CZ267699A3 - Derivatives of arylsulfonylaminohydroxamic acid, pharmaceutical preparation, inhibition method of matrix metalloproteinases or production of tumor necrosis factor and treatment method - Google Patents

Abstract

Derivatives of arylsulfonylaminohydroxamic acid of Formula I are inhibitors of matrix metalloprotein or tumor necrosis factor production and are useful in treatment conditions selected from arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by the activity of matrix metalloproteinase as well as AIDS, sepsis, septic shock and other diseases involving production TNF. In addition, these compounds can be used in the following combination therapy with standard non-steroidal therapies anti-inflammatory drugs (NSAIDs) and analgesics for treatment arthritis and further in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids such as vincristine in the treatment of cancer.

Description

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

Technical field

The invention relates to arylsulfonylaminohydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a condition 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 base membrane matrices such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulcerations (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)

HUNT

R ¹

II

(AND)

where

R ¹ and R ² are each independently C 1 -C 6 alkyl, trifluoromethyl, C 1 -C 6 trifluoromethyl alkyl, C 1 -C 6 alkyl (difluoromethylene), alkyl (difluoro) Methylenealkyl of 1 to 3 carbon atoms in each of the alkyl moieties, aryl of 6 to 10 carbon atoms, heteroaryl of 2 to 9 carbon atoms, arylalkyl of 6 to 10 carbon atoms in aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, or

R ¹ and R ² taken together may form a C 3 -C 6 cycloalkyl ring, a C 3 -C 6 cycloalkyl ring fused to a benzo group or a group of the formula

wherein n and m are each independently 1 or 2; and

X is CF ₂ , sulfur, oxygen or a group

NR ³ , wherein R ³ is 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 parts, heteroarylalkyl of 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl portion, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 10 carbon atoms or acyl; and

Q is (C 1 -C 6) alkyl, (C 6 -C 10) aryl, aryloxy

9 9 9

(C 6 -C 10) aryl group in each of the aryl moieties, (C 6 -C 10) aryl aryl group in each of the aryl moieties, (C 6 -C 10) aryl aryl alkyl in each of the aryl moieties, and (C 1 -C 6) alkyl moieties , (C 6 -C 10) arylheteroaryl and (C 2 -C 9) heteroaryl heteroaryl, (C 6 -C 10) aryl-heteroaryl (C 2 -C 9) heteroaryl, (C 2 -C 9) heteroaryl, (C 2 -C 9) heteroarylheteroaryl up to 9 carbon atoms in each of the heteroaryl moieties, heteroarylaryl having 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety, alkylaryl having 1 to 6 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl moiety, alkoxyaryl 1 to 6 carbon atoms in the alkoxy and 6 to 10 carbon atoms in the aryl moiety, arylalkoxyaryl having 6 to 10 carbon atoms in each of (C až-Cry) aryl, C až-Cryry (C,-Cry až) aryl, (C a-Cry a) arylalkoxyalkyl, (C až-C až až) C až-Cx hetero (C,-C 6 6) heteroaryloxyaryl (C hetero-C hetero hetero) heteroaryloxyaryl (C uhlíku-C a alkyl) alkyl, (C až-C alkylh) alkylheteroaryl, (C až-C až alkyl) heteroaryl, (C až-C alko alko) alkoxyheteroaryl (C až-C až až) heteroaryl, (C až-Cry) aryl-alkoxyheteroaryl (C až-C 10) aryl atoms, 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 moiety, heteroaryloxyalkyl of 2 to carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylarylo (C 1 -C 6) -aryl and (C 6 -C 10) -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 each aryl is optionally substituted by fluorine, chlorine, bromine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 perfluoroalkyl;

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.

9

9 10 «• * ··

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 are phenyl or naphthyl, optionally substituted with one to three substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, trifluoromethoxy, difluoromethoxy and 1-alkyl. up to 6 carbon atoms.

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.

44

4 4 4

4 4 4 4

44

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 R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring, a C 3 -C 6 cycloalkyl ring fused to a benzo group, or a group of the formula

wherein m and n are each independently 1 or 2; X is CF ₂ , sulfur, oxygen or NR ³ , wherein R ³ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of the 6 to 10 carbon atoms, or acyl .

Other preferred compounds are those compounds of formula I wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring or a C 3 -C 6 cycloalkyl ring fused to a benzo group.

Other preferred compounds are those compounds of formula (I) wherein Q is (C 6 -C 10) aryl, (C 6 -C 10) aryl aryl (C 1 -C 10) lary ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ

An aryl moiety, aryloxyaryl of 6 to 10 carbon atoms in each of the aryl moieties, aryloxyheteroaryl of 6 to 10 carbon atoms in the aryl and 2 to 9 carbon atoms in the heteroaryl moiety, heteroaryl of 2 to 9 carbon atoms, heteroarylheteroaryl of 2 up to 9 carbon atoms in each of the heteroaryl moieties, arylheteroaryl of 6 to 10 carbon atoms in the aryl moiety and 2 to 9 carbon atoms in the heteroaryl moiety, heteroarylaryl of 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety, or heteroaryloxyaryl moieties. 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety.

Other preferred compounds are those compounds of formula (I) wherein Q is C 6 -C 10 aryloxyaryl in each of the aryl moieties.

