3-(5)-heteroaryl-substituted pyrazoles as kinase p38 inhibitors

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

 

Cross-reference to related application

This application has a priority of the initial application for U.S. patent 60/047535, filed may 22, 1997

The technical field to which the invention relates.

The present invention relates to a new group pyrazol compounds, to compositions and to methods for treating disorders mediated by kinase R.

Background of invention

Activated mitogen protein kinase (MAP) are a family-controlled Proline serine/threonine kinases that activate their substrates by dual phosphorylation. Kinases are activated by different signals, including food and osmotic stress, UV radiation, growth factors, endotoxin and inflammatory cytokines. Group R MAR-kinase consists of various isoforms of the family MAP, including Rα , Rβ and Rγ and along with other kinases (e.g., MARGAR-2 and MARGAR-3) responsible for Vospominanie and activation of transcription factors (for example, ATF2, CHOP and MEF2C). Isoforms R are activated by bacterial lipopolysaccharide (LPS), physical and chemical stress and proinflammatory cytokines, including tumor necrosis factor (TNF-α ) and interleukin-1 (IL-1). Products phosphorylation R mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.

TNF-α p is ecstasy a cytokine, which initially is produced by activated monocytes and macrophages. Excessive or unregulated production of TNF is one of the factors mediating numerous diseases. Modern research has shown that TNF causes the pathogenesis of rheumatoid arthritis. Additional studies have shown that inhibition of TNF finds wide application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF is also involved in the emergence of viral infections such as HIV infections, agents which among other things are influenza virus, herpes virus, including herpes virus simple type I (HSV-1), herpes virus simple type II (HSV-2), cytomegaly virus (CMV), varicella zoster virus (VZV), the virus of Epstein-Barr, human herpes virus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), the virus rabies and false rhinotracheitis.

IL-8 is a proinflammatory cytokine that is produced by mononuclear cells, fibroblasts, endothelial cells and keratinocytes and which is associated with various conditions, including inflammation.

IL-1 is produced by activated monocytes and macrophages and is involved in inflammatory reactions. IL-1 plays a role in many pathophysiological what their reactions including rheumatoid arthritis, fever, and decreased bone resorption.

TNF, IL-1 and IL-8 effect on many cells and tissues, and they are important as mediators of inflammation wide range of diseases and illnesses. Inhibition of these cytokines by inhibiting kinase R successfully used for eliminating, reducing and alleviating many of these disease conditions.

Various pyrazoles have been described previously. In U.S. patent 4000281 name Beiler and Binon described 4,5-aryl-, heteroelement pyrazoles having antiviral activity against both RNA-type viruses, and DNA-new viruses, such as myxovirus, adenoviruses, rhinoviruses, and various viruses from the group of herpes. In the application WO 92/19615, published on 12 November 1992, pyrazoles described as new fungicides. In U.S. patent 3984431 in the name of Sagamu and Renault describes derivatives of pyrazole-5-acetic acid, which has anti-inflammatory activity. In particular, described [1-isobutyl-3,4-diphenyl-1H-pyrazole-5-yl] acetic acid. In U.S. patent 3254093 on the name of the Huisgen and al. describes a method for pyrazoles. In WO 83/00330, published February 3, 1983, describes a new method of obtaining derivatives of diphenyl-3,4-methyl-5-pyrazole. In WO 95/06036 describes the obtaining of pyrazole and its derivatives. In U.S. patent 5589439 name .Goto and other derivatives described tetrazole and their application in kachestva.gibel. In EP 515041 described derivatives pyrimidinamine of pyrazole as new agricultural fungicides. In Japanese patent 4145081 described derivatives pyrazolylborate acids as herbicides applied in the fields of paddy rice, dry fields, and in areas that do not have agricultural value. In Japanese patent 5345772 described new derivatives of pyrazole with pronounced inhibitory activity against acetylcholinesterase.

Discusses the use of pyrazoles for the treatment of inflammation. In Japanese patent 5017470 described the synthesis of derivatives of pyrazole and as anti-inflammatory, Antirheumatic, anti-bacterial and antiviral drugs. In the application EP 115640, published December 30, 1983, describes derivatives of 4-imidazolidinone as inhibitors of the synthesis of thromboxane. In particular, the described 3-(4-isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole. In the application WO 97/01551, published January 16, 1997, describes pyrazol compounds as antagonists of adenosine. In particular, described 4-(3-oxo-2,3-dihydropyridin-6-yl)-3-phenylpyrazol. In U.S. patent 5134142 in the name of Matsuo and others described 1,5-diarylpyrazole, possessing anti-inflammatory activity.

In U.S. patent 5559137 in the name of Adams and others described new pyrazoles (1,3,4-substituted) as inhibitors of cytokine is, designed for treatment-related cytokines diseases. In particular, the described 3-(4-forfinal)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole. In the application WO 96/03385, published February 8, 1996, describes 3,4-substituted pyrazoles having anti-inflammatory activity. In particular, described 4-[1-ethyl-4-(4-pyridyl)-5-trifluoromethyl-1H-pyrazole-3-yl]benzosulfimide.

It was found that pyrazol compounds according to the invention can be used as inhibitors of the kinase R.

Description of the invention

A class of substituted pyrazolidine compounds suitable for the treatment of kinase mediated R diseases, compounds represented by formula 1:

where R1selected from the group including hydride, alkyl, cycloalkyl, alkenyl, quinil, heterocyclyl, cycloalkylation, haloalkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, mercaptoethyl, achiltibuie, amino, alkylamino, arylamino, aminoalkyl, acylaminoalkyl, heterocyclisation, aminocarbonylmethyl and alkylaminocarbonyl,

R2selected from the group including hydride, alkyl, alkenyl, quinil, heterocyclyl, haloalkyl, geterotsiklicheskikh, amino, alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl, carboxylic, aminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, amino Lionel, alkylsulfonamides, aminosulfonyl, alkylaminocarbonyl, alkynylamino, and heterocyclyl and heterocyclisation group optionally substituted by one or more radicals, independently of one another selected from the group consisting of alkylthio, Acesulfame, alkylsulfonyl, halogen, alkyl, alkoxy, aryloxy, Alcoxy, heterocyclyl, haloalkyl, amino, cyano and hydroxy,

Ar1denotes aryl, optionally substituted by one or more radicals, independently of one another selected from the group comprising halogen, alkyl, alkenyl, quinil, alkoxy, alkenone, alkyloxy, alkylthio, alkylsulfonyl, alkylsulfonyl, amino, aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino, alkylcarboxylic, halocarbonyl, aminoalkyl and haloalkyl, and

HetAr2denotes a pyridinyl, pyrimidinyl or chinoline, optionally substituted by one or more radicals, independently of one another selected from the group consisting of alkylthio, alkylsulfonyl, alkylsulfonyl, halogen, alkyl, heterocyclyl, alkoxy, Alcoxy, haloalkyl, amino, cyano, aralkyl, alkylamino, cyclooctylamine, cyclooctylamine, arylamino, alkylamino, aralkylamines, or their pharmaceutically acceptable salts or tautomers.

The compounds of formula I may, if enetica for the treatment of any disorders or conditions in humans and other mammals which are mediated by or caused by excessive or unregulated production of TNF or kinase R such a mammal, but is not limited to this application. Thus, the present invention relates to a method of treatment mediated by cytokine diseases, which includes the introduction of an effective amount interacts with the cytokine of the compounds of formula I or its pharmaceutically acceptable salt or tautomer.

The compounds of formula I can be used for the treatment of inflammation in a patient and as a fever-reducing medicine for treatment of fever, but is not limited to this application. Compounds according to the invention can be used to treat arthritis, including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, in particular osteoarthritis, gouty arthritis and other related arthritis status, but their use is not limited to these diseases. Such compounds can be used for the treatment of lung disorders or inflammation of the lungs, including respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic inflammatory lung disease. Connections can also be used to treat viral and bacterial infections, including sepsis, septic shock, sepsi is, caused by gram-negative bacteria, malaria, meningitis, cachexia, infection, or malignancy, cachexia induced by acquired immunodeficiency syndrome (AIDS), AIDS related AIDS complex diseases (SCQ), pneumonia, and diseases caused by herpesvirus. Connections can also be used for treatment of diseases associated with bone resorption, such as osteoporosis, endotoxic shock, toxic shock syndrome associated with reperfusion injury, autoimmune diseases, including graft versus host disease and allograft rejection, cardiovascular disease including atherosclerosis, thrombosis, congestive heart failure and is associated with reperfusion of the heart damage associated with reperfusion damage to the kidneys, liver disease, nephritis and related infection myalgia.

Compounds according to the invention can also be used for treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), a disease with cutaneous manifestations, such as psoriasis, eczema, burns, dermatitis, keloid formation, and scarring of the tissue. Compounds according to the invention can also be used to treat disorders of the gastrointestinal tract, such as colitis, Crohn's disease, gastritis, painful syndrome case the reality of the intestine and ulcerative colitis. Connections can also be used to treat eye diseases such as pigmentosa, retinopathy, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds according to the invention can also be used to treat angiogenesis including neoplasia, metastasis, ophthalmological disorders, such as graft rejection cornea, ocular neovascularization, neovascularization of the retina, including neovascularization caused by injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma, ulcerative diseases such as gastric ulcer, pathological, but not associated with malignant tumor disorders, such as hemangioma, including neonatal hemangioma, angiofibroma of the nasopharynx and avascular bone necrosis, diabetic nephropathy and cardiomyopathy and diseases of the female reproductive system such as endometriosis. Compounds according to the invention can also be used to prevent the production of cyclooxygenase-2.

In addition to their use for the treatment of humans, these compounds can also be used in veterinary medicine for the treatment of domestic animals, exotic animals and farm animals, including mammals, rodents, etc. are More preferred group of animals include horses, dogs and cats.

Connection p. the present invention can also be applied to joint therapy partially or completely replacing other conventional anti-inflammatory drugs, as well as together with steroids, inhibitors of cyclooxygenase-2, nonsteroidal anti-inflammatory drugs (NCPUL), DMARDS, immunosuppressants, and inhibitors of 5-lipoxygenase, antagonists LTB4and inhibitors hydrolases LTA4.

In the context of the present description, the term "mediated TNF violation" refers to any and all disorders and painful conditions involving TNF and who are either under the control of the TNF, or under the control of another monokine released under the action of TNF, such as IL-1, IL-6 or IL-8, but are not limited to them. Consequently, a painful condition in which, for example, the main component is IL-1 production or action which is mediated by TNF or it is secreted under the influence of TNF, should be considered as a condition mediated by TNF.

In the context of the present description, the term "mediated R disease" refers to any and all disorders and painful conditions, which involved R and which either are controlled by the kinase R, or under the control of another factor, released under the action of R, such as IL-1, IL-6 or IL-8, but are not limited to them. Consequently, a painful condition in which, for example, the main component is IL-1 production or action which is mediated R or it is secreted under the influence of R, should be considered as a condition mediated R.

Because TNF-β has a distinct structural homology with TNF-α (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, and the synthesis and TNF-α and TNF-β inhibited by compounds of the present invention, in the context of this description, both these factors are referred to as "TNF"unless specifically stated otherwise.

