CZ58999A3 - Derivatives of arylsulfonylaminohydroxamic acid, pharmaceutical preparation, inhibition method of matrix metalloproteinases or production of tumor necrosis factor and therapeutical method - Google Patents

Abstract

Atylsulfonylamino hydroxamic acid derivatives of the formula I wherein η, X, R3, R4 and Q are of particular interest are useful in the treatment of conditions selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase, AIDS, sepsis, septic shock and other diseases involving tumor necrosis factor (TNF) production. In addition, these compounds are useful in combination therapy with standard non-steroidal anti-inflammatory drugs and analgesics and in combination with cytotoxic agents such as adriamycin, daunomycin, cis-platin, etoposide, taxol, taxotere, and other alkaloids such as vincristine in the treatment of cancer.

Description

The invention relates to arylsulfonylaminohydroxamic 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 non-steroidal 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 metalloproteases. Matrix degrading metalloproteases such as gelatinase, stromelysin and collagenase are involved in tissue matrix degradation (e.g. collagen collapse) • and have been linked to many pathological conditions involving abnormal connective tissue metabolism 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).

SUMMARY OF THE INVENTION

The present invention provides arylsulfonylaminohydroxamic acid derivatives of formula (I)

Ck_x

(and)

wherein is from 1 to 6;

represents a group of formula OR ¹ wherein R ¹ is as defined below; azetidinyl, pyrrolidinyl, piX, peridyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, piperazinyl or bridged diazabicycloalkyl ring selected from the group consisting of c, d, a, d, and,

Η Η H

wherein d r is 1, 2 or 3;

m is 1 or 2; and p is 0 or 1;

each of the heterocyclic groups being optionally substituted with one or two substituents 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 10 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 up to 6 carbon atoms in the alkyl portion, 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 portion, acyloxyalkyl of 1 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, alkylthioalkyl groups having 1 to 6 carbon atoms in each of the alkyl moieties, arylthio 6 to 10 carbon atoms, 6 to 10 arylthioalkyl aryl and 1 to 6 carbon atoms in the alkyl moiety, R ⁹ R ¹⁰ N, R ⁹ R ¹⁰ NSO ₂ , R ⁹ R ¹⁰ NCO, R ⁹ R < ¹⁰ > is NCO-C1-C6 alkyl wherein R < ⁹ > and R < ^{10 >} are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5-C9 heteroaryl, (C 6 -C 10) arylalkyl and (C 1 -C 6) -alkyl or (C 5 -C 9) heteroaryl (C 1 -C 6) heteroarylalkyl

The QT Π in the alkyl moiety, or R and R, taken together with the nitrogen atom to which they are attached may form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring; R ¹² SO 2 or R ¹² SO ² NH wherein R ¹² is trifluoromethyl, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 6 -C 10 arylalkyl and C 1 -C 6 alkyl or C 5 -C 9 heteroaryl heteroaryl and C 1 -C 6 alkyl; R ¹³ CONR ⁹ , wherein R ⁹ is as defined above and R ¹³ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,

0 0 · ► · 0 · ► 0 0 0 · 0 0 0 0 aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkylarylalkoxy of 6 to 10 carbon atoms in each of the aryl moieties and in each case having 1 to 6 carbon atoms carbon atoms of the alkyl and alkoxy moieties, or heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; R @ ¹⁴ OOC, R @ ⁴ - OOC alkyl having 1 to 6 carbon atoms in the alkyl moiety, wherein R @ ⁴ * is C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl 5 up to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl portion, 5-indanyl, CHR ⁵ OCOR ⁶ wherein R ⁵ is hydrogen or alkyl of 1 to 6 carbon atoms and R ⁶ is (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or (C 6 -C 10) aryl group; CH ² CONR ⁷ R ⁸ wherein R ⁷ and R ⁸ 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 ¹⁵ O-C 1 -C 6 -alkyl, wherein R ¹⁵ represents a group of the formula H 2 N (CHR ³ - ⁸ ) CO, wherein R ¹⁶ represents a side chain derived from a natural D- or L-amino acid;

R ¹ is aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl moiety, 5-indanyl or CHR ⁵ OCOR ⁶ or CH ₂ CONR ⁷ R ⁸ wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above;

R ³ and R ⁴ are each independently hydrogen, (C 1 -C 6) alkyl, trifluoromethyl, (C 1 -C 6) trifluoromethyl (C 1 -C 6) alkyl, (C 1 -C 6) alkyl (difluoromethylene) or alkyl (difluoromethylene) alkyl of 1 to 3 carbon atoms in each of the alkyl moieties, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety , heteroarylalkyl of 5 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, arylarylalkyl of 6 to 10 carbon atoms in each of the aryl moieties, arylarylalkyl of 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 atoms carbon in the alkyl moiety, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, (C 1 -C 6) hydroxyalkyl, (C 1 -C 10) acyloxyalkyl (C 1 -C 6) alkyl, (C 1 -C 6) alkoxyalkyl (C 1 -C 6) alkyl, (C 1 -C 6) acylaminoalkyl C 10 acyl and 1-6 carbon atoms in the alkyl moiety, piperidyl, C 1-6 alkylpiperidyl, C 6 -C 10 arylalkoxyalkyl, C 1-6 alkoxy and C 1-6 alkyl carbon in the alkyl moiety, heteroarylalkoxyalkyl of 5 to 9 carbon atoms in the heteroaryl, 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl portion, alkylthioalkyl of 1 to 6 carbon atoms in each alkyl moiety, arylthioalkyl of 6 to 10 aryl atoms and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfinylalkyl having 1 to 6 carbon atoms in each alkyl moiety; · · 9 9 9 9 9 999999

9 to 9 carbon atoms, 6 to 10 aryl arylsulphonylalkyl and 1 to 6 carbon atoms in the alkyl moiety, 1 to 6 carbon atom alkylsulfonylalkyl, and 6 to 10 arylsulfonylalkyl and 1 to 6 carbon atoms. 6 carbon atoms in the alkyl moiety, aminoalkyl of 1 to 6 carbon atoms, alkylaminoalkyl of 1 to 6 carbon atoms in each of the alkyl moieties, di (alkylamino) alkyl of 1 to 6 carbon atoms in each of the alkyl moieties, R ¹⁷ CO -alkyl of 1 to 6 carbon atoms in the alkyl moiety wherein R ^x 'is RO or R ⁷ R ⁸ N, wherein R ⁷ , R ⁸ and R ¹⁴ are as defined above; or a group of formula R ¹ -alkyl of 1 to 6

X > 1 phi of the alkyl moiety wherein R is piperazinyl, C 1 -C 10 acylpiperazinyl, C 6 -C 10 arylpiperazinyl, C 5 -C 9 heteroarylpiperazinyl, heteroaryl alkylpiperazinyl C 1 -C 6 alkyl, C 6 -C 10 arylalkylpiperazinyl, C 1 -C 6 alkyl, C 5 -C 9 heteroarylalkylpiperazinyl, C 1 -C 6 alkyl, morpholinyl, thiomorpholinyl , piperidyl, pyrrolidinyl, 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, arylalkylpiperidyl carbon of 6 to 10 carbon atoms 6 carbon atoms in the alkyl moiety, he (C 5 -C 9) heteroaryl and C 1 -C 6 teroarylalkylpiperidyl;

An alkyl moiety or an acylpiperidyl group having from 1 to 10 carbon atoms in the acyl moiety; or

R ³ and R ⁴ , taken together, may form a cycloalkyl ring of 3 to 6 carbon atoms, an oxacyclohexyl thiocyclohexyl, indanyl or tetralinyl ring or a group of the general formula

wherein R ²¹ is hydrogen, C 1 -C 10 acyl, C 1 -C 6 alkyl, 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 portion or alkylsulfonyl of 1 to 6 carbon atoms; and

