1,3,4-oxadiazol-2-ones as ppar-delta modulators and application thereof

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

 

The SCOPE of the INVENTION

This invention relates to new compounds and drugs that act as selective binding agents are ligands of PPAR-Delta receptors, which can be used to modulate PPAR-Delta receptors for the treatment of diseases mediated by nuclear hormone receptors. Binding agents are ligands of PPAR-Delta receptors presented in this invention can be applied as agonists or antagonists of PPAR-Delta receptors.

BACKGROUND of the INVENTION

Receptors activated proliferation peroxisomes (PPAR)are a subfamily of the family of nuclear receptors. It was discovered and cloned four related isoforms, which are known as PPAR-alpha, PPAR-gamma-1, PPAR-gamma-2 and PPAR-Delta. Each receptor subtype has a characteristic DNA-binding domain (DBD) and the ligand-binding domain (LBD), each of which needed to be activated by ligands of gene expression. PPAR contact as heterodimer with retinoid X receptor. Cm. J. Berger and D. E. Miller,Annu. Rev. Med., 2002, 53, 409-435.

PPAR-Delta (also known as PPAR-beta is expressed in a wide range of mammalian tissue, but still very little is known about its biological functions and the complete set of genes that it regulates. However, recently it was found that agonists can the be used to treat such diseases, as dyslipidemia, and some dermatological diseases and antagonists for the treatment of osteoporosis and colorectal cancer (D. Sternbach,Annual Reports in Medicinal Chemistry, Volume 38,A. M. Doherty, ed., Elsevier Academic Press, 2003 pp. 71-80).

PPAR-Delta, apparently, largely is expressed in the Central nervous system, but its function remains unclear. Of exceptional interest is the fact that PPAR-Delta found in oligodendrocytes rodents, the main cells of the CNS that produce lipids (J. Granneman, et al.,J. Neurosci. Res., 1998, 51, 563-573). Moreover, it was also found that selective agonist of PPAR-Delta significantly increases gene expression of myelin oligodendroglial and the diameter of the myelin sheath in cell cultures of mice (I. Saluja et al.,Glia, 2001, 33, 194-204). Thus, activators of PPAR-Delta can be used for the treatment of demyelinating and demyelinizing diseases.

Demyelinating diseases are manifested in the loss of myelin and several dense layers of lipids and proteins, which cover many nerve fibers. Such layers are formed by oligodendroglia in the Central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). In patients with demyelinative pathology of demyelination may be irreversible, and it is usually accompanied or leads to axonal degeneration, and often the cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin in the aberrant immune responses, local trauma, ischemia, metabolic disorders, toxic substances or viral infections (Prineas and McDonald,Demyelinating Diseases. In Greenfield''s Neuropathology, 6.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 demyelinate (demyelinated CNS) occurs in several diseases are often uncertain etiology, which are called primary demyelinating diseases. Among them the most common is multiple sclerosis (MS). Other primary demyelination States are adrenoleukodystrophy (ALD), adrenomyeloneuropathy, using HIV myelopathy myelopathy associated with T-lymphotropic virus human liberovskaya hereditary atrophy of the optic nerves, progressive multifocal leucoencephalopathy (PML), subacute sclerosing panencephalitis, Guillain-Barre syndrome and tropical spastic prepares. In addition, there are acute conditions that may lead to demyelination in the Central nervous system, such as acute disseminated encephalomyelitis and acute viral encephalitis. Moreover, acute transverse myelitis, a syndrome in which the acute transection of the spinal cord of unknown origin damages as gray, and white matter in one or more adjacent thoracic segments, may also lead to demyelination. In addition, violations, in which damaged forming myelin glial cells, also include injury to the spinal cord, nerve disease and nerve damage.

Separate modulators of PPAR-Delta can be useful for the treatment or prevention of other diseases, 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 Staels and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52; 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, Nature, vol 405, 25 May 2000; 421-4; Ines 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).

Compounds that act as modulators of PPAR-Delta can be particularly suitable for the treatment and/or prevention of disorders of fatty acid metabolism and disorders of glucose utilization that are associated with insulin resistance.

Diabetes, especially type II diabetes, including the prevention of associated impacts. Private aspects are hyperglycemia, decrease insulin resistance, increased glucose tolerance, protection of cells in the pancreas, preventing macro - and mi is rassudili violations.

Dyslipidemia and their complications, such as, for example, atherosclerosis, coronary heart disease, cerebral circulation, especially among, but not limited to) characterized by one or more of the following factors: high concentrations of plasma triglycerides, high concentrations of plasma triglycerides occurring after meals, low concentrations of cholesterol alpha-high density lipoprotein, low concentrations of lipoprotein ApoA, elevated concentrations of cholesterol alpha-lipoprotein, low density, small particle size, dense cholesterol low-density lipoprotein, elevated concentrations of lipoprotein ApoB.

With that metabolic syndrome can be associated with various other conditions, such as obesity (overweight), including Central obesity, thrombosis, giperkoagulyaimi and prothrombotic States (arterial and venous), high blood pressure, congestive heart failure, including (among others) coming as a result of myocardial infarction, hypertensive heart disease or cardiomyopathy.

Among other disorders or conditions, which can lead to inflammatory reactions or cell differentiation, can be, for example:

- atherosclerosis, such as, for example(among others), coronary sclerosis including angina pectoris or myocardial infarction, stroke, vascular restenosis or reocclusion, chronic inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, pancreatitis, other inflamed state, retinopathy, tumors of lipocytes, lipomatosis carcinomas, such as liposarcoma, solid tumors and neoplasm, such as, for example (among others), carcinoma of the digestive tract, liver, bile ducts and pancreas, endocrine tumors, carcinomas of the lung, kidney and urinary tract, genital tract, prostate cancer, etc., acute and chronic myeloproliferative disorders and angiogenesis lymphomas,

- neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, erythematosquamous dermatoses, such as psoriasis, common acne.

Other skin disorders and dermatological conditions modulated PRAR-Delta:

- eczema and neurodermatitis, dermatitis, such as, for example, seborrheic eczema or photodermatitis, keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, photoindustrie the keratoses or keratosis acne keloids and their prevention, warts, including genital warts and genital warts, viral infection of the human papilloma virus (HPV), such ill the tion, as, for example, sexually transmitted papilloma, viral warts such as, for example, molluscum contagiosum, leukoplakia-papular dermatoses such as, for example, lichen planus, skin cancer, such as basal cell carcinoma, melanoma and cutaneous lymphoma T-cells, localized benign epidermal tumors such as, for example, keratoderma, epidermal birthmarks and frostbite.

Various other conditions, potentially modulating PPAR-Delta, including syndrome X, polycystic ovarian syndrome, asthma osteoarthritis, systemic lupus erythematosus (KV) or inflammatory rheumatic diseases, such as rheumatoid arthritis, vasculitis, malnutrition (cachexia), gouty ischemia/reperfusion syndrome and acute respiratory distress syndrome (SDPS).

BRIEF description of the INVENTION

The present invention relates to the compound of formula I.

where

ARYL represents phenyl or pyridinyl, where the specified phenyl or pyridinyl may have one or more substituents selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxy (C1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6al is ylamino and C 1-6alkoxycarbonyl;

W is a bond or (CH2)mwhere m is an integer from 1 to 4;

Z represents-O(CH2)n-, -SO2(CH2)n-, -(CH2)n-Y-(CH2)n-, -(CH2)n-CO-, -O(CH2)n-CO - or -(CH2)n-Y-(CH2)n-CO-, where Y denotes NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl, C1-6alkyl, C3-8cycloalkyl or benzyl, n denotes independently an integer from 1 to 5;

X represents NR3, O or S, where R3defined above;

R1represents H, halogen, C1-6alkyl, C1-6alkoxy, C1-6perfluoroalkyl; hydroxy, C1-6alkyl, nitro, cyano, and C1-6alkylamino; and

R2represents a substituted or unsubstituted phenyl, pyridinyl or thienyl, where the substituents are selected from the group including halogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6alkylthio, hydroxy, hydroxy (C1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl; or a stereoisomer, tautomer or MES, or its pharmaceutically acceptable salt.

The present invention also relates to pharmaceutical compositions containing Obedinenie formula I, and methods of using these compounds and compositions for the modulation of PPAR-Delta in patients in need of such modulation, by introducing compounds, preferably modulating the activity of PPAR-Delta. These compounds possess useful activity, modulating PPAR-Delta, and it is assumed that they can be used for treatment or prevention of diseases or conditions that allow the treatment of the mentioned diseases by modulating ligand-binding activity of PPAR-Delta by introducing the patient a therapeutically effective amount of the compounds of formula I.

FULL description of the INVENTION

Used in the present description, the terms have the following meanings:

The expression "C1-6alkyl" includes methyl and ethyl groups, and linear or branched through boutelou, pentelow and hexoloy group. Particular alkyl groups are methyl, ethyl, n-sawn, ISO-propyl and tert-bucilina. Derivatives of these symbols, such as "C1-6alkoxy, C1-6alkoxy, C1-6alkyl", "hydroxy (C1-6alkyl, C1-6alkylaryl", "C1-6alkoxycarbonyl C1-6alkyl, C1-6alkoxycarbonyl", "amino (C1-6alkyl, C1-6allylcarbamate C1-6alkyl, C1-6dialkylamino C1-6al is Il", "mono - or di-C1-6alkylamino C1-6alkyl", "amino (C1-6alkylaryl", "diphenyl C1-6alkyl, aryl (C1-6alkyl, arylcarbamoyl C1-6alkyl and aryloxy C1-6alkyl" should be interpreted accordingly.

The expression "C2-6alkenyl" means ethynyl, and linear or branched propenyl, butenyl, pentenyl and hexenyl. Similarly, the expression "C2-6quinil" means ethinyl and PROPYNYL, as well as linear and branched butenyl, pentenyl and hexenyl.

The term "aryl" means a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracene, phenanthrene, fluorene, indenyl, pentalene, azulene, biphenylyl and the like. To arram also include the partially hydrogenated derivatives of carbocyclic aromatic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphtho and the like.

The term "aryloxy" refers to the group-O-aryl, where aryl described above.

The term "heteroaryl" (by itself or as part of any name, for example "heteroaromatic" or "heteroaromatic") represents a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatom is in, selected from the group comprising N, O or S, such as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, hintline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole or benzimidazole.

The term "heterocyclic" (on its own or as part of any other name, for example "heteroseksualci") refers to a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group comprising N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidin.

The term "C1-6perfluoroalkyl" means that all hydrogen atoms in the specified alkyl group substituted by fluorine atoms. Examples are triptoreline and panafcortelone and linear or branched heptafluoropropyl, nonattribution, undecafluoropentyl and tridecafluorohexyl group. The derived expression "C1-6-performace" should be interpreted accordingly.

The expression "C3-8cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The expression "C3-8cycloalkyl C1-6alkyl" means that C3-8cycloalkyl defined in the present description, is resident to C 1-6the alkyl as defined above. Typical examples are cyclopropylmethyl, 1-cyclobutylmethyl, 2-cyclopentylpropionyl, cyclohexylmethyl, 2-cyclohexylethyl and 2-cyclooctylmethyl and the like.

The term "halogen" or "halo" means chloro-, fluoro-, bromine - or iodine-.

The term "C1-6alkylsulfonyl" in this description refers to the group-S(=O)2C1-6alkyl, where C1-6alkyl is defined above. Typical examples are, but not limited to, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl, n-peterculter, isopentylamine, neopentylene, tert-peterculter, n-hexylsilane, isohexanol and the like.

The term "arylsulfonyl" denotes the group-S(=O)2aryl, where aryl is defined above.

"Heteroarylboronic" denotes the group-S(=O)2heteroaryl where heteroaryl defined above.

The term "stereoisomers" is a General term used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. To them, as a rule, are mirror isomers, which usually exist in the presence of at least one center of asymmetry (enantiomers). If the connection forming the subject nastojasih the invention, have two or more centers of asymmetry, they may also exist in the form of diastereoisomers, in addition, some individual molecules can exist in the form of geometric isomers (CIS/TRANS). It should be understood that all such isomers and mixtures thereof in any proportion are also included in the scope of the present invention.

