MXPA99007143A - Arylsulfonylamino hydroxamic acid derivatives - Google Patents

Abstract

A compound of formula (I) wherein R1, R2 and Q are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Description

DERIVATIVES OF ARILSULFONILAMINOHIDROXAMIC ACIDS The present invention relates to arylsulfonylaminohydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, as such, are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention can be used in combination therapy with nonsteroidal anti-inflammatory drugs (hereinafter referred to as abbreviated NSAIDs) and analgesics for the treatment of arthritis, and combined with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum , etoposide, taxol and taxotero and as alkaloids, such as vincristine, for the treatment of cancer. This invention also relates to a method of using said compounds in the treatment of the above diseases in mammals, especially in humans, and to pharmaceutical compositions useful therefor. There are a number of enzymes that break down structural proteins and that are structurally related metalloproteases. Metalloproteinases that degrade the matrix, such as gelatinase, stromelysin and collagenase, are involved in the degradation of the tissue matrix (for example collagen collapse) and have been implicated in many pathological conditions involving connective tissue and matrix metabolism of the abnormal basement membrane, such as arthritis (for example, osteoarthritis and rheumatoid arthritis), metastasis or invasion of tumors, as well as infection of the human immunodeficiency virus (HIV) [J. Leuk Biol., 52 (2), 244-248, 1992]. It is admitted that the tumor necrosis factor is involved in many infectious and autoimmune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). In addition, it has been shown that TNF is the main mediator of the inflammatory response seen in sepsis and in septic shock (C.

Spooner et al., Clinical Immunology and Immununopathology, 1992, 62 S1 1). The present invention relates to a compound of formula or pharmaceutically acceptable salts thereof, wherein each of R 1 and R 2 are independently selected from C 1 β alkyl, trifluoromethyl, trifluoromethyl (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) difluoromethylene, (C 1 -C 6 alkyl) C3) difluoromethylene (C 1 -C 3 alkyl) C 6 -C 6 aryl, C 2 -C 8 heteroaryl, (C 1 -C 6 aryl) (C 1 -C 6 alkyl) or (C 2 -C 9 heteroaryl) (C 1 -C 6 alkyl) or (C2-C9 heteroaryl) (C6-C6 alkyl), or R1 and R2 can be joined to form a C3-C6 cycloaicyl ring or a C3-C6 cycloalkyl ring fused to a benzene a group of formula wherein m and n are independently 1 or 2, and X is CF2, S, O or NR3, wherein R3 is hydrogen, C? -C6 alkyl, C6-C? aryl, C2-C9 heteroaryl, (C6-aryl) C? 0) (C? -C6 alkyl), (C2-C9 heteroaryl) (C6 alkyl), (C ^ C6 alkyl), sulfonyl, (C6-C? O aryl) suifonyl or acyl and Q is C-alkyl ? -C6, C6-C0 aryl, (C6-C0 aryloxy) (C6-C? Aryl), (C6-C10 aryl) (C6-C10 aryl), (C6-C10 aryl) (C6-C aryl) 0), (C -C6 alkyl), (C6-C10 aryl) (C2-C9 heteroaryl), (C6-C6 aryloxy) (C2-C9 heteroaryl), (C2-C9 heteroaryl), (C2-C9 heteroaryl) ) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl), (C6 alkyl) (C6-C? 0 aryl), (C6-C6 alkoxy) (C6-C? 0 ary) , (C6-C10 aryl) (C6-C6 alkoxy) (C6-C6o aryl), (C6-C6 aryl) (C6-C6 alkoxy) (C4C6 alkyl), (C2-C9 heteroaryloxy) ) (C6-C? aryl), (C? -C6 alkyl) (C2-C9 heteroaryl), (Ci-C? alkoxy) (C2-C9 heteroaryl), (C6-C6 aryl) (C6-alkoxy) ) (C2-C9 heteroaryl), (C2-C9 heteroaryloxy) (C2-C9 heteroaryl), (C6-C6 aryloxy) (C6-C6 alkyl), (C2-C9 heteroaryloxy) (alkoxy) uilo C? -C6), (C? -C6 alkyl) (C6-C0 aryloxy) (C6-C? aryl), (C6 alkyl) (C2-C9 heteroaryloxy) (C6-C10 aryl), (C 1 -C 6 alkyl) (C 6 -C 0 aryloxy) (C 2 -C 9 heteroaryl), (C 1 -C 6 alkoxy) (C 6 -C 0 aryloxy) (C 6 -C 0 aryl), (C 2 alkoxy) ? -C6) (C2-C9 heteroaryloxy) (C6-C? 0 aryl) or (C? -C6 alkoxy) (C6-C? 0 aryloxy) (C2-C9 heteroaryl), wherein each aryl group is optionally substituted by fluorine, chlorine, bromine, Ci-CQ alkyl, C-C alco alkoxy or perfluoro (C 1 -C 3 alkyl). The term "alkyl / alkyl", as used herein, unless otherwise indicated, includes monovalent saturated hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy," as used herein, includes alkyl-O groups, wherein "alkyl" is as defined above. The term "aryl / aryl", as used herein, unless otherwise indicated, influences an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group formed by fluoro, chloro, trifluoromethyl, C6-C6 alkoxy, Ce-Cio aryloxy, trifluoromethoxy, difluoromethoxy and C6-C6 alkyl. The term "heteroaryl / heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from a heterocyclic aromatic compound by removal of a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro , chloro, trifluoromethyl, C-C6 alkoxy, C6-C6-aryloxy, trifluoromethoxy, difluoromethoxy and C-? -C6 alkyl. The term "acyl / acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO, wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy, the terms "alkyl" and "Aryan" as defined above. The term "acyloxy", as used herein, includes acyl-O groups, wherein "acyl" is as defined above. The compound of formula I may have chiral centers and, therefore, may exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. Preferred compounds of formula I include those in which R1 and R2 are joined to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene or a group of formula wherein m and n are independently 1 or 2, and X is CF2 > S, O or NR3, wherein R3 is hydrogen, C -C6 alkyl, Ce-Cio aryl, C2-C9 heteroaryl, (Ce-C aryl) (C6-C6 alkyl), (C2-C9 heteroaryl) (alkyl C? -C6), (Ci-Ce alkyl), sulfonyl, (C6-C? Aryl) sulfonyl or acyl.

