MXPA99007385A

MXPA99007385A - Arylsulfonyl hydroxamic acid derivatives

Info

Publication number: MXPA99007385A
Application number: MXPA/A/1999/007385A
Authority: MX
Inventors: Francis Mcclure Kim
Original assignee: Pfizer Inc
Priority date: 1997-02-11
Filing date: 1999-08-10
Publication date: 2000-07-01

Abstract

A compound of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and Q are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Description

DERIVATIVES OF ARI SULFONIL HYDROXAMIC ACID BACKGROUND OF THE INVENTION The present invention relates to arylsulfonyl hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a disorder selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, vesicular epidermolysis, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, septic shock and other diseases that involve the production of TNF. In addition, the compounds of the present invention can be used in combination treatment with non-steroidal antiinflammatory drugs (hereinafter referred to as NSAIDs) and analgesics for the treatment of arthritis and, in combination 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 such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor.

There are a series of enzymes that produce the decomposition of structural proteins and that are structurally similar metalloproteases. Metalloproteinases that degrade the matrix, such as gelatinase, stromelysin and collagenase, are involved in the degradation of the tissue matrix (eg collagen collapses) and have been linked to many pathological disorders that involve an abnormal metabolism of connective tissue 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 (e.g., Paget's disease and osteoporosis), tumor metastasis or tumor invasion, as well as HIV infection fj. Leuk Biol .. 52. (2): 244-248, 1992). The tumor necrosis factor is known to be involved 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 observed in septicemia and septic shock (EC, Spooner et al., Clinical Immunology and Immunopathologv, 1992, 62, S11).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of the formula or pharmaceutically acceptable salts thereof, wherein the broken line represents an optional double bond; X is carbon, oxygen or sulfur; And it is carbon, oxygen, sulfur, SO, SO2 or nitrogen; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are selected from the group consisting of hydrogen, Ci-Cß alkyl optionally substituted by one or two groups selected from (C 1 -C 4 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, halogen, C6-C? aryl, C5-C9 heteroaryl, (C6-C? 0 aryl) amino, (C6-C? 0 aryl) thio, C6-C10 aryloxy, (Cs-Cgjamino heteroaryl, (C5 heteroaryl -Cg) thio, C5-Cg heteroaryloxy, (C6-C6o aryl) (C6-C6o aryl), C3-C6 cycloalkyl, hydroxy, piperazinyl, (Ce-Cio aryl) (C6-C6 alkoxy), (C5-C9 heteroaryl) (Ci-Cß alkoxy), (C6-C6) acyl amino, (C-Cß-tyl acyl, Ci-Cß acyloxy, (C?-C6 alkyl) sulfinyl, (C6-C? 0 aryl) sulfinyl , (C 1 -C 6 alkyl) sulfonyl, (C 6 -C 0 aryl) sulfonyl, amino, (C 1 -C 6 alkyl) amino or ((C 1 -C 6 alkyl) amino) 2; C2-C6 alkenyl, (C6-C? 0 aryl) (C2-C6 alkenyl), (C5-C9 heteroaryl) (C2-C6 alkenyl), C2-C6 alkynyl, (C? -C-aryl) (C2- alkynyl) C6), (C5-C9 heteroaryl) (C2-C2-alkynyl), (C-Cinylamine alkyl, (C1-C6 alkyl) thio, C6-C6 alkoxy, perfluoro (C6-C6 alkyl), C6-C6 aryl , C5-C9 heteroaryl, (C6-C? o aryl) apnino, (C6-C? o) thio aryl, C6-C? 0 aryloxy, (Cs-Cgjamino heteroaryl, (C5-Cg heteroaryl) thio, C5-heteroaryloxy C9, C3-C6 cycloalkyl, (C 1 -C 6 alkyl) (hydroxymethylene), piperidyl, (C 1 -Ce) piperidyl alkyl, (C -C 6 acyl) amino, (C 1 -C 6 acyl) thio, C 6 -C 6 acyloxy, R 10 (C 1 -C 6 alkyl), wherein R 10 is (C 1 j piperazino acyl, (C 6 -C 6 aryl) piperazino, (C 5 -Cg heteroaryl) piperazino, (C 1 -C 6 alkyl) piperazino, (C 6 aryl) C? 0) (C? -C6 alkyl) piperazino, (C5-C8 heteroaryl) (Ci-C? Xpiperazino alkyl, morpholino, thiomorpholino, pyrrolidino, piperidyl, (CrC? I piperidyl alkyl, (C6-C o aryl) piperidyl, (Cs- heteroaryl Cgjpiperidyl, (C 1 -C 6 alkyl) piperidyl (CrC 6 alkyl), (C 6 -C 6 aryl) piperidyl (CrC 6 alkyl), (C 5 -C 9 heteroaryl) piperidyl (C 1 -C 6 alkyl) or (acyl) C? -C6) piperidyl; Or a group of formula wherein n is from 0 to 6; and is 0 or 1; W is oxygen or NR24, where R24 is hydrogen or C? -C6 alkyl; Z is OR11 or NR24R11, R24 being defined as above and R11 is as defined below; azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a diazabicycloalkyl ring with bridge selected from the group consisting of c wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; Y wherein each heterocyclic group may be optionally substituted by one or two groups selected from hydroxy, C? -C6 alkyl, C? -C alkoxy, C1-C10 acyl, C1-C10 acyloxy, C6-C? aryl, C5-C9 heteroaryl , (C 6 -C 0 aryl) (C 1 -C 6 alkyl), (C 5 -Cg heteroaryl) (C 1 -C 6 alkyl), hydroxy (C 1 -C 6 alkyl), (C 6 -C 6 alkoxy) (C 1 -C 6 alkyl) C6), (C6-C6 acyloxy) (C6-C6 alkyl), (alkyl (C 1 -C 6 alkyl) thio (C 1 -C 6 alkyl), (C 6 -C 0 aryl) thio, (C 6 -C 0 aryl) thio (C 1 -C 6 alkyl), R 12 R 13 N, R 12 R 13 NS 2, R 12 R 13 NCO, R 12 R 13 NCO ( C6-C6 alkyl), R12 and R13 each being independently hydrogen, C1-C6 alkyl, C6-C6 aryl, Cs-Cg heteroaryl, (C6-C aryl) (C6-C6 alkyl) or (C5-C9 heteroaryl) (C6-C6 alkyl) or R12 or R13 can be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; R14SO2, R14SO2NH, where R14 is trifluoromethyl, C1-C6 alkyl, C6-C10 aryl, C5-C9 heteroaryl, (C6-C? Aryl) (C?-C6 alkyl) or (C5-C9 heteroaryl) (C1-6 alkyl) Cß); R 15 CONR 12, where R 12 is as defined above and where R 15 is hydrogen, C -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 0 aryl, C 5 -C 9 heteroaryl, (C 6 -C 10 aryl) (C 1 -C 6 alkyl) (C6-C6 aryl) (C6-C6 alkoxy) or (C5-C8 heteroaryl) (C6-C6 alkyl); R16OOC, R16OOC (C? -C6 alkyl), where R16 is C? -C6 alkyl, C6-C? Aryl, C5-C9 heteroaryl, (C6-C? 0 aryl) (C? -C6 alkyl), 5-indanyl , CHR17OCOR18, where R17 is hydrogen or C -Cß alkyl and R18 is C -Cß alkyl, C?-C6 alkoxy or C6-C? Ar aryl; CH2CONR19R20, wherein R19 and R20 are each, independently, hydrogen or Ci-Cß alkyl or can be taken together with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; or R21O (C? -C6 alkyl), R21 H2N (CHR22) CO being, where R22 is the side chain of a natural D- or L-amino acid; R11 is hydrogen, aryl C6-C? 0, heteroaryl C5-C9, (aryl C6-C? 0) (C alquilo-C6 alkyl), (C5-Cg heteroaryl) (C?-C6 alkyl), (C-C6 alkyl) (C6-C? ar aryl) (C?-C6 alkyl), (C CC alquilo alkyl) ( C5-Cg heteroaryl) (C? -C6 alkyl), 5-indanyl, CHR17OCOR18 or CH2CONR19R20, where R17, R18, R19 and R20 are as defined above; or R1 and R2, or R3 and R4, or R5 and R6 can be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 can be taken together to form a C3-C6 cycloalkyl ring, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl, or a group of formula wherein R23 is hydrogen, C? -C6 acyl, C? -C6 alkyl, (C6-C? o aryl) (C? -C6 alkyl), (C5-CT heteroaryl) (C? -C6 alkyl) or ( C? -C6 alkyl) sulfonyl; Y Q is C1-C10 alkyl, C6-C6 aryl, (C6-C6 aryloxy) (C6-C6 aryl), (C6-C6 aryl), (C6-C aryl) (C6-aryl) C10), (aryl Ce-Cío) (aryl Ce-Cío) (alkyl Ci-Cß), (Ce-Cι aryl) (CrC 6 alkoxy) (C? -C6 alkyl), (Ce-C o aryloxy) (heteroaryl C5-C9), C5-Cg heteroaryl, (CrC6 alkyl) (C6-C? 0 aryl), (alkoxy (C6-C10 aryl), (C6-C? o aryl) (C? -C6 alkoxy) (C6-C? 0 aryl), (C5-C9 heteroaryloxy) (C6-aryl) Cι), (C?-C6 alkyl) (C5-C9 heteroaryl), (Ci-Cß alkoxy) (C5-C9 heteroaryl), (C6-C? O aryl) (CrC6 alkoxy) (C5-Cg heteroaryl), ( C5-Cg heteroaryloxy) (C5-C9 heteroaryl), (C6-C? o aryloxy) (Ci-C? alkyl), (C5-C9 heteroaryloxy) (C? -C6 alkyl), (CrC6 alkyl) (C6-C aryloxy) ? o) (C6-C10 aryl), (C-C6 alkyl) (C5-C9 heteroaryloxy) (C6-C? aryl), (C-C6 alkyl) (C6-C? 0 aryloxy) (C5-C9 heteroaryl) ), (C 1 -C 6 alkoxy) (C 6 -C 0 aryloxy) (C 6 -C 0 aryl), (C 1 -C 6 alkoxy) (C 5 -C 6 heteroaryloxy) (C 6 -C 0 aryl) or (C 1 alkoxy) -Ce) (C6-C? Ar aryloxy) (C5-C9 heteroaryl), optionally substituted by fluoro, chloro, Ci-Cß alkyl, C Cß alkoxy or perfluoro (C 1 -C 3 alkyl); With the proviso that Z must be substituted when it is defined as azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl, (C? -C? O) acyl piperazinyl, (C? -Ce) alkyl piperazinyl (C6-C? 0 aryl) piperazinyl, (C5-Cg heteroaryl) piperazinyl or a bridged diazabicyclic ring; With the proviso that R7 is different from hydrogen only when R8 is other than hydrogen; With the proviso that R is different from hydrogen only when R5 is other than hydrogen; With the proviso that R3 is distinct from hydrogen only when R4 is other than hydrogen; With the proviso that R2 is distinct from hydrogen only when R1 is other than hydrogen; With the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom can not be directly attached at positions 2 or 6; With the proviso that when X is nitrogen, R4 is not present; With the proviso that when X is oxygen, sulfur, SO, SO2, or nitrogen and when one or more of the group formed by R1, R2, R5 and R6 is a substituent comprising a heteroatom, the heteroatom can not be directly attached at positions 4 or 6; With the proviso that when Y is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R3, R4, R7 and R8 are independently, a substituent comprising a heteroatom, the heteroatom can not be joined directly in positions 3 or 5; With the proviso that when X is oxigen, sulfur, SO or SO2, R3 and R4 are not present; With the proviso that when y is 1 and W is NR24 or oxygen, Z can not be hydroxy; With the proviso that when Y is oxygen, sulfur, SO or S02, R5 and Rd are not present; With the proviso that when Y is nitrogen, R6 is not present; With the proviso that when the dashed line represents a double bond, R4 and R6 are not present; with the proviso that when R3 and R5 are, independently, a substituent comprising a heteroatom when the broken line represents a double bond, the heteroatom can not be directly attached at the X and Y positions; with the proviso that when either the X or Y position is oxygen, sulfur, SO, SO2 or nitrogen, the other of X or Y is carbon; with the proviso that when X or Y are defined by a heteroatom, the dashed line does not represent a double bond; with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 should be defined as the group of formula II. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy" as used herein, includes O-alkyl 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 removal of a hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected independently from each other. the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, alkoxy C Ce aryloxy Ce-C or, 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 by removing a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, midazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected independently from the group formed by fluoro, chloro, trifluoromethyl, C 1 -C 6 alkoxy, C 6 -C 0 aryloxy, trifluoromethoxy, difluoromethoxy and C 1 -C 6 alkyl. The term "acyl" as used herein, unless otherwise indicated, includes a radical of the general formula RCO, wherein R is alkyl, alkoxy (such as methyloxycarbonyl), 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. The term "D- or L-amino acid", as used herein, unless otherwise indicated, includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, asparagine, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine or histidine. The ring positions of formula I, as used herein, are defined below: The preferred configuration of the compound of formula I includes the hydroxamic acid axially disposed in the 2-position. The compound of formula I can have asymmetric centers and, therefore, exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. Preferred compounds of formula I include those in which Y is carbon. Other preferred compounds of the formula I include those in which Q is (C 6 -alkoxy) (C 6 -C 6 aryl), (C 6 -C 0 aryl) (C 6 -C 6 alkoxy) (aryl Cedo) or (aryl) Ce-Cι) (C?-C6 alkoxy) (CrC 6 alkyl), each terminal aryl group being optionally substituted by fluoro. Other preferred compounds of formula I include those wherein R 2, R 3, R 6, R 7, and R 9 are hydrogen. More preferred compounds of formula I include those in which Y is carbon, Q is (Ci-Cβ alkoxy) (C6-C ?aryl aryl), (C6-C ?aryl aryl) (Ci-CQ alkoxy) (C6 aryl) C? O) or (C6-C? Aryl) (Ci-C? Alkoxy) (C-C? Alkyl).

