OA11584A - Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. - Google Patents

Abstract

This invention is the coadministration of ACAT and MMP inhibitors for the reduction of both the macrophage and smooth muscle cell component of atherosclerotic lesions, thus impairing the expansion of existing lesions and the development of new lesions and for the prevention of plaque rupture and the promotion of lesion regression in a mammal.

Description

011584 -1-

COADMINISTRATION OF ACAT AND MMP INHIBITORS FOR THETREATMENT OF ATHEROSCLEROTIC LESIONS

BACKGROUND OF THE INVENTION

Enzymes known as native matrix metalloproteinases (MMP) are classes ofnaturally occurring enzymes found in most mammals. They are zinc proteases thathydrolyze collagens, proteoglycans, and glycoproteins. The classes includegélatinase A and B, stromelysin-1 and -2, fibroblast collagénase, neutrophilcollagénase, matrilysin, metalloelastase, and interstitial collagénase. Theseenzymes are implicated in a number of diseases which resuit from breakdown ofconnective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis,multiple sclerosis, and even tumor metastasis. The expression of MMPs inatherosclerosis is discussed in White A., Bocan T.M. A., Boxer P. A., Peterson J.T.,Schrier D. Emerging therapeutic advances for the development of secondgénération matrix metalloproteinase inhibitors. Curr. Pharm. Design3 :45-58 (1997). To date, inhibitors of matrix metalloproteinases hâve not beenutilized with ACAT inhibitors.

United States Patent Application 08/987167 filed December 8, 1997,teaches MMP inhibitors and their préparation and is hereby incorporated byreference.

Compounds which inhibit acyl-coenzyme A:cholesterol acyltransferase areknown as ACAT inhibitors. Certain ACAT inhibitors and the methods forpreparing them are taught in United States Patent 5,491,172 and its divisional5,633,287 which are hereby incorporated by reference.

United States Patent 5,756,545 covers MMP inhibitors especially2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid. This patent ishereby incorporated by reference.

United States Patent 5,441,975 teaches ACAT inhibitors, especiallyN-(2,6-Diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide.This and other patents in the same patent family: 5,646,170; 5,693,657; and5,366,987 are hereby incorporated by reference. -2· 011584

SUMMARY OF THE INVENTION

The instant invention is the coadministration of ACAT and MMPinhibitors for the réduction of both macrophage and smooth muscle cellcomponents of atherosclerotic lésions in a mammal, particularly a human. The 5 . lésions are directly reduced, and so, the expansion of existing lésions and thedevelopment of new ones is impaired.

Certain ACAT inhibitors and certain MMP inhibitors are disclosed assuitable for coadministration.

Pharmaceutical compositions of the inhibitors are also included in the10 invention.

DETAILED DESCRIPTION OF THE INVENTION

Coadministration of a bioavailable ACAT inhibitor with a matrixmetalloproteinase (MMP) inhibitor can blunt the development of atheroscleroticlésions and promote development of a stable plaque morphology. ACAT 15 inhibitors hâve been shown to reduce the accumulation of monocyte-macrophageswithin atherosclerotic lésions of rabbits. In addition, monocyte-macrophages hâvebeen reported to secrete such matrix metalloproteinases as MMP-7 and -9 whilesmooth muscle cells are noted to secrete MMP-1, -2, and -3. Inhibition of ACATwhile directly reducing the accumulation of lipid-filled monocyte-macrophages 20 will decrease the source of MMPs. Inhibition of MMPs will also limit the development of atherosclerotic lésions through reducing smooth muscle cell andmonocyte migration into the development intima by limiting extracellular matrixremodeling. Coadministration of both agents will limit the development of newlésions by inhibiting cellular accumulation and stabilize the developed lésions by 25 preventing both matrix remodeling and reducing the number of lipid-filled monocyte-macrophages, a source of MMP-7 and -9.

The instant invention is a method for treating and/or preventing atherosclerotic lésions comprising coadministrating one or more MMP inhibitors and one or more ACAT inhibitors. -3- 011584

The invention is further a method for preventing plaque rupture and forpromoting lésion régression by administering a combination of an ACAT inhibitorand an MMP inhibitor.

The method is practiced by administering a Chemical compound effective5 in inhibiting the biological activity of a matrix metalloproteinase such as collagénase, stromelysin, gélatinase, or elastase. The numerous compounds knownto be matrix metalloproteinase inhibitors are useful in the practice of thisinvention.

The method is practiced by administering a Chemical compound which10 inhibits the enzyme acyl-coenzyme A:cholesterol acyltransferase. The numerous compounds known as ACAT inhibitors are usefül in the practice of this invention. A “matrix metalloproteinase inhibitor” as used herein is any Chemicalcompound that inhibits by at least five percent the hydrolytic activity of at leastone matrix metalloproteinase enzyme that is naturally occurring in a mammal. 15 Such compounds are also referred to as “MMP inhibitors.” Numerous matrixmetalloproteinase inhibitors are known, and ail are useful in the method of thisinvention. For example, 4-biarylbutyric and 5-biarylpentanoic acid dérivatives aredescribed in United States Patent Application 339846 filed November 15, 1994,which is incorporated herein by reference. The compounds are defined generally 20 as (T)XA-B-D-E-G. Over 400 spécifie compounds are named, and each is incorporated herein and can be etnployed in this invention. Especially preferredcompounds to be utilized include the following: [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-, 25 (5)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-, (*)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro*P-(2-methylpropyl)-y-oxo-, (5);[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-P-(2-methylpropyl)-y-oxo-, 30 (7?)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-bromo-y-oxo-; -4- 011584 [l,l'-Biphenyl]-4-butanoic acid, 4'-fluoro-Y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 2'-fluoro-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 2'-chloro-y-oxo-;[l,l'-Biphenyl]-4-butanoic acid, 2',4'-difluoro-y-oxo-; 5 [l,r-Biphenyl]-4-butanoic acid, 3'-chloro-y-oxo-; [l,l'-Biphenyl]-4-butanoic acid, a-(2-methyl-propyl)-y-oxo-; [ 1, l'-Biphenyl]-4-butanoic acid, 4'-bromo-a-(2-methylpropyl)-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-fluoro-a-(2-methylpropyl)-y-oxo-; [1, r-Biphenyl]-4-J3Utanoic acid, 4'-ethyl-a-(2-methylpropyl)-y-oxo-; 10 [l,l'-Biphenyl]-4-butanoic acid, 2'-fluoro-a-(2-methylpropyl)-y-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 2'-chloro-a-(2-methylpropyl)-y-oxo-;[l,l'-Biphenyl]-4-butanoic acid, 4'-methoxy-a-(2-methylpropyl)-y-oxo-;[l,l'-Biphenyl]-4-butanoic acid, 2',4'-difluoro-a-(2-methylpropyl)-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-methyl-a-(2-methylpropyl)-y-oxo-; 15 [1,l'-Biphenyl]-4-butanoic acid, a-(2-methyl-propyl)-y-oxo-4'-pentyl-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-methylene-y-oxo-; [1, Γ-Biphenyl]-4-butanoic acid, 2'-chloro-a-methylene-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-methyl-y-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-chloro-ü-oxo-a-pentyl-; 20 Benzenebutanoic acid, 4-chloro-a-(2-methylpropyl)-D-oxo-;

Benzenebutanoic acid, 4-methyl-a-methylene-D-oxo-; 2-Butenoic acid, 4-(4'-chloro[ 1,1 '-biphenyl]-4-yl)-4-oxo-, (£)-; 2-Butenoic acid, 4-[4-(4-chlorophenyoxy)-phenyl]-4-oxo, (E)-;[l,l'-Biphenyl]-4-butanoic acid, 4'-hydroxy-a-(2-methylpropyl)-D-oxo-; 25 [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-P-methylene-D-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-chloro- D-hydroxy-a-(2-methylpropyl)- > [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-D-hÿdroxy-a-(2-methylpropyl)-; 30 2(3H)-Furanone, 5-(4'-chloro[l,r-biphenyl]-4-yl)dihydro-3- (2-methylpropyl)-; -5- 011584 2(3H)-Furanone, 5-(4'-chloro[ 1,1 '-biphenyl]-4-yl)dihydro-3-(2-methylpropyl)-; [l,r-Biphenyl]-4-butanoic acid, 3',4'-dichloro-D-oxo-a-(3-phenylpropyl)-; 5 ... [l,l'-Biphenyl]-4-butanoic acid, 3',5'-dichloro-D-oxo-a-(3-phenylpropyl) [l,l'-Biphenyl]-4-butanoic acid, 4'-(acetyloxy)-D-oxo-a-(3-phenylpropyl)-;

Benzenepentanoic acid, a-[2-[4-(5-chloro-2-thienyl)phenyl]-2-oxoethyl]-;10 2-Furancarboxylic acid, 5-[4-(3-carboxy-l-oxo-6-phenylhexyl)phenyl]-;

Benzenepentanoic acid, a-[2-oxo-2-[4-(3-pyridinyl)phenyl]ethyl]-;Benzenepentanoic acid, a-[2-oxo-2-[4-[6-(pentyloxy)-3-pyridinyl]- phenyljethyl]-; [ 1,l'-Biphenyl]-4-butanoic acid, □ -oxo-4'-(pentylthio)-oc-(3-15 phenylpropyl) ; [1,1 '-Biphenyl]-4-butanoic acid, 4'-methoxy- □ -oxo-a-(3-phenylpropyl)-;[l,l'-Biphenyl]-4-butanoic acid, 3'-chloro-4'-fluoro-D-oxo-a-(3- phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-ethoxy-D-oxo-oc-(3-phenylpropyl)-;20 Benzenepentanoic acid, a-[2-oxo-2-[4-(3-thienyl)phenyl]ethyl]-; [l,l'-Biphenyl]-4-butanoic acid, 2',4'-dichloro-D-oxo-ot-(3-phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-formyl-D-oxo-a-(3-phenylpropyl)-;[l,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(3-phenylpropyl)-3',5'- 25 bis(trifluoromethyl)-;

Benzenepentanoic acid, a-[2-oxo-2-[4-(2-thienyI)phenyl]ethyl]-;[l,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(3-phenylpropyl)-3'- (trifluoromethyl)-; [l,l'-Biphenyl]-4-butanoic acid, 2'-formyl-0-oxo-a-(3-phenylpropyl)-;30 [l,l'-Biphenyl]-4-butanoic acid, 4-hydroxy-D-oxo-a-(3-phenylpropyl)-; [1,1 '-Biphenyl]-4-butanoic acid, □-oxo-a-(3-phenylpropyl)-4'-propoxy-, b -6- 011584 [1, Γ-Biphenyl]-4-butanoic acid, □-oxo-4'-(pentyloxy)-a-(3- phenylpropyl)-; [l,r-Biphenyl]-4-butanoic acid, □-oxo-4'-(pentyloxy)-a-(3- phenylpropyl)-, (S)-; [l,r-Biphenyl]-4-butanoic acid, □-oxo-4'-(pentyloxy)-a-(3-phenylpropyl)-, (R)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-(hexyloxy)- □ -oxo-a-(3 -phenylpropyl)- -6- [l,r-Biphenyl]-4-butanoic acid, 4'-butoxy-D-oxo-a-(3-phenylpropyl)-;10 [l,l'-Biphenyl]-4-butanoic acid, □-oxo-4'-(3-phenylpropoxy)-a- (3-phenylpropyl)-; [l,r-Biphenyl]-4-butanoic acid, 4'-(l-methylethoxy)-ü-oxo-a-(3-phenylpropyl)-; [l,r-Biphenyl]-4-butanoic acid, 4'-(heptyloxy)-D-oxo-a-15 (3-phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-(cyclohexyl-methoxy)-D-oxo-a-(3-phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-(2-methyl-propoxy)-Q-oxo-a-(3-phenylpropyl)-; 20 [l,l'-Biphenyl]-4-butanoic acid, D-oxo-oc-(3-phenylpropyl)-4'- (2-propenyloxy)-; [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-heptyl-D-oxo-;[l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-decyl-D-oxo-;[l,r-Biphenylj-4-butanoic acid, 4'-nitro-D-oxo-a-(2-phenylethyl)-; 25 [l,l'-Biphenyl]-4-butanoic acid, 4'-cyano-Q-oxo-a-(2-phenylethyl)-; [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(2-iodophenyl)ethyl]- □ -OXO-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3-iodophenyl)ethyl]- □ -OXO-; 30 [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(4-iodophenyl)ethyl]- □ -OXO-; -Ί- 011584 [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3,5-dimethoxyphenyl)ethyl]- □ -oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-d-oxo-a-phenyl-; [ 1,1 '-Biphenyl]-4-butanoic acid, 4'-chloro- □ -oxo-a-(phenylmethyl)-; 5 [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-D-oxo-a-(2-phenylethyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-D-oxo-a-[(trimethylsilyl)- methyl]-; [ 1,1 '-Biphenyl]-4-butanoic acid, 4'-bromo- □ -oxo-a-(3-phenylpropyl)-;[l,r-Biphenyl]-4-butanoic acid, -□-oxo-a-(3-phenÿlpropyl)-; 10 [1, Γ-Bip henyl]-4-butanoic acid, 4'-amino-0-oxo-a-(2-phenylethyl)-; [l,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(2-phenylethyl)-4'- [[(phenylmethoxy)carbonyl]amino]-; [l,l'-Biphenyl]-4-butanoic acid, 4'-[[(l,l-dimethylethoxy)- carbony l]amino]- □ -oxo-a-(2-pheny lethy 1)-; 15 [l,l'-Biphenyl]-4-butanoic acid, 4’-(acetylamino) Π-οχο-α- (2-phenylethyl)-; [l,r-Biphenyl]-4-butanoic acid, □-oxo-4'-[(l-oxopentyl)amino]-a-(2-phenylethyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-[(3,3-dimethyl-l-oxobutyl)amino]-20 □-oxo-a-(2-phenylethyl)-; [ 1, l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-(methoxycarbonyl)-pheny ljethyl]-□-oxo-; [l,l'-Biphenyl]-4-butanoic acid, a-[2-(2-carboxyphenyl)ethyl]-4'-chloro□-oxo-; 25 [l,l'-BiphenyI]-4-butanoic acid, 4'-chloro-a-[2-[2-[(diethylamino)- carbonyl]phenyl]ethyl]-E3-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino)carbonyl]phenyl]ethyl]-D-oxo-, (5)-; [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-30 [(diethylamino)carbonyl]phenyl]ethyl]-D-oxo-, (R)-, -8- 011584

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-bipheny.l]-4-yl)carbonyl]· 5-[(phenylmethoxy)methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l, r-biphenyl]-4-yl)carbonyl]· 5-(phenoxymethyl)-, (1α,2β,5β)-; 5 Cyclopentanecarboxylic acid, 2-[(benzoyloxy)-methyl]-5-[(4'-chloro[l,r biphenyl]-4-yl)carbonyl]-, (1α,2β,5β)-; 1,2-Benzenedicarboxylic acid, l-[[2-carboxy-3-[(4'-chloro[l,l^biphenyl] 4- yl)carbonyl]cyclopentyl]-methyl]-2-methyl ester, (Ια, 2β, 3a)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]10 5-[(2-thienylthio)methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(benzoylamino)methyl]-5-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl] 5- [[(2-methoxyethoxy)methoxy]methyl]-, (1α,2β,5β)-; 15 Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl] 5-[[(phenylmethyl)thio]methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,r-biphenyl]-4-yl)carbonyl] 5-[(phenylthio)methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,r-biphenyl]-4-yl)carbonyl]20 5-[(propylthio)methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(2-benzothiazolylthio)methyl]-5-[(4'-chloro[l,r-biphenyl]-4-yl)carbonyl]-, (1α,2β,5β)-;

Benzoic acid, 2-[[[2-carboxy-3-[(4'-chloro[l,r-biphenyl]- 4- yl)carbonyl]cyclopentyl]methyl]thio]-, 1-methyl ester, (1α,2β,3α)-; 25 Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl] 5- [[[(phenylmethoxy)carbonyl]-amino]methyl]-, (1α,2β,5β)-;

Benzoic acid, 2-methyl-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]cyclopentyl]methyl ester, (1α,2β,3α)-;

Benzoic acid, 3-methyl-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]-30 4-yl)carbonyl]cyclopentyl]methyl ester, (1α,2β,3α)-; -9- 011584

Benzoic acid, 4-methyl-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]çyclopentyl]methyl ester, (1α,2β,3α)-;

Benzoic acid, 2-methoxy-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]cyclopentyl]methyl ester, (1α,2β,3α)-; 5 Benzoic acid, 3-methoxy-, [2-carboxy-3-[(4'-chloro[l,r-biphenyl]- 4-yl)carbonyl]cyclopentyl]methyl ester, (1α,2β,3α)-;

