2,3-substituted pyrazine sulphonamides as crth2 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

 

The scope to which the invention relates.

The present invention relates to 2,3-substituted personalpronomen for use as pharmaceutical active compounds, and to pharmaceutical compositions containing such 2,3-substituted personalfinance. Mentioned derivatives suitable for the treatment and prevention of allergic diseases and inflammatory dermatoses. Specifically, the present invention relates to the use of 2,3-substituted personalpolitik to modulation, especially inhibition activity chemoattractant receptor homologous molecule expressed on T-helper type 2 (CRTH2). In addition, the present invention relates to new 2,3-substituted personalpronomen, as well as methods for their preparation.

Background of invention

Prostaglandin D2 (PGD2) has long been associated with inflammatory and atopic conditions, especially allergic diseases such as asthma, rhinitis and atopic dermatitis (Lewis and others (1982) J. Immunol. 129, s). PGD2 belongs to a class of compounds derived from 20-carbon fatty acid skeleton arachidonic acid. In response to the antigen target PDG2 is released in large quantities in the respiratory tract, and the skin during acute allergic reactions. The receptor for prostaglandin D2 (DP), which is one is by a member of the subfamily of receptors, associated with G-protein (GPCR), has long been considered the only receptor for PGD2. The role of the DP in allergic asthma has been demonstrated in DP-deficient mice (Matsuoka and others (2000) Science 287, SS-2017). However, despite the increased interest in the role of PGD2 in inflammatory reactions, a direct link between activation of the DP receptor and PGD2-stimulated migration of eosinophils was not installed (Woodward and others (1990) Invest. Ophthalomol Vis. Sci. 31, SS-146; Woodward and others (1993) Eur. J. Pharmacol. 230, c.327-333).

Recently another coupled with G-protein receptor, referred to as "chemoattractant receptor homologous molecule expressed on T-helper 2" (CRTH2) (Nagata and others (1999) J. Immunol. 162, c.1278-1286, Hirai and others (2001) J Exp. Med. c.193, 255-261), was identified as a receptor for PGD2, and this discovery marked the beginning of the elucidation of the mechanism of action of PGD2. CRTH2, which is also referred to as DP2, GPR44 or DLIR, the structure bears little resemblance to the DP receptor and other prostanoid receptors. However, CRTH2 has similar affinity to PGD2. Among T-lymphocytes in the peripheral blood of human CRTH2 selectively expressed on Th2 cells and with a high level is expressed on the cell types associated with allergic inflammation, such as eosinophils, basophils and Th2 cells. In addition, CRTH2 mediates PGD2-dependent cellular migration of eosinophils and basophils in the blood. Moreover, the increased number of the number of circulating blood T cells, expressing CRTH2, correlates with the severity of atopic dermatitis (Cosmi and others (2000) Eur. J. Immunol. 30, c.2972-2979). Interaction with CRTH2 PGD2 plays a key role in induced allergen recovery pool of Th2 cells in target tissues in allergic inflammation. Therefore, compounds that inhibit the binding of CRTH2 with PGD2, should be useful in the treatment of allergic diseases.

Allergic diseases such as asthma, and inflammatory diseases represent the major class of complex and usually chronic inflammatory diseases, which currently affected about 10% of the population and which seem to increase (Bush, R.K., Georgitis J.W., Handbook of asthma and rhinitis. 1st ed. (1997), Abingdon: Blackwell Science, c.270). Atopic dermatitis is a chronic skin disease where the skin is very itchy. He is responsible for 10-20% of all visits to dermatologists. Increasing globally, the number of cases of allergic diseases and inflammatory dermatoses emphasizes the need for new therapies to effectively treat or prevent these diseases. Currently, numerous classes of pharmaceutical agents are widely used for the treatment of these diseases, such as antihistamines, decongestants tools, anticholinergic, methylxanthines, gramolini, corticosteroids and leukotriene modulators. One is about the usefulness of these agents is often limited by side effects and low efficiency.

Recently it was reported that 3-S-substituted derivatives of indole (A) have activity CRTH2 (international application WO 04/106302, AstraZeneca AB) and are potentially useful for the treatment of various respiratory diseases.

International application WO 04/096777 (Bayer Healthcare AG) relates to pyrimidine derivatives, which are useful for treating diseases mediated by CRTH2.

International application WO 04/035543 and WO 05/102338 (Warner-Lambert Company LLC) open derivative tetrahydroquinoline as CRTH2 antagonists (), which, as described, are effective in the treatment of neuropathic pain.

Specific derivative tetrahydroquinoline as modulators of CRTH2 are also international application WO 04/032848 (Millennium Pharmaceutical Inc.) and international application WO 05/007094 (Tularik Inc.). Mentions that these derivative tetrahydroquinoline useful in the treatment of diseases associated with allergic inflammatory processes.

Other species associated with G-protein receptors, namely CCR and CXCR discussed as potential targets of drugs for the treatment of allergic diseases and autoimmune pathologies. International application WO 04/108692 and WO 04/108717 (AstraZeneca AB) reveal personalpronomen compounds that specification is Eski modulate CCR4.

Personalpronomen compounds disclosed in international application WO 04/058265 as compounds that interact with associated with G-protein receptors.

Summary of the invention

One aspect of the present invention is the use of the 2,3-substituted personalpolitik represented by the General formula (I)as pharmaceutical active compounds. Such compounds are suitable for treatment and/or prevention of allergic diseases and inflammatory dermatoses. Mentioned compounds modulate the activity of specific family member associated with G-protein receptors, namely CRTH2. Specifically, the invention relates to 2,3-substituted personalpronomen formula (I)

where a, b, R1, R2, R3and m have the values as described below in a detailed manner, for use as pharmaceuticals.

The invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable excipient or carrier.

The invention also relates to the use of compounds of formula I to obtain drugs for the treatment and/or prevention of diseases selected the s of allergic diseases, such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases or disorders associated with the activity CTRH2. Specifically, the present invention relates to the use of compounds of the formula I to modulation, especially inhibition of CRTH2 activity.

The invention relates also to a method of treating and/or preventing the disease, which the patient suffers selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases is s or violations, associated with activity CTRH2, the introduction of compounds according to formula (I).

The invention relates also to the use of compounds of formula I for the preparation of pharmaceutical compositions.

Finally, the invention relates to new compounds of formula I, and methods of synthesis of these molecules.

Description of the invention

The following paragraphs provide definitions of the various chemical fragments that make up the connection according to the invention, unless otherwise detailed definition does not provide for a broader interpretation.

The term "(1-C6)alkyl" refers to monovalent alkyl groups having 1-6 carbon atoms. This term is illustrated by examples of such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, etc.

The term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl includes phenyl, naphthyl, phenanthrene etc. Aryl ring may be condensed with the heterocyclic group. Such condensed arily include dehydrobenzperidol-2-it, benzo[1,3]dioxol etc.

The term "(1-C6)alkylaryl" refers to (C1-C6)Alki inim groups, having aryl Deputy, such as, for example, benzyl, phenethyl, etc.

The term "heteroaryl" refers to monocyclic aromatic or bicyclic or tricyclic condensed heteroaromatic group. Typical examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, 1,3,4-thiadiazolyl, benzofuran, [2,3-dihydro]benzofuran, isobenzofuran, benzothiazyl, benzotriazolyl, isobenzofuranyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, hemolysins, hintline, phthalazine, honokalani, cinnoline, naphthyridine, pyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, hinely, ethanolic, tetrazolyl, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydro-ethanolic, purinol, pteridinyl, carbazolyl, xantener or benzopinacol etc.

The term "(1-C6)alkylglycerol" refers to (C1-C6)alkyl groups having a heteroaryl Deputy, such as, for example, 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl, etc.

The term "(3-C8)cyclea the keel" refers to a saturated carbocyclic group of 3-8 carbon atoms, having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl etc.

The term "(3-C8)heteroseksualci" refers to (C3-C8)cycloalkyl group as defined above, in which up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, R is defined as hydrogen or methyl. Preferred heteroseksualci includes pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, etc.

The term "(1-C6)alkylsilane" refers to (C1-C6)alkyl groups, having cycloalkenyl Deputy, including cyclohexylmethyl, cyclopentylmethyl etc.

The term "(1-C6)alkylchlorosilanes" refers to (C1-C6)alkyl groups, having heterologously Deputy, including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like

The term "(2-C6)alkenyl" refers to alkyl groups, preferably having 2-6 carbon atoms and having one or more provisions alkenylphenol unsaturation. Preferred alkeneamine groups include ethynyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2and so on

2-C6)quinil" refers to alkynylaryl groups, preferably having 2-6 carbon atoms and having one or more provisions alkenylphenol unsaturation. Preferred alkyline group include ethinyl (-C≡CH), PROPYNYL (-CH2With≡CH), etc.

The term "carboxy" refers to the group-C(O)OR where R includes hydrogen or (C1-C6)alkyl.

The term "acyl" refers to the group-C(O)R where R includes (C1-C6)alkyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylaryl or (C1-C6)alkylglycerol.

The term "acyloxy" refers to the group-OC(O)R where R includes (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylglycerol.

The term "arlacel" refers to aryl groups having acyl Deputy, including 2-acetylphenyl etc.

The term "heteroaryl" refers to heteroaryl groups having acyl Deputy, including 2-acetylpyridine etc.

The term "alkoxy" refers to the group-O-R where R includes (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8)cycloalkyl, heteroseksualci, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylether, (C2-C6 )alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylsilane, (C1-C6)alkylchlorosilanes. Preferred alkoxygroup include as example methoxy, ethoxy, phenoxy etc.

The term "(1-C6)alkylalkoxy" refers to (C1-C6)alkyl groups, having alkoxysilyl, including 2-ethoxyethyl etc.

The term "alkoxycarbonyl" refers to the group-C(O)R where R includes (C1-C6)alkyl or aryl, or heteroaryl, or (C1-C6)alkylaryl, or (C1-C6)alkylglycerol.

The term "aminocarbonyl" refers to the group-C(O)NRR'where each R, R' includes independently hydrogen or (C1-C6)alkyl, or aryl, or heteroaryl, or (C1-C6)alkylaryl, or (C1-C6)alkylglycerol.

The term "acylamino" refers to the group-NHC(O)R'where each R, R' is independently hydrogen or (C1-C6)alkyl, or aryl, or heteroaryl, or (C1-C6)alkylaryl, or (C1-C6)alkylglycerol.

The term "halogen" refers to fluorine atoms, chlorine, bromine and iodine.

The term "sulfonyloxy" refers to the group-OSO2-R, where R is chosen from H, (C1-C6)alkyl, (C1-C6)alkyl substituted by halogen, in the example group - OSO2-CF3, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8)cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylglycerol, (C2-C6)alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylcyclohexane, (C1-C6)alkylchlorosilanes.

The term "sulfonyl" refers to the group-SO2R, where R is chosen from H, aryl, heteroaryl, (C1-C6)alkyl, (C1-C6)alkyl, substituted with halogen, for example the group-SO2-CF3, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8)cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylglycerol, (C2-C6)alkynylaryl, (C2-C6)-alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylcyclohexane, (C1-C6)alkylchlorosilanes.

The term "sulfinil" refers to the group-S(O)R, where R is chosen from H, (C1-C6)-alkyl, (C1-C6)alkyl substituted by halogen, for example the group-SO-CF3, (C2-C6-alkenyl, (C2-C6)Ala the Nile, (C3-C8)cycloalkyl, geterotsiklicheskie aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylglycerol, (C2-C6)alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)-alkylcyclohexane, (C1-C6)alkylchlorosilanes.

The term "sulfanyl" refers to the group-S-R where R includes H, (C1-C6)alkyl, (C1-C6)alkyl, optionally substituted by halogen, for example the group-S-CF3, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8)cycloalkyl, heteroseksualci, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylether, (C2-C6)alkynylaryl, (C2-C6-alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylsilane, (C1-C6)alkylchlorosilanes. Preferred sulfanilimide groups include methylsulfonyl, ethylsulfonyl etc.

