MXPA99007315A - N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases - Google Patents

Abstract

A compound of formula (I) wherein R1, R2, R3, R4 and Q are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use as matrix metalloproteinases inhibitors and for the production of tumor necrosis factor (TNF).

Description

DERIVATIVES OF N-HIDROXI-ß-SULFONILPROPIONAMIDA BACKGROUND OF THE INVENTION The present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of the matrix metalloproteinases or the production of tumor necrosis factor (TNF) and which as such are useful in the treatment of selected states from the group consisting of arthritis, osteoporosis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, such as AIDS, septicemia or septic shock and other diseases in the that TNF production is involved. In addition, the compounds of the present invention can be used in combination therapy with nonsteroidal anti-inflammatory drugs (hereinafter NSAIDs) and conventional 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 several enzymes that carry out the degradation of structural proteins and that are structurally related metalloproteases. Metalloproteinases that degrade the matrix, such as gelatinase, stromelysin, and collagenase, are involved in the degradation of matrix tissue (eg collagen collapses) and have been implicated in many disease states involving a abnormal metabolism of the basal lamina and connective tissue matrix, such as arthritis (eg, osteoarthritis and rheumatoid arthritis), tissue ulceration (eg, corneal, epidermal and gastric ulceration), abnormal wound healing , periodontal disease, bone disease (eg, Paget's disease and osteoporosis), metastasis or tumor invasion, as well as HIV infection (J. Leuk, Biol., 52 (2): 244-248, 1992) . It is known that tumor necrosis factor is involved in many infectious and self-immune diseases (W. Fiers, FEBS Letters, 285, 199, 1991). In addition, TNF has been shown to be the primary mediator of the inflammatory response observed in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 62 S1 1, 1992).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula wherein R 1 is hydrogen, hydroxy, aryl (Ce-Cι) alkoxy (Cβ-Ci), alkoxy (C?-C6), alkyl (d-Ce) (C = O) O-, alkoxy (C -? - C6) (C = O) O-, aryl (C6-C10) (C = O) O-, aryloxy (C6-C? O) (C =) O-, aryl (C6-C0) alkyl (d-) C6) (C = O) O- or aryl (C6-C? O) alkoxy (C? -C6) (C = O) O-; wherein said aryl moiety of the groups aryl (C6-C? 0) alkoxy (CrC6), aryl (Ce-do) (C = O) O-, aryloxy (C6-C? 0) (C = O) O -, aryl (C6-C10) alkyl (d-C6) (C = O) O- or aryl (C-C-io) C6-C6 alkoxy) (C = O) O- Cited is optionally substituted by one or more substituents (preferably one to three substituents) independently selected from fluorine, chlorine, bromine, alkyl (d-C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Cß-C-IO); R2 is hydrogen or alkyl (C? -C6); R3 and R4 are independently selected from the group consisting of hydrogen, (C? -C6) alkyl, trifluoromethyl, trifluoromethylalkyl (d-C?), Alkyl (d-C6) (difluoromethylene), (C1-C3) alkyl ( difluoromethylene) -alkyl (d-C3), aryl (C6-C? o), heteroaryl (C2-C9), aryl (C6-C? o) alkyl (C? -C6), heteroaryl (C2-C9) alkyl ( C? -C6), aryl (C6-C? 0), aryl (C6-C? 0), aryl (C6-C? 0) aryl (C6-C? 0) alkyl (C? -C6), hydroxyalkyl ( C? -C6), alkyl (C? -C6) (C = O) O-alkyl (C? -C6), alkoxy (d-C6) (C = O) O-alkyl (CrC6), aryl (C6-C? o) (C = O) O-alkyl (C? -C6), aryloxy (C6-C? 0) (C = O) O-alkyl (d-C6), aryl (C6-) C? 0) alkyl (d-C6) (C = O) O-alkyl (C? -C6), aryl (C6-C10) alkoxy (C? -C6) (C = 0) O-alkyl (d-? C6), alkoxy (d-C6) alkyl (Ci-Ce), aryloxy (C6-C? 0) alkyl (C? -C6), aryl (C6-C? 0) alkoxy (Ci-C-alkylalkyl (d-C6) , (C2-C9) heteroaryl (C6-6) alkoxy (C6-6) alkyl, aminoalkyl (C6-6), alkylamino (d6-6) alkyl (C6-6), [alkyl (d6-6) ] 2-aminoalkyl (C? -C6), alkyl (C? -C6) (C = 0) NH-aqluyl (dCe), alkoxy (d-C6) (C = 0) NH-alkyl (d-C6), aryl ( Cement) (C = O) NH-alkyl (C? -C6), aryloxy (C6-C? 0) (C = 0) NH-alkyl (C? -C6), aryl (C6-Cio) alkyl (d-? C6) (C = O) NH-alkyl (C-C6), aryl (C6-C? 0) alkoxy (C? -C6) (C = O) NH-alkyl (C? -C6), alkylsulfonyl (d-) Cß) alkyl (d-Cß), aryl (Ce-Cι) sulfonyl alkyl (C?-C6), R5CO-alkyl (Ci-Ce) or Realkyl (C?-C6); or R3 and R4 can be taken together with the carbon atom to which they are attached to form a cycloalkyl ring (C3-O3) or a cycloalkyl (OrC? Jbenzocondensate or a group of formula wherein the carbon atom having the asterisk is the carbon to which R3 and R4 are joined, "n" and "m" are independently selected between the values one and two, and X is CF2, O, SO2 or NR9, wherein R9 is hydrogen, (C? -C6) alkyl, (C6-C? O) aryl, (C2-C9) heteroaryl, (C6-d0) aryl (d-Cs) alkyl, heteroaryl (c2-) C9) alkyl (C? -C6), alkyl (d-C?) Sulfonyl, aryl (C6-C? O) sulfonyl, alkyl (d-C?) (C = O) -, alkoxy (C? -C6) (C = O) -, aryl (C6-C10) (C = O) -, aryloxy (C6-C? 0) (C = O) -, aryl (Ce-Cio) alkyl (d-C6) (C = O) - or aryl (Ce-Cι) alkoxy (d-C6) (C = O) -; where each of the aryl moieties (C6-C? o), heteroaryl (C2-Cg) or cycloalkyl (C3-C6) of the aryl ring (Ce-Cio), heteroaryl (C2-C9), aryl (Ce-Cío) alkyl (C? -C6), heteroaryl (C2-C9) alkyl (d-Cß), aryl (C6-C? 0) aryl (C6-C? 0), aryl (Ce-Cio) aryl (C6-C? o) alkyl (d-C6), aryl (Ce-Cio) (C = O) O-alkyl (d-C6), aryl (C6-C10) alkyl (C? -C6) (C = O) O-alkyl (C? -C6), aryloxy (C6-C? 0) alkyl (C? -6), aryl (C6-d0) alkoxy (C-C6) (C = O) O-alkyl (C? -C6), aryl (C6-C? 0) alkoxy (C? -C6), alkyl (C? -6) heteroaryl (C2-C9) alkoxy (C6-6) alkyl (C6), aryl (C6-C6) ) (C = O) NH-alkyl (d-C6), aryl (Ce-Cio) alkyl (d-C6) (C = O) NH-alkyl (C? -C6), aryl (Ce-Cio) alkoxy ( d-C6) (C = O) NH-alkyl (d-C6), aryl (C6-C? 0) sulfonyl, aryl (Ce-Cι) sulfonyl alkyl (d-C6), aryl (Ce-Cι) (C = O) -, aryl (C6-C? 0) alkyl (d-C6) (C = O) -, aryl (C6-C0) alkoxy (C1-C6) (C = 0) -, cycloalkyl (C3-) Ce) or cited cycloalkyl (C3-C-6) benzocondensate may be optionally substituted at any ring atom. peace of forming an additional bond by a substituent (preferably one to three substituents per ring) selected independently from the group consisting of fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (d-C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio); or when R3 and R4 are taken together with the carbon atom to which they are attached to form a group of formula then any of the carbon atoms of said ring, capable of forming an additional bond, may be optionally substituted by a substituent (preferably from zero to three substitutents) selected independently from the group consisting of fluorine, chlorine, bromine, alkyl (CI-CT), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio); R5 is R6O or R6R7N in which R6 and R7 are each independently selected from the group consisting of hydrogen, (C? -C6) alkyl, aryl (C6-C? O) alkyl (C? -C6) or heteroaryl (C2-Cg) alkyl (C6C6); where each of the aryl (Ce-Cio) and heteroaryl (C2-Cg) moieties mentioned of the aryl groups (C6-C? o) alkyl (C? -C6) or heteroaryl (C2-Cg) alkyl (C? - C6) can optionally be substituted by one or more substituents selected independently from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1 -C3) and aryloxy (Ce-Cio); or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from piperazinyl, alkyl (C? -C6) piperazinyl, aryl (Ce-Cyclo) piperazinyl, heteroaryl (C2-Cg) piperazinyl, aryl (Ce-Cι) alkyl (C?-C6) piperazinyl, heteroaryl (C2-Cg) alkyl (Ci-Cβ) piperazinyl, alkyl (C?-C6) (C = O) -piperazinyl , (d-C6) alkoxy (C = O) -piperazinyl, aryl (C6-C? 0) (C = O) -piperazinyl, aryl (C6-C? 0) alkyl (C? -C6) (C = 0 ) -piperazinyl, aryl (C6-C? 0) alkoxy (d-Cβ) (C = O) -piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl; wherein each of the piperazinyl, alkyl (Ci-Cß) piperazinyl, aryl (C6-C? o) -piperazinyl, heteroaryl (C2-Cg) piperazinyl, aryl (C6-C? o) alkyl (C? -C6) piperazinyl , alkyl (d-C6) (C = O) -piperazinyl, alkoxy (d-C6) (C = O) -piperazinyl, aryl (C6-C? 0) (C = O) -piperzinyl, aryl (C6-C) 0 0) C 1 -C 6 alkyl (C =O) -piperazinyl, aryl (Ce-Cι) (C?-C6) alkoxy (C =O) -piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl mentioned may optionally be substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferably one to three substituents per ring) independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C) -C6), perfluoroalkyl (C1-C3) or perfluoroalkoxy (C1-C3) and aryloxy (C6-C0); R8 is piperazinyl, alkyl (C6C6) piperazinyl, aryl (Ce-Cyz) piperazinyl, heteroaryl (C2-Cg) piperazinyl, aryl (C6-C6) alkyl (C6C6) piperazinyl, heteroaryl (C2-) C9) alkyl (C? -C6) piperazinyl, alkyl (d-C6) (C = O) -piperazinyl, alkoxy (C? -C6) (C = O) -piperazinyl, aryl (C6-C? O) (C = O) -piperazinyl, aryl (C6-C? 0) alkyl (CrC6) (C = 0) -piperazinyl, aryl (C6-C? 0) alkoxy (C? -C6) (C = 0) -piperazinyl, morpholinyl , piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, alkyl (C? -C6) piperidyl, aryl (C6-C? o) -piperidyl, heteroaryl (C2-Cg) piperidyl, aryl (C6-C? 0) alkyl (C ? -C6) piperidyl, heteroaryl (C2-C9) alkyl (C? -C6) piperidyl, alkyl (C? -C6) (C = O) -piperidyl, (C1-C6) alkoxy (C = 0) - piperidyl, aryl (C6-do) (C = 0) -piperidyl, aryl (Cedo) alkyl (C? -C6) (C = 0) piperidyl or aryl (Ce-Cio) alkoxy (d-C6) (C = O ) -piperidyl; wherein each of the piperazinyl, (C-C6) alkyl piperazinyl, aryl (Ce-Cio) -piperazinyl, heteroaryl (C2-C9) piperazinyl, aryl (C6-C0) alkyl (d-C6) piperazinyl, heteroaryl (C2) -C9) alkyl (C? -C6) piperazinyl, alkyl (C? -C6) (C = O) -piperazinyl, alkoxy (C? -C6) (C = 0) -piperazinyl, aryl (C6-C? 0) (C = 0) -piperazinyl, aryl (C6-d0) alkyl (C? -C6) (C = O) -piperazinyl, aryl (C6-do) alkoxy (C? -C6) (C = 0) - piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, alkyl (d-C6) piperidyl, aryl (C6-C? o) piperidyl, heteroaryl (C2-Cg) piperidyl, aryl (C6-do) alkyl (C? -C6) ) piperidyl, heteroaryl (C2-Cg) alkyl (C? -C6) piperidyl, alkyl (C? -C6) - (C = O) -piperidyl, alkoxy (C? -C6) (C = O) -piperidyl, aryl) (Ce-Cio) (C = O) -piperidyl, aryl (C6-C10) alkyl (C? -C6) (C = O) -piperidyl and aryl (C6-C? 0) alkoxy (C? -C6) ( C = O) -piperidyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferred preferably from one to three substituents per ring) independently selected from fluorine, chlorine, bromine, (C1-C6) alkyl, alkoxy (Ci-Ce), perfluoroalkyl (C1-C3) or perfluoroalkoxy (C1-C3) and aryloxy (C6-C? 0); Q is alkyl (C? -C6), aryl (Ce-Cio), aryloxy (C6-C? 0) aryl (C6-C? 0), aryl (Ce-do) aryl (Ce-Cio), aryl (C6-C? 0) aryl (Ce-Cio) alkyl (d-C6), aryloxy (C6-C10) heteroaryl (C2-Cg), heteroaryl (C2-) Cg), heteroaryl (C2-Cg) heteroaryl (C2-Cg), alkyl (C? -C6) aryl (Ce-Cio), alkoxy (C? -C6) aryl (C6-C? O), aryl (C6-) C? O) (C? -C6) alkoxy (C6-C? O) aryl, (C6-C? 0) aryl (C-C6) alkoxy (C? -C6), (C2-C9) aryl heteroaryloxy C6-C10), alkyl (Ci-Ce) heteroaryl (C2-Cg), alkoxy (C6) heteroaryl (C2-C9), aryl (Cedo) alkoxy (C6-6) heteroaryl (C2-Cg), heteroaryloxy ( C2-Cg) hteroaryl (C2-C9), aryloxy (C6-C? 0) alkyl (C-C6), heteroaryloxy (C2-Cg) alkyl (CI-CT) alkyl (C? -6) aryloxy (C6-C) o) aryl (C6-C o), alkyl (CrC6) heteroaryloxy (C2-Cg) aryl (C6-C? 0), alkyl (C? -Ce) -aryloxy (C6-C? 0) heteroaryl (C2-Cg) ), alkoxy (C? -C6), aryloxy (C6-C? 0) aryl (Ce-Cio), alkoxy (d-C6) heteroaryloxy (C2-Cg) aryl (Ce-Cio) or alkoxy (C? -C6) ) aryloxy (C6-C o) -heteroaryl (C2-Cg) in which each of the aryl moieties (C6-C? 0) or heteroaryl (C2-C9) of the aryl (Ce-Cio), aryl xi (C6-C0) aryl (Ce-Cio), aryl (C6-Cio) aryl (C6-C? o), aryl (C6-C10) aryl (C? -C? 0) alkyl (Ci-Ce), aryloxy (C6-C? 0) heteroaryl (C2-Cg), heteroaryl (C2-Cg), alkyl (Ci-Cß) aryl (C6-C 0), alkoxy (C?-C6) aryl (C6-C?) ), aryl (C6-C? o) alkoxy (C? -C6) aryl (Ce-Cio), aryl (C6-C? o) alkoxy (C? -C6) alkyl (C? -6), heteroaryloxy (C2) -Cg) aryl (C6-C? 0), alkyl (d-C) heteroaryl (C2-Cg), alkoxy (C? -C6) heteroaryl (C2-Cg), aryl (C6-C? 0) alkoxy (C ? -C6) heteroaryl (C2-Cg), heteroaryloxy (C2-Cg) heteroaryl (C2-Cg), aryloxy (C6-C? 0) alkyl (CrC6), heteroaryloxy (C2-Cg), alkyl (C-C6) , alkyl (C? -C6) aryloxy (C6-C? 0) aryl (Ce-Cio), alkyl (Ci-C?) heteroaryloxy (C2-C9) aryl (C6-C10), alkyl (C? -6) aryloxy (C6-C? 0) heteroaryl (C2-C9), alkoxy (C-C6) aryloxy (C6-C0) aryl (C6-C? O), alkoxy (d-C6) heteroaryloxy (C2-Cg) aryl ( Ce-Cio) or C 1 -C 6 alkoxy (C 6 -C 0) heteroaryl (C 2 -Cg) mentioned is optionally substituted on any of the carbon atoms of the ring capable of and forming an additional bond by one or more substituents (preferably one to three substituents independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3) ), perfluoroalkoxy (C1-C3) and aryloxy (Ce-C o); with the proviso that if R3 or R4 are hydrogen, or if R3 and R4 are both hydrogen, then R1 and R4 can not both be hydrogen or R1 must be hydroxy, alkoxy (d-C6), aryl (C1-C10) alkoxy (C? -C6), alkyl (C? -C6) (C = O) O-alkyl (d-C6), alkoxy (d-C6) (C = O) O-alkyl (C? -6) , aryl (Ce-C o) (C = O) O-alkyl (d-C6), aryloxy (Ce-Cio) (C = 0) O-arylalkyl (C6-C? 0) (C = O) 0- alkyl (C? -C6) or arylalkoxy (Ce-Cio) (C = O) O-aIlkyl (C? -C6); or a pharmaceutically acceptable salt thereof. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form salts of non-toxic acid addition, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate salts , maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The invention also relates to base addition salts of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of those compounds of formula I which are acidic in nature are those which form non-base salts. toxic with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium). ), ammonium or water-soluble amine addition salts such as N-methyl-glucamine (meglumine), trimethylammonium or diethylammonium and lower alkanolammonium salts such as tris- (hydroxymethyl) methylammon and other base salts of pharmaceutically acceptable organic amines. The term "alkyl", as used herein, unless otherwise indicated, comprises saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, comprises O-alkyl groups in which "alkyl" was defined above. The term "aryl", as used herein, unless otherwise indicated, comprises an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. The term "heteroaryl", as used herein, unless otherwise indicated, comprises an organic radical derived from an aromatic heterocyclic compound by removal of a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl , imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinilyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, dolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl. The term "acyl", as used herein, unless otherwise indicated, comprises a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy, the terms "alkyl" being defined "or" aril "as above.

