Derivatives arylsulfonamides acid, the method of production thereof, pharmaceutical composition, method of inhibiting matrix metalloproteinases and method of treatment

 

(57) Abstract:

Describes derivatives arylsulfonamides acid of General formula I, where Ar, X, n, R3, R4specified in paragraph 1 of the claims, which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor. Can be used to treat arthritis, cancer, ulcer tissue, septic shock. Describes the method of production thereof, method of inhibition, treatment and farbkomposition on the basis of the compounds of formula I. 5 C. and 13 C.p. f-crystals, 1 PL.

This invention relates to a derivative arylsulfonamides acid, which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (hereinafter referred to as TNF) and is therefore useful for the treatment of diseases selected from the group consisting of arthritis, cancer, ulcer tissue, restenosis, periodontal-tion of the disease, congenital bullous of bullosa, scleritis and other diseases characterized by the activity of matrix metalloproteinases, AIDS, sepsis, septic shock and other diseases involving the production of TNF.

This invention also otog people and to pharmaceutical compositions used for this purpose.

There are a number of enzymes, which act destructively on the structural proteins that are structurally related metalloproteinases. Matricerara metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in the destruction of the tissue structure (e.g., collagen deficiency) and are the cause of many pathological conditions involving abnormal metabolism of connective tissue and the basic structure of membranes, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), ulcer tissues (e.g., tissue of the cornea, ulcer and stomach), abnormal wound healing, periodontal disease, bone disease (e.g., Paget's disease and osteoporosis), metastases or invasion of tumors, and HIV infection (J. Leuk.Biol., 52(20): 244-248, 1992).

It is known that tumor necrosis factor is involved in the pathogenesis of many infectious and autoimmune diseases (W. Friers, FEBS Letters, 1991, 285, 199). In addition, it was shown that TNF is a direct mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al. Clinical Immunology and Immunopathology, 1992, 62 Sll).

A brief description of izobreteny is the ol,

where n is from 1 to 6;

X is hydroxyl, (C1-C6)alkoxyl or NR1R2, R1and R2each independently selected from the group consisting of (C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidines, (C6-C10)aryl, (C5-C7)heteroaryl containing as the heteroatom nitrogen, (C6-C10)aryl(C1-C6)alkyl, (C5-C7)heteroaryl(C1-C6)alkyl, containing as the heteroatom nitrogen or R1and R2together form pyrrolidinyl, morpholinyl, piperidyl, (C1-C6)alkylpiperidines, piperazin, N-(C1-C6) alkylpiperazine, N-(C6-C10)arylpiperazine,

R3and R4each independently selected from the group comprising hydrogen, (C1-C6)alkyl,(C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl-(C1-C6) alkyl, (C5-C9) heteroaryl(C1-C6) alkyl, (C6-C10)aryl(C6-C10)aryl, (C3-C6)cycloalkyl and (C3-C6)cycloalkyl (C1-C6)alkyl, or R3and R4together can form a (C3-C6)cycloalkyl, oxocyclohexyl, thiacyclohexane, indanyl and>WITH6)acyl, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl,

(C5-C9)heteroaryl (C1-C6)alkyl or (C1-C6)alkylsulfonyl; Ar means (C6-C10)aryl, (C5-C9)heteroaryl, (C1-C6)alkyl (C6-C10)aryl, (C1-C6)alkoxy (C6-C10)aryl, ((C1-C6) alkoxy)2(C6-C10) aryl, (C6-C10) aryloxy (C6-C10) aryl or (C5-C9)heterokaryotic (C6-C10) aryl.

The term "alkyl", as used here, if not stated otherwise, denotes saturated monovalent hydrocarbon radicals having substituents with a straight, branched chain or cyclic, or combinations thereof.

The term "alkoxy", as used here, denotes an O - alkyl group, where "alkyl" has the above values.

The term "aryl", as used here, if not stated otherwise, denotes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1-3 substituents selected from the group consisting of fluorine, chlorine, SUB>1-C6)alkyl.

The term "heteroaryl" as it is used here, if not stated otherwise, denotes an organic radical derived from aromatic heterocyclic compounds, containing as the heteroatom nitrogen.

The term "acyl", as used here, unless otherwise specified, refers to radicals of the General formula RCO, where R is alkyl, alkoxyl, aryl, arylalkyl or aralkylamines, and the terms "alkyl" or "aryl" is defined above.

The term "acyloxy" as it is used here, includes O-acyl group, where the acyl" is defined above.

The compounds of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereogram compounds of formula I and their mixtures.

Preferred compounds of formula I include those in which n is 2.

Other preferred compounds of formula I include those in which Ar is 4-methoxyphenyl or 4-phenoxyphenyl.

Other preferred compounds of formula I include those in which, or R3or R4is not hydrogen.

Other preferred compounds of formula I in which X is hydroxyl, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, or R3or R4is not hydrogen.

Other preferred compounds of formula I include those in which X is alkoxyl, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, or R3or R4is not hydrogen.

Other preferred compounds of formula I include those in which Ar is 4-methoxyphenyl or 4-phenoxyphenyl, a R3and R4taken together form a (C3-C6)cycloalkenyl, oxocyclohexyl, thiacyclohexane, indanyl or a group of the formula

< / BR>
where R15is (C1-C6)acyl, (C1-C6)alkyl, (C6-C10)aryl- (C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl or (C1-C6- alkylsulfonyl.

More preferred compounds of formula I are those in which n is 2, Ar is 4 - methoxyphenyl or 4 - phenoxyphenyl, R1and R2taken together, constitute piperazinil, (C1-C6)alkylpiperazine, (C6- C10)arylpiperazine or (C5-C9)heteroaryl(C1-C6)alkylpiperazine, or R3or R4not avantime formula I are those in which n is 2, Ar is 4-methoxyphenyl or 4 - phenoxyphenyl, R1is hydrogen or (C1-C6)alkyl, R2is a 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, or R3or R4is not hydrogen, or both R3and R4are not hydrogen.

More preferred compounds of formula I are those in which n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R2is a 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, or R3or R4is not hydrogen, or both, R3and R4are not hydrogen.

Specific preferred compounds of formula I include the following:

2-(R)-N-hydroxy-2- [(4-methoxybenzenesulfonyl) (3 - morpholine-4-yl-3-oxopropyl)amino]-3-methylbutyrate;

2-(R) -2-[(2-benzyl carbamoylethyl)(4-methoxybenzenesulfonyl)amino] -N - hydroxy-3-methylbutyrate;

2-(R)-N-hydroxy-2- ((4-methoxybenzenesulfonyl)(2-[(pyridine-3-ylmethyl) -carbarnoyl]ethyl)amino)-3-methylbutyrate;

2-(R)-N-hydroxy-2-([4-methoxybenzenesulfonyl] [2-(methylpyridin - C-letiltasaval)ethyl]amino)-3-methylbutyrate;

4-(3-[1-(R)-1-hydroxycarbamoyl-2-methylpropyl) (4 - methoxybenzenesulfonyl) amino] p) (3-oxo-3-piperazine-1-ylpropyl)amino)-3 - methylbutylamine hydrochloride;

2-(R)-2-[(benzylcarbamoyl) (4 - methoxybenzenesulfonyl) amino] - N-hydroxy-3-methylbutyrate;

2-(R)-N-hydroxy-2-([4-methoxybenzenesulfonyl] -[(2-morpholine-4 - iletileri) methyl] amino) -3-methylbutyrate and

2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl) ([(pyridine-3-ylmethyl) carbarnoyl)methyl)amino)-3-methylbutyrate.

Other specific compounds of formula I include the following:

2-(R)-3, 3, 3 trifter-N-hydroxy-2- [(methoxybenzenesulfonyl) (3-morpholine-4-yl-3 - oxopropyl) amino] propionamide;

2-(R)-N-hydroxy-2-((4-phenoxybenzenesulfonyl) [2- (methyl-pyridine-4-letiltasaval)ethyl)amino)-3-methylbutyrate;

4-[4-methoxybenzenesulfonyl)(3-morpholine-4-yl-3-oxopropyl) amino] -1-methylpiperidin-4-carboxylic acid hydroxamic;

2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl) - [3-(4-methylpiperazin-1-yl)-3-oxopropyl]amino)-3-methylbutyrate;

2-(R)-2-[(2-carboxyethyl) (4-methoxybenzenesulfonyl)amino] -N-hydroxy-3-methylbutyrate;

[(2-carboxyethyl) (3,4-dimethoxybenzonitrile)amino] -N-hydroxyacetamido;

2-(R)-2-[(2-carbamoylethyl) (4-methoxybenzenesulfonyl) amino]-N-hydroxy-3-methylbutyrate;

2-(R) - 3-(R)-3,N-dihydroxy-2-[(4-methoxybenzenesulfonyl)-(3-oxo - C-piperidine-1-ylpropyl)amino]-butyramide;

2-(R)-BR> 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl) [2- (methylcarbamoylmethyl) ethyl] amino)-3-methylbutyrate;

2-(R)-N-hydroxy-2- ((methoxybenzenesulfonyl) - [(1-methyl-piperidine-4-ylcarbonyl) methyl] amino)-3-methylbutyrate;

2-(R)-2-cyclohexyl-N-hydroxy - 2-((4-methoxybenzenesulfonyl) - [3- (4-methylpiperazin-1-yl) -3 - oxopropyl]amino)-ndimethylacetamide;

2-(R)-N-hydroxy-2-[(methoxybenzenesulfonyl) (3-morpholine-4-yl-3 - oxopropyl) amino]-4-(morpholine-4-yl)butyramide.

This invention also relates to a pharmaceutical composition for (a) treatment of a disease selected from the group consisting of arthritis, cancer, ulcer tissue, recurrent stenosis, periodieskogo disease, congenital bullous of bullosa, scleritis and other diseases characterized by the activity of matrix proteinases, AIDS, sepsis, septic shock and other diseases that are associated with the production of tumor necrosis factor (TNF) or (b) suppression of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including humans, contains a number of compounds according to paragraph 1 or its pharmaceutically acceptable salt, effective for such treatment and a pharmaceutically acceptable carrier.

