MXPA96006744A

MXPA96006744A - Hydroxamic acids substituted by arilic sulfonamide as metaloproteinase mats inhibitors

Info

Publication number: MXPA96006744A
Application number: MXPA/A/1996/006744A
Authority: MX
Inventors: Joseph Macpherson Lawrence; Thomas Parker David; Yingcheu Jeng Arco
Original assignee: Cibageigy Corporation
Priority date: 1994-06-24
Filing date: 1996-12-19
Publication date: 1998-01-01

Abstract

The compounds of the formula I: wherein R, R1, R2, and Ar are as defined in the specification, have valuable pharmaceutical properties, and are effective especially as inhibitors of matrix metalloproteinase, for example, for the treatment of arthritis. They are prepared in a manner known per se

Description

CIDOS HIDRQXA ICOS SUBSTITUTED BY ARILIC SULFONAMIDE AS MATRIX METALOPROTEINASE INHIBITORS The present invention relates to the compounds of the formula I: OR R? CH2 O ll I I II HO- N-C-C-N - S- • Ar II (I) i J wherein: Ar is carbocyclic or heterocyclic aryl; is hydrogen, lower alkyl, arylcarbohydride-lower alkyl, carbocyclic aryl. heterocyclic aryl. diaryl, lower diarylalkyl. aryl heterocyclic ico-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 atoms of carbon, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms-lower alkyl. lower hydroxyalkyl. acyloxyalkyl, lower, lower alkoxy-lower alkyl, alkyl, ipferin- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono-lower alkyl-amino) -alkyl, lower alkyl. acylaminoalkyl the lower. (N-lower alkyl-piperazino or carbocyclic N-aryl or heterocyclic-lower alkyl-J-lower alkyl-piperazole) -alkyl. or (morpholino, thio orfolino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl. . is cycloalkyl of 8 to 10 carbon atoms, (N-acylpiperidyl) -lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl, or N-lower alkyl-piperidyl) - (hydroxy or lower alkoxy) - lower alkyl, pyrrolidinyl, hexahydroazepinyl. N-lower alkyl- (hexahydroazepinyl or pyrrolidinyl), N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl), oxacycloalkyl of 5 to 10 carbon atoms, tiacycloalkyl of 5 to 10 carbon atoms, (hydroxy or oxo) -cycloalkyl of 5 to 10 carbon atoms, hydroxy or oxo) -thiacycloalkyl of 5 to 10 carbon atoms, (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms, (amino, mono- or dialkyl-lower-amino or acylamido) -cycloalkyl from 5 to 10 carbon atoms, 2-oxo- (pyrrolidinyl, piperidyl or hexahydroazepinyl); R2 is hydrogen or lower alkyl; to pharmaceutically acceptable prodrug derivatives thereof; and pharmaceutically acceptable salts thereof: in addition to a process for the preparation of these compounds, to pharmaceutical compositions comprising these compounds, to the use of these compounds for the therapeutic treatment of the human or animal body, or for the manufacture of a composition pharmaceutical Preferred are compounds of the formula I wherein Ar is monocyclic carbocyclic aryl, such as phenyl or phenyl mono-, di-, or tri-substituted by alkoxy of 1 to 10 carbon atoms, hydroxy, carbocyclic aryl or heterocyclic-lower alkoxy , cycloalkylae of 3 to 7 carbon atoms-lower alkoxy, (lower alkyl, carbocyclic aryl or heterocyclic-lower alkyl, or cycloalkyl of 3 to 7 carbon atoms-lower alkyl) -thio, lower alkyloxy-lower alkoxy, halogen , lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfopyl), amino or mono- or di-lower alkyl-amino; or Ar is phenyl substituted on the adjacent carbon atoms by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is heterocyclic monocyclic aryl such as thienyl, or thienyl substituted by lower alkyl; the other symbols have the defined meaning; the pharmaceutically acceptable prodrug derivatives thereof; and the pharmaceutically acceptable salts thereof. Further preferred are compounds of formula I wherein Ar is phenyl which is unsubstituted or mono-. di-, or tri-substituted by alkoxy of 1 to 10 carbon atoms, hydroxy; lower phenylalkoxy, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl: heterocyclic aryl-lower alkoxy, wherein the heterocyclic aryl is selected from pyridyl. tetrazolyl. triazolyl, thiazolyl. thienyl, imidazolium, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; or Ar is phenyl substituted by cycloalkyl of 3 to 7 carbon atoms-lower alkoxy, (lower alkyl, phenylalkyl, or cycloalkyl of 3 to 7 carbon atoms-lower alkyl) -thio, lower alkyloxy-lower alkoxy, halogen, alkyl lower, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amino, mono- or di-lower alkyl-amino: or Ar is phenyl substituted on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thienyl isoxazolyl, or thiazolyl. each of which is unsubstituted or mono- or di-substituted by lower alkyl: R is hydrogen, lower alkyl, phenylalkyl, wherein the fepyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; Fepyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, cyano, nitro. trifluoromethyl, lower alkyl- (thio, sulfinyl or sulfonyl). amino, mono or di-lower alkyl-amylo, or, on adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxaalkyle of 2 to 3 carbon atoms; or a heterocyclic aryl radical selected from pyridyl, tetrazolyl, triazolyl, thiazolyl. thienyl, imidazolyl. and quinolinyl. each unsubstituted or mono- or di-substituted by lower alkyl or halogen; diphenyl phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; diphenylalkyl lower, wherein the diphenylyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; (pyridyl, thienyl, quinolinyl, or thiazolyl) -lower alkyl, trifluoromethyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms carbon, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl, lower hydroxyalkyl. lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or di-lower alkyl-amino) -lower alkyl, lower alkanoyl-lower aminoalkyl, ( N-lower alkyl piperazino or N-phenylalkyl lower piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R is pyrrolidinyl; hexahydroazepinyl; N-lower alkyl- (hexahydroazepinyl or pyrrolidinyl); N-acyl- (hexahydroazepinyl, piperidyl, or pyrrolidinyl): oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) ~ cycloalkyl of 5 to 10 carbon atoms: (hydroxy or oxo) -thiacycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms: o (amino, mono- or di-alkylamino or lower alkanoyl-amino) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; a pharmaceutically acceptable prodrug thereof thereof; or a pharmaceutically acceptable salt thereof. Especially preferred are compounds of formula I wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of 1 to 7 carbon atoms, hydroxy, phenylalkoxy, cycloalkyl of 3 to 7 carbon atoms. carbon-lower alkoxy-lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (sulfipyl or sulfonyl), amino, mono- or dialkyl-lower-amino, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is tiepyl, isoxazolyl or thiazolyl, each of which is unsubstituted or mono- or disubstituted by lower alkyl: R is hydrogen; lower alkyl, lower phenylpylalkyl; phenyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy. halogen, lower alkyl. trifluoromethyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; a heterocyclic aryl radical selected from pyridyl, thiazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl: diphenylyl; diphenylalkyl lower; (pyridyl or thienyl) -lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl; (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl; 5 hydroxyalkyl lower; (N-lower alkyl-piperazino, or N-phenylalkyl-lower piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R is pyrrolidinyl; hexahydroazepinyl; N-alkyl Bottom - (hexahydroazepinyl or pyrrolidinyl); N-acyl- (hexahydroazepinyl, piperidyl, or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tarycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -thiacycloalkyl of 5 to 10 atoms carbon; (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms; or (amino, mono- or di-alkylamino, or lower alkanoyl-amylo) -cycloalkyl of 5 to 10 carbon atoms; Rn is hydrogen or lower alkyl; a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. A particular embodiment of the invention relates to the compounds of the formula II: wherein: R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 7 carbon atoms , cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -, r? > lower alkyl, lower hydroxyalkyl, lower alkylalkyalkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfopyl) -lower alkyl, (amino, mono- or lower-lower alkyl-amino) -lower alkyl, lower acylaminoalkyl, (N lower alkyl-piperazino or carbocyclic N-aryl or heterocyclic-lower alkyl-piperazino) -alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino or N-lower alkyl-piperidi lo) -lower alkyl; R. is pyrrolidipyl, hexahydroazepinyl. N-lower alkyl- (pyrrolidinyl or hexahydroazepinyl), oxacycloalkyl to 7 carbon atoms, tiacycloaicyl of 5 to 7 carbon atoms, (hydroxy or oxo) -cyclohexyl, (amino, mono- or di-lower alkyl-amino) -cyclohexyl, or 2-oxohexahydroazepinyl; R2 is hydrogen; R 4 is hydrogen, lower alkoxy, hydroxy, carbocyclic aryl or heterocyclic-lower alkoxy, lower thioalkyl, or carbocyclic aryl or heterocyclic-lower thioalkyl, lower alkoxy-lower alkoxy, halogen, trifluoromethyl, lower alkyl, nitro, or ciapo; R ^ is hydrogen, lower alkyl, or halogen; or R "and R5, on the adjacent carbon atoms, together represent ethylenedioxy, ethylenediaxy, oxyethylene or oxypropylene; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. Particularly preferred are the compounds of the formula III: wherein R represents lower alkyl, trifluororhethylide. cycloalkyl of 5 to 7 carbon atoms, (oxa or thia) -cycloalkyl of 4 to 5 carbon atoms, biaryl, mono-carboaryl aryl carbocyclic 3 co. or heterocyclic monocyclic aryl: R represents oxacycloalkyl of 5 to 7 carbon atoms, or (hydroxy, oxo, or di-lower alkyl-amino) -cyclohexyl; R ^ represents lower alkoxy or carbocyclic aryl or heterocyclic-lower alkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. Further preferred are compounds of formula III, wherein R represents monocyclic carbocyclic aryl or aryl "" * "monocyclic heterocyclic; Rj and Retain the meaning defined above; pharmaceutically acceptable proformative derivatives; And pharmaceutically acceptable salts thereof. More preferred are compounds of formula III wherein R represents heterocyclic monocyclic aryl selected from tetrazolyl, triazolyl, thiazolyl, imidazolyl, and pyridyl, each unsubstituted or substituted by lower alkyl; or R represents phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; R < represents 2-, or 3-tetrahydrofuranyl; and R ^ represents lower alkoxy or lower phenylalkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. A further preferred embodiment refers to the compounds of the formula III wherein R represents 2-, 3-, or 4-pyridyl or phenyl; R represents 2- or 3-tetrahydrofuranyl; and R? represents lower alkoxy; or a pharmaceutically acceptable prodrug derivative thereof: or a pharmaceutically acceptable salt thereof. Particularly preferred are compounds of formula III wherein R represents 3-pyridyl or 4-pyridyl; R1 represents 2-tetrahydrofuranyl; and R ^ represents lower alkoxy; 5 or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. As the subgroups of any group of compounds of - * - the formula I mentioned herein, are emphasized: (a) the compounds of the formula I wherein R ^ is 0 cycloalkyl of 8 to 10 carbon atoms, (N-lower alkoxycarbonylpiperidyl) - (lower alkoxy) ) -lower alkyl, pyrrolidinyl, N- (lower alkoxy-carbonyl, or lower di-lower alkyl-aminoalkanoyl) - (piperidyl or pyrrolidinyl), oxacycloalkyl of 5 to 10 carbon atoms, hydroxycycloalkyl of 5 to 10 carbon atoms, (hydroxy) -oxacycloalkyl of 5 to 10 carbon atoms, (lower dialkyl-amino, lower dialkyl- to lower alkalamino-amino, or lower alkoxy-carbonylamine) -cycloalkyl of 5 to 10 carbon atoms , or 2-oxopiperidyl; (b) compounds of formula I wherein R ^ is cycloalkyl of 8 to 10 carbon atoms, (N-lower alkoxycarbonylpiperidyl) - (lower alkoxy) -lower alkyl, pyrrolidipyl, N- (lower alkoxycarbonyl or lower dialkyl-lower aminoalkanoyl) - (piperidyl or pyrrolidinyl), oxacycloalkyl of 5 to 10 carbon atoms, hydroxycycloalkyl of 5 to 10 carbon atoms, 5 (hydroxy) -oxacycloalkyl of 5 to 10 carbon atoms, (lower dialkyl- amino or lower dialkyl-a lower aminoalkanoyl amino) -cycloalkyl of 5 to 10 carbon atoms, or 2-oxopiperidyl; (c) compounds of formula I wherein R is lower alkyl, 2-, 3-, or 4-pyridyl or phenyl; (d) the compounds of the formula I wherein R is 2-, 3-, or 4-pyridyl or phenyl; (e) the compounds of the formula I wherein Ar is lower alkoxy-phenyl. The invention relates especially to the compounds • • - specific ones described in the examples, to the pharmaceutically acceptable prodrug derivatives thereof, and to the salts Pharmaceutically acceptable thereof, and in particular to the specific compounds described in the examples and their pharmaceutically acceptable salts. The pharmaceutically acceptable prodrug derivatives are those that can be converted by solvolysis or under physiological conditions., in the free hydroxyl acids of the invention, and represent the hydroxamic acids wherein the group C0NH0H is derived in the form of a 0-acyl or an optionally substituted 0-benzyl derivative. The optionally substituted 0-benzyl derivatives are preferred. The compounds of the invention, depending on the nature of the substituents, possess one or more asymmetric carbon atoms. The resulting diastereoisomers and enantiomers are encompassed by the present invention. The compounds of the invention are preferred in which the asymmetric carbon atom in the above formulas (with which R. and / or R are bound corresponds to that of a D-amino acid precursor, and the configuration is assigned (R The general definitions used herein have the following meaning within the scope of the present invention, unless otherwise specified: The term "lower" referred to above and subsequently herein in relation to the radicals or co organic compounds respectively define branched or unbranched, with up to and including 7, preferably up to and including 4, and conveniently one or two carbon atoms A lower alkyl group is branched or unbranched, and contains 1 at 7 carbon atoms, preferably 1 to 4 carbon atoms, and represents, for example, methyl, ethyl, propyl, butyl, isopropyl, or isobutyl A lower alkoxy (or alkyloxy) group of reference contains from 1 to 4 carbon atoms, conveniently from 1 to 3 carbon atoms, and represents, for example, ethoxy, propoxy. isopropoxy, or more conveniently methoxy. Halogen (halo) preferably represents chlorine or fluorine, but can also be bromine or iodine. Mono- or poly-lower haloalkyl represents lower alkyl preferably substituted by one, two, or three halogen atoms, preferably fluorine or chlorine, for example, trifluoromethyl, or tri-fluoroethyl. Aryl represents carbocyclic or heterocyclic aryl.

