MXPA99006301A - Cyclic sulfone derivatives - Google Patents

Abstract

A compound of formula (I), wherein n, X, Y and Ar are as defined herein, 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

CYCLIC DERIVATIVES OF SULPHONE BACKGROUND OF THE INVENTION The present invention relates to cyclic sulfone derivatives that are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNT) and, as such, are useful in the treatment of a disorder 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 that involve the production of TNF. In addition, the compounds of the present invention can be used in combination therapy with nonsteroidal antiinflammatory drugs (hereinafter referred to as NSAIDs) and analgesics for the treatment of arthritis, and together with cytotoxic drugs such as adriamycin, daunomycin, cisplatin, etoposide, taxol , taxotere and alkaloids, such as vincristine, in 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 series of enzymes that carry out the decomposition of structural proteins and that are structurally related metalloproteases. Metalloproteinases that degrade the matrix, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (eg collagen collapse) and have been implicated in many pathological disorders involving abnormal connective tissue metabolism and from the basement membrane matrix, such as arthritis (e.g., osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g., corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease ( example, Paget's disease and osteoporosis), metastasis or invasion of tumors, as well as infection caused by the human immunodeficiency virus (HIV) (J. Leuk, Biol., 52 (2): 244-248, 1992). It has been recognized that tumor necrosis factor is implicated in many infectious and autoimmune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). In addition, TNF has been shown to be the primary mediator of the inflammatory response seen in sepsis and septic shock (C: E: Spooner et al., Clinical Immunoloqy and Immunopatholoqy, 1992, 62, S11).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond; n is O, 1 or 2; X and Y are each; independently, CR1, wherein R1 is hydrogen, C6-C6 alkyl optionally substituted by (C1-Cß-amino alkyl, (C?-C6 alkyl) thio, C alco-C6 alkoxy, trifluoromethyl, C6-C? ar aryl, C5-C9 heteroaryl, (C6-C? o) aryl amine, (C6-C? 0 aryl) thio, C6-C? 0 aryloxy, (Cs-Cgjamino heteroaryl, (C5-C9 heteroaryl) thio, C5 heteroaryloxy -C9, (C6-C6aryl aryl) (C9-C10 aryl), C3-C6 cycloalkyl, hydroxy (C-? -C6 alkyl), (C? -C6 alkyl) (hydroxymethylene), piperazinyl, (C6- aryl) C10) (C6-C6 alkoxy), (C5-Cg heteroaryl) (C6-C6 alkoxy), (C6-C6) amino, (C6-C6 acyl) thio, C6-C6 acyloxy, C? -C6) sulfinyl, (C6-C? 0 aryl) sulfinyl, (C6 alkyl) sulfonyl, (C6-C? O) sulfonyl, amino, (C? -C6 alkyl) amino or ((Ci- C6) 2) arnino, trifluoromethyl, (C -? - C6 alkyl) (difluoromethylene), (C1-C3 alkyl) (difluoromethylene) (C1-C3 alkyl), C6-C6 aryl, C5-C9 heteroaryl, C3 cycloalkyl -C6, (C? -C6 alkyl) hydroxymethylene, Realkyl C? -C6), wherein R3 is (Cr C6 acyl) piperazine, (C6-C aryl) ) piperazine, (C5-C9 heteroaryl) piperazino, (C1-Cispiperazine alkyl, (C6-C? o aryl) (CrC6 alkyl) piperazino, (C5-C9 heteroaryl) (Ci-C?) piperazino alkyl, morpholino, thiomorpholino, piperidino , pyrrolidino, piperidyl, (C? -C6 alkyl) piperidyl, (C6-C? o) piperidyl aryl, (C5-Cg heteroaryl) piperidyl, (C6 alkyl) piperidyl (Ci-C? alky), (C6 aryl) -C? 0) piperidyl (C? -C6 alkyl), (C5-Cg heteroaryl) piperidyl (C-? C6 alkyl) or (C? -C6 acyl) piperidyl, or a group of formula where r is 0 to 6; D is hydroxy, C? -C6 alkoxy, piperidyl, (C? -C6 alkyl) piperidyl, (C6-C? O) piperidyl aryl, (C5-Cg heteroaryl) piperidyl, (Ci-C? Jpiperidyl acyl or NR4R5, wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl optionally substituted by (Cr C 6 alkyl) piperidyl, (C 6 -C 0 aryl) piperidyl, (Cs-Cgjpiperidyl heteroaryl, C 6 aryl -C-? O, C5-C9 heteroaryl, (C-C-io aryl) (C-C-to aryl) or C3-C6 cycloalkyl, C-C10 aryl, C5-C heteroaryl (C6-C aryl) ? 