Derivatives of imidazo[1,2-c]pyrimidinyl acetic acid

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

 

The present invention relates to a derived pyrimidinemethanol acid, which is suitable as an active ingredient of pharmaceutical preparations. Derived pyrimidinemethanol acid according to the present invention has an antagonistic activity against CRTH2 (G-protein-linked receptor chemoattractant expressed in Th2 cells) and can be used for the prevention and treatment of diseases associated with CRTH2 activity, in particular, for the treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis; diseases associated with eosinophils, such as the syndrome it continues-Strauss and sinusitis; diseases associated with basophils, such as basophilic leukemia, chronic urticaria and basophilic leukocytosis in humans and other mammals; and inflammatory diseases characterized by T-lymphocytes and profuse infiltrates of leukocytes, such as psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, COPD (chronic obstructive pulmonary disorder), and arthritis.

CRTH2 is a G-protein-linked receptor chemoattractant expressed in Th2 cells (Nagata et al. J. Immunol., 162, 1278-1286, 1999), eosinophils and basophils (Hirai et al., J. Exp. Med., 193, 255-261, 2001).

Th2-polarization observed is carried out in allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis (Romagnani S. Immunology Today, 18, 263-266, 1997; one H. et al., Blood, 98, 1135-1141, 2001). Cells regulate Th2 allergic diseases through the production of Th2 cytokines, such as IL-4, EL-5 and DL-13 (Oriss et al., J. Immunol., 162, 1999-2007, 1999; Viola et al., Blood, 91, 2223-2230, 1998; Webb et al., J. Immunol, 165, 108-113, 2000; Dumont F.J., Exp. Opin. Ther. Pat., 12, 341-367, 2002). These Th2 cytokines directly or indirectly induce the migration, activation, priming and prolonged survival of effector cells such as eosinophils and basophils, allergic diseases (Sanz et al., J. Immunol., 160, 5637-5645, 1998; Pope et al, J. Allergy Clin. Immunol, 108, 594-601, 2001; L. M. Teran, Clin. Exp. Allergy, 29, 287-290, 1999).

PGD2the ligand for CRTH2, is produced from fat cells and other important effector cells in allergic diseases (Nagata et al, FEBS Lett. 459, 195-199, 1999; Hirai et al, J. Exp. Med, 193, 255-261, 2001). PGD2induces the migration and activation of Th2 cells eosinophils and basophils in human cells via CRTH2 (Hirai et al, J. Exp. Med, 193, 255-261, 2001; Gervais et al., J. Allergy Clin. Immunol., 108, 982-988, 2001; Sugimoto et al., J. Pharmacol. Exp. Ther, 305, (1), 347-52, 2003).

For this reason, antagonists that inhibit the binding of CRTH2 and PGD2shall be suitable for the treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis.

In addition to this is the few lines of experimental evidence demonstrating the contribution of eosinophils in sinusitis (Hamilos et al., Am. J. Respir. Cell and Mol. Biol., 15, 443-450, 1996; Fan et al., J. Allergy Clin. Immunol., 106, 551-558, 2000), and the syndrome it continues-Strauss (Coffin et al., J. Allergy Clin. Immunol., 101, 116-123, 1998; Kurosawa's way (Kurosawa et al., Allergy, 55, 785-787, 2000). In the tissues of these patients may experience joint localization of mast cells with eosinophils (Khan et al., J. Allergy Clin. Immunol., 106, 1096-1101, 2000). This suggests that the production of PGD2from fat cells induces the recruitment of eosinophils. For this reason, the CRTH2 antagonists are also suitable for treatment of other diseases associated with eosinophils, such as the syndrome it continues-Strauss and sinusitis. The CRTH2 antagonists also may be suitable for treatment of some diseases associated with basophils, such as basophilic leukemia, chronic urticaria and basophilic leukocytosis, due to the high CRTH2 expression on basophils.

A. F. Kluge describes the synthesis of similar imidazo[1,2-c]pyrimidine represented by the General formula

where RA1represents a

(Journal of Heterocyclic Chemistry (1978), 15(1), 119-21).

However, derivative imidazo[1,2-c]pyrimidinemethanol acid, which has antagonistic activity against CRTH2 not been described previously.

Development of a compound that has an effective antagonistic activity against CRTH2 and can be used for the prevention and treatment of Zabol the requirements, associated with CRTH2 activity, is desirable.

The present invention discloses derivatives of imidazo[1,2-c]pyrimidinemethanol acid of the formula (I), their tautomeric and stereoisomeric form, and salts:

where R1represents a

in which

n is an integer from 0 to 6;

Q1represents-NH-, -N(C1-6alkyl) -, or-O-;

Y represents hydrogen, C3-8cycloalkyl, optionally substituted C1-6the alkyl, C3-8cycloalkyl condensed with benzene, aryl or heteroaryl where specified aryl and heteroaryl are optionally substituted at substitutable position by one or more substituents selected from the group consisting of cyano, halogen, nitro, guanidino, pyrrolyl, sulfamoyl, C1-6alkylaminocarbonyl, di (C1-6alkyl) aminosulfonyl, phenyloxy, phenyl, amino, C1-6alkylamino, di(C1-6alkyl) amino, C1-6alkoxycarbonyl, C1-6alkanoyl, C1-6alkanolamine, carbamoyl, C1-6allylcarbamate, di(C1-6alkyl) carbamoyl, C1-6alkylsulfonyl, C1-6the alkyl, optionally substituted mono-, di - or trihalogen, C1-6alkoxy, optionally substituted mono-, di - and who and trihalogen and C 1-6alkylthio, optionally substituted mono-, di - or trihalogen,

or aryl condensed with 1,3-dioxolane;

R2represents hydrogen or C1-6alkyl;

R3represents hydrogen, halogen, C1-6alkyl, optionally substituted mono-, di - or trihalogen,

C1-6alkoxy, optionally substituted mono-, di - or trihalogen,

in which

R3aand R3bindependently represents a C3-8cycloalkyl or C1-6alkyl, optionally substituted carboxy, C3-8cycloalkyl, carbamoyl, C1-6allylcarbamate, aryl-substituted C1-6allylcarbamate, C1-6allylcarbamate, di(C1-6alkyl)carbarnoyl, C3-8cycloalkylcarbonyl, C3-8heterocyclicamines, C1-6alkylamino, di(C1-6alkyl)amino or C1-6alkoxy,

or

in which

q is an integer from 1 to 3;

R3crepresents hydrogen, hydroxy, carboxy, or C1-6alkyl, optionally substituted hydroxy, carboxy, or (phenyl-substituted C1-6alkyl)carbarnoyl;

Xa represents-O-, -S - or-N(R3d)-

in which

R3drepresents hydrogen or C1-6alkyl; and

R4represents hydrogen or C 1-6alkyl.

In one of the embodiments, the compounds of formula (I) are compounds where:

R1represents a

,or

in which

n is an integer from 0 to 2;

Q1represents-NH-, -N(C1-6alkyl) -, or-O-;

Y represents a C3-8cycloalkyl, optionally substituted C1-6the alkyl, C3-8cycloalkyl condensed with benzene, aryl selected from the group consisting of phenyl and naphthyl or heteroaryl selected from the group consisting of indolyl, chinoline, benzofuranyl, furanyl and pyridyl where specified aryl and heteroaryl are optionally substituted at substitutable position by one or more substituents selected from the group consisting of cyano, halogen, nitro, pyrrolyl, sulfamoyl,1-6alkylaminocarbonyl, di(C1-6alkyl) aminosulfonyl, phenyloxy, phenyl, C1-6alkylamino, di(C1-6alkyl) amino, C1-6alkoxycarbonyl, C1-6alkanolamine, carbamoyl, C1-6allylcarbamate, di(C1-6alkyl)carbamoyl, C1-6alkylsulfonyl, C1-6the alkyl, optionally substituted mono-, di - or trihalogen, C1-6alkoxy, optionally substituted mono-, di - or trihalogen, and C1-6Alki is thio, optionally substituted mono-, di - or trihalogen; and

R2represents hydrogen.

In another embodiment, the compounds of formula (I) are compounds where:

R3represents hydrogen, halogen, C1-6alkyl, optionally substituted mono-, di - or trihalogen, C1-6alkoxy, optionally substituted mono-, di - or trihalogen,

in which

R3aand R3bindependently represents a C1-6alkyl, optionally substituted carboxy, C3-8cycloalkyl, carbamoyl, C1-6allylcarbamate, di(C1-6alkyl)carbamoyl, C3-8cycloalkylcarbonyl, C3-8heterocyclisation, C1-6alkylamino, di(C1-6alkyl)amino or C1-6alkoxy,

or

in which

R3crepresents hydrogen, hydroxy, carboxy or C1-6alkyl, optionally substituted by hydroxy, carboxy or phenyl-substituted C1-6alkyl)carbarnoyl;

Xa represents-O-, -S - or-N(R3d)-,

in which

R3drepresents a C1-6alkyl.

