Derivatives of hydroxamic acid

 

(57) Abstract:

The present invention relates to new derivatives of hydroxamic acids of formula (I), where R1denotes Deputy formula II, n is 1-4, m is 0-3, R5denotes hydrogen, alkyl or alkenyl, And denotes hydrogen, alkyl, aryl, arylalkyl, R2denotes alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, R3denotes alkyl, aryl or indolylmethane, R4denotes methyl, pyridyl or X-Y-, where X denotes mahalingappa, pyridyl or aryl, and Y denotes alkylene, in which up to four methylene (-CH2-) links is not necessarily replaced by-CO-, -NH-, -SO2- or O. These compounds possess inhibitory activity against the release of TNF - and due to this property they can be used as pharmaceutical agents. 9 C.p. f-crystals, 2 PL.

< / BR>
A-(O-(CR5N)n)m-O-CH2- (II)

The present invention relates to new compounds based on hydroxamic acids, useful as pharmaceuticals, for example, for the inhibition of matrix metalloproteinases, such as collagenase, and for inhibiting the production of TNF, in particular for the treatment of diseases or SOS is whether (TNF) is a cytokine that initially produced as a precursor associated with the membrane and having a molecular weight of 28 kDa. He then cleaved by an enzyme (TNF-convertase) and is released as a soluble active form with a molecular mass of 17 kDa. Soluble TNF exists in at least two forms of TNF and TNF, of which TNF, apparently, more important clinically. It is assumed that TNF mediates inflammation and other conditions associated with septic shock or acute infections. Probably a long overstimulate TNF plays a role in autoimmune and chronic inflammatory conditions such as arthritis, multiple sclerosis, etc.

It was found that specific inhibitors of matrix metalloproteinases from the class of hydroxamic acids, in particular (7-N-hydroxy)diamides 3-imino-4-oxalate-1,7-diovol acid (which, in addition, optionally can be substituted in the 1-N-, 2-, 5 - and 6-positions), have the ability to mediate the production of TNF, possibly due to inhibition of TNF-convertase. Well-known representatives of this class of compounds are summarized and described, for example, in WO 94/10990.

According to the invention it has been unexpectedly found that the SORS TNF and possess valuable pharmaceutical properties, in particular bioavailability upon oral administration.

New connections are (7-N-hydroxy)diamides 3-imino-4-oxo-6-(oxymethyl)heptane-1,7-diovol acid. Preferably 6-oximately Deputy is a compound of formula II, below, for example hydroxymethyl or mono - or polyalkoxyalkyl. In addition, as is well known in this field, for example as described in WO 94/10990 or as described in this application, the new compounds may have other substitution at the 1-N-, 2 - and 5-positions. For example, the new compounds may be substituted in the l-N-position the stands, pyridium or a group of the formula X-Y - or X'-Y-, as described below, for example, be a (1-N-morpholinoethyl - 7 - N - hydroxy) diamed 3-imino-4-oxo-6-(oxymethyl)heptane-1,7-diovol acid and to be in free form or in the form of pharmaceutically acceptable salts.

The most preferred class of new compounds are (7-N-hydroxy) diamides 3-imino-4-oxo-5-aryl-6- (oxymethyl) heptane -1,7-diovol acid. In addition, as described below, the 5-aryl Deputy, as, for example, when 5-aryl Deputy represents phenyl, optionally can be substituted, preferably in 4-position on what anography. These new compounds having 5-aryl Deputy may be in free form or in the form of pharmaceutically acceptable salts.

Preferred new compounds are compounds of the formula I

< / BR>
where R1denotes Deputy formula II:

A-(O-(CR5H)n)m-O-CH2II

where

n is 1, 2, 3 or 4, preferably 2,

m is 0, 1, 2 or 3,

R5in each case independently denotes H, C1-C10alkyl (optionally substituted by hydroxy, C1-C6alkoxy-, amino-, WITH1-C6alkylamino-, Tilney group, C1-C6allylmercaptan or protected hydroxy-, amino - or Tilney group)2-C6alkenyl, C6-C14aryl (optionally substituted by hydroxy, C1-C6alkoxy-, amino-, WITH1-C6alkylaminocarbonyl, halogen or cyano), or WITH6-C14(aryl)C1-C6alkyl; preferably H, phenyl, benzyl or C1-C5alkyl,