Specific preferred compounds of formula I include the following: (2R, 4R) -1 - [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; Methyl ester of (2R, 4R) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-p-peridine-4-carboxylic acid; (2R, 4R) -1 - [3- (4-fluorophenoxy) -propane-1-sulphonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; Methyl ester of (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; Isopropyl ester of (2R, 3S) - acid. { 1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl-carbamic acid; 3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; 3- (S) -4- [4- (4-Fluorobenzyloxy) benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 4S) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -4-hydroxy-piperidine-2-carboxylic acid; and (2R, 4R) -1- (4-methoxybenzenesulfonyl) -4- (piperazine-1-carbonyl) -piperidine-2-carboxylic acid hydroxyamide hydrochloride; Other compounds of the invention include: (3S) -4- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; (3S) -2,2-Dimethyl-4- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxyamide; (3S) -2,2-Dimethyl-4- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxyamide; Hydroxyamide of (3S) -4- acid. { 4- [2- (4-fluorophenyl) -ethoxy] -benzenesulfonyl} -2,2-dimethyl-t-morpholine-3-carboxylic acid; (3S) -2,2-Dimethyl-4- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxyamide; (3S) -4- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; (3S) -2,2-Dimethyl-4- [4- (5-trifluoromethyl-1-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxyamide; (3S) -2,2-Dimethyl-4- [4- (1 H -tetrazol-5-ylmethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxyamide; Methyl ester of acid (2R, 3S) -. { 1- [4- (2-Chloro-thiazol-5-ylmethoxy) benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 2-hydroxycarbamoyl-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] -piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 2-hydroxycarbamoyl-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] -piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} -carbamic; Methyl ester of (2R, 3S) -1- acid. { 4- [2- (4-fluorophenyl) -ethoxy] -benzenesulfonyl} -2-hydroxycarbamoyl-piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 2-hydroxycarbamoyl-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 1- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -2-hydroxylcarbamoyl-piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 2-hydroxycarbamoyl-1- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidin-3-yl} -carbamic; Methyl ester of acid (2R, 3S) -. { 2-hydroxycarbamoyl-1- [4- (1 H-tetrazol-5-ylmethoxy) -benzenesulfonyl] -piperidin-3-yl} -carbamic; (2R, 3S) -1- [4- (2-Chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -3-hydroxy-1- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -piperidin-2-carboxylic acid; Hydroxyamide of (2R, 3S) -3-hydroxy-1- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; (2R, 3S) -1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -1- acid. { 4- [2- (4-fluorophenyl) ethoxy] -benzenesulfonyl} -3-hydroxy-piperidine-2-carboxylic acid; (2R, 3S) -3-hydroxy-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; (2R, 3S) -1- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R, 3S) -3-hydroxy-1- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -3-hydroxy-1- [4- (1 H-tetrazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; Hydroxyamide of (2R, 3S) -1- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid; (2R, 3S) -3-hydroxy-3-methyl-1- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -3-hydroxy-3-methyl-1- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; (2R, 3S) -1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -1- acid. { 4- [2- (4-fluorophenyl) -ethoxy] -benzenesulfonyl} -3-hydroxy-3-methyl-piperidin-2-carboxylic acid; Hydroxyamide of (2R, 3S) -3-hydroxy-3-methyl-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; (2R, 3S) -1- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 3S) -3-hydroxy-3-methyl-1- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; (2R, 3S) -3-hydroxy-3-methyl-1- [4- (1 H -tetrazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; (3R) -4- [4- (2-Chloro-thiazol-5-ylmethyloxy) -benzenesulfonyl] -2,2-dimethyl-morphoin-3-carboxylic acid hydroxyamide; (3R) -2,2-Dimethyl-4- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -2,2-Dimethyl-4- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; Hydroxyamide of (3R) -4- [4- (4-fIuorobenzyloxy] -benzenesulfonyl] -2,2-dimethyl-morphoin-3-carboxylic acid; Hydroxyamide of (3R) -4-. {4- [ 2- (4-fluorophenyl) -ethoxy] -benzenesulfonyl} -2,2-dimethyl-morpholine-3-carboxylic acid (3R) -2,2-dimethyl-4- [4- (2-pyridine) hydroxyamide; 4-yl-ethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid (3R) -4- [4- (benzothiazol-2-ylmethoxy) -benzenesulfonyl] -2,2-dimethyl-morpholine-3-hydroxyamide -carboxylic acid (3R) -2,2-dimethyl-4- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -2 hydroxyamide 2-dimethyl-4- [4- (1jH-tetrazol-5-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid (2R, 4R) -1- [4- (2-chloro-thiazole-5- ylmethoxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; (2R, 4R) -2-Hydroxycarbamoyl-1 - [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid; (2R, 4R) -2-Hydroxycarbamoyl-1- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid; Acid (2R, 4R) -1 -. { 4- [2- (fluorophenyl) -ethoxy] -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; Acid (2R, 4R) -2-hydroxycarbamoyl-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid; (2R, 4R) -1- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid; Acid (2R, 4R) -2-hydroxycarbamoyl-1 - [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid; (2R, 4R) -2-Hydroxycarbamoyl-1 - [4- (1 jH-tetrazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid; (3R) -4- [4- (2-Chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -3-methyl-morpholine-3-carboxylic acid hydroxyamide; (3R) -3-Methyl-4- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -3-Methyl -4- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -4- [4- (4-Fluorobenzyloxy) benzenesulfonyl] -3-methyl-morpholine-3-carboxylic acid hydroxyamide; Hydroxyamide of (3R) -4- acid. { 4- [2- (4-fluorophenyl) -ethoxy] -benzenesulfonyl} 3-methyl-morpholine-3-carboxylic acid; (3R) -3-Methyl -4- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -4- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -3-methyl-morpholine-3-carboxylic acid hydroxyamide; (3R) -3-Methyl -4- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (3R) -3-Methyl -4- [4- (1 H -tetrazol-5-ylmethoxy) -benzenesulfonyl] -morpholine-3-carboxylic acid hydroxyamide; (2R) -1- [4- (2-Chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide; (2R) -2-Methyl-3-oxo-1- [4- (thiazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; (2R) -2-Methyl-3-oxo-1- [4- (pyridin-4-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; (2R) -1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R) -1- acid. { 4- [2- (4-Fluorophenyl) -ethoxy] benzenesulfonyl} -2-methyl-3-oxo-piperidine-2-carboxylic acid; Hydroxyamide of (2R) -2-methyl-3-oxo-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; (2R) -1- [4- (Benzothiazol-2-ylmethoxy) -benzenesulfonyl] -2-methyl-3-oxo-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R) -2-methyl-3-oxo-1- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; Hydroxyamide of (2R) -2-methyl-3-oxo-1- [4- (1 H -tetrazol-5-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; Hydroxyamide of (2R, 4S) -1- (4-benzyloxy-benzenesulfonyl) -4-butylaminomethyl-4-hydroxy-piperidine-2-carboxylic acid; (2R ,. 4S) -4-Butylaminomethyl-1- [4- (4-fluorobenzezyloxy) -benzenesulfonyl] -4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2 ^ 4S) -4-Benzylamino-1- (4-benzyloxy-benzenesulfonyl) -piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2Rj 4S) -4- benzylamino-1- [4- (4-fluororbenzyloxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide; (2R) -1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl) -4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R ^ 4R) -1- (4-benzyloxy-benzenesulfonyl) -4-oxo-piperidine-2-carboxylic acid; Hydroxyamide of (2 ^ 4R) -1- [4- (4-flurorobenzyloxy) -benzenesulfonyl] -4-hydroxy-pyridine-2-carboxylic acid; Hydroxyamide of (2R) -1- [4- (4-flurorobenzyloxy) -benzenesulfonyl] -4-methyl-piperazine-2-carboxylic acid; Hydroxyamide of the acid (2Rj 5S) -1- [4- (4-flurorobenzyloxy) -benzenesulfonyl] -5-hydroxy-piperidine-2-carboxylic acid; (2R 5S) -1- (4-benzyloxy-benzenesulfonyl) -5-hydroxy-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R, 5S) -1- (4-benzyloxy-benzenesulfonyl) -5-hydroxy-p-peridine-2-carboxylic acid; Hydroxyamide of (2R, 5S) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -5-hydroxy-piperidine-2-carboxylic acid; (2R? 3S) -1- (4-benzyloxy-benzenesulfonyl) -3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2FÍ.4S) -1- (4-benzyloxy-benzenesulfonyl) -4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of (2R ^ 4S) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -4-hydroxy-piperidine-2-carboxylic acid; Hydroxyamide 1- (4-butoxy-benzenesulfonyl) -3- (morpholine-4-carbonyl) -piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of the acid 1 - [4- (4- (4-fluorobenzyloxy) -benzenesulfonyl) -3- (morpholine-4-carbonyl) -piperidine-2-carboxylic acid; Hydroxyamide of the acid 1 - [3- (fluoro-benzyloxy) propane-1-sulfonyl] -3- (morpholine-4-carbonyl) -piperidine-2-carboxylic acid; Hydroxyamide of 1- (4-butoxy-benzenesulfonyl) -3- (pyrroidin-1 -carbonyl) -piperidine-2-carboxylic acid hydroxyamide; Hydroxyamide of the acid 1 - [4- (4-fluorobenzyloxy) -benzenesulfonyl) -3- (pyrrolidine-1-carbonyl) -piperidine-2-carboxylic acid; Hydroxyamide of 1 - [3- (4-fluorobenzyloxy) -propane-1-sulfonyl] -3- (pyrrolidine-1-carbonyl) -piperidine-2-carboxylic acid hydroxyamide; and 1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbomoyl-piperidine-4-carboxylic acid. 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, vesicular epidermolysis, Scleritis, in combination with NSAIDs and conventional analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, Septicemia, septic shock and other diseases that involve the production of tumor necrosis factor (TNF) or (b) inhibit metalloproteinases of the matrix or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, effective in said treatments and a vehicle pharmaceutically acceptable. The present invention also relates to a method for inhibiting (a) matrix metalloproteinases or (b) the production of tumor neocrosis factor (TNF) in a mammal, including a human being, which comprises administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a disorder selected from arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, vesicular epidermolysis, scleritis, the compounds of formula I being used in combination with conventional NSAIDs and analgesics. and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, 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 otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R9, n and Ar in the reaction schemes and the description that follows are as described above.

