MXPA06011064A - 1,3,4-oxadiazol-2-ones as ppar delta - Google Patents

Abstract

The present invention is directed to 1, 3, 4-oxadiazalones, and their pharmaceutically acceptable salts stereoisomers, tautomers, or solvates thereof. The compounds of this invention are modulators of PPARdelta and therefore useful as pharmaceutical agents, especially for the treatment of demyelinating diseases and disorders of fatty acid metabolism and glucose utilization.

Description

1,3,4-OXADIAZOL-2-ONAS AS MODIFIERS OF PPARDELTA AND ITS USE FIELD OF THE INVENTION The present invention relates to new compounds and pharmaceutical formulations that act as selective binders of the ligand receptor of PPARdelta, useful in the modulation of PPARdelta receptors for the treatment of diseases mediated by nuclear hormone receptors. The ligands of the PPARdelta ligand receptor of the present invention are useful agonists or antagonists of the PPARdelta receptor.

BACKGROUND OF THE INVENTION Peroxisome Proliferator Activated Receptors (PPAR) comprise a subfamily of the nuclear receptor superfamily. Four isoforms commonly known as PPARalpha have been identified and cloned, PPARgamma-1, PPARgamma-2 and PPARdelta. Each receptor subtype has a binding domain of a DNA sequence (DBD) and a ligand binding domain (LBD), both of which are necessary for ligand-activated gene expression.

PPARs bind as heterodimers with a retinoid X receptor. See J. Berger and D. E. Miller, Annu. Rev. Med., 2002, 53, 409-435. PPARdelta (also known as PPARbeta) is expressed in a wide range of mammalian tissues, but there is little information about its biological functions or very little has been made clear about the full range of genes regulated by the receptor. However, it has recently been discovered that agonists may be useful for treating diseases such as dyslipidemia and certain dermatological diseases, whereas antagonists may be useful for treating osteoporosis or colorectal cancer (D. Stembach, in Annual Reports in Medicinal Chemistry , Volume 38, AM Doherty, ed., Elsevier Academic Press, 2003 pp. 71-80). The PPARdelta appears to be expressed significantly in the CNS; however, most of its function in this one remains undiscovered. Of particular interest, however, is the discovery that PPARdelta was expressed in rodent oligodendrocytes, the major lipid-producing cells of the CNS (J. Granneman, et al., J. Neurosci Res., 1998, 51, 563 -573). In addition, it was also found that a selective PPARdelta agonist significantly increased the oligodendroglial myelin gene expression and the diameter of the myelin sheath in mouse cultures (I. Saluja et al., Glia, 2001, 33, 194-204).

Therefore, PPAR-delta activators can be used for the treatment of demyelination and demyelination diseases. The demyelination states are revealed by the loss of myelin, the multiple dense layers of lipids and protein that cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (SNP). In patients with demyelination states, the Demyelination can be irreversible; it is usually accompanied or followed by axonal degeneration, and often of cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itself, whether due to aberrant immune responses, local injury, ischemia, metabolic disorders, toxic agents or viral infections (Prineas and McDonald, Demyelinating Diseases. In Greenfield's Neuropathology,? .sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow, eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J .: Merck Research Laboratories, 1999) 1299, 1437, 1473-76, 1483). Central demyelination (demyelination of the CNS) occurs in different states, often of undetermined etiology, which have been known as primary demyelinating diseases. Of these, multiple sclerosis (MS) is the most widespread. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), drenomyeloneuropathy, vacuolar myelopathy associated with AIDS, HTLV-associated myelopathy, Lebe hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, Guillian-Barre syndrome and tropical spastic paraparesis. In addition, there are acute states in which demyelination can occur in the CNS, p. eg, in acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis. In addition, acute transverse myelitis, which is a syndrome in which an acute spinal cord transection of unknown cause affects both the gray and white matter in one or more adjacent thoracic segments, can result in demyelination. Also, disorders in which the myelin-forming cells are damaged, including spinal cord injuries, neuropathies, and nerve injury. Selective modulators of PPARdelta may also be useful for treating or preventing other diseases, see, for example, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, no. 4, 527-550; Steven Kliewer et al., Recent Prog. Horm. Res. 2001; 56: 239-63; Jean-Charles Fruchart, Bart Staeis and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Voi. 44, n °. 5, 345-52; 2001; Sander Kersten, Beatrice Desvergne and Walter Wahli: Roles of PPARs in health and disease, Nature, vol. 405, May 25, 2000; 421-4; Inés Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr. Opin. Lipidol. 12: 2001, 245-254). The compounds that act as modulators of PPARdelta may be particularly suitable for the treatment and / or prevention of disorders of fatty acid metabolism and disorders of glucose use in which insulin resistance is involved. Diabetes mellitus, especially type 2 diabetes, including the prevention of sequelae associated with it. There are particular aspects related to this: hyperglycemia, improvement of insulin resistance, improvement of insulin tolerance, protection of pancreatic ß cells, prevention of macro and microvascular disorders. Dyslipidemias and their sequelae, as for example atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., especially those (but not limited to them) characterized by one or more of the following factors: high concentrations of triglycerides in plasma, high concentrations of triglycerides in postprandial plasma, low concentrations of HDL cholesterol, low ApoA lipoprotein concentrations, high concentrations of LDL cholesterol, low density LDL cholesterol particles, high concentrations of ApoB lipoprotein. Several different disorders that can be associated with the metabolic syndrome, such as: obesity (excess weight), including central obesity, thrombosis, hypercoagulable and prothrombotic states (arterial and venous), hypertension, heart failure, such as for example (but not limited to these), after myocardial infarction, hypertensive heart disease or cardiomyopathy. Other conditions in which inflammatory reactions or cell differentiation may be involved are: atherosclerosis, such as, but not limited to, coronary sclerosis, including angina pectoris or myocardial infarction, stroke, restenosis or vascular reocclusion, chronic inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis, pancreatitis, other conditions inflammatories, retinopathy, adipose cell tumors, lipomatous carcinomas such as, for example, liposarcomas, solid tumors and neoplasms such as, for example (but not limited to), carcinomas of the digestive tract, liver, bile ducts and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary tract, genital tract, prostatic carcinomas, etc., acute and chronic myeloproliferative disorders, and lymphomas, angiogenesis, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease , erythematous-scaly dermatoses such as psoriasis, acne vulgaris. Other dermal disorders and dermatological diseases modulated by PPARdelta: eczemas and neurodermitis, dermatitis such as, for example, seborrheic dermatitis or photodermatitis, keratitis and keratosis such as, for example, seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis or follicular keratosis, keloids and keloid prophylaxis, warts, including condylomata or condilomata acuminata, human papillomavirus (HPV) infections such as, for example, venereal papillomatosis, viral warts such as, for example, molluscum contagiosum , papular dermatosis, for example, lichen planus, skin cancer, for example, basal cell carcinomas, cutaneous melanomas or T-cell lymphomas, localized benign epidermal tumors such as, for example, keratoderma, epidermal nevus and chilblains. Other diseases potentially modulated by PPARdelta, including syndrome X, polycystic ovary syndrome (PCOS), asthma, osteoarthritis, lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example, rheumatoid arthritis, vasculitis, wasting syndrome (cachexia), gout, squemic syndrome / reperfusion and acute respiratory distress syndrome (ARDS).

SUMMARY OF THE INVENTION The present invention relates to a compound of formula I. wherein Aril is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C-? 6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, perfluoroalkyl Ct-6, 'alkylthio d-6, hydroxy, hydroxy-C-? -6 alkyl, acyloxy C? -a, nitro, cyano, alkylsulfonyl C -? - 6, amino, alkylamino C -? - 6 and alkoxycarbonyl C- ?, 6; Z is -0 (CH2) n-, -SO2 (CH2) n-, - (CH2) nY- (CH2) n -, - (CH2) n -CO-, -O (CH2) n -CO-o- (CH2) nY- (CH2) n-CO- wherein Y is NR3, O or S, and R3 is selected from the group consisting of H, C? -6 alkyl, C3-cycloalkyl, C? -6 alkyl -C3-8 cycloalkyl and benzyl, and n is independently an integer between 1 and 5; X is NR3, O or S, wherein R3 is as defined above; R? is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 perfluoroalkyl; hydroxy-C 1-6 alkyl, nitro, cyano and C 1-6 alkylamino; and R 2 is substituted or unsubstituted phenyl, pyridinyl or thienyl, wherein the substituents are selected from the group consisting of halogen, Ci-β alkyl, C 2-6 alkenyl, C 1 --6 alkoxy, C 1 - 6 perfluoroalkyl , C 1-6 alkylthio, hydroxy, hydroxy-C-? - 6 alkyl, acycloxy C? _4, nitro, cyano, C 1-6 alkylsulfonyl, amino, C 1-4 alkylamino and C 1-4 alkoxycarbonyl; with the proviso that when Z is -O (CH2) n- or -S? 2 (CH2) n-, and ARIL is phenyl, then R2 is other than phenyl; or its stereoisomer, tautomer or solvate, or its pharmaceutically acceptable salt. The present invention also relates to pharmaceutical compositions of formula I, and to methods of using said compounds and compositions to modulate the present invention.