And denotes hydrogen, C1-C10alkyl, C6-C14aryl, C6-C14aryl(C1-C6alkyl), (C6-C14aryl)carbonyl or (C1-C10alkyl)carbonyl, predpochitayut2-C12alkyl, C3-C12alkenyl,3-C7cycloalkyl (optionally substituted by hydroxy, C1-C6alkoxy-, amino - or1-C6alkylaminocarbonyl)5-C14aryl or5-C14aryl(C1-C6alkyl), where aryl group optionally substituted by a hydroxy-group, WITH1-C6the alkyl, C1-C6alkoxy-, amino group, halogen or cyano, preferably phenyl, 4-were, 4-methoxyphenyl, cyclohexyl or isobutyl,

R3stands WITH1-C10alkyl (optionally substituted by hydroxy or C1-C6alkoxy-, amino-, WITH1-C6alkylamino-, Tilney group1-C6allylmercaptan or protected hydroxy-, amino - or Tilney group) (for example, tert-butyl or cyclohexylmethyl)6-C14aryl (optionally substituted by hydroxy, C6-C14aryloxy or1-C6alkoxy-, amino-, WITH1-C6alkylaminocarbonyl, halogen or cyano), (for example, benzyl, para-methoxybenzyl, para-benzyloxybenzyl) or indolylmethane (for example, 2-indolylmethane), preferably benzyl or tert-butyl,

R4denotes methyl, pyridyl or a group fo the1-C12alkylen, in which up to four methylene (-CH2-) links is not necessarily replaced by-CO-, -NH-, -SO2- or-O-, for example, methyl, 2-pyridyl, morpholinosydnonimine, 5-(morpholino)pentyl or 5-(morpholinomethyl)pencil.

The term "alkyl" includes linear, cyclic or branched alkyl, and the term "aryl" denotes a monovalent aromatic radical having one or two aromatic rings, for example phenyl, benzyl or tolyl, and includes heteroaryl having one or more heteroatoms, such as N, O or S.

The halogen or halogen in the context of the present description denotes F, Cl, Br or I, unless otherwise indicated.

Preferably R1denotes Deputy formula II'

A-(O-(CH2)n)m-O-CH2- II'

where A, n and m have the above values.

In another embodiment, R1denotes Deputy formula II"

A-(O-(HR5-CH2)n)m'-O-CH2II

where A, n and R5have the above values, and m' is 0, 1 or 2.

If R4in the formula I denotes a group of the formula X-Y-, then preferably it is a surrogate of formula X'-Y-, where X' denotes morpholinopropan, a Y has indicated that independently:

n in formula II is 3 or 4, or

R5in the formula II denotes N or

R2stands WITH7-C12alkyl, C3-C12alkenyl,3-C7cycloalkyl (optionally substituted by hydroxy, C1-C6alkoxy-, amino - or1-C6alkylaminocarbonyl)5-C14aryl or5-C14aryl(C1-C6alkyl), where aryl group optionally substituted by a hydroxy-group, WITH1-C6the alkyl, C1-C6alkoxy-, amino group, halogen or cyano, preferably phenyl, 4-were, 4-methoxyphenyl, or cyclohexyl, or

R3represents C1-C10alkyl (substituted amino, C1-C6alkylamino-, Tilney group1-C6allylmercaptan or protected hydroxy-, amino - or Tilney group)6-C14aryl (substituted amino, C1-C14alkylaminocarbonyl, halogen or cyano), or any aryl group in the formula denotes heteroaryl having one or more heteroatoms, such as N, O or S.

In other embodiments implementing the invention relates to new compounds of the formula I'

< / BR>
in which R1' denotes Deputy to 2,

m' denotes an integer of 0, 1, 2 or 3,

A' denotes hydrogen, C6-C14aryl, C1-C10alkyl, (C6-C14aryl)carbonyl or (C1-C10alkyl)carbonyl, preferably C1-C6alkyl (e.g. methyl or cyclohexyl),

R2' matches WITH2-C6alkyl, preferably isobutyl,

R3' represents C1-C10alkyl (optionally substituted by hydroxy or C1-C6alkoxygroup) (for example, tert-butyl or cyclohexylmethyl)6-C14aryl (optionally substituted by hydroxy, C6-C14aryloxy or C1-C6alkoxygroup) (for example, benzyl, para-methoxybenzyl, para-benzyloxybenzyl) or indolylmethane (for example, 2-indolylmethane), preferably benzyl or tert-butyl,

R4' denotes methyl, pyridyl or Deputy of the formula X-Y-, where X denotes morpholinopropan, pyridyl or aryl (preferably morpholinopropan) and Y represents C1-C12alkylen, in which up to four methylene (-CH2-) links is not necessarily replaced by-CO-, -NH-, -SO2- or-O-, for example, methyl, 2-pyridyl, morpholinosydnonimine, 5-(morpholino)pentyl or 5-(morpholinomethyl)pencil.

