Aminobenzophenone as inhibitors of il-1and tnf-

 

(57) Abstract:

The invention relates to new aminobenzophenone General formula (I)

where R1and R3designate one or more identical or different substituents selected from the group consisting of halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy; provided that, if R1denotes one Deputy, he is in the ortho-position, and if R1refers to several substituents, at least one substituent R1located in the ortho-position; and R2denotes one substituent in the ortho-position, and this Deputy is selected from the group consisting of halogen, (C1-C3)-alkoxy; and R3can additionally denote hydrogen; R4represents hydrogen; X represents oxygen; Q represents -(CO)- or a bond; Y represents (C5-C15)alkyl, (C2-C15)olefinic group; and any of these groups may be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5defined below, except that when Q represents a bond, then Y seat is alkyl, substituted by one or more substituents selected from the group R5; or a group of formula - (Z-O)n- Z, where Z is a (C1-C3)alkyl, n is an integer >1, and the number of atoms in a continuous linear sequence of atoms in the group Y does not exceed 15; R5denotes halogen, hydroxy, amino, (C1-C6)-alkylamino, (C1-C3)alkoxycarbonyl, -COOH, -CONHR' or-COONR'R' R' means (C1-C3)alkyl; or its pharmaceutically acceptable salt. The invention also relates to pharmaceutical compositions for inhibiting the secretion of interleukin 1 (IL-1) and factor and tumor necrosis (TNF). The technical result is to provide new compounds and pharmaceutical compositions based on them in order to use them in medical and veterinary therapeutic practice. 2 S. and 4 C.p. f-crystals, 2 PL.

THE SCOPE OF THE INVENTION

This invention relates to the unknown up to the present class of compounds that have anti-inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage forms such preparations, and to their use for the treatment and profile the ski inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin diseases such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS, and eels.

BACKGROUND OF INVENTION

He previously been described by a number of closely related aminobenzophenone (for example, 4-(2-amino-4-nitro-phenylamino)benzophenone) (Hussein, F. A. et A1., Iraqi J. Sci., 22, 54-66 (1981)). However, there is no description of their use. PCT/DK98/00008 reveals aminobenzophenone inhibitors of secretion of interleukin 1 (IL-1) and tumor necrosis factor (TNF) in vitro, and the above-mentioned compounds can potentially be used for treatment of inflammatory diseases in which involved in the pathogenesis of cytokine production, for example, asthma, rheumatoid arthritis, psoriasis, contact dermatitis and atopic dermatitis. In addition, the compounds described in PCT/DK98/00008, were tested in vivo for anti-inflammatory activity in the mouse model of chronic skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) (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., 262-271 (1991)). In this model of chronic skin inflammation activity of these compounds was close to the activity control soedinyonnih and related compounds, with a higher pharmacological activity.

This goal is achieved by using new aminobenzophenone derivatives corresponding to General formula (I), which, as found, are potent inhibitors of secretion of interleukin 1 (IL-1) and tumor necrosis factor (TNF) in vitro. Numerous information available prior art (in particular, the works listed at the end of this description), allow a high degree of confidence to say that, with the above-mentioned pharmacological activity, consider new connections will be useful for the treatment of inflammatory diseases, including those listed in the introduction of diseases, which in the pathogenesis involved in the secretion and regulation of cytokines, or, more specifically, interleukin 1 (IL-1) and tumor necrosis factor (TNF). The inhibition or regulation of cytokines by type of negative feedback, perhaps, is due to the inhibition of MAP-kinase.

SUMMARY OF INVENTION

Compounds of the present invention represented by the General formula I

where R1, R2and R3designate one or more identical or different SUB>3)alkyl, (C2-C3)olefinic group, (C1-C3)alkoxy, (C1-C3)alkylthio, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, cyano, -N2, phenyl or nitro; in addition, R2may denote hydrogen, and R3may designate carboxy and carbarnoyl;

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

X denotes oxygen or sulfur;

Q represents -(CO)-, -(CS)- or a bond;

Y denotes a (C5-C15)alkyl, (C2-C5)olefinic group, (C3-C10)monocyclic hydrocarbon group; or phenyl; and any of them may be optionally substituted by one or more identical or different substituents selected from the group consisting of compounds of the formula R5defined below; (C1-C4)alkyl, substituted by one or more substituents selected from the group R5; or a group of formula -(Z-O)n-Z, where Z is a (C1-C3)alkyl, n is an integer >1; and the number of atoms in a continuous linear sequence of atoms in the group Y does not exceed 15;

R5denotes halogen, hydroxy, Merino, (C1-C3)alkoxycarbonyl, cyano, azido, nitro, -COOH, -CONH2, -CONHR' or-COONR'R' R' means (C1-C3)alkyl;

or their salts with pharmaceutically acceptable acids, hydrate or solvate.

In the compounds of the formula I R1preferably represents 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, cyano or-N2;

R2represents one or more identical or different substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy, trifloromethyl, amino, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy.

R3represents one or more identical or different substituents selected from the group consisting of hydrogen, halogen, hydroxy, trifloromethyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C1-C3)alkoxy, (C1-C3)alkoxycarbonyl, cyano, carboxy or-N2.

R4will oboznachaet -(CO)- or connection.

Y denotes a (C5-C10)alkyl, (C2-C10)alkenyl; (C3-C8)cycloalkyl; (C5-C8)cycloalkenyl group or phenyl; and any of them may be optionally substituted by one or more identical or different substituents selected from the group consisting of compounds of the formula R5defined below; (C1-C4)alkyl, substituted by one or more substituents having the formula R5; or a group of formula -(Z-O)n-Z, where Z is a (C1-C3)alkyl, n is an integer >1; and the number of atoms in a continuous linear sequence of atoms in the group Y does not exceed 9;

R5denotes halogen, hydroxy, amino, (C1-C2)alkoxy, (C1-C4)alkylamino, (C1-C3)alkoxycarbonyl, cyano, azido, -COOH, -CONH2, -CONHR' or-COONR'R' R' means (C1-C2)alkyl.

More preferably R1represents one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, methyl or methoxy; R2represents one or more identical or different substituents selected and several identical or different substituents, selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy, methyl or methoxy; R4represents hydrogen; X represents oxygen; Q represents -(CO)- or a bond; Y represents C5-C7)alkyl, (C2-C4)alkenyl; any of them may be optionally substituted by one or more identical or different substituents selected from the group consisting of compounds of the formula R5, (C1-C4)alkyl, substituted by one or more substituents having the formula R5; or a group of formula-CH2-O-CH2-CH2-O-CH3; R5preferably denotes fluorine, chlorine, bromine, hydroxy, amino, (C1-C2)alkoxycarbonyl, -COOH, -CONH2-N(CH3)2.

Preferably, if in the compounds of formula I, where Y is CF3, Q represents -(CO)-.

Phenyl group, R1and R2may be optionally substituted, for example, a hydroxyl group; an amino group; a nitro-group; a cyano; halogen, preferably fluorine, chlorine or bromine; stands; or metaxylene group.