The pro-drug acyl derivatives are preferably those derived from an organic carbonic acid, an organic carboxylic acid, or a carbamic acid. An acyl derivative derived from an organic carboxylic acid is, for example, lower alkanoyl, lower phenylalkanoyl, or ipsubstituted or substituted aroyl, such as benzoyl. - "An acyl derivative derived from an organic carbonic acid is, for example, alkoxycarbopyl, especially lower alkoxycarbonyl, which is unsubstituted or substituted by carbocyclic or heterocyclic aryl, or is cycloalkoxycarbopoly, especially C3-C7-cycloalkyloxycarbonyl which is unsubstituted or substituted by lower alkyl A derivative of acyl deriving from a carbamic acid is, for example, an incarbophenyl which is substituted by lower alkyl, carbocyclic aryl or heterocyclic-lower alkyl, carbocyclic or heterocyclic aryl, lower alkylene, or lower alkylene interrupted by 0 or S. The optionally substituted 0-benzyl derivatives of the prodrug, are preferably bepcyl, or mono-, di-, or tri-bepcyl. -substituted, for example, by lower alkyl, lower alkoxy, amino, nitro, halogen, and / or trifluoromethyl, carbocyclic aryl represents monocyclic aryl or Bicyclic, for example, phenyl, or phenyl mono-di-, or tri-substituted by one, two, or three radicals selected from lower alkyl, lower alkoxy, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy, and oxyalkylene from 2 to 3 carbon atoms; or 1- or 2-naphthyl. Lower alkylenedioxy is a divalent substituent attached to 2 adjacent carbon atoms of the phenyl, for example, methylenedioxy or ethylenedioxy. Oxyalkylene of 2 to 3 carbon atoms is also a bivalent substituent bonded to 2 adjacent carbon atoms of the phenyl, for example, oxyethylene or oxypropylene. An example for oxyalkylene of 2 to 3 carbon atoms-phenyl is 2,3-dihydrobenzofuran-5-yl. As the carbocyclic aryl, phenyl or phenyl substituted by lower alkoxy is preferred; halogen, lower alkyl, or trifluoromethyl, especially phenyl, or phenyl monosubstituted by lower alkoxy, halogen, or trifluoromethyl, and in particular phenyl. Heterocyclic aryl represents monocyclic or dicyclic heteroaryl, for example, pyridyl, quinolinyl, isoquinolinyl, benzothienyl, benzofurapyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl. isoxazolyl, triazole-lo, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any of these substituted radicals, especially mono- or di-substituted, for example, by lower alkyl or halogen. Pyridyl represents 2-, 3-, or 4-pyridyl, conveniently 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. conveniently 2-thienyl. Quinolinyl preferably represents 2-, 3-, or 4-quinolinyl, conveniently 2-quinolinyl. Isoquinolinyl preferably represents 1-, 3-, or 4-isoquinolinyl. Benzopyranyl and benzothiopyranyl preferably represent 3-benzopyrapyloyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, suitably 4-thiazolyl. Triazolyl is preferably 1-, 2-, or 5- (1, 2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. Imidazolyl is preferably 4-imidazolyl. Preferably, heterocyclic aryl is pyridyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any of these substituted radicals, especially mono- or di-substituted, by lower alkyl or halogen; and in particular pyridyl. Diaryl is preferably carbocyclic diaryl, for example, diphenyl, ie 2-, 3-, or 4-diphenyl, conveniently 4-diphenyl, each optionally substituted, for example, by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano. Cycloalkyl of 3 to 10 carbon atoms, for example, cycloalkyl of 8 to 10 carbon atoms, represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl containing 3 (or 8, respectively) to 10 ring atoms, and is conveniently cyclopentyl , cyclohexyl, cycloheptyl. or cyclooctyl optionally substituted by lower alkyl.

(Oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, represents a saturated cyclic radical, wherein 1 or 2, preferably 1 oxygen or sulfur atom, and preferably 4 to 5 carbon atoms, form a ring, for example, tetrahi-dropirapile, tetrahydrofuranyl, tetrahydrothiopyranyl, or tetrahydrothienyl. (Oxa or thia) -cycloalkyl of 7 to 10 carbon atoms is defined analogously, and represents, for example, oxacycloheptyl or oxacyclooctyl. Oxacyclohexane means tetrahydropyrazole, and thiacyclohexane means tetrahydrothiopyran. (Oxa or thia) C 5 -cycloalkyl means tetrahydrofuranyl or tetrahydro-tetpyl, respectively [each copying 4 carbon ring atoms and 1 ring hetero atom (oxygen or sulfur, respectively)]. Oxo represents the substituyepte = 0; for example, 4-oxocyclohexyl is identical to "cyclohexapona-4-yl". Carbocyclic-lower alkyl aryl preferably represents arylalkyl of 1 to 4 straight or branched chain carbon atoms, wherein the carbocyclic aryl has the meaning defined above, for example, benzyl or phenyl- (ethyl, propyl or butyl), each unsubstituted or substituted on the phenyl ring, as defined in the above carbocyclic aryl, conveniently optionally substituted benzyl. Heterocyclic-lower alkyl aryl preferably represents heterocyclic aryl-straight or branched chain alkyl of 1 to 4 carbon atoms, wherein the heterocyclic aryl has the meaning defined above, eg, 2-, 3-, or 4-pyridylmethyl, or (2-, 3-, or 4-pyridyl) - (ethyl, 5-propyl, or butyl); or 2- or 3-thienylmethyl, or (2- or 3-thienyl) - (ethyl, propyl, or butyl); 2-, 3-, or 4-quinolinylmethyl or (2-, 3-, or 4-quinolinyl) - (ethyl, propyl, or butyl); or 2- or 4-thiazolylmethyl, or (2- or 4-thiazolyl) - (ethyl, propyl, or butyl). Lower cycloalkylalkyl represents, for example. 10 (cyclopentyl- or cyclohexyl) - (methyl or ethyl). Diarylalkyl represents, for example, 4-diphenylyl- (methyl or ethyl). Acyl is derived from an organic carboxylic acid, carbonic acid, or carbamic acid. Acyl represents, for example, lower alkanoyl. r * carbocyclic aryl-lower alkanoyl, lower alkoxycarbonyl, aroyl, lower dialkyl-aminocarbonyl, or lower dialkyl-aminoalkanoyl the lower. Preferably, acyl is lower alkanoyl. Acylamino represents, for example, lower alkanoyl amino or lower alkoxycarbonylamino. Acylamino lower alkyl ep R is R - ^ - CONH-lower alkyl, where R ^ represents, for example, lower alkyl, lower alkoxy, arylalkyl, arylalkoxy, aryl carbocyclic or heterocyclic. lower-amino dialkyl, N-lower alkyl-piperazipyl, morpholino, thiomorpholino, piperidino, pyrrolidino, N-alkylpiperidyl, or (lower-dialkyl-amino, N-lower alkyl-piperazino, morpholino, thiomorpholino, piperidipy, pyrrolidino, pyridyl or N- lower alkyl-piperidyl) -lower alkyl. Lower alkanoyl represents, for example, alkanoyl of 1 to 7 carbon atoms, including formyl, and is preferably alkanoyl of 2 to 4 carbon atoms, such as acetyl or propyanyl. Aroyl represents, for example, benzoyl, or benzoyl mono- or di-substituted by 1 or 2 radicals selected from lower alkyl, lower alkoxy, halogen, cyano, and trifluoromethyl; or 1- or 2-naphthoyl; and also, for example, pyridylcarbonyl. Alkoxy-ipferiorcarbopril preferably represents alkoxy of 1 to 4 carbon atoms-carbonyl, for example, ethoxycarbonyl. Lower alkylene already represents straight or branched chain alkylene, having 1 to 7 carbon atoms, and preferably represents straight chain alkylene of 1 to 4 carbon atoms, for example, a methylene, ethylene, propylene, or butylene, or said chain of methylene, ethylene, propylene, or butylene mono-substituted by alkyl of 1 to 3 carbon atoms (conveniently methyl), or disubstituted on the same carbon atoms or different carbon atoms by alkyl of 3 to 3 • carbon atoms (conveniently methyl), the total number of carbon atoms up to and including 7. Esterified carboxy is, for example, lower alkoxycarbonyl or benzyloxycarbonyl. Carboxyl is, for example, amidocarbonyl, mono- or di-lower alkyl-to -carbonyl. The pharmaceutically acceptable salts of the acid compounds of the invention are salts formed with bases, ie, cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium salts, as well as as ammonium, such as ammonium salts, trimethyl ammonium, diethyl ammonium, and tris- (hydroxymethyl) -methyl ammonium. Similarly, acid addition salts, such as mineral acids, organic carboxylic acids and organic sulfonic acids, for example, hydrochloric acid, are also possible. methanesulfonic acid, maleic acid, provided that a basic group, such as pyridyl, is part of the structure. The compounds of the invention exhibit valuable pharmacological properties in mammals, including man, and are particularly useful as inhibitors of matrix degrading metalloproteinase (= metalloproteinase) enzymes. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin. and collagenase. are involved in the degradation of the matrix tissue (eg collagen collapses), and have been implicated in many pathological conditions involving abnormal connective tissue and a matrix membrane metabolism of the matrix, such as arthritis (eg, osteoarthritis) and rheumatoid arthritis), tissue ulceration (eg, epidermal, and gastric corneal ulceration), healing of abnormal wounds, periodontal disease, bone disease, (eg, Paget's disease and osteoporosis), metastasis or tumor invasion, as well as infection with HIV (as reported in J. Leuk, Biol. 52 (2): 244-248, 1992). Since the compounds of the invention are inhibitors of stromelysin, gelatinase, and / or collagenase, and inhibit matrix degradation, they are particularly useful in mammals as agents for the treatment of, for example, osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, tumor metastasis, progression of HIV infection. and disorders related to HIV infection, and osteoporosis. Illustrating the inhibitory activity of matrix degrading metalloproteinase, the compounds of the invention prevent the degradation of cartilage caused by exogenous or endogenous elisipa estrus in mammals. They inhibit, for example, the stromelysin-induced degradation of aggrecan (large aggregation proteoglycan). the binding protein or collagen type IX in mammals. The beneficial effects are evaluated in pharmacological tests generally known in this field, and as illustrated in.? "22 this. The aforementioned properties can be demonstrated in ip vitro and in vivo tests, conveniently using mammals, for example, rats, guinea pigs, dogs, rabbits, or isolated organs and tissues, as well as mammalian enzyme preparations. These compounds can be applied in vitro in the form of solutions, for example, preferably aqueous solutions, and in vivo, either enterally or parenterally, conveniently in an oral manner, by example, as a suspension or in an aqueous solution. The in vitro dosage can be between concentrations of approximately 10 molar and 10 Hnolar. The ep vivo dosage may be, depending on the route of administration, between about 0.1 and 50 milligrams / kilograms. ,, Jj5 A test to determine the inhibition of stromelysin activity is based on its hydrolysis of Substance P, using a modified procedure by Harrison et al. (Harrison, RA, Teahan J., and Stein R., A semicontinuous, high performance chromatography based assay for stromelysin, Anal.

Biochem. 180, 110-113 (1989)). In this assay, Substance P is hydrolyzed by recombinant human stromelysin to generate a fragment, Substance P 7-11, which can be quantified by high performance liquid chromatography. In a typical assay, a material solution of 10 mM of a compound to be tested, diluted in the assay buffer to 50 μM, mixed in 1: 1 with 8 micrograms of recombinant human stromelysin (molecular weight 45 to 47 kDa, 2 Units, where 1 Unit produces 20 millimoles of Substance P 7-11 ep 30 minutes), and incubated together with Substance P 0.5 M, in a final volume of 0.125 milliliters for 30 minutes at 37 ° C. The reaction is stopped by the addition of ethylene diamine tetraacetic acid 10 M, and Substance P 7-11 is quantified on high performance liquid chromatography RP-8. The IC ^ Q for inhibition of stromelysin activity, and K ^ are calculated from the control reaction without the inhibitor. Normally, values of ¿from 10 to 200 nM are obtained. The activity of stromelysin can also be determined using human aggrecan as a substrate. This assay allows in vitro confirmation that a compound can inhibit the action of stromelysin on its highly negatively charged natural substrate, aggrecan (large aggregation proteoglycan). Within the cartilage, proteoglycan exists as an aggregate bound to hyaluronate. The human proteoglycan added with the hyaluronate, is used as an enzyme substrate. The assay is established in 96-well microtiter plates, which allow a rapid evaluation of the compounds. The test has three main steps: 1) The plates are coated with hyaluronate (human umbilical cord 400 micrograms / milliliter), blocked with bovine serum albumin (5 milligrams / milliliter), and then proteoglycan is bound (human articular cartilage Dl -condyroiti- passes digested ABC, 2 milligrams / milliliter), with the hyaluronate. The plates are washed between each step. 2) pH regulators + inhibitor are added (1 to 5,000) nM) + recombinant human stromelysin (1 to 3 Units / well), to the wells. The plates are sealed with tape and incubated overnight at 37 ° C. The plates are then washed. * ._ 3) A primary antibody (3B3) (mouse IgM, 1: 10,000) is used to detect the remaining fragments. HE binds a secondary antibody, anti-IgM linked with peroxididase, to the primary antibody. Then 0PD is added as a substrate for the peroxidase, and the reaction is stopped with sulfuric acid. The IC1-Q for the inhibition of stromelysin activity is derived graphically, and the K ^ is calculated. HE obtain IC values of approximately 50 nM or greater. The collagenase activity is determined as follows: first, 96-well flat bottom microtiter plates are coated with bovine collagen I (35 icrogra / well) for a period of 2 days at 30 ° C, using a humidified atmosphere. and then a dry one; the plates are rinsed, air dried for 3 to 4 hours, sealed with Saran wrap, and stored in a refrigerator. The recombinant human fibroblast collagenase and a test compound (or pH regulator) are added to the wells (total volume = 0.1 milliliters) and the plates are incubate for 2 hours at 35 ° C under humidified conditions; the amount of colagepase used per well is what causes approximately 80 percent of the maximum digestion of collagen. The incubation medium is removed from the wells, which are then rinsed with pH regulator, followed by water. Coomasie blue stain is added to the wells for 25 minutes, removed, and the wells are again rinsed with water. Sodium dodecyl sulfate (20 percent ep 50 mg dimethyl formamide in water) is added to solubilize the remaining stained collagen, and the optical density is measured at a length wave of 570 nM. The decrease in optical density due to collagenase (from that of collagen without enzyme) is compared with the decrease in optical density due to the enzyme in the presence of the test compound, and the percentage inhibition of the enzymatic activity. IC50s are determined from a scale of inhibitor concentrations (4 to 5 concentrations, each tested in triplicate), and the K, values are calculated. K ^ values of approximately 50 pM or greater are obtained. The effect of the compounds of the invention in vivo is can determine in rabbits. Normally, 4 rabbits are dosed orally with a compound up to 4 hours before being injected intra-articularly in both knees (N = 8) with 40 Units of recombinant human stromelysin dissolved in 20 mM Tris, 10 mM CaCl 2, and 0.15 M NaCl. at a pH of 7.5. Two hours later, the rabbits are sacrificed, the synovial wash is collected, and the fragments of keratan sulfate (SQ) and sulfated glycosaminoglycan (GAG-S) released to the joint are quantified. The keratan sulfate is measured by an inhibition ELISA using the Thonar method. { Thonar, E.J.-M.A., Lenz, 5 M.E. , Klipsworth, G.K., Caterson, B., Pachman, L.M., Glickman, P., Katz, R., Huff, J., Keuttner, K.E. Quaptitation of keratan sulfate in blood as a marker of cartilage catabolis, Arthr. -__ Rheum. 28, 1367-1376 (1985)). Sulphated glycosaminoglucans are measured by first digesting synovial lavage with hyaluronidase Streptomyces, and then measuring the binding of the DMB dye using the Goldberg method (Goldberg, RL and Kolibas, L. An improved method for determining .proteoglyca synthesized by chondrocytes ip cultivate.Copnect.Tiss Res. 24, 265-275 (1990)). For an intravenous study, the compound is solubilized in 1 milligrams of polyethylene glycol-400, and for an oral study, a compound is administered in 5 milliliters of fortified corn starch per kilogram of body weight. The effect on protection against cartilage degradation in arthritic disorders is determined, for example, in a surgical model of osteoarthritis described in Arthritis and Rheumatism, volume 26, 875-886 (1983). The effect on ulcerations, for example, ocular ulcerations, is determined, for example. in the rabbit, by measuring the reduction of corneal ulceration in followed by an alkaline burn of the cornea.