0) (C6-C? 0 aryl), C3-C6 cycloalkyl, C2-C6 reakyl), (C ^ Cs alkyl) (CHR6) (Ct-Ce alkyl), wherein R6 is hydroxy, acyloxy d-C6 , C 1 -C 6 alkoxy, piperazino, (C 1 -C 6 acyl) amino, (C 1 -C 6 alkyl) thio, (C 6 -C 6 aryl) thio, (C 1 -C 6 alkyl) sulfinyl, (aryl) C 6 -C 6 acyloxy) sulfinyl, (C 1 -C 6 alkyl) sulfoxyl, (C 6 -C 6 aryl) sulfoxy, amino, (CiC ^ amino alkyl, ((C 1 -C 6 alkyl) 2) amino, (Ci-C6 acyl) piperazino, (C? -C6 alkyl) piperazino, (C6-C? 0 aryl) (C? -C6 alkyl) piperac ino, (C5-C9 heteroaryl) (C6-C6 alkyl) piperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; Realkyl C? -C6), (C1-C5 alkyl) (CHR7) (C? -C6 alkyl), wherein R7 is piperidyl or (C? -C6 alkyl) piperidyl; and CH (R8) COR9, wherein R8 is hydrogen, C? -C6 alkyl, (Ce-Cι aryl) (Ci-C? alkyl), (C5-Cg heteroaryl) (C? -C6 alkyl), (C-alkyl) -C6) thio (Ci-Cß alkyl), (C6-C? 0 aryl) thio (C?-C6 alkyl), (CrC6 alkyl) sulfinyl (C?-C6 alkyl), (C6-C? 0 aryl) sulfinyl (C 1 -C 6 alkyi), C 6 alkyl sulfonyl (C 6 -C 6 alkyl), C 6 -C 6 aryl sulfonyl (C 6 -C 6 alkyl), hydroxy (C 6 -C 6 alkyl), amino C?-C6 alkyl), (C?-C6 alkyl) amino (Ci-Cd alkyl), ((Ci-C6 alkyl) amnin) 2 (C -Cß alkyl), R10R11NCO (C?-C6 alkyl) or R10OCO (C? -C6 alkyl), wherein R10 and R11 are each independently selected from the group consisting of hydrogen, CrC? alkyl, (C6-C0 aryl) (Ci-C? alkyl) and (C5-C9 heteroaryl) ( C? -C6 alkyl); and R9 is R12O or R12R13N, wherein R12 and R13 are each independently selected from the group consisting of hydrogen, Ci-Cß alkyl, (C6-C? o aryl) (Ci-Cß alkyl) and (C5-C9 heteroaryl) ) (C6-C6 alkyl); and Ar is C? -C6 alkyl > - C6-C10 aryl, (C6-C? 0 aryloxy) (C6-C? 0 aryl), (C6-C? o aryl) (C6-C? 0 aryl), (C6-C? 0 aryl) (aryl C6-C? O) (C? -C6 alkyl), (C6-C? 0 aryloxy) (Cs-Cg heteroaryl), C5-C9 heteroaryl, (C? -C6 alkyl) (C6-C? 0 aryl), (C 6 -C 6 alkoxy) (C 6 -C 6 aryl), (Ce-Cι aryl) (Ci-Cβ alkoxy) (C 6 -C 6 aryl), (C 6 -C alkoxy) (C C β alkyl), (C 5 heteroaryloxy) -C9) (C6-C? Aryl), (C? -C6 alkyl) (C5-C9 heteroaryl), (C? -C6 alkoxy) (C5-Cg heteroaryl), (C6-C? 0 aryl) (alkoxy) C? -C6) (C5-C9 heteroaryl), (C5-Cg heteroaryloxy) (Cs-Cg heteroaryl), (Ce-Cryloxy aryloxy) (Ci-C? Alkyl), (C5-Cg heteroaryloxy) (C? -C6 alkyl) ), (C? -C6 alkyl) (C6-C? 0 aryloxy) (Ce-Cio aryl), (Ci-C? alkyl) (C5-Cg heteroaryloxy) (C6-C? 0 aryl), (C6 alkyl) (aryloxy Ce-Cι) (C5-C9 heteroaryl), (C alcoß alkoxy) (C6-C? aryloxy) (C6-C? 0 ary), (Ci-Cß alkoxy) (C5-C9 heteroaryloxy) (C6-aryloxy) -C? 0) or (C? -C6 alkoxy) (C6-C? 0 aryloxy) (Cs-Cg heteroaryl), wherein each aryl group is optionally substituted with fluoro, chloro, b blunt, Ci-Cß alkyl, Ci-C alco alkoxy or perfluoro (C 1 -C 3 alkyl). The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic radicals, or combinations thereof. The term "alkoxy", as used herein, includes O-alkyio groups in which "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removing a hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3. substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, Ci-Cß alkoxy, aryloxy Ce-Cio, trifluoromethoxy, difluoromethoxy and C? -C6 alkyl. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound eliminating a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolium, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from independently from the group consisting of fluoro, chloro, trifluoromethyl, C 1 -C 6 alkoxy, C 6 -C 0 aryloxy, trifiuoromethoxy, difluoromethoxy and C -Cß alkyl. The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO, wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms " alkyl "or" aryl "are as defined above. The term "acyloxy", as used herein, includes O-acyl groups in which acyl is as defined above. Preferred compounds of formula I include those in which n is 2. Other preferred compounds of formula I include those in which X e? they are both CR1, with R1 being hydrogen. Other preferred compounds of formula I include those in which Ar is (alkoxy CI-CT) (arium Ce-Cι), (aryl Ce-Cι) (alkoxy C-C6) (aryl Ce-Cι), 4-fluorophenoxy (aryl) C6-C? O), 4-fluorobenzyloxy (aryl C6-? O) or (C6-C6 alkyl) (aryloxy Ce-Cio) (C6-C6 aryl). More preferred compounds of formula I include those in which n is 2, X and Y are both CR1, wherein R1 is hydrogen and Ar is (C6-6 alkoxy) (C6-C6aryl aryl), (aryl C6-C? 0) (C? -C6 alkoxy) (C6-C? 0 aryl), 4-fluorophenoxy (C6-C? Aryl), 4-fluorobenzyloxy (C6-C10 aryl) or (C? -C6 alkyl) ) (aryloxy) C6-C? O) (aryl C6-C? 0).