Typical compounds of formula I are:

N-[2-[3-Chloro-4-(2-methylbenzoyl)phenylamino]Fannie 102),

4-Bromo-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]butanamide (compound 103),

Ethyl-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]succinylate (compound 104),

2-(2-Methoxyethoxy)-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-acetanilide (compound 105),

N,N-dimethyl-N'-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-phenylsuccinic (compound 106),

2-Hydroxy-2'-[3-chloro-4-(2-methoxybenzoyl)phenylamino]-acetanilide (compound 107),

2-Hydroxy-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 108),

2-Hydroxy-2'-[3-fluoro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 109),

2-Amino-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 110),

Ethyl-2-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]aniline]acetate (compound 111),

2-Chloro-4-[2-(6-hydroxyacetylamino)phenylamino]-2'-methylbenzophenone (compound 112),

2-Chloro-4-[2-(3-hydroxypropylamino)phenylamino]-2'-methylbenzophenone (compound 113),

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]hexanamide (compound 114),

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]but-3-enameled (compound 115),

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-4-is inania 117),

N-[5-Bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)phenylamino]-phenyl] succinamide acid (compound 118),

N-[5-Bromo-2-[3-ethoxy-4-(2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 119),

N-[5-Bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)phenylamino]phenyl] succinamide acid (compound 120),

N-[5-Bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 121),

N-[5-Bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 122),

N-[5-Bromo-2-[3-fluoro-4-(2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 123),

N-[5-Bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)phenylamino]phenyl] succinamide acid (compound 124),

N-[5-Bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 125),

N-[5-Bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl] succinamide acid (compound 126),

N-[5-Bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 127),

N-[5-Bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)phenylamino]phenyl] succinamide acid (compound 128),

as well as their salts with pharmaceutically acceptable kikooy below, also in most cases are the preferred

where R1, R2, R3, R4, Q and Y have the above meanings. Typical compounds of formula Ia are:

N-[2-[3-Chloro-4-(2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 129),

2'-[3-Chloro-4-(2-methyl(thiobenzoyl))phenylamino]octanamide (compound 130),

4-Bromo-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]butanamide (compound 131),

Ethyl-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]succinylate (compound 132),

2-(2-Methoxyethoxy)-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]acetanilide (compound 133),

N,N-dimethyl-N'-2- [3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]phenylsuccinic (compound 134),

2-Hydroxy-2'-[3-chloro-4-(2-methoxy(thiobenzoyl))phenylamino]acetanilide (compound 135),

2-Hydroxy-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]acetanilide (compound 136),

2-Hydroxy-2'-[3-fluoro-4-(2-methyl(thiobenzoyl))phenylamino]acetanilide (compound 137),

2-Amino-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]acetanilide (compound 138),

Ethyl-2-[2-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]aniline]acetate (connected to the ptx2">2-Chloro-4-[2-(3-hydroxypropylamino)phenylamino]-2'-methyl-(thiobenzophenone) (compound 141),

5'-Bromine-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]hexanamide (compound 142),

5'-Bromine-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]but-3-enameled (compound 143),

5'-Bromine-2'-[3-chloro-4-(2-methyl(thiobenzoyl))phenylamino]-4-methylpentanoate (compound 144),

2'-[3-Chloro-4-(2-methyl(thiobenzoyl))phenylamino]-2-methylpentanediol (compound 145),

N-[5-Bromo-2-[3-chloro-4-(4-ethoxy-2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 146),

N-[5-Bromo-2-[3-ethoxy-4-(2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 147),

N-[5-Bromo-2-[3-chloro-4-(2,3-dimethyl(thiobenzoyl))phenylamino]-phenyl] succinamide acid (compound 148),

N-[5-Bromo-2-[3-chloro-4-(4-n-butyl-2-methyl(thiobenzoyl))phenylamino]phenyl]succinamide acid (compound 149),

N-[5-Bromo-2-[3-chloro-4-(4-chloro-2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 150),

N-[5-Bromo-2-[3-fluoro-4-(2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 151),

N-[5-Bromo-2-[3-chloro-4-(2,4,5-trimethyl(thiobenzoyl))phenylamino] phenyl] succinamide acid (the connection is giving 153),

N-[5-Bromo-2-[3-chloro-4-(2,5-dimethyl(thiobenzoyl))phenylamino]phenyl] succinamide acid' (compound 154),

N-[5-Bromo-2-[3-fluoro-4-(4-methoxy-2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 155),

N-[5-Bromo-2-[3-chloro-4-(3-chloro-2-methyl(thiobenzoyl))phenylamino]phenyl] succinamide acid (compound 156),

as well as their salts with pharmaceutically acceptable acids, hydrates and solvate.

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

Compounds of formulas I and Ia can be used as salts formed 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, and these examples are not considered as limiting n is defined values:

Alkyl refers to a monovalent group derived from an alkane in the removal of a hydrogen atom bound to any carbon atom, and includes the subclasses of normal Akilov (n-Akilov) and primary, secondary and tertiary alkylene groups, respectively, which have the specified number of carbon atoms, including, for example, (C1-C5)alkyl, (C1-C5)alkyl, (C5)alkyl, (C6-C10)alkyl, (C6-C15)alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the General formula CnH2n+2and, consequently, consisting only of hydrogen atoms and saturated carbon atoms.

Olefinic group refers to a linear or branched acyclic hydrocarbon having one or more carbon-carbon double bonds in the E or Z configuration, if this classification is applicable, and having the specified number of carbon atoms. This term includes, for example, (C2-C15)olefinic group, preferably a (C2-C15)alkenyl; and (C2-C3)olefinic group, preferably a (C2-C3)alkenyl; the only one carbon-carbon double bond, called here alkeneamine.

Alkoxy refers broadly to a radical of the formula-OR, where R is an alkyl, as defined above, for example (C1-C3)alkoxy, (C1-C2)alkoxy, methoxy, ethoxy, n-propoxy, etc.,

(C1-C3)alkylthio refers broadly to a radical of the formula-SR, where R is an alkyl, as defined above, and includes methylthio, ethylthio, n-propylthio and 2 property.

(C1-C3)alkylamino refers broadly to a radical of the formula-or other-NR2where R is an alkyl as defined above having 1 to 6 carbon atoms, and includes, for example, methylamino, dimethylamino, di-(n-propyl)amino and n-butyl(ethyl)amino.

(C1-C3) alkoxycarbonyl refers broadly to a radical of the formula-COOR, where R represents an alkyl, as defined above, and includes methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl and ISO-propoxycarbonyl.

(C3-C10)monocyclic hydrocarbon group includes saturated cycloalkanes and unsaturated cyclic olefins, such as cycloalkane with one endocyclic double bond and from 3 to 10 carbon atoms, and include, e.g. valkanova group and (C3-C8)cycloalkenyl group. Specific examples are cycloprop-2-enyl, cyclobuta-2-enyl, cyclopent-2-enyl, cyclohex-3-enyl and cyclone-4-enyl.

Amino refers to the group-NH2.

Carbarnoyl refers to any group-CONH2, -CONHR, and CONRR', where R and R' represent alkyl, as described above.

Carboxy refers to a radical of the formula-COOH.

Halogen denotes the same or different atoms selected from fluorine, chlorine, bromine and iodine; fluorine, chlorine and bromine are preferred.

PHARMACOLOGICAL METHODS

To study the activity of a compound of the present invention in vitro measure the inhibition of the secretion of IL-1 and TNF - a using the following procedure.

Production of cytokines was measured in the medium stimulated with lipopolysaccharide (LPS) by mononuclear cells of peripheral blood. Mononuclear cells isolated from peripheral blood by fractionation using Limphoprep® (Nycomed, Norway) and suspended in RPMI 1640 (growing medium) containing fetal calf serum (FCS, 2%), with concentration of 5×105cells/ml Cells incubated in 24-hole tablets for the cultivation of tissues in the aliquot volume of the keys to the cells and incubated for 30 minutes, then add LPS (final concentration 1 mg/ml). Tablets incubated for 18 hours and the concentration of IL-1 and TNF - in the medium was determined by enzyme-linked immunosorbent assay. Calculate the average inhibiting concentration (IC50) compounds. The results are shown in table 1.

Compounds of the present invention also exhibit similar activity in terms of their ability to inhibit the secretion of superoxide PMN (polymorphonuclear cells), which also indicates the potential use of these compounds as anti-inflammatory drugs. Compounds are tested using the following methods. Human polymorphonuclear (PMN) granulocytes isolated from human blood by means of precipitation with dextran, fractionation using Limphoprep® and hypotonic lysis present as an impurity of 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 solution Hanks and incubated with test compounds for 10 minutes at 37°C. the Orme cytochrome C (final concentration of 750 μg/ml), bovine serum albumin (BSA, final concentration 1 mg/ml) and formyl-methionyl-leucyl-phenylalanine (FMLP, the final concentration of 10-7M) and incubated for 3 minutes. The cells are cooled on ice and precipitated by centrifugation. The optical density not containing cell supernatant was measured on a spectrophotometer. Calculate an average inhibitory concentration (IC50) compounds. The results are shown in table 1.

