Aminobenzophenones as inhibitors of il-1-beta and tnf-alpha, pharmaceutical composition and method for treatment and/or prophylaxis of inflammatory disease

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

 

The technical field to which the invention relates.

The present invention relates to a previously unknown class of compounds that have anti-inflammatory effects, to pharmaceutical preparations containing these compounds, to a standard dosage forms of these drugs and their use in the treatment and prevention of asthma, allergies, arthritis, including rheumatoid arthritis and spondylarthritis, gout, atherosclerosis, chronic inflammation of the intestine (Crohn's disease), proliferative and inflammatory skin diseases such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS, and acne.

Background of invention

Previously described series of closely related aminobenzophenone (for example, 4-(2-amino-4-nitrophenylamino)benzophenone) (Hussein, F.A. et al., Iraqi J. Sci., 22, 54-66 (1981)). However, there was no description of their use. In PCT/DK98/00008 disclosed aminobenzophenone the secretion inhibitors 1β-interleukin (IL-1β) and α-necrosis factor tumor cells (TNF-α) in vitro, and these compounds are potentially useful for the treatment of inflammatory diseases, which are involved in the pathogenesis of cytokine production, for example, asthma, rheumatoid arthritis, psoriasis, contact dermatitis and atopic dermatitis. In addition, the compounds of document PCT/DK98/00008 would and investigated in vivo in the presence of anti-inflammatory properties in mice with chronic inflammation of the skin, induced by 12-O-tetradecanoylphorbol-13-acetate (TN) (De Young, L.M. et al., Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al., Agents Actions 17, 197-204 (1985); Alford J.G. et al., Agents Actions, 37 (1992); Stanley, P.L. et al., Skin Pharmacol, 4, 262-271 (1991)). In this model of chronic skin inflammation compounds had the same activity as the standard connection hydrocortisone.

The aim of the present invention to provide other pharmacologically active derivatives of aminobenzophenone and related compounds.

This goal was achieved in the development of new derivatives of aminobenzophenone General formula I which are potent inhibitors of secretion 1β-interleukin (IL-1β) and α-necrosis factor tumor cells (TNF-α) in vitro, which makes these compounds potentially useful for the treatment of inflammatory diseases, the pathogenesis of which involves the secretion and regulation of cytokines, or, more specifically, 1β-interleukin (IL-1β) and α-necrosis factor tumor cells (TNF-α). The inhibition or regulation of cytokines by type of negative feedback may be due to the inhibition of MAP-kinase.

Brief description of the invention

Compounds according to the present invention, describes a General formula I

where R1and R2indicate independently one or more of the same is x or different substituents, selected from the group consisting of halogen, hydroxy, mercapto, trifloromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl or nitro; R2can also denote hydrogen;

R3denotes hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy or carbarnoyl;

R4denotes hydrogen, (C1-C3)alkyl or allyl;

Q represents a bond, -SO2- or-C(R6) (R7) (-O-C=O)-, where R6and R7independently denote hydrogen, trifluoromethyl or (C1-C4)alkyl;

Y denotes (C1-C15)alkyl, (C2-C15)olefinic group, (C3-C10)carbocyclic group, or phenyl, each of which may be optionally substituted by one or more identical or different substituents, denoted by the formula, R5; or Y represents a group of formula -(Z-O)n-Z, where Z denotes a (C1-C3)alkyl and n denotes an integer >1 and a continuous lean is ina sequence of atoms in the group Y does not exceed 15;

R5denotes halogen, hydroxy, mercapto, trifluoromethyl, (C1-C4)alkyl, amino, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, azido, nitro, -COOH, -CONH2, -CONHR’ or-CONRR’, where R and R’ denote (C1-C3)alkyl; X represents oxygen or sulfur, or their pharmaceutically acceptable salts, or their hydrate or solvate.

Detailed description of the invention

Preferred embodiments of the inventions

Preferably in the compounds according to the present invention R1represents one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, trifloromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C2)alkoxycarbonyl or cyano; R2represents one or more identical or different substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy, trifloromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy; R3represents one or more identical or different substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy of trifloromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano or carboxy; R4denotes hydrogen, (C1-C2)alkyl or allyl; X represents oxygen; Q represents a bond or-SO2-; Y represents (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (C5-C8)cycloalkenyl group or phenyl, each of which may be optionally substituted by one or more identical or different substituents selected from the group consisting of compounds of the formula R5defined below, and R5denotes fluorine, chlorine, bromine, hydroxy, amino, (C1-C2)alkoxy, (C1-C4)alkylamino, (C1-C3)alkoxycarbonyl, cyano, azido, -COOH, -CONH2, -CONHR’ or-CONR'R’, where R’ denotes a (C1-C1)alkyl.

More preferred compounds of formula I in which R1represents one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, methyl or methoxy; preferably, R1denotes methyl and most preferably, 2-methyl; R2represents one or more identical or different substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy, METI is a or methoxy, preferably, R2denotes Cl and, most preferably, 2-CL; preferably, R3denotes hydrogen, methyl, methoxy, fluorine, chlorine or bromine; R4represents hydrogen; Y represents C1-C6)alkyl, (C3-C7)cycloalkyl or phenyl, each of which may be optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, amino, azido, (C1-C3)alkyl, (C1-C2)alkoxycarbonyl, cyano, -COOH, -N2and-CON(CH3)2. Most preferably, Y represents methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, hexyl, 6-chlorhex, -(CH2)2SOON2CH3, -(CH2)2COOH, tolyl or phenyl.

Other preferred compounds of General formula I are compounds in which R1, R2and R3designate one Deputy. R1and R2preferably located in the ortho-position.

Specific compounds of formula include:

1-cyclohexyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 101),

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 102),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-phenylacetone (compound 103),

1-butyl-3-[2-[3-chloro-4-(2-methylben the oil)phenylamino]phenyl]-urea (compound 104),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-(4-methylphenylsulfonyl)urea (compound 105),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-(phenylsulfonyl)urea (compound 106),

1-tert-butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 107),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-Isopropylamine (compound 108),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-populatemenu (compound 109),

1-methyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]urea (compound 110),

Ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-ureido)propionate (compound 111),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 112),

3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]ureido)propionic acid (compound 113),

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-5-forfinal]urea (compound 114),

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-N-methylpentylamino]-5-forfinal]urea (compound 115),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 116),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl]urea (compound 117),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 118),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 19),

1-ethyl-3-[5-bromo-2-[3-ethoxy-4-(2-methylbenzoyl)phenylamino]phenyl]urea (compound 120),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 121),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)phenylamino]phenyl]urea (compound 122),

1-ethyl-3-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 123),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]urea (compound 124),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 125),

1-ethyl-3-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 126), and their salts with pharmaceutically acceptable acids, hydrate or solvate.

