CZ9902833A3 - Derivatives of arylsulfonyl hydroxamic acids, pharmaceutical preparation, inhibition method of matrix metalloproteinases or production of tumor necrosis factor and therapeutical method - Google Patents

Abstract

Arylsulfonylhydroxamic acid derivatives of the general formula Wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9 and Q are as defined above as claimed in the claims, are useful in treating the conditions selected from arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases including tumor necrosis factor (TNF) production. These compounds are moreover, useful in combination therapy with non-steroidal anti-inflammatory drugs; analgesics and in combination with cytotoxic agents such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids such as vincristine in the treatment of cancer.

Description

Arylsulfonylhydroxamic acid derivatives, pharmaceutical composition, method of inhibiting matrix metalloproteinases or tumor necrosis factor production and method of treatment

Technical field

The invention relates to arylsulfonylhydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or tumor necrosis factor (TNF) production and as such are useful in the treatment of a disease selected from arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity as well as AIDS, sepsis, septic shock and other diseases involving TNF production. In addition, the compounds of the invention may be used in combination therapy together with standard nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cisplatin, etoposide, taxol, taxoter and alkaloids , such as vincristine, in the treatment of cancer.

The invention also relates to a method for the use of these compounds in the treatment of the aforementioned diseases in mammals, in particular humans and pharmaceutical compositions based thereon.

BACKGROUND OF THE INVENTION

There are a number of enzymes that cause the breakdown of structural proteins and which are structurally related to metalloproteinases. Matrix degrading metalloproteinases, such as gelatinase, stromelysin, and collagenase, are involved in the degradation of the tissue matrix (e.g., collagen collapse)

and are associated with many pathological conditions including abnormal metabolism of connective tissue and underlying membrane matrices such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease , bone disease (e.g., Paget's disease and osteoporosis), metastasis or tumor invasion, as well as HIV infection (J. Leuk. Biol. 52 (2)):

244-248, 1992).

Tumor necrosis factor is known to be involved in many infectious and autoimmune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). In addition, TNF has been shown to be the primary mediator of the inflammatory response observed in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 1992 62 Sil).

PCT publication WO97 / 9720824 relates to hydroxamic acids with MMP activity.

SUMMARY OF THE INVENTION

The present invention provides arylsulfonylhydroxamic acid derivatives of the formula I

where the dashed line represents an optional double bond;

X is carbon, oxygen or sulfur;

Y is carbon, oxygen, sulfur, SO or S0 _2, or nitrogen;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen, C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of alkylthio (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, trifluoromethyl, halogen, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 6 -C 10) arylamino, (C 6 -C 10) arylthio , (C 6 -C 10) aryloxy, (C 5 -C 9) heteroarylamino, (C 5 -C 9) heteroarylthio, (C 5 -C 9) heteroaryloxy, (C 6 -C 10) aryl aryl groups in each of the aryl moieties, (C 3 -C 3) cycloalkyl groups 6 carbon atoms, hydroxy, piperazinyl, arylalkoxy of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkoxy moiety, heteroarylalkoxy of 5 to 9 carbon atoms uv heteroaryl and 1 to 6 carbon atoms in the alkoxy moiety, acylamino of 1 to 6 carbon atoms, acylthio of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, arylsulfinyl of 6 to 10 atoms carbon, C 1 -C 6 alkylsulfonyl, C 6 -C 10 arylsulfonyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 alkylamino ₂ in each of the alkyl 4 4 4 4

4 4 4 4 4

4 4

4 parts; (C 2 -C 6) alkenyl, (C 6 -C 10) arylalkenyl, (C 2 -C 6) aryl, (C 2 -C 6) heteroarylalkenyl, (C 2 -C 6) heteroaryl, (C 2 -C 6) alkynyl, (C 2 -C 6) alkynyl 6 carbon atoms, arylalkynyl of 6 to 10 carbon atoms in the aryl and 2 to 6 carbon atoms of the alkynyl moiety, heteroarylalkynyl of 5 to 9 carbon atoms in the heteroaryl and 2 to 6 carbon atoms of the alkynyl moiety, alkylamino of 1 to 6 carbon atoms, (C 1 -C 6) alkylthio, (C 1 -C 6) alkoxy, (C 1 -C 6) perfluoroalkyl, (C 6 -C 10) aryl, (C 5 -C 9) aryl, (C 6 -C 10) arylamino, arylthio (C 6 -C 10) aryloxy group (C 6 -C 10) aryloxy, (C 5 -C 9) heteroarylamino, (C 5 -C 9) heteroarylthio, heteroaryl (C až-C) alkoxy, (C až-C cyk) cycloalkyl, (Cmet-C () alkyl (hydroxymethylene), piperidyl, (C až-C alkyl) alkylpiperidyl, (C až-C ac) acylamino group carbon, acylthio of 1-6 carbon atoms, acyloxy of 1-6 carbon atoms, R ^xu -alkyl of 1-6 carbon atoms in the alkyl moiety, wherein R is acylpiperazino of 1-6 carbon atoms in the acyl moiety, (C až-C 10) arylpiperazino, (C až-C 9l) heteroarylpiperazo, (C až-C alkyl) alkylpiperazino, (C až-Cry a) arylpiperazino and (C až-Cry) alkyl Moieties, heteroarylalkylpiperazino of 5 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, morphol ino, thiomorpholino, pyrrolidino, piperidyl, alkylpiperidyl of 1 to 6 carbon atoms in the alkyl moiety, arylpiperidyl of 6 to 10 carbon atoms in the aryl moiety, heteroarylpiperidyl of 5 to 9 carbon atoms in the heteroaryl moiety of each of the alkylpiperidyl groups from alkyl moieties, arylpiperidylalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl portion, heteroarylpiperidylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl portion, or acylpiperidyl of 1 to 6 carbon atoms in the alkyl acyl moieties; or a group of formula (II) (U), (II) (CH _e ) _n

-n_rtrckde is from 0 to 6;

represents 0 or 1;

represents an oxygen atom or NR ^24, wherein R ²⁴ is hydrogen or alkyl of 1 to 6 carbon atoms ;, • • · «· • • · · · · · · · · · • • ·" represents a group OR ^11, or NR ²⁴ R ¹¹ , wherein R ²⁴ is as defined above and R ¹¹ is as defined below; azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinylskupinu, tetrahydroquinolinyl, tetrahydroisoquinolinyl or a bridged diazabicycloalkyl ring selected from the group _{<CH2) b,} (CH _{2) p.}

H

wherein it is 1, 2 or 3;

represents the number 1 or 2;

represents 0 or 1; and

• · ····

- each heterocyclic group is optionally substituted with one or two groups selected from the group consisting of hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, acyl of 1 to 10 carbon atoms, acyloxy of 1 to 10 carbon atoms , (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 6 -C 10) arylalkyl (C 1 -C 6) alkyl, (C 5 -C 9) heteroaryl (C 1 -C 6) heteroarylalkyl C 1 -C 6 -alkyl, C 1 -C 6 -alkoxyalkyl and C 1 -C 6 -alkoxyalkyl, C 1 -C 6 -acyloxyalkyl and C 1 -C 6 -alkyloxyalkyl , (C 1 -C 6) alkylthio, (C 1 -C 6) alkylthioalkyl, (C 6 -C 10) arylthio groups carbon, arylthioalkyl having 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety, groups of the formula R ¹² R ¹³ N, R ¹² R ¹³ NSO 2, R ¹² R ¹³ NCO, R ¹² R ¹³ NCO-alkyl S C 1 -C 6 alkyl wherein R ¹² and R ¹³ are each independently hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 6 -C 10 arylalkyl atoms in the aryl and 1-6 carbon atoms in the alkyl moiety, or heteroaryl having 5 to 9 carbon atoms in the heteroaryl and 1-6 carbon atoms in the alkyl moiety, or R ^xz 'and R, taken together with the nitrogen atom to which they are attached may form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring; groups of formula R ¹⁴ SO 2 or R ¹⁴ SO ₂ NH, wherein R ¹⁴ represents a trifluoromethyl, alkyl of 1-6 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl moiety or heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl • 4 4 • 44 4 · 4 4 ·· «·

4 and 4 and 1 to 6 carbon atoms in the alkyl moiety; R ¹⁵ CONR ¹² wherein R ¹² is as defined above and R ¹⁵ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, C 5 -C 9 heteroaryl carbon, arylalkylarylalkoxy having 6 to 10 carbon atoms in each of the aryl moieties and each having 1 to 6 carbon atoms in the alkyl and alkoxy moiety or heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; R @ ¹⁶ OOC, R @ ¹⁶ OOC (C1 -C6) -alkyl, wherein R @ ¹⁶ is C1 -C6 alkyl, (C6 -C10) aryl, (C5 -C9) heteroaryl, - arylalkyl); 6 to 10 carbon atoms in the aryl and 1-6 carbon atoms in the alkyl moiety, 5-indanyl, CHR ¹⁷ OCOR ¹⁸ wherein R ¹⁷ is hydrogen or alkyl having 1 to 6 carbon atoms and R ^x ° is an alkyl group having from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms; CH 2 CONR ¹⁹ R ²⁰ , wherein R ¹⁹ and R ²⁰ are each independently hydrogen or C 1 -C 6 alkyl, or taken together with the nitrogen to which they are attached may form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring ; or a group of formula R ²¹ O-C 1 -C 6 -alkyl, wherein R ²¹ is a group of the formula H 2 N (CHR ²² ) CO, wherein R ²² is a side chain derived from a natural D- or L-amino acid;

R ¹¹ is hydrogen, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 6 -C 10) arylalkyl and (C 1 -C 6) alkyl, heteroaryl (C 5 -C 9) heteroaryl; and 1 to 6 carbon atoms in the alkyl moiety, alkylarylalkyl having 1 to 6 carbon atoms in each ta-ta-ta-ta-ta-ta-ta-ta-ta-ta-ta-ta-ta-ta Alkyl and 6 to 10 carbon atoms in the aryl moiety, alkylheteroarylalkyl; alkylheteroarylalkyl; &quot; alkylheteroarylalkyl &quot; having 1 to 6 carbon atoms in each of the alkyl and 5 to 9 carbon atoms in the heteroaryl moiety, a 5-indanyl group or a group of formula CHR ¹⁷ OCOR ¹⁸ or CH ₂ CONR ¹⁹ R ²⁰ , wherein R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are as defined above; or

R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ taken together may form a carbonyl group; or

R ¹ and R ^2, or R ³ and R ^4, or R ⁵ and R ^6, or R ⁷ and R ⁸ taken together may form a cycloalkyl of 3 to 6 carbon atoms, oxacyclohexyl, thiocyklohexylový, indanyl or tetralinyl ring or a group of formula n

where p23

R is hydrogen, C 1 -C 6 acyl, C 1 -C 6 alkyl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl, C 5 -C 9 heteroarylalkyl and heteroaryl; up to 6 carbon atoms in the alkyl moiety or an alkylsulfonyl group having 1 to 6 carbon atoms; and

Q is C 1 -C 10 alkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyaryl in each of the aryl moieties, C 6 -C 10 arylarylalkyl in each of the aryl moieties, C 6 -C 10 arylarylalkyl of carbon in each of the aryl groups 9 9 9 9 9 9

9 99 9 9 9 9 • 9 9 9 9 9 9 9 • 99 9 9 99 9

99 99 ·· and 1 to 6 carbon atoms in the alkyl moiety, arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl moiety, 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, aryloxyheteroaryl of 6 to 10 carbon atoms in aryl and 5 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of 5 to 9 carbon atoms, alkylaryl of 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl moiety, alkoxyaryl of 1 to 6 carbon atoms in the alkoxy and 6 to 6 carbon atoms 10 carbon atoms in the aryl moiety, arylalkoxyaryl of 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety, heteroaryloxyaryl of 5 to 9 atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety, alkylheteroaryl of 1 up to 6 carbon atoms in the alkyl and 5 to 9 carbon atoms in the heteroaryl moiety, an alkoxyheteroaryl group having 1 to 6 carbon atoms in the alkoxy and 5 to 9 carbon atoms in the heteroaryl arylalkoxyheteroaryl of 6 to 10 carbon atoms in the aryl, 1 to 6 carbon atoms in the alkoxy and 5 to 9 carbon atoms in the heteroaryl moiety, a heteroaryloxyheteroaryl of 5 to 9 carbon atoms in each of the heteroaryl moieties, aryloxyalkyl of the 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroaryloxyalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylaryloxyaryl of 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in each of the aryl moieties , (C 1 -C 6) alkylheteroaryloxyaryl, (C 5 -C 9) heteroaryl and (C 6 -C 10) aryl, (C 1 -C 6) alkyllaryloxyheteroaryl (C 6 -C 10) aryl, and (C 5 -C 9) hetero ··

4 4 1 4 1 43 1 4 4 1

4,444 4 4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4 4 4 · 49 44 · 4 44 aryl moieties, alkoxyaryloxyaryl having 1 to 6 carbon atoms in alkoxy and 6 to 10 carbon atoms in each of the aryl moieties, alkoxyheteroaryloxyaryl having 1 to 6 carbon atoms in alkoxy, C 5 -C 9 heteroaryl and C 6 -C 10 aryl or C 1 -C 6 alkoxyaryloxyheteroaryl, C 6 -C 10 aryl and C 5 -C 9 heteroaryl optionally substituted with fluoro, chloro, bromine, (C1-C6) alkyl, (C1-C6) alkoxy or (C1-C3) perfluoroalkyl;

wherein Z must be substituted when it represents an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or piperazinyl ring or an acylpiperazinyl ring of 1 to 10 carbon atoms in the acyl ring of an alkylpiperazinyl ring an arylpiperazinyl ring of 6 to 10 carbon atoms in the aryl portion, a heteroarylpiperazinyl ring of 5 to 9 carbon atoms in the heteroaryl portion, or a bridged diazabicycloalkyl ring;

χ ft χ

R 'is different from hydrogen only when R ° is different from hydrogen;

R ⁶ is different from hydrogen only when R ⁵ is different from hydrogen;

R ³ is different from hydrogen only when R ⁴ is different from hydrogen;

9 9 99 99 99 9

9999 99 99

9 9999 9 · 99 99 «99 9 • 9 9 9999 9999 • 9 9 99 99

R ² is different from hydrogen only when R ¹ is different from hydrogen;

when R ¹ , R ² and R ⁹ are heteroatom-containing substituents, the heteroatom cannot be directly bonded to the 2 or 6 position;

when X represents nitrogen, R ⁴ is absent;

when X represents oxygen, sulfur, SO, SO ₂ or nitrogen and when one or more of R ¹ , R ² , R ⁵ and R ⁶ represents a heteroatom-containing substituent, the heteroatom cannot be directly bonded to the 4 or 6 position;

when Y is oxygen, sulfur, SO, S0 ₂ or nitrogen and when one or more of R ^3, R ^4, R ⁷ and R ⁸ independently represents a substituent comprising a heteroatom, the heteroatom can not be directly bonded to the 3- or 5;

when X represents oxygen, sulfur, SO or SO ₂ , then R ³ and R ⁴ are absent;

when y is 1 and W is NR ²⁴ or oxygen, then Z cannot be hydroxy;

when Y represents oxygen, sulfur, SO or SO ₂ , then R ⁵ and R ⁶ are absent;

when Y represents nitrogen, then R 0 is absent;

when the dashed line represents a double bond, then R ⁴ and R ⁶ are absent;

when R ³ and R ⁵ are independently a heteroatom-containing substituent and when the dotted line represents

9

9 • 9

9,999 • 99

9

99 99 99

99 9 9 99

9 99 9 9 9 9 • 99 999 99 9 • 99 9 9 99 9

9 99 99 99 double bond, then this heteroatom cannot be directly bonded to the X and Y positions;

when one of X and Y is oxygen, sulfur, SO, SO ₂ or nitrogen, the other is carbon;

when X or Y represents a heteroatom, the dotted line does not represent a double bond; and at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ must be a group of formula II;

and pharmaceutically acceptable salts thereof.