Moreover, the invention relates to the use of a compound of the formula I: (a) wherein Ar is carbocyclic or heterocyclic aryl: R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms carbonyl-lower alkyl, lower hydroxyalkyl, lower laxyalkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or di-lower alkyl-amino) -lower alkyl, acylaminoalkyl lower, (N-lower alkyl-piperazino or carbocyclic N-aryl or heterocyclic-lower alkyl-piperazino) -alkyl, or (morpholino, thiomorpholine, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -alkyl lower; R is hydrogen, inner alkyl, aryl cylcocyclic-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 10 carbon atoms , cycloalkyl of 3 to 7 carbon atoms-lower alkyl, hydroxyalkyl, lower acyloxyalkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl) -lower-lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or di-alkyl ipferior-amino) -lower alkyl, (N-lower alkyl-piperazino, or carbocyclic N-aryl or heterocyclic-lower alkyl) -piperazino) -lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl, or N-lower alkyl-piperidyl) -lower alkyl, acylamino-lower alkyl, piperidyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl, or N-lower alkyl-piperidyl) - (hydroxy or lower alkoxy) -lower alkyl, pyrrolidinyl. hexahydroazepinyl, N-lower alkyl, or N-acyl (hexahydroazepinyl, piperidyl, or pyrrolidipyl), oxacycloalkyl of 5 to 10 carbon atoms, tiacycloalkyl of 5 to 10 carbon atoms, (hydroxy- or oxo -) - cycloalkyl of 5 to 10 carbon atoms, (hydroxy- or oxo-) -thiacycloalkyl of 5 to 10 carbon atoms, (hydroxy- or oxo-) -oxacycloalkyl of 5 to 10 carbon atoms, (amino, mono- or di-alkylamino or acylamino) ) -cycloalkyl of 5 to 10 carbon atoms, 2-oxo (pyrrolidinyl, piperidyl, or hexahydroazepinyl): R2 is hydrogen or lower alkyl; or (b) wherein R and R < , together with the chain to which they are attached, form a 1, 2,3,4-tetrahydroisoquinoline, piperidine, oxazolidine, thiazolidine, or pyrrolidine ring, each unsubstituted or substituted by lower alkyl; and Ar and R2 have the meaning defined in (a); or (c) wherein R "and R ^ together with the carbon atom to which they are attached, form a ring system selected from cycloalkane of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl; oxacyclohexane, cyclohexane, indane, tetralin, piperidine, or piperidine substituted on nitrogen by aeyl, lower alkyl, carbocyclic aryl or heterocyclic-lower alkyl, (carboxy, esterified or amidated carboxy) -lower alkyl, or by lower alkyl-sulfonyl; and Ar and R have the meaning defined in (a); pharmaceutically acceptable prodrug derivatives; and pharmaceutically acceptable salts thereof; (for the manufacture of a medicament) for the treatment of conditions that respond to the inhibition of the activity of etaloelasta-sa of macrophage, or for the treatment of atherosclerosis and restenosis, or for ocular applications selected from the pterygium treatment, keratitis, keratoconus, open-angle glaucoma, or retinopathy, and use in conjunction with refractive surgery (laser or incision) to minimize adverse effects.

The inhibitory activity of macrophage metalloelastase (MEM) can be determined, for example, by measuring the inhibition of the degradation of ["" > !] -elastin by the truncated recombinant mouse macrophage metalloelastase, as follows: Approximately 2 nanograms of truncated recombinant mouse macrophage metalloelastase are incubated (FASEB Journal volume 8, A151, 1994), purified by Q- column chromatography. Sepharose, with the test compounds in the desired concentrations, in the presence of CaCl2, 5 nM, NaCl, 400 nM, [^] elastin (60,000 cpm / tube), and Tris, 20 mm, pH 8.0, at 37 ° C overnight. Samples are spun ep microfuge centrifuge at 12,000 rpm for 15 minutes. An aliquot of the supernatant is counted in a scintillation counter to quantify the [pH] degraded elastin. The IC is determined from a scale of concentrations of the test compounds, and the percentage of inhibition of the enzymatic activity is obtained. Typically, ICg0 values of 1 to 10 nM or greater are obtained. The inhibition of macrophage metalloelastase that is involved in the degradation of elastin, makes the compounds of the invention suitable for the treatment of pulmonary (bronchial) disorders, for example, emphysema. The effect of the compounds of the invention for the treatment of emphysema is determined, for example, in animal models described in American Review of Respiratory Disease 117. 1109 (1978).

Effect of the compounds of the invention on arthrosclerosis: The destabilization or rupture of atherosclerotic plaques in mammals by matrix metalloproteinases, is a contributing factor to acute coronary syndrome, heart attacks, and embolisms that occur under atherosclerotic conditions in mammals. The compounds of the invention stabilize atherosclerotic plaques (inhibit their disruption), and therefore, are useful in the treatment of atherosclerosis in mammals. The atherosclerotic plaques of rabbits fed with cholesterol contain activated matrix metalloproteinases, as described by Sukhova et al., Circulation 90, I 404 (1994). The inhibitory effect of the compounds of the invention on the enzymatic activity of the matrix metalloprateinase in rabbit atherosclerotic plaques is determined by on-site cymography, as described by Galis et al., J. Clin. 94, 2493 (1994), and indicates the stabilization of the plate. Effect of the compounds of the invention on resteno-sis: as they are indicative of the effect of the compounds of the invention ep restenosis and vascular remodeling, for example, after angioplasty or after arthrography, the compounds of the invention inhibit the formation of early intimal injury (at 7 and 9 days) followed by balloon aggression in the inflated rat carotid artery model.

Preferably, the invention relates to the use of a compound of the formula I: (a) ep wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of 1 to 10 carbon atoms, hydroxy; lower phenylalkoxy, wherein the fepyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; heterocyclic aryl-lower alkoxy, wherein the heterocyclic aryl is selected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl, amidazolidyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; or Ar is phenyl substituted by cycloalkyl of 3 to 7 carbon atoms-lower alkoxy, (lower alkyl, phenylalkyl, or cycloalkyl of 3 to 7 carbon atoms-lower alkyl) -thio, lower alkyloxy-alkoxy Lower, halogen, lower alkyl, ciapo, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amino, mono- or di-alkyl ipferior-amino; or Ar is phenyla substituted on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thioyl isoxazolyl, or thiazolyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen, lower alkyl, lower phenylalkyl, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl: Fepyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (thio, sulfinyl or sulfonyl), amyl, mono- or di- lower-amino alkyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxa-alkylene of 2 to 3 carbon atoms; or a heterocyclic aryl radical selected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl, imidazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; biphenylyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; lower difpylalkyl, wherein the difpelyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; (pyridyl, thienyl, quinolinyl, or thiazolyl) -lower alkyl, trifluoromethyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl, hydroxyalkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or di-lower alkyl-amino) -alkyl 1 or lower, lower alkyl-aminoalkyl-alkanoyl, (N-lower alkyl-piperazino or N-phenylalkyl-lower piperazino) -alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -alkyl lower: R "is hydrogen; lower alkyl; lower phenylalkyl wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms, or oxyalkylene of 2 to 3 carbon atoms; phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; pyridyl; thienyl; diphenylyl; diphenylaryl lower alkyl; heterocyclic aryl-lower alkyl, wherein the heterocyclic aryl is selected from thiazolyl, pyrazolyl, pyridyl, imidazalyl, and tetrazolyl, each ipsubstituted or substituted by lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl; lower hydroxyalkyl; lower alkanoyloxy-lower alkyl; lower alkoxy-lower alkyl; (phenyl or pyridyl) -lower-lower alkoxy-lower alkyl; lower alkyl- (thio, sulfinyl, or sulfonyl) -lower alkyl; (amino, mono- or di-lower alkyl-amino) -lower alkyl; (N-lower alkyl-piperazino or N-phenylalkyl-lower piperazino) -lower alkyl; (orfoli-no, thiomorpholino, piperidino, pyrrolidino, piperidyl, or N-lower alkyl-piperidyl) -lower alkyl; Lower alkanoyl-aminoalkylamino; R ^ -CONH-lower alkyl, wherein R- * represents (lower-amino dialkyl, N-lower alkyl-piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, or N-alkylpiper idyl) -lower alkyl; piperidyl; pyrrolidinyl: hexahydroazepipyl; N-lower alkyl- or N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) - tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) - oxacycloalkyl of 5 to 10 carbon atoms; (amino, mono- or di-alkylamino or lower-amino-alkanoyl) -cycloalkyl of 5 to 10 carbon atoms; R is hydrogen or lower alkyl; (b) or wherein R and R, together with the chain to which they are attached, form a ring of 1, 2, 3, 4-tetrahydroisoquinoline, piperidine, oxazolidine, thiazolidine, or pyrrolidine, each unsubstituted or mono- or di-substituted by lower alkyl; and Ar and R2 have the meaning defined in (a); (c) or wherein R ^ and R2, together with the carbon atom to which they are attached, form a ring system selected from cycloalkane of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl; oxacyclohexane, cyclohexane, indane, tetralin, and piperidine, which is unsubstituted or substituted on nitrogen by lower alkanoyl, lower dialkyl-lower aminoalkanoyl, lower alkoxycarbonyl, (morpholino, thiomorpholino, or piperidino) -carbonyl, lower alkyl, (phenyl) or pyridyl) -alkyl, lower (carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminocarbonyl, or mono- or di-lower alkyl-arninocarbonyl) -lower alkyl, or by lower alkyl-sulfonyl; and Ar and R have the meaning defined in (a); a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof; Especially, the invention relates to the use of a compound of the formula I: (a) wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of 1 to 7 carbon atoms, hydroxy, lower phenylalkoxy, cycloalkyl of 3 to 7 carbon atoms-lower alkoxy-lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (sulfuryl or sulfonyl), amylo, mono- or di-lower alkyl -amino, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thienyl. isoxazolyl or thiazolyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen; lower alkyl, phenylalkyl lower; phenyl which is ipsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, trifluoromethyl, or, on the adjacent carbon atoms, by 1 to 2 carbon atoms or 2-oxyalkylene alkylenedioxy; to 3 carbon atoms; a heterocyclic aryl radical selected from pyridyl, thiazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl; diphenylyl; diphenylalkyl lower; (pyridyl or thienyl) -lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl: (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms carbon] -lower alkyl; lower hydroxyalkyl; (N-lower alkyl-piperazino, or N-phenylalkyl ipferior-pi? Erazipo) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -alkyl; R, is hydrogen; lower alkyl; lower phenylalkyl, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl. or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms; lower biphenylylalkyl: heterocyclic-lower alkyl aryl, wherein the heterocyclic aryl is selected from thiazolyl, pyrazolyl, pyridyl, imidazolyl, and tetrazolyl, each ipsubstituted or substituted by lower alkyl; cycloalkyl of 3 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-lower alkyl: lower hydroxyalkyl, (phenyl or pyridyl) -lower-lower alkoxy-lower alkyl: lower alkyl- (thio, sulfinyl, or sulfonyl) -lower alkyl; (amino, mono- or di-lower alkyl-amino) -lower alkyl; (N-lower alkyl-piperazino, or N-phenylalkyl-lower-pi perazipo) -lower alkyl; (morpholino, thio orfolino, pipepdino, pyrrolidino, piperidyl, or N-lower alkyl-piperidyl) -lower alkyl; lower alkanoyl-lower aminoalkyl; R-v-CONH-lower alkyl, wherein R- represents (lower-amino dialkyl, N-lower alkyl-piperazino, morpholino, thiomorpholino, piperidipy, pyrrolidipy, or N-alkylpipe-ridyl) -lower alkyl; piperidyl; pyrrolidinyl; hexahydroazepinyl; N-lower alkyl- or N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy-or oxo-) - cycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) - tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) -oxacycloalkyl; (amino, mono- or di-alkylamino, or lower alkanoyl-amino) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; (b) or where R and R ^, together with the chain to which they are attached, form a thiazolidine ring or pyrrolidipa, each unsubstituted or mono- or di-substituted by lower alkyl: and Ar and R2 have the meaning defined in (a); (c) or ep where R < and R2, together with the carbon atom to which they are attached, form a ring system selected from a cycloalkape of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl; oxacyclohexane; cyclohexane; and piperidine which is unsubstituted or substituted on nitrogen by lower alkanoyl, lower dialkyl-aminoalkanoyl lower, lower alkoxycarbonyl, (morpholino, thiomorpholino, or piperidino) -carbonyl, lower alkyl, (phenyl or pyridyl) -low alkyl, (carboxy, lower alkoxycarbonyl, aminocarbonyl, or mono- or di-lower alkyl-aminocarbonyl-lo) -lower alkyl, or by lower alkyl-sulfonyl; and Ar and R have the meaning defined in (a); a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof; In particular, the specific compounds described in the examples are used according to the invention. The compounds of the formula I can be prepared, for example, by the condensation of a carboxylic acid of the formula IV: OR R, CH70 II I II (IV) HO- C - C - N-S-Ar O or a reactive functional derivative thereof, wherein R, R R ^ and Ar have the meaning defined in claim 1, with hydroxylic amine of the formula V: NH? -0H rv optionally in a protected form, or a salt thereof; and if necessary, temporarily protect any reactive groups that interfere, and then release the compound resulting from the invention; and if required or desired, converting a compound resulting from the invention into another compound of the invention, and / or if desired, converting a resulting free compound into a salt, or a resulting salt into a free compound or other salt; and / or separating a mixture of isomers or racemates obtained, into the individual isomers or racemates; and / or if desired, redissolve a racemate in the optical antipodes. In the starting compounds and ep intermediates which are converted into the compounds of the invention in a manner described herein, the functional groups present, such as the amino, carboxyl, and hydroxy groups, are optionally protected by conventional protecting groups that They are common in organic chemistry preparation. The amino groups, carboxyl. and protected hydroxy are those that can be converted, under light conditions, into free amino and hydroxy groups without destroying the molecular structure, or without other undesired side reactions taking place. The purpose of introducing protective groups is to protect the functional groups from undesired reactions with the reaction components under the conditions employed to perform a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art, and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), structure and stability 5 of the molecule of which the substituent is a part, and of the reaction conditions. Well-known protecting groups that meet these conditions, and their introduction and removal, are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Che-jw ~ mistry", Plenum Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1991. In the processes cited herein, the reactive functional derivatives of carboxylic acids represent, by For example, anhydrides, especially mixed anhydrides, acid halides, acid azides, lower alkyl esters, and activated esters thereof. The mixed anhydrides are preferably those of pivalic acid, or a lower alkyl ester (ethyl, isobutyl) of carbonic acid; the acid halides, are, for example, chlorides or bromides; activated esters, for example, succinimido, phthalimido, or 4-nitrophenyl esters; the lower alkyl esters are, for example, the methyl or ethyl esters. Also, an esterified reactive derivative of a 5-alcohol in any of the reactions recited herein, represents said alcohol esterified by strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, hydrobromic, or iohydric acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, for example, methanesulfonic acid, 4-methylbenzenesulfonic acid, or 4-bromobenzenesulfonic acid. An esterified reactive derivative is especially halogen, for example, chlorine, bromine, or iodine, or aliphatic sulfonyloxy or aromatically substituted, for example, methanesulfonyloxy, 4-methylbepcepsulfonyloxy (tosyloxy). . In the above processes for the synthesis of the compounds of the invention, this can be carried out according to the methodology generally known in the art for the preparation of hydroxamic acids and their derivatives. The synthesis according to the above process (which involves the condensation of a free carboxylic acid of the formula IV with an optionally hydroxy-protected hydroxyl amine derivative of the formula V, can be carried out in the The presence of a condensing agent, for example, 1,1'carbonyldi imidazole, or N- (dimethylaminopropyl) -N'-ethyl carbonate, or dicyclohexyl carbodiimide, with or without 1-hydroxybenzotriazole. in an inert polar solvent, such as dimethyl formamide or dichloromethane, preferably at room temperature. The synthesis involving the condensation of a reactive functional derivative of an acid of the formula IV as defined above, for example, a mixed acid or anhydride chloride with hydroxylic amine optionally protected with hydroxy, or a salt thereof, in the presence of a base such as triethyl amine can be carried out at a temperature of preferably from about -78 ° C to + 75 ° C, in an inert organic solvent, such as dichloromethane or toluene. The protected forms of hydroxyl amine (of formula V) in the above process are those in which the ^) hydroxy group is protected, for example, as a tertiary butyl ether, a benzyl ether, or a tetrahydropyranyl ether. The removal of these protecting groups is carried out according to methods well known in the art, for example, hydrogenolysis or acid hydrolysis. The preferred hydroxyl amine is generated at the site from a hydroxyl amine salt, such as hydroxyl amine hydrochloride. The starting carboxylic acids of the formula IV can be prepared as follows: First an amino acid of the formula VI is esterified: twenty Wherein R x and R 2 have the meaning defined herein, with a lower alkanol, for example, methanol, in the presence of, for example, thionyl chloride, to obtain an amino ester, which is treated with a reactive functional derivative of the appropriate arylsulfonic acid of formula VII: ArS03H (VII) wherein Ar has the meaning defined hereinbefore, for example, with the arylsulfonyl chloride, in the presence of a suitable base, such as triethyl amine, using a polar solvent, such as tetrahydrofuran, toluene, acetonitrile, to obtain a composed of the formula VIII: wherein R1 # R2, and Ar have the meaning defined herein, and R6 is a protecting group, eg, lower alkyl. The treatment thereof with an esterified reactive derivative of the formula IX alcohol: R-CH2OH (IX) wherein R has the meaning defined herein, such as the halide, for example the chloride, bromide, or iodide derivative thereof, in the presence of an appropriate base, such as potassium carbonate or sodium hydride, in a polar solvent, such as dimethyl formamide. The resulting compound corresponding to an ester of a compound of formula IV can then be hydrolysed in the acid of formula IV, using conventional moderate methods of hydrolysis with ester, preferably under acidic conditions. 10 The starting materials of formulas VI, VII, and IX, are known in the art, or. they can be prepared by methods well known in the art, or as described herein. The optically active D-amino acids of the formula VI s / (the R-enantiomers) can be prepared according to the methods known in this field, for example, according to the methods described in Tetrahedrop Letters 28, 39 (1987), J. Am.