In another embodiment, the compounds of formula (I-i) are

where

R1represents a

or

in which

n is an integer from 0 to 2;

Q1represents-NH-, -N(C1-6alkyl) -, or-O-;

Y represents phenyl, naphthyl, indolyl, hinely, benzofuranyl, furanyl or pyridyl,

where specified phenyl, naphthyl, indolyl, hinely, benzofuranyl, furanyl and pyridyl are optionally substituted at substitutable position with one or two substituents selected from the group consisting of cyano, halogen, nitro, phenyloxy, phenyl, C1-6the alkyl, optionally substituted mono-, di - or trihalogen, C1-6alkoxy, optionally substituted mono-, di - or trihalogen, and C1-6alkylthio, optionally substituted mono-, di - or trihalogen;

R2represents hydrogen or C1-6alkyl;

R3represents hydrogen, halogen, C1-6alkyl, optionally substituted mono-, di - or trihalogen, C1-6alkoxy,

in which

R3aand R3bindependently represents a C3-8cycloalkyl or C1-6alkyl, optionally substituted C3-8cycloalkyl, carbamoyl, C1-6allylcarbamate, phenyl-substituted C1-6allylcarbamate, C1-6allylcarbamate, di(C1-6alkyl)carbamoyl, C3-8cycloalkylcarbonyl is, C3-8heterocyclisation, C1-6alkylamino, di(C1-6alkyl)amino or C1-6alkoxy,

or

R3crepresents hydrogen, hydroxy, carboxy or C1-6alkyl, optionally substituted hydroxy, carboxy, or (phenyl-substituted C1-6alkyl)carbarnoyl; and

R4represents hydrogen or methyl.

Preferred are the compounds of formula (I)in which R2represents hydrogen.

Preferred are the compounds of formula (I)in which R3represents hydrogen or halogen, preferably chlorine.

Preferred are the compounds of formula (I)in which R4represents hydrogen.

Preferred are the compounds of formula (I)in which R1represents one of the groups

Preferred compounds of the present invention are the following compounds:

[7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid;

(7-chloro-5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetic acid;

{7-chloro-5-[4-(2-naphthylamine)benzyl]imidazo[1,2-c]pyrimidine-8-yl}acetic acid;

[7-chloro-5-(4-{[(2E)-3-phenylprop-2-enoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]xunwu acid;

[7-chloro-5-(4-{[(2E)-3-(4-chlorophenyl)prop-2-enoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid;

(5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetic acid;

[5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid

and their tautomeric and stereoisomeric form, and their salts.

Derivative imidazo[1,2-c]pyrimidinemethanol acid of the formula (I) exhibit excellent antagonistic activity against CRTH2. For this reason, they are suitable in particular for the prevention and treatment of diseases associated with CRTH2 activity.

More specifically, derivatives of imidazo[1,2-c]pyrimidinemethanol acid of the formula (I) and (I-i) are effective for treatment or prevention of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis.

The compounds of formula (I) and (I-i) are also suitable for the treatment or prevention of diseases such as syndrome it continues-Strauss, sinusitis, basophilic leukemia, chronic urticaria and basophilic leukocytosis, because these diseases are also associated with activity in relation to CRTH2.

In addition, the present invention provides a medication that contains one of the compounds described above, and, optionally, the pharmaceutical is Ki acceptable excipients. Alkyl per se and "ALK" and "alkyl" in alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkoxycarbonyl, alkoxycarbonyl, alkanolamine represents an alkyl radical with a straight or branched chain, having, as a rule, 1-6, preferably 1-4, and most preferably 1-3 carbon atoms, it is illustratively and preferably represents methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentox and n-hexose.

Alkanoyl illustratively and preferably represents acetyl and propanol.

Alkylamino is alkylamino radical having one or two (independently selected) alkyl substituent, illustratively and preferably represents methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamine, n-hexylamine, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamine and N-n-hexyl-N-methylamino.

Alkylaminocarbonyl or allylcarbamate is alkylaminocarbonyl radical having one or two (independently selected) alkyl Deputy who, he is illustratively and preferably represents methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, tert-butylaminoethyl, n-intramyocardial, n-mexiletineciclovir, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-n-propylaminosulfonyl, N-tert-butyl-N-methylaminomethyl, N-ethyl-N-n-intramyocardial and N-n-hexyl-N-methylaminoethanol.

Alkylaminocarbonyl is alkylaminocarbonyl radical having one or two (independently selected) alkyl substituent, it is illustratively and preferably represents methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, tert-butylaminoethyl, n-intramyocellular, n-exelonexelon, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-n-propylaminosulfonyl, N-tert-butyl-N-methylaminomethyl, N-ethyl-N-n-intramyocellular and N-n-hexyl-N-methylaminoethanol.

Alkylsulfonamides illustratively and preferably represents methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylbenzylamine, tert-butylsulfonyl, n-pentylaniline and n-GE is silaifolia.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-phenoxycarbonyl and n-hexoxyethanol. Alkoxycarbonyl illustratively and preferably represents methoxycarbonylamino, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonylamino, n-phenoxycarbonylamino and n-hexactinellida.

Alkanolamine illustratively and preferably represents acetylamino, ethylcarbodiimide.

Cycloalkyl itself and in cyclooctylamino, and cycloalkylcarbonyl is cycloalkyl group having, as a rule, 3-8 and preferably 5-7 carbon atoms, it is illustratively and preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cyclooctylamino is cyclooctylamino radical having one or two (independently selected) cycloalkyl deputies, he illustratively and preferably represents cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine.

Cycloalkylcarbonyl illustratively and preferably represents cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohex ylcarbonyl and cyclohexylcarbonyl.

The aryl itself and in arylamino, and arylcarbamoyl represents a mono - to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, it is illustratively and preferably represents phenyl, naphthyl and phenanthrene.

Arylamino is arylamino radical having one or two (independently selected) aryl substituent, it is illustratively and preferably represents phenylamino, diphenylamino, naphtylamine.

Arylcarbamoyl illustratively and preferably represents phenylcarbinol and afterburner.

Heteroaryl itself and in heteroarenes, and heteroarylboronic represents an aromatic mono - or bicyclic radical having generally 5 to 10 and preferably 5 or 6 atoms in the ring and up to 5 and preferably up to 4 heteroatoms selected from the group consisting of S, O and N, it is illustratively and preferably represents thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazoles, benzofuranyl, benzothiophene, chinoline, ethenolysis.

Heteroarenes is heteroarenes radical having one or two (independently selected) heteroaryl substituent, it is illustratively and preferably represents thienylene, pyrilamine, Pyrrhus is leelamine, thiazolidine, oxazolidine, imidazolidine, pyridylamino, pyrimidinamine, pyridinylamino, indoleamine, indazolinone, benzoguanamine, benzothiazinone, hyalinella, ethanolamine.

Heteroarylboronic illustratively and preferably represents thienylboronic, fullcarbon, pyrrolidinones, thiazolidinones, oxazolidinones, imidazolidinyl, pyridylcarbonyl, pyrimidinamine, pyridinylmethyl, indolocarbazole, indazolinone, benzofurazanyl, benzothiazolethiol, chinainternational, izohinolinove.

Heterocyclyl itself and heterocalixarenes represents a mono - or polycyclic, preferably mono - or bicyclic, non-aromatic heterocyclic radical having generally 4 to 10 and preferably 5 to 8 atoms in the ring and up to 3, and preferably up to 2 heteroatoms and/or heterogroup selected from the group consisting of N, O, S, SO and SO2. Heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to a 5-8-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms selected from the group consisting of O, N and S, such as illustratively and preferably, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolyl, piperidinyl, novolin is l, peligrosamente.

Heterocalixarenes illustratively and preferably represents a tetrahydrofuran-2-carbonyl, pyrrolidin-2-carbonyl, pyrrolidin-3-carbonyl, pyrrolidinecarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, perhydrophenanthrene.

The compounds of formula (I) according to the present invention may, but are not limited to, can be obtained by combining various known methods. In some embodiments implement one or more substituents, such as amino group, carboxyl group and hydroxyl group, compounds used as starting materials or intermediates, mainly protected by a protective group known to specialists in this field. Examples of protective groups described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New York 1999.

The compounds of formula (I) according to the present invention may, but are not limited to, to be obtained through the methods [A], [B] [C], [D], [E], [F], [G], [H] or [I], below.

[Method A]

The compounds of formula (I-a) (where R3and R4are as defined above, and R1arepresents a

in which n and Y are as defined above) can, for example, be obtained through the following procedures, in two stages.

1a, R3and R4are as defined above, and Z1represents a C1-6alkyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above) with compounds of the formula (III) (where R1ais the same as defined above, and L1represents a leaving group including, for example, halogen atom such as chlorine atom, bromine and iodine, azole, such as imidazole and triazole, and hydroxy).

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of solvents selected from those listed above may be mixed and used.

The reaction temperature may neoba is consequently to install depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

The reaction may preferably be carried out in the presence of a base, including, for example, sodium carbonate, potassium carbonate, pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline and others.

In the case where L1in the compounds of the formula (III) (where R1arepresents a

or

in which n and Y are as defined above) represents hydroxy, the compounds of formula (IV) (where R3, R4and Z1are as defined above, and R1arepresents a

or

in which n and Y are as defined above) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above) with compounds of the formula (III), using a binding agent including, for example, carbodiimide, such as N,N-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, benzotriazol-1 yloxy-Tris-pyrrolidinone hexaflurophosphate (PyBOP), diphenylphosphinite. N-hydroxysuccinimide, 1-hydroxybenzotriazole monohydrate (HOBt), and the like, can be used as a reaction accelerator.

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

On Stage A-2, the compounds of formula (I-a) (where R1a, R3and R4are as defined above) could the t can be obtained by removing the protective group Z 1compounds of the formula (IV) (where R1a, R3, R4and Z1are as defined above).