PPARdelta in a subject that needs such modulation, administering a compound that preferentially modulates the PPARdelta activity. Another aspect of the present invention describes a method for treating a disease in a mammal, wherein the disease is capable of being modulated by the activity of the PPARdelta ligand, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I. wherein ARIL is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C-? -6 alkyl, C2-6 alkenyl. C6-C6 alkoxy, C6-C6 perfluoroalkyl; alkylthio C6-, hydroxy, hydroxy-C6-6alkyl, acyloxy C1- a, nitro, cyano, alkylsulfonyl C-? -6, amino, alkylamino Ci-β and alkoxycarbonyl Ci-ßiZ is -0 (CH2) n-, -SO2 (CH2) n-, - (CH2) nY- (CH2) n -, - (CH2) n -CO-, -O (CH2) n -CO- or - (CH2) nY- (CH2) ) n-CO- wherein Y is NR3, O or S, and R3 is selected from the group consisting of H, alkyl d-6, cycloalkyl C3-8, alkyl C -? - 6-cycloalkyl C3-8 and benzyl , and n is independently an integer between 1 and 5; X is NR3, O or S, wherein R3 is as defined above; R-i is H, halogen, C? -6 alkyl, C? -6 alkoxy, C?? 6 perfluoroalkyl; hydroxy-alkyl d-e, nitro, cyano and alkylamino Cl-6; and R 2 is substituted or unsubstituted phenyl, pyridinyl or thienyl, wherein the substituents are selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl. C -? - 6 alkoxy, C -? - 6 perfluoroalkyl, dithioalkylthio, hydroxy, hydroxyC? --6 alkyl, acyloxy C? -4, nitro, cyano, alkylsulfonyl C?? 6, amino, C 1-6 alkylamino and C 1-6 alkoxycarbonyl; or its stereoisomer, tautomer or solvate, or its pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION The terms and expressions, as used herein, have the following meanings: As used herein, the expression "alkyl" C? -6"includes methyl and ethyl groups, and straight or branched chain propyl, butyl, pentyl and hexyl groups The particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. "alkoxy d-? 'S" C6-C6-alkoxy-C6-alkyl "," hydroxy-Cyl, "" alkylcarbonyl d-β "," alkoxycarbonyl d-6- C6-alkyl "," alkoxycarbonyl " -6"," amino-C-6 alkyl "," alkylcarbamoyl C-6-C 1-6 alkyl "," dialkylcarbamoyl C 1-6-C 1-6 alkyl "" mono- or dialkylamino d-6-alkyl " C? -6", amino-alkylcarbonyl C? -6", "diphenyl-C1-6alkyl", "aryl-C-? -6alkyl", "arylcarbonyl-C C-6 alkyl" and "aryloxy d-6-alkyl" will be interpreted accordingly. As used herein, the expression "alkenyl" C2-61 'includes ethenyl and straight-chain or branched propenyl, butenyl, pentenyl and hexenyl groups. Similarly, the term "C2-6 alkynyl" includes ethynyl and propynyl groups, and straight or branched chain butynyl, pentynyl and hexynyl groups. As used herein, the term "acyloxy d-" denotes an acyl radical attached to an oxygen atom, some examples include, but are not limited to, acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy , t-butanoyloxy and the like. As used herein "aryl" represents an aromatic and carbocyclic ring system such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Ariio also aims to include the partially hydrogenated derivatives of carbocyclic aromatic systems previously listed. Non-limiting examples of said partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. As used herein, "aryloxy" represents an -O-aryl group, wherein aryl is as defined above. As used herein, "heteroaryl" (by itself or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - is a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S such as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, soquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole , tetrazole, triazole, imidazole or benzimidazole. As used herein, "heterocycle or heterocyclyl" (in itself or in any combination, such as "heterocyclylalkyl") - is a partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydro pyran or imidazolidine. As used herein, the term "perfluoroalkyl d.6" means that all hydrogen atoms in said alkyl group are replaced with fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl groups, and heptafluoropropyl, nonafluorobutyl, straight chain or branched undecafluoropentyl and tridecafluorohexyl. The derivative expression "perfluoroalkoxy C-i-β" should be interpreted accordingly. As used herein, the term "C3.8 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, the term "(C3.8) cycloalkyl- (C? -6) alkyl" means that the C3-8 cycloalkyl as defined herein, is further attached to the C1-6 alkyl as define in this memory. Representative examples include cyclopropylmethyl, 1-cyclobutylethyl, 2-cyclopentylpropyl, cyclohexylmethyl, 2-cycloheptylethyl and 2-cyclooctylbutyl and the like. As used herein, "halogen" means chlorine, fluorine, bromine and iodine. As used in this specification"alkylsulfonyl d-β" in the present context designates a group -S (= O) 2alkyl d.6 in which C1.6alkyl is as defined above. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n -hexylsulfonyl, isohexylsulfonyl and the like. As used herein, "arylsulfonyl" represents a -S (= O) 2-aryl group, wherein aryl is as defined above. As used herein, "heteroarylsulfonyl" represents a -S (= O) 2 -heteroaryl group, wherein heteroaryl is as defined above. The expression "stereoisomers" is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. Typically, it includes the mirror image isomers that are normally formed due to at least one asymmetric center (enantiomers). When the compounds according to the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers, and also some individual molecules may exist as geometric isomers (cis / trans). It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. "Substituted" means substituted with 1 or 2 substituents independently selected from the group consisting, in alkyl d-6, perfluoroalkyl C? _6, hydroxy, -CO2H, an ester, an amide, Ci-C6 alkoxy, perfluoroalkoxy Ci-C6, - NH2, Cl, Br, I, F, -NH-lower alkyl and -N (lower alkyl) 2. The compounds and salts of the present invention may exist in various tautomeric forms, including the enol and imine forms, and the keto and enamine forms and their geometric isomers and mixtures. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually a tautomer predominates. Although a tautomer can be described, the present invention includes all tautomers of the present compounds. As used herein, the term "modulator" refers to a chemical compound capable of either improving (eg, "agonist" activity) or inhibiting (eg, "antagonist" activity) a functional property of biological activity or process (eg, enzymatic activity or receptor binding); said improvement or inhibition may be eventual in the occurrence of a specific event, such as the activation or repression of a signal transduction pathway and / or may be manifest only in particular cell types and may produce a measurable biological change. As used herein, "patient" means a warm-blooded animal, such as, for example, rats, mice, dogs, cats, guinea pigs, and primates such as humans. As used herein, the term "pharmaceutically acceptable carrier" means a solvent, dispersant, excipient, adjuvant or other non-toxic material, which is mixed with the compound of the present invention, in order to allow the formation of a pharmaceutical composition, that is, a dosage form that can be administered to the patient. An example of such a carrier is a pharmaceutically acceptable oil which is typically used for parenteral administration. The term "pharmaceutically acceptable salts", as used herein, means that the salts of the compounds of the present invention can be used in medicinal preparations. However, they can other salts are useful in the preparation of the compounds according to the invention, or of their pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can be formed, for example, by mixing a solution of the compound according to the invention, with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid , sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymeleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2- phenoxyacetic, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Acid metal salts can also be formed, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. In addition, the salts thus formed may be present as mono or di-acid salts and may exist in hydrated form or may be substantially anhydrous. In addition, when the compounds of the invention have an acidic moiety, their suitable pharmaceutically acceptable salts can include alkali metal salts, for example sodium or potassium salts.; alkaline earth metal salts, for example, calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts. The expression "therapeutically effective amount", as used as used herein, means an amount of the compound that is effective to treat the aforementioned disease or disorder. The invention also provides pharmaceutical compositions comprising one or more of the compounds according to this invention, together with a pharmaceutically acceptable carrier. Preferably, these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosols or dosed liquid sprays, drops, ampoules, self-injection devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a reservoir preparation for intramuscular injection. An erodible polymer containing the active ingredient can be contemplated. To prepare solid compositions as tablets, the main active ingredient is mixed with a pharmaceutical carrier, e.g. ex. conventional ingredients for forming tablets, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. ex. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or its pharmaceutically acceptable salt.