< R1denotes a radical of the formula II, as defined above, and R2denotes phenyl, 4-were-or 4-methoxyphenyl.

Especially preferred group of compounds of formula I are compounds in which:

(I) R1denotes a radical of the formula II' or II" (preferably a radical of the formula II') and in formula II represents hydrogen, C1-C6alkyl, for example methyl or cyclohexyl (for example, R1in the formula I denotes, in particular, hydroxymethyl, cyclohexyloxycarbonyl, methoxyethoxyethoxy or hydroxyethoxymethyl) or (C6-C14aryl)carbonyl such as benzoyl (for example, R1in the formula I denotes, in particular, benzoyloxymethyl, benzoylacetonitrile or benzoylacetonitrile),

(II) R2in the formula I denotes cyclohexyl, phenyl, 4-were, 4-methoxyphenyl or isobutyl,

(III) R3in the formula I denotes benzyl or tert-butyl and

(IV) R4in the formula I denotes methyl or morpholinoethyl(C1-C6)alkyl.

New connections can exist in free form or in salt form, and therefore it is understood that the compounds in salt form fall under the scope of the invention. In particular, some new Inania grounds for example, in the form of hydrochloride, oxalates or fumarate.

The structure of the new compounds are preferably described by formula Ia

< / BR>
or formula Ib

< / BR>
most preferably the formula Ia.

The invention includes new connections in the form of mixtures of enantiomers, such as racemic mixtures, although it is preferable that they were in pure or substantially pure enantiomeric form, for example in the form in which the content of individual isomer of a new compound is at least 90%, preferably at least 95% and especially preferably at least 98% (i.e., the content of other isomers of the new compounds is less than 10%, preferably less than 5% and especially preferably less than 2%).

Other objects of the invention relate to new methods for obtaining the compounds of formula I or intermediates of formulas II, IV or V below, including:

a) to obtain the compounds of formula I, as defined above, the interaction of the compounds of formula III

< / BR>
where R1, R2, R3and R4have the values indicated above, with hydroxylamine (not necessarily in the form of a salt or in-substituted form, e.g. in the form of Ki the th product or when necessary, the selection of the desired diastereoisomer,

b) to obtain the compounds of formula III, as defined above, oxidation of olefinic linkages in connection formula IV

< / BR>
where R1, R2, R3and R4have the above values, for example, using oxidation catalyst, such as a hydrate of ruthenium chloride (III), to obtain the acid of formula III, and optionally, if necessary, the selection of the desired diastereoisomer,

to obtain the compounds of formula IV interaction of the carboxylic acid of formula V

CH2=CH-CH(R1)-CH(R2)-COOH

where R1and R2have the above values, with amidon amino acids of the formula VI

NH2-CH(R3)-CO-NH(R4)

where R3and R4have the above values, to obtain the amide corresponding to the formula IV, and optionally, if necessary, the selection of the desired diastereoisomer, and

g) to obtain the compounds of formula V interaction alcohol of the formula IIIV< / BR>
A-(O-(CR5Hn)m-IT IIIV< / BR>
where a has the values specified for the As in the formula II, except when a represents N, And" denotes the O-protecting group (for example, a group capable of forming easily ottsepleny simple ether, for example benzyl) R 1,4-dibromo-2-Yong; obtaining disubstituted R1, haloalkane, for example, R1-CH=CH-CH2-W (TRANS), where W denotes halogen, such as bromine, which is then subjected to interaction with the carboxylic acid corresponding to R2namely R2-CH2COOH, with the formation of ether, which is then subjected to rearrangement, for example, in the presence of organic bases, such as amide diisopropylate, receiving the compound of formula V.

In the above-described methods may not necessarily be included under inclusion and removal of the protective groups, if you want to preserve the integrity of the intermediate products and the final product.

In addition, under the scope of the invention subject to the new intermediates of formulas III and IV, as defined above.