The removal of the protective group Z1can be done through the use of grounds, including, for example, sodium hydroxide, lithium hydroxide and potassium hydroxide, or acids, including, for example, HCl, HBr, triperoxonane acid and BBr3. Removing protection can also be carried out by hydrogenation using a catalyst such as palladium on coal and palladium hydroxide, when Z1represents benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl. Also, removing the protection can be implemented by use of a reagent, such as cerium ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), when Z1is a 4-methoxybenzyl or 3,4-dimethoxybenzyl.

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), su is epoxide, such as dimethylsulfoxide (DMSO), alcohols, such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water, and other. Optionally, two or more of solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

The compounds of formula (III) are commercially available or can be synthesized by conventional methods.

[Method B]

The compounds of formula (I-b) (where R3and R4are as defined above, and Z2represents a

in which n and Y are as defined above) can, for example, be obtained through the following procedures, in two stages.

At the Stage B-1, the compounds of formula (VI) (where R3, R4, Z1and Z2are as defined above) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above) with Conn what changes the formula (V) (where Z 2is such as defined above) using a reducing agent such as sodium triacetoxyborohydride.

The reaction may preferably be carried out in the presence of acid, such as acetic acid or hydrochloric acid, or a dehydrating agent such as molecular sieves.

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as 1,2-dichloroethane, ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

At the Stage B-2, the compounds of formula (I-b) (where R3, R4and Z2are as defined above) can be obtained by removing the protective group Z1compounds fo the formula (VI) (where R 3, R4, Z1and Z2are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (V) are commercially available or can be synthesized by conventional methods.

[Method C]

The compounds of formula (I-c) (where n, R3, R4and Y are as defined above) can, for example, be obtained through the following procedures, in two stages.

Stage C-1, the compounds of formula (VIII) (where n, R3, R4- , Y-and Z1are as defined above) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above) with compounds of the formula (VII) (where n and Y are as defined above).

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxide, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

Stage C-2, the compounds of formula (I-c) (where n, R3, R4and Y are as defined above) can be obtained by removing the protective group Z1compounds of the formula (VIII) (where n, R3, R4- , Y-and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (VII) are commercially available or can be synthesized by conventional methods.

[Method D]

The compounds of formula (I-d) (where n, R3, R4and Y are as defined above) can, for example, be obtained through the following procedures, in two stages.

At Stage D-1, the compounds of formula (X) (where n, R3, R4- , Y-and Z1are as defined above) can be the particular by reaction of compounds of formula (II) (where R 3, R4and Z1are as defined above) with compounds of the formula (IX) (where n and Y are as defined above and L2represents a leaving group including, for example, halogen atom, such as chlorine and bromine).

The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

Stage C-2, connect four is uly (I-d) (where n, R3, R4and Y are as defined above) can be obtained by removing the protective group Z1compounds of the formula (VIII) (where n, R3, R4- , Y-and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (IX) are commercially available or can be synthesized by conventional methods.

[Method E]

The compounds of formula (I-e) (where n, R3, R4and Y are as defined above and Q1represents-NH-, -N(C1-6alkyl)-, or-O-) may, for example, be obtained through the following procedures, in two stages.

At Stage E-1, the compounds of formula (XII) (where n, Q1, R3, R4- , Y-and Z1are as defined above) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above), compounds of formula (XI) (where n, Q1and Y are as defined above) and the agent, including, for example, derived uriformat, such as phenyl chloroformate; derived halogenocarboxylic, such as phosgene, diphosgene and triphosgene; derived carbanilate, such as 1,1-carbonyldiimidazole (CDI) and 1,1'-carbonelli(1,2,4-triazole) (CDT), and the like.

The reaction can OS shall be carried out in a solvent, including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

The reaction may preferably be carried out in the presence of a base, including, for example, organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and others.

At Stage E-2, the compounds of formula (I-e) (where n, Q1, R3, R4and Y are as defined above) can be obtained p the means of removal of the protective group Z 1compounds of the formula (XII) (where n, Q1, R3, R4- , Y-and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (XI) are commercially available or can be synthesized by conventional methods.

[Method F]

The compounds of formula (I-f) (where R1and R4are as defined above), can be obtained through the following procedures.

At Stage F-1, the compounds of formula (XIII) (where R1, R4and Z1are as defined above) can be obtained by reaction of compounds of the formula (II-a) (where R4and Z1are as defined above) in a manner similar to that described in Stage A-1, B-1, C-1, D-1 and E-1.

At Stage F-2, the compounds of formula (XIV) (where R1, R4and Z1are as defined above) can be obtained by reduction of compounds of formula (XIII) (where R1, R4and Z1are as defined above) by hydrogenation using a catalyst such as palladium on coal and platinum on charcoal, in the presence of a base such as potassium acetate.

The reaction may be carried out in a solvent including, for example, ethers, such as simple di is tilby ether, simple isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water, and other.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

At Stage F-3, compounds of formula (I-f) (where R1and R4are as defined above) can be obtained by removing the protective group Z1compounds of the formula (XIV) (where R1, R4and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

[Method G]

The compounds of formula (I-g) (where R1and R4are as defined above, and R3'has the same meaning as R3as defined above, except hydrogen and halogen), can be obtained through the following procedures.

At Stage G-1, the compounds of formula (XVI) (where R1, R3', R4and Z1are as defined above) mo the ut can be obtained by reaction of compounds of formula (XIII) (where R 1, R4and Z1are as defined above) with compounds of the formula (XV) (where R3'is such as defined above).

The reaction can be carried out without solvent or in a solvent including, for example, ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

The reaction may preferably be carried out in the presence of a base, including, for example, organic amines such as pyridine, triethylamine, N,N-diisopropylethylamine, dimethylaniline, IER is ranelin and others.

At Stage G-2, the compounds of formula (I-g) (where R1, R3'and R4are as defined above) can be obtained by removing the protective group Z1compounds of the formula (XVI) (where R1, R3', R4and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

[Method H]

The compounds of formula (I-h) (where R3and R4are as defined above, R1arepresents a

or

in which n and Y are as defined above, and Z3represents hydrogen or C1-5alkyl) can also be obtained through the following procedures.

At Stage H-1, the compounds of formula (XVIII) (where R3, R4, Z1and Z3are as defined above) can be obtained by reaction of compounds of formula (II) (where R3, R4and Z1are as defined above) with compounds of the formula (XVII) (where Z3is such as defined above) in a manner similar to that described in Stage B-1, to obtain compounds of the formula (VI).

At Stage H-2, the compounds of formula (XIX) (where R1a, R3, R4, Z1and Z3are as defined above) can the be obtained by reaction of compounds of formula (XVIII) (where R 3, R4, Z1and Z3are as defined above) with compounds of the formula (III) (where R1aand L1are as defined above) in a manner similar to that described in Stage A-1, to obtain compounds of the formula (IV).

At Stage H-3, compounds of formula (I-h) (where R1a, R3, R4and Z3are as defined above) can be obtained by removing the protective group Z1compounds of the formula (XIX) (where R1a, R3, R4, Z1and Z3are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (XVII) are commercially available or can be synthesized by conventional methods.

[Method I]

The compounds of formula (I) (where R1, R2, R3and R4are as defined above) can be obtained by the following procedures.

On Stage 1-1, the compounds of formula (XXII) (where R1, R2, R3, R4and Z1are as defined above) can be obtained by reaction of compounds of formula (XX) (where R1, R2, R3, R4and Z1are as defined above) with compounds of the formula (XXI).

The reaction may be carried out in a solvent, including the traveler, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); the sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction may preferably be carried out in the presence of a base, including, for example, organic amines such as triethylamine and N,N-diisopropylethylamine and others.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

At Stage I-2, the compounds of formula (XXIII) (where R1, R2, R3, R4and Z1are as defined above) can be obtained pore the means of interaction of the compounds of formula (XXII) (where R 1, R2, R3, R4and Z1are as defined above).

The reaction may be carried out in the presence of the agent, including, for example, an acid such as hydrochloric acid and triperoxonane acid, triperoxonane anhydride, or POCl3, and the like.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

Stage 1-3, the compounds of formula (I) (where R1, R2, R3and R4are as defined above) can be obtained by removing the protective group Z1compounds of the formula (XXIII) (where R1, R2, R3, R4and Z1are as defined above) in a manner similar to the Stage A-2, to obtain the compounds of formula (I-a).

The compounds of formula (XX) and (XXI) are commercially available or can be synthesized by conventional methods.

Obtaining input connections

The compounds of formula (II-c) (where R3', R4and Z1are as defined above) can, e.g. the, to be obtained through the following procedures, in two stages.

At Stage i-1, compounds of formula (XXIV) (where R4and Z1are as defined above) interact with the compounds of the formula (XV) (where R3'is the same as defined above), to obtain the compounds of formula (XXV) (where R3', R4and Z1are as defined above).

The reaction can be carried out without solvent or in a solvent including, for example, ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-organic (NMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxidov, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours,and preferably, from 1 to 12 hours.

The reaction may preferably be carried out in the presence of a base, including, for example, organic amines such as pyridine, triethylamine, N,N-diisopropylethylamine, dimethylaniline, diethylaniline and others.

At Stage i-2, the compounds of formula (II-c) (where R3', R4and Z1are as defined above) can be obtained by reduction of the nitro group of compounds of formula (XXV) (where R3', R4and Z1are as defined above) with the use of the agent, including, for example, metals such as zinc and iron, in the presence of an acid such as hydrochloric acid and acetic acid, and chloride of tin, or by hydrogenation using a catalyst such as palladium on coal and platinum on coal.