Other preferred compounds of formula 1 include those in which R1 and R2 join to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene. Other preferred compounds of formula I include those in which Q is C 6 -C 0 aryl, (C 6 -C 6 aryl) (C 6 -C 6 aryl), (C 6 -C 0 aryloxy) (aryl Cedo), (C6-C6 aryloxy) (C2-C9 heteroaryl), C2-Cg heteroaryl, (C2-C9 heteroaryl), (C2-C9 heteroaryl), (C6-C? 0 aryl), (C2-C9 heteroaryl), (C2-C9 heteroaryl), (C6-C6o aryl), or (C2-C9 heteroaryloxy) (C6-C10 aryl). Other preferred compounds of formula I include those in which Q is (aryloxy CT-CI O) (aryl CT-CIO). Other preferred compounds of formula I include those in which each of R1 and R2 are independently C6-C6 alkyl. More preferred compounds of formula I include those in which R1 and R2 are joined to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene or a group of formula wherein m and n are independently 1 or 2, and x is CF2, S, O or NR3, wherein R3 is hydrogen, C? -C6 alkyl, C6-C? aryl, or C2-C9 heteroaryl, (C6-C aryl) ? 0) (C? -C6 alkyl), C2-C9 heteroaryl) (C? -C6 alkyl), (C? -C6 alkyl) sulfonyl, (C6-C? O) aryl sulfonyl or acyl, and Q is C6 aryl -C? 0, (aryl C6-C? 0) (C6-C? 0 aryl), (C6-Cio aryloxy) (C6-C? 0 aryl), (C6-C? 0 aryloxy) (C2-C9 heteroaryl) ), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl) or (C2-C9 heteroaryloxy) (C6-C0 aryl). More preferred compounds of formula I include those in which R1 and R2 join to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene, and Q is C6-C6aryl aryl, Cι) (C 6 -C 0 aryl), (C 6 -C 0 aryloxy) (C 6 -C 6 aryl), (C 6 -C 0 aryloxy) (C 2 -C 9 heteroaryl), C 2 -C 9 heteroaryl, (heteroaryl) C2-C9) (C2-C9 heteroaryl), (aryl Ce-Cio) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl) or (C2-C9 heteroaryloxy) (C6-C aryl) ?or). More preferred compounds of formula I include those in which each of R 1 and R 2 are independently C 1 -C 6 alkyl and Q is C 6 -C 10 aryl, (C 6 -C 6 aryl) (C 6 -C 6 aryl), (C6-C6 aryloxy) (C6-C10 aryl), (C6-C10 aryloxy) (C2-C9 heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-Cg heteroaryl), (C6- aryl) C? 0), (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl) (C6-C10 aryl). Preferred mpe compounds of formula I include those in which each of R1 and R2 is independently C6-C6 alkyl and Q is (C6-C aryl) (C6-C10 aryl). Specific preferred compounds of formula I include the following: 3- [4- (4-fluorophenoxy) benzenesulfonylamino] azetidine-3-carboxylic acid hydroxyamide, 4- [4- (4-fluorophenoxy) benzenesulfonylamino] piperidine- hydroxyamide 4-carboxylic acid, 1- [4- (4-fluorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide, 1- [4- (4-chlorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide, hydroxyamide of acid 1 - [4- (4-fluorophenoxy) benzenesulfonylamino] cyclobutane-1-carboxylic acid, 1- [4- (4-chlorophenoxy) benzenesulfonylamino) cyclobutane-1-carboxylic acid hydroxyamide, 1- [4- (4-flurofenoxy) hydroxyamide ) benzenesulfonylamino] cyclopentane-1-carboxylic acid 1- [4- (4-fluorophenoxy) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide, 2- [4- (4-fluorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methyropropionamide , 2- [4- (4-chlorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide, N-hydrox i-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) proponamide, 1- (5-pyridin-2-ylthiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide, hydroxyamide of 1 - (4'-fluorobiphenyl-4-sulfonylamino) cyclopropane-1-carboxylic acid, 1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclobutane-1-carboxylic acid hydroxyamide, 1- (4'-fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide, 2- (4-hydroxyamide) -methoxybenzenesulfonylamino) indan-2-carboxylic acid and 2- [4- (4-fluorophenoxy) benzenesulfonylamino] -dan-2-carboxylic acid hydroxyamide. The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa and scleritis , combined with NSAIDs and standard analgesics, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases that involve the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or of the production of tumor necrosis factor (TNF) in a mammal, including man, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in said treatments, and a pharmaceutically acceptable carrier.

The present invention also relates to a process for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including man, which comprises administering said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa and scleritis, the compounds of formula I combined with NSAIDs and standard analgesics and combined with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including man, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective to treat said condition. The following reaction scheme illustrates the preparation of the compounds of the present invention. Unless indicated otherwise, in the reaction schemes and in the discussion that follows R1, R2 and Q are as defined above.