As described below in the examples for testing new compounds are strong inhibitors of the release of TNF, have activity in oral introduction and are not cytotoxic when used in effective doses. The new compounds also inhibit collagenase and stromelysin in concentrations from 0.3 to 10 nm. In addition, the tested new compounds showed activity in the in vivo studies on rats at oral introduction in doses of Maine is about to be transferred in such doses. Therefore, new compounds have pharmaceutical suitability, which are as follows.

The new compounds are suitable for the prevention or treatment of diseases and pathological conditions, oposredovannyh TNF, especially TNF, such as inflammatory conditions, autoimmune diseases, severe infections and rejection of the transplant organ or tissue, for example, in the treatment of recipients who transplanted heart, lung, combination heart-lung, liver, kidney, pancreatic, skin or cornea, and to prevent disease, graft versus host, such as occurs when bone marrow transplantation.

The new compounds are particularly suitable for the treatment, prevention or relief of autoimmune diseases and inflammatory conditions, in particular inflammatory conditions, etiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, a chronic progressive arthritis and arthritis deformans) and rheumatic diseases. Specific autoimmune diseases for which can be applied to new connections include autoimmune haematological disorders (including e.g. hemolytic anaemia, hypoplastic, sclerodoma), Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, severe pseudoparalysis the gravis, psoriasis, and syndrome of Stevens-Johnson, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernally keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with nephropathies syndrome and without it, for example, including idiopathic nephrotic syndrome or minimal change nephropathy).

The new compounds are also suitable for the treatment, prevention or attenuation of asthma, bronchitis, pneumoconiosis, emphysema lung and other obstructive or inflammatory diseases of the respiratory tract.

The new compounds are suitable for treatment of undesirable acute and hyperstretch inflammatory reactions mediated by TNF, especially TNF, in particular acute infections, such as septic shock (in particular, endotoxin bacterialike for the treatment of cachexia or wasting syndrome, associated with pathological release of TNF, which is a consequence of infection, cancer or organ dysfunction, especially cachexia associated with AIDS, in particular associated with or caused by HIV infection.

New connections, besides the fact that they inhibit the release of TNF, especially TNF, resulting in the suppression of TNF-convertase, are also inhibitors of matrix metalloproteinases, in particular collagenase, stromelysin and gelatinase, and, therefore, suitable for the readings, known for collagenase inhibitors or other inhibitors of matrix metalloproteinases, in particular for the treatment of various pathological conditions of the skin, bones and connective tissues, in particular rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoporosis, osteoarthritis, periodontitis, gingivitis and ulceration of the cornea for the treatment of cardiovascular diseases, in particular atherosclerosis and coronary angioplasty, to prevent metastasis and invasion of tumor cells and for the induction of fibrosis tumors, in particular for the treatment of cancer and prevention of neurodegenerative diseases, in particular Alzheimer's disease.

For the above indications, the appropriate dosage Dol is the subject to treatment, the form of administration and the nature and severity of the condition to be treated. However, in General, satisfactory results in animals are using daily doses from about 1 to about 10 mg/kg/day orally. For large mammals, such as humans, the daily dose is from about 50 to about 750 mg new connection, enter orally once or more preferably as divided doses two to four times per day.

The new compounds can be administered by any conventional route, in particular orally, for example in the form of solutions for drinking, tablets or capsules, or parenterally, for example in the form of solutions or suspensions for injection. As a rule, for systematic introduction of a preferred oral dosage form, although for certain indications, the new compounds can also be used locally or applied to the skin, for example, in the form of a skin cream or gel or similar product, or for use on the eye - in the form of an eye cream or gel preparation in the form of eye drops, or may be given by inhalation, in particular, in the treatment of asthma. Suitable standard dosage forms for oral introduction seismogram other objects of the invention are the following:

A. method of inhibiting production of soluble TNF, especially TNF, or reducing inflammation in a patient (e.g., mammal, human) in need of such treatment, comprising administration to the patient an effective amount of a new connection, or a method of treatment of any of the above conditions, especially a method of treating inflammatory or autoimmune disease or condition, in particular multiple sclerosis or rheumatoid arthritis, or alleviate one or more symptoms of any of the above conditions,

B. new compound designed for use as a pharmaceutical, in particular for use as an immunosuppressant or anti-inflammatory agent, or for use to prevent, mitigate or cure any of the above diseases or conditions, in particular autoimmune or inflammatory diseases or conditions,

Century Pharmaceutical composition containing the new compound together with a pharmaceutically acceptable diluent or carrier, for example, intended for use as an immunosuppressant or anti-inflammatory agent, or for the purpose of pre or inflammatory diseases or conditions,

, The use of the new compounds in the manufacture of medicinal products intended for use as an immunosuppressant or anti-inflammatory agent or for use to prevent, mitigate or cure any of the above diseases or conditions, in particular autoimmune or inflammatory diseases or conditions.

