2,6-substituted-4-monosubstituted aminopyrimidines as prostaglandin d2 receptor antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2,6-substituted-4-monosubstituted aminopyrimidines of formula (I) or pharmaceutically acceptable salts thereof, which have prostaglandin D2 receptor antagonist properties. In formula R1 is 2,4-dichlorophenyl or 4-trifluoromethoxyphenyl, and when R1 is 2,4-dichlorophenyl, R2 is 3-carboxypyrrolidinyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperdin-1-yl, 4-aminopiperidin-1-yl, 4-acetamidepiperidin-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylsulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminosulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-thiomorpholin-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonyl-1-methylethyl)phenyl, 3-carboxymethylpiperidin-1-yl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 3-ethylsulphonylaminocarbonylpiperidin-1-yl, 3-tert-butylsulphonylaminocarbonylpiperidin-1-yl, 3-trifluoromethylsulphonylaminocarbonylpiperidin-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidin-1-yl, 3-aminocarbonylpiperidin-1-yl, 3-dimethylaminocarbonylpiperidin-1-yl, 3-dimethylaminosulphonylaminocarbonylpiperidin-1-yl or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and when R1 is 4-trifluoromethoxyphenyl, R2 is 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypiperidinyl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 5-carboxythiophen-2-yl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: high efficiency of using said compounds.

3 cl, 1 tbl, 13 ex

 

The technical FIELD

The invention relates to 2,6-substituted-4-monosubstituted compounds of aminopyrimidine, their receipt, containing these compounds, pharmaceutical compositions and their pharmaceutical use in the treatment of pathological conditions that can be controlled by inhibition of the receptor for prostaglandin D2.

The LEVEL of TECHNOLOGY

It is shown that local stimulation of allergen in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis leads to a rapid rise in the level of prostaglandin D2(PGD2)in nasal and bronchial wash fluid, tears, and water collected from the skin of the bubble method "skin cells". PGD2 can have a number of inflammatory conditions, e.g. to increase the permeability of blood vessels in the conjunctiva and the skin, to increase the resistance of the Airways of the nose, can cause narrowing of the Airways and the infiltration of eosinophils into the conjunctiva and the trachea.

PGD2 is the main ziklooksigenazny product of arachidonic acid produced by mastocytoma immunological stimulation [Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II, prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982]. Activated mastocyte, one of the main sources of PGD2, play a key role in the occurrence of allergic reactions is under such conditions, as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling CE, Bradding P, Pavord ID, Wardlaw AJ, New Insights into the role of the mast cell in asthma, Clin Exp Allergy 33, 550-556, 2003].

Many of the effects of PGD2 mediated by its action at the receptor prostaglandin D ("DP") - receptor-associated G-protein, expressed on the epithelium and smooth muscle.

In asthma respiratory epithelium has long been considered the main source of inflammatory cytokines and chemokines, which determine the development of the disease [Holgate S, Lackie P, Wilson S, Roche W, Davies D, Bronchial Epithelium as a Key Regulator of Airway Allergen Sensitzation and Remodeling in Asthma, Am J Respir Crit Care Med. 162, 113-117, 2000]. In experimental models of asthma mice upon stimulation with antigen is a sharp activation of the DP receptor in the epithelium of the respiratory tract [Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S, prostaglandin D2 as a mediator of allergic asthma, Science 287, 2013-2017, 2000]. In knockout mice with a null DP receptor is markedly reduced the hyperactivity of the Airways and chronic inflammation [Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S, Prostaglandin D2 as a mediator of allergic asthma, Science 287, 2013-2017, 2000] two of the most important characteristic of asthma people.

It is also believed that the DP receptor is involved in allergic rhinitis human is and, common allergic disease characterized by symptoms such as sneezing, itching, rhinorrhea, and nasal congestion. Local application of PGD2 in the nasal cavity causes a dose-dependent increase in nasal congestion [Doyle WJ, Boehm S, Skoner DP, Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy, J Allergy Clin Immunol. 86(6 Pt 1), 924-35, 1990].

It was shown that the DP receptor antagonists reduce airway inflammation in experimental models of asthma Guinea pigs [Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita H (2001), Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751, J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001]. Thus, PGD2, apparently, acts on the DP receptor and plays an important role in identifying some of the main features of allergic asthma.

It has been shown that antagonists of DP can effectively reduce the symptoms of allergic rhinitis in many species, in particular, it was shown that they can suppress induced antigens stuffy nose, the most obvious symptom of allergic rhinitis [Jones, T.R., Savoie, C., Robichaud, A., Sturino, C., Scheigetz, J., Lachance, N., Roy, B., Boyd, M., Abraham, W., Studies with a DP receptor antagonist in sheep and guinea pig models of allergic rhinitis, Am. J. Resp. Crit. Care Med. 167, A218, 2003; and Arimura, A., Yasui K., Kishino j, Asanuma F., Hasegawa h, Kakudo s, Ohtani M., Arita H., Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001].

Antagonists DP so the e effective in experimental models of allergic conjunctivitis and allergic dermatitis [Arimura A., Yasui K., Kishino j, Asanuma F., Hasegawa h, Kakudo s, Ohtani M., Arita H., Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751, J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001; and Torisu K., Kobayashi K., Iwahashi M., Nakai Y., Onoda, T., Nagase, T., Sugimoto I., Okada Y., Matsumoto R., Nanbu F., Ohuchida s, Nakai H., Toda M., Discovery of a new class of potent, selective, and orally active prostaglandin D2 receptor antagonists, Bioorg. & Med. Chem. 12, 5361-5378, 2004].

The INVENTION

This invention relates to the compound of formula (I):

where R1represents 2,4-dichlorophenyl or 4-trifloromethyl, and

when R1represents 2,4-dichlorophenyl, then R2is a 3-carboxypropanoyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperidin-1-yl, 4-aminopiperidin-1-yl, 4-acetamiprid-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylcyclopentadienyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonylmethyl-1-methylethyl)phenyl, 3-(1-thiomorpholine-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminoethyl-1-methylethyl)phenyl, 3-carboxymethylchitin-1-yl, 3-methylsulfonylmethane-1-yl, 3-metilsulfonilmetane-1-yl, 3-tert-butylanthraquinone-1-yl, 3-triftormetilfullerenov-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidine-1-yl, 3-aminocarbonylmethyl-1-yl, 3-dimethylaminocarbonylmethyl-1-the l 3-dimethylaminoethylmethacrylate-1-yl, or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and

when R1is a 4-trifloromethyl, then R2represents a 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypeptidases, 3-methylsulfonylmethane-1-yl, 5-carboxamide-2-yl,

or its pharmaceutically acceptable salt, hydrate or MES, its pharmaceutically acceptable prodrug or pharmaceutically acceptable salt, hydrate or MES prodrugs.

Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds of the present invention, or its pharmaceutically acceptable salt, hydrate or MES, its pharmaceutically acceptable prodrug or pharmaceutically acceptable salt, hydrate or MES prodrugs in a mixture with a pharmaceutically acceptable carrier.

Another aspect of the present invention is a method of treating a patient suffering from a disease mediated by PGD2, including, but not limited to, allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders, SOP is vozdushniye system activation mastocytes, anaphylactic shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itch (such as atopic dermatitis and urticaria), diseases (such as cataract, retinal detachment, inflammation, infection and sleeping disorders)which arise as a secondary diseases as a result of behavior accompanied by itch (such as scratching and rubbing), inflammation, chronic obstructive pulmonary disease, ischemic reperfusion injury, disorder of cerebral circulation, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and similar diseases, including the introduction of a specified patient pharmaceutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, hydrate or MES, its pharmaceutically acceptable prodrug or pharmaceutically acceptable salt, hydrate or MES prodrugs.

DETAILED description of the INVENTION

Definition of terms

Used above and throughout the description of the invention, the following terms, unless otherwise indicated, have adopted the following values:

"Connections, which is the object of the present invention" and similar expressions include those described herein connection fo the formula (I), as well as pharmaceutically acceptable salts, solvate, for example, hydrates, prodrugs and pharmaceutically acceptable salts, solvate and hydrate prodrugs, where permitted by the context. Similarly, the reference to intermediate compounds, regardless of whether they are in the claims or not, is meant to include their salts and solvate in cases where it is allowed by the context.

The term "patient" refers to man and other mammals.

The term "pharmaceutically acceptable salts" means non-toxic, inorganic and organic acid additive and primary additive salts of the compounds which are the object of the present invention. These salts can be obtained in situ during the final phase of isolation and purification of compounds.

The term "pharmaceutically effective amount" means an amount of compound or compounds, which according to the present invention effective to create the desired therapeutic effect, described herein, for example, relieving allergic reactions or inflammation.

Used herein, the term "pharmaceutically acceptable prodrug" means prodrugs of the compounds which are the object of the present invention, in which a framework of sound medical judgment are suitable for use in contact with what Konami patient, when this undesirable toxicity, irritation or allergic reaction within a reasonable relationship between benefits and risks, and are effective for their intended uses of the compounds which are the object of the present invention. The term "prodrug" means compounds that are "in vivo" are transformed with the formation of the source compounds of the present invention, for example, by hydrolysis in blood. Functional groups that can undergo rapid transformations through metabolic decay in vivo, form a class of groups that can react with a carboxyl group of the compounds which are the object of the present invention. These include, in particular, groups such as alkanoyl (for example, acetyl, propanol, butanol and the like), unsubstituted or substituted aroyl (for example, benzoyl or substituted benzoyl), alkoxycarbonyl (for example, etoxycarbonyl), trialkylsilyl (for example, trimethyl - or triethylsilyl) and monetary formed with dicarboxylic acids (for example, succinyl). Due to the ease with which the affected metabolic decomposition group of compounds, which is the object of the present invention, broken down in vivo, compounds with such groups act as prodrugs. Connection with the subject of metabolic decomposition groups possessed by those who benefit, they may show an increased bioavailability as a result of higher solubility and/or rate of absorption of the parent compound due to the presence of exposed metabolic disintegration of the group. A detailed discussion can be found in the works of Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al., Ed., Academic Press, 42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bandaged, ed., Chapter 5; "Design and Applications of Prodrugs" 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, 1-38, (1992); J. Pharm. Sci., 77, 285 (1988); Chem. Pharm. Bull., N. Nakeya et al., 32, 692 (1984); Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, E.B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which, through references to them are included in this document.

"Ester prodrug" means a compound that can be transformed in vivo into metabolic processes (e.g., by hydrolysis) to a compound of the present invention. For example, ester compounds of the present invention containing a hydroxy-group, can be transformed by hydrolysis in vivo to the original molecule. Alternatively, ester compounds of the present invention containing carboxypropyl, can be transformed by hydrolysis in vivo to the original molecule. Examples of the ether prodrugs are:

ethyl ester of (1-{6-[2-(2,4-dichlorophenyl)atrami what about]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid; and

ethyl ester 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid.