This invention also relates to a method of treatment of a disease selected from the group consisting of arthritis, cancer, ulcer tissue, restenosis, Periodontology disease, congenital bullous of bullosa, scleritis and other diseases characterized by the activity of matrix proteinases, AIDS, sepsis, septic shock and other diseases that are associated with the production of tumor necrosis factor (TNF) in a mammal, including humans, comprising an introduction to the specified mammal number of connections in claim 1 or its pharmaceutically acceptable salt, is effective for treatment of such diseases.

A detailed description of the invention

The following scheme of reactions illustrate the formation of compounds of the present invention. Unless stated otherwise, R1, R2, R3, R4, n and Ar in the schemes of reactions and in the description that follows, have the same meaning as above.

In reaction 1 of scheme 1, the amino acid compound of the formula VII, in which R16is (C1-C6

In reaction 2 of scheme 1 arylsulfonamides connection of the formula VI, in which R16is (C1-C6by alkyl, benzyl, allyl or tert-bootrom, converted into the corresponding compound of formula V in which n is equal 1,3,4,5 or 6, by reaction of VI with a reactive derivative of an alcohol of the formula

< / BR>
such as chloride, bromide or iodide, preferably bromide, where R17the protective group is a (C1-C6)alkyl, benzyl, allyl or tert-bootrom, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as dimethylformamide. The reaction mixture was stirred at room temperature over a period of time from about 60 minutes to about 48 hours, preferably about 18 hours. R17the protective group is chosen so that it can be applied in the e same as R16. Remove R17the protective group from compounds of formula V, to obtain the corresponding carboxylic acid of formula IV, in reaction 3 of scheme 1, is carried out under conditions suitable for this specific R17protective groups which do not affect R16the protective group. These conditions include: (a) saponification, when R17is (C1-C6)alkyl, a R16is tert-bootrom, (b) hydrogenolysis, when R17is benzyl, a R16is tert-bootrom or (C1-C6)alkyl, (C) treatment in a strong acid, such as triperoxonane acid or hydrochloric acid, when R17is tert-bootrom, a R16is (C1-C6)alkyl, benzyl or allyl, or (d) processing tributyl-allowoveride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium (II) chloride, when R17is allyl, a R16is (C1-C6)alkyl, benzyl or tert-bootrom.

In reaction 4 of scheme 1 carboxylic acid of formula IV is condensed with an amine, R1R2NH, or its salt to obtain the corresponding amide compounds of formula III. The formation of amides from primary or storycrafting derivative, which further reacts with primary or secondary amine or ammonia with the formation of the amide. Activated functional derivative may be isolated prior to reaction with a primary or secondary amine or ammonia. Alternative carboxylic acid can be treated with oxalylamino or thionyl chloride, pure or in an inert solvent, such as chloroform, at a temperature of from about 25oC to about 80oC, preferably at 50oC, to obtain the corresponding functional chloride derivative of the acid. The inert solvent and the remaining oxalicacid or titillated then removed by evaporation in a vacuum. The remaining functional chloride derivative of the acid then reacts with a primary or secondary amine or ammonia in an inert solvent such as methylene chloride with the formation of the amide. The preferred method of condensation of the carboxylic acid of formula IV with an amine to obtain the corresponding amide compounds of formula III is processing IV (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium hexaflurophosphate in the presence of a base such as triethylamine to obtain in situ benzotriazol-1-hydroxy-ether, which, in turn, reagire what lay amide compounds of formula III.

Remove R16the protective group from compounds of formula III to obtain the corresponding carboxylic acid of formula II in reaction 5 of scheme 1, carried out under conditions suitable for specific R16the protective group. These conditions include: (a) saponification, when R16is lower alkyl, (b) hydrogenolysis, when R16is benzyl, (C) treatment in a strong acid, such as triperoxonane acid or hydrochloric acid, when R16is tert-bootrom or (d) processing the anti-hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride, when R16is allyl.

In reaction 6 of scheme 1, the compound of carboxylic acid of the formula II into a compound hydroxamic acids of formula I by treatment P 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent such as dimethylformamide, followed by addition of hydroxylamine to the reaction mixture through from about 15 minutes to about 1 hour, preferably within 30 minutes. Preferably, the hydroxylamine is formed in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as where the hydroxyl group is protected by obtaining butyl, benzyl or allyl ether, in the presence of (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium hexaflurophosphate and bases, such as N-methylmorpholine. The removal of the protective group of the hydroxylamine is produced by hydrogenolysis in the case of the benzyl protective group or treatment in a strong acid, such as triperoxonane acid, in the case tertbutylphenol protective group. Allyl protective group can be removed by treatment with a hydride and anti-acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride. As protected hydroxylamines derived can also be used N,0 - bis(4-methoxybenzyl)hydroxylamine, and removing the protection is achieved by application of a mixture of methanesulfonic acid and triperoxonane acid.

In reaction 1 of scheme 2 arylsulfonamides compound of formula VI, where R16is (C1-C6)alkyl, benzyl or tert-bootrom, converted into the corresponding compound of formula VIII, where R18is a 2-propanolol or C-butanolom, the reaction of IX with a reactive functional derivative such as a halide, preferably iodide derivative, 2-propen-1-ol, when R18is a 2-propanolol or in the cesium or sodium hydride, preferably, sodium hydride, when R18is a 2-propanolol, or cesium carbonate, when R18is a 3-butanolom. The reaction mixture was stirred in a polar solvent such as dimethylformamide, at room temperature over a period of time equal to from about 2 hours to about 48 hours, preferably for 18 hours.

In reaction 2 of scheme 2, the compound according to formula VIII is converted into a compound of carboxylic acid of the formula IV, where n is equal to 2. The compound of formula VIII, where R18is a 2-propanolol into the compound of the formula IV, where n is 2, the reaction of VIII with borane-dimethylsulfide complex followed by immediate oxidation with chromium trioxide in aqueous acetic acid. Oxidative removal of terminal olefins to carboxylic acids can be carried out by several well-known in this field of technology methods. The preferred method of oxidative cleavage of compounds of formula VIII, where R18is a 3-butanolom to obtain a carboxylic acid of formula IV is that the compound VIII is reacted with periodate sodium in the presence of catalytic amounts of ruthenium chloride (III) in a mixture of carbon tetrachloride, acetonitrile, iislami formula I, where n is 2, by the method described above for reactions 4, 5 and 6 of scheme 1.

An alternative method of synthesis of compounds of hydroxamic acids of formula I where n is 1, a R3and R4are both hydrogens shown in reaction 1 of scheme 3, starting with the reaction iminoxyl acid or a salt thereof with a metal or ammonium ion of the formula X with functional derivatives of the compounds arylsulfonic acid, such as arylsulfonyl at room temperature in the presence of a suitable base, such as triethylamine, and a polar solvent, such as tetrahydrofuran, dioxane, water or acetonitrile, preferably, mixtures of dioxane and water, to obtain the corresponding compounds of dicarboxylic acid of the formula XI.

In reaction 2 of scheme 3, the compound of dicarboxylic acid of the formula XI digitalout obtaining a cyclic anhydride of formula XII. The formation of cyclic anhydrides of dehydration dicarboxylic acids can be implemented in different ways. The preferred method of dehydrogenation of dicarboxylic acid of the formula XI to obtain a cyclic anhydride of formula XII is the treatment of XI with excess acetic anhydride at a temperature in the range from approximately 25oC to about 80

In reaction 3 of scheme 3, the cyclic anhydride of formula XII reacts at room temperature with an amine, NR1R2or a salt of the amine, such as hydrochloride, in the presence of a base, such as triethylamine, to obtain the carboxylic acid of the formula II where n is 1, a R3and R4both are hydrogens. Suitable solvents for the reaction are those which will not react with the source material, and which include chloroform, methylene chloride and dimethylformamide, preferably methylene chloride.

The compound of formula II further reacts with connection hydroxamic acids of formula I where n is 1, a R3and R4are both hydrogen, in accordance with the methodology described above for the reaction of 6 scheme 1.

In reaction 1 of scheme 4, the compound of carboxylic acid of the formula IV, where n is 2, is transformed into the corresponding compound of formula V, where R19is (C1-C6)alkyl or tert-bootrom, the reaction of IV with the compound of the formula

(R19O)2CHN(CH3)2,

where R19is (C1-C6)alkyl or tert-bootrom, oC, preferably about 100oC, during the period of time from about 1 hour to about 3 hours, preferably 2 hours. In reaction 2 of scheme 4 arylsulfonamides-compound of formula VI, where n is 1, 3,4,5 or 6, a R16is (C1-C6)alkyl, benzyl, allyl or tert-bootrom, converted into the corresponding compound of formula XIII, where R19is (C1-C6)alkyl or tert-bootrom, by reaction of VI with a reactive derivative of an alcohol of the formula

< / BR>
such as chloride, bromide or iodine derivative, preferably bromine derivative, where R19is (C1-C6)- alkyl or tert-bootrom, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as dimethylformamide. The reaction mixture was stirred at room temperature over a period of time from about 60 minutes to about 48 hours, preferably for about 18 hours. The protective group R16compounds of formula IV and VI is chosen so that it can be selectively removed in the presence and without loss of R19(C1-C6)alkyl or tert-butilkoi group, so R16may not be Borovoy acid of formula XIV, where n is 1-6, in reaction 3 of scheme 4 are produced under conditions suitable for this specific used R16protective groups which will not affect R19(C1-C6)alkyl or tert-boutelou group. These conditions include: (a) saponification, when R16is (C1-C6)alkyl, a R19is tert-bootrom, (b) hydrogenolysis, when R16is benzyl, a R19is tert-bootrom or (C1-C6)alkyl, (C) treatment in a strong acid, such as triperoxonane acid or hydrochloric acid, when R19is tert-bootrom, and R19is (C1-C6)alkyl, or (d) processing the anti-hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride, when R16is allyl, a R19is (C1-C6)-alkyl or tert-bootrom.

