1,3,4-oxadiazol-2-ons as ppar-delta modulators, based on them pharmaceutical compositions and method of treatment

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

 

The scope of the invention

This invention relates to new compounds and pharmaceutical compositions that act as selective binding agents are ligands of PPAR-Delta receptors, which can be used to modulate PPAR-Delta receptors in the treatment of diseases mediated by nuclear hormone receptors. Binding agents are ligands of PPAR-Delta receptors presented in this invention can be used 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. Were discovered and cloned four related isoforms, which are known as PPAR-alpha, PPAR-gamma-1, R-gamma-2 and PPAR-Delta. Each receptor subtype has a characteristic DNA-binding domain (DBD) and legendbase.ui 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 is to be used for the treatment of such diseases, as dyslipidemia, and some dermatological diseases and antagonists for the treatment of osteoporosis and colorectal cancer (D. Sternbach, inAnnual 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 the hour is about and 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'sNeuropathology, 6.sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow, eds.,The Merck Manual of Diagnosisand Therapy, 17.sup.th ed. (Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1299, 1437, 1473-76, 1483).

Central demyelination (demyelination of the CNS) occurs in some diseases, often of uncertain etiology, which has received the name of demyelinating diseases. Among them the most common is multiple sclerosis (MS). Other primary demyelination diseases are adrenoleukodystrophy (ALD), adrenomyeloneuropathy, using HIV myelopathy myelopathy associated with T-lymphotropic virus human family liberovskaya optic nerve atrophy, 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 the cat the rum acute transection of the spinal cord of unknown origin damages as gray, and white matter of the brain 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.

Selective modulators of PPAR-Delta can be also suitable for the treatment or prevention of other diseases, see, for example, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239-63; Jean-Charles Fruchart, Bart 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-actived 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 2 diabetes, including the prevention of associated impacts. Private aspects are hyperglycemia, decrease insulin resistance, increased glucose tolerance, protection of beta-cells of the pancreas, prevent the of macro - and microvascular disorders.

Dyslipidemia and their complications, such as, for example, atherosclerosis, coronary heart disease, cerebral circulation, especially (among others) characterized by one or more of the following factors: high concentrations of plasma triglycerides, occurring after a meal, the lower the concentration of cholesterol alpha-high density lipoprotein, low concentrations of lipoprotein ApoA elevated concentrations of cholesterol alpha-low-density lipoprotein, small dense particles of 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, vessel is a simple restenosis or reocclusion, chronic inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, pancreatitis, other inflammatory conditions, retinopathy, tumors of lipocytes, lipomatosis carcinomas, such as liposarcoma, solid tumor 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 and other acute and chronic myeloproliferative disorders and angiogenesis of cancer, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, erythemato-squamous dermatoses such as, for example, psoriasis, common acne.

Other skin disorders and dermatological conditions, modulating PPAR-Delta: eczema and neurodermatitis, dermatitis, such as, for example, seborrheic eczema or photodermatitis, keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, 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), diseases such as, for example, sexually transmitted papilloma, viral warts such as, for example, contagious mo is luck, 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 is optionally substituted by one or more substituents selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

Z represents- (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 represents NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl,1-6alkyls3-8cycloalkyl or benzyl, and n is 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; hydraxis1-6alkyl, 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,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

provided that when Z represents- (CH2)n- or-SO2(CH2)n-, and ARYL represents phenyl, R2is not phenyl;

or its stereoisomer, tautomer, or MES, or its pharmaceutically acceptable salt.

The present invention also Rel is belongs to pharmaceutical compositions and methods of using these compounds and compositions for the modulation of PPAR-Delta in patients those in need of such modulation, by introducing compounds, preferably modulating the activity of PPAR-Delta.

Another aspect of the present invention discloses a method of treating disease in a mammal, where 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 the compounds of formula I

where

ARYL represents phenyl or pyridinyl, where the specified phenyl or pyridinyl is optionally substituted by one or more substituents selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

Z represents- (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 represents NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl,1-6alkyls3-8cycloalkyl or benzyl, and n represents independently researched the Simo integer from 1 to 5;

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

R1represents H, halogen, C1-6alkyl, C1-6alkoxy, C1-6perfluoroalkyl; hydraxis1-6alkyl, 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,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl; or its stereoisomer, tautomer or MES, or its pharmaceutically acceptable salt.

Detailed description of the invention

Used in this application, 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-propyl, isopropyl and tert-butyl. Derivatives of these symbols, such as "C1-6alkoxy", "C1-6alkoxyl1-6alkyl, hydroxys1-6alkyl", "C1-6alkylaryl", "C1-6alkoxycarbonyl1-6alkyl", "C1-6alkoxycarbonyl", "amino 1-6alkyl", "C1-6alkylcarboxylic1-6alkyl", "C1-6diallylbarbituric1-6alkyl", "mono - or di-C1-6alkylamino1-6alkyl, amino1-6alkylaryl", "diphenyls1-6alkyl, aryls1-6alkyl, arylcarbamoyl1-6alkyl and aryloxy1-6alkyl"should be interpreted accordingly.

The expression "C2-6alkenyl includes atenilol, and linear or branched propenyloxy, butenyloxy, pantanillo and hexenyl group. Similarly, the expression "C2-6quinil includes etinilnoy and propanolol, as well as linear and branched butenyloxy, Punchinello and hexylamino group.