These results show that the compounds of the present invention is able to inhibit the production of IL-1, TNF - and PMN-superoxide and possess pharmacological activity comparable with the activity of standard connections compare, which makes possible the use of these compounds in the treatment of inflammatory diseases.

To study the activity of the compounds of the present invention in vivo can be used murine model of chronic skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) (De Young, L. M. et al., Agents Action, 26, 335-341 (1989); Carlson, R. P. et al., Agents Action, 17, 197-204 (1985); Alford, J. G/ et al., Agents Action, 37 (1992); Stanley, P. L. et al, Skin Pharmacol, 4. 262-271 (1991)), and the description of the method in PCT/DK98/00008 included in this description by reference. These results demonstrate that the activity of compounds the area, having established side effects, whereas the compounds of the present invention are well-tolerated and non-toxic. Some members of this class of compounds exhibit very low absorption, which makes them particularly useful in the treatment of various dermatological diseases. Typically, they can be introduced, for example, oral, intravenous, intranasal, transdermal way or locally.

THE WAY TO OBTAIN

Compounds of the present invention can be obtained by using a number of methods, well known to experts in the field of organic synthesis. Compounds of the present invention can be synthesized using the methods described below, as well as methods known in the field of synthetic organic chemistry, or modifications that can be made by specialists in this field. Preferred methods include, but are not limited to, those described below.

The new compounds of formula I and Ia can be obtained by using the reactions and techniques described in this section. Reactions are performed in solvents appropriate to the reagents and substances and suitable for the ongoing transformations. In addition rastvoritelya, the reaction atmosphere, reaction temperature, duration of the experiment and processing methods, selected as the standard conditions for this reaction are well known to the person skilled in the art. Specialist in the field of organic synthesis should be understood that the functional groups present on different segments of the selected molecule must be compatible with the proposed reagents and reactions. Not all compounds of formula I, belong to this class may be compatible with certain conditions of the reactions required for some of the described methods. Such restrictions applied to the substituents compatible with the reaction conditions will be apparent to experts in this field, and you can also use alternative methods.

and R1, R2, R3, R4, X and Y have the above values.

Scheme 1

Compounds of the present invention, in which Q represents -(CO)-, can be obtained by the method, comprising the combination of an amine of formula II with an acid of formula III or its activated derivative as shown in scheme 1, where R1, R2, R3, R4X and Y are such as defined in General formula I, for everyone is the combination, may be protected prior to the reaction mix and then deleted.

The reaction mix or condensation is carried out using any of the many ways the formation of amide bonds, well-known specialist in the field of organic synthesis. These methods include, but are not limited to, the use of standard combination methods such as a method using mixed anhydrides of carbonic acid (isobutylparaben), the method using carbodiimide (N,N-dimethylaminopropyl-N'-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide, diisopropylcarbodiimide), the method using activated esters (pentafluorophenyl ester, p-nitrophenyloctyl ester, N-hydroxysuccinimidyl ether), carbonyldiimidazole method, azide method, phosphorus reagents such as THIEF-CL, the transformation of the acid of formula III in the acid chloride. Some of these methods (especially carbodiimide) can be improved by adding 1-hydroxybenzotriazole (HOBt).

Compounds of the present invention, in which C=X and Q simultaneously represent -(CS), can be obtained from the compounds of the present invention, in which C=X or Q or both represent -(CO)-, with the way in which ispolzuyutsa (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiophosphate-2,4-disulfide), etc. The alternate connection of the present invention, in which Q denotes -(CS) can be obtained by the method, comprising the combination of an amine of formula II with thiazolium reagent of formula IV, as shown in scheme 2, where R1, R2, R3, R1That is, x and Y are such as defined in General formula I, except that any Deputy or functional group that can potentially participate in the reaction mix may be protected prior to the reaction mix and then removed. Examples of such tjallingii reagents include, without limitation or complex tenoever, complex dayevery and N-thioacetazone (derived from imidazole, triazole, benzimidazole and benzotriazole).

and R1, R2, R3, R4, X and Y have the above values.

Scheme 2

Compounds of the present invention, in which Q denotes a bond, can be obtained by the method, comprising the combination of an amine of formula II with an alkylating reagent of formula V, as shown in scheme 3, where R1, R2, R3, R4, X and Y have the meanings defined in General formula I, except that any Deputy or functional group that potenziellen.

and R1, R2, R3, R4, X and Y have the above values.

Scheme 3

Usually alkylating reagents of General formula V include, but are not limited to, the iodides (L=I), bromides (L=Br), chlorides (L=Cl) and sulfonates (L=OSO2R, where R denotes a methyl, trifluoromethyl or 4-were).

Compounds of the present invention of General formula II (X=O) can be obtained using several methods known to experts in the field of organic synthesis. One of the sequences used for the synthesis is shown in scheme 4, where the method includes the combination of an amine of formula VII with fluoride, chloride, bromide, iodide or triflate of formula VIII, as shown in figure 4, where R1, R2, R3and R4such as defined in General formula I, to obtain the product of a combination of General formula VI, except that any Deputy or functional group that can potentially participate in the reaction mix may be protected prior to the reaction mix and then removed. This compound VI can then be restored to the corresponding amine with the General formula II by treatment standard of revitalizing Reagan dared, formate, ammonium or hydrazinehydrate, and a catalytic amount of palladium on coal.

L: Br, I, S2CF3or F and CL

Y: Cl, Br, I, S2CF3, S2CH3or OTs

FGI: Vzaimoprevrascheny functional groups.

R1, R2, R3, R4and Y have the above values.

Scheme 4

The reaction mix is performed using any of the methods of obtaining diphenylamino, well-known specialist in the field of organic synthesis. The preferred method is the method of nucleophilic aromatic substitution, which includes a combination of an amine with aristeidou or arylhalides in the presence of a base in a suitable solvent. It is established that for this process the best reason in particular are tert-piperonyl potassium (KOt-Bu), tert-piperonyl sodium (NaOt-Bu), sodium hydride (NaH) and potassium hydride (KN), however, other bases may also be used.

The reaction is usually carried out at ambient temperature (20-25°C) in bipolar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF) or N-organic (NMP), in an inert atmosphere, such as argon atmosphere or in the presence of palladium, which includes a combination of an amine with arylhalides (iodide, bromide, triflate or in some cases, chloride) in the presence of a base, a suitable source of Pd and a suitable phosphine ligand in an inert solvent.

The connection of palladium used in this method is not specially limited, specific examples are 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, 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)the biphenyl and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (Xantphos). The amount of palladium and ligand used in this way is usually from 0.1 to 10 mol.% from the number of aromatic halide (or triflate). It is established that for this process the best reason in particular are tert-piperonyl sodium (NaOt is 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 an atmosphere of argon or nitrogen.

Compounds of the present invention, in which R4is not hydrogen, can be obtained by the method, comprising the combination of an amine of the formula VI (R4=H) with an alkylating reagent, as shown in figure 4, where R1, R2, R3and R4such as defined in General formula I, except that any Deputy or functional group that can potentially participate in the reaction mix may be protected prior to the reaction mix and then deleted.

Usually an alkylating reagent of General formula R-Y include, but are not limited to, the iodides (Y=I), bromides (Y=Br), chlorides (Y=Cl) and sulfonates (Y=OSO2R' R' denotes methyl, trifluoromethyl or 4-were).

Compounds of the present invention in some cases can be obtained by a simple interconversion of functional groups (FGI), which is a standard process known specialists in the field of organic synthesis, where the functional group in the compounds with the General formula I (or any other intermediate compounds described in dandavate to the formation of new compounds with the General formula I. Examples of such methods include, without limitation, the hydrolysis of ester in basic conditions with obtaining acid; removing the protective group of the methyl ester by treatment, for example, borrisrandom (VVG3) to produce phenol; catalytic hydrogenation of the olefin with getting saturated hydrocarbon.

Hal: Br, I

R1and R2have the above values.