When it is indicated that these preformulation compositions are homogeneous, it means that the active ingredient is dispersed uniformly throughout the composition, so that the composition can be easily subdivided into uniform dosage forms equally effective, such as tablets, pills and capsules. . The solid preformulation composition is then subdivided into unit dosage forms of the above-described type, containing from 0.1 to about 500 mg of the active ingredient of the present invention. The uniformized aroma dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the new composition can be reversed or compounded in other ways to provide a dosage form that allows the release of a prolonged action. For example, the tablet or pill may comprise an inferno dosage compound and an exhaustion dosage compound, the latter being in the form of a sheath on the former. The two components can be separated by an enimeric layer, which acyuates to resist the disintegration in the stomach, and allows the infernal component to pass iniacically into the duodenum, or released with rehraso. A variety of materials can be used for such layers or enimeric coatings, said materials including a series of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetamide. The liquid forms in which the new compositions of this invention can be incorporated for oral or median administration Injections include aqueous solutions, suitably scented syrups, aqueous or oily suspensions, and emulsions aromatized with oils such as cottonseed oil, sesame oil, coconut oil or arachis oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as fragrance, gum arabic, alginate, dexirane, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or gelaine. In the course of the various pathological processes as described in this report, a suitable dosage level is from approximately 0.01 to 250 mg / kg daily, preferably from approximately 0.05 to 100 mg / kg daily, and especially from approximately 0.05 to 20 mg / kg daily. The compounds can be administered in a regime of 1 to 4 times daily. As used in the examples and preparations that appear hereinafter, the terms used in them have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, "g" refers to micrograms, "pg" refers to picograms, "mol" refers to moles, "mmol" refers to millimoles, "nmol" refers to nanomoles, "L" refers to liíros, "mL "or" my "refers to milliliters," μL. " refers to microliters, "° C" refers to degrees Celsius, "Rf" refers to retention factor, "mp" or "m.p." refers to melting point, "dec" refers to decomposition, "bp" or "b.p." HE refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to millimeters, "nm" refers to nanometers, "[] 20D" refers to specific rotation of line D of sodium at 20 ° C obtained in a 1 decimetre cell, "c" refers to concentration in g / mL, "THF" refers to tetrahydrofuran, "DMF" refers to dimethylformamide, "NMP" refers to 1 -metol- 2-pyrrolidinone, "brine" refers to an aqueous solution of sodium chloride, "M" refers to molar, "mM" refers to millimolar, "M" refers to micromolar, "nM" is refers to nanomolar, "TLC" refers to thin layer chromatography, "HPLC" refers to high resolution liquid chromatography, "HRMS" refers to high resolution mass spectrum, "CIMS" refers to mass spectrometry by chemical ionization, "ESI" refers to electrospray ionization mass spectrometry, "IR" refers to time of retention , "Ib" refers to pounds, "gal" refers to gallons, "L.O.D." refers to loss in drying, "μCi" refers to microcuries, "i.p." refers to iníraperitoneal way, "i.v." it refers to intravenous route. In one aspect of the present invention, new compounds having the general structure shown in formula I are described: in which ARIL is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally substituted with one or more substituents selected from the group consisting of halogen, d-6 alkyl, C 2-6 alkenyl, d-6 alkoxy, perfluoroalkyl d-β; alkylthio d-6, hydroxy, hydroxy-alkyl d-6, acyloxy C 1-4a, nickel, cyano, alkylsulfonyl C? -6, amino, alkylamino d-6 and alkoxycarbonyl C? -6; Z is -O (CH2) n-, -SO2 (CH2) n-, - (CH2) nY- (CH2) n -, - (CH2) n -CO-, -O (CH2) n -CO-, or - (CH2) pY- (CH2) n-CO- wherein Y is NR3, O or S, and R3 is selected from the group consisting of H, alkyl d_6, cycloalkyl C3-8, alkyl d-6-cycloalkyl C3 -8 and benzyl, and n is independently an integer enire 1 and 5; X is NR3, O or S, where R is ial as defined above; R-i is H, halogen, C? -6 alkyl, C?? 6 alkoxy, C?? 6 perfluoroalkyl; hydroxy-alkyl d-6, nitro, cyano and C 1-6 alkylamino; and R 2 is substituted or unsubstituted phenyl, pyridinyl or thienyl, wherein the substituents are selected from the group consisting of halogen, d 6 alkyl, C 2-6 alkenyl, d 6 alkoxy, d-β perfluoroalkyl, C 1 alkylthio 6, hydroxy, hydroxy-alkyl d-6, acyloxy C? -4, nifro, cyano, alkylsulfonyl d-6, amino, alkylamino d-6 and alkoxycarbonyl C-? -6; with the proviso that when Z is -O (CH2) n- or -SO2 (CH2) n-, and ARIL is phenyl, then R2 is phenylene disfinite; or its stereoisomer, ioiumer or solvate, or its pharmaceutically acceptable salt. In another aspect of this mode, a compound is described in which ARIL is phenyl and X is O or S. In this aspect of this embodiment, a compound is described in which X is O. A compound illustrative of this embodiment is 5- (4-. {2- 2- [5-methyl-2- (4-trifluoromethyl-phenyl) -iazol-4-yl] -ethoxy}. -fenl) -3 - / - [1,4] oxadiazol-2-one. In another embodiment of the present invention, a pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier is described. In another embodiment of the present invention there is described a method for treating a disease in a mammal, wherein the disease is capable of being modulated by the binding activity of the PPARdelia ligand, which comprises administering said mammal having said disease, a therapeutically effective amount of a compound of formula I. wherein ARIL is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C-? -6 alkyl, C2-6 alkenyl. alkoxy d-6, perfluoroalkyl C-? -6, 'C 1-6 alkylthio, hydroxy, hydroxy-alkyl d-6, acyloxy C? -a, nitro, cyano, alkylsulfonyl d-6, amino, alkylamino C? -6 and alkoxycarbonyl d-6; Z is -0 (CH2) n-, -SO2 (CH2) n-, - (CH2) n-Y- (CH2) n -, - (CH2) n -CO-, -O (CH2) n-CO- or - (CH2) nY- (CH2) n-CO- wherein Y is NR3, O or S, and R3 is selected from the group consisting of H, alkyl d-6, cycloalkyl C3-8, alkyl d-6 -C3-8 cycloalkyl and benzyl, and n is independently an integer between 1 and 5; X is NR3, O or S, wherein R3 is as defined above; R-i is H, halogen, C? _6 alkyl, d-6-alkoxy, perfluoroalkyl d-p-hydroxy-C1-6alkyl, nitro, cyano, and C-I-T alkylamino; and R 2 is unsubstituted or unsubstituted phenyl, pyridinyl or thienyl, wherein the susíiuyenyes are selected from the group consisting of halogen, d-6 alkyl. C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 perfluoroalkyl, C 1-6 alkylthio, hydroxy, hydroxy alkyl d 6, acyloxy C? -, nitro, cyano, alkylsulfonyl d-6, amino, alkylamino d-6 and Ci-β alkoxycarbonyl; or its stereoisomer, tautomer or solvate, or its pharmaceutically acceptable salt. In another aspect of this embodiment, a compound is described in which ARIL is phenyl. In another aspect of this embodiment of this invention, a compound is described in which ARIL is phenyl and R2 is phenyl. In another aspect of this embodiment of this method of the invention, a compound is described in which ARIL is phenyl, Z is -O (CH2) n- and R2 is phenyl. Even in another aspect of this embodiment of this method of the invention, a compound is described in which ARIL is phenyl, Z is -O (CH2) n-, X is O or S, and R2 is phenyl. In another aspect of this embodiment of this method of the invention a compound is described wherein ARIL is phenyl, Z is -O (CH2) n-, X is O or S, Ri is alkyl d and R2ß phenyl. In another aspect of this embodiment of this method of the invention, a compound is described in which X is O. Even in another aspect of the present invention of this invention, a compound is described wherein X is S. En o This method describes a period in which said disease is a demyelination disease selected from the group consisting of multiple sclerosis, Charcoi-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre and disorders in which the normal cells that form myelin are damaged, including spinal cord injuries, neuropathies and nerve injuries. In another aspect of this embodiment, a method is described in which the demyelination disease is multiple sclerosis. Even in another aspect of the present invention, a method is described in which said disease is selected from the group consisting of obesity, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, hypercholesterolemia, dyslipidemia, Syndrome X, diabetes mellitus of type II and its complications selected from the group which consists of neuropathy, nephropathy, retinopathy and cataracts, hyperinsulinemia, glucose intolerance, insulin resistance, atherosclerosis, hypertension, coronary heart disease, peripheral vasculopayia or congestive heart failure.

The compounds described herein may be synthesized in accordance with the following Scheme procedures, in which the subscripts Aril, X, Z and R are as idenified for the formula (I) set forth above, unless otherwise indicated. . If necessary, in the following synthetic schemes, the reactive functional groups in the compounds described in the present invention can be protected by suitable progenitor groups. The protecting group can be removed in a subsequent step of the synthesis. Methods for protecting functional reactive groups and their subsequent elimination can be found in TW Greene and PGM Wuis, Protective Groups in Organic Synthesis, Wiley and Sons, 1991. Scheme A shows the synthesis of appropriate imidazole, oxazole or isoazole intermediates for the compounds of formula I, wherein X is O, S or NR3. Heterocycles can be prepared using methods known from the chemical literature (for reviews, see Katriízky, A.R., Rees, C.W. Eds. Comprehensive Heterocyclic Chemstry, Vol. 5, Pergamon Press (1984); Katriízky, A.R .; Rees, C.W .; Scriven, E.F.V. Eds. Comprehensive Heterocyclic Chemstry II; Vols 3 & 4, Pergamon Press (1996)). Specifically, said oxazoies, imidazoles and iazoles can be prepared by melting a suitable halo-D-ketone 1, respectively, with an amide, amidine or thioamide (general formula 2), at temperatures in the range of about 40 ° C to 150 °. C to produce intermediate heyerocycles 3.

Scheme A In Scheme B, the general synthesis of the compounds of formula I is known, in which Z is -O (CH2) n-. Thus, in Efapa B1, the ester of the appropriately substituted carboxylic acid 4, which can be synthesized as outlined in Scheme A, is reduced to alcohol 5 by methods known in the art. For example, the reduction can be effected by aluminum hydrides such as aluminum hydrides and lithium or hydride of dusbuleylaluminium in an inert solvent. In Step B2, the alcohol functional group in compound 5 is converted to a leaving group to produce compound 6, wherein Lg is a leaving group such as halogen, or sulfonated esters, for example, mesylates or tosylates. The conversion to the leaving group can be achieved by reaction of the alcohol with reactants such as N-bromosuccinimide in the presence of triphenylphosphine to produce a compound in which the leaving group is bromide, or reaction with thionyl chloride to produce a compound in which the outgoing group is chloride. If a sulfonated ester is desired, reaction of compound 5 with an appropriate sulfonyl chloride in the presence of a suitable base would produce the desired sulfonate ester. For example, the reaction of compound 5 with measulfonyl chloride in the presence of an organic base such as triethylamine or pyridine in an inert solvent, it would produce compound 6, wherein the leaving group is OSO 2 CH 3. In Step B3, an appropriately substituted hydroxyaryl ester 7 is reacted with the heterocycle 6 to displace the leaving group to produce the coupled ester 8. The displacement reaction is effected under conditions known in the art. Typically, the reaction is carried out in the presence of an alkaline base such as sodium hydride or other inorganic bases such as alkali carbonates or alkali hydroxides in an inert solvent. The temperature of the reaction, although not critical, is between 0 ° C and the reflux temperature of the inert solvent. Compound 8, in Step B4, is then treated with hydrazine, either neat or in a suitable organic solvent at elevated temperatures to produce the acid hydrazide 9. Typically, the reaction is carried out at a temperature of 50 ° C. the reflux time of the organic solvent. The cyclization of the acid hydrazide 9, in step B5, to the target 1,4-oxadiazol-2-ones 10 is achieved by bringing the compound 9 with a chloroform in the presence of an organic base such as pyridine, followed by of irradiation with a strong hindered amine base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) in a suitable organic solvent such as acetonitrile in a sealed tube at elevated temperature. Typically, the reaction is carried out at 100 ° C and 200 ° C. 1,4-Oxadiazol-2-ones can also be synthesized by reacting compound 9 with phosgene.

See Síempel, A., et al., J. Org. Chem. 1955, 20, 412. In EIAPA B6 an alternative synthesis of the coupled ester 8 is illustrated. Accordingly, the alcohol 5 can be reacted with the hydroxyaryl ester 8 in the presence of an aryl or trialkylphosphine, such as triphenylphosphine or N-buyylphosphine and diethylazodicarboxylate in an inert solvent, for example THF or dichloromean, to produce the coupled ester 8. Typically, the reaction is carried out at a temperature between ambient temperature and the reflux time of the inert solvent.

Scheme B Stage B2 4? = O Stage B3 6 R '= alkyl CM Scheme C illustrates the synthesis of the compound of formula I, wherein Z is - (CH 2) n-Y- (CH 2) n-. The scheme is more useful to synthesize compounds in which n represents 1 or 2 in the alkylene chain attached to the ARIL. In EIApa C1, compound 5 (Y = O) is converted to compound 6 (wherein Lg is chloro or bromo) ial as described in Scheme B, EIApa B2. Compound 6 is then reacted with íourea, compound 11, under conditions similar to those found in Treau, M. eí al. Heterocycles, 2001, 55 (9), 1727-1735, to produce the iioi 5a. When the compound 6 is reacted with a primary amine 12, the aminoalkyl heterocycle 5b is produced. Those skilled in the art know this displacement of a leaving group by an amine.