Q is C 1 -C 6 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, aryloxyheteroaryl of 6 to 10 carbon atoms in the aryl moiety and 5 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of 5 to 9 carbon atoms, alkylaryl of the 1 to 6 carbon atoms alkyl and 6 to 10 carbon atoms in the aryl moiety, 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 the aryl groups A (C 1 -C 6) alkoxy group, (C 6 -C 10) arylalkoxyalkyl, (C 1 -C 6) arylalkoxyalkyl; alkoxy and 1 to 6 carbon atoms in the alkyl moiety, heteroaryloxyaryl of 5 to 9 heteroaryl and 6 to 10 carbon atoms in the aryl moiety, alkylheteroaryl of 1 to 6 carbon atoms in the alkyl and 5 to 9 carbon atoms in the heteroaryl moiety, alkoxyheteroaryl with C 1 -C 6 alkoxy and C 5 -C 9 heteroaryl, arylalkoxyheteroaryl C 6 -C 10 aryl, C 1 -C 6 alkoxy and C 5 -C 9 heteroaryl, heteroaryloxyheteroaryl C 5 -C 9 carbon in each of the heteroaryl moieties, aryloxyalkyl of 6 to 10 carbon atoms in the aryl moiety 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, alkylheteroaryloxyaryl of 1 to 6 alkyl, 5 to 9 carbon atoms in heteroaryl and 6 to 10 carbon atoms in the aryl moiety, alkylaryloxyheteroaryl having 1 to 6 carbon atoms in the alkyl, 6 to 10 carbon atoms in the aryl and 5 to 9 carbon atoms in the heteroaryl moiety, alkoxyaryloxyaryl having 1 up to 6 carbon atoms in alkoxy and 6 to 10 carbon atoms in each of the aryl moieties, alkoxyheteroaryloxyaryl of 1 to 6 carbon atoms in the alkoxy, 5 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety or alkoxyaryloxyheteroaryl of 1 to 6 alkoxy, 6 to 10 aryl and 5 to 9 heteroaryl carbon atoms, each of the aryl groups

9 9 9 9 9 99

999 9999

999 9 9 9999

999 99 999 999

9 9 9 9 9 - 2.0 ”··· ··· ··· ♦ ·· ·· ·· is optionally substituted with fluorine, chlorine, bromine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or perfluoroalkyl C 1 -C 3;

wherein X must be substituted when it represents an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or piperazinyl ring, an acylpiperazinyl ring of 1 to 10 carbon atoms in the acyl ring, an alkylpiperazinyl ring of the 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;

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, trifluoromethyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryloxy, tri (III)

ΦΦΦΦΦ · φ ·· · <

• Fluoromethoxy, difluoromethoxy and C 1 -C 6 alkyl.

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 formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl, or arylalkyloxy, wherein alkyl and aryl are as defined 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.

• · ♦ · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

ΦΦΦ φφ

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 n is 2.

Other preferred compounds are those of formula I where R ³ or R ⁴ is not hydrogen.

Other preferred compounds are those compounds of formula (I) wherein Ar is C 1 -C 6 alkoxy and C 6 -C 10 aryl in the aryl moiety, C 6 -C 10 arylalkoxyaryl in each of the aryl moieties, and C 1 -C 6 in the aryl moiety alkoxy, 4-fluorophenoxyaryl of 6 to 10 carbon atoms in the aryl moiety, 4-fluorobenzyloxyaryl of 6 to 10 carbon atoms in the aryl moiety, or alkylaryloxyaryl of 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in each of the aryl moieties .

Other preferred compounds are those compounds of formula (I) wherein X is indolinyl or piperidyl.

More preferred are compounds of formula I wherein n is 2, R ³ or R ^{4 is} not hydrogen; Ar is C 1 -C 6 alkoxyaryl and C 6 -C 10 aryl, C 6 -C 10 arylalkoxyaryl in each aryl moiety and C 1 -C 6 alkoxy, 4-fluorophenoxyaryl 6 to 10 aryl groups, 4-fluorobenzyloxyaryl having 6 to 10 carbon atoms

4 · 4 · · 4 44 44 • 4 4 44 ·· 4444 • 444 4 · 4444

4 4 4 4 4 444 444

4 4 4 4 4

In the aryl moiety or in the alkylaryloxyaryl group having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in each of the aryl moieties; and X is indolinyl or piperidyl.

Specific compounds of formula I according to the invention include:

3 - [(Cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionic acid indan-5-yl ester;

Acetic acid 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl ester;

2-Cyclohexyl-N-hydroxy-2 - [[3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] - (4-methoxybenzenesulfonyl) amino] acetamide;

Benzoic acid 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl ester;

N-hydroxy-2 - [[3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide;

1- {3 - [(cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid;

1- {3 - [(Cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester;

2-Cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} acetamide;

• ·

3- (4-chlorophenyl) -N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} propionamide;

3-Cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} propionamide;

N-hydroxy-2 - [{3- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide;

2,2-dimethylpropionic acid 2- (4- {3 - [(1-hydroxy-carbamoyl-2-methyl-propyl) - (4-methoxy-benzenesulfonyl) -amino] -propionyl} -piperazin-1-yl) -ethyl ester and

Benzoic acid 2- (4- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperazin-1-yl) ethyl ester.

Examples of other compounds of formula (I) of the invention include

2-Cyclohexyl-N-hydroxy-2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] acetamide;

N-hydroxy-2 - [{3- [5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino 3-methylbutyramide;

2 - {(4-benzyloxybenzenesulfonyl) - [3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] amino} -N-hydroxy-3-methylbutyramide;

2-Cyclohexyl-2 - {[4- (4-fluorophenoxy) benzenesulfonyl] - [3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] amino} -N-hydroxyacetamide;

► ·· · · · · · ·

2 - {[4- (4-Butylphenoxy) benzenesulfonyl-3- [3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] amino} -N-hydroxy-3-methylbutyramide;

1 - {[4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} cyclopentanecarboxylic acid hydroxyamide;

4- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperazine-2-carboxylic acid ethyl ester;

3 - [(cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionic acid ethoxycarbonyloxymethyl ester;

3 - [(1-hydroxycarbamoylpentyl) - (4-methoxybenzenesulfonyl) amino] propionic acid ethoxycarbonyloxymethyl ester;

3 - [[4- (4-Fluorobenzyloxy) benzenesulfonyl] - (1-hydroxycarbamoyl-2-methylpropyl) amino] propionic acid ethoxycarbonyloxymethyl ester; and 3 - [[4- (4-fluorophenoxy) benzenesulfonyl] - (1-hydroxycarbamoyl-2-methylpropyl) amino] propionic acid ethoxycarbonyloxymethyl ester.

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 inhibition of tumor necrosis factor (TNF); Matrix metalloproteinases or tumor necrosis factor (TNF) production in mammals, including a human, comprising containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective for such a compound. treating or inhibiting, and a pharmaceutically acceptable carrier.

The 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 said 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 (utilizing synergy with cytotoxic anticancer agents), tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis (combination therapy with standard non-steroidal anti-inflammatory drugs) ) 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) in a mammal, including a human, comprising administering to said mammal a compound of formula I or a pharmaceutically acceptable salt thereof. 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, n, R ³ , R ⁴ , X and Ar in these reaction schemes and discussion are as previously defined.

«·

- 17 Scheme 1

III

Scheme 1 (continued)

··········

I • A A A A

AAA

AA AA A A A

AAA AA «

A <

A A A A

Scheme 2

VIII

IX

IV

Scheme 2 (continued)

IV i

··

4 444

I · · • • · · • ·

In Reaction 1 of Scheme 1, an amino acid compound of formula VII wherein R ¹⁶ is C 1 -C 6 alkyl, benzyl, allyl or tert-butyl is converted to the corresponding compound of formula VI by reacting the compound of formula VII with a reactive functional derivative of arylsulfonic acid such as arylsulfonyl chloride in the presence of a base such as triethylamine and a polar solvent such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred at room temperature for about 10 minutes to about 24 hours, preferably about 60 minutes.