A preferred class of compounds include compounds of formula I, in which

R1selected from the group including hydride, (ness.)alkyl, (ness.)cycloalkyl, (ness.)cycloalkylation, (ness.)haloalkyl, (ness.)hydroxyalkyl, (ness.)alkenyl, (ness.)quinil, (ness.)heterocyclyl, (ness.)aralkyl, (ness.)alkoxyalkyl, (ness.)mercaptoethyl, (ness.)achiltibuie, amino, (ness.)alkylamino, (ness.)arylamino, (ness.)aminoalkyl, (ness.)acylaminoalkyl, (ness.)heterocyclisation, (ness.)aminocarbonylmethyl and (ness.)alkylaminocarbonyl,

R2selected from the group including hydride, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)haloalkyl, (ness.)heterocyclyl, (ness.)heterocyclyl the Yong, amino, (ness.)alkylamino, (ness.)alkynylamino, (ness.)aminoalkyl, (ness.)alkylthio, (ness.)carboxy, (ness.)alkoxycarbonyl, (ness.)carboxyethyl, (ness.)aminocarbonyl, (ness.)alkylaminocarbonyl, (ness.)alkylsulfonyl, (ness.)aminosulfonyl, (ness.)alkylsulfonyl, (ness.)aminosulfonyl and (ness.)alkylaminocarbonyl, and heterocyclyl and heterocyclisation group optionally substituted by one or more radicals, independently of one another selected from the group comprising (ness.)alkylthio, (ness.)Acesulfame, (ness.)alkylsulfonyl, halogen, (ness.)alkyl, (ness.)alkoxy, aryloxy, (ness.)heterocyclyl, (ness.)haloalkyl, amino and cyano,

Ar1selected from the group including phenyl, biphenyl and naphthyl, and Ar1optionally substituted by one or more radicals, independently of one another selected from the group comprising (ness.)alkylthio, (ness.)alkylsulfonyl, aminosulfonyl, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkylsulfonyl, cyano, (ness.)alkoxycarbonyl, aminocarbonyl, formyl, (ness.)alkylcarboxylic, (ness.)haloalkyl, (ness.)alkoxy, (ness.)alkyltins, (ness.)alkenylacyl, amino, (ness.)alkylamino, (ness.)aminoalkyl, arylamino, nitro and halosulfuron, and

HetAr2denotes a pyridinyl or pyrimidinyl, optionally substituted by one or is more radicals, independently from each other selected from the group comprising (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, halogen, (ness.)alkyl, (ness.)heterocyclyl, (ness.)alkoxy, (ness.)arakaki, (ness.)haloalkyl, amino, cyano, (ness.)aralkyl, (ness.)alkylamino, (ness.)cyclooctylamino, (ness.) arylamino, (ness.)alkynylamino and (ness.)aralkylamines,

or pharmaceutically acceptable salts or tautomers of these compounds.

The class of compounds of particular interest consists of compounds of the formula I, in which

R1selected from the group including hydride, methyl, ethyl, isopropyl, tert-butyl, isobutyl, trichlorethyl, pentafluoroethyl, heptafluoropropyl, defloratin, direcror, dichlorethyl, dichloropropyl, vinyl, allyl, ethinyl, propargyl, morpholinyl, piperidinyl, piperazinil, benzyl, phenylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminomethyl, dimethylaminomethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, methylthio and methylthiomethyl,

R2selected from the group including hydride, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, vermeil, deformity, trifluoromethyl, shall loretel, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, diperchlorate, dichloromethyl, defloratin, direcror, dichlorethyl, dichloropropyl, amino, N-methylamino, N,N-dimethylamino, ethynylene, propargylamine, piperidinyl, piperazinil, morpholinomethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, pyrrolidinyl, thienylmethyl, triazolylmethyl, oxazolidinyl, pyrimidinyl, chenailler, izohinolinove, imidazolidinyl, benzimidazolyl, furylmethyl, personality, aminocarbonyl, methylaminoquinoline, dimethylaminocarbonylmethyl, ethylenediamino, diethylaminoethylamine, methylsulfonylamino, ethylsulfonyl, aminosulfonyl, methylmonoethanolamine, dimethylaminopropylamine, ethylaminomethyl, diethylaminoethylamine,

Ar1selected from the group including phenyl, biphenyl and naphthyl, and Ar1optionally substituted by one or more radicals, independently of one another selected from the group include methylthio, methylsulfinyl, methylsulphonyl, fluorine, chlorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, etoxycarbonyl, aminocarbonyl, methylcobalamine, trifluoromethyl, deformity, vermeil, trichloromethyl, dichloromethyl, chloromethyl, allyl, vinyl, ethinyl, propargyl, methoxy, the toxi, propyloxy, n-butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl, N-phenylamino, phenylamino, diphenylamino, nitro and chlorosulfonyl, and

HetAr2selected from the group including pyridinyl and pyrimidinyl, and HetAr2optionally substituted by one or more radicals, independently of one another selected from the group include methylthio, methylsulfinyl, methylsulphonyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxy, ethoxyl, phenoxyl, pentoxil, phenethyl, trifluoromethyl, vermeil, deformity, amino, benzylamino, propargylamine, cyclopropylamino, cyclobutylamine, cyclopentylamine and cyano,

or their pharmaceutically acceptable salts or tautomers.

Another class of compounds of particular interest consists of those compounds of the formula I, in which

R1means hydride, methyl, ethyl, hydroxyethyl, propargyl, dimethylaminoethyl or morpholinoethyl,

R2selected from the group including hydride, methyl, ethyl, amino, aminocarbonyl, methylaminoquinoline, methylsulfonylamino, aminosulfonyl, methylmonoethanolamine,

Ar1denotes phenyl, optionally substituted by one or more radicals, independently of one another selected from the group include methylthio, methylsulfinyl is, methylsulphonyl, fluorine, chlorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, etoxycarbonyl, aminocarbonyl, methylcobalamine, trifluoromethyl, deformity, vermeil, trichloromethyl, dichloromethyl, chloromethyl, methoxy, ethoxy, propyloxy, n-butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, N-methyl, N-phenylamino, phenylamino, diphenylamine, nitro and chlorosulfonyl, and

HetAr2optionally substituted by one or more radicals, independently of one another selected from the group include methylthio, methylsulfinyl, methylsulphonyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxy, ethoxyl, phenoxyl, pentoxil, trifluoromethyl, vermeil, deformity, amino, propargylamine and cyano,

or their pharmaceutically acceptable salts or tautomers.

Another class of compounds of interest consists of those compounds of the formula I, in which

R1means hydride or methyl,

R2means hydride or methyl,

Ar1denotes phenyl, optionally substituted by one or more radicals, independently of one another selected from the group comprising fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and nitro, and

HetAr2optionally substituted od is them or more radicals, independently from each other selected from the group comprising methyl, chlorine, fluorine and trifluoromethyl,

or their pharmaceutically acceptable salts or tautomers.

A family of specific compounds of particular interest among the compounds of formula I consists of compounds and their tautomers and pharmaceutically acceptable salts:

4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine;

4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-methylsulfonyl;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]urea;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]sulphonamide;

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazole-5-amine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-metalmachine;

4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine;

4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine;

4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;

4-(4-forfinal)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;

4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]morpholine;

4-[4-(4-chlorophenyl)-1H-pyrazole-3-yl]pyridine;

4-(4-phenyl-1H-pyrazole-5-yl)pyridine;

1-methyl-4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine;

1-methyl-4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine.

The term "hydride" oboznachaet the monatomic hydrogen (H). This hydrogen radical may be attached, for example, the oxygen atom with getting a hydroxyl radical, or two hydrogen radicals can be joined to the carbon atom with getting methylene (-CH2-) radical. When used either individually or in combination with other terms, such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl", "hydroxyalkyl", "mercaptoethyl", the term "alkyl" refers to linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "(ness.)alkyl" radicals having one to about ten carbon atoms. The most preferred (ness.)the alkyl radicals have from one to about six carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, etc. the Notion of alkenyl" denotes linear or branched radicals having at least one double carbon-carbon bond and containing from two to about twenty carbon atoms or, preferably, from two to twelve carbon atoms. More preferred alkenylamine radicals are "(ness.)alkeneamine" radicals, there is the following from two to about six carbon atoms. Examples alkenyl radicals are ethynyl, propenyl, allyl, butenyl and 4-methylbutanal. The concept of "alkenyl" and "(ness.)alkenyl" denotes radicals having "CIS" and "TRANS"orientations, or alternatively, "E"and "Z"orientation. The concept of "quinil" denotes linear or branched radicals having at least one triple carbon-carbon bond and containing from two to about twenty carbon atoms or, preferably, from two to twelve carbon atoms. More preferred alkenylamine radicals are "(ness.)alkyline" radicals having two to about six carbon atoms. Examples etkinlik radicals are propargyl, 1-PROPYNYL, 2-PROPYNYL, 1-butyn, 2-butenyl and 1-pentenyl. The concept of "cycloalkyl" denotes a saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "(ness.)cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The concept of "cycloalkylation" denotes alkyl radicals, substituted cycloalkenyl radical. More preferred cycloalkylcarbonyl radicals are "(ness.)cycloalkylation" radicals, which indicate (nor the sh.)alkyl radicals, substituted (ness.)cycloalkyl radical, as defined above. Examples of such radicals are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The concept of "cycloalkenyl" refers to partially unsaturated carbocyclic radicals having three to twelve carbon atoms and one or two double bonds, but not necessarily conjugated ("cycloalkenyl"). More preferred cycloalkenyl radicals are "(ness.)cycloalkenyl" radicals having from four to about eight carbon atoms. Examples of such radicals are cyclobutenyl, cyclopentenyl and cyclohexenyl. The concept of "cycloalkenyl" denotes alkyl radicals, substituted cycloalkenyl radical. More preferred cycloalkylcarbonyl radicals are (ness.)cycloalkylation radicals, which represent alkyl radicals, substituted (ness.)cycloalkenyl radical, as defined above. Examples of such radicals are cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The term "halogen" means a halogen, such as fluorine, chlorine, bromine or iodine. The concept of "haloalkyl" refers to radicals in which one or more of the alkyl carbon atoms is substituted with halogen as defined above. In particular, this definition is anomalously, dihaloalkanes and polyalkylene radicals. Monogamously radical as an example can include any of the atoms such as iodine, bromine, chlorine or fluorine. Digalo and polyalkylene radicals may have two or more of the same halogen atoms or a combination of different halogen atoms. The term "(ness.)haloalkyl" denotes radicals having from one to six carbon atoms. Examples haloalkyl radicals are vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, diperchlorate, dichloromethyl, defloratin, direcror, dichlorethyl and dichloropropyl. The concept of "hydroxyalkyl" denotes a linear or branched alkyl radicals having from one to about ten carbon atoms, any of which may be substituted by one or more hydroxyl radicals. Preferred hydroxyalkyl radicals are "(ness.)hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals are hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The concept of "alkoxy" and "alkyloxy" refers to linear or branched radicals that contain oxygraph and it is gdy of which has an alkyl fragments, including from one to about ten carbon atoms. More preferred CNS radicals are "(ness.)CNS" radicals having one to six carbon atoms. Examples of such radicals are methoxy, ethoxy, propoxy, butoxy and tre-butoxy. The concept of "alkoxyalkyl" refers to alkyl radicals having one or more CNS radicals attached to the alkyl radical with the formation of, for example, monoatomically and dialkoxybenzene radicals. "CNS" radicals may be optionally substituted by one or more halogen atoms such as fluorine, chlorine or bromine, with the formation of "haloalkoxy" radicals.

The term "aryl" individually or in combination, denotes a carbocyclic aromatic system containing one, two or three rings, and these rings may be connected to each other in the form of side chains or can be merged. Preferred aryl radicals are 6 to 12-membered aryl radicals. Examples of such radicals are phenyl, naphthyl, tetrahydronaphthyl, indan and biphenyl. Aryl fragments can also be substituted in a suitable replacement for the position by one or more substituents, independently from each other selected from the group including, for example, halogen, alkyl, alkene is, quinil, alkoxy, alkenone, alkyloxy, alkylthio, alkylsulfonyl, alkylsulfonyl, amino, aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino, alkylcarboxylic, halocarbonyl, aminoalkyl and haloalkyl, alkoxyalkyl, acylaminoalkyl, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, Alcoxy, hydroxyl, acyl, carboxy, aminocarbonyl and arelaxation. The notion of "alkyloxy" means alkyloxyalkyl bridge, such as methylendioxyphenyl the bridge between the two ring carbon atoms of aryl fragment.