The reaction may be carried out in a solvent including, for example, ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water, and other.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not Ogre is nicias this, approximately 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

The compounds of formula (II-a) (where R4and Z1are as defined above) can be obtained by reduction of the nitro group of compounds of formula (XXIV) (where R4and Z1are as defined above) in a manner similar to that described in Stage i-2, to obtain compounds of the formula (II-c), as shown in Stage i-3.

The compounds of formula (II-b) (where R4and Z1are as defined above) can be obtained through the recovery of the chlorine group and the nitro group of compounds of formula (XXIV) (where R4and Z1are as defined above) by hydrogenation using a catalyst such as palladium on coal and platinum on charcoal, in the presence of a base such as potassium acetate, as shown in Stage i-4.

The reaction may be carried out in a solvent including, for example, ethers, such as simple diethyl ether, simple, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water, and other.

Temperature reacts is and may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, preferably about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably from 1 to 12 hours.

Obtaining compounds of formula (XXIV)

The compounds of formula (XXIV) (where R4and Z1are as defined above) can, for example, be obtained by the following procedures.

Stage ii-1, the compounds of formula (XXVII) (where R4and Z1are as defined above) can be obtained by reaction of compounds of formula (XXVI) (where R4and Z1are as defined above) with compounds of the formula (XXI) in a manner similar to that described in Stage I-1, to obtain the compounds of formula (XXII).

Stage ii-2, the compounds of formula (XXIV) (where R4and Z1are as defined above) can be obtained by reaction of compounds of formula (XXVII) (where R4and Z1are as defined above) in a manner similar to that described in Stage I-2, to obtain the compounds of formula (XXIII).

Obtaining compounds of formula (XXVI)

The compounds of formula (XXVI) (where R4Z 1are as defined above) can, for example, be obtained by the following procedures.

Stage iii-1, the compounds of formula (XXVDI) (where R4and Z1are as defined above) can be obtained by reaction of compounds of formula (XXIX) (where R4is such as defined above) with compounds of formula (XXX) (where Z1is such as defined above, and Z4represents a C1-6alkyl).

The reaction may preferably be carried out in the presence of a base such as sodium methoxide.

The reaction may be carried out in a solvent including, for example, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol.

The reaction temperature may not necessarily be installed, depending on the connections that need to interact. The reaction temperature is usually, but not limited to, about 0°C-180°C, and preferably, about 20°C-100°C. the Reaction can be carried out, usually within 30 minutes to 24 hours and preferably 1 hour to 12 hours.

Stage iii-2, the compounds of formula (XXVI) (where R4and Z1are as defined above) can be obtained, for example, by reaction of compounds of formula (XXVIII) (where R4and Z1are as defined above) is relevant to the respective halogenation reagent, including, for example, POCl3, PCl5, and the like.

The reaction can be carried out without solvent or in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more solvents selected from those listed above may be mixed and used.

The reaction may preferably be carried out in the presence of a base, such as pyridine, triethylamine and N,N-diisopropylethylamine, N,N-dimethylaniline, diethylaniline and others.

The reaction temperature is usually, but not limited to, about 40°C-200°C, and preferably, about 20°C-180°C. the Reaction can be carried out, usually within 30 minutes to 48 hours, and preferably from 2 hours to 12 hours.

The compounds of formula (XXIX) are commercially available or can be synthesized by conventional methods.

Typical salts of the compounds shown by formula (I)include salts obtained by reaction of compounds of the present invention with a mineral or organic acid, or with organic or inorganic base. Such salts are known as salts of addition of acid and salt add bases respectively.

Acid for the formation of salts of addition of the acid include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, Hydrobromic acid, uudistoodetena acid, and the like, and organic acids such as, without limitation, p-toluensulfonate acid, methanesulfonate acid, oxalic acid, p-bromophenylacetate acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Salt add bases include salts derived from inorganic bases, such as, without limitation, ammonium hydroxide, a hydroxide of an alkali metal, hydroxides of alkaline earth metals, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, Tris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like.

The compound of the present invention or its salts, depending on his / her deputies, can be modified with esters of lower Akilov or other known esters; and/or GI is drugs or other solvate. Such ester, hydrate and solvate are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation, normal tablets, and tablets with integralnym coating, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols and emulsions. They can also be administered in parenteral forms such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like, forms, well known to experts in the field of pharmaceutics. Compounds of the present invention can be administered in intranasal form via topical application of appropriate intranasal carriers, or by percutaneous methods, using systems for percutaneous delivery, well known to specialists in this field.

The dosage when using compounds of the present invention selects one of the experts in this field, taking into account various factors, including, without limitation, age, weight, sex and medical condition of the patient, the severity of the condition that must be treated, the route of administration, the level of metabolic and excretory function of the patient used the dosage form, the specific compound and its salts

Compounds of the present invention preferably are prepared before the introduction together with one or more pharmaceutically acceptable excipients. Fillers are inert substances, such as, without limitation, carriers, diluents, flavouring agents, sweeteners, lubricants, soljubilizatory, suspendresume agents, binders, loosening agents and encapsulating material for tablets.

Another variant implementation of the present invention is a pharmaceutical preparation containing the compound of the present invention and one or more pharmaceutically acceptable excipients that are compatible with other ingredients of the drug and not harmful to the patient who receives it. The pharmaceutical preparations of the present invention receive through associations a therapeutically effective amount of the compounds of the present invention together with one or more pharmaceutically acceptable fillers for them. In the preparation of compositions according to the present invention the active ingredient can be mixed with a diluent, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The media can serve as a diluent, is which may be a solid, semi-solid, or liquid material which acts as a solvent, or may be in the form of tablets, pills, powders, pellets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10 wt.% active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

For oral administration the active ingredient may be combined with oral and non-toxic pharmaceutically acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose and the like; optionally, together with loosening agents, such as, without limitation, corn starch, methylcellulose, agar, bentonite, xanthan gum, alginic acid and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic resins, synthetic resin of acacia, resin tragakant, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, with lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, is takenaway acid, the sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In the form of a powder carrier can be a finely dispersed solid material, which is mixed with finely dispersed active ingredient. The active ingredient can be mixed with a carrier having binding properties, in appropriate proportions, and computerbase in the shape and dimensions desired for the production of tablets. The powders and tablets preferably contain from about 1 to about 99 percent of the mass of the active ingredient, which is a new composition according to the present invention. Suitable for use with solid carriers are magnesium carboxymethylcellulose, low melting wax, and cocoa butter.

Sterile liquid preparations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspendibility in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or in a mixture as sterile water, and sterile organic solvent.

The active ingredient may also be dissolved in an appropriate organic solvent, for example, in an aqueous solution of propylene glycol. Other compositions can be prepared by dispersing m is logispring active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or in a suitable oil.

The drug can be in the form of a standard single dose, which is a physically separate unit containing a unit dose suitable for administration to humans or other mammals. The standard form of a single dosage can be a capsule or tablet, or the number of capsules or tablets. Standard single dosage" represents a specified number of active compounds of the present invention, is designed to provide the desired therapeutic effect, in combination with one or more fillers. The amount of active ingredient in the standard unit dosage may change or be from about 0.1 to about 1000 milligrams or more in accordance with the specific appropriate treatment.

Typical oral dosages of the compounds of the present invention, when used for the indicated effects, will be in the range of from about 1 mg/kg/day to about 10 mg/kg/day. Compounds of the present invention can be administered in a single daily dose, or the total daily dose may be given in divided doses two, three or more times a day. When the delivery is performed through percutaneous forms, of course, the introduction is continuous.

EXAMPLES

The present invention b the children can be described as a form of examples, but they should not, in any case, be considered as the limits and borders of the present invention.

In the examples below, all quantitative data, unless otherwise stated, refer to the percent mass.

Mass spectra were obtained using technologies ionization elektrorazpredelenie (ES) (Micromass Platform LC). The melting temperature is not adjusted. Data of liquid chromatography - mass spectrometry (LC-MS) recorded on Micromass Platform LC with column Shimadzu Phenomenex ODS (diameter 4.6 mm × 30 mm) with elution with a mixture of acetonitrile-water (9:1 to 1:9) at a flow rate of 1 ml/min TLC carried out on the plate with pre-applied silica gel (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) is used for all separations using column chromatography. All chemicals are chemical quality and purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd., Great Britain, Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe hemical Ind. Ltd., Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Germany, Kanto Chemical Co., Ltd.

Spectra1H NMR recorded using either a spectrometer Bruker DRX-300 (300 MHz for1H), or Bruker 500 UltraShield™ (500 MHz to1H). Chemical shifts are recorded in ppm (ppm)with tetramethylsilane was (TMS)as internal standard at zero ppm of the binding Constants are (J) in Hertz, and abbreviations s, d, t, q, m, and width. refer to singlet, doublet, t is iplato, the Quartet, multiplet, and broadened peak, respectively. Determine the mass is realized by means of MAT95 (Finnigan MAT).

All starting materials are commercially available or can be obtained using methods cited in the literature.

The impact of these compounds are examined using the following assays and pharmacological studies.

EXAMPLE 1

[Line L1.2 cells, transfected with the human CRTH2]

cDNA human CRTH2 amplified from cDNA of human eosinophils using gene-specific primers containing restriction sites for cloning into the vector pEAK (Edge Bio Systems). cDNA CRTH2 human clone into expression vector pEAK mammal. This plasmid expression (40 µg) transferout in L1.2 cells, at a density of cells 1×107cells/500 μl, through the use of devices for steam formation (Gene Pulser II, BioRad)at 250 V/1000 UF. One day after transfection, puromycin (1 μg/ml, Sigma) is added to the Cup and cell culture. Two weeks after transfection, the grown cells are selected for further growth.