PREPARATION A V VI SCHEME 1 III II In reaction 1 of preparation A, an amino acid of formula Ili is treated with benzyl alcohol and an acid of formula HX, wherein X is preferably 4-toluensuffonate, in an inert solvent, such as benzene or toluene (toluene is preferred) , obtaining the acid salt of the benzyl ester of formula V. The reaction is usually carried out for a period of time between about 1 hour and about 24 hours, at the boiling temperature of the solvent used. The water formed during the course of the reaction is normally collected in a Dean Stark separator. In reaction 2 of preparation A, the compound of formula V is converted into the corresponding compound of formula VI by reacting V with a reactive functional derivative of a sulphonic acid (QSO2OH), such as sulfonyl chloride (QSO2CI), in the presence of a base, such as sodium hydroxide or triethylamine, and a solvent, such as methylene chloride, tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred at a temperature between about 0 ° C and about 60 ° C, preferably at room temperature, for a period of time between about 10 minutes and about 2 days, preferably about 60 minutes. In reaction 3 of preparation A, the intermediate compound of formula VI is hydrogenolyzed, the intermediate of formula II being provided. The reaction is carried out in a solvent, such as ethanol, under an atmosphere of hydrogen (preferably at 3 atmospheres pressure) using a catalyst, such as 10% palladium on active carbon. Normally, the reaction mixture is stirred at room temperature for a period of time between about 30 minutes and about 24 hours, preferably about 1.5 hours. In reaction 1 of scheme 1, the amino acid of formula III is converted into the corresponding compound of formula II by reacting III with a reactive functional derivative of a sulfonic acid of formula QSO2OH, wherein Q is as defined above, such as sulfonyl chloride (QS02CI), in the presence of a base, such as sodium hydroxide or triethylamine, and a polar solvent, such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred at a temperature between about 0 ° C and about 50 ° C, preferably at room temperature, for a period of time between 10 minutes and about 2 days, preferably for approximately 60 minutes. In reaction 2 of scheme 1, the carboxylic acid of formula II is converted into the hydroxamic acid of formula I by treating II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent, such as N, N -dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a period of time between about 15 minutes and about 1 hour, preferably after about 30 minutes. Preferably the hydroxylamine is generated in situ from a salt, such as hydroxylamine hydrochloride, in the presence of a base, such as triethylamine. Alternatively, instead of hydroxylamine or a hydroxyamine salt, a protected derivative of hydroxylamine or a salt thereof can be used, in which the hydroxyl group is protected by tert-butyl, benzyl, allyl or 2-trimethylsilylethyl ether. The separation of the hydroxyl protecting group is carried out by hydrogenolysis for a benzyl protecting group (5% palladium on barium sulfate is the preferred catalyst) or by treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group can be removed by treatment with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (11) chloride as the catalyst. The 2-trimethylsilylethylether can be removed by reaction with a strong acid, such as trifluoroacetic acid, or by reaction with a fluoride source, such as boron trifluoride etherate. The reaction of 11 with hydroxylamine, with a hydroxylamine salt, with a protected derivative of hydroxylamine or with a salt of a protected derivative of hydroxylamine can also be carried out in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base, such as triethylamine, in an inert solvent, such as methylene chloride. The reaction mixture is stirred at a temperature between about 0 ° C and about 50 ° C, preferably at room temperature, for a period of time between about 1 hour and about 3 days, preferably about 1 day. The preferred procedure for converting compound II to compound I is to react II with O-benzylhydroxylamine hydrochloride in the presence of (benzotraizoi-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and triethylamine using methylene chloride as the solvent. Then, the subsequent removal of the O-benzyl protecting group to give a compound of formula I is carried out by hydrogenolysis under hydrogen at 3 atmospheres, at room temperature, using 5% palladium on barium sulfate as a catalyst. The preferred solvent is methanol. The reaction time may vary from about 1 hour to about 5 hours (3.5 hours is preferred). In certain cases it is preferred to obtain the compound of formula I by reaction of hydroxylamine, a hydroxylamine salt, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine with an activated ester of formula IV, as shown in reaction 3 of the scheme 1. The reaction is carried out in an inert solvent, such as N, N-dimethylformamide, at a temperature ranging from about room temperature to about 80 ° C, preferably at about 50 ° C, for a period of time of about 1 hour to approximately 2 days. If a protected derivative of hydroxylamine or a salt of protected derivative of hydroxylamine is used, removal of the protecting group is carried out as described above. The activated ester derivative of formula IV is obtained by treatment of the compound of formula II with (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoride and a base, such as triethylamine, in an intert solvent, such as methylene chloride (reaction 4). of scheme 1). The reaction mixture is stirred at a temperature between about 0 ° C and about 50 ° C, preferably at room temperature, for a period of time between about 1 hour and about 3 days, preferably about 1 day. With bases, pharmaceutically acceptable salts are formed of the acidic compounds of the invention, namely, cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium and magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium and tris (hydroxymethyl) methylammonium. Similarly, acid addition salts, such as mineral, organic carboxylic and organic sulfonic acids, for example, hydrochloric acid, methanesulfonic acid and maleic acid, are also possible, with the proviso that a basic group, such as pyridyl, constitutes part of the structure. The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter referred to as the compounds of the present invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, to demonstrate their efficacy to treat diseases characterized by matrix metalloproteinase activity or by the production of tumor necrosis factor is demonstrated by the following in vitro tests.

BIOLOGICAL TESTS Inhibition of human collagenase (MMP-1) Recombinant human collagenase is activated with trypsin using the following ratio: 10 μg of trypsin per 100 μg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a 10-fold excess (50 μg / 10 μg trypsin) of soybean trypsin inhibitor is added. 10 mM stock solutions of inhibitors are prepared in dimethyl sulfoxide and then diluted using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM. Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96-well Microfluor plate. The final inhibitor concentration will be a 1: 4 dilution after the addition of enzyme and substrate. Positive controls are prepared (with enzyme and without inhibitor) in wells D1-D6 and blank assays (without enzyme and without inhibitors) in wells D7-D12. Collagenase is diluted to 400 ng / ml and then added to appropriate wells of the Microfluor plate: The final concentration of collagenase in the assay is 100 ng / ml. Substrate [DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2J is prepared as a 5 mM solution in dimethyl sulfoxide and then diluted to 20 μM in assay buffer. The assay is initiated by the addition of 50 μl of substrate per well of the Microfluor plate to give a final concentration of 10 μM. Fluorescence readings were made (excitation 360 nm and emission 460 nm) at time 0 and then at 20 minute intervals. The test is carried out at room temperature with a typical test time of 3 hours. A plot of the fluorescence as a function of time is then constructed, both for the samples containing collagenase and for those of the blank test (in the determinations in triplicate, the mean value is taken). To determine IC50 values, a time is chosen that provides a good signal (blank test) and that is in the linear part of the curve (usually around 120 minutes). The values corresponding to time zero are used as a reference for each compound at each concentration and these values are subtracted from the data corresponding to 120 minutes. The data is plotted as concentration of inhibitor against percent control (fluorescence of the inhibitor divided by collagenase fluorescence alone and multiplied by 100). The IC 50 are determined from the concentration of inhibitor that gives a signal that is 50% of that of the control. If the IC 50's are lower than 0.03 μM, then the inhibitors are tested at concentrations of 0.3 μM, 0.03 μM and 0.003 μM.

INHIBITION OF GELATINASE (MMP-2) The inhibition of gelatinase activity is tested using the substrate [DNP-Pro-Cha-Gly-Cys (Ne) -His-Ala-Lys (NMA) -NH2] (10 μM) under the same conditions as in the test of inhibition of human collagenase (NMP-1). 72 kD gelatinase is activated with 1 mM p-aminopomilmercuric acetate (APMA) for 15 hours at 4 ° C and diluted to give a final concentration in the 100 mg / ml assay. Inhibitors were diluted as in the human collagenase inhibition assay (MMP-1) to give final concentrations in the assay of 30 μM, 3 μM, 0.3 μM and 0.03 μM. Each concentration was done in triplicate. Fluorescence readings were made (excitation 360 nm and emission 460 nm) at time zero and then at 20 minute intervals for 4 hours. The IC 50 were determined as in the human collagenase inhibition assay (NMP-1). If the IC50's are lower than 0.03 μM, then the inhibitors are tested at final concentrations of 0.3 μM, 0.03 μM and 0.003 μM.