Typically, the displacement reaction is carried out in a polar organic solvent in the presence of an organic base that acts as a scavenger of acid. Although not critical, the displacement reaction is carried out at an temperature between room temperature and the reflux temperature of the solvent. In Step C3, compounds 5, 5a and 5b can be reacted with compound 13 to produce the coupled aryl ester 14, wherein Y is O, S or NR3. Therefore, when the compounds 5 (Y = O) and 5a (Y = S) are reacted with 13 to displace the leaving group, the typical reaction will be carried out in the presence of a strong base, for example sodium hydride. , in a polar aprotic solvent, such as DMF or DMSO at temperatures of approximately 0 ° C and 150 ° C. When the compound 5b (Y = NR3) is reacted with 14, conditions identical to those described above are used in the C2 layer for the primary amine. The synthesis of the desired 1,4-oxadiazol-2-ones 16 of compound 14 is achieved in the two steps (C4 and C5) exacfamenie as described in Scheme B, EIApas B4 and B5.

Scheme C or K, NR3 12 Stage C3 5a 13 5b R'OOC- In Scheme D, an alternative approach is shown to the compounds of formula I, wherein Z is - (CH2) n-Y- (CH2) n-. The scheme is most useful for synthesizing compounds in which n represents 3 or 5 in the alkylene chain attached to the ARIL. In Lane D1, the terminal aldehyde compound 17, which can be syntheiZed by the method described in Scheme A, is converted to a two-step reaction sequence to the terminal 19-aceylen. The reaction of 17 with bromomethylenetriphenylphosphorane (FIG. first stage) with pozasium t-BuOK produces an intermediate bromine-olefin (not sample), which was subsequently brought with 2 equivalents of f-BuOK (second layer) to form the 19-acetylene. The reaction sequence for the conversion was describes in Pianeííi, P., Tet. Letters, 1986, 48, 5853-5856. See also Corey, E. J., et al. J. Am. Chem. Soc, 1969, 91, 4318-4320. Alternatively, as shown in Step D2, intermediates of type 19 can be prepared by displacement of a leaving group from a intermediate such as 6 (see Scheme C) using a nucleophile, such as 18, in which a terminal acetylene is incorporated. In Step D3, the Sonogashira coupling of the acetylenic intermediate 19 with the aryl iodide 20 is carried out in the presence of fefrakistriphenylphosphinepalladium (0), cuprous iodide and a suitable organic base in an inert solvent to produce the coupled acetylene-21. The reduction of the acetylene 21 can then be achieved in Eiapa D4 by cationic hydrogenation of compound 21 to produce the saturated ester 14. Typically, the reduction can be achieved by the use of ionic catalysts such as palladium on carbon or chlorofris (friphenylphosphine) rhodium ( ) in an inert organic solvent with hydrogen at pressures between 30 and 300 psi The reduction can be carried out at an ambient temperature ambient temperature of 175 ° C. The synthesis of the desired 1, 3,4-oxadiazoI-2-ones 16 of compound 14 is achieved in two steps (D5 and D6) exactly as described in Scheme B, Steps B4 and B5.

Scheme D base Stage D4 R'OOC - ARIL - = - (CH2) í -? - (CH3IS- <? I 21 R'OOC- Scheme E illustrates a particular synthesis of compounds of formula I in which Z is - (CH2) nNR3 (CH2) p-. In this approach, the linker Z is constructed by a reductive amination of an aldehyde with an amine. For example, in Step E1, the traffic of 5b (wherein Y = NR3) with an aldehyde, such as 4-formyl-benzoic acid methyl ester (n = 1) compound 22, in a polar solvent, usually a alcohol or a mixture of alcohol and THF, followed by treatment with a reducing agent such as sodium triacetoxy borohydride, provides the required intermediate 14a (n = 1). Similarly, in Step E2, the treatment of such an aldehyde as 17a with an amine, such as 4-aminoalkylbenzoic acid methylester (n = 1), compound 23, provides 14a, wherein n is 1 and R3 is H for - (CH2) nNR3. Compound 14a in eiapas E3 and E4 is converted to 1, 3,4, -oxadiazol-2-ones 16a, as described in Scheme B, Steps B4 and B5. More generally, the appropriate amines (R'OOC-ARIL- (CH2) nNHR3) are prepared from the corresponding nitroyl or nitro compounds by catalytic hydrogenation or from acetylenic amines and an aryl bromide or iodide by Sonogashira coupling followed by hydrogenation as described in Scheme D.

Scheme E 16th laa Scheme F illustrates the synthesis of compounds of formula I, in which Z is -SO2 (CH2) n-. In F1, the treatment of a 24-arylsulfonyl chloride with aqueous sodium sulphite provides 25-sulfinic acid. reaction of 25, as in Step F2, with an initial reaction such as 6 in a polar polar solvent such as DMF, acetylortyl or ethylene in the presence of an alkaline base such as DBU, pyridine, sodium meioxide or sodium hydroxide, provides the intermediate 26 Intermediate 26 is converted to the corresponding 1, 3,4-oxadiazol-2-one 28 in Steps F3 and F4, as illustrated in Scheme B, Steps B4 and B5.

Scheme F Stage F2, 24 25 6 26 27 Stage F4 28 Scheme G illustrates the synthesis of the compound of formula I, wherein Z is -O (CH2) nCO-. The scheme illustrates the case where n is 1. The starting heterocycle of 2-acyl 29 can be synthesized from the corresponding carboxylic acid (prepared by the method illustrated in Scheme A), by addition of a suitable Grignard reactant, to an N-meioxy-N-meityl carboxamide intermediate (Khlesfkin, VK et al., Currenf Organic Chemistry, 2003, 7 (10), 967-993, and Singh, J. et al., Journal für Praktische Chemie, 2000, 342, 340-347). The preparation of the intermediate N-methoxy-N-methylcarboxamide is most conveniently carried out by reacting the acid with N-methoxy-N-methylcarboxamide hydrochloride in the presence of a peptide coupling reagent such as EDC, DCC, DMPU and a base of tertiary amine such as diisopropylethylamine or trieylamine. Therefore, 29 jokes to produce bromoketone 30, as shown in Step G1. Bromination can be achieved by known methods, for example reaction of 29 with pyridinium bromide by bromide in acetic acid or reaction of 29 with Br2 in an inert organic solvent such as dichloromethane. The resulting bromoketone 30 in Step G2 is reacted with arylhydroxy ester 7 under the conditions described in Scheme B (Step B3) to produce the coupled ester 31. The functionality of the ketone at 31 is protected as a ketal 32, such as is shown in Step G3 by methods known in the art. Compound 32 is then converted to 1,4-oxadizol-2-one ketal 34 in Steps G4 to G5 by the standard sequence described in Scheme B (B4 and B5). Finally, in Stage G6, the ketal functionality in 34 is split, by example, with mineral acid in THF-methanol-water or other known methods in the technique to produce the target structure 35.

It would be obvious to the person skilled in the art that the procedure of Scheme G above could be used to synthesize analogs in which n is 2-5 for compound 35 starting with a bromoketone, compound 30, with a Larger bromoalkanoyl substituent (Br (CH2) nCO-, where n is 2 to 5).

Scheme G Stage F1 Eta a F2 ._ R'00C-ARIL-S02CI - * ~ 24 25 R R'OC 26 27 H, l Stage F4 N R 35 n = 1 Scheme H illustrates the process for the preparation of compounds of formula I, wherein Z is - (CH 2) nCO-. In Step H1, the suitable methoxycarbonyl-substituted heterocycle 36 is treated with 2 equivalents of lithium enolate of t-butylacetate in a solvent such as THF or DME at an inlet temperature of -78 ° C at room temperature to provide the Ketoacetaium intermediate 37. In Step H2, the ratio of 37 with an alka base as sodium hydride in an inert solvent at an ambient temperature of -10 ° C and ambient temperature, followed by alkylation of the resulting anion with an electrophile such as 13. , produces the advanced intravenous ketodiester 38. The decarboxylation is shown in Step H3 and can be achieved by first isolating 38 with TFA in an inert solvent such as dichloromethane, followed by thermolysis at an hour between 70 ° C and 150 ° C for provide the ceioésíer intermediate 39. The ceíona functionality in 39 is protected as a ceíal 40, as shown in EIApa H4 by methods known in the art. Compound 40 is then converted to 1,4-oxadiazol-2-one ketal 42 in Steps H5 to H6 by the standard sequence, as described in Scheme B (B4 and B5). Finally, in Step H7, the ketal functionality at 42 is cleaved as described above in Scheme G, Ephapa G6, to produce the desired 1,4-oxadiazol-2-one, compound 43.

Scheme H Stage H4 COOR ' R '° OC- ARI Biological Examples: The following assay protocols are used to evaluate the biological properties of the compounds of this invention. The following examples are presented to further illustrate the invention. However, they should not be considered as limiting the invention of no way.

Determination of the EC50 values in the cellular PPARdelta-GAL4 assay: Principle The potency of the susiences, which bind to the human PPAR dellia and agylyze it in an agonisia mode, is analyzed using a HEK transferable cell (HEK = kidney). human embryo) that is here called the PPAR indicator cell . It has two genetic elements, a luciferase indicator element (pdelíaM-GAL4-Luc-Zeo) and a PPAR delta fusion prolein (GR-GAL4-PPAR delta human-LBD), which mediates the expression of the luciferase indicator element that depends on a ligand of the PPAR delta. The fusion protein GR-GAL4-PPAR delta human-LBD expresses consíiíufiva and stably, binds in the cell nucleus of the PPAR delta indicator cell by the part of the GAL4 protein to the DNA binding pads of GAL4, 'runs above the luciferase indicator element that is stably integrated into the genome of the cell . In the absence of a PPAR delta ligand there is only weak expression of the luciferase reporter gene, if fetal calf serum with fatty acid reduction (cs-FCS) is used in the assay. PPAR delta ligands bind to and activate the PPAR delía fusion proiein, and thus express the expression of the luciferase reporter gene. The luciferase that forms can be detected by chemiluminescence through a substrate suitable. Constructing the PPAR delía indicator cell : The production of the PPAR deliaia indicator cell is based on a clone of stable HEK cells that is reliably transfected with an indicator element of luciferase. This stage was already described in the section "Construction of PPAR alpha indicator cell ". In a second step, the PPAR delta fusion protein (human GR-GAL4-PPAR delta-LBD) was stably introduced into this cell clone. For this purpose, the cDNA encoding the 76 N-terminal eminent amino acids of the glucocorticoid receptor (accession no. # P04150) was attached to the cDNA section encoding amino acids 1-147 of the yeast transcription factor GAL4 (no. of access # P04386). The cDNA of the ligand binding domain of the human PPAR delta receptor (amino acids S139-Y441; Accession # L07592) was cloned at the 3 'end of this construct GR-GAL4. The fusion construct prepared from this form (GR-GAL4-PPAR delía humana-LBD) was re-cloned into the plasmid pcDNA3 (Invitrogen) in order to allow expression in the cytomegalovirus promoter. This plasmid was linearized with a rescission endonuclease and was easily transfected into the previously described cell clone containing the luciferase reporter element. The finished PPAR delia receptor cell line that confers a luciferase reporter element and constitutively expresses the PPAR delta fusion protein (GR-GAL4-PPAR delta-human-LBD) was isolated by zeocin selection (0.5 mg / ml) and G418 (0.5 mg / ml).