Suitable esters of compounds of the present invention containing a hydroxy group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-para-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, para-toluensulfonate, cyclohexylsulfamate and hinata.

Suitable esters of compounds of the present invention containing a carboxyl group are, for example, esters, described in F.J. Leinweber, Drug Metab. Res., 1987, 18, page 379.

A particularly useful class of esters of compounds of the present invention containing a hydroxyl group may be formed from acid groups from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)benzoate, for example, dialkylaminomethyl, in which the two alkyl groups may be combined and/or separated by an oxygen atom or a nitrogen atom with a possible substitute, for example, alkilirovanny a nitrogen atom, and particularly (morpholinomethyl)benzoate, for example, 3 - or 4-(morpholinomethyl)benzoate, and (4-alquiler the Razin-1-yl)benzoate, for example, 3 - or 4-(4-alkylpiperazine-1-yl)benzoate.

"MES" means a compound which is the object of the present invention, physically associated with one or more solvent molecules. To the physical linking applies, in particular, the formation of hydrogen bond. In certain cases, the MES can be identified, for example, when one or more solvent molecules included in the crystal lattice of a solid crystalline substance. The term "MES" applies to both the solution phase and allocated a solvate. Typical solvate is a hydrate, ethanolate and methanolate.

Some of the compounds which are the object of the present invention are basic, and such compounds are applicable in the form of free bases or in the form of their pharmaceutically acceptable acid additive salts.

Acid additive salts can be more convenient form for use, and in practice the use of salt forms essentially means the application form of the free base. Acids that can be used to prepare the acid additive salts are preferably such that when mixed with the free base lead to pharmaceutically acceptable salts, i.e. salts, the anions of which are non-toxic to the patient in pharmacologic the ski doses of the salts, so that the beneficial effects of inhibition inherent in the free base are not distorted side effects attributed to the anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all acid additive salts, are useful sources of the free base form even if the particular salt, itself, you need only as an intermediate product, for example, if the salt is obtained solely for the purposes of purification and identification, or when it is used as an intermediate connection when receiving pharmaceutically acceptable salts by ion-exchange processes. In particular, the acid additive salts can be obtained by the independent reaction of the purified compound in free base form with a suitable organic or inorganic acid and allocation thus obtained salt. Pharmaceutically acceptable salts, which fall within the scope of the present invention include salts derived from mineral and organic acids. Examples of the acid additive salts include hydrobromide, hydrochloride, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valerate, oleates, palmitate, hinata, stearates, laurate, borate, benzoate, lactates, phosphates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, naphthalate, mesylates glucoheptonate, lactobionate, sulfamate, malonate, salicylates, propionate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-para-toluoyltartaric, econsultancy, bansilalpet, cyclohexylsulfamate and laurylsulphate. See, for example, the work of S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977), which is incorporated herein by reference.

If the connection, which is the object of the present invention, is substituted by an acid group, can be basically additive salts, which are simply a more convenient form of application, and in practice the use of the salt form is essentially equivalent to its use in the form of the free acid. The bases that can be used for the preparation of primary additive salts are preferably such that when mixed with the free acid lead to pharmaceutically acceptable salts, i.e. salts, the cations of which are non-toxic to the patient in pharmaceutical doses of the salts so that the beneficial effects of inhibition inherent in the free base are not distorted side effects attributed to cations. Basically additive salts can also be obtained independently by the reaction of purified compound in its acid form with a suitable organic or inorganic base, salts formed from alkali or Melo rosemaling metals, and the allocation thus obtained salt. It basically additive salts include pharmaceutically acceptable metal salts and amines. Suitable metal salts include salts of sodium, potassium, calcium, barium, zinc, magnesium and aluminum. In a particular example salts are the sodium and potassium salts. Suitable inorganic basic additive salts derived from bases metals, which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable primary amine additive salts derived from amines, basicity of which is sufficient for the formation of a stable salt, and preferably from amines commonly used in medicinal chemistry because of their low toxicity and suitability for use for medical purposes, for example, ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, diethylamine, piperazine, Tris(hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium, triethylamine, dibenzylamine, fenamin, dehydroabietylamine, N-ethylpiperidine benzylamine, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and d is cyclohexylamine.

Being useful in themselves as active compounds, salts of the compounds which are the object of the present invention, useful for the purposes of cleaning compounds, for example, by using the difference in solubility of the salts and the parent compounds, by-products and/or raw materials by means known in the art methods.

It is obvious that the compounds, which is the object of the present invention may contain asymmetric centers. These asymmetric centers can independently from each other to be in the R - or S-configuration. For the person skilled in the art it is obvious that certain compounds, which is the object of the present invention may also exhibit geometric isomerism. It should be understood that the present invention applies to the individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures of the above compounds of the present invention. Such isomers can be distinguished from their mixtures by known methods or their modifications, for example, chromatographic methods or methods recrystallization or obtained separately from the corresponding isomers of the intermediate compounds. In addition, in situations where the possible tautomers of the compounds of the present invention, the present invention includes all tautomeric forms of such compounds./p>

The specific implementation of the present invention

One specific implementation of the present invention are the following compounds of formula (I):

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methylpyrimidin-4-yl}pyrrolidin-3-carboxylic acid,

2-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-yl)-2-methylpropionate acid,

2-[3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol,

[6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,

[6-(4-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)acetamide", she

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid,

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide 2-methylpropan-2-sulfonic acid,

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide N,N-dimethylamide-2-sulfonic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-thiomorpholine-4-improper-1-he,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)isobutyramide,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N,N-dim is telecomuting,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid,

1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid,

N-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carbonyl)methanesulfonamide,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)methanesulfonamide,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide econsultancy acid,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide 2-methylpropan-2-sulfonic acid,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)-C,C,C-triftormetilfullerenov,

(1H-tetrazol-5-yl)amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,

amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,

dimethylamide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxamide N,N-dimethylamide-2-sulfonic acid,

5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-thiophene-2-carboxylic acid, or

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-the l}-2,3-dihydrobenzofuran-2-carboxylic acid,

or its pharmaceutically acceptable salt, hydrate or MES, its pharmaceutically acceptable prodrug or pharmaceutically acceptable salt, hydrate or MES prodrugs.

Another specific implementation of the present invention are the following compounds of formula (I) or its ester prodrugs:

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methylpyrimidin-4-yl}pyrrolidin-3-carboxylic acid,

2-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-yl)-2-methylpropionate acid,

2-[3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol,

[6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,

[6-(4-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)acetamide", she

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid,

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide 2-methylpropan-2-sulfonic acid,

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide N,N-dimethylamide-2-sulfonic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-thiomorpholine-4-and the propane-1-he,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)isobutyramide,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N,N-dimethylethanamine,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid,

1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid,

N-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carbonyl)methanesulfonamide,

ethyl ester 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid,

ethyl ester of (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)methanesulfonamide,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide econsultancy acid,

(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide 2-methylpropan-2-sulfonic acid,

N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)-C,C,C-triftormetilfullerenov,

(1H-tetrazol-5-yl)amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,

amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-to benovoy acid,

dimethylamide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxamide N,N-dimethylamide-2-sulfonic acid,

5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-thiophene-2-carboxylic acid, or

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid,

or their pharmaceutically acceptable salt, hydrate or MES.

Connection, which is the object of the present invention and used to produce intermediate and source materials are named in accordance with IUPAC nomenclature, in which the characteristic group in the name have the following priority, in descending order of importance: acids, esters, amides, etc. However, it is believed that if any of the compounds represented by structural formula and nomenclature the name, there is a mismatch between the structural formula and nomenclature name, correct it is necessary to consider the structural formula.

Connection, which is the object of this invention exhibit activity as antagonists of the receptor for prostaglandin D2, and can be used as an active pharmacological substances. Accordingly, they are included in the pharmaceutically the compositions and used in the treatment of patients suffering from certain medical disorders.

Compounds covered by the present invention are antagonists of the receptor for prostaglandin D2 according to tests described in the literature, as well as the following section on pharmacological tests, the results of which should correlate to pharmacological activity in humans and other mammals. Thus, in another embodiment, the present invention presents the connection, which is the object of the present invention and compositions containing them, which can be used in the treatment of patients suffering from diseases that can facilitate the introduction of PGD2 antagonist, or exposed to such diseases. For example, the compounds of the present invention can therefore be used for treatment of various diseases mediated by PGD2, including, without limitation, the following, allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itch (such as atopic dermatitis and urticaria), diseases which any (for example, cataract, retinal detachment, inflammation, infection and sleeping disorders)which arise as a secondary diseases as a result of behavior accompanied by itch (such as scratching and rubbing), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, disorders of cerebral circulation, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and similar diseases.

In addition, compounds which are the object of the present invention can be used for treatment in combination with

(i) antihistamines, such as Fexofenadine, loratadine and cetirizine, for the treatment of allergic rhinitis;

(ii) leukotriene antagonists, such as montelukast and zafirlukast, for the treatment of allergic rhinitis, COPD, allergic dermatitis, allergic conjunctivitis, etc. - accurate information, see WO 01/78697 A2;

(iii) beta-agonists, for example, albuterol, salbuterol and terbutalina, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.;

(iv) antihistamines, such as Fexofenadine, loratadine and cetirizine, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.;

(v) inhibitors of PDE4 (phosphodiesterase 4), for example, roflumilast and cyl is mylestom, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.; or

(vi) antagonists TP (thromboxane A2 receptor or antagonists of CrTh2 (molecules homologous to receptor chemoattractant expressed on Th2 cells), for example, ramatroban (BAY u3405), for the treatment of COPD, allergic dermatitis, allergic conjunctivitis, etc.

A specific embodiment of therapeutic methods, which is the object of the present invention is the treatment of allergic rhinitis.

Another specific embodiment of therapeutic methods, which is the object of the present invention is the treatment of bronchial asthma.

In accordance with another aspect of the invention features a method of treating a patient (human or animal)suffering from diseases that may be alleviated by the introduction of an antagonist of the receptor for prostaglandin D2, or exposed to such diseases, as described above, comprising the administration to a patient an effective amount of the compound which is the object of the present invention or its containing composition. By "effective amount" refers to the number of connections, which is the object of the present invention, which is effective as an antagonist of the receptor for prostaglandin D2, and therefore the act is upgr to produce the desired therapeutic effect.

Included here are links to treatment apply as a preventive therapy and treatment of diagnosed diseases.

The present invention also extends to pharmaceutical compositions comprising at least one connection, which is the object of the present invention, in a mixture with a pharmaceutically acceptable carrier.

In practice, the connection, which is the object of the present invention may be administered in the form of pharmaceutically acceptable dosage forms for humans and other animals through local or systemic use, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, intestinal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. You should take into account that the preferred route of administration may vary, for example, depending on the patient's condition.