In the present description, unless otherwise specified, the terms used have the following values.

The term “alkyl” refers to any univalent group derived from an alkane when removing a hydrogen atom from any carbon atom, which includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups, respectively, and contains the specified number of carbon atoms, including, for example, (C1-C3)alkyl, (C1-C4)alkyl, (C5)alkyl, (C5-C15)alkyl, (C6-C10)alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl is t-butyl. The term “alkane” refers to an acyclic branched or unbranched hydrocarbon having the General formula CnH2n+2i.e. consisting entirely of hydrogen atoms and saturated carbon atoms.

The term “olefinic group” refers to linear or branched acyclic hydrocarbon having one or more carbon-carbon double bonds in the spatial orientation of E or Z, where applicable, and with the specified number of carbon atoms. The term includes, for example, (C2-C15) olefinic group, preferably a (C2-C15)alkenyl, (C2-C3) olefinic group, preferably a (C2-C3)alkenyl, vinyl, allyl, 1-butenyl, 2-butenyl and 2-methyl-2-propenyl. The preferred olefinic group having only one carbon-carbon double bond, referred to in the present description by alkenylamine.

The term “alkoxy” includes, in a broad sense, a radical of the formula-OR, where R is alkyl, as defined above, for example, (C1-C3)alkoxy, (C1-C2)alkoxy, methoxy, ethoxy, n-propoxy, etc.

The term “(1-C3)alkylthio” covers a broad sense, a radical of the formula-SR, where R is alkyl, as defined above, and includes methylthio, ethylthio, n-propylthio and 2 property.

The term “(1-C6)alkylamino” cover the displays in a broad sense, a radical of the formula-or other-NR 2where R denotes an alkyl, as defined above, which contains 1-6 carbon atoms and includes, for example, methylamino, dimethylamino, di-(n-propyl)amino and n-butyl(ethyl)amino.

The term “(1-C3)alkoxycarbonyl” covers a broad sense, a radical of the formula-COOR, where R is alkyl, as defined above, and includes methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl and isopropoxycarbonyl.

The term “(3-C10)monocyclic hydrocarbon group includes saturated cycloalkanes and unsaturated cyclic olefins, such as cycloalkane that have a double bond inside the loop and 3-10 carbon atoms and include, for example, (C3-C8)cycloalkyl, cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl, (C6-C10)cycloalkenyl group and (C3-C8)cycloalkenyl group. Specific examples include cycloprop-2-enyl, cyclobuta-2-enyl, cyclopent-2-enyl, cyclohex-3-enyl and cyclone-4-enyl.

The term "amino" denotes the group-NH2.

The term “carbarnoyl” refers to any group of numbers-CONH2, -CONHR and-CONRR’, where R and R’ denote alkyl defined above.

The term “carboxy” refers to a radical of the formula-COOH.

The term “halogen” denotes identical or different fluorine atoms, chlorine, bromine and iodine, with fluorine atoms, chlorine and bromine are preferred.

Phenyl group, R1and R2may be optionally substituted, for example, hydroxy, amino, nitro, cyano, halogen, preferably fluorine, chlorine or bromine, stands or methoxy.

Connections may be used in the form of their salts which they form with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, Hydrobromic and uudistoodetena acid, phosphoric acid, sulfuric acid, nitric acid, p-toluensulfonate acid, methanesulfonate acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, maleic acid, these examples should be considered as examples and not limiting the present invention.

Pharmacological methods

To study the effect of the compounds according to the present invention on the inhibition of the secretion of IL-β and TNF-α in vitro use the following procedure for determining it:

The production of cytokine measured in environments with stimulated by lipopolysaccharide (LPS) peripheral managername blood cells. Menagerie cells separated from peripheral blood by fractionation using Lymphoprep® (Limhr®) (Nycomed, Norway) and suspended in RPMI medium 1640 (growth medium) is fetal calf serum (2% FTS) at a concentration of 5× 105cells/ml Cells incubated in 24-hole tablets for tissue culture in the aliquot in 1 ml of tested compound dissolved in dimethyl sulfoxide (DMSO, 10 mm) and diluted with medium. Compounds added to the cells for 30 minutes and then make LPS (final concentration 1 mg/ml). Tablets incubated for 18 hours and then determine the concentration of IL-β and TNF-α in the medium by the method of enzyme-linked immunosorbent assay. Calculate the average inhibiting concentration (IR50) compounds. The results are shown below in table 1.

Compounds according to the present invention also exhibit similar activity by inhibition of secretion PMA (polymorphonuclear) superoxide, which is also an indicator of possible usefulness as anti-inflammatory drugs. Connection experience using the following methods.

Human polymorphonuclear (PMA) granulocytes isolated from human blood by precipitation with dextran, fractionation using Lymphoprep® and hypotonic lysis of impurities erythrocytes.

The formation of superoxide anion was measured by the level of recovery of the oxidized form of cytochrome C in the system with inhibiting superoxide dismutase recovery (Madhu, S.B. et al., Inflammation, 16, 241 (1992)). Cells suspended in balanced salt cf is de Hank and incubated for 10 minutes at 37°C with the test compounds. Cells will primesouth the addition of TNF-α (at a final concentration of 3 ng/ml) for 10 minutes and then add 3 minutes of the oxidized form of cytochrome C (at a final concentration of 750 μg/ml), bovine serum albumin (BSA, final concentration 1 mg/ml) and formyl-methionyl-leucyl-phenylalanine (fMLP, at a final concentration of 10-7M). The cells are cooled on ice and then separated by centrifugation. Measure the optical density not containing cell supernatant on the spectrophotometer. Calculating the mean inhibitory concentration (IC50) compounds. The results are shown in table 1.

7,1
Table 1
 Inhibition of in vitro production of cytokines and PMA-superoxide compounds according to the present izobreteniya
 The average inhibitory concentration (IC50nm)
Connection#, example (approx.) No.ID-1βTNF-αPMA-superoxide
101, note 1135,04,0
102, note 2222,213
114, Prem7,93,24,0
reference (a)135,0
reference (b)>1000631316
reference: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone, the connection 106, described in PCT/DK98/00008; b) 1-ethyl-3-[2-(4-benzoylamino)phenyl]urea of General formula I of PCT/DK98/00008.

From the above results show that the compounds according to the present invention have the ability to inhibit the production of IL-1β, TNF-α and PMA-superoxide, demonstrating the presence of pharmacological activity comparable to that of the known compounds, indicating a possible value in the treatment of inflammatory diseases.