The term "sulfonylamino" refers to the group-NRSO2R'where each R, R' includes independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8-cycloalkyl, heteroseksualci, aryl, heteroaryl, (C1 -C6)alkylaryl or (C1-C6)alkylether, (C2-C6)alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylsilane, (C1-C6)alkylchlorosilanes.

The term "aminosulfonyl" refers to the group-SO2-NRR'where each R,R' includes independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8-cycloalkyl, heteroseksualci, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylether, (C2-C6)alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylsilane, (C1-C6)alkylchlorosilanes.

The term "amino" refers to the group-NRR'where each R,R' is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C3-C8-cycloalkyl, heteroseksualci, aryl, heteroaryl, (C1-C6)alkylaryl or (C1-C6)alkylether, (C2-C6)alkynylaryl, (C2-C6)alkenylphenol, (C2-C6)alkynylaryl, (C2-C6)alkynylaryl, (C1-C6)alkylsilanes, C 1-C6)alkylchlorosilanes and where R and R' together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered geteroseksualnoe ring.

The term "substituted or unsubstituted": unless otherwise constrained by the definition of the individual substituent, the above groups, such as alkyl, alkenyl, quinil, alkoxy, aryl and heteroaryl, etc. may be optionally substituted by 1-5 substituents selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkylaryl, (C1-C6)alkylglycerol, (C2-C6)alkenyl, (C2-C6)quinil, primary, secondary or tertiary amino groups or Quaternary ammonium fragments, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaromatic, carboxyl, cyano, halogen, hydroxy, nitro, sulfanyl, sulfoxy, sulfonyl, sulfonamida, alkoxy, dialkoxy, trihalomethyl etc. within the present invention assumes that mentioned the term "substitution" also includes cases where adjacent substituents are reactions circuit cycle, particularly when involved vicinal functional substituents, forming thus, for example, lactams, lactones, cyclic anhydrides, but also acetals, thioacetals, aminal, education is consistent with the closure of the cycle, for example, in order to obtain a protective group.

Assume that the expression "pharmaceutically acceptable cationic salts or complexes" defines salt such as alkali metal salts (e.g. sodium and potassium), salts of alkaline-earth metals (e.g. calcium or magnesium), aluminum salts, ammonium salts and salts of organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-methyl-D-glucamine, N,N'-bis(phenylmethyl)-1,2-amandemen, ethanolamine, diethanolamine, Ethylenediamine, N-methylmorpholine, piperidine, benzathine (N,N'-dibenziletilendiaminom), choline, Ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzyldimethyl-Amin), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propandiol), procaine, and amines of the formula-NR,R',R", where R, R', R" means independently hydrogen, alkyl or benzyl. Especially preferred salts are the sodium and potassium salts.

The expression "pharmaceutically acceptable salts or complexes" refers to salts or complexes identified below, compounds of formula I, which retain the desired biological activity. Examples of such salts include, but without limitation, acid additive salts formed with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, posthorn the th acid, nitric acid and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamula acid, alginic acid, polyglutamine acid, naphthalenesulfonate acid, naphthalenedisulfonic acid and polygalacturonase acid. The aforementioned compounds can also be introduced in the form of pharmaceutically acceptable Quaternary salts known to the person skilled in the art, which specifically include the Quaternary ammonium salt of the formula-NR, R', R"+Z-where R, R', R" means independently hydrogen, alkyl or benzyl, and Z means a counterion, including chloride, bromide, iodide, O-alkyl, toluensulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamate, mandelot and diphenylacetate).

The term "pharmaceutically active derivative" refers to any compound that when administered to the recipient is capable of providing directly or indirectly the activity disclosed in the context.

The compounds of formula I of the present invention are useful in the treatment and/or prevention of diseases selected from allergic h the problems such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD).

In one variation of the embodiment of the invention the compounds of formula (I) suitable as modulators, particularly antagonists of CRTH2. Therefore, the compounds of the present invention is particularly useful for the treatment and/or prevention of disorders which are mediated by CRTH2 activity. The said treatment involves the modulation of CRTH2, especially the inhibition of CRTH2, or antagonizers effect CRTH2 in mammals and in particular humans. The CRTH2 modulators selected from the group consisting of an antagonist or inverse agonist, partial agonist and agonist CRTH2.

In another variant embodiment of the invention, modulators of CRTH2 are CRTH2 antagonists.

In one embodiment, the CRTH2 modulators are inverse agonists CRTH2.

In another variant embodiment of the invention, modulators of CRTH2 are partial agonists RTH2.

In another variant embodiment of the invention, modulators of CRTH2 are CRTH2 agonists.

The compounds of formula (I) suitable for use as a medicine.

The compounds of formula (I) also include geometric isomers, optically active forms such as enantiomers, diastereomers, racemic forms and tautomers and pharmaceutically acceptable salts, where:

And means or amine selected from the group consisting of

or alkyl, acyl, aminocarbonyl, or other alternate selected from the group consisting of

where each index n is an integer independently selected from 0, 1, 2, 3 or 4; m is or 1, or 2;

where

R7selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C2-C6)alkenyl, substituted or unsubstituted (C2-C6)quinil, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)hetero is cloacina, carboxyl, cyano, amino and hydroxyl.

R8selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

In selected from the group consisting of substituted or unsubstituted (C2-C6)quinil, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C3-C8)geterotsiklicheskie, substituted or unsubstituted aryl and substituted or unsubstituted monocyclic heteroaryl.

Examples of the substituent include ethinyl, PROPYNYL, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, pyrazolidine, piperidine, piperazinil, pyridyl, imidazolidinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolidine, isoxazolidine, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrimidyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, carbazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, oxolane, pyrrolidinyl, pyrazolidine, piperidine, piperazinil.

According to one variant embodiment of the invention is chosen from the group of substituted or unsubstituted and the sludge, substituted or unsubstituted (C3-C8)geterotsiklicheskie and substituted or unsubstituted quinil.

According to one variant embodiment of the invention means a substituted or unsubstituted aryl group (e.g. phenyl). According to other variant embodiments of the invention mentioned phenyl group is monosubstituted in the ortho-, meta - or para-position.

In another variant embodiment of the invention In means (C3-C8)geterotsyklicescoe group (for example, piperazinil, furyl or thienyl).

According to other variant embodiments of the invention In means alkylamino group (for example, ethinyl or PROPYNYL).

R1means or hydrogen, or substituted or unsubstituted (C1-C6)alkyl. In a preferred embodiment, R1means hydrogen.

R2selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, substituted or unsubstituted (C3-C8)cycloalkyl and substituted or unsubstituted (C3-C8)geterotsiklicheskie.

Examples R2include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, pyrazolidine, piperidine, piperazinil,pyridyl, imidazolidinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolidine, isoxazolidine or morpholinyl, phenyl, naphthyl 1, pyrrolyl, pyrimidyl, hemolysins, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, carbazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuran, isobenzofuran, benzothiazyl, benzotriazolyl, isobenzofuranyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxolane, pyrrolidinyl, pyrazolidine, piperidine, piperazinil, pyridyl, imidazolidinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolidine, isoxazolidine, hintline, phthalazine, honokalani, cinnoline, naphthyridine, hinely, ethanolic, tetrazolyl, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, purinol, pteridinyl, xantener or benzopinacol.

According to one variant embodiment of the invention R2selected from substituted or unsubstituted aryl group (e.g. phenyl).

The substituents in the substituted R2selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, dialkoxy and thioalkyl.

In one variation of the embodiment of the invention R2not necessarily samewe is owned by one or more substituents, selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, dialkoxy and thioalkyl.

According to other variant embodiments of the invention R2is monosubstituted in the ortho-, meta - or para-positions. In one embodiment, R2means chlorophenyl.

According to other variant embodiments of the invention R2is substituted or unsubstituted heteroaryl group (e.g., pyridinyl or Tienam).

According to other variant embodiments of the invention R2is substituted or unsubstituted (C1-C6)alkyl group (e.g., stands).

R3selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, substituted or unsubstituted (C3-C8)cycloalkyl and substituted or unsubstituted (C3-C8)geterotsiklicheskie; where mentioned substituted or unsubstituted aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heteroseksualci may be condensed with one or more substituted or unsubstituted aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heteroseksualnymi groups and can be substituted one or ascoltami substituents, selected from the group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulfoxy, sulfonyl, sulfonamida and trihalo(C1-C6)alkyl.

Examples R3include methyl, ethyl, propyl, butyl, tert-butyl, phenyl, naphthyl, phenanthrene, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, carbazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, benzo(2,1,3)oxadiazolyl, benzo(1,2,5)oxadiazolyl, benzo[1,3]dioxol, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuran, [2,3-dihydro]benzofuran, 3,4-dihydro-1H-benzo[1,4]diazepan-2,5-dione, isobenzofuran, benzothiazyl, benzotriazolyl, isobenzofuranyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridazinyl, pyrimidyl, hemolysins, hintline, phthalazine, honokalani, cinnoline, naphthyridine, hinely, ethanolic, tetrazolyl, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, purinol, pteridinyl, carbazolyl, xantener, benzopinacol, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxolane, pyrrolidinyl, pyrazolidine, piperidine, piperazinil, pyridyl, imidazolidinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxad atomidine, isoxazolidine or morpholinyl.

According to one variant embodiment of the invention R3means substituted or unsubstituted aryl group (e.g. phenyl or naphthyl). The substituents in the substituted R3selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, dialkoxy and thioalkyl.

In one variation of the embodiment of the invention R3optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, dialkoxy and thioalkyl.

Examples of substituted phenyl are 4-trifloromethyl, 3-methoxyphenyl, 4-chlorophenyl, 3, 5dimethylphenyl, 2-benzamide or 2-benzoic acid.

In another variant embodiment of the invention R3means substituted or unsubstituted heteroaryl group (for example, pyridyl, hinely, benzimidazolyl, indolyl, pyridazinyl, pyrazinyl or 1,3,4-thiadiazolyl). An example of a substituted benzimidazole is 2-ethyl-2H-benzimidazolyl.

In another variant embodiment of the invention R3means aryl group condensed with (C3-C8)geteroseksualnoe group (e.g., 1,3-dihydro-benzimidazole-2-one, 3,4-dihydro-1H-benzo[1,4]diazepan-2,5-dione).

In each the m variant embodiment of the invention R 3means substituted or unsubstituted (C3-C8)geterotsyklicescoe group condensed with a substituted or unsubstituted aryl group (e.g., 1,2,3,4-tetrahydro-quinoline, 1,2,3,4-tetrahydroquinoxalin, 2,3-dihydrobenzo-1,4-oxazin, 2,3-degidro-indole or dihydrobenzofuran).

In another variant embodiment of the invention R3means substituted or unsubstituted (C3-C8)geterotsyklicescoe group condensed with a substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group (for example, digitalentertainment).

In another variant embodiment of the invention R3means substituted or unsubstituted alkyl group (e.g., isopropyl).

According to other variant embodiments of the invention, the substituents R2or R3selected from the group consisting of (C1-C6)alkyl, alkoxy, cyano, amino and halogen (for example, methyl, ethyl, butyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenoxy, chlorine, fluorine); where the alkyl, alkoxy or aryloxy are optionally substituted with halogen (e.g., trifluoromethyl, triptoreline);

as well as their isomers and mixtures for use as pharmaceuticals.

Another specific group of compounds of formula (I) are compounds having the formula (I', according to which

A, b, R2and R3have such meanings as defined above, and each

R1can be independently hydrogen or substituted or unsubstituted (C1-C6)alkyl.

In a preferred variant embodiment of the invention R1means hydrogen.