"Substituted" means substituted by one or two substituents, each of which may be C1-6alkyl, C1-6perfluoroalkyl, hydroxy, -CO2H, ester, amide, C1-C6alkoxy, C1-C6perforamce, -NH2, Cl, Br, I, F, -NH - lower alkyl or-N(lower alkyl)2.

Compounds and salts included within the scope of the present invention may exist in tautomeric forms, including the form of enols and Iminov, as well as in the form of ketones, enamines, geometric isomers and mixtures thereof. All such tautomeric forms are also subject of the present invention. The tautomers exist in the form of a mixture of a set of tautomers in solution. In the solid state, usually dominated by one of the tautomers. Even if the described one tautomer, all tautomers of the compounds are the subject of the present invention.

The term "modulator" refers to a chemical compound, having the ability to enhance (i.e. with "agonist" activity) or inhibition is th (that is, with "antagonistic" effect) any functional property or biological function or process (e.g., the enzyme activity or receptor binding); such enhancement or inhibition may occur under certain conditions, such as activation or suppression of the signal channel, and/or may be manifest only in the cells of certain types and lead to measurable biological changes.

The term "patient" means a warm-blooded animal, such as rats, mice, dogs, cats, Guinea pigs and primates, such as humans.

The expression "pharmaceutically acceptable carrier" means a non-toxic solvent, a dispersant, a filler, auxiliary or other substance that is mixed with the compound constituting the object of the present invention, to form a drug that is dosed form, which you can enter the patient. One example of such a carrier is a pharmaceutically acceptable oil, commonly used for parenteral administration.

The term "pharmaceutically acceptable salts" means salts of the compounds of the present invention can be used in medicinal preparations. However, other salts may be useful in the preparation of compounds in accordance with the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acidic the IDT-additive salt, which can be, for example, by mixing the solution of the compounds of the present invention with a solution of a pharmaceutically acceptable acid, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluensulfonate acid, fumaric acid, maleic acid, hydroxymaleimide acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, 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. Can also be acidic metal salts, such as monohydrogenphosphate sodium and potassium hydrosulfate. In addition, the thus obtained salt may be a mono - or disubstituted salts are acidic and can exist in the form of hydrates or be substantially dehydrated. Moreover, if the compounds of the present invention include acid function, suitable their pharmaceutically acceptable salts can be classified as alkali metal salts, for example sodium or potassium, salts of alkaline-earth is yellow, for example, calcium salts or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts.

The term "therapeutically effective amount"as used herein means an amount of compound that is effective for treating the disease or condition.

In the present invention are also pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Preferably, such compositions are presented in dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid spray solutions, drops, ampoules, autoinjector devices or suppositories intended for oral, intranasal, sublingual or rectal injection or administration by inhalation or insufflation. Alternatively, the composition can be in the form suitable for use once a week or once a month; for example, an insoluble salt of the active compounds, such as salts decanoate, can be adapted for cooking depot for intramuscular injection. You can use the collapsing of the polymer containing the active ingredient. For preparing solid comp the dispositions, such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-composition comprising a homogeneous mixture of the compounds of this invention or its pharmaceutically acceptable salt. When the preliminary composition is called homogeneous, it is meant that the active ingredient is mixed evenly throughout the composition, and the composition can be divided into with equal efficacy of a single dose, for example tablets, pills and capsules. Then this solid pre-composition is divided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient constituting the object of the present invention. Scented unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of active ingredient. Pills and tablets these new compositions can have a shell or other coating, to provide a prolonged action dosage forms. For example, the tablet or pill may contain internal and external dosed omponent, when the first is inside the past. Two components can be separated enteric layer, which prevents the destruction in the stomach and permits the inner component in the intact condition to get into the duodenum or to its release has been delayed. As such enteric layers or coatings can be used a variety of substances, including a number of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the new compounds of the present invention can be administered orally or by injection include aqueous solutions, syrups with a suitable flavoring, water and oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing and suspenders agents for aqueous suspensions include synthetic and natural resins, such as tragakant, gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, propylenecarbonate or gelatin.

In the treatment of various pathological conditions described herein, a suitable dose is from about 0.01 to 250 is g/kg / day, preferably from about 0.05 to 100 mg/kg / day, and in particular from about 0.05 to 20 mg/kg / day. Connections can be made in accordance with the scheme 1-4 times a day.

In the following examples and descriptions of the processes of obtaining substances used terms have the following meanings: "kg" means kilograms, "g" means grams, "mg" means milligrams, "μg" means micrograms, "PG" means picogram, "mol" means moles, "mmol" means mmol, "nmol" means nanamoli, "l" means liters, "ml" means milliliters, "μl" means microliter, "°C" means degrees Celsius, "Rf" means retention time, "MP" or "TPL" means melting point, "decomp." means decomposition, "BP" or "BP" means the boiling point, "mm of RT. Art." means millimeters of mercury, "cm" means centimeters, "nm" means nanometers, "[α]20D" means the specific rotation of the D-line of sodium at 20°C in a 1 decimeter cell, "c" means the concentration in g/ml, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "NRM" means 1-methyl-2-pyrrolidinone, "salt solution" means a saturated aqueous sodium chloride solution, "M" means the concentration in moles, "mm" means the concentration in mmol, "μm" means the concentration micromol, "nm" means concentration nanomole, "TLC" means thin layer chromatography, "HPLC" oznachaet high-performance liquid chromatography, "MVR" means of mass spectrometry high resolution, "Shi" means of mass spectrometry with chemical ionization, "MSIE" means of mass spectrometry with ionization by elektrorazpredelenie, "tR" means retention time, "lb" means pound, "Gal." means gallons, "PPV" refers to loss on drying, "µci" means microcurie, "/b" means intraperitoneally, "/" means intravenously.

In the first aspect of the present invention describes new compounds of the General structure represented by the formula Ι:

where

ARYL represents phenyl or pyridinyl, where the specified phenyl or pyridinyl may have one or more substituents selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxy (C1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

W is a bond or (CH2)mwhere m denotes an integer from 1 to 4;

Z represents-O(CH2)n-, -SO2(CH2)n-, -(CH2)n-Y-(CH2)n-, -(CH2)n-CO-, -O(CH2 )n-CO - or -(CH2)n-Y-(CH2)n-CO-, where Y denotes NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl, C1-6alkyl, C3-8cycloalkyl or benzyl, n independently denotes an integer from 1 to 5;

X represents NR3, O or S, where R3defined above;

R1represents H, halogen, C1-6alkyl, C1-6alkoxy, C1-6perfluoroalkyl; hydroxy, C1-6alkyl, nitro, cyano, and C1-6alkylamino; and

R2represents a substituted or unsubstituted phenyl, pyridinyl or thienyl, where the substituents are selected from the group including halogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6alkylthio, hydroxy, hydroxy (C1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl; or a stereoisomer, tautomer or MES, or its pharmaceutically acceptable salt.

In an additional aspect of this embodiment of the invention described connection, in which ARYL represents phenyl.

Preferably the compounds of this embodiment of the invention selected from the group comprising of: 5-{4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}-3H-[1,3,4]oxadiazol-2-it, 5-[4-(4-methyl-2-m-tolila Sasol-5-ylethoxy)phenyl]-3 H-[1,3,4]oxadiazol-2-it, 5-{4-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-it, 5-{3-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-it, 5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorophenyl}-3H-[1,3,4]oxadiazol-2-it, 5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ileocecal]-2-forfinal}-3H-[1,3,4]oxadiazol-2-it, 5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzyl}-3H-[1,3,4]oxadiazol-2-he and 5-(2-{3-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}ethyl)-3H-[1,3,4]oxadiazol-2-it.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl and R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is-O(CH2)nand R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is-O(CH2)n-, X is O or S and R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is-O(CH2)n-, X represents O or S, R represents C1-6alkyl, and R2is phenyl and W denotes the connection.

In one of the following aspects of this embodiment of the invention described compound, in which X represents O.

In one of the following aspects of this embodiment of the invention described compound in which X is S.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is -(CH2)n-Y-(CH2)nand R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is -(CH2)n-Y-(CH2)n-, X represents O or S and R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is -(CH2)n-Y-(CH2)n-, X represents O or S, R1represents C1-6alkyl, and R2is phenyl and W is the connection.

In one of the following aspects of this embodiment of the invention described compound in which X is S.

In one of the following aspects of this embodiment of the invention described compound, in which Y represents O.

In one of the later aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is-O(CH2)nand R2represents phenyl.

In one of the following aspects of this embodiment of the invention described connection, in which ARYL represents phenyl, Z is-O(CH2)n-, X represents O or S and R2represents phenyl, R1represents C1-6alkyl, and R2is phenyl and W is (CH2)mwhere m denotes an integer from 1 to 4.

In one of the following aspects of this embodiment of the invention described compound in which X is S.

In another implementation of the present invention describes a pharmaceutical composition comprising an effective amount of the compounds of formula I and a pharmaceutically acceptable carrier.

In another embodiment, the present invention describes a method of treatment of a mammal when the disease can be modulated by ligand-binding activity of PPAR-Delta by introducing to a mammal suffering from the disease, a therapeutically effective amount of the compounds of formula I.

In one of the following aspects of the implementation of the described method, in which the disease is demyelinizing disorder which is chosen from the group comprising multiple sclerosis, the disease is ü Charcot-Marie-Toot, disease, Pelizaeus-Merzbacher, encephalomyelitis, Milosevic optic nerve, adrenoleukodystrophy, Guillain-Barre syndrome, and disorders in which damaged produce myelin glial cells, including spinal cord injury, neuropathy and nerve damage.

In another aspect of this embodiment of the invention describes the way in which demyelinization disease is multiple sclerosis.

In another aspect of this invention describes the way in which the disease is chosen from the group including obesity, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, hypercholesterolemia, dyslipidemia, syndrome X, diabetes mellitus type II and complications selected from the group including neuropathy, nephropathy, retinopathy and cataracts, hyperinsulinemia, impaired glucose tolerance, insulin resistance, atherosclerosis, hypertension, coronary heart disease, peripheral vascular disease and congestive heart failure.

These compounds may be synthesized using methods according to the schemes, in which the substituents X and R correspond to the definitions given for formula (I) above, unless otherwise specified. It is implied that some of the original substance in these schemes of synthesis are commercially available in either the x synthesis will not cause difficulties by a specialist in this field.

If necessary, the following schemes for the synthesis of chemically active functional groups present in the compounds described in this invention may be protected with appropriate protective groups. The protective group can be removed in one of the subsequent stages of the synthesis. The methodology for the protection of reactive functional groups and their subsequent removal can be found in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Wiley and Sons, 1991.

In the diagram A shows the synthesis of the corresponding imidazole, oxazole and thiazole derivatives of the compounds of the formula I, where X represents O, S, NR3.Heterocycles can be obtained using methods known from the chemical literature (for reviews, see Katritzky, A.R.; Rees, C.W., Eds.Comprehensive Heterocyclic Chemstry ,Vol. 5; Pergamon Press (1984); Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Eds.Comprehensive Heterocyclic Chemstry II; Vols 3 & 4, Pergamon Press (1996)). In particular, these oksazolov, imidazoles and thiazole can be obtained by melting the appropriate α-halo-ketone 1 with amidon, amidino or thioamide respectively (with the General formula 2) at a temperature of from about 40°C to 150°C with intermediate heterocycles 3.

Scheme B illustrates the General synthesis of compounds of formula I, where Z represents-O(CH2)n-. Accordingly, at stage B1 ester of carboxylic acid with the appropriate is a " 4, which can be synthesized as shown in Scheme A, is reduced to alcohol 5 using well known methods. For example, the recovery process can be carried out by aluminum hydrides, such as alumalite lithium or hydride diisobutylaluminum in an inert solvent. On stage B2 functional group of the alcohol compound 5 is converted to a leaving group with the formation of compound 6, where Lg is a leaving group such as halogen or ether sulfonic acids, for example mesilate or toilet. Conversion into a leaving group can be performed by reaction of the alcohol with such reagents as N-bromosuccinimide, in the presence of triphenylphosphine with the formation of compounds in which the leaving group is a bromide, or reaction with thionyl chloride to obtain compounds in which the leaving group is a chloride.

If you want to get the ether sulfonic acids, carried out the reaction of compound 5 with the corresponding sulphonylchloride in the presence of a suitable base. For example, the reaction of compound 5 with methanesulfonamide in the presence of an organic base such as triethylamine or pyridine, in an inert solvent leads to the connection 6, in which the leaving group is

OSO2CH3.