[Measurement of mobilization Ca2+line L1.2 cells, transfected with the human CRTH2] (Analysis 1)

Boot buffer Ca2+prepare by mixing 5 μl of Fluo-3AM (2 mm in DMSO, the final concentration of 1 μm (Molecular Probes) and 10 μl Pluroni F-127 (Molecular Probes) and diluting the mixture in 10 ml of buffer Ca 2+for analysis (20 mm HEPES pH of 7.6, with 0.1% BSA, 1 mm probenecid, Hanks solution). Cells transfetsirovannyh CRTH2, which are Example 1, washed with PBS, re-suspended in loading buffer Ca2+when 1×107cells/ml, and incubated for 60 min at room temperature. After incubation the cells are washed and re-suspended in buffer Ca2+for analysis, distributed in 96-well tablets with a transparent bottom (#3631, Costar)at 2×105cells/well. Cells incubated with different concentrations of the compounds for 5 minutes at room temperature. The fluorescence emitted at 480 nm, measured on the FDSS6000, the device for the measurement of Ca2+(Hamamatsu Photonics, Hamamatsu, Japan). Transfectant demonstrates induced PGD2the mobilization of Ca2+a concentration-dependent manner.

[Analysis of the binding of the receptor CRTH2 person] (Analysis 2)

The CRTH2 transfectants washed once with PBS and re-suspended in the buffer for binding (50 mm Tris-HCl, pH of 7.4, 40 mm MgCl2, 0,1% BSA, 0,1% NaN3). Then 100 μl of cell suspension (2×105cells) [3H]-labeled PGD2and various concentrations of the studied compounds are mixed in a 96-well polypropylene plate with a U-shaped bottom and incubated for 60 min at room temperature in order to make possible the implementation swazilan who I am. After incubation the cell suspension is transferred into a filter tablet (#MAFB, Millipore) and washed 3 times in buffer for binding. In the filter tablet add the scintillation material, and the radioactivity remaining on the filter was measured by TopCount (Packard)scintillation counter. Nonspecific binding is determined by incubating the cell suspension and [3H]-labeled PGD2in the presence of 1 μm unlabeled PGD2. Resistant to puromycin the L1.2 transfectants contact with [3H]-labeled PGD2with high affinity (KD=6,3 nm).

[Analysis of the migration of human eosinophils] (Analysis 3)

Polymorphically human cells isolated from heparinized venous blood of healthy donors by layering the blood on Mono-Poly Resolving Medium (ICN Biomedicals, Inc) and centrifuging it at 400×g for 30 min at room temperature. After centrifugation eosinophils purified from the lower layer polymorphically cells through CD16-negative selection using magnetic beads conjugated with anti-CD16 (Miltenyi Biotech GmbH).

Eosinophils man washed with PBS and re-suspended in buffer for chemotaxis (20 mm HEPES pH of 7.6, with 0.1% BSA solution Hanks), 6×106cells/ml Then fifty μl of cell suspension (3×105cells/well) are distributed in the upper chamber and 30 is CL solution of ligand (PGD 2, final concentration 1 nm) is added to the lower chamber of the 96-hole camera for chemotaxis (diameter = 5 μm, #106-5, Neuro Probe). The cells were pre-incubated with different concentrations of the investigated compounds at 37°C for 10 minutes. Then let be the chemotaxis in a humidified incubator at 37°C, 5% CO2within 2 hours. The number of cells migrating to the lower chamber, consider using a FACScan (Becton-Dickinson).

[Analysis of the migration of T cells CD4+person] (Analysis 4)

Menagerie human cells isolated from heparinized venous blood of healthy donors by layering the blood on Mono-Poly Resolving Medium (ICN Biomedicals, Inc) and centrifuging it at 400×g for 30 min at room temperature. After centrifugation T-lymphocytes CD4+clear of managernew cells through the use of a set for the allocation of T-cells CD4+(Miltenyi Biotec GmbH).

T-lymphocytes CD4+man washed with PBS and re-suspended in buffer for chemotaxis (20 mm HEPES pH of 7.6, with 0.1% BSA solution Hanks), 6×106cells/ml Then fifty μl of cell suspension (3×105cells/well) are distributed in the upper chamber, and 30 μl of a solution of the ligand (PGD2, final concentration 10 nm) is added to the lower chamber of the 96-hole camera for chemotaxis (diameter = 3 mm, #106-3, Neuro Probe). The cells were pre Inc. is berout at various concentrations of the compounds at 37°C for 10 minutes. Then let be the chemotaxis in a humidified incubator at 37°C, 5% CO2within 4 hours. The number of cells migrating to the lower chamber, consider using a FACScan (Becton-Dickinson).

The results of the analysis in the analysis 1 shown in the examples and tables, the Examples section, below. Data correspond to the compounds, as they are obtained by solid-phase synthesis, and thus, the levels of purity from about 40 to 90%. For practical reasons, the compounds are grouped into four activity classes as follows:

IC50=A(< or =)10 nm<B< or =)100 nm<C< or =)500 nm<d

Compounds of the present invention also exhibit excellent selectivity and strong activity in tests 2, 3 and 4 described above.

Z used for the melting temperature, in the next section, means decomposition. All inorganic acids and bases are aqueous solutions, unless approved otherwise. The eluent concentration is expressed as % vol./about.

Obtaining compounds

Methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate

4-Nitrophenylacetonitrile (81,07 g, 500 mmol) is suspended in EtOH (300 ml) and added dioxane (300 ml). After dissolution of all solids, dry gaseous HCl bubbled through the reaction mixture for 1 hour, then paramashiva the t at room temperature for 15 hours. Then add Et2O, and separated solids are collected by suction and washed with Et2O. This intermediate compound is dissolved in EtOH saturated NH3and the solution, thus obtained, was stirred at room temperature for 14 hours. The excess solvent is removed in vacuum, obtaining 2-(4-nitrophenyl)ethanamine hydrochloride (to 73.65 g, yield 68%) as a white powder.

To a mixture of triethyl 1,1,2-acontracorriente (3,51 ml, 15,30 mmol) and 2-(4-nitrophenyl)ethanamine hydrochloride (46,95 g, 217,72 mmol) in anhydrous MeOH (300 ml) at room temperature is added NaOMe (3,8,82 g, 718,49 mmol)and the resulting suspension is heated under reflux for 16 hours. After cooling to room temperature the reaction mixture was cooled to 0°C, acidified with 6 N. HCl and the separated solids are collected by suction and washed with cold water. Then drying in a high vacuum at 45°C for 6 hours to give methyl [4,6-dihydroxy-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (56,48 g, 81% yield) in the form of a dull-white powder.

To a suspension of methyl[4,6-dihydroxy-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (4.12 g, 12,89 mmol) in POCl3(24 ml) at room temperature and in an atmosphere of Ar added N,N-dimethylaniline (8,17 ml, 64,44 mmol)and the resulting dark suspension is heated under reflux for 16 cha is impressive. After cooling to room temperature the excess POCl3is evaporated, and the remaining dark residue is dissolved in EtOAc. Then, the organic layer washed successively with saturated NaHCO3water, and saturated salt solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product, thus obtained, was dissolved in CH2Cl2and passed through a thin layer of silica gel to obtain pure methyl[4,6-dichloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (2,98 g, yield 65%) as a white powder.

Methyl[7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate

A mixture of methyl[4,6-dichloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (2.0 g, 5.6 mmol), aminoacetaldehyde of dimethylacetal (0.68 g, 6.5 mmol) and diisopropylethylamine (1.5 ml, 8.4 mmol) in 1,4-dioxane (50 ml) was stirred at 80°C for 2 hours. The mixture is concentrated under reduced pressure. The residue is extracted with ethyl acetate. The extracts are washed with aqueous solution of NaHCO3and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified using preparative MPLC (liquid chromatography average efficiency (silica gel, hexane: ethyl acetate, 2/1), to obtain methyl[4-chloro-6-[(2,2-dimethoxymethyl)amino]-2-(4-nitrobenzyl)pyrimidine-5-yl]ACE the ATA (1.89 g, 79%) as a gray solid product.

Methyl[4-chloro-6-[(2,2-dimethoxymethyl)amino]-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (100 mg, 0,19 mmol) is treated with 50% triperoxonane acid/dichloromethane (5 ml) at room temperature over night. The mixture was poured into water and extracted with dichloromethane. The extracts are washed with aqueous solution of NaHCO3and saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is dissolved in dichloromethane (5 ml). To the solution add triperoxonane anhydride (0,053 ml, 0.38 mmol). The mixture is stirred at room temperature for 3 hours. The mixture was poured into water and extracted with dichloromethane. The extracts are washed with aqueous solution of NaHCO3and saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified using preparative TLC (silica gel, chloroform: ethanol, 19/1), with methyl[7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (22 mg, 25 %) as a colorless film.

Methyl[7-chloro-5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate

A mixture of methyl[7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (0,383 g, 1.06 mmol) and SnCl2·2H2O (1.44 g, 6,37 mmol) is suspended in EtOH (5 ml) at the temperature of reflux distilled for 1 hour is. After cooling to room temperature the reaction mixture was poured into a saturated aqueous solution of NaHCO3and EtOAc, and the resulting white suspension is filtered through a layer of Celite. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts washed with saturated salt solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo, to obtain methyl[7-chloro-5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (0,322 g, 92%).