Benzoic acid, 4-methoxy-, [2-carboxy-3-[(4'-chloro[l,l'-biphenyl]- 4- yl)carbonyl]cyclopentyl]methyl ester, (1α,2β,3α)-;

Cyclopentanecarboxylic acid, 2-[(2-benzoxazolylthio)methyl]-5-[(4'-10 chloro[l,r-biphenyl]-4-yl)carbonyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l, 1 f-biphenyl]-4-yl)carbonyl]- 5- [(l,3-dihydro-4-nitro-l,3-dioxo-2//-isoindol-2-yl)methyl]-, (1α,2β,5β)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]- 5-[(l,3-dihydro-5-nitro-l,3-dioxo-27f-isoindol-2-yl)methyl]-, (1α,2β,5β)-; 15 2#-Benz[/]isoindole-2-butanoic acid, a-[2-(4'-ethoxy[ 1,1 ’-biphenyl]-4-yl)- 2-oxoethyl] -1,3 -dihydro-1,3 -dioxo-; [1, l'-Biphenyl]-4-butanoic acid, a-(acetylamino)-4'-chloro-Q-oxo-;2Z/-Isoindole-2-hexanoic acid, a-[2-(4'-chloro[ 1, l'-biphenyl]-4-yl)- 2-oxoethyl]-l,3-dihydro-l,3-dioxo-; 20 [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-(methoxycarbonyl)- phenyl]thio]methyl]-D-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[(2,6-(dimethylphenyl)-thio]methyl]-D-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[4-fluoro-25 2-(methoxycarbonyl)phenyl]thio]methyl]-ü-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-[(diethylamino)-carbonyl]phenyl]thio]methyl]- □ -oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[2-[(dimethylamino)-carbonyl]phenyl]thio]methyl]- □ -oxo-; 30 [l,l'-Biphenyl]-4-butanoic acid, 4-chloro-a-[[[3-[(dimethylamino)- carbonyl]phenyl]thio]methyl-]-Q-oxo-; -10- 011584

Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 3-[[4'-(pentyloxy)[l,l'-biphenyl]-4-yl]carbonyl]-, (2-endo,3-exo)-·, l-Cyclopentene-l-carboxylic acid, 5-[(4'-chloro[l,l'-biphenyl]- 4- yl)carbonyl]-; 5 Cyclopentanecarboxylic acid, 2-[(4'-chloro[l, l'-biphenyl]-4-yl)carbonyl]- 5- [(phenylmethyl)thio]-, (1α,2β,5α)-;

Cyclopentanecarboxylic acid, 2-[(4'-chloro[l,l'-biphenyl-4-ÿl)carbonyl]- 5-[(phenylmethyl)thio]-, (1α,2β,5β)-; l-Cyclopentene-l-carboxylic acid, 5-[[4'-(pentyloxy)[l,l'-biphenyl]-10 4-yl]carbonyl]-; l-Cyclopentene-l-carboxylic acid, 5-[[4'-(hexyloxy)[l,r-biphenyl]-4-yl)]carbonyl]-; [1, l'-Biphenyl]-4-butanoic acid, 4'-hydroxy-0-oxo-a-[(phenylthio)-methyl]-; 15 [l,l'-Biphenyl]-4-butanoic acid, a-[2-[2-[(butylamino)- carbonyl]phenyl]ethyl]-4'-chloro-D-oxo-; [1,l'-Biphenyl]-4-butanoic acid, a-[2-(3-carboxyphenyl)ethyl]-4'-chloro-□ -ΟΧΟ-; [1,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino)-20 carbonyl]phenyl]ethyl]-Q-oxo-; [l,l'-Biphenyl]-4-butanoic acid, a-[2-[3-[(butylamino)carbonyl]-phenyl]ethyl]-4'-chloro-ü-oxo-; [1, l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[4-[(diethylamino)-carbonyl]phenyl]ethyl]- □ -oxo-; 25 [l,l'-Biphenyl]-4-butanoic acid, a-[2-[4-[(butylamino)- carbonyl] phenyl]ethy 1] -4'-chloro- □ -oxo-; [1, l'-Biphenyl]-4-butanoic acid, a-[2-(4-carboxyphenyl)ethyl]-4'-chloro- □-OXO-; [l,r-Biphenyl]-4-butanoic acid, 4'-methoxy-D-oxo-a-(2-phenylethyl)-; 30 [l,r-Biphenyl]-4-butanoic acid, 4'-hydroxy-Ü-oxo-a-(2-phenylethyl)-; [1,1 '-Bîphenyl]-4-butanoic acid, 4'-ethoxy- □ -oxo-a-(2-phenylethyl)-; -11- 011584 [1,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(2-phenylethyl)-4'-propoxy-; [1, l'-Biphenyl]-4-butanoic acid, □-oxo-4'-(pentyloxy)-a-(2-phenylethyl)-[1,l'-Biphenyl]-4-butanoic acid, 4'-(hexyloxy)-D-oxo-cc-(2-phenylethyl)-;[l,l'-Biphenyl]-4-butanoic acid, 4'-butoxy-O-oxo-a-(2-phenylethyl)-; 5 [l,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(2-phenylethyl)-4'- (phenylmethoxy)-; [1,l'-Biphenyl]-4-butanoic acid, a-[2-(3-iodophenyl)ethyl]-D-oxo-4'-(pentyloxy)-; [l,l'-Biphenyl]-4-butanoic acid, ct-[2-(3-iodophenyl)ethyl]-D-oxo-4'-10 (phenylmethoxy)-; [l,l'-Biphenyl]-4-butanoic acid, a-[2-(3-[(diethylamino)carbonyl]-phenyljethyl]- □ -oxo-4'-(pentyloxy)-; [1,l'-Biphenyl]-4-butanoic acid, ct-[2-(3-[(diethylamino)carbonyl]-phenyljethyl]- □ -oxo-4'-(phenylmethoxy)-; 15 1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[l,r-biphenyl]- 4-yl)carbonyl]-, l-(phenylmethyl) ester, (2S-trans)-, 1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[l,r-biphenyl]-4-yl)carbonyl]-, l-(phenylmethyl) ester, (2'R-trans)-·, L-Proline, 3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]-20 l-[[(phenylmethyl)amino]carbonyl]-, trans-\ L-Proline, 3-[(4'-chloro[l,r-biphenyl]-4-yl)carbonyl]-l-(l-oxo-3-phenylpropyl)-, trans-, L-Proline, 3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]-l-(phenylacetyl)-, trans-, 25 ' L-Proline, 3-[(4'-chloro[l,l'-biphenyl]-4-yl)carbonyl]-l-(3,3-dimethyl- 1-oxobutyl)-, trans-, [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-heptyl-D-oxo-;[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-decyl-ü-oxo-;[l,l'-Biphenÿl]-4-butanoic acid, 4'-nitro-D-oxo-a-(2-phenylethyl)-; 30 [l,l'-Biphenyl]-4-butanoic acid, 4'-cyano-ü-oxo-a-(2-phenylethyl)-; -12- 011584 [1, l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(2-iodophenyl)ethyl]-0- oxo-; [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3-iodophenyl)ethyl]-D- oxo-; 5 [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(4-iodophenyl)ethyl]-D- oxo-; [1, l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3,5-dimethoxyphenyl)ethyl]-□-OXO-; [l,r-Biphenyl]-4-butanoic acid, 4'-chloro-D-oxo-a-phenyl-; 10 [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-ü-oxo-a-(phenylmethyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-D-oxo-a-(2-phenylethyl)-;[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-D-oxo-à-[(trimethylsilyl)- methyl]-; [ 1, Γ-Biphenyl] -4-butanoic acid, 4'-bromo- □ -oxo-a-(3 -phenylpropyl)-; 15 [l,l'-Biphenyl]-4-butanoic acid, D-oxo-a-(3-phenylpropyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-amino-C-oxo-a-(2-phenylethyl)-;[l,l'-Biphenyl]-4-butanoic acid, □-oxo-a-(2-phenylethyl)-4'- [[(phenylmethoxy)carbonyl]amino]-; [l,r-Biphenyl]-4-butanoic acid, 4'-[[(l,l-dimethylethoxy)- 20 carbonyl]amino]-d-oxo-a-(2-phenylethyl)-; [1, Γ-Bip henyl]-4-butanoic acid, 4'-(acetylamino)-D-oxo-a- (2-phenylethyl)-; [1, l'-Biphenyl]-4-butanoic acid, □-oxo-4'-[(l-oxopentyl)amino]-a-(2-phenylethyl)-; 25 [l,r-Biphenyl]-4-butanoic acid, 4'-[(3,3-dimethyl-l-oxobutyl)amino]-a- oxo-a-(2-phenylethyl)-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-methoxycarbonyl)- phenyljethyl]-□-OXO-; [1,1 '-Biphenyl]-4-butanoic acid, a-[2-(2-carboxyphenyl)ethyl]-4'-chloro- □-OXO-; 30 10 -13- 01158 4 [1,1 '-Biphenyl]-4-butanoic acid, 4'-chIoro-a-[2-[2-[(diethylamino)-carbonyl)phenyl]ethyl]-ü-oxo-; [l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino)-carbonyl)phenyl]ethyl]-D-oxo-, (5)-; and [1,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino)-carbonyl)phenyl]ethyl]-D-oxo-, (R)-.

Fenbufen and compounds related to fenbufen can be utilized. Suchcompounds are described in United States Patent Number 3,784,701 and by Child,étal., J. Pharm. Sri., 1917,66:466-476, and Arzneim-Forsch, 1980;30(4A):695-702, ail ofwhich are incorporated herein by reference. Preferred compounds fromthe fenbufen sériés to be utilized in this invention hâve the formula where R is 15 CCH2CH2COOH (fenbufen), C0CH=CHC00H, SO2NH2, COCH2CHCOOH, CH3

, COCH2CH2SO3Na, CH(OH)CH2CH2COOH, COCH2CHCOOH, COCH2CH2CONHOH, Ç(=NOH)CH2CH2COOH, and 20 25

OH COCH2SCH2COOH.

Numerous peptides are known matrix metalloproteinase inhibitors. Typical of such peptides are those described in United States Patent Number 5,300,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289; and WO 96/11209, ail ofwhich are incorporated herein by reference. Such compounds are illustrated by the formula -14 011584