The term "acyloxy", as used herein, comprises O-acyl groups in which "acyl" was defined above. The compound of formula I can have chiral centers and therefore exist in different diastereomeric or 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 R 1 is OH and R 2 is hydrogen. Other preferred compounds of formula I include those in which R3 and R4 are both alkyl (d-Cß) or R3 and R4 are taken together to form an optionally substituted cycloalkyl (C3-C6) ring or a cycloalkyl ring (C3) -C6) benzocondensate or a group of formula wherein the carbon atom having the asterisk is the carbon to which R3 and R4 are attached, "n" and "m" are independently selected between the values one and two, and X is CF2, O, S02 or NR9, wherein R9 is hydrogen, (C? -C6) alkyl, (C6-C? O) aryl, (C2-C9) heteroaryl, aryl (Ce-Cio) alkyl (Ci-C?), Heteroaryl (C2-) Cg) alkyl (d-C6), alkyl (C6) sulfonyl, aryl (Ce-Cio) sulfonyl, alkyl (d-C6) (C = 0) -, alkoxy (d-C6) (C = O) -, aryl (C6-C? 0) (C = O) -, aryl (Ce-Cio) alkyl (d-C6) (C = O) - or aryl (Ce-Cio) alkoxy (C? -Ce) (C = OR)-; where each of the aryl moieties (Ce-Cio), and heteroaryl (Q? -Cg) cited from the aryl groups (Ce-Cio), heteroaryl (C-Cg), aryl (C6-C? o) alkyl (C ? -C6), heteroaryl (C2 ~ Cg) alkyl (C? -C6), aryl (C6-C? 0) sulfonyl, aryl (C6-C10) (C = O) -, aryl (C6-C? 0) alkyl (C? -C6) (C = O) - and aryl (C6-C0) alkoxy (Ci-Ce) (C = O) - recited may be optionally substituted independently with one or more substituents (preferably one to three substituents) selected independently from the group consisting of fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (C6-C? 0). More preferred compounds of formula I include those in which R3 and R4 are taken together to form an optionally substituted (C3-C6) cycloalkyl ring. Other preferred compounds of formula I include those in which R1 is hydroxy. Other preferred compounds of formula I include those in which Q is aryl (Ce-Cio) or aryloxy (Ce-Cio) aryl (Ce-C? O), wherein each of the aryl moieties (C6-C) 0 0) of the above-mentioned aryl (Ce-C o) or aryloxy (C6-C? 0) aryl (C6-C10) groups may be optionally substituted with one or more substituents independently selected from fluorine, chlorine bromine, alkyl (C? -C6), alkoxy (C? -C6) or perfluoroalkyl (C1-C3). Among the most preferred compounds of formula I are those in which Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (d-? C6) or perfluoroalkyl (C1-C3), more preferably the substituents are selected from fluorine, chlorine, (C1-C6) alkoxy or alkyl (CI-CT), most preferably the substituent is in the 4-position. Particular preferred compounds of formula I include the following: (2S) -2, N-dihydroxy-3- (4-methoxybenzenesulfonyl) -propionamide, 3- [4- (4-fluorophenoxy) phenylsulfonyl] - 2, N-dihydroxy-propionamide, 2, N-dihydroxy-2- [1- (4-methoxybenzenesulfonyl) -cyclobutyl] acetamide, 2, N-dihydroxy-2- [1- (4-methoxybenzenesulfonyl) -cyclopentyl] acetamide, 2- [1- (4-cyclobutoxybenzenesulfonyl) -cyclobutyl] -2, N-dihydroxy-acetamide, 2- [1- (4-butoxybenzenesulfonyl) cyclobutyl] -2, N-dihydroxyacetamide, 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclobutyl} -2, N-d-hydroxy-acetamide, or 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclopentyl} -2, N-dihydroxy-acetamide. Other concrete compounds of formula I include the following: 2, N-dihydroxy-2- [1- (4-phenoxybenzenesulfonyl) -cyclopentyl] acetamide, 2, N-dihydroxy-2- [1- (4-phenoxybenzenesulfonyl) - cyclobutyl] acetamide, ester. { 1 - [4- (4-fluorophenoxy) benzenesulfonyl] cyclopentyl} Hydroxycarbamoylmethyl of acetic acid, ester. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclobutyl} Acetic acid hydroxycarbamoylmethyl, 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclopentyl} -N-hydroxy-2-methoxyacetamide, 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclobutyl} -N-hydroxy-2-methoxyacetamide, 2- [1- (4-butoxybenzenesulfonyl) cyclohexyl} -2, N-dihydroxyacetamide, 2- [1- (4-butoxybenzenesulfonyl) cyclopentyl} -2, N-dihydroxyacetamide, or 2- [1- (4-butoxybenzenesulfonyl) cyclobutyl} -2, N-dihydroxyacetamide. The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease. , epidermolysis hullosa, scleritis, in combination with NSAIDs and conventional analgesics, and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, septic shock and other diseases in which the production of tumor necrosis factor (TNF) is involved or (b) the inhibition of 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 formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier. The present invention also relates to a method of inhibiting d (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, which comprises administering to said mammal a effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, wherein the compounds of Formula I can be 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 in which factor production is involved of tumor necrosis (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 such a condition.

DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, in the reaction schemes and in the subsequent explanation, n, m, R1, R2, R3, R4, R5 R6, R7, R8 Q and X are as defined above.

