylsilane (TMS) using TMS or the residual signal of the solvent (CHC13 = d 7.24, DMSO = d 2.50) as internal standard. The information of H NMR was tabulated in the following format: number of protons, multiplicity (s, simple, d, doublet, t, triplet, q quartet, m multiplet), coupling constant (s) (") in hertz and in selected cases, position assignment The app prefix is occasionally applied in cases where the true signal multiplicity was not resolved and br indicates that the signal in question is extended The combustion analysis was carried out by Laboratorios Robertson Microlit, Inc (Madison, NJ, USA) and the optical rotations were quantified in a Perkin-Elmer 241 MC polarimeter and reported as: [a] t? (C = (g / 100 ml), solvent). carried out in a Fisher-Johns team 12-144 and were not corrected.

Preparation 1. Bromo- (2-chloro-5-trifluoromethyl-phenyl) -acetic acid ethyl ester 49. 2-Chloro-5-trifluoromethylbenzoic acid was dissolved 46 (0.1 mol) in dichloromethane (100 ml). To these were then added thionyl chloride (0.2 mol) and dimethylformamide (0.1 ml). After one hour the solvents were removed under vacuum. The residue was dissolved in ethyl acetate and ethereal diazomethane (0.2 mol) was added. After one hour, the solvents were removed under reduced pressure to obtain diazoketone 47. This compound (0.05 mol) was dissolved in ethanol (100 ml). The solution was allowed to reflux and a solution of silver benzoate (0.02 mol) in triethylamine (5 ml) was added. After 10 minutes, the solution is cooled, filtered and the filtrate concentrated to produce a residue. The residue was subjected to chromatography 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 9) was added.The progress of the reaction was monitored by TLC.When the reaction was completed , the mixture was acidified with dilute hydrochloric acid and extracted with ether, the extract was dried and concentrated to yield (2-chloro-5-trifluoromethyl-phenyl) -acetic acid 48. Using the above procedure, various benzoic acids can be converted to The corresponding phenylacetic acids The acid 48 (0.01 mol) was dissolved in 1,2-dichloromethane (50 ml) Thionyl chloride (0.011 mol) was added and the mixture was heated at 55 ° C for one hour. (0.01 mol) After another 18 hours, the mixture was cooled to 0 ° C and ethanol (50 ml) was added.After two hours, the mixture was added to water and extracted with ether. and concentrated to provide the title compound 49. Uti By carrying out the above procedure, various phenylacetic acids can be converted into the corresponding bromide esters analogous to 49.

Preparation 2. ethyl ester of 2-bromo-2- (3-trifluoromethyl-phenyl) -propionic acid 50 51 52 3-Trifluoromethylbromobenzene 50 (0.2 mol.sup.9 in dry tetrahydrofuran (100 ml) was dissolved in. A small amount of metallic magnesium was added and the mixture was heated until the reaction started.Additional magnesium (0.2 mole) was added. reflux until the magnesium was consumed.An anhydrous zinc chloride solution (0.2 mol) in tetrahydrofuran (50 ml) was added.The mixture was maintained at 55 ° C for two hours and then ethyl 2-bromopropionate (0.2 ml) was added. The mixture was maintained at 55 ° C and the progress of the reaction was monitored by TLC.When the reaction was complete, the mixture was cooled and added into water and ether.The organic layer was dried and concentrated and the The residue was subjected to chromatography to produce the 2- (3-trifluoromethyl-phenyl) -propionic acid ethyl ester 51. Using the above procedure, but using different substituted bromotrifluoromethylbenzenes instead of 50, and different bromoést you are instead of ethyl 2-bromopropionate, the corresponding analogs were obtained for 51. 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 to 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 yield the title compound 52. Using the above procedure, but using different esters instead of 51, prepared as described above, different bromoesters analogous to 52 were obtained.

Preparation 3. Bromo- (4-trif luoromethyl-f-enyl) -acetic acid methyl ester, 56. 4-Trifluoromethylbenzaldehyde 53 (0.1 mol) was dissolved in dichloromethane (150 ml) and a catalytic amount of potassium cyanide and 18-Corona-6 was added. The mixture was cooled on ice and trimethylsilyl cyanide (0.1 mol) was added. After 16 hours at 25 ° C, the solution was washed with aqueous sodium bicarbonate, dried and concentrated to yield silyl cyanohydrin 54. This material was dissolved in methanol (100 ml) and hydrogen chloride was bubbled into the solution for several minutes at 0 ° C. After 16 hours at 25 ° C, the mixture was neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried and concentrated and the residue was subjected to chromatography to produce the methyl ester of hydroxy- (4-trifluoromethyl-phenyl) -acetic acid, 55. Using the above procedures, various substituted trifluoromethylbenzaldehydes can be converted to the esters of hydroxyl. Ester 55 (0.05 mol) and triphenylphosphine (0.05 mol) were dissolved in dichloromethane (250 ml) at 0 ° C and carbon tetrabromide (0.05 mol) was added. After 16 hours at 25 ° C, the solvent was removed and hexane: ethyl acetate (300 ml) was added in a 2: 3 ratio. The precipitate was removed by filtration under vacuum. The residue was subjected to chromatography to yield the title compound 56. Using the above procedure, the various hydroxyesters, prepared above as described in B, can be converted into the corresponding bromoesters.

Preparation 4. 2, 4-bis-trifluoromethyl-benzenethiol, N60 2, -di (trifluoromethyl) phenol 57 (0.1 mol) was dissolved in pyridine (50 ml) and dimethylaminothiocarbamoyl chloride (0.1 mol) was added. The mixture was heated at 60 ° C for 12 hours, then cooled and added to the water. The aqueous solution was extracted with ether and the extract was washed with dilute hydrochloric acid, then dried and concentrated to yield diethio-thiocarbamic acid of 0- (24-bis-trifluoromethyl-phenyl) ester 58. This compound was dissolved in N methylpyrrolidone (50 ml) and the solution was heated to reflux. The progress of the reaction was monitored by TLC. When the reaction was complete, the cold solution was added to the water and extracted with ether. The extract was dried and concentrated or the residue was subjected to chromatography to produce S- (2-dimethyl-thiocarbamic acid., 4-bis-trifluoromethyl-phenyl) ester 59. This compound (0.05 mol) was dissolved in methanol and 1N aqueous sodium hydroxide (0.05 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, the solution was added in dilute hydrochloric acid and extracted with ether. The extract was dried and concentrated to yield the title compound 60. Utilizing the above procedures, but using different phenols substituted with trifluoromethyl, the corresponding thiophenols are obtained.

Preparation 5. mercapto- (4-trif luoromethyl-f-enyl) acetic acid methyl ester 63 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 mol9 eb water (5 ml) was added. the reaction was minotored by TLC.When the reaction was complete, the hydrochloric fcdilide solution was added and extracted with ether.The extract was dried and concentrated to give compound 62. The residue 62 was dissolved in methanol and ammonia was added. 5% aqueous (10 ml) After two hours, the mixture was acidified with dilute hydrochloric acid and extracted with ether, the organic phase was dried and concentrated and the residue was subjected to chromatography to obtain the title compound 63. Using the above procedure, but using different bromoesters, the corresponding mercaptoesters were obtained.