INHIBITION OF THE ACTIVITY OF STROMELYSINE (MMP-3) The inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (H. Weingarten and J. Feder, Spectrophotometric Assay for Vertébrate Collagenase, Anal. Biochem., 147, 437-440, 1985). Hydrolysis of the thiopeptolide substrate [Ac-Pro-Leu-Gly-SCH [CH2CH (CH3) 2] CO-Leu-Gly-OC2H5] gives a mercaptan fragment which can be followed in the presence of Ellman's reagent. Recombinant human proestromelysin is activated with trypsin using a ratio of 1 μl of a trypsin solution of 10 mg / ml per 26 μg of stromelysin. Trypsin and stromelysin are incubated at 37 ° C for 15 minutes, followed by 10 μl of 10 mg / ml soybean trypsin inhibitor for 10 minutes at 37 ° C to suppress trypsin activity. The assays are performed in a total volume of 250 μl of assay buffer (200 mM sodium chloride, 50 mM MES and 10 mM calcium chloride); pH 6.0) in 96-well microtiter plates. The activated stromelysin is diluted in assay buffer at 25 μg / ml. Ellman's reagent (3-carboxy-4-nitrophenyl disulfide) is prepared as a 1 M stock solution in dimethylformamide and diluted to 5 mM in assay buffer with 50 μl per well, giving a final concentration of 1 mM. 10 mM stock solutions of inhibitors are prepared in dimethyl sulfoxide and serially diluted in assay buffer so that the addition of 50 μl to the appropriate wells gives final concentrations of 3 μM, 0.3 μM, 0.003 μM and 0.0003 μM. All conditions are carried out in triplicate. A 300 mM stock solution of the peptide substrate in dimethyl sulfoxide is diluted to 15 mM in assay buffer and the assay is initiated by the addition of 50 μl to each well to give a final substrate concentration of 3 mM. The blank assays consist of the peptide substrate and Ellman's reagent, without the enzyme. The formation of the products was followed at 405 nm with a Molecular Devices UV max plate reader. The IC50 values were determined in the same manner as for collagenase.

INHIBITION OF M P -13 Human recombinant MMP-13 is activated with 2 mM p-aminophenylmercuric acetate (APMA) for 1.5 hours at 37 ° C and diluted to 400 mg / ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, chloride calcium 5 mM, zinc chloride 20 μM and brij at 0.02%). In a 96-well Microfluor plate, twenty-five microliters of diluted enzyme is added. The enzyme is then diluted at a 1: 4 ratio in the assay by addition of inhibitor and substrate to give a final concentration in the 100 mg / ml assay. 10 mM stock solutions of inhibitors are prepared in dimethyl sulfoxide and then diluted in assay buffer as in the dilution scheme of inhibitors of the human collagenase inhibition assay (MMP-1). In the Microfluor plate, twenty-five microliters of each concentration are added in triplicate. The final concentrations in the assay are 30 μM, 3 μM, 0.3 μM and 0.03 μM. Substrate is prepared [DNP-Pro-Cha-Gly-Cys (Me) - His-Ala-Lys (NMA) -NH2] as in the human collagenase inhibition assay (MMP-1) and 50 μl is added to each well to give a final concentration in the assay of 10 μM. Fluorescence readings are made (excitation 360 nm and emission 450 nm) at time 0 and at 5 minute intervals for 1 hour. The positive controls consist of enzyme and substrate, without inhibitor, and blank tests consist only of substrate. IC50's are determined as in the human co-genase inhibition assay (MMP-1). If the IC50's are lower than 0.03 μM, then the inhibitors are tested at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003 μM.

INHIBITION OF TNF PRODUCTION The ability of the compounds or pharmaceutically acceptable salts thereof to inhibit TNF production and, consequently, to demonstrate their efficacy in treating diseases involving the production of TNF is shown by the following in vitro assay: Mononuclear leukocytes were isolated from anticoagulated human blood, using a one-step ficoll-hypaque separation technique. The mononuclear leukocytes were washed three times in Hanks Balanced Salt Solution (HBSS) with divalent cations and resuspended at a density of 2x106 / ml in HBSS containing 1% BSA. The differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that, in these preparations, the monocytes accounted for 17 to 24% of the total leukocytes. Aliquots of 180 μl of the leukocyte suspension were placed in 96-well flat bottom plates (Costar). Additions of compounds and LPS (final concentration of 100 ng / ml) gave a final volume of 200 μl. All conditions were performed in triplicate. After incubation for four hours at 37 ° C in a humidified CO2 incubator, the plates were separated and centrifuged (10 minutes to about 250g), the supernatants were separated and TFA-a was assayed in them using the R & amp;; D ELISA. For administration to mammals, including humans, for the inhibition of matrix metalloproteinases or production of tumor necrosis factor (TNF), a variety of conventional routes including oral, parenteral and topical administration can be used. In general, the active compound can be administered orally or parenterally at daily doses between about 0.1 and 25 mg / kg of body weight of the patient to be treated, preferably of about 0.3 to 5 mg / kg. However, some variation of the dosage may necessarily occur, depending on the condition of the patient to be treated. In any case, the person responsible for the administration must determine the appropriate dose for the individual patient. The compounds of the present invention can be administered in a wide variety of different dosage forms. In general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients may be used, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants, such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates , along with granulation binders, such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are often useful for the formation of the tablets. Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this respect also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, coloring matters and also, if desired, emulsifying and / or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerol and various combinations thereof. In the case of animals, the active ingredients can be advantageously contained in an animal feed or in drinking water at a concentration of 5-5,000 ppm, preferably from 25 to 500 ppm. For parenteral administration (intramuscular, intraperitoneal, subcutaneous or intravenous use), usually a sterile injectable solution of the active ingredient is prepared. Solutions of a therapeutic compound of the present invention may be employed in sesame or peanut oil or in an aqueous propylene glycol. If necessary, the aqueous solutions should be adjusted and suitably buffered, preferably at a pH higher than 8, and first the diluent liquid should be made isotonic. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intramuscularly or subcutaneously at dose levels of approximately 0.1 to 50 mg / kg. day, advantageously from 0.2 to 10 mg / kg. day, given in a single dose or divided up to 3 doses. The present invention is illustrated by the following examples, although not limited to the details thereof.