"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compounds which are the object of the present invention, which include, for example, tablets, pills, powders, elixirs, syrups, liquid formulations, including suspensions, sprays, inhalers, pills, pellets, emulsions, races the thieves, granules, capsules and suppositories, as well as liquid preparations for injections, including liposomal drugs. A General description of the methods and compositions can be found in the latest edition Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

A special aspect of the present invention is a compound which is the object of the present invention, which should be entered in the form of pharmaceutical compositions. In accordance with the present invention the pharmaceutical compositions comprise compounds which are the object of the present invention, and pharmaceutically acceptable carriers.

Pharmaceutically acceptable carriers include at least one of the components, which can be pharmaceutically acceptable carriers, diluents, shell, adjuvants, formative or environment, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, stabilizers of emulsions, suspendresume substances, isotonic agents, sweeteners, flavorings, fragrances, dyes, microbicides, antifungal agents, other therapeutic agents, sliding agents, substances, slowing down or accelerating the suction and dispensing substances, depending on the characteristics of the route of administration and dosage forms.

Examples suspendida substances are ethoxylated izote Silovye alcohols, polyoxyethylenesorbitan and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant or mixtures of these substances.

Examples of bactericidal and antifungal substances that prevent the action of microorganisms, are parabens, chlorobutanol, phenol, sorbic acid and similar substances.

Examples of isotonic substances are sugars, sodium chloride and similar substances.

Examples of substances that slow down and prolong the absorption are aluminum monostearate and gelatin.

Examples of substances accelerate and stimulate absorption, are dimethyl sulfoxide and its analogs.

Examples of diluents, solvents, carriers, solubilizing additives, emulsifiers and emulsion stabilizers are water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl ester of carbonic acid, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butyleneglycol, glycerin, glycols, dimethylformamide, Tween® 60, Span® 60, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate, esters sorbitan and fatty acids, vegetable oils (such as cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame wt is about) and injectable organic esters, such as etiloleat and the like, or suitable mixtures of these compounds.

Examples of formative fillers are lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.

Examples of disintegrating agents include starch, alginic acid and certain complex silicates.

Examples of moving substances are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene glycols of high molecular weight.

The choice of pharmaceutically acceptable carrier, in General, determined in accordance with the chemical properties of the active compound, such as solubility, application method and norms to be followed in pharmacy practice.

Pharmaceutical compositions which are the object of the present invention suitable for oral administration may be a separate unit, such as solid dosage forms such as capsules, pills or tablets, each of which contains a certain amount of the active ingredient, or such as powders or granules, or liquid dosage forms such as solutions or suspensions in aqueous or non-aqueous liquid or liquid emulsion of oil in water or water in oil. The active ingredient can also be in the form of a bolus, electuary or paste.

"Solid dosage form" OSN the dosage form includes connection, which is the object of the present invention, in the form of solids, for example, capsules, tablets, pills, powder, tablets or granules. In such dosage forms, the compound which is the object of the present invention, added to at least one traditionally used inert forming excipient (or carrier)such as sodium citrate or dicalcium phosphate or (a) fillers or additives, such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum, (c) moisturizing agents, such as, for example, glycerol, (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain complex silicates and Na2CO3, (e) moderators education solutions, such as, for example, paraffin, (f) absorption accelerators, such as Quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerylmonostearate, (h) adsorbents, such as kaolin or bentonite, and (i) moving substances such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) fogging components (k) of the buffer substances and substances which dracena releasing the connection or connections, which is the object of the present invention, in a certain part of the intestinal tract.

A tablet may be prepared by compressing or molding and may have one or more auxiliary components. Molded tablets can be obtained by compressing in a suitable machine the active ingredient in granular form, such as powder or granules, which may be mixed with a binder, a sliding agent, inert diluent, preservative, surface active or dispersing agent. Can be used such inert fillers as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and leavening agents, such as starch, alginic acid and certain complex silicates, mixed with sliding agents such as magnesium stearate, sodium lauryl sulfate and talc. A mixture of powdered compounds moistened with an inert liquid diluent, can be molded in a suitable machine to obtain a molded tablets. Tablets may be uncoated or notches, or may have a composition that provide slow or controlled release of the contained active ingredient.

Solid compositions may also be used as fillers in gelatin capsules with soft or hard content with the use of such inert order the residents, as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and similar substances.

If necessary, and for more effective distribution, the compounds can be microencapsulating systems slow or directional release or attached to them, such systems are biocompatible, biodegradable polymeric matrix (e.g., copolymer of d,l-lactide with glycolide), liposomes and microspheres for subcutaneous and intramuscular injection method, called subcutaneous or intramuscular injection, slow absorption, providing a slow release of the compound or compounds in a period of 2 weeks or longer. Connections can be sterilized, for example, by filtration through inhibiting bacteria filter or adding sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately before use.

Liquid dosage form" means a form of active compound that is administered to the patient in liquid form, for example, in the form of a pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compounds, the liquid dosage forms may contain commonly used in this about the Asti inert diluents, such as solvents, solubilizing agents and emulsifiers.

Used aqueous suspensions can contain emulsifying agents or substances that contribute to the formation of suspensions.

Pharmaceutical compositions suitable for topical application, is a composition in the form, allowing for local administration to the patient. The compositions can be in the form of ointments, topical application, balms, powders, sprays and inhalers, gels (water or alcohol based), creams, usually used in this field, or to be included in the matrix base for use as a patch that provides a controlled release of compound through the skin barrier. In the form of an ointment, the active ingredients can be used, or paraffin, or water-soluble bases. Alternatively, the active ingredients can be in the form of a cream with an oil-water basis. Formulations intended for topical use in the eye, are eye drops, in which the active ingredient is dissolved or suspended in a suitable medium, typically an aqueous solvent. Formulations intended for local use through the oral mucosa include medicinal candy, having in its composition the active ingredient in the flavor additive, normally sucrose and gum or tragakant; lozenges with with the tave active ingredient in an inert basis, such as gelatin and glycerol or sucrose and gum; and compositions for rinsing of the mouth, having in its composition the active ingredient in a suitable liquid carrier.

The oil phase of the emulsion pharmaceutical compositions can be obtained in the usual way from the well-known ingredients. This phase can be composed of only the emulsifier (also known emulsifying substance), however, it is desirable that it also included at least one emulsifier containing fat or oil, or emulsifier-containing fat and oil. In one particular implementation of the invention, the formulation includes a hydrophilic emulsifier, together with a lipophilic emulsifier, which acts as a stabilizer. Emulsifier (emulsifying agents) together with anti-roll (stabilizer) or without it (them) form emulgirujushchie wax together with the oil or fat to form emulgirujushchie materials, which is the oily dispersed phase of the cream formulations.

If necessary, the aqueous phase of the cream base may include, for example, not less than 30 wt%. a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol or polyethylene glycol (including PEG 400) and mixtures thereof. Compositions for topical application may, if necessary, to have a connection with kulrawee the absorption or penetration of the active ingredient through the skin or other affected area.

The choice of suitable oils or fats for use in the composition depends on the properties that you want to retrieve. It is desirable that the cream was non-greasy, does not leave stains and washable product with suitable consistency, preventing leakage from tubes or other containers. Can be used with linear and branched one - and dibasic alkalemia esters, such as diisopropylamide, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixture of esters with branched chain, known as Crodamol CAP. They can be used separately or in mixtures, depending on the desired properties. Alternatively can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin and other mineral oils.

Pharmaceutical compositions for rectal or vaginal use are compounds whose shape allows for rectal or vaginal administration to the patient and which contain at least one connection, which is the object of the present invention. Suppositories are one of the forms of such compositions, which can be obtained by mixing the compounds which are the object of this invention with suitable non-irritating inert fillers or carriers, such as cocoa butter, polyethylene glycol or the EGM the financial base of the suppository, which are in a solid state at ordinary temperatures, but become liquid at body temperature and therefore melt at rectal or vaginal insertion and release the active ingredient.

The pharmaceutical composition introduced by injection, may be injected intramuscularly, intravenously, intraperitoneally and/or subcutaneously. The compositions which are the object of the present invention, is prepared in liquid solutions, in particular in physiologically compatible buffers such as the solution of Henk or ringer's solution. In addition, the composition can be prepared in solid form and dissolved or suspended immediately prior to use. It is also possible lyophilized form. The compositions are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions which may contain suspendresume substances, thickeners and anti-oxidants, buffers, bacteriostats and additives that make the composition isotonic, and to have the correct pH level corresponding to the indicator of the patient's blood, which will be introduced in the structure.

Pharmaceutical compositions which are the object of the present invention, suitable for nasal or inhalation use, are compounds which form is suitable for administration to a patient or nasal inhalation. The composition can containing the ü media in the form of powder with particle size, for example, in the range from 1 to 500 microns (including particle sizes in the range from 20 to 500 microns in increments of 5 microns, i.e. with dimensions of 30 microns, 35 microns, etc). Suitable compositions with liquid media for use, for example, as a spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration, can be obtained in accordance with conventional methods and implemented with other therapeutic agents. For the introduction of compounds, which is the object of the present invention, as inhalation therapy can be used dosing inhalers.

The actual dosage of the active ingredient (ingredient), which is the object of the present invention may vary with the purpose of obtaining the amount of the active ingredient (ingredient), effective to produce a desired therapeutic effect for a particular composition and method of its introduction to the patient. Therefore, the dosage selected for each patient depends on many factors such as the desired therapeutic effect, the route of administration, the desired duration of treatment, etiology and severity of the disease, the patient's condition, weight, sex, diet, and age, type, and activity of each active ingredient, the speed of absorption, metabolism and/or separation of the Oia and other factors.

Full daily dose of the compounds which are the object of the present invention, administered to the patient one or more doses can be, for example, from about 0.001 to 100 mg/kg of body weight per day, preferably from 0.01 to 10 mg/kg/day. For example, the adult dose usually ranges from about 0.01 to 100, preferably from about 0.01 to 10 mg/kg of body weight per day by inhalation, from about 0.01 to 100, preferably from 0.1 to 70, preferably from 0.5 to 10 mg/kg of body weight per day by oral administration and from about 0.01 to 50, preferably from 0.01 to 10 mg/kg of body weight per day intravenously. The percentage of active ingredient in the composition may be different, but it should provide a suitable dosage. The dosage form can contain a fraction of a unit dose, allowing to obtain the desired daily dose. Naturally, the form that contains multiple units of dose can be administered at about the same time. The dose may be as frequent as needed to achieve the desired therapeutic effect. Some patients may show a rapid response to a higher or lower dose, and these may be sufficient much weaker dose of support. For other patients may need long-term treatment with cha what Thoth from 1 to 4 doses per day in accordance with the physiological needs of each individual patient. Needless to say, other patients may require no more than one or two doses per day.

Standard dose formulations may be obtained by any of the conventionally used in the pharmaceutical industry methods. These include the stage of linking the active ingredient with a carrier consisting of one or more accessory ingredients. Typically, the compositions will receive a uniform and tight binding of the active ingredient with liquid carriers or fine solid carriers, or both, one or the other, with the subsequent formation of the product if necessary.