where each of the variable groups can include hydrogen alkyl, aryl, heteroaryl,alkenyl, alkynyl, carboxy, and the like. Preferred compounds from within thisclass which can be utilized in the method of this invention include the following: 5 N-[2,3-bis-Acetylmercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-10 phenylalanine N-methylamide; N-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide; 15 N-[2-Acetylmercapto-4-phthalimidobutanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine20 N-methylamide; N-[2,3-Z>A-Mercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide;N-[2-Mercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-4-methoxycarbonylbutanyol]-L-leucyl-L-phenylalanine25 N-methylamide; N-[2-Mercapto-4-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide; -15- 0115 84 N-[2-Mercapto-4-phthalimidobutanoyl]-L-leucyl-phenyl-alanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide; 5 N-[2-Mercapto-6-phthalimidohexanyoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-leucyl-10 L-phenylalanine N-methylamide; N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-valinyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-tryptophan N-methylamide; 15 N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-valinyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-îeucyl-L-tryptophan20 N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-[3-(4-thiazolyl)]alaine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-(P-(2-pyridyl)alanine N-methylamide; 25 N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L- glutamicacid N-methylamide; N-[2-Acetylmercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-2-(3-phthalimido) phenylacetyl]-L-leucyl-30 L-phenylalanine N-methylamide; N-[2-Mercapto-5-methoxycarbonylpentanoyl]-L-phenylalanine N-methylamide; -16- 011584 N-[2-Mercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-trptophan N-methylamide; 5 N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-tryptophan N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[P-10 (4-thiazolyl)alanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[p-(2-pyridyl)]alanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-glutamicacid N-methylamide; 15 N-[2-Mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[N-Mercaptoacetyl)-L-leucyl]-L-phenylalanine N-methylamide;N-[Acetomercaptoacyl)-L-leucyl-L-phenylalanine methylamide;(RS)-2-(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide; 20 (RS)-2-(Acetylthio)propanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-2-phenylacetyl-L-leucyl-L-phenylalanine N-methylamide; 25 (RS)-2-(Acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; N-(Acetylmercaptoacyl)-L-threonyl-L-phenylalanine methylamide; 30 N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide; (RS)-2-Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide;(RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; -V- 011 584 (RS)-2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-2-phenylacetyl-L-leucyl-L-phenylalanine N-methylamide; 5 (RS)-2-Mercapto-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide; 10 N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide; [4-(N-Hydroxyamino)-2(R)-cyclohexylmethylsuccinyl]-L-P- cyclohexylalanine-N-(2-phenylethyl)amide; [4-N-(Hydroxyamino)-2R-isobutylsuccinyl]-L-P-cyclohexylalanine-N- (2-phenylethyl)amide; 15 [4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-3-cyclohexylalanine- N-(2-phenylethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine- N-[2-(N,N-dimethylamino]ethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine-20 N-[2-(p-sulphonamidophenyl)ethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine- N-(2-(p-sulphonylphenyl)ethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine- N-[2-(2-pyridyl)ethyl]amide; 25 [4-(N-Hydroxyamino)-2R-pentylsuccinyl]-L-3-cyclohexylalanine-N- (2-phenylethyl)amide; [4-(N-Hydroxyamino)-2R-isoamylsuccinyl]-L-P-cyclohexylalanine-N-(2-pheny lethyl) amide; [4-(N-Hydroxyamino)-2R-phenylbutylsuccinyl]-L-p-cyclohexylalariine-N30 (2-phenylethyl)amide; [4-=(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine- N-[3-(4-morpholinyl)propyl]amide; -18- 011584 [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-P-cyclohexylalanine- N-[p-alanine]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-P-cyclohexylalanine amide;[4-(N-Hydroxyamino)-2R-(3-phenylpropyl)succinyl]-L-P- 5 cyclohexylalanine amide; [4-(N-Hydroxyamino)-2R-(3-phenylbutyl)succinyl]-L-P- cyclohexylalanine amide; [4-N-(Hydroxyamino)-2R-phenylethylsuccinyl]-L-leucine-N- (2-phenylethyl)amide; 10 [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-leucine-N- (2-phenylethyl)amide; [4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-tryptophan amide;[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-valine amide;[3-Phosphono-2R,S-phenylpropyl-l-oxopropyl]-L-p-cyclohexylalanine-N- 15 (2-phenylethyl)amide, dimethylester; [3-Phosphono-2R-phenylpropyl-l-oxopropyl]-L-P-cyclohexylalanine-N- (2-phenylethyl)amide; [3-Phosphono-2S-phenylpropyl-l-oxopropyl]-L-P-cyclohexylalanine-P- alanine; 20 [3-Phosphono-2R-phenylpropyl-1 -oxopropyl]-L-P-cyclohexylalanine; [3-Phosphono-2S-phenylpropyl-l-oxopropyl]-L-P-cyclohexylalanine-P- alanine, methyl ester; [3-Phosphono-2R,S-phenylpropyl-l-oxopropyl]-L-p-cyclohexylalanine-N-[4(3-aminopropyl)morpholine]amide, bromine sait; 25 [3-Phosphono-2R,S-(4-methylphenyl)propyl-l-oxopropyl]-L-P- cyclohexylalanine-N-(2-phenylethyl)amide, diethylester; [3-Phosphono-2R,S-(4-methylphenyl)propyl-l-oxopropyl]-L-P- cyclohexylalanine-N-(2-phenylethyl)-amide; 4-t-Butoxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-P-cyclohexylalanine-N-30 (2-phenylethyl)amide; 4-Hydroxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-P-cyclohexylalanine-N- (2-phenylethyl)amide; -19- 011584 4-(N-Hydroxyamino-2(R)-[3-(2-phenoxyethyl)succinyl]-L-P- cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2(R)-[3-(4-pyridinium)propyl]succinyl}-L-P- cyclohexylalanine-N-(2-phenylethyl)amide; 5 {4-(N-Hydroxyamino)-2(R)-[3-(4-pyridinium)propyl]succinyl}-L-3- cyclohexylalanine-N-(2-phenylethyl)amide; {4-(N-Hydroxyamino)-2(R)-[3 -(N-methy 1-4-pyri dinium)propyl]succinyl}L-3-cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2-(R)-[3 -(4-methy lphenyl)propyl] succiny 1} -L-β-10 cyclohexylalanine-N-[(2-morpholine-sulphonylamino)ethyl]amide; {4-(N-Hydroxyammo)-2-(R)-[3-(4-rnethylphenyl)propyl]succinyl}-L-P- cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide; {4-(N-Hydroxyamino)-2-(R)-[3-(4-chlorophenyl)propyl]succinyl}-L^- cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide; 15 {4-N-Hydroxyamino)-2-(R)-[3-(4-methylphenyl)propyl]succinyl}-L-P- cyclohexylalanine-N-[(2-dimethylsulphonylamino)propyl]amide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L-[S- (methyl)penicillamine]-N-methylamide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L-[S-20 (methyl)penicillamine]amide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L- penicillamine]amide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-[S- (methyl)penicillaminesulphone]-N-methylamide; 25 {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-[S- (methyl)penicillaminesulphoxide]-N-methylamide; {4-(N-Hydroxÿamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L- penicillamine-N-methylamide; [4-(N-Hydroxyamino)-2(R)-3-(2-methylpropyl)succinyl]-L-[S-30 methyl)penicillamine]-N-methylamide; N^-Hydroxy-Nl-(l-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-4- (chlorophenylpropyl)succinamide; -20- 01 1 584 N4-Hydroxy-N 1 -( 1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4-methylphenylpropyl)succinamide; N4-Hydroxy-Nl-(l-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- methoxyphenylpropyl)succinamide; 5 N4-Hydroxy-N1-(l-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- trifluoromethylphenylpropyl)succinamide; N4-Hydroxy-Nl-(l-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- chloromethylphenylpropyl)succinamide; N-[N-(Mercaptoaeetyl)-L-leucyl]-L-phenylalanine methylamide; 10 N-(Acetomercaptoacyl)-L-leucyl]-L-phenylalanine methylamide; (RS)-2-(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide;(RS)-2-(Acetylthio)propanoyl-L-leucyl-L-phenylalanineN-methylamide;(RS)-2-(Acetylthio)-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; 15 (RS)-2-(Acetylthio)-2-phenylacetyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine20 N-methylamide; N-(Acetylmercaptoacyl)-L-threonyl-L-phenylalanine methylamide;N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide;(RS)-2-Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide;(RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; 25 (RS)-2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-2-phenylacetyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-3-phenylpropanoyl-L-leucyl-L-phenylalanine30 N-methylamide; (RS)-2-Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; -21- 011584 N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide;N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide;A-[2,3-&amp;/s-Acetylmercaptopropanoyl]-Z-leucyl-Z,-phenylalanine A-methylamide; 5 A-[2-Acetylmercapto-3-methoxycarbonylpropanoyl]-Z,-leucyl-L- phenylalanine A-methylamide; A-[2-Acetylmercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-phenylalanine A-methylamide; A-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-Z-leucyl-Z.-10 phenylalanine A-methylamide, A-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-Z-leucyl-Z,-phenylalanine A-methylamide; A-[2-Acetylmercapto-4-phthalimidobutanoyl]-£-leucyl-L-phenylalanine A-methylamide; 15 A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z-leucyl-L-phenylalanine A-methylamide; A-[2-Acetylmercapto-6-phthalimidohexanoyl]-£-leucyl-£-phenylalanine A-methylamide; A-[2,3-ôz,s-Mercaptopropanoyl]-L-leucyl-L-phenylalanine A-methylamide;20 A-[2-Mercapto-3-methoxycarbonylpropanoyl]-L-leucyl-Z-phenylalanine A-methylamide; A-[2-Mercapto-4-methoxycarbonylbutanoyl]-£-leucyl-L-phenylalanine A-methylamide; A-[2-Mercapto-5-methoxycarbonylpentanoyl]-£-leucyl-£-phenylalanine25 A-methylamide; • A-[2-Mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanineA-methylamide; A-[2-Mercapto-4-phthalimidobutanoyl]-£-leucyl-Z,-phenylalanine A-methylamide; 30 A-[2-Mercapto-5-phthalimidopentanoyl]-£-leucyl-Z,-phenylalanine A-methylamide; A-[2-Mercapto-6-phthalimidohexanoyl]-Z-leucyl-Z-phenylalanine A-methylamide; -22- 01 1 5 8 4 A-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-Z-leucyl-Z- phenylalanine A-methylamide; A-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-Z,-leucyl-Z-phenylalanine A-methylamide; 5 A-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-À-valinyl-Z,- phenylalanine N-methylamide; A-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-£-leucyl-Z-tryptophan A-methylamide; A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z,-leucyl-£-phenylalanine10 A-methylamide; A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z-valinyl-Z,-phenylalanine A-methylamide; A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z-leucyl-Z,-tryptophan A-methylamide; 15 N-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z-leucyl-L-[P- (4-thiazolyl)]alanine A-methylamide; A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z,-leucyl-£-[P-(2-pyridyl)] alanine A-methylamide; A-[2-Acetylmercapto-5-phthalimidopentanoyl]-Z-leucÿl-5-methyl-Z-20 glutamic acid A-methylamide; A-[2-Acetylmercapto-6-phthalimidohexanoyl]-Z-leucyl-Z,-phenylalanine A-methylamide, A-[2-Acetylmercapto-2-(3-phthalimido)phenylacetyl]-Z,-leucyl-Z-phenylalanine A-methylamide; 25 A-[2-Mercapto-5-methoxycarbonylpentanoyl]-Z,-leucyl-Z,-phenylalanine A-methylamide; A-[2-Mercapto-6-methoxycarbonylhexanoyl]-Z<-leucyl-Z-phenylalanine A-methylamide, A-[2-Mercapto-6-methoxycarbonylhexanoyl]-Z,-leucyl-Z,-tryptophan30 A-methylamide; A-[2-Mercapto-5-phthalimidopentanoyl]-Z,-leucyl-L-phenylalanine A-methylamide; -η- 011584 N-[2-Mercapto-5-phthalimidopentanoyl]-£-leucyl-£-tryptophan N-methylamide; 7V-[2-Mercapto-5-phthalimidopentanoyl]-£-leucyl-£-[P-(4-thiazolyl)alanine 7V-methylamide; 5 7V-[2-Mercapto-5-phthalimidopentanoyl]-£-leucyl-£-[3-(2-pyridyl)]alanine TV-methylamide; 7V-[2-Mercapto-5-phthalimidopentanoyl]-£-leucyl-5-methyl-£-glutamicacid JV-methylamide; 7V-[2-Mercapto-6-phthalimidohexanoyl]-£-leucyl-£-phenylalanine10 jV-methylamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]- 3- methylbutanamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-3-picolyl)amino]- 2-cyclohexylacetamide; 15 N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]- 4- methylpentanamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanamide hydrochloride; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-20 3-methylbutanamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(4-picolyl)amino]- 2-cyclohexylacetamide; N-Hydroxy-2(R)-[(4-methoxybenzenesulfonyl]-(4-picolyl)amino]- 2- (2-tetrahydrofuranyl)acetamide; 25 N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]- 3- methylbutanamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperàzicacid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N^-(S)-piperazic30 acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N^-(S)-piperazic acid N-methyl amide; -24- 011584 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methoxybenzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiophenylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiobenzylsuccinyl]-N2- (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyammo)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazic10 acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-isopropanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(2-pyridyl)]-N2-(S)-20 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl thio-tert-butanoate]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N2-(S)-piperazicacid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazic acidN-methyl amide; 30 011584 -25- ¢11115®4 [4-(N-Hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthiophenylsuccinyl]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-(methylthio-2-thienyl)succinyl]-N2-10 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazic acidN-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methyl acetate]-N2-(S)-piperazic acidN-methyl amide; 15 [4-(N-Hydroxyamino)-2R-hexyl-3S-methylisopropanoate]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methyl tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthioacetate]-N2-(S)-piperazic ·20 acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthioisopropanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazicacid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazic30 acid N-methyl amide; -26- 01 1 584 [4-(N-Hydroxyamino)-2R-ethylphenyl-3 S-methylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N2- (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamîno)-2R-ethylphenyl-3S-methylthiophenylsuçcinyl]-N2-10 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-thienyl)-succinyl]-N2-(S)-piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-ethylphenyl-3 S-benzylsuccinyl]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3 S-methyl acetate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylisopropanoate]-N2-(S)-20 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methyl-tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthioacetate]-N2-(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthioisopropanoate]-N2- (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2-(S)-piperazic acid30 N-methyl amide; -27- 011584 [4-(N-Hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthiobenzyIsuccinyl]-N2-(S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-octyl-3 S-methylthio-2-thienyl)succinyl]-N 1 - (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3 S-methyl acetate]-N2-(S)-piperazic acidN-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylisopropanoate]-N2-(S)-10 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3 S-methyl tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthioacetate]-N2-(S)-piperazicacid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-octyl-3 S-methylthioisopropanoate]-N2-(S)- piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazic-20 acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazicacid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazicacid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4'(S/R)- benzylpiperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5'(S/R)-benzylpiperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6'(S/R)- 30 benzylpiperazic acid N-methyl amide; -28- 011584 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S)-[5',6'Jbenzopiperazic acid N-methyl amide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-isobutylglycine-(S)-N2-piperazic acidmethyl amide; 5 N-[l(R)-Carboxy-ethyl]-a-(S)-hexylglycine-(S)-N2-piperazic acid methyl amide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-heptylglycine-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxy-ethyl]-a-(S)-octylglycine-(S)-N2-piperazic acid methyl 10 amide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-ethylphenylglycine-(S)-N2-piperazic acidmethyl amide; N-[l(R)-Carboxy-ethyl]-a-(S)-propylphenylclycine-(S)-N2-piperazic acidmethyl amide; 15 N-[l(R)-Carboxy-ethylthiobenzyl]-a-(S)-isobutylglycine-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxy-ethylthiobenzyl]-a-(S)-hexylglycine-(S)-N2-piperazicacid methyl amide; N-[l(R)-Carboxy-ethylthiobenzyl]-a-(S)-ethylphenylglycine-(S)-N2-20 piperazic acid methyl amide; N-[l(R)-Carboxy-ethylthiobenzyl]-a-(S)-propylphenylglycine-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-isobutylglycine-(S)-N2-piperazicacid methyl amide; 25 N-[ 1 (R)-Carboxy-ethyloxybenzyl]-a-(S)-hexylglycine-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-ethylphenylglycine-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-propylphenylglycine-(S)-N2-30 piperazic acid methyl amide; -29- 011584 N-[l(R)-Carboxy-4-(p-toluenesulfonyl)butyl]-a-(S)-phenethylglycyl-(S)-N2-piperazic acid methyl amide; N-[l(R)-Carboxyethyl]-a-[2-(4-phenylphenoxy)ethyl]-glycyl-(S)-N2-piperazic acid methyl amide; 2-[2(R)-[2-[l,l'-Biphenyl)yl]ethyl]-4-butyl-4(S)-carboxy-l-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[l,l'-Biphenyl)yl]ethyl]-4-methyl-4(S)-carboxy-l-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[l,l'-Biphenyl)yl]propyl]-4-butyl-4(S)-carboxy-l-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-(4-Propylphenyl)ethyl)-4-butyl-4(S)-carboxy-l-oxobutyl]-3(S) methylaminocarbonyl-hexahydropyridazine; 2-[2ÇR)-[2-(4-Butylphenyl)ethyl]-4-butyl-4(S)-carboxy-l-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-(4-t-Butylphenyl)ethyl]-4-butyl-4(S)-carboxy-l-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[4-(4-Fluorophenyl)phenyl]ethyl]-4-butyl-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[4-(4-Fluorophenyl)phenyl]ethyl]-4-methyl-4(S)-carboxy-1 -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-n-Octyl-4-methyl-4(S)-carboxy-l-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-l-oxobutyl} 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-methyl-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4(S)- carboxy-l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbûnyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-l-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine; -30- 011584 2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-methyl-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4(S)- carboxy-l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 5 2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-butyl-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-methyl-4(S)-10 carboxy-l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-l-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine; 2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-(3-phenylpropyl)-15 4(S)-carboxy-1 -oxobutyl]-3 (S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-1 -oxobutylj-3 (S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-methyl-4(S)-carboxy- l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;‘ 20 2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4(S)- carboxy-l-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-[3-(phenylpropyl)-4(S)-carboxy-1 -oxobutyl]-3 (S)-methylaminocarbonyl-hexahy dropyridazine; HS(CH2)2-(S-D-Leu)-Phe-NHMe; 25 HS(5)CHMeCH2-(S-Z)-Leu)-Phe-NHMe; HS(5)CH(PhtNBu)CH2-(S-D-Leu)-Phe-NHMe, HS(5)CH(PhtNEt)CH2-(S-£)-Leu)-Phe-NHMe; HS( 1,2-Cyclopentyl)(S-£)-Leu)-Phe-NHMe

Me-S(NH)2-(CH2-DL-Leu)-Trp-NHBn; 30 n-Bu-S(NH)2-(CH2-DL-Leu)-Trp-NHBn; n-Bu-S(NH)2-(CH2-DL-TyrOCH3)-Trp-NHBn; -31- 011584

Me-RS-SO(NH)-(CH2-L-Leu)-Phe-Ala-NH2; n-Bu-RS-SO(NH)-(CH2-L-Leu)-Phe-Ala-NH2; HONH-C-CH2CH(CH2CH(CH3)2)-CO-Nal-Ala-NH2;

O HO-NH-CO-CH2-CH-(CH2-CH(CH3)2-CO-Nal-Pro-NH2; HO-NH-CO-CH(CH3-CH(CH2)-CH(CH3)2)-CO-Nal-Ala-NH2; HON COCH2 —C—CO-Pal—Ala NH, 2 , wherein Pal is 10 3-pyridylalanine;

H HON— COCH2—C CO—Nal(CH2S)Ala NH, HO-NH-CO-CH2-CH(CH2CH(CH3)2)-CONal-(CH2NH)-Ala-NH2;