For studies of the compounds according to the present invention in vivo can be used in model mice with chronic skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TN) (De Young, L.M. et al., Agents Actions, 26, 335-341 (1989); Carlson, R.P. et al., Agents Actions 17, 197-204 1985); Alford J.G. et al., Agents Actions, 37 (1992); Stanley, P.L. et al., Skin Pharmacol, 4, 262-271 (1991)), cf. the description of the specified method in document PCT/DK98/00008, which is mentioned in the present description for details. The results obtained show that the compounds according to the present invention have the same activity as the known standard compounds, for example, hydrocortisone, whose known side effects, while connected to the I according to the present invention are well tolerated and are non-toxic. Some representatives of this class of compounds are characterized by very low absorption, which makes them particularly useful in the treatment of various skin diseases. Basically, they can be entered through methods such as oral, intravenous, intranasal, local or transcutaneous.

The way to obtain

Compounds according to the present invention can be obtained using a variety of methods known to experts in the field of organic synthesis. Compounds according to the present invention can be synthesized using the following techniques in combination with methods known in the art of chemistry organic synthesis or their variations, known to specialists in this field. Preferred methods include the following, but are not limited to. The new compounds of formula I can be obtained by using the reactions and techniques described in this section. Reactions are performed in solvents appropriate for the used reagents and materials and acceptable for carrying out the necessary transformations. In addition, it should be borne in mind that in the following synthesis methods all proposed reaction conditions, including the solvent, the atmosphere of the reaction, the reaction temperature, the duration of the experiment and the procedure of its execution, are chosen as the conditions of a hundred is standard for this reaction, which are well known to specialists in this field. Professionals with an average level of knowledge in the field of organic synthesis it is obvious that the various parts of the selected molecules functional groups must be compatible with the reagents and the proposed reaction mechanisms. Not all compounds of formula I, included in this class can be combined with some of the reaction conditions required in accordance with the described methods. Such restrictions substituents compatible with the reaction conditions, it is obvious to a person skilled in this field, so can be used in alternative methods.

Compounds according to the present invention receive method, comprising the combination of an amine of formula II with an isocyanate of the formula III or a suitable activated derivative of the formula IV, for example, the anhydrides carbamino acids and esters carbamino acid (phenoxy, 4-nitrophenoxy and 2,4,5-trichlorophenoxy) or other activated derivatives of the formula IV, as shown in scheme 1, where R1, R2, R3R4, Q, X, and Y are defined in General formula I, except that any substituents or functional group, which are potentially reactive in the reaction mix may be protected prior to the reaction mix, followed the removal of such a protective group.

Compounds according to the present invention of General formula II (X=O) can be obtained by several methods known to experts in the field of organic synthesis. One is used for this purpose, the sequence of reactions shown in scheme 2, a key process which involves the binding of the amine of formula VII with fluoride, chloride, bromide, iodide or triflate of formula VIII, as shown in scheme 2, where R1, R2, R3and R4defined for General formula I, with the formation of the conjugate of the product of General formula VI, except that any substituents or functional group, which are potentially reactive in binding assays, can be protected before carrying out binding assays with subsequent removal of such protective groups. The specified connection VI can then be restored to the corresponding amine of General formula II when working with standard reducing agents. Examples of such reducing agents include, but are not limited to, chloride dihydrate tin (II), hydrogen, ammonium formate or hydrazine hydrate and a catalytic amount of palladium on coal.

L: Br, I, SO2CF3or F and Cl

Y: Cl, Br, I, OSO2CF3, S2CH3ors

FGI: Vsampler is of functional groups

and R1, R2, R3and R4have the above values.

The reaction mix is performed using any method suitable for obtaining diphenylamino, well-known specialists in the field of organic synthesis. Preferred is the method of nucleophilic aromatic substitution, including linking amine with aristeidou or arylhalides in the presence of a base in a suitable solvent. It is shown that particularly suitable as the best grounds in the specified method are tert-piperonyl potassium (KOt-Bu), tert-piperonyl sodium (NaOt-Bu), sodium hydride (NaH) and potassium hydride (KN), but can also be used for other reasons.

In a typical case, the reaction is carried out at ambient temperature (20-25° (C) in bipolar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF) or N-organic (NRM) in an inert atmosphere, such as argon or nitrogen.

Alternative reaction mix can be carried out according to the method of amination under the conditions of catalysis palladium, which includes linking amine with arylhalides (iodide, bromide, triflate or, in some cases, chloride) in the presence of a base, a suitable source of Pd and acceptable phosphine ligand in an inert solvent.

The choice of palladium compounds used in the present method, not specifically limited, and as specific examples can be given a palladium (II)acetate, palladium (II)chloride, bromide, palladium (II), dichlorobis(triphenylphosphine)-palladium (II), tetrakis(triphenylphosphine)palladium (0), Tris(dibenzylideneacetone)dipalladium (0). The preferred ligand includes, but is not limited to the above list, racemic or narozeniny 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (hereinafter referred to as BINAP), tri-o-tolylphosphino, three-tert-butylphosphine, 1,1’-bis(diphenylphosphino)ferrocene, bis[(2-diphenylphosphino)phenyl]ether (DPEphos), 2-dicyclohexylphosphino-2’-dimethylaminophenyl, 2-(di-tert-butylphosphino)biphenyl and 9,9-dimethyl-4,6-bis(diphenylphosphino)Cantal (Xantphos). The amount of palladium and ligand used in a specified way, is typically from 0.1 to 10 mol.% relative to the number of aromatic halide (or triflate). It is shown that particularly suitable as the best grounds in the specified method are tert-piperonyl sodium (NaOt-Bu) and cesium carbonate (s3), but can also be used and other grounds. The reaction is typically carried out at elevated temperature (80-120° (C) in inert solvents such as 1,4-dioxane, toluene, benzene, and tetrahydrofuran, in an inert atmosphere, such as argon or nitrogen.

Compounds according to the present from which bretania, in which R4is not hydrogen, can be obtained through a process comprising a combination of an amine of the formula VI (R4=H) with an alkylating agent, as shown in scheme 2, where R1, R2, R3and R4defined for General formula I, except that any substituents or functional groups which are potentially reactive in binding assays, can be protected before carrying out binding assays with subsequent removal of the specified protection.

Typical alkylating agents of the General formula CH3-Y include, but are not limited to, the iodides (Y=I), bromides (Y=Br), chlorides (Y=Cl) and sulfonates (Y=OSO2R’, where R’ denotes a methyl, trifluoromethyl or 4-were).

Compounds according to the present invention in special cases can be obtained by simple functional group interconversion (FGI), which is a standard method known to specialists in the field of organic synthesis, in which the functional group in compounds of General formula I (or any other intermediate described in the present description) is transformed into another functional group during one or more stages of the synthesis, which leads to the production of the new compounds of General formula I. Examples of such methods include, but are not limited to, gidrol the C of ester with the formation of acid in alkaline conditions, unprotect methyl ester with obtaining phenol during processing, for example, tribromide boron (VVG3), and catalytic hydrogenation of the olefin with the formation of a saturated hydrocarbon.