Testing and evaluation procedure: The acfivity of PPAR delfa agonisies is determined in a 3-day trial described as follows: Dia l The PPAR delia indicator cell line was taken care of at 80% confluence in DMEM (# 41965 -039, Invitrogen) which is mixed with the following additions: cs-FCS at 10% (fetal calf serum; # SH-30068.03, Hyclone), 0.5 mg / ml zeocin (# R250-01, Invitrogen), 0 , 5 mg / ml G418 (# 10131-027, Invifrogen), 1% penicillin-streptomycin solution (# 15140-122, Invitrogen) and 2 mM L-glumyamine (# 25030-024, Invifrogen). The culture is carried out in standard cell culture bottles (# 353112, Becton Dickinson) in a cell culture incubator at 37 ° C in the presence of 5% CO2. The 80% confluent cells are washed once with 15 ml of PBS (# 14190-094, Inviírogen), framed with 3 ml of syrup solution (# 25300-054, Inviírogen) at 37 ° C for 2 min, absorbed. in 5 ml of DMEM described and stored in a cell conifer. After diluting to 500. 000 cells / ml, 35,000 cells are seeded in each well of a 96-well microtiter plate with an opaque plasmid base (# 3610, Corning Cosíar) in a volume of 180 // L. The plates are incubated in the cell culture incubator at 37 ° C and with 5% CO2 for 24 hours. Day 2 The PPAR delta agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (# 41965-039, Inviírogen) which is mixed with 5% cs-FCS (# SH-30068.03, Hyclone), 2 mM L-glutamine (# 25030-024, Invitrogen) and the previously described antibiotics (zeocin, G418, penicillin and streptomycin). The test substances are tested at 11 different concentrations in the range of 10 μM to 100 pM. The most potent compounds are tested with concentrations in the inervator from 1 μM to 10 pM or between 100 nM and 1 pM. The medium of the cell line with the PPAR delta indicator sown on day 1 is completely eliminated by aspiration or not, and to the cells the test substances diluted in medium are added immediately. The dilution and addition of the substances is carried out by means of a robot (Beckman FX). The final volume of test substances diluted in medium is 100 μl per well of a 96-well microtiter plate. The concentration of DMSO in the assay is less than 0.1% vol / vol in order to avoid cyclo-toxic effects of the solvent. Each plate was loaded with a PPAR delía pairo agonisfa, which was also diluted in 11 different concentrations, in order to demonstrate the performance of the assay in each individual plate. The test plates are incubated in a 37 ° C incubator and 5% CO2 for 24 h. Alferonarily, 20 μL of a final 10x concentration of the test substance are added directly to the 180 μL contained in the cells in the plates. The test substrates are tested in 8 concentrations different, in triplicate, in this type of test plates. Day 3 Cells with the PPAR delta indicator treated with the test substances are removed from the incubator and the medium is aspirated. Cells are used by pipetting 50 μl of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux de Wallac). The measurement time for each well of the microtiter plate is 1 second. Evaluation: The raw data of the luminometer is transferred to a Microsoft Excel file. The graphs of the effect of the dose and the EC50 values of the PPAR agonists are calculated, using the XL.Fit program as specified by the manufacturer (I DBS). The EC50 values of the PPAR delía were measured in the range of 1 nM to >10 μM for the PPAR modulators of the examples of this request. Compounds of the invention of formula I can act as agonists or antagonists. The assay that determines the agonist or antagonist activity is described below. Determination of the efficacy of agonists or partial antagonisms in the PPARdelta receptor This assay determines whether the compounds act as agonists or partial antagonists in the PPARdelía receptor. The preparation and the culture in the test plates are described in Days 1 and 3 defined above. Day 2 The agonist or partial antagonism and a known selective agonism are diluted in DMEM (# 41965-039, Inviírogen), which is mixed with 10% cs-FCS (# SH-30068.03, Hyclone), 2mM L-glumyamine (# 25030-024, Inviírogen) and the previously described antibiotics (zeocin, G418, penicillin and streptomycin) to the desired final concentrations 20X. Ten microliters of the partial agonist or antagonist is added to the assay plate containing the cell. The test plates are incubated in an incubator at 37 ° C and 5% CO2 for 30 minutes. Ten microlipres of the 20X known selective agonistias are then added, after the pre-incubation of agonist or partial antagonism. The test plates are incubated in a 37 ° C incubator and 5% CO2 for 24 h. The effect of EC50 of the known selective agonists is determined for each concentration of agonism or partial antipharyngeal. PPARdelía-LBD binding assay with SPA Stem solutions: 1 M Tris (pH = 8.0 or pH = 7.6) (Gene Medicine Stock Room) 2 M KCl (Powder in N2140) 100 mM DTT Tween 20 13.9 uM GW2331 in HOT EtOH GW 2331 10 mM in DMSO COLD PPAR-alpha (conc varies) Wash Buffer ¡CONSERVATION at 4 ° C. The buffer is kept in good condition for one week) 10 mM Tris (pH = 7.6 or 8) 10 ml 50 mM KCl 25 ml 0.05% Tween 20 0.5 ml Millipore Water 964.5 Conírol PH = 7, 6 Binding buffer: (A new binding buffer is prepared each time) Wash buffer 50 ml DTT IO mM 5,5ml Preparation of reaction reagents for 1 plate: SPA microspheres coated with glutathione Each vial of SPA microspheres contains 500 mg of microspheres 500 mg of SPA microspheres are reconstituted in 5 ml of wash buffer and kept in good condition for a few weeks) Preserved at 4 ° C The SPA microspheres diluted in the binding buffer are prepared. 1 ml of the already reconstituted SPA microspheres is added to 60 ml of the buffer Binding 20 μl of the previously diluted microspheres are added to each well of a 96-well plate. 2 ml of the diluted microspheres are used for each plate (dead volume is not included). 3H GW-2331 plus GST-PPAR delta-LBD (for a 96-well plate with no dead volume) 13.9 μM 40nM / well 3.0 ml / plate (dead volume included) If the specific activity of 3H-GW2331 is 1mci / m! (from Amersham), dilute 17 μg of 3H GW-2331 in 3.0 ml of assay buffer = 0.08 μM. If the protein concentration is 1 mg / ml, add 21 μl of protein to 3.0 ml of binding buffer. In summary: A 96-well plate: 3000 μL binding buffer + 17 μL of 3H-GW2331 + 21 μL of GST-PPAR-delta (1 mg / mL) Control plates A 96-well mother plate (for 2 well plates) control) In column # 1: 5 μl of cold GW2331 (10 mM) is added to the EH wells. 45 μL of DMSO are added to wells A-H. In column # 12 (triple dilution): 10 μL of cold GW2331 (10 mM) are added to well A. Then 90 μL of DMSO is added to well A, the solution is mixed well. μl of DMSO are added to wells B-H. 10 μl of solution from well A to B are passed, mixed well, then 10 μl of solution from B to C are passed, mixed well, then 10 μl of solution from C to D are passed, mixed well. Finally, 10 μl of F are passed to H. Control plate A (for 8 reaction plates) A control plate consists of 1: 10 dilution of the mother plate. The dilution button is the wash button. Sample plates A plate of the fresh CPC library is added with 90 μL of DMSO 10 μl of DMSO dilution is taken and added to 90 μl of wash buffer in a sample plate. Reaction plates: 20 μl of SPA microspheres and 30 μl of 3H-GW2331 are added with GST-PPAR-delía to each well of a reaction plate. 5 μl of the compounds of each well of the sample plate are added in columns 2 to 11 of a reaction plate. 5 μl of compounds from column 1 and column 12 of the control plate are added to column 1 and column 12 of the reaction plate. 96-well SPA protocol: Let the reaction plates equilibrate for 20 minutes at 2 hours. The plates are sealed before confining in a Microbeia conifer (Wallac). The value of Clso- is calculated In the PPAR delia-LBD binding assay with SPA the measured IC 50 values are in the range of 1 nM to > 10 μM for the modulators of PPAR of the examples of this request. The compounds of the invention of formula I can be added as agony or anonymity. RATS / MICE oligodendrocyte cultures Preparation of cells: 1. Primary rary oligodendrocytes are obtained through the neocortex of newborn rats or mice (2-3 days after birth) and are enriched, after the removal of the microglial cells, by mechanical separation of the astrocytic monolayer using a modification of the technique originally described by McCarthy and de Vellis (1980). 2. The meninges of the neonatal rat brain are excised and the tissue is dissociated mechanically. The cells are placed in plates with T75 flasks and the cells are fed with DMEM / F12 + 10% FBS. 3. The oligodendrocytes that develop in the bed layer of astrocytes are collected by the agitation method for fourteen days after the original prep date. The suspension is centrifuged and the cell pellet is resuspended in serum-free medium (SFM, DMEM combined with 25 μg / ml transfer, 30 nM triyodoirionine, 20 nM hydrocortisone, 20 nM progesterone, 10 nM biotin, 1x trace elements, 30 nM selenium, 1 μg / ml putrescine, 0.1% BSA, 5 U / ml PenSírep, 10 μg / ml insulin) enriched with the following growth factors: Platelet-derived AA growth factor ( PDGF) and fibroblast growth factor 2 (FGF). 4. Place the cells in plates coated with PDL and incubate at 37 ° C with 6-7% CO2. 5. The components of the medium are replaced every 48 hours to keep the cells in a parent strand. The passage of progenitor cells is carried out to increase the amount of cells for the assays: 1. When the culture is confluent, the culinary is rinsed with PBS, trypsin is added and incubated for ~ 2-3 min at 37 ° C. 2. The cell suspension is neutralized and centrifuged at 900g for 5 min. 3. The cell pellet is resuspended in SFM + PDGF / FGF. 4. The cells are fed fresh growth factors every 48 hours to keep enriched in order to rapidly divide the progenitor cells. 5. The passage of the cells is carried out no more than 4-5 times before the experimental tests. 6. All experiments involving oligodendrocyte progenitor cells were carried out using cells that were maintained continuously under these conditions. More than 95% of all A2B5 cells were immunopositive and expressed 2'3'-r? Ucleophilic cyclic 3'-phosphodiesierase II mRNA. 7. To generate mature oligodendrocytes, 24 h after plating, the progenitor cells were transferred to SFM enriched with or without IGF-I and developed under these conditions for 7 days before the experimental tests. 8. Alternatively, the Central Glia-4 (CG4) progenitor cell line enriched in rat can be used, which is maintained in a base medium (DMEM, with 2 mM glutamine, 1 mM sodium pyruvate, biotin (40 nM), insulin ( 1 μM) and N1) enriched with 30% conditioned medium from the neuroblastoma cell line B-104. To induce differentiation, CG4 cells are passed to the base medium with 1% fetal calf serum (which is removed after 2 days) and insulin (500 nM). The immunoreactivity of A2B5 and MBP is used to confirm an enrichment > 95% in immature and mature crops, respectively. Treatment with the Rata / Raimon culture compound: 1. 10,000 - 15,000 cells / well are placed in 24-well plates coated with PDL and the cells are cultured in the presence of mitogen (10 ng / ml) overnight. 2. In the presence of mitogen: a. The next day the used medium is eliminated and compounds are added in new medium (with mitogen) b. The evaluations of the dose and the effect of the compound were carried out with 6 different concentrations (10 μM, 1 μM, 100 nM, 10 nM, 1 nM and 0.1 nM); c. Wells are prepared in triplicate for each concentration of the compound. 3. In the absence of mitogen: a. The next day the used medium is eliminated and compounds are added in new medium (without mitogen) b. The dose and effect evaluations are carried out with 6 concentrations (10 M, 1 μM, 100 nM, 10 nM, 1 nM and 0.1 nM); c. Wells are prepared in triplicate for each concentration of the compound. 4. Trailed cells are cultured for 7 days before being used in experimental trials. HUMAN oliqodendrocyte cultures Cell preparation: 1. Human neurospheres of human embryo cortex E19.5-E22 are cultured for 2 weeks in parent medium: DMEM / F12 which confers 100 μg / ml transfer, 30 nM triiodothyronine, 20 nM hydrocortisone , 20 nM progesterone, 10 nM biotin, 1 x trace elements, 30 nM selenium, puiresin 60 uM, 0.1% BSA, 5 U / ml PenSírep, 25 μg / ml insulin) enriched with PDGF and FGF. 2. The neurospheres are dissociated with 20 U / ml papain at 37 ° C for 30-50 min. 3. The cells are plated on PDL coated plates at a density of 50,000-100,000 cell / well in parent medium containing PDGF / FGF and incubated at 37 ° C with 5-6% CO2. 4. The medium and the growth factors are refilled every 48 h. Movement of the human culture compound: 1. 24 to 48 h after placing in plates, the used medium is eliminated and compounds are added in new medium (with mitogen) 2. The dose and effect evaluations are carried out with 3- 6 different concentrations (10 M, 1 μM, 100 nM, 10 nM, 1 nM and 0.1 nM) 3. Wells are prepared in triplicate for each concentration of the compound. 5. Treated cells are grown for 7 days before being used in the experimental trials. Specific immunostaining of oligodendrocytes of RAT / RATON / HUMAN BEINGS: Following the exposure of the compound, oligodendrocyte-specific antibodies are used to evaluate the ability of a compound to accelerate / promote the differentiation of oligodendrocytes (for example, the immunoreactivity of O4, O1 or myelin basic protein in time, send the compound frayado and untreated culinos). 1. The cells are placed in 4-well plates treated with poly-D-lysine at 5x103 to 20x103 cells / well and inoculated as described above. Sequential staining is performed in oligodendrocyte populations with increasing degrees of cell differentiation, as determined by in vitro days without PDGF and FGF. 2. In vivo staining is used for 30 min at 37 ° C to detect the expression of the specific cell surface marker of the oligodendrocyte stage (including A2B5, 04 and 01). 3. Subsequently, the cells are fixed with 4% paraformaldehyde, min at room temperature. 4. Fixed staining procedures are used to detect expression of the specific marker of the oligodendrocyte stage (including myelin basic protein, MBP). 5. Rinse with PBS. 6. It is permeabilized with 0.1% Triton / 0.01% NaAz diluted in 1X PBS for 10 min at ambient temperature. 7. Blocking with 5-10% goat serum in antibody dilution buffer (0.1% Triton-X 100 and 1% IgG-free bovine serum albumin, also used to dilute antibodies), 15 min, temperature ambient. 8. Primary antibody diluted in antibody dilution buffer is added. 9. Incubate overnight, shake moderately at 4 ° C. 10. The next day it is rinsed with PBS 1X 5 min and then with 3X 15 min each at room temperature. 11. Incubate with suitable secondary antibodies for 45 min at room temperature. 12. The cell nuclei are stained with 4,6-diamidino-2-phenylindole (DAPI), 15 min at room temperature. 13. Rinse several times with PBS and evaluate using fluorescent microscopy. 14. The following conditions are compared in time and in different doses of the compound: PDGF / FGF alone, SFM only, SFM-IGF1 alone, PDGF / FGF and composite, SFM and composite. Immunostaining with bromine deoxyuridine (BrdU) in RAT / MOUSE / HUMAN BEING: To confirm that the compounds do not promote cell proliferation. 1. Oligodendrocyte progenitor cells are labeled with 10 μM BrdU for 20 h and then fixed well with 70% ethanol or 4% paraformaldehyde. 2. The cells are incubated successively with biotinylated anti-mouse BrdU and Streptavidin-Peroxidase, interrupting with three PBS washes. 3. The colorimetric visualization of the immunoreactivity of BrdU is developed with DAB and the amounts of toya cells are evaluated using hematoxylin counter staining. 4. Cells with immunopositive BrdU are counted by two independent observers. Analysis of the images of the cultures of RATA / MOUSE / SERES HUMANS: Fluorescent microscopy is used to quantify the degree of differentiation of oligodendrocytes after exposure to the compound. This trial demonstrates that selective agonists accelerate / promote the differentiation of oligodendrocytes. 1. Manual cell count: Four fields were randomly selected for each experimental condition and 500-600 cells were counted in each field. The percentage of MBP (or 04) immunopositive cells (cells with a maturation process with or without myelin sheets) bound to positive cells with DAPI (amount of cells) is compared between the confrol and the groups with the drug. 2. Automatic cell count: Fluorescent microscopy is used to quantify the degree of differentiation of oligodendrocytes after exposure to the compound. Six fields / well were randomly selected to evaluate the amount of differentiation oligodendrocytes among the total population (~ 8 to 15x103 cells / well are counted). The immunofluorescence images were obtained using a Zeiss AxioVision digital imaging system, with a cooled Zeiss AxioCam HRc CCD camera connected to the same microscope. All the parameters of microscopic images were adjusted to acquire images for the analysis of cellular immunofluorescence intensity. The percentage of positive (differentiated) MBP cells was compared to the tola cells (nuclear inhibition DAPI) between the control and the groups brought with the drug. The cellular fluorescence was not deficient under the conditions of the images. 3. Human oligodendrocyte differentiation assay: total amount with manual counting of immunopositive cells 04 / well (bipolar and multipolar). Chain reaction by polymerase (PCR) quantiíaíiva in RAT / MOUSE / HUMAN BEING: To evaluate the acyivation of the PPAR delta pathway induced by the compound and the degree of maturation of oligodendrocytes (changes in mRNA levels). 1. Total RNA is extracted from cultured oligodendrocytes using the TriZol reagent. 2. Subsequently, the mRNA is treated with RNase-free DNase, repurified and then converted to the cDNA template using an RT reaction (Clontech Advaníage RT for Kií PCR). 3. The transcription expression of members of the PPAR delta pathway is quantified using Sybr Green PCR Master Mix. 4. The mixture of 18S ribosomal primer / probe (product 186 bp), suspended in Taqman 2X PCR Master Mix as control, is used internal. 5. Quantitative PCR is carried out using Taqman ™ real-time technology (Gibson, et al., 1996) with a Sequence Detector System Model 7700 (Applied Biosystems, Fosíer City, CA). 6. The results are analyzed using the Sequence Detection Systems, software version 1.91. ELISA test in RATS: To evaluate the activation of the PPAR delta pathway induced by the compound and the degree of maturation of the oligodendrocytes (changes in protein concentrations) 1. Wash the plates with PBS and then keep them on ice.