In reaction 4 of scheme 4 carboxylic acid of formula XIV is converted into a compound hydroxamic acids of formula XV, where n is 1-6, processing XIV 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent such as dimethylformamide, followed by addition of hydroxylamine in the reaction with occhialino receive in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N - methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as tert-butyl, benzyl or allyl ether, can be used in the presence of (benzotriazol-1 yloxy) Tris (dimethylamino) phosphonium hexaflurophosphate and bases, such as N-methylmorpholine. Deleting groups, protecting the hydroxylamine is produced by hydrogenation in the case of the benzyl protective group or treatment in a strong acid, such as triperoxonane acid, in the case of tert-butilkoi protective group. Allyl protective group can be removed by treatment with a hydride and anti-acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride. As a protected derivative of hydroxylamine can also be used N,0-bis(4-methoxybenzyl) hydroxylamine, when R19is (C1-C6)alkyl, in this case, the removal of the protective groups is carried out using the mixture of methanesulfonic acid and triperoxonane acid.

In reaction 5 of scheme 4 amide compound of the formula XV, if required, turns into compliance is the development of a strong acid, such as triperoxonane acid or florodora acid when R19is tert-bootrom.

Pharmaceutically acceptable salts of acidic compounds of this invention are salts formed with bases, i.e. cationic salts such as salts of alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and salts of ammonium, trimethylammonium, diethylamine and Tris-(hydroxymethyl) -methylamine.

Similarly, you may receive the salts accession acids, such as mineral acids, organic carboxylic and organic sulfonic acids, for example hydrochloric acid, methanesulfonate acid, maleic acid, due to the fact that the main group, such as Peregrina is part of the structure.

The ability of compounds of the formula I or their pharmaceutically acceptable salts (hereafter called the compounds of this invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveness for treating diseases characterized by the activity of matrix proteinases or by producing necrosis factor tumors of the Russian collagenase (MMP-1)

Human recombinant collagenase activate trypsin, using the following ratio: 10 μg of trypsin per 100 μg collagenase. Trypsin and collagenase incubated at room temperature for 10 minutes, then add a five-fold excess (50 μg/10 μg of trypsin) inhibitor soybean trypsin.

Prepare a standard 10 mm solutions of inhibitors in dimethyl sulfoxide and then diluted them using the following schema.

10 mm ---> 120 µm ---> 12 μm ---> 1.2 µm ---> 0,12 µm

Twenty-five microlitres solution of each concentration were then added in three repeated corresponding cells in 96-microtiter cell cost. The final concentration of inhibitor will be a dilution of 1:4 after adding the enzyme and substrate. Positive controls (enzyme without inhibitor) are placed in cells D1-D6, and solutions comparison (without enzyme without inhibitor) is placed in cell D7-D12.

Collagenase was diluted to 400 ng/ml and then added to the appropriate wells of microtiter fee. The final concentration of collagenase in the study is 100 ng/ml.

Substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) - NH2) is prepared as a 5 mm standard solution in dimethylsulfoxide microtiter fee to obtain a final concentration of 10 μm.

Indicators fluorescence (excitation 360 nm, emission 460 nm) was determined at time 0 and then in 20-minute intervals. The study was performed at room temperature and normal research time is 3 hours.

Then build a graph of fluorescence from the time for solutions comparison and for samples containing collagenase (the average values determined from three repetitions). The point in time at which received a good signal (the reference solution) and which is located on the linear part of the curve (usually about 120 minutes) is selected for determining the values of the IC50. Zero moment of time used as a comparison for each compound at each concentration, and these values are subtracted from the readings for 120 minutes. Build a graph of the concentration of the inhibitor from % control (fluorescence solution with inhibitor divided by the fluorescence of a solution with a single collagenase x 100). The values of the IC50determined by the concentration of inhibitor that gives a signal equal to 50% of the control.

If it is shown that the values of the IC50< 0.03 µm, the inhibitors evaluated at concentrations of 0.3 μm, 0.03 µm and 0.003 μm.

Inhibition gelatinase (MMP-2)

in the same conditions, as for inhibition of human collagenase (MMP-1).

Gelatinase 72 KD activate 1 mm AFRA (n-AMINOPHENYL-mercury acetate) for 15 hours at 4oC and diluted to obtain the final concentrations for the study, 100 mg/ml Inhibitors diluted in the same manner as for determining the inhibition of human collagenase (MMP-1) to obtain the final concentrations of the study, equal to 30 μm, 3 μm, 0.3 μm and 0.03 μm. Each concentration examined three times.

Indicators fluorescence (excitation 360 nm, emission 460 nm) was determined at zero time and then in 20-minute intervals for 4 hours.

The values of the IC50defined as the inhibition of human collagenase (MMP-1). If notified that the values of the IC50less than 0.03 μm, the inhibitors investigated at final concentrations of 0.3 μm, 0.03 µm, of 0.003 and 0.003 μm μm (see table. 1).

The inhibition activity stromelysin (MMP-H)

Study of the inhibition activity stromelysin based on a modified spectrophotometric study described Weingarten N. and J. Feder (Weingarten, H. and J. Feder, Spectrophotometric Assay for Vertebrate Collagenase, Anal. Boochem. 147, 437-440 (1985)). Hydrolysis dipeptide substrate [Ac - recorded in the presence of the reagent of Ellman.

Human recombinant postremission activate trypsin, using the relation: 1 ál standard trypsin solution with a concentration of 10 mg/ml to 26 µg stromelysin. Trypsin and stromelysin incubated at 37oC for 15 minutes followed by incubation with 10 μl of inhibitor solution of soybean trypsin concentration of 10 mg/ml for 10 minutes at 37oC for repayment of the activity of trypsin.

Studies were performed in a total volume of 250 μl of buffer for research (200 mm sodium chloride, 50 mm MES and 10 mm calcium chloride, pH 6.0) in a 96-cell boards. Activated stromelysin diluted with buffer to research up to 25 µg/ml of the Reagent Ellman (3-carboxy-4-nitrophenylacetic) is prepared in the form of 1M standard solution in dimethylformamide, diluted to 5 mm buffer studies, receiving 50 ál of the cell with a final concentration of 1 mm.

Prepare 10 mm standard solutions of inhibitors in dimethyl sulfoxide and diluted serially buffer for research so that the addition of 50 μl in the corresponding cells gives a final concentration equal to 3 μm, 0.3 μm. of 0.003 0.0003 microns and microns. All tests were repeated three cells.

300 mm standard solution of the peptide substrate in deastore in each cell to obtain a final concentration of 3 mm substrate. Solutions comparison consist of a peptide substrate and reagent of Ellman without enzyme. The formation of the product was detected at 405 nm using a reader for cards Molecular Devices Uvmax.

The values of the IC50was determined in the same way as for collagenase.

Inhibition of MMP-13

Human recombinant MMP-13 activate using 2 mm AFRA acetate n-aminophenylthio for 1.5 hours at 37oC and diluted to 400 mg/ml buffer studies (50 mm Tris, pH 7.5, 200 mm sodium chloride, 5 mm calcium chloride, 20 μm of zinc chloride, of 0.02% brij). Add twenty-five microliters diluted enzyme on the cell 96 - cell card. The enzyme then when the study is diluted in the ratio 1:4 by addition of an inhibitor and substrate to obtain the final concentration of the study, 100 mg/ml

10 mm standard solutions of inhibitors are prepared in dimethyl sulfoxide and then diluted with buffer to research, also on the breeding scheme inhibitor for inhibition of human collagenase (MMP-1). Twenty-five microlitres solution of each concentration is added in three replications in cell microtiter fee (to determine fluorescence). End concentra
) prepare as well as for inhibition of human collagenase (MMP-1) and add to each well 50 μl with a final concentration of study equal to 10 microns.

Indicators fluorescence (excitation 360 nm, emission 450 nm) were removed at time 0 and every 5 minutes for 1 hour.

Positive controls included the enzyme and the substrate without inhibitor, and solutions comparison included only the substrate.

IC50determine as well as with inhibition of human collagenase (MMP-1). If it is shown that the IC50less than 0.03 μm, the inhibitors were then evaluated at final concentrations of 0.3 μm, 0.03 µm, of 0.003 μm and 0,0003 mm.

Inhibition of production of TNF

The ability of the compounds or their pharmaceutically acceptable salts inhibit the production of TNF, and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF, as shown by the following in vitro.

Human menagerie cells were isolated from human antikoagulyantnoe blood using a one-step methods selection Ficoll-hipac (Ficoll-hypaque). Menagerie cells were washed three times balanced with CCPX, containing 1% BSA. Differential number defined using the analyzer cell Abbot Dyn 3500, showed that monocytes in these preparations ranged from 17 to 24% of the total number of cells.

The sample to 180 μl of cell suspension were placed in flat-bottomed 96-cell Board (Costar). Adding compounds and LPS (final concentration 100 ng/ml) gave a final volume of 200 μl. All tests were repeated three times. After four hours incubation at 37oC in a humidified incubator at elevated concentrations of CO2the card was taken out and centrifuged (10 minutes at approximately 250 rpm) and the supernatant was removed and examined for the presence of DHO , using a set of ELlSA R&D).

For introducing people to the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), you can use a variety of conventional routes of administration including oral, parenteral and local. Generally, the active compound may be administered orally or parenterally in doses of from about 0.1 to 25 mg/kg body weight of the subject per day, which needs to be treated, preferably from about 0.3 to 5 mg/kg However, if necessary, can be made some changes to dose depending on the state su is zu, suitable for a specific subject.

The compounds of this invention can be introduced in the form of a number of different dosage forms, mainly therapeutically effective compounds of this invention are present in such dosage forms at concentration in the range of from about 5% to about 70% by weight.

For oral administration may be tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, disubstituted calcium phosphate and glycine, along with various leavening agents, such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with binding agents for granulation, such as polyvinylpyrrolidone, sucrose, gelatin and gum. Additionally, for tabletting is preferable to use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used as fillers for gelatin capsules are preferred ingredients in this case include lactose or milk sugar and high molecular weight glycols. When slishnimi sweetening or improving the taste substances, tinted substances or dyes and, if desired, emulsifying agents and/or suspendresume substances, together with such diluents (solvents) such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration (intramuscular, vnutriplevralnogo, subcutaneous and intravenous) preparing a sterile solution of the active ingredient for injection. Can be used solutions of therapeutic compounds of this invention or in sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions should be suitably driven and buffered, preferably to a pH of more than 8, if necessary, the liquid solvent are doing first, as a result of isotopically. These aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-arterial, intramuscular and subcutaneous injection. Obtaining these solutions under sterile conditions is easily accomplished using standard pharmaceutical techniques well known to specialists.