Preparation 6. 2, 5-bis-trif luoromethyl-benzaldehyde, 66. 64 65 66 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 0 ° C and a solution of sodium nitrite (0.1 mol) and water (50 ml) was added with vigorous stirring. After 10 minutes, the above solution was added to a solution of nickel cyanide (0.1 mol9 in water (100 ml) at 0 ° C. After two hours, the mixture was heated at 60 ° C for 30 minutes, then The mixture was cooled and extracted with ethyl acetate.The extract was dried and concentrated and the residue was subjected to chromatography to obtain 5-bis-trifluoromethylbenzonitrile 65. This compound (0.05 mol) was dissolved in toluene (50 ml). At -80 ° C and a 1.5 M solution of diisobutylaluminum hydride (0.05 mol) in toluene was added, after two hours, the mixture was heated to 50 ° C for one hour, water was added and the organic phase was dried and dried. The residue was subjected to chromatography to obtain the title compound 66. Using the above procedures, different anilines substituted with trifluoromethyl can be converted into the corresponding benzaldehydes.

Preparation 7. 2-trif luoromethyl- -nitro phenol 69 and 2-trif luoromethyl-4-trifluoromethylacetamino-f-enol 71. 1-fluoro-4-nitro-2-tpfluoromethylbenzene 67, was dissolved in tetrahydrofuran (100 ml). The solution was cooled to 0 ° C and sodium methoxide (0.1 mol) was added. The reaction was heated at room temperature for two hours. Water and ethyl acetate were added. The organic phase was dried and concentrated to obtain l-methoxy-4-nitro-2-trifluoromethylbenzene 68. This material was dissolved in methylene chloride (100 ml) and the solution was cooled to -78 ° C. Boron tribromide (0.1 mol) was added. The mixture was heated to room temperature. Water was added and the organic phase was dried and concentrated. Chromatography afforded the title compound 69. L-methoxy-4-nitro-2-trifluoromethylbenzene 68 (0.1 mol) and SnCl 2 (1 mol) were mixed in EtOAc. The mixture was stirred at room temperature for two hours and then refluxed for three hours until TLC indicated the end of the reaction. The reaction mixture was cooled and quenched with aqueous NaHCO3. The solid was filtered through a pad of celite and washed with EtOAc. The organic layer of the filtrate was collected, dried and concentrated to obtain the corresponding aniline. It was added to the aniline (0.05 mol) in methylene chloride (200 ml) Et3N and (CF3CO) 20 at 0 ° C. The reaction was allowed to warm to 25 ° C with stirring. The reaction was worked on EtOAc and water. The organic layer was dried and concentrated. The residue was purified on a column in silica gel to obtain 70. This material was dissolved in methylene chloride (100 ml) and the solution was cooled to -78 ° C. Boron tribromide (0.1 mol) was added. The mixture was heated to room temperature. Water was added and the organic phase was dried and concentrated. Chromatography afforded the title compound 71. Using the above procedures, but employing different substituted fluorobenzenes, the corresponding substituted phenols can be obtained.

Preparation 8. (2-Acetamidoethyl) -4-trif luoromethylphenylbromoacetate 73 73 A 250 ml three neck round bottom flask was equipped with an efficient condenser attached to an acidic cleaner, a magnetic stir bar and placed in an argon atmosphere. 4-Trifluoromethylphenylacetic acid 72 (0.25 mol) was charged, followed by thionyl chloride (0.34 mol). The condenser was cooled with water at 4 ° C. The mixture was heated to an internal temperature of 55-60 ° C. The evolution of the gas was observed and the dissolved solids as well as the internal temperature reached up to 55-60 ° C. Then the mixture was stirred at 55-60 ° C for 45 minutes. Bromide (33.0 ml, 0.33 mol) was charged and the mixture was maintained at 55-60 ° C for 18 hours. The internal temperature then reached 80-85 ° C for 1.5 hours and the heating continued for 18 hours. The mixture was cooled to 20-25 ° C and anhydrous dichloromethane (250 ml) was added. In a separate flask was placed 2-acetylethanolamine (1.03 mole) and anhydrous dichloromethane (250 ml) under an atmosphere - of argon and the mixture was cooled to 2-8 ° C. To this was added an acyl halide solution at a rate to maintain the internal temperature below 21 ° C. After finishing the addition, the mixture was stirred for 0.5 hours. The mixture was carefully added in water (0.75 liters) with a content of sodium bicarbonate (0.9 moles) at a rate where the foam was moderate. The layers were then divided in a separating funnel (100 ml of dichloromethane used in the transfer) and the organic phase was extracted with 125 ml of water, dried over magnesium sulfate (10 g) and filtered. The filtered paste was washed with dichloromethane (150 ml). Rotary evaporation and high vacuum pumping provided an oil, which was mixed in 100 ml hexane: ethyl acetate 870: 30). Additional hexane (150 ml) was added until a white color formed in the upper layer of the biphasic mixture. Vigorous stirring produced a solid which was filtered away from the supernatant to obtain (2-acetamidoethyl-4-trifluoromethylphenylbromoacetate) By using the above procedure, but using substituted phenylacetic acids, the corresponding a-bromo-phenylacetates can be obtained.

Preparation 9. 5-trif luoromethyl-2- (3-trif luoromethyl-f-enoxy) -phenylamine 77.

Phenol 75 (0.5 mol) was stirred at 25 ° C with K2C03 in DMF for two hours. Then the mixture was cooled to 0 ° C to add 74 in DMF slowly. The reaction mixture was stirred and allowed to warm to 25 ° C. The reaction was worked between water and EtOAc after TLC indicated the end of the reaction. The organic layer was dried and concentrated to obtain compound 76. A mixture of compound 76 (100 g) and SnCl2-H20 (321 g) in EtOAc (1000 ml) was stirred at room temperature overnight. The reaction mixture was made basic by adding an aqueous KOH solution. The organic layer was washed with e, dried and concentrated to provide compound 77 as a pale yellow oil, which was used for the next reaction without purification. 1 H NMR (CDC13, 400 MHz) d 7.49-6.90 (m, 7H), 4.06 (s, 2H). Using the above procedure, but using different nitrofluorobenzenes and substituted phenols, the corresponding anilines are obtained.

Preparation 10. a-Bromo- (3-trifluoromethyl-methyl) -acetic acid ethyl ester, 79. benzoyl peroxide (catalyst) "yy ^ CCI4, reflux, overnight 78 79 To a solution of (a, a, a-trifluoro-j7-tolyl) acetic acid 78 (202.36 g, 0.99 mol) in absolute ethanol (1.0 L) at 0 ° C was added thionyl chloride (79 ml, 1.05 g). mol) and then the resulting solution was refluxed for 3 hours. Concentration in vacuo gave a residue that was partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO 3 and e, dried over Na 2 SO 4 and concentrated in vacuo to obtain 220.1 g of the ethyl ester as a pale yellow liquid. To a mixture of crude ethyl ether (119.15 g, 0.51 mol) and NBS (100.48 g, 0.56 mol) in CC14 (1.0 L) was added benzoyl peroxide (1.0 g). The resulting mixture was heated at 75 ° C for 20 minutes and refluxed at 90 ° C overnight (14 hours) until the brown mixture turned pale with a white precipitate. The mixture was cooled to 0 ° C, filtered through a pad of celite, concentrated in vacuo to obtain 151.27 g (95%) of bromide 79 as a light brown liquid. This product is pure enough to be used directly in the subsequent substitute reaction. This product can also be prepared by refluxing the acid (a, a, a-trifluoro-jn-tolyl) acetic acid 78 with bromide in the presence of S0C12 and then quenching the reaction with EtOH. ^? NMR (400 MHz, CDC13): 5 7.80 (HH, s), 7.77 (HH, d), 7.61 (HH, d), 7.51 (1H, t), 5.35 (1H, s), 4.26 (2H, q) , 1.30 (3H, t) ppm. Using the above procedure, but using different substituted phenylacetic acids, the corresponding a-bromo-phenylacetates are obtained.