The compositions can be packaged in a single dose or in several doses, for example, sealed ampoules and vials with elastic tubes and can be stored in a lyophilized condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Individual injection solutions and suspensions may be prepared from sterile powders, granules or pellets of the above described types.

Connection, which is the object of the present invention can be obtained by application or adaptation of known methods, by which is meant methods used above or described in the literature, for example as described in R.C. Larock in Comprehensive OrganicTransformations, VCH publishers, 1989.

According to another characteristic of the invention educated acid additive salts of the compounds which are the object of the present invention, can be obtained by the reaction of the free base with the appropriate acid using known methods or their modifications. For example, educated acid additive salts of the compounds which are the object of the present invention, can be obtained either by dissolving the free base in water or an aqueous solution of ethanol or other suitable solvents containing the appropriate acid and the release of salt by evaporating the solution, or the reaction of the free base and acid in an organic solvent, where the salt precipitates or evaporated from the solution.

Connection, which is the object of the present invention, can be regenerated from their acid additive salts by known methods or their modifications. For example, the parent compound, which is the object of the present invention, can be regenerated from their acid additive salts with alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution.

Connection, which is the object of the present invention, can be regenerated from their salts attach the base using known methods or their modifications. For example, the source connection is to be placed, which is the object of the present invention, can be regenerated from their salts attach the base by treatment with acid, for example hydrochloric acid.

Connection, which is the object of the present invention, it is possible easily to obtain or to form in the process which is the object of the present invention, in the form of a solvate (e.g. hydrate). Hydrates of the compounds which are the object of the present invention can be easily obtained by recrystallization from a mixture of water/organic solvent such organic solvents as dioxane, THF or MeOH.

According to another characteristic of the invention basically additive salts of the compounds which are the object of the present invention, can be obtained by the reaction of the free acid with the appropriate base by means of known methods or their modifications. For example, the main additive salts of the compounds which are the object of the present invention, can be obtained either by dissolving the free acid in water or an aqueous solution of alcohol, or other suitable solvents containing the appropriate base, and the release of salt by evaporating the solution, or the reaction of the free acids and bases in an organic solvent, where the salt precipitates or evaporated from the solution.

Source or intermediate with the unity can be obtained using methods described in this application or adaptation of known methods.

Compounds of the invention, methods for their preparation and their biological activity will be more apparent from the analysis in the following examples, which are given only as illustrations and should not be construed as limiting the scope of the invention. Compounds of the present invention identified, for example, using the following analytical methods.

Experiments on liquid chromatography high pressure and mass spectrometry (LC-MS) to determine retention time (Rt) and associated mass ions was carried out using one of the following methods.

Mass spectra (MS) were recorded on a mass spectrometer Micromass LCT. The method includes the ionization positive elektrorazpredelenie and scan mass m/z 100 to 1000. Liquid chromatography was carried out using a binary pump and degasser Hewlett Packard 1100 Series; stationary phase: column Phenomenex Synergi 2 µ Hydro-RP 20×4.0 mm, mobile phase: A=0.1% of formic acid (FA) in water, B=0,1% FA in MeCN. Volume of 5 μl using system CTC Analytical PAL. The flow rate of eluent is 1 ml/min Gradient from 10% B to 90% B over 3 minutes, and from 90% B to 100% B in 2 minutes. Auxiliary detector: UV detector Hewlett Packard 1100 Series, wavelength = 220 nm, and evaporative light scattering detector (ELS) Sedere SEDE 75, the detector temperature = 46°C pressure N2=4 bar.

The spectra of nuclear magnetic resonance (NMR) 300 MHZ1H was recorded at room temperature on the spectrometer Varian Mercury (300 MHz) with 5 mm ASW sensor. In the NMR values of chemical shift (δ) are quoted in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard.

In the following examples and descriptions of the synthesis, as well as in the rest of the application, the terms used have the following meanings: "kg - kilograms, "g" for grams, "mg" - milligrams, "μg" - micrograms, "mol" - moles, "mmol" mmol, M - moles per liter, mm - mmol per liter, "μm" - micromol per liter, "nm" - nanomole per litre, l - liters, "ml" is milliliter, "μl" - Microlitre, "°C" degrees Celsius, "TPL" melting point "as" boiling point, "mm of Hg" is the pressure in millimeters of mercury, "cm" - centimeters, "nm - nanometers, "abs." absolute, "conc." - concentrated, "c" is the concentration in g/ml, "K.T." room temperature, "TLC" - thin layer chromatography, "HPLC" is a high - performance liquid chromatography, "V/b" intraperitoneally, "/" intravenous, "s" is singlet, d - doublet; t - triplet; "kV" Quartet; m - multiplet, "DD" is doublet of doublets; "ush." broadened, "LC" - liquid chromatograph, "MS" mass spectrograph "ESI/MS" - ionization of electroral the drug/mass spectrograph, "Rt" - retention time, M is the molecular ion, "psi" is pounds per square inch, "DMSO - dimethylsulfoxide, "DMF" - N,N-dimethylformamide, "CDI" - 1,1'-carbonyldiimidazole, "DCM" or "CH2Cl2" - dichloromethane, "HCl" - hydrochloric acid (SPA) - SPA-analysis, "ATTC" American type culture collection, FBS - fetal bovine serum, "IPU" - minimal supportive environment, "imp./minutes - the number of pulses per minute, "EtOAc - ethyl acetate, "PBS" phosphate buffered saline "TMW" - transmembrane domain "IBMX" - 3-isobutyl-1-methylxanthines, cAMP - cyclic monophosphate, "IUPAC international Union of pure and applied chemistry, "MHz - megahertz, "PEG" is a polyethylene glycol, "MeOH - methanol, N - normality, "THF" is tetrahydrofuran, "h" hours, "min" - minute(s), "MeNH2" - methylamine, N2" is gaseous nitrogen, "O.D." - outer diameter, "MeCN" or "CH3CN - acetonitrile, "Et2O - ethyl ester, "prep LC" - preparative liquid flash chromatography, "TPV" - solid-phase extraction, "K2CO3" = potassium carbonate, Na2CO3" = sodium carbonate, "pmol" - picomolar, "heptane" - n-heptane, resin "HMBA-AM - aminomethyl resin, 4-hydroxymethylbenzene acid, "PdCl2(dppf)2" complex dichloride 1,1'-bis(diphenylphosphino)ferienparadies(II) in DCM, "~" - p is blithedale and "IC 50" = concentration of compound giving 50% inhibition in the SPA-analysis of camp in T-cells LS174 person.

EXAMPLES

Example 1

1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}pyrrolidin-3-carboxylic acid

Stage 1: a Solution of 4,6-dichloro-2-methoxypyridine (0.7 g), 2-(2,4-dichlorophenyl)ethylamine [0.74 g) and Na2CO3(0.88 g) in EtOH (25 ml) is heated at 80°C for three hours and poured into water (400 ml). The obtained solid is filtered and dried air, getting (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine.

Stage 2: In vitro mixed (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (300 mg), hydrochloride 3-pyrrolidinecarboxylic acid (341 mg), K2CO3(373 mg) and 1-methyl-2-pyrrolidinone (5 ml). The test tube is sealed, heated to 140°C and stirred for 16 hours. The mixture is cooled to room temperature, diluted with water (60 ml), acidified with 3M HCl and extracted three times with ethyl acetate (60 ml). The organic extracts are combined, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (40 g) with elution with a mixture of from 0 to 20% Meon in dichloromethane, getting 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methylpyrimidin-4-yl}pyrrolidin-3-carboxylic acid (190 mg) as a solid. LC-MS Rt=2,22 min, MS: 411 (M+H).1H NMR [300 MHz, (CD 3)2SO]: δ EUR 7.57 (1H, s); of 7.36 (2H, s); 6,77 (1H, s); free 5.01 (1H, s); and 3.72 (3H, s); 3,5 (6H, m); of 3.12 (1H, m); only 2.91 (2H, t); is 2.09 (2H, m). IC50=9 nm.

Example 2

2-(1-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-yl)-2-methylpropionate acid

Stage 1: a Mixture of ethyl ester of pyrid-3-luxusni acid (12,6 g) and rhodium on aluminium oxide (12,6 g) in ethanol (200 ml) was placed in a Parr apparatus at 60°C and a pressure of 60 psi for 16 hours. The suspension is filtered through celite. The filter is washed with ethanol and the filtrate concentrated to a volume of approximately 50 ml and add water (600 ml). The solution is extracted with EtOAc (3×100 ml). The combined organic layers washed with brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue is dissolved in THF (150 ml) with addition of triethylamine (10,7 ml). The solution is cooled to 0°C and added dropwise to benzylchloride (11 ml). The solution was stirred at 0°C for two hours. The solution is concentrated to approximately 50 ml and add water (600 ml). The solution is extracted with EtOAc (2×150 ml). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining benzyl ester 3-ethoxycarbonylmethylene-1-carboxylic acid (21,5 g), which is used in the next stage without additional about isdi. MS: 306 (M+H);1H NMR (300 MHz, DMSO-d6) δ to 7.3 (m, 5H); of 5.05 (s, 2H); of 3.8-4.1 (m, 4H); 2,5-2,6 (m, 1H); 1.5 and 1.7 (m, 4H); 1-1,4 (m, 4H).

Stage 2: To 1M suspension of tert-butoxide potassium in THF (200 ml) at -78°C is added dropwise a solution of benzyl ester 3-ethoxycarbonylmethylene-1-carboxylic acid (21,5 g) in THF (25 ml) for ten minutes. One portion add methyliodide (6.85 ml). The suspension is stirred at -78°C for one hour at -40°C for one hour and bring to room temperature over night. The suspension is poured into water (800 ml) and extracted with EtOAc (2×150 ml). The combined organic layers washed with brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with a mixture of 100% heptane to 30% EtOAc in heptane, getting benzyl ester 3-(1-etoxycarbonyl-1-methylethyl)piperidine-1-carboxylic acid (151,1 g). MS: 334 (M+H);1H NMR (300 MHz, DMSO-d6) δ to 7.3 (m, 5H); of 5.05 (s, 2H); of 3.8-4.1 (q, 2H); 2,5-2,6 (m, 1H); 1.5 and 1.7 (m, 4H); 1-1,4 (m, 4H); 1 (s, 6H).

Stage 3: a Suspension of benzyl ester 3-(1-etoxycarbonyl-1-methylethyl)piperidine-1-carboxylic acid (3.3 g) and 10% palladium on carbon (500 mg) in glacial acetic acid (2 ml)/methanol (200 ml) was placed in a Parr apparatus at a pressure of 50 psi for 90 minutes at room temperature. The suspension is filtered through celite. The filter is washed with methanol, and filtercontainer up to a volume of approximately 50 ml A solution of methanol diluted with THF (50 ml) and aqueous solution of 2 n potassium hydroxide (50 ml). The solution was stirred at room temperature for 16 hours and concentrated to a volume of 70-80 ml in vacuum. The solution is cooled to 5°C and slowly added concentrated aqueous HCl (8.5 ml). The solution is extracted with EtOAc (3×100 ml). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuum, obtaining 2-methyl-2-piperidine-3-ylpropionic acid (1.1 g), which is used in the next stage without additional purification. MS: 172 (M+H);1H NMR (300 MHz, DMSO-d6) δ 2,5 (m, 1H); 1.5 and 1.7 (m, 4H); 1-1,4 (m, 5H); 1 (s, 6H).