In reaction 2 of Scheme 1, an arylsulfonylamino compound of formula VI wherein R ¹⁶ is C 1 -C 6 alkyl, benzyl, allyl or tert-butyl is converted to the corresponding compound of formula V wherein n is 1,

3, 4, 5 or 6 by reacting a compound of formula VI with a reactive alcohol derivative of formula ¹¹

^± R ^/? C- (CH _{2) n} -OH as chloride, bromide or iodide derivative, preferably the iodide derivative, wherein the protecting group R ¹⁷ is C 1-6 alkyl, benzyl, allyl or tert-butyl. This reaction is carried out in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, in a polar solvent such as dimethylformamide. The reaction mixture is stirred at room temperature for about 60 minutes to about 48 hours, preferably about 18 hours. The protecting group R ¹⁷ is selected such that it can be removed selectively in the presence of the protecting group R ¹⁶ without cleavage, also in the presence of the protecting group R ¹⁶ . Group R ¹⁶ . Therefore, R ¹⁷ cannot be identical to R ¹⁶ . The cleavage of the protecting group R ¹⁷ from the compound of formula V to give the corresponding carboxylic acid of formula IV in reaction 3 of Scheme 1 is carried out under conditions suitable for the particular R ¹⁷ group which will not affect the protecting group R ¹⁶ . These conditions include: (a) saponification when R ¹⁷ is C 1 -C 6 alkyl and R ¹⁶ is tert-butyl; b) hydrogenolysis where R is benzyl and R ¹⁶ is tertiary butyl or alkyl having 1 to 6 carbon atoms; (c) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, provided that R ¹⁷ is tert-butyl and R ¹⁶ is C 1 -C 6 alkyl, benzyl or allyl; or d) treatment with tributyltin hydride and acetic acid in the presence of catalytic chloride bis palladium (triphenylphosphine), when R ¹⁷ is allyl and R ⁶ is C 1 -C 6 alkyl, benzyl or tert-butyl.

In Reaction 4 of Scheme 1, the carboxylic acid of formula IV is condensed with a compound of formula HX, wherein X is as defined above, or a salt thereof, to give the corresponding amide compound of formula III. The formation of amides from primary or secondary amines or ammonia and carboxylic acid is carried out by converting the carboxylic acids into activated functional derivatives which are subsequently reacted with a primary or secondary amine or ammonia to form an amide. Activated functional derivatives may be isolated prior to reaction with the primary or secondary amine or ammonia. Alternatively, the carboxylic acid can be reacted with oxalyl chloride or thionyl chloride, without a solvent or in an inert solvent such as chloroform, at 9 9 9 ·

From about 25 ° C to about 80 ° C, preferably at about 50 ° C, to form the corresponding chloride functional acid derivative. The inert solvent and the remaining oxayl chloride or thionyl chloride are then evaporated under reduced pressure. The resulting acid chloride functional derivative is then reacted with a primary or secondary amine or ammonia in an inert solvent such as methylene chloride to form the amide. In a preferred embodiment, condensation of a carboxylic acid of formula IV with a compound of formula HX, wherein X is as defined above, to give the corresponding amide compound of formula III, is reacted with (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base such as triethylamine to form the benzotriazole-1-oxyester, which is further reacted in situ with a compound of formula HX in an inert solvent such as methylene chloride at room temperature. An amide compound of formula III is obtained.

The cleavage of the protecting group R ¹⁶ from the compound of formula III to give the corresponding carboxylic acid of formula II in reaction 5 of Scheme 1 is carried out under conditions suitable for the particular protecting group R ^{16 used} . These conditions include: a) saponification where ^R16 is lower alkyl; b) hydrogenolysis where ^R16 is benzyl; (c) treatment with a strong acid such as trifluoroacetic acid or hydrochloric acid when R ¹⁶ is tert-butyl; or d) treatment with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride catalyst when R ¹⁶ is allyl.

In reaction 6 of Scheme 1, a carboxylic acid of formula II is converted to a hydroxamic acid compound of formula I by converting it to a compound of formula

• t · · 9

About ··

II is treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent such as dimethylformamide and hydroxylamine is added after about 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-butyl, benzyl, allyl or trimethylsilyl ether in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as N-methylmorpholine. 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 can be removed by treatment with tributyltin hydride and acetic acid in the presence of bis (triphenylphosphine) palladium (II) chloride catalyst. 2-Trimethylsilyl ether can be cleaved by reaction with a strong acid such as trifluoroacetic acid or a fluoride source such as boron trifluoride etherate. 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 1 of Scheme 2, an arylsulfonylamino compound of formula VI wherein R ¹⁶ is C 1 -C 6 alkyl, benzyl or tert-butyl is converted to the corresponding compound of formula VIII by reacting the compound of formula VI with a reactive a functional derivative such as a halide, preferably an iodide derivative of 3- (tert-butyldimethylsilyloxy) -1-propanol, in the presence of a base such as sodium hydride.

4 4 4 4

444

44 ·

44

4 4 4

4 4 ·

444 444

The reaction mixture is stirred in a polar solvent such as dimethyl formamide at room temperature for about 2 to about hours, preferably about 18 hours.

In reaction 2 of Scheme 2, a compound of formula VIII is converted to an alcohol of formula IX by reacting with an excess of an acid such as acetic acid or an excess of a Lewis acid such as boron trifluoride etherate. When an acid such as acetic acid is used, water is added to the reaction mixture and a water-soluble cosolvent such as tetrahydrofuran may be used to improve solubility. The reaction mixture is stirred for about 18 to about 72 hours, preferably about 24 hours, at a temperature from about room temperature to about 60 ° C, preferably at about 50 ° C.

When using a Lewis acid such as boron trifluoride etherate, the reaction mixture is stirred in a solvent such as methylene chloride for about 10 minutes to about 6 hours, preferably about 20 minutes, at a temperature of about -20 ° C to about room temperature. preferably at about room temperature.

In reaction 3 of Scheme 2, an alcohol of formula IX is oxidized to a carboxylic acid of formula IV wherein n is 2 by reacting with an excess of sodium periodate in the presence of a catalytic amount of ruthenium chloride in a solvent mixture consisting of acetonitrile, water and carbon tetrachloride, at room temperature for about 1 hour to about 24 hours, preferably for about 4 hours.

The compound of formula IV, wherein n is 2, is further reacted to form a hydroxamic acid compound of formula I, wherein n is 2, as shown in reactions 4, 5 and 6 of Scheme 1.

»« «· ··· ···

Pharmaceutically acceptable salts of the acidic compounds of the invention are salts 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 with 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.

• · · · · ·

I · · · · · · ··· · ©

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. .

Dilute the collagenase to 400 ng / ml and add 25 μΐ of the diluted product 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 a line-

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AAA AAA of the linear part of the curve (usually about 120 minutes). 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 is 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.

If IC ₅₀ values are less than 0.03μΜ, then inhibitors are tested at concentrations of 0.3μΜ, 0.03μΜ, 0.003μΜ and 0.0003μΜ.

Gelatinase Inhibition (MMP-2)

Inhibition of gelatinase activity is performed using Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ (10μΜ) 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 concentration is given

IC ₅₀ lower than 0.03μΜ, inhibitors are 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 a 10 mg / ml trypsin stock to 26 μg of 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 assay buffer (200 mM sodium chloride, 50 mM MES and 10 mM calcium chloride, pH 6.0) in 250-well 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.

9999

9 9 9 9 9 9 9 9 9 99 999

9 • 9 «9

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.

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, 20μ chlor 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.