Example 1: Obtain {1- [S-phenylalanine-1-methylamide]-4- [N-hydroxyl]}diamide R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid (compound of formula I, where R1means 2,5,8-trioxadecyl, R2represents isobutyl, R3denotes benzyl and R4denotes methyl)

a) a Solution containing TRANS-1,4-dibromo-2-butene (CAS Reg. 821-06-7) (50,00 g), onomatology ether of diethylene glycol (CAS Reg. 111-77-3) (30,89 g), tetrabutylammonium bisulfate (CAS Reg. 32503-27-8) (7,94 g) and 50% aqueous sodium hydroxide solution (113,70 ml) in methylene chloride (200 ml), stirred at room temperature (RT) for 16 h, the Reaction mixture was diluted with water and simple ether, the organic phase is separated and the product in the form of olefin purify by chromatography.

b) a Solution containing the product in the form of TRANS-olefin and obtained in stage a) (27,11 g), and DBU (1,8-diazabicyclo[5.4.0]undec-7-todny sodium carbonate (18 g). The mixture was incubated over night. The organic phase is separated and the product in the form of ester purified by chromatography.

From Diisopropylamine (22,65 ml) and utility in hexane (1,6 N., 99.89 per ml) receive at -70oTo a solution of LDA (amide diisopropylate) in tetrahydrofuran (400 ml). At the same temperature is added a solution of the product obtained in stage b) (43,90 g) in tetrahydrofuran (100 ml). After 30 minutes add chlorotrimethylsilane (20,22 ml). The temperature is first raised to room temperature and then the mixture was kept at the temperature of reflux distilled during the night. The mixture is diluted with simple ether. Non-acidic products are removed from the organic phase, receiving 35,12 g of the crude acid, which was then subjected to chromatography getting 30,70 g of pure product in the form of a carboxylic acid.

g) a Solution containing the product obtained in stage C) (10,50 g), (L)-phenylalanine-1-methylamide (at 8.60 g) (for example, obtained by reacting commercially N-carbobenzoxy-(L)-phenylalanine with methylamine under standard conditions with obtaining methylamide and hydrogenation in the presence of palladium to remove aminosidine group) and 4-dimethylaminopyridine (4,89 g) in methylene chloride (120 ml), handle EDCI (hydrochloride of 1-(3-d dobavlaut simple ether and the organic phase is dried and evaporated. The crude product, which is a mixture of two isomers, chromatographic on silica gel, separating the isomers on the basis of their relative polarity.

d) Intensively mixed solution containing the less polar product obtained in stage g) (5.30 g) in carbon tetrachloride (150 ml), acetonitrile (150 ml) and water (20 ml) is treated with hydrate of ruthenium chloride (III) (0,49 g) and perpetrator sodium (15,16 g). After 2 h, add a simple ether and the pH adjusted to 4. The organic phase is separated, dried and evaporated. The remainder chromatographic on silica gel, receiving pure acid.

e) a Solution containing the product obtained in stage d) (5 g), hydroxybenzotriazole (2.00 g) and EDCI (of 2.51 g) in DMF (N,N-dimethylformamide) (20 ml), incubated at room temperature for 2.5 hours Then add hydroxylamine hydrochloride (1.90 g) and N-methylmorpholin (4.61 in ml) and the mixture was incubated over night. The solvent is evaporated in a high vacuum at 50oC. the Residue is purified using jhud on the type column on silica gel RP18, getting clean hydroxamic acid in the form of a crystalline white powder.

tPL195-197oWith the rotation of the plane of polarization of light []D20=-8,5owith= 0,175 in Magicno method, described in example 1. The product obtained in stage C) of example 1, is subjected to the interaction with the corresponding derivative of amide amino acids, as described for stage d) of example 1. Working according to the ways of stages d) and e) of example 1, get clean hydroxamic acids.

Examples 18-32

To interact with TRANS-1,4-dibromobutane according to stage a) of example 1 instead of nanometrology ether of diethylene glycol used cyclohexylglycine. Working according to the ways of stages b) to (e) of example 1, get clean hydroxamic acids of examples 18-32 table I.