Further preferred are compounds of formula I wherein R ¹ and R ² are each independently C 1 -C 6 alkyl.

More preferred are compounds of formula I wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring, a C 3 -C 6 cycloalkyl ring fused to a benzo group, or a group of the formula

wherein m and n are each independently 1 or 2; X

O is CF ₂ , sulfur, oxygen or NR, wherein R ³ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl 999 99 99 99 99

9 9 9 9 9

9 9 9 * 44 * 9 9 9 4 944 4444 4444

444 44 44 44 44 44 aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroaryl alkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl with 6 up to 10 carbon atoms or acyl; and Q is (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryloxyaryl, (C6 -C10) aryloxyheteroaryl, and (2-9) heteroaryl, C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl, C 2 -C 9 heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety.

More preferred are compounds of formula I wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring or a C 3 -C 6 cycloalkyl ring fused to a benzo group; and Q is (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryloxyaryl, (C6 -C10) aryloxyheteroaryl, and (2-9) heteroaryl C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl, C 2 -C 9 heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety.

«444 44 44 ♦ 4 444

4 4444

444 44 44 44

More preferred are compounds of formula I wherein R ¹ and R 2 are each independently C 1 -C 6 alkyl; and Q is (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryloxyaryl, (C6 -C10) aryloxyheteroaryl, and (2-9) heteroaryl C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl, C 2 -C 9 heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety.

More preferred are compounds of formula I wherein R ¹ and R ² are each independently C 1 -C 6 alkyl; and Q is (C6 -C10) aryloxyaryl in each of the aryl moieties.

Specific preferred compounds of formula I include:

3- [4- (4-Fluorophenoxy) benzenesulfonylamino] azetidine-3-carboxylic acid hydroxyamide;

4- [4- (4-Fluorophenoxy) benzenesulfonylamino] piperidine-4-carboxylic acid hydroxyamide;

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide;

1- [4- (4-chlorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide;

• 9 99 9 99 99 99 99 «· 9 · 9 9 9999 * 9 99999 9999:. ϊ ·: ϊ::

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclobutane-1-carboxylic acid hydroxyamide;

1- [4- (4-chlorophenoxy) benzenesulfonylamino] cyclobutane-1-carboxylic acid hydroxyamide;

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopentane-1-carboxylic acid hydroxyamide;

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide;

2- (4- (4-fluorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide;

2- [4- (4-chlorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide;

N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide;

1- (5-Pyridin-2-ylthiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;

1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclopropane-1-carboxylic acid hydroxyamide;

1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclobutane-1-carboxylic acid hydroxyamide;

1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;

2- (4-methoxybenzenesulfonylamino) indane-2-carboxylic acid hydroxyamide; and • 4 4

4,444 · ♦ ·· · * · · · · <h ··· ··

9 9 4

94 2- [4- (4-Fluorophenoxy) benzenesulfonylamino] indane-2-carboxylic acid hydroxyamide.

The present invention also provides a pharmaceutical composition a) for treating 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 in combination with standard 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 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, tissue ulceration, macular degeneration, restenosis, periodonal disease, epidermolysis bullosa, scleritis, wherein the compound of formula I can be used in combination with standard nonsteroidal anti-inflammatory drugs and analgesics; in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity as well as AIDS, sepsis, septic

ΦΦΦ φφφφ

ΦΦ

ΦΦ

ΦΦ φ

φφφ φ φ φ φ φ

ΦΦ φ φ φ • * φ φ φ φ φ φ φ

ΦΦ

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 preparation of the compounds of the invention is illustrated in the following reaction schemes. Unless otherwise indicated, R ¹ , R ² and Q in these reaction schemes and discussion are as previously defined.

II

VI

• 999 9 9 99 99 9 9 9 9 9 • 9 9 • ♦ 9 9 • 9 « 999 99 99 99 • * ··

Scheme 1

111 -. 11

In Reaction 1 of Preparative Scheme A, an amino acid of formula III is reacted with benzyl alcohol and an acid of formula HX, wherein X is preferably a 4-toluenesulfonate group, in an inert solvent such as benzene or toluene (toluene preferably) to form the corresponding benzyl ester salt. acid. The ester salt corresponds to the general formula V. The reaction is usually carried out for about 1 hour to about 24 hours at the boiling point of the solvent used. The water produced during the reaction is usually collected in a Dean-Stark trap.

In reaction 2 of Preparative Scheme A, a compound of formula V is converted to the corresponding compound of formula VI by reacting a compound of formula V with a reactive functional derivative of a sulfonic acid (QSO ₂ OH), such as a sulfonyl chloride (QSO ₂ C1), presence of a base such as sodium hydroxide or triethyl15

• · »·· ·· · » ·· ♦ ♦ · ♦ « • • · «· • * • · · ♦ · • · • · • ·· · «

amine, in a solvent such as methylene chloride, tetrahydrofuran, dioxane, water or acetonitrile, preferably in a mixture of dioxane and water. The reaction mixture is stirred at a temperature of about 0 to about 50 ° C, preferably at room temperature, for about 10 minutes to about 2 days, preferably for about 60 minutes.