Specific sub-group of the formula (I) and (I') are compounds having formula (Ia-Id), according to which

A, R2and R3have such meanings as defined above, and

Z denotes O or S.

Preferred pharmaceutically acceptable salts of the compounds of formula I and compounds of the sub-groups of the formulas (Ia)-(Id)containing the remainder of the base, such as, for example, primary, secondary or tertiary amine or peredelnyj the rest are acid additive salts formed with pharmaceutically acceptable acids, such as cleaners containing hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrophosphate, acetate, benzoate, succinate, fumaric, Malatya, lactate, citrate, tartrate, gluconate, methanesulfonate, benzolsulfonate and n-toluensulfonate salt.

Compounds of the present invention, which CCA is i.i.d. suitable for use as a medicinal product, include, in particular, the compounds of the group, including:

In the second aspect of the invention provides a pharmaceutical composition comprising 2,3-substituted personalfinance according to the formula (I) together with a pharmaceutically acceptable excipient or carrier.

In the third aspect of the invention provides 2,3-substituted personalfinance according to the formula (I) for drugs for treatment and/or prevention of a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis and other diseases with an inflammatory component such as rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases and disorders associated with the activity CTRH2.

In the fourth aspect of the invention provides a method of treatment and/or prevention of a patient suffering from a disease selected from allergic diseases such as allergic asthma, alle the policy rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases and disorders associated with the activity CTRH2, the introduction of 2,3-substituted personalfinance according to the formula (I).

The term "preventing"as used in the context, should be understood as a partial or complete prevention, suppression, relief or treatment of one or more symptoms or causes of allergic disease or an inflammatory dermatitis.

In the fifth aspect of the invention provides the use of 2,3-substituted personalfinance according to the formula (I) for the preparation of pharmaceutical compositions that are useful for a variety of therapies, including the prevention and/or treatment of a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis,eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases and disorders associated with the activity CTRH2.

The invention also provides the use of 2,3-substituted personalfinance formula (I) for the prevention and/or treatment of a disease selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or allergic reactions, and inflammatory dermatoses such as atopic dermatitis, eczema, allergic contact dermatitis, and urticaria, myositis, neurodegenerative disorders such as neuropathic pain, and other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD) and other diseases and disorders associated with activity CTRH2.

Compounds according to the invention together with commonly used auxiliary substance, carrier, diluent or excipient can be entered in the pharmaceutical compositions and their standard dosage forms and mo is ut be used in the form of solid forms, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and their standard dosage forms may include ingredients or base, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be applied.

Compounds according to formula (I) according to the present invention is generally introduced in the form of pharmaceutical compositions. Such compositions can be prepared in a manner well known in the pharmaceutical field, and include at least one active connection. As a rule, the compounds of this invention administered in pharmaceutically effective amounts. In fact, enter the number of connections will typically be determined by the physician, taking into account the relevant circumstances including the condition to be treated, the chosen route of administration, the specific input connection, the age, body weight and response of the individual patient, the severity of symptoms in a patient, etc.

Pharmaceutical compositions p the present invention can be introduced in various ways, including oral, rectal, cutaneous, subcutaneous, intravenous, intramuscular or intranasal route. Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, most songs are in standard dosage forms to facilitate accurate dosing. The term "standard dosage forms" refers to physically dyskretny units suitable as single doses to humans and other mammals, each unit contains a defined quantity of active material calculated to obtain the desired therapeutic effect, in combination with an appropriate pharmaceutical excipient. Typical standard dosage forms include pre-filled with a measured ampoules or syringes with liquid compositions or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions derived substituted methylamide according to the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), while the rest represents the different bases or carriers and auxiliary processing tools that are useful for the formation of the desired dosage form.

Liquid form, the sentence is nye for oral administration, can include the appropriate aqueous or nonaqueous basis with buffers, suspendresume and dispersing agents, dyes, fragrances and other Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose, disintegrity agent, such as alginic acid, primogel or corn starch; a moving substance, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring, such as peppermint peppermint, methyl salicylate or orange flavoring.

Injectable compositions are usually based on injecting sterile saline or phosphate buffered saline or other injectable carriers known in the art. As reported above, a derivative of the substituted methylamide formula (I) in such compositions is typically a minor component, the content of which often varies in the range between 0.05 to 10% by weight, while the remainder is the injectable carrier and the like,

The above-described components for oral administration or injection of the composition are just RAR the population. Additional materials, as well as technological tools, etc. listed in part 5, Remington''s Pharmaceutical Sciences, 20th-oe ed., 2000, Merck Publishing Company? Easton, Pennsylvania, which is included in the context by quoting.

Compounds according to this invention can also be entered in the forms of slow-release or delivery systems of drugs with a slow release. Description of representative materials delayed delivery can also be found in the materials included in Remington''s Pharmaceutical Sciences.

In the sixth aspect of the invention provides a new 2,3-substituted personalfinance formula (la-Id), where A, R2and R3have such values as described above. The new compounds of formula (Ia-Id), in particular, are compounds of the group consisting of:

N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide,

2-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]pyrazin-2-yl}-benzosulfimide,

N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)-benzosulfimide,

2-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,

2-chloro-N-(3-{4-[(2-naphthyloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,

2-chloro-N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,

2-chloro-N-(3-{4-[(5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,

2-chloro-N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-benzosulfimide,

N-(3-{4-[(1,3-benzodioxol-5-ylamino)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)-benzosulfimide,

N-[3-(4-{[(3-methoxybenzyl)oxy]methyl}phenyl)pyrazin-2-yl]-2-(trifluoromethyl)-benzosulfimide,

3-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]pyrazin-2-yl}-benzosulfimide,

N-[3-(4-{[(4-chlorophenyl)(methyl)amino]methyl}phenyl)pyrazin-2-yl]thiophene-2-sulfonamida,

4 phenoxy-N - {3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}-benzosulfimide,

4-methyl-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]pyrazin-2-yl}benzosulfimide,

4-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide,

4-cyano-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]pyrazin-2-yl}benzosulfimide,

N-[3-(4-{[(4-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,

N-(3-{4-[(methylphenylimino)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,

N-[3-(4-{[(4-cyanophenyl)methylaminomethyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(4-forfinancial)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-(3-{4-[(ethylvanillin)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(2,3-dihydrobenzo[1,4]oxazin-4-ylmethyl)phenyl]pyrazin-2-and the}-2-triftoratsetilatsetonom,

N-[3-(4-{[(3-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(6-chloropyridin-3-intoximeter)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(2-pyridin-2-Jindal-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-[3-(4-phenoxymethyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,

N-[3-(4-{[(4-chlorophenyl)methylamino]were)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,

2-chloro-N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide,

N-[3-(4-{[(3,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(4-cyanoprokaryotes)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-{3-[4-(6-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

2-chloro-N-{3-[4-(5-methoxy-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-benzosulfimide,

N-{3-[4-(4-methoxyphenoxy)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-chloro-benzosulfimide,

N-{3-[4-(2,3-dihydroindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

N-[3-(4-{[(2,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-baselslt the amide,

N-{3-[4-(3-chlorphenoxamine)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

2-chloro-N-[3-(4-{[(2,4-differenl)methylamino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide,

N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,

2-chloro-N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,

2-chloro-N-[3-(4-{[(2-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide,

2-chloro-N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,

N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,

2-chloro-N-(3-{4-[(ethylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-benzosulfimide and

N-{3-[4-(5-chloro-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide.

In the seventh aspect of the invention provides a method of synthesis of compounds according to formula (Ia)to(Id).

2,3-Substituted sulfonamides presented as an example in this invention, can be obtained from readily available starting materials using the following General methods and techniques. It will be recognized that where typical or preferred experimental conditions (i.e. temperature, reaction time, moles of reagents, solvents etc), can also be used and other experimental conditions, unless noted inicial reaction conditions may vary depending on the particular reactants or solvents, but such conditions can be determined by the person skilled in the art using conventional optimization methods.

General description of methods for obtaining compounds of formula (I) is given in the international application WO 04/058265 (PCT/GB03/005668).

The General synthetic approach for obtaining the compounds of formulas (Ia)-(Id) is depicted in scheme 1. In such derivatives of 2,3-substituted sulfonamides according to the formula I can be obtained in 4-5 chemical stages from commercially available 2,3-dichloropyrazine. Synthetic protocols described briefly in schemes 1-10.

In a more specific way sulfonamidnuyu derivative XXI, where R2has such meaning as defined above, to react with 2,3-dichloropyrazine II, giving the corresponding 3-harperentertainment of compound III. Different reaction conditions can be used to implement this first reaction stage, for example, using sulfonamidnuyu derived XXI in the presence of a base such as cesium carbonate, potassium carbonate or the like. This reaction can be carried out in solvents, such as N-organic (NRM), dimethylformamide (DMF) or dimethylacetamide (DMA), at different temperatures, depending on the inherent compounds XXI and II reactivity, using a conventional thermal or microwave pic is BA, using standard conditions well known to the person skilled in the art, or as shown in the following scheme 2:

Scheme 2

Sulfonamidnuyu derivative XXI receive from commercial sources or they can be obtained by treating the corresponding sulphonylchloride XX, using standard conditions well known to the specialist, with a 2 M solution of ammonia in ethanol or dioxane at room temperature for 1 h or it may be carried out at different temperatures, depending on the inherent connections XXI reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist, or as shown in the following scheme 3.

Scheme 3

Derivatives of 2,3-substituted personalfinance according to the General formula Ia can be obtained in 3 stages depending on the availability of source materials and structural blocks. The synthetic path shown in scheme 4. In the first stage derivatives of 2,3-substituted personalfinance IVa emit after condensation of 3-harperentertainment compounds III with baronowie acids XXII. This reaction can be carried out in the presence of an appropriate palladium catalyst, such as dia is Etat palladium, and in solvents such as dioxane, methanol, or solutions containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At a later stage derivatives of 2,3-substituted personalfinance, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds IVa in the presence of thionyl chloride. This reaction is usually carried out at room temperature in solvents, such dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the next stage, as shown in figure 4, derivatives of 2,3-substituted personalfinance Va can be treated with various nucleophiles such as amine XXIV or alcohol XXV, where R4, R5, R6independently selected from the group of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, geterotsiklicheskie or condensed ring systems of these cycles to obtain the expected derivative of 2,3-substituted persinal is named Ia. Nucleophilic substitution of the chlorine atom benzyl parts of the amine XXIV or alcohol XXV is achieved by treatment with an appropriate base, such as sodium hydride or tert-butyl potassium, anhydrous conditions in the presence or in the absence of, for example, sodium iodide or tetrabutylammonium iodide as a catalyst in solvents such as DMF, THF or similar solvents. This reaction can be carried out at different temperatures depending on the inherent connections Va, XXIV and XXV of the reactivity of using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

Derivatives of 2,3-substituted personalfinance according to the General formula Ia can also be obtained in 3 stages depending on the availability of source materials and structural blocks. Other synthetic path shown in scheme 5. In the first stage derivatives of 2,3-substituted personalfinance emit after condensation of 3-harperentertainment compounds III with baronowie acids XXIII. This reaction can be carried out in the presence of an appropriate palladium catalyst such as palladium diacetate, and in solvents such as dioxane, methanol, or the solution containing the BA solvents in different ratios. The reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At a later stage derivatives of 2,3-substituted personalfinance Vb, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds IVb in the presence of oxalicacid or after handling compounds IVb with appropriate condensing agents such as DCC, NATURAL or reagent Mukama, in the presence of a base, such as DIEA or triethylamine. These reactions are usually carried out at room temperature in solvents such as dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the final stage, as shown in figure 5, derived 2,3-substituted personalfinance Vb can be treated with various nucleophiles such as amine XXIV, with the formation of the expected derivative of 2,3-substituted personalfinance Ia. The amide bond formation is achieved by treating an appropriate base, such as DIEA or triethylamine, in a solvent, t is such as DMF, THF or other similar solvents. This reaction can be carried out at different temperatures depending on the characteristic of the compounds Vb and XXIV reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

Derivatives of 2,3-substituted personalfinance according to the General formula Ib can be obtained in 3 stages depending on the availability of source materials and structural blocks. The synthetic path shown in scheme 6. In the first stage derivatives of 2,3-substituted personalfinance (VIa) was isolated after condensation of 3-harperentertainment compounds III with baronowie acids XXVI. This reaction can be carried out in the presence of an appropriate palladium catalyst such as palladium diacetate, and in solvents such as dioxane, methanol, or in a solution containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At last the stage derivatives of 2,3-substituted personalfinance, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds IVa in the presence of thionyl chloride. This reaction is usually carried out at room temperature in solvents, such dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the next stage, as shown in scheme 6, derivatives of 2,3-substituted personalfinance VIIa can be treated with various nucleophiles such as amine XXIV or alcohol XXV, to obtain the expected derivative of 2,3-substituted personalfinance Ib. Nucleophilic substitution of the chlorine atom benzyl parts of the amine XXIV or alcohol XXV is achieved by treatment with an appropriate base, such as sodium hydride or tert-butyl potassium, anhydrous conditions in the presence or in the absence of, for example, sodium iodide or tetrabutylammonium iodide as a catalyst in solvents such as DMF, THF or similar solvents. This reaction can be carried out at different temperatures depending on the inherent compounds VIIa, XXIV and XXV of the reactivity of using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in the data is the second region.