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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 ΙΟμΜ. 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 inhibitors shall be tested at final concentrations of 0.3μΜ, 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. Mononuclear cells are washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 / 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). Přídavkem skú32

«···· • • · ·· ·· 4 ··· • • · · • • · • ·· ··· ··· ··

The volume of each compound and LPS (final concentration 100 ng / ml) is adjusted to 200 μΐ in each well. 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 mg / kg body weight of the subject per day, with a preferred daily dose being 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. Lubricants such as magnesium stearate, sodium lauryl sulphate 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.

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 1

2-Cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3-

- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} acetamide (A) To a solution of D-cyclohexylglycine benzyl ester hydrochloride (17.0 g, 59.9 mmol) and triethylamine (17.6 mL, 126.3 mmol) in water (60 mL) and 1,4-dioxane (100 mL) were added 4-methoxybenzenesulfonyl chloride (13.0 g, 62.9 mmol). The reaction mixture was stirred at room temperature for 16 h. Most of the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed successively with dilute hydrochloric acid solution, water, saturated sodium bicarbonate solution and aqueous sodium chloride solution. The organic solution was dried (MgSO 4) and concentrated. N- (4-methoxybenzenesulfonyl) -D-cyclohexylglycine benzyl ester was obtained as a white solid (24.51 g, 99%). (B) N- (4-methoxybenzenesulfonyl) -D-cyclohexylglycine benzyl ester (12.0 g, 29.16 mmol) was added to a suspension of sodium hydride (0.78 g, 32.5 mmol) in dry N, N-dimethylformamide (100 mL). After 20 min, tert-butyl (3-iodopropoxy) dimethylsilane (9.2 g, 30.6 mmol) was added and the resulting mixture was stirred at room temperature for 16 h before quenching by addition of saturated ammonium chloride solution. The residue is taken up in diethyl ether and the solution is washed successively with dilute hydrochloric acid, water and brine, dried over magnesium sulphate, and the diethyl ether is evaporated under reduced pressure. Flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave [[3- (tert-butyldimethylsilyloxy) propyl] (4-methoxybenzenesulfonyl) amino] cyclohexylacetic acid benzyl ester as a clear oil (13.67 g, 79%). .

(C) To a solution of [[3- (tert-butyldimethylsilyloxy) propyl] (4-methoxybenzenesulfonyl) amino] cyclohexylacetic acid benzyl ester (13.67 g, 23.2 mmol) in methylene chloride (60 mL) was added fluoride etherate at room temperature. boron (21 mL, 171 mmol). After 20 minutes, the reaction was quenched by addition of saturated ammonium chloride solution, then ethyl acetate and water were added. The organic phase was separated, washed with brine, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. Cyclohexyl [(3-hydroxypropyl) (4-methoxybenzenesulfonyl) amino] acetic acid benzyl ester is isolated from the oily residue by flash chromatography on silica gel eluting with 20-40% ethyl acetate in hexane as a clear oil (11.25 g, 100%).

(D) Cyclohexyl [(3-hydroxypropyl) (4-methoxybenzenesulfonyl) amino] acetic acid benzyl ester (45.8 g, 96 mmol) and sodium periodate (92.6 g, 433 mmol) were dissolved in a mixture of acetonitrile (345 mL) , carbon tetrachloride (345 mL) and water (460 mL). To the resulting solution was added ruthenium trichloride monohydrate (4.4 g, 21 mmol) while cooling in an ice bath. The resulting mixture was mechanically stirred under cooling in an ice bath for 30 minutes. The cooling bath was removed and stirring was continued at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvents were evaporated under reduced pressure. 3 - [(Benzyloxycarbonylcyclohexylmethyl) (4-methoxybenzenesulfonyl) amino] propionic acid was isolated as a white foam from a dark oily residue by flash chromatography on silica gel using chloroform first and then 1% methanol in chloroform as eluent. , 60%).

(E) To a solution of 3 - [(benzyloxycarbonylcyclohexylmethyl) (4-methoxybenzenesulfonyl) amino] propionic acid (1.57 g, 3.21 mmol) in methylene chloride (45 mL) was gradually added triethylamine (1.12 mL, 8.04) methylpiperidin-4-ylcarbamic acid tert-butyl ester (0.89 g, 4.15 mmol) and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoroborate (1.56 g, 3.53 mmol). The resulting mixture was stirred at room temperature for 16 hours and then diluted with methylene chloride.

The solution was washed sequentially with 0.5M hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated. The oily residue was chromatographed on silica gel using 50% ethyl acetate in hexane as eluent to give [{3- [4- (tert-butoxycarbonylmethylamino) piperidin-1-yl] -3-oxopropyl} (4-methoxybenzenesulfonyl) benzyl ester amino] cyclohexylacetic acid as an oil (1.89 g, 86%).

(F) To a solution of [{3- [4- (tert-butoxycarbonylmethylamino) piperidin-1-yl] -3-oxopropyl} (4-methoxybenzenesulfonyl) amino] cyclohexylacetic acid benzyl ester (1.89 g, 2.76 mmol) in of ethanol (90 mL) was added 10% palladium on charcoal (0.32 g). The resulting mixture was shaken in a Parr apparatus at 300 psi H 2 for 2 hours. The catalyst is removed by filtration through a 0.45 μπι nylon filter and the solvent is evaporated. [{3- [4- (target-37)] is obtained. [{3- [4- (target-37)] Butoxycarbonylmethylamino) piperidin-1-yl] -3-oxopropyl} (4-methoxybenzenesulfonyl) amino] cyclohexylacetic acid as a white foam (1.65 g, 100%).

(G) To a solution of [{3- [4- (tert-butoxycarbonylmethylamino) piperidin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] cyclohexylacetic acid (1.65 g, 2.76 mmol) in O-benzylhydroxylamine hydrochloride (0.47 g, 2.94 mmol), triethylamine (1.25 mL, 9.0 mmol) and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoroborate (methylene chloride (30 mL)) were added sequentially. 1.36 g, 3.07 mmol). The resulting mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed successively with 0.5M hydrochloric acid solution, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The oily residue was chromatographed on silica gel using 40% hexane in ethyl acetate as eluent. There was obtained (1- {3 - [(benzyloxycarbamoylcyclohexylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester as a clear oil (1.86 g, 96%).

(Η) To a solution of (1- {3 - [(benzyloxycarbamoylcyclohexylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester (1.86 g, 2.65 mmol) in methanol (80 ml) was added 5% palladium on barium sulfate (0.85 g). The resulting mixture was shaken for 2.5 hours in a Parr apparatus under 300 psi of hydrogen. The catalyst is removed by filtration through a nylon filter (0.45 μη aperture size) and the solvent is evaporated from the filtrate. (1- {3 - [(Cyclohexylhydroxycarbamoylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester was obtained as a white foam (1.53 g, 95%).

• · ··

The compounds of Examples 2 to 8 were prepared in a similar manner to that described in Example 1 using the D-valine benzyl ester as the starting material in Step A and the amine in Step E.

Example 2

Acetic acid 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl ester

Coupling with piperidin-4-yl acetic acid ester. MS: 500 (M + 1).

Example 3

Butyric acid 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl ester

Coupling with piperidin-4-yl butyrate. MS: 528 (M + 1).

Example 4

Benzoic acid 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl ester

Coupling with piperidin-4-yl benzoate. MS: 562 (M + 1). Analysis for ^C 27 ^H 35 ^N 3 ° 8 ^{S, 1} ' ^75H 2 ^O: calculated:

H, 6.54; N, 7.08. Found: C, 54.52; H, 6.14; N, 7.85.

Example 5

N-Hydroxy-2 - [[3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide

- 39 Coupling with 4-hydroxypiperidine. MS: 458 (M + 1). Analysis for C ₂₀ H ₃₁ N ₇ O ₃ SH ₂ 0: Calculated: C 50.51, H 6.99, N 8.84 Found: C 50.04, H 6.84, N 9.14.

Example 6 (1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester.

Example 7

1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 513 (M + 1).