PREPARATION 1 XVI 10 VI 20 PREPARATION 2 XVIII XVII SAW twenty SCHEME 1 SCHEME 2 IX Vile SCHEME 3 XII XI X SCHEME 4 XXII fifteen XXI XX SCHEME 4 (continued) XX XIX XIII SCHOOLS XXVI XXV XXIV SCHEME 5 (continued) xxrv XXIII 4 Preparation 1 refers to the preparation of intermediates of formula VI. The compounds of formula VI are converted into compounds of formula I according to the procedure of Scheme 1. The starting materials of formula XVI can be prepared according to procedures well known to those skilled in the art. In reaction 1 of Preparation 1, the compound of formula XVI is converted to the corresponding hydroxy ester compound of formula VI by first reacting XVI with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature of about 20 ° C at about 30 ° C, preferably at room temperature. The compound formed in this way is squently reacted with a compound of the formula. wherein R 25 is carbobenzyloxy, C 1 -C 6 alkyl, benzyl, allyl or tere-butyl, in the presence of sodium hexamethyl disilazane and a solvent mixture of tetrahydrofuran-dimethylformamide at a temperature of about -20 ° C to about 20 ° C, preferably at about 0 ° C, forming the hydroxyester compound of formula VI. Preparation 2 refers to an alternative process for preparing compounds of formula VI. The starting materials of formula XVIII can be prepared according to procedures well known to those skilled in the art. In reaction 1 of preparation 2, the an amine compound of formula XVIII, wherein R25 is as defined above, is converted to the corresponding arylsulfonylamine compound of formula XVII by (1) reaction of XVIII with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent, such as methylene chloride, tetrahydrofuran or dioxane, at a temperature from about 20 ° C to about 30 ° C, preferably at room temperature, (2) reaction of the compound thus formed with a compound of formula in the presence of sodium hexamethyl disilazane and a solvent mixture of tetrahydrofuran-dimethylformamide at a temperature from about -20 ° C to about 20 ° C, preferably at about 0 ° C and (3) squently reacting the compound thus formed with ozone in a solution of methylene chloride-methanol at a temperature of about -90 ° C to about -70 ° C, preferably at -78 ° C. The unstable ozonide compound formed in this way is then reacted with triphenylphosphine to form the arylsulfonylamine compound of formula XVII. In reaction 2 of preparation 2, the arylsulfonylamine compound of formula XVII is converted into the corresponding hydroxy ester compound of formula VI by reaction of XVII with a compound of formula wherein W is lithium, magnesium, copper or chromium. Scheme 1 refers to the preparation of compounds of formula II, which are compounds of formula I wherein X and Y are carbon; R4, R6 and R7 are hydrogen; and the dashed line between X and Y does not exist. In reaction 1 of scheme 1, the compound of formula VI, in which the protecting group R 25 is carbobenzyloxy, C 1 -C 6 alkyl, benzyl, allyl or tertbutyl, is converted to the corresponding morpholinone compound of formula V by lactonation and Subsequent transposition of Claisen of the compound of formula VI. The reaction is facilitated by the removal of the protecting group R25 of the compound of formula VI which is carried out under conditions suitable for this particular protecting group R25 in use. Such conditions include: (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, wherein R25 is carbobenzyloxy, (b) saponification wherein R25 is lower alkyl, (c) hydrogenolysis in ia that R25 is benzyl, (d) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, wherein R25 is tert-butyl, or (e) treatment with tributyl tin hydride and acetic acid in the presence of bis chloride. (triphenylphosphine) palladium (II) as a catalyst in which R25 is allyl.

In reaction 2 of scheme 1, the morpholine compound of formula V is converted to the carboxylic acid compound of formula IV by reaction of V with lithium hexamethyldisilazane in an aprotic solvent, such as tetrahydrofuran, at a temperature of about -90 ° C. at about -70 ° C, preferably at about -78 ° C. Trimethylsilyl chloride is then added to the reaction mixture and the solvent, tetrahydrofuran, is removed in vacuo and replaced with toluene. The resulting reaction mixture is heated to a temperature of about 100 ° C to about 120 ° C, preferably to about 110 ° C and treated with hydrochloric acid to form the carboxylic acid compound of formula IV. In reaction 3 of scheme 1, the carboxylic acid compound of formula IV is converted into the corresponding hydroxamic acid compound of formula III by the treatment of IV with 1- (3-dimethylaminopropyl) -3-ethylcarbodimamide and -hydroxy benzotriazole in a polar solvent, such as dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a period of about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form may be used, in which the hydroxy group is protected as tert-butyl, benzyl or allylic ether, in the presence of hexafluorophosphate of (benzotriazol-1-yloxy) -tris (dimethylamino) phosphonium and a base, such as N-methylmorpholine. The removal of the hydroxylamine protecting group is carried out by hydrogenolysis for a benzyl protecting group or by treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group can be removed by treatment with tributyltin hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride. N, O-bis (4-methoxybenzyl) hydroxylamine can also be used as a protected hydroxylamine derivative, in which deprotection is achieved using a mixture of methanesulfonic acid and trifluoroacetic acid. In reaction 4 of scheme 1, the hydroxamic acid compound of formula III is converted, if desired, to the corresponding piperidine compound of formula II by the treatment of III with hydrogen and a hydrogenation catalyst, such as 10% palladium. on coal. Scheme 2 refers to the preparation of compounds of formula VII, which are compounds of formula I in which Y is nitrogen; X is carbon; R1, R2, R3, R4, R7 and R8 are hydrogen and R6 is not present. The starting materials of formula IX can be prepared according to procedures well known to those skilled in the art. In reaction 1 of scheme 2, the arylsulfonylpiperazine compound of formula IX, wherein R26 is carbobenzyloxy, benzyl or carbo-tert-butyloxy, is converted to the compound of formula VIII by the reaction of IX with a protected derivative of hydroxylamine of formula wherein R27 is tert-butyl, benzyl or allyl, in the presence of dicyclohexylcarbodiimide, dimethylaminopyridine and an aprotic solvent, such as methylene chloride. The protecting group R26 is selected such that it can be removed selectively in the presence of, and without loss of the protecting group R27, therefore, R26 can not be the same as R27. The removal of the protecting group R26 from the compound of formula IX is carried out under conditions suitable for the particular protecting group R26 in use. Such conditions include; (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, in which R26 is carbobenzyloxy, (b) hydrogenolysis in which R26 is benzyl, (c) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, wherein R26 is carbo-tert-butyloxy. In reaction 2 of scheme 2, the compound of formula VIII is converted into the corresponding hydroxamic acid compound of formula VII, wherein R5 is hydrogen or Ci-C alquilo alkyl, by the reaction, if desired, of VIII with a halide of alkyl when R5 is alkyl The subsequent removal of the hydroxylamine protecting group R27 is carried out by hydrogenolysis for a benzyl protecting group or by treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group can be removed by treatment with tributyltin hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (11) chloride.

Scheme 3 refers to the preparation of compounds of formula X, which are compounds of formula I wherein Y is nitrogen; X is carbon; R2, R7, R8, and R9 are hydrogen; R3 and R4, taken together are carbonyl; R5 is hydrogen and R6 is not present. In reaction 1 of scheme 3, the arylsulfonylamine compound of formula XII, wherein R 25 is as defined above, is converted to the corresponding piperazine compound of formula XI by the reaction of XII with a carbodiimide and a base, such as triethylamine . The compound of formula XI is subsequently reacted to give the hydroxamic acid compound of formula X according to the procedure described above in reaction 3 scheme 1. Scheme 4 refers to the preparation of compounds of formula XIII. The starting materials of formula XVIII can be prepared according to procedures well known to those skilled in the art. The compounds of formula XIII are compounds of formula I wherein X is carbon, and the dashed line between X and Y is not present. In reaction 1 of scheme 4, removal of the protecting group R28 and subsequent reductive amination of the compound of formula XXII, wherein Y is oxygen, sulfur or carbon, to provide the corresponding imine compound of formula XXI is carried out under suitable conditions for this particular R28 protecting group in use. Such conditions include those previously used for the removal of the protecting group R26 in reaction 1 of scheme 2.