Example 1 Preparation of (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid 39.

Dimethylformamide (200 ml) is stirred for 16 hours 4-trifluoromethylphenol (43.8 g, 0.27 mol), bromo- (3-trifluoromethyl-phenyl) -acetic acid ethyl ester 79 (70 g, 0.225 mol) and potassium carbonate ( 56 g, 0.405 mol 9. Ethyl acetate and brine are added and the organic phase is dried and concentrated, the residue is subjected to chromatography to obtain the ester of (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid. 80, as an oil This material is dissolved in tetrahydrofuran / methanol (400 ml / 300 ml) and added with lithium hydroxide IN (300 ml) After one hour, IN hydrochloric acid (300 ml) is added. The mixture is extracted with ethyl acetate.The extract is dried and concentrated to obtain the title compound 39 as a white solid.R-NMR (d6-DMSO): d 7.88-7.85 (m, 2H), 7.62-7.55 ( m, 4H), 7.09 (d, 2H), 5.52 (s, ÍH).

Using the above procedures, but replacing the phenols and bromoesters suitable for 79, the following compounds were obtained: (2-trif luoromethyl-f-enoxy) - (3-trifluoromethyl-phenyl) -acetic acid, 82, X H NMR (400 MHz, DMSO-dff): d 7.94 (HH, s), 7.85 (HH, d), 7.72 (HH, d), 7.65 (HH, d), 7.64 (HH, d), 7.59 (1H , t), 7.14 (lH, d), 7.10 (lH, t), 6.01 (lH, s), ppm; (4-trifluoromethyl-phenoxy) - (4-trifluoromethyl-phenyl) -acetic acid, 83.1H NMR (400 MHz, DMSO-dj): d 7.80-7.15 (m, 8H), 6.16 (s, 1H) ); (3,5-bis-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid, 84, XH NMR (400 MHz, DMSO-d6): d 13.80 (s, 1H9, 7.94 (s, 1H) , 7.88 (d, ÍH), 7.78 (d, 1H), 7.73-7.69 (m, 4H), 6.49 (s, ÍH), acid (2-chloro-4-trifluoromethoxy-phenoxy) - (3-trifluoromethyl-phenyl) ) -acetic, 85, ^? NMR (400 MHz, DMSO-dff): d 9.60 (s, ÍH), 7.91 (s, 1H), 7.84 (d, ÍH), 7.68-7.666 (m, 2H), 7.58 -7.54 (m, 1H), 7.44-7.42 (m, 1H), 6.91 (d, 1H), 5.79 (s, 1H), (3-trifluoromethyl-methoxy) - (4-trifluoromethyl-phenyl) -acetic acid, 86,? H NMR (400 MHz, DMSO-dg): d 7.80-7.30 (m, 8H), 6.25 (s, 1H); (2-trifluoromethyl-phenoxy) - (4-trifluoromethyl-phenyl) -acetic acid, 87, XH NMR (400 MHz, DMSO-dg): d 7.90-7.20 (m, 8H), 6.28 (s, 1H), [2-trifluoromethyl-4- (2,2,2-trifluoro-acetylamino) - phenoxy] - (3-trifluoromethyl-phenyl) -acetic, 88, "" "H NMR (400 MHz, DMSO-d6): d 11.40 (s, ÍH), 7.98 (d, ÍH), 7.92-7.85 (m, 3H), 7.77 (d, 1H), 7.72 (m, 1H), 7.25 ( d, 1H), 6.30 (s, 1H); (2-Chloro-4-trifluoromethyl-phenoxy) - (4-trifluoromethyl-phenyl) -acetic acid, 89, ^? NMR (400 MHz, DMSO-d5): d 7.88-7.80 (m, 5H), 7.71 (dd, 1H), 7.28 (d, 1H), 6.34 (s, 1H); and (2-fluoro-5-trifluoromethyl-phenoxy) - (4-trifluoromethyl-phenyl) -acetic acid, 90.1 H NMR (CDC13, 400 MHz): d 7.85 (s, 1H), 7.80 (d, ÍH), 7.68 (d, ÍH), 7.58 (m, ÍH), 7.32-7.23 (m, 3H), 5.78 (s, ÍH).

Example 2 Preparation of (3-fluoro-5-trifluoromethyl-phenyl) - (5-methoxy-2-trifluoromethyl-phenoxy) -acetic acid, 94 The methyl ester of (3-fluoro-5-trifluoromethyl-phenyl) -hydroxy-acetic acid 91 (0.1 mol) is dissolved in dimethylformamide (100 ml) and sodium hydride (0.1 mol) is added. When the hydrogen evolution is stopped, a solution of 2-fluoro-4-chloro-l-trifluoromethylbenzene 92 (0.1 mol) in dimethylformamide (25 ml) is added. The progress of the reaction was monitored by TLC. When the reaction reaches completion, water and ethyl acetate are added. The organic phase is dried and concentrated and the residue is subjected to chromatography to obtain the methyl ester of (3-fluoro-5-trifluoromethyl-phenyl) - (5-chloro-2-trifluoromethyl-phenoxy) -acetic acid 93. Basic hydrolysis of this compound as described in Example 1, then gives the title compound 94.

Using the above procedures, but employing different hydroxyl esters and fluorobenzenes, the analogous compounds corresponding to 94 are synthesized.

Example 3 Preparation of (2,4-bis-trifluoromethyl-f-enoxy) - (3-trifluoromethyl-phenyl) -acetic acid ethyl ester 97 To a solution of 95 (25.0 g, 0.10 mol) in anhydrous THF (150 ml) is added NaOCH3 (7.0 g, 0.13 mol) at 0 ° C. The mixture is then heated at 50 ° C for 6 hours. After cooling to 25 ° C, the reaction mixture is quenched with saturated NH 4 Cl, diluted with EtOAc, washed with brine and concentrated in vacuo to obtain crude methyl ether (17.93 g, 73%) as a colorless liquid. . This product is pure enough to be used directly in the subsequent reaction. H NMR (CDC13, 400 MHz): d 7.83 (H, s), 7.77.