Derivatives of 2,3-substituted personalfinance according to the General formula Ib can also be obtained in 3 stages depending on the availability of source materials and structural blocks. Other synthetic path shown in scheme 7. In the first stage derivatives of 2,3-substituted personalfinance (VIb) was isolated after condensation of 3-chloropyrazine-sulfonamidnuyu compounds III with baronowie acids XXVII. This reaction can be carried out in the presence of an appropriate palladium catalyst such as palladium diacetate, and in solvents such as dioxane, methanol, or in a solution containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At a later stage derivatives of 2,3-substituted personalfinance VIIb, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds VIb in the presence of oxalicacid or after processing VIb compounds with their corresponding condenser the relevant agents, such as DCC, NATURAL or reagent Mukama, in the presence of a base, such as DIEA or triethylamine. These reactions are usually carried out at room temperature in solvents such as dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the final stage, as shown in figure 7, derived 2,3-substituted personalfinance VIIb can be treated with various nucleophiles such as amine XXIV, with the formation of the expected derivative of 2,3-substituted personalfinance Ib. The amide bond formation is achieved by treating an appropriate base, such as DIEA or triethylamine in solvents such as DMF, THF or other similar solvents. This reaction can be carried out at different temperatures depending on the inherent compounds VIIb and XXIV reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

Derivatives of 2,3-substituted personalfinance according to the General formula Ic can be obtained in 3 stages depending on the availability of source materials and structural blocks. The synthetic path shown in scheme 8. On pervosti derivatives of 2,3-substituted personalfinance VIIIa emit after condensation of 3-harperentertainment compounds III with acetylene XXVIII. This reaction can be carried out in the presence of an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)paradigalla, in the presence of copper iodide and potassium acetate as a catalyst in solvents such as dioxane, DMF, or in a solution containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At a later stage derivatives of 2,3-substituted personalfinance ha, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds VIIIa in the presence of thionyl chloride. This reaction is usually carried out at room temperature in solvents such as dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the next stage, as shown in scheme 8, derivatives of 2,3-substituted personalfinance he can be treated with various nucleophiles such as amine XXIV or alcohol XXV, about what adowanie expected derivatives of 2,3-substituted personalfinance Ic. Nucleophilic substitution of the chlorine atom benzyl parts of the amine XXIV or alcohol XXV is achieved by treatment with an appropriate base, such as sodium hydride or tert-butyl potassium, anhydrous conditions in the presence or in the absence of, for example, sodium iodide or tetrabutylammonium iodide as a catalyst in solvents such as DMF, THF or similar solvents. This reaction can be carried out at different temperatures depending on the inherent compounds IXa, XXIV and XXV of the reactivity of using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

Derivatives of 2,3-substituted personalfinance according to the General formula Ic can be obtained in 3 stages depending on the availability of source materials and structural blocks. Other synthetic path shown in scheme 9. In the first stage derivatives of 2,3-substituted personalfinance (VIIIb) was isolated after condensation of 3-chloropyrazine-sulfonamidnuyu compounds III with acetylene XXIX. This reaction can be carried out in the presence of an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)paradigalla, p is outstay of copper iodide and potassium acetate, in solvents such as dioxane, DMF, or in a solution containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

At a later stage derivatives of 2,3-substituted personalfinance IXb, in accordance with which the substituent R2has such meaning as defined above, emit after chlorination of the intermediate compounds VIIIb in the presence of oxalicacid or after connection processing VIIIb with appropriate condensing agents such as DCC, NATURAL or reagent Mukama, in the presence of a base, such as DIEA or triethylamine. These reactions are usually carried out at room temperature in solvents such as dichloromethane, dichloroethane or DMF), using standard conditions well known to the specialist in this field.

At the final stage, as shown in figure 9, derived 2,3-substituted personalfinance IXb can be treated with various nucleophiles such as amine XXIV, with the formation of the expected derivative of 2,3-substituted personalfinance Ic. Coord the amide bond is achieved by treating the corresponding base, such as DIEA or triethylamine in solvents such as DMF, THF or other similar solvents. This reaction can be carried out at different temperatures depending on the inherent connections IXb and XXIV reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

Derivatives of 2,3-substituted personalfinance according to the General formula Id can be obtained in 3 stages depending on the availability of source materials and structural blocks. The synthetic path shown in scheme 10. In the first stage derivatives of 2,3-substituted personalfinance X emit after condensation of 3-harperentertainment compounds III tert-butyl ether piperazine-1-carboxylic acid XXX. This reaction can be carried out in the presence of an appropriate base, such as DIEA or triethylamine, in a solvent, such NRM, DMF, or in a solution containing both solvent in different ratios. This reaction can be carried out at different temperatures depending on the inherent connections III reactivity using the conventional thermal method or using microwave technology, using the UYa standard conditions, well-known specialist in this field.

At the next stage derivatives of 2,3-substituted personalfinance X, in accordance with which the substituent R2has such meaning as defined above, this will release in acidic conditions, using or triperoxonane acid (TFA)or HCl at various concentrations. This reaction is usually carried out at room temperature in solvents such as dichloromethane, dichloroethane or DMF), using standard conditions well known to the person skilled in the art. At the next stage, as shown in scheme 10, derivatives of 2,3-substituted personalfinance XI can be treated with various electrophiles, such as alkylhalides XXXIa, in the presence of an appropriate base, such as Cs2CO3DIEA or triethylamine, or by acylchlorides or carboxylic acid XXXIb, pre-activated by treatment with an appropriate condensing reagent such as DCC, the reagent Mukama, hexaflurophosphate benzotriazol-1-electroparadise (Pybop)to get the expected derivative of 2,3-substituted personalfinance Id. Nucleophilic substitution of the halogen atom or the formation of amide linkages with alkylhalides XXXIa or acylchlorides, or carboxylic acid XXXIb respectively can be carried out at various t is mperature depending on the inherent connections XI, XXIa or XXXIb reactivity using the conventional thermal method or using microwave technology, using standard conditions well known to the specialist in this field.

The following abbreviations refer respectively to the following definitions:

min (minute), h (hour), g (grams), MHz (megahertz), ml (milliliters), mmol (millimoles), mm (mylibrary), CT (room temperature), ATP (adenosine triphosphate), BSA (bovine serum albumin), DHM (dichloromethane), DCC (DICYCLOHEXYL-carbodiimide), DIEA (diisopropylethylamine), DMSO (dimethyl sulfoxide), a reagent Mukama (iodide, 1-methyl-2-chloropyridine), DMF (dimethylformamide), CsCO3(cesium carbonate), CGC (cyclohexane), Et3N (triethylamine), EA (ethyl acetate), EtON (ethanol), K2CO3(potassium carbonate), NaI (sodium iodide), NaH (sodium hydride), NaHCO3(sodium bicarbonate), NH4Cl (ammonium chloride), tea (triethylamine), TFA (triperoxonane acid), THF (tetrahydrofuran), Pd(PPh3)4(tetrakis(triphenyl-phosphine)palladium), CuI (copper iodide), Pd(SLA)2(palladium(II)acetate), Pd(PPh3)2Cl2(chloride bis(triphenylphosphine)palladium(II)), CH3The Sook (potassium acetate), PPh3(triphenylphosphine), GATA hexaphosphate N,N,N',N'-tetramethyl-O-(7-asobancaria-1-yl)Urania, (CO)2Cl2(oxalyl the ID), SOCl2(thionyl chloride),

tert-BuOK (tert-butyl potassium), Meon (methanol), MgSO4(magnesium sulfate), NRM N-organic, PE (petroleum ether), CT (room temperature). HPLC high performance liquid chromatography), PF (flash chromatography on silica gel), MS (mass spectrometry), NMR (nuclear magnetic resonance), SFR (phosphate buffered saline), SPA (matching scintillation), TLC (thin layer chromatography), UV (ultraviolet light).

If the above set of General methods of synthesis not applicable for producing compounds according to formula (I) and/or the necessary intermediates for the synthesis of compounds of formula (I), should be used in appropriate ways to get known to the person skilled in the art. As a rule, synthetic path for any individual compound of formula (I) will depend on the specific substituents in each molecule, and the degree of availability of the necessary intermediates; and again, such factors are recognized experts in this field. For all methods of protection and release, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd edition, 1999.

Compounds according to this invention can be isolated in Association with solvent molecules the way the crystallization in the process of evaporation of the appropriate solvent. Pharmaceutically acceptable acid additive salts of compounds of formula (I)which contain a basic centre can be obtained by a commonly known method. For example, a solution of the free base may be treated with the appropriate acid, or as such or in a suitable solvent, and the resulting salt allocate or by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable basic additive salts can be obtained in a similar way by treating a solution of the compounds of formula (I) with an appropriate base. Both types of salts can be formed and vzaimoprevrascheny using ion-exchange resins.

In the following description, the present invention will be illustrated by some examples, which should not be construed as limiting the scope of the invention.

Experimental part

Data HPLC, NMR and MS provided in the examples described below, was prepared as follows: HPLC: column Waters Symmetry C8, 50×4.6 mm, conditions: MeCN/H2O, 5-100% (8 min), Max. curve 230-400 mesh nm; MS: instrument PE-SCIEX API 150 EX (chemical ionization at atmospheric pressure (APCI) and electrospray ionization (ESI)), LC/MS-spectrum: the instrument Waters ZMD (ES);1H-NMR: the instrument Bruker DPX-300 MHz.

Purification preparative HPLC was carried out with the system Waters Prep LC 4000, supplied the military columns Prep Nova-Pak ®HR C18, 6 μm, 60Å, 40×30 mm (up to 100 mg) or XTerra®Prep MS C8, 10 μm, 50×300 mm (up to 1 g). All cleaning was carried out with a gradient of MeCN/H2O (0,09% TFA). Prepreparation HPLC on reversed phase was carried out with the system Biotage Parallex Flex, equipped with a column Supelcosil™ ABZ+Plus (25 cm × 21,2 mm, 12 μm); UV detection at 254 nm and 220 nm; flow rate 20 ml/min (up to 50 mg). TLC analysis was performed on plates coated with Merck layer of silica gel 60 F254. Purification using flash chromatography was carried out on the media SiO2using as eluents mixture CGC/EA or DHM/Meon.