The term "C1-4acyloxy" denotes the acyl radical attached to the oxygen atom, some examples include, but are not limited to, atomic charges, propionyloxy, butanoyloxy, isobutoxy, sec-butanoyloxy, tert-butanoyloxy and the like.

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 HYDR is generowania derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphtho and the like.

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

The term "heteroaryl" (by itself or as part of any value, for example, "heteroaromatic" or "heteroaromatic") represents a 5-10 membered aromatic 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, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, hintline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole or benzimidazole.

The term "heterocyclic or heterocyclyl" (by itself or as part of any other values, 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, nonafterburning the traveler, undecafluoropentyl and tridecafluorohexyl group. The derived expression "1-6perforamce" should be interpreted accordingly.

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

The expression "C3-8cycloalkyl1-6alkyl" means that3-8cycloalkyl defined in this application, attached to C1-6the alkyl, as defined in this description. Typical examples are cyclopropylmethyl, 1-cyclobutylmethyl, 2-cyclopentylpropionyl, cyclohexylmethyl, 2-cyclohexylethyl and 2-cyclooctylmethyl and the like.

The term "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

The term "C1-6alkylsulfonyl" in this context refers to the group-S(=O)2C1-6alkyl, where C1-6alkyl is defined above. Typical examples include, but are 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.

The term "heteroarylboronic" gr denotes the PPU-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. They usually include mirror isomers, which usually exist in the presence of at least one center of asymmetry (enantiomers). If the compounds of the present 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, independently selected from the group comprising From1-6alkyl, C1-6perfluoroalkyl, hydroxy, -CO2N, ester, amide, With1-6alkoxy, C1-6perforamce, -NH2, Cl, Br, I, F, -NH-lower alkyl and-N(lower alkyl)2.

Compounds and salts of the present invention can exist in several 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 included in the scope of this image is to be placed. 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, the present invention includes all tautomers of the presented compounds.

In this application, the term "modulator" refers to a chemical compound, having the ability to enhance (i.e. with "agonist" activity) or suppress (i.e. with "antagonistic" effect) any functional property of biological activity or process (e.g., 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, for example, rats, mice, dogs, cats, Guinea pigs and primates, like humans.

The expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersing agent, excipient, subsidiary or other substance that is mixed with the compound of the present invention for the formation of a pharmaceutical composition, i.e. the dosage form, which can enter the TB 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 obtaining compounds in accordance with the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid additive salts, which can be obtained, for example, by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate 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, coal KIS the PTA or phosphoric acid. Can also be obtained 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 group, appropriate their pharmaceutically acceptable salts may include alkali metal salts, for example sodium or potassium, salts of alkaline earth metals such as calcium salt or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts.

The term "therapeutically effective amount", as used in this application means the amount of compound that is effective for treating the disease or condition.

In the present invention are also pharmaceutical compositions containing one or more compounds of the present invention and a pharmaceutically acceptable carrier. Preferably such compositions are presented in standard dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid spray solutions, drops, ampoules, autoinjector give the TBA or suppositories, intended for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation. Alternatively, these compositions may be presented in a form suitable for use once a week or once a month; for example, an insoluble salt of the active compounds, such as decanoate salt, can be adapted for the preparation of depot preparation for intramuscular injection. You can use the collapsing of the polymer containing the active ingredient. For preparing solid compositions 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 preliminary composition containing a homogeneous mixture of the compounds of this invention or its pharmaceutically acceptable salt. When such prior structures are called homogeneous, it is meant that the active ingredient is mixed evenly throughout the composition, and the composition can be divided into with equal efficiency standard dosage forms, such as tablets is etki, pills and capsules. Then this solid preliminary list divided into standard dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Flavored dosage forms contain from 1 to 100 mg, for example, 1, 2, 5, 10, 25, 50 or 100 mg of active ingredient. The tablets or pills of these new compounds may 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 components 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 compositions of the present invention can be administered orally or by injection include aqueous solutions, syrups with a suitable flavoring, aqueous or oil suspensions and aromatizers is installed emulsions with edible oil, such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume substances for water suspensions include synthetic and natural resins, such as tragakant, gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of various pathological conditions described in this application, a suitable dose is from about 0.01 to 250 mg/kg / day, preferably from about 0.05 to 100 mg/kg / day, and especially from about 0.05 to 20 mg/kg / day. The compounds may be introduced by the scheme 1-4 times a day.

In the examples below, and get 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 Hg" refers to millimeters of mercury article the forehead, "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, "NMP" refers to 1-methyl-2-pyrrolidinone, "a saturated solution of salt" 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 the concentration in nanomolar, "TLC" means thin layer chromatography, "HPLC" means high performance liquid chromatography, "HRMS" refers mass spectrometry high resolution, "CIMS" means of mass spectrometry with chemical ionization, ESI" means of mass spectrometry with ionization by elektrorazpredelenie, tR" means retention time, "CFT" means pounds, "Gal." means gallons, "PPV" refers to loss on drying, "µci" means microcurie, "/b" means intraperitoneally, "/" means intravenously.