Compounds according to the present invention, in which C=X denotes -(CS), can be obtained from the compounds according to the present invention (or any other intermediate described in the present description), where C=X represents -(CO)-, with the method including the use of appropriate thiocarbanilide agent, such as pentasulfide phosphorus (P4S10or reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,2,3,4-dithiophosphate-2,4-disulfide) or other

Compounds according to the present invention of General formula VII can be obtained in several ways, known to experts in the field of organic synthesis. One used the sequence of reactions shown in scheme 3. The key stage of the reaction sequence involves the binding of bromide (or iodide) of General formula X with an acid chloride of General formula XI with the formation of the benzophenone of the General formula IX. The specified connection IX can then be restored to the corresponding amine of General formula VII when working with standard reducing agents. Examples of such reducing agents include, but are not limited to IVaS them the chloride dihydrate tin (II), hydrogen, ammonium formate or hydrazine hydrate and a catalytic amount of palladium on coal. The reaction mix is conducted by transforming bromide (X) reactive ORGANOMETALLIC intermediate, for example, by treatment with butyllithium obtaining lithium derivative or processing of magnesium with obtaining magnesium derivative. Reactivity specified intermediate is then modulated by transmetilirovanie, such as zinc, by processing ZnCl2, ZnBr2or Znl2. The specified zinc-organic compound then combines with the acid chloride of General formula XI under the influence of a complex of palladium (0) in catalytic amount. Examples of such a catalyst include, but are not limited to the specific examples, tetrakis(triphenylphosphine)palladium (0), tetrakis(triphenylarsine) palladium (0), dichlorobis(triphenylphosphine)palladium (II) or benzylchloride(triphenylphosphine)palladium (II).

In some cases it may be more advantageous to change the sequence of stages in the above-described method. For obtaining compounds of General formula I according to the present invention is not limited to the described sequence and change the sequence of reactions is an obvious alternative for professionals in the field of the organic synthesis.

The considered compounds are intended for use in pharmaceutical compositions, which are used in the treatment of the aforementioned diseases and conditions.

The number of the desired compounds of formula I (hereinafter referred to as “active ingredient”) to achieve a therapeutic effect will vary depending on how the particular compound, its mode of administration, and the particular mammal undergoing treatment. Acceptable dose of a compound of formula I for the system is from 0.1 to 200 mg/kg body weight, the most preferred dosage is from 0.2 to 50 mg/kg body weight of the mammal with the introduction of its one or more times daily.

Despite the fact that in relation to this active ingredient is possible to consider the introduction itself directly as a chemical, it is preferable to include it in the form of pharmaceutical compositions. Accordingly, the active ingredient is from 0.1 wt.% to 100 wt.% from the composition.

In a convenient case of a standard dose of the composition contain from 0.07 mg to 1 g of the active ingredient. For the case of local injection of the active ingredient is preferably from about 1 wt.% up to 20 wt.% from the composition, however, the active ingredient may be also up to 50 wt.%. Compositions suitable DL the nasal or transbukkalno introduction, may include from 0.1 to 20 wt.%, for example, about 2 wt.% the active ingredient.

The term “standard dose” means a single, i.e. a single dose which may be administered to the patient and which can be readily handled and Packed, remaining as a physically and chemically stable standard units comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

Compositions according to the present invention, intended for both veterinary and medical use in humans, contain the active ingredient in combination with pharmaceutically acceptable carrier and optionally with another(them) therapeutic(them) ingredient(s). The carrier(s) need(s) to be acceptable(s)” in the sense of compatibility with other ingredients of the composition and do not adversely impact on the recipient.

Consider compositions include compositions that are in a format suitable for oral, ocular, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intradermal, intraarticular, local, or nasal transbukkalno introduction.

Accordingly, the compositions can be presented in the form of standard dosage forms and can be obtained by using ubago known in the field of pharmacy techniques. All methods include the stage of bringing the active ingredient into contact with the carrier, which consists of one or more accessory ingredients. Basically, the compositions have when implementing uniform and close contact of the active ingredient with liquid carriers or finely ground solid carrier or both of them and then, if necessary, shaping the product form the desired composition.

Compositions according to the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, tablets or lozenges, each of which contains a defined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid; or as an emulsion of the type oil-in-water or water-in-oil”. The active ingredient may also be introduced in the form of a bolus, electuary or paste.

Compositions for rectal injection can be presented in the form of suppositories comprising the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Compositions suitable for parenteral administration, in a convenient case include sterile oil or aqueous preparation of active ingredient, which is preferably isotonic to blood rezip the enta.

Compositions suitable for intraarticular injection, can be in the form of a sterile aqueous preparation of the active ingredient, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal compositions or biodegradable polymer systems can also be used as forms of active ingredient intended for intraarticular injection, and eye injection.

Compositions suitable for topical administration, comprising means for treatment of the eye include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, emulsions of the type oil-in-water or water-in-oil”, such as creams, ointments or pastes or solutions or suspensions such as drops.

Compositions suitable for injection into the nose or in the buccal cavity, include powder, kumarapalayam and sprayable compositions, such as sprays and atomizers. In addition to the above ingredients, the compositions according to the present invention can include one or more additional ingredients.

The composition may also include other therapeutically active compounds usually applied in the treatment of the above-mentioned pathological conditions, for example, glucocorticoids, vitamin D, antihistamines, and tagonist factor, causing the activation of platelets (FOP), anticholinergics, methylxanthines, β-adrenergic tools, salicylates, indomethacin, flufenamic, naproxen, timelady, gold salts, penicillamine, means for reducing the level of cholesterol in blood serum, retinoids, zinc salts and salicylazosulfapyridine (salazopyrin).

The new compounds according to the present invention are important in clinical practice in humans and in veterinary practice as a systemic and local therapeutic agent used in the treatment and prevention of diseases. The new compounds show anti-acne properties, and in particular, anti-inflammatory and cytokine-regulatory effects, possibly due to inhibition of MAP-kinase, and are useful in the treatment and prevention of asthma, allergies, arthritis, including rheumatoid arthritis and spondylarthritis, gout, atherosclerosis, chronic inflammation of the intestine (Crohn's disease), proliferative and inflammatory skin diseases such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, and osteoporosis.

Hereinafter the invention is described using the non-limiting General procedures, methods of preparation and examples.