SCHEME 1 VI V IV SCHEME 2 XIV XIII X IX VIII SCHEME 3 XV XVI XVII SCHEME 4 Scheme 1 refers to the preparation of compounds of formula I, wherein R3 and R4 are hydrogen. As regards scheme 1, a compound of formula I is prepared from a compound of formula II by hydrogenolysis under a hydrogen atmosphere in the presence of a catalyst in a solvent inert in the reaction. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The aforesaid reaction can be carried out at a pressure of between about 1 and about 5 atmospheres, preferably at about 3 atmospheres. Appropriate temperatures for the reaction mentioned above range from about 20 ° C (room temperature) to about 60 ° C, preferably the temperature can range from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is terminated between about 0.5 hours and about 5 hours, preferably about 3 hours. The compound of formula II is prepared from a compound of formula III by reaction with O-benzylhydroxylamine hydrochloride, an activating agent and a base in a solvent inert in the reaction. Suitable activating agents include (benzotriazol-1-yloxy) tris (dimethylammonium) phosphonium hexafluorophosphate or 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, preferably (benzotriazol-1-yloxy) hexafluorophosphate. ) tris (dimethylammonium) phosphonium. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N, N-dimethyi-aminopyridine, preferably triethylamine. The aforesaid reaction temperature may range from about 0 ° C to about 60 ° C, preferably it is from about 20 ° C (room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, the solvent is preferably methylene chloride. The reaction is terminated between about 4 hours and about 48 hours, preferably about 16 hours. The compound of formula III is prepared from a compound of formula IV by hydrogenolysis under a hydrogen atmosphere in the presence of a catalyst in a solvent inert in the reaction. Suitable catalysts include palladium or 5-10% palladium on activated carbon, preferably 10% palladium on activated carbon. Suitable solvents include acetic acid, alcohols such as ethanol, methanol or isopropanol, preferably ethanol. The aforesaid reaction can be carried out at a pressure of between about 1 and about 5 atmospheres, preferably at about 3 atmospheres. Appropriate temperatures for the reaction mentioned above range from about 20 ° C (room temperature) to about 60 ° C, the temperature can preferably range from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is terminated between about 0.5 hours and about 24 hours, preferably about 3 hours. The compounds of formula IV can be prepared from compounds of formula V by reaction with an oxidant in a solvent inert in the reaction. Suitable oxidants include o? -chloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably meia-chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. Appropriate temperatures for the aforesaid reaction range from about 0 ° C to about 60 ° C, the temperature preferably ranging from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is terminated between about 0.5 hours about 24 hours, preferably about 3 hours. The compounds of formula V, in which Ri is hydroxy, can be prepared from the compounds of formula VI by reaction with a Grignard reagent and a thiol of formula QSH in a solvent inert in the reaction. Suitable Grignard reagents include ethyl magnesium bromide or phenyl magnesium bromide, preferably ethyl magnesium bromide. Suitable solvents include esters such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably the solvent is a mixture of tetrahydrofuran and diethyl ether. Appropriate temperatures for the aforesaid reaction are between about -78 ° C and about 50 ° C, preferably between about 0 ° C and about 25 ° C (i.e., room temperature). The reaction is completed between about 1 and about 24 hours, preferably about 3 hours. The compounds of formula V, wherein R 1 is aryl (C 6 -C 6) alkoxy (Ci-Cß) or (C? -C6) alkoxy, can be prepared from compounds of formula V, wherein R1 is hydroxy, by reaction with a compound of formula R1aL, wherein L is a leaving group and R1a is aryl (Ce-Cio) alkyl (C? -C6) or alkyl (C? -C6), in the presence of a strong base in a polar aprotic solvent. Suitable leaving groups include chlorine, fluorine, bromine, mesylate, triflate or tosylate. Preferably, the leaving group is iodine. Suitable bases include sodium hydride, lithium dialkylamides such as lithium N-isopropyl-N-cyclohexylamine or lithium diisopropyl amide, potassium t-butoxide, sodium amide or potassium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1,2-dimethoxyethane), preferably THF. The aforesaid reaction is carried out between about -78 ° C and about 0 ° C, preferably at about 0 ° C. The compounds of formula V, wherein R 1 is alkyl (CrC 6) (C = 0) 0-, alkoxy (d-C 6) (C = 0) O-, aryl (Ce-Cι) (C = 0) 0- , aryloxy (Ce-Cι) (C = 0) 0-, aryl (Ce-Cι) alkyl (Ci-Ce) (C = O) O- or aryl (Ce-Cι) alkoxy (d-Ce) (C = O) O-, can be prepared from compounds of formula V, wherein R1 is hydroxy, by reaction with a compound of formula R1bL, wherein L is a leaving group and R1b is alkyl (C? -C6) - (C = O) O-, alkoxy (C? -C6) (C = O) O-, aryl (Ce-Cio) (C = O) O-, aryloxy (C6-C? 0) (C = 0) ) O-, aryl (C6-C10) alkyl (C C6) (C = 0) O- or aryl (Ce-Cio) alkoxy (C? -C6) (C = O) O-, in the presence of a base in an inert solvent in the reaction. Suitable leaving groups include chlorine, fluorine, bromine or R1bO (ie, an anhydride). Preferably, the leaving group is chloro. Suitable base bases include tertiary base amines such as triethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine. The temperature of the reaction mentioned above is between about 0 ° C and about 30 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction takes place between about 1 hour and about 24 hours, preferably about 2 hours. The compounds of formula VI can be prepared by methods well known to those of ordinary skill in the art. The compounds of formula VI can also be prepared by permeated oxidation (for example, with mefa-chloroperbenzoic acid) of the corresponding benzylic, β-unsaturated esters as described in Jerry March, Advanced Organic Chemistry, 735 (3rd Ed., 1985). ). The corresponding α, β-unsaturated benzylic esters can be prepared by condensation of Knovenagel between a monobenzyl ester of malonate and paraformaldehyde in the presence of piperidine as described in H. O.

House, Modern Synthetic Reactions, 649-651 (2nd Ed., W.A. Benjamin, Menlo Park, California, 1972). Compounds of formula VI, wherein R 2 is hydrogen, can also be prepared in racemic or enantiomerically pure form by conversion of L-, D- or D, L-serine as reported by W. Roush and B. Brown, J. Org. Chem., 47, 3387 (1992). Scheme 2 refers to the preparation of compounds of formula I, where R2 is hydrogen and R1 is OH. As regards scheme 2, the compounds of formula I can be prepared from compounds of formula VII by hydrogenolysis under hydrogen atmosphere in the presence of a catalyst in a solvent inert in the reaction. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The aforesaid reaction may be carried out at a pressure of between about 1 and about 5 atmospheres, preferably at about 3 atmospheres. Suitable temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 60 ° C, the temperature preferably ranging from about 20 ° C to about 25 ° C (i.e. at room temperature). The reaction is terminated between about 0.5 hours and about 5 hours, preferably about 3 hours.

The compounds of formula VII can be prepared from compounds of formula VIII by reaction with an alkali metal hydroxide in a polar solvent. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide. The reaction mentioned above can be carried out at a temperature between about 0 ° C and about 60 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and, optionally, a water-miscible ether such as tetrahydrofuran or 1,2-dimethoxyethane. Preferably, the solvent system is methane / water / tetrahydrofuran. The reaction takes place between about 1 and about 72 hours, preferably about 24 hours. The compound of formula VIII is prepared from a compound of formula IX by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in a solvent inert in the reaction. Suitable catalysts include (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate or 1- (3- (dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, preferably (benzotriazol-1-yloxy) hexafluorophosphate ) tris (dimethylamino) phosphonium Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or dimethylamino-pyridine, preferably triethylamine The temperature of the reaction mentioned above is between about 0 ° C and about 60 ° C , preferably between about 20 ° C and about 25 ° C (i.e., at room temperature). Suitable solvents include hologenated solvents such as methylene chloride or chloroform, preferably methylene chloride.The reaction takes place between about 4 hours and about 48 hours, preferably about 16 hours.The compound of formula IX is prepared from a comp of formula X by reaction with an excess of sodium periodate in the presence of ruthenium trichloride hydrate catalytic. The aforesaid reaction is carried out at a temperature between about 0 ° C and about 35 ° C, preferably 25 ° C (that is, at room temperature). Suitable solvents include acetone or a mixture of acetonitrile, carbon tetrachloride and water, preferably a 1: 1: 2 mixture of acetonitrile, carbon tetrachloride and water. The reaction takes place between about 0.5 and about 2 hours, preferably about 1.25 hours. The compound of formula X, wherein "P" is pivaloyl, acetyl or benzoyl, is prepared by reaction of a compound of formula XI with a group protecting reagent in the presence of a base in a reaction-inert solvent. Suitable group protective reagents include pivaloyl chloride, pivaloic anhydride, acetyl chloride, acetic anhydride, benzoyl chloride or benzoic anhydride, preferably acetic anhydride. Suitable bases include tertiary amines such as pyridine or 4-N, N-dimethylaminopyridine, preferably 4-N, N-dimethylaminopyridine. The temperature of the reaction mentioned above is between about 0 ° C and about 30 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction takes place between about 1 hour and about 24 hours, preferably about 2 hours. The compound of formula XI is prepared from a compound of formula XII by reaction with 2-furaldehyde and a strong base in a polar aprotic solvent. Suitable bases include potassium ferric butoxide, lithium diisopropylamide and butyllithium, preferably n-butyllithium 2.5 M in haxane. The temperature of the reaction mentioned above is between about -78 ° C and about 0 ° C, preferably at about -78 ° C. Suitable solvents include diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, the solvent is preferably tetrahydrofuran. The reaction takes place between about 0.25 and about 6 hours, preferably about 0.33 hours. The compound of formula XII is prepared from a compound of formula XIII by reaction with an oxidant in a solvent inert in the reaction. Suitable oxidants include meta-chloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably acid / nefa-chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. Appropriate temperatures for the reaction mentioned above range from about 0 ° C to about 60 ° C, the temperature 20 ° C and about 25 ° C (i.e., room temperature). The reaction is terminated between about 0.5 hours and about 24 hours, preferably about 3 hours. The compound of formula XIII is prepared from a compound of formula XIV by reaction with a thiol of formula QSH in the presence of a base in an aprotic solvent. Suitable bases include sodium hydride, ethyl magnesium bromide, lithium diisopropylamide, potassium hydride or sodium methoxide, preferably sodium hydride. The temperature of the reaction mentioned above is between about 0 ° C and about 60 ° C, preferably between 20 ° C and about 25 ° C (i.e., room temperature). Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N, N-dimethylformamide, preferably N, N-dimethylformamide. The reaction takes place between about 1 and about 48 hours, preferably about 16 hours. Compounds of formula XIV and QSH are commercially available or can be prepared by methods well known to someone as is normal knowledge in the art. Compounds of formula QSH can also be prepared by reaction of an alkyl or aryl halide with sodium sulfide as described in Jerry March, Advanced Organic Chemistry, 360 and 589 (3rd Ed., 1985). Alternatively, compounds of formula QSH can also be prepared by reaction of an aryldiazonium salt with sodium sulfide as described in March id. 601. Alternatively, compounds of formula QSH can also be prepared by reaction of a Grignard reagent with sulfur as described in March id. 550. Alternatively, compounds of the formula QSH can also be prepared by reduction of a sulfonyl chloride, sulfonic acid or disulfide as described in March id. 1 107 and 1 1 10. Scheme 3 refers to the preparation of compounds of formula I, wherein R 1 is other than hydroxy and R 2 is hydrogen. As regards scheme 3, the compounds of formula I are prepared from compounds of formula XVII by hydrogenolysis according to procedures analogous to the processes described for the conversion of the compounds of formula VII to the compounds of formula I in the scheme 2. The compounds of formula XVII are prepared from compounds of formula XVI by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in a solvent inert in the reaction according to procedures analogous to those of the conversion of the compounds of formula IX in those of formula VIII as described above in scheme 2. Compounds of formula XVI are prepared from compounds of formula XV by reaction with an excess of sodium periodate in the presence of a catalyst according to analogous procedures to the employees for the conversion of the compounds of formula X into those of formula IX as described above in scheme 2. Compounds of formula XV, wherein R1 is aryl (Ce-C? O) alkoxy (C -CT) or alkoxy (Ci-Cß), can be prepared from compounds of formula XI by reaction with a compound of formula R1aL, wherein L is a leaving group and R1a is aryl (Ce-Cio) alkyl (d-C6), or alkyl (d-Cß) in the presence of a strong base in a polar aprotic solvent. Suitable leaving groups include chlorine, fluorine, bromine, mesylate, triflate or tosylate.