The concept of "heterocyclyl" denotes a saturated, partially unsaturated and unsaturated containing heteroatom ring radicals, which can also be referred to as "heterocyclyl", "geteroseksualen and heteroaryl", respectively, and the heteroatoms may be selected from the group comprising nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals are saturated 3-6 membered heterophilically group containing 1-4 carbon atoms (for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinil etc.); saturated 3-6 membered heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom (for example, morpholinyl etc.); saturated 3-6 membered heterophilically group containing 1-2 sulfur atom and 1 to 3 atom is zhota (for example, diazolidinyl etc). Examples of partially unsaturated heterocyclyl radicals are dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazolo. Heterocyclyl radicals, such as radicals of tetrazole and pyridinium may include patibility nitrogen. The concept of "heteroaryl" means anisidine heterocyclyl radicals. Examples of heteroaryl radicals are unsaturated 3-6 membered heterophilically group containing 1-4 nitrogen atom, for example pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc), tetrazolyl (for example, 1H-tetrazolyl 2N-tetrazolyl etc), etc; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, tetrathyridia (for example, tetrazole[1,5-b]pyridazinyl etc), etc; unsaturated 3-6 membered heterophilically group containing an oxygen atom, such as pyranyl, furyl, etc.; unsaturated 3-6 membered heterophilically group containing a sulfur atom, such as thienyl etc; unsaturated 3-6 membered heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example oxazolyl, isoxazolyl, acsadi who was Salil (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc), etc; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atom (for example, benzoxazolyl, benzoxadiazole etc.); unsaturated 3-6 membered heterophilically group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, for example thiazolyl, thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl etc), etc; unsaturated condensed heterocyclyl group containing 1-2 sulfur atom and 1 to 3 nitrogen atom (for example, benzothiazolyl, and benzothiadiazole etc) and so the Concept of "heteroaryl" also designates the radicals in which heterocyclyl radicle condensed with aryl radicals. Examples of such fused bicyclic radicals are benzofuran, benzothiophene, etc. Such heterocyclyl group can have from 1 to 3 substituents such as alkyl, hydroxyl, halogen, alkoxy, oxo, amino, alkylamino. The concept of "heterocyclisation" means substituted by heterocyclyl alkyl radicals. More preferred "heterocyclyl-alkionovymi" radicals "(ness.)heterocyclisation" radicals having one to six carbon atoms and heterocyclyl radical.

The notion of "alkylthio" denotes radicals, soderjashie linear or razvetvlennye alkyl radicals, R is the following from one to about ten carbon atoms, attached to the divalent sulfur atom. The preferred alkilirovannami are (ness.)alkylthiomethyl having from one to six carbon atoms. Examples of such "(ness.)alkylthiomethyl are methylthio, ethylthio, propylthio, butylthio and hexylthio. The concept of "achiltibuie" refers to radicals containing alkylthio radical attached through a divalent sulfur atom to the alkyl radical, having from one to about ten carbon atoms. More preferred allylthiourea radicals denote "(ness.)allylthiourea" radicals, including alkyl radicals having from one to six carbon atoms. Examples of such (ness.)allylthiourea radicals include methylthiomethyl. The concept of "alkylsulfonyl" refers to radicals containing a linear or branched alkyl radical having from one to about ten carbon atoms, attached to the divalent radical-S(=O). More preferred alkylsulfonyl radicals are "(ness.)alkylsulfonyl" radicals, including alkyl radicals having from one to six carbon atoms. Examples of such (ness.)alkylsulfonyl radicals are methylsulfinyl, ethylsulfinyl, butylsulfonyl and exisulind. The concept of "sulfonyl"when it is used individually or in op is Tania's story with other concepts, such as "alkylsulfonyl" or "halosilver", denotes a divalent radical, i.e, -SO2-. The term "alkylsulfonyl" refers to alkyl radicals attached to sulfonylurea the radical, and the alkyl has the above values. More preferred alkylsulfonyl radicals are "(ness.)alkylsulfonyl" radicals having one to six carbon atoms. Examples of such (ness.)alkylsulfonyl radicals are methylsulphonyl, ethylsulfonyl and propylsulfonyl. "Alkylsulfonyl" radicals may be further substituted by one or more halogen atoms such as fluorine, chlorine or bromine, with the formation of haloalkaliphilic radicals. The concept of "halosilver" refers to the halogen atoms attached to sulfonylurea the radical. Examples of such halosulfuron radicals are chlorosulfonyl and bromsulphalein. The concept of "sulfamyl", "aminosulfonyl" and "sulfonamides" denote NH2O2S.

The term "carbonyl" regardless of whether it is individually or in combination with other concepts, such as "alkoxycarbonyl"means a radical -(C=O)-. The concept of "carboxy" or "carboxyl" regardless of whether they are used individually or in combination with other concepts, such as "carboxyethyl ' denote the radical-CO2 N. The concept of "carboxylic" denotes alkyl radicals, substituted carboxyl radical. More preferred are "(ness.)carboxialkilnuyu" radicals, which indicate (ness.) alkyl radicals, as defined above, substituted by carboxypropyl. Examples of such (ness.)carboxialkilnuyu radicals are carboxymethyl, carboxyethyl and carboxypropyl. The concept of "alkoxycarbonyl" denotes a radical containing CNS radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "(ness.)alkoxycarbonyl" radicals, alkyl fragments of which have one to six carbon atoms. Examples of such (ness.)alkoxycarbonyl (ester) radicals are methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxybenzoyl. The concept of "alkoxycarbonyl" denotes alkyl radicals, substituted alkoxycarbonyl radical, as defined above. More preferred are "(ness.)alkoxycarbonylmethyl" radicals, alkyl fragments of which have one to six carbon atoms. Examples of such (ness.)alkoxycarbonylmethyl radicals are methoxycarbonylmethylene, ethoxycarbonylmethylene, methoxycarbonylethyl and ethoxycarbonylethyl. The notion of "alkylborane is" denotes radicals, in which the alkyl radicals attached to the carbonyl radical. Examples of such radicals are methylcarbamyl, ethylcarboxyl, propylmalonic, butylcarbamoyl and internabonal. The concept of "aralkyl" denotes alkyl radicals, substituted by aryl. Preferred Uralkalij radicals are "(ness.)kalkilya" radicals, in which (ness.) alkyl groups substituted by one or more archlinux groups. Examples of such groups are benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylether. Aryl in the specified aralkyl may optionally be substituted with halogen, alkyl, alkoxygroup, haloalkyl and haloalkoxy. The term "benzyl" and "phenylmethyl" are interchangeable. The concept of "heterocyclisation" denotes a saturated, partially unsaturated and unsaturated alkyl radicals, substituted by heterocyclyl, such as pyrrolidinyl, pyridylmethyl, chenailler, thienylmethyl, purolater and hemolysates. Heteroaryl in heteroalkyl (unsaturated substituted heterocyclyl alkyl radicals may be optionally substituted with halogen, alkyl, alkoxygroup, haloalkyl and haloalkoxy. The notion of "aryloxy" refers to aryl radicals attached through an oxygen atom to other radicals. The notion of "arakaki" means kalkilya radicals, connected yennie through an oxygen atom to other radicals.

The concept of "aminoalkyl" denotes alkyl radicals, substituted by amino groups. More preferred are "(ness.)aminoaniline" radicals. Examples of such radicals are aminomethyl, aminoethyl etc. the Notion of "alkylamino" will denote an amino group substituted by one or two alkyl radicals. Preferred are(ness.)alkylamino", in which the alkyl fragments are from one to six carbon atoms. Acceptable (ness.)alkylamino can be monozamyescyennymi N-alkylaminocarbonyl or diamesinae N,N-alkylaminocarbonyl, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like, the Term "arylamino" means an amino group substituted by one or two aryl radicals, such as N-phenylamino. "Killingry" can be additionally substituted on the aryl ring fragment radical. The concept of "aminocarbonyl" denotes an amide group of the formula-C(=O)NH. The concept of "alkylaminocarbonyl" means aminocarbonyl group, substituted by one or two alkyl radicals on the nitrogen atom of the amino group. Preferred radicals are N-alkylaminocarbonyl" and "N,N-dialkylaminoalkyl". More preferred are radicals "(ness.)-N-alkylaminocarbonyl" and "(ness.)-N,N-dialkylaminoalkyl", in which (ness.)the alkyl fragments are above mn of the treatment. The notion of "aminocarbonyl" denotes radicals having one or more aminocarbonyl radicals attached to the amino group. The notion of "alkylaminocarbonyl" denotes radicals having one or more alkyl radicals attached to aminocarbonylmethyl. Preferred are radicals "(ness.)alkylaminocarbonyl", in which (ness.)alkyl fragments have the above values. The notion of "alkylcarboxylic" means an amino group substituted by one or more alkylcarboxylic radicals. More preferred "alkylcarboxylic "groups are the radicals "(ness.)alkylcarboxylic", in which (ness.)acylcarnitine radicals having the above values attached to the amino groups. The concept of "acylaminoalkyl" refers to radicals in which one or more alkyl radicals attached to aminoalkylindole the radical. The notion of "alkylsulfonyl" refers to radicals in which one or more alkylsulfonyl radicals attached to the amino group. Preferred are radicals "(ness.)alkylsulfonyl", in which (ness.)alkyl fragments have the above values. The notion of "aminosulfonyl" refers to radicals in which one or more amine is sulfanilic radicals attached to the amino group. The notion of "alkylaminocarbonyl" refers to radicals in which one or more alkyl radicals attached to aminosulfonates. Preferred are radicals "(ness.) alkylaminocarbonyl", in which (ness.)alkyl fragments have the above values.

Additional concepts that are used to describe the Vice-pyrazol ring is not specifically defined in the present description are defined in the same way as illustrated in the above definitions. As indicated above, the preferred substituents are the substituents that contain (ness.)-the radicals. Unless otherwise indicated, the term "(ness.)" in the context of the present description denotes each alkyl radical, which is the Deputy pyrazol ring, in which one or more alkyl radicals have from one to about six carbon atoms; each alkanniny radical, which is the Deputy pyrazol ring, in which one or more alkenyl radicals has from two to about six carbon atoms; each alkynylaryl radical, which is the Deputy pyrazol ring, in which one or more etkinlik radicals has from two to about six carbon atoms; each cycloalkyl or cleanenergy radical, which Deputy pyrazol ring, in which one or more cycloalkyl and/or cycloalkenyl radicals is a 3-8-membered ring cycloalkenyl or cycloalkenyl radical, respectively; each aryl radical, which is the Deputy pyrazol ring, in which one or more aryl radicals represents a monocyclic aryl radical; each heterocyclyl radical, which is the Deputy pyrazol ring, in which one or more heterocyclyl radicals represents a 4-8-membered ring heterocyclyl.

The present invention comprises the tautomeric forms of the compounds of formula I. As described below, the pyrazoles of formula I and I' are equivalent in magnetic characteristics and structure due to protopapas tautomeric nature of hydrogen:

The present invention also relates to compounds of formula I having one or more asymmetric carbon atoms. For specialists in this field it is evident that those pyrazoles of the present invention, which have asymmetric carbon atoms may be in the form of diastereomers, racemates or optically active forms. All these forms fall under the scope of the invention. Over concr the IDT present invention includes enantiomers, diastereomer, racemic mixtures and other mixtures thereof.