EXAMPLES

General procedures, methods of preparation and examples

Examples of compounds of formula I are listed in table 2. All points of the square is the exercise not adjusted. For spectra1H and13Nuclear magnetic resonance (NMR) (300 MHz) the values of chemical shifts (δ) (in ppm) indicated, unless explicitly noted, for solutions deuterochloroform (CDCl3and hexacyanometallate (DMSO-d6) relative to the internal standard tetramethylsilane (δ 0,00) or chloroform (1H NMR δ 7,25;13With NMR δ 76,81). The value for the multiplet (m)or marked doublet (d), triplet (t), Quartet (j)or not defined, indicates to approximately the mid-point, if only a range is not specified (s - singlet, sh - wide). Used organic solvents are anhydrous. The term “chromatography” refers to column chromatography using flash method, which is carried out on silica gel.

In the description uses the following abbreviations:

Adoes Acetate silver

CPD Bis(trichloromethyl)carbonate

CDCl3Deuterochloroform

DMF N,N-dimethylformamide

DMSO-d6Hexacyanometallate

Et3N Triethylamine

EtOAc ethyl Acetate

Et2O Diethyl ether

GMFA of Hexamethylphosphoric triamide

NMM N-methylmorpholine

THF Tetrahydrofuran

TLC Thin layer chromatography

Table 2

Compounds of General formula I
Connection # Example No.XR1R2R3R4QY
1011O2-Me2-CLNNLink-cyclohexyl
1022O2-IU2-CLHNLink-CH2CH3
1033O2-IU2-CLNNLink-phenyl
1044O2-IU2-CLHNLink-(CH2)3CH3
1055O2-IU2-CLHN-(SO2)--tolyl
1066O2-IU2-CLHN-(SO2)--phenyl
1077O2-IU2-CLHNLink-The(CH 3)3
1088O2-IU2-CLHNLink-CH(CH3)2
1099O2-IU2-CLHNLink-(CH2)2CH3
11010O2-IU2-CLHNLink-CH3
11111O2-IU2-CLHNLink-(CH2)2COOCH2CH3
11212O2-IU2-CL4-VGNLink-CH2CH3
11313O2-IU2-CLHNLink-(CH2)2COOH
11414O2-IU2-CL4-FNLink-CH2CH3

O
115152-Me2-CL4-FCH3Link-CH2CH3
11616O2-Me, 4-Bu2-CL4-VGNLink-CH2CH3
11717O2-Me, 5-Me2-CL4-VGNLink-CH2CH3
11818O2-Me, 3-Cl2-CL4-VGNLink-CH2CH3
11919O2-Me, 4-t2-CL4-VGNLink-CH2CH3
12020O2-Me2-OEt4-VGNLink-CH2CH3
12121O2-Me, 4-CL2-CL4-VGNLink-CH2CH3
12222O2-Me, 3-Me2-CL4-VGNLink12323O2-Me, 4-OMe2-F4-VGNLink-CH2CH3
12424O2-Me, 4-Me, 5-Me2-CL4-VGNLink-CH2CH3
12525O2-Me, 4-F2-CL4-VGNLink-CH2CH3
12626O2-Me2-F4-VGNLink-CH2CH3

The numbers in table 2 refer to the numbering in the formula below.

General procedure 1: the Binding of compounds of General formula II with compounds of General formula III with obtaining compounds of General formula I or their protected derivatives.

To a solution of suspension of amine (1.0 mmol) of General formula II in an inert solvent (10 ml, in a typical case in toluene, pyridine or EtOAc) slowly add the isocyanate (1.1 to 2.5 mmol) of General formula III. Stirring is continued at room temperature for 24 hours or until the disappearance of starting material, according to TLC. The reaction is ionic mixture was concentrated in vacuo to obtain the crude product. In a typical case, this crude product is purified by chromatography and/or crystallization to obtain specified in the connection header.

Example 1

1-cyclohexyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (soedinenie 101)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: cyclohexylsulfamate.

The solvent for the reaction: EtOAc.

Purification: chromatography using EtOAc/hexane, 1:1 as eluent, followed by the rubbing of EtgO.

TPL 154-155oC.

1H NMR (DMSO-d6):δ a 8.34 (s, 1H), with 8.05 (d, 1H), 7,76 (s, 1H), 7,41 (m, 1H), 7,35-7,10 (m, 6N), to 6.95 (m, 1H), of 6.68 (m, 2H), to 6.57 (m, 1H), 3,44 (m, 1H), to 2.29 (s, 3H), 1.77 in (m, 2H), and 1.63 (m, 2H), of 1.52 (m, 1H), 1,40 to 1.00 (m, 5H).

Example 2

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-machovina (compound 102)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction: hexane.

Cleaning: listed in the title compound crystallized by adding water to the reaction mixture. Filtration, washing (water) and dried to give pure crystalline product.

TPL 158,3-159,8°C.

1H NMR (DMSO-d6): δ (a 8.34 (s, 1H), 8,04 (d, 1H), 7,79 (s, 1H), 7,42 (m, 1H), 7,10-7,34 (m, 6N), of 6.96 (m, 1H), 6,67 (m, 2H), to 6.57 (m, 1H), of 3.07 (m, 2H), 229 (, 3H), of 1.02 (t, 3H).

Example 3

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-metalmachine (compound 103)

General procedure: 1 except that the reaction mixture is heated to 100°C for 4 h.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: phenylisocyanate.

The solvent for the reaction include pyridine.

Purification: crystallization from Et2O.

TPL 163-166,8°C.

1H NMR (DMSO-d6): δ (to 9.15 (s, 1H), 8,43 (s, 1H), 8,13 (s, 1H), of 8.09 (d, 1H), 7,10-to 7.50 (m, 11N), 7,05 (m, 1H), of 6.96 (m, 1H), 6.75 in (d, 1H), 6,63 (DD, 1H), 2,28 (s, 3H)).

Example 4

1-butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 104)

General procedure: 1 except that the reaction mixture is heated to 100°C for 4 h.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction: toluene.

Purification: chromatography using a mixture tO/pentane 3:7 as eluent, followed by crystallization from Et2O.

TPL 104-106°C.

1H NMR (DMSO-d6): δ (8,35 (s, 1H), 8,04 (d, 1H), 7,80 (s, 1H), 7,41 (m, 1H), 7,08-7,34 (m, 6N), 6,97 (m, 1H), 6,70 (t, 1H), 6,66 (d, 1H), to 6.57 (DD, 1H), 3,05 (m, 2H), to 2.29 (s, 3H), 1,20-1,40 (m, 4H), 0,86 (t, 3H))).

Example 5

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-(4-methylphenylsulfonyl)urea (with the Association 105)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: p-toluensulfonate.

The solvent for the reaction: toluene.

Cleaning: the product is filtered and washed with Et2O obtaining specified in the connection header.

TPL 180-185°C.

13With NMR (DMSO-d6): δ (195,3, 150,3, 149,0, 143,9, 139,1, 136,7, 136,4, 133,9, 133,4, 133,4, 131,0, 130,7, 129,5, 129,3, 129,2, 128,8, 127,2, 126,4, 126,3, 125,6, 125,5, 124,1, 120,5, 114,7, 111,4, 20,9, 19,7).