PREPARATION A 4- (4-fluorophenoxy) benzenesulfonyl chloride Chlorosuiphonic acid (26 ml, 0.392 mol) was added dropwise to ice-cold 4-fluorophenoxybenzene (36.9 g, 0.196 mol), stirring mechanically. When the addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4- (4-fluorophenoxy) benzenesulfonyl chloride (18.6 g, 33%), was collected by filtration and air dried.

PREPARATION B 4- (3-Meti I butoxy) sodium benzenesulfonate A solution of 4-hydroxybenzenesulfonic acid (10.0 g, 43.1 mmol) and sodium hydroxide (3.3 g, 83 mmol) in water (40 ml) was mixed with a solution of 1-iodo-3-methylbutane (1.3 ml 1.3, 86.4 mmol). ) in isopropanol (60 ml) and the resulting mixture was refluxed for 2 days. The isopropanol was removed by evaporation in vacuo. The title compound (10.0 g, 87%) was collected by filtration, washing with isopropanol.

PREPARATION C 4- (3-, Methylbutoxy) benzenesulfonyl chloride A mixture of sodium 4- (3-methylbutoxy) benzenesulfonate (2.5 g, 9.4 millimole, thionyl chloride (10 ml) and 5 drops of N, N-dimethylformamide was heated at reflux for 5 hours. Excess thionyl was evaporated and the residue was taken up in ethyl acetate.The solution was cooled in an ice bath and water was added.The organic phase was separated and washed with water and brine, after drying over sodium sulfate, evaporated the solvent to give the title compound as an oil (2.34 g, 95%).

PREPARATION D sodium 4- (2-cyclopentylethoxy) benzenesulfonate A solution of 4-hydroxybenzenesulfonic acid (6.5 g, 28.2 mmol) and sodium hydroxide (2.2 g, 55 mmol) in water (15 ml) was mixed with a solution of 2- (bromoethyl) cyclopentane (15.0 g, 84.7 mmol in isopropanol (40 ml) and the resulting mixture was heated to reflux for 2 days.The isopropanol was removed by evaporation in vacuo The title compound (4.7 g, 57%) was collected by filtration, washing with isopropanol.

PREPARATION E 4- (3-Methylbutoxy) benzenesulfonyl chloride A mixture of sodium 4- (2-cyclopentylethoxy) benzenesulfonate (2.5 g, 8.6 mmol), thionyl chloride (15 ml) and a few drops of N, N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated giving the title compound as an oil (2.24 g, 90%) PREPARATION F 4'-Fluorobiphenylsulfonyl Chloride In an ice bath, chlorosulfonic acid (8.7 ml, 0.13 mol) to 4-fluorobiphenyl (10.2 g, 59 mmol) was added dropwise with stirring. Stirring was continued under ice cooling for 0.5 hour and the reaction mixture was poured after ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate and a white solid was concentrated. The desired product, 4'-fluorobiphenylsulfonyl chloride (4.3 g, 27%) was separated from 4'-fluorobiphenylisulfonic acid (an unwanted by-product) by crystallization of the latter and crystallizing from hexane the resulting material.

PREPARATION G 4- 4-Fluorobenzyloxy) sodium benzenesulfonate A solution of 4-fluorobenzyl bromide (3.3 ml, 26.5 mmol) in ethanol (20 ml) was added to a solution of 4-hydroxybenzenesulfonic acid (5.13 g, 22.1 mmol) in 1 N aqueous sodium hydroxide solution (23 ml). . The resulting mixture was heated to reflux for 2 days. After cooling and allowing to stand, a white solid precipitated. The precipitated product, sodium 4- (4-fluorobenzyoxy) benzenesulfonate (4.95 g, 74%), was collected by filtration, washing with ethyl acetate and diethyl ether.

PREPARATION H 4- (4-Fluorobenzyloxy) benzenesulfonyl chloride Phosphorus pentachloride (275 mg, 1.31 mmol) was added to a suspension of sodium 4- (4-fluorobenzyloxy) benzenesulfonate (0.5 g, 1.64 mmol) in methylene chloride (5 ml). The resulting mixture was heated to reflux for 7 hours. After cooling in an ice bath and quenching the reaction with water (15 ml), the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 4- (4-fluorobenzyloxy) benzenesulfonyl chloride as a white solid (130 mg, 26%).

PREPARATION I Chloride of 4- (4-chlorophenoxy) benzenesulfonyl Chlorosulfonic acid (9.7 ml, 0.147 mol) was added at room temperature to 4-chlorophenoxybenzene (12.6 ml, 73.4 mmol). When the addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, air dried and recrystallized from petroleum ether and ethyl acetate to give 4- (4-chlorophenoxy) benzenesulfonyl chloride (7.43 g, 33%).

EXAMPLE 1 1- (4-Methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide (A) 4-Methoxybenzenesulfonyl chloride (10.6 g, 51.3 mmol) was added to a solution of 1-aminocyclopentane-1-carboxylic acid (6.0 g, 46. 5 mmol) and triethylamine (14 ml, 100 mmol) in dioxane (90 ml) and water (90 ml). The resulting mixture was stirred at room temperature for 4 hours, acidified with 1N hydrochloric acid aqueous solution and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to give a brown solid which was triturated with chloroform to give 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid as a solid. white (5.42 g, 39%). (B) (Benzotriazol-1-yl-oxy) tris (dimethylamino) phosphonium hexafluorophosphate (7.4 g, 16.3 mmol) was added to a solution of 1- (4-methoxybenzenesulfonymylamino) cyclopentane-1-carbonyl acid (4.65 g, 15.2 millimoles) and triethylamine (2.5 ml, 17.9 mmol) in methylene chloride (120 ml). The resulting mixture was stirred at room temperature for 2.5 days. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with 0.5 N hydrochloric acid aqueous solution, water and brine. After drying over magnesium sulfate, the solvent was evaporated giving 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzotria-zol-1-yl ester as a yellow solid. This was dissolved in N, N-dimethylformamide (120 ml) and to the resulting solution was added diisopropylethylamine (5.3 ml, 30 mmol) and O-benzylhydroxylamine hydrochloride (3.2 g, 20 mmol). The mixture was heated for 20 hours in an oil bath at 50 ° C. The solvent was evaporated and ethyl acetate was added. The mixture was filtered collecting a white solid. The filtrate was washed successively with 0.5N hydrochloric acid aqueous solution, saturated aqueous sodium bicarbonate solution and brine. After evaporating the solvent, a solid was obtained which was combined with that which had been isolated by filtration and triturated with ethyl acetate to give 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzyloxyamide as a white solid (2.92 g, 47%). (C) A solution of 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzyloxyamide (1.50 g, 3.71 mmol) in methanol (200 ml) was treated with 5% palladium on barium sulfate (0.75 g) and hydrogenated at 3 atmospheres of pressure for 3.5 hours on a Parr shaker. The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated to give 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide as a white solid (1.13 g, 97% ). MS: 313 (M-1). The compounds of Examples 2-8 s prepared by a procedure analogous to that described in Example 1 using the reagents indicated in each example.