Examples 33 and 34

To interact with TRANS-1,4-dibromobutane according to stage a) of example 1 instead of nanometrology ether of diethylene glycol used monobenzylether or onomatology ether (2-benzyl) glycol. Working according to the ways of stages b) to (e) of example 1, get hydroxamic acids of formula I with R1protected by a benzyl hydroxy-group. The benzyl group is removed by hydrogenation in the presence of catalytic amounts of palladium or barium sulfate and after cleaning using jhud on the type column on silica gel RP18 obtain the corresponding pure compounds of formula I (see table I).

1group benzoyloxymethyl. The benzyl group is removed by hydrogenation in the presence of catalytic amounts of palladium or barium sulfate and after cleaning using jhud on the type column on silica gel RP18 obtain the corresponding pure products of examples 35-59 table I.

All compounds were characterized using mass spectroscopy and1H-NMR spectroscopy. Table II summarizes the analytical data for the compounds of examples 1-59.

Example test 1: Inhibition of release of TNF

Mononuclear cells obtained from peripheral blood of healthy volunteers by fractionation on the basis of density using ficoll-hipac according to Hansell, etc., J. Imm. Methods (1991) 145: 105 and used at a concentration of 105cells/well in RPMI medium 1640, supplemented with 10% FCS (fetal calf serum). Cells incubated with serial dilutions of test compounds for 30 min at 37oSince before adding IFN (100 units /ml) and LPS (5 μg/ml) and then further incubated in tacheny fluid is measured using a commercially available ELISA kit (Innotest hTNF, supplied by the company Innogenetics N.V. , Zwijnaarde, Belgium). New connections are tested in concentrations from 0 to 10 μm. This analysis is shown in the examples of the compounds of formula I and especially of formula Ia inhibit the release of TNF with the value of the IC50from approximately 50 nm to approximately 5 μm.

Sample test 2: Cytotoxicity

Cytotoxicity was determined on cells TNR (5x104cells/well), which is incubated at 37oC for 24 h in the presence of IFN (100 units/ml) and LPS (5 μg/ml) and in the presence of test compounds or without him. The percentages of live and dead cells is assessed using the colorimetric method exception (MMT), which allows the detection of mitochondrial dehydrogenase enzymes in living cells, as described in Mosman, J. Imm. Methods (1983) 65: 55. Investigated new compounds exhibit less than 50% cytotoxicity at a concentration of 10 μm, and this suggests that the new compounds are not cytotoxic at concentrations sufficient to suppress TNF.

Example test 3: Inhibition of collagenase

Inhibition of collagenase appreciate using active with collagenase MMP-substrate containing dipeptide, according to the method of ml by the addition of substrate at pH 6.5, 25oWith a buffer of 2-morpholinepropanesulfonic acid (50 mm), supplemented with 10 mm CaCl2. The absorbance was measured at 405 nm at regular intervals for 40 minutes Inhibitory activity of the test compounds determined as a function collagenase activity in control in the presence of test compounds and without it. The new compounds possess significant dose-dependent ability to inhibit collagenase in low nanomolar concentrations, in particular below 10 nm.

Example test 4: bioavailability in oral introduction

Analysis method of the previous example have been standardized by measuring the specific activity of the tested compounds at various known concentrations and used for measuring the concentration of the test compound in the plasma after oral administration. The test compound is administered orally in conscious rats at a dose of 10 mg/kg of blood Samples taken from the cut tip of the tail after 30, 60, 120 and 240 minutes after oral administration. The plasma is subjected to extraction with trichloroacetic acid. The extract is tested according to the above-described method of inhibiting collagenase to obtain estimates concentratingon the introduction, and their plasma concentrations are 300-5000 nm after 30 min and 50-500 nm after 240 minutes So pharmaceutically effective levels in the plasma (as described in the examples to test 1 and 3) are easily achievable with oral introduction of regulated doses, in particular 10 mg/kg also achieved plasma levels significantly below the cytotoxic level, and in rats was not observed any side effects when using this dose.