Preferably, the leaving group is iodine. Suitable bases include lithium dialkylamides such as lithium N-iopropyl-N-cyclohexylamide or lithium diisopropylamide, potassium io-butoxide, sodium amide or potassium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1,2-dimethoxyethane), preferably THF. The aforesaid reaction is carried out between about -78 ° C and about 0 ° C, preferably at about 0 ° C. The compounds of formula XV, wherein R 1 is alkyl (d-C 6) (C = O) O-, (C 6) alkoxy (C = O) 0-, aryl (Ce-Cι) (C = O) 0 -, aryloxy (Ce-Cio) (C = O) O-, aryl (C6-C? 0) alkyl (C? -C6) (C = O) O-, or aryl (C6-C? 0) alkoxy ( d-C6) (C = O) O-, can be prepared from compounds of formula XI by reaction with a compound of formula R1 bL, wherein L is a leaving group and R b is alkyl (d-Ce) (C = O) O-, alkoxy (d-C6) (C = O) O-, aryl (C6-C? O) (C = O) O-, aryloxy (C6-Cio) (C = 0) O -, aryl (C6-do) alkyl (Ci-Ce) (C = O) O-, or aryl (C6-C? 0) alkoxy (C? -C6) (C = O) O-, in the presence of a base in an inert solvent in the reaction. Suitable leaving groups include chlorine, fluorine, bromine or (R1b) O- (ie, an anhydride). Preferably, the leaving group is chloro. Suitable base bases include tertiary base amines such as triethylamine, pyridine or 4-dimethylamino-pyridine, preferably triethylamine. The temperature of the reaction mentioned above is between about 0 ° C and about 30 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction takes place between about 1 hour and about 24 hours, preferably about 2 hours. The compounds of formula XI can be prepared according to the procedures of scheme 2. Scheme 4 refers to the preparation of compounds of formula I, where R2 is different from hydrogen and R3 and R4 are other than hydrogen. As regards scheme 4, the compounds of formula I are prepared from compounds of formula XXIII by hydrogenolysis under hydrogen atmosphere in the presence of a catalyst in a solvent inert in the reaction. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The reaction mentioned above can be carried out at a pressure of about 1 and about 5 atmospheres, preferably at about 3 atmospheres. Appropriate temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 60 ° C, the temperature preferably ranging from about 20 ° C to about 25 ° C (i.e. at room temperature). The reaction is terminated between about 0.5 hours and about 5 hours, preferably about 3 hours. The compound of formula XXIII is prepared from a compound of formula XXII by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in a solvent inert in the reaction. Suitable catalysts include (benzotriazol-1-yloxy) tris (dimethylamine) phosphonium hexafluorophosphate or 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, preferably (benzotriazole-1-hexafluorophosphate) iloxy) tris (dimethylamino) phosphonium. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or dimethylamino-pyridine, preferably triethylamine. The temperature of the reaction mentioned above is between about 0 ° C and about 60 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction takes place between about 4 hours and about 48 hours, preferably about 16 hours. The compound of formula XXII can be prepared by deprotection of a compound of formula XXI by reaction with an alkali metal hydroxide in a polar solvent. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide. The reaction mentioned above can be carried out at a temperature between about 0 ° C and about 60 ° C, preferably between about 20 ° C and about 25 ° C (that is, at room temperature). Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and, optionally, a water-miscible ether such as tetrahydrofuran or 1,2-dimethoxyethane. Preferably, the solvent system is methanol / water / tetrahydrofuran. The reaction takes place between about 1 and about 72 hours, preferably about 24 hours.

The compounds of formula XXI can be prepared from compounds of formula XII by reaction with a compound of formula XXVII wherein P 'is methyl, ethyl or benzyl, and a strong base in a polar aprotic solvent. Suitable bases include sodium hydride (NaH), potassium tert-butoxide, lithium diisopropylamide and butyllithium, preferably n-butyllithium 2.5M in hexane. The temperature of the reaction mentioned above is between about -78 ° C and about 0 ° C, preferably at about -78 ° C. Suitable solvents include diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, the solvent is preferably tetrahydrofuran. The reaction takes place between approximately 0. 25 and about 6 hours, preferably about 0.33 hours. Alternatively the compounds of formula I, wherein R 1 is other than hydroxy, R 2 is other than hydrogen and R 3 and R 4 are other than hydrogen, can be prepared from compounds of formula XXV by analogous methods to those of the conversion of the compounds of formula XXII in compounds of formula I, as described above in Scheme 4.

The compounds of formula XXV can be prepared from compounds of formula XXIV, wherein P 'is benzyl by hydrogenolysis under hydrogen atmosphere in the presence of a catalyst in a solvent inert in the reaction. Suitable catalysts include palladium or 5-10% palladium on activated carbon, preferably 10% palladium on activated carbon. Suitable solvents include acetic acid, alcohols such as ethanol, methanol or isopropanol, preferably ethanol. The aforesaid reaction can be carried out at a pressure of between about 1 and about 5 atmospheres, preferably at about 3 atmospheres. Appropriate temperatures for the reaction mentioned above range from about 20 ° C (room temperature) to about 60 ° C, the temperature can preferably range from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is terminated between about 0.5 hours and about 24 hours, preferably about 3 hours.

The compounds of formula XXIV, wherein R is aryl (Ce-C? O) (C? -C6) alkoxy or (Ci-C?) Alkoxy, can be prepared from compounds of formula XXI by reaction with a halide of alkylaryl or alkyl in the presence of a base in an aprotic solvent. Suitable bases include sodium hydride, ethyl magnesium bromide, lithium diisopropylamide, potassium hydride or sodium methoxide, preferably sodium hydride. The temperature of the reaction mentioned above is between about 0 ° C and about 60 ° C, preferably between 20 ° C and about 25 ° C (i.e., room temperature). Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N, N-dimethylformamide, preferably N, N-dimethylformamide. The reaction takes place between about 1 and about 48 hours, preferably about 16 hours.

Alternatively, the compounds of formula XXIV, wherein R 1 is alkyl (d-C 6) (C = O) O-, alkoxy (Ci-Ce) (C = O) O-, aryl (Ce-Cι) ( C = O) O-, aryloxy (Ce-Cio) (C = O) O-, aryl (C6-C 0) alkyl (d-C6) (C = O) O- or aryl (C6-C? O) alkoxy (d-C6) (C = O) O-, can be prepared from compounds of formula XXI by reaction with an aryl acyl or acyl halide in the presence of a base in an aprotic solvent. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N, N-dimethylaminopyridine, preferably triethylamine. The temperature of the reaction mentioned above may range from about 0 ° C to about 60 ° C, preferably about 20 ° C (room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, the solvent is preferably methylene chloride. The reaction is terminated between about 4 hours and about 48 hours, preferably about 16 hours.

The compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter simply to the free base compound by treatment with an alkaline reagent and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in an appropriate organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride salts, hydrobromide, acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie, 1,1'-methylene- bis- (2-hydroxy-3-naphthoate)].

Those compounds of formula I which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and specifically the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases which are employed as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I which are described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they could also be prepared by mixing together lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxides, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reagents are preferably employed in order to ensure that the reaction reaches completion and the product yield is maximum.

The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, therefore, , demonstrating its effectiveness in treating diseases characterized by matrix metalloproteinase or the production of tumor necrosis factor is shown by the following in vitro assays.

BIOLOGICAL ASSAY Inhibition of human collagenase (MMP-1) Recombinant human collagenase is activated with trypsin using the following ratio: 10 mg of trypsin per 100 mg of collagenase. Trypsin and collagenase are incubated for 10 minutes at room temperature and then a five-fold excess (50 mg / 10 mg trypsin) of soybean trypsin inhibitor is added. mM stock solutions of the inhibitors are prepared in dimethyl sulfoxide and then diluted using the following scheme: mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM Then 25 μl of each concentration was added in triplicate to the appropriate wells of a 96-well microfluor plate. The final inhibitor concentration will be a 1: 4 dilution after the addition of enzyme and substrate. In wells D1-D6 positive controls are placed (enzyme, without inhibitor) and in wells D7-D12, white (without enzyme, without inhibitors).

The collagenase is diluted to 400 ng / ml and then 25 ml is added to the appropriate wells of the microfluor plate. The final concentration of collagenase in the assay is 100 ng / ml.

A 5 mM stock solution of the substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared in dimethyl sulfoxide and then diluted to 20 mM in test tube. The assay is initiated by the addition of 50 ml of substrate per well of the microfluor plate to give a final concentration of 10 mM.

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.

The fluorescence is plotted against the time of the white samples and those containing collagenase (the data of the determinations are averaged in triplicate). Choose a time point that has a good signal (the target) and that is in the linear part of the curve (usually around 120 minutes) to determine the IC50 values. Zero time is used as the target of each compound at each concentration and these values are subtracted from the data at 120 minutes. The data is plotted as concentration of inhibitor versus control% (fluorescence of the inhibitor divided by the fluorescence of collagenase alone x 100). Cl50's are determined from the concentration of inhibitor that gives a signal that is 50% of that of the control.

If Cl50 are given as < 0.03 mM then the inhibitors were tested at concentrations of 0.3 mM, 0.03 mM, 0.03 mM and 0.003 mM.

Inhibition of qelatinase (MMP-2) Inhibition of gelatinase activity is assessed using the substrate DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2 (10 mM) under the same conditions as for the inhibition of human collagenase (MMP-1).

Activate 72 kD gelatinase with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4 ° C and dilute to give a final concentration in the 100 mg / ml assay. The inhibitors are diluted as for the inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 mM, 3 mM, 0.3 mM and 0.03 mM. Each concentration was done in triplicate.

Fluorescence readings (360 nm excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervals for 4 hours. The IC50's were determined as for the inhibition of human collagenase (MMP-1). If the IC50's are given as < 0.03 mM then the inhibitors were tested at final concentrations of 0.3 mM, 0.03 mM, 0.003 mM and 0.003 mM.

Inhibition of stromelysin activity (MMP-3) Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J., Spectrophotometric Assay for Vertébrate Collagenase, Anal. Biochem ., 147, 437-440 (1985)). Hydrolysis of the thiopeptolide substrate [Ac-Pro-Leu-Gly-SCH [CH2CH (CH3) 2] CO-Leu-Gly-OC2H5] gives a mercaptan fragment that can be controlled in the presence of Eilman reagent. Recombinant human proestromelysin is activated with trypsin using a ratio of 1 ml of a 10 mg / ml stock solution of trypsin to 26 mg of stromelysin. Trypsin and stromelysin are incubated for 15 minutes at 37 ° C followed by 10 ml of 10 mg / ml soybean trypsin inhibitor for 10 minutes at 37 ° C to quench trypsin activity. The assays are performed in a total volume of 250 ml of test tube (200 mM sodium chloride, 50 mM MES and 10 mM calcium chloride), pH 6.0) in 96-well microplates. The activated stromelysin is diluted in a test tube at 25 mg / ml. The Ellman reagent (3-carboxy-4-nitrophenyl disulfide) is prepared as a 1 M stock solution in dimethylformamide and diluted to 5 mM in a test tube with 50 ml per well to give a final concentration of 1 mM. Stock solutions of 10 mM inhibitors are prepared in dimethylsulfoxide and serially diluted with assay buffer so that each addition of 50 ml to the appropriate wells of final concentrations of 3mM, 0.3mM, 0.3mM, 0.003mM and 0.0003mM. All conditions were carried out in triplicate. A 300 mM stock solution of the substrate peptide is diluted in 15 mM dimethyl sulfoxide with assay buffer and the assay is initiated by the addition of 50 ml to each well to give a final concentration of 3mM substrate. The targets consisted of substrate peptide and Ellman's reagent without the 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 the 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 mM sodium chloride, 5 mM calcium chloride, 20 mM zinc chloride, 0.02% brijol). 25 μl of diluted enzyme per well was added from a 96-well microfluor plate. The enzyme is then diluted in a 1: 4 ratio in the assay to give a final concentration in the 100 mg / ml assay. 10 mM stock solutions of the inhibitors are prepared in dimethylsulfoxide and then diluted in assay buffer as in the dilution scheme of the human collagenase inhibition inhibitor (MMP-1): 25 μl of each is added to the microfluor plate. concentration in triplicate. The final concentrations in the assay are 30 mM, 3 mM, 0.3 mM and 0.03 mM. The substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as for the inhibition of human collagenase (MMP-1) and 50 ml is added to each well to give a final concentration in the 10 mM assay. Fluorescence readings were taken (360 nm excitation, 450 nm emission) in time 0 and every 5 minutes for 1 hour. Positive controls consisted of enzyme and substrate without inhibitor and targets only of substrate. The IC5o's were determined as for the inhibition of human collagenase (MMP-1). If Cl50 are given as < 0.03 mM then the inhibitors were assayed at final concentrations of 0.3 mM, 0.03 mM, 0.003 mM and 0.0003 mM. All the compounds of the invention were analyzed in the inhibition assay of MMP-13 had Cl50 less than 50 nM.