The term alkyl, as used herein, unless otherwise indicated, refers to straight chained, branched or cyclic saturated monovalent hydrocarbon radicals or combinations thereof.

The term alkoxy as used herein refers to groups of the formula O-alkyl, wherein alkyl is as defined above.

The term aryl, as used herein, unless otherwise indicated, means organic radicals derived from aromatic hydrocarbons by removal of one hydrogen atom. Examples of aryl include phenyl or naphthyl optionally substituted with one to three substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro of trifluoromethyl, alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms, trifluoromethoxy, trifluoromethoxy, and alkyl groups of 1 to 6 carbon atoms.

·· ·

0 0

0 ··

0,000 ·

0 0

0 ··

0 0 0

0 0 0 »0 0 0 0

0 0 0

0 ·

00

0 0 0

0 «0

0 0 0 0

0 0 0

00

The term heteroaryl as used herein, unless otherwise indicated, means organic residues derived from aromatic heterocyclic compounds by removal of one hydrogen atom. Examples of heteroaryl groups include pyridyl-, furyl-, pyroyl-, thienyl-, isothiazolyl-, imidazolyl-, benzimidazolyl-, tetrazolyl-, pyrazinyl-, pyrimidinyl-, quinolyl-, isoquinolyl-, benzofuryl-, isobenzofuryl-, benzothienyl- , pyrazolyl-, indolyl-, isoindolyl-, purinyl-, carbazolyl-, isoxazolyl-, thiazolyl-, oxazolyl-, benzthiazolyl- or benzoxazolyl, each of which is optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, trifluoromethoxy, difluoromethoxy and C 1 -C 6 alkyl.

The term acyl, as used herein, unless otherwise indicated, means radicals of the formula RCO wherein R is alkyl, alkoxy (such as methyloxycarbonyl), aryl, arylalkyl or arylalkyloxy wherein alkyl and aryl are as defined herein. above.

Acyloxy means O-acyl, wherein acyl is as defined above.

The term D- or L-amino acid as used herein, unless otherwise indicated, includes, for example, glycine, alanine, valine, leucine, isoleucine, phenylalanine, asparagine, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine or histidine.

The positions of the circle in formula I are numbered as follows:

> 9 «

9 * 9 9

• »φ • * · • · · 9« · 999 «• · 9

9 »9 9 • 9 9 4 • 99

9 9 «

I 9 9 4

99

For compounds of formula I, it is preferred that the hydroxamic acid residue is located axially in the 2-position.

The compounds of formula I may contain chiral centers and therefore may exist in various enantiomeric forms. The present invention includes all optical isomers and stereoisomers of the compounds of formula (I) and mixtures thereof.

Preferred are compounds of formula I wherein Y is carbon.

Other preferred compounds are those compounds of formula I wherein Q is C 1 -C 6 alkoxyaryl and C 6 -C 10 aryl of the aryl moiety, C 6 -C 10 arylalkoxyaryl of each of the aryl moieties, and C 1 -C 6 carbon atoms an alkoxy moiety or an arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in each of the aliphatic moieties, wherein each terminal aryl group is optionally substituted with fluorine.

Further preferred compounds are those compounds of formula I wherein R ³ , R ³ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , R ⁶ , and R ⁹ represent hydrogen atoms.

More preferred are compounds of formula I wherein Y is carbon and Q is C 1 -C 6 alkoxyaryl and C 6 -C 10 aryl of the aryl moiety, C 6 -C 10 arylalkoxyaryl of each of the aryl moieties, and 1 to 6 carbon atoms. 6 carbon atoms in the alkoxy moiety or arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in each of the aliphatic moieties

Preferred compounds of formula (I) according to the invention are:

(2R, 4R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2- hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [3] methyl ester - (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 3S) - {1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidin-3-yl isopropyl ester } carbamic acids;

3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide, 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl) hydroxyamide -2,2-dimethylthiomorpholine-3-carboxylic acid, (2R, 4S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, and (2R, 4R) -1-hydroxyamide hydrochloride - (4-Methoxybenzenesulfonyl) -4- (piperazine-1-carbonyl) piperidine-2-carboxylic acid.

flfl flfl fl flfl flfl fl fll fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Fl Fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Fl

Examples of other compounds of the invention include:

(3S) -4- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide, (3S) -2,2-dimethyl-4- [4- ( thiazol-5-ylmethoxy) benzenesulfonyl] thiomorpholine-3-carboxylic acid, (3S) -2,2-dimethyl-4- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] thiomorpholine-3-carboxylic acid hydroxyamide, hydroxyamide (3S) ) -4- {4- [2- (4-fluorophenyl) ethoxy] benzenesulfonyl} -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide (3S) -2,2-dimethyl-4- [4- (2- pyridin-4-ylethoxy) benzenesulfonyl] thiomorpholine-3-carboxylic acid, (3S) -4- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide, hydroxyamide (3S) -2,2-dimethyl-4- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] thiomorpholine-3-carboxylic acid, hydroxyamide (3S) -2,2-dimethyl-4- [4- (1H-tetrazole) (2R, 3S) - {1- [4- (2-Chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -2-hydroxycarbamoyl-5-ylmethoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid methyl ester 1-piperidin-3-yl} -carbamic acid;

(2R, 3S) - {2-Hydroxycarbamoyl-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidin-3-yl} carbamic acid methyl ester,

·· • · « ·· ·· • • • • « • · · • • 9 • • 9 • • ·· on · • φ • • ···· • · • • • · fc · • • • 9 • * • • • · · • • ·· • ··

(2R, 3S) - {2-Hydroxycarbamoyl-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] piperidin-3-yl} carbamic acid methyl ester, (2R, 3S) - {1- [4- (4) methyl ester -fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidin-3-yl} carbamic acid, (2R, 3S) - {1- [4- (4-Fluorophenyl) ethoxy] benzenesulfonyl} -2-hydroxycarbamoylpiperldin-3-yl} carbamic acid methyl ester (2R, 3S) - {2-Hydroxycarbamoyl-1- [4- (2-pyridin-4-yl-ethoxy) -benzenesulfonyl] -piperidin-3-yl} -carbamic acid methyl ester, (2R, 3S) - {1- [4] methyl ester - (benzothiazol-2-ylmethoxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidin-3-yl} carbamic acid, (2R, 3S) - {2-hydroxycarbamoyl-1- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] methyl ester piperidin-3-yl} carbamic acid, (2R, 3S) - {2-hydroxycarbamoyl-1- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] piperidin-3-yl} carbamic acid methyl ester, hydroxyamide (2R) 3S) -1- [4- (2-chlorothiazol-5-ylmethoxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-1- [4- ( thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide (2R, 3S) -3-hydroxy-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] piperidin-2-ylcarboxylic acid, ·· ·

(2R, 3S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 3S) -1- {4- [2- (4-fluorophenyl) ethoxy] hydroxyamide benzenesulfonyl} -3-hydroxypiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-1- [4- (2-pyridin-4-ylethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide, hydroxyamide ( 2R, 3S) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-1- [4- (5-trifluoromethylbenzothiazole) hydroxyamide; 2-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-1- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R) 3S) -1- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide (2R, 3S) -3-hydroxy-3-methyl-1 - [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-3-methyl-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] hydroxyamide piperidin-2- (2R, 3S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide, (2R, 3S) -1- {4- [2- (4-fluorophenyl) ethoxy] benz of ensulfonyl} -3-hydroxy-3-methylpiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-3-methyl-1- [4- (2-pyridine- 4-Ylethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R, 3S) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -3-hydroxy-3-methylpiperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R, 3S) -3-hydroxy-3-methyl-1- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, hydroxyamide (2R, 3S) -3-hydroxy-3- methyl 1- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid (3R) -4- [4- (2-chlorothiazol-5-ylmethoxy) benzenesulfonyl] -2,2-hydroxyamide -dimethylmorpholine-3-carboxylic acid, (3R) -2,2-dimethyl-4- [4-thiazol-5-ylmethoxy) benzenesulfonyl] morpholine-3-carbonyl acid hydroxyamide, (3R) -2,2-dimethyl- 4- [4- (py Ridin-4-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid hydroxyamide (3R) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylmorpholine-3-carboxylic acid hydroxyamide (3R) -4- {4- [2- (4-Fluorophenyl) ethoxy] benzenesulfonyl} -2,2-dimethylmorpholine-3-carboxylic acid, (3R) -2,2-dimethyl-4- [4- (2-pyridine-4-) hydroxyamide (ethoxy) benzenesulfonyl] morpholine-3-carboxylic acid, (3R) -4- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -2,2-dimethylmorpholine-3-carboxylic acid hydroxyamide, (3R) -2,2 hydroxyamide -dimethyl-4- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid, (3R) -2,2-dimethyl-4- [4- (1H-tetrazole-5-) hydroxyamide (2R, 4R) -1- [4- (2-chlorothiazol-5-ylmethoxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -2-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid -hydroxycarbamoyl-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-4-carboxylic acid, (2R, 4R) -2-hydroxycarbamoyl-1- [4- (pyridin-4-ylmethoxy) benzene ulphonyl] piperidine-4-carboxylic acid, (2R, 4R) -1- {4- [2- (4-fluorophenyl) ethoxy] benzenesulfonyl} -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -2- hydroxycarbamoyl-1- [4- (2-pyridin-4-ylethoxy) benzenesulfonyl] piperidine-4-carboxylic acid, (2R, 4R) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine- 4-carboxylic acid, (2R, 4R) -2-hydroxycarbamoyl-1- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] piperidine-4-carboxylic acid, (2R, 4R) -2-hydroxycarbamoyl-1- [4- (1H-Tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-4-carboxylic acid, (3R) -4- [4- (2-chlorothiazol-5-ylmethoxy) benzenesulfonyl] -3-methylmorpholin-3- hydroxyamide carboxylic acids ··· ·································· (3R) -3-Methyl-4- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid hydroxyamide (3R) -3-methyl-hydroxyamide ( 3R) -3- methyl-4- (pyridin-4-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid, (3R) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-methylmorpholine-3-carboxylic acid hydroxyamide, hydroxyamide (3R) ) -4- {4- [2- (4-fluorophenyl) ethoxy) benzenesulfonyl} -3-methylmorpholine-3-carboxylic acid, (3R) -3-methyl-4- [4- (2-pyridine-4-) hydroxyamide ylethoxy) benzenesulfonyl] morpholine-3-carboxylic acid, (3R) -4- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -3-methylmorpholine-3-carboxylic acid hydroxyamide, (3R) -3-methyl hydroxyamide -4- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] morpholine-3-carboxylic acid, (3R) -3-methyl-4- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] morpholine hydroxyamide -3-carboxylic acids, (2R) -1- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -2-methyl-3-oxopiperidine-2-carboxylic acid hydroxyamide, (2R) -2-methyl-hydroxyamide 3-Oxo-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R) -2-methyl-3-oxo-1- [4- (pyridin-4-ylmethy) hydroxyamide oxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-methyl-3-oxopiperidine-2-carboxylic acid hydroxyamide, (2R) -1- { 4- [2- (4-fluorophenyl) ethoxy] benzenesulfonyl} -2-methyl-3-oxopiperidine-2-carboxylic acid, (2R) -2-methyl-3-oxo-1- [4- (2-pyridine) hydroxyamide (4-ylethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, hydroxyamide (2R) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -2-methyl-3-oxopiperidine-2-carboxylic acid, hydroxyamide (2R) 2-Methyl-3-oxo-1- [4- (5-trifluoromethyl-benzothiazol-2-ylmethoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxyamide (2R) -2-methyl-3-oxo-1- [4 - (1H-Tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, (2R, 4S) -1- (4-benzyloxybenzenesulfonyl) -4-butylaminomethyl-4-hydroxypiperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R) 4S) -4-butylaminomethyl-1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid, hydroxyamide (2R, 4S) -4-benzyl amino-1- (4-benzyloxybenzenesulfonyl) piperidine-2-carboxylic acid, (2R, 4S) -4-benzylamino-1- [4- (4-fluorobenzyloxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-oxopiperidine-2-carboxylic acid, hydroxyamide (2R) (4R) -1- (4-benzyloxybenzenesulfonyl) -4-hydroxypiperidine-2-carboxylic acid, (2R, 4R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-methylpiperazine-2-carboxylic acid hydroxyamide, (2R, 5S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -5-hydroxypiperidine hydroxyamide -2-carboxylic acids, (2R, 5S) -1- (4-benzyloxybenzenesulfonyl) -5-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 5R) -1- (4-benzyloxybenzenesulfonyl) -5-hydroxypiperidine-2 hydroxyamide -carboxylic acids, (2R, 5R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -5-hydr hydroxyamide oxypiperidine-2-carboxylic acids, (2R, 3S) -1- (4-benzyloxybenzenesulfonyl) -3-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 4S) -1- (4-benzyloxybenzenesulfonyl) -4-hydroxypiperidine- 2-carboxylic acids, (2R, 4S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, 1- (4-butoxybenzenesulfonyl) -3- (morpholine-4-) morphamide carbonyl) piperidine-2-carboxylic acid, 1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3- (morpholine-4-carbonyl) piperidine-2-carboxylic acid hydroxyamide, · · · ··· · · · 1- [3- (fluorobenzyloxy) propane-1-sulfonyl] -3- (morpholine-4-carbonyl) hydroxyamide piperidine-2-carboxylic acid 1- (4-butoxybenzenesulfonyl) -3- (pyrrolidine-1-carbonyl) piperidine-2-carboxylic acid hydroxyamide 1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3- (pyrrolidine) hydroxyamide 1-carbonyl) piperidine-2-carboxylic acid 1- [3- (4-fluorobenzyloxy) propane hydroxyamide -1-sulfonyl) -3- (pyrrolidine-1-carbonyl] piperidine-2-carboxylic acid; and 1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid.

The invention also provides a pharmaceutical composition a) for the treatment of a condition selected from the group consisting of arthritis, cancer (in the form of a synergistic combination with cytotoxic anticancer agents), tissue ulceration, macular degeneration, restenosis, periodonal disease, epidermolysis bullosa, scleritis non-steroidal anti-inflammatory drugs and analgesics) and other diseases characterized by matrix metalloproteinase activity as well as AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF); or b) for inhibiting matrix metalloproteinases or tumor necrosis factor (TNF) production in mammals. , including a human, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective for such treatment or inhibition, and a pharmaceutically acceptable carrier.

The present invention also provides a method of inhibiting (a) matrix metalloproteinases or (b) producing tumor necrosis factor (TNF) in a mammal, including a human, comprising: Administering to such a mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The invention further provides a method of treating conditions selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, optionally in combination with standard non-steroidal anti-inflammatory drugs, analgesics or anti-cancer agents, and other diseases characterized by activity metalloproteinases, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat such a condition.

The following is a detailed description of the invention.

The preparation of the compounds of the invention is illustrated in the following reaction schemes. Unless otherwise indicated, the symbols R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , on Ar in these reaction schemes and accompanying discussion have the meanings given above.

