MXPA97005331A - Sulf cyclic derivatives - Google Patents

Abstract

A compound of formula (See Formula) wherein n, q, p, X, Y, Z and Ar are as defined herein, useful in the treatment of arthritis, cancer, tissue ulceration, restenosis, disease periodontal, epidermolysis ampoilosa, scleritis or other diseases characterized pro activity of matrix metalloproteinases, as well as AIDS, sepsis, septic shock or other diseases that involve the production of T

Description

CYCLIC DERIVATIVES OF SULFONfi BACKGROUND OF THE INVENTION The present invention relates to cyclic sulfone derivatives which are inhibitors of the rnatricial metalloprotemases or the production of tumor necrosis factor (TNF) 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 in chickens, scleritis and other diseases characterized by activity of etaloproteinases matnciales, as well as SIDO (acquired immunodeficiency syndrome), sepsis, septic shock and other diseases that involve the production of TNF . 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 effect the decomposition of structural proteins and that are structurally related to the etaloproteases. Metalloproteinases that degrade the matrix, such as gelatinase, estrous elisma and collagenase, are involved in tissue matrix degradation (eg, collapse of collagen) and have been implicated in many disorders pathological conditions that involve abnormal me + bolism of the connective tissue and the basement membrane matrix, such as arthritis (eg, os + eoartp + is and reu atoid arthritis), tissue ulceration (eg, corneal, epidermal, and gastric ulceration) , abnormal wound healing, pepodon + al disease, bone disease (eg, Paget's disease and osteoporosis), metastasis or tumor invasion, as well as infection caused by human immunodeficiency virus (HIV) (3. Leu-, Biol., 52 (2): 244-248, 1992). It has been recognized that the tumor necrosis factor is involved in many infectious and autoimmune diseases (W. Fr ers, FEBS Letters, 1991, 2B5, 199). In addition, TNF has been shown to be the principal mediator of the inflammatory response seen in sepsis and septic shock (C. Spooner et al., Clinical Irnmunology and Immunopathology, 1992, 62, Sil).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula), or to a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond; is 0, 1 or 2; p is 0 or 1; q is 0, 1 or 2; X, Y and Z are each, independently CR * R2, in which R * and R2 are each independently hydrogen, Ci-Cd alkyl optionally substituted by (Ci-Cβ lamino alkylamino, Ci-Celtio alkyl, alkoxy Ci-Cß, trifluorornetile, aryl Ce-Cio, hete or rile Cs-C9, (aryl Ce -Ciolamino, (aryl Cé-C? O) thio, aryloxy Ce -Cio, (C5-C9 heteroaryl lamino, (Cs-C9 heteroaryl) thio, C5-C9 heteroaryloxy, (C aryl C -CycloC1 -Cyclocarbon), C3Ce cycloalkyl, hydroxyCalkyl Ci -Ce), (Ci-Cß alkoxy) (hydroxymethylene), piperazinyl, (C aryl) -Cio) (Ci-Cß alkoxy), (C5-C9 heteroaryl) (Ci-C 1 alkyl, (C-Cι-lamino acyl, (Ci-Celtium acyl, Ci-C acyloxy) (Ci-Cß-Isulfinyl alkyl, (aryl Ce -Cio-Isulfinyl, (Ci- C-Isulfonyl) alkyl, (C aryl) sulfonyl, amino, (Ci-C-lamino or (C 1 -Ce> 2) amino alkenyl C 2 -C e alkenyl, (aryl C & -Cy (C2-C2-alkenyl), (C5-C9-heteroaryl) (C2-C2-alkenyl), C2-C3-alkynyl (aryl Ce-C2) (C2-C2-alkynyl) (C5-C9 heteroaryl) (C2- alkynyl) Ce), (C 1 -Ce) amino alkyl, (Ci-Celthio alkyl, C 1 -Ce-trifluoromethyl alkoxy, (C 1 -C e alkyl) (difluoromethylene), (Ci-C 3 alkyl) (difluoromethylene) (C 1 -C 3 alkyl ), aryl Ce -Cio, C5-C9 heteroaryl (aryl Ce -Cio) to ino, (C C-CιHι aryl, C C-Cι aryloxy (C 5 -C 9 heteroaryl lamino, (heteroaryl CS-C RÍ0, heteroaryloxy CS-C, C3-Cβ cycloalkyl (Ci-Cβ alkyl, hydroxy, piperidyl, Ci-Cβ alkylpiperidyl, Ci-C-acyl acyl, Ci-Cßlthyl acyl, Ci-Cβ acyloxy , R3 (Ci-Cß alkyl), wherein R 3 is (C 1 -C e acyl piperazine, (C aryl Ipiperazine, (C 5 -C 9 heteroaryl Ipiperazine, (C 1 -C e alkylpiperazine, (C aryl C y)) (Ci C e alkylpiperazine, (C 5 heteroaryl -C9) (Ci-C 1 alkyl piperazino, morpholino, thio orpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 1 alkyl piperidyl, (C 1 -C 10 arylpiperidyl, (C 5 -C 6 heteroaryl, pperidyl, (C 1 -Ce alkylpiperidyl (C 1 -C e alkyl), (C arylCyclo) iperidyl (Ci-C alkyl), (C 5 -Cio heteroaryl Ipiperidyloalkyl Ci -Ce 1, (Ci-Cé acylpiperidyl acyl, or a group of formula where r is 0 to 6; D is hydroxy, Ci-C alkoxy or NR «RS, in which R * and RS are each independently selected from the group consisting of hydrogen, Ci-Cß alkyl optionally substituted by (C 1 -C 4 alkylpiperidyl, Cio Ipiperidyl, (heteroaryl CS-C) piperidyl, aryl Ce-Cío, heteroaryl C5-C9, (aryl Ce-Cío) (aryl Ce-Cío) or cycloalkyl C3-C6; piperidilo, (Ci -e alkylpiperidyl, (aryl Ce -Cío)? Iperidilo, (heteroaryl CS-C9) piperidyl, (acyl Ci-C) piperidyl, aryl Cß-Cι, C5-C9 heteroaryl, (Cß-io aryl) (Cé-Cι aryl), C 3 -C 6 cycloalkyl, R 6 (C 2 -C 1 alkyl, (C 1 -C 5 alkyl (CHR *) (Ci-Cß alkyl, wherein Rβ is hydroxy, acyloxy Ci-Cβ, alkoxy Ci-Cβ, piperazino, (acyl Ci-Celamino, (alkyl C -Celtio, (aryl Ce -Cio Rio, (alkyl Ci-C 1 sulfinyl, (aryl C & ~ Cio Isulfinyl, (Ci-C-Isulfoxyl) alkyl (Ce-Cyl isulfoxyl, amino, (Ci-C-lamino, alkyl (Ci-Ce) 2 -lamino alkyl, (C 1 -C e -piperazine acyl, Ci-C-alkylpiperazine, (C ar-Cι aryl) (C 1 -C 4 alkylpiperazine, (C 5 -C 91 heteroaryl (Ci-Cβ alkylpiperazine, rnorfolino, thiornorfolino, piperidino or pyrrolidino; R? (Ci-Cß alkyl), (C 1 -C 5 alkyl) (CHR ?) (Ci-C 1 alkyl, wherein R is piperidyl or (Ci-C 1 -piperidyl alkyl; and CH (R 8) C 0 R *, wherein R 3 is hydrogen, Ci-C 1 alkyl, (C aryl C 1 -C y) ( Ci-Cß alkyl), (C5-C9 heteroaryl) (Ci-Ce alkyl) (Ci-C e alkyl) thio (Ci-C e alkyl), (C aryl) C10 Itiofalkyl Ci -C & 1, (Ci-C-alkylsulfinyl) alkyl (Ci-C-alkyl), (C 1 -Cy-arylsulfonyl) Ci-C 1, (Ci-C-alkylsulfonyl) alkyl (Ci-C6 alkyl), (C aryl) sulfonyl (alkyl) Ci-Cé), hydroxy (Ci-Cß alkyl), Ci-Cß -noalkyloxy), (Ci-Cß alkyl) awino (Ci-Ce alkyl), ((Ci-C) amino) alkyl) (C-Ce alkyl) , Rio RII NCO (on the quilo Ci-Ce) or Riooc? (Ci-Ce alkyl), wherein Rio and Rii are each independently selected from the group consisting of hydrogen, Ci-Ce alkyl (aryl Ce -Cio) ( C -Cß alkyl) and (C5-C9 heteroaryl) (Ci-Cß alkyl); and R9 is R120 or R12R13N, wherein R12 and Ri3 sß each independently select from the group consisting of hydrogen, Ci-Cß alkyl, (Cß-Cι aryl) (Ci-Ce alkyl) and (C 5 -C 9 heteroaryl) (Ci-Cß alkyl); and Ar is aryl Cé-Cio or heteroaryl Cs-C9, each of which may be substituted by C 1 -Cy aryl, heteroaryl CS-C 9, (aryl Ce-Cι) (C 2 -Ce 1 alkyl, C 5 heteroaryl -C9) (C2-C2 alkenyl), C2-C2 alkynyl, (aryl Ce -Cio 1 (C2-C6 alkylene) or (C5-C9 heteroaryl) (C2-C1 alkynyl, optionally substituted by Ci-Ce alkyl, Ci-C-amino alkyl, Ci-Celtio alkyl, Ci-Cß alkoxy , pfluorornethyl, aplo Ce -Cio, C5-C9 heteroaryl, (C aryl-Ciolamino aryl, (C-CioRio aryl, C-Cio aryloxy, C5-C9 heteroaryl lamino, (C5-C heteroaryl RIO, C5-C heteroaryloxy (aryl Ce-Cio) (aryl Ce-Cio), C3-C6 cycloalkyl, hydroxy (Ci-C-alkyl, (Ci-Ce alkyl (hydoxymethylene), piperazinyl, Ce -Cio) (Ci-Cβ alkoxy), (CS-C9 heteroaryl) (Ci-C alkoxy), (Ci-Celamino acyl, (Ci-CßRio acyl, C -C acyloxy, (Ci-Ce alkyl isulfinyl, ( aryl Ce -Cio-Isulfinyl, (Ci-Ce alkyl sulphonyl, (Ce-1-sulphonyl, amino, aryl, Ci-C-lamino, ((C 1 -Ce) alkyl) amino or R 3 -alkyl, wherein R 3 is defined as above, halogen, hydroxy, Ci-Cß alkyl or Ci-Cß alkoxy, wherein the alkyl or alkoxy groups may be optionally substituted by (C?-C e) amino alkyl, (Ci-CeRio alkyl, Ci-C alkoxy) , trifluoroethyl, aryl Ce-Cι.-C5-C9-heteroaryl, (C-aryl-C-lamino, aryl Ce-Rio, C-Cι aryloxy, Cs-C9 heteroaryl, (C-Celtio heteroaryl, C5-C9 heteroaryloxy , (aryl Ce -Cio) (aryl Ce -Cio), cycloalkyl C3-Ce, hydroxy (Ci-Ce alkyl), uilo Ci -Ce) (hydroxy ethylene), piperazinyl, (aryl Ce -Cio 1, (alkoxy Ci-C), (heteroaryl C5-C9) (alkoxy Ci-Ce 1, acyl Ci-C-lamino, acyl Ci-Celtio, acyloxy Ci- Ce, (Ci-C alkyl Isulfinyl, (C 1 -C 6 aryl Isulfinyl, Ci-Cß alkyl) -phonomethyl, (C ar-Cι-aryl) sulfonyl, amino, (C?-C6 alkyl) amino, or ((Ci-Ce alkyl) ) 2-lamino; C2-C2-alkenyl (C6-C6-aryl (C2-C3-alkenyl, Cs-C91-heteroaryl (C2-C2-alkenyl, C2-C3-alkynyl, (C-C6-arynyl (C2-C alkynyl) , (C5-C9 heteroaryl) (C2-C1 alkynyl, (Ci-C-lamino alkyl, (C1-Celtio-alkyl, Ci-C-alkoxy, trifluoromethyl or, (Ci-C 1 alkyl (difluoromethylene),C1-C3) (di-fluoromethylene) (Ci-C3-alkyl), aryl-Ce-C6, C5-C9-heteroaryl, (C2-C6-aryl) -no, (C2-C6-aryl) thio, C2-C6-aryloxy, (heteroaryl Cs) -C9) amino, (Cs -C) heteroaryl thio, CS-C9 heteroaryloxy, C3-C6 cycloalkyl, (Ci-C-alkyl) (hydroxymethylene), piperidyl, (Ci-Ce alkylpiperidyl, (acyl C? -Ce) amino, (acyl C? ~ Ce) thio, acyloxy Ci-C, R3 (Ci-Cs alkyl) or R3 (Ci-C alkoxy), wherein R3 is (Ci-Ce acyl) piperazine, (aryl Ce -C or Ipiperazine, (C5-C heteroaryl) piperazine, (Ci-C-alkyl) piperazino, (aryl Ce-Cio) (Ci-Ce alkyl) piperazino, (C5-C heteroaryl) (Ci-alkyl) Cβ) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (Ci-C-alkyl) piperidyl, (aryl) Cepi Ipiperidyl, (heteroaryl Cs-C9-piperidyl, (Ci-C-piperidyl-alkyl (Ci-C-alkyl), ) piperidyl (Ci-Cß alkyl), C 1-9 heteroaryl Ipiperidyl (Ci-Cß alkyl), acylCi-Cβ) piperidyl, or a group of formula where r and D are as defined above; provided that when q is 1 and X and Y are CRi R2, in which one of R1 or R2 must be hydrogen, p must be 1; provided that, when q is 0, the compound of formula I is not bicyclic; and provided that, when the dashed line of formula I represents a double bond, R2 does not exist. 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-alkyl groups in which "alkyl" is co or 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-C alkoxy, aryloxy Ce -Cio, trifluoro ethoxy, difluoro ethoxy and Ci-Ce alkyl- The term "heteroaryl", as used in the present, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removing a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, i-idazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl. , isoquinyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indoyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro , trifluoromethyl, Ci-C alkoxy, aryloxy Ce-Cι, trifluoro etho, difluoro ethoxy and Ci-C alquilo 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 0-acyl groups, wherein "acyl" is as defined above. Preferred compounds of formula I include those in which q is 0 or 2. Other preferred compounds of formula I include those in which q is 0 or 1. Other preferred compounds of formula I include those in which n is 2.