The present invention also relates to a pharmaceutical composition for, (a) the treatment of a disorder selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa , scleritis, along with NSAIDs and conventional analgesics, and other diseases characterized by matrix meta-proteasease 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 the production of tumor necrosis factor in a mammal, including a human being, comprising an amount of a compound of formula I or of one of its pharmaceutically acceptable salts, effective in said treatments, and a pharmaceutically acceptable vehicle. The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human being, comprising administering to said mammal a 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 disorder selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, the compounds of formula I together with NSAIDs being used. and conventional analgesics, and together 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 a human , which comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in the treatment of said disorder.

DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless indicated otherwise, in the following reaction and description schemes X, Y and Ar are as defined above.

SCHEME 1 Vil VI V IV In reaction 1 of scheme 1, the aryl sulfonyl chloride compound of formula VII is converted to the corresponding sodium aryl sulfonate compound of formula VI by reacting VIL with sodium iodide in the presence of a polar aprotic solvent, such as acetone, in an atmosphere inert. The reaction mixture is stirred at room temperature, for a period of about 12 hours to about 18 hours, preferably about 15 hours. In reaction 2 of scheme 1, the compound of formula VI is converted to the corresponding compound 2-iodo-3- (arii) sulfonylpropionic acid of formula V by reacting VI with acrylic acid and iodine in the presence of an aprotic solvent polar, such as methylene chloride. The reaction mixture is stirred in an inert atmosphere, at room temperature and for a period of about 12 hours to about 3.5 days, preferably about 3 days. In reaction 3 of scheme 1, the compound of formula V is converted to the corresponding acid (E) -3- (aryl) sulfonyl-prop-2-enoic compound of formula IV by treating V with a base, such as triethylamine, in a polar aprotic solvent, such as methylene chloride, in an inert atmosphere. The reaction is stirred at room temperature, for a period of from about 10 hours to about 24 hours, preferably about 12 hours.

In reaction 4 of scheme 1, the compound of formula IV is converted to the corresponding carboxylic acid compound of formula III by heating IV with an excess amount of a compound of formula to reflux in the presence of a polar aprotic solvent, such as toluene, for a period of from about 24 hours to about 56 hours, preferably about 48 hours. In reaction 5 of scheme 1, the compound of formula III is converted to the corresponding N- (R14) -carboxamide compound of formula II, wherein R14 is O-substituted oxy, such as O-benzylhydroxy or trimethylsilyl ethylhydroxy by reacting III. with an activating agent, such as dimethylaminopyridine / dicyclohexyl carbodiimide, and O-substituted hydroxylamine such as benzylhydroxylamine hydrochloride or o-trimethyl-silylethylhydroxylamine, in the presence of a polar aprotic solvent, such as methylene chloride in an inert atmosphere. The reaction mixture is stirred, at room temperature for a period of about 15 hours to about 25 hours, preferably about 20 hours. In reaction 6 of scheme 1, the compound of formula II is converted to the corresponding hydroxamic acid compound of formula I, (I) by treating II with hydrogen in the presence of a catalyst, such as 5% palladium on barium sulfate and a solvent polar aprotic, such as methanol, (2) trying II with trifluoroacetic acid or diethyl ether-boron trifluoride in a polar aprotic solvent, such as methylene chloride, or (3) by treating II with tetrabutyl ammonium fluoride in a polar aprotic solution, such as tetrahydrofuran. The reaction mixture is stirred for a period of from about 2 hours to about 4 hours, preferably about 3 hours. The pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely, cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium and magnesium, as well as ammonium salts such as ammonium salts, trimethylammonium, diethylammonium and tris (hydroxymethyl) methylammonium. Likewise, addition salts of acids, such as mineral acids, organic carboxylic acids and organic sulfonic acids, for example, hydrochloric acid, methanesulfonic acid and maleic acid, are also possible, provided that a basic group, such as pyridyl, forms part of the structure. The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter referred to as compounds of the present invention) to inhibit matrix metaioproteinases or the production of tumor nerosis factor (TNF) and, therefore, demonstrate their efficacy in treating diseases characterized by matrix metalloproteinases or by the production of tumor necrosis factor, is shown by the following in vitro assays.