In reaction 2 of scheme 4, the imine compound of formula XXI is converted into the corresponding piperidine compound of formula XX, by the reaction of XXI with a nucleophile of formula R2M, wherein M is lithium halide, magnesium halide or cerium. The reaction is carried out in stereo solvents, such as diethyl ester or tetrahydrofuran, at a temperature from about -78 ° C to about 0 ° C, preferably at about -70 ° C. In reaction 3 of Scheme 4, the sulfonation of the piperidine compound of formula XX to provide the corresponding arylsulfonylpiperidine compound of formula XIX is carried out by the reaction of XX with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent, such as chloride of methylene, tetrahydrofuran or dioxane, at a temperature of about 20 ° C to about 30 ° C preferably at room temperature. In reaction 4 of Scheme ^ the arylsulfonylpiperidine compound of formula XIX is converted to the hydroxamic acid compound of formula XIII according to the procedure described above in reaction 3 of Scheme L. Scheme 5 refers to the preparation of compounds of formula XIV, which are compounds of formula I in which Y is nitrogen, X is carbon, the dashed line between X and Y is not present, R5 is hydrogen and R6 is not present. In reaction 1 of Scheme 5 ^ the compound of formula XXVI, in which the protective groups R29 and R31 are each selected from independently from the group consisting of carbobenzyloxy, benzyl and carbo-tert-butyloxy and R 30 is carbobenzyloxy, C 1 -C 6 alkyl, benzyl, allyl or tertbutyl, is converted to the corresponding imine compound of formula XXV by removal of the protecting group R 29 and the subsequent reductive amination of the compound of formula XXVI. The protecting group R29 is chosen such that it can be removed selectively in the presence of, and without loss of the protecting group R31. The removal of the protecting group R29 from the compound of formula XXVI is carried out under conditions suitable for this particular protecting group R29 in use which will not affect the protecting group R31. These conditions include; (a) treatment with hydrogen and a hydrogenation catalyst, such as 10% palladium on carbon, wherein R29 is carbobenzyloxy and R31 is tert-butyl, (b) saponification wherein R29 is C1-C6 alkyl and R31 is tert-butyl, (c) hydrogenolysis wherein R29 is benzyl and R31 is C6-C6 alkyl or tert-butyl, (d) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, wherein R29 is tert. -butyl, and R31 is Ci-Cβ alkyl, benzyl or allyl or, (e) treatment with tributyl tin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride, wherein R29 is allyl and R31 is C-Cß, benzyl or tert-butyl alkyl. The protecting group R30 can be selected such that it can be removed in the same reaction step as the protective group R2g. In reaction 2 of Scheme 5 ^ the imine compound of formula XXV is converted to the corresponding compound of formula XXIV by the reaction of XXV with a nucleophile of formula R2M, wherein It is lithium, magnesium halide or calcium halide. The reaction is carried out in ethers as solvents, such as diethyl ether or tetrahydrofuran at a temperature from about -78 ° C to about 0 ° C, preferably at -70 ° C. In reaction 3 of the Scheme, the sulfonation of the piperidine compound of formula XXIV to give the corresponding arylsulfonylpiperidine compound of formula III is carried out according to the procedure described above in reaction 3 of the Scheme, In reaction 4 of Scheme 5j, the compound Arylsulfonylpiperidine of formula XXII! is converted to the hydroxamic acid compound of formula XIV by (1) removal of R30, if necessary, and protecting groups R31 of XXIII, followed by (2) reaction of XXIII according to the procedure described above in reaction 3 of the Scheme. The removal of the protecting groups R30 and R31 of the compound XXIII is carried out under conditions suitable for the particular protecting groups R30 and R31 in use. Such conditions include those previously used to remove the protecting group R25 in reaction 1 of Scheme 1. The pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely, cationic salts such as alkali and alkali metal salts. ferrous metals, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as salts of ammonium, trimethyl ammonium, diethyl ammonium and tris- (hydroxymethyl) methylammonium. Likewise, acid addition salts, such as those of mineral acids, organic carboxylic acids and organic sulfonic acids, for example, hydrochloric acid, methanesulfonic acid, maleic acid, are also possible as long as a basic group, such as pyridyl, forms part of the structure. The ability of the compounds of formula I or their pharmaceutically acceptable salts (the compounds of the invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, therefore, demonstrate their efficacy for the treatment of diseases characterized by matrix metalloproteinases or production of tumor necrosis factor is demonstrated in the following in vitro assays. BIOLOGICAL ASSAY Inhibition of Human Enasa Tail (MMP-1) Recombinant human collagenase is activated with trypsin using the following ratio: 10 μg of trypsin per 100 μg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a five-fold excess (50 μg / 10 μg trypsin) of soybean trypsin inhibitor is added. 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 mM > 0.12 μm. Twenty-five microliters of each concentration is then added in triplicate to the appropriate wells of a 96-well Microfluor plate. The final inhibitor concentration will be a 1: 4 dilution after adding the enzyme and the substrate. The positive controls (enzyme, without inhibitor) are placed in wells D1-D6 and blanks (without enzyme, without inhibitors) are placed in wells D7-D12. Collagenase is diluted to 400 ng / ml and then added μl to the appropriate wells of the Microfluor plate. The final concentration of collagenase in the assay is 100 ng / ml The substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as a 5mM stock solution in sulfoxide of dimethyl and then diluted to 20 μM in assay buffer. The assay is initiated by the addition of 50 μl of the well substrate of the Microfluor plate to give a final concentration of 10 μM. The fluorescence readings (360 nm excitation, 460 nm emission) were taken 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.

Fluorescence versus time is plotted for the white and collagenase-containing samples (the data from the triplicate determinations are averaged). The point that provides a good signal (white) and that is in a linear part of the curve (usually around 120 minutes). It is chosen to determine the IC50 values. Zero time is used as a target for each compound at each concentration and these values are subtracted from the data at 120 minutes. Data are plotted as concentration of inhibitor against percent control (fluorescence of the inhibitor divided by fluorescence of collagenase alone x 100). Cl50's are determined from the concentration of inhibitor that provides a signal that is 50% control. If the Cl50 described are less than 0.03 μM, then the inhibitors are tested at concentrations of 0.3 μM, 0.03 μM, 0.003 μm and 0.0003 μM.

Inhibition of Gelatinase (MMp-2) The inhibition of gelatinase activity is tested using the substrate Dnp-Pro-Cha-Gly-Cys- (Me) -His-Ala-Lys (NMA) -NH2 (10 μM) under the same conditions as for the inhibition of human collagenase (MMP-1) - 72 kD of gelatinase are activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4 ° C and diluted to provide a final concentration in the assay of 100 mg / ml. The inhibitors are diluted as in the inhibition of human collagenase (MMP-I) to provide final concentrations in the assay of 30 μM, 3 μM, 0.3 μM, and 0.03 μm. Each concentration is done in triplicate. The fluorescence readings (360 nm excitation and 460 nm emission) are taken at zero time and then at 20 minute intervals for 4 hours. The Cl50 are determined as in the inhibition of human collagenase (MMP-1). If the IC 50 obtained 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 Estrornelisin Activity (MMP-3) Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingaten 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) provides a tractable mercaptan fragment in the presence of Ellman's reagent. Recombinant human proestromelisin is activated with trypsin using a ratio of 1 μl of a 10 mg / ml trypsin stock solution to 26 μg of stromelysin. Trypsin and stromelysin are incubated at 37 ° C for 15 minutes, followed by 10 μl of soybean trypsin inhibitor 10 mg / ml for 10 minutes at 37 ° C to quench trypsin activity.

The assays are carried out in a total volume of 250 μl of assay buffer (200 mM sodium chloride, 50 mM MES and 10 nM calcium chloride, pH 6.0) in 96-well microtiter plates. The activated stromelysin is diluted in assay buffer to 25 μg / ml. Ellman's reagent (3-carboxy-4-nitrophenyl disulfide) is prepared as a 1M stock in dimethylformamide and diluted to 5 mM in assay buffer with 50 μl per well, giving a final concentration of 1 mM. The 10 mM stock solutions of inhibitors are prepared in dimethyl sulfoxide and serially diluted in assay buffer such that addition of 50 μl to the appropriate wells yields final concentrations of 3 μM, 0.3 μM, 0.003 μM, and 0.0003 μM. All conditions are completed in triplicate. A stock solution of 300 mM dimethyl sulfoxide of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by the addition of 50 μl to each well to provide a final concentration of 3 nM substrate. The targets are composed of peptide substrate and Ellman's reagent without enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader. The IC50 values were determined in the same way as for collagenase.

Inhibition of MMP-13 Recombinant human MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours at 37 ° C and diluted to 400 mg / ml in assay buffer (50 mM Tris, pH 7.5, 200 nM sodium chloride, 5 mM calcium chloride, 20 μM zinc chloride, 0.02% brijol). Twenty-five microliters of diluted enzyme is added per well of a 96-well Microfluor plate. The enzyme is then diluted in a 1: 4 ratio in the assay by the addition of inhibitor and substrate to provide a final concentration in the 100 mg / ml assay. The 10 mM stock solutions of inhibitors are prepared in dimethyl sulfoxide and then diluted in assay buffer according to the human collagenase inhibition dilution scheme (MMP-1): Twenty-five microliters of each concentration is added in triplicate 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 for inhibition of human collagenase (MMP-1) and 50 μl is added to each well for provide a final assay concentration of 10 μM. The fluorescence readings (360 mm excitation and 450 nm emission) are taken at time 0 and every 5 minutes for one hour. The positive controls are composed of enzyme and substrate without inhibitor and the targets are composed only of substrate.

The IC50's are determined as for the inhibition of human collagenase (MMP-1). If the IC50 obtained are less than 0.03 μM, the inhibitors are then assayed at final concentrations of 0.3 μM, 0.03 μM, 0.0003 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 for the treatment of diseases involving the production of TNF is shown by the following test in vitro: Human mononuclear cells were isolated from human blood coagulated with antigen using a Ficoll-hypaque one-step separation technique. (2) The mononuclear cells were washed three times in Hanks Balanced Salt Solution (HBSS) with divalent cations and resuspended to a density of 2 x 106 / ml in HBSS containing 1% BSA. Differential counts determined using an Abbott Cell Cyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells of these preparations. Aliquots were divided into 180 μl of cell suspension in 96 well plates with flat bottom (Costar). Additions of the compounds and LPS (final concentration of 100 ng / ml) yielded a final volume of 200 μl. All conditions were carried out in triplicate. After a four-hour incubation at 37 ° C in an incubator humidified with CO2, the plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants were removed and assayed for TNF & using the ELISA R & D kit. For administration to mammals, including humans for the inhibition of matrix metalloproteinases or production of tumor necrosis factor (TNF), a variety of conventional routes including oral, parenteral and topical can be used. In general, the active compound will be administered orally or parenterally in dosages of about 0.1 to 25 mg / kg of body weight of the patient to be treated per day, preferably of about 0.3 to 5 mg / kg. However, there will necessarily be some variation in the dosage depending on the condition of the patient in question. In any case, the person responsible for the administration will determine the appropriate dose for each patient. The compounds of the present invention can be administered in a wide range of different dosage forms. In general, the therapeutically active compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% in weigh. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), acid alginic and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this regard include lactose or milk sugar, as well as high molecular polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes, and, if desired, emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerol and various combinations thereof. In the case of animals, they will 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 (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of active ingredient is generally prepared. Solutions of a therapeutic compound of the present invention may be employed either in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions should be suitably adjusted and buffered, preferably at pH greater than 8, if necessary and initially made the isotonic liquid diluent. These aqueous solutions are suitable for injection purposes intravenous Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily carried out 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 dose levels of approximately 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day, administered in a single dose or in up to 3 doses. divided doses. The present invention is illustrated by the following examples, but is not limited to the details thereof.