Example 6

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-(phenylsulfonyl)urea (compound 106)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: benzosulfonazole.

The solvent for the reaction: toluene.

Cleaning: the product is filtered and washed with Et2O obtaining specified in the connection header.

TPL 196-201°C.

13With NMR (DMSO-d6): δ (195,3, 150,3, 139,6, 139,1, 136,4, 133,8, 133,7, 133,4, 131,7, 131,0, 130,7, 130,3, 129,3, 129,0, 128,8, 128,4, 127,2, 126,4, 126,4, 125,6, 125,5, 124,1, 120,5, 116,3, 114,7, 111,4, 19,7).

Example 7

1-tert-butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 107)

General procedure: 1 except that the reaction mixture is heated to 50°C for 6 hours.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

And the output connection III: tert-utilitzant.

The solvent for the reaction include pyridine.

Cleaning: listed in the title compound crystallized by adding water to the reaction mixture. Filtration, washing (water) and dried to give pure crystalline product.

TPL 159-161°C.

1H NMR (DMSO-d6): δ 8,32 (s, 1H), with 8.05 (d, 1H), 7,73 (s, 1H), 7,07-7,46 (m, 7H), to 6.95 (m, 1H), to 6.67 (d, 1H), 6,60 (s, 1H), to 6.57 (DD, 1H), to 2.29 (s, 3H), 1.26 in (C, N).

Example 8

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-Isopropylamine (compound 108)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: isopropyltoluene.

The solvent for the reaction: toluene.

Purification: chromatography using a mixture of EtOAc/pentane 3:7 as eluent, followed by crystallization from water.

TPL 103-106°C.

1H NMR (DMSO-d6): δ a 8.34 (s, 1H), 8,07 (d, 1H), 7,74 (s, 1H), 7,42 (m, 1H), 7,10-7,35 (m, 6N), to 6.95 (m, 1H), 6,66 (m, 2H), 6,56 (DD, 1H), 3,71 (m, 1H), to 2.29 (s, 3H), 1.06 a (d, 6N).

Example 9

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-proprotein (compound 109)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: propositional.

The solvent for the reaction include pyridine.

Purification: crystallization from Et2O.

TPL 133-135°C.

13With NMR (DMSO-d6) δ 195,2, 155,1, 150,7, 139,4, 136,3, 136,2, 133,5, 130,9, 130,5, 128,6, 128,3, 126,1, 125,8, 125,5, 121,8, 120,3, 114,7, 111,4, 40,8, 22,8, 19,6, 11,3.

Example 10

1-methyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 110)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: methyl isocyanate.

The solvent for the reaction include pyridine.

Purification: crystallization from Et2O.

TPL 154-155°C.

1H NMR (DMSO-d6): δ 8,35 (s, 1H), 8,01 (d, 1H), to 7.84 (s, 1H), 7,40 (m, 1H), 7,09-7,35 (m, 6N), 6,97 (m, 1H), of 6.68 (d, 1H), 6,59 (m, 2H), 2,61 (d, 3H), to 2.29 (s, 3H).

Example 11

Ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-ureido)propionate (compound 111)

General procedure: 1.

The original compound II: 4-(2-aminophenylamino)-2-chloro-2’-methylbenzophenone.

The original connection III: ethyl-3-isocyanatopropyl.

The solvent for the reaction include pyridine.

Purification: chromatography using a mixture of EtOAc/pentane 3:2 as eluent to obtain specified in the connection header in the form of syrup.

13With NMR (CDCl3): δ 196,7, 172,9, 156,3, 148,8, 139,2, 137,8, 135,0, 133,6, 133,0, 131,9, 131,3, 130,9, 129,6, 128,5, 125,4, 125,4, 124,2, 123,8, 116,4, 112,7, 60,9, 36,0, 34,7, 20,4, 14,1.

Example 12

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 112)

General procedure: 1.

The original compound II: 4-[(2-amino-4-bromophenyl)amino]-2-chloro-2’-methylbenzoate the N.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of EtOAc/pentane 1:1.

TPL 125-127°C.

13With NMR (CDCl3): δ 197,5, 155,8, 149,2, 138,9, 137,7, 135,2, 135,0, 133,6, 131,4, 131,2, 129,8, 129,7, 128,2, 126,8, 126,2, 125,5, 125,0, 118,7, 116,1, 112,3, 35,2, 20,5, 15,2.

Example 13

3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]ureido)-propionic acid (compound 113)

Ethyl 3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-ureido)propionate (compound 111, at 6.25 mmol) and K2CO3(9.4 mmol) is stirred in a mixture of Meon (25 ml) and water (8 ml) for 4 hours at ambient temperature. Add additional water (13 ml) and the reaction mixture was stirred over night. Next, the reaction mixture was poured into EtOAc and water, the pH value was adjusted to about 4 with glacial acetic acid. The organic phase is separated, washed with water and saturated salt solution, then dried (MgS4), filtered and concentrated in vacuo to obtain faintly colored oily crude product. Cleaning is performed by chromatography using a mixture of CH2Cl2/MeOH/CH3COOH, 250:10:1 as eluent to obtain specified in the connection header.

13With NMR (Dl3): δ 197,5, 176,3, 157,0, 148,9, 138,9, 137,9, 134,9, 133,5, 132,8, 131,7, 131,3, 131,1, 129,8, 128,4, 125,6, 125,5, 124,4, 123,9, 116,3, 112,6, 35,8, 34,5, 20,7, 20,5.

Example 14/p>

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-5-forfinal]urea (compound 114)

General procedure: 1.

The original compound II: 2-chloro-4-[(4-fluoro-2-AMINOPHENYL)-amino]-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: chromatography using a mixture of EtOAc/pentane 1:2 as eluent to obtain specified in the connection header in the form of syrup.

13With NMR (Dl3): δ 197,2, 162,9, 159,6, 155,1, 150,2, 138,9, 137,8, 137,4, 137,2, 135,1, 133,6, 131,4, 131,1, 129,7, 128,4, 128,0, 127,9, 125,5, 124,7, 115,6, 111,8, 110,1, 109,8, 108,2, 107,9, 35,2, 20,5, 15,1.

Example 15

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)-N-methylpentylamino]-5-forfinal]urea (contents 115)

General procedure: 1.

The original compound II: 4-(2-amino-4-bromo-N-methylpentylamino)-2-chloro-2’-methylbenzophenone.

Purification: chromatography using a mixture of EtOAc/pentane 1:5 as eluent.