Inhibition of TNF production The ability of the compounds or pharmaceutically acceptable salts thereof to inhibit TNF production and, therefore, demonstrate their effectiveness in treating diseases in which TNF production is involved is shown by the next in vitro test. Human mononuclear cells were isolated from anticoagulated human blood using a Ficoll-Hypaque separation technique in one step. (2) The mononuclear cells were washed three times in Hanks Balanced Salt Solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 6 / ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 assay indicated that monocytes ranged from 17 to 24% of the total cells in these preparations. 180 ml aliquots of the cell suspension were applied in 96-well flat bottom plates (Costar). Additions of compounds and LPS (final concentration of 100 ng / ml) gave a final volume of 200 ml. All conditions were performed in triplicate. After four hours of incubation at 37 ° C in a humidified C02 incubator, the plates were removed and centrifuged (10 minutes at approximately 250 xg) and the supernatants were removed and the TNFa was assessed using the kit R &D ELISA Kit For the administration to mammals, including humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), various conventional routes could be used, including oral, parenteral (for example, intravenous, intramuscular or subcutaneous), buccal, rectal and topical. In general, the active compound will be administered at dosages between about 0.1 and 25 mg / kg body weight of the subject to be treated per day, preferably between about 0.3 and 5 mg / kg. Preferably the active compound will be administered orally or parenterally. However, some variation will necessarily occur depending on the condition of the subject to be treated. The person responsible for the administration will determine, in any case, the appropriate dose for the individual subject. The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. 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), alginic acid and certain silicates complexes, together with granulation binders such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc for compression are often very useful. Solid compositions of the same type can also be used as gelatin capsule filling; Lactose or milk sugar as well as high molecular weight polyethylene glycols are also included among the preferred materials. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, emulsifying and / or suspending agents together with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. In the case of animals, they are advantageously contained in the animal feed or in the drinking water at a concentration of 5-5000 ppm, preferably from 25 to 500 ppm. For parenteral administration (intramuscular, intraperitoneal, subcutaneous or intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be employed in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions should be adjusted and buffered in a suitable manner, preferably at a pH higher than 8, if necessary and the diluent liquid first made isotonic. These aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily achieved by conventional pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day given as a single dose or in up to three divided doses. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently administered in the form of a solution or suspension from a pump spray container that is tightened or pumped by the patient or as a spray presentation at aerosol from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by a valve that provides a measured quantity. The pressurized container or the nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The following Examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data are given in parts per million (d) and are inferred from the deuterium stabilization signal of the sample solvent (deuterochloroform unless otherwise indicated). Commercial reagents were used without further purification. THF refers to tetrahydrofuran ,. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and carried out under nitrogen pressure conditions (flash chromatography). The ambient temperature refers to 20-25 ° C.

All non-aqueous reactions are carried out under a nitrogen atmosphere for convenience and to maximize yields. The concentration under reduced pressure means that a rotary evaporator was used.

EXAMPLE 1 (2S, -2, N-DIHYDROXY-3- (4-METOXYBENENOSULFONYL, -PROPIONAMIDE (A) Benzyl ester (2S) -2-hydroxy-3-, 4-methoxy-phenylsulfanyl, propionic acid. A solution of 1 M ethyl magnesium bromide in diethyl ether (16.6 ml, 16.7 mmol) was diluted with tetrahydrofuran (32 ml) and cooled in an ice bath. A solution of 4-methoxybenzenethiol (2.3 grams, 16.7 mmol) in anhydrous tetrahydrofuran (5 ml) was added dropwise. The resulting mixture was allowed to stir at 0 ° C for 1 hour and then a solution of (2S) benzylic glycidate (2.3 grams, 12.9 mmol) in tetrahydrofuran (5 ml) was added. The mixture was stirred at room temperature for 3 hours. After quenching with water, the mixture was extracted with ether. The aqueous layer was acidified to pH 5 and extracted again with diethyl ether. The combined diethyl ether extracts were washed with water and brine, dried over magnesium sulfate and concentrated to an oil. The product, (2S) -2-hydroxy-3- (4-methoxyphenylsulfanyl) -propionic acid benzyl ester (3.6 grams, 88%) was isolated as a light yellow oil by chromatography on silica gel using diethyl ether / hexane 1 : 1 as eluent.

(B) Benzyl ester of (2S, -2-hydroxy-3- (4-methoxybenzenesulfonyl, propionic acid) A solution of (2S) -2-hydroxy-3- (4-methoxyphenylsulfanyl) propionic acid benzyl ester (3.6) grams, 11 mmol) in methylene chloride (25 ml) in an ice bath and a solution of 50% meta-chloroperbenzoic acid (8.4 grams, 24 mmol) in methylene chloride (75 ml) was added dropwise. The resulting mixture was stirred at room temperature for 4 hours.After quenching with a saturated aqueous sodium bisulfite solution, the mixture was extracted with diethyl ether.The extract was washed with a saturated aqueous sodium bicarbonate solution and brine, dried magnesium sulfate and concentrated to a white solid, recrystallization from hexane / ethyl acetate 1: 1 gave the (2S) -2-hydroxy-3-methoxybenzenesulfonyl) propionic acid benzyl ester (3.2 grams, 84%). %) as a white crystalline solid.

(C) (2S, -2-hydroxy-3- (4-methoxybenzenesulfonyl) propionic acid) A solution of (2S) -2-hydroxy-3- (4-methoxybenzenesulfonyl) propionic acid benzyl ester (1.0 grams, 2.8 mmol) in methanol (70 ml) with 10% palladium on activated charcoal (100 mg) and hydrogenated at 3 atmospheres of pressure for 3 hours on a Parr shaker. The catalyst was removed by filtration through the earth. diatomaceous earth and the filtrate was concentrated to give (2S) -2-hydroxy-3- (4-methoxybenzenesulfonyl) propionic acid as a white foam (729 mg, 100%).

(D) (2S, -N-benzyloxy-2-hydroxy-3- (4-methoxybenzenesulfonyl) propionamide To a solution of (2S) -2-hydroxy-3- (4-methoxybenzenesulfonyl) propionic acid (800 mg, 3.0 mmol), O-benzylhydroxylamine hydrochloride (526 mg, 3.3 mmol) and triethylamine (1.2 ml, 9.0 mmol 9) in methylene chloride (80 ml) was added with (benzotriazol-1-yloxy) tris hexafluorophosphate ( dimethylamino) phosphonium (1.4, grams 3.3 mmol.) The reaction mixture was stirred at room temperature for 16 hours and then diluted with methylene chloride.The solution was washed successively with a solution of saturated aqueous sodium bicarbonate, water, solution of 0.5 M aqueous hydrochloric acid and saturated brine.After drying over magnesium sulfate, the solvent was evaporated to give an oil.The desired product, (2S) -N-benzyloxy-2-hydroxy-3- (4-methoxybenzene) sulfonyl) propionamide (400 mg, 36%), was isolated by flash chromatography on silica gel eluting successively with chloroform, 1% methanol in chloroform and 2% methanol in chloroform.

(E) (2S, -2, N-dihydroxy-3- (4-methoxybenzenesulfonyl, -propionamide) A solution of (2S) -N-benzyloxy-2-hydroxy-3- (4-methoxybenzenesulfonyl) propionamide (400 mg , 1.0 mmol) in methanol (30 ml) with 5% palladium on barium sulfate (200 mg) and hydrogen at 3 atmospheres pressure for 4 hours on a Parr shaker. The catalyst was removed by passing it through a filter. 0.45 μm nylon and the filtrate was concentrated The desired product, (2S) -2, N-dihydroxy-3- (4-methoxybenzenesulfonyl) propionamide (180 mg, 65%), was isolated by flash chromatography on silica gel eluting with 5% methanol in chloroform followed by recrystallization from chloroform / methanol, melting point: 138-144 ° C, MS m / z 276 (M + 1), analysis calculated for C? oH? 3NO6S: C, 43.63; , 4.76; N, 5.09. Found: C, 43.51; H, 4.68; N, 4.95.

EXAMPLE 2 3-r4- (4-fluorophenoxy, phenylsulfonyl-2, n-dihydroxypropionamide) 3- [4- (4-Fluorophenoxy) phenylsulfonyl] -2, N-dihydroxypropionamide was prepared by a procedure similar to that described in Example 1 using (4-fluorophenoxy) -phenylthiol as starting material. It was recrystallized from chloroform. Operating point: 129-130 ° C; MS m / z 356 (M + 1); analysis calculated for C? 5H14FN? 6S-0.75 H2O: C, 48.84; H, 4.24; N, 3.80. Found: C, 49.03; H, 4.06; N, 3.86.

EXAMPLE 3 2.N-dihydroxy-2-ri- (4-methoxybenzenesulfonyl) -cyclobutylacetamide (A) 1-Cyclobutylsulfanyl-4-methoxybenzene 4-methoxybenzenethiol (5.7 g, 40.7 mmol) was added to a suspension of sodium hydride (1.17 grams, 49 mmol) in dry N, N-dimethylformamide ((50 mL). stirring for 1 hour, cyclobutyl bromide (6.0 grams, 44.4 mmol) was added The reaction mixture was stirred for 16 hours and quenched by the addition of a saturated aqueous ammonium chloride solution The solvents were evaporated The residue was collected in diethyl ether and washed successively with 0.5N aqueous hydrochloric acid solution, water and brine.After drying over magnesium sulfate, the diethyl ether was evaporated to give 1-cyclobutylsulfanyl-4-methoxybenzene as an oil (7.9 grams, 100%).

(B) 1-Cyclobutylsulfonyl-4-methoxybenzene A solution of 1-cyclobutylsulfanyl-4-methoxybenzene (7.9 grams, 40.7 mmol) in methylene chloride (50 ml) was cooled in an ice bath and a solution was added dropwise. of 57% m-chloroperbenzoic acid (28 grams, 92 mmol) in methylene chloride (100 ml). The resulting mixture was stirred at room temperature for 7 days. After being extinguished with a solution of saturated aqueous sodium bisulfite, the mixture was filtered to remove a white precipitate and extracted with methylene chloride. The extract was washed successively with a solution of saturated aqueous sodium bicarbonate, water and brine. After drying over magnesium sulfate, the solution was concentrated to a white solid. It was recrystallized from ethyl acetate to give 1-cyclobutyl-sulfonyl-4-methoxybenzene (7.28 grams, 79%) as a white crystalline solid.