Stage 4:

Method A. a Solution of (4-trifloromethyl)acetonitrile (of 5.05 g) in MeOH (75 ml) saturated with gaseous ammonia and treated with Raney Nickel in water (2 ml, 50%). The suspension is placed in a Parr apparatus at a pressure of 50 psig and 50°C for 3 hours and filtered through celite. The filtrate is evaporated and the residual oily substance is distributed between water and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in MeOH and add the solution is treated with concentrated hydrochloric acid (1 ml). The solution is evaporated in a vacuum to obtain a solid substance, which is ground to powder in the air and dry air, getting hydrochloride 2-(4-trifter ethoxyphenyl)ethylamine (5,15 g). MS: 206 (M+H)1H NMR (CDCl3): δ 8,2 (2H, m); of 7.4 (2H, d, J=5 Hz); and 7.3 (2H, d, J=5 Hz); 3-3,1 (2H, m); 2,9-3 (2H, m).

Method B. a Solution of 4-triphtalocyaninine (1 g) and nitromethane (0.96 g) in acetic acid (10,6 ml) is treated with ammonium acetate (1.01 g) and heated in a microwave oven to 150°C for 15 minutes. The reaction mixture was diluted with water and three times extracted with DCM (50 ml). The combined extracts washed sequentially 2 N. sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel and receive a 4-triptoreline-(2-nitrovinyl)benzene (1.23 g) as a solid. Part 4-triptoreline-(2-nitrovinyl)benzene (0,504 g) hydronaut hydrogen from a cylinder, 10% Pd/C (115 mg) in MeOH (22 ml), containing concentrated hydrochloric acid (0,27 ml)at room temperature for 15 hours. The mixture is filtered and the filtrate concentrated to a solid, which was washed with Et2O getting hydrochloride 2-(4-trifloromethyl)ethylamine (0.3 g) as a solid. LC-MS: MS: 206 (M+H).

Stage 5: Method similar to that described in example 1, step 1, but using 4,6-dichloro-2-methoxypyridine (0.39 g), hydrochloride 2-(4-trifloromethyl)ethylamine (0,38) and sodium bicarbonate (0.74 g) receive (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine (0,61 g). MS: 360 (M+H)1H the Mr (CDCl 3): δ of 7.4 (2H, d, J=7 Hz); and 7.3 (2H, d, J=7 Hz); 6,2 (1H, s); and 3.8 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t).

Step 6: a Solution of 2-methyl-2-piperidine-3-ylpropionic acid (0.6 g), (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine (0,46 g) and K2CO3(0,46 g) in 1-methylpyrrolidine-2-Ohe (10 ml) is heated at 140°C for 16 hours. The solution is cooled and poured into water (200 ml). The aqueous solution is acidified to pH~6 glacial acetic acid and extracted with EtOAc (3×100 ml). The combined organic layers washed with brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with 5% MeOH in EtOAc, receiving 2-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-yl)-2-methylpropionic acid (105 mg). MS: 483 (M+H);1H NMR (300 MHz, DMSO-d6) δ was 7.45 (d, J=3, 2H); and 7.3 (d, J=3, 2H), and 5.5 (s, 1H); of 3.95 (s, 3H); 3,6 (m, 2H); 2,9 (t, 2H); to 2.7 (m, 1H); 1.7 to 1.9 (m, 4H); 1,3-1,4 (m, 3H); 1,1 (d, J=3, 6H). IC50=2 nm.

Example 3

2-[3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol

Stage 1: a Solution of dimethyl-5-bromoisophthalate (5 g) in THF (250 ml) is cooled to

-78°C and added dropwise a solution of 3M methylacrylamide in ether (36,6 ml), keeping the temperature below -70°C. the Solution was stirred at -78°C for 2 hours and brought to room temperature in those who tell the night. The solution was diluted with ether (300 ml) and cooled to 0°C. 1 N. aqueous HCl (100 ml) is added dropwise. The combined organic layers washed with brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with 60% EtOAc in heptane, receiving 2-[3-bromo-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol (4.1 g). MS: 272 (M+H);1H NMR (300 MHz, DMSO-d6) δ of 7.5 (s, 1H); 7.4 for (s, 2H); further 5.15 (s, 2H); 1,4 (s, 12H).

Stage 2: 2-[3-Bromo-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol (1.08 g), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]-dioxaborolane] (1.12 g), potassium acetate (0,78 g) and PdCl2(dppf)2(42 mg) suspicious in DMSO (20 ml) and Tegaserod for 20 minutes. The suspension is heated at 90°C for 16 hours. The solution was poured into water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic layers washed with brine, dried (Na2SO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with 50% EtOAc in heptane, receiving 2-[3-(1-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]propan-2-ol (0.9 g). MS: 285 (M+H);1H NMR (300 MHz, DMSO-d6) δ of 7.5 (s, 1H); 7,2 (s, 2H); further 5.15 (s, 2H); 1,6 (s, 12H); 1,4 (s, 12H).

Stage 3: a Solution of 2-[3-(1-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]propan-2-ol (0.35 g), (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.2 g), CT is onata cesium (0,58 g) and tetrakis(triphenylphosphine)palladium(0) (41 mg) in 20 ml of water/80 ml dimethoxyethane Tegaserod for 20 minutes and heated at 90°C for 16 hours. The solution is evaporated in vacuum. The residue is purified by chromatography with elution with 70% EtOAc in heptane, receiving 2-[3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol (0,44 g). MS: 491 (M+H);1H NMR (300 MHz, DMSO-d6) δ 7,9 (s, 2H), and 7.8 (s, 1H); 7,45 (s, 1H); 7,2-7,3 (m, 2H); 6.5 in (s, 1H); of 3.95 (s, 3H); of 3.85 (m, 2H); 3,1 (t, 2H); 1,6 (s, 12H). IC50=730 nm.

Example 4

[6-(3-Aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine

Stage 1: a Method similar to that described in example 1, step 2, but using 3-N-Boc-aminopiperidine (450 mg) instead of hydrochloride of 3-pyrrolidinecarboxylic acid and purifying the reaction product flash chromatography on a column of silica gel (40 g) with elution with a mixture of from 20 to 50% EtOAc in heptane, to obtain tert-butyl methyl ether (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)carbamino acid (281 mg).1H NMR [300 MHz, (CD3)2SO]: δ EUR 7.57 (1H, s); of 7.36 (2H, s); 6,9 (2H, m); from 5.29 (1H, s); 4 (2H, m), 3,71 (3H, s); 3,41 (5H, m); only 2.91 (2H, t); to 2.65 (2H, m); 1,82 (1H, s); and 1.63 (1H, s); of 1.39 (9H, s).

Stage 2: a Solution of tert-butyl methyl ether (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)carbamino acid (234 mg) in dichloromethane (4 ml) is treated triperoxonane acid (4 ml). The mixture is stirred at room temperature for 3 hours and concentrated in vacuo. OST is OK dissolved in a saturated solution of sodium bicarbonate (25 ml) and extracted twice with ethyl acetate (25 ml). The organic extracts are combined, washed with saline (20 ml), dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (12 g) with elution with a mixture of from 0 to 10% MeOH in dichloromethane, receiving [6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine (157 mg) as a solid. LC-MS Rt= 1,77 min, MS: 396 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ to 7.59 (1H, s); of 7.36 (2H, s); 6,86 (2H, m); to 5.93 (1H, ush.); of 5.29 (1H, s); 4,16 (2H, d); 3,82 (2H, d); to 3.73 (3H, s); to 3.41 (4H, m); only 2.91 (4H, m); at 1.91 (1H, m); 1,69 (1H, m); of 1.41 (2H, m); 1,23 (1H, s). IC50=985 nm.

Example 5

(a) [6-(4-Aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine

Stage 1: a Method similar to that described in example 1, step 2, but using 4-N-Boc-aminopiperidine (450 mg) instead of hydrochloride of 3-pyrrolidinecarboxylic acid and purifying the reaction product flash chromatography on a column of silica gel (40 g) with elution with a mixture of from 0 to 40% EtOAc in heptane, to obtain tert-butyl methyl ether (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)carbamino acid (320 mg).

Stage 2: a Solution of tert-butyl methyl ether(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)carbamino acid (300 mg) in DCM (5 ml) is treated with triethylsilane (194 μl) followed by the addition triperoxonane acid (106 ml). The mixture is peremeshivayte at room temperature for 20 hours and concentrated in vacuo. The residue is dissolved in saturated sodium bicarbonate solution (30 ml) and twice extracted with ethyl acetate (30 ml). The organic extracts are combined, washed with saline (20 ml), dried over magnesium sulfate and concentrated, obtaining [6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine (230 mg) as a solid.

(b) N-(1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)ndimethylacetamide

To a mixture of [6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine (190 mg), triethylamine (134 μl, 0.96 mmol) and N,N-dimethylaminopyridine (6 mg) in tetrahydrofuran (6 ml) add acetylchloride (41 μl, of 0.58 mmol). The reaction mixture is stirred for 17 hours, quenched by addition of water (20 ml) and twice extracted with ethyl acetate (25 ml). The organic extracts are combined, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (12 g) with elution by the mixture from 0% to 12% MeOH in CH2Cl2receiving N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)ndimethylacetamide (48 mg) as a solid. LC-MS Rt=1,9 min, MS: 438 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7,81 (1H, d); to 7.59 (1H, s); of 7.36 (2H, s); 6,79 (2H, m); 5,31 (1H, s); 4,07 (2H, m); of 3.78 (1H, d); 3,71 (3H, s); to 3.41 (2H, m); only 2.91 (4H, m); of 1.78 (3H, s); of 1.73 (1H, m); 1,25 (4H m). IC50=26 nm.

Example 6

5-{6-2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid

Stage 1. To a mixture of ethyl-5-bromoindole-2-carboxylate (2.5 g) in DMF (20 ml) add a solution of 60% NaH (485 mg) in DMF (10 ml). The resulting mixture is stirred for 15 minutes and added dropwise through a syringe itmean (0,638 ml). The reaction mixture was stirred at room temperature for 20 minutes. Add water (200 ml) and the mixture is extracted twice with ethyl acetate (100 ml). The organic extracts are combined, washed with water (3×50 ml) and once with brine (50 ml), dried over magnesium sulfate and concentrated, obtaining the ethyl ester of 5-bromo-1-methyl-1H-indole-2-carboxylic acid (1.28 g) as a solid.1H NMR [300 MHz, CDCl3]: δ 7,79 (1H, d); 7,41 (1H, DD); 7,27 (1H, t); 7,2 (1H, s); 4,39 (2H, q); of 4.05 (3H, s); of 1.41 (3H, t).