The present invention further relates to pharmaceutical compositions intended for the treatment of mediated TNF disorder mediated by kinase R disorder, inflammation and/or arthritis, which comprises a therapeutically effective amount of the compounds of formula I or a therapeutically acceptable salt or tautomer in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also relates to a therapeutic method of treatment mediated TNF disorder mediated by kinase R disorder, inflammation and/or arthritis in a patient, and the method involves treating a patient having such disorder or susceptible to such disorder or condition, a therapeutically effective amount of the compounds of formula I

where R1selected from the group including hydride, alkyl, cycloalkyl, alkenyl, quinil, heterocyclyl, cycloalkylation, haloalkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, mercaptoethyl, achiltibuie, amino, alkylamino, arylamino, aminoalkyl, acylaminoalkyl, heterocyclisation, aminocarbonylmethyl and alkylaminocarbonyl,

R2selected from the group including hydride, lkil, alkenyl, quinil, heterocyclyl, haloalkyl, geterotsiklicheskikh, amino, alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl, carboxylic, aminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, aminosulfonyl, alkylsulfonyl, aminosulfonyl, alkylaminocarbonyl, alkynylamino, and heterocyclyl and heterocyclisation group optionally substituted by one or more radicals, independently of one another selected from the group consisting of alkylthio, alkylsulfonyl, alkylsulfonyl, halogen, alkyl, alkoxy, aryloxy, Alcoxy, heterocyclyl, haloalkyl, amino, cyano and hydroxy,

Ar1denotes aryl, optionally substituted by one or more radicals, independently of one another selected from the group comprising halogen, alkyl, alkenyl, quinil, alkoxy, alkenone, alkyloxy, alkylthio, alkylsulfonyl, alkylsulfonyl, amino, aminocarbonyl, cyano, alkoxycarbonyl, formyl, aminosulfonyl, alkylamino, nitro, arylamino, alkylcarboxylic, halocarbonyl, aminoalkyl and haloalkyl, and

HetAr2denotes a pyridinyl, pyrimidinyl or chinoline, optionally substituted by one or more radicals, independently of one another selected from the group consisting of alkylthio, alkylsulfonyl, alkylsulfonyl, halogen, alkyl, heterocyclyl, ALCO is si, arakaki, haloalkyl, amino, cyano, aralkyl, alkylamino, cyclooctylamine, cyclooctylamine, arylamino, alkylamino, aralkylamines,

or its pharmaceutically acceptable salt or tautomer.

To the family of compounds of formula I also include their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that are normally used to obtain the alkali metal salts and to obtain additive salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid additive salts of compounds of formula I can be obtained from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric, Hydrobromic, uudistoodetena, nitric, carbonic, sulfuric and phosphoric acid. Acceptable organic acids may be selected from the group which includes such classes of organic acids, both aliphatic, cycloaliphatic, aromatic, analiticheskie, heterocyclyl, carboxylic and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyro is Vinogradnaya, aspartic, glutamic, benzoic, Anthranilic, musilova, stearic, salicylic acid, para-hydroxybenzoic, phenylacetic, almond, albanova (AMOVA), methansulfonate, econsultancy, benzolsulfonat, Pantothenic, toluensulfonate, 2-hydroxyethanesulfonic, sulfanilic, cyclohexanesulfonyl, alginic, β -hydroxybutiric, galactosemia and galacturonic acid. Suitable pharmaceutically acceptable salts formed by the addition of bases to compounds of formula I, include metal salts and organic salts.

Preferred metal salts include salts of alkali metal (group Ia), salts of alkaline-earth metal (group IIA), and salts of other physiologically acceptable metal, but is not limited to them. Such salt may be a salt of aluminum, calcium, lithium, manganese, potassium, sodium and zinc. Preferred organic salts are salts of tertiary amines and Quaternary ammonium compounds, including, in particular, tromethamine, diethylamine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be obtained by conventional means from the corresponding compounds of formula I by reacting, for example, the appropriate acid or base with the compound of the formula I.

General synthesis methods

Compounds according to the invention can be synthesized according to the following methods are presented in schemes I-VI, where the substituents R1-R3and Ar1, HetAr2have the meanings given above for formula I, unless otherwise indicated.

In the diagram I presented a three-stage process pyrazole 5 of the present invention. In stage 1 interaction obtained from arylmethyl ketone 1 with that obtained from pyridine aldehyde 2 or in a solvent such as benzene or toluene, in the presence of a base, such as pyridine, or mixtures of acids such as acetic acid and Hydrobromic acid, receive α ,β -unsaturated ketone 3. In stage 2 in the presence of a base such as sodium hydroxide, α ,β -unsaturated ketone 3 is transformed into the corresponding epoxide 4 by treatment with a hydrogen peroxide solution at room temperature. At stage 3 epoxide 4 condensed with hydrazine in an appropriate solvent, such as ethanol, at a temperature, an upper limit which corresponds to the boiling point, receiving the pyrazole 5. In another embodiment, the pyrazole 5 can be obtained by treatment of the ketone 3 hydrazide of Totila in the presence of acid, such as acetic acid, by boiling under reflux.

In scheme II presents three ways of synthesis of pyrazole 12 containing heteroaromatic ring. According to the first way of synthesis of ketone 6 condensed with hydrazine 7 obtaining substituted hydrazine 9, which is then subjected to interaction with acylhalides or anhydride 10 at a low temperature, receiving acylhydrazone 11. By heating up to 200° hydrazone 11 turn in the pyrazole 12. According to the second path synthesis acylhydrazone 11 is obtained directly by the interaction of the ketone 6 with acylhydrazides 8 at room temperature. Acylhydrazides 8 can be obtained by the interaction of hydrazine with ether carboxylic acid. Heating acylhydrazone 11, as described above, receive pyrazole 12. According to the third path of synthesis of ketone 6 is treated with acylhydrazides 8 at a temperature in the range from room temperature up to ~200° directly receiving the pyrazole 12. In another embodiment, the condensation reaction can be carried out in an acidic solvent such as acetic acid, or in a solvent containing acetic acid.

Lanceton 13 can be synthesized according to the method described I. Lantos and others, J.Org. Chem., volume 53, str-4227 (1988), for the synthesis of compounds having fluorine in the para-position (X is a para-F). This method included in the present description by reference, can primantis the synthesis of lanceton, such as 12, in which X is chosen, for example, from the group comprising halogen, alkyl and alkoxy. Ciancarini, such as 13, may be converted into pyrazoles 14 interaction with hydrazine in an appropriate solvent such as benzene or toluene. Can be used catalyst, such as acetic acid. When used unsubstituted hydrazine obtained in this ring nitrogen atoms of the pyrazole do not have any substituents, in addition to hydrogen on one of the ring nitrogen atoms. When using the substituted hydrazine such as methylhydrazine, the resulting reaction product, i.e. the pyrazole 14 has a substituent on the ring nitrogen atom adjacent to laminirovannyy ring carbon atom, as shown in scheme I. the resulting aminopyrazole 14 may be allerban or sulfonylureas obtaining substituted aminopyrazole 15 processing activated carboxylic or sulfonic acid in an acceptable solvent such as pyridine. Examples of acceptable image of an activated carboxylic acid include acetic anhydride or benzoyl chloride. Examples of suitably activated sulfonic acid include methylsulfonylamino, para-toluensulfonyl or sulfurylchloride.

Scheme IV illustrates the synthesis of 3-pyridyl-4-arylpyrazole really the invention. Benzoate 16 is first subjected to interaction with pyridine 17 in the presence of a base such as an alkoxide of an alkali metal (preferably sodium methoxide, in an acceptable solvent such as tetrahydrofuran. Subsequent treatment with an acid, preferably a mineral acid, such as hydrochloric acid, receive deoxybenzoin 18. This deoxybenzoin 18 then converted into the ketone 19 by treatment with excess of dimethylacetal of dimethylformamide. Then the ketone 19 is subjected to interaction with hydrazine in an appropriate solvent, such as ethanol, receiving a mixture of pyrazoles 20 and 21. In scheme IV R4represents one or more radicals, independently of one another selected from the optional substituents described above for Ar, a R5represents one or more radicals, independently of one another selected from the optional substituents described above for HetAr2.

3 pirimidil-4-arylpyrazole of the present invention can be synthesized according to scheme IV by replacing pyridine 17 to the corresponding pyrimidine.

In scheme V hydroxyalprazolam 22 and 23 in turn sulphonate derivatives interaction with the alkyl - or arylsulfonate. These sulfonates are then subjected to the interaction with ammonia or with primary or secondary is mi amines, obtaining the appropriate 1-aminopyrazole 24 and 25, respectively. In scheme V n is 1, 2, 3, 4 or 5, R4and R5have the meanings specified for scheme IV, a R6and R7independently from each other chosen, for example, from the group comprising hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached, form a 4-8-membered ring which may contain one or more additional heteroatoms selected from oxygen, nitrogen and sulphur.

Scheme VI a similar scheme IV except that deoxybenzoin 18 is first subjected to interaction with hydrazine in an appropriate solvent, such as ethanol, receiving hydrazine 26. Hydrazine 26 then turn to the pyrazole 20 (and not in a mixture of pyrazoles 20 and 21, as shown in scheme IV) by treatment with excess of dimethylacetal of dimethylformamide. In scheme VI, R4and R5have the meanings specified for schema V.

The following examples detail the methods of making compounds of formula I. These detailed descriptions fall under the scope of the invention and serve to illustrate the above General synthesis methods, which are an integral part of the invention. These detailed descriptions are given only for illustration purposes and are not intended to limit the scope of the invention. All parts are Soboh the mass part, and temperatures are indicated in degrees centigrade, unless otherwise indicated. For all compounds are given NMR spectrum consistent with the established structure. In some cases, the fixed structure is confirmed in experiments using nuclear Overhauser effect (AEO).

In the examples used the following abbreviations and symbols:
HClhydrochloric acid
MgSO4magnesium sulfate
Na2SO4the sodium sulfate
NaIO4periodate sodium
NaHSO3sodium bisulfite
NaOHsodium hydroxide
KONthe potassium hydroxide
P2O5the phosphorus pentoxide
Meonmethanol
EtOHethanol
SPLA (or Asón)acetic acid
EtOActhe ethyl acetate
H2Aboutwater
H2O2the peroxide
CH2Cl2methylene chloride
NaOMethe sodium methoxide
hhour(s)
minminute (s)
THFtetrahydrofuran
TLCthin-layer chromatography
DSKdifferential scanning calorimetry
tKipboiling point
tPLmelting point
EQ.equivalent to

Example 1

4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine

Stage 1: Obtain 3-phenyl-4-(4-pyridyl)-3-butene-2-it

3-phenyl-4-(4-pyridyl)-3-butene-2-he received according to the method described by Reichert and Lechner, Arzneim.-Forsch. 15, 36 (1965) (this publication is included in the present description by reference).

Stage 2: Obtain 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone

To a stirred solution of 3-phenyl-4-(4-pyridyl)-3-butene-2-it (stage 1) (500 mg, 2,24 mmol) in methanol (10 ml) at room temperature was added an aqueous solution (9 ml) of sodium hydroxide (100 mg, 2,24 mmol) and hydrogen peroxide (0.5 ml 30%aqueous solution, 4.4 mmol). After stirring for 2 h was added to the sodium chloride and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum, obtaining the crude 3-phenyl-4(4-pyridyl)-3,4-epoxy-2-butanone (385 mg, 65%) as oil. It was used in the next stage without additional purification.

Stage 3: Obtain 4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine

A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (stage 2) (350 mg, of 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) in ethanol (3 ml) was kept boiling under reflux for 4 hours the Reaction mixture was cooled and the solvent evaporated to dryness. The resulting residue was purified by chromatography (silica gel, mixture of acetone/hexane 1:1)to give the desired product as a crystalline solid, which was recrystallized from ethyl acetate and hexane, obtaining pure 4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine (145 mg, 42%): tPL164-165° C.

Elemental analysis: calculated for C15H13N3(235,29): 76,57, N 5,57, N 17,86; found: 76,49, N Of 5.45, N 17,70.

The compounds of examples 2 to 8 were synthesized according to the above method (in particular according to the scheme III), using an appropriate source reagents.