EXAMPLE 2 1- (4-Methoxybenzenesulfonylamino) cyclohexane-1-carboxylic acid hydroxyamide 1-aminocyclohexane-1-carboxylic acid and 4-methoxybenzenesulfonyl chloride. MS: 327 (M-1).

EXAMPLE 3 Hydroxyamide of 1-r4- (4-fluoro-phenoxy) benzenesulfonylamino) cyclopentane-1-carboxylic acid 1-aminocyclopentane-1-carboxylic acid and 4- (4-fluorophenoxy) benzenesulfonyl chloride. MS: 393 (M-1). Analysis calculated for C18H19FN2O5S 0.25H2O: C 54.19; H 4.93; N 7.02. Found: C54.20; H 5.13; N 7.08.

EXAMPLE 4 Hydroxyamide 1- [4- (4-fluorophenyl) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide 1-aminocyclohexane-1-carboxylic acid and 4- (4-fluorophenoxy) benzenesulfonyl chloride. It was recrystallized from chloroform. P.f. 174 ° C. MS: 407 (M-1).

ELEMPLO 5 Hydroxyamide of 1-f4- (4-fluoro-phenoxy) benzenesulfonylamino-cyclopropane-1-carboxylic acid 1-aminocyclopropane-1-carboxylic acid and 4- (4-fluorophenoxy) benzenesulfonyl chloride. P.f. 184 ° C. MS: 365 (M-1). Analysis calculated for C16Hi5FN2? 5S: C 52.45; H 4.13; N 7.65. Found: C 52.20; H 4.34; N 7.44.

EXAMPLE 6 Hydroxyamide of 1- (4'-fluoro-biphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid 1-aminocyclopentane-1-carboxylic acid and 4'-fluorobiphenylsulfonyl chloride. It was recrystallized from chloroform. P.f. 159 ° C. MS: 377 (M-1).

EXAMPLE 7 Hydroxyamide of 1-r4- (4-fluoro-phenoxy) benzenesulfonylamino-1-cyclobutane-1-carboxylic acid hydroxyamide 1-aminocyclobutane-1-carboxylic acid and 4- (fluorophenoxy) benzenesulfonyl chloride. MS: 379 (M-1).

EXAMPLE 8 Hydroxyamide of 1-r4- (4-fluorobenzyloxy) benzenesulfonylamino-cyclopropane-1-carboxylic acid 1-aminocyclopropane-1-carboxylic acid and 4- (4-fluorobenzyloxy) benzenesulfonyl chloride. MS: 379 (M-1).

EXAMPLE 9 N-Hydroxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide (A) A solution of 2-amino-2-methyl-propionic acid benzyl ester hydrochloride (12.0 g, 52.2 mmol) and 4-methoxybenzenesulfonyl chloride (1.9 g, 57.6 mmol) in an ice bath was cooled in an ice bath. dioxane (100 ml) and water (100 ml). Triethylamine (18.2 ml, 0.13 mol) was then added. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 days. The solvents were removed in vacuo and the residue was taken up in ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid aqueous solution and brine. After drying over sodium sulfate, the solvent was evaporated giving a yellow oil (19.3 g), a portion of which was chromatographed on silica gel eluting with 3: 7 ethyl acetate: hexane, after recrystallization from ethyl acetate. hexane, 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid benzyl ether in the form of a white solid (6.59 g, 67%). (B) A solution of 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid benzyl ether (1.5 g, 4.13 mmol) in ethanol (80 ml) was treated with 10% palladium on carbon (0.17 g) and hydrogenated at 3 atmospheres of pressure for 1.5 hours on a Parr shaker. The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated to give 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid as a white solid (1.09 g, 96%). (C) A solution of 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid (1.08 g, 3.95 mmol) in methylene chloride (120 ml) was cooled in an ice bath. Subsequently, triethylamine (2.2 ml, 15.8 mmol), (benzotriazol-1-yloxy) -tris (dimethylamino) phosphonium hexafluorophosphate (2.6 g, 5.88 mmol) and O-benzylhydroxylamine hydrochloride (0.96 g, 5.95 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, saturated aqueous solution of sodium bicarbonate and brine. After drying over sodium sulfate, the solvent was evaporated giving an oil from which the desired product was obtained, N-benzyloxy-2- (4-methoxybenzenesulfonymymino) -2-methylpropionamide (1.41 g, 95%), a white solid, chromatography on silica gel eluting with ethyl acetate: hexanes 1: 2. (D) A solution of N-benzyloxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide (1.40 g, 3.70 mmol) in methanol (80 ml) was treated with 5% palladium on barium sulfate (0.75 g) and hydrogenated at 3 atmospheres of pressure for 1.5 hours on a Parr shaker. The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated to give N-hydroxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide as a white solid (1.06 g, 100%). p.f. 122-125 ° C. MS: 289 (M + 1). Analysis calculated for CnH? 6N2? 5S: C 45.82; H 5.59; N 9.72. Found: C 45.88; H 5.60; N 9.69. The compounds of examples 10-12 were prepared by a procedure analogous to that described in example 9 using the reagents indicated in each example.

EXAMPLE 10 2-r4- (4-Fluorophenoxy) benzenesulfonylaminol-N-hydroxy-2-methyl-propionamide 2-Amino-2-methylpropionic acid benzyl ester hydrochloride and 4- (4-fluorophenoxy) benzenesulfonyl chloride. P.f. 133- 134 ° C. MS: 369 (M + 1). Analysis calculated for C16H17FN2? 5S: C 52.17; H 4.65; N 7.60. Found: C 52.21; H 4.83; N 7.80.