(HH, d, J = 8.4 Hz), 7.09 (HH, d, J = 8.4 Hz), 3.97 (3H, s) ppm. A solution of methyl ether 96 (9.98 g, 0.04 mol) in Anhydrous CH2C12 (150 ml) was cooled to -78 ° C and subjected to treatment with BBr3 (6.0 ml, 0.063 mol). The resulting brown mixture is stirred for one hour at -78 ° C and then heated to 25 ° C for 4 hours and then quenched with water. The organic layer is separated and washed with saturated NaHCO and brine, dried over Na2SO4, concentrated to ~13 ml in vacuo below 0 ° C and used directly in the next substitution reaction. This solution (calculated 1.15 ml) is taken and diluted with DMF (8 ml) and subjected to treatment with K2C03 (1.27 g) and bromine 79 (1.72 g). The resulting mixture is stirred at room temperature for one hour, diluted with EtOAc, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified by flash chromatography (5:95 EtOAc / hexanes) on silica gel and then recrystallized with 10% EtOAc / hexanes to obtain a pure ester 97 as a white solid. H NMR (400 MHz, DMSO-d5): d 8.60 (H, d, J = 2.2 Hz), 8.17 (H, d, J = 8.6, 2.2 Hz), 7.96 (H, s), 7.91 (H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.74 (IH, t, J = 7.8 Hz), 7.38 (1H, 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 To a solution of 5- (trifluoromethyl) -2-pyridinol 98 (2.11 g, 12.9 mmol) in DMF (20 ml) is 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 is washed with saturated NaHCO 3 and brine, dried over Na 2 SO 4, concentrated in vacuo and purified by flash chromatography on silica gel (5:95 EtOAc / hexanes) to obtain 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 / H20 (10 ml / 3 ml) at room temperature is added monohydrated lithium hydroxide (0.31 g, 7.39 mmol). The resulting solution is stirred at room temperature for two hours. The reaction is quenched with IN aqueous HCl and the mixture is extracted with EtOAc. The organic layer is washed with brine, dried over Na 2 SO and concentrated in vacuo to obtain acid 100 (0.53 g, 94%) as a brown liquid. H NMR (400 MHz, DMS0-d6): d 8.55 (H, s), 8.08 (1 H, dd, J = 8.8, 2.6 Hz), 7.89 (H, s), 7.86 (1 H, d, J = 8.0 Hz), 7.71 (HH, d, J = 8.0 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.14 (1H, d, J = 8.0 Hz), 6.19 (HH, s) ppm. Using the above procedures, but using different bromo-phenylacetic and iridinole esters, the analogous compounds can be obtained for 100.

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 105.

A one-neck round bottom flask was fitted with a Claisen adapter, temperature probe, water condenser and nitrogen line. The equipment is put in flow with nitrogen. The system is loaded with potassium acetate (1.52 g, 15.5 mmol), acetic anhydride (69 ml), (a, a, a-trifluoro-p-tolyl) acetic acid (2.97 g, 14.5 mmol) and, a, a -trifluoro-m-tolualdehyde (2 ml, 2.6 g, 14.9 mmol) with stirring. When the solution is hot, all solids dissolve around 75 ° C and the solution becomes light yellow. The mixture is heated at 106 ° C for 18.5 hours. The heat is removed and the conversion of the reaction is verified by TLC. Deionized water (16 ml) is added to the reaction flask at a rate such that the reaction temperature is maintained at 70-80 ° C. An additional 20 ml of deionized water is added after the solution has cooled to room temperature and this generates crystals that initiate the precipitate. Finally, an additional 20 ml of deionized water is added and the solution is allowed to stir overnight at room temperature. The solution is filtered under vacuum at room temperature and the crystals are washed twice with 20 ml of deionized water. The crystals are dried under high vacuum to obtain a bone-colored powder of cis-3- (3-trifluoromethylphenyl9-2- (4-trifluoromethylphenyl) -propenoic acid 104 (3.542 g, 9.8 mmol).

A 100 ml round neck flask was fitted with an addition funnel (filled with a 3A molecular sieve), water condenser, oil bath and nitrogen line which was charged with Z-3- acid [3]. -trifluoromethylphenyl) -2- (4-trifluoromethylphenyl) -acrylic (1.2 g, 3.33 mmol), N-acetylethanolamine (7 ml), dry dimethoxyethane (36 ml) and concentrated sulfuric acid (0.05 ml). The reaction mixture is heated to reflux for 16.5 hours. After the solution is cooled to room temperature, it is divided between 100 ml of ethyl acetate and 100 ml of water. The layers are separated and the organic layer is washed with a solution of aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate and concentrated by rotovap and high vacuum to obtain 1.55 g of a brown viscous oil. The product is purified by flash chromatography using a solvent system consisting of 5% acetic acid in chloroform. The fractions containing the product were combined and washed with water (2 x 100 mL), a saturated sodium bicarbonate solution (100 mL), dried over magnesium sulfate and concentrated by rotary evaporator to obtain 2-acetamidoethanol-Z -3- (3-trifluoromethylphenyl) -2- (4-trifluoromethylphenyl) -acrylate 104 (855 mg, 1.9 mmol). The trans adduct can be synthesized by isomerizing the cis-carboxylic acid with a sun lamp.

A one-liter three-necked round bottom flask was fitted with condenser, thermometer, nitrogen line and magnetic stirrer and charged with Z-3- (3-trifluoromethylphenyl) -2- (4-trifluoromethylphenyl) -acrylic acid (103 , 2.28 g, 6.3 mmol), ethanol (104 ml), black palladium (101.1 mg) and ammonium formate (1608 g, 25.5 mmol). The reaction mixture was heated at 80 ° C for 4 hours. An aliquot was taken and TLC (the solvent system was 20% ethyl acetate in hexanes with a peak of acetic acid) showed absence of the raw material. The solution was cooled to ambient temperature and filtered in a vacuum using a smoked glass funnel. The solution was concentrated by rotary evaporation and high vacuum, obtaining 3- (3-trifluoromethylphenyl) -2- (4-trifluoromethylphenyl) -propionic acid (2.83 g) 105. • 3- (3-trifluoromethylphenyl) -2- acid (4-trifluoromethylphenyl) -propionic (105, 2.43 g, crude) was dissolved in anhydrous THF (6 ml 9 at room temperature.) CDl (1.64 g, 10.1 mmol) was charged as a solid followed by EtOAc (4 ml), to wash The flask, the internal temperature remained between 20-21 ° C during the addition, N-acetylethanolamine (3.6 ml, 39 mmol) was added, while the temperature reached 24.5 ° C. The mixture was stirred overnight (16 hours). ) at 23-24 CC and then the rotary evaporation gave a gummy residue, which was chromatographed on silica gel using EtOAc: hexane (70:30 v / v) (Rf = 0.35-0.40) to obtain 2-acetamidoethyl- 3- (3-trifluoromethylphenyl) -2- (4-trifluoromethylphenyl) propionate 105A (185 g). Using the above procedures, but employing different phenylacetic and benzaldehyde esters, analogous compounds 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 Using the procedures of Example 1, bromo- (3-methylsulfanyl-5-trifluoromethyl-phenyl) -acetic acid methyl ester and 4-nitro-2-trifluoromethyl-benzothiol 107 are prepared as described in Preparation 7 where are prepared to form the methyl ester of (3-methylsulfanyl-5-trifluoromethyl-phenyl) - (4-nitro-2-trifluoromethyl-phenylsulfanyl) -acetic acid, 108, where they are then hydrolyzed under basic conditions to obtain the title compound 109. Using the above procedure, different bromoesters and thiols are reacted together to obtain the corresponding compounds 1 wherein X is S.