EXAMPLE 1 Hydroxyamide of (2R, 4R) -1- (4-methoxy-benzenesulfonyl) -4- (piperazine-1-carbonyl) -piperidine-2-carboxylic acid hydroxyamide. (a) To a cold, stirred solution (-78 ° C) of 1-tert-butyl ester, (2R) -2-benzyloxycarbonylamino-pentanedioic acid-5-methyl ester (5.6 g, 15.9 mmol) , prepared as described in J. Org. Chem 5J. 1711-1721 (1990) and J. Med. Chem. 39, 73-85 (1996), in 30 ml of tetrahydrofuran, lithium bis (trimethylsilyl) amide (40 ml, 1 M in tetrahydrofuran, 39.8 mmol was added. ). The resulting mixture was stirred for 1 hour at -45 ° C and re-cooled to -78 ° C. Allyl bromide (5.2 ml, 63.7 mmol) was then added. After 2 hours, the reaction was quenched by the addition of chloride of aqueous 1 M aqueous hydrogen at -78 ° C. The mixture was then extracted with diethyl ether. The combined ether extracts were washed with brine and the mixture was dried over sodium sulfate. After filtering and concentrating the filtrate, the crude product was purified by chromatography on silica gel (elution with ethyl acetate: hexanes 1.%) to give 1-tert-butyl ether, 5-methyl ester of (2R, 4R) -4-Allyl-2-benzyloxycarbonylamino-pentanedioic acid. (b) Gaseous ozone was bubbled through a stirred (-78 ° C) solution of 1-tert-butyl ester, (2R, 4R) -4-allyl-2-benzyloxycarbonylamino-pentanedioic acid-5-methyl ester ( 5.0 g, 12.8 mmol) in 100 ml of methanol: methylene chloride 10: 1 and 0.73 ml of acetic acid, until the blue color remained. Nitrogen gas was bubbled through the solution until the blue color dissipated. The mixture was warmed to room temperature and dimethyl sulfide (2.8 ml, 3.83 mmol) was added. The mixture was stirred for 48 hours, diluted with methylene chloride and washed with 10% sodium carbonate, brine and the mixture was dried over sodium sulfate. Filtration and concentration of the filtrate gave 1-benzyl ester, 2-tert-butyl ester, (2R, 4R) -6-methoxy-piperidine-1,2,4-tricarboxylic acid 4-methyl ester, as a light oil, which was used in the next step without purification. (c) Was stirred under an atmosphere of hydrogen gas at 3.10 x 105 Pa for 1.5 hours a mixture of 1-benzyl ester, 2-tert-butyl ester, (2R, 4S) -6-methoxy-piperidine-1,2,4-tricarboxylic acid 4-methyl ester (4.85 g , 11, 9 mmol) and 10% palladium on carbon (500 mg) in 100 ml of ethanol. The mixture was filtered through nylon and the filtrate was concentrated to provide 2-tert-butyl ester, (2R, 4R) -piperidine-2,4-dicarboxylic acid 4-methyl ester as a light yellow oil, which was used in the next stage without further purification. (d) To a stirred cold solution (0 ° C) of 2-tert-butyl ester, 4-methyl ester of (2R, 4R) -piperidine-2,4-dicarboxylic acid (2.7 g, 11.1) mmol) and triethylamine (4.6 mL, 33.3 mmol) in 30 mL of methylene chloride was added 4-methoxy-benzenesulfonyl chloride (2.3 g, 11.1 mmol). The mixture was warmed to room temperature and stirred for 4 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and the organic mixture was dried over sodium sulfate. After filtering and concentrating the filtrate, the resulting crude product was purified by chromatography on silica gel (elution with 3: 8 ethyl acetate: hexanes), yielding 2-tert-butyl ester, 4-methyl ester of (2R) acid , 4R) -1- (4-methoxy-benzenesulfonyl) -piperidine-2,4-d-carboxylic acid. (e) To a cold, stirred solution (0 ° C) of 2-tert-butyl ester, 4-methyl (2R, 4R) -1- (4-methoxy-benzenesulfonyl) -piperidine-2, 4-methyl ester. dicarboxylic acid (4.4 g, 10.6 mmol) in 30 ml of methylene chloride was added 10 ml of trigluoroacetic acid, dropwise. The mixture was stirred for 1 hour at 0 ° C and for 8 hours at room temperature. The concentration gave 4-methyl ester of (2R, 4R) -1- (4-methoxy) benzenesulfonyl) -piperidine-2,4-dicarboxylic acid, which was used in the next step without purification. (f) To a stirred solution of 4-methyl ester of the acid (2R), 4R) -1- (4-methoxy-benzenesulfonyl) -piperdidine-2,4-dicarboxylic acid (4.4 g, 12.3 mmol), O-benzylhydroxylamine hydrochloride (2.15 g, 13.5 mmol) and triethylamine (5.15 ml, 36.9 mmol) was added benzotriaol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (6.0, 12.3 mmol) at room temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate and brine. The organic mixture was dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude residue was purified by chromatography on silica gel (eluting with 5% methanol in methylene chloride) to give (2R, 4R) -2-benzyloxycarbamoii-1- (4-methoxy-benzenesulfonyl) -piperidine methyl ester. -4-carboxylic acid as a colorless solid. (g) To a cold stirred solution (0 ° C) of acid methyl ester (2R, 4R) -2-benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperdidine-4-carboxylic acid (4.0 g, 8.6 mmol) in 10 ml of methanol-freeza 9: 1 was added lithium hydroxide monohydrate (1.8 g, 43 mmol). The mixture was stirred for 2 hours before adding Amberlite IR-120 resin (96 g). After 15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R, 4R) -2-benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid, which was used in the next reaction without purification. (h) To a stirred solution of (2R, 4R) -2-benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid (500 mg, 1.11 mmol), butoxycarbonyl piperazine (226 mg, 1.21 mmol) and triethylamine (0.47 mL, 3.33 mmol) was added benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (535 mg, 1.21 mmol) at room temperature ambient. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate and brine. The organic mixture was dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude residue was purified by chromatography on silica gel (eluting with 2% methanol in methylene chloride) to give (2R, 4R) -4- [2-benzyloxycarbamoyl-1- (4-methoxy) tert -butyl ester. -benzenesulfonyl) -piperidine-4-carbonyl] -piperazine-1-carboxylic acid as a colorless solid. (i) A mixture of (2R, 4R) -4- [2-benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperidine-4-carbonyl] -piperazine-1-carboxylic acid tert -butyl ester (500 mg 0.81 mmol) and 5% palladium on barium sulfate (250 mg) in 10 ml of methanol was stirred under an atmosphere of hydrogen gas at 2.76 x 10 5 Pa for 1.5 hours. Filtration through nylon and concentration of the filtrate gave the (2R, 4R) -4- [2-hydroxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperdidine-4 -] - piperazine-1-tert-butyl ester. -carboxylic acid as a colorless solid, which was used in the next step without purification. 0) Gaseous hydrogen chloride was bubbled through a cold solution (0 ° C) of (2R, 4R) -4- [2-hydroxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperidine tert -butyl ester) -4-carbonyl] -piperazine-1-carboxylic acid (420 mg, 0.8 mmol) for 10 minutes. After a further 20 minutes, the mixture was concentrated, yielding (2R, 4R) -1- (4-methoxy-benzenesulfonyl) -4- (piperazine-1-carbonyl) -piperidine-2-carboxylic acid hydroxyamide hydrochloride as a colorless solid: Mass spectrum (chemical ionization at atmospheric pressure, basic mode) m / z (m + H) 427, 366; 1 H NMR (DMSO-d 6, 400 MHz, ppm) d 10.70 (width d, 1 H, J = 2.7 Hz), 9.06 (width s, 1 H), 8.84 (width s, 1 H), 7.70 ( dd, 2H, J = 8.9, 2.9 Hz), 7.06 (dd, 2H, J = 8.9, 2.9 Hz), 4.42 (broad s, 1 H), 3.80 (s, 3H), 3.80-3.20 (m, 6H), 3.04 (m, 4H), 2.76 (m, 1 H), 1.79 (width d, 1 H, J = 13.5 Hz), 1.52 (width d, 1 H, J = 12.6 Hz), 1.32 (m, 1 H), 1, 14 (m, 1 H).

EXAMPLE 2 (2R, 4R) -1-r3- (4-Fluorophenoxy) -propane-1-sulfonip-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester (a) To a stirred solution of 2-tert-butyl ester, 4-methyl ester of (2R, 4R) -piperidine-2,4-dicarboxylic acid (920 mg, 3.78 mmol) and triethylamine (1.58 ml) , 11.3 mmol) in 10 ml of methylene chloride was added a solution of 3- (4-fluorophenoxy) -propane-1-sulfonyl chloride (1.05 g, 4.16 mmol) in 2 ml of sodium chloride. methylene under a nitrogen atmosphere. The The mixture was stirred for 16 hours at room temperature (22 ° C), then diluted with 20 ml of 1 N hydrochloric acid and 20 ml of methylene chloride. The organic layer was separated and washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave 2.8 g of a yellow oil, which was purified by flash chromatography (hexanes: ethyl acetate, 3: 2) yielding 1.15 g of 2-tert-butyl ester, 4-methyl acid ester (2R) , 4R) -1 - [3- (4-fluoro-phenoxy) -propane-1-sulfonyl] -piperidine-2, 4-dicarboxylic acid as a yellow oil. (b) To a stirred, cold solution (0 ° C) of 2-tert-butyl ester, 4-methylic ester of (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl ester ] -piperidine-2,4-dicarboxylic acid (1.15 g, 2.5 mmol) in 10 ml of methylene chloride were added 10 ml of trifluoroacetic acid. The mixture was allowed to warm to room temperature (22 ° C) for 16 hours. The mixture was concentrated in vacuo to provide 970 mg of (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -piperidine-2,4-dicarboxylic acid 4-methyl ester. like an orange solid. (c) To a stirred solution of (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -piperidine-2,4-dicarboxylic acid 4-methyl ester (970) mg, 2.4 mmol) in 5 mL of methylene chloride was added triethylamine (1.0 mL, 7.2 mmol) and O-benzylhydroxylamine hydrochloride (410 mg, 2.64 mmol) at room temperature (22 ° C. ). To the resulting solution was added benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (1.17 g, 2.64 mmol) and the mixture was stirred for 16 hours under a nitrogen atmosphere.

The mixture was diluted with 25 ml of 1N hydrochloric acid and 25 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organics were washed with saturated aqueous sodium carbonate (1x) and brine (1x). The organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. Purification of the viscous yellow residue by flash chromatography (eluting with 1: 1 ethyl acetate / hexanes) provided 810 mg of (2R, 4R) -2-benzyloxycarbamoyl-1- [3- (4-fluorophenoxy) - methyl ester - propane-1-sulfonyl] -piperidine-4-carboxylic acid as a clear oil. (d) A mixture of (2R, 4R) -2-benzyloxycarbamoyl-1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -piperidine-4-carboxylic acid methyl ester ( 800 mg, 1.57 mmol) and 200 mg of 5% palladium on barium sulfate in 15 ml of methanol was stirred in a Parr apparatus under an atmosphere of hydrogen gas at 2.76 x 105 Pa for 2 hours. The catalyst was removed by passing the mixture through a 0.45 μm nylon filter and the filtrate was concentrated to give 650 mg of (2R, 4R) -1 - [3- (4-fluorophenoxy) -propane-1-methyl ether) sulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid as a white foam: MS (chemical ionization at atmospheric pressure, acid mode), 417 (M-1); 1 H NMR (400 MHz, CDCl 3) d 6.94-6.97 (m, 2 H), 6.80-6.83 (m, 2 H), 4.56 (s, 1 H), 4.03 (t, 2 H, J = 5.3 Hz), 3.83 ( d, 1H, J = 12.9 Hz), 3.68 (s, 3H), 3.15-3.28 (m, 3H), 2.76 (t, 1 H, J = 11.5 Hz), 2.54 (d, 1H, J = 13.5 Hz) , 2.26 (d, 2H, J = 5.9 Hz), 2.02 (m, 1H, J = 13.0 Hz), 1.73-1.78 (m, 1 H), 1.56-1.62 (m, 1 H).