Example 2

4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine

Lanceton 1, is shown in scheme III, where X denotes fluorine in the para-position was synthesized according to the method described in I. Lantos and others, J. Org. Chem., 53, 4223-4227 (1988) (publication included in the present description by reference). The solution containing qi is nceton (10 g, 41 mmol), hydrazine hydrate (2.5 ml) and acetic acid (5.2 ml) in benzene (100 ml), kept at boiling under reflux for 4 hours the Reaction mixture was cooled and was extracted with 3 N. Hcl. The combined acidic extracts were podslushivaet to pH 10 with concentrated ammonium hydroxide while cooling. The alkaline aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over magnesium sulfate.

The desiccant was filtered and the filtrate was concentrated in vacuum, obtaining the crude 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine, which was purified by recrystallization from ethyl acetate and hexane. Purified 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine had tPL178-180° (capillary).

Elemental analysis: calculated for C14H11N4F· 0,25H2O: 64,99, N 4,48, N 21,65; found: 64,99, N 4,48, N 21,54.

Example 3

N-[4-(4-forfinal)-5-(4-pyridinyl)-1-H-pyrazole-3-yl]methanesulfonamide

A solution containing 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine (200 mg, 0.77 mmol)obtained according to example 2, and methanesulfonamide (90 mg) in pyridine (5 ml)was stirred at room temperature overnight. The pyridine was removed in vacuum and the residue was treated with methylene chloride and water. The precipitate was filtered, obtaining N-[4-(4-f is arvanil)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide. An additional portion of N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide contained in methylenchloride layer. Methylenchloride layer was evaporated in vacuum and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and methanol as eluents. Purified N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide had tPL168-170° C.

Elemental analysis: calculated for C15H13N4SO2F· 0,25H2O: 53,48, N. Android 4.04, N 16,63; found: 53,41, N Of 3.78, N 16,52.

Example 4

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-methylsulfonyl

Methylsulfinylpropyl synthesized, withstanding boiling under reflux the solution methylsulfanyl acid (1.0 g) in phosphorus oxychloride (10 ml) for 6 hours, the Excess phosphorus oxychloride was removed in vacuo and the remaining oil was used for synthesis of the product without additional processing. A solution of 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine (200 mg, 0.77 mmol)obtained according to example 2, and about 1 mmol of the above oil in pyridine (5 ml) was stirred at room temperature for 2 hours, the Reaction mixture was evaporated in vacuum and the residue was purified by chromatography on silica gel using ethyl acetate and mixtures of ethyl acetate and methanol as eluents, receiving N-[4-(4-FPO is phenyl)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-methylsulfonyl in the form of a crystalline solid, tPL194-195° C.

Elemental analysis: calculated for C15H14N5SO2F· 1,0H2O: 49,31, N To 4.41, N 19,17; found: 49,13, N Of 3.97, N 19.01 in.

Example 5

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]urea

The suspension containing 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine (200 mg, 0.77 mmol)obtained according to example 2, the solution dicret-BUTYLCARBAMATE (185 mg, 0.9 mmol) and 4-dimethylaminopyridine (DMAP) (10 mg) in methylene chloride (10 ml)was stirred at room temperature for 20 min, and at this time suspendiruemye product was dissolved. Was added N-Propylamine (50 mg) and continued stirring for 1 h at room temperature. Then the reaction mixture was kept boiling under reflux for 15 min, cooled and evaporated in vacuum. Treatment of ethyl acetate and hexane resulted in the precipitation of crystals of tert-butoxycarbonyl derived, tPL183-184° C.

Elemental analysis: calculated for C19H19N4O2F: 64,40, H 5.40, Is N 15,81; found: 64,66, N 5,63, N 15,63.

A solution of the above tert-butoxycarbonyl derivative (100 mg, 0.3 mmol) in tetrahydrofuran was treated with ammonia at 80° in a thick-walled bottle for reactions under pressure for 12 hours, the Reaction mixture was evaporated in vacuum and the mod is to was purified by chromatography on silica gel, using as eluents mixture of ethyl acetate and methanol. Thus obtained purified [4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl] urea had tPL224-225° C.

Elemental analysis: calculated for C15H12N5O: 60,60, N 4,07, N 23,56; found: 60,21, N 4,11, N 23,30.

Example 6

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl] sulphonamide

Sulphonylchloride synthesized from chlorosulfonylisocyanate according to the method described R.Graft in Chemische Berichte, str (1959) (this publication is included in the present description by reference). A solution containing 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine (200 mg, 0.77 mmol)obtained according to example 2, sulphonylchloride (100 mg, 0.8 mmol) and triethylamine (200 mg, 2 mmol) in benzene (5 ml), and acetonitrile (5 ml) was stirred at room temperature for 2 hours, the Reaction mixture was evaporated in vacuo, the residue was treated with water and podslushivaet to pH 7 with ammonium hydroxide. The resulting residue was purified by chromatography on silica gel, using as eluents mixture of ethyl acetate and methanol. Thus obtained purified [4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl] sulphonamide had tPL201-202°C.

Elemental analysis: calculated for C14H12N5SO2F: 50,44, N 3,63, N 21,01; found: 50,43, N Of 3.45, N 20,89.

When is EP 7

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazole-5-amine

The solution containing the above in scheme III lanceton 1 (1.5 g, 5,19 mmol)in which X denotes chlorine in the para-position, methylhydrazine (0.35 ml) and acetic acid (0.75 ml) in benzene (15 ml), kept at boiling under reflux for 3.5 hours the Reaction mixture was cooled and was extracted with 3 N. Hcl. The aqueous layer was concentrated on a rotary evaporator and then podslushivaet using ammonium hydroxide. The precipitate was recrystallized from methanol, obtaining pure 4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazole-5-amine, tPL257-258° C.

Elemental analysis: calculated for C15H13N4Cl: With 63,27, N 4,60, N 19,68; found: 62,93, 4,45 N, N 19,64.

Example 8

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-metalmachine

A solution containing 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-amine (100 mg, 0,39 mmol), obtained according to example 2, methylisocyanate (22 g, 0.38 mmol) and 4-dimethylaminopyridine (2.5 mg) in methylene chloride (10 ml)was stirred at room temperature for 30 minutes, the Reaction mixture was evaporated in vacuum. The residue is triturated with hexane and the solid product was filtered, obtaining pure N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-metalmachine, tPL212-213�B0; C.

Elemental analysis: calculated for C16H14N5FO: 61,73, N 4,53, N 22,50; found: 61,63, N 4,55, N 22,47.

Compounds of examples 9-11 was synthesized according to the methods described above (particularly in scheme IV), using the appropriate starting reagents.

Example 9

4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine

Stage 1

Methylethanolamine (of 13.7 g, 0.1 mol) and ethyl-4-perforateed (18.2 g, 0.1 mol) were mixed together and then added sodium methoxide (8.1 g, 0.15 mmol). The mixture was heated to 60-70° C for 24 h, passing through the flask nitrogen to remove methanol. Then added concentrated hydrochloric acid (50 ml) and the reaction mixture is kept boiling under reflux for 3 hours After adding water (30 ml) the reaction mixture was extracted with chloroform and the aqueous phase is neutralized to pH 6-7 with aqueous sodium hydroxide (1M). The precipitate was collected by filtration, washed with water and dried in vacuum to give 10 g of 2-(4-forfinal)-1-(4'-pyridyl)Ethan-1-she (yield: 46%).1H-NMR: consistent with the established structure of the product and/or its tautomer.

Stage 2

Obtained by the above method 2-(4-forfinal)-1-(4'-pyridyl)Ethan-1-he (1 g) was dissolved in 50 ml of tetrahydrofuran was added dimethylacetal N,N-dimethylformamide (5 ml). CME is ü stirred at room temperature for 2 days. After evaporation of the solvent, the resulting solid product was washed with hexane and was obtained 1 g of vinylamine. This vanillin (0.5 g) was dissolved in ethanol (15 ml) was added hydrazine hydrate (5 ml). The mixture was stirred at 0° C for 2 h and then evaporated to dryness. After recrystallization from methanol/water received 400 mg of 4-[4-(4-forfinal)-1H-pyrazole-3-yl] pyridine with the release of 91%. MS 240 (M+1);1H-NMR: consistent with the established structure of the product.

Elemental analysis: calculated for C14H10FN3·0,2H2O: 69,24, N 4,32, N 17,30; found: 69,54, N 4,06, N 17,43.

Example 10

4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine

When replacing in stage 2 in example 9 of hydrazine hydrate on methylhydrazine was obtained 4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine (N-methyl derivative corresponding to the compound of example 9). After purification by recrystallization from toluene and hexane were obtained pure 4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl] pyridine to yield 57%. MS m/z: 254 (M+1).1H-NMR: consistent with the established structure of the product.

Elemental analysis: calculated for C15H12FN3: 71,13, N 4,78, N 16,69; found: 70,99, N. And 4.68, N 16,65.

Example 11

4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and 4-(forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol

Worked as in example 9 except that the hydrazine hydrate was replaced with 2-hydroxyethylhydrazine. After recrystallization from toluene and hexane was obtained 4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol and 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol in the form of a mixture with a yield of 67%.1H-NMR: consistent with the established structure of the product. MS m/z: 284 (M+1).

Elemental analysis: calculated for C16H14FN3O: 67,83, N To 4.98, N 14,83; found: 67,86, N 5,04, N 14,85.

The compounds of examples 12 and 13 was synthesized according to the above method (in particular, according to scheme V), using an appropriate source reagents.

Example 12

4-(4-forfinal)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine and 4-(4-forfinal)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanamine

4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or 4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol) (1,36 g)obtained according to example 11, was dissolved in 30 ml of pyridine and cooled to 0° C, after which was added methanesulfonamide (0.6 ml). After stirring at 0° C for about 12 h was added about 20 g of ice and the mixture was extracted with toluene (300 ml). The residue obtained after evaporation was used without additional purification. 0.7 g obtained above compound was dissolved settled in methanol (25 ml) was added a solution of dimethylamine/THF (4M, 2 ml). The reaction mixture was kept boiling under reflux for 12 h, then evaporated to dryness. The residue was purified by chromatography (methanol/dichloromethane, 1:10). Thus was obtained a mixture of 4-(4-forfinal)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine and 4-(4-forfinal)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanamine.1H-NMR: consistent with the established structure of the product. MS m/z: 311 (M+1).

Elemental analysis: calculated for C18H19F· 0,N2: 67,50, N 6,33, N 17,49; found: 67,21, N 6,46, N 17,14.

Example 13

4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]morpholine and 4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]morpholine

To obtain a mixture of 4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]the research and 4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]the research worked analogously to example 11 except that dimethylamine was replaced with morpholine. MS m/z: 353 (M+1).

Elemental analysis: calculated for C20H21N4OF· 0,5H2: 66,47, N 6,14, N 15,50; found: 66,57, N 6,27, N 15,14.

The compound of example 14 was synthesized according to the above method (in particular, according to scheme VI)using appropriate initial reagents.

Example 14

4-[4-(4-forfinal)--methyl-1H-pyrazole-3-yl]pyridine

2-(4-forfinal)-1-(4'-pyridyl)Ethan-1-he (0.5 g, 0,00232 mol), obtained in stage 1 in example 9 was mixed with 98%methylhydrazine (0.2 g, 0,00462 mol) in 10 ml of ethanol containing 0.1 ml of acetic acid in an Erlenmeyer flask 50 ml After careful boiling (30 min in the steam room) took a small sample of the mixture was placed in a deep vacuum and examined by NMR to confirm the completion of the formation of the hydrazone. The reaction mixture was concentrated to a pasty mass, after which was added 3.6 ml of dimethylacetal DMF (0,027 mol) and was heated up to 80° C for 30 min, it was obtained a transparent viscous solution is yellow. Tested, the results of reaction (by TLC or NMR), and the mixture was concentrated and dissolved in 20 ml of chloroform. After washing with water (10 ml) the organic layer was extracted with 15 ml of 10%Hcl. The aqueous layer was then treated with 0.5 g of activated charcoal at 70° C for 10 min, filtered through celite, carefully neutralized to pH 7-8 with vigorous stirring and cooling. Fine-grained whitish precipitate was filtered and dried. Using NMR established that the structure of the product was consistent with the expected. Was obtained with a quantitative yield of the precipitate, representing 4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine, which was filtered, washed with simple ether and dried. In the move: 0.45 g (77%). MS m/z: 254.