Add 200 μl of used lysis buffer (50mM Tris, pH7.4, 2mM MgCl2, 1mM EDTA, 5mM β-mercaptoetanol, 1% Nonidei P-40, protease inhibitor cocktail (Roche): 1 tablet / 50ml) to each well. 2. Cells are lysed using a pipeline and the plates are cenfrifuged at 2000 rpm at 4 ° C for 5 min. The supernatant is lysium to use. 3. 50 μl of controls and standard samples are pipetted into the wells. 4. Add 50 μl of MBP Assay Buffer to each well. 5. Incubate the well, shaking at 500-700 rpm in an orbital microplate shaker for 2 h at room temperature. 6. Add 100 μl of Biotin Conjugate-MBP Antibody to each well. 7. The well is incubated, shaking at 500-700 rpm in an orbital microplate shaker for 1 h at room temperature. 8. Wash the well 5 times with Washing Solution. It is dried by inverting the plate in absorbent material. 9. Dilute the conjugated sirapevidin-enzyme to a concentration of 1: 50 with Elisa MBP assay buffer. (it must be diluted immediately before being used for the test). 10. Add 100 μl of solutions with streptavidin-enzyme conjugate to each well. 11. Incubate the well, shake at 500-700 rpm in the orbital microplate shaker for 30 min at room temperature. 12. Wash 5 times with the Washing Solution. It is dried by inverting the plate in absorbent material. 13. Add 100 μl of Chromogen TMB solution to each well. 14. The well is incubated, shaken at 500-700 rpm in the orbital microplate agifer for 10-20 min at room temperature. Exposure to direct sunlight is avoided. 15. Add 100 μl Stopping solution to each well. The absorbance of the solution in the wells is read within 30 min, using a microplate reader adjusted to 450 nM. Live test of the conceptual models Focal lesions: (used to assess whether compounds protect the integrity of myelin or accelerate / increase the rate of remyelination). 1. Rats of 7 weeks of age are provided with unlimited access to water and feed, and are acclimated for a minimum of 4 days before being used in the experiments. 2. Before each animal is weighed. The rat was then anesthetized with cefamine (100 mg / ml) combined with xylazine (20 mg / ml) in a ratio of 1.8: 1. The rats were injected with 0.15 ml / 180 g body weight i.p. of the anesthetic solution before the surgical procedure. The animal is prepared for surgery using aseptic conditions in accordance with the IACUC guidelines. All surgical instruments are sterilized in an autoclave. The hair is collected with a clip between the ears and this region is rubbed with Betadine, washed with sterile saline solution and finally rubbed with a sterile swab soaked in alcohol. 3. For the surgical procedure, the rafa is disposed on its venial surface in a stereotaxic animal insírumenío designed to hold the head firmly. The incision bar is always adjusted to -3.9 mm, since it has been demonstrated that a flat skull position is achieved in SD rails. 4. An incision is made in the previously shaved skin that covers the skull between the ears.