In one aspect of the present invention describes new compounds of the General structure represented by the formula I:

where

ARYL represents phenyl or pyridinyl, where the specified phenyl or pyridinyl is optionally substituted one and the multiple substituents, selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

Z represents- (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 represents NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl,1-6alkyls3-8cycloalkyl or benzyl, and n is 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; hydraxis1-6alkyl, 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,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkyl is Mino and C 1-6alkoxycarbonyl;

provided that when Z represents- (CH2)n- or-SO2(CH2)n- and ARYL represents phenyl, R2is not phenyl;

or stereoisomers, tautomers, or a solvate or pharmaceutically acceptable salt.

In one additional aspect of this embodiment of the invention described connection, in which ARYL represents phenyl and X represents O or S.

In another aspect of this implementation is described compound, in which X represents O.

Example of the compounds of this implementation is 5-(4-{2-[5-methyl-2-(4-triptoreline)thiazol-4-yl]ethoxy}phenyl)-3H-[1,3,4]oxadiazol-2-it.

In yet 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 aspect of the present invention is disclosed a method of treating disease in a mammal, where the disease can be modulated by the binding activity of PPAR-Delta ligands, which comprises the administration to a mammal suffering from the disease, a therapeutically effective amount of the compounds of formula I

where

ARYL represents phenyl or pyridinyl, where the specified phenyl or pyridi the sludge is optionally substituted by one or more substituents, selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkylamino and C1-6alkoxycarbonyl;

Z represents- (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 represents NR3, O or S, and R3selected from the group including H, C1-6alkyl, C3-8cycloalkyl,1-6alkyls3-8cycloalkyl or benzyl, and n is 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; hydraxis1-6alkyl, 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,1-6alkoxy, C1-6perfluoroalkyl; C1-6alkylthio, hydroxy, hydroxys1-6alkyl, C1-4acyloxy, nitro, cyano, C1-6alkylsulfonyl, amino, C1-6alkyl is Mino and C 1-6alkoxycarbonyl; or its stereoisomer, tautomer or MES, or its pharmaceutically acceptable salt.

In one of the following aspects of the implementation of the method of the invention described connection, in which ARYL represents phenyl.

In another aspect of this implementation of the method of the invention described connection, in which ARYL represents phenyl and R2represents phenyl.

In another aspect of this implementation of the method of the invention described connection, in which ARYL represents phenyl, Z represents

- (CH2)nand R2represents phenyl.

In another aspect of this implementation of the method of the invention described connection, in which ARYL represents phenyl, Z represents

- (CH2)n-, X represents O or S and R2represents phenyl.

In another aspect of this implementation of the method of the invention described connection, in which ARYL represents phenyl, Z represents- (CH2)n-, X represents O or S, R1represents a C1-6alkyl, and R2represents phenyl.

In one of the additional aspects of the implementation of the method of the invention described compound, in which X represents O.

In another aspect of the present from which retene, this method of the invention described compound, in which X represents S.

In one of the following aspects of the implementation of the described method, where the named disease is demyelinizing disease selected from the group comprising multiple sclerosis, a disease 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 described method, where demyelinizing disease is multiple sclerosis.

In another aspect of the present invention described method, where the disease is selected 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 or congestive heart failure.

Described here is soedineniya can be synthesized in accordance with the following methods according to the diagrams where the ARYL substituents, X, Z and R are as defined for formula (I) above, unless otherwise indicated. 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 un Organic Synthesis, Wiley and Sons, 1991.

On the diagram And shows the synthesis of the corresponding imidazole, oxazole or thiazole intermediates for compounds of formula I, where X represents O, S or NR3. Heterocyclic compounds can be obtained using methods known from the chemical literature (reviews, see Katritzky, A.R.; Rees, C.W., Eds.Comprehensive Heterocyclic ChemistryVol. 5; Pergamon Press (1984); Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Eds.Comprehensive Heterocyclic Chemistry II; Vols 3 & 4, Pergamon Press (1996)). In particular, these oksazolov, imidazoles and thiazole can be obtained by condensation of a suitable α-halogenation1accordingly, with amidon, amidino or thioamide (General formula 2), at a temperature of from about 40 to 150°C To produce intermediate heterocycles3.

Scheme And

A diagram illustrates the General synthesis of compounds of formula I, where Z represents- (CH2)n-. Accordingly, at stage B1, the corresponding substituted ester of carboxylic acid4that can be synthesized as shown in scheme A, to restore alcohol5ways, well known in this field. 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 compound5is converted into a leaving group and formation of compound6where Lg is a leaving group such as halogen or an ester of sulfonic acids, for example mesilate or toilet. Conversion to a leaving group can be done through the interaction of alcohol with such reagents as N-bromosuccinimide, in the presence of triphenylphosphine with the formation of compounds in which the leaving group is a chloride, or by reacting with thionyl chloride to obtain compounds in which the leaving group is a chloride. If you want an ester of sulfonic acids, can be obtained by reacting compounds5with the appropriate sulphonylchloride in the presence of a suitable base. For example, the interaction of the connection5since methane is sulfonylurea in the presence of an organic base, such as triethylamine or pyridine, in an inert solvent leads to the connection6where the leaving group is OSO2CH3.