Other preferred compounds of formula I include those in which X and Y are both CRi R2, where R * and R2 are hydrogen. Other preferred compounds of formula I include those in which Ar is methoxy phenyl, phenoxy phenyl, benzoxyphenyl or halophenyl. More preferred compounds of formula I include those in which q is 0, p is 1, is 2, X and Y are CRiR2, where R1 and R2 are hydrogen, and Ar is methoxyphenyl, phenoxyphenolo or benzoxyphenyl. The most preferred compounds of formula I include those in which q is 0, p is 0, rn is 2, X and Y are CRi R2, where R1 and R2 are hydrogen, and Ar is methoxyphenyl, phenoxyphenolo or benzoxyphenyl. The present invention also relates to a pharmaceutical composition for, (a) the treatment of a disorder selected from the group consisting of arthritis, cancer, tissue ulceration, retinitis, periodontal disease, epidermolysis in chickens, scleritis and other diseases characterized by activity of matrix metalloproteinases, AIDS, sepsis, septic shock and other diseases that involve the production of tumor necrosis factor or, (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor in a mammal, including a human being , which comprises an amount of a compound of formula T or of one of its pharmaceutically acceptable salts, effective in said treatments or inhibition, and a pharmaceutically acceptable vehicle. The present invention also relates to a method for inhibiting tumor (a) rnetaloproteinase (TNF) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or of a its pharmaceutically acceptable salts. The present invention also relates to a method for treating a disorder selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis arnpollosa, scleritis and other diseases characterized by activity of materi metalloproteinases, AIDS, sepsis. , septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of formula T or of one of its pharmaceutically acceptable salts , 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, p, q, X, Y, Z and Ar are as defined above.