·· ··

Preparative scheme • * · · · · · · · · · · · · · · · · ·

VI

Preparative scheme · ·· 99 99

999 999 9,999

9999 9 9 99

9,999 99 9 9 9 · · 99 9

9,999 9 9 9 9

9 99 «99 99 99

XVI I I

VI

Scheme 1 · · ta ta ta ta ta ta ta ta ta ta ta ta ta ta ta ta ta ta ata ta ta ata ta ata ta ta • ta · ···· · · · · · · · · · · · · · · · · · · · · · ·

CX. iiimijX— (mimiiQí> - «umu Q £

00 ♦ 0 0

0 0 0

0 0 0

0 0 0

00

0 * ·

00 00 «

Scheme 2 • 0 00 0 0 0 0

0 0 0 0 0 0 0

0 0 0 · 0 _R 26

IX

VIII

R ⁵

VII

9 9 9

9 9 9

9

9 9 9

99

Scheme 3 ·· 9 • 9 9 • 9 9 9 9 9999 9

9

99

9 9 9 * 9

9 9 9

9 9 9

99 • 4 »

XII

X

9999

Scheme 4 »4 44 44 ·· · 4 4 4 44 4

44 44 444

4,444 444 44 4

4444 4444

44

θ 'θ'

XX ·

9 9

9

9 9

9

9 9 9 9 9 9

99,999 99 9

- 33 Scheme 4 - continued

XX

XIX

XIII

• · ·

9

Scheme 5 • · · 9999 9 9

9 99

9

XXVI

«Λ /,

XXIV ·

• ·

9 9 9

9

9 9 9

9 99

9 9 9

9 9 9

99

9 9 9

9 9 9

9

9 9 9

99

Scheme 5 - continued

XXIV

XIV · · IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV IV · <♦ <<<<4 4 4 4 4 4 4 4 4

Preparative Scheme 1 relates to the preparation of intermediates of formula VI. Compounds of formula VI are converted to compounds of formula I by the methods depicted in Scheme 1. Starting materials of formula XVI may be prepared using procedures known to those skilled in the art.

In Reaction 1 of Preparative Scheme 1, a compound of formula XVI is converted to the corresponding hydroxyester compound of formula VI by first reacting a compound of formula XVI with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent such as methylene chloride, tetrahydrofuran or dioxane at about 20 to about 30 ° C, preferably at room temperature. The resulting compound is further reacted with a compound of formula

COoR ²⁵

Wherein R ₂₅ is benzyloxycarbonyl, C 1 -C 6 alkyl, benzyl, allyl or tert-butyl, in the presence of sodium hexamethyldisilazane and a mixture of tetrahydrofuran and dimethylformamide as solvent, at a temperature of about -20 to about 20 ° C, preferably at 0 ° C to give the hydroxyester compound of formula VI.

Preparative Scheme 2 relates to an alternative process for preparing compounds of Formula VI. The starting compound of formula (XVIII) may be prepared by methods well known to those skilled in the art. In reaction 1 according to Preparative Scheme 2, the amine compound of general formula (I) is reacted

9 φ φ ves ves ves ves ves ves ves ves ves i i i i i i i i i vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce vzorce wherein R ²⁵ is as defined above, converted to the corresponding arylsulfonylamine of formula XVII by (1) reacting a compound of formula XVIII with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent such as methylene chloride, tetrahydrofuran or dioxane at about 20 to about 30 ° C, preferably at room temperature, (2) reacting the resulting compound with a compound of formula

Br in the presence of sodium hexamethyldisilazane and a mixture of tetrahydrofuran and dimethylformamide as solvent at a temperature of about -20 to about 20 ° C, preferably at 0 ° C, and 3) reacting the obtained compound with ozone in methylene chloride / methanol at a temperature of about -90 to about -70 ° C, preferably at about -78 ° C. The unstable ozonide compound thus prepared is then reacted with triphenylphosphine to form the arylsulfonylamine of formula XVII. In reaction 2 of Preparative Scheme 2, the arylsulfonylamine of formula XVII is converted to the corresponding hydroxyester of formula VI by reacting a compound of formula XVII with a compound of formula

wherein W represents lithium, magnesium, copper or chromium.

Scheme 1 relates to the preparation of compounds of formula II which are compounds of formula I wherein X and Y are carbon atoms, R ⁴ , R ⁶ and R ⁷ are hydrogen and the dashed line between X and Y is absent. In Reaction 1 of Scheme 1, a compound of formula VI wherein:

44 • 4 4 • 4 4 4 4 4 4 4 4 4 4 4 4 4

4 4 4

The protecting group R ²⁵ is benzyloxycarbonyl, C 1 -C 6 alkyl, benzyl, allyl or tert-butyl, converted to the corresponding morpholinone compound of formula V by lactonization and subsequent Claisen rearrangement of the compound of formula VI. This reaction is facilitated by removal of the R ²⁵ protecting group from the compound of Formula VI and carried out under conditions that are appropriate for the particular R ²⁵ protecting group used. Examples of such conditions are: (a) reaction with hydrogen and a hydrogenation catalyst such as 10% palladium on carbon when R ²⁵ is benzyloxycarbonyl, (b) saponification when R ²⁵ is lower alkyl, (c) hydrogenolysis when R ² (d) reaction with a strong acid such as trifluoroacetic acid or hydrochloric acid when R ²⁵ is t-butyl; or (e) reaction with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride as a catalyst when R ²⁵ is allyl.

In Reaction 2 of Scheme 1, a morpholinone compound of formula V is converted to a carboxylic acid of formula IV by reacting a compound of formula V with lithium hexamethyldisilazane in an aprotic solvent such as tetrahydrofuran at a temperature of about -90 to about -70 ° C. preferably at -78 ° C. Trimethylsilyl chloride was then added to the reaction mixture and tetrahydrofuran was removed under reduced pressure, which was then replaced with toluene. The resulting reaction mixture is heated to a temperature of about 100 ° C to about 120 ° C, preferably about 110 ° C, and reacted with hydrochloric acid to form the carboxylic acid of formula IV.

In Reaction 3 of Scheme 1, the carboxylic acid of Formula IV is converted to the corresponding hydroxamo.

- 39 the acid of the general formula (III) so that the compound of formula IV is reacted with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent such as dimethylformamide, and hydroxylamine is added after 15 minutes to 1 hour, preferably about 30 minutes. The hydroxylamine is preferably formed in situ from its salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected hydroxylamine derivative or salt form thereof in which the hydroxyl group is protected by the formation of tert-butylbenzyl or allyl ether in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as N-methylmorpholine may be used. The cleavage of the hydroxylamine protecting group is accomplished by hydrogenolysis of the benzyl protecting group or, in the case of a tert-butyl protecting group, by treatment with a strong acid such as trifluoroacetic acid. The allyl protecting group may be removed by treatment with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride catalyst. N, O-bis- (4-methoxybenzyl) hydroxylamine can also be used as a protected hydroxylamine derivative, in which case the deprotection is carried out using a mixture of methanesulfonic acid and trifluoroacetic acid.

In Reaction 4 of Scheme 1, the hydroxamic acid of formula III is converted, if desired, to the corresponding piperidine of formula II by reacting the compound of formula III with hydrogen and a hydrogenation catalyst such as 10% palladium on carbon.

Scheme 2 relates to the preparation of compounds of formula VII which are compounds of formula I wherein Y is nitrogen, X is carbon, R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ are hydrogen and R ⁶ is absent . Starting compound · · · · · · · · «« «· · · · · · · · · · · · The formula (IX) can be prepared by methods well known to those skilled in the art. In Reaction 1 of Scheme 2, an arylsulfonylpiperazine compound of formula IX wherein R is benzyloxycarbonyl, benzyl or tert-butoxycarbonyl is converted to a compound of formula VIII by reacting a compound of formula IX with a protected hydroxylamine derivative of formula

R ²⁷ ONH ₂ .HC1 wherein _R27 is tertbutyl, benzyl or allyl, in the presence of dicyclohexylcarbodiimide, dimethylaminopyridine and an aprotic solvent such as methylene chloride. The protecting group R is selected such that it can be selectively removed in the presence of the protecting group R ²⁷ without loss of the protecting group R ²⁷ . Thus, the protecting group R ²⁶ cannot be the same as the protecting group R ²⁷ . The cleavage of the protecting group R ²⁶ from the compound of formula IX is carried out under conditions suitable for the particular R group used. Examples of such conditions are: (a) reaction with hydrogen and a hydrogenation catalyst such as 10% palladium on carbon when R is benzyloxycarbonyl, (b) hydrogenolysis when R ²⁶ is benzyl, or (c) reaction with a strong acid such as trifluoroacetic acid or hydrochloric acid where R ²⁶ is t-butoxycarbonyl.

In reaction 2 of Scheme 2, a compound of formula VIII is converted to the corresponding hydroxamic acid of formula VII wherein R ⁵ is hydrogen or C 1 -C 6 alkyl by reacting, if desired, a compound of formula VIII with an alkyl halide, wherein R ⁵ is an alkyl group having 1 to 6 atoms, and is an alkyl halide, wherein R ⁵ is an alkyl group having 1 to 6 atoms. · · · · ············· · · · Subsequently, the hydroxylamine protecting group R is removed by hydrogenolysis in the case of a benzyl protecting group, or by reaction with a strong acid such as trifluoroacetic acid in the case of a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltin hydride and acetic acid in the presence of a catalytic amount of bis (triphenylphosphine) palladium (II) chloride.

Scheme 3 relates to the preparation of compounds of formula X, which are compounds of formula I wherein Y is nitrogen, X is carbon, R ² , R ⁷ , R ⁸ and R ⁹ are hydrogen, R ³ and R ⁴ taken together, are carbonyl; R ⁵ represents hydrogen and R ⁸ is absent.

In Reaction 1 of Scheme 3, an arylsulfonylamine of formula XII wherein R ²⁵ is as defined above is converted to the corresponding piperazine compound of formula XI by reacting a compound of formula XII with a carbodiimide and a base such as triethylamine. The compound of formula XI is further reacted as described above and shown in Scheme 1 as reaction 3 to give the hydroxamic acid of formula X.

Scheme 4 relates to the preparation of compounds of Formula XIII. The starting compounds of formula (XVIII) may be prepared by methods known to those skilled in the art. Compounds of formula XIII are compounds of formula I wherein X is carbon and the dashed line between X and Y is absent. In Reaction 1 of Scheme 4, the protecting group no

R followed by reductively amination of a compound of formula XXII, wherein Y is oxygen, sulfur or carbon, to give an imine of formula XXI, under conditions appropriate to the particular protecting group R ^{28 used} . By way of example, the conditions described for deprotection of R ²⁶ in reaction 1 of Scheme 2 are described.

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99

In Reaction 2 of Scheme 4, an imine compound of formula XXI is converted to the corresponding piperidine compound of formula XX by reacting a compound of formula XXI with a nucleophilic reagent of formula R ² M wherein M is lithium, a residue of magnesium halide or cerium halide . This reaction is carried out in ether solvents such as diethyl ether or tetrahydrofuran at a temperature of about -78 to about 0 ° C, preferably at -70 ° C.

In reaction 3 of Scheme 4, sulfonation of the piperidine compound of formula XX yields the corresponding arylsulfonylpiperidine compound of formula XIX.

This reaction is carried out by reacting a compound of formula XX with an arylsulfonyl halide in the presence of triethylamine and an aprotic solvent such as methylene chloride, tetrahydrofuran or dioxane at a temperature of about 20 to about 30 ° C, preferably at room temperature.

In Reaction 4 of Scheme 4, the arylsulfonylpiperidine compound of Formula XIX is converted to the hydroxamic acid of Formula XIII as described above for Reaction 3 of Scheme 1.

Scheme 5 relates to the preparation of compounds of formula XIV which are compounds of formula I wherein Y is nitrogen, X is carbon, the dashed line between X and Y is absent, R ⁵ is hydrogen and R ⁶ is absent. In reaction 1 of Scheme 5, a compound of formula XXVI, wherein R and R ³¹ are each independently a protecting group selected from the group consisting of carbobenzyloxy, benzyl and t-butoxycarbonyl groups n and R ^JU is benzyloxycarbonyl, C 1-6 alkyl, benzyl, allyl or tert-butyl is converted to the corresponding imine compound of formula XXV by:

The R ²⁹ protecting group is removed and the compound of formula XXVI is subsequently subjected to reductive amination. The R ²⁹ protecting group is selected such that it can be selectively removed in the presence of the R protecting group without losing the R ³¹ protecting group. The deprotection of R ²⁹ is carried out under conditions that are suitable for the particular R protecting group used and will not affect the R ³¹ protecting group. Examples of such conditions include: (a) reaction with hydrogen and a hydrogenation catalyst such as 10% palladium on carbon when R is benzyloxycarbonyl and R ³¹ is tert-butyl; (b) saponification when R is C 1-6 alkyl atoms, and R @ ³ is tertbutyl, (c) hydrogenolysis where R ²⁹ is benzyl and R ³¹ is C 1-6 alkyl or tertbutyl, (d) treatment with a strong acid, such as Q * 9 with trifluoroacetic acid or hydrochloric acid when R is tert-butyl and R ³¹ is C 1-6 alkyl, benzyl or allyl, or (e) reaction with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride as a catalyst when R ²⁹ R @ ³¹ is allyl and R @ ³¹ is C1 -C6 alkyl, benzyl

O or t-butyl. The protecting group R can be selected so that it can be removed in the same reaction step as the protecting group R.

In Reaction 2 of Scheme 5, an imine compound of formula XXV is converted to the corresponding compound of formula XXIV by treating a compound of formula XXV with a nucleophilic reagent of formula R ² M, wherein M is lithium or a residue of magnesium or calcium halide. This reaction is carried out in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature from about -78 to about 0 ° C, preferably at -70 ° C.

• · · · ·

»·· <

ta · * ta

In reaction 3 of Scheme 5, the piperidine compound of formula XXIV is sulfonated to give the corresponding arylsulfonylpiperidine compound of formula

III. This reaction is carried out as described above for Reaction 3 of Scheme 4.

In Reaction 4 of Scheme 5, an arylsulfonylpiperidine compound of formula XXIII is converted to a hydroxamic acid of formula XIV by (1) removing the R ³¹ protecting group from the compound of formula XXIII and, if desired, the R ³⁰ protecting group, and then (2) reacting the compound of formula XXIII as described above in Reaction 3 of Scheme 1. The deprotection of the R and R protecting groups from the compound of formula XXIII is carried out under conditions suitable for the particular R ³⁰ protecting groups used; R ³¹ . Examples of such conditions are those described above for deprotection of R ²⁵ in reaction 1 of Scheme 1.

Pharmaceutically acceptable salts of the acidic compounds of the invention are those formed with bases, i.e. salts with cations such as alkali and alkaline earth cations such as sodium, lithium, potassium, calcium, magnesium, and also ammonium salts such as ammonium, trimethylammonium. , diethylammonium and tris (hydroxymethyl) methylammonium salts.

When a basic group such as pyridyl is also part of the structure of the compounds of the invention, acid addition salts such as mineral acids, organic carboxylic acids and organic sulfonic acids such as hydrochloric, methanesulfonic and maleic acids are also possible.

• · · · · · · · · · · · · · · · · ·

The ability of the compounds of formula I or their pharmaceutically acceptable salts (collectively referred to herein as the compounds of the invention) to inhibit matrix metalloproteinases or tumor necrosis factor (TNF) production, and thus the efficacy of the compounds of the invention in the treatment of diseases characterized by matrix metalloproteinase or tumor necrosis factor production is demonstrated in the following in vitro assay procedures.

Biological tests

Inhibition of human collagenase (MMP-1)

Human recombinant collagenase is activated by trypsin at a ratio of 10 μg trypsin to 100 μg collagenase.

The trypsin and collagenase are incubated at room temperature for 10 minutes and then a 5-fold excess (50 μg / 10 μg trypsin) of the soybean trypsin inhibitor is added to the incubation mixture.

Stock solutions of 10 mM inhibitors were made using dimethyl sulfoxide and then diluted according to the following scheme:

lOmM -> 120μΜ -> 12μΜ -> 1.2μΜ -> 0.12μΜ

25 µl of solution ο each concentration is then added (3 replications) to the appropriate wells of a 96-well microfluor plate. Final inhibitor concentration after enzyme and substrate addition is reduced by 1: 4. Positive controls (enzyme but no inhibitor) are placed in wells D1 to D6 and blanks (no enzyme, no inhibitor) are placed in wells D7 to D12. .