(C) Furan-2-yl-H - (4-methoxybenzenesulfonyl) -cyclobutylmethanol A solution of 1-cyclobutyl-sulfonyl-4-methoxybenzene (4.0 grams, 17.7 mmol) in dry tetrahydrofuran (80 ml) was cooled to -78 ° C. ) and a solution of 2.5 M n-butyllithium in hexane was added in. The sample was allowed to warm to -50 ° C and re-cooled to -78 ° C. Then 2-furaldehyde was added ( 4 ml, 48 mmol) After stirring for 20 minutes at -78 ° C, the reaction was quenched by the addition of a saturated aqueous ammonium chloride solution, The resulting mixture was extracted with ethyl acetate. Water and brine were then dried over magnesium sulfate, and evaporation of the solvent gave an oil from which furan-2-yl- [4-methoxybenzenesulfonyl) cyclobutyl] methanol (4.3 grams, 75%) was isolated. Flash chromatography on silica gel eluting with ethyl acetate / hexane 1: 3.

(D) Furan-2-yl- (4-methoxybenzenesulfonyl, 2,2-dimethyl-propionic acid-cyclobutymethyl ester) A solution of furan-2-yl- [1- (4-methoxybenzenesulfonyl) was cooled in an ice bath. ) cyclobutyl] -methanol (1.57 grams, 4.9 mmol) and 4-dimethylaminopyridine (0.89 grams, 7.3 mmol) in methylene chloride (50 ml), Pivaloyl chloride (0.66 ml, 5.4 mmol) was added. at 0 ° C for 2 hours, it was diluted with methylene chloride and extracted successively with 0.5 N hydrochloric acid and brine, after drying over MgSO 4, the solvent was evaporated to leave an oil from which the desired product was isolated, 2,2-dimethyl-propionic acid furan-2-yl [1- (4-methoxybenzenesulfonyl) cyclobutyl] methyl ester (1.60 grams, 81%), by flash chromatography eluting with 16% ethyl acetate in hexane .

(E) 2,2-dimethylpropionic acid carboxy [1- (4-methoxybenzenesulfonyl) -cyclobutylmethyl ester To a solution of furan-2-yl [1- (4-methoxy-benzenesulfonyl) cyclobutyl] ester] 2,2-dimethylpropionic acid methyl ester (1.6 grams, 3.94 mmol) in acetonitrile (12 ml), carbon tetrachloride (12 ml) and water (22 ml) at room temperature was added sequentially with sodium periodate (6.73). grams, 31 mmol) and ruthenium chloride (III) hydrate (21 mg). The mixture was stirred at room temperature for 1.25 hours and then diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate to obtain the crude product, the carboxy [1- (4-methoxybenzenesulfonyl) cyclobutyl] -methyl ester of 2,2-dimethylpropionic acid, as an oil.

(F) Benzyloxycarbamoyl- [1- (4-methoxybenzenesulfonyl) 2,2-dimethylpropionic acid cyclobutymethyl ester The entire crude carboxy [1- (4-methoxybenzenesulfonyl) cyclobutyl] methyl ester sample of 2,2-dimethylpropionic acid obtained in the step E in methylene chloride (60 ml) Next, O-benzylhydroxylamine hydrochloride (0.69 grams, 4.3 mmol), triethylamine (1.6 ml, 1.5 mmol) and (benzotriazol-1-yloxy) hexafluorophosphate were sequentially added. tris- (dimethylamino) phosphonium (1.91 grams, 4.3 mmol) The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo.The residue was taken up in ethyl acetate and the resulting solution was washed successively with a solution of 0.5M aqueous hydrochloric acid, aqueous sodium bicarbonate solution and brine.After drying over magnesium sulfate, the solvent was evaporated to give an oil.The desired product, benzyloxycarbamoyl ester 2,2-dimethylpropionic acid [1- (4-methoxybenzenesulfonyl) -cyclobutyl] methyl] (0.87 grams, 46%) was isolated by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane.

(G) N-benzyloxy-2-hydroxy-2- [1- (4-methoxybenzenesulfonyl) cyclobutipacetamide To a solution of the benzyloxycarbamoyl- [1- (4-methoxybenzenesulfonyl) cyclobutyl] methyl ester of 2,2-dimethylpropionic acid (0.87) grams, 1.78 mmol) in methanol (10 ml), tetrahydrofuran (5 ml) and water (5 ml) was added lithium hydroxide hydrate (0.37 grams, 8.8 mol). The mixture was stirred at room temperature for 24 hours. Then the ion exchange resin Amberlite IR.120 washed with methanol (6 grams) was added. After stirring for 15 minutes, the mixture was filtered. The filtrate was concentrated and the residue was taken up in ethyl acetate. The resulting solution was washed with a saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give the desired product, N-benzyloxy-2-hydroxy-2- [1- (4-betoxybenzenesulfonyl) - cyclobutyl] acetamide, as an oil (0.72 grams, 100%).

(H) Nd-Hydroxy-2-ri- (4-methoxybenzenesulfonyl) -cyclobutylacetamide A solution of N-benzyloxy-2-hydroxy-2- [1- (4-methoxybenzenesulfonyl) cyclobutyl] acetamide (0.13 grams, 0.32 g. mmol) in methanol (30 ml) with 5% palladium on barium sulfate (0.07 grams) and hydrogenated at 3 atmospheres pressure for 4 hours on a Parr shaker. The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated. The desired product, 2, N-dihydroxy-2- [1- (4-methoxybenzenesulfonyl) -cyclobutyl-acetamide (0.061 grams, 65%), was isolated as a foam by flash chromatography on silica gel eluting sequentially with chloroform, methanol 1 % in chloroform and 2% methanol in chloroform .EM m / z 314 (M-1).

EXAMPLE 4 2, N-Dihydroxy-2-ri- (4-methoxybenzenesulfonyl) -cyclopentynacetamide 2, N-Dihydroxy-2- [1- (4-methoxybenzenesulfonyl) cyclopentyl-acetamide was prepared by a procedure similar to that described in Example 3 using 4-methoxybenzenethiol and cyclopentyl bromide as starting materials. MS m / z 328 (M-1). EXAMPLE 5 2-. { 1-f4- (4-fluorophenoxy) benzenesulfonylpcyclobutyl > -2.N-dihydroxyacetamide. 2- was prepared. { 1 - [4- (4-fluorophenoxy) benzenesulfonyl) cyclobutyl} -2, N-dihydroxyacetamide by a procedure similar to that described in Example 3 employing 4- (4-fluorophenoxy) benzenethiol and cyclobutyl bromide as starting materials. MS m / z 394 (M-1). 4- (4-fluorophenoxy) benzenethiol was obtained in the following manner. Chlorosulfonic acid (26 ml, 0.392 mol) was added dropwise to ice-cold 4-fluorophenoxybenzene (36.9 grams 0.196 mol) with mechanical stirring. Once the addition was completed, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4- (4-fluorophenoxy) benzenesulfonyl chloride (18.6 grams, 33%) was collected by filtration and air dried. The 4- (4-fluorofenixi) benzenesulfonyl chloride (5.1 grams, 17.7 mmol) was added to an ice-cooled mixture of concentrated sulfuric acid (7 ml) and water (37 ml) with mechanical stirring. Then zinc powder (6.2 grams, 95 mmol) was added in portions. The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours and reflux for 3 hours. After cooling to room temperature, the mixture was quenched by the addition of ice. The resulting mixture was extracted with toluene. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to give 4- (4-fluorophenoxy) -benzenethiol as a white solid (3.3 grams, 84%).

EXAMPLE 6 2-. { 1-r4- (4-fluorophenoxy) benzenesulfon-p-cyclopentyl-2, N-dihydroxyacetamida It was prepared 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclopentyl} -2, N-dihydroxyacetamide by a procedure similar to that described in Example 3 employing (4-fluorophenoxy) benzenethiol and cyclopentyl bromide as starting materials. MS m / z 408 (M-1).

EXAMPLE 7 2-p- (4-cyclobutoxybenzenesulfonyl) cyclobutyn-2, N-dihydroxy acetamide 2- [1- (4-Cyclobutoxybenzenesulfonyl) -cyclobutyl] -2, N-dihydroxyacetamide was prepared by a procedure similar to that described in Example 3 employing 1-cyclobutoxy-4-cyclobutylsulfanylbenzene as the starting material in step B. MS: 354 (M-1).

EXAMPLE 8 2-ri- (4-butoxybenzenesulfonyl) cyclobutyl 1-2, N-dihydroxy acetamide 2- [1- (4-Butoxybenzenesulfonyl) cyclobutyl] -2, N-dihydroxyacetamide was prepared by a procedure similar to that described in Example 3 using 1-butoxy-4-cyclobutylsulfanylbenzene as the starting material in step B. MS: 356 (M-1).

PREPARATION A 4- (4-fluorophenoxy, benzenesulfonyl chloride Chlorosulfonic acid (26 ml, 0.392 mol) was added dropwise to ice-cold 4-fluorophenoxybenzene (36.9 grams, 0.196 mmol) with mechanical agitation. Once the addition was completed, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The title product was collected by filtration and air dried.

PREPARATION B 4- (4-fluorophenoxy benzenethiol 4- (4-Fluorophenoxy) benzenesulfonyl chloride (5.1 grams, 17.7 mmol) was added to an ice-cooled mixture of concentrated sulfuric acid (7 ml) and water (37 ml) with mechanical stirring. Then zinc powder (6.2 grams, 95 mmol) was added in portions. The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours and reflux for 3 hours. After cooling to room temperature, the mixture was quenched by the addition of ice. The resulting mixture was extracted with toluene. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to give the title compound as a white solid (3.3 grams, 84%).

PREPARATION C 4-cyclobutylsulfanylphenol 4-Hydroxybenzenethiol (10.0 grams 79.3 mmol) was added to a suspension of sodium hydride (1.9 grams 79.2 mmol) in N, N-dimethylformamide (50 ml). Cyclobutyl bromide (11.4 grams, 84.4 mmol) was added after the production of hydrogen was complete and the mixture had cooled to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and then quenched by the addition of water and 6N hydrochloric acid aqueous solution. The mixture was extracted with diethyl ether. The organic extract was washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil. Approximately half of this material was chromatographed on silica gel eluting with hexane / ethyl acetate / methylene chloride 9: 1: 1 to give the title compound as a clear oil (8.85 grams).

PREPARATION D 1 -CILOBUTOXI-4-CICLOBUTILSULFANILBENCENO A suspension of 60% sodium hydride in oil (1.97 grams, 49 mmol) was added to a solution of 4-cyclobutylsulfanylphenol (7.2 grams, 40 mmol) in N, N-dimethylformamide (25 ml). Once hydrogen production was complete, cyclobutyl bromide (6.4 grams, 47 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then in an oil bath at 70 ° C for 16 hours. After cooling and quenching with water, the mixture was extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to give an impure sample of the title compound as an oil. This was used without further purification.

PREPARATION E 1-BUTOXI-4-CICLOBUTILSULFANILBENCENO A suspension of 60% sodium hydride in oil (2.2 grams, 55 mmol) was added to a solution of 4-cyclobutylsulfanylphenol (8.85 grams, 49.1 mmol) in ice-cold N, N-dimethylformamide (35 mL). Once hydrogen production was complete, -1-bromo-butane (6.7 ml, 58.9 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. After cooling and quenching with water, the mixture was extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to give an impure sample of the title compound as an oil. This was used without further purification.