Intermediate compound 1: 2-(trifluoromethyl)benzosulfimide (cf. scheme 3, compound XXI)

To a solution of 2-(trifluoromethyl)benzosulfimide (5 g, 20,44 mmole, 1.00 EQ.) in anhydrous THF (5,00 ml) was added 71 ml of ammonia 2 M solution of ammonia in ethanol in a nitrogen atmosphere at room temperature. The reaction mixture was shaken for 20 h at room temperature. The solvent was evaporated and the residue pererestorani in EA (150 ml), the resulting solution was washed with a saturated aqueous solution of ammonium chloride (50 ml) and saturated saline (50 ml). The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to obtain pure 2-(trifluoromethyl)benzosulfimide in the form of a yellowish solid (4,6g, yield 89%, HPLC purity 98.6 per cent). This compound was used as such for the next reaction.

1H-NMR (300 MHz, CDCl3): 5,0 (m, 2H), 7.6 (m, 2H), and 7.8 (m, 1H), 8.3 (m, 1H). MC (ESI-): 224,1.

Intermediate compound 2: 2-chloro-N-(3-chloropyrazine-2-yl)benzosulfimide

(cf. scheme 2, compound III)

2,3-Dichloropyrazine (1 g, of 6.71 mmole, 1.00 EQ.) and 2-dichlorobenzenesulfonate (1.29 g, of 6.71 mmole, 1.00 EQ.) mixed in NRM (9 ml). To the reaction mixture were added cesium carbonate (2 g, 6 mmol, 0.90 or equiv.) and the reaction mixture was stirred and heated at 130°C for 20 hours, the Reaction mixture was cooled to room temperature, added to water (98 ml) and washed with EA (2×30 ml). The aqueous phase was acidified with citric acid and was extracted with EA (3×60 ml). The organic extracts were combined, washed with saturated saline (10 ml), dried over magnesium sulfate and evaporated. The residue was purified flash chromatography using a gradient of EA/CGC, 2:8 to 100% of EA for 45 min, after filtration and evaporation was allocated is specified in the header connection. The solid is recrystallized from a mixture of EA:CGC (30:70) to give the pure 2-chloro-N-(3-chloropyrazine-2-yl)benzosulfimide in the form of a yellowish solid (1 g, yield 49%, HPLC purity 100%).

1H-NMR (300 MHz, CDCl3): 7,3-7,5 (m, 3H), 7,8-8,0 (m, 3H), 8.3 (m, 1H). MC (ESI+): 304,1; MC (ESI-):302,0.

Intermediate compound 3: N-(3-chloropyrazine-2-yl)-2-(trifluoromethyl)benzosulfimide

(cf. scheme 2, compound III)

According to the General method as described for intermediate 2, on the basis of 2,3-dichloropyrazine and 2-(trifluoromethyl)benzosulfimide, after evaporation and recrystallization allocated is specified in the title compound as a yellowish solid with a yield of 63% (HPLC purity 97%).

1H-NMR (300 MHz, CDCl3): of 7.6 to 7.8 (m, 4H), of 7.9 to 8.1 (m, 2H), 8,5 (m, 1H). MC (ESI+): 338,0; MC (ESI-): 336,0.

Intermediate compound 4: 2-chloro-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzosulfimide

(cf. scheme 4, compound (IVa)

Dissolve 2-chloro-N-(3-chloropyrazine-2-yl)benzosulfimide (2.2 g, 7.23 percent mmole, 1.00 EQ.) and 4-gidroksietilirovannogo acid (0.21 g, of 7.96 mmole, of 1.10 EQ.) in 48 ml of a mixture of dioxane:methanol, 1:1, which had previously degirolami. To the reaction mixture were added potassium carbonate (2,75 g, 19,89 mmole, of 2.75 equiv.) and triphenylphosphine (284,58 mg of 1.08 mmole, of 0.15 EQ.) in nitrogen atmosphere, then palladium(II) (81,19 mg of 0.36 mmole, of 0.05 EQ.). Then the reaction mixture was heated at 110°C. in a nitrogen atmosphere for 30 minutes, the Reaction mixture was cooled to room temperature, diluted with diethyl ether (50 ml) and water (25 ml) and filtered through a layer of celite. The aqueous layer was separated and the organic layer was washed with water (50 ml). The combined aqueous solutions were washed with diethyl ether (50 ml), then aqueous layer was acidified 5 N. HCl and was extracted with EA. The organic extracts were combined, washed with saturated saline (10 ml), dried over magnesium sulfate and evaporated to obtain pure 2-chloro-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzosulfimide in the form of a yellowish solid (2.5 g, yield 91%, HPLC purity 98%). This compound was used as such for the next reaction.

1H-NMR (300 MHz, CDCl3): and 4.68 (m, 2H), and 7.5 to 7.7 (m, 7H), of 8.1 to 8.2 (m, 3H), 8,3 (m, 1H). MC (ESI+): 376,1; MC (ESI-): 374,1.

The intermediate compound 5: 2-trifluoromethyl-N-{3-[4-(hydroxymethyl)phenyl]-pyrazin-2-yl}benzosulfimide

(cf. scheme 4, compound IVa)

According to the General method as described for intermediate 4, proceeding from N-(3-chloropyrazine-2-yl)-2-(trifluoromethyl)benzosulfimide and 4-gidroksietilirovannogo acid, after evaporation and recrystallization allocated is specified in the title compound as a yellowish solid with a yield of 85% (HPLC purity 97%).

1H-NMR (300 MHz, CDCl3): a 4.83 (m, 2H), 7,5-7,9 (m, 8H), 8,1 (m, 1H), 8,3 (m, 1H), 8,64 (m, 1H). MC (ESI+): 410,3; MC (ESI-): 408,5.

The intermediate compound 6: 4-(3-{[(2-chlorophenyl)sulfonyl]amino}pyrazin-2-yl)benzoic acid

(cf. scheme 5, compound IVb)

With the General public the way as described for intermediate 4, from 2-chloro-N-(3-chloropyrazine-2-albenzaalbenza and 4-carboxybenzoyl-Bronevoy acid, after evaporation and recrystallization allocated is specified in the title compound as a yellowish solid with a yield of 83% (HPLC purity 96%).

1H-NMR (300 MHz, CDCl3): of 7.5 to 7.7 (m, 4H), of 7.9 to 8.0 (m, 2H), an 8.1-8.4 (m, 5H). MC (ESI+): 390,8; MC (ESI-): 388,9.

Intermediate compound 7: 4-(3-{[(2-triptoreline)sulfonyl]amino}-pyrazin-2-yl)benzoic acid

(cf.. scheme 5, compound IVb)

According to the General method as described for intermediate 4, proceeding from N-(3-chloropyrazine-2-yl)-2-(trifluoromethyl)benzosulfimide and 4-carboxybenzeneboronic acid, after evaporation and recrystallization allocated is specified in the title compound as a yellowish solid with a yield of 80% (HPLC purity 98%). MC (ESI+): 424,4; MC (ESI-): 422,2.

Intermediate compound 8: 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide

(cf. scheme 4, compound Vb)

Dissolve 2-chloro-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzosulfimide (3,15 g, 8.4 mmole, 1.00 EQ.) in dichloromethane (80 ml) was added dropwise thionyl chloride (8.5 ml, 117 mmol, 14 EQ.). The reaction mixture was stirred over night. The reaction to the offer was carefully poured into a mixture of ice/water (200 ml) and stirred until the formation of a transparent layer. The mixture was separated and the organic layer was dried over magnesium sulfate and evaporated to obtain the crude solid, which was recrystallized from a mixture of EA/cyclohexane to obtain pure 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide in the form of a white solid (3,02 g, yield 95%, HPLC purity 99%).

1H-NMR (300 MHz, CDCl3): 4,69 (m, 2H), 7,45-to 7.6 (m, 3H), 7,65 to 7.7 (m, 5H), and 8.0 (m, 1H), 8,3 (m, 1H), scored 8.38 (m, 1H). MC (ESI+): 396,1; MC (ESI-): 393,1.

Intermediate compound 9: N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide

(cf. scheme 4, compound Vb)

According to the General method as described for intermediate 8, from 2-trifluoromethyl-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzosulfimide and thionyl chloride, after evaporation and recrystallization allocated is specified in the title compound as a white solid with a yield of 96% (HPLC purity 97%).

MC (ESI+): 428,9; MC (ESI-): 426,7.

Intermediate compound 10: N-[3-(3-hydroxyprop-1-Jn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide

(cf. scheme 8, compound VIIIa)

Method And

Was dissolved N-(3-chloropyrazine-2-yl)-2-(trifluoromethyl)benzosulfimide (1.35 g, 4.0 mmole, 1.00 EQ.) and 2-propyne-1-ol (336 mg, 6.0 mmol, 1.5 equiv.) in 10 ml of DMF under nitrogen atmosphere. To react the Onna mixture was added CH 3COOK (588 mg to 6.0 moles, 1.5 EQ.) and Pd(Ph3)4(232 mg, 0.2 mmole) under nitrogen atmosphere. Then the reaction mixture was heated at 100°C for 2 hours After removal of the solvent by distillation in vacuo, the residue triturated with water (40 ml) and was extracted with diethyl ether (3×30 ml). The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified column chromatography on silica gel using a mixture of hexane and EA, to obtain N-[3-(3-hydroxyprop-1-Jn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide in the form of a yellowish solid (686 mg, yield 48%, HPLC purity 98%).

Method B

Was dissolved N-(3-chloropyrazine-2-yl)-2-(trifluoromethyl)benzosulfimide (1.35 g, 4.0 mmole, 1.00 EQ.) and 2-propyne-1-ol (336 mg, 6.0 mmol, 1.5 equiv.) in 10 ml of DMF under nitrogen atmosphere. To the reaction mixture was added CH3COOK (588 mg to 6.0 moles, 1.5 EQ.), CuI (40 mg, 0.2 mmole, of 0.05 EQ.) and Pd(Ph3)2Cl2(28 mg, 0.04 mmole) under nitrogen atmosphere. Then the reaction mixture was heated at 100°C for 2 hours After removal of the solvent by distillation in vacuo, the residue triturated with water (40 ml) and was extracted with diethyl ether (3×30 ml). The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified column chromatography on silica gel using a mixture of hexane and EA, to obtain N-[3-(3-hydroxyprop-1-Jn-1-yl)pyrazin-2-yl]-2-(triptime the Il)benzosulfimide in the form of a yellowish solid (702 mg, the yield is 50%, HPLC purity 98%).

MC (ESI+): 358,6; MC (ESI-): 356,5.

Intermediate compound 11: N-(3-piperazine-1-Alperin-2-yl)-2-(trifluoromethyl)benzosulfimide

(see scheme 10, the compound (XI)

Was dissolved tert-butyl 4-[3-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)-pyrazin-2-yl]piperazine-1-carboxylate (1,46 g, 3 mmole) in dichloromethane (50 ml) and was added at 0°C triperoxonane acid (4.5 g, 40 mmol). The reaction mixture was stirred for 2 h the Solvent was evaporated, and the residue pererestorani in dichloromethane (50 ml) and evaporated to dryness to obtain the desired product, N-(3-piperazine-1-Alperin-2-yl)-2-(trifluoromethyl)benzosulfimide, in the form of a yellow solid (1.1 g, yield 95%, HPLC purity 95%).

MC (ESI+): of 388.4; MC (ESI-): 386,3.

Example 1: General method for the synthesis of derivatives 2.3-substituted personalfinance General formula I and z as defined above (scheme 1, 4, 5, 6, 7, 8, 9 and 10): N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide

Method And

To a solution of 1H-indole (234 mg, 2.0 mmole, 1 EQ.) in dimethylformamide (10 ml) was added sodium hydride (80 mg, 2 mmole, 1 EQ.). After cessation of hydrogen was added N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide (intermediate compound 26) (854 mg, 2 mmole, 1 EQ is.) in dimethylformamide (5 ml) and the reaction mixture was heated at 80°C for 3 hours The reaction mixture was cooled, diluted with 30 ml water and was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, evaporated and the residue was purified flash chromatography on silica gel, elwira EA and cyclohexane to obtain N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide in the form of a yellow solid (630 mg, 1,24 mmole, yield 62%, HPLC purity 97%).