The invention is illustrated by the following examples, but is not limited to their details.

Example 1

2-(R)-N-Hydroxy-2-[(methoxybenzo is a D-valine (2.4 grams, 10 mmol) and triethylamine (2.5 g, 3.5 ml, 25 mmol)in water (50 ml) and 1,4-dioxane (50 ml) was added 4-methoxybenzenesulfonamide (2.3 g, 11 mmol). The mixture was stirred at room temperature for 1 hour and then the greater part of the solvent was removed by evaporation in a vacuum.

The mixture was diluted with ethyl acetate and successively washed with diluted hydrochloric acid, water and salt solution. The organic solution was dried over magnesium sulfate and concentrated, and getting-(4-methoxybenzenesulfonyl)-D - validentry ether in the form of a white solid, 3.6 g (97%); so pl. 92-94oC.

N-(4-methoxybenzenesulfonyl)-D - validentry ester (1.50 g, 4.0 mmole) was added to a suspension of sodium hydride (0.1 g, 4.2 mmole) in dry dimethylformamide (20 ml) and after 30 minutes was added tert-butylbromide (0.8 ml, 4.2 mmole). The resulting mixture was stirred over night at room temperature and then the reaction was stopped by adding a saturated solution of ammonium chloride (3 ml). The dimethylformamide was removed by evaporation in a vacuum. The residue was dissolved in ethyl acetate and washed with water and salt solution. After drying over magnesium sulfate the ethyl acetate evaporated, receiving the oil, masljanoi acids using thin layer chromatography on silica gel and elution with 15% ethyl acetate in hexane in the form of a clear oil (1.92 g, 98%).

To a cold (0oC to a solution of benzyl ether of 2-(R)-2-

[tert-butoxycarbonylmethyl (4-methoxybenzenesulfonyl)amino] -3-methylmalonic acid (1,92 g, 3.9 mmole) in methylene chloride (28 ml) was added triperoxonane acid (7 ml). The resulting solution was allowed to warm to room temperature and was stirred overnight. Methylene chloride and triperoxonane acid evaporated in vacuum, obtaining the benzyl ether of 2-(R)-2- [carboxymethyl(4-methoxybenzenesulfonyl)amino)] - 3-methylmalonic acid in the form of a clear oil of 1.70 grams (100%).

To a solution of benzyl ether of 2-(R)-2- [carboxymethyl(4-methoxybenzenesulfonyl)amino)] -3-methylmalonic acid (573 mg, 1,32 mmole) in methylene chloride (12 ml) were added successively triethylamine (and 0.46 ml of 3.28 mmole), morpholine (to 0.127 ml of 1.46 mmole) and hexaflurophosphate (benzotriazol-1 yloxy)Tris (dimethylamino)phosphonium (646 mg, of 1.46 mmole). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically on silica gel using 40% ethyl acetate in hexane, getting benzinga oil, 590 mg (89%).

To a solution of benzyl ether of 2-(R)-2-[(4 - methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxyethyl)amino] -3 - methylmalonic acid (590 mg, of 1.17 mmole) in ethanol (50 ml) was added 10% palladium on charcoal (200 mg). The mixture was which at a pressure of 3 atmospheres of hydrogen in a Parr shaker for 2 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated, obtaining 2-(R)-2-[(4 - methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl) amino] -3 - methylmalonyl acid as a white foam, 485 mg (100%).

To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl) amino]-3-methylmalonic acid (485 mg, of 1.17 mmole) in methylene chloride (12 ml) were added successively triethylamine (0,52 ml, 3,71 mmole) of the hydrochloride of o-benzylhydroxylamine (205 mg, of 1.28 mmole) and hexaflurophosphate (benzotriazol-1 yloxy)Tris (dimethylamino)phosphonium (570 mg of 1.29 mmole). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed successively with 0.5 N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically C is in-4-yl-2-oxoethyl)amino] - methylbutylamine in the form of a white foam, 510 mg (84%).

To a solution of 2-(R)-N-benzyloxy-2-[(4-methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl) amino]-3-methylbutylamine (510 mg, and 0.98 mmole) in methanol (50 ml) was added 5% palladium on charcoal (120 mg). The mixture was which at 2 atmospheres of hydrogen in a Parr shaker for 2 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated, obtaining 2-(R)-N-hydroxy-2-[(methoxybenzenesulfonyl) (2-morpholine-4-yl-2 - oxoethyl)amino] -3-methylbutyrate in the form of a white solid, 418 mg

(99%);1H-NMR (CDCI3): 10,3 (Shir. S.,1H), of 7.90 (Shir. s, 1H, overlapped), 7,86 (d, J =8,8 Hz, 2H, overlapped), 6,94 (d, J = 8,8 Hz, 2H), 4,39 (d, J= 17,1 Hz, 1H), 4.09 to(d, J= 17,1 Hz, 1H), 3,84(s, 3H), 3,80-of 3.48(m, 9H), 2,20-of 1.95(m, 1H), 0,82(d, J=6.5 Hz, 3H), 0,45(d, J=6.5 Hz, 3H), MC(LSIMS): m/z 430 (M+H).

Example 2

2-(R)-N-hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholine-4-yl - C-oxopropyl) amino]-3-methylbutyrate

To a solution of N-(4-methoxybenzenesulfonyl)-D-balinasloe ether (2.2 grams of 5.83 mmole) in dry dimethylformamide (40 ml) was added cesium carbonate (2.3 g, 7.1 mmole) and 1-iodine-3-butene (1.3 g, 7.1 mmole). The mixture was stirred at room temperature overnight and then poured into water. The mixture was extracted twice avowal under reduced pressure. The residue was collected in 20% ethyl acetate/hexane; starting material N-(4-methoxybenzenesulfonyl)-D-validentry ether (1.5 g) was led from the mixture and was separated by filtration. The filtrate was concentrated in vacuo and the residue was chromatographically on silica gel using 20% ethyl acetate/hexane as eluent to obtain benzyl ester 2-(R)-2-[but-3-enyl (4 - methoxybenzenesulfonyl) amino] -3-methylmalonic acid in the form of a clear oil 404 mg (16%).

To a mixture of benzyl ester of 2-(R)-2- [but-3-enyl (4-methoxybenzenesulfonyl) amino] -3-methylmalonic acid (780 mg, is 1.81 mmole) and hydrate, ruthenium (III) chloride (10 mg, 0,048 mmole) in acetonitrile (6 ml), carbon tetrachloride (6 ml) and water (8 ml) was added periodate sodium (1.7 grams of 7.9 mmole). After stirring at room temperature for 2 hours the mixture was diluted with methylene chloride and filtered through datamove the ground. The organic layer was separated, washed with diluted hydrochloric acid and brine, dried over magnesium sulfate and concentrated, obtaining the benzyl ether of 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino] -3-methylmalonic acid in the form of oil, 710 mg (87%).

Alternative intermediate connection benzyl ed with a higher yield.

N-(4-methoxybenzenesulfonyl)-D-validentry ether (18,8 g, 49.8 mmole) was added to a suspension of sodium hydride (1.3 g, 54 mm) in dry dimethylformamide (200 ml) and 1.5 hours solution was added allylbromide (4,7 ml, 54 mmole). The resulting mixture was stirred over night at room temperature and then the reaction was stopped by adding a saturated solution of ammonium chloride. The dimethylformamide was removed by evaporation in a vacuum. The residue was dissolved in ether and washed with water and brine. After drying over magnesium sulfate the ether evaporated, getting benzyl ether of 2-(R)-2-[(4-methoxime solarpanel) prop-2 - enylamine] -3-methylmalonic acid, clear oil (18,1 g, 87%) were identified by thin layer chromatography on silica gel with elution with 10% ethyl acetate in hexane and then with 20% ethyl acetate in hexane.

To a 1 M solution of borane complex/disulfide in methylene chloride (1,45 ml of 2.9 mol) was added to a solution of benzyl ether of 2-(R)-2-[(4-methoxybenzenesulfonyl) prop-2 - enylamine] -3-methylmalonic acid (3.6 g, 8.6 mmole) in methylene chloride (8 ml). The solution was stirred at room temperature for 4 hours, and during this additional time was added 1 M solution of borane complex/disulfide is m) was added to a mechanically stirred solution of chromium trioxide (5,1 g, 51,6 mol) in acetic acid (31 ml) and water (3.5 ml) while maintaining the internal temperature between -5oC to 10oC. After stirring at room temperature overnight the mixture was diluted with water and extracted with methylene chloride. The extract was washed with saline, dried (magnesium sulfate) and concentrated. The residue was chromatographically on silica gel, elwira successively with chloroform and 2% methanol in chloroform to obtain benzyl ester 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3 - methylmalonic acid in the form of oil (2.42 g, 63%).

To a solution of benzyl ether of 2-(R)-2-[2-carboxyethyl(4 - methoxybenzenesulfonyl)amino]-3-methylmalonic acid (710 ml, was 1.58 mmole) in methylene chloride (15 ml) was sequentially added triethylamine (of 0.47 ml, at 3.35 mmole) morpholine (0.15 ml, 1,72 mmole) and (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium hexaflurophosphate (769 mg, of 1.74 mmole). The mixture was stirred at room temperature overnight and then diluted with methylene chloride. The solution was washed with 0.5 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuum. The solid residue was subjected to chromatographicaliy on silica gel using 20% hexane in at-methylmalonic acid in the form of a clear oil, 725 mg (88%).

To a solution of benzyl ether of 2-(R)-2-[(4-methoxybenzenesulfonyl) -(3-morpholine-4-yl-3-oxopropyl) amino] -3 - methylmalonic acid (725 mg, of 1.40 mmole) in ethanol (35 ml) was added 10% palladium on charcoal (50 mg). The mixture which was under 3 atmospheres of hydrogen in a Parr shaker for 3 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated, obtaining 2-(R)-(2)-[(4- methoxybenzenesulfonyl)-(3-morpholine-4-yl-3-oxopropyl) amino]-3 - methylmalonyl acid as a white solid, 540 mg (90%).