On stage B3 corresponding substituted hydroxyarylalkyl ester7interacts with the heterocycle6replacing a leaving group, with formation of ester linked8. The substitution reaction is conducted under conditions well known in the art. Typically, this reaction is carried out 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 connection8on stage B4 is treated with hydrazine, either pure or in a suitable organic solvent at an elevated temperature with the formation of the hydrazide acid9. Typically, this reaction is carried out at a temperature from 50°C to a temperature of phlegmy organic solvent.

The cyclization of a hydrazide acid9on stage B5 to target 1,3,4-oxadiazol-2-ones10performed by processing the connection9chloroformate in the presence of organic bases such as pyridine, followed by treatment of the strong base with steric the ski 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 sealed flask at elevated temperatures. Typically, the reaction is carried out at a temperature of from 100 to 200°C. 1,3,4-Oxadiazol-2-ones can also be synthesized by reacting compound9with phosgene. Cm. Stempel, A., et al.,J. Org. Chem. 1995, 20, 412.

On stage B6 is an alternative synthesis of ester linked8. Accordingly, alcohol5can interact with hydroxyarylalkyl complex air8in 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 linked8. Typically, this reaction is carried out at a temperature of from room temperature to the temperature of phlegmy inert solvent.

Scheme

The scheme 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 ARIL, is 1 or 2. At the stage S1 connection5(Y = O) is converted into compound6(in which Lg represents a chlorine or bromine), as described in the diagram In stage B2. Then the connection6 interacts with thiourea, connection11in conditions similar to those described in Treau, M. et al.Heterocycles, 2001, 55 (9), 1727-1735, with the formation of thiol5A.

When communicating connection6with the primary amine12formed aminoalkyl a heterocycle5b. Such substitution of the leaving group of the amine is well known to specialists in this field. As a rule, the substitution reaction is carried out in a polar organic solvent in the presence of an organic base, which is used to neutralize 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.

On stage C3 connection5,5Aand5bcan interact with the connection13with the formation associated kilowog of ester14in which Y represents O, S or NR3. Thus, the interaction of compounds5(Y = O) and5A(Y = S) with the connection13for substitution of the leaving group, such interaction is usually 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 to 150°C. If the connection5b(Y = NR3) interacts with the connection14use conditions identical to those described above in stage C2 to the primary amine.

the Synthesis of the desired 1,3,4-oxadiazol-2-ones 16from the connection14carried out in two stages (C4 and C5) exactly as described in scheme B, stage B4 and B5.

Scheme

In scheme D illustrates 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 ARIL, is from 3 to 5.

On stage D1 connection with the terminal aldehyde17that can be synthesized by the method shown in the diagram And transform in the process of two stages in root acetylene19. Thus, the interaction of the connection17with bromotrinitromethanes (first stage) with potassium t-BuOK gives intermediate bromelein (not shown), which is then treated with two equivalents of t-BuOK (second stage) with the formation of acetylene19. This sequence of reactions converting 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. Alternatively, as shown at stage D2, the intermediate compounds of type19can be obtained by substitution of the leaving group from such intermediate connections, as the connection6(see diagram C) with the help of a nucleophile, such as the connection18that includes the terminal acetylene.

At stage D3 combination of Sonagas the market acetylene intermediate 19with urealyticum20carried out in the presence of tetranitroaniline(0), copper iodide(I) and a suitable organic base in an inert solvent with the formation of the associated terminal acetylene21. The recovery of acetylene21you can then perform on stage D4 catalytic hydrogenation of compounds21with the formation of a saturated ether complex14. 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 solvent with hydrogen at a pressure of from 30 to 300 pounds per square 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-ones16from the connection14carried out in two stages (D5 and D6) exactly as described in scheme B, stage B4 and B5.

Scheme D

Scheme E illustrates a special case of the synthesis of compounds of formula I, where Z represents -(CH2)nNR3(CH2)n-. In this approach, the linker Z design by reductive amination of the aldehyde with the amine. For example, at stage E1 process connection5b(where Y = NR3) aldehyde, such as methyl ether 4-formylbenzoate acid (n=1), the connection22in the polar solvent, usually alcohol or with whom thou alcohol and THF, followed by treatment with reducing agent, such as triacetoxyborohydride sodium, obtaining the desired intermediate compound14a(n=1).

Similarly, at the stage of E2 treatment of the aldehyde, for example connection17A, an amine, such as methyl ether 4-aminoalkylindoles acid (n=1), the connection23that leads to the connection14awhere n is 1, and R3in -(CH2)nNR3represents H. the Connection14astages of E3 and E4 is converted into 1,3,4-oxadiazol-2-ones16Aas shown in the diagram, 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 by catalytic hydrogenation, or of acetylamino and arisitide or bromides combination Sonogashira with subsequent catalytic hydrogenation as described for scheme D.

Scheme E

Scheme F illustrates the synthesis of compounds of formula I in which Z represents-SO2(CH2)n-. On stage F1 processing arylsulfonamides24aqueous sodium sulfite gives sulinowo acid25. Interaction connection25as shown in stage F2, with such intermediate connection, as the connection6in a polar solvent such as DMF, acetonitrile or ethanol, in the presence of base, t is anyone as DBU, pyridine, sodium methoxide or sodium hydroxide, gives the intermediate connection26. The intermediate connection26transform into the corresponding 1,3,4-oxadiazol-2-he28on stages F3 and F4, as shown in the diagram, stage B4 and B5.