BIOLOGICAL ASSAY Inhibition of human collagenase (MMP-1) Recombinant human collagenase is activated with trypsin using the following ratio: 10μg of trypsin per 100μg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a five-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 Then twenty-five microliters of each concentration is added in triplicate to appropriate wells of a plate of 96-well microflora. 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 the D1-D6 wells, and blank assays (without enzyme and without inhibitor) in the DJ-D12 wells. The collagenase is diluted to 00400 mg / ml and then 25 μl is added to the 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) -NH2) is prepared as a 5 mM stock 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 taken (excitation at 360 nm; emission at 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. The fluorescence is then plotted as a function of time, both for the blank samples and for those containing collagenase (the mean of the determination data made in triplicate is made). A point of time that provides a good signal (the target) and that is in the linear part of the curve (normally around 120 minutes) is chosen to determine IC50 values. Zero time is used as a target for each compound at each concentration and these values are subtracted from the 120 minute data. The data are plotted as concentration of inhibitor as a function of% control, (fluorescence of the inhibitor divided by fluorescence of collagenase alone and multiplied by 100). The IC50 values are determined from the concentration of inhibitor that gives a signal that is 50% of that of the control. It is verified that Cl50 is < 0.03 μM when the inhibitors are tested at concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM.

INHIBITION OF GELATINASE (MMP-2) The inhibition of gelatinase is tested using the substrate Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2 (10 μM) under the same conditions as the inhibition of human collagenase (MMP-1) ). J2 kD gelatinase is activated with 1 mM p-aminophenylmercuric acetate (APMA) for 15 hours at 4 ° C and diluted to give a final concentration in the 100 mg / ml assay. The inhibitors are diluted as in the inhibition of human collagenase (MMP-1) to provide final concentrations in the assay of 30 μM, 3.0 μM, 0.3 μM and 0.03 μM. Each concentration is done in triplicate. Fluorescence readings are taken (excitation at 360 nm, emission at 460 nm) at time zero and then at 20 minute intervals for 4 hours. The Cl50 values are determined as in the inhibition of human collagenase (MMP-1). If the IC 50 values 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 0.003 μM.

INHIBITION OF THE ACTIVITY OF STROMELYSINE (MMP-3) The inhibition of stromelysin activity is based on a modified spiketrophotometric assay, described by Weingarten and Feder (Weingarten, H. and Feder, J., 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 controlled in the presence of Ellman's reagent. Recombinant human proestromelysin is activated with trypsin using a ratio of 1 μl of a trypsin stock 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 quench the 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. 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 addition of 50 μl to the appropriate wells yield final concentrations of 3 μM, 0.3 μM, 0.003 μM and 0.0003 μM. All conditions were performed 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 addition of 50 μl to each well, giving a final substrate concentration of 3 mM. The blank assays are composed of Ellman's peptide substrate and reagent, without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader. The IC 50 values were determined in the same manner as for the collagenase.

INHIBITION OF MMP-13 Human recombinant MMP-13 is activated with 2 mM p-aminophenyl mercuric 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, calcium chloride 5 mM, zinc chloride 20 μM and brij at 0.02%). Twenty-five microliters of diluted enzyme per well are added from a 96-well microfluor plate. The enzyme is then diluted in 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 human collagenase inhibitors (MMP-1): Twenty-five microliters of each concentration, in triplicate, is added to the plate of microfluor. The final concentrations in the assay are 30 μM, 3 μM, 0.3 μM and 0.03 μM. The substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as in the inhibition of human collagenase (MMP-1) and 50 μl is added to each well. to give a final concentration in the 10 μM assay. Fluorescence readings are taken (excitation at 360 nm; emission at 450 nm) at time 0 and every 5 minutes for 1 hour. The positive controls are composed of enzyme and substrate, without inhibitor, and the blank assays are composed only of substrate. The Cl 50 values are determined as in the inhibition of human collagenase (MMP-1). If the IC50 values 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, therefore, demonstrate their efficacy in treating diseases involving the production of TNF is shown by the following in vitro assay: Human mononuclear cells were isolated from anticoagulated human blood, using a Ficoll-hypaque separation technique in one step. (2) The mononuclear cells were washed three times in Hanks Balanced Salt Solution (HBBS) with divalent cations and resuspended to a density of 2 x 106 cells / ml in HBSS containing 1% BSA The differential counts determined using the Abbott Cell analyzer Dyn 3500 indicated that monocytes varied from 17 to 24% of the total cells in these preparations. Aliquots of 180 μl of the cell suspension were taken in 96-well flat-bottomed plates (Cos-tar). 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 removed and centrifuged (for approximately 10 minutes 250 xg), the supernatants were separated and assayed in these TNFa using the ELISA R &; D. For administration to humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor, various conventional routes can be used, including oral, parenteral and topical administration. In general, the active compound will be administered orally or parenterally, at a daily dose ranging from about 0.1 to 25 mg / kg body weight of the patient to be treated, preferably from about 0.3 to 5 mg / kg. However, some variation of the dose may necessarily occur, depending on the disorder of the patient to be treated. In any case, the person responsible for the administration will determine the appropriate dose for each individual patient. The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the 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, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, are sometimes very useful for the manufacture of tablets. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Lactose or milk sugar as well as high molecular weight polyethylene glycols are also included in the preferred materials. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening and flavoring agents, colorants or dyes, as well as with emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerol and various similar combinations thereof. In the case of animals, these may be advantageously contained in the animal's food or drinking water at a concentration of 5-5,000 ppm, preferably from 25 to 500 ppm. For parenteral administration, (for intramuscular, intraperitoneal, subcutaneous and intravenous use), a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be employed in sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions must be adjusted and properly buffered, preferably at a pH higher than 8, if necessary, and the diluting liquid should first 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 conventional pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day in a single dose up to three divided doses. It is also possible to administer the compounds of the present invention topically, for example, when treating inflammatory disorders of the skin, and this can be done by means of creams, gelatins, gels, ointments and ointments, in accordance with conventional pharmaceutical practice. The present invention is illustrated by the following examples, but is not limited to the details thereof.