To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)-(3-morpholine - 4-yl-3-oxopropyl) amino]-3-methylmalonic acid (540 mg, of 1.26 mmole) and 1-hydroxybenzotriazole (205 mg, of 1.33 mmole) in dry dimethylformamide (12 ml) was added 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (289 mg and 1.51 mmole). After stirring for 30 minutes was added hydroxylamine hydrochloride (350 mg, 5,04 mmole) and triethylamine (1.0 ml, 7,17 mmole). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution is then washed with water, 0.5 N solution of hydrochloric acid and a salt solution. The solution is then dried over magnesium sulfate and koncentrirebuli. The residue is triturated with ether to obtain 2-(R)-N-hydroxy-2-[(4 - methoxybenzenesulfonyl)-(3-morpholine-4-yl-3-oxopropyl) amino]-3 - methylbutylamine in the form of solids, 200 mg (36%);

1H-NMR (CDCl3) 9,35 (Shir. s, 1H), 7,73 (d, J=8,9 Hz, 2H), 6,95 (d, J = 8,9 Hz, 2H), 3,86 (s, 3H), 3,83-of 3.73 m,1H),

3,70-to 3.52 (m, 7H), of 3.46-3.43 points (m, 2H), 3,41-3,29 (m,1H), 2,92-2,69 (m, 2H), 2,30-2,17 (m, 1H), 0,84 (d, J=6.5 Hz, 3H), 0,41 (d, J=6.5 Hz, 3H); MS (particle beam); m/z 444 (M+ H), 428, 383, 329; HR Mass spectrum calculated for C19H30N3O7S (M+N): 444.1804 found: 464.1818.

Compounds named in the titles of examples 3-6 were obtained by the method similar to that described in example 2, using the benzyl ester of 2-(R)-2-[2 - carboxyethyl(4-methoxy-benzazolyl)amino] -3-methylmalonic acid as starting material, which is reacted with the specified amine.

Example 3

2-(R)-2-[(2-Benzylcarbamoyl) (4 - methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyrate

The reaction benzylamino:1H NMR (DMSO-d6): of 10.72 (s,1H) 8,89 (s,1H), 8,39 (m, 1H), 7,74 (d, J=9,Q Hz, 2H), 7,32-7,21 (m, 5H), 7,05 (d, J=9.0 Hz, 2H), 4,21 (d, J=5,9 Hz, 2H), was 4.02 - a 3.87 (m, 1H), 3,82 (s, 3H), 3,63 (d, J = 10,8 Hz, 1H), 3,29-3,17 (m, 1H), 2.71 to to 2.57 (m, 1H), 2,52-to 2.40 (m, 1H), 2.06 to was 1.94 (m, 1H), 0,77 (d, J= 6.6 Hz, 3H), of 0.74 (d, J=6.5 Hz, 3H), MS (LSIMS): m/z 464 (M+H); HR Macc-spectrum calculated for C22H30) (2-[(pyridine-3-ylmethyl)carbarnoyl]ethyl)amino)-3-methylbutyrate

Reaction with 3-pyridylmethylamine:1H NMR (DMSO-d6): of 10.72 (c,1H), 8,89 (s, 1H), 8,49-8,42 (m, 3H), 7,73(d, J=8,9 Hz, 2H), 7,63-of 7.60 (m, 1H), 7,32 (DD, J =4,8; and 7.8 Hz, 1H), 7,05 (d, J=8,9 Hz, 2H), 4,23 (d, J =5.8 Hz, 2H), 4,00-3,88 (I. , 1H), 3,81 (s, 3H), 3,62 (d, J =10,8 Hz, 1H), 3.27 to-3,17 (m, 1H), 2,69 - of 2.58 (m, 1H), 2,52-to 2.41 (m, 1H), 2,07-of 1.94 (m, 1H), 0,76 (d, J = 6.5 Hz, 3H), 0,72 (d, J=6.4 Hz, 3H); MS (LSIMS): m/z 465 (M+H).

Example 5

2-(R)-N-hydroxy-2-([4-methoxybenzenesulfonyl] [2-(methylpyridin-3-letiltasaval)ethyl]amino)-3 - methylbutyrate

Reaction with 3-(N-methylaminomethyl) pyridine1H NMR (DMSO - d6): 10,75 (Shir. S. , 1H), of 8.92 (s,1H), charged 8.52-8,29 (m,2H), of 7.75 (d, J =8,8 Hz, 1.4 N), to 7.67 (d, J =8,8 Hz, 0.6 H), 7,62-7,58 (m, 1H), 7,42-7,32 (m, 1H), 7,06 (d, J = 8,8 Hz, 1.4 N), 7,01 (d, J =8,8 Hz, 0.6 H), 4,55-to 4.41 (m,2H), 3,94-3,82 (m, 1H), 3,81 (C, 2,1 H), 3,80(c, 09H), 3,68-of 3.60 (m,1H), 3.33 and-3,19(m,1H), 2,90-of 2.50(m, 2H), 2,88(c, 2,1 H, overlapped), and 2.79 (s, 0,9 H), 2.05 is and 1.80 (m, 1H), 0,79-0.69(m,6H); MS (thermocapillary): m/z 479(M+H), 364.

Example 6

4-(3-[(1-(R)-1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl) piperazine-1-carboxylic acid tert-butyl ether

The reaction with tert-butyl-1-piperidinecarboxylate:1H NMR (DMSO-d6): 10,77 (W, s, 1H), 8,93 (s,IH), 7,74 (d, J =8,9 Hz, 2H); 7,06 (d, J=8,9 Hz, 2H), 3,90-of 3.80(m, 1H), 3,82(s, 3H, overlapped), to 3.64 (d, J =10,8 Hz, 1H), 3,60-and 3.16(m, 9H), 2,80 - a 2.71 (m,1H), 2,59-2,47 (m, 1H), 2,03 is 1.91(m,1H), 1.39 in (c, 9H), of 0.77 (d, J =6.5 Hz, 3H), of 0.71 (d, J =6,5, 3H); MS (terlipressin-1-ylpropyl) amino] -3-methylbutylamine hydrochloride

The solution 4-(3-[(1-(R)-1-hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl) piperazine-1-carboxylic acid tert-butyl ester (example 6) (430 mg, of 0.79 mmole) in methylene chloride (11 ml) was cooled to 0oC. and Then through a solution of missed gaseous hydrogen chloride for about 0.5 minutes. The solution was allowed to warm to room temperature with stirring for 1 hour. Volatiles were removed by evaporation and the residue was filtered, washing with methylene chloride, getting solid hydrochloride of 2-(R)-N-hydroxy-2- [(4-methoxybenzenesulfonyl) (3-oxo-3-piperazine-1-ylpropyl) amino]-3-methylbutylamine, 375 mg (99%).

1H NMR (DMSO-d6): 10,78 (Shir. s, 1H), 9,16 (Shir. s, 1H), 7,74 (d, J = 8,8 Hz, 2H), 7,07 (d, J =8,9 Hz, 2H), 3,82 (s, 3H), 3,62 (Shir. s, 4H), 3,38-3,18 (m, 1H), 3,16-3,07 (Shir. s, 2H), 3,07-2,98 (Shir. s, 2H), 2,83-by 2.73 (m, 1H), 2,65 of $ 2.53 (m, 1H), 2.06 to 1,90 (m, 1H), 0,76 (d, J=6.5 Hz, 3H), 0,72 (d, J =6.5 Hz, 3H). A broad peak of water is between 4.0 and a 3.5 obscures some signals of this compound; MS (thermocapillary): m/z 443 (M+H), 382, 328.

Example 8

2-(R)-2-[(Benzylcarbamoyl) (4 - methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyrate

To a solution of benzyl ether of 2-(R)-2-[carboxymethyl(4 - methoxybenzenesulfonyl) amino]-3-methylmalonic acid Lamin (0.25 ml, to 2.29 mmole) and (benzotriazol-1 yloxy)Tris(dimethylamino) phosphonium hexaflurophosphate (1,01 grams of 2.28 mmole). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically on silica gel using methylene chloride/ethyl acetate/hexane in the ratio 2:5:16 obtaining benzyl ester 2-(R)-2-[(benzylcarbamoyl) (4-methoxybenzenesulfonyl) amino]-3-methylmalonic acid in the form of a clear oil, 933 ml (86%).

To a solution of benzyl ether of 2-(R)-2- [(benzylcarbamoyl) (4-methoxybenzenesulfonyl) amino]-3 - methylmalonic acid (933 mg, of 1.17 mmole) in ethanol (50 ml) was added 10% palladium on activated carbon (85 mg). The mixture was stirred under 3 atmospheres of hydrogen in a Parr shaker for 4 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated, obtaining 2-(R)-2- [(benzylcarbamoyl) (4-methoxybenzenesulfonyl) amino]-3 - methylmalonyl) acid as a white foam, 755 mg (98%).

To a solution of 2-(R)-2-[(benzylcarbamoyl)(4-methoxybenzenesulfonyl) -amino-3-methylmalonic acid (which of lore 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (316 mg, 1.65 mmole). After stirring for 30 minutes was added hydroxylamine hydrochloride (416 mg, 6.0 mmole) and then N-methylmorpholine (0,99 ml, 9.0 mmole). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed successively with water, 0.5 N solution of hydrochloric acid and a salt solution. The solution is then dried over magnesium sulfate and concentrated in vacuum, obtaining a white foamy substance was subjected to chromatography on silica gel, elwira with ethyl acetate to obtain 2-(R)-2-[(benzylcarbamoyl) - (4-methoxybenzenesulfonyl)-amino] -N-hydroxy-3-methylbutylamine in the form of a white foam, 570 mg (84%); 1H NMR (DMSO-d6): 10,75 (Shir. s, 1H), of 8.90 (s, 1H), of 8.47 m, 1H), a 7.85 (d, J = 8,9 Hz, 2H), 7,83-7,19 (m, 5H),? 7.04 baby mortality (d, J= 8,9 Hz, 2H), 4,37 (d, J = 11,4 Hz, 1H), 4,28 (d, J =5,9 Hz, 2H), 3,89(d, J =11,4 Hz, 1H), 3,82(s, 3H), of 3.45(d, J = 10.3 Hz, 1H), 1,90-to 1.79 (m, 1H), 0,73 (d, J =6.3 Hz, 6H); MS (LSIMS): m/z 450 (M+H).