O 10 15 -32- Ο

II HONHC— CH?-CHC— Ν-2 | Η

CHO 011584 chch2schconh2 çh9 CH,

CH 1 <<<

(CH3)2 O o oo

il II II NONH-C— CH2-ÇHC-NH—ÇHC—NH~ ÇH2- conh2

4-(l,3-Dihydro-l,3-dioxo-2H-benz[f|isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(2-morpholin-4-ylethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1 -(S)-[[methylamino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(lH-imidazol-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(lH-tetrazol-5-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[[(2-(phenyl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(pyridin-3-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3-Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methyl-l-(S)-[[(2-methyl-2H-tetrazo-5-ylmethyl)amino]carbonyl]butyl]amino]-butanoicacid: -33- 011584 4-( 1,3-Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-y l)-2-(R)-[[3-methyl-l-(S)-[[(4-hydroxy-2-methyl-pyrimidin-5-ylmethyl)amino]carbonyl]butyl]-amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-5 l-(S)-[[[2-(2-pyridin-3-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f|isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[l-(lH-tetrazol-5-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l_(S)"[[(5-amino-4H-[l,2,4]-triazol-3-ylmethyl)amino]carbonyl]butyl]amino]- 10 butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[[l-(6-oxo-l,6-dihydro-pyridazin-3-yl)ethyl]amino]carbonyl]butyl]-amino]-butanoic acid; 4-( 1 ,-3 -Dihydro-1,3 -dioxo-2H-benz[f]i soindol-2-yl)-2-(R)-[[3 -methyl-15 l-(S)-[[(phenyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)- [[3 -methyl-1 -(S)-[[(benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(pyridin-4-ylmethyl)amino]carbohyl]butyl]amino]-butanoic acid; 20 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindoI-2-yl)-2-(R)-[[3-methyl- l-(S)-[[[2-(lH-imidazol-4-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(pyridin-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3-Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methyl-25 l-(S)-[[(4-sulfamoyl-phenyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-l"(S)-[[(3-sulfamoyl-phenyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l~(S)-[[(4-dimethylamino-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 30 4-(l ,3-Dihydro-1,3-dioxo-2H-benz[ f]isoindol-2-yl)-2-(R)-[[3-methyl- l~(S)-[[[l-(S)-phenyl-ethyl]amino]carbonyl]butyl]amino]-butanoic acid; -34- 011584 4-(1,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(l,l-dioxo-tetrahydro-thiophen-3-yl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-5 1 -(S)-[[(4-sulfamoyl-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methÿl-1 -(S)-[ [[ 1 -(R)-phenyl-ethyl]amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l"(S)-[[(3-fluorobenzyl)amino]carbonyl]butyl]amino]-butanoic acid; 10 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- 1 -(S)-[[(furan-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3 -methyl-1 -(S)-[ [( 1 -methy 1- lH-tetrazol-5-ylmethyl)amino] carbonyljbutyl] amino] -butanoicacid; 15 4-(1,3 -Dihydro-1,3 -dioxo-2H-benz[f] isoindol-2-y l)-2-(R)-[[3 -methy 1- l-(S)-[[(l,2,3,4-tetrahydro-naphthalen-l-yl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f] isoindol-2-y l)-2-(R)-[[3 -methy 1-l-(S)-[[(2,4-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 20 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(3-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(4-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f] isoindol-2-yl)-2-(R)-[[3 -methyl- 25 l-(S)-[[(4-methanesulfonylamino-benzyl)amino]carbonyl]butyl]amino]-butanoicacid; 4-( 1,3 -Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(3-methanesulfonylamino-benzyl)amino]carbonyl]butyl]amino]-butanoicacid; 30 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(3,4-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(1,3 -Dihydro-1,3 -dioxo-2H-benz[f] isoindol-2-yl)-2-(R)-[[3 -methyl-l-(S)-[[(3-trifluoromethyI-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; -35- 011584 4-[2-(S)-[l-(R)-Carboxy-3-(l,3-dioxo-l,3-dihydro-benzo[f]isoindol-2-yl)-propylamino]-4-methyl-pentanoylamino-methyl)-benzoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(2-hydroxy-l,l-bis-hydroxymethyl-ethyl)amino]carbonyl]butyl]amino]- 5 butanoic acid; 4-(1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-y l)-2-(R)-[[3 -methy 1-l-(S)-[[(3,5-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[benzylmethyl-amino]carbonyl]butyl]amino]-butanoic acid; 10 4-(1,3 -Dihydro-1,3 -dioxo-2H-benz[f] isoindol-2-y l)-2-(R)- [[3 -methy 1- l-(S)-[[(2-dimethylaminoethyl)-methyl-amino]carbonyl]butyl]amino]-butanoicacid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[fjisoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(l-azabicyclo[2.2.2]-oct-3(R)-amino]carbonyl]butyl]amino]-butanoic acid; 15 4-(l ,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methyl- l-(S)-[[(l-azabicyclo[2.2.2]oct-3-(S)-yl)amino]carbonyl]butyl]amino]-butanoicacid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(3-(R)-4-(S)-5-(R)-6-tetrahydrox-tetrahydra-pyran-2-(R)-ylmethyl)amino]- 20 carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(N,N'-dimethyl-hydrazino)carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(methylmethoxy)amino]carbonyl]butyl]amino]-butanoic acid; 25 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-y.l)-2-(R)-[[3-methyl- l-(S):[[(dimethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1, 3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methy 1-l-(S)-[[(2-oxo-tetrahydro-thiophen-3-(R)-yl)amino]carbonyl]butyl]amino]-butanoic acid; 30 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(2-oxo-tetrahydro-thiophen-3-(S)-yl)amino]carbonyl]butyl]amino]-butanoic acid; -36- 01 1 5 8 4 4-(1,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(3-(R)-acetylamino-4-(S)-5-(S)-dihydroxy-6-(R)-hydroxymethyl-tetrahydro-pyran-2-yl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-5 l-(S)-[[[benzyl(2-hydroxyethyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1 -(S)-[3,4-dihydro-1 H-isoquinoline-2-carbonyl]butyl] amino]-butanoic acid ; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[4-methylpiperazine-l-carbonyl]butyl]amino]-butanoic acid; 10 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[l-oxo-[l,4]thiazinane-4-carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[morpholine-4-carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-15 l-(S)-[4-(2-3-dihydroxy-propyl)-piperazine-l -carbonyl]butyl]amino]-butanoic acid; 4-(1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-y l)-2-(R)- [[3 -methy 1-1 - ( S )-[3,4,5,6-tetrahydro-H-[2,3 ] b ipy r i d iny 1-1 ] carbonyljbutyl] amino] -butanoicacid; 20 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[(l-methyl-8-oxo-l,7-diazacyclotridec-9-yl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[[methyl-l-methyl-piperidin-4-yl)amino]carbonyl]butyl]amino]-butanoic 25 acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1 -(S)-[[(4-hydroxy-1,1 -dioxo-tetrahydro-thiophen-3 -yl)amino]carbonyl]butylj-amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[fjisoindol-2-yl)-2-(R)-[[3 -methy 1-30 l-(S)-(4-ethoxycarbonylmethyl-piperazine-l-carbonyl)butyl]amino]-butanoic acid; .37. 01 1 584 4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methy 1-l-(S)-[[(l,l-dioxo-tetrahydro-thiophen-3-yl)-methyl-amino]carbonyl]butyl]-amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methyl-5 l-(S)-[2-(R)-(pyridin-3-yl)-pyrrolidinecarbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[2-(S)-(pyridin-3-yl)-pyrrolidinecarbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[3-oxo-2-(R)-phenyl-piperazine-l-carbonyl]butyl]amino]-butanoic acid; 10 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-y l)-2-(R)-[[3 -methy 1- l-(S)-[3-oxo-2-(S)-phenyl-piperazine-l-carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[(pyridine-3-carbonyl-hydrazino)carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-15 1 -(S)-[[(benzenesulfonyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[(3-aminobenzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-( 1,3 -Dihydro-1,3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3 -methy 1-l-(S)-[[[4-(trifluoro-methanesulfonylamino)benzyl]amino]carbonyl]butyl]amino] 20 butanoic acid; 4-(l,3-Dihydro-l,3-dîoxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-l-(S)-[[[2-hydroxy-(R)-bicyclo[4.3.0]nona-3,6(l)-diene]amino]carbonyl]butyl]-amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-25 l-(S)-[[[2-hydroxy-(S)-bicyclo[4.3.0]nona-3,6(l)-diene]amino]carbonyl]butyl]- amino]-butanoic acid; 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l'(S)“[[(N-methyl-pyrrolidine)-methyl-amino]carbonyl]butyl]amino]-butanoic acid; 30 4-(l,3-Dihydro-l,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- l-(S)-[(N-ethoxycarbonylmethyl-piperazine)-l-carbonyl]butyl]amino]-butanoicacid; -38- 011584 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-bromo- 1,3 -dioxo-1,3 -dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-propoxy- 1,3 -dioxo-1,3 -dihydro-isoindol-2-yl)-butanoic acid; 5 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-nitro- 1.3- dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4*(5-amino- 1,3 -dioxo-1,3 -dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-methyl- 10 l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-methoxy- 1.3- dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4r(5-benzyloxy-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 15 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-phenyl- lJ3-dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)- [ 1 -(S)-(B enzylamino)carbonyl-3 -methy lbutylamino]-4-(l ,3 -dioxo- 1,3 -dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5- 20 methanesulfonylamino-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5- benzenesulfonylamino-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[l-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-hydroxy- 1,3 -dioxo-1,3 -dihy dro-isoindol-2-yl)-butanoic acid; 25 2-(R)-[[3-Methyl-l-(S)-[[(pyridin-3-ylmethyl)amino]carbonyl]- butyl]amino]-4-(l,3,5,7-tetraoxo-3,5,6-tetrahydro-lH-pyrolo[3,4-f]isoindol-2-yl)butanoic acid;

EtONHCONMe-CH2CH(iBu)-CO-L-Trp-NHEt;

EtCONOH-CH2CH(iBu)-CO-L-Trp-NHEt; 30 n-PrCONOEt-CH2CH(iBu)-CO-L-Trp-NHEt;

EtNHCONOMe-CH2CH(iBu)-CO-L-Trp-NHEt;

MeNHCONOH-CH2CH(iBu)-CO-L-Trp-NHEt; -39- 011584

EtONHCONMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;

EtCONOH-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; n-PrCONOEt-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;

EtNHCONOMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; 5 MeNHCONOH-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; HONHCONHCH2CH(iBu)-CO-L-TrpNHMe;HONHCONHCH2CH2CH(iBu)-CO-L-TrpNHMe;HONHCONHCH(iBu)-CO-L-TrpNHMe;H2NCON(OH)CH(iBu)-CO-L-TrpNHMe; 10 N(OH)CH2CH(iBu)-CO-L-TrpNHMe; H2NCON(OH)CH2CH2CH(iBu)-CO-L-TrpNHMe; CH3CON(OH)CH(iBu)-CO-L-TrpNHMe; CH3CON(OH)CH2CH(iBu)-CO-L-TrpNHMe; CH3CON(OH)CH2CH2CH(iBu)-CO-L-TrpNHMe; 15 NHOHCOCH2CH(i-Bu)CO-L-Trp-NHMe; HONHCONHCH2CH(i-Bu)CONHCHCOOH or

I R4 ROOCCH2CH(i-Bu)CONHCHCOOH; 20 | R4 N-{D,L-2-(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2'-naphthyl)alanyl-L-alanine, 2-(amino)ethyl amide; N-{D,L-2-(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L- 25 3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide; 4(S)-[3-Hydroxyaminocarbonyl-2(R)-(2-methylpropyl)propanoyl]amino- l,2,3,4,5-tetrahydro-3H-2-benzazepin-3-one; [4-(N-Hydroxyamino)-(2R)-isobutyl-3-methylsuccinyl]-L-phenylglycine N-methylamide; 30 4($)-[2(R)-[l(R)-Hydroxycarbamoyl-2-morpholinoethyl]- 4-methylvaleryl]amino-l,2,4,5-tetrahydro-3H-2-benzazepine-3-one; -40- 011584 (lR,4S)-4-[(2R)-Hydroxycarbamoylmethÿl-4-methylvaleryl]amino-3-oxo-l,2,4,5-tetrahydro-3H-2-benzazepine-l-carboxylic acid; 3-[2-(N-Methylcarbamoyl)ethylsulfinyl]-5-methylhexanohydroxamic acid;N-[(2-Thenoylmercapto-3-methyl)-butanoyl]-homocysteine thiolactone; 5 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-isoleucine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, 10 N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine,N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-benzyl ether, N-phenylamide; 15 N-[l(R)-Carboxy-ethyl]-cc-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(2-phenyl-ethyl)glycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine, 20 N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-valine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine,N-phenylamide hydrochloride; 25 N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-asparagine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-threonine,N-phenylamide hydrochloride; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, 30 N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid,N-phenylamide; -41- 011584 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine,N-phenylamide hydrochloride; N-[l(R)-Carboxy-5-(l,3-dioxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide; 5 N-[l(R)-Carboxy-5-(l-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl) glycine-(S)-leucine, N-phenylamide hydrochloride; N-[ 1 (R)-Carboxy-5-( 1 -oxo-isoindolin-2-y l)pentyl ] -a-(S)-(2-phenyl-ethyl)gIycine-(S)-arginine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-oc-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S)-10 leucine, N-phenylamide hydrochloride; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-(4-methylphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-(2'-thienyl)ethyl)glycine-(L)-leucine, N-phenylamide; 15 N-[ l(R)-Carboxy-ethyl]-a-(S)-(2-(4-ethylphenyl)ethyl)glycine-(L)- leucine, N-phenylamide; N-[l(R)-Carboxy-5-(l-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-20 leucine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(2-cyclohexyl-ethyl)glycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(cyclohexyl)glycine, N-phenylamide; 25 . N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)- (cyclohexylmethyl)glycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-3-naphthylalanine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-a-30 naphthylalanine, N-phenylamide; -42- 011584 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, α,δ-bis-N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-cyclohexylamîde; 5 N-[(l(R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)- (4-hydroxyphenyl-ethyl)glycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid,10 Ng-benzylamide, Na-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-ornithine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-arginine, N-phenylamide; 15 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)- (3-phenylpropyl)glycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-n-octylglycine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, 20 N-(4-carboxyphenyl)amide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-trifluoromethylphenyl)amide; N-[l(R)-Carboxy-ethyl]-oc-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide; 25 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl)amide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-(2-4-propylphenyl)ethyl)glycine-(L)-30 arginine, N-phenylamide; -43- 011584 N-[l(R)-Carboxy-ethyl]-a-(S)-(2-(3,4-dimethylphenyl-ethyl)glycine-(L)-leucine, N-phenylamide; (2-(((4-(1,3-Dihydro-l, 3-dioxo-2H-isoindol-2-yl)butyl)-hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide; 5 (2-(((4-(1,3-Dihydro-l-oxo-2H-isoindol-2-yl)butyl)- hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide; (2-(((4-(1,3 -Dihydro-1 -oxo-2H-isoindol-2-y l)butyl)(2-methy 1-1 -( 1 -oxopropoxy)propoxy)phosphinyl)methy l)-4-pheny lbutanoyl)-L-leucine,N-phenylamide; 10 (2-((Hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide; [[Hydroxy[l(R)-[N-(N-acetyl-L-prolyl-L-alanyl)-amino]-ethyl]-phosphinyl]-methyl]-4-phenyl-butanoyl-L-leucyl, N-phenylamide; [Hydroxy-[N-(N-(berizoyl)-L-prolyl)aminobutyl]phosphinyl]methyl]-15 4-phenyl-butanoyl-L-Ieucine, N-phenylamide; [Hydroxy-[2-Methylpropyloxycarbonyl-aminobutyl]-phosphinyl]methyl]-4-phenylbutanoyl-L-leucine, N-phenylamide; [Hydroxy-[l-Methylethylaminocarbonyl-aminobutyl]-phosphinyl]methyl]-4-phenylbutanoyl-L-leucine, N-phenylamide; 20 N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucinamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-phenylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-benzylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-(2-phenylethyl)amide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalaninamide; 25 N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine N-phenylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine N-benzylamide; N-(2-ThiomethylT4-phenylbutanoyl)-(L)-phenylalanine-b-alanine; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-(L-leucine,N-phenylamide)amide; 30 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-(2(S)-t- butyl)glycine, N-phenylamide)amide; -44- 01 1 584 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-l,5-pentanedioic a.cid l-(2(S)-t-butyl)glycine, N-(4-pyridylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1 -(L-arginine,N-methylamide)amide; 5 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-methyl-1, 5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid l-(2(S)-t-butyl)glycine, N-phenylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-methyl-l,5-pentanedioic acid10 l-(2(S)-(4-thiazolylmethyl)glycine, N-phenylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-methyl-1,5 -pentanedioic acid 1- (2(S)-(3-pyridylmethyl)glycine, N-phenylamide)amide;. 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-methyl-l,5-pentanedioic acid1 -(L-leucine, N-(4-pyridyl)amide)amide; 15 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-methyl-l,5-pentanedioic acid 1 -(2(S)-(2-pyridylmethy l)glycine, N-phenylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid1 -(L-arginine, N-phenylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-methyl-l,5-pentanedioic acid20 l-(L-phenylalanine, N-4-pyridylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(l-(4-(N-(2-oxoisoindolinyl))-butyl))-1,5-pentanedioic acid 1-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-( 1 -(4-(N-(2-oxoisoindolinyl))-but- 2- enyl))-l,5-pentanedioic acid l-(L-leucine, N-phenylamide)amide; 25 2(R)-(2-(4-(4-Fluorophenyl)phenyl)ethyl)-4-methyl-l,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(Phenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(4-Methoxyphenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic30 acid 1-(L-leucine, phenylamide)amide; 2(R)-(2-(4-(4-Methylphenyl)phenyl)ethyl)-4-methy 1-1,5 -pentanedio ic acid1-(L-leucine, phenylamide)amide; -45- 011584 2(R)-(2-(4-(4-Hydroxy-n-butyl)-phenyl)-ethyl)-4-methylpentanedioic acid1 -(S-leucine, phenylamide)amide; 2(R),4(S)-(2-(4-(3-Hydroxy-n-propyl)phenyl)ethyl)-4-methyl- 1,5-pentanedioic acid l-(L-leucine, N-phenylamide)amide; 5 2(R)-(2-PhenylethyI)-4-methyl-l,5-pentanedioic acid l-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-(L-leucine,N-ethylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-(L-leucine, 10 N-isopropylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)propyl)-1,5-pentanedioic acid 1 -(2(S)-tert-butyl-glycine, N-4-pyridyl)amide)amide; 2(R)-(3-(4-(l-n-Propyl)phenyl)propyl)-l,3-pentanedioic acid l-(L-leucine,N-phenylamide)amide; 15 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-hexyl-l,5-pentanedioic acid 1-(L- leucine, N-phenylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-butyl-1, 5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-(3-methylbenzyl)-1,5-pentanedioic20 acid l-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-(2-benzimidazolyl)butyl)- 1,5-pentanedioic acid l-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-(4-(2-benzthiazolyl)butyl)- 1.5- pentanedioic acid l-(L-leucine, N-phenylamide)amide; 25 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-(2-benzoxazolyl)butyl)- 1.5- pêntanedioic acid l-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acidl-(L-leucine, N-phenylamide)amide 9-piperidineamide; 2(R)-(2-(4-(l-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acid 1-(L-30 leucine, N-methylamide)amide 9-phenylamide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acidl-(L-leucine, N-methylamide)amide 9-tert-butylamide; -46- 011584 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acidl-(L-leucine, N-methylamide)amide 9-benzylamide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethy l)-4-carboxy-1,9-nonanedioic acidl-(L-leucine, N-methylamide)amide 9-morpholineamide; 5 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acid l-(L-leucine, N-methylamide)amide 9-(l(R)-phenylethyl)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l ,9-nonanedioic acidl-(L-leucine, N-methylamide)amide 9-(l(S)-phenylethyl)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acid10 l-(L-leucine, N-methylamide)amide 9-(N-methyl-N-phenyl)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-carboxy-l, 9-nonanedioic acidl-(L-leucine, N-methylamide)amide 9-(N'-methylpiperazine)amide trifluoroaceticacid sait; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid15 1 -(L-leucine, N-methylamide)amide 9-(3-pyridyl)amide; 2(R)-(2-(4-(l-Propyl)phenyl)ethyl)-4-carboxy-l,9-nonanedioic acid 1-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-((R)-(S-p-methoxybenzyl)penicillamine, N-phenylamide)amide; 20 2(R)-(2-(4-(l-Propyl)phenyl)ethyl)-l,5-pentanedioic acid l-((R)-(S-p- methoxybenzyl)penicillamine sulfone, N-phenylamide)amide; 2-(2-(4-(l-Propyl)phenyl)ethyl)-4-(l-(4-(2-phthalimido))butyl)- 1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-benzoylamino-l-butyl)-25 1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-pivaloylamino-l-butyl)- 1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-phenylsulfonylamino-l-butyl)- 1,5-pentandioic acid l-(L-leucine, N-methylamide)amide; 30 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-(N'-phenylureido)-l-butyl)- 1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide; 4Ί- 011584 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-phenyloxycarbonylamino-1-butyl)-1,5-pentandioic acid l-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-N'-benzyloxycarbonylamino-L-prolylamino)-l-butyl)-l,5-pentandioic acid l-(L-leucine, N-methylamide)amide; 5 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-(4-cyclopentylamino-1 -butyl)- 1,5-pentandioic acid l-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l-n-Propyl)phenyl)ethyl)-4-(4-(2-carboxybenzoylamino)-l-butyl)-l,5-pentandioic acid l-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(l -n-Propyl)phenyl)ethyl)-4-(4-cyano-1 -butyl)-1,5-pentandioic10 acid l-(L-leucine, N-phenylamide)amide; N-[l(R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-leucine, N-phenylamide; N-[l(R)-Carboxyethyl]-a-(S)-(n-octyl)]glycine-(L)-leucine, N-phenylamide; 15 N-[ 1 (R)-Carboxyethyl]-a-(S)-(n-octyl)]glycine-(L)-arginine, N-phenylamide; N-[l(R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-arginine, N-phenylamide; N-[ 1 (R)-Carboxyethyl]-a-(S)-(n-decyl)]glycine-(L)-leucine, 20 N-phenylamide; l-(2-(4-Propylphenyl)ethyl)cyclopentane-l,3-dicarboxylic acid 1-(L-leucine, N-phenylamide)amide; l-(2-(4-Propylphenyl)ethyl)cyclohexane--l,3-dicarboxylic acid 1-(L-leucine, N-phenylamide)amide; 25 N-[l(R)-Carboxyethyl]-a-(S)-2-(4-fluorobiphenyl)-glycyl-(S)-2-(Zer/- butyl)glycine, N-phenylamide; 3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxy- 3,4-dihydrocarbostyril; 3S-[4-(N-Hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]- 30 amino-3,4-dihydrocarbostyril; 3 S-[4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]amino- 1-methoxy-3,4-dihydrocarbostyril; -48- 011584 3 S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1 -jnethoxymethyl- 3,4-dihydrocarbostyril; 1- Carboxymethyl-3S-[4-N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril; 5 3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino- l-methoxyethoxymethyl-3,4-dihydrocarbostyril; 3S-[4-(N-Hydroxyamino)-2R-heptylsuccinyl]amino-l-methoxy- 3,4-dihydrocarbostyril; 7-Chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino- 10 l-methoxymethyl-3,4-dihydrocarbostyril; 3 S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1 -methoxyethyl- 3,4-dihydrocarbostyril; 3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethyl- 6,7-methylenedioxy-3,4-dihydrocarbostyril; 15 3R-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl] amino-1 -methoxyethyl- 6,7-methylenedioxy-3,4-dihydrocarbostyril; 2- (R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-oxopropyl)amino]-3-methyl-butyramide; 2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxy-benzeriesulfonyl)- 20 amino]-N-hydroxy-3-methylbutyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-[(pyridin-3- ylmethyl)carbamoyl]ethyl)amino)-3-methylbutyramide; 2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl]-[2-(methylpyridin- 3-ylmethylcarbamoyl)ethyl]amino)-3-methylbutyramide; 25 4-(3-[ 1 -(R)-1 -Hydroxy carbamoy 1-2-methylpropyl)- (4-methoxybenzenesulfonyl)amino]propionyl)piperazine-l-carboxylic acid,tert-butyl ester; 2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-l-ylpropyl)amino)-3-methylbutyramide hydrochloride; 30 2-(R)-2-[(BenzylcarbamoyIethyl)(4-methoxy-benzenesulfonyl)amino]- N-hydroxy-3 -methylbutyramide; 2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl][(2-morpholin-4- ylethylcarbamoyl)methyl]amino]-3-methylbutyramide; -49- 011584 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) ([(pyridin-3-ylmethyl)-carbamoyl]methyl)amino)-3-methylbutyramide; 2-(R)-3,3,3,-Trifluoro-N-hydroxy-2-[(methoxy-benzenesulfonyl)(3- morpholin-4-yl-3-oxopropyl)amino]propionamide; 5 2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)[2-methylpyridin- 4-ylmethylcarbamoyl)ether]amino)-3-methylbutyramide; 4-[4-Methoxybenzenesul fony 1)(3 -morpholin-4-y 1-3 -oxopropyl)amino]-1 -methylpiperidene-4-carboxylic acid hydroxyamide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-10 l-yl)-3- oxopropyl]amino)-3-methylbutyramide; 2-(R)-2-[(2-Carboxyethyl)(4-methoxybenzene-sulfonyl)amino]-N-hy droxy-3 -m ethy lbutyramide ; [(2-Carboxyethyl)(3,4-dimethoxybenzene-sulfonyl)amino]-N-hydroxy-acetamide; - 15 2-(R)-2-[(2-Carbamoylethyl)(4-methoxybenzene-sulfonyl)amino]-N- hydroxy-3 -methylbutyramide; 2-(R), 3-(R)-3,N-Dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperidin-l-ylpropyl)amino]-butyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[3-(methyipyridin-20 3-ylmethylcarbamoyl)propyl]amino)-3-methylbutyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[2- (methylcarboxymethylcarbamoyl)ethyl]amino)-3-methyl-butyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[(l- methylpiperidin-4-ylcarbamoyl)methyl]amino)-3-methylbutyramide; 25 2-(R)-N-Cyclohexyl-N-hydroxy-2-((4-methoxy-benzenesulfonyl)- [3 -(4-methylpiperazin-1 -y l)-3 -oxopropyl] amino)-acetamide; 2-(R)-N-Hydroxy-2-[(methoxybenzenesulfonyl)(3-morpholin-4-yl- [3-oxopropyl)amino]-4-(morpholin-4-yl)butyramide; [4-N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl 30 ester; [4-N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminolaurolactam; -50- 011584