Elemental analysis: calculated: 62,18, N To 4.52, N 14,50; found: 62,39, N 4,07, N 14.24 from.

Example 15

4-[4-(4-chlorophenyl)-1H-pyrazole-3-yl]pyridine

4-[4-(4-chlorophenyl)-1H-pyrazole-3-yl]pyridine was obtained according to example 9 except that the ethyl-4-perforateed was replaced by ethyl-4-chlorophenylacetic; tPL204-207° C.

Elemental analysis: calculated: 65,76, N 3,94, N 16,43; found: 65,44, N Of 3.78, N 16.04.

Example 16

4-(4-Phenyl)-1H-pyrazole-5-yl)pyridine

4-(4-phenyl)-1H-pyrazole-5-yl)pyridine was obtained according to example 9 except that the ethyl-4-perforateed replaced ethylvinylacetate.

Example 17

1-methyl-4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine and 1-methyl-4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine

These compounds can be obtained by the synthesis method described in example 11, replacing hydroxyethylhydrazine 4 hydrazino-N-methylpiperidin. 4 hydrazino-N-methylpiperidin synthesized according to the method described in Ebnoether, etc., Helv. Chim. Acta (1959) 42, 533, 541, 560. The resulting mixture was divided into the respective pure substance specified in the header by chromatography on silica gel, using as eluent methanol/dichloromethane (1:10) or other PR is a suitable solvent system.

Biological assessment

Analysis of kinase R

Cloning of the human kinase Rα

The coding region of cDNA of human Rα received PCR amplification of RNA extracted from cell lines of human monocytes TNR. The first chain cDNA was synthesized using total RNA as follows. 2 µg of RNA was annealed to 100 ng of random review of the primers in a 10 μl reaction mixture by heating to 70°C for 10 min, followed by holding for 2 min on ice. Then synthesized cDNA by adding 1 ál RNAsin(company Promega, Madison, items of Wisconsin), 2 μl of 50 mm dNTP, 4 ál of five times (5x) buffer, 2 μl of 100 mm DTT and 1 μl (200 units) reverse transcriptase AMV (virus myeloblastosis birds) from a set of Superscript II™ . Arbitrary primer, dNTP and reagents Superscript™ acquired the firm Life Technologies, Gaithersburg, PCs Minnesota. The reaction mixture was incubated at 42° C for 1 h Amplification of cDNA R was performed by adding 5 µl aliquot of the reaction mixture containing reverse transcriptase, 100 μl of the reaction mixture for PCR (polymerase chain reaction)containing the following components: 80 ál DN2Oh, 2 μl of 50 mm dNTP, 1 µl of each primers for synthesis in the course and progress against transcription (50 pmol/ál), 10 ál of 10x buffer and 1 ál of polymerase Expand™ (firm Boehringer Mannheim). HRC is-primers were provided by the inclusion of BamHI sites at the 5'- and 3'-ends of the amplified fragment, and they were obtained from Genosys company. Primers for synthesis along and against the course of transcription, had the following sequence:

5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3' and

5'-GATCGAGGATTCTCAGGACTCCATCTCTTC-3'

respectively. PCR amplification was carried out in thermoacetica type DNA Thermal Cycler, Perkin Elmer) by the following 30 cycles: 94° for 1 min, 60° for 1 min and 68° within 2 minutes After amplification, excess primers and uninvolved dNTP removed from the amplified fragment using the set Wizard™ PCR prep (firm Promega) and digested with BamHI (company New England Biolabs). BamHI-fragment ligated treated with BamHI DNA plasmids pGEX 2T (firm PharmaciaBiotech) using T-4 DNA ligase, New England Biolabs) according to the method described in T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The resulting ligation product was used to transform chemically competent cells of E. coli strain DH10B, supplied by the firm Life Technologies) following the manufacturer's instructions. Plasmid DNA was isolated from the resulting colonies of bacteria using a set of Pi omega Wizard™ miniprep. Plasmids containing the corresponding BamHI-fragment sequenced in thermoacetica type DNA Thermal Cycler, Perkin Elmer) using Prism™ (company Applied Biosystems Inc.). Identified cDNA clones that encode two isoforms of the human RA (Lee and others, Nature 372, 739). One of the clones, which materialcan Rα -2 (CSBP-2)built into the cloning site of the plasmid pGEX 2T, located on the 3'end of the GST coding region, identified as pMON 35802. Set the sequence of this clone corresponded exactly to the sequence of the cDNA clone described by Lee and others This plasmid expression allows to obtain a fused protein GST-p38α .

Expression of human Rα

Fused protein GST/p38a expressed using plasmid pMON 35802 in E. coli strain DH10B (Life Technologies, Gibco-BRL). The cultures were grown overnight in Luria broth (LB)containing 100 mg/ml ampicillin. The next day, 500 ml of fresh LB-broth was inoculable 10 ml grown overnight culture and grown in a flask with a volume of 2 l at 37° C with constant shaking until the culture absorbance of 0.8 at 600 nm. The expression of the fused protein was induced by adding isopropyl-b-D-thiogalactoside (IPTG) to final concentration of 0.05 mm. The culture was shaken for 3 h at room temperature and collecting the cells by centrifugation. Cellular debris was stored frozen until purification of the protein.

Cleaning kinase Rα

All chemical reagents obtained from the company Sigma Chemical Co., if not stated otherwise. After fermentation in five shake flasks with a volume of 1 l was collected 20 g of cell debris of E. coli and resuspendable volume suboofer the frame phosphate fiziologicheskii restore (SFR) (140 mm NaCl, 2.7 mm KCl, 10 mm Na2HPO4, 1.8 mm KN2RHO4pH 7,3), 200 ml. Concentration dithiotreitol (DTT) in the cell suspension was brought to 5 mm using 2M DTT and then distributed equally between the five conical Falcon tubes with a volume of 50 ml of Cells were irradiated with ultrasound (device Ultrasonics, model W375) using a probe size of 1 cm three times for 1 min (ripple) on ice. Lysed cell material was removed by centrifugation (12000× g, 15 min) and the clarified supernatant was made in glutathione-separato resin (firm Pharmacia).

Glutathione-Savarona affinity chromatography

To 200 ml of the clarified supernatant was added to 20 ml of a 50%suspension of glutathione-sepharose in SFR and incubated portions over 30 min at room temperature. The resin was collected by centrifugation (600× g, 5 min) and washed 2× 150 ml SPR/1% Triton X-100, and then 4× 40 ml SPR. To highlight kinase R of the fused protein GST-p38 glutathione-separato resin resuspendable in 6 ml SPR containing 250 units of thrombin protease (firm Pharmacia, specific activity>7500 units/mg) and gently stirred for 4 h at room temperature. Glutathione-supersnow the resin was removed by centrifugation (600× g, 5 min) and washed 2× 6 ml SPR. Washed SFR faction and split the supernatant containing the protein kinase, were combined and the concentration of f is dimetilsulfoksida (FMSF) brought up to 0.3 mm.

Uninominal chromatography on a column of Mono Q

Split thrombin-protease kinase R further purified using uninominal GHBR - liquid chromatography quick resolution) chromatography. Split thrombin-protease sample was diluted 2-fold with buffer A (25 mm HEPES, pH 7.5, 25 mm beta-glycerol, 2 mm DTT, 5% glycerol) and loaded into uninominal column Mono Q HR 10/10 (firm Pharmacia), equilibrated with buffer A. the Column was suirable gradient of salt (160 ml 0.1m-0.6m NaCl/buffer And a flow rate of 2 ml/min). Collected peak kinase R, eluruumist at a concentration of 200 mm NaCl, and concentrated to 3-4 ml with hub type Filtron 10 (Filtron company Corp.).

Gel filtration on Sephacryl S100

The concentrated sample kinase R obtained after chromatography on a column of Mono Q purified by gel-filtration (column HiPrep 26/60 Sephacryl S100 firm Pharmacia, balanced with buffer B (50 mm HEPES, pH 7.5, 50 mm NaCl, 2 mm DTT, 5% glycerol)). The protein was suirable from the column with buffer B at a flow rate of 0.5 ml/min and protein was detected by absorbance at 280 nm. Containing kinase R fractions (identified by electrophoresis in polyacrylamide gel in the presence of sodium dodecyl sulfate (LTOs)) were combined and frozen at -80° C. As a rule, of the purified protein obtained after fermentation of E. coli in shake flasks with a volume of 5 l, received 35 m the kinase R.

In vitro

The ability of compounds to inhibit human kinase R35α has been evaluated in vitro by two methods. The first method is based on the ability of activated human kinase RA to fosforilirovanii biotinylated substrate PHAS-I (fosforilirovanii, resistant to temperature and acidic environment induced by insulin protein) in the presence of γ -32P-ATP (32P-ATP). PHAS-I was biotinilated to analysis and later in the analysis process revealed the phosphorylated substrate. Kinase R activated using MCC. Compounds were tested in the concentration range from 100 to 0.001 microns, obtained using 10-fold serial dilution in 1%DMSO. Each concentration of inhibitor was tested three times.

All reactions were performed in 96-well tablets from polypropylene. Each reaction well contained 25 mm HEPES, pH 7.5, magnesium acetate (10 mm) and unlabeled ATP (50 μm). To achieve a sufficient level signal when the analysis was necessary activation R. Biotinylated PHAS-I used at 1-2 μg per volume of reaction mixture of 50 μl at a final concentration of 1.5 μm. Activated human kinase Rα used in quantities of 1 μg in 50 μl volume reaction mixture at a final concentration of 0.3 microns. γ -32P-ATP was used to identify the process of phosphorylation of PHAS-I In the recreational activity 32P-ATP was 3000 CI/mmol and was used at 1.2 µci/50 μl volume reaction mixture. The reaction was carried out either for 1 h or overnight at 30°C.

After incubation, 20 µl of reaction mixture was transferred into a filtration device with adsorbed streptavidin with high affinity to Biotin (SAM-streptavidin-matrix, the firm Promega), pre-moistened with phosphate buffered saline. Made contact, the reaction mixture is transferred from streptavidin membrane tablet company Promega within 1-2 minutes After the capture of the biotinylated PHAS-I enabled mark32P in order to remove those that are not32P-ATP to each well three times washed with 2M NaCl with 1% phosphoric acid, washed three times with distilled water and finally once were washed in 95%ethanol. Filtration tablets were dried in air and the wells were added 20 μl of scintillation fluid. The tablets were sealed and counted radioactivity.

Also used the second method of analysis is based on the ability of the kinase Rα to induce phosphorylation EGFRP (receptor peptide epidermal growth factor, 21-d) in the presence of33P-ATP. Compounds were tested in the concentration range from 100 to 0.001 microns, obtained using 10-fold serial dilutions in 1%DMSO. Each concentration is July inhibitor was tested three times. The activity of compounds was evaluated in a reaction volume of 50 μl in the presence of 25 mm HEPES, pH 7.5, 10 mm magnesium acetate, 4% glycerol, and 0.4% bovine serum albumin, 0.4 mm DTT, 50 μm unlabeled ATP, 25 μg EGFRP (200 μm) and 0.05 µci γ -33P-ATP. The reaction was initiated by adding of 0.09 µg purified activated fused protein GST-human kinase Rα . Activation was performed using GST-MKK6 (5:1, R:MCC) for 1 h at 30° in the presence of 50 μm ATP. After incubation for 60 min at room temperature the reaction was stopped by adding 150 μl of resin type AG H 900 mm sodium formatnum buffer, pH 3 (1 volume of resin to 2 parts buffer). The mixture was stirred three times with a pipette and the resin was allowed to settle. The upper fraction of the clarified solution with a total volume of 50 µl was transferred from the reaction wells on the tablets of the type Microlite-2. Then to each well of the tablet Microlite was added 150 μl of scintillation fluid Microscint 40 and the tablets were sealed, mixed, and the radioactivity was counted.