99 · 4 · 4 · 4 · 4 99 4 · 4 99 4

4

- 46 Collagenase is diluted to 400 ng / ml and 25 μΐ of the diluted product is added to the appropriate wells of the microfluor plate. The final collagenase concentration in this assay is 100 ng / ml.

The substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) NH ₂ ) was prepared as a 5 mM dimethylsulfoxide stock solution and then diluted to 20μΜ with assay buffer. The test is started by adding 50 μΐ of substrate to the well of the microfluor plate to give a final concentration of 10 μΜ.

Fluorescence readings (excitation 360 nm and emission 460 nm) are read at time 0 and then at 20 minute intervals. The test is carried out at room temperature with a typical duration of 3 hours.

Fluorescence versus time (plots from three replications are averaged) is then plotted for both blank and collagenase-containing assays. To determine IC ₅₀ values, a time point that provides a good signal (blank) and which is found in the linear part of the curve (usually about 120 minutes) is selected. The values at time 0 are used for all concentrations of all compounds as a reference value, which is subtracted from the data at 120 minutes. Data are plotted as inhibitor concentration versus percent suppression (inhibitor fluorescence ratio and fluorescence of collagenase alone multiplied by 100). IC ₅₀ values are determined from the concentration of inhibitor that provides a signal representing 50% suppression.

When these IC _5Q below 0,03μΜ, inhibitors are then assayed at concentrations 0,3μΜ, 0,03μΜ, and 0,03μΜ 0,003μΜ.

»94 · 4 44 ·· • ·. · 9 9 9 9 9 9 9 9 9 9 4 4

4 4 9 4

44

Inhibition of gelatinase (ΜΜΡ-2)

Inhibition of gelatinase activity is performed using Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ (ΙΟμΜ) substrate under the same conditions as described above for the human collagenase inhibition assay. (MMP-1).

The gelatinase (72 kD) was activated with 1 mM ΑΡΜΑ (p-aminophenylmercuriacetate) for 15 hours at 4 ° C and then diluted to a final assay concentration of 100 ng / ml. Dilute inhibitors in the same manner as in the human collagenase inhibition (MMP-1) assay to give final assay concentrations of 30μΜ, 3μΜ, 0.3μΜ and 0.03μΜ. Each concentration was tested in triplicate. Fluorescence (excitation 360 nm, emission 460 nm) is read at time 0 and then at 20 minute intervals for 4 hours.

IC ₅₀ values are determined as in the human collagenase (MMP-1) inhibition assay. If IC ₅₀ concentrations are less than 0.03μΜ, inhibitors shall be tested at final concentrations of 0,3μΜ, 0,03μΜ, 0,003μΜ and 0,0003μΜ.

Inhibition of stromelysin activity (MMP-3)

The stromelysin activity inhibition assay is a modified spectrophotometric assay described by Weingarten and Feder (Weingarten H. and Feder J., Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem., 147, 437-440 (1985)). Hydrolysis of the thiopeptolide substrate [Ac-Pro-Leu-Gly-SCH [CH ₂ CH (CH ₃ ) ₂ ] CO-Leu-Gly-OC ₂ H ₅ ] provides a mercaptan fragment that can be monitored in the presence of Ellman's reagent.

Human recombinant prostromelysin is activated by trypsin at a ratio of 1 μΐ of trypsin stock at a rate of 1 μΐ of trypsin stock solution. 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

9 99 99 99 99 concentration of 10 mg / ml per 26 μg stromelysin. The trypsin and stromelysin are incubated at 37 ° C for 15 minutes and then the incubation mixture is treated for 10 minutes at 37 ° C with 10 μΐ of 10 mg / ml soybean inhibitor to eliminate trypsin activity.

Assays are performed in a total volume of 250 ml assay buffer (200 mM sodium chloride, 50 mM MES and 10 mM calcium chloride, pH 6.0) 250 µΐ in 96-well microtiter plates. Dilute activated stromelysin to 25 μg / ml with assay buffer. Ellman's reagent (3-carboxy-4-nitrophenyldisulfide) was prepared as a 1M stock solution in dimethylformamide and then diluted to 5 mM with assay buffer. The diluted solution thus obtained is added to each well at 50 μΐ so that the final concentration is 1 mM.

Stock solutions of 10 mM inhibitors were made using dimethyl sulfoxide and then serially diluted in assay buffer to give a final concentration of 3μΜ, 0.3μΜ, 0.003μΜ, and 0.0003μΜ when 50 µΐ of the appropriate dilution was added to a suitable well.

Under all conditions, assays are performed with three replicates each.

The 300mM peptide substrate dimethylsulfoxide stock solution is diluted to 15mM with assay buffer. The test is started by adding 50 μΐ of the diluted solution thus obtained to each well (thus achieving a final substrate concentration of 3 mM). The blank wells contain the peptide substrate and the enzyme-free Ellman reagent. Product formation is monitored at 405 nm using a Molecular Devices UVmax Plate Reader.

IC ₅₀ values are determined in the same manner as the collagenase inhibition assay.

• * 99 99 99 99

9 9 9 9 9

9 9 9 9 99 99 9 9 9 9

9,999 9 9 9 9 9 9 9 9 9 ·

9 9 9 9 9 9

9 99 99 99

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2 mM ΑΡΜΑ (p-aminophenylmercuriacetate) for 1.5 hours at 37 ° C and then diluted with assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20μΜ zinc chloride , 0.02% surfactant Brij) to a concentration of 400 ng / ml. Add 25 μΐ of diluted enzyme to each well of a 96-well microfluor dish. In the well, the enzyme is further diluted 1: 4 in the assay by the addition of inhibitor and substrate so that its final assay concentration is 100 mg / ml.

Dimethyl sulfoxide inhibitor stock solutions of 10 mM were made and diluted with assay buffer using the inhibitor dilution system reported in the human collagenase inhibition assay (MMP-1). Add 25 μΐ of each concentration (3 replicates) to the wells of the microfluor plate. The final test concentration is 30μΜ, 3μΜ, 0.3μΜ and 0.03μΜ.

The substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) NH ₂ ) is treated as in the human collagenase inhibition (MMP-1) assay and 50 µΐ is added to each well. of the resulting solution to give a final test concentration of 10μΜ. Fluorescence (excitation 360 nm, emission 450 nm) is read at time 0 and then every 5 minutes for 1 hour.

Positive control samples contain enzyme and substrate without inhibitor, while blank samples contain substrate alone.

IC ₅₀ values are determined in the same manner as the human collagenase inhibition (MMP-1) assay. If IC ₅₀ values are less than 0.03μΜ, then the inhibitors

ΦΦ φ φφ »Φ φ 4

Testing at final concentrations of 0.3μ ·, 0.03μΜ, 0.003μΜ and 0.0003μΜ.

Inhibition of TNF production

The ability of the compounds of the invention and their pharmaceutically acceptable salts to inhibit TNF production and hence their utility in the treatment of TNF production diseases is demonstrated by the following in vitro assay.

Human mononuclear cells are isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation procedure. The mononuclear cells are washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 ⁶ / ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer show that in these preparations monocytes make up 17 to 24% of the total cell count.

Place 180 μΐ of cell suspension in 96-well flat-bottom dishes (Costar). Adjust the volume in each well to 200 μΐ by adding test compound and LPS (final concentration 100 ng / ml). The tests are performed in all conditions with three replications. After four hours incubation at 37 ° C in a humidified carbon dioxide atmosphere incubator, the dishes were removed and centrifuged (10 minutes at about 250 x g). The supernatants were collected and analyzed for TNF-α using an R&D ELISA kit.

For administration to mammals, including humans, to inhibit matrix metalloproteinases or to produce tumor necrosis factor (TNF), various conventional routes may be used, such as oral, parenteral and topical administration. Typically, the active compound will be administered orally or parenterally at a dose ranging from about 0.1 to about 25

100 9 «100 99

999 9900 9 9 9 9

9999 99 99

Mg / kg body weight of the subject to be treated per day, with the preferred daily dose being in the range of about 0.3 to 5 mg / kg. Certain dosage variations will necessarily occur depending upon the condition of the subject being treated. The appropriate dose for the individual patient will in any case be determined by the attending physician.

The compounds of the invention may be administered in a wide variety of dosage forms in which the therapeutically active compounds of the invention will be present in a concentration ranging from about 5.0 to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used together with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates and also granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also often very useful for tabletting. Solid compositions of a similar type may also be employed as fillers for gelatin capsules; lactose and high molecular weight polyethylene glycols are also preferred. When aqueous suspensions and / or elixirs are to be used for oral administration, the active ingredient is mixed with various sweetening or flavoring agents, pigments or colorants and, if necessary, emulsifiers and / or suspending agents as well as diluents such as water, ethanol, propylene glycol, glycerol and various mixtures thereof. When administered to animals, these are preferably included in animal feed or drinking water at a concentration of 5 to 5000 ppm, preferably 25 to 500 ppm.

99 9 9 9 9 9 9

9 9 9 9 9 99 9 9 9 • 9 9999 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

9 ··

For parenteral administration, e.g., intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile injectable solutions of the active ingredients are usually employed. Solutions of the therapeutically active compound of the invention in either sesame or peanut oil or in aqueous propylene glycol may also be used. The pH of the aqueous solutions should, if necessary, be appropriately adjusted and buffered, preferably above 8, and the liquid diluent first rendered isotonic. Such aqueous solutions are suitable for administration by intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. All of these solutions are manufactured under sterile conditions in accordance with standard pharmaceutical technologies well known to those skilled in the art. When administered to animals, the compounds may be administered intramuscularly or subcutaneously, wherein the daily dosage level is in the range of about 0.1 to about 50 mg / kg, preferably 0.2 to 10 mg / kg, and may be administered in the form of a single or up to three sub-doses.

The invention is illustrated by the following examples. These examples are illustrative only, and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example l

(2R, 4R) -1- (4-Methoxybenzenesulfonyl) -4- (piperazine-1-carbonyl) piperidine-2-carboxylic acid hydroxyamide hydrochloride (a) To a stirred cold (-78 ° C) solution of 1-tert-butyl ester (2R) -2-Benzyloxycarbonylamino-5-methyl ester

ft »9 • 9

9 9 9

9 9999

9 9

9

9

9

9 9

9 pentanedioic acid (5.6 g, 15.9 mmol), prepared as described in J. Org. Chem., 55, 1711-1721 (1990) and J. Med. Chem., 39, 73-85 (1996) in 30 mL of tetrahydrofuran was added lithium bis (trimethylsilyl) amide (40 mL, 1M in tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred at -45 ° C for 1 hour, re-cooled to -78 ° C and allyl bromide (5.2 mL, 63.7 mmol) was added. After 2 hours, the reaction was quenched by the addition of 1 M aqueous hydrogen chloride solution at -78 ° C. The resulting mixture was extracted with diethyl ether. The combined ether extracts were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography eluting with ethyl acetate / hexane (1: 5). (2R, 4R) -4-Allyl-2-benzyloxycarbonylaminopentanedioic acid 1-tert-butyl ester 5-methyl ester was obtained.

(b) A cold (-78 ° C) solution of (2R, 4R) -4-allyl-2-benzyloxycarbonylaminopentanedioic acid 1-tert-butyl ester 5-methyl ester (5.0 g, 12.8 mmol) in 100 mL of methanol and 10: 1 methylene chloride and 0.73 ml of acetic acid were bubbled through the ozone while stirring until a permanent blue color was obtained. Nitrogen gas was bubbled through the solution until the blue color disappeared. The resulting mixture was warmed to ambient temperature and dimethylsulfide (2.8 mL, 3.83 mmol) was added. The mixture was stirred for 48 hours and diluted with methylene chloride. The methylene chloride mixture was washed with 10% aqueous sodium carbonate and brine, dried over sodium sulfate and filtered. The filtrate was concentrated to give the 1-benzyl ester

(2R, 4S) -6-Methoxy-piperidine-1,2,4-tricarboxylic acid 2-tert-butyl ester 4-methyl ester as a clear oil, which was used in the next step without purification.

9 99 99 9 9 r r 9 9 <

9 9 9 9

9 9 9

99 y «9

9 9

9 9 9

9 9999

9 9

9

99 • 9 • 99

9 9 · 9

9 · 9 * 9 · 9 (c) A mixture of (2R, 4S) -6-methoxy-piperidine-1,2,4-tricarboxylic acid 2-tert-butyl ester 4-methyl ester 4-methyl ester (4,85 g, 11,9 mmol) ) and 10% palladium on carbon (500 mg) in 100 ml of ethanol are shaken under a hydrogen pressure of 30 psi for 1.5 hours. The reaction mixture was filtered through nylon and the filtrate was concentrated. (2R, 4R) -Piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester was obtained as a pale yellow oil which was used in the next step without purification.

(d) To a cold (0 ° C) solution of 2-tert-butyl ester

(2R, 4R) -Piperidine-2,4-dicarboxylic acid 4-methyl ester (2.7 g, 11.1 mmol) and triethylamine (4.6 mL, 33.3 mmol) in 30 mL of methylene chloride are added with stirring -methoxybenzenesulfonyl chloride (2.3 g, 11.1 mmol). The reaction mixture was warmed to ambient temperature, stirred for 4 hours and quenched by the addition of aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium chloride solution and the organic mixture was dried over sodium sulfate and filtered. The filtrate was concentrated and the resulting crude product was purified by silica gel chromatography eluting with ethyl acetate / hexanes (3: 8). (2R, 4R) -1- (4-Methoxybenzenesulfonyl) piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester was obtained.

(e) To a cold (0 ° C) solution of (2R, 4R) -1- (4-methoxybenzenesulfonyl) piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (4.4 g, 10.6 mmol) 10 ml of trifluoroacetic acid in 30 ml of methylene chloride are added dropwise with stirring. The resulting mixture was stirred for 1 hour at 0'C and 8 hours at room temperature and concentrated. There was thus obtained (2R, 4R) -1- (4-methoxybenzenesulfonyl) piperidine-2,4-dicarboxylic acid 4-methyl ester which was used in the next step without further purification.

«99 99 99 99 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 99 99 99 99 (f) To a stirred solution of (2R, 4R) -1- (4-methoxybenzenesulfonyl) piperidine-2,4-dicarboxylic acid 4-methyl ester (4.4 g, 12.3 mmol), O- benzylhydroxylamine (2.15 g, 13.5 mmol) and triethylamine (5.15 mL, 36.9 mmol) were added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (6.0 g, 12.3 mmol) at room temperature. . The resulting mixture was stirred for 24 hours and diluted with ethyl acetate. The ethyl acetate mixture was washed with 1M aqueous hydrochloric acid, aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The organic mixture was dried (MgSO 4), filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with 5% methanol in methylene chloride.

(2R, 4R) -2-Benzyloxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid methyl ester is obtained as a colorless substance.

(g) To a cold (0 ° C) solution of (2R, 4R) 2-benzyloxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid methyl ester (4.0 g, 8.6 mmol) in 10 mL of methanol mixture and water 9: 1 lithium hydroxide monohydrate (1.8 g, 43 mmol) was added. The resulting mixture was stirred for 2 hours. Amberlite IR-120 resin (96 g) was added. After 15 minutes, the resulting mixture was filtered and the filtrate was concentrated. There was thus obtained (2R, 4R) -2-benzyloxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid which was used in the next step without further purification.

(h) To a stirred solution of (2R, 4R) -2-benzyloxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (500 mg, 1.11 mmol), tert-butyloxycarbonylpiperazine (226 mg, 1.21) mmol) and triethylamine (0.47 mL, 3.33 mmol) were added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (535 mg, 1.21 mmol) at ambient temperature. The resulting mixture was stirred for 24 hours, diluted with ethyl acetate and washed with 1M aqueous hydrogen chloride, aqueous sodium bicarbonate, and aqueous sodium chloride. The organic mixture was dried (MgSO 4), filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with 2% methanol in methylene chloride. (2R, 4R) -4- [2-Benzyloxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carbonyl] piperazine-1-carboxylic acid tert-butyl ester is obtained as a colorless solid.