SCHEME 1 VI I VI I I I I SCHEME 2 X! , VI I I SCHEME 3 TBDMS XIX XVIII XVI XVII XV SCHEME 3 (continued) XI XIII SCHEME 4 XXIV XXI I I r XXI XXI I XX XIX SCHEME 5 XX I I I 'XVI XXVI XXV In Reaction 1 of Scheme 1, the sulfonyl chloride compound of formula VTT is converted to the corresponding sodium sulphite compound of formula VI by the reaction of VII with sodium iodide in the presence of a polar aprotic solvent, such as acetone, in an inert atmosphere. 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 2-iodo-3- (aryl) sulphonylpropionic acid compound of formula V by reaction 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 for a period of about 2.5 days to about 3.5 days, preferably about 3 days. In reaction 3 of Scheme 1, compound V is converted to the corresponding (E) -3- (aryl) sulfonyl-prop-2-enoic acid compound of formula IV by treatment of V with a base, such as triethylamine, in an inert atmosphere. The reaction is stirred at room temperature for a period of about 10 hours to about 14 hours, preferably about 12 hours. In reaction 4 of Scheme 1, the TV compound in the corresponding carboxylic acid compound of formula ITT by heating TV with an excess amount of a compound of formula where q is 1 and p is 1, or in an excess amount of the compound diene of formula \\ // (X) p Y wherein q is 0 and p is 1, at reflux in the presence of a polar aprotic solvent, such as toluene, for a period of about 40 hours to about 56 hours, preferably about 48 hours. In the ratio 5 of Scheme 1, the compound of formula III is converted to the corresponding N- (benzyloxy) carboxarnide compound of formula II by reacting III with benzylhydroxylahydrochloride, diraethylaminopi-ridine and dicyclohexylcarbodi-ida in the presence of a solvent polar aprotic, 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 hydroxarnic acid compound of formula T, treating TI with hydrogen in the presence of a catalyst-, such as 5% palladium on barium sulfate and an aprotic solvent. polar as inert. The reaction mixture is stirred for a period of from about 2 hours to about 4 hours, preferably about 3 hours. In reaction 1 of Scheme 2, the cycloalkenecarboxylate compound of formula XIT, wherein p is 0 or 1 and X is CH2, it is converted to the corresponding arylthiocycloalkanecarboxylate compound of formula XI by addition of a solution of XII in a polar aprotic solvent such as tetrahydrofuran, to a solution of an arylthio compound of the formula ArSH and a base such as butyl lithium in a solvent polar aprotic, tetrahydrofuran, in an inert atmosphere at a temperature from about -75 ° C to about -85 ° C, preferably about -78 ° C. The reaction mixture is allowed to warm to room temperature over a period of about 10 hours to about 14 hours, preferably about 12 hours. In reaction 2 of Scheme 2, the compound is oxidized XI to the corresponding sulfone compound of formula X treating XI with a suitable oxidant, such as a catalytic amount of osmium tetraoxide and a reoxidant such as N-oxide.

Methylnorpholine in a polar aprotic solvent such as isopropanol. The reaction is carried out in a polar aprotic solvent such as isopropanol for a period of from about hours to about 24 hours, preferably about 12 hours. In reaction 3 of Scheme 2, the compound of formula X is converted into the corresponding carboxylic acid compound of formula IX by breaking the ester radical of X by hydrolysis, using a suitable base such as sodium hydroxide in a polar solvent or aqueous tetrahydrofuran, or by hydrogenolysis using hydrogen in the presence of a polar solvent such as rnetanol, and a catalyst with 10% palladium on carbon, at a pressure of about 2.75 x 10 5 to 4.13 x 10 5 Pa, preferably at 3.45 x 10 5 Pa. it is stirred for a period of about 2 hours to about 12 hours, preferably about 8 hours. In reaction 4 of Scheme 2, the carboxylic acid compound of formula IX is converted into the corresponding hydroxy acid compound of formula VIII by treating II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent such as This is followed by the addition of hydroxylamine to the reaction mixture after a period of time from about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, 17 as hydroxyl-hydroxyrate, in the presence of a base such as N-rnethylrnorpholine. As an alternative, a protected derivative of hydroxylamine or one of its salts can be used, in which the hydroxyl group is protected with tert-butyl, benzyl or allyl ether, in the presence of (benzotop zol-1-? Lox?) Hexafluorophosphate. tris (d? et? the ino) phosphonium and a base such as N-methylmorpholma. The removal of the hydroxylanine protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, co or tri-fluorouracetic acid, for a tere-butyl protecting group. The allyl protecting group can be removed by treatment with tpbu ilestane hydride and acetic acid in the presence of bis (triphenylphosphine) palladium chloride in catalytic amounts, N, 0-bis (4-methoxybenzyl) can also be used. ) hydroxyl as a protected hydroxylamine derivative in which the deprotection is achieved using a mixture of ethanesulphonic acid and tpfluoroacetic acid. In reaction 1 of Scheme 3, the compound of formula XIX is converted, wherein p is 0 or 1, X is CH2 and R16 is a protecting group, such as benzyl, in the corresponding compound of formula XVIII, by reacting XIX with a 4-tert-butyldi-ethyisyl-ilapltium compound, according to the procedure described above in reaction 1 of Scheme 2. In reaction 2 of Scheme 3, compound XVIII is converted to the corresponding compound of formula XVII by the addition of aqueous hydrofluoric acid to a solution of XVITI in a polar aprotic solvent co or acetom p lo. The reaction mixture is stirred at room temperature, for a period of from about 2 hours to about 5 hours, preferably about 4 hours. In reaction 3 of Scheme 3, the compound of formula XVII is converted to the corresponding compound of formula XVI, wherein R 1 * is hydrogen, or C 1 -C 4 alkyl, optionally substituted by C 1 -C 4 alkyl, (C 1 -C 4 alkyl) Celtium, Ci-C alkoxy, trifluoromethyl, aryl C &-Cy, heteroaryl Cs-C9, (aryl Ce -C o) ammon, (aplo Ce -Cio) uncle, aploxy Ce -Cio, (heteroaryl C5 -exa io , (C5-C9H10 heteroaryl, C5-C heteroaryl, (C6-C10 aplo) (C6-Cio aryl), C3-C3 cycloalkyl, hydroxy (Ci-C-alkyl), (Ci-C-alkyl) (hydroxy-ethylene), piperazin lo, (aryl Ce -Cio) (alkoxy Ci-Ce), (heteroaryl C5-C9) (alkoxy Ci-Ce), (acyl Ci-C) arnmo, (acyl C? -C6) t? o, acyloxy Ci-C, (alkyl Ci-C) sulphonyl, ( C 1 -C 10 aryl) sulfonyl, (Ci-C) alkylsulfonyl, (aplo Cedo) sulfonyl, amino, (C 1 -C e) amino or ((C 1 -C 6) alkyl) amine or R 3 -alkyl wherein R3 is as defined above, by stirring XVII and a suitable primary or secondary alcohol in a polar aprotic solvent such as tetrahydrofuran in an inert atmosphere. An azidodicarboxylate is added as diethyl azidodicarboxylate and a tpalkyl or tparylphosphine as tnphenylphosphine and the resulting reaction mixture is stirred for a period of about 10 hours at about 14 hours, preferably about 12 hours. In reaction 4 of Scheme 3, the compound of formula XVI is oxidized to the corresponding sulfone compound of formula XV according to the procedure described above in reaction 2 of Scheme 2. In reaction 5 of Scheme 3, the compound of formula XV is converted in the carboxylic acid compound of formula XIV according to the procedure described in reaction 3 of Scheme 2. In reaction 6 of Scheme 3, the compound of formula XVI is converted to the corresponding hydroxarnic acid compound of formula XIII according to the procedure described above. in reaction 4 of Scheme 2. In reaction 1 of Scheme 4, the compound of formula XXIV is converted, wherein p is 0 or 1, X is CH2 and R16 is a protective group, such as benzyl, in the corresponding compound of formula XXIII by reaction of XXIV with a 4-halot of-ofenol such as 4-bromothiophenol, according to the procedure described above in reaction 1 of Scheme 2. In the reaction 2 of Scheme 4, the compound of formula XXIII is converted to the corresponding compound of formula XXII according to the procedures described above in reaction 4 of Scheme 3. In reaction 3 of Scheme 4, the compound of formula XXII in the corresponding compound of formula XXI, wherein R s is hydrogen, (aryl Ce-Cι) (C 2 -C β alkenyl), (Cs-Cι heteroaryl) (C 2 -C alkenyl), C 2 -C 4 alkynyl (aryl Ce -Cio) (C2-C2 alkynyl), (CS-C9 heteroaryl) (C2-C6 alkynyl), aryl Ce-C, or C5-C9 heteroaryl optionally substituted by Ci-C-alkyl (Ci-C-lamino alkyl) (C alquilo-C6 alkyl) thio, Ci-C alco alkoxy, trifluorornetyl, Cι-Cι, C 5 -C 9 heteroaryl, (C aryl Cι-lamino, (C 6 -C 6 aryl) thio, aryloxy Ce Cio, (heteroaryl C5-C larni.no, (heteroaryl Cs-C9) thio, heteroaryloxy Cs ~ Cg, (aryl Ce-Cio) (aryl Ce-Cio), cycloalkyl C3-C6, hydroxy (alkyl Ci-C), (alkyl) Ci-Ce) (hydroxymethylene), piperazinyl, (aryl Ce-Cι) (alkoxy Ci-C), (heteroaryl C 5-9) (alkoxy Ci-Ce), (acyl Ci-C 6) arnino, (acyl C? -Ce ) thio, Ci-Ci-alkoxy (Ci-C-Isyl-linoyl, (aryl Ce-Cio) sulfinyl, (Ci-C-Isulfonyl) alkyl, (C aryl) sulfonyl, ino, (C1-C-alkyl) lamino or ((Ci-Ce) 2 -lamino alkyl; or R3 -alkyl, wherein R3 is co or defined above. The couplers of coupling could be aryl- or heteroarylboronic acids, aryl- or heteroaryl stannanes or vinyl compounds. In reaction 4 of Scheme 4, the compound of formula XXI is converted to the corresponding compound of formula XX according to the procedure described above in reaction 3 of Scheme 2. In reaction 5 of Scheme 4, the compound of formula XX in the corresponding compound of formula XIX according to the procedure described above in reaction 4 of Scheme 2. In reaction 1 of Scheme 5, the compound of formula XXVIII is converted, wherein p is 0 or 1, X is CH2 and R16 is a protecting group, such as benzyl, in the corresponding compound of formula XXVII according to the procedure described above in reaction 3 of Scheme 2. In reaction 2 of Scheme 5, the compound of formula XXVII is converted to the corresponding compound of formula XXVI according to the procedure described above in reaction 4 of Scheme 2. In reaction 3 of Scheme 5, the thioether compound of formula XXVI is oxidized to the corresponding sulphoxide compound of formula XXV using a suitable oxidizing agent such as rn-chloroperbenzoic acid, in a polar aprotic solvent such as dichloromethane , at a temperature of from about 010 ° C to about 10 ° C, preferably at about 0 ° C, for a period of about 30 minutes to about 4 hours, preferably about 2 hours. The pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, 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 salts of ammonium, trimethylammonium, diethylamine and tris (hydroxymethyl) methylammonium.