Scheme F

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 heterocycle29can be synthesized from the corresponding carboxylic acid (obtained by 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 is usually performed by reacting acid hydrochloride N-methoxy-N-methylhydroxylamine in the presence of peptide reagent combinations, such as EDC, DCC, DMPU, and a tertiary amine base, such as diisopropylethylamine or triethylamine.

The compound obtained29bromilow with getting bracelona30as shown in G1 phase. Bromination can hold well-known methods, for example, the interaction connection29with pyridinium bromide in acetic acid or interaction of the compound 29with Br2in an inert organic solvent such as dichloromethane. The resulting Bratton30interacts on stage G2 with arylhydroxylamine7under the conditions described in the diagram In (stage B3) with the formation of ester linked31. Ketone group in connection31protect as Catala32as shown in stage G3, by methods known to experts in this field. Connection32then convert ketal 1,3,4-oxadiazol-2-it34stages of G4 and G5 in the standard sequence described in scheme V (B4 and B5). Finally, at the stage G6 catalog group in connection34split, for example, mineral acid in a mixture of THF-methanol-water or by other known methods, to obtain the desired connection35.

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 in the connection35is 2-5, if the original connection to use Bratton, the connection30with larger bromelicola Deputy (Br(CH2)nCO-, where n is 2-5.

Scheme G

Scheme H illustrates the process of producing compounds of the formula I in which Z represents -(CH2)nWITH-. At the stage of H1 corresponding methoxycarbonylmethyl a heterocycle3637. On stage N2 processing connection37base, such as sodium hydride, in an inert solvent at a temperature from -10°C to room with subsequent alkylation of the resulting anion with the electrophile, such as the connection13gives a branched intermediate ketotifen38. Decarboxylation shown in stage N3, can be carried out by treating compound38TFUK in an inert solvent, such as dichloromethane, followed by thermolysis at a temperature of from 70 to 150°C receives the intermediate ketoester39. Ketone group in connection39protect as Catala40as shown in stage N4, by methods well known in the art. Connection40then convert ketal 1,3,4-oxadiazol-2-it42stages of H5 and H6 in a standard sequence, as described in the diagram In (B4 and B5). Finally, at the stage H7 catalog group in connection42split, as described above in scheme G, step G6, obtaining the desired 1,3,4-oxadiazol-2-it, the connection43.

Scheme H

Biological examples

Following the protocols of tests used to confirm the biological properties of the compounds of the present invented who I am. The following examples are given to further illustrate the invention. However, they should not be understood as limiting in any way 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 transtitional cell line HEK (SOME 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-human PPAR delta-LBD), which regulates the expression of the reporter element luciferase depending on PPAR-Delta ligand. Stably and constitutively expressed protein GR-GAL4-human PPAR 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. There is 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 is intended to bind and activate protein PPAR-Delta and thus, stimulate the expression of the reporter gene luciferase. The resulting luciferase you can register using chemiluminescence with the participation of a suitable substrate.

Construction of reporter cell line PPAR-Delta

Obtaining a stable reporter cell line PPAR-Delta based on stable HEK-cell clone that stably transfirieran 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-human PPAR 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. Received, therefore, the slit design (GR-GAL4-human PPAR delta-LBD) was re-cloned into plasmid pcDNA3 (Invitrogen)to allow constitutive expression promoter of cytomegalovirus. This plasmid was linearized by restriction enzyme and stable transliterowany in the previously described cell clone containing an element of reporter luciferase is. Derived 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).

The procedure for conducting analysis and assessment

The activity of agonists of PPAR-Delta determine 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°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°C for 2 minutes, placed in 5 ml described DMEM and believe in the cytometer. After dilution to 500,000 cells/ml in each well in a volume of 180 μl were seeded 35000 cells in 96-cell tablets for micrometrology with a base of transparent plastic (#3610, Corning Costar). Tablets incubated Incubus the Torah to cell cultures at 37°C and 5% CO 2within 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 tested at 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, subjects substances 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 tablet 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 tablet. Analytical tablets incubated in the incubator at 37°C and 5% CO2 within 24 hours.

Alternatively, 20 μl of 10-fold the final concentration of the analyte added directly to 180 μl of cells in cells of the tablet. 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 tablet for micrometrology. After incubation at room temperature in the dark for 10 minutes tablets for micrometrology analyze in a luminometer (Trilux production Wallac). The measurement time of each cell tablet for micrometrology is 1 sec.

Assessment

The raw data luminometer transferred into a Microsoft Excel file. Graphs of the effect of dose and values EC50PPAR-agonists calculated using 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. The compounds of formula I of this invention can function as agonists or antagonists. The following analysis to determine the 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 described previously with 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 of the partial agonist or antagonist.

Analysis of binding SPA PPAR-Delta-LBD

The original solutions

1 M Tris (pH 8.0 or pH 7,6)(Gene Mdicine 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 KCl25 ml
0,05 % Tween 200.5 ml
The water treated at the facility Millipore964,5
Check pH of 7.6

Binding buffer: (Every time to prepare fresh binding buffer).

Wash buffer50 ml
10 mm DTT5.5 ml

Preparation of reaction reagents for a single 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.