Na-[4-(N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-Ne-(N-benzyloxycarbonylglycyl)-L-lysyl-L-alanine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine ethyl ester; 5 [4-(N-Hydroxyamino)-2(RS)-isobutyl succinyl] -L-leucylglycine isopentylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-valylglycirie ethylamide;[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine ethylamide; 10 Na-[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-Ne- tert.butoxycarbonyl-L-lysylglycine ethylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-L-tyrosinylglycine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-L-15 tyrosinylglycine ethylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine isopentyl ester; 20 [4-(N-Hydroxyamino)-2(R)-propylsuccinyl]-L-leucylglycine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-sec.butylsuccinyl]-L-leucylglycine ethyl ester; [4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine;[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine methyl 25 ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylsarconsine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-proline ethyl ester; 30 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-L-alanine isopropyl ester; -51- 011584 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2- oxopropylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2- methoxyethylamide; 5 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2,2- dimethoxyethylamide;

Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-glycyl-L-lysine methylamide;

Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne- 10 (4-carboxybenzoyl)-L-lysl-L-alanine ethyl ester;

Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne- (4-carboxybenzoyl)-L-lysyl-L-aline; [4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminooctahydro- 2H-azonin-2-one; 15 [4-(N-Hydroxyamino)-3(S)-methyl-2(R)-isobutyl-succinyl]-L- leucylglycine ethyl ester; [(3 - Aminophthalimido)methyl] [(RS)-4-methyl-2-[[(S)3 -methyl-1 -(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid; [(RS)-4-Methyl-2-[[(S)-3-methyl-1 -(methyl-carbamoyl)butyl]- 20 carbamoyl]pentyl](l,8-naphthalenedi-carboximidomethyl)phosphinic acid; [(R or S)-4-Methyl-2-[[(R or S)-2-oxo-3-azacyclotridecyl]- carbamoyl]pentyl](1.8-naphthalenedicarboximidomethyl)phosphinic acid;N-[N-[(R or S)-2[[[[[N-[l-(Benzyloxÿ)cârbonyl]-L-prolyl]-L- leucyl]amino]methyl]hydroxyphosphinyl]-methyl]-4-methylvaleryl]-L- 25 leuCyl]-L-alanine; [[l,4-Dihydro-2,4-dioxo-3(2H)-quinazolinyl]-methyl][[(R or S)-4-methyl-2-[[(R or S)-2-oxo-3-azacyclotridecyl]carbamoyl]pentyl]phosphinic acid; N2-[(R)-Hydroxycarbamoylmethyl]-4-methylvaleryl]-N^,3- dimethyl-L-valinamide; 30 N-^-[2(Ror S)-[[[(5-Bromo-2,3-dihydro-6-hydroxy)-l,3*dioxo-lH- benz[d,e]isoquinol-2-yl)methyl]-[(hydroxy)phosphinyl]methyl]-4-methylvaleryl] N1,3 -dimethyl-L-valinamide; -52- 011584 N2-[(Ror S)-[[(R)-(Amino)[(5-bromo-2,3-dihydro-6-hydroxy-l,3'dioxo-lH-benz[d,e]isoquinol-2-yl)methyl](hydroxy)phosphinyl]methyl]-4-methylvaleryl]-N^,l-dimethyl-L-valinamide hydrobromide; N2-[2(R or S)-[l(S)-(Hydroxycarbamoyl)ethyl-4-methylvaleryl]-5 N\3-dimethylvalinamide; N2-[2(R)-[l(Ror S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-Nl,3-dimethyl-L-valinamide; N2-[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-4-(methoxy-carbonyl)butyl]-4-methylvaleryl]-N^,3-dimethyl-L-valinamide; 10 M2-[2(R)-[l(Ror S)-(Hydroxycarbamoyl)-4-phenyl-butyl]- 4-methylvaleryl]-Nl,3-dimethyl-L-valinamide; N2-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-succinimidoethyl]-4-methylvaleryl]-N^,3-dimethyl-L-valinamide; 4-[2(R)-[l(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-15 methylvaleryl]morpholine; 4-[2(R)-[l(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-l ,4-thiazine; 1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinol; 20 1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(l,2-dimethyl-3,5- dioxo-l,2,4-triazolidin-4-yl)ethyl]-4-methylvaleryl]piperidine; 4-[2(R)-[l(R or S)-(Hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo-l-imidazolidinyl)ethyl]-4-methylvaleryl]tetrahydro-l,4-thiazine;

Hexahydro-2-[2(R)-[ 1 (R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-25 4-methylvaleryl]-N-methyl-3(S)-pyridazinecarboxamide; l-[2(R)-(Ror S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol; [4-(N-Hydroxyamino)-2(R or S)-heptylsuccinyl]-L-leucyl-L-leucine ethylamide; 30 [4-(N-Hydroxyamino)-2(R or S)-nonylsuccinyl]-L-leucyl-L-leucine ethylamide; -53- 011584 [4-(N-Hydroxyamino)-2(R or S)-heptyl-3(S)-methylsuccinyl]-L-leucyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-(phthalimidomethyl)-succinyl]-L-leucyl-L-leucine ethylamide; 5 [4-(N-Hydroxyamino)-2(RS)-nonylsuccinyl]-L-tert.butylglycine methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-phthalimidomethyl)-10 succinyl]-L-tert.butylglycine methylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(Ror S)-(3-phenylpropyl)-succinyl]L-leucyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucine methylamide;[4-(N-Hydroxyaminô)-2(RS)-heptylsuccinyl]-L-leucine neopentylamide; 15 [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-alanyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-(Ne-phthaloyl)-lysyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-undecylsuccinyl]-L-leucyl-L-leucine20 ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-nonalyl-L-leucine ethylamide; 25 [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-phenylalanine tert.bùtylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-tert,butylglycine methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-neopentylglycine30 methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-homophenylalanyl-L-leucine ethylamide; -54- 01 1 584 [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-cyclohexylalanine methylamide; [4-(N-Hydroxyamino)-2(RS)-isooctylsuccinyl]-L-phenylalanine methylamide; 5 [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-L-neonpentylglycine methylamide; [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-β,β-dimethylphenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-threo-10 β-methylphenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-DL-erthro-β-methylphenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-[(3-methyl-2,5-dioxo-l-imidazolidinyl)methyl]succinyl]-L-leucyl-L-leucine ethylamide; 15 N2-[3-Cyclobutyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-propionyl]- N^,3-dimethyl-L-valinamide; N2-[3-Cyclopropyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-propionyl]-Nl,3-diniethyl-L-valinamide; N2-[3-Cyclopentyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-20 propionyl]-Nl,3-dimethyl-L-valinamide; N2-[3-Cyclopropyl-2(R)-[l(R or S)-[(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-Nl,3-dimethyl-L-valinamide; N2-[3-Cyclopropyl-2(R)-[l(R or S)-[(hydroxy-carbamoyl)-25 4-phenylbutyl)]propionyl]-N1,3-dimethyl-L-valinamide; N2-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-4-phenylbutyl]propionyl]-N1,3-dimethyl-L-valinamide; N2-[3-Cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-4-phenylbutyl]propionyl]-N1,3-dimethyl-L-valinamide; -55- 01 1 5 8 4 l-[3-Cyclopropyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine; l-[3-Cyclopropyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol; 5 l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine·, l-[3-CyclobutyI-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol; l-[3-Cyclopentyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-10 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-piperidinol; l-[3-Cyclopentyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethyl]propionyl]piperidine; 3-[3-Cyclobutyl-2(R)-[l(Ror S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2,5-dioxo-bimidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane; 15 3-[3-Cyclopropyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane; 3- [3-Cyclopentyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane; l-[3-Cyclohexyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-20 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]piperidine; 4- [3-Cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine; 4-[3-Cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine 25 S,S-dioxide; 4-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]tetrahydro-l,4-thiazine; · 3- [3-Cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl- 30 [4(R)-thiazolidinecarboxamide; 4- [3-Cyclopentyl-2(R)-[l(R or S)-(hydroxycarbamoy 1)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]morpholine; -56- 01 1 584 3- [3-Cyclopentyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide; 4- [3-Cyclobutyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4- 5 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine; 4-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethyl]propionyl]morpholine; ’ l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]pyrrolidine; 10 8-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4- trimethyl-2,5 -dioxo-1 -imidazolidinyl)ethyl]propionyl]-1,4-dioxa-8-azaspiro [4,5]decane; l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4j4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine; 15 l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]octahydroazocine; l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine; l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2-(3,4,4- 20 trimethyl-2,5-dioxo-l-imidazolidinyl)ethyl]propionyl]hexahydroazepine; 1 -[3 -Cyclobuty 1-2(R)- [2-(hexahy dro-1,3 -dioxo-pyrazolo [ 1,2-a] [1,2,4]- triazol-2-yl)-l(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine;l-[3-Cyclobutyl-2(R)-[l(R or S)-(hydroxycarbamoyl)-2- phthalimidoethyl]propionyl]piperidine; 25 2-[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]- hexahydro-N-methyl-3(S)-pyridazinecarboxamide; N-Cyclohexyl-hexahydro-2-[2(R)-[l(RS)-(hydroxycarbamoyl)-4- phenylbutyl]nonanoyl]-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R)-[l(RS)-(hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]- 30 N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide; 1-[2(R)-[1(R or S)-Hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]- piperidine; -57- 011584 N2-[2(R)-[l(RS)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidiny l)ethy l]nonanoyl]-N 1 -methyl-L-prolïnamide ; 1 -[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethyl]nonanoyl]piperidine; 5 Hexahydro-2-[2(R)-l(Ror S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5- dioxo-l-imidazolidinyl)ethyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[l (S)-(hydroxycarbamoyl)-3-phenylpropyl]-undecanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)-3-phenylpropyl]-10 undecanoyl]-N-methoxy-N-methyl-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[(l(S)-(hydroxycarbamoyl)-3-phenylpropyl]-undecanoyl]-N-(l,2,2,6,6-pentamethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[ 1 (S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N-15 methyl-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)-3-phenylpropyl]-nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)ethyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide; 20 l-[2(Ror S)-[l(S)-(Hydroxycarbamoyl)ethyl]undecanoyl]piperidine; l-[2-(R or S)-[l(S)-(Hydroxycarbamoyl)-3-phenylpropyl]undecanoyl]- piperidine;