Likewise, addition salts of acids, co or mineral acids, organic carboxylic acids and sulphonic organic acids, for example, hydrochloric acid, ethanesulphonic acid and rnaleic acid, are also possible, provided that a basic group, such as pyridyl, , be 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 netaloproteinases or the production of turnoral necrosis factor (TNF) and, therefore, demonstrate their efficacy to treat diseases characterized by atricial metalloprotemases 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: 10 ug of trypsin per 100 μg 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 l .2 μM 0.12 JJM Twenty-five milliliters of each concentration are 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 inhibitor) in wells D7-D12. The collagenase is diluted to 400 ng / ml and then 25 μl is 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) -H? S-Ala-Lys (NMA) -NH2) is prepared as a 5 M stock solution in dimethyl sulfoxide and then diluted to 20 μM in Lampon de test. 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. The fluorescence readings were converted (360 n excitation, 460 nm emission) 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 blank samples or for those containing collagenase (the mean of the triplicate determinations data is made). You choose a point of time that provides a good signal (white) and is in the linear part of the curve (usually around 120 minutes) to determine IC50 values - Zero time is used co or white for each compound at each concentration and these values are subtract 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 the collagenase alone and multiplied by 100). The values of the CIso are determined from the concentration of inhibitor that gives a signal that is 50% of that of the control. It is verified that the IC50 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) ). 72-kD gelatinase is activated with 1 mM p-aminophenyl-eracryl acetate (APMA) for 15 hours at 4 ° C and diluted to give a final concentration in the assay of 100 ng / ml. 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. The fluorescence readings (360 nrn excitation, 460 nm emission) are converted at time zero and then at 20 minute intervals for 4 hours. The IC50 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 0.003 μM.

INHIBITION OF THE ACTIVITY OF STROMELYSINE (MMP-3) The inhibition of estrornelisin activity is based on a modified spectrophotometric assay, described by Weingarten and Feder (Ueingarten, H. and Feder, J., S pe ctrophot orne trie Assay for Vertébrate Collagenase, Anal.

Biochem. , 174, 437-440. (1985)). Hydrolysis of the thiopeptolide substrate tAc-Pro-Leu-Gly-SCHCCH2 CH (CH3 h3CO-Leu-Gly-OC2 Hs 3) gives a mercaptan fragment that can be controlled in the presence of Ell an reagent. Recombinant human proestromelysin is activated with trypsin using a ratio of 1 μg of a 10 mg / ml trypsin stock solution to 26 μg of estrus elisine, Trypsin and stromelysin are incubated at 37 ° C for 15 minutes, followed by 10 μl of soybean trypsin inhibitor. of 10 mg / ml for 10 minutes at 37 ° C to suppress the activity of trypsin.

The assays are carried out in a total volume of 250 μl of test tank (200 mM sodium chloride, 50 mM MES and 10 M calcium chloride, pH 6.0) in 96 well microplates. Activated rhenelysis is diluted in a test tube at 25 μg / ml. Ellrnan's reagent (3-carboxy-4-n-tropholene disulfide) is prepared in the form of a 1M stock solution in dimethylformamide and diluted to 5 mM in the assay with 50 μl per well, giving a concentration end of 1 mM. 10 M stock solutions of inhibitors in dimethyl sulfoxide are prepared and serially diluted in assay tabs, so that the addition of 50 μl to the appropriate wells provides final concentrations of 3 μM, 0.3 μM, 0.003 μM and 0. 0003 μM. All conditions were performed in triplicate. A 300 M solution of the peptide substrate in dimethyl sulphite is diluted to 15 mM in test beaker and the assay is initiated by adding 50 μl to each well, giving a final substrate concentration of 3 mM.

The blank assays consist of Ell an peptide substrate and reagent, without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices plate reader UVrßax. The values of the CIso were determined in the same way as for the collagenase.

INHIBITION OF MMP-13 Human recombinant MMP-13 is activated with p-amiprophenyl mercuric acetate (APMA) 2 rnM for 1.5 hours at 37 ° C and diluted to 400 ng / ml at the assay level (50 mM FTps).; pH 7.5; 200 mM sodium chloride, 5 rnM calcium chloride, 20 μM zinc chloride and 0.02% bpj). 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 on the assay by addition of inhibitor and substrate to give a final concentration in the assay of 100 ng / ml. 10mM of inhibitor 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, are added to the microfluor plate. 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 assay of 10 μM. Fluorescence readings are taken (excitation at 360 nm, emission at 450 nm) at time 0 and every 5 minutes for 1 hour. Positive controls consist of enzyme and substrate, without inhibitor, and blank tests consist of only on substrate. The values of the CTso are determined as in the inhibition of human collagenase 8MMP-1). Without the values of the If they are less 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, demonstrate their efficacy in treating diseases involving the production of TNF is shown by the following in vitro assay: Human mononuclear cells were isolated of anticoagulated human blood, using a one-step Ficoll-Hipaque separation technique. (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBBS) with divalent cations and resuspended at a density of 2 x 10 6 cells / ml in HBSS containing IX of BSA. The differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that the onocitoe ranged from 17 to 24% of the total cells in these preparations. 180 μl aliquots of the cell suspension were applied in 96-well flat bottom plates (Costar). Additions of compounds and LPS (concentration final of 100 ng / ml) provided 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 10 minutes at approximately 250 x g), the supernatants were separated and the TNFor was assayed therein. using the ELISA R & D kit. For administration to humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), 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 approximately 0.1 to 25 rng / 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 starch, potato or tapioca), alginic acid and Certain complex silicates, together with granulation binders, such as vimlpyrrolidone pol, sucrose, gelatin and gum arabic, additionally, for the purpose of tableting, lubricating agents, co or magnesium stearate, sodium phosphate are often very useful. and talcum powder. Solid compositions of a similar type can also be used as fillers in gelatin capsules; the preferred materials also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions 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 u various similar combinations thereof. For parenteral administration, (for intramuscular, mtraperitoneal, 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. The aqueous solutions they should be adjusted and suitably placed, preferably at a pH higher than 8, if necessary, and the diluent liquid should first be made isotomically. 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 in the art. Additionally, it is possible to administer the compounds of the present invention topically, for example, when treating inflammatory skin disorders, and this may be accomplished by means of creams, jellies, 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 N-hydroxy-3- (4-enoxy-benzenesulonyl) -bicycloC2.2.23octane-2-carboxamide A mixture of 0-benzyl hydroxarnate was placed (0.17 g, 0.36 mmol) and 5% palladium on barium sulfate (0.30 g) in methanol (50 nl) in a hydrogen atmosphere (2.75 x 10 Pa) and stirred vigorously for 3 hours. The reaction mixture was then filtered and concentrated in vacuo. providing a solid vitro (0.15 g). Purification by flash chromatography (30: 70: 2.5: 0.5 ethyl acetate: hexanes-acetic acid: methanol) on silica gel yielded pure hydroxaric acid as an off-white foamy solid (96 mg, 60%). P.f. 39.9-91.8 ° C; NMR of * H (250 MHz, Di-MeOH) d 7.80 (d, 2H, .1 = 8.6 Hz), 7.43 (t, 2H, 3 = 7.6 Hz), 7.23 (t, 1H, 3 = 7.3 Hz), 7.11 (t, 4H, 3 = 9.1 Hz), 3.88 (d, 1H, 3 = 7.7 Hz), 2.84 (d, 1H, 3 = 7.2 Hz), 2.18 (width s, 2H), 1.80-1.40 (rn, 4H); 13 Q NMR (75.5 MHz, D ^ -MeOH) 21.5, 25.9, 26.6, 27.4, 32.3, 42.4, 63.6, 118.8, 121.5, 126.2, 131.3, 132.0, 1.33.1, 156.6, .164.1, 171.8; IR (absorption bands): 3303-3230, 2943, 2870, 1665, 1582, 1488, 1247, 1143 crtri. HRM ?: calculated for C21N24NO5 402.1375; Found 402.1352.