Analyses of cellular TNF

Isolation of mononuclear cells from human peripheral blood

Whole human blood was collected in tubes of the type Vacutainer containing add as an anticoagulant. A blood sample (7 ml) was carefully applied layers 5 ml of medium for isolation of PMN cells (firm Robbins Scientific) in a round bottom centrifuge vitro volume of the IOM 15 ml. The sample was centrifuged at 450-500× g for 30-35 minutes in a centrifuge with a swinging rotor at room temperature. After centrifugation, the upper layer of cells was removed and washed three times with SFR, including calcium or magnesium. The cells were centrifuged at 400× g for 10 min at room temperature. Cells resuspendable in serum-free culture medium for macrophages (Macrophage Serum Free Medium) (company Gibco BRL) at a concentration of 2 million cells/ml

Stimulation with LPS mononuclear cells from peripheral blood (PCR)

The PCR-cells (0.1 ml, 2 million/ml) was co-incubated with 0.1 ml of compound (final concentration 10-0,41 μm) for 1 h in flat-bottomed 96-well microtiter plates. Connection pre-dissolved in DMSO and diluted in SCI to final concentration of DMSO of 0.1%. Then added LPS (firm Calbiochem, final concentration 20 ng/ml) in volume 0,010 ml Culture was incubated over night at 37° C. Then supernatant were removed and tested by ELISA against TNF-α and IL-β . Viability was analyzed using the MTS. After removing 0.1 ml supernatant to the remaining 0.1 ml of cells was added 0,020 ml MTS. Cells were incubated at 37° C for 2-4 h, and then measured the optical density (OD) at 490-650 nm.

Maintenance and differentiation of the cell line human is eskay histochemically lymphoma U937

Cell line U937 (ATS) were propagated in RPMI medium 1640 containing 10% fetal bovine serum, 100 units/ml penicillin, 100 μg/ml streptomycin and 2 mm glutamine (firm Gibco). 50 million cells in 100 ml medium induced the final differentiation of monocytes by 24-hour incubation with 20 ng/ml phorbol-12-myristate-13-acetate, Sigma). Cells were washed by centrifugation (200× g for 5 min) and resuspendable in 100 ml of fresh medium. After 24-48 h, the cells were collected, centrifuged and resuspendable in the culture medium at the rate of 2 million cells/ml

Stimulation with LPS, the production of TNF-cell line U937

Cell line U937 (0.1 ml, 2 million/ml) were incubated with 0.1 ml of compound (final concentration of 0.004-50 μm) for 1 h in 96-well microtiter plates. Compounds were prepared as 10 mm mother solutions in DMSO and diluted in culture medium, receiving the final concentration of DMSO of 0.1%, which was used in experiments on cells. Then added 0,02 ml LPS (E. coli, the final concentration of 100 ng/ml). After incubation for 4 h at 37° using the ELISA was determined by the quantitative content of TNF-α released into the culture medium. The inhibitory activity was expressed as IC50(μm).

A study on rats

The effectiveness of the new compounds in relation to inhibition of production of TNF that the same has been evaluated, using as a model rats, which were injected LPS. As this model was used male rats Harlen Lewis [Sprague Dawley Co.]. Each rat weighing approximately 300 g were not given food during the night before the experience. Typically, compounds were administered orally via a stomach tube (although in some cases also used intraperitoneal, subcutaneous and intravenous) for 1-24 h before LPS injection. Rats were injected intravenously through the tail vein 30 µg/kg LPS [Salmonella typhosa, the firm Sigma Co.]. After 1 h after administration of LPS samples were taken of blood by cardiac puncture. Serum samples were stored at -20° to quantify TNF-α using enzyme-linked immunosorbent assay ("ELISA") [Biosource]. Additional details of the analysis are described in Perretti, M. and others in Br.J.Pharmacol. (1993), 110, 868-877) publication included in the present description by reference).

A study on mice

Modeling in mice LPS-induced production of TNF-α

The production of TNF-α induced 10-12-week-old female mice of BALB/c mice by injection through the tail vein with 100 ng of lipopolysaccharide (S.typhosa) in 0.2 ml of saline. After 1 h, the mice took the blood from retroorbital sine and using ELISA, quantitatively assessed the concentration of TNF in the serum obtained after coagulation. As a rule, the maximum is some amount of TNF in the serum was in the range of from 2 to 6 ng/ml after 1 h after injection of LPS.

The test compounds were injected hungry mice orally via a stomach tube in the form of a suspension in 0.2 ml of a mixture containing 0.5% methylcellulose and 0.025% Tween-20 in water for 1 h or 6 h before LPS injection. The results obtained after 1 h, allow to evaluate the potency of the compound, expressed as a maximum concentration in plasma (Cmax), and the results obtained after 6 h, allow to estimate the duration of the connection. Efficiency at each time point was determined as the percentage of inhibition of the levels of TNF in the serum compared with data obtained for mice, which were injected LPS and only media.

Induction and assessment of collagen-induced arthritis in mice

Arthritis was induced in mice according to the method described in J.M.Stuart, Autoimmune Collagen Arthritis, Annual Rev. Immunol. 2: 199 (1984) (publication included in the present description by reference). In particular, arthritis was induced in 8-12-week-old male mice of the DBA/I is injected into the base of the tail at 0 day 50 mg collagen type II chicken (S) (provided by Dr. Marie Griffiths, University of pieces Utah, salt lake city, pieces Utah) in complete Freund's adjuvant (firm Sigma). The volume of solution for injection was 100 µl. Animals did on the 21st day of the booster injection, for which we used 50 mcg SR in incomplete Freund's adjuvant (100 μl). Animals were examined n is the number of times each week in respect of the symptoms of arthritis. Every animal that had found redness or swelling of the paws, it was considered ill with arthritis. Quantitative assessment of arthritic paws scoring was carried out according to the method described by Wooley et al., Genetic Control of Type II Collagen Induced Arthrotis in Mice: Factors influencing Disease Susceptibility and Evidence for Multiple MHC Accociated Gene Control., Trans. Proc. 15: 180 (1983). The severity of the disease each paw was assessed as a score, using a-point scale (maximum score for each animal 12). The presence in animals of any redness or swelling of the fingers or paws were evaluated score of 1. Severe swelling of the entire paw or deformation was evaluated by a score of 2. Ankylosis of the joints was evaluated by a score of 3. Animals were examined at 8 weeks. Each group used 8-10 animals.

Preparation and introduction connections

Compounds that were tested in mice with collagen-induced arthritis, were prepared as a suspension in 0.5%methylcellulose (firm Sigma, St. Louis, PCs Missouri), of 0.025%Tween-20, Sigma). Suspensions of the compounds was administered orally via a stomach tube in a volume of 0.1 ml twice a day. Treatment was started on day 20 after injection of collagen and continued daily until the last examination on day 56. The scoring defeat arthritic paws were conducted according to the above-described method.

The results obtained in the above experiments are shown below in table the price. Results on the determination of inhibition R and obtained using cell line U937, expressed as IC50values (μm). The results obtained in mice using FSC (MLPs), expressed as percent inhibition.

Table
Examplep38α1(µm)2(µm)U937 (µm)MLPs (6 h at 30 mpk)
130,0013,3510,00 
2 6,2110,61 
3 2,55>10,00 
4 0,234,7054
51,98 of 5.53 
6  10,00 
7 5,4810,00 
8  10,00 
92,44of 3.460,647442
10of 7.23 0,41,598776
110,6951040 
120,94110-5 
130,86>1022 
155,90,75 32
Notes:

1results for Rα in vitro analysis using PHAS-I,

2results for Rα in vitro analysis using EGFRP.

The present invention also relates to a class of pharmaceutical compositions comprising as active substances of the compounds of the present invention in combination with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (generally indicated in the present description as "carriers"), and optionally with other active ingredients. The active substances according to the invention can be any suitable for this purpose method, preferably in the form of pharmaceutical compositions intended for the selected route of administration, and in a dose effective for appropriate treatment. The active substance and the compo is icii, for example, can be administered orally, intravenously, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration the pharmaceutical composition can be manufactured in the form of, for example, tablets, capsules, soft or hard surface, cakes, dispersible powders, suspensions or liquid. The pharmaceutical composition is preferably made in the form of a standard dose containing a certain amount of the active substance. Examples of such standard doses are tablets or capsules. The active substance may also be introduced by injection (intravenously, intramuscularly, subcutaneously or inkjet) in the form of a composition in which as acceptable carrier can be used, for example, saline, dextrose or water. The pH value of the composition can be adjusted if necessary acceptable acid, base or buffer. The composition may also be included acceptable fillers, dispersing agents, wetting or suspendresume agents, including mannitol or PEG 400. Acceptable parenteral composition may also include a connection is made in the form of sterile solid compositions, in particular in the form of lyophilized powder in vials for injection. For dissolution of the composition before injection can be added to water is Astor. The amount of therapeutically active compounds that can be administered, and the dosage regimen for the treatment of painful conditions using the compounds and/or compositions according to the invention depends on various factors, including age, weight, sex and medical condition of the patient, the severity of the inflammation or associated with inflammation disorders, route and frequency of administration, and specific applicable connection and, thus, may vary within wide limits. The pharmaceutical compositions may contain the active substance in the range of from about 0.1 to 1000 mg, preferably in the range of from about 7.0 to 350 mg Daily dose can be from about 0.01 to 100 mg/kg body weight, preferably from about 0.1 to about 50 mg/kg body weight and most preferably from about 0.5 to about 30 mg/kg of body weight. The daily dose may be administered one to four times per day. In case of skin diseases may be preferable to apply topically preparative form of the compounds of the present invention over the affected area 2-4 times a day. In diseases of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied in the form of gel, spray, ointment or cream for topical application or in the form of a suppository with a total content of active substances, for example, from 0,075 up to 30 wt.%, p is edocfile from 0.2 to 20 wt.% and most preferably from 0.4 to 15 wt.%. In the preparation of formulation in the form of ointment active ingredients can be applied either with a paraffin base or mixed with water-based ointments. In another embodiment, the active substances can be produced in the form of emulsion cream base type oil-in-water. If necessary, the aqueous phase of the basics of the cream may include at least 30 wt.% a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, glycols and mixtures thereof. Composition for topical application may optionally include a compound which enhances absorption or penetration of the active substance through the skin or other affected areas. Examples of such substances that enhance penetration through the skin include dimethylsulfoxide and close substitutes. Compounds according to the invention can be administered using a transdermal device. Preferably, the local application may be implemented using devices such as plaques, consisting of either of the reservoir and porous membrane type or of a solid matrix of various types. In any case, the active substance is continuously released from the reservoir or microcapsules through a membrane permeable to the active substance is an adhesive layer which is in contact with the skin or mucosa of the recipient. If active is emesto absorbed by the skin, the recipient active substance is introduced in a controlled and predetermined rate. In the case of microcapsules kapsulirujushchej agent may also function as a membrane. Transdermal plaque can include connections to fit the solvent system together with an adhesive system, such as an acrylic emulsion and polyester plaque. The oil phase of the emulsion according to the invention can be obtained from known ingredients in a known manner. Although the phase may consist only of emulsifier, it can also include a mixture of at least one emulsifier and fat or oil or grease, and oil. Preferably hydrophilic emulsifier include together with a lipophilic emulsifier, which acts as a stabilizer. It is preferable to include both oil and fat. Together, the emulsifier(s) with stabilizer(s) or without it (them) forms(comply) with the so-called emulsion wax, and the wax together with the oil and fat forms a so-called base emulsion ointment base which forms the oily dispersion phase compositions in the form of a cream. Emulsifiers and emulsion stabilizers suitable for use in preparative form of the present invention include, inter alia, tween 60, span 80, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate. Choosing the acceptable oils or fats for the formulation is based on achieving the desired cosmetic properties, because the solubility of the active ingredient in most oils, which are preferably used in the pharmaceutical compositions in the form of an emulsion, is very low. Thus, the cream should preferably be a low-fat, no staining and washable product with reasonable consistency to avoid leakage from tubes or other containers. Can be used alkalemia esters of one or dibasic acids with straight or branched chain, such as digitariat, isolatedstore, diesters of propylene glycol and fatty acids of coconut oil, isopropylmyristate, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixture of esters with branched chain. They can be used individually or in combination depending on the desired properties. In another embodiment, can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin or other mineral oils.