Example 9

2-(R)-2-[(Benzenedicarboxylate) (4 - methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylbutyryl

To a solution of benzyl ester 2-(R)-2-[carboxymethyl(4 - methoxybenzenesulfonyl) amino]-3-methylmalonic acid (example 1) (1,05 g, is 2.41 mmole) in methylene chloride (20 ml) were added successively triethylamine (from 0.84 ml, 6 mmol), 2,69 mol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was subjected to chromatography on silica gel using 35% ethyl acetate in hexane (plus a small amount of methylene chloride to load the sample into the column), with benzyl ether of 2-(R)-2- [benzenedicarboxylate) (4-methoxybenzenesulfonyl)amino] -3 - methylmalonic acid in the form of a clear oil of 1.14 g (88%).

To a solution of benzyl ether of 2-(R)-2-[(benzenedicarboxylate) (4-methoxybenzenesulfonyl) amino]-3-methylmalonic acid (1,14 g, 2.12 mmole) in ethanol (100 ml) was added 10% palladium on charcoal (400 mg). The mixture which was under 3 atmospheres of hydrogen in a Parr shaker for 3 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated, obtaining 2-(R)-2-[(benzenedicarboxylate) (4 - methoxybenzenesulfonyl) amines-3-methylmalonyl acid as a white foam, 902 mg (95%).

To a solution of 2-(R)-2- [(benzenedicarboxylate) (4-methoxybenzenesulfonyl) amino]-3 - methylmalonic acid (902 mg, 2.01 mmole) in meters (242 mg, 2.21 mmole) and hexaflurophosphate(benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (978 mg, 2.21 mmole).

The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically on silica gel using 40% hexane in ethyl acetate to obtain 2-(R)-N-allyloxy-2-[(benzenedicarboxylate) (4-methoxybenzenesulfonyl) amino] - 3-methylbutylamine in the form of oil, 1,008 grams (100%).

To a solution of 2-(R)-N - allyloxy-2-[(benzenedicarboxylate) (4-methoxybenzenesulfonyl) amino] -3-methylbutylamine (500 mg, 0.99 mmole) in methylene chloride (40 ml) was added bis(triphenylphosphine) palladium (II) chloride (280 mg, 0.4 mmole) and then, dropwise, anti-hydride (of 0.43 ml, 2.2 mmole). The solution was stirred at room temperature for 1 hour, diluted with methylene chloride, washed with 1 N hydrochloric acid, dried over magnesium sulfate and concentrated. The residue was dissolved in ethyl acetate and filtered to remove solids. After concentration of the filtrate was chromatographically on silica gel, elwira chloroform and then droxy-3-methylbutylamine in the form of a white solid (340 mg, 74%).1H NMR (DMSO-d6): 10,66 (Shir.s, 1H), 8,87 (Shir. s, 0.6 H), 8,84 (s, 0.4 H), to $ 7.91 (d, J = 8,9 Hz, 1.2 H), 7,78 (d, J= 8,9 Hz, 0.8 H), 7,43-7,21 (m, 5H), 7,05 (d, J =8,9 Hz, 1.2 H), of 7.00 (d, J=8,9 Hz, 0.8 H), 4.72 in (d, J =17.7 and Hz, 0.4 H), 4,70 (d, J =17.7 and Hz, 0.6 H), 4,59 was 4.42 (m,1H), 4,25 (d, J =17,8 Hz, 0.6 H), 4,07 (d, J =17.7 and Hz, 0.4 H), 3,82 (s,3H), 3.46 in is 3.40 (m, 1H), 2.91 in (s, 1.8 H), and 2.83 (s, 1.2 H), 1,92 is 1.70 (m,1H), 0,75-0.69 (m, 6H); MS (thermocapillary) m/z 464 (M+H), 307, 239.

Connection header examples 10-11 were obtained by the method similar to that described in example 9, using benzyl ether of 2- (R)-2-[carboxymethyl (4-methoxybenzenesulfonyl) amino] -3-methylmalonic acid (example 1) as a starting material, which is reacted with the specified amine.

Example 10

2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl] - [(2-morpholine-4-iletileri) methyl] amino) -3-methylbutyrate

Reaction with 4-(2-amino-ethyl) - morpholine:1H NMR (DMSO-d6): a 10.74 (Shir.s, 1H), 8,90 (Shir.s, 1H), 7,84 (Shir.s, 1H, overlapped), to 7.84 (d, J=8,8 Hz, 2H), 7,06 (d, J =8,8 Hz, 2H), 4,33 (d, J=17.5 Hz, 1H), 3,83 (s,3H), of 3.78 (d, J = 17.5 Hz, 1H), 3,57-of 3.54 (m, 4H), 3,49(d, J =10,2 Hz, 1H), 3,28-of 3.06 (m, 2H), 2,34-of 2.30 (m, 6H), of 1.93-1.77 in (m, 1H), 0.77-a of 0.74 (m, 6H).

Example 11

2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl) (2-oxo-2-pyrrolidin-1-retil) amino]-3-methylbutyrate

The reaction pyrrolidino:1H NMR (CD3OD): of 7.90 (d, J = 8,9 Hz, 2H),? 7.04 baby mortality (d, J =8,9 Hz, 2H is (e): m/z 414 (M+1); HRMC calculated for C18H28N3O6S (M+N): 414,1699. Found 414,1703.

Example 12

2-[Dimethylcarbamoyl (4-methoxybenzenesulfonyl) amino] -N - hydroxy-3-methylbutyrate

A solution of benzyl ether of 2- (R) -2- [carboxymethyl (4 - methoxybenzenesulfonyl) amino] -3-methylmalonic acid (example 1) (1.89 g, 4,34 mmole) in thionyl chloride (25 ml) was heated under reflux for 1 hour. After cooling, the excess thionyl chloride are evaporated. The residue was dissolved in methylene chloride (50 ml) and the solution was cooled in an ice bath. After the solution was slowly passed dimethylamine gas for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated, obtaining benzyl ether dimethylcarbamoyl-(4 - methoxybenzenesulfonyl)amino-3-methylmalonic acid in the form of oil, 1.77 g (88%).

To a solution of benzyl ether dimethylcarbamoyl (4-methoxybenzenesulfonyl) amino-3-methylmalonic acid (1.77 g, a 3.83 mmole) in ethanol (100 ml) was added 10% palladium on charcoal (644 mg). The mixture which was under 3 atmospheres of hydrogen in a Parr shaker for 1.5 casuistically (4 methoxybenzenesulfonamide-3-methylmalonyl acid as a white foam, 1.42 g (100%).

K the solution dimethylcarbamoyl(4-methoxybenzenesulfonyl)amino - 3-methylmalonic acid (1.42 g, 3,81 mmole) and 1 - hydroxybenzotriazole (687 mg, 4,48 mmole) in dry dimethylformamide (7 ml) was added 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (974 mg, 5.08 mmole). After stirring for 30 minutes was added hydroxylamine hydrochloride (1,17 g, a 16.8 mmole) and then N-methylmorpholine (2.8 ml, 25.5 mmole). The mixture was stirred at room temperature overnight and then concentrated in vacuum. The residue was dissolved in ethyl acetate and the resulting solution was washed successively with water, 0.5 N solution of hydrochloric acid and a salt solution. The solution is then dried over magnesium sulfate and concentrated in vacuum, obtaining oil, which was chromatographically on silica gel, elwira sequentially with ethyl acetate, 5% methanol in chloroform and 10% methanol in chloroform to obtain 2-[dimethylcarbamoyl(4-methoxybenzenesulfonyl)amino] -N-hydroxy-3 - methylbutylamine in the form of a white solid. 390 mg (26%).1H NMR (DMSO-d6): 10,70 (Shir.s,1H), 8,89 (s, 1H), 7,80 (d, J =8,9 Hz, 2H), 7,10 (d, J=8,9 Hz, 2H), to 4.62 (d, J =17.7 and Hz, 1H), 4,14 (d, J = 17.7 and Hz, 1H), 3,84 (s,3H), 3,40 (d, J =10.4 Hz, 1H), 2,97 (s,3H), 2,82 (s, 3H), 1,88-1,72 (m, 1H), 0,72 (d, J = 6.5 Hz, 6H CLASS="ptx2">

Example 13

2-R)-2-N-Hydroxy-2- ((4 - methoxybenzenesulfonyl) ([pyridine-3-ylmethyl) -carbarnoyl] methyl) amino) -3-methylbutyrate

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) ([pyridine - Z-ylmethyl) -carbarnoyl] methyl) amino) -3-methylbutyrate was obtained by the method similar to the method of example 12, on the basis of the benzyl ether of 2-(R)-2-[carboxymethyl (4-methoxybenzenesulfonyl)-amino] -3 - methylmalonic acid (example 1), which reacts with 3-pyridylmethylamine via an intermediate acid chloride acid.1H NMR (CD3OD): 8,55 are 8.53 (m, 1H), 8,43-to 8.40 (m, 1H), of 7.90-of 7.82 (m, 1H, overlapped), 7,86 (d, J = 8,9 Hz, 2H), 7,40 (DD, J = 4,8, and 7.8 Hz, 1H),? 7.04 baby mortality (d, J = 8,9 Hz, 2H), 4,50 (d, J=17.5 Hz, 1H), 4,39 (d, J =17.5 Hz, 1H), 4,32 (d, J =and 17.7 Hz, 1H), was 4.02 (d, J =17.7 and Hz, 1H), a 3.87 (s,1H), 3,60 (d, J =10.3 Hz, 1H), 2,08-of 1.93 (m, 1H), 0,85 (d, J =6.5 Hz, 3H), 0,70 (d, J =6,5 Hz, 2H); MS (thermocapillary): m/z 451 (M+H), 336, 320.