(i) A mixture of (2R, 4R) -4- [2-Benzyloxycarbamoyl-1- (4-methoxy-benzenesulfonyl) -piperidine-4-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.81 mmol) and 5 % palladium on barium sulfate (250 mL) in 10 mL of methanol was added

Shake for 1.5 hours under 50 psi H 2, filter through nylon and concentrate the filtrate. (2R, 4R) -4- [2-Hydroxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carbonyl] piperazine-1-carboxylic acid tert-butyl ester is obtained as a colorless solid, which is used as is in the following stage. cleaning.

(j) (2R, 4R) -4- [2-Hydroxycarbamoyl-1- (4-methoxybenzenesulfonyl) piperidine-4-carbonyl] piperazine-1-carboxylic acid tert-butyl ester (420 mg, 0) (8 mmol) was bubbled with hydrogen chloride gas with stirring for 10 minutes. After an additional 20 minutes, the reaction mixture was concentrated. This gave (2R, 4R) -1- (4-methoxybenzenesulfonyl) -4- (piperazine-1-carbonyl) piperidine-2-carboxylic acid hydroxyamide hydrochloride as a colorless solid. Mass spectrum (atmospheric pressure chemical ionization, base mode) m / z (M + H) 427, 336; NMR (dimethylsulfoxide-Dg, 400 MHz, ppm): δ 10.70 (bd, 1H, J = 2.7 Hz), 9.06 (bs, 2H), 8.84 (bs, 1H) 7.70 (dd, 2H, J = 8.9, 2.9 Hz), 7.06 (dd, 2H, J = 8.9, 2.9 Hz), 4.42 (bs, 1H), 3.80 (s, 3H), 3.80-3.20 (m, 6H), 3.04 (m, 4H), 2.76 (m, 1H),

1.79 (bd, 1H, J = 13.5 Hz), 1.52 (bd, IH, J = 12.6 Hz), 1.32 (m, IH), 1.14 (m, IH)

Example 2

(2R, 4R) -1- [3- (4-Fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid methyl ester (a) To a stirred solution of 4-methyl ester 2-tert-butyl ester (2R, 4R) 1-Piperidine-2,4-dicarboxylic acid (920 mg, 3.78 mmol) and triethylamine (1.58 mL, 11.3 mmol) in 10 mL of methylene chloride was added a solution of 3- (4-fluorophenoxy) propane under a nitrogen atmosphere. -1-sulfonyl chloride (1.05 g, 4.16 mmol) in 2 mL of methylene chloride. The reaction mixture was stirred at ambient temperature (22 ° C) for 16 hours, diluted with 20 mL of 1M hydrochloric acid and 20 mL of methylene chloride. The organic layer was removed, washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to 2.8 g of a yellow oil. The residue was purified by flash chromatography on silica gel (hexanes / ethyl acetate 3: 2). 1.15 g of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonylpiperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester is obtained as a yellow oil.

(b) To a cold (0 ° C) solution of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonylpiperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester 15 g (2.5 mmol) in 10 ml of methylene chloride was added with stirring 10 ml of trifluoroacetic acid. The reaction mixture was allowed to warm to room temperature (22 ° C) over 16 hours and concentrated under reduced pressure. 970 mg of crude (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] piperidine-2,4-dicarboxylic acid 4-methyl ester is obtained as an orange solid.

··· ···· · · · · · · · · · • · · · · · · · · · ♦ ♦ ♦ · · · · (B) To a stirred solution of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] piperidine-2,4-dicarboxylic acid 4-methyl ester (970 mg, 2.4 mmol) in 5 mL of methylene chloride at room temperature (22 ° C) was added triethylamine (1.0 mL,

7.2 mmol) and O-benzylhydroxylamine hydrochloride (410 mg,

2.64 mmol). To the resulting solution was added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.17 g, 2.64 mmol). The reaction mixture was stirred under a nitrogen atmosphere for 16 hours and diluted with 25 mL of 1M hydrochloric acid and 25 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (x2). The combined organic layers were washed with saturated aqueous sodium carbonate (1x) and brine (1x). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The viscous yellow residue was purified by flash chromatography using a 1: 1 mixture of ethyl acetate and hexanes as eluent. 810 mg of (2R, 4R) -2-benzyloxycarbamoyl-1- [3- (4-fluorophenoxy) propane-1-sulfonyl] piperidine-4-carboxylic acid methyl ester is obtained as a clear oil.

(d) A mixture of (2R, 4R) -2-benzyloxycarbamoyl-1- [3- (4-fluorophenoxy) propane-1-sulfonyl] piperidine-4-carboxylic acid methyl ester (800 mg, 1.57 mmol) and 200 mg of 5 The palladium-on-barium sulphate in 15 ml of methanol was shaken for 2 hours in a Parr apparatus under 50 psi hydrogen and the catalyst was removed by filtration through a 0.45 µm nylon filter. The filtrate was concentrated to give 650 mg of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid methyl ester as a white foam. MS (atmospheric pressure chemical ionization, acid mode), 417 (M-1); ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.94 6.97 (m, 2H), 6.80-6.83 (m, 2H), 4.65 (s, 1H), 4.03 ( t,

2H, J = 5.3 Hz), 3.83 (d, 1H, J = 12.9 Hz), 3.68 (s, 3H), 3.15-3.28 (m, 3H), 2, 76 (t, 1 H, J = 11.5 Hz), 2.54 (d, 1 H,

J = 13.5 Hz), 2.26 (d, 2H, J = 5.9 Hz), 2.02 (m, 1H, J = 13.0 Hz), 1.73-1.78 (m, 1H), 1.65-1.62 (m, 1H)

Example (2R, 4R) -1- [3- (4-Fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid

To a cold (0 ° C) solution of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid methyl ester (400 mg, 0.96 mmol) in Lithium hydroxide monohydrate (120 mg, 2.88 mmol) was added with stirring to 5 mL of 10: 1 methanol: water. After 3 hours at 0 ° C, Amberlite resin (4.1 g) previously rinsed with methanol was added to the mixture. The mixture was filtered and the filtrate was concentrated. 370 mg of (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid are obtained in the form of a white foam: MS (chemical ionization at atmospheric pressure, acid mode) ), 403 (M1)

Example 4

(2R, 4R) -1- [4- (4-Fluoro-benzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester

The title compound was prepared according to the procedure in Example 2 using 4- (4-fluoro-benzyloxy) -benzenesulfonyl chloride. MS: 465 (M-1);

Example 5 (2R, 4R) -1- [4- (4-Fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid MS: 451 (M-1)

The title compound was prepared according to the procedure in Example 3, starting from (2R, 4R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid methyl ester.

Example 6

2R, 3S- {1- [4- (4-Fluoro-benzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} -carbamic acid isopropyl ester (a) To a cold (0'C) solution of the known (Agami, C., Hamon, L., Kadouri-Puchot, C., Le Guen, V., J. Org. Chem., 1996, 61, 5736-5742) [4S-4a, 9a, 9aa] -1-oxo-4-phenyl-octahydropyrido methyl ester [ 2,1-c] [1,4] oxazine-9-carboxylic acid (8.28 g, 2.86 mmol) in 100 mL tetrahydrofuran was added with stirring 2.39 mL concentrated hydrochloric acid. After 5 minutes, the reaction mixture was concentrated to dryness. The solid residue was suspended in ethyl acetate. The resulting mixture was stirred for 1 hour and filtered off the solid, which was then washed with ethyl acetate and dried. 9.04 g of a white solid are obtained.

Two grams of this solid were dissolved in 26 mL of 6M hydrochloric acid. The resulting solution was heated to reflux for 6 hours. The reaction mixture was cooled to 0 ° C and neutralized with 3M sodium hydroxide and concentrated under reduced pressure. The solid residue is suspended in chloroform and passed through a nylon filter (45 μπι). The filtrate was concentrated and the yellow oily residue was purified by flash chromatography using 2: 1 hexanes / ethyl acetate containing 1% acetic acid as eluent. 802 mg of [4S-4a, 9a, 9aa] -1-oxo-4-phenyl-octahydropyrido [2,1-c] [1,4] oxazine-9-carboxylic acid are obtained in the form of a white solid.

(B) To a stirred solution of [4S-4a, 9a, 9aa] -1-oxo-4-phenyl-octahydropyrido [2,1-c] [ 1,4] oxazine-9-carboxylic acid (568 mg, 2.06 mmol) in 15 mL benzene at 22 ° C under nitrogen atmosphere was added triethylamine (0.28 mL, 2.06 mmol) and diphenylphosphoryl azide (0.44) mL, 2.06 mmol). The reaction mixture was stirred at 22 ° C for 45 min and at reflux for 50 min. 2-Propanol (3.2 mL, 41.2 mmol) was added. After an additional 20 hours at reflux, the reaction mixture was cooled to 22 ° C and concentrated under reduced pressure. The residue was taken up in ethyl acetate and the resulting solution was washed with 5% citric acid, water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The yellow residue was purified by flash chromatography using 3: 1 hexanes / ethyl acetate as eluent. 402 mg of [4S-4a, 9a, 9aa] (1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) -carbamic acid isopropyl ester is obtained as a white solid.

(c) A mixture of [4S-4a, 9a, 9aa] (1-oxo-4-phenyl-octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) -carbamic acid isopropyl ester (900 mg, 2.71 mmol) ) and 20% palladium hydroxide on carbon (920 mg) in 77 ml of a 10:

The mixture was shaken for 72 hours in a Parr apparatus under a hydrogen pressure of 309.15, and then the catalyst was removed by filtration through a 0.45 µm nylon filter. The filtrate was concentrated to give 610 mg of 2R, 3S-3-isopropoxycarbonylaminopiperidine-2-carboxylic acid as a white solid. MS: 229 (M-1) (d) To a stirred solution of 2R, 3S-3-isopropoxycarbonylaminopiperidine-2-carboxylic acid (320 mg, 1.39 mmol) in 5 mL of methylene chloride was added triethylamine (0.58 mL, 4.17 mmol). ) followed by 4- (4-fluorobenzyloxy) benzenesulfonyl chloride (460 mg, 1.53 mmol). After 16 hours at 22 ° C, the reaction mixture decomposes, and then the reaction mixture is divided into two parts: 0 000 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 between 1M hydrochloric acid and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated to give 480 mg of crude 2R, 3S-1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-isopropoxycarbonylaminopiperidine-2-carboxylic acid as a pale yellow solid.

(e) To a cold (0 ° C) solution of crude 2R, 3S-1- [4- (4-fluorobenzyloxybenzenesulfonyl) -3-isopropoxycarbonylaminopiperidine-2-carboxylic acid (380 mg, 0.77 mmol) in 5 mL Triethylamine (0.32 mL, 2.31 mmol) was added with stirring, followed by benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (510 mg, 1.15 mmol) and the resulting solution was stirred at 0 ° C for 2 min. 0- (trimethylsilylethyl) hydroxylamine hydrochloride (195 mg, 1.15 mmol) was added and the reaction mixture was allowed to warm slowly to 22 ° C over 14 h and concentrated under reduced pressure, the residue diluted with dilute water and extracted three times with ethyl acetate. and diethyl ether (1: 1) The combined organic extracts were washed with saturated aqueous carbonate (2 x), water (2 x) and brine.

The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The yellow residue was purified by flash chromatography using a 65:35 hexanes / ethyl acetate mixture as eluent. 300 mg of 2R, 3S- [1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2- (2-trimethylsilanylethoxycarbonyl) piperidin-3-yl] carbamic acid isopropyl ester are obtained in the form of a white foam. MS: 610 (M + 1) (f) To a cold (0 ° C) 2R, 3S- [1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2- (2-trimethylsilanylethoxycarbonyl) piperidin-3-yl isopropyl ester solution ] carbamic acid (265 mg, 0.44 mmol) in 4 mL methylene chloride was added

9 * 99 99 99 • 99 9 9 9 9999

9999 99 99 9999 9 · 9999 9 9 99 999 99 9 - 63 - 999 99999999 · * · ····

9 with 3 ml of trifluoroacetic acid are added with stirring. The resulting colorless solution was allowed to warm to 23 ° C over 2 hours, stirred for an additional 28 hours, and concentrated under reduced pressure. The solid / foam residue was suspended in a 1: 6 mixture of ethyl acetate and hexanes. The resulting suspension was stirred for 10 hours, then a white solid was collected by filtration, rinsed with hexanes and purified by flash chromatography using a 7: 3 mixture of ethyl acetate and hexanes containing 1% acetic acid as eluent. 130 mg of 2R, 3S-1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidin-3-yl] carbamic acid isopropyl ester is obtained as a white solid / foam. MS: 510 (M + 1);

Example 7

3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide (a) To a stirred solution of the known (PCT publication WO 97/20824) 3- (S) -dimethylthexylsilyl-2,2-dimethyltetrahydro-2H-1,4-thiazine-3-carboxylate (1.17 g, 3.70 mmol) in 6 mL of methylene chloride was added triethylamine (1.02 mL, 7.40 mmol), and followed by 4'-fluorobiphenylsulfonyl chloride (1.0 g, 3.70 mmol). The resulting solution was stirred at 23 ° C for 56 hours. The reaction mixture was diluted with methylene chloride and washed with water. The organic layer was concentrated under reduced pressure. The residue was dissolved in methanol, and the methanol mixture was heated to reflux for 6 hours, cooled to 23 ° C and concentrated in vacuo. The residue was purified by flash chromatography using a 3: 7 mixture of ethyl acetate and hexanes containing 1% acetic acid as eluent. It is obtained

3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid as a white foam / solid. MS: 427 (M + _NH4)

9 99 99 99 99

9 9 9 99 9

9 9 9 9 99 99 9 9 9 9

9 · 999 9 9 9 9 9 9 9 9 9 9

(9) a cold (0 ° C) solution of 3- (S) -4- (4'-fluorobiphenyl-4-sulfonyl) -2, 2-Dimethylthiomorpholine-3-carboxylic acid (605 mg, 1.48 mmol) in 5 mL of methylene chloride was added with triethylamine (0.62 mL, 4.43 mmol) under stirring under nitrogen. To this was added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (980 mg, 2.22 mmol). The resulting solution was stirred for 5 minutes and O- (trimethylsilylethyl) hydroxylamine hydrochloride (376 mg, 2.22 mmol) was added. The ice bath was removed, the reaction stirred at 23 ° C for 20 hours, then diluted with aqueous ammonium chloride and extracted with 1: 1 ethyl acetate: diethyl ether (3x). The combined organic extracts were washed with saturated aqueous sodium carbonate (2x), water (1x) and aqueous sodium chloride solution (1x). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The yellow oil was purified by flash chromatography using a 3: 7 mixture of ethyl acetate and hexanes as eluent. There were obtained 650 mg of (2-trimethylsilanyl-ethoxy) -amide 3- (S) -4- (4 ¹ fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid. MS:

523 (M1) (c) 3- (S) 4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid (2-trimethylsilanylethoxy) amide (650 mg, 1.24 mmol) ) in 8 ml of trifluoroacetic acid was stirred at 22 ° C for 16 hours. The resulting mixture was concentrated under reduced pressure and the residue triturated with methylene chloride and diethyl ether. Evaporation of the solvent gave 550 mg of a tan solid which was suspended in a 1: 1 mixture of diethyl ether and hexanes. The resulting suspension was stirred gently for 20 minutes. The solid was collected by filtration (washing with diethyl ether: hexanes 1: 1).