Chem. Soc. 109, 7151 (1987) and J. Am. Chem. Soc. 110. 1547 (1988). The reactions mentioned above are carried out According to conventional methods, in the presence or absence of a diluent, preferably those which are inert to the reactants and are solvents thereof, of catalysts, said other agents condensing, respectively, and / or in atmospheres inert, at low temperatures, at temperature Environment, or at elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or superatmospheric pressure. Preferred solvents, catalysts, and reaction conditions are stipulated in the accompanying illustrative examples. The invention also includes any variant of the present processes, wherein an intermediate product that can be obtained at any stage thereof, such as the starting material, is used, and the remaining steps are performed, or the process is discontinued at any stage of it, or where ~ '> the starting materials are formed at the site under the conditions of the reaction, or where the reaction components are used in the form of their optically pure salts or antipodes. The compounds of the invention and the intermediates 5 can also be converted to one another according to methods generally known per se. The invention also relates to any novel starting materials and processes for their manufacture. Depending on the choice of the starting materials 0 and the methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), optical isomers (antipodes), racemates, or mixtures thereof. Possible isomers or mixtures thereof, mentioned above, are within the scope of this invention.

Any resulting mixtures of isomers can be separated ep base to the physicochemical differences of the constituents, in the isomers, diastereoisomers, or pure or optical geometrical racemates, for example, by chromatography and / or fractional crystallization. Any racemates resulting from the final products or intermediates can be redissolved at the optical antipodes by known methods, for example, by separation in the diastereomeric salts of the , which are obtained with an optically active acid or base, and releasing the optically active acidic or basic compound. The hydroxamic acids or the carboxylic acid intermediates can be redissolved in this way in their optical antipodes, for example, by fractional crystallization of amine d- or 1- "'* *" (alpha-methylbenzyl, cinchonidine, cinchonine, quinine , quipidine, ephedrine, dehydroabietyl amine, brucine, or strychnine) -sales. Finally, the acidic compounds of the invention are obtained in the free form, or as a salt of them. The acidic compounds of the invention can be converted to salts with pharmaceutically acceptable bases, for example, an aqueous alkali metal hydroxide, conveniently in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the latter solutions, the salts can be precipitated with ethers, for example, diethyl ether. The resulting salts can be converted into the free compounds by their treatment with acids. These or other salts can also be used for the purification of the obtained compounds. In view of the close relationship between the compounds In the case of free compounds and compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also involved, whenever possible or appropriate according to the circumstances. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The pharmaceutical compositions according to the invention are those suitable for enteral administration, such as oral or rectal, transdermal, and parenteral to mammals, including man, to inhibit matrix degrading metalloproteinases, and for the treatment of Disorders responsive thereto, which comprise an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof together or in admixture with excipients or vehicles suitable for enteral or parenteral application.The tablets and gelatine capsules comprising the active ingredient together with: a) diluents are preferred, example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone; if desired d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors, and sweeteners. The injectable compositions are preferably aqueous isotonic solutions or suspensions, and the suppositories are conveniently prepared from emulsions or fat suspensions. These compositions may be sterilized and / or may contain auxiliaries, such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating the osmotic pressure, and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain from about 0.1 to 75 percent, preferably from about 1 to 50 percent, of the active ingredient. Formulations suitable for transdermal application include an effective amount of a compound of the invention with a carrier. Convenient vehicles include pharmacologically acceptable solvents that can be absorbed to assist passage through the host's skin. Characteristically, the transdermal devices 5 are in the form of a bandage comprising a backing member, a reservoir containing the compound optically with vehicles, optionally a control barrier with indices to apply the compound to the skin of the host at a controlled rate predetermined for a prolonged period of time and ele- ments to secure the device to the skin. Formulations suitable for local application, for example, to the skin and to the eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art. The pharmaceutical formulations contain an inhibitory amount. of effective matrix degrading metalloproteinase of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, for example, an anti-inflammatory agent with cyclooxygepase inhibitory activity, each in an effective therapeutic dose as it is reported in the technique. These therapeutic agents are well known in the art. Examples of the apti inflammatory agents with cyclooxygenase inhibitory activity are diclofenac sodium, naproxen. ibuprofen, and the like. In conjunction with another active ingredient, a compound of the invention can be administered either simultaneously, before, or after the other active ingredient, either separately by the same route of administration or by a different one, or together in the Same pharmaceutical formulation. The dosage of the active compound administered depends on the species of warm-blooded animal (mammal), the weight of the body, the age, and the individual condition, and the manner of administration. A unit dosage for oral administration to a mammal of about 50 to 70 kilograms may contain between about 25 and 250 milligrams of the active ingredient. The following examples are intended to illustrate the invention, and should not be interpreted as limitations thereof. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are carried out under reduced pressure, preferably between about 15 and 100 mm Hg (= 20-133 mbar). The structure of the final products, of the intermediates, and of the starting materials is confirmed by conventional analytical methods, for example, microanalysis and spectroscopic characterization (e.g., EM, IR, NMR). The abbreviations used are those conventional in the art. The concentration for the determinations of [o] gse expressed in milligrams / milliliter. Example 1: The following compounds, for which, surprisingly, the new use of treatment conditions responding to the inhibition of macrophage metalloelastase activity, as well as the treatment has been discovered of atherosclerosis and restenosis, as well as the treatment of ocular conditions selected from pterygium, keratitis, keratoconus, glaucoma to open angle, and retinopathies, as well as its application in conjunction with refractive surgery (laser or incision) to minimize effects Adverse reactions are already described in EP-A-606,046: (a) N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methyl, the hydrochloride , the salt of L-tartaric acid, the salt of metapsulfonic acid, and the salt of maleic acid thereof, (b) Butapamide hydrochloride N-hydroxy-2 (S) - [[4-methoxyben-0-censo-sulfopyl] (3) -picolyl) amino] -3-methyl, (c) pentanamide hydrochloride N-hydroxy-2 (R) - [[4-methoxy-bep-sulphonyl] (3-picolyl) amino] -4-methyl ica, (d) Pentanamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (6-chloropiperonyl) amino] -4-methyl ica, > * v (e) Pentanamide N-hydroxy i-2 (R) - [[4-methoxybenzenesulfonyl] (piperonyl) amino] -4-methyl ica, (f) Pentanamide N-hydroxy-2 (R) - [[ 4-methoxybenzenesulfonyl] (2-picolyl) amyl] -4-methyl ica, (g) Butanamide hydrochloride N-hydroxy-2 (R) - [[4-methoxyben-0-cenphulphonyl] (2-picolyl) amino] -3 -methyl, (h) Pentanamide hydrochloride N-hydroxy-2 (R) - [[4-methoxy-benzenesulfonyl] (3-picolyl) amino] -4,4-dimethyl, (i) N-hydroxy acetamide hydrochloride 2 (R) - [[4-methoxybenzensulfoni 1] (3-picol il) amino] -2-cyclohexy lica, 5 (j) Butanarnide hydrochloride N-hydroxy-2 (R) - [[2,3-dihydro] -bepzofuran) -5-sulfonyl] - (3-picolyl) amino] -3-methyl, butanamide hydrochloride N-hydroxy-2- [[4-methoxybenzene-sulfonyl] (3-picolyl) amino] -3-methyl, (1) Butanamide Hydrochloride N-Hydroxy-2 (R) - [[4-ethoxy-benzo-sulphonyl] (3-picolyl) amino] -3-methyl, (m) Acetamide hydrochloride N-hydroxy-2 (R) - [[4-methoxyben-censulphonyl] (2-picolyl) amino] -2-cyclohexyl, (n) acetamide hydrochloride N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2-methylthiazol-4-ylmethyl) to ino] -2-cyclohexyl. (o) Acetamide hydrochloride N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2-quinolipylmethyl) amino] -2-cyclohexyl, (p) Pentanamide N-hydroxyt2 (R) - [[4-methoxybenzenesulfonyl] ] (benzylated) amino] -4-methyl, (q) Acetamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (benzylated) amino] -2-phenyl, (r) Acetamide N- hydroxy-2- [[4-methoxybencepsulfonyl] (benzyl) amino] -2-butyl tertiary, (s) Pentamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (4-f1uorobenzyl) amino] -4- methyl ica, (t) Butanamide N-hydroxy-2 (R) - [[4-metaxibencensul fo-nyl] (bep-cil) amycto] -3-methyl, (u) Pentanam ida N-hydrox i-2 ( R) - [[4-methoxybenzylsulphonyl] (benzykyl) atino] -4,4-di ethylene, (v) Propanam ida N-hydrox i-2 (R) - [[4-m ethoxyben ulf o-ni] 1 (ben-ci l) ai no] -3-hydroxy l, (w) 4 (S) carboxamide N-hydroxy-3- [4-methoxybencepsulfonyl] -5,5-di-ethylthiazole idinica, (x) 2 (2) carboxamide N-hydroxy-l- [4-methoxybenzenesulfonyl] -pyrrolidinic, (y) Acetamide N-hydroxy-2- [[4-methoxybenzenesulfopyl] (be ncil-) amino] -2- [2- (4-morpholino) -ethyl), (z) Acetamide N-hydroxy-2- [[4-methoxybenzenesulfopyl] (isobutyl) amino] -2- [2- (4-morpholype ) ethyl ica], (aa) Acetamide Dihydrochloride N-hydroxy-2- [[4-methoxyben-censulfonyl] (2-picolyl) amypo] -2- [2- (4-morpholino) ethyl], (ab) Acetamide N-Dihydrochloride hydroxy-2- [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -2- [2 -, (4-morpholino) ethyl], (ac) Acetamide Dihydrochloride N-hydroxy-2- [[4- methoxybenzenesulfonyl] (2-methylthiazol-4-ylmethyl) amino] -2- [2- (4-morpholino) e-tica], (ad) Acetamide N-hydroxy-2- [[4-methoxy-cep-sulfonyl] (benzyl) amino] -2- [2- (4-thiomorpholino) ethyl], (ae) Acetamide N-hydroxy-2- [[4-methoxybenzenesulfonyl] (bepcyl) amino] -2- [2-methyl-lithiazole-4-] ilmetilica], (af) Acetamide N-hydroxy-2- [[4-methoxybenzenesulfopyl] (benzyl) amino] -2- [6-chloropipepropyl 1], (ag) Acetamide N-hydroxy-2- [[4- methoxybenzenesulfonyl] (benzyl-) amino] -2- [(1-pyrazolyl) ethyl], (af) Acetamide Dihydrochloride N-hydroxy-2- [[4-methoxy-cepulfonyl] (3-picolyl) amino] -2- [3-picolyl ica]. (ai) Acetamide Hydrochloride N-hydroxy-2- [[4-methoxybenzenesulfonyl] (benzyl) amino] -2- [(1-methyl-4-imidazolyl) methyl], (aj) N-hydroxy Acetamide Hydrochloride -2- [[4-methoxybenzenesulfonyl] (isobutyl) amino] -2- [(l-methyl-4-imidazolyl) methyl], (ak) Acetamide hydrochloride N-hydroxy-2- [[4-methoxybenzene] sulfopyl] (3-picolyl) amino] -2- [(1-methyl-4-imidazolyl) methyl], (al) Acetamide hydrochloride N-hydroxy-2- [[4-methoxybenzene-sulfopyl] (2-picolyl) amino] -2- [(1-methyl-4-imidazolyl) methyl], (am) Acetamide hydrochloride N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2-methylthiazol-4-ylmethyl) amino] - 2- [(1-methyl-4-imidazo-lly) methyl], (ap) Acetamide Hydrochloride N | -hydroxy-2- [[4-methoxybenzenesulfonyl] (piperonyl) amino] -2- [(1- methy1-4-imidazole il) methyl], (ao) N-hydroxy-2- [[4-methoxybensulphonyl] (benzyl) amino] prapionamide, (ap) 2- [[4-methoxybenzenesulfonyl] (benzyl) Methyl] -propionate, (aq) Butyramide N-Hydrylsi-2- [[4-methoxybenzenesulfopyl] (benz) il) amino] -4-thiomethyl. (ar) Butyramide N-hydroxy-2- [[4-methoxybenzenesulfopyl] (benzyl) amyl] -4- (ethylsulfonyl), (as) Propiopamide of N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (ben-cil) amypo], (at) Acetamide of N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (benzylated) amino] -2-benzyl, (au) hexanamide hydrochloride of N-hydroxy-2 (R) - [[4-methoxy-benzenesulfonyl] (benzyl) amino] -6- (N, N-dimethylamino), (av) hexanamide