Stage 2. To a solution of ethyl ester of 5-bromo-1-methyl-1H-indole-2-carboxylic acid (1.28 g) in triperoxonane acid (10 ml) add cyanoborohydride sodium (680 mg) at 0°C. the Reaction mixture is brought to room temperature, stirred for 20 hours and quenched with water (100 ml). Alkalinized with NaOH and extracted with Et2O (3×50 ml). The organic extracts are combined washed with brine (30 ml), dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (34 g) with elution by the mixture from 0% to 25% ethyl acetate in heptane, obtaining the ethyl ester of 5-bromo-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid (800 m is in the form of a solid substance. 1H NMR [300 MHz, CDCl3]: δ 7,19 (1H, d); 7,21 (1H, s); 6,34 (1H, d); of 4.25 (2H, CWD); 4,06 (1H, t); is 3.21 (2H, m); 2,82 (3H, s); of 1.30 (3H, t).

Stage 3. A mixture of ethyl ester of 5-bromo-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid (800 mg), bis(pinacolato)Debora (1.5 g), potassium acetate (1.47 g) and PdCl2(dppf)2(139 mg) in dimethyl sulfoxide (10 ml) Tegaserod by blowing nitrogen for 5 minutes. The mixture is heated to 90°C for 4 hours. The reaction mixture is cooled, diluted with water (75 ml) and ethyl acetate (100 ml) and stirred with decolorizing charcoal. A two-phase mixture is filtered through celite and the filtrate twice extracted with EtOAc (50 ml). The organic extracts are combined, washed three times with water (50 ml), once with brine (30 ml), dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (34 g) with elution by the mixture from 0% to 20% ethyl acetate in heptane, obtaining the ethyl ester of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-1H-indole-2-carboxylic acid (903 mg) as a solid.1H NMR [300 MHz, (CD3)2SO]: δ 7,39 (1H, d); 7,28 (1H, s); 6,46 (1H, d); 4,18 (3H, m); 3,3 (1H, d); of 2.97 (1H, m), and 2.79 (3H, s); 1,24 (12H, s); 1,22 (3H, t).

Stage 4: a Mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (200 mg), ethyl ester of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-1H-indole-2-carboxylic acid (300 mg), Cs2CO3(390 mg) and tetrakis(triphenyl spin)palladium (35 mg) in water (0.4 ml) and dimethyl ether of ethylene glycol (1.6 ml) Tegaserod by blowing nitrogen for 5 minutes and heated at 90°C for 19 hours. The reaction mixture is cooled, diluted with water (50 ml) and twice extracted with ethyl acetate (50 ml). The organic extracts are combined, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel (40 g) with elution by the mixture from 0% to 40% ethyl acetate in heptane, obtaining the ethyl ester of 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid (110 mg) as a solid. LC-MS Rt=5,57 min, MS: 501 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7,72 (2H, m); to 7.59 (1H, s); 7,37 (3H, s); is 6.54 (1H, d); 6.42 per (1H, s); 4,30 (1H, m); 4,17 (2H, CWD); of 3.84 (3H, s); of 3.54 (2H, ush.); to 3.41 (1H, m); a 3.06 (1H, m); of 2.97 (2H, t); and 2.83 (3H, s); of 1.23 (3H, t).

Stage 5: the Monohydrate of lithium hydroxide (1.28 mmol) are added to stir the mixture ethyl ester 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid (0.43 mmol) in MeOH/H2O (10 ml, 9:1). The reaction mixture was stirred over night at room temperature. The reaction mixture was diluted with water and the volatiles removed in vacuum. The aqueous phase is once extracted with Et2O, acidified to pH 4 (1H, HCl) and extracted twice with ethyl acetate. The combined organic layer is dried (MgSO4) and concentrated in vacuo, receiving 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid.

Example 7

(a) [2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide 2-methylpropan-2-sulfonic acid

Step 1: To a solution of Diisopropylamine lithium in a mixture of THF/n-heptane/ethylbenzene (1,8M, 17 ml) at 0°C, add a solution of 2-(3-bromophenyl)propionic acid (3 g) in THF (5 ml) dropwise within 15 minutes. The solution is stirred for 1 hour, followed by adding dropwise under the conditions (4,93 g) in THF (5 ml) for 10 minutes. The reaction mixture is stirred for 15 hours, quenched with 2 N. hydrochloric acid, concentrated in vacuo and dissolved in ether (150 ml). The ether layer is washed with 2 N. hydrochloric acid and extracted three times 2 N. sodium hydroxide (50 ml). The combined layers of sodium hydroxide acidified with 6 N. hydrochloric acid to pH~1 and extracted three times with ether (75 ml). The combined organic layers washed with brine, dried over sodium sulfate and concentrated, obtaining 2-(3-bromophenyl)-2-methylpropionic acid solids (is 3.08 g), which is used further without additional purification. LC-MS: 243 (M+H)

Stage 2: a solution of 2-(3-bromophenyl)-2-methylpropionic acid (2,18 mmol) in anhydrous ether (20 ml) is added tert-utility (1,7M in pentane, to 5.4 ml, 9,16 mmol) dropwise at -78°C and the mixture stirred for 30 minutes with tributyrate (2,34 ml 8,72 mmol). The reaction mixture is avodat to room temperature, stirred for 15 hours, diluted with ether and quenched with 1M H3PO4. After stirring for 30 minutes, the ether layer is separated and extracted with 2 N. aqueous sodium hydroxide (3×20 ml). The combined extracts with sodium hydroxide acidified with 6 N. hydrochloric acid to pH~1 and extracted three times with ether (50 ml). The combined organic extracts washed with brine, dried over sodium sulfate and concentrated, obtaining 3-(1-carboxy-1-methylethyl)phenylboronic acid, which is further used without additional purification.

Stage 3: a Solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.51 mmol) and 3-(1-carboxy-1-methylethyl)phenylboronic acid (0.61 mmol) in MeCN (2.5 ml) and aqueous solution of Na2CO3(0,4M, 2.5 ml) Tegaserod nitrogen for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (29.5 mg). A reaction chamber is pressurized and heated in the microwave to 130°C for 30 minutes. To the reaction mixture add 2 ml of water, pH adjusted to ~7 with the help of 2 N. aqueous hydrochloric acid and this mixture thrice extracted with EtOAc (30 ml). The combined extracts washed with brine, dried over sodium sulfate and concentrated. The obtained oily substance chromatographic on silica gel with elution by the mixture from 0% to 7% MeOH in DCM, receiving 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxide midin-4-yl}phenyl)-2-methylpropionic acid (205 mg) as a solid. LC-MS: Rt=2,39 min, MS: 460,2 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 12,38 (1H, s), of 7.36-8 (7H, m), to 6.58 (1H, s), of 3.84 (3H, s)to 3.58 (2H, m), 2,98 (2H, m), and 1.54 (6H, s).

Stage 4: the Hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.23 mmol) is added to stirred ice-cold solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid (0.22 mmol), tert-butylsulfonyl (0.23 mmol) and 4-dimethylaminopyridine (0.22 mmol) in dry DCM under nitrogen atmosphere. The ice bath removed and the reaction mixture is stirred over night at 60°C. the Volatiles removed under reduced pressure, the residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue purified by chromatography (column with SiO2) with elution EtOAc/DCM, receiving [2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide 2-methylpropan-2-sulfonic acid (25 mg). LC-MS: Rt=2,67 min, MS: 579, 581 (M+H). IC50=2 nm.

(b) [2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide N,N-dimethylamide-2-sulfonic acid

By a method similar to that described in example 7(a), stage 4, but using N,N-dimethylsulfone instead of tert-butylsulfonyl receive [2-(3-{6-[2-(2,4-dichloro enyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide N,N-dimethylamide-2-sulfonic acid (185 mg). LC-MS: Rt=of 2.26 min; MS: 566, 568 (M+H).

(c) 2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-thiomorpholine-4-improper-1-he

By a method similar to that described in example 7(a), stage 4, but using thiomorpholine instead of tert-butylsulfonyl will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-thiomorpholine-4-improper-1-he (120 mg). LC-MS: Rt=2,68 min, MS: 545, 547 (M+H). IC50=383 nm

(d) 2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)isobutyramide

By a method similar to that described in example 7(a), stage 4, but using ammonium bicarbonate instead of tert-butylsulfonyl will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)isobutyramide (120 mg). LC-MS: Rt=2,01 min, MS: 459, 461 (M+H).

(e) 2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N,N-dimethylethanamine

By a method similar to that described in example 7(a), stage 4, but using dimethylamine instead of tert-butylsulfonyl will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N,N-dimethylethanamine (186 mg). LC-MS: Rt=2,44 min, MS: 487, 489 (M+H).

Example 8

(1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid

Stage 1: a Solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (3 mmol), ethyl ester of piperidine acetic acid (7.5 mmol) and K2CO3(9 mmol) in 1-methyl-2-pyrrolidinone (10 ml) is stirred overnight at 145°C. the Reaction mixture is cooled to room temperature, diluted with water (60 ml) and twice extracted with DCM. The aqueous layer was slowly acidified with 1 N. hydrochloric acid to pH 4, vigorously stirring, and stirring is continued for 1.5 hours. The formed precipitate is filtered by suction and air-dried, obtaining the ethyl ester of (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid (1.42 g). LC-MS: Rt=2,35 min, MS: 467, 469 (M+H).

Stage 2: the Monohydrate of lithium hydroxide (54 mg) is added to a mixed solution of ethyl ester (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid (0.2 g) in MeOH/H2O (10 ml, 9:1). The reaction mixture was stirred over night at room temperature. The reaction mixture was diluted with water and the volatiles removed in vacuum. The aqueous phase is once extracted with Et2O, acidified to pH 4 (1H, HCl) and extracted twice with ethyl acetate. The combined organic layer is dried (MgSO4) and concentrated in vacuo, obtaining (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)criminal code of usnow acid (180 mg). LC-MS: Rt=2,08 min, MS: 439, 441 (M+H). IC50=0.5 nm.

Example 9

1-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid

A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine (1 g), nicotinebuy acid (0,93 g) and K2CO3(1.19 g) in 1-methyl-2-pyrrolidinone (10 ml) is stirred overnight at 145°C. the Reaction mixture is cooled to room temperature, diluted with water (60 ml) and twice extracted with dichloromethane. The aqueous layer was slowly acidified with 1 N. hydrochloric acid to pH 4, vigorously stirring, and stirring is continued for 1.5 hours. The formed precipitate is filtered by suction and dried in the air, getting 1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid in powder form (0,99 g). LC-MS: Rt=2,07 min, MS: 441 (M+H). IC50=9 nm.