EXAMPLE 3 Acid (2R, 4R) -1-r3- (4-fluorophenoxy) -propane-1-sulfonin-2-hydroxycarbamoyl-piperidine-4-carboxylic acid To a cold stirred solution (0 ° C) of acid methyl ester (2R, 4R) -1 - [3- (4-fluorophenoxy) -propane-1-sulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid (400 mg, 0.96 mmol) in 5 ml of a methanol mixture ( 10: 1) was added lithium hydroxide monohydrate (120 mg, 2.88 mmol). After 3 hours at 0 ° C, Amberlite resin (4.1 g) previously washed with methanol was added. The mixture was filtered and the filtrate was concentrated affording 370 mg of (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid as a foam white: MS (chemical ionization at atmospheric pressure) acid mode, 403 (M-1).

EXAMPLE 4 (2R, 4R) -1-r4- (4-Fluorobenzyloxy) -benzenesuifon-p-2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester 4- (4-Fluoro-benzyloxy) -benzenesulfonyl chloride. MS: 465 (M-1) - The title compound of Example 4 was prepared by a procedure analogous to that described in Example 2 using the reagents.

EXAMPLE 5 Acid (2R, 4R) -1-r4- (4-Fluorobenzyloxy) -benzenesulfonyl-2-hydroxycarbamoyl-piperidine-4-carboxylic acid MS: 451 (M-1). The title compound of Example 5 was prepared by a procedure analogous to that described in Example 3, starting with 1 - [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-methyl ester carboxylic EXAMPLE 6 Isopropyl ester of 2R, 3S- acid. { 1-r4- (4-Fluorobenzyl) - benzenesulfonM1-2-hydroxycarbamoyl-piperidin-3-yl} -carbamic (a) To a stirred and cold solution (0 ° C) of the known one (Agami, C; Hamon, L .; Kadouri-Puchot, C; Le Guen, V. J. Ora, chem. 1996, 61 .. 5736-5742) [4S-4, 9a, 9aa] -1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazine-9- methyl ester carboxylic acid (8.28 g, 2.86 mmol) in 100 ml of tetrahydrofuran was added 2.39 ml of concentrated hydrochloric acid. After 5 minutes, the mixture was concentrated to dryness. The resulting solid was suspended in ethyl acetate and the mixture was stirred for one hour. The solids were collected by filtration, rinsed with ethyl acetate and dried to give 9.04 g of a white solid. Two grams of this solid were dissolved in 26 ml of 6N hydrochloric acid and heated to reflux for 6 hours. The mixture was cooled to 0 ° C and neutralized with 3N sodium hydroxide and concentrated in vacuo. The resulting solids were suspended in chloroform and passed through a 45 μm nylon filter. The filtrate was concentrated to a yellow oil which was purified by flash chromatography (eluting with hexane: ethyl acetate 2: 1 with 1% acetic acid). providing 802 mg of acid [4S-4a, 9a, 9aa] -1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazine-9-carboxylic acid as a white solid. (b) To a solution of [4S-4a, 9, 9aa] -1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazine-9-carboxylic acid (568 mg, 2.06 mmol) in 15 ml of benzene was added triethylamine (0.28 ml, 2.06 mmol) and diphenylphosphoryl azide (0.44 ml, 2.06 mmol) at 22 ° C under a nitrogen atmosphere. The mixture was stirred at 22 ° C for 45 minutes and refluxed for 50 minutes before adding 2-propanol (3.2 ml, 41.2 mmol). After a further 20 hours at reflux, the mixture was cooled to 22 ° C and concentrated in vacuo. The residue was suspended in ethyl acetate and the resulting solution was washed with 5% citric acid, water, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatography (eluting with hexanes: ethyl acetate 3: 1), yielding 402 mg of [4S-4a, 9, 9aa] - (1-oxo-4-phenyl-octahydro) isopropyl ester. pyrid [2,1-c] [1,4] oxazin-1-yl) -carbamic acid as a white solid. (c) A mixture of [4S-4a, 9a, 9aa] - (1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazin-1-yl isopropyl ester) -carbamic acid (900 mg, 2.71 mmol) and 20% palladium hydroxide on carbon (920 mg) in 77 ml ethanol / water (10: 1) was stirred in a Parr apparatus under a hydrogen gas pressure of 3.10 x. 105 Pa for 72 hours. The catalyst was removed by passing the mixture through a 0.45 μm nylon filter and the filtrate was concentrated to provide 610 mg of 2R, 3S-3-isopropoxycarbonylamino-piperidine-2-carboxylic acid as a solid MS: 229 (m-1) . (d) To a stirred solution of 2R, 3S-3-isopropoxycarbonylamino-piperidine-2-carboxylic acid (320 mg, 1.39 mmol) in 5 mL of methylene chloride was added triethylamine (0.58 mL, 4.17 mmol), followed by chloride of 4- (4- fluorobenzyloxy) -benzenesulfonyl (460 mg, 1.53 mmol). After 16 hours at 22 ° C, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave 480 mg of crude 2R, 3S-1 - [4- (4-fluorobenzyloxy) -benzenesulfonyl] -3-isopropoxycarbonylamino-piperidine-2-carboxylic acid as a light yellow solid, (e) A a cold, stirred solution (° C) of crude 2R, 3S-1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -3-isopropoxycarbonylamino-piperidine-2-carboxylic acid (380 mg, 0.77 mmol) in 5 mL of methylene chloride was added triethylamine (0.32 mL, 2.31 mmol), followed by benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (510 mg, 1.15 mmol). The resulting solution was stirred for 2 minutes at 0 ° C under a nitrogen atmosphere before adding O- (trimethylsilylethyl) hydroxylamine hydrochloride (195 mg, 1.15 mmol). The mixture was allowed to slowly warm to 22 ° C for 14 hours. The mixture was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate / diethyl ether (1: 1; 3x). The organic extracts (2 x), water (2 x) and brine (1 x). The organic layer was dried (magnesium sulfate), filtered and the filtrate was concentrated in vacuo. The yellow residue was purified by flash chromatography (eluting with hexanes / ethyl acetate 65:35), yielding 300 mg of 2R, 3S-1- [4- (4-fluorobenzyloxy) -benzenesulfonyl isopropyl ester. ] -2- (2-trimethylsilanyl-exocarbamoyl) -piperidin-3-yl] -carbamic acid as a white foam. MS: 610 (m + 1). (f) To a stirred cold solution (° C) of the isopropyl ester of 2R, 3S-1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2- (2-trimethylsilanyl-ethoxycarbamoyl) -piperidin-3 acid -yl] -carbamic acid (265 mg, 0.44 mmol) in 4 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The resulting colorless solution was allowed to warm to 23 ° C for 2 hours and stirred for another 28 hours. The mixture was concentrated in vacuo to a solid / foam, which was suspended in ethyl acetate / hexanes (1: 6) and stirred for 10 hours. The white solids were collected by filtration, rinsed with hexanes and further purified by flash chromatography (eluting with 7: 3 ethyl acetate / hexanes with 1% acetic acid) to provide 130 mg of 2R, 3S- isopropyl ester. { 1- [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} -carbamic as a solid / foam. MS: 510 (M + 1).

EXAMPLE 7 Hydroxyamide of 3 (s) -4- (4'-fluorobiphenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid (a) To a stirred solution of the known (PCT document publication WO 97/20824) 3- (S) -dimethyl-hexylsilyl-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylate (1.17 g, 3.70 mmol) in 6 mL of methylene chloride was added triethylamine (1.02 mL, 7.40 mmol), followed by 4'-fluorobiphenylsulfonyl chloride (1.0 g, 3.70 mmol). The resulting solution was stirred during 56 hours at 23 ° C. The reaction mixture was diluted with methylene chloride and washed with water. The organic layer was concentrated in vacuo; the residue was dissolved in methanol and the mixture was heated to reflux for 6 hours. The mixture was cooled to 23 ° C and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 3: 7 ethyl acetate / hexanes, with 1% acetic acid), yielding 670 mg of 3- (S) -4- (4'-fluorobiphenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid as a white foam / solid. MS: 427 (M + NH 4). (b) To a stirred, cold (0 ° C) solution of 3- (S) -4- (4'-fluoro-phenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid (605) mg, 1.48 mmol) in 5 mL of methylene chloride was added triethylamine (0.62 mL, 4.43 mmol) under a nitrogen atmosphere. Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (980 mg, 2.22 mmol) was added and the resulting solution was stirred for 5 minutes before adding O- (trimethylsilylethyl) hydroxylamine hydrochloride (376 mg, 2.22 mmol). The ice bath was removed and the mixture was stirred at 23 ° C for 20 hours. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate / diethyl ether 1: 1 (3 x). The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x), water (1 x) and brine (1 x). The organic layer was dried (magnesium sulfate), filtered and the filtrate was concentrated in vacuo. The residual yellow oil was purified by flash chromatography (eluting with 3: 7 ethyl acetate / hexanes), affording 650 mg of 3- (S) -4- (4'-fluorob) (2-trimethylsilyl-ethoxy) -amide. Phenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid as a white foam. MS: 523 (M-1). (c) A solution of 3- (S -4- (4'-fluorobiphenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic (2-trimethylsilyan-ethoxy) -amide (650 mg, 1.24 mmol) in 8 ml of trifluoroacetic acid was stirred at 22 ° C. for 16 hours.The mixture was concentrated in vacuo and the residue was triturated with methylene chloride and diethyl ether.The solvent was removed leaving 550 mg of a tan solid. The solid was suspended in diethyl ether: hexanes 1: 1 and stirred gently for 20 hours.The solids were collected by filtration (rinsing with diethyl ether / hexanes 1: 1) and dried to give 470 mg of 3- (hydroxyamide. S) -4- (4'-Fluorobiphenl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid as a white solid MS: 423 (m-1).