Hexabydro-2-[2(R or S)-[l(S)-(hydroxyearbamoyl)-3-phenylpropyl]-undecanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide; 25 Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N- (2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide; l-[2(Ror S)-[l(S)-(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl]-piperidine; 4-[2(R or S)-[l(S)-(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl]-.30 morpholine; l-(Benzyloxycarbonyl)-hexahydro-2-[2(R)-[(R or S)-(hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]-N-(a(S)-methylbenzyl)-3(S)-pyridazinecarboxamide; -58- 01 1 5 8 4 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(carboxy)pentanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; 5 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(propylamino)- 6-(oxo)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6-(hydroxy)heptanoyl]-L-phenylalanine N-methylamide; (2S)-N-2-[(2R)-2i-[2''-(Hydroxyamino)-2''-(oxo)ethyl]-6'-10 (hydroxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2-[(2'R)-2'-[2'-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(4'-oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide; 15 2(S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'-(oxo)-6'- (propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[( l'S)-1 '-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide;. N-[(2R)-2-[( l'S)-1 '-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-20 (oxo)-6-(propylamino)hexanoyl]-L-phenylalanine N-methylamide; (2S)-N-2[(2'R)-[(1"R)-1 "-(1,3 -Dihydro- l,3-dioxo-2H-isoindol-2-yl)methyl-2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]-amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-25 (propylamino)hexanoyl]-L-phenylalanine N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-l"-(Methyl)-2"-(hydroxyamino)-2"-(ôxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acidN-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-l”-(Methyl)-2"-(hyroxyamino)-2"- 30 (oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3’dimethylbutanoic acid N-2-phenylethylamide; -59- 011584 (2S)-N-2-[(2'R)-2'-[( 1 "S)-1 ”-(Methyl)-2''-(hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acidN-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-[(2'R)-2'-[2"-(Hydroxyamino)-2”-(oxo)ethyl]-6'-5 (phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'- sulfamoyl)phenylethylamide; N-[2R)-2-[2’-(Hydroxyamino)-2'-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]-L-(3,5-dimethyl)phenylalanine N-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2”-(oxo)ethyl]-6'-[(4-10 methoxy)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'- sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acidN-2-(4'-sulfamoyl)phenylethylamide; 15 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'- [( 1 -oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acidN-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l”S)-l"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid 20 N-methylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-r'-(2-Methylpropyl)-2”-(hydroxyamino)-2”-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acidN-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)hexanoyl]-L-25 phenÿlalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenoxy)heptanoyl]-L-phenÿlalanine N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2- 30 phenylethylamide; -60- 011584 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(phenylmethoxy)-5 pentanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenylmethoxy)-heptanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2,-(oxo)ethyl]-6-(phenyloxy)hexanoyl]-L-phenylalanine N-methylamide; 10 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]- L-phenylalanine N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(qxo)ethyl]-6'-[(2-phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acidN-methylamide; 15 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'- [(4-methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2”-(oxo)ethyl]-6'-[(4-chlorophenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2”-(Hydroxyamino)-2"-(oxo)ethyl]-6'-20 [(3-methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl]-amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(carboxy)pentanoyl]-L-phenylalanine N-methylamide; 25 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenylmethoxy)- hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(propylamino)-6-(oxo)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6-(hydroxy)-30 heptanoyl]-L-phenylalanine N-methylamide; -61- 011584 (2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(hydroxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylarnide; 5 N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(4'- oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide; 2(S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[( l'S)-1 '-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-10 6-(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[(l'S)-l'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-(propylamino)hexanoyl]-L-phenylalanine N-methylamide; (2S)-N-2[(2'R)-[(r'R)-l"-(l,3-dihydro-l,3-dioxo-2H-isoindol-2- yl)methyl-2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]- 15 amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-(propylamino)hexanoyl] -L-phenylalanine N-2-phenylethylamide; (2S)-N-2-[(2,R)-2'-[(l”S)-l"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid 20 N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-l"-(Methyl)-2''-(hydroxyamino)-2H-(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acidN-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-l"-(MethyI)-2"-(hydroxyamino)-2"-25 (oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide; · (2S)-N-[(2'R)-2'-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'- (phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'- sulfamoyl)phenylethylamide; 30 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6'-(phenylmethoxy)- hexanoyl]-L-(3,5-dimethyl)phenylalanine N-2-(4'-sulfamoyl)phenylethylamide; ’62- 01 1 584 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]r6'-[(4-methoxy)phenoxyjhexanoyl]amino-3,3-dimethylbutanoic acidN-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2”-(Hydroxyamino)-2''-(oxo)ethyl]-6,-[(4-5 methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'- sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(l-.oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)phenylethylamide; 10 (2S)-N-2-[(2'R)-2'-[(l"S)-l"-(Methyl)-2"-(hydroxyamino)-2”- (oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acidN-methylamide; (2S)-N-2-[(2'R)-2'-[(r'S)-l"-(2-Methylpropyl)-2"-(hydroxyamino)-2''-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid 15 N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenoxy)heptanoyl]-L-phenylalanine N-methylamide; 20 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'- (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acidN-2-phenylethylamide; (2S)-N-2'-[(2'R)-2,-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'- 25 sulfamoyl)phenylethylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5- (phenylmethoxy)pentanoyl]-L-phenylalanine N-methylamide;N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]- 7-(phenylmethoxy)heptanoyl]-L-phenylalanine N-methylamide; 30 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6- (phenyloxy)hexanoyl]-L-phenylelanine N-methylamide; -63- 011584 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]-L-pheny1alanine N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(2-phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acid 5 N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-methy!phenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2''-(oxo)ethyl]-6'-[(4-chlorophenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 10 (2S)-N-2'-[(2/R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(3- methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-(Carboxymethyl)-6’-(3-methylphenoxy)hexanoyl]-amino-3,3-dimethylbutanoic acid N-methylamide; (37?, 10<S)-5-Methyl-3-(9-oxo-l,8-diazatricyclo[10.6.1.O]nonadeca-15 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; (37?,100)-2V-Hydroxy-5-methyl-3-(9-oxo-l,8-diazatricyclo[10.6.1.0]-nonadeca-12( 19), 13 ( 18), 14,16-tetraen-10-ylcarbamoyl)hexanamide; (37?, 115)-2V-Hydroxy-5 -methyl-3 -( 10-oxo-l, 9-diazatricyclo[ 11.6.1.0]-eicosa-13 (20), 14( 19), 15,17-tetraen-11 -y lcarbamoy l)hexanamide; 20 (37?,96)-5-Methyl-3-(8-oxo-l,7-diazatricyclo[9.6.1.0]octadeca- 11(18), 12(17), 13,15-tetraen-9-ylcarbamoyl)hexanoic acid; (37?,90)-7V-Hydroxy-5-methyl-3-(8-oxo-l,7-diazatricyclo[9.6.1.0]octadeca11 (18), 12(17), 13,15-tetraen-9-ylcarbamoyl)hexanamide; (105)-[4-Methyl-2-(9-oxo-l,8-diazatricyclo[10.6.1.0]nonadeca-25 12( 19), 13 ( 18), 14,16-tetraen-10-y lcarbamoyl)pentyl]-(quinolin-2- ylthiomethyl)phosphinic acid; (37?,10.S)-7V-Hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-l,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-y lcarbamoy 1)-hexanamide; 30 N-(4-Methyl-2-carboxymethylpentanoyl)-L-leucine-jV- (4-methoxycarbonylphenyl)carboxamide; -64- 011584 7V-(4-Methyl-2-(2V’,,-hydroxycarbamoyl)methylpentanoyl)-L-leucine- jV'-(4-methoxycarbonylphenyl)carboxamide; 7V-(4-Methyl-2-(77'-hydroxycarbamoyl)methylpentanoyl)-L-leucine-7/- (4-carboxyphenyl)carboxamide; 5 JV-(4-Methyl-2-(2V"-hydroxycarbamoyl)methylpentanoyl)-L- tryptophan-Ar-(4-carboxyphenyl)carboxamide; 77-(4-Methyl-2-(//"-hydroxycarbamoyl)methylpentanoyl)- L-cyclohexylglycine-7'/'-(4-methoxycarbonylphenyl)carboxamide; 7V-(4-Methyl-2-(7\7z-hydroxycarbamoyl)methylpentanoyl)-L-/-leucine-7V-10 (4-methoxycarbonylphenyl)carboxamide; (3R, 105)-6-Biphenyl-4-yl)-3 -(9-oxo-1, 8-diazatricyclo[ 10.6.1.O]onadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; (37?, 100)-3 -(9-Oxo-1,8-diazatricyclo[ 10.6.1.O]nonadeca-12( 19), 13(18), 14,16-tetraen-10-ylcarbamoyl)-5-(thiophen-2-yl)pentanoic acid; 15 (37?, 105)-3-Cyclopentyl-3-(9-oxo-l,8-diazatricyclo[10.6.1 .OJnonadeca- 12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)propionic acid; (37?, 105)-4-Cyclopentyl-3 -(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)butanoic acid; (37?,105)-4-Cyclopropyl-3-(9-oxo-l,8-diazatricyclo[10.6.1.0]nonadeca-20 12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)butanoic acid; (37?, 105)-5-Methyl-3-(9-oxo-l ,8-diazatricyclo[ 10.6.1 .OJnonadeca-12( 19), 13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid; (37?, 105)-7V-Hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]-nonadeca-12( 19), 13 ( 18), 14,16-tetraen-10-y lcarbamoy l)hexanamide; 25 (37?, 11 S)-7V-Hydroxy-5 -methy 1-3-( 10-oxo-1,9-diazatricyclo [11.6.1.0]- eicosa-13 (20), 14( 19), 15,17-tetraen-11 -y lcarbamoy l)hexanamide; (37?,9S)-jV-5-Methyl-3-(8-oxo-l,7-diazatricyclo[9.6.1.0]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid; (37?,90)-77-Hydroxy-5-methyl-3-(8-oxo-l,7-diazatricyclo[9.6.1.0]octadeca- 30 11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; (105)-2-Mercaptomethyl-4-methyl-iV-(9-oxo-l,8-diazatricyclo[10.6.1.0]- nonadeca-12( 19), 13 ( 18), 14,16-tetraen-10-y lcarbamoyl)pentanamide; -65- 011584 ( 105)-2- Acetylthiomethyl-4-methyl-7V-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]-nonadeca-12( 19), 13( 18), 14,16-tetraen-l 0-ylcarbamoyl)pentanamide; (37Î, 105)-2-(Methanesulfbnamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1 .Ojnonadeca-12( 19), 13 ( 18), 14,16-tetraen-10-ylcarbamoyl)- 5 hexanoic acid; (3Æ,105)-2-(3-Ethylureidomethyl)-5-methyl-3-(9-oxo-l,8-diazatricyclo[ 10.6.1 .Ojnonadeca-12( 19), 13 ( 18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid; (3/?,95)-N-Hydroxy-2-hydroxy-5-methyl-3-(8-oxo-l,7-10 diazatricyclo[9.6.1. Ojoctadeca-11 ( 18), 12( 17), 14,16-tetraen-9- ylcarbamoyl)hexanamide or its (2S,3R,9S) stereoisomer; (37?, 105)-7V-Hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-l,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)-hexanamide; 15 (3R,9S)-5-Methyl-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca- ll(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-Cyclobutylmethyl-N-(8-oxo-4-oxa- l,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)succinamic acid; (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca-20 1 l(18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid; (3R,9S)-5-(4-Chlorophenoxy)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0j-octadeca-1 l(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid; (3R,9S)-5-(4-Chlorophenoxy)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1 .Oj-octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid ethyl ester; 25 (3R,9S)-3-(8-Oxo-l,7-diazatricyclo[9.6.1.0joctadeca-l 1(18),12,14,16- tetrae'n-9-ylcarbamoyl)pentanoic acid ethyl ester; (3R,9S)-6-(4-Hydroxy-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca-11 ( 18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1 .Ojoctadeca-30 11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic acid; (3R,9S)-6-[4-(3-Hydroxy-propoxy)-phenyl]-3-(8-oxo-4-oxa- l,7-diazatricyclo[9.6.1.0joctadeca-l l(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; -66- 011584 (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1 .OJoctadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-5-(4-phenoxy-phenyl)pentanoic acid; (3R,9S)-6-[4-(2-Hydroxy-ethoxy)-phenyl]-3-(8-oxo-4-oxa- 1.7- diazatri cyclo [9.6.1.0] oct adeca-11 ( 18), 12,14,16-tetraen- 5 9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1 .Ojoctadeca-11 ( 18), 12,14,16-tetraen-9-y lcarbamoyl)-6-[4-(2-pyrrolidin-1 -yl-ethoxyphenyl]hexanoic acid; (3R,9S)-6-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]-10 octadeca-ll(18),12,14,16-tetraen-9-ylcarbamoyi)hexanoic acid; (3R,9S)-6-[4-(2-Methoxy-ethoxy)-phenyl]-3-(8-oxo-4-oxa- 1.7- diazatricyclo[9.6.1.0]octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1 .OJoctadeca-15 11 ( 18), 12,14,16-tetraen-9-ylcarbamoyl)-5-phenyl-pentanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1 .Ojoctadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6-phenyl-hexanoic acid; (3R,9S)-6-(3-Hydroxy-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]-octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; 20 (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca- 11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(3-piperidin-l-yl-propoxy)phenyl]hexanoic acid; (3R,9S)-6-[4-(3-Dimethylamino-propoxy)-phenyl]-3-(8-oxo-4-oxa- 1.7- diazatricyclo[9.6.1.0]octadeca-11 (18), 12,14,16-tetraen- 25 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-(8-oxo-4-oxa- 1.7- diazatricyclo[9.6.1 .Ojoctadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-(4-Cyano-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0j- 30 octadeca-ll(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-Naphthalen-2-yl-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0j- oçtadeca-11 ( 18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; 6Ί- 011584 (3R,9S)-3-(8-Oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6-(4-pyrrol-l-yl)hexanoic acid; (3R,9S)-6-(4-Hydroxy-3-methyl-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1. Ojoctadeca-11 ( 18), 12,14,16-tetraen- 5 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-(4-Benzyloxy-phenyl)-3-(8-oxo-4-oxa- I ;7 -diazatricy clo[9.6.1. Ojoctadeca-11 ( 18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-[4-(4-Aminobutoxy-phenyl)j-3-(8-oxo-4-oxa-10 l,7-diazatricyclo[9.6.1.0]octadeca-ll(18),12,14,16-tetraen- 9-ylcarbamoyl)hexanoic acid; (3R,9S)-5-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0]octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid; (3R,-9S)-6-(4-Amino-phenyl)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.0j-15 octadeca-1 l(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3 -(8-Oxo-4-oxa-1,7-diazatricyclo [9.6.1 .0 joctadeca- II ( 18), 12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(pyridin-4-ylmethoxy)phenylj-hexanoic acid; (3R,9S)-6-(4-Acetylamino-phenyl)-3-(8-oxo-4-oxa-l,7-20 diazatricyclo[9.6.1.0]octadeca-l 1(18), 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; N^-[[3-(N-Hydroxycarbamoyl)-4-methylthio-2-propoxymethyljbutylylj-Ν,Ο-dimethyltyrosine amide;

Na-[[3-(N-Hydroxycarbamoyl)-4-isopropylthio-2-propoxymethylj-25 butylyl]-N,O-dimethyltyrosine amide;

Na-[[3-(N-Hydroxycarbamoyl)-2-propylthio]butylyl]-N,O-dimethyltyrosine amide; N-[N-(l-Phosphono-3-phenylpropyl)-(S)-leucylj-(S)-phenylalanine-N- methylamide; 30 N-[N-(l-Phosphono-3-(4-bromo-l,8-naphthalene-dicarboximido)propyl)· (S)-leucyl]-(S)-phenylalanine methylamide; -68- 011584 N-[N-(l-Phosphono-3-(benzyloxycarbonylamino)propyl)-(S)-leucyl]-(S)-phenylalanine methylamide; N-[N-(l-Phosphono-3-(2-hydroxyphenyl)propyl)-(S)-leucyl]-(S)-phenylalanine methylamide; 5 N-[N-(l-Phosphono-3-(methylmercapto)propyl)-(S)-leucyl]-(S)- phenylalanine-N-methylamide; N-[N-( 1 -Phosphono-3 -(methylsulphinyl)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide; N-[N-(l-Phosphono-3-(methylsulphonyl)propyl)-(S)-leucyl]-(S)- 10 phenylalanine-N-methylamide; N-[N-(l-Phosphono-3-(l,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-tryptophan-N-methylamide; N-[N-(l-Phosphono-3-(l,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-methylamide; 15 N-[N-(l-Phosphono-3-(l,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (-)-aminoazacyclotridecan-2-one; N-[N-(l-Phosphono-3-(l,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-(aminoethyl)amide; N-[N-(l-Phosphono-3-(l,8-naphthalenedicarboximido)propyl)-(S)-leucyl] 20 (S)-lysine-N-(ethylpyrrolidine)amide; N-[N-( 1 -Phosphono-3 -( 1,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-(ethyl-N-methylpiperazine)amide; N-[N-(l-Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S)- leucyl]-(S)-phenylalanine-N-methylamide; and 25 N-[N-(l-Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S)- leucyl]-(S)-lysine-N-methylamide.