In reaction 3 of Preparative Scheme A, intermediate of formula (VI) is hydrogenolyzed to give intermediate of formula (II). This reaction is carried out in a solvent such as ethanol under a hydrogen atmosphere (preferably at 50 psi) in the presence of a catalyst such as 10% palladium on charcoal. The reaction mixture is usually stirred at room temperature for about 30 minutes to about 24 hours, preferably for about 1.5 hours.

In Reaction 1 of Scheme 1, the amino acid compound of formula III is converted to the corresponding compound of formula II by reacting the compound of formula III with a reactive functional sulfonic acid derivative of formula QSO ₂ OH, wherein Q is as defined above, such as sulfonyl chloride. (QSO ₂ Cl), in the presence of a base such as sodium hydroxide or triethylamine, in a polar solvent such as tetrahydrofuran, dioxane, water or acetonitrile, preferably in a mixture of dioxane and water. The reaction mixture is stirred at a temperature of about 0 to about 50 ° C, preferably at room temperature, for about 10 minutes to about 2 days, preferably for about 60 minutes.

In reaction 2 of Scheme 1, the carboxylic acid of formula II is converted to the hydroxamic acid compound of formula I by reacting the compound of formula II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as Ν, Ν-dimethylformamide and after about 15 minutes to about 1 hour, preferably after about 30 minutes

99 * 9 9 9 9 9 9 99 99 9 9 9 9 9 9 9

9 999 * 9 9 9 * · 99 999 99 9 ♦ 9 9 · 9 99 9 · * ·· 99 99 add hydroxylamine. Preferably, the hydroxylamine is generated in situ from its salt form, such as hydroxylamine hydrochloride, in the presence of a base such as triethylamine. 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 2-trimethylsilylethyl ether may be used in place of hydroxylamine or hydroxylamine salt. The cleavage of the hydroxy protecting group is carried out by hydrogenolysis in the case of a benzyl protecting group in which 5% palladium on barium sulfate is the preferred catalyst 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. The reaction of a compound of formula II with hydroxylamine or hydroxylamine salt or protected hydroxylamine derivative or protected hydroxylamine derivative salt can also be carried out in the presence of (benztriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent such as methylene chloride. The reaction mixture is stirred at a temperature from about 0 to about 50 ° C, preferably at room temperature, for about 1 hour to about 3 days, preferably for about 1 day. The compound of formula II is preferably converted to the compound of formula I by reacting the compound of formula II with O-benzylhydroxylamine hydrochloride in the presence of (benztriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and triethylamine using methylene chloride as solvent. Subsequent deprotection of the O-benzyl group to give a compound of formula I is accomplished by hydrogenolysis at 50 psi hydrogen at room temperature at room temperature.

• «** · • 9 • 9 99 99 9 · · 9 9 9 9 9 • 999 • · · 9 9 9 94 • 9 99 99

using 5% palladium on barium sulfate as a catalyst. The preferred solvent is methanol. The reaction time may range from about 1 hour to about 5 hours and preferably is

3.5 hours.

In certain instances, it is preferred to prepare a compound of formula I by reacting hydroxylamine or a salt thereof or a protected hydroxylamine derivative or salt thereof with an activated ester of formula IV as shown in reaction 3 of Scheme 1. This reaction is carried out in an inert solvent, as N, N-dimethylformamide, at a temperature ranging from about room temperature to about 80 ° C, preferably at about 50 ° C, for about 1 hour to about 2 days. When a protected hydroxylamine derivative or a protected hydroxylamine derivative salt is used, the protecting group is removed as described above. The activated ester of formula (IV) is obtained by reacting the compound of formula (II) with (benztriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent such as methylene chloride (reaction 4 of Scheme 1). The reaction mixture is stirred at a temperature from about 0 to about 50 ° C, preferably at room temperature, for about 1 hour to about 3 days, preferably for 1 day.

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

4 4 ··· 45 * ·

4 4 • · ···

4 4 4

44 «4 4

4 4 4

4 4 4

4 4 4

44 sulfonic acids such as hydrochloric, methanesulfonic and maleic acids.

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 gg trypsin per 100 gg collagenase.

Trypsin and collagenase are incubated at room temperature for 10 minutes and then a 5-fold excess (50 gg / 10 gg trypsin) of 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. The final inhibitor concentration after addition of enzyme and substrate is reduced by 1: 4. In wells D1 to D6 «···«

· Ale «ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale ale no better control positive controls (enzyme, inhibitor) are placed and are placed in wells D7 to D12 with sy (no enzyme, no inhibitor).

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 stock solution in dimethylsulfoxide and then diluted to 20μΜ in 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. 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 (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 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. 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, 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 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. 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 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. 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 ftft. ftft ftft ftft ft ftft 9 ftft ftft 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. In this connection, solutions of the therapeutically active compound according to the invention can be used either in sesame or peanut oil or in aqueous propylene glycol. 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

Preparative procedure

4- (4-Fluorophenoxy) benzenesulfonyl chloride • 44 44 44 44

4,444,444 ·

4, 44, 444, 4444

44

Chlorosulfonic acid (26 mL, 0.392 mol) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 g, 0.196 mmol) with mechanical stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours and then poured into ice water. The product, 4- (4-fluorophenoxy) benzenesulfonyl chloride (18.6 g, 33%) was collected by filtration and air dried.