To prepare resbalon the e SPA-beads 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.

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

3H-GW2331 plus GST-PPAR-Delta-LBD (for one 96-cell tablet without dead volume) of 13.9 μm and 40 nm for 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 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 uterine tablet (2 control tablets)

Column # 1

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

Add 45 ál of DMSO in cell A-N.

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 and mix the solution.

Add 20 ál of DMSO in the wells-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 mix well,

then take 10 μl of the solution of the C 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 the fallopian 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 added to 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 analysis SPA

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

To seal the tablets before to count in the cytometer Microbeta (Wallac).

To calculate 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. The compounds of formula I of this invention can function as agonists or antagonists.

Cultures of the oligodendrocyte 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 the Pia mater of 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, 1× trace elements, 30 nm selenium, 1 μg/ml of putrescine, 0.1% of bovine serum albumin, 5 units/ml PenStrep, 10 μg/ml insulin) by adding the following growth factors: platelet-derived growth factor-AA (PDGF) and fibroblast growth factor-2 (FGF).

4. Place cells in a Cup, covered with PDL (poly-D-lysine), and incubated at 37°C With 6-7% CO2.

5. Components replaced every 48 hours, so that the cells remained in the original state is.

The passage of progenitor cells to increase the number of cells for screening analysis

1. When culture becomes confluentes, washed with physiological solution with PBS buffer, add trypsin and incubated 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 to keep them in the enriched condition for rapidly dividing progenitor cells.

5. Cells passedout 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, 24 hours after placing of progenitor cells in the tablets, they were moved in their 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 (CG4) rats, which maintain Auda in 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 cells on the cell 24-cell tablets 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 with 6 different concentrations (10 μm, 1 μm, 100 nm, 10 nm, 1 nm and 0.1 nm).

c. For each concentration of the compound evaluation performed 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 perform at 6 concentrations (10 μm, 1 μm, 100 nm, 10 nm, 1 nm and 0.1 nm).

c. For each concentration of the compound evaluation performed on three cells.

4. Cultivate treated cells for 7 days before they are used is by Finance 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 μg/ml portable substance, 30 nm triiodothyronine, 30 nm hydrocortisone, 20 nm progesterone, 10 nm Biotin, 1× trace elements 30 nm selenium, 60 μm putrescine, 0.1% of bovine serum albumin, 5 units/ml PenStrep, 25 μg/ml insulin, with the addition of PDGF and FGF.

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

3. The cells were placed in cups with PDL-coated at a density 50000-100000 cells to a 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.

Processing the connection of human culture

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

2. Evaluation of dose-response connections are performed with 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 evaluation performed on three cells.

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

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

P the following processing connection use oligodendrocytes antibodies to assess the ability of compounds to accelerate or promote the differentiation of oligodendrocytes (for example, immunoreactivity O4, O1 or myelin basic protein shortly after processing the connection is between treated and untreated cultures).

1. Cells are placed on the treated poly-D-lysine 4-cell chamber tablets at a density of 5×103up to 20×103cell to cell and grown as described above. Subsequent staining 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) use the staining of living cells for 30 minutes at 37°C.

3. The cells are then fixed with 4% paraformaldehyde for 10 minutes at room temperature.

4. The procedure for staining fixed cells are 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 4°C.

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

In order to ensure that the connection does not promote 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 visual is tion of immunoreactivity of BDU performed using DAB (diaminobenzidine) and estimate the 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 oligodendrocytes 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 the 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 Axio Vision with a cooled CCD camera the 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 (differentiated) cells relative to the total number of cells (nuclei stained 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).

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 quantify, using Sybr Green PCR Master Mix.

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

5. Quantitative PCR is carried out with the use of technology 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

In 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 (50 mm Tris, pH 7.4, MgCl22 mm, 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 4°C 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. Incubi the Ute cell shaking her at 500-700 rpm on a rotating microplate shaker for 1 hour at room temperature.

8. Washed 5 times the cell proryvnym solution. Get wet 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 cell.

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

12. Washed 5 times the cell proryvnym solution. Get wet the tablet dry, turning it on absorbent material.

13. Add 100 ál of the TMB Chromogen solution to each well.

14. Incubate the cell, shaking it at 500-700 rpm on a rotating microplate shaker for 10-20 minutes at room temperature. Do not allow 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.

Model validation the concept of "in vivo"

Local damage: (used to assess the ability of the 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) against

of 1.8:1. Before surgery, rats introducing/b 0.15 ml/180 g body weight anesthetic solution. Animals prepare for surgery under aseptic conditions in accordance with the guidelines of the IACUC. All surgical instruments autoclave. The hair between the ears shear off, and this region is cleaned with a solution Betadine, 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 set 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 on pre-shaved skin covering the skull between the ears.

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

6. Bone is removed and the rat Inuktitut 2 μl of ethidiumbromid, lysolecithin or SIN-1 in the right-ka is a distant 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 left in this position for 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 her return to the cage. We cannot allow in the cell there were more than two rats, as they may damage each other seams.

11. A similar procedure is performed and mice.

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

Experimental allergic encephalomyelitis (EAE) is an animal 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 components (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 auto is monnow 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 the methods used 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 In 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(approximately 720 animals):

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

2. Add 5 g of the spinal cord B5 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 complete adjuvant's adjuvant N Ra, supplemented with 200 mg TB bacilli (20 mg/ml complete adjuvant's adjuvant N Ra).