Example 1-1

[7-Chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid

To a solution of methyl[7-chloro-5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (of 0.081 g, 0,243 mmol), 3,4-dichlorobenzoyl acid (0,070 g, 0,365 mmol) and WSCI (0,070 g, 0,365 mmol) in CH2Cl2(5 ml) is added N,N-diisopropylethylamine (to 0.127 ml, at 0.730 mmol). After stirring at room temperature for 20 hours, the reaction mixture is condensed under reduced pressure, to obtain crude product as a thick oil, which was purified using chromatography on silica gel, elwira 30% EtOAc in CHCl3with the receipt of methyl[7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate as a white solid product (0,100 g, 82%).

To a solution of methyl[7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]the of cetate (0,100 g, 0,199 mmol) in dioxane (1,00 ml) is added 6 N. aqueous solution of HCl (0.5 ml) and heated to 100°C for 22 hours. After cooling to room temperature, the volatile products are removed under reduced pressure, to obtain the residue which is suspended in water, collected by suction, washed with water and simple diethyl ether and dried in high vacuum to obtain [7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid as a white powder (0,020 g, 20%).

1H-NMR (500 MHz, DMSO-d6): δ of 3.96 (s, 2H), to 4.52 (s, 2H), 7,39 (d, J=8 Hz, 2H), 7,73 (d, J=1.5 Hz, 1H), 7,74 (l, J=8 Hz, 2H), to $ 7.91 (d, J=8 Hz, 2H), 8,13 (d, J=8 Hz, 2H), 8,19 (d, J=1.5 Hz, 1H), 10,48 (s, 1H), 12,71 (Sirs, 1H)

Melting point: 201 Z°C

Molecular weight: 488,85

Mass spectrometry: 489

The level of activity in vitro: B

In a manner similar to that described in Example 1-1, synthesize compounds in Examples 1-2 to 1-5, as shown in table 1.

Table 1
Example No.StructureMolecular massExact massMass spectrometryTPL(°C)Class activity
1-2489,75488489180ZA
1-3470,92470471204ZB
1-4446,90446447184ZA
1-5481,34480481205ZB

Methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate

A mixture of methyl[7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (150 mg, 0.42 mmol) and Pd/C (wet, 45 mg) in methanol (10 ml) - THF (5 ml) is stirred in hydrogen atmosphere (0.4 MPa) for 2 days. After removal of Pd/C by filtration through a layer of Celite, the filtrate contentresult vacuum. The crude product is purified using preparative TLC (silica gel, chloroform:methanol, 95/5, 0.1% triethylamine), with methyl[5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (16 mg, 13%) as a slightly yellowish solid product.

Example 2-1

[5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid

A mixture of methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (17 mg, 0.06 mmol), p-triftormetilfullerenov (0.01 ml, 0.07 mmol) and triethylamine (to 0.016 ml, 0.11 mmol) in dichloromethane (1 ml) was stirred at room temperature for 1 hour. The reaction is quenched with water and extracted with chloroform. The extracts washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified using preparative TLC (silica gel, chloroform:methanol, 95/5), with methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (21,5 mg, 80%) as a slightly yellowish solid product.

To a solution of methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (20 mg, 0.04 mmol) in methanol (1 ml) is added 1M aqueous NaOH solution (0.2 ml) at room temperature, and the mixture is stirred for 1 hour. After removal of methanol under reduced pressure to the residue we use the t water. The solution was washed with simple diethyl ether and neutralized with aqueous hydrochloric acid. The resulting precipitates are collected by filtration and dried under reduced pressure, to obtain[5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidine-8-yl]acetic acid (14,2 mg, 73%) as a slightly brownish solid product.

1H-NMR (500 MHz, DMSO-d6): δ is 3.82 (2H, s), 4,48 (2H, s), 7,38 (2H, d, J=8.5 Hz), 7,63 (1H, d, J=1,6 Hz), 7,72 (2H, d, J=8.5 Hz), 7,82 (1H, s), to $ 7.91 (2H, d, J=8,2 Hz), 8,08 (1H, d, J=1.3 Hz), to 8.12 (2H, d, J=7.9 Hz), 10,45 (1H, s), 12,48 (1H, Sirs)

Melting point: 205-207°C

Molecular weight: 454,41

Mass spectrometry: 453 (M-H)-, 455 (M+H)+

The level of activity in vitro: B

Diethyl 2-formylamino

To a mixture of sodium (1.66 g, 72,13 mmol) in simple diethyl ether (35 ml) add diethylamine (10 ml, 60,11 mmol) and ethyl formate (of 8.25 ml, 102,18 mmol)at room temperature, and the reaction mixture heated under reflux for 5 hours. After cooling to room temperature, water is added to the mixture up until the sodium has dissolved completely, and the aqueous layer was separated. The aqueous layer was neutralized with 6M hydrochloric acid (10,8 ml) and extracted with a simple diethyl ether. The extracts are washed with saturated solution of NaHCO3, dried over Sul is blockhead sodium, filter and concentrate under reduced pressure. The crude product is purified via distillation (115-120°C, 10 mmHg), to obtain diethyl 2-formylbenzoate (6,55 g, 54%) as a colourless oil.

Methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate

To a mixture of 2-(4-nitrophenyl)ethanamine hydrochloride (6,06 g, 28,12 mmol) and diethyl 2-formylbenzoate (6,54 g, 32,34 mmol) in methanol (100 ml) is added sodium methoxide (28% in methanol, and 11.2 ml, 56,25 mmol)at room temperature, and the reaction mixture stirred at 90°C during the night. After cooling to room temperature, the reaction is quenched with acetic acid (3,38 ml, 59,06 mmol) and add water (100 ml). The resulting precipitates are collected by filtration and washed with water and acetone/simple diisopropyl ether (3/2), with methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (5,41 g, 64%) as a brown solid product.

Methyl [4-chloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate

A mixture of methyl[4-hydroxy-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (4.0 g, 13,19 mmol), phosphorus oxychloride (x 6.15 ml, 65,95 mmol) and N,N-dimethylaniline (of 2.51 ml, 19,78 mmol) was stirred at 150°C for 3 hours. After removal of excess phosphorus oxychloride residue was dissolved with ethyl acetate. The organic layer is washed with water and Ishenim salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (hexane: ethyl acetate, 7/3), with methyl[4-chloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (2.70 g, 64%) as an orange solid product.

Methyl [5-(4-nitrobenzyl)imidazo[1,2-c)pyrimidine-8-yl]acetate

To a solution of methyl[4-chloro-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (2.70 g, 8,39 mmol) and aminoacetaldehyde of dimethylacetal (1,83 ml, 16.78 in mmol) in dioxane (40 ml) is added N,N-diisopropylethylamine (1,46 ml, 8,39 mmol). The mixture is stirred at 85°C for 1 day. After cooling to room temperature, the reaction is quenched with water and extracted with ethyl acetate. The extracts washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (ethyl acetate), to obtain methyl[4-[(2,2-dimethoxymethyl)amino]-2-(4-nitrobenzyl)-pyrimidine-5-yl]acetate (2,41 g, 74%) as a brown oil.

A solution of methyl[4-[(2,2-dimethoxymethyl)amino]-2-(4-nitrobenzyl)pyrimidine-5-yl]acetate (1,99 g, 2.56 mmol) and HCl (1,0 M in water, of 3.84 ml of 3.85 mmol) in dioxane (10 ml) was stirred at 85°C for 1 hour. After removal of the solvent in vacuum, to the residue water is added. An aqueous solution of n is italist with 1M NaOH and extracted with ethyl acetate. The extracts are washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. To the obtained crude product added phosphorus oxychloride (1.4 ml) and the mixture was stirred at 85°C for 3 hours. After removal of excess phosphorus oxychloride residue was dissolved with ethyl acetate. The organic layer is washed with water, saturated solution of NaHCO3and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (chloroform:methanol, 98/2), with methyl[5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (28 mg, 3%) as a brown oil.

Methyl (5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetate

A mixture of methyl[5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (28 mg, 0.09 mmol) and Pd/C (wet, 3 mg) in methanol (1 ml) is stirred under hydrogen atmosphere for 1 hour. After removal of Pd/C by filtration through a layer of Celite, the filtrate was concentrated in vacuo. The resulting crude methyl[5-(4-aminobenzyl)imidazo[1,2-c]pyrimidine-8-yl]acetate (26 mg, 0.09 mmol) was dissolved with dichloromethane (1 ml). To this solution was added 3,4-dichlorobenzoyl acid (20,1 mg, 0.11 mmol), 1-hydroxybenzotriazole (14,2 mg, 0.11 mmol) triethylamine (0.037 ml, 0.26 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (to 21.9 mg, 0.11 mmol)at room temperature. The mixture is stirred at room temperature overnight and diluted with ethyl acetate. The solution is washed with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified using preparative TLC (silica gel, chloroform:methanol, 19:1), to obtain methyl(5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetate (29 mg, 70%) as a slightly yellow oil.