EXAMPLE 1 3- (4-Methoxyphenylsuifonyl-7-oxabicycloic-2-2.1-heptane-2-carboxylic acid hydroxyamide (a) Sodiumiodide (21.76 grams (g), 145.2 mmol) and 4-methoxybenzenesulfonyl chloride (10.0 g, 48.39 mmol) were combined in dry acetone (dried over MgSO4 and filtered) (200 ml) and stirred at room temperature for the night. The fine white solids were collected by suction filtration. They were dried under high vacuum to give 9.1 1 g of sodium 4-methoxybenzenesulfinate as a pale yellow powder (97% yield). (b) Water (0.85 g, 0.85 ml) was added, followed by acrylic acid (3.42 g, 3.25 ml), then 12 (12.04 g, 47.41 mmol) to a suspension of sodium 4-methoxybenzenesulfinate (9.11 g, 46.94 mmole) in methylene chloride (150 ml). More methylene chloride (100 ml) was added to be able to stir the suspension. It was stirred at room temperature throughout the weekend. The reaction solution was washed with 1 N Na 2 S 2 O 3 (aqueous) (3 x 150 ml) until the organic layer was colorless. The organic layer was washed with brine. It was dried (MgSO 4), filtered and concentrated in vacuo to give 4.23 g (25%) of crude 2-iodo-3- (4-methoxyphenylsulfonyl) propionic acid. (c) 2-iodo-3- (4-methoxyphenylsulfonyl) -propionic acid (4.23 g, 11.43 mmol) and Et3N (3.22 mL, 2.34 g, 23.09 mmol) in methylene chloride (150 mL) were combined and stirred at Room temperature during the night. The reaction mixture was diluted with 1N hydrochloric acid (aqueous) (100 ml). The separated aqueous layer was extracted with Et2O (2 times). The dried combined organic extracts (MgSO 4) were then filtered and concentrated in vacuo to provide 2.58 g of crude product. This was filtered, the filtrate was concentrated and the residue was suspended in methanol, filtered and the filtrate was concentrated giving 1.87 g of crude product. This was suspended in hot methylene chloride. Fine crystals appeared. The filtrate was decanted. The crystals were washed with methylene chloride (2 x 1 ml) (wash water was decanted). The crystals were dried under high vacuum to give 0.396 g of 3- (4-methoxyphenylsuifonyl) -propenoic acid as a pale yellow solid (mp 123 ° C-128.5 ° C). The filtrate was concentrated to give 1.42 g of yellow solid which was subjected to flash chromatography (60% EtOAc / hexane / 2% HOAc / 0.5% methanol) yielding 1.42 g of 3- (4-) acid. methoxyphenylsulfonyl) propenoic acid. A second chromatography (40% EtOAc / hexane / 2% HOAc / 0.5% methanol) provided 0.588 g of pure 3- (4-methoxyphenylsulfonyl) -propenoic acid. (d) Combined and heated to 55 ° C (at which time the starting material went into solution) overnight 3- (4-methoxyphenylsulfonyl) propenoic acid (200 mg), excess furan (5.0 ml) and dry toluene (5.0 ml). The cooled reaction was concentrated in vacuo to give a tan solid which was a mixture of starting material and product. The material was suspended in toluene (5 ml) and furan (10 ml) and heated to 69 ° C overnight. The cooled reaction mixture was concentrated in vacuo to give 251 mg of crude 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid as a dark brown solid. (e) O-Benzylhydroxylamine-hydrochloric acid (0.387 g, 2.43 mmol) was added to a stirred solution of 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid in methylene chloride (5 ml). 4-Dimethylaminopyridine (0.306 g, 2.51 mmol) was added and stirred for about half an hour (until the solids dissolved), then 1,3-dicyclohexylcarbodiimide (0.250 g, 1.21 mmol) was added and stirred at room temperature during the night. The reaction was filtered through a pad of Celite® and the filtrate was concentrated in vacuo yielding 1.06 g of 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid benzyloxyamide. This was suspended in methanol and the filtrate was decanted into fines acicular crystals. The concentration of the filtrate gave 0.82 g of 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid benzyloxyamide. (f) 5% palladium / barium sulfate (0.80 mg) was added to 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid benzyloxyamide (0.82 g) in 30 ml of methanol and subjected to hydrogenation at 3.10 x 10 5 Pa at room temperature on a Parr shaker for 4 hours. The reaction was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The proton NMR of the residue showed only that the double bond had been removed. The residue was subjected to flash chromatography (50% EtOAc / hexane) affording 0.126 g of intermediate. 5% palladium / barium sulfate (0.126 g) in methanol (30 ml) was added thereto and the hydrogenation was prolonged on a Parr shaker at 3.10 x 10 5 Pa at room temperature for one hour and three quarters. The reaction was filtered through a bed of Celite® and the filtrate was concentrated to give 0.101 g of 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid hydroxyamide. It was subjected to flash chromatography (EtOAc / hexane / methanol / HOAc) (70/30/8/1) to give 77.1 mg of 3- (4-methoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane- hydroxyamide. 2-carboxylic acid Proton NMR (CD3OD) d 1.6 (2H, m), 1.8 (2H, m), 3.1 1 (1 H, t), 3.82 (1 H, d), 3.88 (3H, s), 4.63 (1 H, t), 4.91 (1 H, d), 7.12 (2H, d), 7.80 (2H, d); HRMS M ++ H +, calculated: 328.0855, found: 328.0872.