EXAMPLE 8 3- (S) -4,44- (4-Fluorobenzyloxy) benzenesulfonyl-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide (a) To a stirred cold solution (0 ° C) of the known one (Belgian Patent Publication BE 893025), 2,2-dimethyl-thiomorpholine-3-carboxylic acid (600 mg, 3.42 mmol) in 10 ml of water / dioxane 1: 1 was added 6N sodium hydroxide (1.2 ml, 7.1 mmol). To the resulting solution, 4- (4-fluorobenzyloxy) benzenesulfonyl chloride (1.08 g, 3.77 mmol) was added. After 30 and 60 minutes, 1 g of 4- (4-fluorobenzyloxy) benzenesulfonyl chloride and 1.2 ml of 6N sodium hydroxide were added. The mixture (pH of about 12) was diluted with water and extracted with diethyl ether (1 x). The ether layer was washed with 1 N sodium hydroxide; the combined basic aqueous layers were acidified to pH 3 using concentrated hydrochloric acid, and the acid mixture was extracted with ethyl acetate (3 x). The combined organic extracts were dried (sodium sulfate), filtered and the filtrate was concentrated in vacuo to provide 820 mg of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2, 2-dimethyl-thiomorpholine-3-carboxylic acid as a white solid. MS: 438 (M-1). (b) To a stirred, cold (0 ° C) solution of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid (820 mg, 1.87 mmol) in 5 ml of methylene chloride was added triethylamine (0.52 ml, 3.74 mmol) under a nitrogen atmosphere. Benzotriazole-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (1.24 g, 2.81 mmol) was added and the resulting solution was stirred for 5 hours before adding O- (tert-butyldimethylsilyl) hydroxylamine (550 mg, 3.74 mmol). The ice bath was removed and the mixture was stirred at 23 ° C for 16 hours. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine and dried over sodium sulfate. Filtration and concentration of the filtrate gave a viscous yellow oil, which was purified by flash chromatography (eluting with ethyl acetate / hexanes 1: 3), yielding 3- (S) -4- [3- (S) -4- (tert-butyldimethylsiloxy) amide. 4- (4-Fluorobenzyloxy) benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid as a white foam. MS: 569 (M + 1). (c) To a cold, stirred solution (0 ° C) of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3- (tert-butyldimethylsiloxy) -amide. dimethyl-thiomorpholine-3-carboxylic acid (270 mg, 0.47 mmol) in 10 ml of tetrahydrofuran was added two drops of concentrated hydrochloric acid. After 30 minutes, the mixture was diluted with 15 ml of tetrahydrofuran and the mixture was concentrated in vacuo to a volume of approximately 5 ml. The volume was adjusted to approximately 25 ml with tetrahydrofuran and the mixture was again concentrated to approximately 5 ml. This procedure was repeated two more times before concentrating the mixture finally to dryness. The resulting solids were suspended in a mixture of hexanes and diethyl ether and the mixture was stirred for 16 hours. The solid was collected by filtration, rinsed with diethyl ether and dried to give 180 mg of 3- (S) -4- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2,2-dimethylol hydroxyamide. omorpholine-3-carboxylic acid as a white solid. MS: 453 (M-1). 1 H NMR (400 MHz, DMSO-de) d 10.63 (s, 1 H), 8 ^ 80 (broad s, 1 H), 7.59-7.61 (m, 2H), 7.46-7.50 (m, 2H), 7.17 -7.21 (m, 2H), 7.09-7.12 (m, 2H) 5.12 (s, 2H), 3.99 (s, 1 H), 3.87-3.93 (m, 1 H), 3.69 (d, 1 H, J = 12.7 Hz), 2.78-2.86 (m, 1 H), 2.44-2.50 (m 1 H), 1.35 (s, 3H), 1.12 (s, 3H).

PREPARATION 1 4- (4-Fluorobenzyloxy) benzenesulfonyl chloride To a stirred solution of dihydrated sodium salt of 4-hydroxybenzenesulfonic acid (5.13 g, 22.1 mmol) in 23 ml of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 ml, 26.5 mmol) in 20 ml of ethanol. The mixture was refluxed for two days, then cooled to room temperature (22 ° C), forming a white precipitate. The white flaky solids were collected by filtration, rinsed with ethyl acetate and diethyl ether and dried to give 4.95 g of 4- (4-fluoro-benzyloxy) -benzenesulfonic acid sodium salt. A stirred solution of 4- (4-fluoro-benzyloxy) -benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 ml of thionyl chloride and two drops of dimethylformamide was heated to a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to give 11.2 g of 4- (4-fluoro-benzyloxy) -benzenesulfonium chloride as a light yellow solid: 1 H NMR (400 MHz, CDCl 3) d 7.95-7.98 (m, 2H), 7.38-7.41 ( m, 2H), 7.08-7.12 (m, 4H), 5.12 (s, 2H) PREPARATION 2 3- (4-fluorophenoxy) -propane-1-sulfonyl chloride To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL of toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at room temperature (22 ° C). After 20 minutes, a solution of 1,3-propane sulfone (3.9 ml, 44.6 mmol) in toluene was added slowly and the mixture was stirred for 16 hours. The reaction was quenched by the addition of methanol and the mixture was concentrated in vacuo to an off-white solid. This solid was suspended in ethyl acetate, filtered and the solids were collected and dried to give 10.9 g of the sodium salt of 3- (4-fluorophenoxy) -propane-1-sulfonic acid as an off-white powder. A stirred solution of 3- (4-fluorophenoxy) -propane-1-sulfonic acid sodium salt (2.0 g, 7.8 mmol) in 10 ml of trionyl chloride and a few drops of dimethylformamide was heated at reflux for 16 hours. The mixture was then cooled to 0 ° C, diluted with 25 ml of diethyl ether and the reaction quenched by the slow addition of water. The organic layer was removed and the aqueous layer was extracted with 25 ml of diethyl ether. The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration afforded 1.75 g of 3- (4-fluoro-phenoxy) -propane-1-sulfonyl chloride as a yellow oil: 1 H NMR (400 MHz, CDCl 3) d 6.96-7.00 (m, 2H), 6.80 -6.84 (m, 2H), 4.10 (t, 2H, J = 5.5 Hz), 3.91 (t, 2H, J = 7.5 Hz), 2.47-2.54 (m, 2H).

PREPARATION 3 4'-Fluorobiphenylsulfonyl Chloride Chlorosulphonic acid (8.7 ml, 0.13 mol) to stirred and cold 4-fluorobiphenyl (0 ° C) (10.2 g, 59 mmol) was added dropwise. After 30 minutes at 0 ° C the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, brine, dried over magnesium sulfate and concentrated to give a white solid. The desired 4'-fluorobiphenylsulfonyl chloride (4.3 g) was separated from 4'-fluorobiphenylsulfonic acid by crystallization of the latter in ethyl acetate and crystallization of the remaining material in hexanes.