Example 7 Preparation of (3-trifluoromethyl-phenyl) - (2-trifluoromethyl-phenylamino) -acetic acid, 112 117 118 Acid (3-trifluoromethyl-phenyl) - (2-trifluoromethyl-phenylamino) -acetic acid: A clean mixture of o-trifluoromethylaniline (1.63 g, 10.1 mmol), bromide 79 (1.11 g, 3.57 mmol) and diisopropylethylamine (1.56 g) , 12.1 mmol) were stirred in a stoppered flask at 105 ° C for 6 hours. The mixture is cooled to room temperature, diluted with EtOAc and washed with water. The organic layer is washed with brine, dried over Na 2 SO 4, concentrated in vacuo and purified by flash chromatography on silica gel (5:95 EtOAc / hexanes) to obtain pure ester 111 (0.19 g, 14%) as a transparent liquid. ^? NMR (400 MHz, DMSO-d6): d 7. 86 (ÍH, s), 7.76 (ÍH, d), 7.69 (ÍH, d), 7.63 (ÍH, t), 7.49 (ÍH, dd), 7.33 (ÍH, t), 6.77 (1H, t), 6.66 (lH, d), 5.88 (ÍH, d), 5.73 (1H, d), 4.18 (2H, m), 1.11 (3H, t) ppm. To a solution of ester 111 (0.19 g, 0.49 mmol) in THF / H20 (4 ml / l.5 ml) at room temperature is added lithium hydroxide monohydrate (0.10 g, 2.38 mmol). The resulting solution is stirred at room temperature for one hour, quenched with 1N aqueous HCl and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain acid 112 (0.13 g, 99%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d ^): d 13.84 (ΔI, br, COOiT), 7.84 (1H, s), 7.75 (1H, d), 7.68 (ΔI, d, J = 8.0 Hz), 7.62 ( HH, t), 7.48 (HH, dd), 7.30 (HH, t), 6.74 (1H, t), 6.59 (HH, d), 5.96 (1H, d), 5.56 (HH, d) ppm. (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) is added K2C03 (2.10 g, 0.015 mol ) followed by bromide 79 (3.41 g, 0.011 mol). The resulting mixture is stirred at 55 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with EtOAc and lacquered with water. The organic layer is washed with water and brine, dried over Na 2 SO 4, concentrated in vacuo and purified by flash chromatography on silica gel (5:95 EtOAc / hexanes) to obtain the ester (0.87 g, 22%) as a yellow liquid 1 H NMR (400 MHz, DMSO-d 6): d 8.21 (1H, s), 8.14 (H, d), 7.84.

(HH, t), 7.58 (HH, d), 7.28 (HH, S), 7.27 (1H, d), 4.16 (2H, m), 0.91 (3H, t) ppm. To a solution of the above ester (0.82 g, 2.10 mmol) in THF / H20 (15 ml / 5 ml) at room temperature is added lithium hydroxide monohydrate (0.53 g, 12.6 mmol). The resulting solution is stirred at room temperature for 2 hours, quenched with 1 N aqueous HCl with EtOAc. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to yield the acid 117 (0.69 g, 90%) as a solid. X H NMR (400 MHz, DMS0-d 5): d 8.21 (H, s), 8.14 (H, d), 8.05 (1 H, d), 7.84 (H, t), 7.58 (H, d), 7.28 (H) , S), 7.27 (lh, d). Using the above procedures, but substituting the appropriate anilines and bromoesters for 79 and 110, the following compounds were obtained: (3-triluoromethyl-phenyl) - [5-trylfuoromethyl-2- (3-trifluoromethyl-phenoxy) -phenylamino] - acetic acid 113. XH NMR (CDC13, 400 MHz): d 7.46 (s, 1H), 7.38-7.28 (m, 4H), 7.11 (m, 2H), 6.97 (s, ÍH), 6.85 (d, 1H), 6.66 (d, ÍH), 6.52 (s, 1H); (3, 5-bis-trifluoromethyl-phenylamino) - (3-trifluoromethyl-phenyl) -acetic acid 114. 1 H NMR (CDC13, 400 MHz): d 7.78 (s, ÍH), 7.71 (d, 1H), 7.64 ( d, 1H), 7.56-7.53 (m, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 5.22 (s, 1H); (3-trifluoromethyl-phenyl) - (4-trifluoromethyl-phenylamino) -acetic acid 115. 1 H NMR (400 MHz, DMSO-dg): d 7.87 (HH, s), 7.79 (1H, d), 7.66 (1H, d), 7.60 (1H, t), 7.34 (2H, d), 7.10) ΔH, d), 6.78 (2H, d), 5.39 (1H, d) ppm; (4-isopropyl-2-trifluoromethyl-phenylamino) - (3-trifluoromethyl-phenyl) -acetic acid 116, XH NMR (400 MHz, DMS0-d5): d 8.17 (HH, d), 8.15 (1H, s), 8.04 (1H, d), 7.79 (1H, t), 7.17 (1H, d), 7.14 (1H, d), 2.77 (1H, m), 1.13 (6H, d) ppm; (-trifluoromethyl-phenyl) - (2-trifluoromethyl-phenylamino) -acetic acid 118, 1 H NMR (DMSO, 400 MHz): d 7.80-6.50 (, 8H), 5.98 (d, ÍH), 5.52 (d, ÍH) .

Example 8 Preparation of 2- (4-trifluoromethyl-phenoxy) -2- (3-trifluoromethyl-phenyl-9-propionic acid To a solution of ester 80 (3.01 g, 7.69 mmol) in anhydrous THF (30 ml) is added NaH (60% in oil, 0.80 g, 0. 020 mol). The resulting solution is then stirred at room temperature for two hours and iodomethane (2.5 ml, 0.040 mol.sup.9) is added.The resulting mixture is stirred at room temperature overnight.The reaction is quenched with saturated NHC1, concentrated in vacuo and purifies by rapid chromatography on silica gel (5:95 EtOAc / hexanes) to obtain ester 119 (3.18 g, 87%) as a colorless liquid. XR NMR (400 MHz, DMSO-d5): d 7.91 (1H, s), 7.88 (HH, d), 7.7 (HH, d), 7.69 (HH, d), 7.65 (2H, d), 7.02 (HH, 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 / H20 (15 ml / 5 ml) at room temperature is added lithium idroxide monohydrate (0.95 g, 0.022 mol). The resulting solution is refluxed at room temperature for one hour, cooled to room temperature, quenched with 1N aqueous HCl and extracted with EtOAC. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to obtain acid 120 (0.93 g, 96%) as a pale yellow liquid. Using the above procedures, but substituting the appropriate a-phenoxyphenylacetic esters for 80, the following compounds were obtained: 2- (4-trifluoromethyl-phenoxy) -2- (4-trifluoromethyl-phenyl) -propionic acid, 121; 2- (2-trifluoromethyl-phenoxy) -2- (3-trifluoromethyl-phenyl) -propionic acid, 122, 1 H NMR (d-DMSO, 400 MHz): d 13.85 (s, ÍH), 8.04 (s, ÍH) , 7.86 (d, ÍH), 7.74 (d, ÍH), 7.70-7.66 (m, 3H), 7.56 (m, ÍH), 7.15 (m, ÍH), 6.89 (d, 1H), 1.89 (s, 3H ).

Example 9 Preparation of (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetaldehyde, 124 The (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid 39 (0.05 mol) is dissolved in dichloromethane (50 ml) and thionyl chloride (5 ml) and dimethylformamide (0.1 ml) are added. After two hours, the solvents are removed under vacuum to obtain (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetyl chloride, 123. This compound (0.01 mol) is dissolved in ether (25 ml) and the solution is cooled to -80 ° C and lithium aluminum tri-tertiary butoxide hydrate (0.01 mol) is added. The progress of the reaction is monitored by TLC. When the reaction is complete, the mixture is warmed to room temperature and water is added. The organic phase is dried and concentrated and the residue is subjected to chromatography to obtain the title compound 124.