On stage B3 ester of hydroxyaryl with suitable substituents 7 reacts with g is therotical 6, replacing a leaving group, with the formation of the bound ether 8. The substitution reaction is carried out under conditions well known in the art. Typically, this reaction is conducted in the presence of a base such as sodium hydride, or other inorganic bases, such as the carbonate or hydroxide of an alkali metal, in an inert solvent. The reaction temperature, although it is not the critical factor should be between 0°C to temperature phlegmy inert solvent.

Then the connection 8 at the stage B4 is treated with hydrazine, pure or in a suitable organic solvent, at an elevated temperature with the formation of acid hydrazide 9. Typically, this reaction is conducted at a temperature from 50°C to a temperature of phlegmy organic solvent.

Cyclization of the acid hydrazide 9 at the stage B5 to the desired 1,3,4-oxadiazol-2-ones 10 is produced by processing the compound (9) by CHLOROFORMATES in the presence of organic bases such as pyridine, followed by treatment of the strong base with a sterically hindered amino group, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable organic solvent, such as acetonitrile, in a hermetically sealed flask at elevated temperatures. Typically, the reaction is carried out at a temperature from 100°C to 200°C. 1,3,4-oxadiazol-2-ones can be so is e to synthesize by reaction of compound (9) with phosgene. Cm. Stempel, A., et al.,J. Org. Chem.1955, 20, 412.

On stage B6 provides an alternative synthesis of the bound ether 8. Accordingly, the alcohol 5 can react with the complex air hydroxyaryl 8 in the presence of Triaryl or trialkylphosphine, such as triphenylphosphine or tri-n-butylphosphine, and diethylazodicarboxylate in an inert solvent, for example THF or dichloromethane, with the formation of ester linked 8. Typically, this reaction is carried out at a temperature of from room temperature to the temperature of phlegmy inert solvent.

Scheme C illustrates the synthesis of compounds of formula I in which Z represents -(CH2)n-Y-(CH2)n-. This pattern is most convenient for the synthesis of compounds in which n in alkalinous chain attached to ARYL, a is 1 or 2. On stage C1 connection 5 (Y=O) is converted to compound 6 (where Lg is chlorine or bromine), as described in scheme B, step B2. Then, the compound 6 is reacted with thiourea, compound 11, in conditions similar to those described in Treau, M. et al.Heterocycles,2001, 55 (9), 1727-1735, with the formation of thiol 5a.

The reaction of compound 6 with a primary amine 12 is formed a heterocycle of the alkylamine 5b. Such substitution of the leaving group of the amine is well known to experts in the field. As a rule, the substitution reaction is carried out in a polar organic solvent in outstay organic bases, which is used to neutralize the acid. While it is not absolutely necessary condition, the substitution reaction is carried out at a temperature from room temperature to the temperature of phlegmy solvent.

At the stage of C3 compounds 5, 5a and 5b by reacting compound 13 with the formation of the associated alleyra 14, in which Y represents O, S or NR3. Thus, the reaction of compounds 5 (Y=O) and 5a (Y=S) from 13 to displace the leaving group such interaction, as a rule, is carried out in the presence of a strong base such as sodium hydride, in a polar aprotic solvent such as DMF or DMSO, at temperatures from about 0°C to 150°C. If the compound 5b (Y=NR3) reacts with 14 apply conditions identical to those described above for stage C2 to the primary amine.

The synthesis of the desired 1,3,4-oxadiazol-2-ones 16 from the connection 14 is performed in two stages (C4 and C5), exactly as described in scheme B, stage B4 and B5.

Scheme D provides an alternative approach to obtaining the compounds of formula I in which Z represents -(CH2)n-Y-(CH2)n-. This scheme is most convenient for the synthesis of compounds in which n in alkalinous chain attached to the ARYL is from 3 to 5.

On stage D1 connection with terminal aldehyde 17, which may be synthesized according to the method, showing Nomo in scheme A, turns into a terminal acetylene 19 reaction in two stages. Thus, the reaction of 17 with bromotrinitromethanes (first stage) with potassium t-BuOK gives intermediate bromelein (not shown), which is then treated with 2 equivalents of t-BuOK (second stage) with the formation of acetylene 19. This sequence of reactions transformations described in Pianetti, P.,Tet. Letters, 1986, 48, 5853-5856. Cm. also Corey, E. J., et al.J. Am. Chem. Soc.,1969, 91, 4318-4320. As shown at stage D2, as an alternative intermediate connection 19 can be obtained by substitution of the leaving group of this intermediate compound 6 (see diagram C) with a nucleophile, such as 18, which includes the terminal acetylene.

At stage D3 combination Sonogashira acetylene intermediate compound 19 with arriagada 20 is carried out in the presence of tetranitroaniline (0), copper iodide (I) and an appropriate organic base in an inert solvent with the formation of the associated terminal acetylene 21. The recovery of acetylene 21 can then be carried out at the stage of D4 by catalytic hydrogenation of compound 21 with the formation of the saturated complex ester 14. Typically, the recovery can take place under the action of catalysts, such as palladium on carbon or chlorotris(triphenylphosphine)rhodium(I) in an inert, organic the immediate vicinity of the solvent with hydrogen at a pressure of from 30 to 300 pounds per square the inch. Recovery can be performed at a temperature from room temperature up to 175 ° C.

The synthesis of the desired 1,3,4-oxadiazol-2-ones 16 from the connection 14 is performed in two stages (D5 and D6), exactly as described in scheme B, stage B4 and B5.

In scheme E is a special case of the synthesis of compounds of formula I, where Z represents -(CH2)nNR3(CH2)n-. In this approach, the linker Z is constructed by reductive amination of the aldehyde with the amine. For example, at the stage of E1 in the treatment of compound 5b (where Y=NR3) aldehyde, such as an ester of 4-formylbenzoate acid (n=1), the connection 22 in a polar solvent, usually alcohol or mixture of alcohol and THF, followed by treatment with a reducing agent, such as triacetoxyborohydride sodium, lead to the desired intermediate compound 14a (n=1).

Similarly, at the stage of E2 treatment of the aldehyde, for example, 17a, an amine, such as methyl ether 4-aminoalkylindoles acid (n=1), compound 23, leads 14a, where n is 1, and R3in -(CH2)nNR3represents H. the Connection 14a on stage E3 and E4 becomes 1,3,4-oxadiazol-2-ones 16a, as shown in scheme B, stage B4 and B5.

In the more General case, the corresponding amines (R OOC-ARYL-(CH2)NOther3) is obtained from the corresponding NITRILES or nitro compounds is ay catalytic hydrogenation or of acetylamino and arisitide or bromides through a combination of Sonogashira with subsequent catalytic hydrogenation, as described for scheme D.

Scheme F illustrates the synthesis of compounds of formula I in which Z represents-SO2(CH2)n-. On stage F1 processing arylsulfonamides 24 aqueous sodium sulfite gives sulfonic acid 25. The reaction 25, as shown in stage F2, with such intermediate connection, as 6, in a polar solvent, such as DMF, acetonitrile or ethanol, in the presence of a base, such as DBU, pyridine, sodium methoxide or sodium hydroxide, gives the intermediate connection 26. The intermediate connection 26 into corresponding 1,3,4-oxadiazol-2-he's 28 stages F3 and F4, as shown in scheme B, stage B4 and B5.

Scheme G illustrates the synthesis of compounds of formula I in which Z represents-O(CH2)nCO. Shown in this diagram, the case n = 1. The original 2-acetyl heterocycle 29 can be synthesized from the corresponding carboxylic acid (obtained according to the method shown in the diagram (A) by adding the appropriate Grignard reagent to an intermediate N-methoxy-N-methylcarbamate (Khlestkin, V.K. et al.; Current Organic Chemistry, 2003, 7(10), 967-993 and Singh, J. et al., Journal für Praktische Chemie, 2000, 342, 340-347). The intermediate N-methoxy-N-methylcarbamate most often carried out by reaction of the acid with the hydrochloride of N-methoxy-N-methylhydroxylamine in the presence of the tvii peptide reagent combination, such as EDC, DCC, DMPU and a tertiary amine base, such as diisopropylethylamine or triethylamine.

The compound obtained 29 bromilow and get Bratton 30, as shown in G1 phase. Bromination can hold well-known methods, for example by reaction of the compound 29 with pyridinium bromide in acetic acid or by reaction of the compound 29 with Br2in an inert organic solvent such as dichloromethane. The resulting Bratton 30 responds to the stage G2 with arylhydroxylamine 7 under the conditions described for scheme B (stage B3), associated with the formation of a complex ester 31. Ketone function 31 is protected as ketal 32, as shown in stage G3, by methods known to experts in this field. Compound 32 is then translated into ketal 1,3,4-oxadiazol-2-34 it on stages G4 and G5 in the standard sequence described for scheme B (B4 and B5). Finally, at the stage G6 Catalina function 34 is cleaved, for example, mineral acid in a mixture of THF-methanol-water or by other known methods with the formation of the desired compound 35.

For professionals it is obvious that the above described method for the circuit G can be used for the synthesis of similar compounds, where n connection 35 accepts values from 2 to 5, if the source connection to use Bratton, the connection 30, with larger bromoalkane is the principal Deputy (Br(CH 2)nCO-, where n takes values from 2 to 5).

Scheme H illustrates the process of producing compounds of the formula I in which Z represents -(CH2)nCO. At the stage of H1 corresponding methoxycarbonyl-substituted heterocycle 36 is treated with 2 equivalents of lithium enolate tert-butyl acetate in a solvent such as THF or DME at a temperature of from-78ºC to room with education ketoacidotic intermediate 37. On stage H2 processing 37 base, for example sodium hydride, at temperatures from-10ºC to room with subsequent alkylation of the resulting anion with the electrophile, for example, 13 gives the branched intermediate ketotifen 38. Decarboxylation shown on stage H3, can be carried out by treating compound 38 TFA in an inert solvent, such as dichloromethane, followed by thermolysis at temperatures between 70º C to about 150ºc with the formation of intermediate keeeper 39. Ketone function in 39 protected as ketal 40, as shown in stage H4, by methods well known in the art. The connection 40 is then translated into ketal 1,3,4-oxadiazol-2-it 42 stages of H5 and H6 in a standard sequence, as described for scheme B (B4 and B5). Finally, at the stage H7 Catalina function 42 is cleaved as described above for scheme G, step G6, with the formation of the desired 1,3,4-xavator-2-it, the connection 43.

Biological examples:

Following the protocols of tests used to confirm the biological properties of the compounds constituting the object of the present invention. The following examples are provided to further illustrate the invention. However, they should not be understood as limiting the present invention.

The determination of the values of EC50in the cellular analysis of PPAR-Delta-GAL4:

The principle of analysis

The activity of substances that bind PPAR-Delta human and activate its agonistic way, analyze using stable transfectional line HEK cells (HEK - kidney of a human embryo), which is here called the reporter cell line PPAR-Delta. Reporter cell line PPAR-Delta contains two genetic element - reporter element luciferase (pdeltaM-GAL4-Luc-Zeo) and PPAR-Delta protein (GR-GAL4-humanPPAR delta-LBD), which regulates the expression of the reporter element luciferase depending on PPAR-Delta ligand. Stably and constitutively expressed protein GR-GAL4-humanPPAR delta-LBD bound in the nucleus of the cell reporter cell line PPAR-Delta through a portion of protein with GAL4 binding motifs GAL4 DNA in 5'-direction from the reporter element luciferase, which is stably integrated into the genome of a cell line. On udaetsya only a weak expression of the reporter gene luciferase in the absence of PPAR-Delta ligand, if the analysis is used depleted fatty acids fetal calf serum (cs-FCS). Ligands of PPAR-Delta bind and activate protein PPAR-Delta and, thus, stimulate the expression of the reporter gene luciferase. The resulting luciferase may be logged using chemiluminescence with the participation of a suitable substrate.