Preparative procedure B

Sodium 4- (3-methylbutoxy) benzenesulfonate

A solution of 4-hydroxybenzenesulfonic acid (10.0 g, 43.1 mmol) and sodium hydroxide (3.3 g, 83 mmol) in water (40 mL) was treated with a solution of 1-iodo-3-methylbutane (11.3 mL). (86.4 mmol) in isopropyl alcohol (60 mL). The resulting mixture was heated to reflux for 2 days, then isopropyl alcohol was evaporated under reduced pressure. The title compound (10.0 g, 87%) was collected by filtration while washing with isopropyl alcohol.

Preparative Procedure C

4- (3-Methylbutoxy) benzenesulfonyl chloride

A mixture of 4- (3-methylbutoxy) benzenesulfonate (2.5 g, 9.4 mmol), thionyl chloride (10 mL) and 5 drops of N, N-dimethylformamide was refluxed for 5 hours, cooled and excess thionyl chloride evaporated. . The residue was taken up in ethyl acetate. The ethyl acetate solution was cooled in an ice bath and water was added. The organic phase was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated. Obtained as the title compound as an oil (2.34 g, 95%).

• 9 9 9 9 9 9 9 9 9 99

9 9 9 9 9 9999

9 9 9 999 9

999 99 999 99

999 9999

999 99 99 99 99 99

Preparative procedure

Sodium 4- (2-cyclopentylethoxy) benzenesulfonate

A solution of 4-hydroxybenzenesulfonic acid (6.5 g, 28.2 mmol) and sodium hydroxide (2.2 g, 55 mmol) in water (15 mL) was treated with a solution of 2- (bromoethyl) cyclopentane (15.0 g, 8 [mu], 7 mmol) in isopropyl alcohol (40 mL). The resulting mixture was heated to reflux for 2 days, then isopropyl alcohol was evaporated under reduced pressure. The title compound (4.7 g, 57%) was collected by filtration while washing with isopropyl alcohol.

Preparative procedure

4- (3-Methylbutoxy) benzenesulfonyl chloride

A mixture of sodium 4- (2-cyclopentylethoxy) benzenesulfonate (2.5 g, 8.6 mmol), thionyl chloride (15 mL) and a few drops of N, N-dimethylformamide was refluxed for 5 hours, cooled and the excess evaporated. thionyl chloride. The residue was taken up in ethyl acetate. The ethyl acetate solution was cooled in an ice bath and water was added. The organic phase was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated. Obtained as the title compound as an oil (2.24 g, 90%).

Preparative procedure F

4'-Fluorobiphenylsulfonyl chloride

Chlorosulfonic acid (8.7 mL, 0.13 mmol) was added dropwise to 4-fluorobiphenyl (10.2 g, 59 mmol) with stirring in an ice bath. Stirring with ice cooling is continued after • 9999 99 99 · 9 9 9 9 • 9 99 ···

99

999 99 99 99 for 0.5 hour, then pour the reaction mixture on ice. The resulting 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 product, 4'-fluorobiphenylsulfonyl chloride (4.3 g, 27%) is separated from the undesired by-product, 4'-fluorobiphenylsulfonic acid by crystallizing 4'-fluorobiphenylsulfonic acid from ethyl acetate and 4'-fluorobiphenylsulfonyl chloride crystallizing from hexane.

Preparative procedure

4- (4-Fluorobenzyloxy) benzenesulfonate

To a solution of 4-hydroxybenzenesulfonic acid (5.13 g, 22.1 mmol) in 1M aqueous sodium hydroxide solution (23 mL) was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in ethanol (20 mL). . The resulting mixture was refluxed for 2 days, cooled and allowed to stand, giving a white solid. The precipitated product, 4- (4-fluorobenzyloxy) benzenesulfonate (4.95 g, 74%) was collected by filtration, washing with ethyl acetate and diethyl ether.

Preparative procedure H

4- (4-Fluorobenzyloxy) benzenesulfonyl chloride

To a suspension of 4- (4-fluorobenzyloxy) benzenesulfonate (0.5 g, 1.64 mmol) in methylene chloride (5 mL) was added phosphorus pentachloride (275 mg, 1.31 mmol). The resulting mixture was refluxed for 7 h, cooled in an ice bath, and quenched with water (15 mL). The aqueous mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. 4- (4-fluoro29) 0009 »9 9«

0 099

0 99999

9 0 0 0 0

9 0 9 9 8

99990 09 90

09 /

9 9 9 • · · ·

9 0 9

9 0 0

9 (00 benzyloxy) benzenesulfonyl chloride as a white solid (130 mg, 26%)

Preparative procedure

4- (4-Chlorophenoxy) benzenesulfonyl chloride

Chlorosulfonic acid (9.7 mL, 0.147 mmol) was added dropwise to 4-chlorophenoxybenzene (12.6 mL, 73.4 mmol) at room temperature with stirring. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, air dried and recrystallized from petroleum ether and ethyl acetate. Obtained 4- (4-chlorophenoxy) benzenesulfonyl chloride (7.43 g, 33%).