As noted above, numerous inhibitors of matrix metalloproteinases areknown. A large number of inhibitors are characterized as hydroxamic acid-basedand/or carboxylic acid-based compounds. Typical of such compounds are those 30 described in the following references, ail of which are incorporated herein by reference, since ail of the disclosed compounds can be used in the method of this invention. US 4,599,361 (Searle) -69- 011584 US 4,771,038 (ICI) US 4,996,358 (Roche) US 4,918,105 (Bellon) US 5,304,604; US 5,514,677 (British Biotechnology) US 5,240,958; US 5,310,763; US 5,530,161 (British Biotechnology) 10 US 5,453,438US 5,239,078US 5,183,900US 5,270,326WO 92/17460US 5,300,501US 5,304,549US 5,256,657 15 20 (British Biotechnology) (Glycomed) (Glycomed) (Glycomed) (Smith-Kline Beecham) (Celltech) (Roche) (Sterling Winthrop) US 5,300,674; US 5,412,145 (British Biotechnology) US 5,387,610; US 5,616,605 (Research Corporation Technologies)US 5,442,110; US 5,473,100 (Yamanouchi) US 5,643,908 (Sankyo) US 5,525,629 (British Biotechnology) US 5,569,665 (Celltech) US 5,530,128 (Celltech) US 5,318,964; US 5,447,929 (Roche) US 5,643,964; US 5,700,838 (British Biotechnology) WO 97/27174 (Shionogi)

An especially preferred group of compounds to be employed in the présent25 method are those described in WO 95/35275 and WO 95/35276, both of which areincorporated herein by reference. Typical compounds front within these groups.to be employed include: N-Hydroxy-2-[[(2-(4-methoxy-phenoxy)-ethyl-(toluene-4-sulfonyl)- aminoj-acetamide; 30 N-Hydroxy-2-[(4-phenoxy-ethyl)-toluene-4-sulfonyl) amino]-acetamide; N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-nonyl-amino]-acetamide; 2-[-Decyl-(toluene-4-sulfonyl)-amino]-N-hydroxy-acetamide; -70- 10 15 20 25 30 011584 2-Benzyl-(octane-1 -sulfonyl)-amino]-N-hydroxy-acetamide;N-Hydroxy-2-[(2-methoxy-benzyl)-(octane-l-sulfonyl)-amino]-acetamide;2-[(2-Ethoxy-benzyl)-(octane-l-sulfonyl)-amino]-N-hydroxy-acetamide;N-Hydroxy-2-[(naphthalen-2-yl-methyl)-(octane-l-sulfonyl)-amino]- acetamide; 2-[(4-Chloro-benzyl)-(octane-l-sulfonyl)-amino]-N-hydroxy-acetamide,and salts, solvatés, or hydrates thereof.

Another class of matrix metalloproteinase inhibitors are aryl sulfonamidesof the formula O R1 OIl I π

Ar-S—N—C—C-NHOH Λ 1 >2 0 ch2rr2 where Ar is carbocyclic or heterocyclic aryl, and R, R1, and R2 include hydrogen,alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. Thesecompounds are disclosed in European Patent Number 0606046, incorporatedherein by reference. Spécifie compounds to be employed in the présent methodinclude: N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl) amino]acetamide;N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclo-hexylmethyl)amino]- acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclo-hexyl)amino]- acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](phenethyl)amino]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-methylbutyl)amino]- acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](sec-butyl)amino]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](tert-butyl)amino]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-fluorobenzyl)amino]- acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-chlorobenzyl)amino]- acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isopropyl)-amino]acetamide; -71- 011584 N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-methylbenzyl)amino]- acetamide; 4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]-l-[dimethylaminoacetyl]-piperidine hydrochloride; 5 4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)- amino]-1 - [3-picoly l]-piperidine dihydrochloride; 4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]-l-[carbomethoxymethyl]-piperidine hydrochloride; 4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-10 amino]-1 -piperidine trifluoroacetate; 4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]-l-[t-butoxycarbonyl]-piperidine; 4-N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyI(benzyl)-amino]-1 -[methylsulfonyl]-piperidine; 15 N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]- 1 -[4-picoly]-piperidine hydrochloride; N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)amino]-l-[morpholinocarbonyl]-piperidine hydrochloride; and N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl (benzyl)amino]-2-[2-(4-20 morpholino)ethyl]acetamide.

The following compounds are prepared similarly to Example 7:N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)-amino-2-(2-(4- morpholino)ethyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-picoly)-amino-2-(2-(4-25 morpholino)ethyl]acetamide dihydro-chloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[2-(4-morpholino)ethyl]acetamide dihydrochloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-methyl-thiazol-4-ylmethyl)amino]-2-[2-(4-morpholino) ethyl]acetamide dihydrochloride; 30 N-Hydroxy-2-[[4-methoxybenzenesulfonyl]benzyl)amino]-2-[2-(4- thiomorpholino]ethyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4- methylthiazol-4-ylmethyl]acetamide; 011584 N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)amino]-2-[(6- chloropiperonyljacetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)amino]-2-[(l- pyrazolyl)methyl]acetamide; 5 N-Hydroxy-2-[[4-methoxybenzenesulfonyl(3-picolyl)amino]-2-[3- picolyljacetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)-amino]-2-[(l-methyl-4-imidazolyl)methyl]acetamide hydrochloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(isobutyl)amino]-2-[(l-methyl-10 4-imidazolyl)methyl]acetamide hydrochloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[(l-methyl-4-imidazolyl)methyl]acetamide hydrochloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(2-picolyl)amino]-2-[(l-methyl-4-imidazolyl)methyl]-acetamide hydrochloride; and 15 N-Hydroxy-2-[[4-methoxybenzenesulfonyl] (2-methylthiazol- 4-ylmethyl)amino-2-[(l-methyl-4-imidazolyl)methyl]acetamide hydrochloride.

Another group of small peptide matrix metalloproteinase inhibitors aredescribed in United States Patent Numbers 5,270,326, 5,530,161, 5,525,629, and5,304,604 (incorporated herein by référencé). The compounds are hydroxamic 20 acids defined by the formula

O O

Il I

HONHCCH-CH-CN-CHCOX

I I I I R1 R2 R3 R4

where R^, R2, R3, and R4 can be hydrogen or alkyl and X is OR$ or NHR5 where R$ includes hydrogen, alkyl and aryl, A includes alkyl, and n is 0 to 2. Typical compounds to be employed in the instant method include the 25 following: 011584 N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-D-tryptophan methylamide; N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-N-methyl-L-tryptophan methylamide; 5 N-[2-Isobutyl-3-(N-hydroxycarbonylamido)-propanoyl]-L-3-(2- naphthyl)-alanine methylamide; N-[2-Isobutyl'3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan 2-hydroxyethylamide; N-[2-Isobutyl-3-(N’-hydroxycarbonylamido)-propanoyl]-L-tryptophan10 amylamide; N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan piperidinamide; N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl-L-tryptophan dodecylamide; 15 N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L- tryptophan(S)-methylbenzylamide; N-[L-2-Isobutyl-3 -(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan(6-phenylmethoxycarbonyl-amino-hexyl-1 )amide; 2S-Hydroxy-3R-[ 1 S-(3-methoxy-2,2-dimethyl-propylcarbamoyl)-20 2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]6-(4-chloro)phenyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(methylcarbamoÿl)-2,2-dimethyl-propylcarbanioyl]octanohydroxamic acid; 25 2S-Hydroxy-3R-[ 1 S-(pyridin-2-ylmethylcarbamoyl)-2,2-dimethyl- propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-ilS-(pyridin-3-ylmethylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(pyridin-4-ylmethylcarbamoyl)-2,2-dimethyl- 30 propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 4-methoxy-butanohydroxamic acid; 011584 2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-4-benzyloxy-butanohydroxamic acid; 2S-Hydroxy-3R-[lS-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]- 4- benzylthio-butanohydroxamic acid; 5 2S-Hydroxy-3R-[1 S-(methylcarbamoyl)-2,2-dimethyl-buten- 3-ylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[1 S-(ter/-butylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(N,N-dimethyl-carbamoyl)-2,2-dimethyl-10 propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(3-hydroxy-2,2-dimethyl-propylcarbamoyl)-2,2-dimethyl-propylcarbanoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[lS-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-6-phenyl-hexanohydroxamic acid; 15 2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-butylcarbamoyl]- 5- methyl-hexanohydroxainic acid; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (2-hydroxyethyl)-amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylàlaninyl-proline; 20 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (2-hydroxyethyl)-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalaninyl-D-prolinol; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalaninyl-L-prolinol; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L“phenylalanine-N-(5-N- 25 methyl-pentylcarboxamide)amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (2-ethylthioethyl)amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (2-methoxyethyl)amide; 30 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-N- acetylethyl)amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (3 -(2-pyrrolidone)propyl)amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)propyl)amide sodium sait; [4-(N-Hydroxyamino)-2R-isobutylsuccinyI]-L-phenylalanine-N- (2-acetoxyethyl)amide; 5 [4-(N -Hydroxyamino)-2R-isobutyl-3 S-methylsucciny l]-L-phenylalanine- N-(3-(2-pyrrolidone)propyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine- N-methyl-N-(2-hydroxyethyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-10 N-(2-hydroxyethyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalaninyl- D-prolinol; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)propyl)amide sodium sait; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine- N-(3-(2-pyrrolidone)propyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)propyl)amide or a sait thereof; N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-20 isobutylsuccinyl]-N^-fér/-butyloxycarbonyl-L-lysine-N^ -methylamide; N^-[4-(N-Hydroxyamino)-3 S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-N6-terr-butyloxycarbonyl-N6-(4-hydroxyphenylthiomethyl)-L-lysine-N^ -methylamide; N^-[4-(N-Hydroxyamino)-3S-(2-thienylthiomethyl)-2R-isobutylsuccinyl]-25 N^-terZ-butyloxycarbonyl-L-lysine-Nl-methylamide; N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-O-/er/-butyl-L-threonine-N 1 -methylamide; N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-L-glutamine-Nl ,N^-dimethylamide; 30 N2-[4-(N-Hydroxyamino)-3 S-(4-hydroxyphenylsulphonylmethyl)-2R- isobutylsuccinyl]-N^-acetyl-L-lysine-N^-methylamide; 011584 3R-(3-Methoxycarbonyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-2S-2-propenyl-hexanohydroxamic acid; 3R-( 1 S-Methylcarbamoyl-2-thien-2-yl-ethylcarbamoyl)-5 -methyl-2 S -2-propenyl-hexanohydroxamic acid; 5 3R-(3-Methyl-l S-methylcarbamoyl-butylcarbamoyl)-5-methyl-2S- 2-propenyl-hexanohydroxamic acid; 2S-[lS-Methylcarbamoyl-2-oxadiazol-5-yl-ethylcarbamoyl)-5-methyl-2S-2-propenyl-hexanohydroxamic acid; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxylic10 acid)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N- methylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-beta- alanine)phenylalanine-N-methylamide; 15 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L- (4-oxymethylcarboxyglycine)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N- benzylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-cyario)phenylalanine-N-20 methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-acetamido)- phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L- (4-oxymethylcarboxamide)-henylalanine-N-methylamide; 25 [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethylsuccinyl]-L- (4-N-acetylamino)-henylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethylsuccinyl]-L- (4-N-methylsuccinylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)- 30 succinyl]-L-(4-N-(methylsuccinylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4- aminophenylthiomethylsuccinyl]-L-(4-N-(4-(4-oxobutanoic acid)- aminophenylalanine-N-methylamide; -ΊΊ- 011584 [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)~ succinyl]-L-(4-N-methylsuccinylamido)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)-succinyl]-L-(4-N-(4-(4-oxobutanoic acid)aminophenylalanine-N-methylamide, 5 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(2-thienylthiomethyl)-succinyl]-L- (4-oxymethylcarboxymethyl)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L-(4-N-(oxymethylcarboxylic acid)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L- 10 4-oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L- 4-oxymethylcarboxyglycine)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-succinyl]-L- 4-(oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl)-succinyl]-L- 4-(oxymethylcarboxyglycine)-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-4-oxymethylnitrile)- phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-( 1 -(2- 20 methyloxycarbonyl)-ethyl)-4-methoxyphenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-(hydroxymethyl)- 4-methoxyphenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-methyl- 4-methoxyphenylalanine-N-methylamide; 25 2-[Benzyl-(octane-l-sulfonyl)-amino]-N-hydroxy-acetamide; N-Hydroxy-2-[(2-methoxy-benzyl)-(octane-l-sulfonyl)-amino]-acetamide; 2-[(2-Ethoxy-benzyl)-(octane-l-sulfonyl)-amino]-N-hydroxy-acetamide; N-Hydroxy-2-[(naphthalen-2-yl-methyl)-(octane-l-sulfonyl)-amino]- acetamide; 30 2-[(4-Chloro-benzyl)-(octane-l-sulfonyl)-amino]-N-hydroxy-acetamide; N2-[3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-leucine- N^-methylamide; -78- N2-[3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)]-5-methyl-L-glutamic acid-N^-methylamide; N2-[3 S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)]-L-phenylalanine-N^ -methylamide; 5 , [4-(N-Hydroxyamino)-2R-isobutyl-3S-(thieilylthiomethyl)succinyl]-L- phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-phenylthiomethyl)succinyl]-L- phenylalanine-N-methylamide; 2S-(4-Methoxyphenylsulfanylmethyl)-3R-(2-phenyl-1 S-methylcarbamoyl-10 ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(3-Chlorophenylsulfanylmethyl)-3R-(2-phenyl-lS-methylcarbamoyl-ethylcarbamoyî)-5-methyl-hexanohydroxamic acid; 2S-(Phenylsulfanylmethyl)-3R-(2-phenyl-lS-(pyrid-3-ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 15 2S-(3-Methylphenylsulfanylmethyl)-3R-(2-phenyl-1 S-methylcarbamoyl- ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Thien-2-ylsulfanylmethyl)-3R-(2-(4-carboxymethoxyphenyl)-lS-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxarnic acid; 2S-(Thien-2-ylsulfanylmethyl)-3R-(2-phenyl-1 S-(pyrid-3-20 ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(2-phenyl-l S-(pyrid-3-ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Thien-2-ylsulfanylmethyl)-3R-(2-naph-2-yl-lS-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 25 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(2R-hydroxy-l S- methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(5-acetamido-lS-methylcarbamoyl-pentylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(3-[l,l-30 dimethylethoxycarbonyl]-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl- hexanohydroxamic acid; -79- 2S-(Thien-2-ylsulfonylmethyI)-3R-(2-phenyl-lS-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 3S-(2-[4-Acetamido-phenyl]-lS-methylcarbamoyl-ethylcarbamoyl)- 5-methyl-hexanohydroxamic acid; 5 2S-(4-Phthalimido-butyl)-3R-(3-methyl-lS- ethoxycarbonylmethylcarbamoyl-butylcarbamoyl)-5-methyl-hexanohydroxamic acid; 3R-(2-[4-Methoxy-phenyl]-1 S-methylcarbamoyl-ethylcarbamoyl)- 2S,5-dimethyl-hexanohydroxamic acid; 10 3R-(2-Phenyl-1 S-[2-oxo-pyrolid-1 -yl]-propylcarbamoyl-ethylcarbamoyl)- 5-methyl-hexanohydroxamic acid; 3R-(2-[4-Methoxy-phenyl]-lS-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 3R-(2-Phenyl-lS-[pyrid-3-ylmethylcarbamoyl]-ethylcarbamoyl)-5-methyl 15 hexanohydroxamic acid; 3R-(2,2-Dimethyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;