Scheme 5

Compounds of the present invention of General formula VII can be obtained by several methods known to experts in the field of organic synthesis. One of the sequences used for the synthesis is shown in scheme 5. The main stage includes a combination of bromide (or iodide) of General formula X with an acid chloride of the acid of General formula XI with getting benzophenone of the General formula IX. This compound IX can then be restored to the corresponding amine of General formula VII by treatment with standard reducing agents. Examples of such reducing reagents include, but are not limited to, chloride dihydrate tin (II), hydrogen, formate, ammonium or hydrazinehydrate, and a catalytic amount of palladium on coal. The reaction mix provider, by processing butyllithium obtaining a derivative of lithium or by treatment with magnesium obtaining a derivative of magnesium. The reactivity of this intermediate compound is then modulate by transmetallation, for example, derivatization of zinc by processing ZnCl2, ZnBr2or ZnI2. Received tsinkorganicheskih connection then subjected to reaction combination with the acid chloride of the acid of General formula XI in the presence of a catalytic amount of a complex of palladium(0). Examples of such a catalyst include, in particular not limited to, 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 described above. The described sequence of methods should not be construed as limiting the formation of compounds of the present invention of General formula I, and a change in the sequence of reactions is an alternative that is obvious to experts in the field of organic synthesis.

Suppose that the compounds of the present invention can be used.

The amount of the compounds of formula I and Ia (hereinafter referred to as active ingredient), necessary to obtain a therapeutic effect, of course, will vary depending on how the particular compound, the route of administration, and the mammal to be treated. A suitable dose of a compound of formula I for the system is from 0.1 to 200 mg/kg of body weight, the most preferred dose, administered once or several times a day, varies from 0.2 to 50 mg/kg of body weight of the mammal.

Although the active ingredient may be introduced separately as the raw chemical, it is preferable to include it in the form of pharmaceutical compositions. Is appropriate, if the mass of active ingredient is from 0.1 to 100% by weight of the composition. In the case of dosage forms of the composition contain from 0.07 mg to 1 g of the active ingredient. The local introduction of the mass of the active ingredient is preferably from 1 to 20% by weight of the composition, however, the weight of the active ingredient can be up to 50 wt.%.

Compositions suitable for nasal or transbukkalno introduction may include from 0.1 to 20 wt.%, for example, about 2 wt.%, active who may be injected into a patient and which can be easily processed and packaged, remaining as a physically and chemically stable dose comprising either the active material as such or a mixture with a solid or liquid pharmaceutical diluents or carriers.

Compositions of the present invention, intended for use in veterinary medicine and for treatment of humans, contain the active ingredient in combination with pharmaceutically acceptable carrier and optionally other(s) therapeutic(s) ingredient(s). The carrier(s) must be acceptable in the sense that it must be compatible with other ingredients of the composition and must not be detrimental to the recipient.

Songs include forms suitable for oral, ocular, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, local, or nasal transbukkalno introduction.

Typically, the compositions can be presented in a dosage form and may be obtained using any method known in the field of pharmacy. All methods include the stage of combining the active ingredient with the carrier which comprises one or more additional ingredients. In VI is or finely divided solid carrier, or with both of them and then if necessary shaping the product into the target composition.

Compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or pellets, each of which contains a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in aqueous 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 in the form of suppositories comprising the active ingredient and the media, as coconut oil, 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 the blood of the recipient.

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 ustavnogo, and for ocular injection can also be used liposomal composition or biodegradable polymer systems.

Compositions suitable for topical administration, including processing of the eye include liquid or semi-liquid preparations such as liniments, lotions, gels, means applying the emulsion 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 administration to the nasal or buccal cavity, include powder, kumarapalayam and sprayable compositions, such as aerosols and sprays.

In addition to the above ingredients the composition of this invention can include one or more additional ingredients.

In addition, the composition can contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, such as glucocorticoids, vitamin D, antihistamines, antagonists of platelet activating factor (PAF), anticholinergic agents, methylxanthines, -adrenergic agents, salicylates, indomethacin, flufenamic, naproxen, timelady, gold salts, penicillamine, agents, lowering the Ural branch of the new compounds of this invention are useful for veterinary and medical practice as systemic and local therapeutic agents intended for the treatment and prevention of diseases. The new compounds possess protivougrevoe activity and, among other things, anti-inflammatory and cytokine-regulating action, possibly through inhibition of map-kinase and can be used for the treatment and prevention of asthma, allergies, arthritis, including rheumatoid arthritis and spondylarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin diseases such as psoriasis and atopic dermatitis, uveitis, septic shock, AIDS and osteoporosis.

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

EXAMPLES

General methods, methods of preparation and examples

Specific examples of compounds of formula I are listed in table 2.

All melting points are uncorrected. The values of chemical shifts () (M. D.) spectra (300 MHz)1H and13Nuclear magnetic resonance (NMR) are shown, unless otherwise indicated, for solutions in deuterium chloroform and hexacyanometallate, in relation to the internal signals standardising (doublet (d), triplet (t), Quartet (q)), or uncertain, given approximately at the midpoint, if you do not specify the interval (singlet, Shir. wide). Use anhydrous solvents. The term "chromatography" refers to column chromatography carried out on silica gel using flash techniques.

This specification uses the following abbreviations: Dl3= deuterochloroform, DMF = N,N-dimethylformamide, DMSO-d6hexacyanometallate, Et3N = triethylamine, EtOAc = ethyl acetate; Et2O=diethyl ether, NMRA = hexamethylene phosphorus, NMM=N-methylmorpholine, THF = tetrahydrofuran, THIEF-CL = bis(2-oxo-3-oxazolidinyl)phosphinic acid, acid chloride, TLC=thin-layer chromatography.

The numbers in table 2 correspond to the numbering in the formula below

General methods

The combination of the compounds of General formula II with compounds of General formula III (Z=Cl) to obtain the compounds of General formula I (Q=O) or their protected derivatives.

To a cooled (0°C) solution of amine (0.9 mmol) of General formula II and Et3N (2.7 mmol) in CH2CL2(5 ml) is added slowly a solution of carboxylic acid (1.2 mmol) of General formula III in CH2Cl2and the solution successively washed with 2M Hcl, water and saturated salt solution, then dried (PA2SO4), filtered and concentrated in vacuo. The residue is purified either by crystallization or chromatography, getting anilide General formula I or a protected derivative.

General method 2

The combination of the compounds of General formula II with compounds of General formula III (Z=OH) to obtain the compounds of General formula I (Q=O) or their protected derivatives.

NMM (2.8 mmol) are added to a solution of acid (2.8 mmol) of General formula III (Z=O) in THF (10 ml) at -15°C, and then added dropwise to isobutylparaben (2.8 mmol). The mixture is stirred for 30 minutes, add a solution of amine (2.0 mmol) of General formula II in THF (10 ml) and the resulting suspension stirred for 1 h at 0°C and at RT over night. The reaction mixture was poured into EtOAc and the solution successively washed with 1M Hcl, 25% Panso3and saturated salt solution, then dried (gSO4), filtered and concentrated in vacuo. The residue is purified or crystallization, or by chromatography, getting anilide General formula I or a protected derivative.

General method 3

The alkylation of compounds of General formula II with compounds of General formula V with PL) of General formula II, TO2CO3(2.0 mmol) and KI (0.1 mmol) in DMF (5 ml) is added alkylating reagent (1.0 mmol) of General formula V. the Mixture is stirred for 24 h at 25°C or up until starting material is no longer detected by TLC. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated in vacuum. The residue is purified by chromatography, getting alkilirovanny amine of General formula I or a protected derivative.

General method 4

The combination of the compounds of General formula II with compounds of General formula III (Z=YCOO) to obtain the compounds of General formula I (Q=O) or their protected derivatives.

To a solution of amine (2.9 mmol) of General formula II in acetic acid (100%, 8 ml) is added slowly to the acid anhydride (3.8 mmol) of General formula III. The mixture is stirred for 2 h at RT or until until starting material is no longer detected by TLC. To the reaction mixture, water is added, the solution stirred for 30 min and then twice extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified either by crystallization or chromatography, p is benzoyl)phenylamino]phenyl]succinamide acid (compound 101)

A solution of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone (3.0 mmol) in glacial acetic acid (5.0 ml) with stirring, heated to 70°C, then add the anhydride of succinic acid (4.0 mmol). Within 20 min keep the temperature at 100°C, after which the reaction mixture was concentrated in vacuo, receiving light brown syrup-like substance which crystallizes upon standing. After trituration with a mixture of Et2O/CH2Cl23:1, followed by filtration and washing, get the product as white crystals.13With NMR (DMSO-d6): 195,3, 173,9, 170,6, 149,3, 142,4, 139,4, 136,5, 133,5, 132,4, 131,8, 131,1, 130,7, 128,8, 126,5, 125,7, 125,3, 125,1, 124,5, 123,7, 115,3, 112,2, 30,8, 29,1, 19,8.