EXAMPLE 2 3- (4-Phenoxyphenylsulfonyl) -7-oxabicyclo2.2.1heptane-2-carboxylic acid hydroxyamide Cs- 3- (4-Phenoxyphenylsulfonyl) propenoic acid prepared from phenoxyphenylsulfonyl chloride and acrylic acid was subjected as described in Example 1, Steps A and B, to flash chromatography (60/40 / 1.5 / 0.5- EtOAc / hexane / HOAc / methanol) yielding 1.12 g of product as an off-white solid. This crystallized from EtOAc / hexane (3: 1) to give 0.61 g of pure product as fine white crystals. (b) 3- (4-Phenoxyphenylsulfonyl) -propenoic acid (250 mg, 0.82 mmol) in toluene (5.0 ml) (starting material insoluble in toluene at room temperature), furan (10 ml) was added and the Mix at gentle reflux at approximately 70 ° C. After about half an hour, the reaction mixture was a solution. After 18 hours of reflux, the TLC of the milky white solution showed that the starting material had been consumed. The reaction mixture was cooled and the white precipitate was collected by suction filtration and washed with toluene (2 x 1 ml). The solids were dissolved in hot methanol and concentrated in vacuo to give 0.267 g of 2- (4-phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid as a white crystalline solid. (c) 3- (4-Phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid (0.243 g, 0.65 mmol) was subjected to hydrogenation in a Parr shaker over 5% palladium barium sulfate (0.125 g) in methanol (30 ml) at room temperature and 3.10 x 105 Pa for 3 hours. The reaction was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford 0.216 g of 3- (4-phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid. (d) O-Benzylhydroxylamine-hydrochloric acid (0.28 g, 1.73 mmol) was added to 3- (4-phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid (0.216 g, 0.58 mmole), dissolved in CHCI3 with heating to dissolve it. Then 4-dimethylaminopyridine (0.22 g, 1.79 mmol) was added and the mixture was stirred until complete dissolution occurred in about 5 minutes. Then 1,3-dicyclohexylcarbodiimide (0.18 g, 0.87 mmol) was added. After 18 hours of stirring at room temperature, the reaction was concentrated in vacuo yielding 1.05 g of crude product. Flash chromatography (40% EtOAc / hexane / 2% HOAc / 0.5% methanol) provided 0.32 g of impure product. Flash chromatography (40% EtOAc / hexane) gave 0.212 g (75%) of 3- (4-phenoxyphenylisulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid benzyloxyamide as a foamy solid colored snow White. (e) 3- (4-Phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid (0.21 g, 0.438 mmol), 5% palladium / barium sulfate (0.11 g) in methanol ( 20 ml) and hydrogenated on a Parr shaker at room temperature and 3.10 x 105 Pa for one hour and three quarters. The reaction mixture was filtered and concentrated in vacuo to afford 0.175 g of 3- (4-phenoxyphenylsulfonyl) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid hydroxyamide as a snow white, foamy solid, m.p. 88.9-92.9 ° C. Proton NMR (CD3OD) d 2.5-2.7 (2H, m), 2.7-2.9 (2H, m), 3.11 (1H, t), 3.84 (1H, d), 4.64 (1H, t), 4.94 (1 H, d), 7.10 (4H, d), 7.23 (1 H, t), 7.44 (2H, t), 7.82 (2H, d); mass spectrum M ++ NH4 + 407. HRMS M + H +, calculated: 390.1011, found 390.1022.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond; n is 0, 1 or 2; X and Y are each, independently, CR1, wherein R1 is hydrogen, C? -C6 alkyl optionally substituted by (C? -C6 alkyl) amino, (C? -C6 alkyl) thio, C6 alkoxy, trifluoromethyl, C6-C6 aryl, C5-C9 heteroaryl, (C6-C? 0 aryl) amino, (C6-C? o) thio aryl, C6-C? aryloxy, (Cs-Cgjamino heteroaryl, C5-C9 heteroaryloxy, (C 6 -C 0 aryl) (Ce-Cι aryl), C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) (hydroxymethylene), piperazinyl, (C 6 -C 6 aryl) (C-C6-alkoxy), (C5-C9-heteroaryl) (C-C6-alkoxy), (C-C6-acyl) amino, (C- -Ce) thio acyl, Ci-C- acyloxy, (C1-C6-alkyl) sulfinyl, (C6-C? 0 aryl) sulfinyl, (C? -C6 alkyl) sulfonyl, (C6-C? 0 