Example 10 Preparation of 2- (4-trifluoromethyl-phenoxy) -2- (3-trifluoromethyl-phenyl) -ethanol, 125. 124 125 Dissolve in isopropanol (20 ml) (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetaldehyde, 124 (0.02 mol) and add sodium borohydrate (0.02 mol). The progress of the reaction is monitored by TLC. When the reaction ends, water and ether are added. The organic phase is dried and concentrated and the residue is subjected to chromatography to obtain the title compound 125. ^? NMR (d-DMSO, 400 MHz): d 7.75-7.24 (m, 8H), 5.59 (μs, 1H), 5.22 (m, ÍH), 3.70 (m, 2H). 126. To a solution of ester 126 (1.04 g, 2.65 mol, prepared as described for 80) in anhydrous THF (15 ml) at 0 ° C is added LiAlH4 (0.10 g, 2.64 mmol). After being stirred at 0 ° C for 0.5 hours, the reaction mixture is quenched with 15% aqueous NaOH (0.15 ml), filtered through a pad of celite, washed with EtOAc, concentrated in vacuo and the residue chromatograph on silica gel (2: 8 EtOAc / hexanes) to obtain 127 (0.71 g, 81%) as a colorless liquid. X H NMR (400 MHz, DMSO-dí): d 7.79 (H, s), 7.71 (H, d), 7.65 (H, d), 7.58-7.62 (H, m), 7.50 (H, t), 7.22 (HH, d), 7.03 (1H, t), 5.71 (1H, t), 5.14 (HH, t), 3.80-7.85 (HH, m), 3.77-3.72 (HH, m) ppm. Using the above procedures, but using different aldehydes and esters instead of 124 and 126, the carbinols 128-134 can be obtained.

Example 11 Preparation of propionic acid ester 2- (4-trifluoromethyl-phenoxy) -2- (3-trifluoromethyl-phenyl) -ethyl, 135 They are dissolved in pyridine (20 ml, 2- (4-trifluoromethyl-phenoxy) -2- (3-trifluoromethyl-phenyl) -ethanol, 125, (0.01 mol) and the solution is cooled to 0 ° C. Propionyl chloride is added (0.015 mol) The progress of the reaction is monitored by TLC.When the reaction is complete, ether and water are added.The organic phase is washed with dilute hydrochloric acid, dried and concentrated.The residue is subjected to chromatography to obtain the title compound 135. Using the above procedure, but using different carbinoles and / or different acyl chlorides, the corresponding analog esters 111 can be obtained.

Example 12 Preparation of the (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid 2-acetylamino-ethyl ester, 136.

To a mixture of acid 39 (25.8 g, 0.071 mol) in 1,2-dichloroethane anhydrous 8380 ml) is added thionyl chloride (16.0 ml, 0.21 mol) and then the resulting mixture is refluxed for two hours. The mixture was cooled to room temperature, diluted with dry THF (150 ml) until the cloudy mixture became clear and then N-acetylethanolamine (39.12 g, 0.38 mol) was added. The resulting solution is stirred at room temperature overnight. The reaction is carefully quenched with NaHCO 3, diluted with EtOAc and washed with water. The organic layer is recrystallized from iPrOH / hexanes (llml / 31.5 ml) to obtain pure product 136 (22.78 g, 71%) as an off-white solid. XH NMR (400 MHz, CDC13): d 7.89 (HH, s), 7.80 (HH, d), 7.69 (HH, d), 7.57-7.61 (3H, t), 7.06 (2H, t), 5.78 (1H, s ), 5.27 (1H, br), 4.24 (2H, m), 3.45 (2H, dd), 1.81 (3H, s) ppm.

Using the above procedure, but using different carboxylic acids and / or different alcohols, the corresponding analogue esters 136 are obtained.

Example 13 Preparation of (3- trifluoromethyl-phenyl) - (6-trifluoromethyl-pyridin-3-yloxy) -acetic acid morpholin-4-yl-ethyl ester The (3-trifluoromethyl-phenyl) - (5-trifluoromethyl-pyridin-2-yloxy) -acetic acid, 100, is prepared as described in Example 4, (0.05 mol) and converted to the acid chloride using the procedure from Example 6. The acid chloride (0.01 mol) is dissolved in tetrahydrofuran (25 ml) and N, -dimethylaniline (2 ml) and morpholinoethanol is added. (2 ml). The progress of the reaction is monitored by TLC.

When the reaction is complemented, ether and water are added. The organic phase is washed with dilute hydrochloric acid, dried and concentrated. The residue is subjected to chromatography to obtain the title compound, 137. Using the above procedure, but using different carboxylic acids and / or different alcohols, the corresponding analogue esters 137 are obtained.

Example 14 Preparation of (5- [(4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -methyl] -lH-tetrazole 140.

Dimethylammonium amide is prepared by adding anhydrous toluene (60 ml) to the ammonium chloride (2.14 g). The mixture is cooled to 0 ° C and trimethylaluminum in toluene (2.0 M, 20 ml) is added dropwise. The reaction is allowed to stir at 0 ° C for 15 minutes before being warmed to room temperature for two hobby hours. To the prepared fresh dimethylaluminum amide is added ester 80 (6.0 g) in toluene (20 ml). The reaction is then heated to 100 ° C and allowed to stir overnight. The reaction is cooled to room temperature and Na2SO4-10H2O is added and stirred for an additional hour. Ña filtration followed by the concentration of the solution provides a yellow liquid. Purification by flash column chromatography (hexanes / ethyl acetate 1: 4) gives the amide 138 (2.7 g, 49%) as a light yellow solid. 1H NMR (CDC13, 400 MHz,): d 7.81-7.51 (m, 6H), 7.02 (d, 2H), 6.60 (br. ÍH), 5.78 (br. ÍH), 5.63 (s, 1H). The amide 138 (2.7 g) is dissolved in dichloromethane and (methoxycarbonylsulfamoyl) triethylammonium hydroxide and inert salt is added (1.3 g). The resulting mixture is stirred overnight and concentrated. Purification is carried out by flash column chromatography (hexane / ethyl acetate 5: 1) and gives the nitrile 139 as a white solid. XH NMR (CDC13 400 MHz,): d 7.87-7.64 (, 6H), 7.19 (d, 2H), 5.96 (s, 1H). Nitrile 139 (1.05 g) is dissolved in anhydrous THF (40 ml). Trimetilinazide (1.3 ml) is then added. The reaction mixture is refluxed overnight. The solution is then cooled to room temperature, diluted with HCl (0.5 N), and extracted with ethyl acetate. The organic solution is dried over sodium sulfate and concentrated. Purification by flash column chromatography (ethyl acetate) provides 1.15 g of tetrazole 140 (98%) as a white solid. xl NMR (CDC13 400 MHz,): d 7.85-7.51 (m, 6H), 7.04 (d, 2H), 6.85 (s, 1H). Using the above procedure, but using different carboxylic acids, the corresponding analog tetrazoles are obtained.

Example 15 Preparation of sodium salt of (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid 141.

A solution of the acid in EtOAc is subjected to treatment with 1 eq. NaOH IN and the resulting product is recrystallized from EtOAc / hexanes to obtain the sodium salt as a white product 141.

Using the above procedure, but using different carboxylic acids, the corresponding analogous salts are obtained 141.