1) and dried. 470 mg of 3- (S) -4- (4'-fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide are obtained as a white solid. MS: 423 (M-1) · fl · fl · · · · fl fl fl fl::::::::::::::: Ml · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 8

3- (S) -4- [4- (4-Fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide (a) To a stirred (0 ° C) solution known (Belgian Patent Publication BE 893025) 2 2-dimethylthiomorpholine-3-carboxylic acid (600 mg, 3.42 mmol) in 10 mL of 1: 1 water / dioxane was added with stirring 6M sodium hydroxide (1.2 mL, 7.1 mmol). To the resulting solution was added 4- (4-fluorobenzyloxy) benzenesulfonyl chloride (1.08 g,

3.77 mmol). After 30 and 60 minutes, an additional 1 g of 4- (4-fluorobenzyloxy) benzenesulfonyl chloride and 1.2 ml of 6M sodium hydroxide were added. The resulting mixture (about pH 12) was diluted with water and the aqueous mixture was extracted with diethyl ether (x1). The ether layer was washed with 1M sodium hydroxide, the combined basic aqueous layers were acidified using concentrated hydrochloric acid to pH 3, and the acidic mixture was extracted with ethyl acetate (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. 820 mg of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid are obtained as a white solid. MS: 438 (M-1) (b) To a cold (0 ° C) solution of 3- (S) -4- (4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethyl-thiomorphine-3-carboxylic acid ( 820 mg (1.87 mmol) in 5 mL of methylene chloride was added triethylamine (0.52 mL, 3.74 mmol) under stirring under nitrogen and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.24) was added. g, 2.81 mmol) The resulting solution was stirred for 5 minutes and added

O- (tert-butyldimethylsilyl) hydroxylamine (550 mg, 3.74 mmol). The ice bath was removed and the reaction mixture was stirred at 23 ° C for 16 h, diluted with aqueous ammonium chloride and extracted with ethyl acetate (3x). Wash the combined organic extracts with water. 9 99 99 99 99 99 999 9999

9999 99 99

9,999 99,999,999 9

9,999,999

9 99 99 99 99 and brine, dried over sodium sulfate and filtered. The filtrate was concentrated to give a yellow oily residue which was purified by flash chromatography using 1: 3 ethyl acetate / hexanes as eluent. 270 mg of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylthiomorphine-3-carboxylic acid (tert-butyldimethylsiloxy) amide are obtained in the form of a white foam. MS: 569 (M + 1) (c) To a cold (0 ° C) 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylthiomorpholine- (tert-butyldimethylsiloxy) amide solution 3-Carboxylic acid (270 mg, 0.47 mmol) in 10 mL of tetrahydrofuran was added with stirring 2 drops of concentrated hydrochloric acid. After 30 minutes, the reaction mixture was diluted with 15 mL of tetrahydrofuran. The tetrahydrofuran mixture was concentrated under reduced pressure to a volume of about 5 mL and made up to a volume of about 25 mL with tetrahydrofuran. The mixture was re-concentrated to a volume of 5 mL. This procedure was repeated twice and finally the mixture was concentrated to dryness. The solid residue is suspended in a mixture of hexanes and diethyl ether. The resulting mixture was stirred for 16 hours. The solid was collected by filtration, rinsed with diethyl ether and dried. 180 mg of 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide is obtained as a white solid. MS: 453 (M) ¹ H NMR (400 MHz, DMSO-d 6): δ 10.63 (s, 1H), 8.80 (bs, 1H), 7.59-7.61 (m, 2H), 7.46-7.50 (m, 2H), 7.17-7.21 (m, 2H), 7.09-7.12 (m, 2H), 5.12 (s, 2H), 3, 99 (s, 1H), 3.87-3.93 (m, 1H), 3.69 (d, 1H, J = 12.7 Hz), 2.78-2.86 (m, 1H), 2 44-2.50 (m, 1H), 1.35 (s, 3H), 1.12 (s, 3H)

Preparative procedure

4- (4-Fluorobenzyloxy) benzenesulfonyl chloride chlor

φ * φ • • · Φ • • · φ · · · · ·

Κ a stirred solution of 4-hydroxybenzenesulfonic acid sodium dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1M sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The reaction mixture was heated at reflux for 2 days, then cooled to ambient temperature (22 ° C), whereupon a white precipitate formed. The flaky solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried. 4.95 g of 4- (4-fluorobenzyloxy) benzenesulfonic acid sodium salt are obtained. To a stirred solution of 4- (4-fluorobenzyloxy) benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 ml of thionyl chloride and 2 drops of dimethylformamide was heated to gentle reflux for 8 hours and then concentrated. The yellow solid residue was suspended in ethyl acetate and the resulting suspension was filtered. The filtrate was concentrated to give 11.2 g of 4- (4-fluorobenzyloxy) nenesulfonyl chloride as a light yellow solid. 1 H NMR (400 MHz, CDCl 3): δ 7.95-7.98 (m, 2H), 7.38-7.41 (m, 2H), 7.08-7.12 (m, 4H), 5.12 (s, 2H).

Preparative procedure 2

3- (4-Fluorophenoxy) propane-1-sulfonyl chloride

To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at ambient temperature (22 ° C). ). After 20 minutes, a solution of 1,3-propanesulfone (3.9 mL, 44.6 mmol) in toluene was slowly added. The resulting mixture was stirred for 26 hours and then quenched by the addition of methanol. The methanol mixture was concentrated under reduced pressure. The off-white solid residue was suspended in ethyl acetate, filtered, and the collected solid was dried. 10.9 g of 3- (4-fluorophenoxy) propane-1-sulfonic acid sodium salt are obtained in the form of an off-white powder. Mixed solution of sodium salt of 3- (4-fluorophenoxy) propan-1 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

-sulfonic acid (2.0 g, 7.8 nunol) in 10 ml of thionyl chloride and 1 drop of dimethylformamide was heated to reflux for 16 hours, then cooled to 0 ° C, diluted with 25 ml of diethyl ether and quenched by slow addition of water. The organic layer was separated and the aqueous layer was extracted with 25 mL diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to give 1.75 g of 3- (4-fluorophenoxy) propane-1-sulfonyl chloride as a yellow oil. NMR (400 MHz, CDCl ₃ ): δ 6.96-7.00 (m, 2H), 6.80-6.84 (m, 2H), 4.10 (t, 2H, J = 5.5 Hz) 1.91 (t, 2H, J = 7.5Hz), 2.47-2.54 (m, 2H)

Preparative procedure

4'-Fluorobiphenylsulfonyl chloride

Chlorosulfonic acid (8.7 mL, 0.13 mol) was added dropwise to a stirred cold (0 ° C) solution of 4-fluorobiphenyl (10.2 g, 59 mmol). After 30 minutes at 0 ° C, the reaction mixture was poured on ice. The precipitated white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate, and concentrated to a white solid. The desired 4'-fluorobiphenylsulfonyl chloride (4.3 g) was separated from 4'-fluorobiphenylsulfonic acid by crystallizing the acid from ethyl acetate and leaving the remaining material to crystallize from hexanes.

Claims (42)