Example 2-2

(5-{4-[(3,4-Dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetic acid

To a solution of methyl(5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetate (25 mg, 0.05 mmol) in methanol (1 ml) is added 1M aqueous NaOH solution (0.2 ml)at room temperature and the mixture is stirred for 1 hour. After removal of methanol under reduced pressure, to the residue water is added. The solution was washed with simple diethyl ether and neutralized with aqueous hydrochloric acid. The resulting precipitates are collected by filtration and dried under reduced pressure, to obtain (5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidine-8-yl)acetic acid (17,2 mg, 71%) as a slightly yellowish solid is the product.

1H-NMR (500 MHz, DMSO-d6): δ a 3.83 (2H, s), 4,48 (2H, s), 7,37 (2H, d, J=8.5 Hz), 7,63 (1H, d, J=1.3 Hz), of 7.70 (2H, d, J=8.5 Hz), 7,81 (1H, d, J=8.5 Hz), 7,82 (1H, s), 7,92 (1H, DD, J=1,9, 8.5 Hz), 8,08 (1H, d, J=1.3 Hz), 8,19 (1H, d, J=2.2 Hz), 10,38 (1H, s), 12,47 (1H, Sirs)

Melting point: 185-188°C

Molecular weight: 455,30

Mass spectrometry: 455 (M+H)+

The level of activity in vitro: C.

1. Derivative imidazo[1,2-C]pyrimidinemethanol acid of the formula (I) or its salt

where R1represents a
,
in which n is an integer from 0 to 6;
Y represents an aryl, where the specified aryl is optionally substituted at substitutable position by one or more substituents selected from the group consisting of halogen or C1-6the alkyl optionally substituted by mono-, di - or trihalogen;
R2represents hydrogen;
R3represents hydrogen or halogen; and
R4represents hydrogen.

2. Derived imidazo[1,2-C]pyrimidinemethanol acid of the formula (I) or its salt according to claim 1,
where R1represents a
,
in which n is an integer from 0 to 2;
Y is an aryl selected from the group consisting of phenyl and naphthyl, where is the th aryl is optionally substituted at substitutable position by one or more substituents, selected from the group consisting of halogen or1-6the alkyl, optionally substituted mono-, di - or trihalogen; and
R2represents hydrogen.

3. Derived imidazo[1,2-c]pyrimidinemethanol acid of the formula (I-i) or its salt

where R1represents a
,
in which n is an integer from 0 to 2;
Y represents phenyl or naphthyl,
where specified phenyl or naphthyl are optionally substituted at substitutable position with one or two substituents selected from the group consisting of halogen or1-6the alkyl, optionally substituted mono-, di - or trihalogen;
R2represents hydrogen;
R3represents hydrogen or halogen,
R4represents hydrogen.

4. Derived imidazo[1,2-C]pyrimidinemethanol acid of the formula (I) or its salt according to claim 1, where the specified derived imidazo [1,2-c]-pyrimidinemethanol acid of the formula (I) are selected from the group consisting of:
[7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-C]pyrimidine-8-yl]acetic acid;
(7-chloro-5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-C]pyrimidine-8-yl)acetic acid;
{7-chloro-5-[4-(2-naphthylamine)benzyl]imidazo[1,2-C]pyrimidine-8-yl}acetic acid;
[7-chlor-(4-{[(2E)-3-phenylprop-2-enoyl]]amino}benzyl)imidazo[1,2-C]pyrimidine-8-yl]acetic acid;
[7-chloro-5-(4-{[(2E)-3-(4-chlorophenyl)prop-2-enoyl]amino}benzyl)imidazo[1,2-C]pyrimidine-8-yl]acetic acid;
(5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-C]pyrimidine-8-yl)acetic acid; and
[5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-C]pyrimidine-8-yl]acetic acid.

5. Drug that has activity against CRTH2 containing derived imidazo[1,2-C]pyrimidinemethanol acid or its physiologically acceptable salt according to claim 1, as an active ingredient.

6. The drug according to claim 5, additionally containing one or more pharmaceutically acceptable excipients.

7. The drug according to claim 5, where the specified derived imidazo[1,2-C]pyrimidinemethanol acid of the formula (I) or its physiologically acceptable salt is an antagonist of CRTH2.

8. The drug according to claim 5 for the treatment and/or prevention of disorders or diseases associated with CRTH2 activity.

9. The drug of claim 8, where the specified disorder or disease selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis.

10. The drug of claim 8, where the specified disorder or disease selected from the group consisting of syndrome it continues-Strauss, sinusitis, basophilic leukemia, khron is over urticaria and basophilic leukocytosis.

11. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment and/or prevention of disorders or diseases associated with CRTH2 activity.

12. The drug according to claim 6, where the filler is chosen from carriers, diluents, flavouring agents, sweeteners, lubricants, solubilization, suspendida agents, binders, loosening agents, and encapsulating material for tablets.

13. The drug is indicated in paragraph 12, where the filler is a carrier selected from lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulphate and methyl cellulose.

14. The drug is indicated in paragraph 13, where the medicinal product, in addition, includes loosening agent selected from corn starch, methylcellulose, agar, bentonite, xanthan resin and alginic acid.

15. Drug for 14, where the carrier is in the form selected from tablets, pills, powders, lozenges, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, soft or hard gelatin capsules, suppositories, sterile injectable solution, and sterile packaged powder.

16. The drug is indicated in paragraph 12, where the excipient is a binder selected from gelatin, p is arodnogo sugar, beta-lactose, a sweetener, corn-based, natural or synthetic resins, Arabian, gums, tragakant, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.

17. The drug is indicated in paragraph 12, where the filler is a lubricating substance selected from magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and talc.

18. The drug according to claim 5, where the amount of active ingredient is from about 1 to about 99 wt.% calculated on the total weight of the pharmaceutical composition.

19. The drug is in the form of a standard unit dosage containing a derivative of imidazo[1,2-C]pyrimidinemethanol acid or its physiologically acceptable salt defined in claim 1, as active agent, where the amount of active agent is from 0.1 to about 1000 MMG.

20. The application of claim 11, where the specified disorder or disease is a asthma, allergic rhinitis, atopic dermatitis or allergic conjunctivitis.

21. The application of claim 11, where the specified disorder or disease is a syndrome it continues-Strauss, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis.

22. Derived imidazo[1,2-C]pyrimidinemethanol acid according to claims 1-4, not only the abuser a compound of formula (I).

23. Derived imidazo[1,2-C]pyrimidinemethanol acid according to claims 1 to 4, in the form of a salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: pharmacology.

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

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

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: according to the invention there is provided substituted indolequinoxalines of the formula (I), where R1 represents hydrogen or represents one or more similar or different substituent in positions from 7 to 10, selected of the group of halogen, low alkyl/alkoxy, hydroxy, triflouromethyl, trichloromethyl, triflouromethoxy, R2 represents similar or different C1-C4 alkyl substituents, X represents CO or CH2, Y represents OH, NH2, NH-(CH2)n-R3, where R3 represents low alkyl, OH, NH2, NHR4 or NR5R6, where R4, R5 and R6 represent low alkyl or cycloalkyl independently and n represents integer from 2 to 4 provided that X represents CH2, Y represents OH or NH-(CH2)n-OH and its pharmaceutically acceptable salt. There is also provided pharmaceutical composition, containing these compounds, methods of compound producing, formula (I).

EFFECT: compounds are applied as medicine for treatment and prevention of autoimmune diseases.

15 cl, 1 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to antagonists of serotonin 5-HT6 receptors - substituted 4-sulphonylpyrazoles and 3-sulphonyl-pyrazolo[1,5-a]pyrimidines of general formula 1 or general formula 1.2. These compounds can be used for treating and preventing development of different cognitive and neurodegenerative diseases of the central nervous system. In general formulae 1 and 1.2, 1 1.2 respectively, Ar is optionally substituted phenyl or optionally substituted 5-6-member heteroaryl, containing a nitrogen, oxygen or sulphur atom as a heteroatom; R1 is a hydrogen atom, optionally substituted C1-C5 alkyl, lower acyl or optionally substituted phenyl; R2 is an optionally substituted amino group or substituted hydroxy group or R1, together with the nitrogen atom to which it is bonded, and R2, together with the carbon atom to which it is bonded, form a substituted pyrimidine ring; R3 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R5 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R7 and R9 independently represent a hydrogen atom, C1-C3alkyl or phenyl, R8 is a hydrogen atom.

EFFECT: new compounds have useful biological properties.

13 cl, 2 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: new derivative of diaminopyrroloquinazolines of formula (I) and their pharmaceutically acceptable salts possess properties of proteintyrosine posphatase PTP1 inhibitors which can be used for treating the diseases mediated by action of the latter, particularly for decreasing glucose content in blood. In formula (I) , A stands for 6-membered aromatic ring, or 5- or 6-membered aromatic ring which contains 1 or 2 heteroatoms chosen from S, N and O; R1 is specified from the group including the following radicals: C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl), benzyloxyC1-6alkyl and phenyl-(C1-6alkoxy)C1-6alkyl; R2 is specified from the group including the following radicals: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl) and phenyl-(C1-6alkoxy)C1-6alkyl; R3 represents hydrogen or methyl; Ra is specified from the group including the following radicals: hydrogen, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl(C1-6alkyl), benzyloxyC1-6alkyl or ; R10 represents hydrogen or ; x and y separately stand for integers 0 to 4; Rb and Rc are separately specified from the group including the following radicals: hydrogen, C1-6alkyl, perfluorochemical C1-6alkyl, substituted C1-6alkyl, C1-6alkoxy, phenoxy, halogen, (unsubstituted C1-6alkyl)-(substituted phenyl)-(C1-6alkyl), phenyl-(C1-6alkoxy) or ; R11 represents hydrogen, phenyl or unsubstituted C1-6alkyl; p stands for integer 0 to 1; Rd represents hydrogen, substituted C1-6alkyl or perfluorochemical C1-6alkyl; Re represents hydrogen, halogen, substituted C1-6alkyl and perfluorochemical C1-6alkyl; Rf represents hydrogen or C1-6alkyl; the substitutes found in alkyl groups are independently specified from the following groups: hydroxy, C1-6alkoxy, C1-6alkanoyl; and the substitutes found in substituted phenyl as Rb and Rc, are independently specified from the following groups: C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, hydroxyl, hydroxylC1-6alkoxy, halogen, perfluorC1-6alkyl and C1-6alkanoyl.