Example 14

N-Hydroxy-[(4-methoxybenzenesulfonyl) (2 - morpholine-4-yl-2-oxoethyl) amino] ndimethylacetamide

To a solution of the monohydrate disodium salt iminoxyl acid (5.0 grams of 25.6 mmole) in dioxane (50 ml) and water (50 ml) was added triethylamine (5.3 ml, 38 mmol) followed by addition of 4-methoxybenzenesulfonamide (5.8 g, 28,0 mmole). The mixture was stirred over night at room temperature and was diluted with methylene chloride. Rasti was concentrated in vacuum, getting [carboxymethyl (4-methoxybenzenesulfonyl)amino] acetic acid as a white solid, a 3.83 g (49%).

[Carboxymethyl (4-methoxybenzenesulfonyl) aminouksusnoy acid (0.5 g, 1.65 mmole) was dissolved in acetic anhydride (15 ml) with mild heating. The resulting solution was stirred at room temperature overnight. Acetic anhydride was removed by evaporation in vacuo, the residue was dissolved in methylene chloride and was added morpholine (0.16 ml, equal to 1.82 mmole).

The mixture was stirred over night at room temperature and concentrated in vacuum. The residue was dissolved in etelaat-e, washed with I N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated to obtain [(4 - methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl)amino] acetic acid in the form of oil, 0.33 g (54%).

To a solution of [(4 - methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl)-amino] acetic acid (0.33 g, of 0.89 mmole) in methylene chloride (10 ml) was sequentially added triethylamine (of 0.43 ml, 3.1 mmole) of the hydrochloride of o-benzylhydroxylamine (0.15 g, of 0.94 mmole) and hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (0,43 g, 0.97 mmole). The mixture was stirred at to what the target of hydrochloric acid, water and saline, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically on silica gel using ethyl acetate to obtain N-benzyloxy-[(4 - methoxybenzenesulfonyl) (2-morpholine-4-yl-2 - oxoethyl)amino]ndimethylacetamide in the form of a white solid, 0.33 g (78%).

To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl) (2 - morpholine-4-yl-2-oxoethyl)amino]ndimethylacetamide (0.33 g, to 0.69 mmole) in methanol (35 ml) was added 5% palladium on activated carbon (85 mg). The mixture was which at 2 atmospheres of hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent evaporated. The residue was chromatographically on silica gel, elwira 5% methanol in methylene chloride to obtain N-methoxy[(4-methoxybenzenesulfonyl) (2-morpholine-4-yl-2-oxoethyl) amino] ndimethylacetamide in the form of a white solid, 65 mg (24%);1H NMR CD3OD): of 7.82 (d, J = 9.0 Hz, 2H), was 7.08 (d, J =9.0 Hz, 2H), 4,24 (s, 2H), 3,88 (s, 3H), of 3.84 (s, 2H), 3,68-to 3.64 (m,4H), to 3.58-to 3.50 (m,4H); MS (thermocapillary): m/z 388 (M+1), 387 (M); HRMC calculated for C16H22N3O7S (M+N): 388,1178. Found: 338,1180.

Substances named in the titles of examples 15-16 were obtained by the method similar to the method described in example 14 and when, the which after treatment with acetic anhydride reacted with the specified amine.

Example 15

N-Hydroxy [(4-methoxybenzenesulfonyl) (2-oxo-2 - pyrrolidin-1-retil)amino]ndimethylacetamide

The reaction pyrrolidino:1H NMR (DMSO-d6): of 11.26 (Shir. s, 1H), 8,89 (s, 1H), 7,81 (d, J =8,9 Hz, 2H), 7,10 (d, J = 8,9 Hz, 2H), 4.09 to (s,2H), 3,85 (s,3H), 3,74 (s,2H), 3.45 points-of 3.25 (m,4H), 1.93 and-1,72 (m, 4H); MS (thermocapillary): m/z 372 (M+1): Analysis calculated for C15H21N3O6S: C, 48,51; H, 5,70; N 11,31. Found: C, 48,51; H Of 5.82; N 11,24.

Example 16

2 [Dimethylcarbamoyl (4-methoxybenzenesulfonyl) amino]-N - hydroxyacetamido

Reaction with dimethylamine: so pl.: 170oC (decomp.):1H NMR (DMSO-d6): 10,69 (Shir. s, 1H), 8,88 (s, 1H), to $ 7.91 (d, J = 8,9 Hz, 2H), 7,06 (d, J= 8,9 Hz, 2H), 4,19 (s, 2H), 3,85 (s, 3H), of 3.73 (s, 2H), equal to 2.94 (s, 3H), 2,84 (s, 3H); MS (thermocapillary): m/z 346 (M+1); Analysis calculated for C13H19N3O6S, 45,21; H OF 5.55; N, 12,17. Found: C, 44,93; H, 5,61; N A 12.03.

Example 17

2-(R)-2-[(2-Carbamoylethyl) (4-methoxybenzenesulfonyl)-amino] -N-hydroxy-3-methylbutyrate

To a solution of benzyl ether of 2-(R)-2-[(2-carboxyethyl (4 - methoxybenzenesulfonyl)amino] -3-methylmalonic acid (example 2) (900 mg, 2.0 mmole) in methylene chloride (10 ml) was added thionyl chloride (0.16 ml, 2.2 mmole) is IU. After dissolution of the residue in methylene chloride (10 ml), after the solution was passed ammonia gas for 0.5 minutes. The solution was stirred at room temperature overnight and concentrated in vacuum. Thin layer chromatography of the residue on silica gel with elution with 2% methanol in chloroform gave the benzyl ether of 2-(R)- 2- [(2-carbamoylethyl) (4-methoxybenzenesulfonyl) amino] -N-hydroxy - Z-methylmalonic acid as a clear oil (275 mg, 31%).

To a solution of benzyl ether of 2-(R)-2-[(2-carbamoylethyl)-(4 - methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylmalonic acid (275 mg, and 0.61 mmole) in ethanol (15 ml) was added 10% palladium on charcoal (30 mg). The mixture which was under 3 atmospheres of hydrogen in a Parr shaker for 5 hours. The catalyst was removed by filtration through datamove Sanlu and the solvent evaporated, obtaining 2-(R)-2-[(2-carbamoylethyl)-(4-methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylmalonyl acid as a white foam, 211 mg (96%).

To a solution of 2-(R)-2-[(2-carbamoylethyl) (4 - methoxybenzoyl-sulfonyl) amino]-N-hydroxy-3-methylmalonic acid (205 mg, 0.57 mmole) and 1-hydroxybenzotriazole (85 mg, 0.55 mmole) in dry dimethylformamide (5 ml) was added 1-(3 - dimethylaminopropyl)-3-Atilla the chloride (158 mg, 2.3 mmole) and then N-methylmorpholine (0,37 ml, 3.4 mmole). The mixture was stirred overnight and then diluted with ethyl acetate. The solution was washed with water and brine. Then the solution was dried over magnesium sulfate and concentrated in vacuum, obtaining oil, which was chromatographically on silica gel, elwira 2% methanol in chloroform to obtain 2-(R)-2-[(2-carbamoylethyl) (4-methoxybenzenesulfonyl) amino]-N-hydroxy-3-methylbutylamine in the form of a white solid, 45 mg (21%);1H NMR (DMSO-d6) a 10.74 (Shir. s, 1H), 8,91 (Shir.s, 1H), 7,74 (d, J =8,8 Hz, 2H), 7,33 (Shir.s, 1H), 7,07 (d, J =8,8 Hz, 2H), 6,79 (Shir.s, 1H), 3,93-3,82 (m, 1H, overlapped), 3,83 (s, 3H), of 3.64 (d, J =10,7 Hz, 1H), 3.25 to of 3.12 (M, 1H), 2,62-2,48 (m, 1H), 2,42-of 2.30 (M , 1H), 2.06 to was 1.94 (m, 1H), 0,79 (d, J =6.6 Hz, 3H), 0,76 (d, J =6.6 Hz, 3H); MS (thermocapillary): m/z 374 (M+H).

Example 18

2-(R)-2-[(2-tert-butoxycarbonylmethyl) (4 - methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylbutyrate

A solution of N, N-dimethylformamide-di-tert-butylacetate (1.9 ml, of 7.9 mmole) in toluene (15 ml) was added dropwise to a solution of benzyl ether of 2-(R)-2-[(2-carboxyethyl(4-methoxybenzenesulfonyl) amino] -3-methylmalonic acid (example 2) (900 mg, 2.0 mmole) in toluene at 80oC. After heating for 2 hours at 80oC the mixture was cooled and concentrated, gaining lantern[(2-tert-butoxycarbonylmethyl) (4-methoxybenzenesulfonyl) amino] -3-methylmalonic acid in the form of oil, 3.75 mg (37%).

To a solution of benzyl ether of 2-(R)-2-[(2-tert-butoxycarbonylmethyl) (4-methoxybenzenesulfonyl) amino]-3-methylmalonic acid (370 mg, 0.73 mmole) in ethanol (20 ml) was added 10% palladium on charcoal (40 mg). The mixture which was under 3 atmospheres of hydrogen in a Parr shaker for 5 hours. The catalyst was removed by filtration through datamove the earth and the solvent evaporated, obtaining 2-(R)-2-[(2-tert-butoxycarbonylmethyl) (4 - methoxybenzenesulfonyl) amino] -3-methylmalonyl) acid as a white foam, 30 mg (100%).

To a solution of 2-(R)-2-[(2-tert-butoxycarbonylmethyl) (4-methoxybenzenesulfonyl)amino] -3 - methylmalonic acid (303 mg, 0.73 mmole) and 1 - hydroxybenzotriazole (108 mg, 0,70 mmole) in dry dimethylformamide (10 ml) was added the hydrochloride of 1-(3 - dimethylaminopropyl)-3-ethylcarbodiimide (153 mg, 0,80 mmole). After stirring for 45 minutes, was added hydroxylamine hydrochloride (203 mg, 2.9 mmole) and then N-methylmorpholine (of 0.48 ml, 4.4 mmole). The mixture was stirred at room temperature overnight and then concentrated in vacuum. The residue was chromatographically on silica gel, elwira 2% methanol in chloroform and again 10% ethyl acetate in hexane to obtain 2-(R)- 2-[(2-tert-butoxycarbonylmethyl) (4-methoxybenzo is with, 1H), 7,74 (d, J = 8,9 Hz, 2H), was 7.08 (d, J =8,9 Hz, 2H), 3,93-3,82 (m, 1H, overlapped), 3,83 (s, 3H), of 3.64 (d, J =10,8 Hz, 1H), 3,26-3,14 (m, 1H), 2,70-2,60 (m, 1H), 2,50-of 2.38 (m, 1H), 2,04 is 1.91 (m, 1H), to 1.38 (s, 9H), 0,78 (d, J =6.5 Hz, 3H), 0,72 (d, J =6.5 Hz, 3H); MS (thermocapillary): m/z 431 (M+H), 375, 314.