EXAMPLE 2 3- (4-Phenoxy-benzenesulonyl) -bicycloC2.2.23oct-5-en-2-carboxylic acid A stirred solution of vinylsulfonyl carboxylate (0.34 g, 1.1 mmol) and 1,3-cyclohexadiene (5 mL, excess) in dry toluene (10 mL) was heated at reflux (120 ° C) for 48 hours. The reaction was concentrated in vacuo to give a greenish-blue oil (0.73 grams) which was purified by flash chromatography (20% ethyl acetate, 2% acetic acid, 2% methanol in hecanes on silica gel) to provide the bicyclic sulfone as a light yellow oil (0.24 grams, 56%).

Major diastereoisomer: NMR of * H (250 MHz, CDCI3) 6 7.85-7.74 (, 2H), 7.44-7.37 (rn, 2H), 7.22 (c, 1H), 7.10-7.01 (m, 4H), 6.30 (t , 1H, 3 = 6.9 Hz), 6.11 (t, IH, 3 = 6.9 hZ), 3.13 (d, 1H, 3 = 4.9 Hz), 2.89 (dd, 1H, 3 = 5.8, 2.1 Hz), 2.63-2.57 (in, 2H), 1.90-1.16 (, 4H). LRMS: 385 (M + 1), 402 (M + 1?).

EXAMPLE 3 N-Hydroxy-2- (4-methoxybenzenesulfonyl) -cyclohexane-l-carboxamide N-Butyl lithium (0.56 mL of a 2.5M solution in hexanes) was added to a stirred solution of 4-methoxythiophenol (1.94 grams, 13.9 mmol) in tetrahydrofuran (40 mL) at 78 ° C under a nitrogen atmosphere. After one hour, a solution of l-cyclohexane-1-benzylcarboxylate (6 grams, 27.8 mrnol) in tetrahydrofuran (5 ml) was added via a cannula and the reaction mixture was allowed to warm to room temperature for 12 hours. The reaction was quenched with saturated sodium chloride solution and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 98% hexane / 2% ethyl acetate) to give 2- (4-methoxybenzenethio) -l-cyclohexane-benzyl carboxylate. Osmium tetraoxide (1.85 ml of a 2.5% solution in 2-methyl-2-propanol) was added to a stirred solution of 2- (4-methoxybenzenesulfonyl) -l-cyclohexane-1-carboxylate. benzyl (3.3 grams, 9.27 mmol) and 4-methylrnorpholine N-oxide (2.71 grams, 23. 2 mrnol) in aqueous acetone (40 ml of water / 80 ml of acetone) at room temperature. After 2 hours, the solvent was removed in vacuo and the residue was partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 90% hexane / 10% ethyl acetate) to give 2 ~ (4-methoxybenzenesulfon? D-1-cyclohexane-1-benzyl carboxylate. ml of ethyl alcohol 2- (4-rnetoxybenzenesulfonyl) -l-cyclohexane-1-carboxylic acid benzyl ester (3.1 grams, 8.0 mmol) 10% palladium on carbon (0.3 grams) was added and the mixture was heated of reaction at 60 ° C at a pressure of 3.45 x 10 Pa of hydrogen for 12 hours The mixture was cooled, the catalyst was removed by filtration and the solvent was concentrated The crude mixture was purified by chromatography on silica gel ( elution with 95% dichloromethane / 5% methanol) to give 2- (4-rnetoxy-benzenesulfonyl) -1-c-clohexane-1-carboxylate 1-hydroxybenzotriazole (0.49 grams, 3.6 mmol) and l- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide (0.69 grams, 3.6 mmol) to a stirred solution of 2- (4-methoxybenzenesulfonyl) -l-cyclohexane-1-ca rboxylate (0.9 grams, 3.0 mmol) in dimethyl formamide (20 ml) at room temperature.

After 30 minutes, hydrochloride hydroxylanine (0.83 grams, 12.0 mmol) and triethylamine (1.83 grams, 18.1 mol 1) and the mixture was stirred for 12 hours.The reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution.The organic layer was washed with 2M hydrochloric acid, then brine and dried (sodium sulfate) before concentrating.The product was purified by recrystallization (ethyl acetate / methanol) to give N-hydroxy-2- (4-metho-1-enosulfonyl) -cyclohexane-l- carboxarnide with a crystalline solid The relative stereochemistry of the two constituents at the junction of the ring was shown to be cis by X-ray crystallography. Mass spectrum (thermonebulization): m / z 331.1 (MNH «+). (CDCl 3, 400 MHz, ppm) d 9.00 (s, 1H), 7.80 (d, 2H), 7.05 (d, 1H), 3.90 (s, 3H), 3.15 (dt, IH), 3.10 (ra, IH) , 2.20-1.85 (, 4H), 1.80-1.20 (, 6H) Analysis found: C 53.69; H, 6.15; N, 4.37 C14H1 NSOS requires C, 53.66; H, 6.11; N, 4.47.

EXAMPLE 4 N-hydroxy-2- (4- (2-N-phthalimido) ethoxy-benzenesulonyl) -cyclohexane-1-carboxamide N-Butyl lithium (1.5 ml of a 2.5M solution in hexanes) was added to a stirred solution of 4-t-butyldimethylsilyloxythiophenol (14.8 g, 61.7 mmol) in tetrahydrofuran (300 ml) at -78 ° C under an atmosphere of nitrogen. After 1 hour, a solution of benzyl l-cyclohexano-l-carboxylate (8 grams, 37 mmol) in tetrahydrofuran (15 ml) was added via cannula and the reaction allowed to warm to room temperature for 12 hours. The reaction was quenched with saturated sodium chloride solution and diluted with ethyl acetate. The organic layer was separated, dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 98% hexane / 2% ethyl acetate) to give 2- (4-t-butyldirnethylsilyloxybenzenethio) -l-cyclohexane-1-benzyl carboxylate. Hydrofluoric acid (5 ml of a 40% aqueous solution) was added to a stirred solution of benzyl 2- (4-t-butyldimethylsilyl ibencenothio) -l-cyclohexane-1-carboxylic acid (5 grams, 11.3 mmol) in acetonitrile ( 50 ml) at room temperature. After 12 hours, the reaction mixture was poured into aqueous ionic chloride and extracted with dichloromethane. The organic extracts were dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 97% dichloromethane / 3% methanol) to give benzyl 2- (4-hydroxybenzenethio) -l-cyclohexane-1-carboxylate. 2- (4-hydroxybenzenethio) -l-cyclohexane-1-carboxylic acid benzyl ester (1 gram, 2.92 mmol) and N- (2-hydroxyethyl phthalimide (0.56 grams, 292 mmol) were dissolved in tetrahydrofuran (30 ml) and stirred at 0 ° C in an atmosphere of nitrogen. Then, tri enylphosphite (0.84 grams, 3.22 mmol) and diethyl azodicarboxylate (0.61 grams, 3.51 mol) were added and the solution was stirred for 12 hours at 50 ° C. The mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 99% dichloromethane, 1% methanol) to give 2- (4- (2-N-phthalimido) ethoxy-benzenethio) -l-cyclohexane-1-carboxylate. ethyl. Osmium tetraoxide (0.38 ml of a 2.5% solution in 2-metii-2-propanol) was added to a solution of 2- (4- (2-N-phthalimido) ethoxy-benzenethio) -l-cyclohexane-l- ethyl carboxylate (0.98 grams, 1.91 mmol) and 4-methylmorpholine N-oxide (0.56 grams, 4.77 mmol) in aqueous acetone (7 ml of water per 14 ml of acetone) at room temperature. After 12 hours, the solvent was removed in vacuo and the residue partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 99% dichloromethane / 1% methanol) to provide 2- (4- (2-N-phthalimido) ethoxy-benzenethio) -l-cyclohexane-1-carboxylate of ethyl. Ethyl 2- (4- (2-N-phthalimido) ethoxy-benzenethio) -l-cyclohexane-1-carboxylate (0.54 grams, 1.0 mmol) was dissolved in 60 rnl of ethyl alcohol. 10% palladium on carbon (60 ng) was added and the reaction mixture was heated at 60 ° C under pressure of 3. 45 x 10 »Pa of hydrogen for 12 hours. The mixture was cooled, the catalyst was removed by filtration and the solvent was concentrated. The crude mixture was purified by chromatography on silica gel (elution with 98% dichloromethane / 2% methanol) to give? - (4- (2-N-phthalimidoletoxy-benzene? O) -1-c-clohexane-1 -carboxylate: 1-hydroxy benzotriazole (78 mg, 0.58 mmol) and l- (3-dimethylaminopropyl) -3-ethylcarboxy (0.11 grams, 0.58 mol) were added to a stirred solution of 2- ( 4- (2-N-phthalamide) ethoxy? -benzenethyl) -l-c-clohexane-1-carboxylate (0.22 grams, 0.48 mmol) in dimethyl formamide (5 nmol) at room temperature. 30 minutes, hydroxylamine hydrochloride (0.13 grams, 1.92 mmol) and triethylamine (0.29 grams, 2.89 moles) were added and the mixture was stirred for 12 hours.The reaction mixture was diluted with ethyl acetate and washed with bicarbonate solution. The organic layer was washed with 2M hydrochloric acid, then with brine and dried (sodium sulfate) before concentrating.The product was purified by chromatography on silica gel (eluting with dicl. 98% oromethane / 2% methanol), yielding N-hydroxy-2- (4- (2-N-phthalimido) ethoxy-benzenethyl) -l-cyclohexane-l-carboxy ida. Mass spectrum (thermospray): rn / z 473 (MH +). 1 H NMR (CDC13, 400 MHz, ppm) d 7.90-7.80 (rn, 4H), 7.75 (d, 2H), 7.10 (d, 2H), 4.40 (t, 2H), 4.10 (t, 2H), 2.80 (m, 1H), 2.40 (dt, 1H), 1.90-1.20 (m, 8H). Analysis found: C 57.85; H, 5.30; N, 5.94. C23H24N2SO7 • H20 requires C, 57.37; H, 5.23; N, 5.82. The title compounds of Examples 5 to 6 were prepared by a procedure analogous to that described in Example 4.