EXAMPLE 11 N-Hydroxy-2-methyl-2-r4- (3-methyl-butoxy-benzenesulfonylamino-propionamide) 2-Amino-2-methylpropionic acid benzyl ester hydrochloride and 4- (3-methylbutoxy) benzenesuifonyl chloride. It was recrystallized from ethyl acetate / hexane. P.f. 126.5-128 ° C. MS: 343 (M-1). Analysis calculated for C15H2 N2? 5S: C 52.31; H 7.02; N 8.13. Found: C 52.30; H 7. 07; N 8.16.

EXAMPLE 12 2-r4- (2-Cyclopentylethoxy) benzenesulfonylaminol-N-hydroxy-2-methylpropionamide 2-Amino-2-methylpropionic acid benzyl ester hydrochloride and 4- (2-cyclopentylethoxy) benzenesulfonyl chloride. It was recrystallized from ethyl acetate / hexane. P.f. 126-127 ° C. MS: 369 (M-1). Analysis calculated for C17H26N2? 5S: C 55.12; H 7.07; N 7.56. Found: C 55.46; H 7. 09; N 7.38.

EXAMPLE 13 N-Hydroxy-2-methyl-2- (5-pyridin-2-yl thiophene-2-sulfonylamino) proponamide (A) 5-Pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 g, 32.4 mmol) was added to a solution of 2-amino-2-methylpropionic acid (2.0 g, 19.4 mmol) in 1 N aqueous sodium hydroxyl. (45 ml) and dioxane (45 ml). The resulting mixture was stirred at room temperature for 16 hours. Additional 1N sodium hydroxide solution (45 ml) was added to the reaction mixture, which was then extracted with diethyl ether. The organic extracts were discarded. The aqueous layer was acidified with 1 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried over magnesium sulfate and concentrated to give 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionic acid as a white solid (2.18 g). , 3. 4%). (B) To a solution of 2-methyl-2- (5-pyridin-2-yl-thiophene-2-sulfonylamino) propionic acid (1.60 g, 4.91 mmol) in methylene chloride (160 ml) was added triethylamine (2.3 ml, 16.5 mmol), (benzotriazol-1-yl-oxy) tris (dimethylamino) phosphonium hexafluorophosphate (2.4 g, 5.41 mmol) and O- (2-trimethylsilylethyl) hydroxylamine hydrochloride (0.92 g, 5.41 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the dissolver was evaporated to give a white foam from which the desired product was isolated, 2-metii-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -N- (2-trimethylsilanylelyxy) ) propionamide (220 mg, 10%), a white solid, by chromatography on silica gel eluting with 3: 2 ethyl acetate: hexanes. (C) 2-Methylene-2- (5-pyridin-2-ylthiophene-2-sulphonylamino) -N- (2-trimethylsilanylethoxy) propionamide (80 mg, 0.18 mmol) was dissolved in trifluoroacetic acid and the The resulting solution was stirred at room temperature for 16 hours. The trifluoroacetic acid was evaporated in vacuo, adding methanol, giving N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide, a yellow oil (60 mg, 97% ), which was crystallized in ethanol. P.f. 165-166 ° C. MS: 342 (M + 1). The compounds of Examples 14-15 were prepared by a procedure analogous to that described in Example 13 using the reagents indicated in each example.

EXAMPLE 14 1- (5-Pyridin-2-yl-thiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide 1-aminocyclopentane-1-carboxylic acid and 5-pyridin-2-iithiophene-2-sulfonyl chloride. MS: 368 (M + 1).

EXAMPLE 15 Hydroxyamide of 1-r4- (4-chlorophenoxy) benzenesulfonylamino-cyclopropane-1-carboxylic acid 1-aminocyclopropane-1-carboxylic acid and 4- (4-chlorophenoxy) benzenesulfonyl chloride. MS: 381 (M-1).

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or the pharmaceutically acceptable salts thereof, wherein each of R 1 and R 2 are independently selected from C 1 -C 6 alkyl, trifluoromethyl, trifluoromethyl (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) difluromethylene, (C 1 alkyl) -C3) difluoromethylene (C1-C3 alkyl), C6-C6 aryl), C2-C9 heteroaryl, (C6-C6aryl aryl) (Ci-Cß alkyl) or (C2-C9 heteroaryl) (C C-alkyl) C6), or R and R2 join to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene or a group of formula wherein m and n are independently 1 or 2, and X is CF2, S, O or NR3, wherein R3 is hydrogen, C? -C6 alkyl, C6-C? aryl, or C2-C9 heteroaryl, (C6-aryl) C? O) (C? -C6 alkyl), (C2-C9 heteroaryl) (C? -C6 alkyl), (C? -C6 alkyl) sulfonyl, (C6-C? Oaryl) sulfonyl or acyl; and Q is C?-C6 alkyl, Ce-C ar ar aryl, (C--CIO aryloxy) (C6-C? ar aryl), (C6-C10 aryl) (C6-C? ar aryl). (aryl C6-C10) (aryl C6-C? 0) (C? -C? alkyl), (aryl Ce-Cio) (C2-C9 heteroaryl), (C6-C? aryloxy) (C2-Cg heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl), (C? -C6 alkyl) (C6-C? 0 aryl), ( C6-C6 alkoxy) (C6-C aryl), (C6-C10 aryl) (C6-6 alkoxy) (C6-C6 aryl), (C6-C10 aryl) (C6-C6 alkoxy) C6-C6 alkyl), (C2-C9 heteroaryloxy) (C6-C6 aryl), (C6-C6 alkyl) (C2-C9 heteroaryl), (C6-C6 alkoxy) (C2-C9 heteroaryl), (C6-aryl) -C? 0) (C? -C6 alkoxy) (C2-C9 heteroaryl), (C2-C9 heteroaryloxy), (C6-C? O aryloxy) (C? -C6 alkyl), (C2-C9 heteroaryloxy) (alkyl C? -C6), (C? -C6 alkyl) (C6-C? 0 aryloxy) (C6-C? 0 aryl), (C-C6 alkyl) (C2-C9 heteroaryloxy) (C6-C0 aryl), (C 1 -C 6 alkyl) (C 6 -C 0 aryloxy) (C 2 -C 9 heteroaryl), (C 1 -C 6 alkoxy) (C 6 -C 0 aryloxy) (C 6 -C 0 aryl), (C 6 -C 6 alkoxy) ) (C2-C9 heteroaryloxy) (C6-C0aryl aryl) or (C1-C6alkoxy) (C6-C6aryloxy) (C2-C9 heteroaryl), in which each aryl group is optionally substituted by fluo R, chlorine, bromine, C -Cß alkyl, CI-CT alkoxy or perfluoro (C 1 -C 3 alkyl).