Example 8

(4- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperazin-1-yl) acetic acid ethyl ester

Coupling with piperazin-1-ylacetic acid ethyl ester. HRMS calcd for C ₂₃ H ₃₇ N ₄ O _g S (M +): Calculated: 529.2332, Found: 529.2366.

The compounds of Examples 9-10 were prepared in a similar manner to that described in Example 1 using the benzyl ester of the ester. D-leucine as the starting material in step A and said amine in step E.

Example 9 (1- {3 - [(1-Hydroxycarbamoyl-3-methylbutyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 585 (M + 1).

Example 10

1- {3 - [(1-Hydroxycarbamoyl-3-methylbutyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. Mp 78-80 ° C. MS: 528 (M + 1).

The compounds of Examples 11 to 13 were prepared in a similar manner to that described in Example 1 using the D-norleucine benzyl ester as starting material in Step A and said amine or alcohol in Step E.

Example 11 (1- {3 - [(1-Hydroxycarbamoylpentyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester.

φ φ φ φ φ φ φ φ φ φ · · · · · ·

Example 12

1- {3 - [(1-Hydroxycarbamoylpentyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 528 (M + 1).

Example 13

3 - [(1-hydroxycarbamoylpentyl) (4-methoxybenzenesulfonyl) amino] propionic acid indan-5-yl ester

Coupling with 5-indanol. MS: 505 (M + 1).

The compounds of Examples 14-15 were prepared in a similar manner to that described in Example 1 using the D-tert-butylalanine benzyl ester as the starting material in Step A and said amine in Step E.

Example 14 (1- {3 - [(1-Hydroxycarbamoyl-3,3-dimethylbutyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 599 (M + 1).

Example 15

1- {3 - [(1-Hydroxycarbamoyl-3,3-dimethylbutyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

100 ► 9 9 «

9 9

9

9 9

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 542 (M + 1).

The compounds of Examples 16-18 were prepared in a similar manner to that described in Example 1 using the D-cyclohexylglycine benzyl ester as the starting material in Step A and the amine or alcohol in Step E.

Example 16

2-Cyclohexyl-N-hydroxy-2 - [[3- (4-hydroxypiperidin-1-yl) -3-oxopropyl] - (4-methoxybenzenesulfonyl) amino] acetamide

Coupling with 4-hydroxypiperidine. MS: 498 (M + 1). Analysis C23H35N3O7S.0,5H ₂ O: Calculated: C 54.53, H 7.16, N 7.16 Found: C 54.21, H 6.98, N 8.21

Example 17

1- {3 - [(Cyclohexylhydroxycarbamoylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 554 (M + 1). Analysis for ^C 26 ^H 39 ^N 8 ^S 3 ° ⁰ * ^'5H 2 ^O: Calculated: C 55.59, H 7.16, N 7.47 Found: C 55.53, H 7.18, N 7 (57)

Example 18

3 - [(Cyclohexylhydroxycarbamoylmethyl) (4-methoxybenzenesulfonyl) amino] propionic acid indan-5-yl ester

Coupling with 5-indanol. MS: 531 (M + 1). Analysis for ^C 27 ^H 34 ^N 2 ° 7 ^{S, H} 2 ^{O: C 59} H ¹¹ / H 6/61, N 5.10, Found: C 59.40, H 6.17, N 5,06 • © · © · ♦ · · · · · · · · · · ·

The compounds of Examples 19 to 20 were prepared in a similar manner to that described in Example 1 using the D-phenylalanine benzyl ester as the starting material in Step A and the amine in Step E.

Example 19 (1- {3 - [(1-Hydroxycarbamoyl-2-phenylethyl) (4-methoxybenzenesulfonyl) amino] propionyl-piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 619 (M + 1);

Example 20

1- {3 - [(1-Hydroxycarbamoyl-2-phenylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 561 (M + 1).

The compounds of Examples 21-22 were prepared in a similar manner to that described in Example 1 using the D-4-fluorophenylalanine benzyl ester as the starting material in Step A and said amine in Step E.

Example 21 (1- (3 - [[2- (4-Fluorophenyl) -1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester.

• 999 9

99 • 9 9 · 9 9

999 999

9

99

Example 22

1- {3 - [[2- (4-Fluorophenyl) -1-hydroxycarbamoylethyl] - (4-methoxybenzenesulfonyl) amino] propionyl] piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 580 (M + 1). Analysis for ^C 27 ^H 34 ^FN 3 ° 8 ^{S Calculated:} C 55.95, H 5.91, N 7.25 Found: C 55.72, H 5.79, N 7.08

The compounds of Examples 23 to 24 were prepared in a similar manner to that described in Example 1 using D-4-homophenylalanine benzyl ester as starting material in Step A and said amine in Step E.

Example 23 (1- {3 - [(1-Hydroxycarbamoyl-3-phenylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl] piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 633 (M + 1);

Example 24

1- {3 - [(1-Hydroxycarbamoyl-3-phenylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 576 (M + 1) • φ · · · φ φ • • φ φ φ φ φ φ φ φ φ

The compounds of Examples 25 to 26 were prepared in a similar manner to that described in Example 1 using D-O-tert-butylserine benzyl ester as the starting material in Step A and the amine in Step E.

Example 25 (1- {3 - [(2-tert-Butoxy-1-hydroxycarbamoylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 615 (M + 1).

Example 26

1- {3 - [(2-tert-Butoxy-1-hydroxycarbamoylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 558 (M + 1).

The compounds of Examples 27 to 28 were prepared in a similar manner to that described in Example 1 using the D-cyclohexylalanine benzyl ester as starting material in Step A and said amine in Step E.

Example 2- (1- {3 - [(2-Cyclohexyl-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester • 0 99 9

9 9

999

9 9 9 9 9 9

99 ► 9 9 ·> t ·

999 999 *

· »99

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester. MS: 625 (M + 1);

Example 28

1- {3 - [(2-Cyclohexyl-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 568 (M + 1).

The compounds of Examples 29 to 30 were prepared in a similar manner to that described in Example 1 using the D-1-naphthylalanine benzyl ester as the starting material in Step A and the amine in Step E.

Example 29 (1- {3 - [(1-Hydroxycarbamoyl-2-naphthalen-1-yl-ethyl) (4-methoxy-benzenesulfonyl) -amino] -propionyl) -piperidin-4-yl) -methyl-carbamic acid tert-butyl ester

Coupling with methylpiperidin-4-ylcarbamic acid tert-butyl ester.

Example 30

1- {3 - [(1-Hydroxycarbamoyl-2-naphthalen-1-ylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester

Coupling with piperidine-4-carboxylic acid ethyl ester. MS: 611 (M + 1).

Example 31 · 9 • 9 9 9 9 99 99

9999

9

9,999,999

9 9

999 99 99

2-Cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylamino-piperidin-1-yl) -3-oxopropyl-amino] -acetamide

A solution of 1- {3 - [(cyclohexylhydroxycarbamoylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester (1.53 g, 2.50 mmol) in methylene chloride (70 mL) was added for 2 minutes gaseous hydrogen chloride is bubbled through. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour and the solvent was evaporated. Methanol was added twice to the residue and the methanol mixture was evaporated. There was obtained 2-cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino] acetamide dihydrochloride dihydrate as a white solid (1.22 g, 90%). MS: 511 (M + 1).

For ^C 24 ^H 39 ^C 4 ^N 4 ^O 6 ^S · ^2H 2 ^O: Calculated: C 49.43, H 7.43,

N, 9.61. Found: C, 49.86; H, 7.23; N, 9.69

The compounds of Examples 32 to 41 were prepared in a similar manner to that described in Example 33 using the starting material.

Example 32

N-hydroxy-2 - {(4-methoxybenzenesulfonyl) [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -3-methylbutyramide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester using methylpiperidin-4-ylcarbamic acid tert-butyl ester acid. MS: 471 (M + 1).