aryl) sulfonyl, amino, (CrC6 alkyl) amino or ((C? -C6 alkyl) 2) amino trifluoromethyl, (d-C6 alkyl) (difluoromethylene), (C1-C3 alkyl) (difluoromethylene) - (C1-C3 alkyl), C6-C10 aryl, C5-C9 heteroaryl, C3-C6 cycloalkyl, (C? C6) hydroxymethylene, R 3 (C 1 -C 6 alkyl), wherein R 3 is (d-C 6 acyl) piperazine, (C 6 -C 6 aryl) piperazino, (C 5 -Cg heteroaryl) piperazino, (C 1 -C 6 alkyl) piperazino , (aryl C6-C? 0) (C 1 -C 6 alkyl) piperazino, (C 5 -C 9 heteroaryl) (C 1 -C 6 alkyl) piperazin, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 1 aryl) - C? O) piperidyl, (C5-Cg heteroaryl) piperidyl, (C? -C6 alkyl) piperidyl (C-alkyl) C6), (C6-C? O aryl) piperidyl (C? -C6 alkyl), (C5-Cg heteroaryl) piperidyl (alkyl) C? -C6) or (C? -C6 acyl) piperidyl, or a group of formula where r is 0 to 6; D is hydroxy, C? -C6 alkoxy, piperidyl, (C? -Ce) piperidyl alkyl, (C6-C? O) piperidyl aryl, (Cs-Cgjpiperidyl heteroaryl, (C? -C6 acyl) piperidyl or NR4R5, that R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl optionally substituted by (Ci-C 1 -piperidyl alkyl, (C 6 -C 0 aryl) piperidyl, (C 5 -C 6 heteroaryl) piperidyl, C6-C6 aryl, C5-Cg heteroaryl, (C6-C6aryl aryl) (C6-C6aryl aryl) or C3-C6 cycloalkyl, C6-C10 aryl, C5-C9 heteroaryl, (aryl CT-CIO) (C6-C? aryl), C3-C6 cycloalkyl, R6 (C2-C6 alkyl), (C1-C5 alkyl) (CHR6) (C?-C6 alkyl), wherein R6 is hydroxy, Ci-Cß acyloxy , C6-C6 alkoxy, piperazino, (C6-C6 acyl) amino, (C6Ce) thio alkyl, (C 6 -C 6 aryl) thio, (C 1 -C 6 alkyl) sulfinyl, (C 6 -C 6 aryl) sulfinyl, (C 6 alkyl) sulfoxyl, (C 6 -C o aryl) sulfoxyl, amino, (alkyl) C? -C6) amino, ((C1-Ce alkyl) 2) amino, (C? -Ce acyl) piperazino, (C? -C6 alkyl) piperazino, (C6-C? 0 aryl) (C? -C6 alkyl) piperazino, (C5-Cg heteroaryl) (C? -Ce alkyl) piperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R7 (C -Cß alkyl), (C1-C5 alkyl) (CHR7) (C? -C6 alkyl), wherein R7 is piperidyl or (C? -Ce) piperidyl alkyl; and CH (R8) COR9, wherein R8 is hydrogen, C? -C6 alkyl, (C6-C? 0 aryl) (C-C6 alkyl), (C5-Cg heteroaryl) (C? -C6 alkyl), (C-alkyl) ? -C6) thio (C? -C6 alkyl), (C6-C? O) thio aryl (C? -C6 alkyl), (C? -C6 alkyl) sulfinyl (C? -C6 alkyl), (C6-aryl) C? O) sulfinyl (Ci-Cß alkyl), (C?-C6 alkyl) sulfonyl (Ci-Cß alkyl), (C 6 -C 6 aryl) sulfonyl (C?-C6 alkyl), hydroxy (C alquilo-alkyl) C6), amino (C? -C6 alkyl), (C? -C6 alkyl) amino (C? -C6 alkyl), ((C? -C6 alkyl) amino) 2 (C? -C6 alkyl), R10R11NCO (alkyl) C? -C6) or R10OCO (C? -C alkyl), wherein R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl CI-CT, (C6-C? Aryl) (C? -C6 alkyl) ) and (C5-C9 heteroaryl) (C6-C6 alkyl); and R9 is R12O or R12R13N, wherein R12 and R13 are each independently selected from the group consisting of hydrogen, Ci-Cß alkyl, (C6-C? ar aryium) (C -Cß alkyl) and (C5-Cg heteroaryl) ) (C -C6 alkyl); and Ar is C 1 -C 6 alkyl, Ce-Cι aryl, (C 6 -C 10 aryloxy) (C 6 -C 6 aryl), (C 6 -C 0 aryl) (C 6 -C 0 aryl), (C 6 aryl) C 0) (aryl C6-C? 0) (C? -C6 alkyl), (C6-C? 0 aryloxy) (C5-Cg heteroaryl), C5-Cg heteroaryl, (C? -C6 alkyl), (C6-aryl) -C?), (C? -C6 alkoxy) (C6-C0 aryl), (C6-C? 0 aryl) (C6-C6 alkoxy) (C6-C0-aryl), (C6-C? Aryl) (CrC6 alkoxy) (C? -C6 alkyl), (C5-C9 heteroaryloxy) (C6-C? 0 aryl), (CrC6 alkyl) (C5-Cg heteroaryl), (C6-C6 alkoxy) (C5-Cg heteroaryl), (C6-C10 aryl) (C6-C6 alkoxy) (C5-C9 heteroaryl), (C5-C9 heteroaryloxy) ) (C5-Cg heteroaryl), (aryloxy Ce-Cι) (C alquilo-C6 alkyl), (C5-C9 heteroaryloxy) (C?-C6 alkyl), (C?-C6 alkyl) 5 (C6-C? 0 aryloxy) (C6-C? Ar aryl), (C?-C6 alkyl) (C5-C9 heteroaryloxy) (C6-C? Ar aryl), (C 1 -C 6 alkyl) (C 6 -C 0 aryloxy) (C 5 -C 9 heteroaryl), (C 6 alkoxy) (C 6 -C 0 aryloxy) (C6-C? aryl), (C? -C6 alkoxy) (C5-C9 heteroaryloxy) (C6-C? 0 aryl) or (C? -C6 alkoxy) (C6-C6o aryloxy) (C5-Cg heteroaryl), wherein each aryl group is optionally substituted with fluoro, chloro, bromo, Ci-Ce alkyl, C6-C6 alkoxy or perfluoro 10 (C1-C3 alkyl).