Construction of reporter lines PPAR-Delta:

Obtaining a stable reporter cell line PPAR-Delta based on stable HEK-cell clone that stably transfection reporter element luciferase. This stage has already been described above in the section "construction of reporter cell line PPAR-alpha. In the second phase protein PPAR-Delta (GR-GAL4-humanPPAR delta-LBD) was stably introduced into this cell clone. For this purpose, the cDNA encoding for the N-terminal 76 amino acids of the glucocorticoid receptor (catalog No. P04150) was associated with the region cDNA encoding amino acids 1-147 of the transcription factor of yeast GAL4 (catalog No. P04386). cDNA ligand-binding region of PPAR-Delta receptor human (amino acids S139-Y441; catalog No. L07592) cloned at the 3'-end of this design GR-GAL4. Thus obtained fused design (GR-GAL4-humanPPAR delta-LBD) was re-cloned into plasmid pcDNA3 (Invitrogen)to facilitate the constitutive expression promoter of cytomegalo the Rus. This plasmid was linearized by restriction enzyme and stable transfection in the previously described cell clone containing an element of the reporter luciferase. The resulting reporter cell line PPAR-Delta, which contains an element luciferase reporter and constitutively expresses a fused protein PPAR-Delta (GR-GAL4-human PPAR delta-LBD)was isolated by selection seosenok (0.5 mg/ml) and G418 (0.5 mg/ml).

Analysis and evaluation:

The activity of agonists of PPAR-Delta is determined during the 3-day analysis, which is described below:

Day 1

Reporter cell line PPAR-Delta to cultivate confluently 80% DMEM (# 41965-039, Invitrogen), which is mixed with the following additives: 10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027, Invitrogen), 1% solution penicillin-streptomycin (#15140-122, Invitrogen) and 2 mm L-glutamine (#25030-024, Invitrogen). Cultivation occurred in standard flasks for cell cultivation (# 353112, Becton Dickinson) in the incubator for growing cells at 37 degrees C in the presence of 5% CO2. Cells with confluently 80% once washed with 15 ml of PBS (phosphate buffered saline) (#14190-094, Invitrogen), treated with 3 ml trypsin solution (#25300-054, Invitrogen) at 37 degrees C for 2 minutes, placed in 5 ml described DMEM and believe in the cytometer. After dilution to 500 000 cells/ml, in each cell in oyeme ál sow 35 000 cells in 96-cell planchettes for micrometrology with a base of transparent plastic (#3610, Corning Costar). Tablets incubated in the incubator for cell cultures at 37 degrees C and 5% CO2within 24-hours.

Day 2

PPAR-delta agonists, which should be investigated, dissolved in DMSO at a concentration of 10 mm. The resulting stock solution diluted in DMEM (#41965-039, Invitrogen), which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mm L-glutamine (#25030-024, Invitrogen) and described previously with antibiotics (zeocin, G418, penicillin and streptomycin).

Analyte test in 11 different concentrations ranging from 10 μm to 100 PM. The most active compounds tested in concentration ranges from 1 μm to 10 PM, or from 100 nm to 1 PM.

Environment reporter cell line PPAR-Delta, seeded on day 1, or completely removed by suction or leave, and diluted in the environment of the test substance immediately added to the cells. Dilution and addition of substances performs laboratory robot (Beckman FX). The final volume of the analyzed substances diluted in medium, 100 μl of the cell 96-cell planchettes for micrometrology. The concentration of DMSO in the analytical mixture is less than 0.1% by volume to avoid the cytotoxic effects of solvent.

Each tablet was administered the standard agonist of PPAR-Delta, which is similarly diluted in 11 different concentrations, in order to demonstrate the analysis process in each of the separate tablet. Analytical tablets incubated in the incubator at 37°C and 5% CO2within 24-hours.

Alternatively, 20 μl of 10-fold the final concentration of the analyte added directly to 180 μl of cells in cells planchettes. Analyte triple tested at 8 different concentrations in this analytical tablet.

Day 3

Reporter cells PPAR-Delta process the analyzed substances and removed from the incubator, and then the medium is sucked off. Cells are lysed by adding pipette 50 ál Bright Glo (manufactured by Promega) to each well of 96-cell planchettes for micrometrology. After incubation at room temperature in the dark for 10 minutes planchettes for micrometrology analyze in a luminometer (Trilux production Wallac). The measurement time of each cell planchettes for micrometrology is 1 sec.

Rating:

The raw data luminometer transferred into a Microsoft Excel file. Graphs of the effect of dose and values EC50PPAR-agonists calculated using the program XL.Fit as described by the manufacturer (IDBS).

Measured values of EC50PPAR-Delta in the range from 1 nm to >10 μm for PPAR modulators shown in the examples of this application. Connection with formula I, comprising the subject matter of this invention may function as agonists or antagonists. N the same analysis described for determination of partial agonistic or antagonistic activity.

Determining the effectiveness of partial agonists or antagonists at the receptor PPAR-Delta

This analysis allows you to determine whether compounds as partial agonists or antagonists at the receptor PPAR-Delta.

Cultivation and collection of cells in the analytical tablets described in the sections "Day 1 " and "Day 3" above.

Day 2

Partial agonist or antagonist and a known selective agonist diluted in DMEM (#41965-039, Invitrogen), which is mixed with 10% cs-FCS (#SH-30068.03, Hyclone), 2 mm L-glutamine (#25030-024, Invitrogen) and previously described antibiotics (zeocin, G418, penicillin and streptomycin) to 20-fold the desired final concentration. In analytical tablet with cells add ten microlitres partial agonist or antagonist. Analytical tablets incubated in the incubator at 37°C and 5% CO2within 30 minutes. Then after pre-incubation, partial agonist or antagonist add ten microlitres known selective agonists in the 20-fold concentration. Analytical tablets incubated in the incubator at 37°C and 5% CO2within 24-hours. Determine the effect of known selective agonists EC50for each concentration selective agonist or antagonist.

Analysis of binding SPA PPAR Delta-LBD

Original solution:

1 M Tris (pH 8.0 or pH 7,6) (GeneMedicine Stock Room)

2 M KCl (powder in N2140)

Tween 20

100 mm DTT

of 13.9 μm GW2331 in HOT EtOH

10 mm GW2331 in DMSO COLD

PPAR-alpha (concentration varies)

Ex: 0,884 µg/µl

Wash buffer:(Store at 4°C. the shelf Life of the buffer one week.)

10 mm Tris (pH of 7.6 or 8) 10 ml

50 mm KCl 25 ml

0.05 % of Tween 20 0.5 ml

The water treated at the facility Millipore 964.5

Check pH of 7.6

Binding buffer:(Every time cook fresh binding buffer.)

Wash buffer 50 ml

10 mm DTT 5.5 ml

Obtaining the reaction reagents for 1 tablet:

Covered with glutathione SPA-granules

Each vial with SPA-granules contains 500 mg of granules.

Dissolve 500 mg of SPA pellet in 5 ml aqueous buffer, and it retains its suitability for use in a few weeks.

Store at 4°C.

Getting diluted SPA granules in binding buffer.

Add 1 ml of dissolved SPA granules in 60 ml of binding buffer.

Add 20 ál of the dissolved pellet in each well of 96-cell tablet.

Apply 2 ml of the dissolved granules for each tablet (excluding dead volume).

3H-GW2331 plus GST-PPAR Delta-LBD (for one 96-cell tablet without dead volume) 13.9 mm 40 nm on the cell

3.0 ml of the tablet (including dead volume)

If the specific activity of 3H-GW2331 is 1 µci/ml (production Amersham), diluted with the 17 μl of 3H-GW2331 in 3.0 ml of binding buffer = 0,08 mm.

If the protein concentration is 1 mg/ml, add 21 µl of protein in 3.0 ml of binding buffer.

In conclusion: ONE 96-cell tablet: 3000 ál binding buffer + 17 μl of 3H-GW2331 + 21 ál of GST-PPAR-Delta (1 mg/ml).

Control tablets

96-cell maternal tablet (2-x test tablets)

Column # 1:

Add 5 ál of cold GW2331 (10 mm) in cell E-H.

Add 45 ál of DMSO in cell A-H.

In column No. 12 (3-fold dilution):

Add 10 ál of cold GW2331(10 mm) in the cell A.

Then add 90 ál of DMSO in the cell A and the well-stirred solution.

Add 20 ál of DMSO in cell B-H.

Take 10 ál of the solution from cells A and B and mix well,

then take 10 ál of the solution from cell B to C and well stirred,

then take 10 ál of a solution of cells from C to D and mix well.

......

Finally, take 10 ál of the solution from the cell from F to H.

Control tablet (8 reaction tablets)

In the control tablet contains the solution of maternal tablet, diluted 1:10. The dilution buffer is wash buffer.

Tablets samples

Fresh tablet library CPC add 90 ál of DMSO.

Take 10 ál of the solution, diluted with DMSO, and add 90 ál of wash buffer to the tablet with the sample.

The reaction tablets:

Add 20 ál of granules of sodium polyacrylate and 30 μl of 3H-GW2331 with GST-PPAR-Delta in each well of the reaction plate.

Add 5 μl of the compounds from each of the wells with the sample in columns 2 through 11, the reaction of the tablet.

Add 5 μl of the compounds from the column 1 and column 12 of the control tablet in column 1 and column 12 the reaction of the tablet.

The Protocol for 96-cell tablet analysis SPA:

Wait until the equilibrium in the reaction tablets - it will take from 20 minutes to 2 hours.

Tablets sealed before to count in the cytometer Microbeta (Wallac).

The calculation of the IC50.

In the analysis of binding SPA PPAR Delta LBD of PPAR modulators shown in the examples of this application were measured IC50in the range from 1 nm to >10 μm. Connection with formula I, comprising the subject matter of this invention may function as agonists or antagonists.

Culture oligodendrocytes RATS/MICE

Preparation of cells:

1. Primary cells-the precursors of oligodendrocytes derived from the cerebral cortex of newborn (2-3 postnatal day) in rats or mice after removal of microglia by mechanical separation by separation from astrocytoma monolayer using a modified method, first described in the work of McCarthy and de Vellis (1980).

2. Remove soft brain oblock is from the brain of newborn rats and mechanically separate the fabric. Place cells in a T75 flask and add nutrient medium for the cells in DMEM/F12 + 10% FBS.

3. Collect oligodendrocytes growing on astrocytomas substrate, method of shaking off fourteen days after the initial cooking. Centrifuged the suspension and weighed again cellular precipitate in not containing serum medium (SFM; DMEM, mixed with 25 μg/ml portable substance, 30 nm triiodothyronine, 20 nm hydrocortisone, 20 nm progesterone, 10 nm Biotin, 1x trace elements, 30 nm selenium, 1 μg/ml of putrescine, 0.1% of bovine serum albumin, 5 units/ml PenStrep, 10 μg/ml insulin) supplemented with the following growth factors: Platelet-derived growth factor-AA (PDGF) and the growth factor of the fibroblast-2 (FGF). Place cells in a Cup, covered with PDL (poly-D-lysine), and incubated at 37°C with 6-7% CO2. Components replaced every 48 hours to save precursor cells.

Passerovannye precursor cells to increase the number of cells for screening analysis:

1. When the culture becomes confluent, washed with physiological solution with PBS buffer, add trypsin and incubate for ~2-3 minutes at 37°C.

2. Neutralized and centrifuged cell suspension at 900 g for 5 minutes.

3. Resuspending cellular precipitate in SFM + PDGF/FGF.

4. Add nutrition to the cells with fresh growth factors every 48 hours, so in order to keep them in the enriched condition for rapidly dividing progenitor cells.

5. Cells passer no more than 4-5 times before experimental analysis.

6. All experiments with cells-precursors of oligodendrocytes were performed with cells that are constantly maintained in these conditions. More than 95% of all cells were A2B5-immunopositivity and expressed mRNA 2'3'-cyclic nucleotide 3'-phosphodiesterase II.

7. For the generation of Mature oligodendrocytes in 24 hours after placing of progenitor cells in the tablets they moved in free serum medium with addition of insulin growth factor IGF-I or without him and were grown in these conditions for 7 days prior to experimental analysis.

8. Alternatively can be used enriched line precursor cells Central Glia-4 (CG4) rats, which are stored in the basic medium (DMEM with 2 mm glutamine, 1 mm sodium pyruvate, Biotin (40 nm), insulin (1 μm) and N1) with the addition of 30% conditioned medium from cell lines of neuroblastoma B-104. To induce differentiation, cells CG4 placed in a basic medium with 1% fetal calf serum (deleted in 2 days) and insulin (500 nm). To confirm the enrichment of >95% in Mature and immature cultures used A2B5 immunoreactivity and exchange rate (myelin basic protein), respectively.