Example 16 Preparation of enantiomers of (4-trifluoromethyl-phenoxy) - (4-trifluoromethyl-phenyl) -acetic acid 83 83 83-A (enantiomer 1) 83-B (enantiomer 2) 83 A mixture of racemic acid 83 (7.97 g) and (IR, 2R) - (-) - 2-amino-l- (4-itrophenyl) -1,3-propanediol (CAF D BASE) (2.56 g, 0.55 eq.) Is dissolved in 70 ml of 2-pro? Anopl by heating at 75 ° C for 30 minutes. The solution is cooled slowly to room temperature and then allowed to remain at 4 ° C overnight. The solid (3.4 g) is collected by filtration. The solid is dissolved in 50 ml of 2-propanol at 80 ° C. The solution is slowly cooled to room temperature. The crystals (2.4 g) are collected by filtration. The crystals are mixed with 1N HCl (50 ml) and extracted with ethyl acetate. The organic solution is dried over Na 2 SO 4. The solvent is removed under vacuum to generate 1.6 g of the enantiomerically enriched solution 83-A (20%) as a solid white color. 1 H NMR (DMSO, 400 MHz,): d 7.80-7.18 (m, 8H), 6.20 (s lH). Using the same procedure as described above, 83-B is obtained by using (+) -2-amino-1- (4-nitrophenyl) -1,3-piperanediol as the chiral base. ""? NMR (DMSO, 400 MHz,): d 7.80-7.18 (m, 8H), 6.20 (s, ÍH). Using the above procedure, but using different carboxylic acids and chiral bases, the corresponding analogue enantiomers are obtained 83.

Example 17 Preparation of enantiomers of (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid, 39 The optically pure salt (-) - 39 is obtained by classical resolution by serial recrystallization of the racemic acid salt 39 with (IR, 2R) - (-) -2-amino-1- (4-nitrophenyl) -1 , 3-propanediol (0.55 eq.) In EtOAc / hexanes of 75 ° C at room temperature. The first crystal collected produces salt (-) - 39. The serial recrystallization of the mother liquor produces the other optically pure salt (+) - 39. After acidifying both salts with 1 N HCl in EtOAc, the optically pure salts (-) - 39 and +39 are obtained as white solids, respectively. (+) - 39, [a] 25? = + 74.6 (c = 0.55, CH3OH) and (-) - 39, [a] 25? = + 74.8 (c = 0.89, CH3OH). The analysis of enantiomers was carried out by chiral HPLC a? = 220 nm by injecting 10 μL of an approximate 0.5 mg / mL solution of the sample dissolved in the mobile phase on a 15 μm Ehelk-0 25 cm x 4.6 mm Regis Technologies (R, R) column with a flow rate of 1.5 ml / min (1.5 / 98.5 / 0.05) iPrOH / hexanes / TFA. Under these conditions, the (+) - enantiomer is eluted at 6.6 minutes and the (-) enantiomer at 8.8 minutes (approximate retention times).

Example 18 Separation of enantiomers from (4-trifluoromethyl-phenoxy) - (3-trifluoromethyl-phenyl) -acetic acid, 39 by chiral HPLC The racemic compound 39 is resolved into the enantiomers by using chiral HPLC. A column 10/100 WHELK-0 2 of 25 cm x 2.1 mm Regis Technologies (R, R) at room temperature. The sample injection contains 5.0 ml of 12 mg / ml of racemic acid 39 in isopropanol: hexane, 2: 3. The column is 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 obtain the individual (+) - 39 and (-) - 39 enantiomers. The above procedure can be applied for other racemic acids of the present invention to obtain their enantiomers separately.

Example 19 Preparation of esterified compounds Dissolve in isopropanol (40 ml) potassium hydroxide (2.6 g, 0.046 mol) under argon atmosphere by heating at 50-60 ° C. The solution is cooled to 0-10 ° C in an ice bath. To this is added 3-trifluoromethylphenol (6.5 ml (8.7 g), 0.053 mole), which raises the temperature to 10-20 ° C.

They are dissolved in 12 ml of isopropanol and cooled to 0-10 ° C (2-acetamidoethyl) -4-trifluoromethylphenylbromoacetate 73 (16.2 g, 0. 044 moles). The phenoxide solution is added to the bromoester which reaches an internal temperature of 5-15 ° C. The resulting mixture is stirred for 4 hours in the ice bath. Citric acid (1.6 g, 0.0084 mol) is added in 12 ml of water. The mixture is filtered to remove the white potassium bromide and the slurry is washed with isopropanol (20 ml). The isopropanol is rotated and the residue is dissolved in ethyl acetate (72 ml) and extracted with water (24 ml). The ethyl acetate phase is dried over sodium sulfate and the filtrate and the filtered slurry are dissolved in ethyl ether: hexane (1: 1), diluted with hexane, where after a certain part of the material becomes oily. The mixture is cooled in an ice bath at 2-5 ° C and then a white solid is formed which is filtered and washed with ethyl ether: hexane (1: 1) to obtain 142, after drying under vacuum. • Using the above procedures, but replacing the phenols and bromo esters suitable for 73, the following compounds 143-147 are obtained.

Example 20 In vivo activities The anti-diabetic actvity of the compounds is evaluated in the C57BL / 6J ob / ob mouse model. A. Materials and Methods Male C57BL / 6J ob / ob mice, 7-9 weeks old, were purchased from The Jackson laboratory (Bar Harbor, ME, USA). The animals were housed (4-5ratons / cage) under conventional laboratory conditions at 22 + 3 ° C temperature and 50-4-20% relative humidity and were maintained with a diet of mouse croquettes of Purina and water ad libitum. Before treatment, blood was collected from the caudal vein of each animal. Mice that were used and did not fast had plasma glucose levels between 250 and 500 mg / dL. At the beginning of the study, each treatment group consisted of 8-10 mice that were distributed until the glucose levels were equivalent in each group. Mice were dosed orally on average once a day for 1-4 days with the vehicle and one or more doses of the test compound at a dose in the range of 5 to 125 mg / kg. The compounds were released in a liquid formulation containing 5% (v / v) of dimethylsulfoxide (DMSO), 1% (v / v) of Tween 80® and 0.9% (w / v) of methylcellulose. The average volume was 10 ml / kg. Blood samples were taken 6 hours after each dose and analyzed for plasma glucose. Daily intake of food and body weight was quantified. Plasma glucose concentrations were determined colorimetrically using a commercial glucose oxidase method (Sigma Chemical Co., San Luis, MO, USA). Significant differences between the groups were evaluated (comparing the treatment drug with the treatment vehicle) using the unpaired Student t test. B. Results Table 1 provides the relative potency of some selected compounds of the invention. Compounds that were effective in reducing glucose levels at a dose of < 125 mg / kg were assigned with a power of ++; compounds that were less effective in reducing glucose levels, generally showed activity at multiple doses or at a high dose of > 125 mg / kg and assigned with a power of +.