1. Derivatives of hydroxamic acids of formula I

< / BR>
where R1denotes Deputy formula II

A-(O-(CR5H)n)m-O-CH2II

where n is 1, 2, 3, or 4

m is 0, 1, 2 or 3,

R5in each case independently denotes H, C1-C10alkyl, C2-C6alkenyl;

And denotes hydrogen, C1-C10alkyl, C6-C14aryl, C6-C14aryl(C1-C6alkyl);

R2stands WITH3-C12alkyl, C3-C12alkenyl,3-C7cycloalkyl,5-C14aryl or5-C14aryl(C1-C6alkyl), where aryl group optionally substituted by a hydroxy-group, WITH1-C6the alkyl, C1-C6alkoxy - or holography;6-C14aryl (optionally substituted by hydroxy, C6-C14aryloxy or1-C6alkoxygroup) or indoleacetic;

R4denotes methyl, pyridyl or Deputy of the formula X-Y-, where X denotes morpholinopropan, pyridyl or aryl, and Y represents C1-C14alkylen, in which up to four methylene (-CH2-) links is not necessarily replaced by-CO-, -NH-, -SO2- or-O-,

in free form or in the form of pharmaceutically acceptable salts.

2. Connection on p. 1, where R1denotes Deputy formula II'

A-(O-(CH2)n)m-O-CH2- II'

where A, n and m have the meanings specified in paragraph 1.

3. Connection on p. 1, where R1denotes Deputy formula II"

A-(O-(HR5-CH2)n)m'-O-CH2II

where a and R5have the values listed in paragraph 1, n is 1 or 2, and m' is 0, 1 or 2.

4. Connection PP. 1-3, where R4in the formula I represents a Deputy of the formula X-Y-, when m in formula II is equal to zero.

5. The compound of formula I under item 1, in which independently:

n in formula II is 3 or 4, or

R5in the formula II denotes N or

R2stands WITH7-C12and the Rhyl(C1-C6alkyl), where aryl group optionally substituted by a hydroxy-group, WITH1-C6the alkyl, C1-C6alkoxy - or holography, or

R3stands WITH1-C10alkyl, C6-C14aryl or any aryl group in the formula denotes heteroaryl having one or more heteroatoms, such as N, O or S.

6. Connection on p. 1 of the formula I'

< / BR>
where R'1denotes Deputy formula II"'

A'-(O-(CH2)n')m'-O-CH2II"'

where n' denotes an integer equal to 1 or 2,

m' denotes an integer of 0, 1, 2 or 3,

A' denotes hydrogen, C6-C14aryl, C1-C10alkyl,

R'2stands WITH2-C6alkyl,

R'3stands WITH1-C10alkyl (optionally substituted by hydroxy or C1-C6alkoxygroup)6-C14aryl (optionally substituted by hydroxy, C6-C14aryloxy or1-C6alkoxygroup) or indolylmethane,

R'4denotes methyl, pyridyl or Deputy of the formula X-Y-, where X denotes morpholinopropan, pyridyl or aryl, and Y represents C1-C14alkylen, in which up to four methyleneimine acceptable salt.

7. The compound according to any one of paragraphs. 1-6, where

(I) R1denotes a radical of the formula II' or II" and in the formula II denotes hydrogen or C1-C6alkyl;

(II) R2in the formula I denotes cyclohexyl, phenyl, 4-were, 4-methoxyphenyl or isobutyl,

(III) R3in the formula I denotes benzyl or tert-butyl and

(IV) R4in the formula I denotes methyl or morpholinoethyl(C1-C6)alkyl.

8. The compound according to any one of paragraphs. 1-7, having structural formula Ia

< / BR>
9. The compound according to any one of paragraphs. 1-8, selected from compounds

{ 1-[S-phenylalanine-1-methylamide] -4-[N-hydroxy] } -diamide R-2-isobutyl-S-3-(2,5,8-trioxadecyl)-succinic acid;

{ 1-[S-phenylalanine-1-(2-(morpholino)ethyl) - amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-phenylalanine-1-(5-(para-tosylamide)pentyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-phenylalanine-1-(2-(morpholinomethyl)ethyl) - amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-phenylalanine-1-m(2-(para-tosylamide)ethyl) - amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-phenylalanine-1-(1-S-(methylcarbamoyl)ethyl)amide][N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-trimethylene-1-(morpholinoethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-trimethylene-1-(2-(morpholinomethyl)ethyl) - amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-trimethylene-1-(5-(morpholinomethyl)pentyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-trimethylene-1-(2-pyridyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-(para-methoxyphenyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[R-(tert-butylacetyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[R-(benzoyloxymethyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-(para-benzyloxyphenyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[S-(3-methylindole)glycine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{ 1-[R-(hydroxymethyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(2,5,8-trioxadecyl)succinic acid;