the dashed line represents an optional double bond; X is carbon, oxygen or sulfur; Y is carbon, oxygen, sulfur, SO or S0 _2, or nitrogen; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen, hydroxy, C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, trifluoromethyl, halogen, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylamino, C 6 -C 10 arylthio carbon atoms, aryloxy groups having 6 to 10 carbon atoms, heteroarylamino groups having 2 to 9 carbon atoms, heteroarylthio groups having 2 to 9 atoms 9 9 9 · · «« »· 9 9 9 9 9 9 99 9 9 9 • 9 9999 9 9 9 9 · · <·· 9 9 9 9 9 9 9 9 9 9 9 99 9 99 99 99 99 carbon, heteroaryloxy of 2 to 9 carbon atoms, arylaryl of 6 to 10 carbon atoms in each of the aryl moieties, cycloalkyl of 3 to 6 carbon atoms, hydroxy, piperazinyl, arylalkoxy of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkoxy moiety, heteroarylalkoxy of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkoxy moiety, acylamino of 1 to 6 carbon atoms, acylthio of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, C 1 -C 6 alkylsulfinyl, C 6 -C 10 arylsulfinyl, C 1 -C 6 alkylsulfonyl, C 6 -C 10 arylsulfonyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino carbon atoms in each alkyl moiety; (C 2 -C 6) alkenyl, (C 6 -C 10) arylalkenyl, (C 2 -C 6) aryl, (C 2 -C 6) heteroarylalkenyl (C 2 -C 9) heteroaryl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl 6 carbon atoms, arylalkynyl of 6 to 10 carbon atoms in the aryl and 2 to 6 carbon atoms of the alkynyl moiety, heteroarylalkynyl of 2 to 9 carbon atoms in the heteroaryl and 2 to 6 carbon atoms of the alkynyl moiety, alkylamino of 1 to 6 carbon atoms, (C 1 -C 6) alkylthio, (C 1 -C 6) alkoxy, (C 1 -C 6) perfluoroalkyl, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylamino, (C 6 -C 6) arylthio group up to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroarylamino of 2 to 9 carbon atoms; heteroarylthio of 2 to 9 carbon atoms, heteroaryloxy of 2 to 9 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkyl (hydroxymethylene) of 1 to 6 carbon atoms in the alkyl moiety, piperidyl, alkylpiperidyl of 1 to 6 carbon atoms alkyl, acylamino having 1 to 6 carbon atoms, acylthio having from 1 to 6 carbon atoms, acyloxy having 1 to 6 carbon atoms, a radical R ¹⁰ -alkyl, C 1 -C 6 alkyl or a group of the formula II / <w > _v (II) where <CH 2) _n n y w z is from 0 to 6; represents 0 or 1; represents an oxygen atom or a group> NR ²⁴ , 941 9411 is -OR ^xx , or -NR R, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, di-ring, dihydro-isoquinolyl, tetrahydroisoquinolyl, tetrahydroisoquinoline De wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and V is hydrogen, alkyl of 1 to 3 carbon atoms or alkyl (C = O) of 1 to 6 carbon atoms in the alkyl moiety, alkoxy (C = O) of 1 to 6 carbon atoms in the alkoxy moiety, aryl (C = O) - with 6 to 10 carbon atoms in the aryl moiety, aryloxy (C = O) with 6 to 10 carbon atoms in the aryl moiety, aryl · Alkyl (C = O) - having 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety, arylalkoxy (C = O) with 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkoxy moiety, or alkoxy (C = O) -O- having 1 to 6 carbon atoms in the alkoxy moiety; each heterocyclic group (i.e., each cyclic group containing one or more heteroatoms contained in the substituent Z) is optionally substituted with one or two groups independently selected from the group consisting of hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 10) acyl, (C 1 -C 10) acyloxy, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylalkyl and (C 1 -C 6) alkyl group , heteroarylalkyl of 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, acyloxyalkyl of 1 up to 6 carbon atoms in the acyl and 1 to 6 carbon atoms in the alkyl moiety, alkylthio groups having 1 to 6 carbon atoms, (C 1 -C 6) alkylthioalkyl, (C 6 -C 10) arylthio, (C 6 -C 10) arylthioalkyl (C 1 -C 6) alkyl group, R ¹² R ¹³ N, R ¹² R ¹³ NSO 2, R ¹² R ¹³ NCO, R ¹² R ¹³ NCO-C 1 -C 6 alkyl, R ¹⁴ SO 2, R ¹⁴ SO ₂ NH, R ¹⁵ CONR ¹² R ¹⁶ O (C = O) R ¹⁶ O (C = O) -alkyl of 1 to 6 carbon atoms in the alkyl moiety; 1 Ω R is acylpiperazinyl having 1 to 6 carbon atoms in the acyl moiety, arylpiperazinyl having 6 to 10 carbon atoms in the aryl moiety, heteroarylpiperazinyl having 2 to 9 carbon atoms in the heteroaryl moiety, alkylpiperazinyl having 1 to 6 carbon atoms in the aryl moiety C 6 -C 10 arylalkylpiperazinyl, C 1 -C 6 arylalkylpiperazinyl, C 2 -C 9 heteroarylalkylpiperazinyl, C 1 -C 6 alkyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl C 1 -C 6 alkyl, C 6 -C 10 arylpiperidyl, C 2 -C 9 heteroarylpiperidyl, C 1 -C 6 alkylpiperidylalkyl, C 6 -C 10 arylpiperidylalkyl aryl and 1 to 6 carbon atoms carbon atoms in the alkyl portion, heteroarylpiperidylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl portion, or acylpiperidyl of 1 to 6 carbon atoms in the acyl portion; R ¹¹ is hydrogen, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl, C 2 -C 9 heteroarylalkyl and heteroaryl; C 1 -C 6 alkyl, C 1 -C 6 alkylarylalkyl, C 6 -C 10 aryl, C 1 -C 6 alkylheteroarylalkyl, C 2 -C 9 heteroaryl , 5-indanyl or a group of formula CHR ^3-O (C = O) R ^18, or CH ₂ (C = O) NR ¹⁹ R ^20; • · · · · · · · · · · · · · · · · · · · R ¹² and R ¹³ are each independently hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl alkyl moieties or heteroarylalkyl having 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, or R ¹² and R ¹³ taken together with the nitrogen atom to which they are attached may form azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or a thiomorpholinyl ring; R ¹⁴ is trifluoromethyl, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl or heteroarylalkyl 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; R ¹⁵ is hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylalkylarylalkoxy group, and in each case having 1 to 6 carbon atoms in the alkyl and alkoxy moiety or heteroarylalkyl having 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl part; R ¹⁶ is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 aryl 9 9 99 99 99 999 9 9 9 9 9 9 9 9 9 9 9 9 · 9 99 · 9 9 · 9999999 99 999 99 9 99 « 99 9 99 · 9 99 99 carbon in the alkyl moiety, 5-indanyl group - [CH (R ¹⁷ ) O- (C = O) R ¹⁸ , -CH ₂ (C = O) -NR ¹⁹ R ^20, or R ^{21 is} C 1 -C 6 -alkyl; R ¹⁷ is hydrogen or C 1 -C 6 alkyl; R ¹⁸ is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 10 aryl; R ¹⁹ and R ²⁰ are each independently hydrogen or C 1 -C 6 alkyl, or may be taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring; R ²¹ is H ₂ N (CHR ²² ) (C = O) -; R ²² represents a side chain derived from natural D- or L-amino acids; R ²³ is hydrogen, C 1 -C 6 acyl, C 1 -C 6 alkyl, C 6 -C 10 arylalkyl and C 1 -C 6 alkyl, heteroaryl C 2 -C 9 heteroaryl, and C 1 -C 6 alkyl or C 1 -C 6 alkylsulfonyl; R ²⁴ at each occurrence is independently hydrogen or C 1 -C 6 alkyl; or R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ , or R ⁷ and R ⁸ taken together, may form a carbonyl group; or R ¹ and R ^2, or R ³ and R ^4, or R ⁵ and R ^6, or R ⁷ and R ⁸ taken together may form a cycloalkyl of 3 to 6 carbon atoms, oxacyclohexyl, thiocyklohexylový, indanyl or tetralinyl ring or a group of the general formula Q is C 1 -C 10 alkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyaryl in each of the aryl moieties, C 6 -C 10 arylarylalkyl in each of the aryl moieties, C 6 -C 10 arylarylalkyl carbon in each of the aryl moieties and 1 to 6 carbon atoms in the alkyl moiety, arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl moiety, 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, aryloxyheteroaryl of 6 to 10 carbon atoms aryl and 2 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of 2 to 9 carbon atoms, alkyl aryl of 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl portion, alkoxyaryl of 1 to 6 carbon atoms in the alkoxy and 6 up to 10 carbon atoms in the aryl moiety, arylalkoxyaryl having 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety, heteroa C 2 -C 9 heteroaryl and C 6 -C 10 aryl aryl, C 1 -C 6 alkylheteroaryl C 2 -C 6 alkylheteroaryl C 2 -C 6 alkylheteroaryl C 2 -C 6 alkylheteroaryl · · · · · · · · · · · · · · · · · · · · · · · · · · 9 carbon atoms in the heteroaryl moiety, alkoxyheteroaryl having 1 to 6 carbon atoms in the alkoxy and 2 to 9 carbon atoms in the heteroaryl moiety, arylalkoxyheteroaryl having 6 to 10 carbon atoms in the aryl, 1 to 6 carbon atoms in the alkoxy and 2 to 9 carbon atoms in the heteroaryl moiety heteroaryl moieties, heteroaryloxyheteroaryl of 2 to 9 carbon atoms in each heteroaryl moiety, aryloxyalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroaryloxyalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, C 1 -C 6 alkylaryloxyaryl and 6-10 carbon atoms in each of the aryl moieties, C 1 -C 6 alkylheteroaryloxyaryl, 2 to 9 carbon heteroaryl and 6 to 10 carbon atoms in the aryl moiety, (C 1 -C 6) alkylaryloxyheteroaryl, (C 6 -C 10) aryl, (C 2 -C 9) aryl teroaryl moieties, alkoxyaryloxyaryl having 1 to 6 carbon atoms in alkoxy and 6 to 10 carbon atoms in each of the aryl moieties, alkoxyheteroaryloxyaryl having 1 to 6 carbon atoms in alkoxy, 2 to 9 carbon atoms in heteroaryl and 6 to 10 carbon atoms in the aryl moiety or alkoxyaryloxyheteroaryl having 1 to 6 carbon atoms in alkoxy, 6 to 10 carbon atoms in aryl and 2 to 9 carbon atoms in the heteroaryl moiety optionally substituted by fluorine, chlorine, bromine, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon or perfluoroalkyl of 1 to 3 carbon atoms; wherein when Q is different from arylalkyl having 6 to 10 carbon atoms in each of the aryl moieties, arylalkoxyaryl having 6 to 10 carbon atoms in each of the aryl moieties 9 · 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 · 9 9 9999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 99 9 9 9 9 99 moieties and 1 to 6 carbon atoms in the alkoxy moiety or arylalkoxyheteroaryl of 6 to 10 carbon atoms in the aryl moiety, 1 to 6 carbon atoms in the alkoxy and 1 to 9 carbon atoms in the heteroaryl moiety, then R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ must be defined as a general group of formula II; wherein when y is zero, Q is different from arylalkyl of 6 to 10 carbon atoms in each of the aryl moieties, arylalkoxyaryl of 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms of the alkoxy moiety or arylalkoxyheteroaryl of 6 up to 10 aryl atoms, 1 to 6 carbon atoms in alkoxy and 1 to 9 carbon atoms in the heteroaryl moiety, and any one of R ¹ to R ⁹ represents a group of formula II, then Z must be defined as substituted azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, piperazinyl, acylpiperazinyl of 1 to 10 carbon atoms in the acyl moiety, alkylpiperazinyl of the alkyl of 1 to 6 carbon atoms, up to 9 atoms a carbon in the heteroaryl moiety or a bridged diazabicycloalkyl ring; wherein when Q is a (C 6 -C 10) aryl aryl group of each of the aryl moieties, (C 6 -C 10) arylalkoxyaryl of each of the aryl moieties and 1 to 6 carbon atoms of the alkoxy moiety, or an arylalkoxyheteroaryl of 6 to 10 carbon atoms in the aryl moiety, 1 to 6 carbon atoms in the alkoxy and 1 to 9 carbon atoms in the heteroaryl moiety, then R ¹ to R ⁹ may be different from the group of formula II, but when R 1, R ² , R ³ , R ⁴ , R ⁵ , R R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or C 1 -C 6 alkyl, either X or Y being oxygen, sulfur or "9" 9 9 9 9 9 • 9 9 9 9 9 99 9 9 9999 9 9 9 9 9 99 · 99 9 9 • 9 9 9 9 9 9 9 SO, -SO ₂ - or nitrogen, or the dotted line represents a double bond; wherein when R ¹ , R ² , R ⁵ and R ⁶ represents a heteroatom-containing substituent; then this heteroatom cannot be directly bonded to the 2 or 6 position of the ring; wherein, when X is nitrogen, R ⁴ is absent; wherein when X represents oxygen, sulfur, SO, SO ₂ or nitrogen and when one or more of R ¹ , R ² , R ⁵ and R ⁶ represents a heteroatom containing substituent, the heteroatom cannot be directly bonded to the 4 or 6 position ; wherein when Y represents oxygen, sulfur, SO, SO ₂ or nitrogen and when one or more of R ³ , R ⁴ , R ⁷ and R ⁸ is independently a heteroatom-containing substituent, the heteroatom cannot be directly bonded to the 3-position or 5; wherein when X represents oxygen, sulfur, SO or SO ₂ , then R ³ and R ⁴ are absent; wherein when y is 1 and W is 0 and A is NR or oxygen, then Z cannot be hydroxy; wherein when Y represents oxygen, sulfur, SO or SO ₂ , then R ⁵ and R ⁶ are absent; wherein when Y is nitrogen, then ^R8 is absent; wherein, when the dashed line represents a double bond, then R ⁴ and R ⁶ are absent; 44 44 4 4 4 4 4 4 9 · 9 · · · 9 4 9 4 4 9 4 4 4 » 9 9 9 4 9,999 · 4 9 4 49 99 4 9 9 94 • 4 9 9 9 Wherein when R ³ and R ⁵ are independently a heteroatom-containing substituent and when the dotted line represents a double bond, the heteroatom cannot be directly bonded to the X and Y positions; wherein when one of X and Y is oxygen, sulfur, SO, SO ₂ or nitrogen, the other is carbon; and wherein when X or Y is a heteroatom, the dotted line does not represent a double bond; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to general formula I Q dashed line represents an optional double bond; X is carbon, oxygen or sulfur; Y is carbon, oxygen, sulfur, SO or S0 _2, or nitrogen; 99 99 99 99 9 99 9 9 9 99 9 «99 999 99 9 99 9 99 99 99 99 * 9 R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen, C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of alkylthio (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, trifluoromethyl, halogen, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylamino, (C 6 -C 10) arylthio , (C 6 -C 10) aryloxy, (C 2 -C 9) heteroarylamino, (C 2 -C 9) heteroarylthio, (C 2 -C 9) heteroaryloxy, (C 6 -C 10) aryl aryl groups in each of the aryl moieties, (C 3 -C 3) cycloalkyl groups 6 carbon atoms, hydroxy, piperazinyl, arylalkoxy of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkoxy moiety, heteroarylalkoxy of 2 to 9 carbon atoms heteroaryl and 1 to 6 carbon atoms in the alkoxy moiety, 1 to 6 carbon acylamino, 1 to 6 carbon acylthio, 1 to 6 carbon acyloxy, 1 to 6 carbon alkylsulfinyl, 6 to 10 arylsulfinyl carbon atoms, C 1 -C 6 alkylsulfonyl, C 6 -C 10 arylsulfonyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety; (C 2 -C 6) alkenyl, (C 6 -C 10) arylalkenyl, (C 2 -C 6) aryl, (C 2 -C 6) heteroarylalkenyl (C 2 -C 9) heteroaryl, (C 2 -C 6) alkynyl, (C 2 -C 6) alkynyl 6 carbon atoms, arylalkynyl of 6 to 10 carbon atoms in the aryl and 2 to 6 carbon atoms of the alkynyl moiety, heteroarylalkynyl of 2 to 9 carbon atoms in the heteroaryl and 2 to 6 carbon atoms of the alkynyl moiety, alkylamino of 1 to 6 carbon atoms, (C 1 -C 6) alkylthio, (C 1 -C 6) alkoxy, (C 1 -C 6) perfluoroalkyl, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylamino, arylthio 6 to 10 carbon atoms, 6 to 10 carbon aryloxy, 2 to 9 carbon heteroarylamino, 2 to 9 carbon heteroarylthio, heter (C 2 -C 9) oaryloxy, (C 3 -C 6) cycloalkyl, (C 1 -C 6) alkyl (hydroxymethylene), piperidyl, (C 1 -C 6) alkylpiperidyl, (C 1 -C 6) acylamino group carbon, acylthio of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, R ^xu -alkyl of 1 to 6 carbon atoms in the alkyl moiety or a group of formula II (II) wherein the number is 0 to 6; represents 0 or 1; represents an oxygen atom or a group> NR 99 99 9 9 9 * • · 9 9 9 99 99 4 · · 9 9 · 9 8 · | ·· « 9 9 9 99 9 99 99 9 9 9 9 99 99 Ί 1 9 Δ Ί Ί represents a group of the formula -OR, or -NR R, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydrofluoroalkyl, or a bridged dihydro, or a dihydro group; , c, daede wherein r is 1, 2 or 3; m is 1 or 2; • · 4 14 9 49 44 91 91 99 · 4 4 4 9 9 1 1 93 4 4 4 4 9 4 9 4 9 4 4 4 4 4 4 4 9 4 5 4,493,444,444 p is 0 or 1; and V is hydrogen, alkyl of 1 to 3 carbon atoms or alkyl (C = O) of 1 to 6 carbon atoms in the alkyl moiety, alkoxy (C = O) of 1 to 6 carbon atoms in the alkoxy moiety, aryl (C = O) - having 6 to 10 carbon atoms in the aryl moiety, aryloxy (C = O) with 6 to 10 carbon atoms in the aryl moiety, arylalkyl (C = O) - having 6 to 10 carbon atoms in the aryl moiety and 1 to 10 carbon atoms 6 carbon atoms in the alkyl moiety, arylalkoxy (C = O) of 6 to 10 carbon atoms in the aryl moiety and 1 to 6 carbon atoms in the alkoxy moiety or alkoxy (C = O) -O- of 1 to 6 carbon atoms in the alkoxy moiety; each heterocyclic group (i.e., each cyclic group containing one or more heteroatoms contained in the substituent Z) is optionally substituted with one or two groups independently selected from the group consisting of hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 10) acyl, (C 1 -C 10) acyloxy, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylalkyl and (C 1 -C 6) alkyl group , heteroarylalkyl of 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, acyloxyalkyl of 1 up to 6 carbon atoms in the acyl and 1 to 6 carbon atoms in the alkyl moiety, alkylthio groups having 1 to 6 carbon atoms, (C 1 -C 6) alkylthioalkyl, (C 6 -C 10) arylthio, (C 6 -C 10) arylthioalkyl (C 1 -C 6) alkyl group, R ¹² R ¹³ N, R ¹² R ¹³ NCO ₂ , R ¹² R ¹³ NCO, R ¹² R ¹³ NCO-alkyl S 1 to 6 in Φ · · · · φ φ Φ · φ φφ φφ • 9 Φ 9 «9 11 1 1 11 Φ Φ · Φ • Φ Φ * • Φ · Φ Φ Φ Φ Φ Φ Φ Φ · 11 * Φ Φ φ φ φ φ φφ φφ carbon atoms in the alkyl portion, SO 2 R ^14, R ¹⁴ SO2NHA, CONR ¹⁵ R ^12, R ¹⁶ O (C = O) R ¹⁶ O (C = O) -C 1 up to 6 carbon atoms in the alkyl moiety; R ¹⁰ is acylpiperazinyl having 1 to 6 carbon atoms in the acyl moiety, arylpiperazinyl having 6 to 10 carbon atoms in the aryl moiety, heteroarylpiperazinyl having 2 to 9 carbon atoms in the heteroaryl moiety, alkylpiperazinyl having 1 to 6 carbon atoms in the alkyl moiety, arylalkylpiperazines up to 10 aryl and 1-6 carbon atoms of the alkyl moiety, heteroarylalkylpiperazinyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl, alkylpiperidyl 6 alkyl in the alkyl moiety, C 6 -C 10 arylpiperidyl aryl, C 2 -C 9 heteroarylpiperidyl heteroaryl, C 1 -C 6 alkylpiperidylalkyl in each alkyl moiety, C 6 -C 10 arylpiperidylalkyl and 1-C 1 arylpiperidyl alkyl up to 6 carbon atoms alkyl, heteroarylpiperidylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl portion, or acylpiperidyl of 1 to 6 carbon atoms in the acyl portion; R ¹¹ is hydrogen, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylalkyl and (C 1 -C 6) alkyl, heteroarylalkyl (C 2 -C 9) heteroaryl; Φ ΦΦ ΦΦ • · 9 · * · • · · ΦΦ • Φ Φ Φ · «· 94 Φ Aryl and 1 to 6 carbon atoms in the alkyl moiety, alkylarylalkyl of 1 to 6 carbon atoms in each of the alkyl and 6 to 10 carbon atoms in the aryl moiety, alkylheteroarylalkyl of 1 to 6 carbon atoms in each from alkyl and 2 to 9 carbon atoms in the heteroaryl moiety, 5-indanyl or CHR ¹⁷ O (C = O) R ¹⁸ or CH ₂ (C = O) NR ¹⁹ R ²⁰ ; R ¹² and R ¹³ are each