• A A • A * AAA φ A

AA AA

AA AA AAAA

A A A A A ·

AA AAA AAA

A A A A

AAA AAA AA AA

Example 33

2 - {(4-Methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -4-methylpentanoic acid hydroxyamide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-3-methylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. Melting point: 170-173 ° C. MS: 485 (M + 1).

Example 34

Hydroxyamide hydrochloride 2 - {(4-methoxybenzenesulfonyl) - [3-

- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} hexanoic acid

Starting material: (1- {3 - [(1-Hydroxycarbamoylpentyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 485 (M + 1). For ^C 21 ^H 34 ^N 4 ^O 6 ^s * ^{HCl, 4H} 2 ^O: Calculated: C 43.5,

H, 7.48; N, 9.67. Found: C, 43.65; H, 7.03; N, 9.79

Example 35

2 - {(4-Methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -4,4-dimethylpentanoic acid hydroxyamide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-3,3-dimethylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 499 (M + 1) &lt; + &gt;

000 »0» 0

000 t

Example 36

N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -3-phenylpropionamide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-2-phenylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 519 (M + 1).

Example 37

3- (4-Fluorophenyl) -N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} propionamide hydrochloride

Starting material: (1- {3 - [[2- (4-Fluorophenyl) -1-hydroxycarbamoylethyl] - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester (see Example 21). MS: 537 (M + 1). Analysis for ^C 25 ^H 33 ^FN 4 ^S ° 6 - ^HC1,2H 2 ^O: Calculated: C, 49.30, H, 6.29, N, 9.20 Found: C 49.14, H 5.82, N 9, 24.

Example 38

N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -4-phenylbutyramide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-3-phenylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 533 (M + 1). Melting point 160-170 ° C. Analysis for ^C 26 ^H 36 ^N 6 ^S 4 ° - ^{HC1,1 '5H} 2 ^O: Calculated: C 52.38, H 6.76, N 9.40 Found: C 52.25, H 6.40, N 9,00 99 9 9 9

999 999

9

99

Example 39

3-tert-Butoxy-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} propionamide hydrochloride

Starting material: (1- {3 - [(2-tert-Butoxy-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 515 (M + 1).

Example 40

3-Cyclohexyl-N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} propionamide hydrochloride

Starting material: (1- {3 - [(2-Cyclohexyl-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 525 (M + 1).

Example 41

N-hydroxy-2 - {(4-methoxybenzenesulfonyl) - [3- (4-methylaminopiperidin-1-yl) -3-oxopropyl] amino} -3-naphthalen-1-ylpropionamide hydrochloride

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-2-naphthalen-1-ylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidin-4-yl) methylcarbamic acid tert-butyl ester. MS: 569 (M + 1)

4 4

4 •

444 φ

Example 42

1- {3 - [(Cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

To a solution of 1- {3 - [(cyclohexylhydroxycarbamoylmethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester (0.62 g, 1.16 mmol) (Example 17) in ethanol (45 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.24 g, 5.72 mmol). After stirring at room temperature for 3 hours, Amberlite IR-120 cation exchange resin washed with methanol (6 g) was added to the mixture. Stirring was continued for 15 minutes and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give 1- {3 - [(cyclohexylhydroxycarbamoylmethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid monohydrate as a white solid (0.52 g, 88%) . MS: 526 (M + 1). Analysis for C 24 ^H 35 ^N 3 ° 8 ^S * ^H 2 ^O: C 53.03,

H, 6.86; N, 7.73. Found: C, 53.53; H, 7.15; N, 7.70

The compounds of Examples 43-53 were prepared in a similar manner to that described in Example 45 using the starting materials.

Example 43

1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 486 (M + 1) · · · · · · · · · · · · · · · · · · · · · · · · · · · · »·· 99

Example 44 (4- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperazin-1-yl) acetic acid

Starting material: (4- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperazin-1-yl) acetic acid ethyl ester (Example 8). MS: 500 (M + 1);

Example 45

1- {3 - [(1-Hydroxycarbamoyl-3-methylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-hydroxycarbamoyl-3-methylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. Melting point: 118-120 ° C. MS: 500 (M + 1);

Example 46

1- {3 - [(1-Hydroxycarbamoylpentyl) - (4-methoxybenzenesulfonyl) amino] propionyl) piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-hydroxycarbamoylpentyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 500 (M + 1);

Example 47

1- {3 - [(1-Hydroxycarbamoyl-3,3-dimethylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-Hydroxycarbamoyl-3,3-dimethylbutyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 514 (M + 1) · · 0 · 0 0 0 · · 0 · 0 · 0 0 0

0 · «* ·· 0 0

00

Example 48 1- {3 - [(1-Hydroxycarbamoyl-2-phenylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-hydroxycarbamoyl-2-phenylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 534 (M + 1).

Example 49

1- {3 - [[2- (4-Fluorophenyl) -1-hydroxycarbamoylethyl] - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [[2- (4-Fluorophenyl) -1-hydroxycarbamoylethyl] - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 552 (M + 1). Analysis for ^C 25 ^H 30 ^FN 3 ^S * 8 ° ^{0 '5H} 2 ^O: C 53.56, H 5.57, N 7.50 Found: C 53.53, H 5.39, N 7.28

Example 50 (1- {3 - [(1-Hydroxycarbamoyl-3-phenylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: (1- {3 - [(1-Hydroxycarbamoyl-3-phenylpropyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester, m.p. 85-92 ° C. MS: 598 ( M + l)

Example 51

1- {3 - [(2-tert-Butoxy-1-hydroxycarbamoylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid • 44 ·

44

4 44 44 444 444

4 • 4 * 4

Starting material: 1- (3 - [(2-tert-Butoxy-1-hydroxycarbamoylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester MS: 529 (M + 1)

Example 52

1- {3 - [(2-Cyclohexyl-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(2-Cyclohexyl-1-hydroxycarbamoylethyl) - (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid ethyl ester. MS: 540 (M + 1);

Example 53

1- {3 - [(1-Hydroxycarbamoyl-2-naphthalen-1-ylethyl) (4-methoxybenzenesulfonyl) amino] propionyl} piperidine-4-carboxylic acid

Starting material: 1- {3 - [(1-Hydroxycarbamoyl-2-naphthalen-1-yl-ethyl) (4-methoxy-benzenesulfonyl) -amino] -propionyl} -piperidine-4-carboxylic acid ethyl ester. MS: 584 (M + 1).

Example 54

N-Hydroxy-2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide (A) To a 2- [benzyl ester solution] (2-carboxyethyl) - (4-methoxybenzenesulfonyl) amino] -3-methylbutyric acid (prepared from D-valine benzyl ester, as described in Example 1, steps A to D) (1.35 g, 3.0 mmol) in methylene chloride (45 mL) was sequentially added triethylamine (0.92 mL, 6.9 mmol), 2-piperazin-1-ylethanol

• ···· • · • ·· ·· • 4 ·· • • · < • • 4 • · »· · «

·· <

(0.43 g, 3.3 mmol) and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoroborate (1.53 g, 3.45) mmol). The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and the resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The oily residue was chromatographed on silica gel using 5% methanol in chloroform as eluent. There was thus obtained 2 - [{3- [4- (2-hydroxyethyl) piperazine-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyric acid benzyl ester as an oil (1.40). g, 83%). The product obtained is then converted to the hydrochloride salt using anhydrous hydrogen chloride in cold (0 ° C) methylene chloride.

(Β) To the benzyl ester hydrochloride solution of 2 - [{3 -

- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyric acid (1.49 g, 2.49 mmol) in ethanol (80 mL) 10% palladium on charcoal (0.11 g) was added. The resulting mixture was shaken in a Parr apparatus at 300 psi H 2 for 16 hours. The catalyst is removed by filtration through a nylon filter (0.45 μιη aperture size) and the solvent is evaporated. There was obtained 2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyric acid hydrochloride as a white solid (1.16). g, 92%).