{Is;

{ 1-[S-phenylalanine-1-(2-pyridyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-phenylalanine-1-(3,6-dioxa-8-oxo-9-imino-11-morpholinoethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-phenylalanine-1-(5-(morpholino)pentyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-phenylalanine-1-(morpholino)butyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-phenylalanine-1-(3,6-dioxa-8-oxo-8-morpholinoethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1-(3-imino-8-phenylethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1-(5-(benzyloxycarbonylamino)pentyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1-(6-imino-7-oxo-10-methylundecyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1-(2-pyridyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-(para-methoxyphenyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-(methyl-3-indolyl)glycine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[R-(tert-butylacetyl)alanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(cyclohexyloxycarbonyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxyethoxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxy-2-ventilationsystem)succinic acid;

{ 1-[S-phenylalanine-1-methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1-(6-imino-7-oxo-l0-methylundecyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1-(6-imino-8-phenylethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid is yl)succinic acid;

{ 1-[S-trimethylene-1-(morpholinoethyl)amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1-(2-(morpholinomethyl)ethyl) - amide] -4-[N-hydroxy] } diamid R-2-isobutyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-n-propyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-isopropyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-cyclopropyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(3-methylbutyl)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-cyclopentyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-cyclohexyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-cyclopentylmethyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-cyclohexylmethyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(2-methoxyethyl)-S-3-(Gimmel)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-benzyl-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(4-phenylphenyl)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(2-phenylethyl)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(2-naphthyl)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(3-were)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(4-were)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(4-methoxyphenyl)-S-3-(hydroxymethyl)succinic acid;

{ 1-[S-trimethylene-1 methylamide] -4-[N-hydroxy] } diamid R-2-(4-forfinal)-S-3-(hydroxymethyl)succinic acid.

10. The compound of formula 1 according to any one of paragraphs. 1-9, intended for use as pharmaceutical agents having inhibitory activity against the release of TNF-.

Priority points:

02.10.1996 - PP. 1-5, 7-10;

02.04.1997 - PP. 6-10.

 

Same patents:

Cytotoxic agents // 2187499

The invention relates to new aryl-S(O)n-substituted carboxylic/hydroxamic acids of formula I, where Y represents hydroxy, XONH-where X is H, C1-C6alkyl; R1means H, C1-C6alkyl; R2means H, C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl - C2-C8alkyl, tetrahydropyranyl, piperidinyl, -NR6R7where R6means H, C1-C6alkyl, aryl; R7means H, C1-C6alkyl, aryl, aryl - C1-C8alkyl, -SO2NR8R9aryloxyalkyl, C1-C8alkoxycarbonyl, -C(O)-O-CH2Rdwhere Rdmeans phenyl; or a group NR6R7means valinamide; R8and R9independently mean H, C1-C6alkyl; or R1and R2together with the carbon atom to which they are attached form a C3-C8cycloalkyl or possibly substituted lower alkyl piperidinyl or tetrahydropyranyl; R3means H, C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C8alkyl, aryl, aryl - C1-C8alkyl, piperidinyl, tetrahydropyranyl; R4means H, C1-C6alche are C3-C8cycloalkyl, R3and R4together represent C3-C8cycloalkyl; R5means aryl, possibly substituted

The invention relates to therapeutically active hydroxamic acids and derivatives of carboxylic acids, processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of such compounds in medicine

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

The invention relates to therapeutically active derivatives of hydroxamic acids, processes for their preparation, pharmaceutical compositions containing them and to the use of such compounds in medicine
The invention relates to medicine, in particular to orthopedics, and can be used for the treatment of osteochondropathy
The invention relates to medicine, namely to traumatology and can be used for regeneration of articular cartilage
The invention relates to medicine, therapy, can be used to treat an unquenchable pain syndrome arthritisarthritis knee

The invention relates to medicine, in particular to Hematology and arthrology, and for the treatment of hemophilic arthropathy

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)
The invention relates to medicine, in particular to rheumatology, and for the treatment of rheumatoid arthritis
The invention relates to medicine, in particular to the means for local Antirheumatic therapy
The invention relates to medicine, namely to rheumatology, and is intended for the treatment of rheumatoid arthritis
The invention relates to medicine, namely to pharmacology

The invention relates to medicine

The invention relates to veterinary science and medicine
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