Example 19

2-(R)-2-[(2-Carboxyethyl) (4-methoxybenzenesulfonyl)amino] -N-hydroxy - Z-methylbutyrate

To a solution of 2-(R)-2-[(2-tert-butoxycarbonylmethyl)(4-methoxybenzenesulfonyl) -amino]-N-hydroxy-3-methylbutylamine (example 18) (100 mg, to 0.23 mmole) in methylene chloride (1 ml) at 0oC

added triperoxonane acid (1 ml). The mixture was allowed to warm to room temperature with stirring overnight. After evaporation triperoxonane acid and methylene chloride, the residue was chromatographically on silica gel, elwira 5% methanol in chloroform. Concentration of the appropriate fractions gave 2-(R)-2-[2-carboxyethyl (4-methoxybenzenesulfonyl)-amino]- N-hydroxy-3-methylbutyrate in the form of a white solid, 35 mg (41%).1H NMR (DMSO-d6AMCO-d6): 10,79 (Shir.s, 1H), 8,97 (Shir.s, 1H), 7,76 (d, J =8,9 Hz, 2H), to 7.09 (d, J =8,9 Hz, 2H), 3.95 to 3,82 (m, 1H, overlapped), of 3.84 (s, 3H), 3,66 (d, J =10,8 Hz, 1H), 3,30-3,20 (m,1H), 2,73-2,62 (m,1H), 2,50 - to 2.40 (m, 1H), 2,07-of 1.94 (m, 1H), 0,80 (d, J = 6.5 Hz, 3H), of 0.74 (d, J = 6.5 Hz, 3H); MS (thermocapillary): m/z 375 (M+H), 314.

1. Derivatives arylsulfonate from 1 to 6;

X is hydroxy, (C1- C6)alkoxy or NR1R2where R1and R2each independently selected from the group consisting of (C1- C6)alkyl, piperidinyl, (C1- C6)alkylpiperidines, (C6- C10)aryl, (C5- C7)heteroaryl containing as the heteroatom nitrogen, (C6- C10)aryl(C1- C6)alkyl, (C5- C7)heteroaryl(C1- C6)alkyl, containing as the heteroatom nitrogen, or R1and R2together form pyrrolidinyl, morpholinyl, piperidyl, (C1- C6)alkylpiperidines, piperazin, N-(C1- C6)alkylpiperazine, N-(C6- C10)arylpiperazines;

R3and R4each independently selected from the group comprising hydrogen, (C1- C6)alkyl, (C6- C10)aryl, (C5- C9)heteroaryl, (C6- C10)aryl(C1- C6)alkyl, (C5- C9)heteroaryl(C1- C6)alkyl, (C6- C10)aryl(C6- C10)aryl, (C3- C6)cycloalkyl and (C3- C6)cycloalkyl(C1- C6)alkyl, or R3and R4together can form a (C3- C6)cycloalkyl, oxocyclohexyl, thiacyclohexane, and indanyl - C6)acyl, (C1- C6)alkyl, (C6- C10)aryl(C1- C6)alkyl, (C5- C9)heteroaryl(C1- C6)alkyl or (C1- C6)alkylsulfonyl;

Ar means (C6- C10)aryl, (C5- C9)heteroaryl, (C1- C6)alkyl(C6- C10)aryl, (C1- C6)alkoxy(C6- C10)aryl, ((C1- C6)alkoxy)2(C6- C10)aryloxy(C6- C10)aryl or (C5- C9)heterokaryotic(C6- C10)aryl.

2. Connection on p. 1, where n is equal to 2.

3. Connection on p. 1, where Ar is 4-methoxyphenyl or 4-phenoxyphenyl.

4. Connection PP.1, 2 or 3, where either R3or R4is not hydrogen.

5. Connection on p. 1, where n is 1 and either R3or R4is hydrogen.

6. Connection on p. 4, where X is hydroxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl.

7. Connection on p. 4, where X is alkoxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl.

8. Connection on p. 1, where Ar is 4-methoxyphenyl or 4-phenoxyphenyl, and R3or R4taken together form a (C3- C4)cycloalkyl, oxacillin, (C1- C6)alkyl, (C6- C10)aryl, (C1- C6)alkyl, (C5- C9)heteroaryl(C1- C6)alkyl or (C1- C6)alkylsulfonyl.

9. Connection on p. 1, where n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1and R2taken together, constitute piperazin, N-(C1- C6)alkylpiperazine, N'-(C6- C10)-arylpiperazine, or R3or R4is not hydrogen, or both R3and R4are not hydrogen.

10. Connection on p. 1, where n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1is hydrogen or (C1- C6)alkyl, R2is a 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, or R3or R4is not hydrogen, or both R3and R4are not hydrogen.

11. Connection on p. 1, where n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1is hydrogen, R2is a 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R3or R4is not hydrogen or both R3and R4are not hydrogen.

12. Connection on p. 2, where Ar is 4-methoxyphenyl, R1is is UP> is piperidinol and either R3or R4are not hydrogen, or both R3and R4are not hydrogen.

13. Connection on p. 1, where n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1is hydrogen , R2is R5(C2- C6)alkyl, where R5is piperidinol, and either R3and R4are not hydrogen, or both R3and R4are not hydrogen.

14. Connection on p. 1, where the specified connection is selected from 2-(R)-N-hydroxy-2-[(4-methoxybenzenesulfonyl)(3-morpholine-4-yl-3-oxopropyl)amino] -3-methylbutylamine; 2-(R)-2-[(2-benzylcarbamoyl)(4-methoxybenzenesulfonyl)amino] -N-hydroxy-3-methylbutylamine; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)(2-[(pyridine-3-ylmethyl)-carbarnoyl] ethyl)amino)-3-methylbutylamine; 2-(R)-N-hydroxy-2-([4-methoxybenzenesulfonyl][2-(methylpyridin-3-letiltasaval)ethyl] amino)-3-methylbutylamine; 4-(3-[1-(R)-1-hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino] propionyl)piperazine-1-carboxylic acid tert-butyl ester; 2-(R)-N-hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperazine-1-ylpropyl)amino)-3-methylbutylamine hydrochloride; 2-(R)-2-[(benzylcarbamoyl)(4 methoxybenzo carbamoyl)methyl] amino)-3-methylbutylamine, 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)([(pyridine-3-letiltasaval] )methyl)amino)-3-methylbutylamine, 2-(R)-3,3,3-Cryptor-N-hydroxy-2-[(methoxybenzenesulfonyl)(3-morpholine-4-yl-3-oxopropyl)amino]propionamide; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)[2-(methylpyridin-4-letiltasaval)ethyl] amino)-3-methylbutylamine; 4-[4-methoxybenzenesulfonyl)(3-morpholine-4-yl-3-oxopropyl)amino] -1-methylpiperidin-4-carboxylic acid hydroxyamide; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)[3-(4-methylpiperazin-1-yl)-3-oxopropyl] amino)-3-methylbutylamine; 2-(R)-2-[(2-carboxyethyl)(4-methoxybenzenesulfonyl)amino] -N-hydroxy-3-methylbutylamine; [(2-carboxyethyl)(3,4-dimethoxybenzonitrile)amino] -N-hydroxyacetamido; 2-(R)-2-[(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino] -N-hydroxy-3-methylbutylamine; 2-(R) - 3-(R)-3,N-dihydroxy-2-[(4-methoxybenzenesulfonyl)-(3-oxo-3-piperidine-1-ylpropyl)amino] -butyramide; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)[3-(methylpyridin-3-letiltasaval)propyl] amino)-3-methylbutylamine; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)[2-(methylcarbamoylmethyl)ethyl] amino)-3-methylbutylamine; 2-(R)-N-hydroxy-2-((4-methoxybenzenesulfonyl)[(1-methylpiperidin-4-ylcarbonyl)methyl] amino)-3-methylbutylamine; 2-(R)-2-cyclohexyl-N-guide is cybersolutions)(3-morpholine-4-yl-3-oxopropyl)amino]-4-(morpholine-4-yl)butyramide.

15. Pharmaceutical composition for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), including an active compound and a pharmaceutically acceptable carrier, wherein the active compounds it contains a compound of formula I under item 1 in an effective amount.

16. A method of inhibiting matrix metalloproteinases or the production of tumor necrosis factor (TNF), including the introduction of the active substance to a mammal, characterized in that the active substance is injected connection on p. 1 in an amount of 0.1 - 25 mg/kg

17. The method of treatment of a condition selected from the group consisting of arthritis, cancer, ulcer tissue, recurrent stenosis, Periodontology disease, congenital bullous of bullosa, scleritis and other diseases characterized by activity matrix metalloproteinase, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including man, characterized in that it includes an introduction to the specified mammal connection on p. 1 or its pharmaceutically acceptable salt in an amount of 0.1 - 25 mg/kg

18. The way the floor , Ar, X, n take the values specified in paragraph 1,

characterized in that the compound of the formula

< / BR>
where R3, R4, Ar, X, n take values above

subjected to interaction with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide, 1-hydroxybenzotriazole and hydroxylamine.

 

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< / BR>
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-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

The invention relates to a new group of imidazole compounds, method of their production and use for the treatment of diseases, mediasound cytokines, as well as to pharmaceutical compositions used for such therapy

The invention relates to new derivatives of camptothecin with enhanced antitumor activity, and intermediate products for their production

The invention relates to physiologically active agents that produce nitric oxide, process for their preparation, containing compositions, and methods of use thereof
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