Method B

Was dissolved in N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide (intermediate compound 26) (854 mg, 2 mmole, 1 EQ.) and 1H-indole (234 mg, 2.0 mmole, 1 EQ.) in tetrahydrofuran (20 ml) and heated to 50°C for 10 minutes To the reaction mixture was added tert-butyl potassium (4,5 ml of 1 M solution in THF). The reaction mixture was maintained at 50°C for 5 h and then cooled to room temperature. The reaction mixture was treated with 10 ml of an aqueous solution of citric acid (20 g in 100 ml water and was extracted with EA. The organic layer was dried over magnesium sulfate and evaporated. The crude residue was purified as in method A, to obtain pure N-{3-[4-(1H-indol-1-ylmethyl)phenyl]-pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide in the form of a yellow solid (691 mg, of 1.36 mmole, HPLC purity 98%).

1H-NMR (300 MHz. CDCl3): 5,50 (m, 2H), 6,5 (m, 1H), 7,0-7,2 (m, 2H), 7,4-the 7.65 (m, 8H), 7,65 to 7.7 (m, 2H), 8,0 (m, 2H), 8,3 (m, 1H), scored 8.38 (m, 1H),

MC (ESI+): 509,5, (ESI- ) 507,6.

Example 2: 2-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)-phenyl]pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and N-methyl-4-(triptoreline)aniline was isolated specified in the title compound as a yellow solid with a yield of 72% (HPLC purity 99%).

MC (ESI+): 550,1, (ESI-) 547,8.

Example 3: N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2-ethylbenzamide, allocated specified in the title compound as a yellow solid with a yield of 63% (HPLC purity 96%).

MS (ESI+): 538,6, (ESI-) to 536.5.

Example 4: 2-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and N-methylaniline were allocated specified in the title compound as yellow is solid substance with a yield of 83% (HPLC purity 99%).

MS (ESI+): 465,6, (ESI-) 463,8.

Example 5: 2-chloro-N-(3-{4-[(2-naphthyloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide

According to the General method as outlined in example 1 (method a), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and 2-hydroxynaphthalene, allocated specified in the title compound as a yellow solid with a yield of 72% (HPLC purity 99%).

MC (ESI+): 503,4, (ESI-) 501,2.

Example 6: 2-chloro-N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and 1H-indole was isolated specified in the title compound as a yellow solid with a yield of 71% (HPLC purity 98%).

MC (ESI+): 475,9, (ESI-) 473,5.

Example 7: 2-chloro-N-(3-{4-[(5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl]phenyl}-pyrazin-2-yl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and 6-hydroxy-1,2,3,4-tetrahydronaphthalene, allocated specified in the title compound as a yellow solid substances is and with the release of 69% (HPLC purity 99%).

MC (ESI+): 507,6, (ESI-) 505,2.

Example 8: 2-chloro-N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide (intermediate compound 8) and 2-ethylbenzamide, allocated specified in the title compound as a yellow solid with a yield of 65% (HPLC purity 96%).

MS (ESI+): 505,4, (ESI-) 503,2.

Example 9: N-(3-{4-[(1,3-benzodioxol-5-ylamino)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3,4-(methylenedioxy)aniline was isolated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 96%).

MS (ESI+): 529,7, (ESI-) 527,5.

Example 10: N-[3-(4-{[(3-methoxybenzyl)oxy]methyl}phenyl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3-Anisimova alcohol, allocated specify the OU in the title compound as a yellow solid with a yield of 64% (HPLC purity 92%).

MS (ESI+): 530,4, (ESI-) 528,8.

Example 11: 3-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl) phenyl]pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 3-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide and N-methyl-4-(triptoreline)aniline was isolated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 94%).

MS (ESI+): 550,2, (ESI-) 547,6.

Example 12: N-[3-(4-{[(4-chlorophenyl)(methyl)amino]methyl}phenyl)pyrazin-2-yl]-thiophene-2-sulfonamide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}thiophene-2-sulfonamida and N-methyl-4-Chloroaniline, allocated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 94%).

MS (ESI+): 472,8, (ESI-) 570,7.

Example 13: 4-phenoxy-N-{3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}benzosulfimide

To a solution of 4-phenoxy-N-(3-piperazine-1-Alperin-2-yl)benzosulfimide (411 mg, 1.0 mmol, 1 EQ.) in dimethylformamide (10 ml) was added the hydrochloride of 2-(chloromethyl)quinoline (214 mg, 1 mmol, 1 EQ.) and DIEA (322 mg, 2.5 mmole, 2.5 EQ.). The reaction mixture was heated at 50°C for 1 h, the Reaction mixture Oh what was Adali, was diluted with 30 ml water and was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, evaporated and the residue was purified flash chromatography on silica gel, elwira EA and cyclohexane, to obtain 4-phenoxy-N-{3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}benzosulfimide in the form of a yellow solid (419 mg, from 0.76 mmole, yield 76%, HPLC purity 97%).

MS (ESI+): 553,6, (ESI-) 551,2.

Example 14: 4-methyl-N - {3-[4-({methyl[4-(triptoreline)phenyl]amino}-methyl)phenyl]-pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-4-methylbenzenesulfonamide and N-methyl-4-(triptoreline)aniline was isolated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 94%).

MS (ESI+): 529,5, (ESI-) 526,6.

Example 15: 4-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]-benzosulfimide

According to the General method as outlined in example 1 (method B), starting from 4-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzosulfimide and N-methyl-aniline, were isolated specified in the title compound as a yellow solid with a yield of 76% (HPLC purity 96%).

MS (ESI+): 465,6, (ESI-) 463,7.

Example 16: 4-cyano-N-{3-[4-({methyl[4-(driftor is ethoxy)phenyl]amino}-methyl)phenyl]pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method D), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-4-cyanobenzenesulfonyl and N-methyl-4-(triptoreline)aniline was isolated specified in the title compound as a yellow solid with a yield of 70% (HPLC purity 92%).

MS (ESI+): 540, 6L, (ESI-) 538,5.

Example 17: N-[3-(4-{[(4-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-fluoro-N-methylaniline, allocated specified in the title compound as a yellow solid with a yield of 78% (HPLC purity 98%).

MS (ESI+): 517,9, (ESI-) 515,8.

Example 18: N-(3-{4-[(methylphenylimino)methyl]phenyl}pyrazin-2-yl)-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and N-methylaniline were allocated specified in the title compound as a yellow solid with a yield of 75% (HPLC purity 99%).

MS (ESI+): 499,9, (ESI-) 497,8.

Example 19: N-[3-(4-{[(4-cyanophenyl)is ethylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-(N-methylamino)benzonitrile, allocated specified in the title compound as a yellow solid with a yield of 71% (HPLC purity 94%).

MS (ESI+): 524,6, (ESI-) 522,4.

Example 20: N-{3-[4-(4-forfinancial)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-terfenol, allocated specified in the title compound as a yellow solid with a yield of 67% (HPLC purity 95%).

MS (ESI+): 504,6, (ESI-) 502,6.

Example 21: N-(3-{4-[(ethylvanillin)methyl]phenyl}pyrazin-2-yl)-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and N-methylaniline were allocated specified in the title compound as a yellow solid with a yield of 70% (HPLC purity 96%).

MC (ESI+): 513,6, (ESI-) 511,7.

Example 22: N-{3-[4-(2,3-d is hydrobenzo[1.4]oxazin-4-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3,4-dihydro-2H-1,4-benzoxazine, allocated specified in the title compound as a yellow solid with a yield of 65% (HPLC purity 97%).

MS (ESI+): 527,7, (ESI-) 525,5.

Example 23: N-[3-(4-{[(3-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3-fluoro-N-methylaniline, allocated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 92%).

MS (ESI+): to 517.7, (ESI+) 515,6.

Example 24: N-{3-[4-(6-chloropyridin-3-intoximeter)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2-chloro-5-hydroxypyridine, allocated specified in the title compound as a yellow solid with a yield of 73% (HPLC purity 98%).

MS (ESI+): 522,1, (ES -) 520,1.

Example 25: N-{3-[4-(2-pyridin-2-Jindal-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2-pyridin-2-yl-1H-indole was isolated specified in the title compound as a yellow solid with a yield of 56% (HPLC purity 92%).

MS (ESI+): 586,8 (ESI-) 584,6.

Example 26: N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 5-fluoro-indole was isolated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 99%).

MS (ESI+): 527,6, (ESI-) 525,7.

Example 27: N-[3-(4-phenoxymethyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and phenol, were isolated specified in the title compound as a yellow solid from what hodom 75% (HPLC purity 98%).

MS (ESI+): 486,8, (ESI-) 484,7.

Example 28: N-[3-(4-{[(4-chlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-chloro-N-methylaniline, allocated specified in the title compound as a yellow solid with a yield of 72% (HPLC purity 94%).

MS (ESI+): 534,1, (ESI-) 532,1.

Example 29: 2-chloro-N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 4-(N-methylamino)benzonitrile, allocated specified in the title compound as a yellow solid with a yield of 52% (HPLC purity 99%).

MS (ESI+): 491,0, (ESI-) 489,0.

Example 30: N-[3-(4-{[(3,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3,4-dichloro-N-methylaniline, the separation is whether specified in the title compound as a yellow solid with a yield of 63% (HPLC purity 91%).

MS (ESI+)): 569,6, (ESI-) 565,1.

Example 31: N-{3-[4-(4-cyanoprokaryotes)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-cyanophora, allocated specified in the title compound as a yellow solid with a yield of 73% (HPLC purity 93%).

MS (ESI+): 511,6, (ESI-) 509,6.

Example 32: N-{3-[4-(6-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 6-fluoro-1H-indole was isolated specified in the title compound as a yellow solid with a yield of 77% (HPLC purity 97%).

MS (ESI+): 527,8, (ESI-) 525,6.

Example 33: 2-chloro-N-{3-[4-(5-methoxy-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2-methyl-5-methoxyindole allocated is specified in the header connection in vitilligo solids with a yield of 72% (HPLC purity 98%).

MS (ESI+): 520,2, (ESI-) 518,3.

Example 34: N-{3-[4-(4-methoxyphenoxy)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 4-hydroxyanisole, allocated specified in the title compound as a yellow solid with a yield of 48% (HPLC purity 91%).

MS (ESI+): 516,6, (ESI-) 514,5.

Example 35: N-(3-{4-[(benzylpyridine-2-ylamino)methyl] phenyl}pyrazin-2-yl)-2-chlorobenzenesulfonamide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2-benzylaminopurine, allocated specified in the title compound as a yellow solid with a yield of 35% (HPLC purity 94%).

MS (ESI+): 543,3, (ESI-) 541.3.

Example 36: N-{3-[4-(2,3-dihydroindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2,3-dihydro-1H-indole was isolated specified in the header soy is inania in the form of a yellow solid with a yield of 66% (HPLC purity 94%).

MS (ESI+): 511,6, (ESI-) 509,4.

Example 37: N-[3-(4-{[(2,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2,4-dichloro-N-methylaniline, allocated specified in the title compound as a yellow solid with a yield of 69% (HPLC purity 96%).

MS (ESI+): 569,6, (ESI-) 566,8.

Example 38: N-{3-[4-(3-chlorphenoxamine)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 3-chlorophenol were allocated specified in the title compound as a yellow solid with a yield of 70% (HPLC purity 98%).

MS (ESI+): 521,0, (ESI-) 519,0.

Example 39: 2-chloro-N-[3-(4-{[(2,4-differenl)methylamino]methyl}phenyl)-pyrazin-2-yl]benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2,4-debtor-N-methylaniline, allocated mentioned in the title the connection information in the form of a yellow solid with a yield of 77% (HPLC purity 92%).