EXAMPLE 5 N-hydroxy-2- (4- (encyloxy) benzenethio) -cyclohexane-l-carboxamide Mass spectrum (earth fogging): m / Z 407.1 (MNH «+). NMR of * H (CDCl 3, 400 MHz, ppm) d 7.80 (d, 2H), 7.50-7.30 (m, 5H), 7.20 (d, 2H), 5.20 (d, 2H), 2.80 (m, IH), 2.40 (dt, 1H), 1.90-1.30 (, 8H). Analysis found: C, 59.90; H, 5.83; N, 3.08. C20H23NSOS • 0.5H2O requires C, 60.28; H, 6.07; N, 3.52.

EXAMPLE 6 N-hydroxy-2-f4- (4-methoxyphenylpropyloxy) benzenethio) -cyclohexane-1-carpoxy amine Mass spectrum (thermospray): m / Z 449.2 (MH +). 1 H NMR (CDCl 3, 400 MHz, ppm) d 9.30 (1H, broad s), 7. 75 (2H d), 7.10 (d, 2H), 7.00 (d, 2H), 6.85 (d, 2H), 4.60 (d, 1H), 4.00 (t, 2H), 3.85 (m, 1H), 3.80 ( s, 3H), 3.10 (dt, 1H), 2. 75 (t, 3H), 2.25 (d, 1H), 2.10 (m, 2H), 1.70-1.10 (m, 8H).

EXAMPLE 7 N-hydroxy-2- (4- (2-methoxy-5-pyridyl) encenothio) -cyclohexane-1-carboxamide Ae added n-butyl lithium (0.92 mL of a 2.5M solution in hexanes) to a stirred solution of 4-bromothiophenol (4.37 grams, 23 mmol) in tetrahydrofuran (30 mL) at -78 ° C in a nitrogen atmosphere. After 1 hour, a solution of benzyl 1-cyclohexane-1-carboxylate (5 grams, 23 mmol) in tetrahydrofuran (10 ml) was added via a cannula and the reaction mixture was heated to room temperature for 12 hours . The reaction was quenched with saturated sodium chloride solution and diluted with ethyl acetate. The organic layer was separated, dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 95% hexane / 5% ethyl acetate) to give benzyl 2- (4-bromobenzenethio) -l-cyclohexane-1-carboxylate. Osmium tetraoxide (1.53 ml of a 2.5% solution in 2-methyl-2-propanol) was added to a stirred solution of benzyl 2- (4-bromobenzenethio) -l-cyclohexane-1-carboxylate (3.1 grams, 7.65 mmoDy 4-methylmorpholine N-oxide (2.24 grams, 19 mmol) in aqueous acetone (15 ml of water per 30 ml of acetone) at room temperature.

The solvent was removed in vacuo and the residue partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with dichloromethane) to give benzyl 2- (4-bromobenzenethio) -l-cyclohexane-1-carboxylate. Tetrakis- (tr? Phenolphosphine) palladium (65 mg, 0.057 mmol) was added to a stirred solution of 2-methox? Ir? Dil-5-boronic acid (460 mg, 2.4 mmol) and 2- (4-bromobenzene) 0) -1-benzyl cyclohexane-1-carboxylate (712 mg, 1.6 mmol) in a mixture of toluene (9 ml), ethanol (5 ml) and saturated sodium bicarbonate solution (4 ml). The mixture was refluxed for 3 hours, after which time the organic solvent was removed by evaporation. The residue was extracted with ethyl acetate and the organic extracts were washed with water and saturated sodium chloride solution. The organic extracts were dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 99% dichloromethane / 1% methanol), affording 2- (4- (2-methoxy-5-pyridyl) -benzenethio) -l-cyclohexane-1. -carboxylate benzyl. 2- (4 ~ (2-methoxy-5 ~? Iridyl) -benzenethio) -l-cyclohexane-1-carboxylic acid benzyl ester (230 mg, 0.49 mmol) was dissolved in 20 ml of ethanol. 10% Palladium on carbon (30 mg) was added and the reaction mixture was heated at 60 ° C under a pressure of 3.45 x 105 Pa of hydrogen for 12 hours. The mixture was cooled, the catalyst was removed by filtration and the solvent was concentrated. The crude mixture was purified by chromatography on silica gel (elution with 99% dichloromethane / 5% methanol), affording 2- (4- (2-methoxy-5-pyridyl) -benzenethio) -1-cyclohexane- 1-carbox? lato. 1-Hydroxybenzotriazole (B80 mg, 0.6 mmol) and l- (3-dimethylamino-yl) -3-ethylcarbodimide (143 ng, 0.7 mrnol) were added to a stirred solution of 2- (4-2-rnetox) ? -5-? R? Dil) benzene) -lc? Clohexane-1-carboxylate (200 mg, 0.5 mmol) in dichloromethane (8 ml) at room temperature. After 30 minutes, tert-butyldimethylsilylhydroxylanine (157 mg, 1 mmol) and 4-rnetiimorpholine (0.14 nmol, 1 nmol) were added and the mixture was stirred for 12 hours. The solvent was removed and the reaction mixture was stirred for 2 hours in methanol / water (10 ml / 4 ml). The reaction mixture was concentrated and the crude mixture was purified by chromatography on silica gel (elution with 98% dichloromethane / 2% methanol) to afford N-Hydroxy-2- (4- (2-methoxy-5-pyridyl ) -benzenothio) -cyclohexane-l-carboxamide. Mass spectrum (thermonebulation): m / Z 391 (MH +, 408 (MNH4 +). 1 H NMR (CDC13, 400 MHz, ppm) d 8.40 (s, 1H), 7.90 (d, 2H), 7.80 (d, 1H) ), 7.65 (d, 2H), 6.80 (d, 1H), 4.00 (s, 3H), 3.20 (m, 1H), 3.05 (m, 1H), 2.30-1.20 (m, 8H).