Example 1

1- (4-Methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide (A) To a solution of 1-aminocyclopentane-1-carboxylic acid (6.0 g, 46.5 mmol) and triethylamine (14 mL, 100 mmol) in dioxane ( 90 mL) and water (90 mL) was added 4-methoxybenzenesulfonyl chloride (10.6 g, 51.3 mmol). The resulting mixture was stirred at room temperature for 4 hours, acidified with aqueous 1M hydrochloric acid solution and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried (MgSO 4) and concentrated. The tan solid was triturated with chloroform to give 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid as a white solid (5.42 g, 39%).

• • 44

44 44 44

444 4444 • 44444 4444

443 44 443 44 4

444 4 4444

(44) 44 (44) (Β) Κ of a solution of 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid (4.65 g, 15.2 mmol) and triethylamine (2.5 mL, 17.9 mmol) in methylene chloride ( 120 mL) was added (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (7.4 g, 16.3 mmol). The mixture was stirred at room temperature for 2.5 days and the solvent was evaporated. The residue was taken up in ethyl acetate. The ethyl acetate solution was washed sequentially with 0.5 M aqueous hydrochloric acid, water and brine, dried over magnesium sulfate, and the solvent was evaporated. 1- (4-Methoxybenzenesulfonylamino) cyclopentanecarboxylic acid benzotriazol-1-yl ester was obtained as a yellow solid. This material was dissolved in N, N-dimethylformamide (120 mL). To this was added diisopropylethylamine (5.3 mL, 30 mmol) and O-benzylhydroxylamine hydrochloride (3.2 g, 20 mmol). The mixture was heated in an oil bath for 20 hours and the solvent was evaporated. Ethyl acetate was added to the residue, and the resulting mixture was filtered to collect a white solid. The filtrate was washed sequentially with a 0.5 M aqueous hydrochloric acid solution, an aqueous saturated sodium bicarbonate solution and an aqueous sodium chloride solution, and the solvent was evaporated therefrom. The solid residue was combined with a white solid isolated by filtration and triturated with ethyl acetate. 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzyloxyamide was obtained as a white solid (2.92 g,

%).

(C) A solution of 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzyloxyamide (1.50 g, 3.71 mmol) in methanol (200 mL) was treated with 5% palladium on barium sulfate (0.75 g) . The mixture was hydrogenated in a Parr apparatus at 50 psi for 3.5 hours and then the catalyst was removed by filtration through a 0.45 µm nylon mesh filter. The filtrate was concentrated to give the hydroxyamide.

44 44 44 444 4444

44,444 4,444 4 · 44 444,444 4

4444 444 «

44

1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid as a white solid (1.13 g, 97%). MS: 313 (M-1).

The compounds of Examples 2 to 8 were prepared in a similar manner to that described in Example 1 using the reagents mentioned.

Example 2

1- (4-Methoxybenzenesulfonylamino) cyclohexane-1-carboxylic acid hydroxyamide

1-Aminocyclohexane-1-carboxylic acid; 4-methoxybenzenesulfonyl chloride. MS: 327 (M-1)

Example 3

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopentane-1-carboxylic acid hydroxyamide

1-Aminocyclopentane-1-carboxylic acid; 4- (4-Fluorophenoxy) benzenesulfonyl chloride. MS: 393 (M-1). Analysis for C ₁₈ H _ig FN ₂ O ₅ S.0,25H ₂ O: Calculated: C 54.19, H 4.93, N 7.02 Found: C 54.20, H 5.13, N 7 08 /

Example 4

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide

1-Aminocyclohexane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. Recrystallization from chloroform. 174 ° C, MS: 407 (M-1), 9 (9), 9 9, 9, 9, 9 ··· 9 9 «9 9 9

9 9 9 9 9 9 9 9 9

Example 5

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide

1-Aminocyclopropane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. Melting point 184 ° C. MS: 365 (M-1). Analysis for C ₁₆ H ₁₅ FN ₂ O ₅ S: calcd; c 52,45,

H, 4.13; N, 7.65. Found: C, 52.20; H, 4.34; N, 7.44

Example 6

1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide

1-Aminocyclopentane-1-carboxylic acid; 4'-fluorobiphenylsulfonyl chloride. Recrystallization from chloroform. 159 ° C. MS: 377 (M-1).

Example 7

1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclobutane-1-carboxylic acid hydroxyamide

1-Aminocyclobutane-1-carboxylic acid; 4- (fluorophenoxy) benzenesulfonyl chloride. MS: 379 (M-1).

Example 8

1- [4- (4-Fluorobenzyloxy) benzenesulfonylamino] cyclopropanecarboxylic acid hydroxyamide

1-Aminocyclopropane-1-carboxylic acid; 4- (4-fluorobenzyloxy) benzenesulfonyl chloride. MS: 379 (M-1).

• · « 99 • · • • · • • Φ • « • • • * • 9 • « • • · * ·· »Φ * Φ Λ9 Φ β

Example 9

N-Hydroxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide (A) A solution of 2-amino-2-methylpropionic acid benzyl ester hydrochloride (12.0 g, 52.2 mmol) and 4-methoxybenzenesulfonyl chloride (11.9 g, 57.6 mmol) in dioxane (100 mL) and water (100 mL) was cooled in an ice bath and triethylamine (18.2 mL, 0.13 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 days. The solvents were then removed under reduced pressure. The residue was taken up in ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium bicarbonate solution, a 1M aqueous hydrochloric acid solution, and an aqueous sodium chloride solution. Drying over sodium sulfate and evaporation of the solvent gave a yellow oil (19.3 g). A portion of this residue (10 g) was chromatographed on silica gel using 3: 7 ethyl acetate / hexane as eluent. Recrystallization from ethyl acetate / hexane gave 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid benzyl ester as a white solid (6.59 g, 67%).