MS (ESI+): 502,0, (ESI-) 500,0.

Example 40: N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2-methyl-1H-indole was isolated specified in the title compound as a yellow solid with a yield of 70% (HPLC purity 98%).

MS (ESI+): 523,5, (ESI-) 521,5.

Example 41: 2-chloro-N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 5-farindola, allocated specified in the title compound as a yellow solid with a yield of 72% (HPLC purity 96%).

MS (ESI+): 493,9, (ESI-) 491,9.

Example 42: 2-chloro-N-[3-(4-{[(2-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2-fluoro-N-methylaniline, allocated specified in the title compound as a yellow solid in the society with the release of 79% (HPLC purity 99%).

MS (ESI+): Ozenmunaygas given KZT 484.1 ecological, (ESI-) 482,1.

Example 43: 2-chloro-N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2-methyl-1H-indole was isolated specified in the title compound as a yellow solid with a yield of 81% (HPLC purity 96%).

MS (ESI+): 490,0, (ESI-) 488,1.

Example 44: N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and N-(2-pyridine)benzylamine, allocated specified in the title compound as a yellow solid with a yield of 79% (HPLC purity 98%).

MS (ESI+): 576,6, (ESI-) to 574.6.

Example 45: 2-chloro-N-(3-{4-[(ethylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)benzosulfimide

According to the General method as outlined in example 1 (method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro)benzosulfimide (intermediate compound 8) and 2-(ethylamino)pyridine, was isolated specified in the header of the connection in view of the yellow solid with a yield of 64% (HPLC purity 96%).

MS (ESI+): 481,0, (ESI-) 478.1.

Example 46: N-{3-[4-(5-chloro-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom

According to the General method as outlined in example 1 (method a), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzosulfimide (intermediate compound 9) and 2-methyl-5-chloroindole, allocated specified in the title compound as a yellow solid with a yield 719% (HPLC purity 958%).

MS (ESI+): 558,3, (ESI-) 556,4.

Example 47: preparation of a pharmaceutical composition

The following examples of formulations illustrate representative pharmaceutical compositions of the present invention, not as a constraint.

Part 1 - pill

Derived 2,3-substituted personalfinance formula I in the form of dry powder was mixed with a dry gelatin as a binder in a ratio of about 1:2 by weight. As the moving substance was added a small amount of magnesium stearate. The mixture was formed into tablets 240-270 mg (80-90 mg of active 2,3-substituted personalhomepage connection on the tablet) using a tablet press.

Part 2 - capsules

Derived 2,3-substituted personalfinance formula I in the form of dry powder was mixed with starch as diluent in soothes the Sri approximately 1:1. The mixture was filled in capsules of 250 mg (125 mg of active 2,3-substituted personalhomepage compound per capsule).

Part 3 - fluid

Derived 2,3-substituted personalfinance formula I (1250 mg), sucrose (1.75 g) and xanthan resin (4 mg) are blended, passed through a 10 mesh sieve (US) and then mixed with a previously prepared solution of microcrystalline cellulose and carboxymethylcellulose sodium form (1:89, 50 mg) in water. Sodium benzoate (10 mg), flavouring and colouring agent was diluted with water and added with stirring. Then water was added in sufficient quantity to obtain a total volume of 5 ml

Part 4 tablets

Derived 2,3-substituted personalfinance formula I in the form of dry powder was mixed with a dry gelatin as a binder in a ratio of about 1:2 by weight. As the moving substance was added a small amount of magnesium stearate. The mixture was formed into tablets 450-900 mg (150-300 mg of active 2,3-substituted personalhomepage connection on the tablet) using a tablet press.

Part 5 - injection

Derived 2,3-substituted personalfinance formula I was dissolved in sterile SFR as a medium for injection to a concentration of approximately 5 mg/ml

Biological assays

Example 48: construction of expression century the ora mammals rser-hCRTH2

Amplified cDNA of human CRTH-2 by PCR using the cDNA library of human bladder as template and specific primers containing restriction sites HindIII and BamHI for cloning in the vector rser (Invitrogen). Vector design is described in detail Sawyer and others, Br. J. Pharmocol 2002, 137, s-1172. The nucleotide sequence of the cloned cDNA was identical to the previously described sequence hCRTH2 (Nagata et al, 1999, J. Immunol. 162, c.1278-1286).

Example 49: establishment of cell lines pCEP4-hCRTH2-HEK293 (EBNA)

Cells NEC (EBNA) was transfusional with the design pCEP4-hCRTH2 using the technique with calcium phosphate. Cells were maintained in culture at 37°C in an atmosphere of 5% CO2in a modified method of Dulbecco environment Needle F12 (Invitrogen)containing 10% inactivated by heating fetal bovine serum (TerraCell International, Canada), 2 mm glutamine, 100 units/ml penicillin and 100 µg/ml streptomycin (Invitrogen). After 48 h of transliterowany cells were grown in the presence of 300 mcml of hygromycin (Invitrogen) for 4 weeks, and resistant to the antibiotic amplified cells to obtain a cell membrane.

Example 50: obtaining expressing hCRTH2 membranes

Fused cells NEC (EBNA)expressing hCRTH2, were cultured in culture flasks at 225 cm3(Corning, USA) in 30 ml of medium. After two washes with ZFR cells you asifali in 10 ml SFR, containing 1 mm etc, centrifuged at 500g for 5 min at 4°C and frozen at -80°C. Rainfall is again suspended in 50 ml of Tris-HCl, pH of 7.4, 2 mm add, 250 mm sucrose containing tablets inhibitor cocktail for protease (full free add, Roche, Germany), and incubated for 30 min at 4°C. the Cells were destroyed by cavitation with nitrogen (Parr Instruments, USA) at 4°C (800 lb-ft2within 30 min) and centrifuged at 500g for 10 min at 4°C. the Precipitate, containing nuclei and cell debris was discarded, and the supernatant was centrifuged for 60 min at 4°C at 45000g. Sediment membranes again suspended in storage buffer (10 mm HEPES/KOH, pH of 7.4, 1 mm add, 250 mm sucrose, tablets inhibitory cocktail of protease), using the method of homogenization Dance, and frozen in liquid nitrogen and kept at -80°C.

Example 51: analysis of the binding of the ligand

Compounds of the present invention inhibit the binding of PGD2 to its receptor CRTH2. Inhibitory activity can be investigated by analyzing the binding of radioligand (Sawyer and others, Br. J. Pharmocol 2002, 137, s-72). Analysis of the binding of radioligand was carried out at room temperature in the buffer for binding (10 mm HEPES/KOH, pH of 7.4, 10 mm MnCl2with tablets inhibitory cocktail of protease), containing 1.5 nm [3H]PGD2(Amersham, 156 CI/mmol) and 10 μg protein of cell membranes hCRTH2 NECK (EBNA) in which heme 100 μl in 96-well plates (Corning, USA). Nonspecific binding was determined in the presence of 1 μm PDG2 (Cayman, USA). Competing personalfinance was dissolved in dimethyl sulfoxide to the total amount of DMSO was kept constant at 1% dimethyl sulfoxide (Me2SO). Was added 10 μl of personalpolitik. Incubation (60 min at room temperature) was interrupted by rapid filtration through a 96-well tablets with hydrophobic filter GF/C Unifilter (Whatman, USA). Filters were washed twice with 250 μl of Tris-HCl, pH of 7.4, 10 mm MnCl2and residual radioligand associated filters, mixed with 100 μl of liquid scintillation cocktail (Optiphase Supermix, Perkin Elmer, USA) and was determined by counting residual radioligand using scintillation micro-β-counter 1450 (Wallac, UK). The results of the analysis of the binding shown in table 1.

Example 52: definition of Ki(analysis of binding radioligand)

Values of Kiwere determined using experiments equilibrium of competitive binding in comparison with [3H]PDG2. Values of Kicalculated by the formula below and represent the average of at least three independent experiments, the dose-effect. Values To the mean of ligand concentration required for inhibition of 50% of the tie is of [ 3H]PDG2 with CRTH2.

Ki=IC50/(1+[ligand concentration]/Kd)]

All experiments were performed in 96-well tablets in a final volume of 100 μl in accordance with the above analysis filtering. The concentration of membranes and [3H]PDG2, as well as positive and negative controls were identical to the conditions described above.

In one variation of the embodiment of personalfinance of the present invention inhibit CRTH2 at a concentration of less than 100 microns. In another variant embodiment of personalfinance of the present invention inhibit CRTH2 at a concentration of less than 10 μm. In a preferred variant embodiment of personalfinance of the present invention inhibit CRTH2 at a concentration of less than 5 microns. In an additional preferred variant embodiment of personalfinance of the present invention inhibit CRTH2 at a concentration of less than 1 micron.

Values of Kishown in table 2. It follows that the above-mentioned compounds according to formula I show significant inhibition of the binding of PGD2 to CRTH2.

/tr>
Table 2
Connection # Ki[µm]Connection # Ki[µm] Connection # Ki[µm]
11,01170,3833of 2.21
21,26180,40342,60
30,45190,47352,64
4of 1.57200,48362,69
52,32210,59372,82
62,12220,62382,90
72,59230,70392,95
81,42240,72403,06
92,98250,85413,90
101,40260,95423,90
115,16271,32434,11
128,43281,4744of 4.44
134,03291,49454,51
145,85301,58464,65
15 311,59
165,71321,93

Example 53: analysis of the binding of [35S]|γS

The analysis of [35S] γS measures the increase in exchange Gurinovich nucleotides in the G-proteins in cell membranes, resulting from the binding of the agonist (PDGF2) with CRTH2. This process can be monitored in vitro, incubare cell membranes containing G-proteins and CRTH2, with GDF and [35S]γS, radioactively labeled, resistant to hydrolysis of the GTP analogue (see Harrison and others, Life Sciences 74, 489-508, S. 2003). The addition of personalfinance leads to binding to CRTH2 and, consequently, inhibition of the binding of the agonist, which can be controlled, as inhibition of the stimulation of the exchange of GTP/GDF.

Conditions of analysis were identical to those described for analysis of binding of radioligand as described in example 21. Analysis of the binding of [35S] γS was carried out at 30°C With careful mixing in 96-well scintillation white polystyrene plates (Perkin Elmer, USA) in a final volume of 200 μl containing 2% dimethyl sulfoxide. Incubated 2,3-substituted personalfinance in the volume of 20 mm HEPES/KOH, pH of 7.4, 10 mm MgCl 2, 10 μg/ml saponin, 3 μm (GDF), 150 mm NaCl containing 10 μg of membranes expressing the hCRTH2 receptor (Euroscreen, Belgium), within 10 minutes of non-specific binding was determined in the presence of 10 μm γS. Samples were incubated for 30 min in the presence of increasing concentrations of PGD2 to determine agonistic activity or 80 nm PGD2 to determine the antagonistic activity, respectively. Then each sample was added to 0.15 nm [35S]γS, and after incubation for 30 min the reaction was stopped by centrifugation at 1000 g at 4°C for 10 min. the Supernatant was removed, and the binding of [35S] γS was determined using scintillation micro-β-counter 1450. Data were analyzed using the program Prism (GraphPad Software, Inc. San Diego, USA). The determination of the values of IC50(i.e. the amount necessary to achieve 50% inhibition of binding (μm)) was performed in 96-well tablets in a final volume of 100 μl in accordance with the above analysis filtering. The concentration of membranes and radioactive ligand, as well as positive and negative controls were identical to the conditions used and described above in examples 21 and 22.

The compound of example 1 has a value IC50of 1.9 μm. The compound of example 2 has the value IC50of 4.6 μm, and the compound of example 3 has the value of the IC501.4 µm.