Processing the connection culture rats/mice:

1. Put 10000-15000 tile is to the cell 24-cell tablet, coated with PDL, and cultured cells in the presence of mitogen (10 ng/ml) during the night.

2. In the presence of mitogen:

A. The next day remove the old medium and add the connection in a fresh environment (mitogen).

b. Evaluation of dose-response connections are performed at 6 different concentrations (10 μm, 1 μm, 100 nm, 10 nm, 1 nm and 0.1 nm).

c. For each concentration of the compound evaluated on three cells.

3. In the absence of mitogen:

a. The next day remove the old medium and add the connection in fresh medium (without mitogen).

b. Evaluation of dose-response connections are performed at 6 concentrations (10 μm, 1 μm, 100 nm, 10 nm, 1 nm and 0.1 nm).

c. For each concentration of the compound evaluated on three cells.

4. Cultivate treated cells for 7 days before using them in the experimental analysis.

Culture of oligodendrocytes PERSON

Preparation of cells:

1. Neurosphere man, taken from the cortex of a human embryo E19.5 - E22 cultured for 2 weeks in an environment of progenitor cells: DMEM/F12 containing 100 mg/ml portable substance, 30 nm triiodothyronine, 20 nm hydrocortisone, 20 nm progesterone, 10 nm Biotin, 1x trace elements, 30 nm selenium, 60 μm putrescine, 0.1% of bovine serum albumin, 5 units/ml PenStrep, 25 μg/ml insulin) supplemented with PDGF and FGF factor R is a hundred fibroblast.

2. Neurosphere dissociatively using 20 units/ml papain at 37°C for 30-50 minutes.

3. Cells were sown in a Cup with PDL-coated at a density of 50 000-100 000 cells per cell in the environment precursor cells containing PDGF/FGF and inkubiruemykh at 37°C with 5-6% CO2.

4. Environment and growth factors were added every 48 hours.

Treatment with combination of cultures of a person:

1. 24-48 hours after placing the tablet to remove the old medium and add the connection in a fresh environment (mitogen).

2. Evaluation of dose-response connections are performed at 3-6 different concentrations (10 μm, 1 μm, 100 nm, 10 nm, 1 nm and 0.1 nm).

3. For each concentration of the compound evaluated on three cells.

5. Cultivate treated cells for 7 days before using them in the experimental analysis.

Specific immune staining of oligodendrocytes of the RAT/MOUSE/HUMAN:

After processing the connection oligodendrocyte-specific antibodies are used to assess the ability of compounds to accelerate or promote the differentiation of oligodendrocytes (for example, immunoreactivity O4, O1 or myelin basic protein through some time after processing the connection is between treated and untreated cultures).

1. Cells are placed on the treated poly-D-lysine 4-cell chamber planches is you, at a density of 5×10 3up to 20×103cells on the cell and grown as described above. Subsequent staining is performed on populations of oligodendrocytes with increasing speed of cell differentiation, as described by days in vitro without PDGF and FGF.

2. To determine stagespecific expression of the surface marker of cells of the oligodendrocyte (including A2B5, O4, and O1) is used staining of living cells for 30 minutes at 37°C.

3. Then the cells fixed with 4% paraformaldehyde for 10 minutes at room temperature.

4. The procedure of staining of fixed cells is used to determine stagespecific expression of a marker of oligodendrocytes (including myelin basic protein, exchange rate).

5. Washed with PBS buffer.

6. Permeabilizing with 0.1% Triton/0,01% NaAz diluted in 1X PBS buffer for 10 minutes at room temperature.

7. Block 5-10% goat serum in dilution buffer antibody (0,1% Triton-X 100 and 1% bovine serum albumin that do not contain IgG; also used for dilution of antibodies) for 15 minutes at room temperature.

8. Add the primary antibody diluted in buffer dilution of antibodies.

9. Incubated overnight with continuous shaking at 4ºC.

10. The next day wash buffer 1X PBS for 5 minutes, and then 3X for 15 minutes each at whom atoi temperature.

11. Incubated with appropriate secondary antibodies for 45 minutes at room temperature.

12. Cell nuclei stain 4,6-diamidino-2-phenylindole (DAPI) for 15 minutes at room temperature.

13. Washed several times with PBS buffer and explore using fluorescence microscopy.

14. Over time and with different doses of compounds match the following conditions: only PDGF/FGF, only SFM, SFM only-IGF1, PDGF/FGF and connection, SFM and connection.

Immune staining of bromosuccinimide (BDU) RAT/MOUSE/HUMAN:

To ensure that connections do not contribute to cell proliferation

1. Precursor cells of the oligodendrocyte mark 10 μm BDU for 20 hours, and then fixed using either 70% ethanol or 4% paraformaldehyde.

2. Cells sequentially incubated biotinylated anti-BDU mice and streptavidin-peroxidase with three intermediate washes with PBS buffer.

3. Colorimetric visualization of immunoreactivity of the BDU is performed using DAB (diaminobenzidine) and estimated total number of cells using contrasting hematoxylin.

4. Counting the BDU-immunopositive cells are carried out by two independent researchers.

Image analysis of the culture of the RAT/MOUSE/HUMAN:To quantify the degree of differentiation of the of isodendrion after processing the connection using fluorescent microscopy. This analysis shows that selective agonists accelerate or favor the differentiation of oligodendrocytes.

1. Manual counting of cells: For each of the experimental conditions chosen four random fields and in each area there 500-600 cells. The percentage of the exchange rate (or O4) immunopositive cells (Mature b cells, in which the process takes place with myelin sheets or not) depending on DAPI-positive cells (total number of cells) is compared in the control and treated drug groups.

2. Automatic counting of cells: To quantify the degree of differentiation of oligodendrocytes after processing the connection using fluorescent microscopy. To estimate the number differentiating oligodendrocytes in the population (calculated from ~8 to 15×103cells per cell) were randomly selected six areas/cells. Image immunofluorescence assay was obtained using a system of digital imaging Zeiss AxioVision with a cooled CCD camera Zeiss AxioCam HRc attached to the same microscope. All parameters of the formation of microscopic images were set so that the images will be used to analyze the intensity of immunofluorescence assay cells. The percentage exchange rate is positive (differe is qualified) cells relative to the total number of cells (nuclei, painted DAPI) was compared in control and treated drug groups. In the formation of the images to register the autofluorescence was impossible.

3. Analysis of differentiation of oligodendrocytes person: hand count total O4 immunopositive cells to the cell (bipolar and multipolar).

Results for cultures of rat oligodendrocytes in the table. As can be seen from the results, the compounds of the present invention increase or accelerate the differentiation of oligodendrocytes in rats, as measured by increased expression of myelin basic protein compared with untreated control samples. This result indicates that examples of the compounds shown in the table, should improve, accelerate or stimulate the differentiation of oligodendrocytes and the formation of myelin in vivo in the patient or damaged CNS, including in the case of multiple sclerosis and other demyelinating diseases.

The results for compounds in the analysis of differentiation of primary rat oligodendrocytes
# exampleThe growth factor in the expression of myelin basic protein in the analysis of differentiation of oligodendrocytes (con who entrace in microns)
101.5 times (10)
141.5 times (1)
232 times (1)
312 times (1)

Quantitative analysis of polymerase chain reaction (PCR) RAT/MOUSE/HUMAN:In order to evaluate the induced connection activation path PPAR-Delta and Mature oligodendrocytes (changes in mRNA levels).

1. All RNA extracted from cultured oligodendrocytes using TriZol reagent.

2. Then mRNA is treated with Dnazol, not containing RNase, clean again, and then transformed into a matrix of cDNA using the reverse transcription reaction (set Clontech Advantage RT for PCR).

3. The expression of transcripts member path PPAR-Delta quantitatively assessed using Sybr Green PCR Master Mix.

4. A mixture of primer and probe ribosomal RNA 18S RNA (186 base pairs), suspended in Taqman 2X PCR Master Mix is used for internal control.

5. Quantitative PCR is performed using real-time Taqman™ (Gibson, et al., 1996) on the model 7700 Sequence Detector System (Applied Biosystems, Foster City, CA).

6. The results analyzed using the software Sequence Detection Systems version 1.91.

Enzyme-linked immunosorbent assay cultures of RATS: Order to evaluate the induced connection activation path PPAR-Delta and Mature oligodendrocytes (changes in protein levels).

1. Tablets washed with PBS buffer, and then stored on ice. Add 200 ál of ice-lyse buffer (Tris 50 mm, pH 7,4, Mgl2mm, EDTA 1 mm, β-mercaptoethanol 5 mm, Nonidet P-40 1%, a cocktail of protease inhibitors (Roche): 1 tablet/50 ml) in each cell.

2. Cells are lysed pumping a pipette, and rotate the tablets with a speed of 2000 rpm at 4ºC for 5 minutes. The supernatant is ready for use.

3. The pipette is placed in a cell 50 ál of standard, control solution and samples.

4. In each cell add 50 ál analytical buffer myelin basic protein.

5. Incubate the cell, shaking it at 500-700 rpm on a rotating microplate shaker for 2 hours at room temperature.

6. Add to each well 100 ál conjugate antibodies to myelin basic protein exchange rate with Biotin.

7. Incubate the cell, shaking it at 500-700 rpm on a rotating microplate shaker for 1 hour at room temperature.

8. 5-fold washed cell proryvnym solution. Wipe the tablet dry, turning it on absorbent material.

9. Dilute the concentrate conjugate of streptavidin and enzyme 1:50 analytical buffer exchange rate ELISA (need to dilute immediately before use in the analysis).

10. Add 100 ál of a solution of streptavidin conjugate and enzyme in each the cell.

11. Incubate the cell, shaking it at 500-700 rpm on a rotating microplate shaker for 30 minutes at room temperature.

12. 5-fold washed cell proryvnym solution. Wipe the tablet dry, turning it on absorbent material.

13. Add 100 ál of Chromogen solution-TMB into each well.

14. Incubate the cell, shaking it at 500-700 rpm on a rotating microplate shaker for 10-20 minutes at room temperature. Avoid exposure to direct sunlight.

15. Add 100 ál of stop solution to each well.

Measure the absorption solution in the wells for 30 minutes using a microplate apparatus for reading set at 450 nm.

In vivo analysis of the General model

Local damage: (used to assess the ability of compounds to protect myelin integrity and to speed up or increase the rate of remyelination)

1. Rats aged 7 weeks give free access to food and water, and they will acclimatise for at least 4 days before using them in the experiment.

2. Before surgery, each animal is weighed. Then the rat subjected to anesthesia with ketamine (100 mg/ml) in combination with xylazine (20 mg/ml) in the ratio of 1.8:1. Before surgery, rats introducing/b 0.15 ml/180 g body weight anesthetic solution. The animal is prepared for surgery under aseptic conditions in accordance with the guidelines of the IACUC. All surgical instruments autoclaved. The hair between the ears shear off and the area is cleaned with Betadine solution, washed with sterile saline and finally rubbed with alcohol swabs in sterile packaging.

3. For surgery, the rat is placed on the abdominal surface in a small stereotactic device for animals intended for stable retention of the head. Cutting arc is established on -3,9 mm, as it has been shown that it helps to set the flat position of the skull of SD rats.

4. The incision is made at a pre-shaved skin covering the skull between the ears.

5. A small area of the bone (0.75 mm in diameter) drilled in the following coordinates: AP -1,8, ML -3,1 from lambda.

6. Bone is removed and the rat Inuktitut 2 ál of ethidium bromide, lysolecithin or SIN-1 in the right caudal cerebellar leg, DV -7,1 mm, for 2 minutes Microlitre syringe and needle Hamilton. Alternatively, the injection can be done in the spinal cord, corpus callosum or the cerebral cortex.

7. The needle remains in this position during the next 2 minutes.

8. After removal of the needle cut impose a seam.

9. Each rat receives I/m injection of 0.003 mg of buprenorphine in the hind leg.

10. The rat is placed in a heating Cabinet it until it will not regain consciousness. Then it returns the t cell. Do not allow in the cell there were more than two rats, as they may damage each other seams.