dihydrochloride of N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -6- (N, N-dimethylamino), (aw) ida hexanade hydrochloride of N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (2- picolyl) amino] -6- (N, N-dimethylamino), (ax) Hexaneamide hydrochloride of N-hydroxy-2 (R) - [[4-methoxybencepsulfonyl] (bepcil) amypo] -6- [(N, N -dimet i lgl ici 1) amino], (ay) 4- [N-hydroxy-carbamoyl] -4- [[4-methoxybenzenesulfonyl] (benzyl) amino] -tetrahydrothiopyran, (az) 4- [N-hydroxy] -carbamoyl] -4- [[4-methoxybenzenesulfo-nyl] (benzyl) amyl] -tetrahydropyran ,, (ba) l- [N-hydroxy-carbamoyl] -l - [[4- methoxy benzenesulfonyl] (bepcyl) -amino] -cyclohexane, (bb) 1 - [Nh i dr oxy-carba oi 1] - 1 - [[4-met oxy benzenesul f-nil] (bepcil ) -amino] -cyclopentane, (be) 1- [N-hydroxy-carbamoyl] -l- [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -cyclohexapo, (bd) l- [N-hydroxy] -hydrochloride carbamoyl] -l- [[4-methoxyben-censulfonyl] (3-picolyl) amino] -cyclopropane, (be) Piperidine 4- [N-hydroxy-carbamoyl] -4- [[4-methoxyben-censulfonyl] (benzyl) amino] -1- [benzyl], (bf) Piperidine hydrochloride 4- [N-hydroxy-carbamoyl] -4- [[4-me toxybenzenesulfonyl] (benz 1) -a ino] -1- [di t to inoacetyl-ca], (bg) Piperidine dihydrochloride 4- [N-hydroxy-carbamoyl] -4- [[4-methoxybenzenesulfonyl] (benzyl) -amino] -1- [3-picolylic], (bh) Hydrochloride of piperidine 4- [N-hydroxy-carbamoyl] -4- [[4-methoxy-bensulfonyl] (benzyl) -amino] -1- [carbomethoxymethyl], (bi) piperidine trifluoroacetate of 4- [N-hydroxycarba- moil] -4- [[4-methoxybencepsulfonyl] (benzyl) -am do not]; (bj) Piperidine 4- [N-hydroxy-carbamoyl] -4- [[4-methoxy-cep-sulphonyl] (benzyl) -amipo] -l- [tert-butoxy-carbonyl]. (bk) Piperidine 4- [N-hydroxy-carbamoyl] -4- [[4-methoxyben-censulfonyl] (benzyl) -amino] -l- [methylsulfonyl], (bl) piperidine hydrochloride 4-fN-hydroxy-carbamoyl ] -4- [[4-methoxybenzenesulfonyl] (benzyl) -amino] -1- [methyl], (bm) Piperidine 4- [N-hydroxy-carbamoyl] -4- [[4-methoxyben-censulfonyl] (benzyl) -a ino] -1- [morpholinocarbopylic], (bn) piperidine dihydrochloride 4- [N-hydroxy-carbamoyl] -4- [[4-methoxybensulfophenyl] (benzyl) -amino] -1- [4-picolylic] ], (b) Acetamide of N-hydroxy-2- [[4-methoxybensulfonyl] (benzyl) amino], (bp) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (iso-butyl) amino], (bq) ) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (cyclohexylmethyl) amino], (br) Acetamide of N-hydroxy-2- [[4-methoxybensulfonyl] (cyclohexyloxy)] , (bs) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (fe-netyl) amino], (bt) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (3-methylbutyl) amino], (bu) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (secondary butyl) amino ], (bv) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (tertiary butyl) amino], (bw) Acetamide of N-hydroxy-2- [[4-methoxybencepsulfonyl] (4-fluorobenzyl) amino] , (bx) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-chlorobenzyl) amino], (b) N-hydroxy-2 - [? [4-methoxybenzenesulfonyl] (isopropyl) amino] acetamide, (bz) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-methylbenzyl) amino], (ca) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (3-phenyl-1-propyl) amino), (cb) N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-phenyl-butyl) amino] acetamide, (ce) N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2-cyclohexylethyl) acetamide amino), (cd) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-phenylebenzyl) amino], (ce) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2, -2, 2-trifl uoroethyl) amino], (cf) Acetamide of N-hydroxy-2- [[benzenesulfopyl] (isobutyl) a-mino], (cg) Acetamide of N-hydroxy-2- [[4-trifluoromethylbenzenesulfopyl] - (isobutyl ) amino], (ch) Acetamide of N-hydroxy-2- [[4-chlorobepcensulfonyl] (iso-butyl) amino], (ci) Acetamide of N-hydroxy-2- [[4-methylbenzenesulfonyl] (iso-butyl) amino), (cj) Acetamide of N-hydroxy-2- [[4-fluorobenzenesulfonyl] (iso-butyl) amylo], (ck) Acetamide of N-hydroxy-2- [[benzenesulfonyl] (bepcil) amylo], (cl) Acetamide of N-hydroxy-2- [[4-nitrobenzenesulfonyl] (iso-butyl) amino], (cm) Acetamide of N-hydroxy-2- [[4-butyl- (tertiary) -bepcen-sulfonyl] (isobutyl) to ino], (cn) Acetamide of N-hydroxy-2- [[4-methylsulfophenylbenzenesulfonyl] (isobutyl) amino], (co) Acetamide of N-hydroxy-2- [[3-trifluoromethylbencepsul-fopil] ] (isobutyl) amino], (cp) Acetamide of N-hydroxy-2- [[2,4,6-trimethylbenzenesulfonyl] (isobutyl) a ino], (cq) Acetamide of Nh? droxi-2- [[2, 5-d? Methoxybencepsul-fonyl] (isobutyl) amino], (cr) Acetamide of N-hydroxy-2- [[3,4-d? Methoxybenzene sulphonyl] (isobutyl) amyl], (cs) Acetamide of N-hydroxy-2- [[2,6,6-tri isopropylbenzoprofonyl] ] (isobutyl) amino], (ct) Acetamide of N-hydroxy-2- [[3,5-dimethylisoxazole-4-sulfo-nyl] - (benzyl) amino], (cu) Acetamide of N-hydroxy-2- [[2,4-dimethylisoxazole-5-sulfo-nyl] - (benzyl) amino], (cv) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-methoxybenzyl) amino], (c) Acetamide of N-hydroxy-2- [[4-methoxybencepsulfonyl] (2-picolyl) amino], (ex) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (3-picolyl) amino], (cy) Acetamide of N-hydroxy-2- [[4-methoxybencepsulfonyl] (pi-peronyl) amino], (cz) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (2-piperidinylethyl) amino], (da) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (2-quinolinylmethyl) amino], (db) Acetamide hydrochloride of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (4-picolyl) amino], (de) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (6-chloropiperonil) amylo], (dd) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (3, 4-, 5, -tri ethoxybenzyl) amino), (de) Acetamide of N-hydroxy- 2- [[4-methoxybenzenesulfonyl] (3-methoxy-benzyl) amino], (df) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfopyl] (2- [4-morpholipyl] ethyl) amino], (dg) Acetamide of N-hydroxy-2- [[4-aminobenzenesulfonyl] (iso-butyl) amyl], (dh) Acetamide of N-hydroxy-2- [[4-dimethylaminobenzenesulfonyl] (isobutyl) amino], (di) Acetamide of N-hydroxy-2- [[4-hexyloxybenzenesulfonyl] (isobutyl) amino], (dj) Acetamide of N-hydroxy-2- [[4-ethoxybenzenesulfonyl] (iso-butyl) amino], (dk) Acetamide of N-hydroxy-2- [[4-butyloxybenzenesulfonyl] (isobutyl) a ino], (di) Acetamide of N-hydroxy-2- [[4- (3-methyl) butyloxybenzene-sulfopyl] (isobutyl) amino ], (dm) Acetamide of N-hydroxy-2- [[4-heptyloxybenzenesulfonyl] (isobutyl) amino], (dn) Acetamide of N-hydroxy-2- [[4- (cyclohexylmethoxy) benzenesulfonyl] ( isobutyl) amino], (do) Acetamide of N-hydroxy-2- [[4 -isopropyloxycepcepsulfo-nyl] (isobutyl) amino], (dp) Acetamide of N-hydroxy-2- [[4-ethoxyethoxybenzenesulfo-nyl] (isobutyl) amino], (dq) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfoni 1] (ben-cil) amido] -2- [(2-methy1-5-tetrazolyl) methyl], (dr) N-hydroxy-2- [[4-methoxybenzenesulfonyl] (benzyl) amypo] acetamide] -2- [(l-methyl- 5-tetrazolyl) methyl], (ds) Acetamide of N-hydroxy-2- [[4-methoxybenzenesulfonyl] (bep-cyl) amino] -2- [(5-tetrazolyl) methyl], (dt) Acetamide of N- hydroxy-2- [[4-methoxybenzenesulfonyl] (4-pheny1benzyl) amino] -2- [(5-tetrazolyl) methyl], (du) Butapamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfopyl] (3 -picolyl) amino] -3-methylilica, and the hydrochloride thereof, (dv) Butanamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amyl] -3-methyl, and the hydrochloride the same, (dw) N-linked (N-benzyloxy) -2 (R) - [[4-methoxybenzenesulfo-ni 1] (3-picolyl) amypo] -3-methyl ica, (dx) Butanamide N- (4) -methoxybenzyloxy) -2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amypo] -3-methyl ica, (dy) Butanamide N- (4-met oxibencyloxy) -2 (R) - [[4-methoxy-cephenesulfonyl] (3-picolyl) amino] -3-methyl-ica, (dz) Butanamide N- (2,4-dimethoxybenzyloxy) -2 (R) - [ [4-methoxy-benzenesulfopyl] (3-picolyl) amino] -3-methyl-ica, (ea) Butapamide N- (2-methoxybenzyloxy) -2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methyl ica, (eb) butanamide dihydrochloride N-hydroxy-2 (R) - [[4-methoxy-benzenesulfonyl] (3-picol i 1) amino] -3 (R) - (3-picoli) loxi 1 ica), (ec) Acetamide hydrochloride N-hydroxy-2 (R) - [[4-methoxyben-censulfonyl] (4-picol i 1) to ipo] -2-cyclohexy 1 ica, (ed) Acetamide N -hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (2- (2-pyridi1) ethyl] amino] -2-cyclohexyl, (ee) Acetamide N-hydrsxy-2 (R) - [[4-methoxybenzenesulfonyl] (3- (3-pyridyl) propyl] amino] -2-cyclohexyl, (ef) Acetamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (2-rnethyl-pyrid-5-ylmethyl) amyg] - 2-cyclohexy lica, (eg) Acetamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (4-tetrahydro-iranmethyl) amino] -2-cyclohexyl, (eh) Hydrochloride of acetamide N-hydroxy-2 (R) [(4-methoxybenzenesulfonyl] (benzyl) amino] -2- (4-N-methylpiperidinyl). It should be understood that each compound mentioned in Example 1, can be used either in neutral form, or in the form of a pharmaceutically acceptable salt, for example, in the specific salt form mentioned in the above list. Reference Example A (corresponds to Example 1 (a) of EP-A-606,046): (a) Butanamide N- (tertiary butyloxy) -2 (R) - [[4-methoxybenzenesulfopyl] (3-picolyl) is dissolved amido] -3-methyl ica (4.1 grams, 9.13 mmol) in dichloroethane (150 milliliters), containing ethanol (0.53 milliliters, 9.13 millimoles), in a round bottom flask, and the reaction is cooled to -10 ° C. Hydrochloric acid gas (from a supply bottle) is bubbled for 30 minutes. The reaction mixture is sealed, allowed to slowly warm to room temperature, and stirred for 2 days. The solvent is reduced to one third of the volume by evaporation, and triturated with ether. The mixture is filtered, the filter cake is removed, and dried under vacuum to provide butanamide hydrochloride N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methylilica as a white solid, mp .169-170 ° C (decomposition). The starting material is prepared as follows: (b) To a solution of D-valine (15.0 grams, 128.0 millimoles) in 1: 1 dioxane / water (200 milliliters) containing triethyl amine (19.4 grams, 192.0 millimoles) a at room temperature, 4-methoxybenzenesulfonyl chloride (29.0 grams, 141.0 mmol) is added, and the reaction mixture is stirred at room temperature overnight. The mixture is then diluted with methylene chloride, washed with IN aqueous hydrochloric acid, and water. The organic layer is washed again with brine, dried (Na ^ SO ^), and the solvent is evaporated to give N- [4-methoxybenzenesulfonyl] - (D) -valipa as a crude product. A solution of this crude product (15.0 grams) in toluene (100 milliliters) containing tertiary dibutyl acetal of formamide N, N-dimethyl (50 milliliters, 206.5 millimoles) is heated at 95 ° C for 3 hours. Then the solvent evaporates. The crude product is purified by chromatography on silica gel (30 percent ethyl acetate / hexanes) to provide tertiary butyl ester of N- [4-methoxybenzenesulfonyl] - (D) -valine. (c) To a solution of tertiary butyl ester of N- [4-methoxybencepsulfonyl] - (D) -valipa (4.38 grams, 13.0 mi 1 imoles) in dimethylformamide (200 milliliters), chlorhydrate, drained from 3-picolyl chloride (2.3 grams, 14.0 mmol), followed ~ * ~ by potassium carbonate (17.94 grams, 130.0 mmol). The reaction mixture is stirred at room temperature for 2 days. The mixture is then diluted with water, and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate), to give 2 (R) - [N- [4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methyl tertiary butyl butanoate. (d) 2 (R) - [[4-Methoxybenzenesulfonyl] (3-picolyl) amino] -3-methylbutanoate tertiary butyl (5.3 grams, 12.2 mmol) is dissolved in methylene chloride (150 milliliters), and cooled to -10 ° C. Hydrochloric acid gas is bubbled into the solution for 10 minutes. The reaction mixture is then sealed, heated to room temperature, and stirred for 4 hours. The solvent is then evaporated to give 2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methylbutanoic acid hydrochloride. (e) 2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methylbutanoate hydrochloride (5.0 grams, 12.06 mmol), l-hydroxybenzotriazole (1.63 grams, 12.06.0) are dissolved. millimoles), 4-methyl morpholine (6.6 milliliters, 60. 31 millimoles), and tertiary-hydroxylic 0-butyl amine hydrochloride (54.55 grams, 36.19 millimoles) in ethylene chloride (200 milliliters). Carbodiimide hydrochloride N- [dimethylapopropyl] -N'-ethyl is added (3.01 grams, 15.68 mmol), and the reaction is stirred overnight. The reaction is then diluted with water, and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na), and the solvent is evaporated The crude product is purified by chromatography on silica gel (2 percent methanol / methylene chloride) to give butanamide N - (tertiary butyloxy) -2 (R) - [[4-methoxybencepsulfonyl] (3-picolyl) amino] -3-methyl ica.