. A small area of bone is perforated (0.7 5 mm in diameter) at the coordinates AP -1.8, ML -3.1 of lambda. 6. The bone is removed, and the rats are injected with 2 μl of ethidium bromide, lysolecithin or SIN-1 in the right caudal cerebellar peduncle, DV -7.1 mm, for a period of 2 min by syringe and Hamilton needle. μl.

Alternatively, the injections are applied to the spinal cord, corpus callosum or cortex. 7. Leave the needle there for 2 min. Subsequent 8. After removing the needle, the incision is sutured. 9. Each rale receives an injection i.m. of 0.003 mg of buprenorphine in one of the back pads. 10. The rat is placed in a heating cabinet until it regains consciousness. At that time, it is transferred back to its cage. No more than 2 rats per cage are allowed, since sutures will be removed from each other. 11. Similar procedures are performed using mice. Model of Experimental Allergic Encephalomyelitis (EAE) in the Root: Experimental Allergic Encephalomyelitis (EAE) is a T-cell mediated autoimmune disease of the central nervous system that develops in susceptible animals after sensitization, either with spinal cord homogenates total or just one component of that (myelin basic protein). The EAE rodent model is an appropriate tool to study inflammation of the brain and spinal cord, which observed in patients with MS. In rodents, the injection of the total spinal cord or some components of the spinal cord, such as the myelin basic protein, induces an immune-immune response that is based on the accumulation of T lymphocytes. Clinical disease typically manifests itself around the day 8-10 after inoculation, and is observed as a broad specimen of behavioral abnormalities ranging from a mild alteration in gait or aphonia of the tail to complete paralysis and death. Typically, weight loss occurs. In animals that survive, spontaneous recovery occurs, accompanied by the variable recovery of most of the motor function. Depending on the species, the allergen and the methodology used, the animals tested by the EAE model may experience a single attack (acute EAE) or various attacks (chronic EAE with recurrence). Several different paradigms can be used: the drug or the choice ingredient can be administered during immunization, during the asymptomatic period or during clinical illness. Animals: Female Lewis rats, 160-220g (Charles River) Antigen: Whole guinea pig spinal cord (Harían Biosciences). Complete Freund's Adjuvant H37 Ra [1 mg / ml Mycobacterium Tuberculosis H37 Ra] (Difco). Additional antigen: Mvcobacterium Tuberculosis (Difco). Bordeiella Períussis [exterminated by ca] or (Difco). Preparation of antigens: (for approximately 720 animals): 1. We weigh 5 grams of frozen spinal cord from guinea pig. 2. 5g of spinal cord is added to 5 ml of saline solution 0.9% (1g / ml) in a round bottom centrifuge tube 3. It is homogenized on ice with Tissue-tech until the molecule is completely broken (approximately 5 minutes). 4. Add 10 ml of complete Freund's adjuvant H37 Ra enriched with 200 mg of Mycobacterium Tuberculosis (20 mg / ml adjuvant Freund complete H37 Ra). 5. Remove the homogenate / adjuvant from the tube by aspirating it with a 10 ml syringe equipped with an 18 gauge emulsifying needle. 6. Emulsify between two 30 ml glass syringes until it becomes difficult to continue passing the material through the needle.

(Approximately 5 minutes. {There should be no separation between the oil phase and the aqueous phase.}.). 7. Use immediately or keep on ice until it is used (no more than 30 min) (do not freeze). Protocol 1. Female Lewis rats (Charles River) are provided with unlimited access to food and water, and acclimated for a minimum of 3 days before used in experiments. 2. Rats weighing 160 and 220 grams are initially induced with 5% isoflurane (Aerrane, Fort Dodge), 30% O2, 70% N2O for 2-5 minutes. 3. The rat is then placed in a warming blanket with circulating water (Gaymar) (dorsal surface upwards) and a nasal cone is placed for spontaneous breathing of anesthetic gases. Isoflurane is reduced to 2%. 4. Two subcutaneous injections (0.1 ml each) of either antigen or normal saline are applied to the ventral surface of the hind paws. ^ 5. The nasal cone is removed, weighed and numbered. 6. Rats are allowed to awaken from anesthesia and are placed in individual cages. 7. The animals are observed daily to detect signs of EAE induction (see criteria below) STAGE 0 NORMAL STAGE 1 Abnormal gait and tail atony STAGE 2 Mild but specific weakness of one or both of the feather ducks STAGE 3 Intense weakness of one or both hind legs or mild ataxia STAGE 4 Intense paraparesis and minimal movements of the hind legs STAGE 5 No movement of the hind legs and paraplegia STAGE 6 Moribund state without spontaneous movement and respiratory distress. There may also be an increasing degree of involvement of the forepaw and fecal and urinary incontinence STAGE 7 DEATH Treatment begins on day 10 after immunization. Since the symptoms of disease in this model typically appear on days 10-11 after inoculation, it can be considered that this point of time represented the initial phase of an acute episode of MS. It is judged that this delay at the start of the procedure mimicked the clinical situation more precisely than the traditionally used protocols in which the drugs were administered at the time of inoculation or even earlier (Teitelbaum D. et al., Proc Nati Acad Sci USA 1999; 96: 3842-3847 and Brod S.A., et al., Ann Neurol 2000; 47: 127-131). This invention is further illustrated by the following examples of compounds used herein, which are provided for illusory purposes and in no way limit the scope of the present invention. Synthetic Examples General The commercial reactants and solvents were used as received. The 1 H NMR spectra were recorded on a Varian MercuryPlus-300 (300 MHz) or Varian Unity Inova (400 MHz) spectrometer, as indicated.