Example 2.

2'-[3-Chloro-4-(2-methylbenzoyl)phenylamino]octanamide (compound 102)

General methods: 1

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

The original connection III: octanolwater.

Purification: chromatography using as eluent a mixture of EtOAc/pentane 1:3.

13With NMR (Dl3): 196,8, 172,8, 148,9, 139,2, 137,6, 135,1, 133,7, 132,8, 131,8, 131,2, 130,8, 129,5, 128,3, 126,2, 125,6, 125,4, 124,8, 124,1, 116,0, 112,4, 37,2, 31,6, 29,1, 29,0, 25,7, 22,6, 20,3, 14,0.

Example 3.

4-Bromo-2'-[3-chloro-4-(2-meth is II: 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone.

The original compound III: 4-bromobutyrate.

Purification: chromatography using as eluent CH2Cl2and then a mixture of EtOAc/CH2Cl21:20

13With NMR (Dl3): 196,8, 171,1, 148,8, 139,1, 137,8, 135,1, 133,6, 132,5, 131,8, 131,3, 130,9, 129,6, 128,7, 126,3, 125,9, 125,4, 125,0, 123,8, 116,1, 112,5, 44,3, 33,8, 27,9, 20,4.

Example 4.

Ethyl-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]succinylate (compound 104)

General method: 2

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

The original connection III: monoethylamine.

Purification: chromatography using as eluent a mixture of EtOAc/pentane 1:4 and 1:2.

13With NMR (Dl3): 196,5, 173,4, 171,0, 148,5, 139,2, 137,9, 135,0, 133,5, 133,4, 131,3, 130,8, 129,6, 128,9, 126,5, 125,4, 125,2, 124,7, 123,8, 116,5, 112,6, 61,2, 29,7, 20,4, 14,2, 14,2.

Example 5.

2-(Methoxyethoxy)-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-acetanilide (compound 105)

General method: 2

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

The original compound III: 2-(2-methoxyethoxy)acetic acid.

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

,1, 20,4.

Example 6.

N,N-dimethyl-N'-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenylsuccinic (compound 106)

General method: 2

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

The original connection III: N,N-dimethylsuccinic acid.

Purification: chromatography using EtOAc as eluent

13With NMR (Dl3): 196,5, 172,2, 148,5, 139,4, 137,8, 134,9, 133,7, 133,5, 131,2, 130,7, 130,3, 129,6, 128,5, 126,2, 125,3, 125,3, 124,4, 122,5, 116,7, 112,5, 37,1, 35,8, 32,4, 29,6, 20,4.

Example 7.

2-Hydroxy-2'-[3-chloro-4-(2-methoxybenzoyl)phenylamino]-acetanilide (compound 107)

General methods: 1

The original compound II: 4-(2-aminophenylamino)-2-chloro-2'-methoxybenzophenone.

The original connection III: acetoxyacetyl.

Purification of O-acetylated derivative (I) is carried out by chromatography using as eluent a mixture of Et2O/pentane 1:4. Removing the protective groups of the protected derivative (I) (0.38 mmol) and K2CO3(0.5 mmol) is stirred for 1 h at Meon (5 ml) at ambient temperature. The reaction mixture was poured into EtOAc, and the solution successively washed with water and saturated salt solution, then dried (Na

13With NMR (DMSO-d6): 192,3, 170,5, 157,1, 149,7, 133,7, 133,4, 132,8, 132,4, 130,6, 129,4, 129,2, 126,8, 125,7, 125,4, 124,8, 122,2, 120,4, 114,7, 112,0, 111,7, 61,5, 55,6.

Example 8

2-Hydroxy-2'-[3-chloro-4-(2-methylbenzoyl)-phenylamino]acetanilide (compound 108)

The target connection receive according to the method of example 7, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methoxybenzophenone using 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone. The connection additionally purified by chromatography, using as eluent a mixture of EtOAc/pentane 1:1.

So pl.: 127-129°C.

13With NMR (DCl3): 197,4, 170,9, 149,0, 138,8, 138,0, 135,0, 133,5, 132,1, 131,4, 131,4, 131,2, 129,9, 128,6, 126,4, 126,2, 125,4, 125,3, 123,4, 116,1, 112,4, 62,4, 20,5.

Example 9.

2-Hydroxy-2'-[3-fluoro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 109)

The target connection receive according to the method of example 7, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methoxybenzophenone using 4-(2-aminophenylamino)-2-fluoro-2'-methylbenzophenone. Connection optionally purified by crystallization from CH2Cl2.

So pl.: 149-150°C.

13With NMR (DMSO-d6): 192,8, 170,5, 164,6, 161,2, 152,6, 152,4, 140,5, 134,9, 133,4, 132,9, 130,5, 130,3, 129,8, 127,3, 126,0, 125,7, 125,4, 124,8, 122,3, 115,7, 115,5, 109,8, 100,0, 99,7, 61,5, 19,2.

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

The original connection III: N-(9-fluorenylmethoxycarbonyl)glycine.

Cleaning of the FMOC-protected derivative (I) is carried out by chromatography using as eluent a mixture of E2SLA/pentane 1:4 and 1:2. Removing the protective groups of the Protected derivative (I) (0.16 mmol) and CsF (0.33 mmol) is stirred in a mixture of CH2CL2(6 ml) and CH3SP (2 ml) for 6 days at ambient temperature. The reaction mixture was poured into water and EtOAc and the organic phase is separated. The aqueous phase is extracted with additional EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo, obtaining the crude product, which was purified by chromatography, using as eluent a mixture of EtOAc/pentane 1:2.

13With NMR (Dl3): 196,6, 171,8, 148,8, 139,3, 137,7, 135,0, 133,6, 132,6, 131,5, 131,2, 130,8, 129,5, 128,5, 126,2, 125,7, 125,3, 124,8, 123,4, 116,1, 112,4, 44,9, 20,4.

Example 11.

Ethyl-2-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]aniline]acetate (compound 111)

General method: 3

The original compound II: 4-(2-aminophenylamino)-2-chloro-2'-methyl-benzophenone.

The original connection V: ethylbromoacetate.

Example 12.

2-Chloro-4-[2-(6-hydroxyacetylamino)phenylamino]-2'-methyl-benzophenone (compound 112).

To a solution of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone (0.50 mmol) in NMRA (5 ml) is added 6-bromhexina (from 0.76 mmol) and Panso3(5.0 mmol). The mixture is stirred for 24 h at 60°C, add an additional amount of 6-Bromhexine (0.36 mmol) and stirring is continued for 6 hours, the Reaction mixture was poured into ice water and extracted with EtOAc. The combined organic extracts washed with saturated salt solution, dried (gSO4), filtered and concentrated in vacuo. The residue is twice purified by chromatography, using as eluent a mixture of EtOAc/hexane 1:2 and then Et2O/hexane 1:4, receiving alkilirovanny aniline in the form of oil.

1H NMR (Dl3): 7,05-7,40 (m, 8H), 6,60-to 6.80 (m, 3H), 6,53 (DD, 1H), 5,49 (s, 1H), 3,97 (Shir.s, 1H), 3,60 (Shir.t, 2H), 3,13 (Shir.t, 2H), 2,47 (s, 3H), 1,20-1,70 (m, 8H).

Example 13.

2-Chloro-4-[2-(3-hydroxypropylamino)phenylamino]-2'-methylbenzophenone (compound 113)

To a solution of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone (10.0 mmol) in NMR (50 ml) is added 3-BV ice water and the precipitated product is filtered, washed with water and dried. The crude product is purified by chromatography, using as eluent a mixture of EtOAc/Et2O 1:9, to obtain the alkylated aniline in the form of oil.