independently hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl alkyl moieties or heteroarylalkyl having 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, or R ¹² and R ¹³ taken together with the nitrogen atom to which they are attached may form azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or a thiomorpholinyl ring; R ¹⁴ is trifluoromethyl, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl or heteroarylalkyl 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; R ¹⁵ is hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, (C 2 -C 9) heteroaryl, (C 6 -C 10) arylalkylarylalkoxy group, and in each case having 1 to 6 carbon atoms in the alkyl and alkoxy groups of the alkyl and alkoxy groups; C 2 -C 9 heteroarylalkyl or C 1 -C 6 heteroaryl and C 1 -C 6 alkyl; R ¹⁶ is C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl, C 1 -C 6 alkyl, 5-indanyl, - [CH (R ¹⁷ ) O- (C = O) R ¹⁸ , -CH ₂ (C = O) -NR ¹⁹ R ²⁰ or R ²¹ O-C 1 -C 6 alkyl; R ¹⁷ is hydrogen or C 1 -C 6 alkyl; R ¹⁸ is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 10 aryl; R ¹⁹ and R ²⁰ are each independently hydrogen or C 1 -C 6 alkyl, or may be taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring; R ²¹ is H ₂ N (CHR ²² ) (OO) -; R ²² represents a side chain derived from natural D- or L-amino acids; R ²³ is hydrogen, C 1 -C 6 acyl, C 1 -C 6 alkyl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl, heteroaryl Alkyl of 2 to 9 carbon atoms in the heteroaryl group; and an alkyl group of 2 to 9 carbon atoms in the heteroaryl group; C 1 -C 6 alkyl or C 1 -C 6 alkylsulfonyl; R ²⁴ at each occurrence is independently hydrogen or C 1 -C 6 alkyl; or R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ taken together may form a carbonyl group; or R ¹ and R ^2, or R ³ and R ^4, or R ⁵ and R ^6, or R ⁷ and R ⁸ taken together may form a cycloalkyl of 3 to 6 carbon atoms, oxacyclohexyl, thiocyklohexylový, indanyl or tetralinyl ring or a group of the general formula Q is C 1 -C 10 alkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyaryl in each of the aryl moieties, C 6 -C 10 arylarylalkyl in each of the aryl moieties, C 6 -C 10 arylarylalkyl carbon in each of the aryl moieties and 1 to 6 carbon atoms in the alkyl moiety, arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl moiety, 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, aryloxyheteroaryl of 6 to 10 carbon atoms in aryl and 2 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of 2 to 9 carbon atoms, alkyl aryl of 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl portion, alkoxyaryl of 1 to 6 carbon atoms; · · 6 carbon atoms in alkoxy and 6 to 10 carbon atoms in the aryl moiety, arylalkoxyaryl of 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety, heteroaryloxyaryl of 2 to 9 atoms in the heteroaryl and 6 to 10 atoms C 1 -C 6 alkylheteroaryl, C 2 -C 9 heteroaryl, C 1 -C 6 alkoxyheteroaryl and C 2 -C 9 heteroaryl, arylalkoxyheteroaryl C 6 -C 10 aryl, 1 to 6 carbon atoms in alkoxy and 2 to 9 carbon atoms in the heteroaryl moiety, heteroaryloxyheteroaryl of 2 to 9 carbon atoms in each of the heteroaryl moieties, aryloxyalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl parts, heteroaryloxyalkyl of 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylaryloxy (C 1 -C 6) -aryl and (C 6 -C 10) -aryl aryl, (C 1 -C 6) alkylheteroaryloxyaryl, (C 2 -C 9) heteroaryl and (C 6 -C 10) aryl, (C 1 -C 6) alkylaryloxyheteroaryl; 6 carbon atoms in the alkyl, 6-10 carbon atoms in the aryl and 2 to 9 carbon atoms in the heteroaryl moiety, alkoxyaryloxyaryl of 1 to 6 carbon atoms in the alkoxy and 6 to 10 carbon atoms in each of the aryl moieties, alkoxyheteroaryloxyaryl of the 1 to 6 atoms C 2 -C 9 heteroaryl and C 6 -C 10 aryl or C 1 -C 6 alkoxyaryloxyheteroaryl, C 6 -C 10 aryl and C 2 -C 9 heteroaryl, optionally substituted • • • • • • • • • • • • • • • • • • • • • • • • • • • (C 1 -C 6), (C 1 -C 6) alkoxy or (C 1 -C 3) perfluoroalkyl; wherein when y is zero, Q is different from arylalkyl of 6 to 10 carbon atoms in each of the aryl moieties, arylalkoxyaryl of 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms of the alkoxy moiety or arylalkoxyheteroaryl of 6 up to 10 aryl atoms, 1 to 6 alkoxy atoms and 1 to 9 carbon atoms in the heteroaryl moiety, and any one of R ¹ to R ⁹ represents a group of formula II, then Z when defined as a substituted azetidinyl group, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, piperazinyl, acylpiperazinyl having 1 to 10 carbon atoms in the acyl moiety, alkylpiperazines of 6 to 6, alkylpiperazinyl, 6-alkylpiperazinyl having 2 to 9 carbon atoms or a bridged diazabicycloalkyl ring must be substituted; wherein when y is zero and Q is different from arylalkyl having 6 to 10 carbon atoms in each of the aryl moieties, arylalkoxyaryl having 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety or arylalkoxyheteroaryl having 6 up to 10 carbon atoms in the aryl, 1 to 6 carbon atoms in the alkoxy and 1 to 9 carbon atoms in the heteroaryl moiety, then at least one of the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ must be defined as a group of formula II; wherein, when Q is a (C 6 -C 10) aryl aryl group in each of the aryl moieties, arylalkoxyaryl-92- (arylalkoxyaryl) is arylalkoxyaryl; 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety or arylalkoxyheteroaryl of 6 to 10 carbon atoms in aryl, 1 to 6 carbon atoms in alkoxy and 1 to 9 carbon atoms in the heteroaryl moiety, then R to R may be different from the group of formula II, but when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or C 1 -C 6 alkyl, either X or Y is oxygen, sulfur or SO, -SO ₂ - or nitrogen, or the dotted line represents a double bond; whereas, R ⁷ Yippee different from hydrogen, only when R ⁸ Yippee different from hydrogen 7 whereas, R ⁶ Yippee different from hydrogen, only when R ⁵ Yippee different from hydrogen t whereas, R ³ Yippee different from hydrogen, only when R ⁴ Yippee different from hydrogen 7 whereas, R ² Yippee different from hydrogen, only when R ¹ Yippee different from hydrogen • t whereas, when R ¹ , R ² and R ⁹ are substituents obs a heteroatom which may not be directly attached to the 2 or 6 position of the ring; wherein, when X is nitrogen, R ⁴ is absent; wherein when X represents oxygen, sulfur, SO, SO ₂ or nitrogen and when one or more of R ¹ , R ² , R ⁵ and R ⁶ represents a heteroatom containing substituent, the heteroatom cannot be directly bonded to the 4 or 6 position ; Wherein when Y represents oxygen, sulfur, SO, SO ₂ or nitrogen and when one or more of R ³ , R ⁴ , R ⁷ and R ⁸ represents independently a substituent containing a heteroatom, then the heteroatom cannot be directly bonded to the 3 or 5 position; wherein when X represents oxygen, sulfur, SO or SO ₂ , then R ³ and R ⁴ are absent; wherein when y is 1 and W is NR ²⁴ or oxygen, then Z cannot be hydroxy; wherein when Y represents oxygen, sulfur, SO or SO ₂ , then R ⁵ and R ⁶ are absent; wherein when Y represents nitrogen, then R ⁶ is absent; wherein, when the dashed line represents a double bond, then R ⁴ and R ⁶ are absent; wherein when R ³ and R ⁵ are independently a heteroatom-containing substituent and when the dotted line represents a double bond, the heteroatom cannot be directly bonded to the X and Y positions; wherein when one of X and Y is oxygen, sulfur, SO, SO ₂ or nitrogen, the other is carbon; and wherein when X or Y is a heteroatom, the dotted line does not represent a double bond; and pharmaceutically acceptable salts thereof. ·· · · · · · Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein Y represents oxygen, carbon, sulfur or SO, SO; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein Q represents arylaryloxy group having 6 to 10 carbon atoms in each of the aryl moieties, arylalkoxyheteroarylalkoxyaryl having 6 to 10 carbon atoms in each of the aryl moieties, 1 to 6 carbon atoms in each (C až-C alko) heteroaryl, (C až-C 10 a) arylalkoxyaryl (C až-C až a) aryl or C až až-Cry a (C až-Cry a) aralkoxyalkyl; in alkoxy and 1 to 6 carbon atoms in the alkyl moiety in which each terminal aryl group is optionally substituted with fluorine; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein R ² , R ³ , R ⁶ , R ^{7 *} and R ⁹ are hydrogen atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein Y represents carbon and Q represents alkoxyaryl of 1 to 6 carbon atoms in the alkoxy and 6 to 10 carbon atoms in the aryl moiety, arylalkoxyaryl of 6 to 10 carbon atoms in each of aryl moieties having 1 to 6 carbon atoms in the alkoxy moiety or arylalkoxyalkyl having 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in each of the aliphatic moieties; and pharmaceutically acceptable salts thereof. 9 9 • 9 • 9 9 9 9 0 9 9 Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein Y represents oxygen, sulfur or SO or SO ₂ ; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein Y represents oxygen, sulfur or SO or SO ₂ ; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein at least one of the radicals R ⁷ to R ⁹ is different from hydrogen; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein at least one of the radicals R ⁷ to R ⁹ is different from hydrogen; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 7, wherein at least one of the radicals R ⁷ to R ⁹ is different from hydrogen; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein at least one of the radicals R ⁷ to R ⁹ is different from hydrogen; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein at least one of the radicals R ⁷ to R ⁹ is C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. 4 4 5 9 9 9 9 Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein at least one of the radicals R ⁷ to R ⁹ is C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 7, wherein at least one of R ⁷ to R ⁹ is C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein at least one of R ⁷ to R ⁹ is C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein at least one of the radicals R ⁷ to R ⁹ is methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein at least one of the radicals R ⁷ to R ⁹ is methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 7, wherein at least one of the radicals R ⁷ to R ⁹ is methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein at least one of the radicals R ⁷ to R ⁹ is methyl; and pharmaceutically acceptable salts thereof. • 9 9 9 9 9 99 9 9 9 9 9 9 9 ·· 9 9 · 99 9 9 9 9 · 9 · 99 9 9 9 9 9 9 9 9 9 • 9 9 9 Arylsulfonylhydroxamic acid derivatives according to claim 1 or 2, wherein R ⁷ and R ⁸ taken together form a carbonyl group and R ⁹ represents an alkyl group having 1 to 6 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein R ⁷ and R ⁸ taken together form a carbonyl group and R ⁹ represents an alkyl group having from 1 to ⁵ carbon atoms. 6 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 7, wherein R ⁷ and R ⁸ taken together form a carbonyl group and R ⁹ represents an alkyl group having from 1 to ⁵ carbon atoms. 6 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein R ⁷ and R ⁸ taken together form a carbonyl group and R ⁹ represents an alkyl group having from 1 to ⁵ carbon atoms. 6 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1, wherein R ⁷ and R ⁸ are each methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 4, wherein R ⁷ and R ⁸ are each methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 7, wherein R ⁷ and R ⁸ are each methyl; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein R ⁷ and R ⁸ are each methyl; and pharmaceutically acceptable salts thereof. 00 00 0 0 0 · ♦ · · · 0 0 · · 0 0 0 00 ·· · 0 · 0 • «· · 29. Arylsulfonylhydroxamic acid derivatives according to 7 D of claim 1 or 2 of formula I, wherein R and R, taken together, form a C 3 -C 6 cycloalkyl group; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 3, wherein R and R, taken together, form a cycloalkyl group having 3 to 6 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 6, wherein R ⁷ and R ⁸ taken together form a C 3 -C 6 cycloalkyl group; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 8, wherein R ⁷ and R ⁸ taken together form a C 3 -C 6 cycloalkyl group; and pharmaceutically acceptable salts thereof. Compounds according to claim 1 selected from the group consisting of (2R, 4R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [4] methyl ester - (4-fluorobenzyloxy) benzenesulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [3- (4-fluorophenoxy) propane-1-sulfonyl] -2-hydroxycarbamoylpiperidine-4-carboxylic acid, (2R, 4R) -1- [3- (4-Fluoro-phenoxy) -propane-1-sulfonyl] -2-hydroxycarbamoyl-piperidine-4-carboxylic acid methyl ester, 99 99 9 9 9 9 · 9 9 9 9 · 9 9 9 · 99 99 9 9 9 9 99 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 (2R, 3S) - {1- [4- (4-Fluoro-benzyloxy) -benzenesulfonyl] -2-hydroxycarbamoyl-piperidin-3-yl} -carbanoic acid isopropyl ester; 3- (S) -4- (4'-Fluorobiphenyl-4-sulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxyamide, 3- (S) -4- [4- (4-fluorobenzyloxy) benzenesulfonyl) hydroxyamide (2R, 4R) -1- (4-Methoxybenzenesulfonyl) -4- (piperazine-1-carbonyl) piperidine-2-carboxylic acid hydroxy-2,2-dimethylthiomorpholine-3-carboxylic acid and hydroxyamide hydrochloride. 34. Derivatives arylsulfonylhydroxamové acid according to claim 1 of formula I wherein X is carbon and R ³ is hydroxy; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 2, wherein X is carbon and R ⁴ is hydroxy; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 1, wherein X is carbon and R ⁵ is hydroxy; and pharmaceutically acceptable salts thereof. 37. Derivatives arylsulfonylhydroxamové acid according to claim 1 of formula I wherein X is carbon and R @ ⁶ is hydroxy; and pharmaceutically acceptable salts thereof. Arylsulfonylhydroxamic acid derivatives according to claim 36, wherein X represents carbon and R ⁸ 99 99 9 9 9 9 9 9 99 99 100 ·· · 9 · 9 9 9 9 9 9999 9 9 9 9 9 9 9 · 9 9 9 9 9 represents a hydroxy group; and pharmaceutically acceptable salts thereof. 39. Arylsulfonylhydroxamic acid derivatives selected from the group consisting of (2R, 3S) -1- [4- (2-chlorothiazol-5-ylmethoxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 3S) hydroxyamide - (2R, 3S) -3-Hydroxy-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] piperidine-3-hydroxy-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid (2R, 3S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 3S) -1- {4- [2- (4-Fluorophenyl) ethoxy] benzenesulfonyl} -3-hydroxypiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-1- [4- (2-pyridin-4-ylethoxy) benzenesulfonyl] piperidine-2- hydroxyamide (2R, 3S) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -3-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 3S) -3-hydroxy-1- [4- (5-trifluoromethylbenzothiazol-2-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide (2R, 3S) -3-hydroxy-1- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, Φ ΦΦ · · · · φ φ φ φ φ · 101 (2R, 3S) -1- [4- (2-chloro-thiazol-5-ylmethoxy) -benzenesulfonyl] -3- (2R, 3S) -hydroxyamide hydroxyamide hydroxy-3-methylpiperidine-2-carboxylic acid, (2R, 3S) -3-hydroxy-3-methyl-1- [4- (thiazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R) (2R, 3S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -3-hydroxy-3-methyl-1- [4- (pyridin-4-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide -3-hydroxy-3-methylpiperidine-2-carboxylic acid, (2R, 3S) -1- {4- [2- (4-fluorophenyl) ethoxy] benzenesulfonyl} -3-hydroxy-3-methylpiperidine-2- hydroxyamide (2R, 3S) -3-Hydroxy-3-methyl-1- [4- (2-pyridin-4-ylethoxy) benzenesulfonyl] piperidine-2-carboxylic acid hydroxyamide, (2R, 3S) -1- [4- (benzothiazol-2-ylmethoxy) benzenesulfonyl] -3-hydroxy-3-methylpiperidine-2-carboxylic acid (2R, 3S) -3-hydroxy-3-methyl-1- [4- (5- trifluoromethylbenzothiazol-2-ylmethoxy) be (2R, 3S) -3-hydroxy-3-methyl-1- [4- (1H-tetrazol-5-ylmethoxy) benzenesulfonyl] piperidine-2-carboxylic acid, hydroxyamide (2R) 4S) -1- (4-benzyloxybenzenesulfonyl) -4-butylaminomethyl-4-hydroxypiperidine-2-carboxylic acid, 99 99 9 9 9 · 9 9 9 · 9 9 9 · 9 9 9 « 99 9 < 99 99 9 9 9 9 9 · 99 102 • 9 9 · 9 (2R, 4S) -4-Butylaminomethyl-1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R) -1- [4- (4-fluorobenzyloxy) hydroxyamide benzenesulfonyl] -4-oxopiperidine-2-carboxylic acid, (2R, 4R) -1- (4-benzyloxybenzenesulfonyl) -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, (2R, 4R) -1- [4- ( 4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid, (2R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-methylpiperazine-2-carboxylic acid hydroxyamide, hydroxyamide (2R, 5S) - 1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -5-hydroxypiperidine-2-carboxylic acid, (2R, 5S) -1- (4-benzyloxybenzenesulfonyl) -5-hydroxypiperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R, 5R) -1- (4-benzyloxybenzenesulfonyl) -5-hydroxypiperidine-2-carboxylic acid, (2R, 5R) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -5-hydroxypiperidine-2-carboxylic acid hydroxyamide, hydroxyamide (2R, 3S) -1- (4-Benzyloxybenzenesulfonyl) -3-hydroxypiperidine-2-carbox (2R, 4S) -1- (4-benzyloxybenzenesulfonyl) -4-hydroxypiperidine-2-carboxylic acid hydroxyamide; and 99 99 9 9 9 9 • 9 · 9 9 9 9 9 99 99 103 9 9 9 9 99 < 9 (99R) (2R, 4S) -1- [4- (4-fluorobenzyloxy) benzenesulfonyl] -4-hydroxypiperidine-2-carboxylic acid hydroxyamide, 40. A pharmaceutical composition for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodonal disease, epidermolysis bullosa, scleritis, in combination with standard nonsteroidal anti-inflammatory drugs and analgesics, and in combination with cytotoxic anti-cancer agents. and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF); A compound according to claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective for such treatment or inhibition, and a pharmaceutically acceptable carrier. 41. A method for inhibiting (a) matrix metalloproteinases or (b) producing tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of an arylsulfonylhydroxamic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof. salts. 42. A method of treating conditions selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodonal disease, epidermolysis bullosa, scleritis, in combination with standard nonsteroidal anti-inflammatory drugs and analgesics, and in combination with cytotoxic anti-cancer agents and other diseases characterized matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases including 104 ·· «·» ·· ·· ··. · * T t t t t t t t t t t t t t t t t t t t t t t t t t t t Production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an arylsulfonylhydroxamic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof in an amount effective to treat such a condition.