Compositions suitable for local injection into the eye, can also be a eye drops, in which the active substance is dissolved or suspended in an acceptable active substance carrier, primarily in the aqueous solvent. Anti-inflammatory active substances are preferably present in such to whom Nasiriyah in a concentration of from 0.5 to 20%, preferably from 0.5 to 10% and particularly preferably in a concentration of about 1.5 wt.%. For therapeutic purposes, the active substance of this composition according to the invention typically combined with one or more adjuvants suitable for the desired route of administration. When ingested compounds may be admixed with lactose, sucrose, powdered starch, cellulose ethers and alkanovykh acids, alkylamino esters of cellulose, talc, stearic acid, magnesium stearate; magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, Arabic gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may include a composition with controlled access, which can be a dispersion of the active substance in the hypromellose. Compositions for parenteral administration can be prepared in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions can be obtained from sterile powders or granules having one or more carriers or diluents mentioned above in the description of the composition for oral administration. The compounds may be dissolved in the e, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers. Other adjuvants and methods of injection well and widely known in the pharmaceutical field.

All patents and patent applications mentioned in the present description, is included as a reference. Although the invention is described on the example of a specific variants of its exercise of such options shall not be construed as limiting the scope of invention.

1. 3(5)-Heteroarylboronic pyrazole, his tautomer or pharmaceutically acceptable salt of this compound or tautomer, where the compound corresponds to the structure of formula I

where R1selected from the group including hydride, piperidinyl, replaced by stands, (bottom.)alkyl, (bottom.)alkyl, substituted hydroxy, (bottom.)alkyl, substituted (nih.)alkylamino, (bottom.)alkyl, substituted morpholino;

R2selected from the group including hydride, (ness.)alkyl, amino, aminocarbonyl, (ness.) alkylaminocarbonyl, (ness.)alkylsulfonamides, aminosulfonyl and (ness.)alkylaminocarbonyl;

Ar1denotes phenyl, optionally substituted by one or more independently selected halogen substituents;

2denotes a pyridinyl, provided that R2does not mean amino, n-propyl, when HetAr2is pyridinyl, and provided that HetAr2does not mean 2-pyridinyl, when R2means hydrogen, (ness.)alkyl.

2. The compound, salt or tautomer according to claim 1, in which R1selected from the group including hydride, (ness.)alkyl, (ness.)alkyl, substituted hydroxy, (ness.)alkyl, substituted (ness.)alkylamino, (ness.)alkyl, substituted morpholino, and R2selected from the group including hydride, (ness.)alkyl, amino, aminocarbonyl, (ness.)alkylaminocarbonyl, (ness.)alkylsulfonamides, aminosulfonyl and (ness.)alkylaminocarbonyl.

3. The compound, salt or tautomer according to claim 2, in which R1selected from the group including hydride, methyl, ethyl, isopropyl, tert-butyl, isobutyl, morpholinomethyl, morpholinoethyl, methylaminomethyl, dimethylaminomethyl, methylaminomethyl, dimethylaminomethyl, hydroxymethyl and hydroxyethyl, and R2selected from the group including hydride, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, amino, aminocarbonyl, methylaminoquinoline, dimethylaminocarbonylmethyl, ethylenediamino, diethylaminoethylamine, methylsulfonylamino, ethylsulfonyl, aminosulfonyl, methylmonoethanolamine, dimethylaminopropylamine, ethylaminomethyl is, diethylaminoethylamine, Ar1denotes phenyl, optionally substituted by one or more substituents independently selected from the group comprising fluorine, chlorine and bromine.

4. The compound, salt or tautomer according to claim 3 in which R1selected from the group including hydride, methyl, ethyl, hydroxyethyl, dimethylaminoethyl and morpholinoethyl, and R2selected from the group including hydride, methyl, ethyl, amino, aminocarbonyl, methylaminoquinoline, methylsulfonylamino, aminosulfonyl, methylmonoethanolamine.

5. The compound, salt or tautomer according to claim 4, in which R1selected from the group including hydride and methyl, R2selected from the group including hydride and methyl, Ar1denotes phenyl, optionally substituted by one or more substituents, independently from each other selected from the group comprising fluorine and chlorine.

6. The compound, salt or tautomer according to any one of claims 1 to 5, where HetAr2denotes pyridinyl.

7. The compound, salt or tautomer according to any one of claims 1 to 3, in which R2means hydride and HetAr2denotes pyridinyl.

8. The compound, salt or tautomer according to claim 4 or 5, in which R2means hydride and HetAr2denotes pyridinyl.

9. 3(5)-Heteroarylboronic pyrazole, his tautomers and pharmaceutically acceptable salts of the compounds or tautomers, where the compound is chosen from gr is PPI, including

4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-methylsulfonyl;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]urea;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]sulphonamide;

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazole-5-amine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-metalmachine;

4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine;

4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine;

4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;

4-(4-forfinal)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;

4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]morpholine;

4-[4-(4-chlorophenyl)-1H-pyrazole-3-yl]pyridine;

1-methyl-4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine;

1-methyl-4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine.

10. The compound, salt or tautomer according to claim 1, in which R1selected from the group including hydride, (ness.)alkyl, (ness.)alkyl, substituted hydroxy, (ness.)alkyl, substituted alkylamino, (ness.)alkyl, substituted morpholino, and R2selected from the group including hydride, (ness.)alkyl, aminocarbonyl, (ness.) alkylaminocarbonyl, (ness.)alkylsulfonamides aminosulfonyl and (ness.)alkylaminocarbonyl, and Ar1denotes phenyl, optionally substituted by one or more independently selected halogen substituents, and HetAr2denotes pyridinyl.

11. The compound, salt or tautomer of claim 10, in which R1selected from the group including hydride, methyl, hydroxyethyl, dimethylaminoethyl and morpholinoethyl, and R2selected from the group including hydride, methyl, ethyl, aminocarbonyl, methylaminoquinoline, methylsulfonylamino, aminosulfonyl, methylmonoethanolamine.

12. The compound, salt or tautomer according to any one of claims 1 to 6, 10 and 11, in which R2means hydride.

13. Pharmaceutical composition having inhibitory activity against R kinase, TNF, inflammation and/or arthritis and comprising a therapeutically effective amount of a compound, salt or tautomer according to any one of claims 1 to 12.

14. The method of treatment mediated TNF disorders, including the treatment of the patient with the breach or sensitive to this violation, a therapeutically effective amount of a compound, salt or tautomer according to any one of claims 1 to 12.

15. The method of treatment mediated by kinase R disorders, including the treatment of the patient with the breach or sensitive to this violation, a therapeutically effective amount of a compound, salt or tautomer for any who one of claims 1 to 12.

16. The method of treatment mediated by kinase R inflammation, including the treatment of a patient having a specified state or sensitive to this condition, a therapeutically effective amount of a compound, salt or tautomer according to any one of claims 1 to 12.

17. The method of treatment mediated by kinase R arthritis, including the treatment of a patient having a specified state or sensitive to this condition, a therapeutically effective amount of a compound, salt or tautomer according to any one of claims 1 to 12.

18. The method according to 14 or 15, characterized in that the disturbance is chosen from the group including disorders associated with bone resorption, graft versus host disease, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, respiratory distress syndrome, adult asthma, a chronic inflammatory lung disease associated with reperfusion of the heart damage associated with reperfusion kidney damage, thrombosis, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammation of the digestive tract and cachexia.

19. The method according to 14, where the violation is an inflammation.

20. The method according to 14 or 15, where the infringement is arthritis.

21. The method according to 14 or 15, where the infringement is asthma.

22. The method according to p-16 or 17, where the unity is chosen from the group including

4-(3-methyl-4-phenyl-1H-pyrazole-5-yl)pyridine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]methanesulfonamide;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-methylsulfonyl;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]urea;

[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]sulphonamide;

4-(4-chlorophenyl)-1-methyl-3-(4-pyridinyl)-1H-pyrazole-5-amine;

N-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-3-yl]-N'-metalmachine;

4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine;

4-[4-(4-forfinal)-1-methyl-1H-pyrazole-3-yl]pyridine;

4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol;

4-(4-forfinal)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine;

4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]ethyl]morpholine;

4-[4-(4-chlorophenyl)-1H-pyrazole-3-yl]pyridine;

1-methyl-4-[2-[4-(4-forfinal)-3-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine;

1-methyl-4-[2-[4-(4-forfinal)-5-(4-pyridinyl)-1H-pyrazole-1-yl]]piperidine.

23. Connection, tautomer or salt according to claim 1, where the compound is 4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine.

24. The method according to 14 or 15, characterized in that the compound is a 4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine.

25. The method of treatment mediated by kinase R disorders, including the treatment of the patient with the breach or Chu is responsive to this violation, a therapeutically effective amount of 4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine, tautomer 4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine or a pharmaceutically acceptable salt of 4-[4-(4-forfinal)-1H-pyrazole-3-yl]pyridine or its tautomer.



 

Same patents:

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to 1-(6-amino-3,5-differencein-2-yl)-8-bromo-7-(3-acylaminoalkyl-1-yl)-6-fluoro-4-oxo-1,4-dihyd-rhinolin-3-carboxylic acid or its salt, as well as to antimicrobial drug and compositions on the basis of this compound or its salt

The invention relates to organic chemistry, in particular to derive SIM-triazine-2-ethylamino-4-piperidyl-6-[(4’-methylcarbamyl-5’-methyl-1’,2’,3’,-triazole)-1-yl]-1,3,5-triazine structure:

as an antidote from fetotoksicheskoe action of the herbicide 2,4 - dichlorophenoxyacetic acid on the sunflower sprouts

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: veterinary science.

SUBSTANCE: the suggested method should be implemented under conditions of experimental modeling dystrophic process due to intramuscular injection of glucosamine hydrochloride at the dosage of 15-25 mg/kg once or twice weekly for 1 mo. The method provides good effect in treating a lesion induced in the course of an experiment due to matching adequate dosages and a certain mode of injecting chondroprotector in animals.

EFFECT: higher efficiency of correction.

6 dwg

FIELD: veterinary science.

SUBSTANCE: the suggested method should be performed under conditions of experimental modeling dystrophic process due to intraosseous introduction of glucosamine hydrochloride at the dosage of 15-25 mg/kg 1-2 times weekly during a month. The method provides high local concentrations of medicinal preparation, at its steady entering the circulation by leaving aside hepatic barrier and, as a result, optimization of chondroprotector action of glucosamine hydrochloride and better treatment of articular alterations induced in the course of an experiment in animals.

EFFECT: higher efficiency of correction.

8 dwg, 1 ex

The invention relates to medicine and for the preparation of biotransplant and treatment of degenerative and traumatic diseases of the articular cartilage
The invention relates to medicine, namely to traumatology and orthopedics, and refers to undifferentiated cells of humans and animals and methods of their preparation

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to pharmaceutical industry and relates to the establishment of preventive and curative remedies herbal treatment for arthritis and arthrosis

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

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