11. Similar procedures are performed with the mouse.

The model of experimental allergic encephalomyelitis in rats (EAE rats):

Experimental allergic encephalomyelitis (EAE) - this is an autoimmune disease of the nervous system, mediated by T-cells that develops in susceptible animals after sensitization or cell homogenate of the spinal cord or one of the component (myelin basic protein). Model EAE rodents is a suitable tool to study inflammation of the brain and spinal cord observed in patients suffering from multiple sclerosis. In rodents, the injection of the spinal cord or components of the spinal cord, such as myelin basic protein, causes an autoimmune reaction, based on the activation of T-lymphocytes. Clinical disease usually manifests itself after about 8-10 days after inoculation and observed in a wide range of behavioral anomalies, from mild disturbances of gait and atony of the tail to complete paralysis and death. Usually weight loss. In surviving animals is spontaneous recovery, followed by recovery of the majority of motor functions. Depending on the type of allergen and used IU the W animals studied on the model of EAE may have one (acute EAE) or more (chronic recurrent, AAA) attacks. You can use several approaches to treatment. The selected remedy or the treatment can be applied to immunization, during the asymptomatic period or during clinical disease.

Animals:

Female mice Lewis 160-220 g (Charles River)

Antigen:

Whole spinal cord of the Guinea pig(Harlan Biosciences).

Full beta-blockers H37 Ra[1 mg/ml tubercle Bacillus Mycobacterium Tuberculosis H37 Ra] (Difco).

Additional antigen:

Mycobacterium tuberculosis(Difco).

Bordetella pertussis [killed by heating] (Difco).

Preparation of antigen: (about 720 animals):

1. Weigh 5 grams frozen spinal cord of Guinea pigs.

2. Add 5 g of the spinal cord in 5 ml of 0.9% saline solution (1 g/ml) in a round-bottom centrifuge tube.

3. Homogenized on ice using a Tissue-tech to the complete destruction of tissue (approximately 5 minutes).

4. Add 10 ml of complete adjuvant's adjuvant H37 Ra, supplemented with 200 mg TB bacilli (20 mg/ml complete adjuvant's adjuvant H37 Ra).

5. The homogenate was extracted with/adjuvant test-tube, sucking it in 10-ml syringe with emulsifying needle 18 size.

6. Emuleret between the two 30 ml glass syringes, yet who will ikot difficulties of the selection of the material through the needle. (About 5 minutes {should not benoseparation between fat and water phase}.)

7. Use immediately or store on ice until required (no more than 30 minutes) (do not freeze).

Protocol

1. Female Lewis rats (Charles River) give free access to food and water, and they will acclimatise for at least 3 days before use in experiments.

2. Rats weighing 160 and 220 grams first induced with 5% isoflurane (Aerrane, Fort Dodge), 30% O2,70% N2O within 2-5 minutes.

3. Then the rat was placed on a blanket with a heating circulating water (Gaymar) (dorsal surface facing up) and in the nose cone for spontaneous inhalation of anesthetic gases. The concentration izoflurana reduced to 2%.

4. Make two intradermal injections (0.1 ml each) of antigen or normal saline into the ventral surface of the hind paws.

5. Animals removed from the nose cone, weighed and numbered.

6. Rats given an opportunity to recover from anesthesia, and then put them in separate cells.

7. Animals see daily on the subject of induction EAE (see criteria below).

STAGE 0: NORMAL.

STAGE 1: Pathological behavior and atony of the tail.

STAGE 2: a Small but definite weakness of one or both hind legs.

STAGE 3: the pronounced weakness of one or both hind legs or mild ataxia

STAGE 4: Severe prepares and minimum mobility of the hind legs.

STAGE 5: the Absence of movements of the hind legs and paralysis of the lower body.

Step 6: pre-Death without spontaneous movements and impaired breathing.

Also there is a growing degree of the damage of the front legs and urinary and fecal incontinence.

STAGE 7: DEATH.

Treatment was started on day 10 after immunization. Because the symptoms of the disease in this model occur, as a rule, 10-11 days after inoculation, we can assume that this point represents the initial phase of acute multiple sclerosis. It is believed that this delay the start of treatment more accurately simulates the clinical situation than the traditionally used protocols when the medication is used at the time of inoculation or even before it (Teitelbaum D. et al., Proc Natl Acad Sci USA 1999; 96: 3842-3847 and Brod, S. A., et al., Ann Neurol 2000; 47: 127-131).

The present invention is further illustrated by the following examples of compounds which are given for purposes of explanation and not in any way limit the scope of the present invention.

Examples synthesis

General information

Commercially available reagents and solvents were used without pretreatment. Spectra1H NMR were recorded on a spectrometer Varian MercuryPlus-300 (300 MHz) or Varian Unity Inova (400 MHz), as indicated by texte. Proton chemical shifts are given in δ MD relative to the internal standard tetramethylsilane (0,0 MD). The data of mass spectrometry (IHMS) obtained using time-of-flight mass spectrometer Micromass LCT with ionization elektrorazpredelenie and a measuring time of 5 minutes for m/z 100 to 1000. LC (IHMS) is carried out on a column of Hypersil C18 (of 4.6×50 mm, 3.5 µm) with a mobile phase of 0.1 % TFA in H2O (A) and 0.1% TFA in ACN (B), and gradient from 5% to 100% B over 3 minutes, then 2 minutes at 100% B. alternatively, the Platform can be used LC-MS with electrospray source system HP1100 LC operating at 2.0 ml/min 200 ál/min, consisting of a source of ionization elektrorazpredelenie with built-in detector HP1100 DAD and detector SEDEX ELS. Use column Luna C18(2) (30×4.6 mm 3 µm) with a gradient from 5% to 95% B over 4.5 min with a mobile phase of 0.1% formic acid in H2Oh and 0.1% formic acid in ACN (B). Purification HPLC is performed on the system Varian ProStar using columns for obremenitve chromatography C18 with a linear gradient of ACN/H2O containing 0.1% triperoxonane acid. Microwave synthesis was performed using a microwave reaction system Personal Chemistry Smithcreator with two reactors with volumes 2 or 5 ml

Example 1

Intermediate compound: methyl ether 4-methyl-2-m-tolyl-oxazol-5-carbon is th acid

Pure mixture of methyl 2-chloroacetoacetate (914 ml, 7.5 mmol) and 3-methylbenzamide (676 mg, 5 mmol) is heated to 120°C and stirred at this temperature for 12 hours. The reaction mixture is cooled to room temperature and diluted with ethyl acetate, washed with saturated sodium bicarbonate solution (3 times), water (twice) and brine, the organic extract is dried with MgSO4and concentrate. The resulting residue is purified flash chromatography (eluent 10% ethyl acetate in heptane) to obtain the specified title compound as a yellow oil (492 mg).

Example 2

The intermediate connection: [4-methyl-2-(4-triptoreline)thiazol-5-yl]methanol

A solution of lithium aluminum hydride (10 ml, 1 M in THF) is cooled (0°C) and add a solution of 4-methyl-2-(4-triptoreline)thiazole-5-carboxylic acid (commercially available, 2,87 g, 10 mmol) in THF (20 ml). After adding remove the cold bath and stirred for 3.5 hours. The solution is cooled to 5°C and then added dropwise water (0.25 ml), then add a solution of NaOH (0.25 ml, 5 M in water) and water (0.5 ml). The resulting mixture is diluted with ethyl acetate, and then filtered through a layer of celite. Wash the solids with dichloromethane, and then concentrate the combined filters under reduced pressure to obtain specified in the header with the unity in the form of a yellow solid (2,59 g).

Mass spectroscopy (ionization elektrorazpredelenie): m/z 274 (M+H); 1H NMR (CDCl3) δ 1,87 (user., 1H), 2.49 USD (s, 3H), a 4.86 (s, 2H), to 7.67 (d, J=8 Hz, 2H), 8,02 (d, J=8 Hz, 2H).

Example 3

The intermediate connection: [4-methyl-2-m-tolyloxy-5-yl]methanol

Repeat example 2, but using the compound of example 1 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z204 (M+H); 1H NMR (CDCl3) δ of 2.25 (s, 3H), 2.40 a (t, J=7 Hz, 1H), 2,42 (s, 3H), 4,70 (d, J=7 Hz, 2H), 7,25 was 7.36 (m, 2H), 7,75-a 7.85 (m, 2H).

Example 4

Intermediate compound: 5-methyl bromide-4-methyl-2-(4-triptoreline)thiazole

Cool (10°C) solution of [4-methyl-2-(4-triptoreline)thiazol-5-yl]methanol (example 2, 753 mg, 3 mmol) in THF (12 ml), add triphenylphosphine (864 mg, 3.3 mmol), and then svejeprigotovlennyN-bromosuccinimide (587 mg, 3.3 mmol). After you add clean cold bath and continuously stirred for 45 minutes. The resulting mixture was concentrated under vacuum and the residue purified flash chromatography (eluent mixture of 10% ethyl acetate/10% dichloromethane in heptane) to obtain the specified title compound as an orange solid (846 mg).

Mass spectroscopy (ionization elektrorazpredelenie):m/z336,338 (M+H); 1H NMR (CDCl3) δ 2,48 (s, 3H), 4.72 in (s, 2H), 7,69 (d, J=8 Hz, 2H), 8,01 (d, J=8 Hz, 2H).

Example 5

Intermediate compound: methyl ether methanesulfonate acid [2-(3-were)-4-methoxazole-5-yl]

Cooled (0°C) solution of [2-(3-were)-4-methoxazole-5-yl]methanol (example 3, 756 mg, 4 mmol) in dichloromethane (16 ml) and sequentially add dimethylaminopyridine DMAP (51 mg, 0.4 mmol), triethylamine (552 μl, 4 mmol) and methanesulfonamide (323 μl, 4.2 mmol). The resulting solution is stirred for 5 minutes, remove the cooling bath and stirred for 25 minutes. The resulting solution was diluted with ether, washed with hydrochloric acid (5 ml, 2 M), with brine, dried over MgSO4and concentrate to obtain specified in the title compound (743 mg).

Example 6

Intermediate compound: methyl ether

4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzoic acid

To a mixture of methyl ester of 4-hydroxybenzoic acid (152 mg, 1 mmol) and potassium carbonate (152 mg, 1.1 mmol) is added acetonitrile (4 ml). To the resulting mixture are added 5-methyl bromide-4-methyl-2-(4-triptoreline)thiazole (example 4, 314 mg, 1 mmol). The resulting reaction mixture is heated to 60°C and stirred at this temperature for 5 hours. A mixture of ohlord the Ute to room temperature, dilute with ethyl acetate, washed with water, then with brine, dried over MgSO4, filtered and concentrated to obtain specified in the title compound as a white solid (364 mg).

Mass spectroscopy (ionization elektrorazpredelenie):m/z408 (M+H); 1H NMR (CDCl3) δ of 2.53 (s, 3H), 3,90 (s, 3H), to 4.52 (s, 2H), 7,00 (d, J=9 Hz, 2H), 7,68 (d, J=8 Hz, 2H), 8,02 (m, 4H).

Example 7

Intermediate compound: methyl ester of 4-(4-methyl-2-m-tolyloxy-5-ylethoxy)benzoic acid

Repetition of example 6, but using the compound of example 5 as the starting material to obtain the specified connection.

Mass spectroscopy (ionization elektrorazpredelenie):m/z338 (M+H); 1H NMR (CDCl3) δ is 2.30 (s, 3H), 2,41 (s, 3H), 3,90 (s, 3H), 5,11 (s, 2H), 7,03 (d, J=9 Hz, 2H), 7,25 (m, 1H), 7,33 (t, J=8 Hz, 1H), 7,81 (d, J=8 Hz, 1H) 7,87 (users, 1H) 8,02 (d, J=9 Hz, 2H).

Example 8

The intermediate connection: hydrazide 4-[4-methyl-2(4-triptoreline)thiazole-5-ylethoxy]benzoic acid

To a suspension of methyl ester 4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzoic acid (example 6, 364 mg, 1 mmol) and methanol (10 ml) is added anhydrous hydrazine (128 ml, 4 mmol). The resulting mixture is heated to 60°C and stirred at this temperature for 18 hours. The resulting RAS is a thief cooled to room temperature and add three drops of water. The solution is concentrated under vacuum, and purified flash chromatography (eluent 5% methanol in dichloromethane) to obtain the specified title compound (271 mg).