(B) A solution of 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid benzyl ester (1.5 g, 4.13 mmol) in ethanol (80 mL) was treated with 10% palladium on carbon (0.17 g). The resulting mixture was hydrogenated in a Parr apparatus at 50 psi for 1.5 hours and passed through a 0.45 μπι nylon filter to remove the catalyst. The filtrate was concentrated to give 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid as a white solid (1.09 g, 96%).

Tftfwtf tftf tff tff tff tff tff tff tff tff tff tff tff (C) A solution of 2- (4-methoxybenzenesulfonylamino) -2-methylpropionic acid (1.08 g, 3.95 mmol) in methylene chloride (120 mL) was cooled in an ice bath and gradually To this was added triethylamine (2.2 mL, 15.8 mmol), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (2.6 g, 5.88 mmol) and O-benzylhydroxylamine hydrochloride (0.95 g). , 5.95 mmol). The resulting mixture was stirred at room temperature for 16 hours and the solvent was evaporated. The residue was taken up in ethyl acetate. The ethyl acetate solution was washed successively with 1M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and the solvent was evaporated. The oily residue was chromatographed on silica gel using ethyl acetate / hexanes (1: 2). The desired product N-benzyloxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide (1.41 g, 95%) was obtained.

(D) A solution of N-benzyloxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide (1.40 g, 3.70 mmol) in methanol (80 mL) was treated with 5% palladium on barium sulfate (0.75 g). ). The mixture was hydrogenated in a Parr apparatus at 50 psi for 1.5 hours and then the catalyst was removed by filtration through a 0.45 µm nylon mesh filter. The filtrate was concentrated to give N-hydroxy-2- (4-methoxybenzenesulfonylamino) -2-methylpropionamide as a white solid (1.06 g, 100%), mp 122-125 ° C. MS: 289 (M + 1). Analysis for ^{C 11 H} 16 ^N 2 ^O 5 ^S: calculated: C 45.82, H 5.59, N 9.72. Found: C 45.88, H 5.60, N, 9.69.

The compounds of Examples 10-12 were prepared in a similar manner to that described in Example 9 using the reagents mentioned.

• ···· · ·························

Example 10

2- [4- (4-Fluorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide

2-Amino-2-methyl-propionic acid benzyl ester hydrochloride; 4- (4-fluorophenoxy) benzenesulfonyl chloride. M.p. 133-134 ° C. MS: 369 (M + 1). Analysis for ^C 16 ^H 17 ^FN 2 O5 ^S: Calculated: C, 52.17; H, 4.65; N, 7.60 Found:

H, 4.83; N, 7.80

Example 11

N-Hydroxy-2-methyl-2- (4- (3-methylbutoxy) benzenesulfonylaminopropionamide

2-Amino-2-methyl-propionic acid benzyl ester hydrochloride; 4- (3-methylbutoxy) benzenesulfonyl chloride. Recrystallization from ethyl acetate / hexane. Melting point

126.5-128 ° C. MS: 343 (M-1). Analysis for C ₁₅ H ₂₄ N ₂ O ₅ S: Calculated: C 52.31, H 7.02, N 8.13 Found: C 52.30, H 7.07, N 8.16

Example 12

2- [4- (2-Cyclopentylethoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide

2-Amino-2-methyl-propionic acid benzyl ester hydrochloride; 4- (2-cyclopentylethoxy) benzenesulfonyl chloride. Recrystallization from ethyl acetate / hexane. Melting point 126-127 ° C. MS: 369 (M-1). Analysis for C ₁₇ H ₂₆ N ₂ O ₅ S: C 55.12, H 7.07, N 7.56, found: C 55.46, H 7.09, N 7.38 ·· · ··· · «·« · · · · · · ····

Example 13

N-Hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide (A) To a solution of 2-amino-2-methylpropionic acid (2.0 g, 19.4 mmol) in 1M aqueous sodium hydroxide solution (45 mL) and dioxane (45 mL) were added 5-pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 g, 32.4 mmol). The resulting mixture was stirred at room temperature for 16 hours. An additional 1M aqueous sodium hydroxide solution (45 mL) was added. The reaction mixture was then extracted with ethyl acetate. The organic extracts are discarded. The aqueous layer was acidified with 1M hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried (MgSO 4) and concentrated. Obtained 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionic acid as a white solid (2.18 g, 34%).

(Β) To a solution of 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionic acid (1.60 g, 4.91 mmol) in methylene chloride (160 mL) was added triethylamine (2.3 mL). ml,

16.5 mmol), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (2.4 g, 5.41 mmol) and O- (2-trimethylsilylethyl) hydroxylamine hydrochloride (92 g, 5.41 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was taken up in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The foam residue was chromatographed on silica gel using ethyl acetate / hexanes (3: 2) as the eluent to isolate the desired product, 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -N- (237) · · · · · · · · · · · · · · · · · · · · · · · · · · ·

(trimethylsilylethoxy) propionamide (220 mg, 10%) as a white solid.