Table 1. Power of the compounds of the invention It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in clarity of this may be suggested by one skilled in the art and that are included within the spirit and field of this application as well as in the scope of the attached claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims (21)

1. CLAIMS 1. A compound that has the formula and all its pharmaceutically acceptable salts and prodrugs thereof, characterized in that: X is a member selected from the group comprising O, S, SO, S02, CHR and NR, where R is H, alkyl (Cx-C8), CORa, COORa and CONRaRb where Ra and Rb are each indistinctly selected from the group comprising H and alkyl (C? -C8); Y is a member selected from the group comprising CH2ORc, C02Rc, tetrazolo, CHO, CONRcRm, CH (= NRC) and CH (= NORc), where Rc is a member selected from the group comprising H, alkyl (C? -C8) , (C3-C8) alkenyl, (C3-C8) alkynyl, (C3-C7) cycloalkyl, (C-C8) cycloalkylalkyl, aryl, aryl (Ci-Ca) alkyl and Z-alkylene (Ci-Cß), where Z is selected from the group comprising CORd, COORd, NRRe, NRdCONReRf, NRdCORe, NRdCOORe and CONRdRe where Rd, Re and Rf are each indistinctly selected from the group comprising H, alkyl (C? ~ C8) and phenyl, or optionally two of Rd, Re and Rf are attached to the same nitrogen atom that combines to form a five or six membered ring; and wherein Rm is selected from the group comprising H, alkyl (C? ~ C8), aryl and OH and Rm and Rc are optionally combined with the nitrogen atom where each is attached to form a five or six membered ring; each R1 and R3 represents a member selected from the group consisting of halogen, hydroxyl, alkyl (C? ~ C8), alkenyl (C2-C8), alkynyl (C2-C8), alkoxy (C? ~ C8), cycloalkyl (C3_C7), cycloalkylalkyl (C4-C8), haloalkyl (Ca-Cs), heteroalkyl (Cx-C8), heterocyclyl (C2-C5), cycloalkyl (C3-C7) heterosubstituted, cycloalkyl ( C3-C7) heteroalkylsubstituted, O-haloalkyl (C? -8), nitro, cyano, phenyl, O-phenyl, NRj-phenyl, S (O) r-phenyl, CORj, COORj, NRjRk, S (0) rRj, S02NRjRk, NR ^ ONR ^ 1, NRjCORk, NRjCOORk and CONRjRk, where the phenyl ring is optionally substituted and Rj, Rk and R1 are each indistinctly selected from the group comprising H and (C? -C8) alkyl, including haloalkyl (Cx) -Cs), or optionally two of Rj, R and R1 when grouped to the same nitrogen atom are combined to form a five or six member ring and the superscript r is an integer from 0 to 2; R2 is a member selected from the group comprising H and alkyl (C? -C8); Q represents CH or N; the subscript m is an integer from 0 to 3; and the subscript p is an integer from 0 to 2. The compound according to claim 1, characterized in that Q is CH. 3. The compound according to claim 2, characterized in that X is selected from the group comprising 0, S and NR. 4. A compound according to claim 3, characterized in that Y is C02Rc. The compound according to claim 4, characterized in that the subscript m is from 0 to 2 and the subscript p is from 0 to 1. 6. The compound according to claim 5, characterized in that each R3 is selected from the group comprising halogen, nitro, alkyl (C? -8), haloalkyl (C? -8), alkoxy (C? -8) and haloalkoxy (C? -8). 7. The compound according to claim 5, characterized in that each R1 is selected from the group comprising halogen, nitro, alkyl (C? -8), haloalkyl (C? -8), alkoxy (C? -8) and haloalkoxy (C? -C8). 8. The compound according to claim 5, characterized in that Rc is selected from the group comprising H, (C? -C8) alkyl and Z (C? -C8) alkylene. 9. A compound according to claim 8, characterized in that R2 is H or CH3. 10. A compound according to claim 1, characterized in that Q is CH; X is selected from the group comprising O and NR; Y is selected from the group comprising CH2ORc and C02Rc; the subscript m is from 0 to 2 and the subscript p is from 0 to 1; each R1 is selected from the group consisting of halogen, nitro, alkyl (C? -8) and alkoxy (C? -C8); each R3 is selected from the group consisting of halogen, nitro, alkyl. { C? -Cs) and alkoxy (C? -C8); and R2 is H or CH3. 11. The compound according to claim 10, characterized in that X is O and Y is C02Rc. 12. The compound according to claim 10, characterized in that X is O and Y is CH2ORc. 13. The compound according to claim 10, characterized in that X is NH and Y is C0Rc. 14. The compound according to claim 10, characterized in that X is NH and Y is CH2ORc. 15. A composition comprising a pharmaceutically acceptable excipient and a compound having the formula: and all pharmaceutically acceptable salts and prodrugs thereof, characterized in that: X is a member selected from the group comprising O, S, SO, S02, CHR and NR, where R is H, alkyl (Ci-C8), CORa, C00R and CONRaRb where Ra and R are each indistinctly selected from the group comprising H and alkyl (C? -C8); And it is a selected member of group that comprises CH2ORc, C02Rc, tetrazolo, CHO, CONRcRm, CH (= NRC) and CH (= NORc), where Rc is a member selected from the group comprising H, alkyl (C? -8), alkenyl (C3-C8), alkynyl (C3-C8), cycloalkyl (C3-C7), cycloalkylalkyl (C4-C8), aryl, aryl (C? -8) alkyl and alkylene-Z (C? -8), where Z is selected from the group comprising CORd , COORd, NRdRe, NRdCONReRf, NRdCORe, NRdCOORe and CONRdRe where Rd, Re and Rf are each indistinctly selected from the group comprising H, alkyl (C? ~ C8) and phenyl, or optionally two of Rd, Re and Rf are attached to the same nitrogen atom that combines to form a five or six member ring; and wherein Rm is selected from the group comprising H, (C? -C8) alkyl, aryl and OH and Rm and Rc are optionally combined with the nitrogen atom where each is linked to form a five or six membered ring; each R1 and R3 represents a member selected from the group consisting of halogen, hydroxyl, alkyl (C? -C8), alkenyl (C2-C8), alkynyl (C2-C8), alkoxy (C? ~ C8), cycloalkyl (C3_C7) ), cycloalkylalkyl (C4-C8), haloalkyl (C? -8), heteroalkyl (C? -8), heterocyclyl (C2-C5), cycloalkyl (C3-C7) heterosubstituted, cycloalkyl (C3-C7) heteroalkylsubstituted, O- haloalkyl (C? -C8), nitro, cyano, phenyl, O-phenyl, NRj-phenyl, S (O) r-phenyl, CORj, COORj, NRjRk, S (0) rRj, S02NRjR, NR ^ ONR ^ 1, NRjCORk, NRjCOOR and CONRjR, where the phenyl ring is optionally substituted and R ^, R and R1 are each indistinctly selected from the group comprising H and (C? -C8) alkyl, including haloalkyl (C? -C8), or optionally two of B? , Rk and R1 when grouped to the same nitrogen atom are combined to form a five or six member ring and the superscript r is an integer from 0 to 2; R2 is a member selected from the group comprising H and alkyl (C? -C8); Q represents CH or N; the subscript m is an integer from 0 to 3; and the subscript p is an integer from 0 to 2. 16. A method for the treatment of an inflammation or a metabolic disorder selected from the group comprising Type UU diabetes, hyperlipidemia, hyperuricemia and disorders associated with insulin resistance, this method is characterized in that it comprises administering to a subject in need of this treatment, a compound of claim 1. 17. A method according to claim 16, characterized in that the metabolic disorder is diabetes Type II. 18. A method according to claim 16, characterized in that the metabolic disorder is hyperlipidemia. 19. A method according to claim 16, characterized in that the metabolic disorder is a disease associated with insulin resistance. 20. A method according to claim 16, characterized in that the compound is administered in combination with a second agent for the treatment of metabolic disorders. 21. A method according to claim 16, characterized in that the compound is administered to a patient having an inflammation condition.