Example 54: mod the al contact hypersensitivity (AU)

The model of contact hypersensitivity can be used to evaluate therapeutic efficacy of 2,3-substituted personalpolitik in skin inflammation mediated by T-cells. The model is well justified to characterize compounds such dermatological indications, as psoriasis and allergic contact dermatitis (Xu and others J Exp Med. 183, s-1012, 1996). It includes a phase of sensitization and subsequent stimulation with antigen (2,4-dinitrofluorobenzene, DNFB). This leads to skin inflammation with the formation of edema and cell infiltration in the skin. Swelling can be measured by the instrument to determine the thickness of the skin fold at the site of stimulation (ear in mice). Intravenous administration of the compounds according to the invention for 30 minutes before stimulation with DNFB reduces swelling and, consequently, reduces inflammation in the skin compared with positive controls treated only with filler before stimulation with antigen. Mice of the negative control is not sensibiliser, but is subjected to stimulation with DNFB, therefore, dependent T-cell inflammation is not observed, and the swelling is not formed. Mice of Balb/c mice were obtained from Charles River (Calcco, Italy). Animals were kept in conventional conditions. Treatment was started at an average age of 8-12 weeks. DNFB (2,4-dinitrophenol) was obtained from Sigma-Aldrich (St.Louis, MO, USA).

Behold civilizacia and stimulation of SHS with DNFB

Mice were senzibilizirani and stimulated to achieve SHS to DNFB. Phase sensitization was accompanied by the stimulation phase. Bred DNFB in a mixture of acetone/olive oil (1) immediately before use. Mice were senzibilizirani to DNFB, dealing 25 μl of 0.5% solution DNFB on the shaved skin of the back. After 5 days, put 10 ál of 0.2% solution DNFB on both sides of the right ear (stimulation). The ear thickness was controlled on day 6 (after 1 day after stimulation), using the tool to determine the thickness of the skin fold at the site of stimulation (Mitutoyo, Milan, Italy).

The ear swelling was calculated as (Tn-T5)right ear - (Tn-T5)in the left ear, where Tn and T5 represent the magnitude of the thickness of the ear on day n research and day 5 before stimulation, respectively.

The list of references

Cosmi and others (2000) Eur. J. Immunol. c.30, 2972-2979.

Bush, R.K., Georgitis J.W., Handbook of asthma and rhinitis. 1st ed. (1997), Abingdon: Blackwell Science, c.270.

Harrison and others (2003) Life Sciences 74, c.489-508.

Hirai and others (2001) J Exp. Med. 193, c.255-261.

Lewis and others (1982) J. Immunol. 129, s.

Matsuoka and others (2000) Science 287, c.2013-2017.

Nagata and others (1999) J. Immunol. 162, c.1278-1286.

Sawyer and others (2002) Br. J. Pharmacol. 137, c.1163-1172.

Woodward and others (1990) Invest. Ophthalomol Vis. Sci. 31, c.138-146.

Woodward and others (1993) Eur. J. Pharmacol. 230, c.327-333.

Xu and others (1996) J Exp Med. 183, c.1001-12.

WO 04/106302.

WO 04/096777.

WO 04/035543.

WO 04/032848.

WO 05/007094.

WO 04/108692.

WO 04/108717.

WO 04/058265.

WO 05/102338.

1. 2,3-Substituted pyrazinyl foamed, selected from the group consisting of
N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide,
2-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
2-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-(3-{4-[(2-naphthyloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
2-chloro-N-(3-{4-[(5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
N-(3-{4-[(1,3-benzodioxol-5-ylamino)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
N-[3-(4-{[(3-methoxybenzyl)oxy]methyl}phenyl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide,
3-chloro-N-{3-[4-({methyl-[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-chlorophenyl)(methyl)amino]methyl}phenyl)pyrazin-2-yl]thiophene-2-sulfonamida,
4 phenoxy-N-{3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}benzosulfimide,
4-methyl-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
4-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide
4-cyano-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-(3-{4-[(methylphenylimino)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(4-forfinancial)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-(3-{4-[(ethylvanillin)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(2,3-dihydrobenzo[1,4]oxazin-4-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-[3-(4-{[(3-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(6-chloropyridin-3-intoximeter)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(2-pyridin-2-Jindal-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-phenoxymethyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(4-chlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
2-chloro-N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-[3-(4-{[(3,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-bensalah is named,
N-{3-[4-(4-cyanoprokaryotes)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(6-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-methoxy-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-{3-[4-(4-methoxyphenoxy)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-chlorobenzenesulfonamide,
N-{3-[4-(2,3-dihydroindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(2,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(3-chlorphenoxamine)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-[3-(4-{[(2,4-differenl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
2-chloro-N-[3-(4-{[(2-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-triftoratsetilatsetonom,
2-chloro-N-(3-{4-[(ethylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)benzosulfimide, and
N-{3-[4-(5-chloro-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-tripto is methylbenzenesulfonamide.

2. The use of 2,3-substituted personalfinance selected from the group consisting of
N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide,
2-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
2-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-(3-{4-[(2-naphthyloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
2-chloro-N-(3-{4-[(5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
N-(3-{4-[(1,3-benzodioxol-5-ylamino)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
N-[3-(4-{[(3-methoxybenzyl)oxy]methyl}phenyl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide,
3-chloro-N-{3-[4-({methyl-[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-chlorophenyl)(methyl)amino]methyl}phenyl)pyrazin-2-yl]thiophene-2-sulfonamida,
4 phenoxy-N-{3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}benzosulfimide,
4-methyl-N - {3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
4-chloro-N-[3-(4-{[methyl(Fe who yl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
4-cyano-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-(3-{4-[(methylphenylimino)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(4-forfinancial)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-(3-{4-[(ethylvanillin)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(2,3-dihydrobenzo[1,4]oxazin-4-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-[3-(4-{[(3-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(6-chloropyridin-3-intoximeter)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(2-pyridin-2-Jindal-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-phenoxymethyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(4-chlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
2-chloro-N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-[3-(4-{[(3,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-bensalah is named,
N-{3-[4-(4-cyanoprokaryotes)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(6-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-methoxy-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-{3-[4-(4-methoxyphenoxy)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-chlorobenzenesulfonamide,
N-{3-[4-(2,3-dihydroindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(2,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(3-chlorphenoxamine)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-[3-(4-{[(2,4-differenl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
2-chloro-N-[3-(4-{[(2-forfinal)methylamino]methyl)phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-triftoratsetilatsetonom,
2-chloro-N-(3-{4-[(ethylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)benzosulfimide and
N-{3-[4-(5-chloro-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-Cryptor is ethylbenzaldehyde,
for the treatment of allergic diseases, inflammatory dermatoses, immunological disorders and neurodegenerative disorders.

3. Pharmaceutical composition having inhibitory activity against receptor CRTH2, containing the 2,3-substituted personalfinance selected from the group consisting of
N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)-benzosulfimide,
2-chloro-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
2-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-(3-{4-[(2-naphthyloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
2-chloro-N-(3-{4-[(5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
2-chloro-N-(3-{4-[(2-ethyl-1H-benzimidazole-1-yl)methyl]phenyl}pyrazin-2-yl)benzosulfimide,
N-(3-{4-[(1,3-benzodioxol-5-ylamino)methyl]phenyl}pyrazin-2-yl)-2-(trifluoromethyl)benzosulfimide,
N-[3-(4-{[(3-methoxybenzyl)oxy]methyl)phenyl)pyrazin-2-yl]-2-(trifluoromethyl)benzosulfimide,
3-chloro-N-{3-[4-({methyl-[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-chlorophenyl)(methyl)amino]methyl}phenyl)pyrazin-2-althofen-2-sulfonamida,
4 phenoxy-N-{3-[4-(quinoline-2-ylmethyl)piperazine-1-yl]pyrazin-2-yl}benzosulfimide,
4-methyl-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
4-chloro-N-[3-(4-{[methyl(phenyl)amino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
4-cyano-N-{3-[4-({methyl[4-(triptoreline)phenyl]amino}methyl)phenyl]-pyrazin-2-yl}benzosulfimide,
N-[3-(4-{[(4-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-(3-{4-[(methylphenylimino)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(4-forfinancial)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-(3-{4-[(ethylvanillin)methyl]phenyl}pyrazin-2-yl)-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(2,3-dihydrobenzo[1,4]oxazin-4-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-[3-(4-{[(3-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(6-chloropyridin-3-intoximeter)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(2-pyridin-2-Jindal-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom,
N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-phenoxymethyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-[3-(4-[(4-chlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
2-chloro-N-[3-(4-{[(4-cyanophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-[3-(4-{[(3,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(4-cyanoprokaryotes)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-{3-[4-(6-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-methoxy-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-{3-[4-(4-methoxyphenoxy)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-chlorobenzenesulfonamide,
N-{3-[4-(2,3-dihydroindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
N-[3-(4-{[(2,4-dichlorophenyl)methylamino]methyl}phenyl)pyrazin-2-yl]-2-triftoratsetilatsetonom,
N-{3-[4-(3-chlorphenoxamine)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-[3-(4-{[(2,4-differenl)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-trifluoromethyl-benzosulfimide,
2-chloro-N-{3-[4-(5-Florinda-1-ylmethyl)phenyl]pyrazin-2-yl)benzosulfimide,
2-chloro-N-[3-(4-{[(2-forfinal)methylamino]methyl}phenyl)pyrazin-2-yl]benzosulfimide,
2-chloro-N-{3-[4-(2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}benzosulfimide,
N-(3-{4-[(benzylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)-2-which of diftormetilirovaniya,
2-chloro-N-(3-{4-[(ethylpyridine-2-ylamino)methyl]phenyl}pyrazin-2-yl)benzosulfimide and
N-{3-[4-(5-chloro-2-methylindol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-triftoratsetilatsetonom.

4. The pharmaceutical composition inhibiting chemoattractant receptor homologous molecule expressed on T-helper 2 containing the compound of formula (I)

together with a pharmaceutically acceptable excipient or carrier, where a is selected from the group consisting of


n means an integer independently selected from 0, 1, 2, 3 or 4;
m denotes 1 or 2;
In selected from the group consisting of phenyl or piperazinil;
R1means hydrogen;
R2means phenyl, where R2optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, (C1-C6)alkyl;
R3selected from the group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylglycerol, (C3-C8)cycloalkyl and (C3-C8)geterotsiklicheskie, where each of the specified (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkyl is Rila, (C1-C6)alkylglycerol, (C3-C8)cycloalkyl and (C3-C8)geterotsiklicheskie optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, dialkoxy and thioalkyl, or where specified aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylether, (C3-C8)cycloalkyl or (C3-C8)heteroseksualci may be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)geteroseksualnoe groups and may be substituted by one or more substituents selected from the group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulfoxy, sulfonyl, sulfonamida and trihalomethyl;
R7selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)geterotsiklicheskie, carboxyl, cyano, amino and hydroxy;
aryl selected from phenyl or naphthyl; and
heteroaryl selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, chinoiserie.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula I in which R1 is chosen from the group including: H; alkyl; alkylenearyl and pyridin; R2 is chosen from the group including: cycloalkyl; aryl; CO-NH-cycloalkyl; CO-NH-aryl either unsubstituted or substituted with the help of halogen, CF3; SO2-aryl either unsubstituted or substituted with the help of alkyl; or in which R1 and R2 together form a 5- or 6-membered ring that does not need to contain 1 additional nitrogen heteroatom and that may also be substituted with the help of aryl; and that may also contain a carbonyl group; and that may also be condensed with aryl; R3 and R4 denote H; and acid additions to their physiologically acceptable salts. Invention also refers to a pharmaceutical composition, to the way of production of the formula I compound, to application of the formula I compound, and to the way of treatment or prevention of fatty degeneration, type II diabetes, metabolic syndrome and associated and/or secondary diseases or pathologic conditions endured by mammals.

EFFECT: production of new bioactive compounds that inhibit the isoenzyme of hydroxy citric acid II (hCA II).

11 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

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