Reference example B (corresponds to Example 32 of EP-A-606,046): (a) Acetamide N- (tertiary butyloxy) -2 (R) - [(4-methoxybencepsulfonyl) (benz 1) amino] -2- (4-N-methylpiperidinic acid (733.0 milligrams, 1.46 millimoles) in sodium chloride is dissolved. methylene (60 milliliters) containing etapol (67.0 milligrams, 146 mi 1 imoles), and the reaction is cooled to -10 ° C. Hydrogen chloride gas is bubbled (from a supply bottle) for 15 minutes. it is sealed, allowed to slowly warm to room temperature, and stirred for 6 days.The solvent is reduced to one third of the volume by evaporation, and triturated with ether.The mixture is filtered, the filter cake is removed, and dried in vacuo to provide acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (bepcyl) amyl] -2- (4-N-methylpiperidinyl) acetic acid as a light tan solid, mp; 160 ° C (decomposition).

The starting material is prepared as follows: (b) To a solution of ethyl 4-pyridylacetate (11.17 grams, 67.62 mmol) in 2N hydrochloric acid (100 milliliters), platinum (IV) oxide (275 milligrams) is added. The mixture is stirred in a Parr hydrogenation apparatus for 60 hours under a hydrogen pressure of 50 psi (= 3.45 bar). The reaction mixture is gasified to a pH of 8-9 with saturated aqueous sodium carbonate, and then washed with methylene chloride. The aqueous layer is concentrated in vacuo to give 4-piperidyl sodium acetate as a white solid. To a solution of the crude product (5.0 grams, 30.3 millimoles) in 3: 1 water / dioxane (200 milliliters) at 0 ° C, a solution of tertiary dibutyl dicarbonate (6.38 grams, 29.3 millimoles) in dioxapo ( 25 milliliters) in one portion. The nebulous reaction mixture is warmed to room temperature, and stirred overnight. The mixture is then filtered, cooled to 0 ° C, and acidified with cold 6N hydrochloric acid (pH = 2-3). This solution is extracted with ethyl acetate. The combined organic layers are dried (Na ^ -SO ^, and the solvent is evaporated to give N-t-B0C-piperidin-4-acetic acid as a white crystalline solid. (c) To a solution of Nt-BOC-piperidin-4-acetic acid (4.67 grams, 19.22 millimoles) in tetrahydrofuran at -78 ° C, triethyl amine (2.53 grams, 24.99 mmol) is added, followed by sodium chloride. pivaloílo (2.55 grams, 21.14 millimoles). The resulting white paste is stirred at -78 ° C for 15 minutes, heated at 0 ° C for 45 minutes, and then re-cooled to -78 ° C. In a separate flask, dissolve • », (R) - (+) - 4-benzyl-2-oxazolidinone (4.09 grams, 23.1 mmol) in tetrahydrofuran (50 milliliters), and 1 M normal butyl lithium in hexanes (14.4 milliliters, 23.06 mmol) at -78 ° C. The solution is added by means of a cannula to the aforementioned white paste at -78 ° C. The mixture of The reaction is stirred at -78 ° C for 15 minutes, then warmed to room temperature for 2.5 hours. The mixture is quenched with saturated aqueous sodium carbonate, and the tetrahydrofuran is evaporated in vacuo. The remaining aqueous layer is diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, and dried (Na2SO4), and the solvent is evaporated in vacuo. The product is purified by chromatography on silica gel (75 percent to 50 percent hexane / ethyl acetate), to give 3- [2- (Nt-BOC-4-piperidinyl) -l-oxaethyl] -4 ( R) - (benzyl) -2-oxazolidinone. 25 (d) To a solution of 3- [2- (Nt-B0C-4-piperidinyl) -l-oxoethyl] -4 (R) - (benzyl) -2-oxazolidipone (7.54 grams, 18.76 mmol) ep tetrahydrofuran ( 175 milliliters) at -78 ° C, a 0.5 M solution of bis (trimethylsilyl) amide of potassium in toluene (37.5 milliliters, 18.76 millimoles) is added dropwise. After stirring for 20 minutes at -78 ° C, a pre-cooled solution of trisilyl azide (7.25 grams, 23.4 millimoles) ep tetrahydrofurapo (55 milliliters) is added via a cannula at -78 ° C. The mixture is stirred for 15 minutes at -78 ° C, then acetic acid (3.38 grams, 56.28 millimoles) is added, followed by immediate heating to room temperature through immersion in a water bath. The reaction mixture is stirred for 1.5 hours at room temperature. The tetrahydrofurapo is removed in vacuo, and the resulting residue is partitioned between saturated aqueous sodium carbonate and ethyl acetate. The aqueous layer is removed and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na 30 °, and concentrated in vacuo.The product is purified by silica gel chromatography (30 percent to 50 percent ethyl acetate / hexapos), give 3- [2- (R) -azido-2- (Nt-B0C-4-piperidinyl) -l-oxo-ethyl] -4 (R) - (benzyl) -2-oxazolidinone. (e) To a solution of 3- [2- (R) -azido-2- (N-BOC-4-pi per di nil) -1 -oxoet i 1] - (R) - (bepci 1) -2 -oxazole idinone (5.8 grams, 13.17 millimoles) in 3: 1 tetrahydrofuran / water (200 milliliters) at 0 ° C, 30 percent aqueous hydrogen peroxide (5.12 milliliters, 52.67 millimoles) is added, followed by monohydrate of lithium hydroxide (1.11 grams, 26.34 millimoles). The reaction mixture is stirred at 0 ° C for 1 hour. The mixture is quenched by the addition of sodium sulfite (7.1 grams) at 0 ° C. The tetrahydrofuran is removed in vacuo, and the resulting aqueous layer is further diluted with water. This aqueous layer is then washed with methylene chloride, and acidified with IN hydrochloric acid. The resulting aqueous acid layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4), and concentrated in vacuo to give crude 2- (R) -azido-2- (N-t-BOC-4-piperidinyl) acetic acid. (f) To a previously stirred solution of tin (II) chloride (3.14 grams, 16.55 mmol) in methanol (100 milliliters) at 0 ° C, 2- (R) -azido-2- (Nt-) acid is added. BOC-4-piperidinyl) acetic (2.35 grams, 8.27 mmol) in methanol (25 milliliters) per drop. The reaction mixture is stirred at 0 ° C for 10 minutes, and then warmed to room temperature overnight. The methanol is removed in vacuo to give crude R- (N-t-B0C-4-piperidinyl) glycine, which is used directly in the next reaction without purification. The crude product of the above reaction is dissolved in 2: 1 dioxane / water (120 milliliters) and triethyl amine (7.53 grams, 74.43 mmol), and cooled to 0 ° C. To this mixture is added 4-methoxybenzenesulfonyl chloride (2.22 grams), 10.75 mmol), and then the reaction mixture is warmed to room temperature overnight. The dioxane is removed in vacuo, and the residue is partitioned between dilute aqueous sodium bicarbonate and ethyl acetate. The basic aqueous layer is removed, acidified with IN hydrochloric acid, and extracted with ethyl acetate. The resulting emulsion is passed through a pad of celite, washing with ethyl acetate. The organic filtrate is dried (Na2SO4) and concentrated in vacuo to provide 2 (R) - [(4-methoxybenzenesulfonyl) amino] -2- (N-t-BOC-4-piperidinyl) acetic acid as a crude product. (g) A solution of crude 2 (R) - [(4-methoxybenzenesulfonyl) amino] -2- (Nt-BOC-4-piperidinyl) acetic acid (2.88 grams) in dimethyl formamide (60 milliliters) containing amine (N, N-dicyclohexyl (1.22 grams, 6.73 millimoles) and benzyl bromide (1.15 grams, 6.73 millimoles), is stirred at room temperature for 3.5 hours.To this same reaction mixture is added again benzyl bromide (1.26). grams, 7.4 mmol), followed by potassium carbonate (6.5 grams, 47.11 mmol) The reaction mixture is stirred over the weekend at room temperature, the mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, and dried (Na2SO4), and concentrated in vacuo The crude product is purified by silica gel chromatography (15 percent to 25 percent ethyl acetate / hexane) to provide a saturated solution. (R) - [(4-methoxy-cep-sulphonyl) (benzyl) amino] -2- (Nt-B0C-4-piperidinyl) acetat or benzyl. (h) A solution of 2 (R) - [(4-methoxybenzenesul-fopyl) (bephenyl) amino] -2- (Nt-B0C-4-piperidinyl) bephenyl acetate (2.0 grams, 3.3 mmol) in dichloromethane (50 g) milliliters) is cooled to 0 ° C, and hydrochloric acid gas (from a reading bottle) is bubbled in for 10 minutes. The reaction mixture is heated at room temperature for 30 minutes. The solvent is removed in vacuo to give 2 (R) - [(4-methoxybenzenesulfopyl) (benzyl) amino] -2- (N-t-BOC-4-piperidipi 1) benzyl acetate hydrochloride as a white foam. (i) To a solution of 2 (R) - [(4-methoxybencepsulfopyl) (benzyl) amino] -2- (Nt-BCC-4-piperidinyl) benzyl acetate hydrochloride salt (1.28 grams, 2.35 mmol), heated to reflux, sodium format (480.0 milligrams, 7.06 millimoles), and formic aldehyde (0.57 milliliters, 7.06 millimoles) are added. The reaction mixture is refluxed for 10 minutes, and then additional aliquots of formic aldehyde (0.57 milliliters, 7.06 millimoles) are added at 10 minute intervals. The reaction mixture is refluxed for an additional 3 hours.

The formic acid is removed in vacuo, and the residue is partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The basic aqueous layer is further extracted with ethyl acetate. The combined organic extracts are washed with brine, dried and concentrated in vacuo to give 2 (R) - [(4-methoxybenzenesulfonyl) benzyl) amino] -2- (4-N-methylpiperidinyl) benzyl acetate as a crude product. . A solution of this crude product (1.23 grams) in 3N HCl (40 milliliters) is refluxed at 120 ° C for 2 days. The mixture is concentrated in vacuo to provide acid as a crude product. To a solution of this crude product (1.08 grams) in methylene chloride (75 milliliters), is added 1-hydroxybenzotriazole (0.312 grams, 2.31 millimoles), morpholine 4-methyl (1.64 grams, 16.17 millimoles), amine hydrochloride 0 tertiary-hydroxylicbutyl (870.0 milligrams, 6.93 millimoles), followed by N- [dimethylaminopropyl] -N'-ethyl carbodiimide hydrochloride (576.0 milligrams, 3.0 millimoles). The reaction mixture is stirred at room temperature overnight. The reaction is then diluted with water, and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (a ^ SOy), and the solvent is evaporated. The crude product is purified by chromatography on silica gel (3 percent to 7 percent methanol / methylene chloride containing 0.5 percent ammonium hydroxide), to give acetamide N- (tertiary butyloxy) -2 (R ) - [(4-methoxybencepsulfonyl) - (benzyl) amino] -2- (4-N- * methylpiperidinyl)).

Example 2: (a) Acetamide N-hydroxy-2 (R) - [(4-ethoxybenzenesulfonyl) (benzyl) amino] -2- [N- (dimethylaminoacetyl) -4-pyridinyl], m.p. 130-150 ° C, in a manner similar to acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (benzyl) amino] -2- (4-N-methylpiperidinyl) [see the example reference B, or European Patent Number EP-A-606,046, Example 32, pages 34-35]. 0 The required intermediary is prepared as follows: Al 2- (R) - [(4-methoxybenzenesulfonyl) (benzyl) amyl] -2- (4- piperidinyl) benzyl acetate [0.866 grams, obtained by separation of the BOC group in the product of the example of '* - * reference B (g) in a usual manner, for example, by treatment with HCl gas] in methylene chloride (50 milliliters), N, N-dimethyl glycine (0.172 grams), N-ethyl morpholine is added (0.7 milliliters), 1-hydroxybenzotriazole (0.215 grams), 0 and carbodiimide l- (3-dimethylamino-ropil) -3-ethyl (0.610 grams). The mixture is stirred at room temperature over the weekend, diluted with water, and extracted with methylene chloride. The combined organic extracts are dried over and evaporated to dryness to give 2 (R) - [(4-methoxybenzenesulfo-5 nyl) (benzyl) amine] -2 [(N-dimethylaminoacetyl) -4-piperidinyl] benzyl acetate. This benzyl ester is converted to the corresponding acid, for example, by hydrogenation in the presence of Pd / C. The conversion of the acid to the hydroxamic acid protected with BOC is carried out as described in Reference Example B (i). The BOC group is removed as described in Reference Example A (a). (b) Prepared in a similar manner - see in particular Reference Example B (c) to (i) and Reference Example A (a) - also acetamide hydrochloride N-hydroxy-2- (R) ) - [(4-methoxybenzenesulfonyl) (benzyl) amino] -2- (3-pyrrole idynyl), mp 160 ° C, decomposition, starting with N-butoxy tertiary-rio-carbonyl-3-pyrrolidineacetic acid. (c) Prepared in a similar manner - see in particular Reference Example B (c) to (i) and Reference Example A (a) - also acetamide N-hydroxy-2 (R) - [(4) -methoxybenzene-sulfonyl) (benzyl) amino] -2-N-butoxy tereary-carboni 1-3-pyrrole i-dinilica, mp 120 ° C. decomposition, starting with tertiary-N-butoxy-carbonyl-3-pyrrolidipacetic acid. (d) Prepared in a similar manner - see in particular Reference Example B and Reference Example A (a) -also acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (4-picol il) amino] -2- (4-tetrahydropyranilica). p.f. > 152 ° C, decomposition, starting with tetrahydropyranyl-4-acetic acid. Example 3: Prepared in a manner similar to Reference Examples A and B (as well as Examples 1-32 of European Patent Number EP-A-606,046) - in particular Reference Example A - Acetamide N-Hydrochloride -hydroxy-2 (R) - [(4-ethoxybenzenesulfonyl) (3-picolyl) amino] -2- (trans-4-hydroxycyclohexyl), mp 130-155 ° C.

The starting material is prepared as follows: Glycine D-4-hydroxyphenyl (10 grams) is dissolved in 3N sodium hydroxide (20 milliliters). Water (180 milliliters) and then Raney nickel (27 grams) are added. The reaction mixture is hydrogenated at a pressure of about 3 atmospheres [= 3.04 bar], and at 50 ° C-80 ° C overnight. The reaction mixture is filtered and reduced in volume to about 85 milliliters, and dioxane (85 milliliters) is added. The 4-hydroxycyclohexyl glycine solution (see Coll. Czech, Chem. Comm. 49, 712-742 (1984)) is cooled to 0 ° C, and treated with triethyl amine (11.37 milliliters) and 4-methoxybenzenesulfonyl chloride (10.95). grams). The reaction mixture is allowed to warm to room temperature, and is stirred over the weekend. The dioxane is removed in vacuo, and the remaining aqueous solution is diluted with IN hydrochloric acid. The resulting precipitate is collected, washed with water and ether, to give glycine (R) -N- (4-methoxybenzenesulfonyl) -4-hydroxycyclohexyl, which is converted to the methyl ester with methanol in the presence of chloride of thionyl. To a solution of glycine methyl ester (R) -N- (4-methoxybensulfonyl) -4-hydroxycyclohexyl ester (0.859 grams) in methylene chloride (8 milliliters), acetic anhydride (2.26 milliliters) and pyridipate (3.90) are added. milliliters). The reaction mixture is stirred at room temperature overnight, quenched with methanol, washed with IN hydrochloric acid. and it is extracted with methylepo chloride. The methylepoyl chloride extract is dried over sodium sulfate and evaporated to dryness to give gylcoxy (R) -N- (4-methoxybenzenesulfonyl) -4-acetyloxycyclohexyl methyl ester. Heating with 3N HCl under reflux for 24 hours, produces glycine (R) -N- (4-methoxybenzenesulfonyl) -4-hydroxycyclohexyl.