13With NMR (CDCl3): δ 197,6, 162,2, 154,8, 152,8, 139,4, 138,8, 137,1, 135,4, 133,9, 131,3, 130,9, 129,6, 129,0, 128,5, 126,3, 125,5, 114,9, 111,1, 109,3, 107,1, 39,4, 34,9, 20,3, 14,8.

Example 16

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 116)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-4’-n-butyl-2-chloro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

13N I Is R (DMSO-d 6): δ at 8.36 (m, 1H), of 8.27 (s, 1H), 7,94 (s, 1H), 7,24 (d, 1H), a 7.2 to 7.0 (m, 5H), 6,86 (t, 1H), 6,69 (d, 1H), return of 6.58 (DD, 1H), is 3.08 (m, 2H), 2,59 (t, 2H), 2,32 (s, 3H), and 1.56 (m, 2H), 1,30 (m, 2H), 1,15 is 0.80 (m, 6N).

Example 17

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl]urea (compound 117)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-chloro-2’,5’-dimethylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 195,5, 154,8, 150,3, 139,2, 138,1, 134,7, 133,6, 133,5, 133,4, 131,4, 131,0, 129,1, 127,8, 127,4, 126,5, 124,2, 121,9, 118,4, 115,1, 111,6, 33,9, 20,4, 19,4, 15,2.

Example 18

1-ethyl-3-[5-bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 118)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2,3’-dichloro-2’-dimethylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 193,8, 154,6, 151,0, 142,3, 138,0, 134,5, 134,4, 134,1, 133,2, 130,7, 127,9, 127,2, 127,0, 126,5, 124,9, 124,1, 121,9, 118,6, 115,2, 111,5, 33,8, 16,6, 15,1.

Example 19

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 119)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-chloro-4’-ethoxy-2’-METI is benzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 194,5, 160,8, 154,8, 149,6, 140,6, 138,0, 132,9, 132,5, 132,3, 130,6, 128,2, 127,8, 127,6, 124,2, 121,9, 118,2, 117,3, 114,7, 111,8, 111,1, 63,3, 33,9, 20,8, 15,2, 14,6.

Example 20

1-ethyl-3-[5-bromo-2-[3-ethoxy-4-(2-methylbutyl)phenylamino]phenyl]urea (compound 120)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-ethoxy-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 195,2, 160,2, 154,7, 151,9, 143,1, 137,4, 134,2, 132,3, 129,9, 128,6, 128,3, 127,1, 126,3, 125,0, 124,1, 122,2, 118,0, 117,5, 106,6, 97,2, 62,9, 33,8, 19,2, 15,1, 13,5.

Example 21

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 121)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2,4’-dichloro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 194,1, 154,6, 150,6, 139,0, 138,0, 135,1, 133,6, 133,5, 130,6, 130,4, 127,8, 127,2, 125,9, 125,6, 124,1, 121,8, 118,4, 114,9, 111,6, 45,0, 33,8, 19,4, 15,1.

Example 22

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)-phenylamino]Fe is Il]urea (compound 122)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-chloro-2’,3’-dimethylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMCO-d6): δ 195,6, 154,6, 150,5, 140,3, 138,0, 137,4, 134,2, 134,0, 133,7, 131,5, 127,8, 127,2, 126,0, 125,6, 125,1, 124,1, 121,8, 118,4, 115,1, 111,4, 33,8, 19,6, 16,0, 15,1.

Example 23

1-ethyl-3-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 123)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-fluoro-4’-methoxy-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 192,0, 162,3, 160,8, 154,6, 152,2, 138,9, 138,0, 133,1, 132,3, 131,1, 127,8, 127,6, 124,2, 122,0, 118,4, 116,6, 116,4, 110,7, 109,8, 100,1, 55,3, 33,9, 20,2, 15,2.

Example 24

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)phenylamino]phenyl]urea (compound 124)

General procedure: 1.

The original connection II:

4’-(2-amino-4-brompheniramine)-2’-chloro-2,4,5-trimethylbenzene.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 195,2, 154,7, 149,9, 139,6, 137,9, 136,4, 134,2, 133,2, 133,0, 1324, 130,3, 127,6, 127,5, 127,1, 124,1, 121,8, 118,2, 114,8, 111,6, 33,8, 19,4, 19,2, 18,6, 15,1.

Example 25

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 125)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-chloro-4’-fluoro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13With NMR (DMSO-d6): δ 194,1, 162,9, 154,6, 150,3, 140,4, 138,0, 135,6, 133,3, 131,6, 127,7, 127,3, 126,4, 124,1, 121,8, 118,3, 117,7, 114,8, 112,4, 111,6, 33,8, 19,8, 15,1.

Example 26

1-ethyl-3-to 5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)-phenylamino]phenyl]urea (compound 126)

General procedure: 1.

The original compound II: 4-(2-amino-4-brompheniramine)-2-fluoro-2’-methylbenzophenone.

The original connection III: utilitzant.

The solvent for the reaction include pyridine.

Purification: crystallization from a mixture of 1,2-dichloroethane/hexane.

13C-NMR (DMSO-d6): δ 192,9, 163,0, 154,8, 153,0, 140,7, 138,0, 135,0, 133,3, 130,6, 129,9, 128,0, 127,2, 125,5, 124,2, 122,0, 118,6, 115,5, 109,9, 100,1, 33,9, 19,3, 15,2.

Example 27

Tablet containing compound 102

Compound 102 (active substance) 50 mg

Lactose 125 mg

Starch 12mg

The methylcellulose 2 mg

Sodium carboxymethylcellulose 10 mg

Magnesium stearate 1 mg

The active ingredient, lactose and starch are mixed to a homogeneous state in a suitable when esitle and moisturize the addition of 5% aqueous solution of methylcellulose with a viscosity of 15 centipoise. Stirring is continued until the formation of granules. If necessary, the wet granules are passed through a suitable sieve and dried to a water content less than 1% in a suitable dryer, for example, in the fluidized bed or in a drying Cabinet. The dried granules are passed through a sieve with openings of 1 mm and mixed until a homogeneous state with sodium carboxymethylcellulose. Adds magnesium stearate and stirring is continued for a short period of time. Granules on a suitable tablet machine get tablets weighing 200 mg.

Example 28

Composition for injection containing compound 102

Compound 102 (active substance) 1%

Sodium chloride q.s.

Ethanol 10%

Water for injections to reach 100%

The active substance is dissolved in ethanol (10%) and then add up to 100% water for injection, which by means of sodium chloride doing isotonic. The mixture is filled ampoules and sterilized them.