2. A compound according to claim 1, wherein n is 2.

3. A compound according to claim 1, wherein X and Y are both CR1 with R1 being hydrogen.

4. A compound according to claim 1, wherein Ar is (C 1 -C 6 alkoxy) (C 6 -C 6 aryl), (C 6 -C 0 aryl) (C 6 -C 6 alkoxy) (C 6 aryl) C o), 4-fluorophenoxy (C6-C? Aryl), 4-fluorobenzyloxy (C6-C? 0 aryl) or (C? -C6 alkyl) (C-Cio aryloxy) (C6-C? Aryl).

5. A compound according to claim 1, wherein n is 2, X and Y are both CR1, wherein R1 is hydrogen and Ar is (Ci-Cß alkoxy) (C6-C? Aryl), 20 ( aryl C6-C? 0) (C? -C6 alkoxy) (C6-C? 0 aryl), 4-fluorophenoxy (C6-C? aryl), 4- fluorobenzyloxy (C6-C? 0 aryl) or (alkyl) C? -C6) (C6-C? 0 aryloxy) (C6-C? 0 aryl).

6. A pharmaceutical composition for, (a) the treatment of a disorder selected from the group consisting of arthritis, cancer, ulceration of , / tissues, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, along with NSAIDs and conventional analgesics, and together with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, 5 AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or, (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor in a mammal, including a human being, comprising an amount of a compound according to claim 1, effective in said treatment and a pharmaceutically vehicle 10 acceptable.

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

8. The use of a compound of claim 1 or the combination of said compound of claim 1 with NSAID's and standard analgesics and in combination with cytotoxic anti-cancer agents, for the manufacture of a medicament for treating a disorder selected from group formed by 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 Tumor Necrosis Factor (TNF) in a mammal, including a human.