2. A compound according to claim 1, wherein R1 and R2 join to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene or a group of formula wherein m and n are independently 1 or 2, and X is CF2, S, O or NR3, wherein R3 is hydrogen, Ci-Cß alkyl, C6-C ar aryl, or C2-C9 heteroaryl, (C6-C aryl) 0) (C 6 -C 0 alkyl), (C 2 -C 9 heteroaryl) (C 6 -C 10 alkyl), (C 6 alkyl) sulfonium, (aryl Ce-Cι) sulfonyl or acyl.

3. A compound according to claim 2, wherein R1 and R2 are joined to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene.

4. A compound according to claim 1, wherein Q is aryl C6-C? 0, (aryl C6-C? 0) (aryl C6-C? 0), (aryloxy Ce-Cio) (aryl CT -CIO), (aryloxy C6-C? O) (C2-C9 heteroaryl), C2-C9 heteroaryl), (C2-C9 heteroaryl) (heteroaryl C2-C9), (C6-C6 aryl) (C2-Cg heteroaryl), (C2-C9 heteroaryl) (C6-C? 0 aryl) or (C2-C9 heteroaryloxy) (C6-C? 0 aryl).

5. A compound according to claim 4, wherein Q is (C6-C? 0 aryloxy) (C6-C? 0 aryl).

6. A compound according to claim 1, wherein each of R1 and R2 are independently Ci-Ce alkyl.

7. A compound according to claim 1, wherein R1 and R2 join to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene or a group of formula wherein m and n are independently 1 or 2, and X is CF2, S, or NR3, wherein R3 is hydrogen, C? -C6 alkyl, C6-C? aryl, or C2-C9 heteroaryl, (C6-C aryl) o) (C 1 Ce alkyl), (C 2 -C 9 heteroaryl) (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) sulfonyl, (C 6 -C 0 aryl) sulfonyl or acyl; and Q is aryl C6-C? 0, (aryl C6-C? 0) (aryl C6-C? o), (aryloxy C6-C? 0) (aryl C6-C? 0), (aryloxy C6-C? 0) (C2-Cg heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-Cg heteroaryl), (C6-C6 aryl) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (aryl C6-C? 0) or (C2-C9 heteroaryloxy) (C6-C? 0 aryl).

8. A compound according to claim 1, wherein R1 and R3 are joined to form a C3-C6 cycloalkyl ring or a C3-C6 cycloalkyl ring fused to a benzene; and Q is C 1 -C aryl, (C 6 -C 0 aryl) (C 1 -C 10 aryl), (C 6 -C 0 aryloxy) (C 6 -C 0 aryl), (C 6 -C 0 aryloxy) (heteroaryl C2-C9), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C aryl; 0) or (C-C9 heteroaryloxy) (C6-C10 aryl).

9. A compound according to claim 1, wherein each of R1 and R2 are independently Ci-Cß alkyl and Q is C 1 -C 0 aryl, (C 6 -C 6 aryl) (C 6 -C 0 aryl) ), (C6-C? aryloxy) (C6-C? 0 aryl), (C6-C? 0 aryloxy) (C2-C9 heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl) ), (C6-C6 aryl) (C2-C9 heteroaryl), (C2-Cg heteroaryl) (C6-C0 aryl) or (C2-C9 heteroaryloxy) (Ce-Cι aryl).

10. A compound according to claim 1, wherein each of R1 and R2 are independently Ci-Cß alkyl and Q is (aryloxy Cedo) (C6-C6 aryl).

11. A compound according to claim 1, wherein said compound is selected from the group consisting of: 3- [4- (4-fluorophenoxy) benzenesulfonylamino] azetidine-3-carboxylic acid hydroxyamide, hydroxyamide of the acid - [4- (4-fluorophenoxy) benzenesulfonymymino] piperidine-4-carboxylic acid 1- [4- (4-fluorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide, hydroxyamide of 1- [4- (4 -chlorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid, hydroxyamide of 1 - [4- (4-fluorophenoxy) benzenesulfonic acid] cyclobutane-1-carboxylic acid, hydroxyamide of 1- [4- (4-chlorophenoxy) benzenesulfonymymino] cyclobutane 1-carboxylic acid, 1- [4- (4-fluorophenoxy) benzene-suifonylamino] cyclopentane-1-carboxylic acid hydroxyamide, 1- [4- (4-fluorophenoxy) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide, - [4- (4-fluorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide, 2- [4- (4-chlorophenoxy) benzenesulfonylamine] -N-hydroxy-2-methylpropionamide, N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide, hydroxyamide of 1- (5-pyridin-2-ylthiophene- 2-sulfonyl amine) cyclopentane-1-carboxylic acid, 1- (4'-fluorobiphenyl-4-sulfonylamino) cyclopropane-1-carboxylic acid hydroxyamide, 1- (4'-fluorobiphenyl-4-sulfonylamino) cyclobutane-1- hydroxyamide carboxylic acid, 1- (4'-fluorobiphenyl-4-sulfonylamino) -cyclopentane-1-carboxylic acid hydroxyamide, 2- (4-methoxy-benzenesulfonyl) indan-2-carboxylic acid hydroxyamide and 2- [4- hydroxy] (4-fluorophenoxy) benzenesulfonylamino] indan-2-carboxylic acid.

12. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa and scleritis, combined with NSAIDs and standard analgesics and combined with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases that involve the production of tumor necrosis factor (TNF), or (b) the inhibition of matrix metalloproteinases or production of tumor necrosis factor (TNF), in a mammal, including man, comprising an amount of a compound according to claim 1, effective in said treatment, and a pharmaceutically acceptable carrier.

13. The use of a compound according to claim 1, for the manufacture of a medicament for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including the man.

14. The use of a compound according to claim 1 or the combination of said compound of said claim with NSAIDs and standard analgesics and combined with cytotoxic anticancer agents, for the manufacture of a medicament for treating a condition selected from the group consisting of arthritis, osteroporosis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermoiysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases that involve the production of tumoral necrosis factor (TNF), in a mammal, including man.