(C) To a solution of 2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyric acid (1.10 g, 2.17 mmol) in methylene chloride (50 mL) and N, N-dimethylformamide (0.5 mL) were added sequentially O-benzylhydroxylamine hydrochloride (0.41 g, 2.60 mmol), triethylamine (0.91 mL, 6 mL). , 5 mmol) and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoroborate (1.20 g, 2.71 mmol). The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in ethyl acetate and the solution is washed successively with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The oily residue was chromatographed on silica gel using 3% methanol in chloroform as eluent. There was thus obtained N-benzyloxy-2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide as a clear oil (0, 85 g, 68%). This product was then converted to the hydrochloride salt using anhydrous hydrogen chloride in cold (0 ° C) methylene chloride.

(D) To a solution of N-benzyloxy-2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide hydrochloride (0.39) g (0.63 mmol) in methanol (30 mL) was added 5% palladium on barium sulfate (0.19 g). The resulting mixture was shaken for 2.25 hours in a Parr apparatus under 300 psi of hydrogen. The catalyst is removed by filtration through a nylon filter (0.45 μιη aperture size) and the solvent is evaporated. The golden brown foam residue was chromatographed on silica gel using 15% methanol in chloroform containing 0.5% ammonium hydroxide as eluent. Pure fractions containing the desired product were taken up in saturated sodium bicarbonate solution. The resulting mixture was extracted several times with ethyl acetate. The combined extracts were concentrated to give N-hydroxy-2 - [{3- [4- (2-hydroxyethyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide in oil. This product was converted to the hydrochloride salt (0.20 g, 61%) using anhydrous hydrogen chloride in cold (0 ° C) methanol. MS: 487 (M + 1). Analysis for C ₂₁ H ₃₄ N ₄ O ₇ S.HCl. 0.5H ₂ O: C, 47.41; H, 6.82.

N, 10.53. Found: C, 47.41; H, 7.11; N, 9.91

• · · ·

The compounds of Examples 55-57 were prepared in a similar manner to that described in Example 58 using the amine in Step A.

Example 55

2 - [[3- (4-Dimethylaminopiperidin-1-yl) -3-oxopropyl] - (4-methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylbutyramide

Coupling with dimethylpiperidin-4-ylamine. MS: 485 (M + 1).

Example 56

N-Hydroxy-2 - [{3- [4- (3-hydroxypropyl) piperazin-1-yl] -3-oxopropyl} - (4-methoxybenzenesulfonyl) amino] -3-methylbutyramide

Coupling with 3-piperazin-1-ylpropan-1-ol. MS: 500 (M + 1).

Example 57

2 - [(3- [1,4 '] Bipiperidyl-1'-yl-3-oxopropyl) - (4-methoxybenzenesulfonyl) amino] -N-hydroxy-3-methylbutyramide

[1,4 '] - Bipiperidyl coupling. MS: 525 (M + 1). Analysis calculated for C ₂₅ H ₄ N ₄ O ₆ S.HCl.1.5H ₂ O: C, 51.05;

H, 7.54; 9.52. Found: C, 50.80; H, 7.45; N, 9.36

Example 58

1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) - (4-phenoxybenzenesulfonyl) amino] propionyl] piperidine-4-carboxylic acid ethyl ester

The title compound was prepared in a manner analogous to EXAMPLE 1 using D-valine benzyl ester and 4-phenoxybenzenesulfonyl chloride as starting material in Step A and piperidine-4-carboxylic acid ethyl ester in Step E. Analysis for ^C 28 ^H 37 ^N ° 3 8 ^{S 0,1CH} 2 ^Cl 2 ^calculated: C 57.78, H 6.42, N 7.19 found: C 57.46, H 6.41, N 7.11

Example 59

1- {3 - [(1-Hydroxycarbamoyl-2-methylpropyl) - (4-phenoxybenzenesulfonyl) amino] propionyl] piperidine-4-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 42 using 1- {3 - [(1-hydroxycarbamoyl-2-methylpropyl) - (4-phenoxybenzenesulfonyl) amino] propionyl] piperidine-4-carboxylic acid ethyl ester (from Example 58) as starting material.

MS: 548 (M + 1). Analysis for ^C 26 ^H 33 ^N 3 ^S · 8 ° θ ^'5H 2 ^O: Calculated: C 56.10, H 6.16, N 7.75 Found: C 55.99, H 6.06, N 7 43

Claims (7)