Example 4: Prepared in a manner similar to Reference Examples A and B and Examples 2-3 (as well as to Examples 1-32 of European Patent Number EP-A-606, 046): (a) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-metaxybenzenesulfonyl) (benzyl) amypo] -2- (trans- dimethylaminocyclohexyl), m.p. 138 ° C-146 ° C (see in particular Reference Example A).

The starting material is prepared as follows: A solution of oxalyl chloride (1.25 grams) in methylene chloride (30 milliliters) is cooled to -78 ° C, and dimethyl sulfoxide (1.16 milliliters) is slowly added. The reaction mixture is stirred at -78 ° C for about 30 minutes, and a solution of glycine methyl ester (R) -N- (4-methoxybenzenesulfonyl) -4-hydroxycyclohexyl (2.34 grams) in sodium chloride is added dropwise. methylene (30 milliliters). Stirring is continued for 30 minutes at -78 ° C, and then at 0 ° C for 30 minutes. The reaction mixture is cooled again to -78 ° C, triethyl amine (7.3 milliliters) is added dropwise, and the reaction mixture is stirred at -78 ° C for 30 minutes, allowed to warm to room temperature for 1 hour. , diluted with methylene chloride, washed first with hydrochloric acid IN, and then with brine. The organic layer is dried over sodium sulfate, evaporated to dryness, and the resulting product is purified by evaporation chromatography using 50-60 percent ethyl acetate in hexane to give glycine methyl ester (R) -N- ( 4-methoxybenzenesulfonyl) -4-oxocyclohexylic acid as a white solid. Treatment with benzyl bromide in dimethyl formamide in the presence of potassium carbonate at room temperature produces glycine (R) -N- (4-methoxybenzenesulfonyl) -N-benzyl-4-oxocyclohexylic acid methyl ester as an oil . The ketone (2.2 grams) is dissolved in methylene chloride (3 milliliters) and isopropanol (60 milliliters). Molecular sieves (3A, 1.5 grams), sodium ciapoborohydride (0.311 grams), and ammonium acetate (3.81 grams) are added. The reaction mixture is stirred at room temperature overnight, filtered and evaporated to dryness. The residue is partitioned between water and methylene chloride, and the product is extracted with methylepochloride. The resulting product is purified by evaporation chromatography using metapol / methylene chloride / 0.5 percent ammonium hydroxide as the eluent, to give glycine methyl ester (R) -N- (4-methoxybenzenesulfonyl) -N-benzyl- 4-aminocyclohexyl. N-methylation with formic acid / formic aldehyde / sodium axis formiate at the reflux temperature, followed by hydrolysis with 3N hydrochloric acid at reflux, produces 2- (R) - [(4-methoxybenzenesulfonyl) acid) (benzyl) amino] -2- (traps-4-di-ethylamino-cyclohexy-1-acetic acid). (b) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (benzyl) amino] -2- [trans -4- (dimethylazoleacetylamino) cyclohexyl], m.p. 163-170 ° C, obtained from glycine benzyl ester (R) -N- (4-methoxybensulphonyl) -N-benzyl-4-aminocyclohexyl, which in turn is prepared from glycine benzyl ester (R ) -N- (4-methoxybenzenesulfonyl) -4-hydroxycyclohexyl (see in particular Example 2 (a) and Reference Example A).

Example 5: Prepared in a manner similar to Reference Examples A and B, and to Examples 2-4 (as well as to Examples 1-32 of European Patent Number EP-A-606, 046): (a) Acetamide N-hydroxy-2 (R) - [(4-methoxybencepsulfonyl) (4-5 picolyl) amino] -2- (2-tetrahydrofuranyl), mp 89-92 ° C, [o] D25 + 4.82 (c8, CH1) H). The starting material, glycine R- (2-tetrahydrofuranilica) is prepared according to J. Am. Chem. Soc. 110 (1988) 1547. 0 (b) Acetamide N-hydroxy-2 (R) - [( 4-methoxy-cepsulfonyl) (3-picolyl) amino] -2- (2-tetrahydrofuranyl), mp 91-93 ° C, [o] D25 + 0.62 (c7.0, CH ^ DH). (c) Acetamide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (benzyl) amino] -2- (2-tetrahydrofurapilica), m.p. 143-144 ° C, [o] D25 + 5 1.03 (c 6.4, CH- ^ DH). '~ s (d) Acetamide N-hydroxy-2 (S) - [(4-methoxybencepsulfonyl) (3-picolyl) amypo] -2- (2-tetrahydrofuranyl), m.p. 162-163 ° C, [a] D25- 4.22 (c 6.5, CH-) H). (e) Acetamide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (ben-0 cyl) amino] -2- (traps-4-hydroxy-2-tetrahydrofuranyl), m.p. 53-56 ° C, as a mixture of diastereoisomers; The starting material, glycine trans- (4-hydroxy-2-tetrahydrofuran), is prepared according to J.Am. Chem. Soc. 110 (1988) 4533; (f) Acetamide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (ben-5-cyl) amino] -2- (4-oxacycloocty1lica), m.p. 152-157 ° C. as a mixture of diastereoisomers; (g) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzensulfonyl) - (4-picolyl) amino] -2- (4-oxacycloheptyl), m.p. 130-145 ° C, as a mixture of diastereoisomers; 5 (h) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzensulfonyl) (4-picolyl) amino] -2-cyclooctilica, m.p. 124-140 ° C; (i) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzensulfonyl) (4-picolyl) amino] -2- (2-oxohexahydroazepip-5-yl), diastereoisomer A, m.p. 160-172 ° C decomposition; 10 (j) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzensulfonyl) (4-picolyl) amyl] -2- (2-oxohexahydroazepip-5-yl), diastereoisomer B, m.p. 155-170 ° C; (k) Acetamide N-hydroxy-2 (R) - [(4-methoxy-cepcensulfonyl) (bepcyl) amyl] -2- (2-oxohexahydroazepin-5-yl), diastereoisomer A, p.f. 115-130 ° C; "_> (1) Acetamide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) l (benzyl) amyl] -2- (2-oxohexahydroazepin-5-yl), diastereoisomer B, p. f 120-140 ° C; (m) Butanamide N-hydroxy-2 (R) - [(4-methoxybenzenesulfoni I) (pr-20 opyl normal) amino] -3,4-dimethoxy, mp 53-55 ° C; (n) Propionamide N-hydroxy-2 (R) - [(4-methoxybensulphonyl) (propyl normal) arnino] -3, methoxy-3- (N-butoxy tertiary-carbonyl-4-piperidyl) mp 102- 103 ° C; (o) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxybenzyl-cenphulphonyl) (4-pical i 1) amino] -2- (N-ethoxycarboni 1-4-piperidi 1 ica-acetic, mp 145-158 ° C (decomposition); [o] n2 '= + 19.83 (c = 5.56 mg / ml, methanol); (p) Acetamide hydrochloride N-hydroxy-2- [(4-methoxybenzene) sulfonyl) (4-picolyl) amino] -2- (tetrahydro-2H-pyran-2-yl, 5 diastereoisomer A, mp 169-170 ° C (decomposition); (q) Acetamide hydrochloride N-hydroxy-2- [(4-methoxy-cepsenesulfonyl) (4-picolyl) amino] -2- (tetrahydro-2H-pyran-2-yl, diaest ereoisomer B, p.f. 158-161 ° C (decomposition); (r) Acetamide hydrochloride N-hydroxy-2 (R) - [(4-methoxy-cep-0-cenulphonyl) (4-picolyl) amypo] -2- (2-cis-4-hydroxycyclohexalic, mp 175-180 ° C , [o] n25 = + 14.04 (c = 6.37 mg / ml, metapol); (s) Acetamide N-hydroxy-2 (R) - [, (4-methoxybenzenesulfonyl) (benzyl) amino] -2- [trans] 4- (ethoxycarbonylamino) cyclohexyl], mp 105-115 ° C. Example 6: Preparation of 3,000 capsules, each containing one 25 milligrams of the active ingredient, eg, a compound mentioned in one of Examples 1- 5: Active ingredient 75.00 grams Lactose 750.00 grams 0 Avicel pH 102 (microcrystalline cellulose) 300.00 grams Polyplasdone XL (polyvinyl pyrrolidone) 30.00 grams Purified water qs 5 Magnesium stearate 9.00 grams The active ingredient is passed through a manual mesh Number 30 The active ingredient, lactose, Avicel pH 102, and Polyplasdone XL, are mixed for 15 minutes in a mixer, the mixture is granulated with sufficient water (approximately 500 thousand illitros), dried in an oven at 35 ° C overnight, and passed through a No. 20 mesh. Magnesium stearate is passed through a No. 20 mesh, added to the granulation mixture, and the mixture is - /. Mix for 5 minutes in a mixer. The mixture is encapsulated in hard gelatin capsules Number 0, each containing an amount of the mixture equivalent to 25 milligrams of the active ingredient.

Claims

1. A compound of the formula I wherein: Ar is carbocyclic or heterocyclic aryl; R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 1 carbon atoms, cycloalkyl of 3 at 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl, lower hydroxyalkyl, acyloxyalkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or dialkyl-lower-amino) -alkyl lower, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-aryl carbocyclic or heterocyclic-lower alkyl-piperaz non-lower alkyl, or (marfolyl, thiomorphyl, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl. R is cycloalkyl of 8 to 10 carbon atoms, (N-acylpiperidyl) -lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl, or N-lower alkyl-piperidyl) - (hydroxy or lower alkoxy) ) -lower alkyl, pyrrolidinyl, hexahydroazepinyl, N-lower alkyl- (hexahydroazepinyl or pyrrolidinyl), N-acyl- (hexahydroazepipyl, piperidyl or pyrrolidipyl), -oxacycloalkyl of 5 to 10 carbon atoms, tiacycloalkyl of 5 to 10 carbon atoms (hydroxy or oxo) -cycloalkyl of 5 to 10 carbon atoms, hydroxy or oxo) -thiacycloalkyl of 5 to 10 carbon atoms, (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms, (amino, mono - or lower dialkyl amino or acylamino) -cycloalkyl of 5 to 10 carbon atoms, 2-oxo- (pyrrolidinyl, piperidyl or hexahydroazepini-lo); R2 is hydrogen or lower alkyl; a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

2. A compound of the formula I according to claim 1, wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of 1 to 10 carbon atoms, hydroxy; phenylalkoxy lower, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; heterocyclic aryl-lower alkoxy, wherein the heterocyclic aryl is selected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl, imidazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; or Ar is phenyl substituted by cycloalkyl of 3 to 7 carbon atoms-lower alkoxy, (lower alkyl, phenylalkyl, or cycloalkyl of 3 to 7 carbon atoms-lower alkyl) -thio, lower alkyloxy-lower alkoxy, halogen, alkyl lower, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amino, mono- or di-lower alkyl-amino; or Ar is phenyl substituted on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thienyl isoxazolyl, or thiazolyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen, lower alkyl, lower phenylalkyl, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; phenyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (thio, sulfinyl or sulfonyl), amino, mono or di-alkyl lower-amino, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxaalkylene of 2 to 3 carbon atoms; or a heterocyclic aryl radical selected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl, imidazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; biphenylyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; diphenylalkyl lower, wherein the diphenylyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; (pyridyl, tiepyl, quinolinyl, or thiazolyl) -lower alkyl, trifluoromethyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa tia) -cycloalkyl of 3 to 6 carbon atoms carbon, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl, lower hydroxyalkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl , (amino, mono- or di-lower alkyl-amylo) -low alkyl, lower alkanoyl-a lower inoalkyl, (N-lower alkyl-piperazino or N-phenylalkyl-lower piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidipy, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R is pyrrolidinyl; hexahydroazepinyl; N-lower alkyl- (hexahydroazepinyl or pyrrolidipyl); N-acyl- (hexahi-droazepinyl, piperidyl, or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -thiacycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms; or (amino, mono- or di-alkylamino, or lower alkanoyl-amylo) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

3. A compound of the formula I according to claim 1, wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of 1 to 7 carbon atoms, hydroxy, phenylalkoxy, cycloalkyl from 3 to 7 carbon atoms-lower alkoxy-lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amino, mono- or di-alkyl ipferior-amypo, or , on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thienyl, isoxazolyl or thiazalyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen; lower alkyl, phenylalkyl lower; phenyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, trifluoromethyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; a heterocyclic aryl radical selected from pyridyl, thiazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl; diphenylyl: difeni lalqui lower: (pyridyl or thienyl) -lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl; (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl; lower hydroxyalkyl; (N-lower alkyl-piperazino, or N-phenylalkyl-lower piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; Rj is pyrrolidipyl; hexahydroazepinyl; N-lower alkyl- (hexahydroazepinyl or pyrrolidinyl); N-acyl- (hexahi-droazepinyl, piperidyl, or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tarycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy or oxo) -thiacycloalkyl of 5 to 10 carbon atoms: (hydroxy or oxo) -oxacycloalkyl of 5 to 10 carbon atoms; or (amino, mono- or di-alkylamino, or lower alkanoyl-amino) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

4. A compound according to the rei indication 1. of the formula I I: or R, CH2 or a. !! II HO-NCC- iS! - / / 'rx) (! I, H R7 or R5 wherein: R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, aryl heterocyclic-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [ (oxa or thia) -cycloalkyl of 3 to 6 carbopo atoms - lower alkyl, lower hydroxyalkyl, lower acyloxyalkyl, lower alkoxy-lower alkyl, lower alkyl (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or lower dialkyl-amylo) -lower alkyl, lower acylaminoalkyl, (N-lower alkyl-piperazipy or carbocyclic N-aryl or heterocyclic-lower alkyl-pi? erazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, or N-alkyl • - "lower-piperidyl) -lower alkyl; R, is pyrrolidinyl, hex ahydroazepipyl, N-lower alkyl- (pyrrole, idinyl or hexahydroazepinyl), oxacycloalkyl, 5 to 7 carbon atoms, tiacycloalkyl of 5 to 7 carbon atoms, (hydroxy or oxo) -cydohexyl, (amino, mono- or di-lower alkyl-amino) -cydohexyl, or 2-oxohexahydroazepinyl; R2 is hydrogen; R is hydrogen, lower alkoxy, hydroxy, carbocyclic aryl or heterocyclic-lower alkoxy, lower thioalkyl, or carbocyclic aryl or heterocyclic-thiaalkylamino. lower alkoxy-lower alkoxy, halogen, trifluoromethyl, lower alkyl, nitro, or cyano; Rr is hydrogen, lower alkyl, or halogen; 0 R4 R5 > on the adjacent carbon atoms, together they represent methylenedioxy, ethylenedioxy, oxyethylene or oxypropylene; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, of formula III: wherein R represents lower alkyl, trifluoromethyl, cycloalkyl of 5 to 7 carbon atoms, (oxa or thia) -cycloalkyl of 4 to 5 carbon atoms, biaryl, carbocyclic monocyclic aryl, or heterocyclic monocyclic aryl; R < represents oxacycloalkyl of 5 to 7 carbon atoms, or (hydroxy, a or. or di-lower alkyl-amino) -cydohexyl; R represents lower alkoxy or carbocyclic or heterocyclic-lower alkoxy aryl; or a pharmaceutically acceptable prodrug derivative of the rnisrr.r. : or a pharmaceutically acceptable salt thereof.