(C) 2-Methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -N- (2-triemethylsilanylethoxy) propionamide (80 mg, 0.18 mmol) was dissolved in trifluoroacetic acid. The resulting solution was stirred at room temperature for 16 hours and then trifluoroacetic acid was evaporated under reduced pressure. The residue was distilled with methanol. There was thus obtained N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide as a yellow oil (60 mg, 97%) which was crystallized from ethanol. Melting point: 165-166 ° C. MS:

342 (M + 1)

The compounds of Examples 14 and 15 were prepared in a similar manner to that described in Example 13 using the reagents mentioned.

Example 14

1- (5-Pyridin-2-yl-thiophene-2-sulfonylamino) -cyclopentane-1-carboxylic acid hydroxyamide

1-Aminocyclopentane-1-carboxylic acid;

5-Pyridin-2-ylthiophene-2-sulfonyl chloride. MS: 368 (M + 1).

Example 15

1- [4- (4-chlorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxylamine

1-Aminocyclopropane-1-carboxylic acid; 4- (4-chlorophenoxy) benzenesulfonyl chloride. MS: 381 (M-1).

Claims (14)

PATENT CLAIMS general Claims 1. Arylsulfonylaminohydroxamic acid derivatives of the formula I HIM II N-C AND H R ¹ i CR ² (i) where R ¹ and R ² are each independently C 1 -C 6 alkyl, trifluoromethyl, trifluoromethyl C 1 -C 6 alkyl, C 1 -C 6 alkyl (difluoromethylene), C 1 -C 6 alkyl; C 1 -C 3 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl, C 1 -C 6 alkyl, C 2 -C 6 heteroarylalkyl C 9 heteroaryl and 1 to 6 carbon atoms in the alkyl moiety; or R ¹ and R ² taken together may form a cycloalkyl ring of 3 to 6 carbon atoms, a cycloalkyl ring of 3 to 6 carbon atoms fused to a benzo group, or a group of the formula wherein each is independently 1 or 2; and is CF ₂ , sulfur, oxygen or NR ³ where R ³ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl aryl of 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of the 6 to 10 carbon atoms or acyl; and is (C 1 -C 6) alkyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxyaryl, (C 6 -C 10) aryl, (C 6 -C 10) aryl, (C 6 -C 10) arylarylalkyl carbon in each of the aryl moieties and 1 to 6 carbon atoms in the alkyl moiety, arylheteroaryl of 6 to 10 carbon atoms in the aryl and 2 to 9 carbon atoms in the heteroaryl moiety, aryloxyheteroaryl group of 6 to 10 carbon atoms in the aryl and 2 to 9 carbon atoms heteroaryl, heteroaryl of 2 to 9 carbon atoms, heteroarylheteroaryl of 2 to 9 carbon atoms in each heteroaryl moiety, heteroaryl of 2 to 9 carbon atoms in heteroaryl and 6 to 10 carbon atoms in the aryl moiety, alkylaryl of 1 to 6 atoms an alkyl of 6 to 10 carbon atoms in the aryl moiety, an alkoxyaryl group of 1 to 6 carbon atoms in the alkoxy and 6 to 10 carbon atoms, and arylalkoxyaryl having 6 to 10 carbon atoms in each of the aryl moieties and 1 to 6 carbon atoms in the alkoxy moiety, arylalkoxyalkyl of 6 to 10 carbon atoms in the aryl moiety; C 1 -C 10 aryl, C 1 -C 6 alkoxy and C 1 -C 6 alkyl, heteroaryloxy (C 2 -C 9) heteroaryl and C 6 -C 10 aryl, C 1 -C 6 alkylheteroaryl and 2 to 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. 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 moiety, heteroaryloxyalkyl of 2 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, 2 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 2 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, 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety or alkoxyaryloxyheteroaryl of 1 to 6 carbon atoms in alkoxy, 6 9 98 99 • 9 9 9 9 99 99 to 10 aryl atoms and 2 to 9 carbon atoms in the heteroaryl moiety, each of the aryl groups being optionally substituted with fluoro, chloro, bromo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 1-perfluoroalkyl up to 3 carbon atoms; and pharmaceutically acceptable salts thereof. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring, a C 3 -C 6 cycloalkyl ring fused to a benzo group or a group of the formula (CH _2). ( _n / CH ₂ ), -X 'wherein m and n are each independently 1 or 2; X is CF ₂ , sulfur, oxygen or NR ³ , wherein R ³ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 2 -C 9 heteroaryl, C 6 -C 10 arylalkyl aryl and 1 to 6 carbon atoms in the alkyl moiety, heteroarylalkyl of 2 to 9 carbon atoms in the heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of the 6 to 10 carbon atoms, or acyl . Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 2, wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring or an alkyl group having from 3 to 6 carbon atoms. A cycloalkyl ring of 3 to 6 carbon atoms fused to a benzo group. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein Q is C 6 -C 10 aryl, C 6 -C 10 aryl aryl in each of the aryl moieties, C 6 -C 10 aryloxyaryl in each of the aryl moieties, aryloxyheteroaryl (C až-C a v) aryl and C až-C 9 hetero heteroaryl, (C 9-C hetero hetero) heteroaryl, (C částí-C až hetero) heteroarylheteroaryl, (C až-C 10 aryl aryl) arylheteroaryl and (C až-C 10 aryl) aryl; up to 9 carbon atoms in the heteroaryl moiety, heteroarylaryl having 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6 to 10 carbon atoms in the aryl moiety. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 4, wherein Q represents aryloxyaryl group having 6 to 10 carbon atoms in each of the aryl moieties. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein R ¹ and R ² are each independently C 1 -C 6 alkyl. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring, a C 3 -C 6 cycloalkyl ring fused to a benzo group or a group of the formula 4,444 ·· 44 44 «4,444 4 4 4444 44 44 4 4 4 4 4 «3« 4 4 4 4 444 44 44 44 44 44 (CH ₂ ) _n (CH ₃ ). wherein m and n are each independently 1 or 2; X is CF ₂ , sulfur, oxygen or NR ³ where O R is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 2 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 2 to 9 carbon atoms in heteroaryl and 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl of 6 to 10 carbon atoms or acyl; and Q is (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryloxyaryl, (C6 -C10) aryloxyheteroaryl, and (2-9) heteroaryl, C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl, C 2 -C 9 heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety. Arylsulfonylaminohydroxamic acid derivatives of general formula I according to claim 1, wherein R ¹ and R ² taken together form a C 3 -C 6 cycloalkyl ring or a C 3 -C 6 cycloalkyl ring fused to each other. 9 9 9 9 9 9 • 9 9 9 9 9 999 99 99 99 9 99 ·· to the benzo group; and Q is C 6 -C 10 aryl, C 6 -C 10 aryl-aryl, C 6 -C 10 aryloxyaryl, C 6 -C 10 aryloxyheteroaryl and 2-9 heteroaryl, C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl and C 2 -C 9 heteroaryl heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein R ¹ and R ² are each independently C 1 -C 6 alkyl; and Q is (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryl, (C6 -C10) aryloxyaryl, (C6 -C10) aryloxyheteroaryl, and (2-9) heteroaryl, C 2 -C 9 heteroaryl, C 2 -C 9 heteroarylheteroaryl, C 6 -C 10 arylheteroaryl and C 2 -C 9 heteroaryl heteroaryl, heteroaryl C 2 -C 9 heteroaryl 9 heteroaryl and 6-10 carbon atoms in the aryl moiety or heteroaryloxyaryl having 2 to 9 carbon atoms in the heteroaryl and 6-10 carbon atoms in the aryl moiety. Arylsulfonylaminohydroxamic acid derivatives of the general formula I according to claim 1, wherein R ¹ and R ² are each independently C 1 -C 6 alkyl; * * «·· ·· f · 99 · 9 9 · 9 9 9 999 9 9 9 9 9 99 99 • 9 9 9 • 9 9 t 99 99 99 99 And Q is a (C 6 -C 10) aryloxyaryl group in each of the aryl moieties. The arylsulfonylaminohydroxamic acid derivative according to claim 1 which is 3- [4- (4-fluorophenoxy) benzenesulfonylamino] azetidine-3-carboxylic acid hydroxyamide; 4- [4- (4-Fluorophenoxy) benzenesulfonylamino] piperidine-4-carboxylic acid hydroxyamide; 1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide; 1- [4- (4-chlorophenoxy) benzenesulfonylamino] cyclopropane-1-carboxylic acid hydroxyamide; 1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclobutane-1-carboxylic acid hydroxyamide; 1- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -cyclobutane-1-carboxylic acid hydroxyamide; 1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclopentane-1-carboxylic acid hydroxyamide; 1- [4- (4-Fluorophenoxy) benzenesulfonylamino] cyclohexane-1-carboxylic acid hydroxyamide; 2- [4- (4-fluorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide; 2- [4- (4-chlorophenoxy) benzenesulfonylamino] -N-hydroxy-2-methylpropionamide; • 9 4 9 N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide; 1- (5-Pyridin-2-ylthiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide; 1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclopropane-1-carboxylic acid hydroxyamide; 1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclobutane-1-carboxylic acid hydroxyamide; 1- (4'-Fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide; 2- (4-methoxybenzenesulfonylamino) indane-2-carboxylic acid hydroxyamide; and 2- [4- (4-fluorophenoxy) benzenesulfonylamino] indane-2-carboxylic acid hydroxyamide. Pharmaceutical composition a) for the treatment of 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 as well as AIDS, sepsis, septic shock, and other diseases involving production of tumor necrosis factor (TNF); or b) for inhibiting matrix metalloproteinase or tumor necrosis factor (TNF) production in mammals, including humans, characterized by characterized in that it comprises an arylsulfonylaminohydroxamic acid derivative of the general formula I according to claim 1 or a pharmaceutically acceptable salt thereof 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 A suitable salt in an amount effective for such treatment or inhibition, and a pharmaceutically acceptable carrier. 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 an arylsulfonylaminohydroxamic acid derivative of the Formula I according to claim 1 or a pharmaceutically acceptable salts. A method of treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodonal disease, epidermolysis bullosa, scleritis, wherein the compound of formula I can be used in combination with standard non-steroidal anti-inflammatory drugs and analgesics or in combination with cytotoxic anticancer agents, 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 an arylsulfonylaminohydroxamic acid derivative of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof in an amount effective to treat such a condition.