Mass spectroscopy (ionization elektrorazpredelenie):m/z408 (M+H); 1H NMR (DMSO) δ of 2.51 (s, 3H), 4,4 (users, 2H), 5,42 (s, 2H) 7,10 (d, J=9 Hz, 2H), 7,82 (d, J=9 Hz, 2H), a 7.85 (d, J=8 Hz, 2H) to 8.12 (d, J=8 Hz, 2H) 9,63 (users, 1H).

Example 9

The intermediate connection: hydrazide of 4-(4-methyl-2-m-tolyloxy-5-ylethoxy)benzoic acid

Repetition of example 8, but using the compound of example 7 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z338 (M+H); 1H NMR (DMSO) δ 2,24 (s, 3H), of 2.38 (s, 3H), 4,43 (users, 2H), 5,26 (s, 2H) 7,11 (d, J=9 Hz, 2H), 7,34 (d, J=8 Hz, 1H), 7,41 (t, J=8 Hz, 1H) 7,74-7,83 (m, 4H) 9,63 (users, 1H).

Example 10

5-{4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}-3H-[1,3,4]oxadiazol-2-he

To a suspension of the hydrazide of 4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzoic acid (example 8, 271 mg of 0.74 mmol) in dichloromethane (7 ml) add phenylcarbamate (94 μl, 0.75 mmol)and then pyridine (132 μl, and 1.63 mmol). The resulting mixture was stirred at room temperature until they use up all of the starting material (by TLC analysis). Mixture to the will centerour, next, the residue added to acetonitrile (10 ml). To the obtained mixture is added DBU (220 μl, 1.5 mmol). The resulting solution tightly closed; heat it to 180°C in a microwave oven Personal Chemistry™ and stirred at this temperature for 15 minutes. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with a solution of 1 M HCl (or a saturated solution of NaH2PO4), dried over MgSO4and concentrate. The resulting residue is triturated several times with dichloromethane to obtain specified in the title compound as a yellowish brown solid (69 mg).

Mass spectroscopy (ionization elektrorazpredelenie):m/z365 (M+H); 1H NMR (DMSO) δ of 2.51 (s, 3H), 4,4 (users, 2H), 5,42 (s, 2H) 7,10 (d, J=9 Hz, 2H), 7,82 (d, J=9 Hz, 2H), a 7.85 (d, J=8 Hz, 2H) to 8.12 (d, J=8 Hz, 2H) 9,63 (users, 1H).

Example 11

5-[4-(4-methyl-2-m-tolyloxy-5-ylethoxy)phenyl]-3H-[1,3,4]oxadiazol-2-it.

Repetition of example 10, but using the compound of example 9 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z364 (M+H); 1H NMR (DMSO) δ of 2.25 (s, 3H), of 2.38 (s, 3H), and 5.30 (s, 2H) of 7.23 (d, J=9 Hz, 2H), 7,34 (d, J=8 Hz, 1H), 7,41 (t, J=8 Hz, 1H) 7,75-7,79 (m, 4H) to 12.44 (users, 1H).

Example 12

Intermediate is the compound: methyl ester of 4-([4-methyl-2-(4-triptoreline)thiazol-5-yl)ethoxymethyl]benzoic acid

A suspension of NaH (84 mg, 60% dispersion in mineral oil, 2.05 mmol) in THF (4 ml) is cooled (-5°C) and add a solution consisting of 2-([4-methyl-2-(4-triptoreline)thiazol-5-yl)methanol (546 mg, 2 mmol) and methyl ester 4-bromomethylphenyl acid (458 mg, 2 mmol) in THF (5 ml). The resulting mixture is stirred for 5 minutes, then remove the cold bath and stirred for another 3 hours. To the reaction mixture add a solution of 1 M HCl, then diluted with ethyl acetate, washed with brine and dried over MgSO4. The resulting solution was concentrated under vacuum and the residue purified flash chromatography (eluent 20% ethyl acetate in heptane) to give the product (377 mg) as a white solid.

Mass spectroscopy (ionization elektrorazpredelenie):m/z422 (M+H); 1H NMR (CDCl3) δ is 2.44 (s, 3H), 3,92 (s, 3H), with 4.64 (s, 2H), 4,71 (s, 2H), 7,42 (d, J=8 Hz, 2H), 7,66 (d, J=8 Hz, 2H) 8,00 (m, 4H).

Example 13

The intermediate connection: hydrazide of 4-([4-methyl-2-(4-triptoreline)thiazol-5-yl)ethoxymethyl]benzoic acid

Repetition of example 8, but using the compound of example 12 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z422 (M+H); 1H NMR (CDCl3) δ is 2.44 (s, 3H), 4.09 to (users, 2H), 4,63 (s, 2H), 4,71 (s, 2H), 7,30 (OSiR.the., 1H), 7,44 (d, J=8 Hz, 2H), 7,66 (d, J=8 Hz, 2H), 7,73 (d, J=8 Hz, 2H) 8,00 (d, J=8 Hz, 2H).

Example 14

5-{4-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 13 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z448 (M+H); 1H NMR (DMSO) δ 2.40 a (s, 3H)and 4.65 (s, 2H), 4,78 (s, 2H) 7,50 (d, J=8 Hz, 2H), 7,78 (d, J=8 Hz, 2H), 7,82 (d, J=8 Hz, 2H) 8,10 (d, J=8 Hz, 2H) 12,54 (users, 1H).

Example 15

Intermediate compound: methyl ester of 4-([3-methyl-2-(4-triptoreline)thiazol-5-yl)ethoxymethyl]benzoic acid

A solution of 2-([4-methyl-2-(4-triptoreline)thiazol-5-yl)methanol (450 mg, of 1.64 mmol) in THF cooled (0°C) and add NaH (70 mg, 50% dispersion in mineral oil, about 1.75 mmol). The resulting mixture is stirred for 5 minutes. Remove the cold bath and continue to stir for another 1 hour. To this mixture is added methyl ether 3-(methyl bromide)benzoic acid (450 mg, of 1.95 mmol). The resulting mixture is stirred for 3 hours and then the reaction mixture was quenched with saturated solution of NH4Cl. The mixture is diluted with ether, washed with brine, dried over MgSO4and concentrate under vacuum. The residue is purified fluorescence is W-chromatography (eluent 30% solution of ethyl acetate in heptane) to obtain the specified title compound (181 mg) as an oily substance.

Mass spectroscopy (ionization elektrorazpredelenie):m/z422 (M+H); 1H NMR (CDCl3) δ is 2.44 (s, 3H), 3,92 (s, 3H), 4,63 (s, 2H), 4,71 (s, 2H) 7,44 (t, J=8 Hz, 1H), 7,56 (d, J=8 Hz, 1H), 7,66 (DD, J=8 Hz, 2H)), 7,00 (m, 4H).

Example 16

The intermediate connection: hydrazide of 4-([3-methyl-2-(4-triptoreline)thiazol-5-yl)ethoxymethyl]benzoic acid

Repetition of example 8, but using the compound of example 15 as the starting material to obtain specified in the connection header.

Example 17

5-{3-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 16 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z448 (M+H); 1H NMR (DMSO) δ 2.40 a (s, 3H)and 4.65 (s, 2H), 4,79 (s, 2H) 7,53 (m, 2H), 7,72 (m, 1H), to 7.77 (s, 1H), 7,82 (d, J=8 Hz, 2H), 8,10 (d, J=8 Hz, 2H), 12.5cm (users, 1H).

Example 18

Intermediate compound: methyl ester of 4-butyl-2-(4-triptoreline)thiazole-5-carboxylic acid

To a solution of methyl ester 3-exogamous acid (5.0 g, of 31.6 mmol) in dry dichloromethane (80 ml) add sulfurylchloride (2,82 ml). The reaction mixture was stirred at room temperature in ECENA 30 minutes then add water (20 ml) and the reaction mixture is extracted five times with 30 ml dichloromethane. The combined organic fractions washed with water, saturated aqueous NaHCO3and with brine, and then dried over MgSO4. The solvent is removed under reduced pressure and obtain methyl ester of 2-chloro-3-exogamous acid (6.0 g), which use in the next stage without additional purification. To a solution of methyl ester of 2-chloro-3-exogamous acid (6.0 g, 31,1 mmol) in ethanol (50 ml) is added 4-(trifluoromethyl)thiobenzamide (6.4g, and 31.2 mmol). The reaction mixture is heated under reflux during the night. The solvent is removed under reduced pressure and the residue purified by chromatography on silica gel (eluent with a gradient of n-heptane:ethyl acetate (from 100:1 to 60:1)) to give the methyl ester of 4-butyl-2-(4-triptoreline)thiazole-5-carboxylic acid (7.4 g) as a yellow oily substance.

Mass spectroscopy (ionization elektrorazpredelenie):m/z344 (M+H).

Example 19

The intermediate connection: [4-butyl-2-(4-triptoreline)thiazol-5-yl]methanol

To a solution of lithium aluminum hydride (1.2 g) in dry tetrahydrofuran (100 ml) is added methyl ether 4-butyl-2-(4-triptoreline)thiazole-5-carboxylic acid (5.3g, to 15.4 mmol), dissolved in Tetra is hydrofuran (100 ml). The reaction mixture was stirred at room temperature for one hour. Add saturated aqueous solution of ammonium chloride (50 ml)and then 1-molar aqueous solution of hydrochloric acid (50 ml). The reaction mixture is extracted with five portions of 60 ml of ethyl acetate. Mixed residue is dried over MgSO4the solvent is removed under reduced pressure to obtain [4-butyl-2-(4-triptoreline)thiazol-5-yl]methanol (4.6 g) as a yellow oily substance, which hardens at room temperature.

Mass spectroscopy (ionization elektrorazpredelenie):m/z316 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, J=7.0 Hz, 3H), of 1.35 (m, 2H), 1,64 (m, 2H), 2,70 (m, 2H), 4,68 (osirm, 2H), 5,63 (osirm, 1H), 7,83 (userd, J=8.5 Hz, 2H), 8,09 (userd, J=8.5 Hz, 2H).

Example 20

Intermediate compound: 4-butyl-5-chloromethyl-2-(4-triptoreline)thiazole

To a solution of [4-butyl-2-(4-triptoreline)thiazol-5-yl]methanol (1.0 g, 3.1 mmol) in dichloromethane (50 ml), add triethylamine (0,88 ml) and methanesulfonamide (0,39 ml). The reaction mixture was stirred at room temperature for three hours, and then added dichloromethane (100 ml). The reaction mixture was washed with saturated aqueous NaHCO3(50 ml), water and salt solution. The organic layer is dried over MgSO4remove the solvent under reduced pressure and obtaining 4-butyl-5-chloromethyl-2-(4-triptoreline)thiazole (1.0 g) as a yellow oily substance.

Mass spectroscopy (ionization elektrorazpredelenie):m/z334 (M+H); 1H NMR (DMSO-d6) δ 0,92 (t,J=7.5 Hz, 3H), of 1.37 (m, 2H), by 1.68 (m, 2H), 2,80 (m, 2H), 5,14 (s, 2H), 7,86 (userd,J=8.5 Hz, 2H), 8,12 (userd,J=8.5 Hz, 2H).

Example 21

Intermediate compound: methyl ester of 4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorbenzoyl acid

To a cooled with ice to a solution of [4-butyl-2-(4-triptoreline)thiazol-5-yl]-methanol (1.0 g, 3,17 mmol), methyl ester 2-chloro-4-hydroxybenzoic acid (592 mg, 3,17 mmol) and triphenylphosphine (832 mg, 3,17 mmol) in dichloromethane add diethylazodicarboxylate (0,567 ml, 3,17 mmol). The reaction mixture is stirred for 2 hours, while allowing it to warm to room temperature. The solvent is removed under reduced pressure, the residue is purified flash chromatography on silica gel to obtain methyl ester 4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorbenzoyl acid (600 mg).

Mass spectroscopy (ionization elektrorazpredelenie):m/z484 (M+H).

Example 22

The intermediate connection: hydrazide 4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorbenzoyl acid

Repetition of example 8, but using the compound of example 21 as the starting material to obtain specified the CSOs in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z484 (M+H).

Example 23

5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorophenyl}-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 22 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z510 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, 3H), of 1.37 (m, 2H), by 1.68 (m, 2H), and 2.83 (t, 2H), 5,50 (s, 2H), 7,19 (DD, J=9 and 2.5 Hz, 1H), 7,40 (d, J=2.4 Hz, 1H), to 7.77 (d, J=8.6 Hz, 1H), 7,86 (d, J=8.0 Hz, 2H), 8,13 (d, J=8,3 Hz, 2H), 12,64 (users, 1H).