5. To extract the homogenate/adjuvant test-tube, sucking it in 10-ml syringe with emulsifying needle 18 size.

6. Emulsify between the two 30 ml glass syringes until the difficulties of the selection of the material through the needle. (About 5 minutes {there should be no separation 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 induce a 5% isoflurane (Aerrane, Fort Dodge), 30% O270% of 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 who eraut of 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: NORM

STAGE: 1 Pathological behavior and atony of the tail

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

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

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

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

STAGE: 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 a drug 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 invented the e further illustrated by the following examples 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 MHz) or Varian Unity Inova (400 MHz), as indicated in the text. Proton chemical shifts are given in δ ppm relative to internal standard tetramethylsilane (0,0 ppm). The data of mass spectrometry (LC/MS) were 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 (LC/MS) performed on a column of Hypersil C18 (of 4.6×50 mm, 3.5 µm) with a mobile phase of 0.1% TFUK in H2O (A) and 0.1% TFUK in ACN (B), and gradient from 5 to 100% B over 3 minutes, then 2 minutes at 100% B. alternatively, you can use Platform 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 H2O and 0.1% formic acid in ACN (B). Purification HPLC performed on the system Varian ProStar, using a column for reversed-phase chromate is graphy C18 with a linear gradient of ACN/H 2O containing 0.1% triperoxonane acid. Microwave synthesis was performed using microwave system Personal Chemistry Smithcreator with two reactors with a volume of 2 or 5 ml

Example 1

Intermediate compound: ethyl ester of [5-methyl-2-(4-triptoreline)thiazol-4-yl]acetic acid

To a solution of 4-triftoratsetofenona (1,845 g, 9 mmol) in ethanol (15 ml, 200%) are added ethyl-4-bromo-3-oxopentanoate (2,07 g, 9 mmol). The solution tightly closed and heated to 170°C in a microwave oven Personal Chemistry™ and stirred at this temperature for 20 minutes the resulting solution is cooled to room temperature, concentrated under reduced pressure and purified flash chromatography (elwira a mixture of 30% ethyl acetate/10% dichloromethane in heptane) to obtain the specified title compound as a white solid (1.4 g).

MS (ESI)m/z330 (M+H);1H-NMR (CDCl3) δ 1,87 (Sirs, 1H), 2.49 USD (s, 3H), a 4.86 (s, 2H), to 7.67 (d, J=8gts, 2H), 8,02 (d, J=8gts, 2H).

Example 2

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

Cooled (0°C) solution of lithium aluminum hydride (5,3 ml, 1 M in THF) and add a solution of ethyl ester [5-methyl-2-(4-triptoreline)thiazol-4-yl]acetic acid (example 1, 1.4 g of 4.25 mmol) in THF (15 ml). After adding daring is t cold bath and stirred for 2 hours. The solution is cooled to 5°C and then added dropwise water (0.2 ml), then add a solution of NaOH (0.2 ml, 5 M in water) and water (0.2 ml). The resulting mixture was diluted with ethyl acetate and then filtered through a layer of celite. The solids washed with dichloromethane and then concentrate the mixture of the filtrate under reduced pressure. The residue is purified flash chromatography (elwira a mixture of 30% ethyl acetate and 40% dichloromethane in heptane) to obtain the specified title compound as a yellow solid (0,879 g). As the source material using the compound of example 1 to obtain specified in the connection header.

MS (ESI)m/z288 (M+H);1H-NMR (CDCl3) δ is 2.44 (s, 3H), only 2.91 (t, J=Hz, 2H), 3,62 (t, J=Hz, 1H), 4,01 (dt, J=7, Hz, 2H), 7,66 (d, J=8gts, 2H), of 7.96 (d, J=8gts, 2H).

Example 3

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

To a solution of 4-(2-hydroxyethyl)-5-methyl-2-(4-triptoreline)thiazole (example 3, 288 mg, 1.0 mmol) in THF (3 ml) is added methyl ester of 4-hydroxybenzoic acid (167 mg, 1.1 mmol) and then triphenylphosphine (288 mg, 1.1 mmol). To the resulting solution was added dropwise diethylazodicarboxylate (174 μl, 1.1 mmol). After adding the obtained red solution is stirred for 20 minutes. The resulting mixture was concentrated p and reduced pressure and the residue purified flash chromatography (elwira a mixture of 15% ethyl acetate/15% dichloromethane in heptane) to obtain the specified title compound as a white solid (410 mg).

MS (ESI)m/z422 (M+H);1H-NMR (DMSO) δ of 2.51 (s, 3H), 3,19 (t, J=Hz, 2H), 3,80 (s, 3H), and 4.40 (t, J=Hz, 2H), 7,05 (d, J=Hz, 2H), 7,83 (d, J=8gts, 2H), 7,88 (d, J=8gts, 2H) with 8.05 (d, J=8gts, 2H).