Example 10

N-(1-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carbonyl)methanesulfonamide

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (68 mg) is added to stirred ice-cold solution of 1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid (150 mg), methanesulfonamide (48.6 mg) and 4-dimethylaminopyridine (50 mg) in su is ω DCM in an atmosphere of N 2. The ice bath removed and the reaction mixture is stirred overnight, bringing to room temperature. The mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (column with SiO2) with elution EtOAc/DCM, receiving N-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carbonyl)methanesulfonamide (65 mg). LC-MS: Rt=2,09 min, MS: 518 (M+H). IC50=22 nm.

Example 11

(a) N-(1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)methanesulfonamide

Stage 1: In vitro mixed (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (200 mg), nicotinebuy acid (194 mg), K2CO3(249 mg) and 1-methyl-2-pyrrolidinone (2.5 ml). The test tube is sealed, heated to 140°C and stirred for 5 hours. The mixture is cooled to room temperature, leave it for 12 hours, diluted with water (20 ml) and acidified with 3M aqueous HCl. The resulting precipitate is collected by filtration and dried in high vacuum, obtaining 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (121 mg) as a solid. LC-MS Rt=2,15 min, MS: 425 (M+H).

Stage 2: N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide drochloride (71 mg) is added to stirred ice-cold solution of 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (150 mg), methanesulfonamide (43,6 mg) and 4-dimethylaminopyridine (52 mg) in dry dichloromethane in the presence of N2. The ice bath removed and the reaction mixture is stirred over night at room temperature. The mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (column with SiO2) with elution EtOAc/DCM, receiving N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)methanesulfonamide (145 mg). LC-MS: Rt=1,88 min, MS: 502, 504 (M+H). IC50=1 nm.

(b) (1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide econsultancy acid

By a method similar to that described in example 11(a), stage 2, but using econsultant instead of methanesulfonamide, get (1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide econsultancy acid (125 mg). LC-MS: Rt=2,12 min, MS: 516, 518 (M+H).

(c) (1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide 2-methylpropan-2-sulfonic acid

By a method similar to that described in example 11(a), stage 2, but using tert-butylsulfonyl instead of methanesulfonamide, get (1-{6-[2-(2,4-dichlorophen the l)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide 2-methylpropan-2-sulfonic acid (132 mg). LC-MS: Rt=2,2 min, MS: 544, 546 (M+H).

(d) N-(1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)-C,C,C-triftormetilfullerenov

By a method similar to that described in example 11(a), stage 2, but using triftormetilfullerenov instead of methanesulfonamide receive N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)-C,C,C-triftormetilfullerenov (257 mg). LC-MS: Rt=2,3 min, MS: 556, 558 (M+H). IC50=18 nm.

(e) (1H-Tetrazol-5-yl)amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid

By a method similar to that described in example 11(a), stage 2, but using 1H-tetrazol-5-ylamine instead of methanesulfonamide receive (1H-tetrazol-5-yl)amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (15 mg). LC-MS: Rt=1,81 min, MS: 492, 494 (M+H). IC50=4,4 nm.

(f) Amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.23 mmol) is added to stirred ice-cold solution of 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (0.22 mmol), acanaloniidae (0.23 mmol) and 4-dimethylaminopyridine (0.22 mmol) in dry chlormethine in the atmosphere N 2. The ice bath removed and the reaction mixture is stirred over night at 60°C. the Mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1 n HCl, brine and water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is purified by chromatography (column with SiO2) with elution EtOAc/DCM, getting amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (75 mg). LC-MS: Rt=1,77 min, MS: 424, 426 (M+H).

(g) Dimethenamid 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid

By a method similar to that described in example 11(a), stage 2, but using dimethylamine instead of methanesulfonamide receive dimethylamide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid (65 mg). LC-MS: Rt=1,88 min, MS: 452, 454 (M+H).

(h) 1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxamide N,N-dimethylamide-2-sulfonic acid

By a method similar to that described in example 11(a), stage 2, but using N,N-dimethylsulfone instead of methanesulfonamide, get 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxamide N,N-dimethylamide-2-sulfonic acid (241 mg). LC-MS: Rt=2.5 minutes, MS: 531, 533 (M+H) IC 50=14 nm.

Example 12

5-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-thiophene-2-carboxylic acid

Stage 1: 5-(Dihydroxyaryl)-2-thiencarbazone acid (527 mg) and 2,2-DIMETHYLPROPANE-1,3-diol (361 mg) was stirred at room temperature in THF (10 ml) for 19 hours and was concentrated in vacuo, obtaining 5-(5,5-dimethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid (748 mg) as a solid. LC-MS: Rt=1,15 min;1H NMR [300 MHz, (CD3)2SO]: δ 13,15 (1H, s), and 7.7 (1H, m); 7,45 (1H, m); of 3.75 (4H, s); of 0.95 (6H, s).

Stage 2: a Mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine (267 mg), 5-(5,5-dimethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid (277 mg), cesium fluoride (351 mg) and tetrakis(triphenylphosphine)palladium (71 mg) in water (1.6 ml) and dimethyl ether of ethylene glycol (6,4 ml) Tegaserod by blowing nitrogen for 5 minutes and heated to 85°C for 16 hours. The reaction mixture is cooled, diluted with water (150 ml) and brine (25 ml), twice extracted with EtOAc (100 ml)and the extracts concentrated in vacuo. The residue is purified flash chromatography on a column of silica gel (10 g) with elution with a mixture of from 0 to 5% MeOH in EtOAc. The obtained solid crystalline substance is ground to powder in DCM (5 ml) and ether (5 ml) and dried, obtaining 5-{2-methoxy-6-[2-(4-trifloromethyl)this is laminitis]pyrimidine-4-yl}-thiophene-2-carboxylic acid (42 mg) as a solid. MS: 440; LC-MS: Rt=3,48 min;1H NMR [300 MHz, (CD3)2SO]: δ is 7.7 (3H, m); to 7.35 (2H, m); of 7.25 (2H, m), and 6.6 (1H, s); of 3.85 (3H, s); to 2.55 (2H; m); 1,9 (2H, t, J=7 Hz). IC50=2 nm.

Example 13

Hydrochloride 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid

Step 1: To a solution of 2,3-dihydrobenzofuran-2-carboxylic acid (510 mg) in glacial acetic acid (4 ml) is added dropwise bromine (497 mg). After 16 hours the reaction is quenched with water (100 ml) and sodium bisulfite (1 g) and twice extracted with EtOAc (100 ml). The extracts are concentrated in vacuo and dried in high vacuum, receiving 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid (811 mg) as a solid. MS: 241 (M+H)1H NMR [300 MHz, (CD3)2SO]: δ of 13.05 (1H, s); 7,4 (1H, s); of 7.25 (1H, d); 6,8 (1H, m); 5.25-inch (1H, HF), 3,55 (1H, DD); to 3.25 (1H, m).

Stage 2: a Mixture of 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid (0.74 g), bis(pinacolato)Debora (1.51 g), potassium acetate (1.47 g, 15 mmol) and PdCl2(dppf)2(115 mg, 0.14 mmol) in dimethyl sulfoxide (10 ml) Tegaserod by blowing nitrogen for 5 minutes. The mixture is heated to 90°C for 16 hours. The reaction mixture is cooled, diluted with water (200 ml) and brine (25 ml) and filtered through celite, and then add water (200 ml) and EtOAc (200 ml). The filtrate is twice extracted with EtOAc (200 ml)and the extracts concentrated in vacuo. About who headed the remainder of the purified flash chromatography on a column of silica gel (4 g) with elution with a mixture of from 80 to 100% EtOAc in heptane, receiving 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylic acid (715 mg) as an oily substance. MS: 289 (M-H)1H NMR [300 MHz, (CD3)2SO]: δ of 13.05 (1H, s); 7,5 (2H, m); 6,8 (1H, m); and 5.2 (1H, m); 3,6 (1H, m); 3,3 (1H, m); of 1.05 (12H, s).

Stage 3: a Mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (212 mg), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylic acid (124 mg), cesium carbonate (414 mg) and tetrakis(triphenylphosphine)palladium (49 mg) in water (1.2 ml) and dimethyl ether of ethylene glycol (4.8 ml) Tegaserod by blowing nitrogen for 5 minutes and heated to 70°C for 64 hours. The reaction mixture is cooled, diluted with water (150 ml) and brine (25 ml) and twice extracted with EtOAc (150 ml)and the extracts concentrated in vacuo. The residue is purified flash chromatography on a column of silica gel (4 g) with elution with a mixture of from 0 to 25% MeOH in EtOAc, receiving 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid (80 mg) as an oily substance. MS: 460; LC-MS: Rt=2,81 minutes

Stage 4: Part 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid handle flash chromatography on a column of silica gel (5 g) with elution by the mixture from 0% to 25% MeOH in EtOAc. The product is dissolved in MeOH and treated with 0,5M hydrochloric acid in MeOH and will contentresult in vacuum. The product is dissolved in THF (3 ml) and ether (10 ml). The precipitate is removed and dried, obtaining the hydrochloride of 5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid (20 mg) as a solid. LC-MS: Rt=2,79 min; MS: 460. IC50=2 nm.

PHARMACOLOGICAL TEST

The inhibitory effect of the compounds which are the object of the present invention, assessed using the functional analysis of prostaglandin D man. Applied analysis of camp using a cell line of human LS174T expressing endogenous receptors of prostaglandin D. Protocol similar to that described previously (Wright DH, Ford-Hutchinson AW, Chadee K, Metters KM, The human prostanoid DP receptor stimulates mucin secretion in LS174T cells, Br J Pharmacol. 131(8):1537-45 (2000)).

The SPA Protocol-analysis of camp in cells LS174 T person

Materials

- PGD2 (Cayman Chemical, cat. No. 12010)

- IBMX (Sigma cat. No. 5879)

- Direct screening SPA-analysis of camp (code Amersham RPA 559)

- 96-hole plates to cell cultures (Wallac cat. No. 1450-516)

- Scintillation counter Wallac 1450 Trilux Microplate (PerkinElmer)

- Device for sealing tablets

- Centrifuge tubes Eppendorf

- Saline solution in phosphate buffer (PBS) Dulbecco (Invitrogen cat. No. 14040-133)

- Distilled water

- Shaker

- Magnetic stirrer and a set of anchors

Reagent preparation

Before rasba the population all reagents should be brought to room temperature.

Analytical buffer 1X

Transfer the contents of the bottle 500 ml beaker repeated washing with distilled water. Bring total volume to 500 ml by adding distilled water, and mix thoroughly.

Lyse reagent 1 and 2

Dissolve each of the lytic reagents 1 and 2 in 200 ml of analytical buffer, respectively. Leave on for 20 minutes at room temperature to dissolve.

Granules of rabbit antibodies for SPA-analysis

Add in a bottle of 30 ml lyse buffer 2. Gently shake the bottle for 5 minutes.

Immune serum

Add 15 ml of lyse buffer 2 in each vessel and the contents gently mixed until dissolved.

Marker (I125-camp)

Add 14 ml of lyse buffer 2 in each vessel and the contents gently mixed until dissolved.