EXAMPLE 8 N-hydroxy-2- (4-bromobenzenesulfoxy) -cyclohexane-1-carboxamya Ae added n-butyl lithium (2.86 mL of a 2.5M solution in hexanes) to a stirred solution of 4-bromot-ofenol (14.8 grams, 78.5 inmol) in (300 rnl) at -78 ° C in an atmosphere of nitrogen. After 1 hour, a solution of methyl lc-clohexane-1-carboxylate (10 grams, 71.4 mrnol) in tetrahydrofuran (20 nmol) was added via a cannula and the reaction mixture was allowed to warm to room temperature during 12 hours. The reaction was quenched with saturated sodium chloride solution and diluted with ethyl acetate. The organic layer was separated, dried (sodium sulfate) and concentrated. The crude mixture was dissolved in dioxane (250 mL) and water (80 mL) and 2M sodium hydroxide solution (100 mL) was added. The mixture was stirred for 12 hours and then the pH was adjusted to pH 1-3 with concentrated hydrochloric acid. The dioxane was removed by evaporation and the product was extracted into dichloromethane. The organic layer was dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 30% ethyl acetate / 70% hexane) to give 2- (4-bromobenzenethio) -l. -cyclohexane-1-carboxylate (contaminated with cyclohexene-1-carboxylate). 1-Hydroxybenzotriazole (1.9 grams, 14 mmol) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide were added (2.69 grams, 14 mmol) was added to a stirred solution of 2- (4-brornobenzenethio) -l-cyclohexane-1-carboxylate (3.69 grams, 11.6 mrnol) in dimethyl formamide (50 ml) at room temperature. After 30 minutes, hydroxylamine hydrochloride (3.25 grams, 47 mmol) and triethylamine (9.7 mL, 70 mmol) were added and the mixture was stirred for 12 hours. The solvent was removed and the reaction mixture was extracted into water with ethyl acetate. The organic extracts were concentrated and the crude mixture was purified by chromatography on silica gel (elution with 98% dichloromethane / 2% methanol) to yield N-hydroxy-2- (4-bromobenzenethio) -cyclohexane-1. -carboxamide. Acid -chloroperbenzoid (273 mg, 0.8 mrnol of 50% pure solid) was added to a stirred solution of N-hydroxy-2 ~ (4-bromobenzenethio) -cyclohexane-1-carboxamide (290 mg, 0.88 mmol) in dichloromethane (5 mi) to D ° C. After 2 hours, the mixture was diluted with additional dichloromethane and washed with brine. The organic layer was dried (sodium sulfate) and concentrated. The crude mixture was purified by chromatography on silica gel (elution with 98% dichloromethane / 2% rnetanol), provided with N-hydroxy-2- (4-bromobenzenesulfoxido) -cyclohexane-1-carboxaraide. Mass spectrum (thermospray): m / Z 346 (MH +). NMR of * H (CDCl 3, 400 MHz, ppm) d 10.50 (broad s, 7.70 (d, 2H), 7.55 (d, 2H), 2.95 (m, 1H9, 2.80 (, 1H), 2.20-2.00 (m, 2H), 1.90-1.10 (, 6H).

EXAMPLE 9 N-hydroxy-2- (4-methoxybenzenesulfoxy) -cyclohexane-l-carboxamide The title compound of Example 9 was prepared by a procedure analogous to that described in Example 8. Mass spectrum (earth fogging): m / Z 298.0 (MH +). 1 H NMR, 400 MHz, pprn) d 7.60 (d, 2H), 7.10 (d, 2H), 3. 90 (s, 3H), 3.00 (, 1H), 2.90 (, 1H), 2.25 (m, 1H), 2.10-1.40 (rn, 7H).

Claims (11)