13With NMR (DMSO-d6): 195,0, 151,0, 144,2, 139,6, 136,1, 133,6, 130,9, 130,4, 128,5, 127,0, 126,1, 125,5, 125,2, 124,6, 115,6, 114,3, 111,2, 110,6, 58,6, 39,9, 31,7, 19,6.

Example 14

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]hexanamide (compound 114)

General methods: 1

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

The original connection III: hexanoate.

Purification: chromatography using as eluent a mixture of EtOAc/pentane 1:4.

13With NMR (Dl3): 196,8, 172,5, 148,3, 138,9, 137,9, 135,0, 133,5, 133,5, 131,4, 131,3, 131,1, 129,7, 129,3, 129,0, 126,3, 125,4, 118,5, 116,2, 112,7, 37,3, 31,3, 25,2, 22,4, 20,5, 13,9.

Example 15

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]but-3-enameled (compound 115)

General method: 2

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

The original connection III: 3-butenova acid.

Purification: chromatography using as eluent dichloromethane.

13With NMR (CDCl3): 196,9, 169,8, 148,5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-4-methylpentanoate (compound 116)

General methods: 1

The original compound II: 4-(2-aminophenylamino)-2-chloro-2'-methyl-benzophenone.

The original compound III: 4-methylpentanoate.

Purification: chromatography using as eluent a mixture of EtOAc/pentane 1:6.

13With NMR (Dl3): 196,7, 172,7, 148,3, 138,9, 138,0, 135,0, 133,5, 133,4, 131,4, 131,3, 131,1, 129,7, 129,4, 129,0, 126,3, 125,4, 118,5, 116,3, 112,7, 35,3, 34,3, 27,7, 22,3, 20,5.

Example 17.

2'-[3-Chloro-4-(2-methylbenzoyl)phenylamino]-2-methylpentanediol (compound 117)

General methods: 1

The original compound II: 4-(2-aminophenylamino)-2-chloro-2'-methyl-benzophenone.

The original compound III: 2-methylpentanoate.

Purification: chromatography using as eluent a mixture of EtOAc/pentane 1:4.

13With NMR (dl3): 196,6, 176,0, 148,9, 139,2, 137,8, 135,1, 133,6, 132,6, 132,1, 131,3, 130,8, 129,6, 128,8, 126,3, 126,1, 125,4, 123,8, 115,8, 112,3, 42,0, 36,6, 20,6, 20,4, 17,9, 14,0.

Example 18.

N-[5-Bromo-2-[3-chloro-4-(4-ethoxy-2-methylbenzoyl)phenylamino]-phenyl]succinamide acid (compound 118)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-chloro-4'-ethoxy-2'-methylbenzoate is USD 114.9, 113,7, 111,1, 63,7, 30,4, 29,1, 21,9, 14,7.

Example 19.

N-[5-Bromo-2-[3-ethoxy-4-(2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 119)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-ethoxy-2'-methylbenzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13WITH NMR(): 195,3, 173,7, 170,8, 160,0, 150,1, 142,9, 134,3, 132,6, 132,2, 132,1, 129,9, 128,7, 127,5, 126,8, 126,5, 125,0, 124,5, 118,6, 114,7, 107,2, 98,1, 62,9, 30,7, 28,8, 19,2, 13,5.

Example 20.

N-[5-Bromo-2-[3-chloro-4-(2,3-dimethylbenzoyl)phenylamino]phenyl]succinamide acid (compound 120)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-chloro-2',3'-dimethylbenzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13WITH NMR(): 195,6, 173,7, 170,7, 148,9, 140,3, 137,4, 134,2, 133,8, 133,6, 133,3, 131,6, 131,2, 127,5, 126,7, 126,6, 125,7, 125,3, 125,1, 115,7, 112,1, 30,7, 28,8, 19,6, 16,0.

Example 21.

N-[5-Bromo-2-[3-chloro-4-(4-n-butyl-2-methylbenzoyl)phenylamino]-phenyl]succinamide acid (compound 121)

Relevo the ut 4-(2-amino-4-brompheniramine)-4'-n-butyl-2-chloro-2'-methylbenzophenone.

13With NMR (Dl3): 199,4, 178,9, 170,9, 147,9, 147,0, 139,4, 135,1, 134,4, 133,6, 132,0, 131,9, 131,5, 130,2, 129,5, 128,4, 125,7, 122,0, 116,6, 115,2, 113,6, 35,6, 33,2, 30,4, 29,1, 22,4, 21,2, 13,9.

Example 22.

N-[5-Bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 122)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2,4'-dichloro-2'-methyl-benzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13With NMR (DMSO-d6): 194,1, 173,7, 170,7, 148,9, 139,1, 137,9, 135,1, 133,4, 133,3, 131,2, 130,7, 130,5, 127,5, 126,7, 126,4, 125,6, 125,3, 115,8, 115,5, 112,3, 30,7, 28,8, 19,4.

Example 23.

N-[5-Bromo-2-[3-fluoro-4-(2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 123)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-fluoro-2'-methylbenzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13With NMR (DMSO-d6): 192,8, 173,7, 170,8, 162,7, 151,3, 140,5, 134,9, 133,4, 133,1, 131,1, 130,5, 129,8, 127,5, 127,3, 126,7, 125,6, 125,4, 116,0, 115,9, 110,3, 100,6, 30,7, 28,8, 19,2.

Example 24.

ptx2">The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone use 4'-(2-amino-4-brompheniramine)-2'-chloro-2,4,5-trimethylbenzene. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13With NMR (DMSO-d6): 195,2, 173,7, 170,7, 148,2, 139,7, 136,2, 134,3, 133,2, 133,1, 132,8, 132,8, 132,4, 131,5, 130,4, 127,8, 127,5, 126,7, 124,9, 115,5, 115,4, 112,3, 30,7, 28,8, 19,4, 19,2, 18,6.

Example 25.

N-[5-Bromo-2-[3-chloro-4-(4-fluoro-2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 125)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-chloro-4'-fluoro-2'-methylbenzophenone.

13With NMR (Dl3): 197,7, 178,6, 170,9, 164,5, 147,6, 142,4, 134,3, 134,0, 133,6, 133,5, 132,0, 130,8, 129,6, 129,1, 128,0, 123,1, 118,6, 116,4, 116,1, 113,5, 112,7, 30,7, 29,1, 21,1.

Example 26.

N-[5-Bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl]succinamide acid (compound 126)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-chloro-2',5'-dimethylbenzophenone. The connection is additionally crystal clear 133,2, 133,2, 131,3, 130,9, 129,1, 127,5, 127,0, 126,7, 125,1, 115,6, 112,3, 30,7, 28,8, 20,3, 19,3.

Example 27.

N-[5-Bromo-2-[3-fluoro-4-(4-methoxy-2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 127)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2-fluoro-4'-methoxy-2'-methylbenzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13With NMR (DMSO-d6): 191,9, 173,7, 170,8, 162,0, 160,7, 150,4, 138,9, 133,2, 132,8, 132,1, 131,4, 131,1, 127,5, 126,7, 125,2, 117,0, 116,3, 115,6, 110,6, 110,4, 100,7, 55,2, 30,7, 28,8, 20,1.

Example 28.

N-[5-Bromo-2-[3-chloro-4-(3-chloro-2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 128)

The target connection receive according to the method of example 1, but instead of 4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone using 4-(2-amino-4-brompheniramine)-2,3'-dichloro-2'-methylbenzophenone. Connection optionally purified by crystallization from mixtures of dichloromethane and n-hexane.

13With NMR (DMSO-d6): 193,8, 173,7, 170,7, 149,4, 142,2, 134,5, 134,2, 134,0, 133,5, 133,2, 130,9, 130/7, 127,5, 127,2, 126,7, 126,6, 125,6, 125,4, 116,0, 115,7, 112,2, 30,7, 28,8, 16,6.

Example 29.