Preparation of immunoreagent

1) Add an equal volume marker of immune serum and SPA-reagent antibodies rabbit in a vessel that was prepared sufficient for the desired number of holes (150 μl per well).

2) mix Thoroughly.

3) you Must prepare a fresh solution of immunoreagent before each analysis and are not reusable.

Standard

1) Add 1 ml of lyse buffer 1 and cautiously p is remediat contents until dissolved.

2) the Final solution contains camp at a concentration of 512 pmol/ml

3) Mark 7 polypropylene or polystyrene tubes of 0.2 pmol, 0.4 pmol, 0.8 pmol, 1.6 pmol, 3.2 pmol, 6.4 and 12.8 pmol pmol.

4) Pipette add 500 ál lyse buffer 1 in all test tubes.

5) In a test tube "12.8 pmol" add by pipette 500 ál of standard mixture (512 pmol/ml) and mix thoroughly. Transfer 500 ál from tube "12.8 pmol" in the tube "6.4 pmol and mix thoroughly. Repeat the dilution procedure twice with the rest of the tubes.

6) portions of 50 μl in duplicate from each serial dilution and standard source solution allow you to get 8 standard camp levels in the range from 0.2 to 25.6 pmol.

Dilution buffer connection

Add 50 ál of 1 mm IBMX in 100 ml of PBS to obtain a final concentration of 100 μm, and treated with ultrasound at 30°C for 20 minutes.

Preparation PGD2

Dissolve 1 mg of PGD2 (FW, AZN 352.5) 284 μl DMSO to obtain the original solution of 10 mm, and stored at 20°C. Before each analysis it is necessary to prepare a fresh solution. Add 3 ál of 10 mm initial solution in 20 ml of DMSO, mix thoroughly and transfer 10 ml to 40 ml PBS.

Dilution connection

The dilution of the compounds is carried out in Biomex 2000 (Beckman) using method 11 points camp DP.

5 µl of each link is 10 mm tablets of the standard solutions of the compounds are transferred into the wells of 96-hole tablet, as indicated below.

G
123456789101112
A1
B2
C3
D4
E5
F6
7
HControl

Fill the tablet 45 μl of DMSO, except column 7 where add 28 μl of DMSO. Carefully measure the pipette contents of columns 1 and transfer 12 ál in parallel in column 7. Perform a serial dilution of 1:10 from column 1 to column 6 and column 7 to column 11, transferring from 5 ál 45 ál DMSO to obtain the following concentrations:

0.03 µm
The first tabletThe final concentration
Column 120
Column 11
Column 100,3 ám
Column 93 microns
Column 80.03 mm
Column 70.3 mm
Column 60.01 µm
Column 50.1 ám
Column 41 micron
Column 30,01 mm
Column 20.1 mm
Column 11 mm

Add in a new 96-well plate of 247.5 μl of dilution buffer for the connection. Transfer of 2.5 μl of serially diluted compounds from cooked above tablet in new (dilution 1:100) as follows:

The first tabletThe second tabletThe final concentration
Column 12Column 10
Column 6 Column 20.1 nm
Column 11Column 30.3 nm
Column 5Column 41 nm
Column 10Column 53 nm
Column 4Column 60.01 µm
Column 9Column 70.03 µm
Column 3Column 80.1 ám
Column 8Column 90,3 ám
Column 2Column 101 micron
Column 7Column 113 microns
Column 1Column 1210 µm

The growth of cells

1. LS174 T always grown in MEM (ATCC cat. No. 30-2003), 10% FBS (ATCC cat. No. 30-2020) and an additional 2 mm L-glutamine, at 37°C and 5% CO2.

2. Heating the Ute 0.05% trypsin, versine (Invitrogen cat. No. 25300-054) at 37°C in a water bath.

3. Remove environment for the growth of cells. The cells in the flask bulldozer t165 washed twice with 4 ml of trypsin, and then incubated at 37°C and 5% CO2within 3 minutes.

4. Add 10 ml of medium and pipette carefully separate and count the cells.

5. Bring the density of the cells to 2.25×105cells per ml and plated at 200 μl cells per well (45,000 cells per well) in 96-well tablet 1 day before analysis.

Order analysis

Day 1

Sow 45,000 cells per well in 200 μl of medium in 96-well plates. Incubated tablets with cells at 37°C, 5% CO2and 95% humidity during the night.

Day 2

1. Perform dilutions of the compounds.

2. Prepare analytical buffer lyse buffers 1 and 2, PGD2 and standard.

3. Remove the medium from the cells by aspiration and add 100 ál of a solution of the compound, following the Protocol of camp DP Zymark Sciclone-ALH/FD.

4. Incubate cells at 37°C, 5% CO2and 95% humidity for 15 minutes.

5. Add 5 ál of 300 nm PGD2 (20×15 nm final concentration) to each well using a Protocol Zymark camp DP PGD2 and incubated the cells at 37°C, 5% CO2and 95% humidity for another 15 minutes.

6. Remove the medium from the cells by aspiration and add 50 ál lyse buffer 1 using the Protocol Zymark camp DP lysis and incubated at room temperature with shaking for 30 minutes.

7. Add recipients who are into each well, 150 μl of immunoreagent (total volume 200 μl per well).

8. Seal tablet, shaken for 2 minutes and placed in a scintillation camera counter for microtiter tablets Wallac for 16 hours.

Day 3

Spending by the number of [125I] camp for 2 minutes in a scintillation counter 1450 Trilux.

Data processing

Postpone a standard dependence camp on the number of pulses per minute.

Table 1
Typical data analysis for standard
camp (pmol/ml)Pulse/minCf. pulse/min
0,2572557695530
0,4536752596317
0,8469547966507
1,6425141786581
3,234343429 6601
6,4275827166711
12,8209420546680
25,6153115736653

Concentration camp (pmol/ml) of unknown samples are calculated according to a standard based camp on the number of pulses per minute. The percentage inhibition is calculated according to the following formula:

% inhibition =(pmol in the sample - pmol sample)×100
pmol in the control sample (cells + PGD2)

The implementation of the present invention may take other specific forms, which will not affect the essence of the invention or its main provisions.

1. The compound of formula (I)

where R1represents 2,4-dichlorophenyl or 4-trifloromethyl, and
when R1represents 2,4-dichlorophenyl, then R2is a 3-carboxypropanoyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperidin-1-yl, 4-am is epipedon-1-yl, 4-acetamiprid-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylcyclopentadienyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonylmethyl-1-methylethyl)phenyl, 3-(1-thiomorpholine-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminoethyl-1-methylethyl)phenyl, 3-carboxymethylchitin-1-Il,
3-methylsulfonylmethane-1-Il,
3-metilsulfonilmetane-1-Il,
3-tert-butylanthraquinone-1-Il,
3-triftormetilfullerenov-1-Il,
3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidine-1-Il,
3-aminocarbonylmethyl-1-yl, 3-dimethylaminocarbonylmethyl-1-Il,
3-dimethylaminoethylmethacrylate-1-yl or
2-carboxy-2,3-dihydrobenzofuran-5-Il,
and when R1is a 4-trifloromethyl, then R2represents a 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypeptidases,
3-methylsulfonylmethane-1-yl, 5-carboxamide-2-Il,
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is a
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}pyrrolidin-3-carboxylic acid
2-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-yl)-2-methylpropionic acid,
2-[3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-m is oxypyridine-4-yl}-5-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol,
[6-(3-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,
[6-(4-aminopiperidin-1-yl)-2-methoxypyridine-4-yl]-[2-(2,4-dichlorophenyl)ethyl]amine,
N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-4-yl)acetamide", she
5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-1-methyl-2,3-dihydro-1H-indole-2-carboxylic acid,
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide 2-methylpropan-2-sulfonic acid,
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide N,N-dimethylamide-2-sulfonic acid,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-thiomorpholine-4-improper-1-he,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)isobutyramide,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N,N-dimethylethanamine,
(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-yl)acetic acid,
1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carboxylic acid
N-(1-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}piperidine-3-carbonyl)methanesulfonamide,
N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)methanesulfonamide,
(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carb the Nile)amide econsultancy acid,
(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)amide 2-methylpropan-2-sulfonic acid,
N-(1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carbonyl)-s,s-triftormetilfullerenov,
(1H-tetrazol-5-yl)amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,
amide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,
dimethylamide 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid,
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxamide N,N-dimethylamide-2-sulfonic acid,
5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-thiophene-2-carboxylic acid, or
5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid,
or its pharmaceutically acceptable salt.

3. Pharmaceutical composition having the properties of a receptor antagonist of prostaglandin D2, comprising pharmaceutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry. Pharmaceutical compositions including, at least, one compound of formula where -X- represents, for instance, group of formula and Y represents, for instance, group of formula or its pharmaceutically acceptable salts, esters or amides, or pro-drugs and pharmaceutically acceptable carrier, which is acceptable in therapy, can be applied for modulation in vitro and in vivo processes of binding, mediated by binding of E-, P- or L- selectin.

EFFECT: obtaining novel floroglucin derivatives.

9 cl, 10 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula I: , where R1 and R2 independently denote Ph; mono- or disubstituted in different positions of the ring Ph, where substitute denotes -OCH3; C5-heteroaryl with one heteroatom selected from O or S; R2 denotes H, NO2, NH2, C(O)NH2; R4 denotes H, a straight or branched C1-C6-alkyl; n equals the number of methylene groups and is between 1 and 8 inclusively; X denotes O, S, NH; Y NH, -CH2-; Z denotes O, S; W denotes -OH, hydroxylamine, hydrazine, alkylhydrazine.

EFFECT: compounds can inhibit histone deacetylase, which enables their use in cancer treatment.

10 cl, 9 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: chemistry.

SUBSTANCE: method is realised by reacting 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)benzimidazole with a compound of formula

, in which Z denotes a leaving group. The compound obtained this way undergoes suitable treatment if necessary. The cyano group of the obtained 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl]biphenyl of formula

is then converted to an acid functional group through hydrolysis at temperature ranging from 140°C to 200°C in the presence of a base in a system of high-boiling solvents, and the obtained telmisartan is converted to a hydrochloride during processing if necessary.

EFFECT: easy processing, treatment and extraction of telmisartan.

12 cl, 7 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyridazine compound of formula (1), in which R1 is a chlorine atom, bromine atom, C1-C4 alkyl group of C1-C4 alkoxy group, R2 is a C1-C4 alkyl group, R3 is a halogen atom, m equals 0 or 1, Q is a 6-member aromatic heterocyclic group selected from a pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group, wherein the said aromatic heterocyclic group is optionally substituted with at least one substitute selected from a group comprising halogen atoms, C1-C4 alkyl group optionally substituted with at least one halogen atom, and C1-C4 alkoxy group optionally substituted with at least one halogen atom. This compound has excellent plant disease suppression.

EFFECT: compound can be used plant disease control.

10 cl, 11 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

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