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; p is 0 or 1; q is 0, 1 or 2; X, Y and Z are each, independently CR1R2, wherein R * and R2 are each independently hydrogen, Ci-Ce alkyl optionally substituted by (C?-Ce) amino amino, (Ci-CßHio alkyl, alkoxy Ci-Cβ, trifl? Oromethyl, aryl Ce-Cι, heteroaryl Cs-C9 (aryl Ce-Cι) amino, (aryl Cβ-CioHio, aryloxy Ce-Cι (heteroaryl Cs-C9) amino, (heteroaryl Cs-CgHio, heteroaryl Cs -C9, (aryl Ce -Cio) (aryl Ce -Cio), cycloalkyl C3-Ce, hydroxy (Ci-Cβ alkyl (Ci-Ce alkyl) (hydroxymethylene), piperazinyl, (aryl Cedo) (Ci-Cβ alkoxy) , (CS-C9 heteroaryl) (Ci-Cβ alkoxy) (C? -C6 acyl) amino, (C? -Ce) thio acyloxy, Ci-C acyloxy, (Ci-C? Jsulfinyl alkyl, (C aryl) sulphinyl, (C 1 -C 6 alkyl) sphonyl, (C aryl) sulfonyl, amino (C 1-6 alkyl) or (C 1 -C 4 alkyl) amino; C 2 -C e alkenyl, (C 6 -C 6 aryl)
1. Cι) (C6-alkenyl), (C5-C9 heteroaryl) (C2-6 alkenyl), C2-C6 alkynyl, (C ar-Cι aryl) (C2-C alqu alkynyl), (C5-C9 heteroaryl) (C2- alkynyl C6), (C 1 -Ce) amino alkyl, (C 1 -C 3 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, (C -C 3 alkyl) (difluoromethylene), (C 1 -C 3 alkyl) (difluoromethylene) (alkyl
2. C1-C3) (difluoromethylene (Ci-C3 alkyl), Ce-C aryl, C5-C9 heteroaryl, (aryl Ce-Cio) amino, (C-CioHio aryl, aryloxy Ce-Cio, (C5-C9 heteroaryl) arnino, (C5-C9 heteroaryl) thio, Cs-C9-heteroaryloxy, C3-C3 cycloalkyl, (C1-Ce-1-hydroxymethylene alkyl, piperidyl, (Ci-C-alkyl, piperidyl, (acyl C? ~ Ce) amino, (acyl C? -Ce) thio, acyloxy Ci-C, R3 (Ci-C? alkyl), wherein R3 is (acyl Ci-C and Ipiperazine, (aryl C &-C.sub.10 -piperazine) , (C5-C9 heteroaryl) pi-erazine, (Ci-C-alkyl) piperazino, (aryl Ce-Cio) (Ci-Cs alkyl) pi-erazino, (CS-C9 heteroaryl) (Ci-Ce alkyl) piperazino, morpholino , tiornorfolino, piperidino, pyrrolidino, piperidyl, (Ci-Ce) piperidyl, (aryl Ce-Cι-piperidyl, (heteroaryl Cs-C) piperidyl, (Ci-C-alkyl) piperidyl (Ci-C-alkyl), (aryl Cß-Cio)? Iperidyl (Ci-C alkyl), (C5-C9 heteroaryl), (Ci-Ce) piperidyl acyl, or a group of formula where r is 0 to 6; D is hydroxy, Ci-Ce alkoxy or NR * RS, in which R4 and R5 are each independently selected from the group consisting of hydrogen, Ci-Ce alkyl optionally substituted by (Ci-C-e-piperidyl) alkyl, (C ar-C ar aryl) Ipiperidyl, heteroa < ril Cs-C9) iperidyl, aryl Ce-Cι, heteroaryl C5-C9, (aryl Ce-Cι) (aryl Ce-Cι) or cycloalkyl C 3 -C 6; piperidyl, (C 1 -C 4 alkyl) piperidyl, (aryl Ce-C10 Ipiperidyl, (heteroaryl Cs-C9) piperidyl, (acyl Ci-C 1 piperidyl, aryl Ce-Cι, hete roa rilo C5-C9, (aryl Ce-Cι) (aryl Ce-Cι), cycloalkyl C 3 -Ce, R3 (C2 -Ce alkyl), (alkyl)
3. Ci-Cβ) (CHR6) (Ci-Ce alkyl), wherein R6 is hydroxy, Ci-Cß acyl, Ci-C alkoxy, pipericino, (Ci-C acyl) arnino, (Ci-CßRio alkyl, (aryl Ce -C 0) thio, (Ci-C-alkylsulfinyl), (C-C-cyclobisulfinyl aryl, (Ci-C-alkylsulfoxy) alkyl, (C aryl-C 1-4 -alkyl, amino, (C 1-4 -alkyl) alkyl, ( alkyl Ci-Ce) 2-lamino, (acyl Ci -Ce Ipiperazine, (Ci-Ce alkyl) p? peracino, (aryl Ce-Cio) (Ci-Ce alkyl) piperazino, (Cs-C9 heteroaryl) (Ci-C e alkyl) ) piperazine, orfolin, thiomorpholino, piperidino or pyrrolidino, R7 (Ci-Cs alkyl), (Ci-Cs alkyl) (CHR?) (Ci-Cs alkyl), wherein R7 is piperidyl or (Ci-Ce alkyl) Ipiperidyl, and CH (Rβ) C0R9, wherein Rβ is hydrogen, Ci-Cß alkyl, (Cß-Cι aryl) (Ci-C alquilo alkyl), (Cs-C * heteroaryl) (Ci-Cß alkyl) (Ci alkyl) -Cß) thio (Ci-C-alkyl), (C-C10-aryl) thio (Ci-C-alkyl), (Ci-Ce) sulfinyl-alkyl (Ci-Ce alkyl), (Ce-C-aryl) sulfinyl (Ci-alkyl) Ce), (Ci- C6 alkyl) sulfonyl (Ci-C alkyl) ), (aryl Ce -Cio) sulfonyl (alkyl)
4. Ci-Cß), hydroxy (Ci-Cß alkyl), amino (Ci-Cß alkyl), (Ci-Cß alkyl) amino (Ci-Cß alkyl), ((Ci-C) amino) alkyl) 2 (C alquilo alkyl) Ce), Ri? RHNCO (Ci-Ce alkyl) or Ci-C 1 Rioocoalkyl, wherein Rio and R 11 are each independently selected from the group consisting of hydrogen, Ci-C-alkyl (aryl Ce -Cio)
5. (Ci-Cß alkyl) and (Cs -C heteroaryl) (Ci-Cß alkyl); and R9 is R120 or R12R13N, wherein * 2 and R * 3 are each independently selected from the group consisting of hydrogen, Ci-Cß alkyl, (Ce-C aryl) (Ci-Cß alkyl) and (C5- heteroaryl) C9) (Ci-C alkyl); and Ar is aryl Ce -Cio or C5-C heteroaryl, each of which may be substituted by C 1 -C 10 aryl, C 5 -C 9 heteroaryl, (Ce-C aryl) (C 2 -C 4 alkyl), (C 5 -C 9 heteroaryl) (C2-C2 alkenyl), C2-C2 alkynyl, (C6-Cio aryl) (C2-Ce alkynyl) or (C5-C9 heteroaryl) (C2-Ce alkynyl), optionally substituted by Ci-C alkyl, (Ci-alkyl) Ce lamino, (Ci-CßHio alkyl, Ci-Cß alkoxy, trifluoromethyl, C -C-Cι aryl, Cs-C9 heteroaryl, (C ar-Cιo) arylamino, (Cß-CioKio aryl, C -C-C ar aryloxy, Cs-C9 heteroaryl )Not me,
6. (Cs-C9 heteroaryl) thio, C5-C9 heteroaryloxy. (aryl Ce -Cio) (aryl Ce -Cio), cycloalkyl C3-Ce, hydroxy (Ci-C-alkyl,
7. (Ci-Cβ alkyl (hydoxymethylene), piperazinyl, (C aryl Cιι) (Ci-Cβ alkoxy), (C5-C9 heteroaryl) (Ci-C alkoxy), (Ci-Cß acyl) amino, (Ci-CßHio acyl) , Ci-C acyloxy, Ci-C-alkylsulfinyl, (aryl Ce-Cι) sulfinyl, (Ci-Ce alkyl) sulfonyl, (aryl Ce-Cι) sulfonyl, amino, (Ci-C alquilo alkyl) amino, (( Ci-C alkyl) 2) amino or R 3 -alkyl, wherein R 3 is define as above; halogen, hydroxy, Ci-C6 alkyl or Ci-Ce alkoxy, wherein the alkyl or alkoxy groups may be optionally substituted by Ci-C-lamino alkyl, Ci-Celtio alkyl, Ci-C alkoxy, trifluoromethyl, aryl Ce ~ Cι-heteroaryl Cs -C9, (C aryl-C-arylamino, (Ce-Ciolthio aryl, C-Cio aryloxy, Cs-C9 heteroaryl), (Cs-C9Hι heteroaryl, Cs -C 9 heteroaryloxy, (Ce-Cι aryl) ( aryl Ce -Cio) / cycloalkyl C3-Ce, hydroxy (Ci-C-alkyl), (Ci-C-alkyl) (hydroxymethylene), piperazinyl, (aryl Ce-Cio), (alkoxy Ci-C), (C5-heteroaryl C9) (alkoxy Ci-C), (acyl Ci-C) arnino, (acyl Ci -Celtium, acyloxy Ci-Ce, (Ci-Ce) s-l-lylyl, (aryl Ce-Cι) sulfinyl, (Ci-C-alkyl) -phonyl, (aryl Ce-Cι) sulfonyl, amino, (Ci-alkyl) -C-amino, or ((Ci-C6 alkyl) 2) aio; C2-C2-alkenyl (Ce-C6 aryl) (C2-Ce alkenyl), (CS-C9 heteroaryl) (C2-C6-alkenyl), C2-alkynyl C6, (aryl
8. Cβ-Cι (C 2 -C 6 alkynyl), (C 5 -C 9 heteroaryl) (C 2 -C 1 alkynyl, C alquilo -Cβ) amino, (C?-Ce) alkyl, C -C-C alco alkoxy, trifluoromethyl, ( Ci-C-alkyl) (difluoromethylene), (C1-C3-alkyl) (difluoromethylene) (C-C3-alkyl), C-C-aryl, C5-C9-heteroaryl, (C2-C2-aryl) amino, (C2-C-aryl) thio , C2-C6 aryloxy, (Cs-C9 heteroaryl) amino, (Cs-C9 heteroaryl) thio, C5-C9 heteroaryloxy, C3-C6 cycloalkyl, (Ci-C) alkyl (hydroxymethylene), piperidyl, (Ci-C alkyl) piperidyl, (C 1 -C 6 acyl) amino, (acyl C -Celtium, acyloxy Ci -Ce, R 3 (Ci-Cß alkyl) or R 3 (Ci-C alkoxy), wherein R 3 is (C-C ac acyl) piperazine , (aryl Ce -Cio) piperazino, (heteroaryl Cs-
9. C 9 Ipiperazine, (C 1 -C 4 alkylpiperazine, (C 1 -C 6 aryl) (Ci-Ce alkylpiperazine, (CS-C heteroaryl) (Ci-Cβ alkylpiperazine, orpholino, thionorphoryl, piperidino, pyrrolidino, piperidyl, -Ce Ipiperidyl, (aryl C & C10 -piperidyl, (C5-C9 heteroaryl Ipiperidyl, Ci-C-alkylpiperidyl (Ci-C-alkyl), (aryl-Cyclo) piperidyl (Ci-Cß alkyl), Heteroaryl Cs -C9 ) iperidyl (Ci-C e alkyl), cyclo-Ci-piperidyl acyl, or a group of formula wherein r and D are as defined above; provided that when q is 1 and X and Y are CR * R2, in which one of R1 or R2 must be hydrogen, p must be 1; provided that, when q is 0, the compound of formula I is not bicyclic; and provided that, when the dashed line of formula I represents a double bond, R2 does not exist. 2. The compound according to claim 1, wherein q is 0 or 2. 3. The compound according to claim 1, wherein q is 0 or 1. 4. The compound according to claim 1, wherein which n is 2. 5. The compound according to claim 1, wherein
10. X and Y are both CRiR2, with R and R2 being hydrogen 6. The compound according to claim 1, wherein Ar is rnetoxyphenyl, phenoxyphenyl, benzoxyphenyl or halofen lo. 7. The compound according to claim 1, wherein q is 0, p is 1, m is 2, X and Y are CR R2, where R1 and R2 are hydrogen, and Ar * is rethoxyphenyl, phenoxyphenyl or benzoxyphenyl 8.- The compound according to claim 1, wherein q is 0, p is 0, m is 2, X and Y are CR1 R2, where R1 and R2 are hydrogen, and Ar is r-ethoxyphenyl, phenoxyphenyl or benzoxy phenyl 9.- A pharmaceutical composition for (a) 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 involving the production of tumor necrosis factor (TNF) or, (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human being, comprising a of a compound according to the claim 1 or a pharmaceutically acceptable salt thereof, effective in said treatments and a pharmaceutically acceptable carrier. 10. The use of an effective amount of a compound according to claim 1 or of one of its pharmaceutically acceptable salts, in the preparation of compositions for the inhibition of, (a) matriatelee (a) rnetaloproteinases or, (b) the production of tumor necrosis factor (TNF) in a mammal, including a human.
11. 11. The use of a compound according to claim 1 or one of its pharmaceutically acceptable salts, in the preparation of compositions for treating a disorder selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermal isis, pollens, scleritis, and other diseases characterized by activity of marketal metalloprotinasinases, AIDS, sepsis, septic shock, and other diseases that involve the production of tumor necrosis factor (TNF) in a mammal, including a human being.