Example 29

The composition is in the form of a cream containing compound 101

Compound 101 (10 g) dissolved in octyldodecanol (250 g) with the formation of part A. Methylparaben (1 g) and propyl paraben (0.2 g) dissolved in Phenoxyethanol (6 g) and mixed with 0.025 M phosphate buffer pH 7.5 (632,8 g) forming part of the Century Cetosteatil alcohol (50 g) and ARLACEL 165® (50 g) is melted in a vessel at a temperature of 70-80oC. DOB is given in part a and heat up everything to a temperature of 60-70°C. Similarly heated water phase to 60-70oC and added slowly to the melted oil phase under high speed stirring. Homogenized components cooled to room temperature.

1. The compound of the formula I

where R1means independently one or more identical or different substituents selected from the group consisting of halogen, hydroxy, mercapto, trifloromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, carbamoyl, phenyl or nitro, provided that when R1means one Deputy, he is anthopology and when R1means more than one Deputy, at least one of R1the Deputy is orthopaedie;

R2means one Deputy in anthopology, and specified the Deputy is chosen from the group consisting of halogen, (C1-C3)alkyl, (C1-C3)alkoxy;

R3means hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, (C1-C3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1/sub> -C6)alkylamino, (C1-C3)alkoxycarbonyl, phenyl, cyano, carboxy or carbarnoyl;

R4means hydrogen or (C1-C3)alkyl;

Q means a bond or-SO2-;

Y means (C1-C15)alkyl, (C3-C10)carbocyclic group, or phenyl, each of which may be optionally substituted by one or more identical or different substituents, denoted by the formula, R5;

R5means halogen, (C1-C4)alkyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl or-COOH;

X denotes oxygen or sulphur,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, characterized in that the independent R1means one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, trifloromethyl, amino, (C1-C2)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl or cyano; R2means one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, (C1-C2)alkyl, (C1-C3)alkoxy; R3means one or more identical or different substituents selected from g is PI, consisting of hydrogen, fluorine, chlorine, bromine, (C1-C3)alkyl, (C1-C3)alkoxy; R4means hydrogen, (C1-C2)alkyl; X is oxygen; Q represents a relationship or-SO2-; Y represents (C1-C6)alkyl, (C3-C6)cycloalkyl or phenyl, each of which may be optionally substituted by one or more identical or different substituents selected from the group consisting of a residue of the formula R5where R5means fluorine, chlorine, bromine, (C1-C2)alkoxy, (C1-C3)alkoxycarbonyl, -COOH.

3. The compound according to any one of the preceding paragraphs, in which R1means one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, methyl or methoxy.

4. The compound according to any one of the preceding paragraphs, in which R1means methyl and R2means C1.

5. The compound according to claim 1, selected from the group including

1-cyclohexyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 101),

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-

urea (compound 102),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-phenyl-urea (compound 103),

1-butyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 104),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-Isopropylamine (compound 108),

1-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-3-populatemenu (compound 109),

1-methyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl]-urea (compound 110),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 112),

1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-5-fluoro-phenyl]urea (compound 114),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl]urea (compound 117),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 121),

1-ethyl-3-[5-bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 123),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)-phenylamino]phenyl]urea (compound 124),

1-ethyl-3-[5-bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)-phenylamino]phenyl]urea (compound 125),

1-ethyl-3-[5-bromo-2-[3-fluoro-4-(2-methylbenzoyl)phenylamino]-phenyl]urea (compound 126), and their salts with pharmaceutically acceptable acids.

6. The compound according to any one of claims 1 to 5, applicable for obtaining a medicinal product intended for the treatment and/or prevention of inflammatory diseases, such as skin diseases such as psoriasis, atopic dermatitis.

7. Pharmaceutical to notice, having the properties of an inhibitor of cytokine secretion, more specifically 1β -interleukin(IL-1β ) and α -necrosis factor tumor cells(TNF- α), and secretion of polymorphonuclear (PMA) superoxide containing as active ingredient a compound according to any one of claims 1 to 5 together with a pharmaceutically acceptable carrier.

8. The method of treatment and/or prevention of inflammatory diseases such as skin diseases, such as psoriasis, atopic dermatitis, characterized in that it comprises the administration to a patient suffering from at least one of these conditions, an effective amount of one or more compounds according to any one of claims 1 to 5 as an active ingredient alone or optionally together with a pharmaceutically acceptable carrier.

9. The method of treatment of claim 8, comprising the administration to a mammal in need of systemic treatment, suitable doses of the compounds of formula I, component of from 0.1 to 200 mg/kg body weight, preferably from 0.2 to 50 mg/kg body weight, once or several times a day.



 

Same patents:

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.

EFFECT: valuable medicinal properties of compound.

1 cl, 7 tbl, 3 ex

FIELD: medicine, cardiology.

SUBSTANCE: traditional therapy of myocardial infarction should be supplemented with granocyte introduced either subcutaneously or intravenously at the dosage of 0.48 mln IU/kg body weight daily for 5 d.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: one should introduce 1.0% serotonin adipinate solution intravenously due to infusion once daily for 10-12 d. The method enables to increase visual functions due to decreased tissue hypoxia and normalization of retinal microcirculation, resorption of hemorrhages, reverse development of retinal edema, normalization of functional thrombocytic activity and hemostatic values.

EFFECT: higher efficiency for therapy.

1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, phthisiology, anesthesiology.

SUBSTANCE: during the day of operation one should perform autohemotransfusion, then introduce epocrine intravenously by drops at the dosage of 50-200 U/kg patient's body weight; next day after interference one should inject epocrine subcutaneously at the dosage of 25-100 U/kg; at hematocrit level being below 35% 48 h after operation it is necessary to repeat subcutaneous injection of the above-mentioned preparation at the dosage not exceeding 50 U/kg. The present innovation favors hemopoiesis stimulation in postoperational period, that, in its turn, accelerates postoperational rehabilitation in patients of this group and enables, also, to avoid allotransfusions being dangerous because of immunoconflicting reactions.

EFFECT: higher efficiency of compensation.

1 ex, 1 tbl

The invention relates to pharmaceutical industry and relates to a method of producing iron-containing drug for the treatment and prevention of iron deficiency anemia in animals by the interaction of organic acids with gemostimuliruyuschee properties, isolated from extracts of peat, with a hydroxide of iron (11), selected from water-soluble salts of iron (11) the deposition of the alkaline solution with the subsequent laundering of water impurities

The invention relates to preparations for the prevention and treatment of Pets and farm animals, as well as to maintain the microelemental composition of the feed, and can be used in animal breeding and fur farming

The invention relates to experimental medicine, may find application in radiobiological experiments, and further in clinical practice

The invention relates to organic chemistry and pharmacology, and relates new connection - 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia

The invention relates to biotechnology and is used for the preparation of recombinant human erythropoietin (EPO)
The invention relates to medicine, surgery and intensive care, to a method of replacement of massive blood loss of any Genesis

The invention relates to medicine, in particular to the pharmaceutical industry, and can be used as adjuvant iron deficiency anemia
Up!