Claims (29)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula wherein R1 is hydrogen, hydroxy, aryl (C6-C0) alkoxy (C? -C6) alkoxy (d-C6), alkyl (C? -C6) (C = O) O-, alkoxy (d-C6) ) (C = O) O-, aryl (C6-C? 0) (C = O) O-, aryloxy (Ce-Cio) (C = O) O-, aryl (C6-C? 0) alkyl (C ? -C6) (C = O) O- or aryl (Ce-Cι) alkoxy (C? -C6) (C = O) O-; wherein said aryl moiety of the groups aryl (C6-C? 0) alkoxy (C? -C6), aryl (Ce-Cio) (C = O) O-, aryloxy (C6-Cio) (C = O) ) O-, aryl (Ce-Cι) alkyl (C? -C6) (C = O) O- or aryl (C6-C? 0) alkoxy (d-C6) (C = O) O- Cited is optionally substituted by one or more substituents (preferably one to three substituents) independently selected from fluorine, chlorine, bromine, alkyl (Ci-Cß), alkoxy (CrC6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (C6-C? 0); R2 is hydrogen or alkyl (C? -C6); R3 and R4 are independently selected from the group consisting of hydrogen, alkyl (d-C6), trifluoromethyl, trifluoromethylalkyl (C-C6), alkyl (C6-C6) (difluoromethylene), (C1-C3) alkyl ( difluoromethylene) -, (C1-C3) alkyl, (C6-C6) aryl, (C2-Cg) heteroaryl, (C6-C6) aryl (CrC6) alkyl, (C2-C9) heteroaryl (C? -C6), aryl (C6-C? 0) aryl (C6-C? 0), aryl (C6-C? 0) aryl (C6-C? 0) alkyl (C? -C6), hydroxyalkyl (d-Ce) ), alkyl (d-C6) (C = O) O-alkyl (Ci-Ce), alkoxy (C? -C6) (C = O) O-alkyl (C? -C6), aryl (Ce-Cío) (C = O) O-aikyl (d-Ce), aryloxy (C6-C? 0) (C = O) O-alkyl (C? -C6), aryl (C6-do) alkyl (C? -C6) (C = O) O-alkyl (d-C6), aryl (Ce-Cι) alkoxy (C? -C6) (C = O) O-alkyl (C? -C6), alkoxy (Ci-Ce) alkyl ( d-C6). aryloxy (C6-C? 0) alkyl (Ci-C?), aryl (C6-C? 0) alkoxy (C? -C6) alkyl (C? -C6), heteroaryl (C2-Cg) alkoxy (C? C6) alkyl (C? -C6), aminoalkyl (C? -C6), alkylamino (C? -C6), alkyl (C? -C6), [(C? -C6) alkyl] 2 aminoalkyl (C? -C6) ), alkyl (d-C6) (C = O) NH-alkyl (C? -C6), alkoxy (d-C6) (C = O) NH-alkyl (C? -6), aryl (C6-C? 0) (C = O) NH-alkyl (C? -C6), aryloxy (C6-C? 0) (C = O) NH-alkyl (C? -C6), aryl (Ce-Cio) alkyl (d-) C6) (C = O) NH-alkyl (d-C6), aryl (Ce-Cio) alkoxy (C? -C6) (C = O) NH-alkyl (d-C6), alkylsulfonyl (Ci-Ce) alkyl (C? -C6), aryl (C6-C? 0) sulfonyl alkyl (d-C6), R5CO-alkyl (d-Cß) or Realkyl (C? -C6); or R3 and R4 can be taken together with the carbon atom to which they are attached to form a cycloalkyl ring (O Cß) or a benzo-condensed cycloalkyl (OrCβ) or a group of formula in which the carbon atom having the asterisk is the carbon to which R3 and R4 are bound, "n" and "m" are independently selected between the values one and two, and X is CF2, O, SO2 or NRg, wherein R9 is hydrogen, (C1-C6) alkyl, aryl (C6-C? 0), heteroaryl (C2-Cg), aryl (C6-C or) alkyl (C-C6), heteroaryl (C2- Cg) (C1-C6) alkyl, alkyl (CI-CT) sulfonyl, aryl (C6-C? 0) sulfonyl, alkyl (d-Cß) (C = O) -, alkoxy (C? -C6) (C = O) -, aryl (C6-C10) (C = O) -, aryloxy (C6-C10) (C = O) -, aryl (Ce-Cio) alkyl (d-C6) (C = O) - or aryl (C6-C? 0) alkoxy (d-C6) (C = O) -; where each of the aryl moieties (Ce-C o), heteroaryl (C2-Cg) or cycloalkyl (C3-C6) of the aryl ring (C6-C? 0), heteroaryl (C2-Cg), aryl (C6-C) ? 0) alkyl (C? -C6), heteroaryl (C2-C9) alkyl (C? -C6), aryl (C6-C? 0) aryl (C6-C? 0), aryl (C6-C10) aryl ( C6-C? 0) alkyl (C? -C6), aryl (C6-C? 0) (C = O) O-alkyl (C? -C6), aryl (C6-C10) alkyl (d-C6) ( C = O) O-alkyl (C? -C6), aryl (Ce-Cio) alkoxy (d-C6) (C = O) O-alkyl (d-Ce), aryloxy (Ce-Cio) alkyl (d-? C6), aryl (Ce-Cio) alkoxy (C? -C6) alkyl (C? -C6), heteroaryl (C2-C9) alkoxy (C-C6) alkyl (d-C6), aryl (C6-C? 0 ) (C = O) NH-alkyl (C? -C6), aryl (Cedo) alkyl (CrC6) (C = O) NH-alkyl (C? -C6), aryl (Ce-Cio) alkoxy (C? C6) (C = O) NH-alkyl (d-C6), aryl (C6-C? 0) sulfonyl, aryl (C6-C? 0) sulfonyl alkyl (C? -C6), aryl (C6-C? ) (C = O) -, aryl (Ce-Cio) alkyl (d-C6) (C = O) -, aryl (C6-C? 0) alkoxy (C? -C6) (C = O) -, cycloalkyl (C3-C6) or cycloalkyl (C3-C6) benzocondensate mentioned may be optionally substituted in any ring atom capable of forming an additional bond by a substituent selected independently from the group consisting of fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (Ci-Cß), perfluoroalkyl (C1-C3), perfluoroalkoxy (C 1 -C 3) and aryloxy (C 6 -C 0 0); or when R3 and R4 are taken together with the carbon atom to which they are attached to form a group of formula then any of the carbon atoms of said ring, capable of forming an additional bond, may be optionally substituted by a substituent selected independently from the group consisting of fluorine, chlorine, bromine, alkyl (d-Cß), alkoxy ( C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio); R5 is R6O or R6R7N wherein R6 and R7 are each independently selected from the group consisting of hydrogen, (C? -C6) alkyl, aryl (C6-C? O) alkyl (d-Cß) or heteroaryl (C2-C9) alkyl (C6C6); where each of the aryl (Ce-Cio) and heteroaryl (C2-Cg) moieties mentioned of the aforementioned aryl (C6-do) alkyl (d-Cß) or heteroaryl (C2-C9) alkyl groups (C-C6) can optionally being substituted by one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (C1-Ce), alkoxy (d-Cß), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy ( C6-C10); or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from piperazinyl, alkyl (d-Cß), piperazinyl, aryl (C6-C? o) piperazinyl, heteroaryl (C2-C9) ) piperazinyl, aryl (Ce-Cι) alkyl (Ci-Ce) piperazinyl, heteroaryl (C2-Cg) alkyl (C?-C6), piperazinyl, (C?-C6) alkyl (C = O) -piperazinyl, alkoxy ( C? -C6) (C = O) -piperazinyl, aryl (C6-C? 0) (C = O) -piperazinyl, aryl (Ce-Cι) (C = O) -piperazinyl, aryl (Ce-do) alkyl (C? -C6) (C = O) -piperazinyl, aryl (Ce-Cι) alkoxy (C? -C6) (C = O) -piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl; wherein each of the piperazinyl, alkyl (CI-CT) piperazinyl, aryl (Ce-Cι) -piperazinyl, heteroaryl (C2-C8) piperazinyl, aryl (C6-C? 0) alkyl (C?-C6) piperazinyl, heteroaryl (C2-Cg) alkyl (C? -C6) piperazinyl, alkyl (C? -C6) (C = O) -piperazinyl, alkoxy (C-CT) (C = O) -piperazinyl, aryl (C6-C? ) (C = O) piperazinyl, aryl (C6-C? 0) alkyl (CrC6) (C = O) -piperazinyl, aryl (C6-C? O) alkoxy (dC?) (C = O) -piperazinyl, morpholinyl selected, piperidinyl, pyrrolidinyl or azetidinyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferably one to three substituents per ring) independently selected from fluorine, chlorine, bromine, alkyl (C -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3) or perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio); R8 is piperazinyl, alkyl (C6C6) piperazinyl, aryl (Ce-Cyz) piperazinyl, heteroaryl (C2-Cg) piperazinyl, aryl (C6-C6) alkyl (C-C6) piperazinyl, heteroaryl (C2-Cg) ) alkyl (C? -C6) piperazinyl, alkyl (C? -C6) (C = O) -piperazinyl, alkoxy (d-C6) (C = O) -piperazinyl, aryl (C6-C? 0) alkyl (C) ? -C6) (C = O) -piperazinyl, aryl (C6-C10) alkoxy (Ci-Cβ) (C = O) -piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, alkyl (d-C6) piperidyl, aryl (C6-C? o) -piperidyl, heteroaryl (C2-C8) piperidyl, aryl (C6-C? o) alkyl (Ci-C?) piperidyl, heteroaryl (C2-Cg) alkyl (d-Ce) piperidyl, alkyl (C? -C6) (C = O) -piperidyl, alkoxy (Ci-Ce) (C = O) -piperidyl, aryl (C6-C? O) (C = O) piperidyl or aryl (Ce-Cio) alkyl (Ci-Ce) (C = O) -piperidyl or aryl (Ce-Cι) alkoxy (Ce-Cι); wherein each of the piperazinyl, alkyl (CI-CT) piperazinyl, aryl (C6-C? o) -piperazinyl, heteroaryl (C2-Cg) piperazinyl, aryl (C6-C or) alkyl (CI-CT) piperazinyl, heteroaryl (C2-C9) alkyl (C-Ce) piperazinyl, alkyl (C = O) -piperazinyl, alkoxy (d-C6) (C = O) -piperazinyl, aryl (C6-C? O) (C = O) - piperazinyl, aryl (C6-C? o) alkyl (d-Cβ) (C = O) -piperazinyl, aryl (Ce-Cι) alkoxy (C? -C6) (C = O) -piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperidyl, alkyl (C? -C6) piperidyl, aryl (C6-C? o) piperidyl, heteroaryl (C2-Cg) piperidyl, aryl (C6-C? 0) alkyl (d-C?) piperidyl, heteroaryl (C2-Cg) alkyl (CrC6) piperidyl, alkyl (C? -C6) - (C = O) -piperidyl, alkoxy (Ci-Ce) (C = O) -piperidyl, aryl (Ce-Cio) (C = O) -piperidyl, aryl (C6-C? 0) alkyl (C? -C6) (C = O) -piperidyl and aryl (Ce-Cio) alkoxy (Ci-C?) (C = O) -piperidyl, mentioned may be optionally substituted at any ring carbon atom capable of forming an additional bond l with a substituent selected independently from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (Ci-Ce), perfluoroalkyl (C1-C3) or perfluoroalkoxy (C1-C3) and aryloxy (C6-C) ?or); Q is alkyl (C? -C6), aryl (Ce-Cio), aryloxy (Ce-Cio) aryl (C6-C? O), aryl (Ce-Cio) aryl (Ce-Cio), aryl (Ce-Cio) ) aryl (C6-C10) alkyl (d-C6), aryloxy (Ce-Cio) heteroaryl (C2-C9), heteroaryl (C2-C9), heteroaryl (C2-Cg) heteroaryl (C2-Cg), alkyl (d) -C6) aryl (C6-C10), alkoxy (C? -C6) aryl (C6-C? O), aryl (Ce-Cio) alkoxy (C? -C6) aryl (C6-C? O), aryl ( C6-C? 0) alkoxy (C? -C6) alkyl (Ci-Cß), heteroaryloxy (C2-Cg) aryl (Ce-Cio), alkyl (CI-CT), heteroaryl (C2-C9), alkoxy (Ci) -Ce) heteroaryl (C2-C9), aryl (C6-C? O) alkoxy (C-C6) heteroaryl (C2-C9), heteroaryloxy (C2-Cg) heteroaryl (C2-Cg), aryloxy (C6-C10) alkyl (d-Cß), heteroaryloxy (C2-Cg) alkyl (C? -C6), alkyl (C? -C6) aryloxy (C6-C10) aryl (C6-C? 0), alkyl (C? -6) heteroaryloxy (C2-Cg) aryl (C6-C? o), alkyl (C? -C6) -aryloxy (Ce-Cio) heteroaryl (C2-Cg), alkoxy (Ci-C?) aryloxy (C6-do) aryl ( Ce-Cio), C 1 -C 6 alkoxy heteroaryloxy (C 2 -C 9) aryl (C 6 -C 0) or alkoxy (dC 6) aryloxy (C 6 -do) -heteroaryl (Q = -Cg) wherein each of the aryl moiety (C6-C? o) or heteroaryl (C2-C9) of the aryl (C6-C10), aryloxy (Ce-Cio) aryl (Ce-Cio), aryl (Ce-Cio) aryl ( Cedo), aryl (C6-C? O) alkyl (C? -C6), aryloxy (Ce-Cio) heteroaryl (C2-Cg), heteroaryl (C2-C9), alkyl (C? -C6) aryl (Ce- Cio), alkoxy (d-C6) aryl (Ce-Cio), aryl (Ce-Cio) alkoxy (C? -C6) aryl (Ce-Cio), aryl (C6-do) alkoxy (d-C6) alkyl ( Ci-Ce), heteroaryloxy (C2-CT) aryl (C6-C? O), alkyl (C? -C6) heteroaryl (C2-Cg), aryl (C6-C? 0) alkoxy (C? -6) heteroaryl (C2-Cg), heteroaryloxy (C2-Cg) heteroaryl (C-Cg), aryloxy (C6-C? O) alkyl (C? -C6), heteroaryloxy (C2-Cg) alkyl (Ci-C?), Alkyl ( d-Cβ) aryloxy (C6-C? o) aryl (C6-C10), alkyl (C? -C6) heteroaryloxy (C2-Cg) aryl (C6-C10), alkyl (C? -6), aryloxy (C? -do) heteroaryl (C2-Cg), alkoxy (C6-6) aryloxy (C6-C6o) aryl (Ce-Cio), alkoxy (Ci-C4) heteroaryloxy (C2-C9) aryl (Ce-Cio) or (C6-Cg) -alkoxy (d-C-) aryloxy (C6-C) or heteroaryl (C2-Cg) mentioned is optionally substituted in any of the ring carbon atoms capable of forming an additional bond by one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (d-Cß), alkoxy (d-C6), perfluoroalkyl (C1-C3) , perfluoroalkoxy (C1-C3) and aryloxy (C6-C? o); with the proviso that if R3 or R4 are hydrogen, or if R3 and R4 are both hydrogen, then R and R2 can not both be hydrogen or R1 must be hydroxy, alkoxy (d-C6), aryl (C6-C? 0) (C1-C6) alkoxy, alkyl (d-C6) (C = O) O-alkyl (d-C6), (C6) alkoxy (C = O) O-alkyl (C6-6), aryl (C6-C? 0) (C = O) O-aikyl (C? -C6), aryloxy (C6-C? 0) (C = O) O-, arylalkyl (Ce-Cio) (C = O) O -alkyl (C? -C6) or arylalkoxy (C6-C? 0) (C = O) O-alkyl (C? -C6); and the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R1 is OH and R2 is hydrogen.