6. A compound of formula III according to claim 5, wherein R represents heterocyclic monocyclic aryl selected from tetrazolyl, triazolyl, thiazolyl, imidazolyl, and pyridyl, each unsubstituted or substituted by lower alkyl; or R represents phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; R ^ represents 2-, or 3-tetrahydrofuranyl; and RM represents lower alkoxy or lower phenylalkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

7. A compound of the formula III according to claim 5. wherein R represents 2-. 3-, or 4-pyridyl or phenyl; R. represents 2- or 3-tetrahydrofuranyl; and R "represents lower alkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

8. A compound of the formula III according to claim 5, wherein R is lower alkyl, 2-, 3-, or 4-pyridyl or phenyl; Rj is cycloalkyl of 8 to 10 carbon atoms, (N-lower alkoxycarbopypiperidyl) - (lower alkoxy) -lower alkyl, pyrrolidinyl, N- (lower alkoxycarbonyl or lower dialkyl-aminoalkanoyl lower) - (piperidyl) dilo or pyrrolidinyl), oxacycloalkyl of 5 to 10 carbon atoms, hydroxycycloalkyl of 5 to 10 carbon atoms. (hydroxy) -oxacycloalkyl of 5 to 10 carbon atoms, (lower dialkyl-amino or lower dialkyl-lower aminoalkanoyl-amino or lower alkylcarbonylamino) -cycloalkyl of 5 to 10 carbon atoms, or 2-oxopiperidyl; and Rj represents lower alkoxy; or a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof.

9. A compound according to any of claims 1 to 8, wherein the asymmetric carbon atom with which Rj is bound has the (R) configuration assigned.

10. A compound according to claim 1, which is amide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (4-picolyl) amyl] -2- (2-tetrahydrofurapyl) -acetic, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1, which is amide N-hydroxy-2 (R) - [(4-methoxybenzenesulfonyl) (4-picolyl) amino] -2- (N-ethoxycarbonyl-4-piperidyl) - acetic, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any of claims 1 to 11, and a pharmaceutically acceptable carrier.

13. A compound according to any of claims 1 to 11, for use in a method for the therapeutic treatment of the animal or human body.

14. A compound according to any of claims 1 to 11, for use in the treatment of matrix degrading metalloproteipase-dependent conditions.

15. The use of a compound according to any of claims 1 to 11, for the manufacture of a pharmaceutically composition for the treatment of matrix degrading metalloproteinase-dependent conditions.

16. A process for the preparation of a compound of the formula I according to claim 1, which comprises condensing a carboxylic acid of form-IV: O R, ¿H-.0 II I I "II (IV) HO-C - C -N - S -Ar wherein R, Rlf R2, and Ar have the meaning defined in claim 1, or a reactive functional derivative thereof, with hydroxylic amine of formula V: NH2-OH (V) optionally in a protected form, or a salt thereof; and if necessary, temporarily protect any reactive groups that interfere, and then release the resulting compound of the invention; and if required or desired, converting a compound resulting from the invention into another compound of the invention, and / or if desired, converting a resulting free compound into a salt, or a resulting salt into a free compound or other salt; and / or separating a mixture of isomers or racemates obtained, into the individual isomers or racemates; and / or if desired, redissolve a racemate in the optical antipodes.

17. The use of a compound of the formula I: 0 «i H2 O 1! 1 1 I I N - C - C - N - s Ar (I) 1 i I I H o. or (a) wherein Ar is carbocyclic or heterocyclic aryl; R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 7 carbon atoms , cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or aunt) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl. hríro /? I rent the inferior. lower alkyl acryloxy, lower alkoxy] -r-, alkyl? Rut, alkyl (thio, sulfinyl or sulfonyl) -low alkyl, (amino, mono- or dialkyl-lower-amino) -low alkyl, acylamino-lower alkyl, (N-lower alkyl-piperazino or N-aryl carbocyclic or heteroaryl-lower alkyl -piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R. is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, diaryl, lower diarylalkyl, heterocyclic aryl-lower alkyl, mono- or poly-lower haloalkyl, cycloalkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, hydroxyalkyl, lower, acyloxyalkyl lower, lower alkoxy-lower alkyl, (carbocyclic or heterocyclic aryl) - lower alkoxy-lower alkyl, lower alkyl- (thio, sulfinyl or sulfonyl) -lower alkyl, (amino, mono- or di-alkyl ipferior-amino) -lower alkyl, (N-lower alkyl-piperazino, or N-carbocyclic aryl or heterocyclic-lower alkyl-piperazino) -lower alkyl, (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acyl, or N-alkyl ipferior-piperidyl) -low alkyl, acylamino-lower alkyl, piperidyl, (morpholino, thiomorpholino, piperidino pyrrolidipy, piperidyl, N-acyl, or N-lower alkyl-piperidyl-lo) - (hydroxy or lower alkoxy) -lower alkyl, pyrrolidipyl, hexahydroazepipyl, N-lower alkyl, or N-acyl (hexahydroazepi-nyl, piperidyl, or pyrrolidinyl), oxacycloalkyl of 5 to 10 carbon atoms, tiacycloalkyl of 5 to 10 carbon atoms, (hydroxy- or oxo-) -cycloalkyl of 5 to 10 carbon atoms, (hydroxy- or oxo-) tiacycloalkyl of 5 to 10 carbon atoms, (hydroxy) or oxo-) - oxacycloalkyl of 5 to 10 carbon atoms, (amyl, mono- or di-alkylamino or acylamino) -cycloalkyl of 5 to 10 carbon atoms, 2-oxo (pyrrolidinyl, piperidyl, or hexahydroazepinyl); R ^ is hydrogen or lower alkyl; or (b) wherein R and Rj, together with the chain to which they are attached, form a ring of 1, 2,3, 4-tetrahydroisoquinolipa, piperidine, oxazolidine, thiazolidine, or pyrrolidine, each unsubstituted or substituted by alkyl lower; and Ar and R2 have the meaning defined in (a); or (c) where R, and R ^ together with the carbon atom to which they are attached, form a ring system selected from * starting from cycloalkane of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl; oxacyclohexane, cyclohexane, indane, tetralin, piperidine, or piperidine substituted on nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, (carboxy, esterified or amidated carboxy) -low alkyl, or by lower alkyl-sulfonyl; and Ar and R have the meaning defined in (a); pharmaceutically acceptable prodrug derivatives: and pharmaceutically acceptable salts thereof; (for the manufacture of a medicament) for the treatment of conditions that respond to the inhibition of the activity of the macrophage metalloelastase, or for the treatment of atherosclerosis and restenosis, or for ocular applications selected from the pterygium treatment, keratitis, keratoconus, open-angle glaucoma, or retinopathies, and use in conjunction with refractive surgery (laser or incision) to minimize adverse effects.

18. The use according to claim 17, wherein the compound used is a compound of the formula I, (a) wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of to 10 carbon atoms, hydroxy; phenylalkoxy lower, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; heterocyclic aryl-lower alkoxy, wherein the heterocyclic aryl is selected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl, amidazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; or Ar is phenyl substituted by cycloalkyl of 3 to 7 carbon atoms-lower alkoxy, (lower alkyl, phenylalkyl, or cycloalkyl of 3 to 7 carbon atoms-lower alkyl) -thio, lower alkyloxy-lower alkoxy, halogen, alkyl lower, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amino, mono- or di-lower alkyl-amino; or Ar is phenyl substituted on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; D Ar £ > .-? thienyl isoxazolyl, or thiazolyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen, lower alkyl, lower phenylalkyl, wherein the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; phenyl which is ipsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (thio, sulfinyl or sulphoyl), amino, mono or di-alkyl lower-amino, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxaalkylene of 2 to 3 carbon atoms; or a heterocyclic aryl radical selected from pyridyl. tetrazolyl, triazolyl, thiazolyl, thienyl, imidazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl or halogen; diphenylyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; lower biphenylalkyl, wherein the diphenylyl is ipsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or cyano; (pyridyl, thienyl, quinolinyl, or thiazolyl) -alkyl, trifluoromethyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl, (oxa or tia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] - lower alkyl, lower hydroxyalkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl- (thio, sulfipyl or sulfonyl) -lower alkyl, (amino, mono- or di-lower alkyl-amino) -lower alkyl, lower alkanoyl-lower aminoalkyl, (N-lower alkyl-piperazino or N-phenylalkyl ipferior-piperazipro) -lower alkyl, or (morpholipid, thiomorpholipid, piperidipy, pyrrolidine, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R "is hydrogen; lower alkyl; phenyl-lower alkyl wherein the phenyl is ipsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms, or oxyalkylene of 2 to 3 carbon atoms; phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or trifluoromethyl; pyridyl; thienyl; diflililil; diphenylpylalkyl lower; heterocyclic aryl-lower alkyl, wherein the heterocyclic aryl is selected from thiazolyl, pyrazolyl, pyridyl, imidazolyl, and tetrazolyl, each unsubstituted or substituted by lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl; lower hydroxyalkyl; lower alkanoyloxy-lower alkyl; lower alkoxy-lower alkyl; (phenyl or pyridyl) -lower-lower alkoxy-lower alkyl; lower alkyl- (thio, sulfinyl, or sulfonyl) -lower alkyl; (amino, mono- or di-lower alkyl-amino) -lower alkyl; (N-alkylated lower piperazino or N-phenylalkyl lower piperazino) -lower alkyl; (morpholinyl, thiomorpholino, piperidino, pyrrolidino, piperidyl, or N-lower alkyl-piperidyl) -lower alkyl; lower alkanoyl-amino-lower alkyl; R3-CONH-lower alkyl, wherein R3 represents (lower-amino dialkyl, N-lower alkyl-piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, or N-alkylpiperidyl) -lower alkyl; piperidyl; pyrrolidinyl; hexahydroazepinyl; N-lower alkyl- or N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) -thiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) -oxacycloalkyl of 5 to 10 carbon atoms; (amino, mono- or di-alkylamino or lower alkanoyl-amino) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; (b) or wherein R and R1 (together with the chain to which they are attached, form a 1,2,3,4-tetrahydroisoquinoline, piperidine, oxazolidine, thiazolidine, or pyrrolidine ring, each unsubstituted or mono- or di-substituted by lower alkyl, and Ar and R2 have the meaning defined in (a), (c) or wherein Rj and R2, together with the carbon atom with which they are attached, form a ring system selected from of cycloalkane of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl, oxacyclohexane, cyclohexane, indane, tetralin, and piperidine, which is unsubstituted or substituted on nitrogen by lower alkanoyl, lower dialkyl-aminoalkanoyl, lower alkoxy lower carbonyl, (morpholino, thiomorpholino, or piperidino) -carbonyl, lower alkyl, (phenyl or pyridyl) -lower alkyl, (carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminocarbonyl, or mono- or di-alkyl ipferior-aminocarbonyl) -lower alkyl, or by alkyl the lower sulfonyl; and Ar and R have the meaning defined in (a); a pharmaceutically acceptable prodrug derivative thereof; or a pharmaceutically acceptable salt thereof. The use according to claim 17, wherein the compound used is a compound of the formula I, (a) wherein Ar is phenyl which is unsubstituted or mono-, di-, or tri-substituted by alkoxy of at 7 carbon atoms, hydroxy, phenylalkoxy lower, cycloalkyl of 3 to 7 atoms of carbopo-lower alkoxy-lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro, trifluoromethyl, lower alkyl- (sulfinyl or sulfonyl), amyl , mono- or di-lower alkyl-amylo, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; or Ar is thienyl, isoxazolyl or thiazolyl, each of which is unsubstituted or mono- or di-substituted by lower alkyl; R is hydrogen; lower alkyl, lower phenylalkyl; phenyl which is unsubstituted or mono-, di-, or tri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, trifluoromethyl, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms or oxyalkylene of 2 to 3 carbon atoms; a heterocyclic aryl radical selected from pyridyl, thiazolyl, and quinolinyl, each unsubstituted or mono- or di-substituted by lower alkyl; biphenylyl; lower biphenylalkyl; (pyridyl or thienyl) -lower alkyl; trifluoromethyl; cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms-lower alkyl; (oxa or thia) -cycloalkyl of 3 to 6 carbon atoms, [(oxa or thia) -cycloalkyl of 3 to 6 carbon atoms] -lower alkyl; lower hydroxyalkyl; (N-alkyl ipferior-piperazype, or N-phenylalkyl-lower piperazino) -lower alkyl, or (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl or N-lower alkyl-piperidyl) -lower alkyl; R ^ is hydrogen; lower alkyl; lower phenylalkyl, in which the phenyl is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoroethyla, or, on the adjacent carbon atoms, by alkylenedioxy of 1 to 2 carbon atoms: diphenyl lower alkyl; heterocyclic-lower alkyl aryl, wherein the heterocyclic aryl is selected from thiazolyl, pyrazolyl, pyridyl, imidazolyl, and tetrazolyl, each unsubstituted or substituted by lower alkyl; cycloalkyl of 3 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-lower alkyl; lower hydroxyalkyl, (phenyl or pyridyl) -lower-lower alkoxy-lower alkyl; lower alkyl- (thio, sulfinyl, or sulfonyl) -low alkyl; (amino, mono- or di-lower alkyl-amino) -5 lower alkyl; (N-lower alkyl-piperazino, or N-phenylalkyl-piperazino) -lower alkyl; (morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, or N-lower alkyl-piperidyl) -lower alkyl; lower alkanoyl-lower aminoalkyl; R3-CONH-lower alkyl, wherein R3 represents < (lower-amino dialkyl, N-lower alkyl-piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, or N-alkylpiperidyl) -lower alkyl; piperidyl; pyrrolidinyl; hexahydroazepinyl; N-lower alkyl- or N-acyl- (hexahydroazepinyl, piperidyl or pyrrolidinyl); oxacycloalkyl of 5 to 10 carbon atoms; tiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) -cycloalkyl of 5 to 10 carbon atoms; (hydroxy-u-oxo-) -thiacycloalkyl of 5 to 10 carbon atoms; (hydroxy- or oxo-) -oxacycloalkyl; (amino, mono- or di-alkylamino, or lower alkanoyl-amino) -cycloalkyl of 5 to 10 carbon atoms; R2 is hydrogen or lower alkyl; (b) or wherein R and R1 (together with the chain to which they are attached, form a thiazolidine or pyrrolidine ring, each unsubstituted or mono- or di-substituted by lower alkyl, and Ar and R2 have the defined meaning in (a); 5 (c) or where R? and R2, together with the carbon atom to which they are attached, form a ring system selected from cycloalkane of 3 to 7 carbon atoms, which is unsubstituted or substituted by lower alkyl, oxacyclohexapo, thiacyclohexane, and piperidine which is unsubstituted or substituted on nitrogen by lower alkanoyl, lower dialkyl-lower aminoalkanoyl, lower alkoxycarbonyl, (morpholino, thiomorpholino, or piperidino) -carbonyl, lower alkyl, ( phenyl or pyridyl) -lower alkyl, (carboxy, lower alkoxycarbonyl, aminocarbonyl, or mono- or di-lower alkyl-to ipocarbopy-lo) -lower alkyl, or by lower alkyl-sulfonyl, and Ar and R have the meaning defined in (a); a profármac derivative or pharmaceutically acceptable thereof; or a pharmaceutically acceptable salt thereof. 20. The use according to claim 17, wherein the compound used is butanamide N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -3-methyl, or a pharmaceutically salt acceptable of it.