PATENT CLAIMS general Arylsulfonylaminohydroxamic acid derivatives of the formula I HO-N0 II -Cp3 <W « Ϊ “ ^{Νχ /} / ^θ R ⁴ S _K // in Q (i) where n X is 1 to 6; represents a group of formula OR ¹ wherein R ¹ is as defined below; azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, piperazinyl or bridged diazabicycloalkyl ring selected from the group consisting of moieties of formula a, b, c, da · Where it represents 1, 2 or 3; represents the number 1 or 2; a is 0 or 1; each of the heterocyclic groups being optionally substituted with one or two substituents 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 5 -C 9) heteroaryl, (C 6 -C 10) arylalkyl (C 1 -C 6) alkyl, (C 5 -C 9) heteroaryl (C 1 -C 6) heteroarylalkyl carbon 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 to 6 carbon atoms in the acyl and 1 to 6 carbon atoms in the alkyl moiety , (C 1 -C 6) alkylthio, (C 1 -C 6) alkylthioalkyl in each of the alkyl moieties, 99 99 »9 9 999 999 9 9 9 to 9 aryl arylthio groups having 6 to 10 carbon atoms, arylthioalkyl groups having 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl moiety, groups of the formula R ⁹ R ¹⁰ N, R ⁹ R ¹⁰ NSO 2, R ⁹ R ¹⁰ NCO , R ⁹ R ^{10 is} NCO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, wherein R ⁹ and R ¹⁰ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl portion or heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl portion, or R ⁹ and R ¹⁰ taken together together with the nitrogen atom to which they are attached may form an azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ring; groups of formula R ¹² SO 2 or R ¹² SO ₂ NH, wherein R ¹² 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 and 1 to 6 carbon atoms in the alkyl moiety; R &lt; ¹³ &gt; CONR &lt; ^{9 &gt}; wherein R &lt; ⁹ &gt; is as defined above and R &lt; ¹³ &gt; is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C6-C10) aryl, (C6-C9) heteroaryl carbon, arylalkylarylalkoxy having 6 to 10 carbon atoms in each of the aryl moieties having from 1 to 6 carbon atoms in the alkyl and alkoxy moieties, or heteroarylalkyl having 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; R ( ¹⁴⁾ OOC, R ( ¹⁴⁾ OOC alkyl of 1 to 6 carbon atoms in the alkyl moiety, wherein R ( ¹⁴⁾ is alkyl of 1 to 6 carbon atoms, aryl (6 to 10 carbon atoms), heteroaryl (5 to 9 carbon atoms), arylalkyl (C 6 -C 10) aryl group and (C 1 -C 6) alkyl group, 5-indanyl, CHR ⁵ OCOR ⁶ , wherein R ⁵ is hydrogen or 9 9 9 9 9 9 ·· ·· 9 «9 99 9999 99 »9 9 9999 99 9 9 9 999 999 C 1 -C 6 alkyl and R ⁶ is C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 10 aryl; CH ² CONR ⁷ R ⁸ wherein R ⁷ and R ⁸ 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 ¹⁵ O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, wherein R ¹⁵ represents a group of the formula H 2 N (CHR ¹⁶ ) CO, wherein R ¹⁶ represents a side chain derived from a natural D- or L-amino acid; R ¹ is aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl moiety, 5-indanyl or CHR ⁵ OCOR ⁶ or CH ₂ CONR ⁷ R ⁸ wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above; R ³ and R ⁴ are each independently hydrogen, (C 1 -C 6) alkyl, trifluoromethyl, (C 1 -C 6) trifluoromethyl alkyl, (C 1 -C 6) alkyl (difluoromethylene) or alkyl (difluoromethylene) alkyl of 1 to 3 carbon atoms in each of the alkyl moieties, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl portion, heteroarylalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, arylarylalkyl of 6 to 10 carbon atoms in each of the aryl moieties, arylarylalkyl of 6 to 10 carbon atoms φφφ φφφ in each of the aryl moieties and 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 10 acyloxyalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl and C 1 -C 6 alkoxyalkyl; 6 carbon atoms in the alkyl moiety, acylaminoalkyl of 1 to 10 carbon atoms in the acyl and 1 to 6 carbon atoms in the alkyl moiety, piperidyl, alkylpiperidyl of 1 to 6 carbon atoms in the alkyl moiety, arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl moiety, 1 up to 6 carbon atoms in alkoxy and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkoxyalkyl of 5 to 9 carbon atoms in the heteroaryl, 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl moiety, alkylthioalkyl of 1 to 6 carbon atoms in each of the alkyl moieties, arylthioalkyl of 6 to 10 carbon atoms in the aryl and 1 to 6 carbon atoms in the alkyl portion, alkylsulfinylalkyl of 1 to 6 atoms C 6 -C 10 arylsulfinylalkyl; C 1 -C 6 arylsulfonylalkyl; and C 1 -C 6 alkyls; C 1 -C 6 alkylsulfonylalkyl; C 6 -C 10 arylsulfonylalkyl; (C 1 -C 6) alkyl, (C 1 -C 6) aminoalkyl, (C 1 -C 6) alkylaminoalkyl, (C 1 -C 6) alkyl (C 1 -C 6) alkyl, R CO-alkyl of 1 to 6 carbon atoms in the alkyl moiety wherein R ¹⁷ is R ¹⁴ O or R ⁷ R ⁸ N, wherein R ⁷ , R ⁸ and R ¹⁴ are as defined above; or a group of formula R-alkyl of 1 to 6 carbon atoms in the alkyl moiety, wherein R is piperazinyl, acylpiperazinyl of 1 to 10 carbon atoms in the acyl moiety, arylpiperazinyl of 6 to 10 carbon atoms in the aryl moiety, heteroarylpiperazinyl of 5 to 9 carbon atoms in the heteroaryl moiety, alkylpiperazinyl of 1 to 6 carbon atoms in the alkyl moiety, arylalkylpiperazinyl of 6 to 10 carbon atoms in the aryl moiety and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkylpiperazinyl of 5 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms alkyl, morpholinyl, thiomorpholinyl, piperidyl, pyrrolidinyl, C 1 -C 6 alkylpiperidyl, C 6 -C 10 arylpiperidyl, aryl C 5 -C 9 heteroarylpiperidyl, C 5 -C 9 heteroarylpiperidyl aryl and 1 to 6 carbon atoms; C 1 -C 6 heteroarylalkylpiperidyl having 1 to 6 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety or acylpiperidyl having 1 to 10 carbon atoms in the acyl moiety; or R ³ and R ⁴ taken together may form a cycloalkyl ring of 3 to 6 carbon atoms, an oxacyclohexyl thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula 9 • • 9 99,999 Wherein R ²¹ is hydrogen, C 1 -C 10 acyl, C 1 -C 6 alkyl, C 6 -C 10 arylalkyl and C 1 -C 6 arylalkyl, C 5 -C 9 heteroarylalkyl heteroaryl and 1 to 6 carbon atoms in the alkyl moiety or alkylsulfonyl of 1 to 6 carbon atoms; and Q is C 1 -C 6 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, aryloxyheteroaryl of 6 to 10 carbon atoms in the aryl moiety and 5 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of the 5 to 9 carbon atoms, alkyl and 6 to 10 carbon atoms in the aryl moiety, 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 the aryl moieties and 1 to 6 carbon atoms in the aryl moiety alkoxy moieties, 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, heteroaryl (C 5 -C 9) heteroaryl and C 6 -C 10 aryl group, (C 1 -C 6) alkylheteroaryl and C 5 -C 9 heteroaryl, (C 1 -C 6) alkoxyheteroaryl (C 5 -C 9) alkoxyheteroaryl 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 5 to 5 carbon atoms in the heteroaryl moiety; 9 carbon atoms in the heteroaryl moiety, heteroaryloxyheteroaryl of 5 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 moiety, heteroaryloxyalkyl of 5 to 9 carbon atoms in the heteroaryl and 1 up to 6 carbon atoms in the alkyl moiety, alkylaryloxyaryl having 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in each of the aryl moieties, alkylheteroaryloxyaryl having 1 to 6 in the alkyl, 5 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety, C 1 -C 6 alkylaryloxyheteroaryl, C 6 -C 10 aryl and C 5 -C 9 heteroaryl, C 1 -C 6 alkoxyaryloxyaryl and C 6 -C 10 in each aryl alkoxyheteroaryloxyaryl having 1 to 6 carbon atoms in alkoxy, 5 to 9 carbon atoms in heteroaryl and 6 to 10 carbon atoms; aryl or C 1 -C 6 alkoxyaryloxyheteroaryl, C 6 -C 10 aryl and C 5 -C 9 heteroaryl, each aryl being optionally substituted with fluoro, chloro, bromo, C 1 -C 6 alkyl C 6 -C 6 alkoxy, C 1 -C 6 alkoxy or C 1 -C 3 perfluoroalkyl; wherein X must be substituted when it represents an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or piperazinyl ring, an acylpiperazinyl ring of 1 to 10 carbon atoms in the acyl ring, an alkylpiperazinyl ring of the alkylpiperazinyl ring parts, arylpiperazinyl ring with 6 to 10 atoms · »φ φ · uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku uhlíku in the aryl moiety, a heteroarylpiperazinyl ring of 5 to 5 carbon atoms; 9 carbon atoms in the heteroaryl moiety or a bridged diazabicycloalkyl ring; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives according to claim 1, wherein n is 2; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives according to claim 1, wherein R ³ or R ^{4 is} not hydrogen; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives according to claim 1, in which Q represents alkoxyaryl having 1 to 6 carbon atoms in the alkoxy moiety and 6 to 6 carbon atoms. (C uhlíku-C) aryl group, (C až-C 10 a) arylalkoxyaryl, (C každé-C až a) aryl, (C až-C f f) phenoxyaryl, (C--C 10 10) 4-fluorophenoxyaryl aryl moieties, 4-fluorobenzyloxyaryl having 6 to 10 carbon atoms in the aryl moiety, or alkylaryloxyaryl having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in each of the aryl moieties; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives according to claim 1, in which X is indolinyl or piperidyl. Arylsulfonylaminohydroxamic acid derivatives according to claim 1, wherein n is 2, R ³ or R ^{4 is} not hydrogen; Q is C 1 -C 6 alkoxyaryl and C 6 -C 6 alkoxyaryl; • • 44 4 · 4 44 4 4 • 4 4 4 4 4 4 4 4 4 4 4 44 4 4 4 4 4 4 • 4 4 4 4 4 44 4 4 4 4 • 4 4 • 4 4 444 4 4 4 44 4 4 (C uhlíku-C) aryl group, (C až-C 10 a) arylalkoxyaryl, (C každé-C až a) aryl, (C až-C f f) phenoxyaryl, (C až-C 10 10) 4-fluorophenoxyaryl (C,-C 10) aryl moieties, 4-fluorobenzyloxyaryl having 6 to 10 carbon atoms in the aryl moiety, or alkylaryloxyaryl having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in each of the aryl moieties; and pharmaceutically acceptable salts thereof; and X is indolinyl or piperidyl; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives according to claim 1 which are