3. A compound according to claim 1, wherein R3 and R4 are both alkyl (d-C6) or R3 and R4 are taken together with the carbon atom to which they are attached to form a cycloalkyl ring (C3- C6) optionally substituted or a benzo-condensed (C3-C6) cycloalkyl ring or a group of formula in the "n" and "m" are independently selected between the values one and two, and X is CF2, O, SO2, or NR9, wherein R9 is hydrogen, alkyl (d-Cß), aryl (C6) -C?), Heteroaryl (C2-C9), aryl (C6-do) alkyl (C? -C6), heteroaryl (C2-C9) alkyl (C? -C6), alkyl (C? -6), sulfonyl , aryl (C6-C? o) sulfonyl, alkyl (Ci-Cß) (C = 0) -, alkoxy (C C6) (C = 0) -, aryl (C6-C? 0) (C = 0) - , aryl (C6-C? 0) alkyl (d-C6) (C = 0) - or aryl (Cedo) alkoxy (C-C6) (C = O) -; wherein each of the aryl (Ce-Cio) and heteroaryl (C2-C9) moieties mentioned of the aryl groups (C6-C? o), heteroaryl (C2-C9), aryl (C6-C? 0) alkyl (d-C6), heteroaryl (C2-C9) alkyl (C? -C6), aryl (C6-C? 0) sulfonyl, aryl (Ce-Cio) (C = O) -, aryl (C6-C? 0 ) alkyl (d-C6) (C = O) - and aryl (G6-C? 0) alkoxy (Ci-C) (C = O) - mentioned may be optionally substituted independently with one or more substituents selected in a independently from the group consisting of fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (C6-C? ).

4. A compound according to claim 2 wherein R3 and R4 are both alkyl (C? -C6) or R3 and R4 are taken together with the carbon atom to which they are attached to form a cycloalkyl ring (C3- C6) or a benzo-condensed alkyl (drCβ) ring or a group of formula in which "n" and "m" are independently selected from values one and two, and X is CF2, O S02 or NR9, in the that R9 is hydrogen, alkyl (Ci-Cd), aryl (C6-C? o), heteroaryl (C2-C6), aryl (C6-C10) alkyl (C? -6), heteroaryl (C2-C8) alkyl ( d-Os), alkyl (C? -C6) sulfonyl, aryl (C6-C? o) sulfonyl, alkyl (Cr C6) (C = O) -, alkoxy (C? -C6) (C = O) -, aryl (Ce-Cio) (C = O) -, aryl (C6-C? 0) alkyl (Ci-C6) (C = O) - or aryl (C6-C? 0) alkoxy (C? -C6) ( C = O) -; wherein each of the aryl (Ce-Cio) and heteroaryl (C2-Cg) moieties mentioned of the aryl groups (C6-C? 0), heteroaryl (C2-C9), aryl (Ce-Cio) alkyl (d) -C6), heteroaryl (C2-C9) alkyl (d-C6), aryl (Cedo) sulfonyl, aryl (Ce-Cio) (C = O) -, aryl (Ce-Cio) alkyl (Ci-Ce) (C = O) - and aryl (Cedo) (C? -C6) alkoxy (C = O) - mentioned may be optionally substituted independently with one or more substituents selected independently from the group consisting of fluorine, chlorine, bromine , alkyl (Ci-Ce), alkoxy (C-C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio).

5. A compound according to claim 1, wherein R3 and R4 are taken together to form an optionally substituted cycloalkyl (C3-C6) ring.

6. A compound according to claim 2, wherein R3 and R4 are taken together to form an optionally substituted cycloalkyl ring (OrCß).

1. - A compound according to claim 1, wherein Q is aryl (C6-C0) or aryloxy (C6-C10) aryl (C6-C or), wherein each of the aryl residues (Ce-Cio) ) of the above-mentioned aryl (C6-C? 0) or aryl (C6-C? o) aryl (C6-C? 0) groups may be optionally substituted with one or more substituents selected independently from fluorine, chlorine, bromine (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or (C 1 -C 3) perfluoroalkyl.

A compound according to claim 2, wherein Q is aryl (C6-C? O) or aryloxy (C6-C10) aryl (Ce-C o), wherein each of the aryl groups (C6) -C?) Or aryloxy (Ce-Cι) aryl (Ce-Cι) mentioned may be optionally substituted with one or more substituents selected independently from fluorine, chlorine, bromine, alkyl (d-ds), alkoxy (Ci) -Cß) or perfluoroalkyl (C 1 -C 3).

9. A compound according to claim 3, wherein Q is aryl (C6-C? O) or aryloxy (Ce-Cio) aryl (Ce-Cio), wherein each of the aryl moieties (C6- do) of the above-mentioned aryl (C6-do) or aryloxy (C6-C0) aryl (C6-C? 0) groups may be optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (d-d.), alkoxy (C? -C6) or perfluoroalkyl (C1-C3).

10. A compound according to claim 4, wherein Q is aryl (C6-C? 0) or aryloxy (C6-C? o) aryl (Ce-Cio), wherein each of the aryl residues (Ce-Cio) of the aryl groups (Ce -Cio) or aryloxy (C6-do) aryl (C6-C? O) mentioned may be optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (Ci-C6), alkoxy (C -C6) or perfluoroalkyl (C1-C3).

11. A compound according to claim 5, wherein Q aryl (Ce-Cio) or aryloxy (Ce-Cio) aryl (C6-C? 0), wherein each of the aryl moieties (C6-C) 0 0) of the above-mentioned aryl (C6-C? 0) or aryl (C6-C? 0) aryl (C6-C? 0) groups may be optionally substituted with one or more substituents independently selected from fluorine, chlorine , bromine, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or (C 1 -C 3) perfluoroalkyl.

12. A compound according to claim 1, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C?) Or perfluoroalkyl (C1-C3).

13. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (d-C6), alkoxy (C? -C6) or perfluoroalkyl (C1-C3).

A compound according to claim 3, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (d-C6), alkoxy (C? C6) or perfluoroalkyl (C1-C3).

15. A compound according to claim 4, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (Cr C6), alkoxy (C? C6) or perfluoroalkyl (C1-C3).

16. A compound according to claim 5, wherein Q is a phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C1) -O3) or perfluoroalkyl (C1-C3).

17. A compound according to claim 8, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, alkyl (d-CQ), alkoxy (Ci-Cß) ) or perfluoroalkyl (C1-C3).

18. A compound according to claim 1,. wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, (C? -C6) alkoxy or (C? -C6) alkyl.

19. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, (C? -C6) alkoxy or alkyl (Ci-C?) .

20. A compound according to claim 5, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, (C? -C6) alkoxy or alkyl (C? -C6) ).

21. A compound according to claim 8, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, (C? -C6) alkoxy or (d-C6) alkyl.

22. A compound according to claim 1, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, (C? -C6) alkoxy or alkyl (d-C6) and wherein the substituents are in the 4-position.

23. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, alkoxy ( C? -C6) or alkyl (C? -C6) and in which substituent is in the 4-position.

24. A compound according to claim 5, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluorine, chlorine, alkoxy (Ci-Cß) or alkyl (C6C6) and wherein the substituent is in the 4-position.

A compound according to claim 8, in which that Q is phenyl or phenoxyphenyl optionally substit with one or more substituents independently selected from fluorine, chlorine, alkoxy (Ci-Cß) or alkyl (C? -C6) and in which the substituent is in position 4.

26. A compound according to Claim 1, wherein said compound is selected from the group consisting of: (2S) -2, N-dihydroxy-3- (4-methoxybenzenesulfonyl) -propionamide, 3- [4- (4-fluorophenoxy) phenylsulfonyl] - 2, N-dihydroxy-propionamide, 2, N-dihydroxy-2- [1- (4-methoxybenzenesulfonyl) -cyclobutyl] acetamide, 2, N-dihydroxy-2- [1- (4-methoxybenzenesulfonyl) -cyclobutyl] acetamide, 2- [1- (4-cyclobutoxybenzenesulfonyl) cyclobutyl] -2, N-dihydroxyacetamide, 2- [1- (4-cyclobutoxybenzenesulfonyl) cyclobutyl] -2, N-dihydroxyacetamide, 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclobutyl} -2, N-dihydroxyacetamide, and 2-. { 1- [4- (4-fluorophenoxy) benzenesulfonyl] cyclopentyl} -2, N-dihydroxyacetamide.

27. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, 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 in which the production of tumor necrosis factor (TNF) or (b) is involved the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.

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

29. The use of a compound of claim 1 or the combination of said compound of claim 1 with NES and conventional analgesics, and in combination with anti-cancer cytotoxic agents, for the preparation of a medicament for treating a condition selected from the group formed by arthritis, osteoporosis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis huullosis, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, septicemia, septic shock and other diseases in the that the production of tumor necrosis factor (TNF) is involved in a mammal, including a human.