Tablet containing compound 111, the components of cellulose 2

Carboxymethylcellulose sodium 10

Magnesium stearate 1

The active ingredient, lactose and starch pereshivayut to a homogeneous state in a suitable mixer and moistened with a 5% aqueous solution of methyl cellulose 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 until the water content becomes less than 1%, in a suitable drying apparatus, for example in a furnace for processing in a fluidized bed or in a drying oven. The dried granules are passed through a sieve with the hole diameter of 1 mm and mixed with carboxymethylcellulose sodium to a homogeneous state. Add magnesium stearate and stirring is continued for a short period of time. Using a suitable device for tableting of pellets get tablets weighing 200 mg.

Example 30

Composition for injection containing compound 111, components, %:

Compound 111 (active substance) 1

Sodium chloride q.s.

Ethanol 10

Water for injection to 100

The active substance is dissolved in ethanol (10%), then add water for injection to 100%, of which pre-cooked ISAT the CLASS="ptx2">Example 31

The composition of the cream containing compound 101

Compound 101 (10 g) dissolved in octyldodecanol (250 g), receiving 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), receiving part of the Century Cetosteatil alcohol (50 g) and ARLACEL 165® (50 g) is melted in a vessel at 70 to 80°C. Add part a and heated to 60-70°C. the Aqueous phase is also heated to 60-70°C and added slowly to the melted oil phase under high speed stirring. Homogenized components cooled to room temperature.

Sources of information

Barnes, Peter J.; Cytokine-directed therapies for asthma, Journal of Allergy and Clinical Immunology (2001), 108 (2, Suppl.), S72-Set S76.

Rusznak, Csaba; New approaches for the treatment of allergic conditions, Current Medicinal Chemistry: Anti-Inflammatory &Anti-Allergy Agents(2003), 2 (2), 107-118.

Sieper, Joachim; Braun, Juergen; Anti-TNF agents for the treatment of spondyloarthropathies. Expert Opinion on Emerging Drugs(2002), 7 (2), 235-246.

Sebastiani, Silvia; Albanesi, Cristina; De Pita, Ornella; Puddu, Pietro; Cavani, Andrea; Girolomoni, Giampiero; The rote of chemokines in allergic contact dermatitis, Archives of Dermatological Research(2002), 293 (11), 552-559.

Nahar, Ibrahim K.; Shojania, Kam; Marra, Carlo A.; Alamgir, Abul H.; Anis, Aslam H.; Infliximab treatment of rheumatoid arthritis and Crohn's disease; Annals of Pharmacotherapy(2003), 37 (9), 1256-1265.

Taylor, Peter C.; An the potential role for anti-tumor necrosis factor therapy in heart disease; Pharmacology & Therapeutics(2002), 94 (1-2), 123-135.

Kam, Lori Y.; Targan, Stephan R.; TNF antagonists for the treatment of Crohn's disease; Expert Opinion on Pharmacotherapy(2000), 1 (4), 615-622.

LaDuca, Jeffrey R.; Gaspari, Anthony A.; Targeting tumor necrosis factor alpha: New drugs used to modulate inflammatory diseases; Dermatologic Clinics(2001), 19 (4), 617-635.

Girolomoni, Giampiero; Pastore, Saveria; Albanesi, Cristina; Cavani, Andrea; Targeting tumor necrosis factor - as a potential therapy in inflammatory skin diseases; Current Opinion in Investigational Drugs (PharmaPress Ltd.) (2002), 3 (11), 1590-1595.

Sebastiani, Silvia; Albanesi, Cristina; De Pita, Ornella; Puddu, Pietro; Cavani, Andrea; Girolomoni, Giampiero; The role of chemokines in allergic contact dermatitis; Archives of Dermatological Research(2002), 293 (11), 552-559.

Reimold, A. M.; TNF - as therapeutic target: New drugs, the more applications; Current Drug Targets: Inflammation & Allergy(2002), 1 (4), 377-392.

Rabinovici, Reuven; Yue, Tian Li; Vernick, Jerome; Feuerstein, Giora; PAF and TNF - interactions in the pathophysiology of septic shock; Advances in Experimental Medicine and Biology (1991), 314 (Cell-Cell Interact. Release Inflammatory Mediators), 193-203.

Rifas, L; Bone and cytokines: beyond JL-1, IL-6 and TNF-; Calcified Tissue International(1999), 64 (1), 1-7.

Gougeon, Marie-Lise; Ledru, Eric; IMaora, Honami; Bocchino, Marialuisa; Lecoeur, Herve; HIV, cytokines and programmed cell death (PCD): A subtle interplay; Annals of the New York Academy of Sciences (2000), 926 (Mechanisms of Cell Death II), 30-45.

1. The compound of General formula I

where R1and R3designate one or more identical or different substituents selected from the group consisting of halogen, (C1-C3) what I anthopology, and if R1refers to several substituents, at least one substituent R1is orthopaedie;

R2denotes one Deputy in anthopology, and this Deputy is selected from the group consisting of halogen and (C1-C3) alkoxy;

R3can additionally denote hydrogen;

R4denotes hydrogen;

X denotes oxygen;

Q represents -(CO)- or a bond;

Y denotes (C5-C15) alkyl, (C2-C15) olefinic group;

with any of these groups may be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5defined below, except that when Q represents a bond, then Y denotes unsubstituted (C6-C15)alkyl or (C5-C15)-alkyl, substituted groups R5; AND (C1-C4)alkyl, substituted by one or more substituents selected from the group R5; or a group of formula -(Z-O)n-Z, where Z is a (C1-C3)alkyl, n is an integer >1; and the number of atoms in nepreryvnosti, amino, (C1-C6)alkylamino, (C1-C3)alkoxycarbonyl, -COOH, -CONHR' or-COONR'R' R' means (C1-C3) alkyl,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where R1represents one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, (C1-C2)alkyl and (C1-C3)alkoxy; R2denotes one Deputy selected from the group consisting of fluorine, chlorine, bromine, and (C1-C3)alkoxy; R3represents one or more identical or different substituents selected from the group consisting of hydrogen, halogen, (C1-C3)alkyl and (C1-C3)alkoxy; R4represents hydrogen; X represents oxygen; Q represents -(CO)- or a bond; Y represents (C6-C10)alkyl, (C2-C10)olefinic group; and any of them can be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5defined below; and (C1-C5)alkyl, substituted by one or more substituents of formula R5; or the group testo atoms in contiguous linear sequence of atoms in the group Y is not greater than 9; preferably Q-Y represents -(CO)-(C5)alkyl which may be optionally substituted by one or more identical or different substituents represented by the formula, R5; R5denotes halogen, hydroxy, amino, (C1-C4)alkylamino, (C1-C3) alkoxycarbonyl, -COOH or-COONR'R' R' means (C1-C2) alkyl.

3. The compound according to any one of the preceding paragraphs, where R1represents one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, methyl or methoxy; R2denotes one Deputy selected from the group consisting of fluorine, chlorine, bromine and methoxy; R3represents one or more identical or different substituents selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxy, methyl and methoxy; R4represents hydrogen; Y represents (C5-C7) alkyl or (C2-C4) alkenyl; and any of them may be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5; or (C1-C4) alkyl, substituted od is2-alkoxycarbonyl, -COOH or SOP(CH3)2; or a group of formula-CH2-O-CH2-CH2-O-CH3.

4. Connection on p. 1, selected from the group consisting of the following compounds:

N-[2-[3-Chloro-4-(2-methylbenzoyl)phenylamino]phenyl]succinamide acid (compound 101),

2'-[3-Chloro-4-(2-methylbenzoyl)phenylamino]octanamide (compound 102),

4-Bromo-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]butanamide (compound 103),

Ethyl-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]succinylate (compound 104),

2-(2-Methoxyethoxy)-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-acetanilide (compound 105),

N,N-Dimethyl-N'-2-[3-chloro-4-(2-methylbenzoyl)phenylamino]phenyl-succinamide (compound 106),

2-Hydroxy-2'-[3-fluoro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 109),

2-Amino-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]acetanilide (compound 110),

Ethyl-2-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]aniline]acetate (compound 111),

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]but-3-enameled (compound 115),

5'-Bromine-2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]-4-methylpentanoate (compound 116),

N-[5-Bromo-2-[3-ethoxy-4-(2-mail)phenylamino]-phenyl]succinamide acid (compound 120),

N-[5-Bromo-2-[3-chloro-4-(4-chloro-2-methylbenzoyl)phenylamino]-phenyl]succinamide acid (compound 122),

N-[5-Bromo-2-[3-fluoro-4-(2-methylbenzoyl)phenylamino]phenyl]-succinamide acid (compound 123),

N-[5-Bromo-2-[3-chloro-4-(2,4,5-trimethylbenzoyl)phenylamino]-phenyl]succinamide acid (compound 124),

N-[5-Bromo-2-[3-chloro-4-(2,5-dimethylbenzoyl)phenylamino]phenyl]-succinamide acid (compound 126),

and its salts with pharmaceutically acceptable acids, hydrates and solvate.