Example 24

Intermediate compound: methyl ester of 2-fluoro-4-methylbenzoic acid

To a solution of 2-fluoro-4-methylbenzoic acid (1.1 g, 7,13 mmol) in methanol (20 ml) is added thionyl chloride (1,02 g, 8,56 mmol). The resulting mixture is stirred overnight, then concentrated under vacuum to obtain specified in the title compound (1.2 g) as a white solid.

Mass spectroscopy (ionization elektrorazpredelenie):m/z169 (M+H); 1H NMR (DMSO-d6) δ is 2.37 (s, 3H), 3,83 (s, 3H), 7,12-7,21 (m, 2H), 7,79 (t, J=8.0 Hz, 1H).

Example 25

Intermediate compound: methyl ether 4-methyl bromide-2-fermenting acid

To a solution of methyl ester 2-fluoro-4-methylben oinoi acid (1.12 g, of 6.66 mmol) in carbon tetrachloride (12 ml) is added N-bromosuccinimide (1.18 g, of 6.66 mmol) and benzoyl peroxide (10 mg). The resulting mixture was heated to 60°C for 15 hours, then concentrated under vacuum to half and filtered. The filtrate is concentrated under vacuum and the crude product was then purified flash chromatography on silica gel (eluent a mixture of heptane/ethyl acetate in the ratio of 5/1) to obtain the specified title compound (1.35 g) as a white solid.

Mass spectroscopy (ionization elektrorazpredelenie):m/z247 (M+H); 1H NMR (DMSO-d6) δ 3,85 (s, 3H), to 4.73 (s, 2H), 7,37-of 7.48 (m, 2H), 7,88 (t, J=8.0 Hz, 1H).

Example 26

Intermediate compound: methyl ester of 4-[4-butyl-2-(4-triptoreline)thiazole-5-ileocecal]-2-fermenting acid

To a solution of [4-butyl-2-(4-triptoreline)thiazol-5-yl]methanol (1,02 g, 3,24 mmol) in anhydrous DMF (150 ml) is added cesium carbonate (2.7 g, 8,10 mmol) and 4-methyl ether methyl bromide-2-fermenting acid (0.8 g, 3,24 mmol). The resulting mixture is stirred overnight, then poured into 1 M aqueous solution of discalificata and extracted three times in the presence of diisopropyl ether. Combined fractions washed with water, dried over MgSO4, filtered and concentrated under vacuum. The residue is purified flash chromatography on silica the Le (eluent with a gradient solution of heptane/ethyl acetate) to obtain the specified title compound (0.3 g) as an orange solid.

Mass spectroscopy (ionization elektrorazpredelenie): m/z 482 (M+H); 1H NMR (DMSO-d6) δ of 0.89 (t, J=7.5 Hz, 3H), of 1.33 (m, 2H), 1,65 (m, 2H), 2,72 (m, 2H), 3,86 (s, 3H), of 4.67 (s, 2H), 4,80 (s, 2H), 7,28-7,34 (m, 2H), 7,86 (userd, J=8.5 Hz, 2H,), of 7.90 (t, J=8.0 Hz, 1H), 8,11 (userd, J=8.5 Hz, 2H).

Example 27

The intermediate connection: hydrazide 4-[4-butyl-2-(4-triptoreline)thiazole-5-ileocecal]-2-fermenting acid

Repetition of example 8, but using the compound of example 26 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z482 (M+H); 1H NMR (DMSO-d6) δ of 0.90 (t, J=7.5 Hz, 3H), of 1.33 (m, 2H), 1,65 (m, 2H), 2,72 (m, 2H), 4.53-in (users, 2H), to 4.62 (s, 2H), 4,79 (s, 2H), 7,20-7,29 (m, 2H), EUR 7.57 (users, J=8.0 Hz, 1H), 7,84 (users, J=8.5 Hz, 2H,), 8,12 (userd, J=8.5 Hz, 2H), 9,51 (m, 1H).

Example 28

5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ileocecal]-2-forfinal}-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 27 as a starting substance to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z508 (M+H); 1H NMR (DMSO-d6) δ of 0.89 (t, J=7.5 Hz, 3H), of 1.33 (m, 2H), 1,65 (m, 2H), by 2.73 (m, 2H), and 4.68 (s, 2H), to 4.81 (s, 2H), 7,33-7,40 m, 2H), 7,80 (t, J=8.0 Hz, 1H), 7,85 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H), 12,70 (osirm, 1H).

Example 29

Intermediate compound: methyl ester {4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}acetic acid

To a solution of 4-butyl-5-chloromethyl-2-(4-triptoreline)thiazole (278 mg, 0.83 mmol) in anhydrous DMF (5 ml) is added cesium carbonate (297 mg, of 1.66 mmol) and methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol). The resulting mixture is stirred overnight, then poured into water and extracted twice with ethyl acetate. Combined fractions washed with water, dried over MgSO4, filtered and concentrated under vacuum to obtain specified in the title compound (290 mg) as a yellowish solid.

Mass spectroscopy (ionization elektrorazpredelenie):m/z508 (M+H); 1H NMR (DMSO-d6) δ of 0.90 (t, J=7.5 Hz, 3H), of 1.36 (m, 2H), 1,67 (m, 2H), 2,80 (m, 2H), 3,60 (s, 3H), 3,61 (s, 2H), 5,33 (s, 2H), 7,00 (users, J=8.5 Hz, 2H), 7,21 (userd, J=8.5 Hz, 2H), 7,84 (userd, J=8,5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H).

Example 30

The intermediate connection: hydrazide {4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}acetic acid

Repetition of example 8, but using the compound of example 29 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z464 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, J=7.5 Hz, 3H), of 1.36 (m, 2H), 1,67 (m, 2H, 2,80 (m, 2H), or 3.28 (s, 2H), 4,17 (userd, J=4.0 Hz, 2H), 5,32 (s, 2H), 6,97 (userd, J=8.5 Hz, 2H), 7,19 (userd, J=8.5 Hz, 2H), 7,84 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H), 9,13 (ushort, J=4.0 Hz, 1H).

Example 31

5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzyl}-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 30 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z490 (M+H); 1H NMR (DMSO-d6) δ of 0.90 (t, J=7.5 Hz, 3H), of 1.36 (m, 2H), by 1.68 (m, 2H), 2,80 (m, 2H), a 3.87 (s, 2H), 5,33 (s, 2H), 7,03 (userd, J=8.5 Hz, 2H), 7,24 (userd, J=8.5 Hz, 2H), 7,85 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H), 11,7-12,4 (osirm, 1H).

Example 32

Intermediate compound: methyl ester of 3-{3-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}propionic acid

To a solution of 4-butyl-5-chloromethyl-2-(4-triptoreline)thiazole (300 mg, 0.90 mmol) in anhydrous DMF (5 ml) is added cesium carbonate (586 mg, of 1.80 mmol) and methyl 3-(3-hydroxyphenyl)propionate (178 mg, 0,99 mmol). The resulting mixture is stirred overnight, then poured into water and extracted twice with ethyl acetate. Combined fractions washed with water, dried over MgSO4, filtered and concentrated under vacuum. The residue is purified flash chromatography on silica compound is barely (eluent 5% solution of ethyl acetate in heptane) to obtain the specified title compound (290 mg) as a yellow oily substance.

Mass spectroscopy (ionization elektrorazpredelenie):m/z478 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, J=7.5 Hz, 3H), of 1.37 (m, 2H), by 1.68 (m, 2H), 2,64 (m, 2H), was 2.76-is 2.88 (m, 4H), to 3.58 (s, 3H), 5,33 (s, 2H), 6,82-6,91 (m, 2H), 6,93 (users, 1H), 7,22 (t, J=8.0 Hz, 1H), 7,85 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H).

Example 33

The intermediate connection: hydrazide 3-{3-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}propionic acid

Repetition of example 8, but using the compound of example 32 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie):m/z478 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, J=7.5 Hz, 3H), of 1.36 (m, 2H), by 1.68 (m, 2H), 2,33 (m, 2H), 2,80 (m, 4H), 4,14 (userd, J=4.0 Hz, 2H), 5,32 (s, 2H), 6,79-6,92 (m, 3H), 7,21 (t, J=7.5 Hz, 1H), 7,85 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H), 8,94 (osirm 1H),

Example 34

5-(2-{3-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}ethyl)-3H-[1,3,4]oxadiazol-2-he

Repetition of example 10, but using the compound of example 33 as the starting material to obtain specified in the connection header.

Mass spectroscopy (ionization elektrorazpredelenie): m/z 504 (M+H); 1H NMR (DMSO-d6) δ of 0.91 (t, J=7.5 Hz, 3H), of 1.36 (m, 2H), 1,67 (m, 2H), 2,80 (m, 2H), 2,88 (m, 4H), 5,33 (s, 2H), 6,83-6,93 (m, 2H), 6,97 (users, 1H), 7.23 percent (t, J=8.0 Hz, 1H), 7,85 (userd, J=8.5 Hz, 2H), 8,12 (userd, J=8.5 Hz, 2H), 11,5-1,5 (osirm, 1H).

1. Derivatives of 1,3,4-oxadiazol-2-it formula I:

where ARYL represents phenyl which may have one Deputy,
selected from halogen;
W is a bond or (CH2)mwhere m denotes an integer from 1 to 4;
Z represents-O(CH2)n-, -(CH2)n-Y-(CH2)n-where Y denotes O, n independently denotes an integer from 1 to 5;
X represents O or S;
R1represents a C1-6alkyl;
R2represents a substituted phenyl where the substituents are selected from the group including C1-6alkyl, C1-4perfluoroalkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which ARYL is phenyl.

3. The compound according to claim 1, in which X represents O.

4. Connection by claim 11, in which X is S.

5. The compound according to claim 1, selected from the group consisting of:
5-{4-[4-methyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}-3H-[1,3,4]oxadiazol-2-it,
5-[4-(4-methyl-2-m-tolyloxy-5-ylethoxy)phenyl]-ZN-[1,3,4]oxadiazol-2-it,
5-{4-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-it,
5-{3-[4-methyl-2-(4-triptoreline)thiazol-5-yl)methoxymethyl]phenyl}-3H-[1,3,4]oxadiazol-2-it,
5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]-2-chlorophenyl}-3H-[1,3,4]oxadiazol-2-it,
5-{4-[4-b the Teal-2-(4-triptoreline)thiazole-5-ileocecal]-2-forfinal}-3H-[1,3,4]oxadiazol-2-it,
5-{4-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]benzyl}-3H-[1,3,4]oxadiazol-2-he
5-(2-{3-[4-butyl-2-(4-triptoreline)thiazole-5-ylethoxy]phenyl}ethyl)-3H-[1,3,4]oxadiazol-2-it.

6. Pharmaceutical composition having agonistic or antagonistic activity against PPAR-Delta receptor containing an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

7. A method of treating disease in a mammal in which the disease can be modulated by the binding activity of PPAR-Delta ligands, by introducing to a mammal suffering from the disease, a therapeutically effective amount of a compound according to claim 1.

8. The method according to claim 7, in which the disease is demyelinizing disease.

9. The method according to claim 8, in which demyelinization disease is multiple sclerosis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula: I where R1 represents hydrogen or C1-7-alkyl; R2 and R3 independently represent hydrogen; R4 and R5 independently represent hydrogen; R6, R7, R8 and R9 independently represent hydrogen, C1-7-alkyl; and one of R6, R7 and R8 represents where R10 represents hydrogen, C1-7-alkyl; R11 represents hydrogen, C1-7-alkyl; one of R12 or R13 represents hydrogen, C1-7-alkyl or fluorine-C1-7-alkyl; and the other represents undivided electron pair; R14 represents hydrogen, C1-7-alkyl, halogen; R15 represents aryl or aryl substituted with 1-3 groups chosen from C1-7-alkyl C1-7-alkoxy, halogen, fluorine-C1-7-alkyl and fluorine-C1-7-alkoxy; and n has a value 1, 2 or 3; and to all their enantiomers and to pharmaceutically acceptable salts and/or esters. The invention also concerns the pharmaceutical compositions.

EFFECT: production of new biologically active compounds with agonist activity with respect to PPARδ and PPARα.

20 cl, 25 ex, 1 tbl

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