EFFECT: improved properties of the derivatives.

29 cl, 2 dwg, 48 ex

FIELD: medicine.

SUBSTANCE: invention covers new pyrrolopyrimidine and pyrrolotriazine derivatives substituted with carbamoyl group of formula [I], characterised as a CRF (corticotrophin release factor) receptor antagonist. The compounds can be effective as a therapeutic or preventive agent for such diseases, as depression, anxiety, Alzheimer's disease, Parkinson's disease, etc. in formula [I]: E means N or CR10; R1 means -OR4, -S(O)1R4 or-NR4R5; R2 means hydrogen, C1-6alkyl; R3 means hydrogen; R4 and R5 are identical or different, and independently mean hydrogen, C1-9alkyl, di(C3-7cycloalkyl)-C1-6alkyl, C1-6alkoxy-C1-6alkyl, di(C1-6alkoxy)-C1-6alkyl, hydroxy-C1-6alkyl, cyano-C1-6alkyl, carbamoyl-C1-6alkyl or di(C1-6alkyl)amino-C2-6alkyl, or R4 and R5 together form (CH2)m-A-(CH2)n where A means CHR9; R9 means hydrogen, hydroxy-C1-6alkyl, or cyano-C1-6alkyl; R10 means hydrogen; I means an integer 0, 1 and 2; m means an integer 1, 2, 3 and 4; n means an integer 0, 1, 2 and 3; Ar means phenyl, and specified phenyl is substituted by one or more substitutes being identical or different, and chosen from the group consisting of halogen, C1-6alkyl, trifluoromethyl; their individual isomers or pharmaceutically acceptable salts.

EFFECT: extended application.

9 cl, 2 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I where R1 stands for phenyl; G stands for C1-C7-alkylene; Q stands for -NH-; and X stands for C1-C7- alkylene, or to its salts. In addition, the invention concerns a pharmaceutical composition, to application of compound of formula I as defined in claims 1-5 item, as well as the method for making the compound of formula I.

EFFECT: production of the new biologically active compounds inhibiting protein tyrosine kinase.

8 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

FIELD: medicine.

SUBSTANCE: there are disclosed polypeptide variants containing Fc-areas IgG, having amino acid modifications providing changed effector functions Fc in specified polypeptides. There is disclosed composition for antibody targeting on antigen, containing the specified polypeptide. There is described method for preparing the specified polypeptide. Also, there are disclosed the methods for treating V-cell tumour or a malignant disease characterised by V-cell expression of CD20, treating chronic lymphocytic leukosis, relieving the symptoms of the V-cell controlled autoimmune disease, treating a angiogenesis-associated disorder, treating HER2-expressing cancer, treating LFA-1-mediated involvement, treating IgE-mediated involvement wherein specified methods imply introduction to the patient of the therapeutically effective amount of said polypeptide.

EFFECT: higher clinical effectiveness.

63 cl, 6 ex, 13 dwg, 10 tbl

FIELD: medicine.

SUBSTANCE: treating allergies is ensured by introduction of antiprotozoan preparations and probiotics, including at first "Balance Narine-F", then "Narine". To prevent re-infection of the patient, antiprotozoan preparations are used to treat persons being in contact with him.

EFFECT: reduced time and improved clinical effectiveness due to normalisation of microbial balance and recovery of enzyme intestinal system that acts the important part in allergic pathogenesis.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to dimetansulphonate N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, method of producing thereof, pharmaceutical compositions based on the said compound and a peroral pharmaceutical composition.

EFFECT: wider field of use of the compounds.

9 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: present invention concerns area of medical products, in particular, to a pharmaceutical composition in the form, suitable for introduction in a nose or eyes, containing from 0.0005 to 2% of azelastin hydrochloride in a combination with from 0.5 to 1.5 % of fluticasone or its ester. The invention also concerns a pharmaceutical product containing (i) azelastin hydrochloride and (ii) fluticasone, represented in the form of an aerosolic composition for delivery by means of MDI (a dosing out inhaler), in the form of a insufflation powder or in the form of a nasal spray.

EFFECT: stability improvement, and also maintenance of the improved efficiency of a medical product.

27 cl, 14 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) or its pharmaceutically acceptable salt where radicals R1, R2, n1 and n2, Y and X are valued in the description, R3 stands for heterocyclic group of corollary formula (bb) (specified below). These compounds are phosphodiesterase (PDE) inhibitors, particularly PDE4 inhibitors. There is also disclosed production process of pharmaceutical compositions containing compound of formula or its pharmaceutically acceptable salt as an active component, and their application in manufacturing of a medicine for treatment and/or prevention of inflammatory and/or allergic disease in mammals, including humans, e.g. asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, allergic rhinitis, rheumatoid arthritis, disseminated sclerosis, Alzheimer's disease, depression or pain in mammals, including humans.

EFFECT: higher effectiveness of the composition and medication therapy.

20 cl, 686 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula 1: where R1 stands for cycloalkyl containing 3 to 10 carbon atoms, R2 stands for alkyl containing 1 to 4 carbon atoms, R3 stands for pyridylmethyl, R4 stands for phenyl unsubstituted or substituted with carboxy-, cyanogroup or alkoxycarbonyl; or to its pharmaceutically acceptable salts provided the specified compounds is not 4-(2-chlor-4-methoxyphenyl)-5-methyl-2-[N-(1-propylindazole-6-yl)-N-propylamino]thiazole where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures, or to compounds of formula II: where R3 stands for hydrogen or pyridylmethyl, R4 stands for hydrogen or phenyl unsubstituted or substituted with carboxy-, cyanogroup, alkoxycarbonyl, tetrazole-5-yl or phenylsulphonyl aminocarbonyl; R7 stands for alkoxygroup containing 1 to 4 carbon atoms being branched or nonbranched; R8 stands for -CO-C1-4- alkyl or dioxanyl, and at least one of R3 and R4 is different from hydrogen, or to its pharmaceutically acceptable salts where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures. Additionally, the invention refers to pharmaceutical enzyme PDE4, based on compounds of formula I and II and to their application for producing medical products for enzyme PDE4 inhibition in treatment of various diseases.

EFFECT: compound improvement.

35 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of formula (I) , where X is O or S; R1 is C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylmethyl, any of which can be optionally substituted by one or more methal groups or halogen atoms, or R1 is 4-(diethylamino)sulfonylphenyl, 2,6-difluorophenyl, 4-methoxyphenyl, 4-cyanomethyl, 3-difluoromethylthiopnehyl, 5-chloro-4-methoxy-thiophene-3-yl, 2-isopropyl-1,3-thiazol-4-yl, quinoline-2-yl, 5-trifluoromethyl-furan-2-yl, 5-methylsulfonyl-thiophene-2-yl, 5-methylthio-thiophene-2-yl, or 5-ethylisoxazene-2-yl; R2 is hydrogen, methyl which can be either in α- or β-configuration; R3 and R4 are the same or different, each is independently hydrogen, halogen, and is simple or double link; or its pharmaceutically acceptable salt or solvate.

EFFECT: obtaining compound with glycocorticosteroid effect.

20 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: description is given of diazepane derivatives with formula I where R1 stands for C1-C4alkyl, R2 stands for unsubstituted C1-C4alkyl or C1-C4alkyl, substituted with quinolinyl, benzo[1,3]dioxolyl, phenyl, phenyl, substituted with 1-3 substitutes, chosen from a group, comprising halogen, halogen(C1-C4)alkyl, C1-C4alkoxy, cyano, amino, dimethylamino, carboxy(C1-C2)alkylcarbonylamino, amino(C1-C2)alkylcarbonylamino, C2-C4alkylenecarbonylamino, heterocyclylcarbonyl(C1-C2)alkylcarbonylamino, where heterocyclyl contains 6 atoms in the ring and 2 heteroatoms, chosen from N or N and O, R3 stands for phenyl, substituted with one or two substitutes, chosen from a group, comprising halogen, halogen(C1-C6)alkyl, halogen(C1-C6)alkoxy, cyano, phenyl or aromatic heterocyclyl, containing 6 atoms in a ring and two nitrogen heteroatoms.

EFFECT: obtaining compounds with inhibiting effect on LFA-1/ICAM-1.

6 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medical products and covers applications of O- and S-glycosides 5-hydroxy-1,4-naphthoquinone (judlone) derivatives of formula 1 as an agent that stimulates human leukaemia cell apoptosis. Disclosed compounds selectively stimulate human leukemia cell apoptosis as comparrf with a prototype juglone without affecting normal cells of human immune system (neutrophils).

EFFECT: invention allows extending range of products selectively stimulating leukaemia cell apoptosis.

4 cl, 13 dwg, 5 tbl, 14 ex

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