The chemical shifts of protons are indicated in d ppm relative to internal tetramethylsilane (0.0 ppm). The MS data (LC-MS) is obtained using a Micromass LCT flight time mass spectrometer with electrospray ionization and a datum acquisition time of 5 min for m / z 100 to 1000. The LC (LC-MS ) was performed using a Hypersil C18 column (4.6x50mm, 3.5D with mobile phase of 0.1% TFA in H2O (A) and 0.1% TFA in ACN (B) and a gradient of 5% to 100% B for 3 min followed by 2 min to 100% B. Alternatively, LC-MS Platform with electrospray source can be used with an HP1100 LC system operating at 2.0 ml / min, 200 μL / min injected to the ESI source by means of a flow division system with HP1100 DAD detection and SEDEX ELS deification.A Luna C18 (2) column (30x4, 6mm 3μ with a gradient of 5% to 95% B for 4.5 min with mobile phase of 0) is used. , 1% formic acid in H2O and 0.1% formic acid in ACN (B) Purification by HPLC is carried out in a Varian ProStar system, using a C18 reverse phase column with a gradient li ACN / H O neal containing 0.1% urea fluoride. The microwave syntheses are made using a microwave reaction system Personal Chemisíry Smiíhcreaíor that uses 2 or 5 mL of reactor vessels. Example 1 Intermediate: F5-meityl-2- (4-irifluoromethyl-phenyl) -iiazole-4-ip-acetic acid ethyl ester To a solution of 4-frifluoromethyl-benzene-thioamide (1, 845g, 9mmol) in ethanol (15 mL , 200 test) is added ethyl-4-bromo-3-oxo-pentanoafo (2.07 g, 9 mmol). This solution is sealed and heated to 170 ° C in a Personal Chemisíry® microwave oven and stirred at this temperature for 20 min. The resulting solution was cooled to ambient temperature, concentrated under reduced pressure and the residue was purified by flash chromatography (eluted with 30% ethyl acetate / 10% dichloromethane in heptane) and the title compound was obtained as a solid. white (1, 4g). MS (ESI) m / z 330 (M + H); H1 NMR (CDCl3) d 1.87 (bs, 1H), 2.49 (s, 3H), 4.86 (s, 2H), 7.67 (d, J = 8Hz, 2H), 8.02 ( d, J = 8Hz, 2H). Example 2 Intermediate: 4- (2-hydroxy-ethylD-5-methyl-2- (4-trifluoromethyl-phenytoiazole) A solution of lithium aluminum hydride (5.3 mL, 1 M in THF) is cooled (0 ° C) and a solution of [5-mephyl-2- (4- trifluoromethyl-phenyl) -thiazol-4-yl] -acetic acid (Example 1, 1, 4g, 4.25 mmol) in THF (15 mL). After completing the addition, the cold bath was removed and stirred for 2 hours. This solution is cooled to 5 ° C, and then water (0.2 mL) is added dropwise, followed by dissolution of NaOH (0.2 mL, 5M in water) and water (0.2 mL). The resulting mixture is diluted with ethyl acetate and then filtered through a pad of celite. The solids are washed with dichloromethane and then the combined filtrates are concentrated under reduced pressure. The residue is purified by flash chromatography (eluted with 30% ethyl acetate 40% dichloromethane in heptane) to give the title compound as a yellow solid (0.879 g). The compound of Example 1 is used as the starting material to obtain the compound of the compound. MS (ESI) m / z 288 (M + H); H1 NMR (CDCl3) d 2.44 (s, 3H), 2.91 (t, J = 7Hz, 2H), 3.62 (t, J = 6Hz, 1 H), 4.01 (dt, J = 7, 6Hz, 2H), 7.66 (d, J = 8Hz, 2H), 7.96 (d, J = 8Hz, 2H). Example 3 Intermediate product: 4- [5-meityl-2- (4-trifluoromethyl-pheno-thiazole-4-ylethoxyl-benzoic acid methyl ester To a solution of 4- (2-hydroxy-ethyl) -5-methyl-2- (4-trifluoromethyl-phenyl) thiazole (Example 3, 288 mg, 1.0 mmol) in THF (3 mL) is added ester 4-hydroxy-benzoic acid methyl ester (167 mg, 1.1 mmol) followed by triphenylphosphine (288 mg, 1.1 mmol). To this solution is added, dropwise, diethyl azodicarboxylate (174 μL, 1.1 mmol). Upon completion of the addition, the resulting red solution was stirred for 20 min., Concentrated under reduced pressure and purified by flash chromatography (eluted with 15% ethyl acetate / 15% dichloromean in heptane) to yield the title as a white solid. (410 mg). MS (ESI) m / z 422 (M + H); H1 NMR (DMSO) d 2.51 (s, 3H), 3.19 (t, J = 7Hz, 2H), 3.80 (s, 3H), 4.40 (t, J = 7Hz, 2H), 7.05 (d, J = 9Hz, 2H), 7.83 (d, J = 8Hz, 2H), 7.88 (d, J = 8Hz, 2H) 8.05 (d, J = 8Hz, 2H) . Example 4 Intermediate product: Hydrazide of acid 4-. { 2-yl-meityl-2- (4-trifluoromethyl-phenyl) -thiazole-4-ip-eioxy) -benzoic acid To a suspension of 4- [5-Methyl-2- (4-trifluoromethyl-phenyl) -methyl ester) -Iiazol-4-ylenoxy] -benzoic acid (Example 4, 410 mg, 1 mmol) in methane] (3 mL) was added anhydrous hydrazine (0.32 mL, 10 mmol). The resulting mixture was heated to 60 ° C and stirred at this temperature for 66 hours. The resulting solution was cooled to room temperature and 3 gofas of water were added. The precipitate was filtered and washed with ether to yield the title compound (279 mg). MS (ESI) m / z 422 (M + H); H1 NMR (DMSO) d 2.51 (s, 3H), 3.17 (t, J = 7Hz, 2H), 4.36 (t, J = 7Hz, 2H), 4.38 (bs, 2H), 6.98 (d, J = 9Hz, 2H), 7.77 (d, J = 9Hz, 2H), 7.83 (d, J = 8Hz, 2H) 8.06 (d, J = 8Hz, 2H) 9.58 (bs, 1 H). Example 5 - (4- {2-R5-Methyl-2- (4-trifluoromethyl-phenyl) -iiazole-4-yn-ethoxy) -phenyl} -3H- [1,3,4-oxadiazol-2-one A a suspension of: 4- hydrazide. { 2- [5-methyI-2- (4-trifluoromethyl-phenyl) -thiazol-4-yl] -efoxy} -benzoic acid (Example 4, 276 mg, 0.65 mmol) in dichloromethane (4 mL) was added pyridine (104 μL, 1.3 mmol) followed by phenylchloroform (0.88 μL, 0.71 mmol). The resulting mixture was stirred at room temperature until all the starting material had been consumed (by TLC analysis). The mixture was diluted with ethyl acetate and washed with water, then with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is Absorbed in acetonitrile (5 mL). DBU (106 μL, 0.71 mmol) was added to this mixture. The resulting dissolution is sealed; it was heated to 170 ° C in a Personal Chemisery® microwave oven and stirred at this temperature for 120 min.

The reaction was cooled to room temperature, diluted with ethyl acetate, washed with 1 M HCl solution (or saturated NaH2PO solution), dried over MgSO and concentrated. The resulting residue was triturated with dichloromethane several times to give the title compound as a tan solid. (137 mg). (recrystallized from ethyl acetate in a sealed tube at 140 ° C). MS (ESI) m / z 448 (M + H); H1 NMR (DMSO) d 2.51 (s, 3H), 3.19 (t, J = 7Hz, 2H), 4.40 (t, J = 7Hz, 2H), 7.10 (d, J = 8Hz , 2H), 7.70 (d, J = 8Hz, 2H), 7.83 (d, J = 8Hz, 2H) 8.05 (d, J = 8Hz, 2H) 12.41 (bs, 1H).

Claims (16)

1. CLAIMS 1.- A compound of formula wherein ARIL is phenyl or pyridinyl, wherein said phenyl or pyridinium is optionally substituted with one or more substituents selected from the group consisting of halogen, d-6 alkyl, C 2-6 alkenyl, d 6 alkoxy, perfluoroalkyl C 1-6 6; alkylthio C6-hydroxy, hydroxy-alkyl d-e, acyloxy C6-a, nitro, cyano, alkylsulfonyl d-6, amino, alkylamino d-6 and alkoxycarbonyl C-? - 6; Z is -O (CH2) n-, -SO2 (CH2) n-, - (CH2) nY- (CH2) n -, - (CH2) n -CO-, -O (CH2) n -CO-, or - (CH2) nY- (CH2) n-CO- wherein Y is NR3, O or S, and R3 is selected from the group consisting of H, d-β alkyl, C3.8 cycloalkyl, C6-alkyl -C3-8 cycloalkyl and benzyl, and n is independently an integer between 1 and 5; X is NR3, O or S, wherein R3 is as defined above; R-i is H, halogen, C? 6 alkyl, C? -6 alkoxy, perfluoroalkyl d-β; hydroxy-C6-alkyl, nickel, cyano and C6-6 alkylamino; and R2 is substituted or unsubstituted phenyl, pyridinyl or thienyl, in e! that the substitutes are selected from the group consisting of halogen, C6 alkyl, C2-6 alkenyl, C1-6 alkoxy, perfluoroalkyl C6-6, alkylthio d6, hydroxy, hydroxy-C6 alkyl, acyloxy d-4, nitro, cyano, alkylsulfonyl d-6, amino, alkylamino d_6 and alkoxycarbonyl d-6, 'with the proviso that when Z is -O (CH2) n- or -SO2 (CH2) n-, and ARIL is phenyl, then R2 is different from phenyl; or its stereoisomer, tautomer or solvate, or its pharmaceutically acceptable salt.
2. 2. The compound according to claim 1, wherein ARIL is phenyl; and X is O or S
3. 3. The compound according to claim 2, wherein X is O.
4. 4.- A compound that is 5- (4-. {2- 2- [5-meityl-2- (4- frifluoromethyl-phenyl) -yiazol-4-yl] -ioxy}. phenyl) -3 / - / - [1,4] oxadiazol-2-one.
5. 5. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 6. A method to eradicate a disease in a mammal, in which the disease is capable of being modulated by the binding activity of the ligand of the mammal. PPARdelía, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I: wherein ARIL is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally susiiuid with one or more susifluyenis selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl, d 6 alkoxy, perfluoroalkyl C 1-6 6 C? -6 alkyl, hydroxy, hydroxyC? -6 alkyl, C? -ay acyloxy, nifro, cyano, alkylsulfonyl d-6, amino, C1-6 alkylamino and alkoxycarbonyl d-
6. 6. Z is -O (CH2) n-, -SO2 (CH2) n-, - (CH2) nY- (CH2) n -, - (CH2) n -CO-, -O (CH2) n -CO- 'or - (CH2) nY- (CH2) n-CO- in which Y is NR3, O or S, and R3 is selected from the group consisting of H, C1-6 alkyl, C3-8 cycloalkyl, alkyl d-6- C3-8 cycloalkyl and benzyl, and n is independently an integer between 1 and 5; X is NR3, O or S, wherein R3 is as defined above; R-i is H, halogen, C 1-6 alkyl, d-6 alkoxy, perfluoroalkyl d-e; hydroxy-C6-6 alkyl, nifro, cyano and alkylamino d-6; and R 2 is unsubstituted or unsubstituted phenyl, pyridinyl or thienyl, wherein the substituents are selected from the group consisting of halogen, d-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, perfluoroalkyl d-6, alkylthio C? .6, hydroxy, hydroxy-alkyl d6, acyloxy C1-4, nyl, cyano, alkylsulfonyl d-6, amino, C1-6 alkylamino and C6-6 alkoxycarbonyl or its stereoisomer, tautomer or solvate, or its pharmaceutically acceptable salt.
7. 7. The method according to claim 6, wherein ARIL is phenyl.
8. 8. The method according to claim 6, wherein ARIL is phenyl; Y R2 is phenyl.
9. 9. The method according to claim 6, wherein ARIL is phenyl; Z is -O (CH2) n-; and R2 is phenyl.
10. 10. The method according to claim 6, wherein ARIL is phenyl; Z is -O (CH2) n-; X is O or S, and R2 is phenyl.
11. 11. The method according to claim 6, wherein ARIL is phenyl; Z is -O (CH2) n-; X is O or S; and Ri is alkyl d-β; and R2 is phenyl.
12. 12. The method according to claim 11, wherein X is O.
13. 13. The method according to claim 12, wherein X is S.
14. 14. The method according to claim 6, wherein said disease is a demyelination disease selected from the group consisting of multiple sclerosis, Charcoi-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, optic neuromyelitis, adrenoleukodystrophy, Guillian-Barre syndrome and írasíomos in which the normal cells are damaged. they form myelin, including spinal cord injuries, neuropathies, and nerve injuries.
15. 15. The method according to claim 14, wherein the demyelinating disease is multiple sclerosis.
16. 16. - The method according to claim 6, wherein said disease is selected from the group consisting of obesity, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, hypercholesterolemia, dyslipidemia, Syndrome X, type II diabetes mellitus and its complications selected from the group consisting of neuropathy , nephropathy, retinopathy and cataracts, hyperinsulinemia, glucose intolerance, insulin resistance, atherosclerosis, hypertension, coronary heart disease, peripheral vascular disease or congestive heart failure.