5. The compound according to any one of paragraphs.1-4, applicable for obtaining a medicinal product intended for the treatment and/or prevention of asthma, allergies, arthritis, including rheumatoid arthritis and spondylarthritis, gout, atherosclerosis, chronic inflammatory bowel disease (Crohn's disease), proliferative and inflammatory skin diseases such as psoriasis, atopic dermatitis, uveitis, septic shock, AIDS, osteoporosis and acne.

6. Pharmaceutical composition for inhibiting the secretion of interleukin 1(IL-1) and tumor necrosis factor (TNF), containing as active ingredient a compound according to any one of paragraphs.1-4 together with a pharmaceutically acceptable carrier and naticoides, vitamins D, antihistamine drugs, antagonists of platelet activating factor (PAF), anticholinergic agents, methylxanthines, -adrenergic agents, salicylates, indomethacin, flufenamic, naproxen, cimegidine, gold salts, penicillamine, agents that lower the cholesterol level in serum, retinoids, zinc salts and salicylazosulfapyridine (salazopyrin).



 

Same patents:

The invention relates to new N-arylamido-3N-arylamino-4-amino-(4-nitrophenyl)butane acid, which has the ability to activate the germination of wheat seeds, formula I, where AG = C6H5(1), -CH2-C6H5(2)

The invention relates to new derivatives of glycinamide formula (I), which, as agonists of the receptors, cholecystokinin, can be used in pharmaceuticals, which allows to treat some digestive disorders, obesity, psychosis and other

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to compounds of formula (1)

< / BR>
in which R1means aliphatic, linear or branched (C1-C12)-alkyl group, aryl group, possibly substituted by one or more groups of CF3; R2means a hydrogen atom, halogen atom, HE, OR7in which R7means a linear or branched aliphatic (C1-C4)-alkyl radical; R3means a linear or branched, mono - or polygalacturonic (C1-C4)-alkyl radical or phenyl; R4means linear or branched (C1-C4)-alkyl radical, possibly substituted by a halogen atom, or denotes a radical of CF3

The invention relates to improvements in the area of contrast media, in particular to iodinated Radiocontrast agents

The invention relates to a derivative of hemin or their pharmaceutically acceptable salts and inhibitors of proteolytic enzymes, which are the compounds of General formula (I)

where R1and R2- substituents, which may represent amino acids, derivatives of amino acids, peptides, consisting of 1-15 amino acid residues, derived peptides consisting of 1-15 amino acid residues, and-carboxyl group of amino acids or peptides and side groups of amino acids or peptides can be modified, and it is possible that R1=R2or R1R2=OH; carboxyl group of the porphyrin can be modified methyl or other C2-C8-ester or a physiologically acceptable salt; Y-represents Cl-CH3SOO-; Me represents Fe, with the exception of compounds where

Me=Fe3+, Y-=Cl-,

R1=-LeuLeuValPheOMe, R2=-OH; R1=-ValPheOMe, R2=-OH; R1=-LeuHisOMe,

R2=-OH; R1=-LeuHisAlaOMe, R2=-OH; R1=-LeuHisNHC10H20COOMe, R22=-LeuHisNHC10H20COOMe; R1=-Lys(Tfa)AlaAlaOMe, R2=-OH;

R1=-ValPheOMe, R2=-LeuHisOMe; R1=-LeuLeuValPheOMe, R2=-LeuHisOMe;

R1=-LeuLys(Tfa)LeuOMe, R2=-OH; R1=-LeuLys(Tfa)LeuOMe, R2=-LeuHisOMe;

R1=-Lys(Tfa)AlaAlaOMe, R2=-AlaHisLys(Cbz)LeuOMe; R1=-GlyOBzl,

R2=-GlyOBzl; R1=-HisOMe, R2=-HisOMe; R1=-LeuHisOMe, R2=-LeuHisOMe;

R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-LeuHisLeuGlyCys(Bzl)OBzl;

R1=-LeuHisOMe, R2=-OEt; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OEt; R1=-OBzl,

R2=-OBzl; R1=-OBzl, R2=-OH; R1=-AlaOMe, R2=-OBzl; R1=-HisOMe, R2=-OBzl;

R1=-LeuHisOMe, R2=-OBzl; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OBzl;

R1=-LeuHisAlaLys(Cbz)GlyCys(Bzl)OBzl, R2=-OBzl; R1=-LeuHisLys(Cbz)OMe,

R2=-OH; R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OH; R1=-LeuHisOMe, R2=-OMe;

R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OMe,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisAlaLys(Cbz)Cys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisOMe, R2=-OMe;

R1=-GlyProArgGlyGlyOMe, R2=-OH;

R1=-ArgProProGlyPheSer(Bzl)PheArgGlyGlyOMe, R2=-OH,

two ways to get hemin derivatives of General formula I, hemin derivatives of the formula I, formerly known above, as inhibitors of proteolytic enzymes: the HIV protease, pepsin, trypsin, chymotrypsin

The invention relates to pharmaceutical industry and relates to the creation of a means for inhibiting reproduction enveloped viruses

The invention relates to the field of medicine and pharmaceutics and relates to a composition for the prevention and treatment of HIV-1 infection, including nucleoside reverse transcriptase FROM HIV-1, representing heterocyclics(ACS/thio)anilide, a second inhibitor of HIV-1, which does not choose the same HIV-1 mutant strain, or strains, select the first compound is an inhibitor of HIV-1

The invention relates to bicyclerelated analogues of General formula (1) and the oligonucleotides on the basis thereof, containing one or more structural units of the General formula (1A), where R1represents a hydrogen atom, a protective group, the group of phosphoric acid, etc., R2is sidegroup or amino group which may be substituted, represents a purine-9-ilen, or 2-oxo-1,2-dihydropyrimidin-1-ilen group which may be substituted by one or more substituents

The invention relates to pharmaceutical compositions for inhibiting integrase, which contains as active substance a compound of the formula (I)

where X denotes a hydroxy-group; Y represents a group-COORAin which RArepresents hydrogen or ester residue, or denotes a group-CONRINRCin which RINand RCeach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl, and1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or AND1denote optionally substituted indol-3-yl, or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate, compounds of formulas I, II

where X, Y described above, AND1- optional replaced heteroaryl; Z1and Z2indicate the relationship; Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO; Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-; R1means neobyzantine substituted heterocycle, R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxy or halogen; R=0 or 1, with the exception of compounds in which (1) Y and/or AND1denotes optionally substituted indol-3-yl and (2) X denotes a hydroxy-group, Y represents 2-thienyl, AND1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH-, R1denotes phenyl or para-tolyl and p=0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, AND1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, AND1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-met is 1 denotes phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen or ethyl, AND1signifies 3-indolyl, imidazo[1,2-a]pyridine-3-yl or imidazo[2,1-b] thiazole-5-yl, Z1, Z2and Z3each represents a bond, R1denotes optionally substituted phenyl, and tautomer, prodrug, pharmaceutically acceptable salt or hydrate; various farmkompanijam, comprising as active ingredient the compound II, the drug compound having anti-HIV activity; the method of obtaining compounds of formula III

as well as the intermediate products of the formula

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2and R1denotes phenyl, substituted with fluorine, and

where And denotes C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, Q denotes trail and L denotes ethoxypropan

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc
Up!