Claims

NOVELTY OF THE INVENTION CLAIMS t

1. - A compound of the formula: or the pharmaceutically acceptable salts thereof, wherein the line 15 discontinuous represents an optional double bond; X is carbon, oxygen or sulfur; And it is carbon, oxygen, sulfur, SO, SO2 or nitrogen; R1, R2, R3, R4, R5, R6, R7 R8, and R9 are selected from the group consisting of hydrogen, CI-CT alkyl optionally substituted by one or two groups selected from (Ci-Cß-alkyl, Ci-Cß alkoxy, trifluoromethyl, halogen, aryl Ce-Cio, C2-C9 heteroaryl, (C6-C? O) amino aryl, (Ci-Cjjthio aryl, aryloxy Ce-Cio, (C2-C9 heteroaryl) amino, (C2-C9 heteroaryl) thio, C2-C9 heteroaryloxy, (aryl) Cedo) (Ce-Cι aryl), Ca-Cβ cycloalkyl, hydroxy, piperazinyl, (Ce-Cι aryl) (Ci-Cβ alkoxy), (C2-Cg heteroaryl) (CI-CT alkoxy), (Ci-Cemino acid, (acyl C? -C6) thio, acyloxy C -Cβ, (Ci-Cß alkyl) sulfinyl, (C?-C6 aryl) sulfinyl, (Ci-Ce alkyl) sulfonyl, (Ce-Cι aryl) sulfonyl, amino, (dCα alkyl) amino or ((alkyl) Ci-C6) 2amino); C2-C6 alkenyl, (Ce-C o aryl) (C2-C6 alkenyl), (C2-Cg heteroaryl), (C2-C6 alkenyl), d-Cß alkynyl, (Ccy-Ce aryl) (d-Cß alkynyl) , (C2-C8 heteroaryl) (C2-C6 alkynyl), (C6-C6 alkyl) amino, (C6-C6 alkyl) thio, C-C2 alkoxy, perfluoro (Ci-C3 alkyl), Ce-Cio aryl, C2-Cg heteroaryl, (Cß-C ?o) aryl amino, (C6-C? 0) aryl, C6-C ar aryloxy, (C2-C9 heteroaryl) amino, (C2-Cg heteroaryl) t, C2-Cg heteroaryloxy, C3-C6 cycloalkyl, (C-C6 alkyl) (hydroxymethylene), piperidyl, (C6-C6 alkyl) piperidyl, (d-C6 acyl) amino, (C6-C6 acyl) thio, acyloxy d-C6, R10 (C? -C6 alkyl) or a group of formula wherein n is from 0 to 6; and is 0 or 1; W is oxygen or > NR24; Z is -OR11, -NR24R11, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a diazabicycloalkyl ring with bridge selected from the group consisting of b and wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and V is hydrogen, C1-C3 alkyl, (d-C6 alkyl) (C = 0) -, (C6 alkoxy) (C = 0) -, (C6-C? 0 aryl) (C = 0) -, (aryloxy Cedo) (C = 0) -, (C6-C? o aryl) (d-C6 alkyl) (C = 0) -, (C6-C? 0 aryl) (d-C6 alkoxy) (C = 0 ) - or (d-Cß alkoxy) (C = 0) -O; wherein each heterocyclic group (ie, each cyclic Z group containing one or more heteroatoms) may be optionally substituted by one or two groups selected from hydroxy, C? -C6 alkyl, d6C6 alkoxy? C1-C10 acyl, C1-C10 acyloxy, C6-C6 aryl, heteroaryl C2-C9, (C6-C? 0 aryl) (C? -C6 alkyl), (C2-C8 heteroaryl) (Ci-C? Alkyl), hydroxy (d-C6 alkyl), (C? -C6 alkoxy) (alkyl) d-Cß), (acyloxy d-C6), (C? -C6 alkyl), (C? -Ce) thio alkyl, (C6 alkyl) thio (alkyl, C? -C6), (C6-C10 aryl) ) thio, (aryl C6-C? 0) thio (alkyl d-C6), R12R13N-, R2R13NSO2-, R12R13N (C = O) -, R12R13N (C = O) - (CrC6 alkyl), R14SO2-, R14SO2NH -, R15 (C = O) - [NR12] -, R16O (C = O) - or R16O (C = O) - (Ci-Ce alkyl); wherein R10 is (acyl d-C6) piperazinyl, (aryl C? -Ce) piperazinyl, (C2-Cg heteroaryl) piperazinyl, (C? -C6 alkyl) piperazinyl, (C? -C6 aryl) (alkyl) C -C6) piperazinyl, (C2-Cg heteroaryl) (C? -Ce alkyl) piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, (d-C6 alkyl) piperidyl, (Ce-C o) piperidyl aryl, (C2- heteroaryl) Cg) piperidyl (d-Cß alkyl), (C 6 -C 6 aryl) piperidyl (d-Cß alkyl), (C 2 -Cg heteroaryl) piperidyl (C 1 -C 6 alkyl) or (C 1 -C 6 aryl) piperidyl; R11 is hydrogen, aryl Ce-Cio, heteroaryl C2-C9, (aryl C? -C6) (C? -C6 alkyl), (heteroaryl C2-Cg) (C6 alkyl), (alkyl d-C6) (aryl C6C6), (C6C6 alkyl) (d6C6 alkyl), (C2-C9 heteroaryl) (d6C6 alkyl), 5-dannyl, -CHR17O- (C = O) -R18 or - CH2 (C = O) -NR19R20; R12 and R13 are each independently hydrogen, C?-C6 alkyl, C2-C9 heteroaryl, (C6-C? Ar aryl) (d-C6 alkyl) or (C2-Cg heteroaryl), (d-Cß alkyl) or R12 and R13 may be taken together with the nitrogen to which they are attached and form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; R14 is trifluoromethyl, C6 alkyl, aryl Ce-C or, heteroaryl C2-Cg, (aryl C6-C? 0) (alkyl d-C6) or (heteroaryl C2-Cg) (C1-C? Alkyl); R15 is hydrogen, C -Cß alkyl, C?-C6 alkoxy, Ce-Cι aryl) (d-Cß alkyl) (Ce-Cι aryl) (C?-C6 alkoxy) or (C 2 -Cg heteroaryl) (C alquilo alkyl? -C6); R16 is alkyl C? -C6, C6-C? 0 aryl, C2-Cg heteroaryl, (C6-C? 0 aryl) (C? -C6 alkyl), 5-indanyl, -CHR17O- (C = O) -R18, -CH2 (C = O) -NR19R200 or -R21O (C6 alkyl); R17 is hydrogen or C? -C6 alkyl; R 18 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 6 aryl; R19 and R20 are each independently, hydrogen or C? -C6 alkyl, or can be taken together with the nitrogen to which they are attached and form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl ring; R21 is H2N (CHR22) (C = O) -; R22 is the side chain of a natural D- or L-amino acid; R23 is hydrogen, C? -C6 acyl, d-C6 alkyl, (Ce-Cio aryl) (Ci-C? Alkyl), (C2-C9 heteroaryl) (d-C? Alkyl) or (d-C6 alkyl) sulfonyl; R24, whenever it appears is independently hydrogen or Ci-Cß alkyl; or R1 and R2, or R3 and R4, or R5 and R6 can be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R5 and R6, or R7 and R8 can be taken together to form a cycloalkyl or, C3-C6, oxacyclohexyl, thiocyclohexyl, indanyl tetralinyl ring or a group of formula Q is C 1 -C 10 alkyl, C 6 -do aryl, (C 6 -C 0 aryloxy) (C 6 -C 0 aryl), (C 6 -do aryl) (C 6 -do aryl), (Ce-Cι aryl) (aryl Ce-Cío) (alkyl d-Cß), (aryl Ce-Cio) (C6-C6 alkoxy) (C6-C6 alkyl), (C6-C6-aryloxy) (C2-C9 heteroaryl), (C? -C6 alkyl) (C6-C? o aryl), (C6-alkoxy) (C6-C? 0 aryl), (C6-do aryl) (alkoxy) C? -C6) (Ce-Cι aryl), (C2-C9 heteroaryloxy) (C1-C6 alkyl), (d-Cß alkyl) (aryloxy Ce-Cio) (aryl Ce-Cι), (alkyl d-Cß), (heteroaryloxy C2-C8) (aryl C6-d0), (alkyl d-C6), (aryloxy C6-C? O) (heteroaryl C2- C8), (CrC6 alkoxy) (aryloxy Cedo) (C6-C0 aryl), (C1-C6 alkoxy) (C2-C9 heteroaryloxy) (Ce-C o aryl) or (C6-C6 alkoxy) (aryloxy Ce -Cio) (C2-C9 heteroaryl), optionally substituted by Fluoro, chloro, C? -C6 alkyl, C? -C6 alkoxy or perfluoro (C1-C3 alkyl); with the proviso that when y is zero, Q is different from (aryl Ce-Cio) (aryl Cedo), (aryl Ce-Cio) (alkoxy C? -C6) (aryl Ce-Cío) or (aryl Ce-Cío) ) (d-Cβ alkoxy) (C? -C9 heteroaryl), and any of R1-R9 is a group of formula II, then Z must be substituted when it is defined as azetidinyl, pyrrolidinyl, 10 morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, * tetrahydroisoquinolinyl, piperazinyl, (C 1 -C 10 acyl) piperazinyl, (d-Cß alkyl) piperazinyl (Ce-Cι aryl) piperazinyl, (C2-Cg heteroaryl) piperazinyl or a bridged diazabicyclic ring; with the proviso that when y is zero, Q is different from (aryl C6-C? 0) (aryl Ce-Cio), (aryl C6-C? 0) (C6-C6 alkoxy) (aryl C6-15 C10) ) or (Ce-Cι aryl) (Ci-Cβ alkoxy) (Ci-Cg heteroaryl), then at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 should be defined as the group of formula II; with the proviso that when Q is (aryl C6-C? o) (aryl Ce-C o), (aryl Cedo) (alkoxy CrC6) (aryl C6-C? o) or (aryl Ce-Cio) (alkoxy C) ? -C6) (heteroaryl d- C9), then R1-R9 may be different from formula II but when R1, R2, R3, R4, R5, R6, R7, R8 and R9 are all defined by hydrogen or C1-C6 alkyl, X or Y is oxygen, sulfur, SO, SO2- or nitrogen, or the broken line represents a double bond; with the proviso that R7 is other than hydrogen only when R8 is other than hydrogen; with the proviso that R6 it is distinct from hydrogen only when R5 is other than hydrogen; with the proviso that R3 is other than hydrogen only when R4 is other than hydrogen; with the proviso that R2 is other than hydrogen only when R1 is other than hydrogen; with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom can not be directly attached at the 2 or 6 positions of the ring; with the proviso that when X is nitrogen, R4 is not present; with the proviso that when X is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group consisting of R1, R2 and R5 and R6 is a substituent comprising a heteroatom, the heteroatom can not be directly attached at the positions 4 or 6; with the proviso that when Y is oxygen, sulfur, SO, SO2 or nitrogen and when one or more of the group formed by R3, R4 and R7 and R8 are, independently, a substituent comprising a heteroatom, the heteroatom can not be directly attached in positions 3 or 5; with the proviso that when y is 1 and W is NR24 or oxygen, Z can not be hydroxy; with the proviso that when Y is oxygen, sulfur SO or SO2, R5 and R6 are not present; with the proviso that when Y is nitrogen, R6 is not present; with the proviso that when the dashed line represents a double bond, R4 and R6 are not present; with the proviso that when R3 and R5 are, independently, a substituent comprising a heteroatom when the broken line represents a double bond, the heteroatom can not be directly attached at the X and Y positions; with the condition that when, either the X or Y position is oxygen, sulfur, SO, SO2 or nitrogen, the other X or Y is carbon; with the proviso that when X or Y is defined by a heteroatom, the dashed line does not represent a double bond.

2. A compound according to claim 1, wherein Y is oxygen, carbon, sulfur, SO or SO2.

3. A compound according to claim 1, wherein Q is (aryl) Ce-Cio) - (Ce-Cι aryl), (C6-C 0 aryl) (C6-C6 alkoxy) (C2-Cg heterooryl) (C-alkoxy) C6), (aryl Ce-Cι) (aryl C6-do) (alkoxy CrC6) (alkyl C? -6) or (aryl C6-do) (C6-C6 alkoxy) (C6-C6 alkyl), each terminal aryl group being optionally substituted by fluoro.

4. A compound according to claim 1, wherein R2, R3 R6 R7 and R9 are hydrogen.

5. A compound according to claim 1, wherein Y is carbon; Q is (C -C6 alkoxy) (C6-do aryl), (C6-d0 aryl) (C6-C6 alkoxy) (Ce-do aryl) or (C6-C6 alkoxy) (d-C6 alkyl).

6. A compound according to claim 1, wherein Y is oxygen, sulfur, SO or SO2.

7. A compound according to claim 3, wherein Y is oxygen, sulfur, SO or SO2.

8. A compound according to claim 1, wherein at least one of R7-R9 is other than hydrogen.

9. A compound according to claim 3, wherein at least one of R7-R9 is other than hydrogen.

10. - A compound according to claim 6, wherein at least one of R7-R9 is other than hydrogen.

11. A compound according to claim 7, wherein at least one of R7-R9 is other than hydrogen.

12. A compound according to claim 1, wherein at least one of R7-R9 is C6-C6 alkyl 6-

13. A compound according to claim 3, wherein at least one of R7-R9 is C? -C6 alkyl.

14. A compound according to claim 6, wherein at least one of R7-R9 is d-C6 alkyl.

15. A compound according to claim 7, wherein at least one of R7-R9 is Ci-Cß alkyl.

16. A compound according to claim 1, wherein at least one of R7-R9 is methyl.

17. A compound according to claim 3, wherein at least one of R7-R9 is methyl.

18. A compound according to claim 6, wherein at least one of R7-R9 is methyl.

19. A compound according to claim 7, wherein at least one of R7-R9 is methyl.

20. A compound according to claim 1, wherein R7 and R8 are taken together to form a carbonyl and R9 is CrC6 alkyl.

21. - A compound according to claim 3, wherein R7 and R8 are taken together to form a carbonyl and R9 is Ci-Cß alkyl.

22. A compound according to claim 6, wherein R7 and R8 ) l are taken together to form a carbonyl and R 9 is C 1 -C 5 alkyl-

23. A compound according to claim 7, wherein R 7 and R 8 are taken together to form a carbonyl and R 9 is C 6 alkyl .

24. A compound according to claim 1, wherein R7 and R8 are each methyl.

25. A compound according to claim 3, wherein R7 and R8 are each methyl.

26. A compound according to claim 6, wherein R7 and R8 are each methyl.

27. A compound according to claim 7, wherein R7 and R8 are each methyl.

28. A compound according to claim 1, wherein R7 and R8 are taken together to form a C3-C6 cycloalkyl group.

29. A compound according to claim 3, wherein R7 and R8 are taken together to form a C3-C6 cycloalkyl group.

30. A compound according to claim 6, wherein R7 and R8 are taken together to form a C3-C6 cycloalkyl group.

31. A compound according to claim 8, wherein R7 and R8 are taken together to form a C3-C6 cycloalkyl group.

32. - A compound according to claim 1, said compound being selected from the group consisting of: acid (2 R, 4 R) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4 -carboxylic; the (2R, 4R) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -2- V 5 hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester; (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-sulfonyl] -2-hydroxycarbamoyl-p -peridine-4-carboxylic acid; (2R, 4R) -1- [3- (4-fluorophenoxy) -propane-1-suphonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester; isopropyl ester of (2R, 3S) - acid. { 1 - [4- (4-Fluorobenzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} - 10 carbamic; 3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; 3- (S) -4- [4- (4,1-Fluorobenzyloxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; hydroxyamide of (2R, 4S) -1- [4- (4-fluorobenzyloxy) -benzenesulfonyl] -4-hydroxy-piperidine-2-carboxylic acid; and acid hydroxyamide hydrochloride 15 (2R, 4R) -1 - (4-methoxybenzenesulfonyl) -4- (piperazine-1 -carbonyl) -piperidine-2-carboxylic acid; 33.- A pharmaceutical composition for (a) the treatment of a disorder selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, 20 vesicular epidermolysis, scleritis, in combination with NSAIDs and conventional analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, septic shock and other diseases that they involve 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 * an amount of a compound of claim 1 effective in said treatment and a pharmaceutically acceptable carrier. 34. The use of a compound according to claim 1 for the manufacture of a medicament for inhibiting (a) the metalloproteinases of the matrix or (b) the production of the tumor necrosis factor (TNF) in a mammal, including a human being. 10 35.- The use of a compound in accordance with the »Claim 1 or the combination of said compound according to claim 1 with conventional NSAIDs and analgesics and in combination with cytotoxic anticancer agents, for the manufacture of a medicament for treating a disorder selected from among arthritis, osteoporosis, cancer, 15 tissue ulceration, macular degeneration, restenosis, periodontal disease, vesicular epidermolysis, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, septic shock and other diseases involving the production of tumor necrosis factor (TNF) ) in a mammal, including a being 20 human.