Example 4

The intermediate connection: hydrazide 4-{2-[5-methyl-2-(4-triptoreline)thiazol-4-yl]ethoxy}benzoic acid

To a suspension of methyl ester 4-[5-methyl-2-(4-triptoreline)thiazole-4-ylethoxy]benzoic acid (example 4, 410 mg, 1 mmol) in methanol (3 ml) is added anhydrous hydrazine (0,32 ml, 10 mmol). The resulting mixture was heated to 60°C and stirred at this temperature for 66 hours. The resulting solution was cooled to room temperature and add three drops of water. The precipitate was separated by filtration, washed with ether to obtain specified in the title compound (279 mg).

MS (ESI)m/z422 (M+H);1H-NMR (DMSO) δ of 2.51 (s, 3H), 3,17 (t, J=Hz, 2H), 4,36 (t, J=Hz, 2H), to 4.38 (Sirs, 2H), 6,98 (d, J=Hz, 2H), to 7.77 (d, J=Hz, 2H), 7,83 (d, J=8gts, 2H) of 8.06 (d, J=8gts, 2H) 9,58 (Sirs, 1H).

Example 5

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

To a suspension of the hydrazide of 4-{2-[5-methyl-2-(4-triptoreline)thiazol-4-yl]ethoxy}benzoic acid (example 4, 276 mg of 0.65 mmol) in dichloromethane (4 ml) is added pyridine (104 μl, 1.3 mmol) and then phenylcarbamate (0,88 μl, 0.71 mmol). The resulting mixture was stirred at room te is the temperature, until they use up all of the starting material (by TLC analysis). The mixture is diluted with ethyl acetate, washed with water, then with saturated salt solution, dried over MgSO4and concentrate under reduced pressure. The residue is placed in acetonitrile (5 ml). To the obtained mixture is added DBU (106 μl, 0.71 mmol). The resulting solution was tightly closed, heated to 170°C in a microwave oven Personal Chemistry™ and stirred at this temperature for 120 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 obtaining specified in the title compound as a brown solid (137 mg) (recrystallized from ethyl acetate in a sealed tube at 140°C).

MS (ESI)m/z448 (M+H);1H-NMR (DMSO) δ of 2.51 (s, 3H), 3,19 (t, J=Hz, 2H), and 4.40 (t, J=Hz, 2H), 7,10 (d, J=8gts, 2H), of 7.70 (d, J=8gts, 2H), 7,83 (d, J=8gts, 2H) with 8.05 (d, J=8gts, 2H) 12,41 (Sirs, 1H).

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

where Aryl represents phenyl;
z represents-O(CH2)nand n is independently an integer from 1 to 5;
X represents S;
R1represents a C1-6alkyl; and
R2represents phenyl,substituted C 1-6the perfluoroalkyl;
or its pharmaceutically acceptable salt.

2. The Union, representing 5-(4-{2-[5-methyl-2-(4-triptoreline)thiazol-4-yl]ethoxy}phenyl)-3H-[1,3,4]oxadiazol-2-it.

3. 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.

4. A method of treating disease in a mammal, where the disease can be modulated by the binding activity of PPAR-Delta ligands, through the introduction of the mammal suffering from the disease, a therapeutically effective amount of the compounds of formula I

where Aryl represents phenyl;
z represents-O(CH2)nand n is independently an integer from 1 to 5;
X represents S;
R1represents a C1-6alkyl; and
R2represents phenyl, substituted C1-6the perfluoroalkyl;
or its pharmaceutically acceptable salt.

5. The method according to claim 4, where the specified condition is demyelinizing disease selected from the group comprising multiple sclerosis, a disease Charcot-Marie-Toot, disease, Pelizaeus-Merzbacher, encephalomyelitis, Milosevic optic nerve, adrenoleukodystrophy syndrome is Ian Barre and violations when damaged produce myelin glial cells, including spinal cord injury, neuropathy and nerve damage.

6. The method according to claim 5, where demyelinizing disease is multiple sclerosis.

7. The method according to claim 4, where the disease is selected 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 or congestive heart failure.



 

Same patents:

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

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry, medicine.

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8 cl, 1 tbl, 7 ex

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In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: or its pharmacologically acceptable salts, where n equals 1, 2 or 3; and values of R1, R2, R3, R4, R3', R10, R11 are given in i.1 of formula.

EFFECT: compounds I have ability to inhibit release and/or synthesis of β-amyloid peptide, which allows to apply them in pharmaceutical composition.

25 cl, 3 dwg, 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

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of formula I: , where M is macrolide subunit of substructure II: , L is chain of substructure III: -X1-(CH2)m-Q-(CH2)n-X2-, D is steroid or non-steroid subunit derived from steroid or non-steroid NSAID medicines (nonsteroid anti-inflammatory drug) with anti-inflammatory effect; pharmaceutically acceptable salts and solvates of claimed compounds; methods and intermediary compounds for obtainment of claimed compounds.

EFFECT: improved therapeutic effect, application in inflammatory disease and state treatment for humans and animals.

37 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to salt of 2-ethyl-6-methyl-3-hydroxypyridine with fumaric acid, to method of its obtaining, as well as to method of metabolic malfunctions correction in case of pancreatic diabetes and functional malfunctions in myocardium.

EFFECT: obtaining of salt, which has metabolic and cardioprotective activity and can be applied in endocrinology, cardiology, emergency therapy and reanimation.

4 cl, 2 tbl, 3 ex

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