Isobutylmalonoyl-L-alanine-furfurylamide hydroxamate;2-Isobutyl-3-carbonyl-3'-(4-acetylaniline)propionic acid; 20 N-Benzyloxycarbonyl-D-phosphonoglycyl-L-alanine iurfurylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(phenylthiomethyl)succinyl] -L- phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-methoxyphenylthiomethyl)-succinyl]-L-phenylalanine-N-methylamide; 25 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-hydroxyphenylthiomethy 1)- succihyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2,4-dimethylphenylthiomethyl)^ succinyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(3-bromophenylthiomethyl)- 30 succinyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(3-chlorophenylthiomethyl)~ succinyl]-L-phenylalanine-N-methylamide; -80- 011584 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(3 -methylphenylthiomethyl)-succinyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-(N-acetyl)-amino- phenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3S-phenylsulphinylmethylsuccinyl]-L- phenylalanine-N-methylamide; 3R-(3 -Methoxycarbonyl-1 S-methylcarbamoyl-propylcarbamôyl)-5-methyl-2S-phenylsulfanylmethyl- hexanohydroxamic acid; 3R-(3-Methoxycarbonyl-l S-methylcarbamoyl-propylcarbamoyl)-10 5-methyl-2S-(thien-2-ylsulfanylmethyl)-hexanohydroxamic acid; 2S-(4-Methoxy-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Amino-phenylsulfanylmethyl)-3R-(3 -methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 15 2S-(Ethylsulfanylmethyl)-3R-(3-methoxycarbonyl-1 S-methylcarbamoy 1- propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Acetylsulfanylmethyl)-3R-(3-methoxycarbonyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Benzylsulfanylmethyl)-3R-(3 -methoxycarbonyl-1 S-methylcarbamoyl-20 propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(/erZ-Butylsulfanylmethyl)-3R-(3-methoxycarbonyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-Thiomethyl-3R-(3-methoxycarbonyl-lS-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 25 2S-(4-Hydroxy-phenylsulfanylmethyl)-3R-(2-ZerZ-butoxycarbonyl-1S- methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxy-phenylsulphinylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxy-phenylsulphonylmethyl)-3R-(3-methoxycarbonyl-1S- 30 methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[l-(2- aminoethyl)-pyrrolidine]amide; 011584 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[l-(3- aminopropyl)-2(RS)-methylpiperidine]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[2-(2- aminoethyl)-l-methylpyrrole]amide; 5 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3- aminomethylpyridine)amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- (2-aminomethylpyridine)amide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-10 (4-aminomethylpyridine)amide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-( 1 -(3 -aminopropyl)-imidazole)amide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N- (2-aminomethylbenzimdazole)amide; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine N-[4-(2-aminoethyl)-morpholino]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- [4-(2-aminoethyl)-morpholine]amide; [4-(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N-20 [2-(2-aminoethyl)-pyridine]amide; [4-(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N- [4-(2-aminopropyl)-morpholine]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-aminomethylpyridine)amide hydrochloride; and 25 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N- [4-(2-aminoethyl)-morpholine]amide hydrochloride.

In a preferred embodiment, tricyclic butyric acid dérivatives which areinhibitors of matrix metalloprotienases are employed in the instant invention. Apreferred group of tricyclic butyric acid dérivatives are defined by the formula: 30

-82- 011584

Ο X

Il II wherein one of RJ or R7 s -C-CH-(CH)a-C-R^

I I 5 R Ra wherein X is O, N-0r6 wherein R^ is hydrogen, -(CH2)n-aryl wherein n is zéro or an integer of 1 to 5‘, alkyl, or 10 -(CH2)n-cycloalkyl wherein n is as defined above, or N-N-R6 wherein R^ and R^a are each the same or different and &amp;6a each is as defined above for R^; 15 R and Ra are each the same or different and each is hydrogen, -(CH2)n-aryl wherein n is as defined above, -(CH2)n-heteroaryl wherein n is as defined above, -(CH2)p-R^-(CH2)q-aryl wherein R7 is O or S and p or q is each zéro oran integer of 1 to 5 and the sum of p + q equals an integer of 5, 20 -(CH2)p-R7'(CH2)q-heteroaryl wherein p, q, and R7 are as defmed above, alkyl, -(CH2)n-cycloalkyl wherein n is as defined above, or-(CH2)r-NH2 wherein r is an integer of 1 to 9; a is zéro or an integer of 1 to 3; 25 R5 is OH, OR6 wherein R^ is as defined above, NR6 wherein R^ and R^a are each

I R6a 30 the same or different and are as defined above for R^, or NH-OR6 wherein R^ is as defined above; R-l and R^ are each the same or different and each is hydrogen, 011584 -83- alkyl, NO2,halogen, OR6 wherein R6 is as defined above, 5 CN, CO2R6 wherein R6 is as defined above, SO3R6 wherein R6 is as defined above, CHO,

O 10 11 -C-R wherein R is as defined above,

O

II -C-N-R^ wherein R^ and R^a are each the same or

15 II R6a different and are as defined above for R^, or-(CH2)n-N-R6 wherein R^ and R^a are each the same or

I 20 Rôa different and are as defined above for R^; W, W*, Z, and are each the same or different and each is CR3 wherein R3 is asdefined above, or N providing only one of W or W1 is25 N and/or only one of Z or Z1 is N; and Y is· -N- wherein R is as defined above,

I

R -o-, 30 -S-(O)m- wherein m is zéro or an integer of 1 or 2, -CH2-, -c-,

I o 011584 -C- wherein R^ is as defined above, N-OR6 -CH- wherein R6 is as defined above,

5 I OR6 -C- wherein R6 and R6a are the same or different and are as definedN-N-R6 10 | Rôa above for R6, -C-N- wherein R6 is as defined above,

Il I 15 OR6 -N-C- wherein R6 is as defined above,

Il Ir6o-c-o-,

20 R

O -o-c-,

II

O 25 -CH2-O-, -o-ch2-, -CH2-S(O)m- wherein m is as defined above, -S(O)m-CH2- wherein m is as defined above, -CH2-N- wherein R6 is as defined above,

I R6 -N-CH2- wherein R6 is as defined above, R6 -CH=N-, or-N=CH-; 35 -85- 011584 with the proviso that when X is O, and r4 is not NH-OR^, at least one of R or Rais not hydrogen; and corresponding isomers thereof; or a pharmaceuticallyacceptable sait thereof.

Typical compounds from this class include: 5 4-Dibenzofùran-2-yl-4-hydroxyimino-butyric acid; 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-4-methyl-pentanoic acid;2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-phenyl-pentanoic acid; 4- Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid; 5- (4-Chloro-phenyl)-2-(2-dibenzofiiran-2-yl-2-hydroxyimino-ethyl)-10 pentanoic acid; 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-fluoro-phenyl)-pentanoic acid; 2- (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-methoxy-phenyl)-pentanoic acid; 15 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-p-tolyl-pentanoic acid; 3- (Dibenzofuran-2-yl-hydroxyimino-methyl)-5-methyl-hexanoic acid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-phenyl-hexanoic acid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-phenyl-pentanoic acid; 6- (4-Chloro-phenyl)-3-(dibenzofuran-2-yl-hydroxyimino-methyl)-20 hexanoic acid; 3 -(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-fluoro-phenyl)-hexanoic acid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxyphenyl)-hexanoic acid; and 25 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoic acid; and corresponding isomers thereof;or a pharmaceutically acceptable sait thereof.

Tricyclic butyric acids having an D-amino substituent are defined by theformula: -86- 011584 NR4R5 * CE^CHCO^ 10 15 20

R7 and R7a independently.arehydrogen, cl"c20 alkyl or substituted C4-C2O alkyl,(CH2)o-6-aryl, (CH2)o-6~beteroaryl, or(CH2)o_6-cycloalkyl; R{ and R2 independently arehydrogen, cl_c20 alkyl or substituted C4-C20 alkyl,halo, NO2, CN, CHO, CORô, coor6, SO3R6, OR6, CONR4R5,(CH2)o-6-aryl,(CH2)o-6‘beteroaryl, or(CH2)o_6-cycloalkyl;

Rg is hydrogen, 25 -87- 011584 C1-C20 alkyl or substituted C1-C20 alkyl;aryl is phenyl or substituted phenyl; R3 is hydroxy, O-C1-C20 alkyl or substituted O-C1-C20 alkyl, 5 0-(0¾) i_3 aryl, or NHORô; R4 and R5 independently are hydrogen, C1-C20 alkyl or substituted C1-C20 alkyl, (CH2)o-6-aryI, (CH2)o_6-heteroaryl; or one of R4 and R5 is hydrogen and the other is: CORg, CSRg, CONRgRç, CSNRgRç, 15 COORg, COSRg, COCHRg,

I NRj-R2 20 CON-CONR8R9,

I

Rl CON-COORg,

I 25 Ri CON-COSRg, or

I

Ri CON-SO2NRgR9; 30 |

Rl CON-SO3Rg; -88- 011584 10 15 20 25 30

Ri Y is -N-,

Ri -O-, -S(0)o, l or 2>-CH2-, -c-,

O -c-,

II nor8 -CH-,

Il . ORg -c-,

II N-N-RgRç) -C-N-,

Il I O r8 -N-C-,

I II

R8 O -C-O,

II o -ch2-o-, -o-ch2-,-CH2S(O)0j ! or 2,-S(O)0> 1 or2-CH2-,-CH2-N-,

I r8 35 -89- 011584 -n-ch2-,

I

Rs -CH=N, or 5 -N=CH-;

Rg and R9 independently are hydrogen, C1-C20 alkyl or substituted C4-C20 alkyl, (CH2)0.6-aryl, 10 (CH2)Q_6-heteroaryl, or (CH2)o-6-cycloalkyl; W, Wl, Z, and independently are CR j or N; and the pharmaceutically acceptable salts, isomers, stereoisomers, and solvatésthereof. 15 Spécifie examples of compounds to be employed in the présent method include: (S)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid; (R) -4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric 20 acid; (S) -2-Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid;(S)-2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric;(S)-4-Dibenzofuran-2-yl-2-[3-(2,6-diisopropyl-phenyl)-ureido]-4-oxo- butyric acid; 25 . (S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butÿric acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid;(S)-4-Dibenzofuran-2-yl-4-oxo-2-(3-phenyl-propionylamino)-butyric acid;(S)-4-Dibenzofuran-2-yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid;(S)-2-[(Biphenyl-4-carbonyl)-amino]-4-dibenzofuran-2-yl-4-oxo-butyric 30 acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-(dodècanoyl-amino)-butyric acid; -90- acid; 011584 (S)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric (R)-4~Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric 10 15 acid; (S)-2-Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid;(S)-2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;(S)-4-J)ibenzofuran-2-yl-2-[3-(2,6-diisopropyl-phenyl)-ureido]-4-oxo- butyric acid; (S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;(S)-4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid;(S)-4-Dibenzofuran-2-yl-4-oxo-2-(3-phenyl-propionylamino)-butyric acid;(S)-4-Dibenzofuran-2-yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid;(S)-2-[(Biphenyl-4-carbonyl)-amino]-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-(octanoylamino)-butyric acid; and(S)-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid.Tricyclic sulfonamide matrix metalloproteinase inhibitors include compounds of the formula 20

wherein M is a natural (L) alpha amino acid dérivative having the structure,1

—N-H COR1

H X is O, S, S(O)n, CH2, CO, or NH; R is a side chain of a natural alpha amino acid;Rl is C1-C5 alkoxy, hydroxy, or -NHOR^; -91- 011584 R.2 and R4 are independently hydrogen, -C1-C5 alkyl, -NO2, halogen, -OR5, -CN,-CO2R5, -SO3R5,-CHO, -COR5, -CONR5R6, -(CH2)nNR5R6, -CF3, or-NHCOR5; each R5 and R^ are independently hydrogen or C1-C5 alkyl; and 5 n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides, and prodrugsthereof.

Spécifie compounds from this class to be employed include:(L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid; 10 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-propionic acid;(L)-2-(Dibenzofuran-2-suIfonylamino)-3-methyl-butyric acid;(Dibenzofuran-2-sulfonylamino)-acetic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-succinic acid; 15 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid; (L)-2-(Dib enzofuran-2-sulfonylamino)-3 -mercapto-propionic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-3 -methy 1-pentanoic acid hydroxyamide; (L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid; 20 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-propionic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;(Dibenzofuran-2-sulfonylamino)-acetic acid; 25 · (L)-2-(Dibenzofuran-2-sulfonylamino)-succinic acid; (L)-2-(Dibenzofuran-2-sulfbnylamino)-3-tritylsulfanyl-propionic acid;(L)-2-(Dibenzofuran-2-sulfonylamino)-3 -mercapto-propionic acid; and(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide. 30 Additional tricyclic sulfonamides are defined by the formula: -92- 011584 10 15

wherein Q is an un-natural amino acid; X is O, S, S(O)n, CH2, CO, or NH; R2 and R4 are independently hydrogen, C1-C5 alkyl, -NO2, halogen, -OR5, -CN,-CO2R5, -SO3R5, -CHO, -COR5, -CONR5R6, -(CH2)nNR5R6, -CF3, or-NHCOR5; each R5 and R^ are independently hydrogen or C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugsthereof.

Spécifie examples of such compounds include:(S)-2-(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid; 2 (S)-3-[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid;(S)-2-(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid; and2 (S)-3-[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid.Another general class of matrix metalloproteinase inhibitors, which are useful to treat and prevent heart failure and ventricular dilatation, are biphenylbutyric acid dérivatives, including compounds of the formula:

20 wherein R and Rl are the same or different and arehydrogen,alkyl,halogen,nitro,cyano, trifluoromethyl, 25 -93- 011584 -OR.6 wherein is hydrogen,alkyl,aryl, arylalkyl, 5 heteroaryl, or cycloalkyl, -N-R6 wherein R^ and R^a are the same or different and are as

I R6a 10 defined above for r6

O

II -O-C-R6 wherein R^ is as defined above,

O 15 II . -NH-C-R6 wherein R^ is as defined above,

O

II -S-C-R6 wherein R^ is as defined above, 20 -SR6 wherein R^ is as defined above,

O

II -C-R6 wherein R6 is as defined above, -CH2-OR6 wherein R6 is as defined above, 25 -CH2-N-R6 wherein R6 and R6a are the same or different and are as

I R6a defined above for R6,

O 30 fl -C-N-R6 wherein R6 and R6a are the same or different and are as

I R6a defined above for R6, -94- 0 011584 -S-R6 wherein is as defined above,

II

5 O cycloalkyl, or heteroaryl, with the proviso that R and R1 are not both hydrogen; R2 is -OR6 wherein R^ is as defined above, or -N-R6 wherein R6 and R6a are the same or different and are as 10 | R6a defined above for R^; r3, p3a, r4, ancj p4a are same or different and arehydrogen, 15 fluorine, alkyl, -(CH2)n-aryl wherein n is an integer from 1 to 6, -(CH2)n-heteroaryl wherein n is as defined above, -(CH2)n-cycloalkyl wherein n is as defined above, 20 -(CH2)p-X-(CH2)q-aryl wherein X is O, S, SO, SO2, or NH, and p and q are each zéro or an integer of 1 to 6, and the sum of p + q is notgreater than six, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above,or 25 -(CH2)n-R2 wherein R2 is N-phthalimido, N-2,3-naphthyimido, -OR6 wherein R^ is as defined above, -N-R^ wherein R^ and R^a are the same or different and are as 30 | R6a defined above for r6 -95- 011584 -SR.6 where is as defined above,

O -S-R6 wherein R^ is as defined above,

5 O 11 -S-R6 wherein R^ is as defined above,

II o

10 O

I -O-C-R6 wherein R^ is as defined above,

O

II 15 -N-C-R6 wherein R^ and R^a are the same or different and are as

I ' R6a defined above for R^,

O

20 II -S-C-R6 wherein R^ is as defined above,

O

II -C-R6 wherein R^ is as defined above,

25 O «

-C-OR^ wherein R^ is as defined above, orO

II 20 -C-N-R6 wherein R^ and R^a are the samé or different and are as

I R6a . . defined above for R^, andn is as defined above; 35 R5 is OH or SH; with the proviso that R^, R3a, r4, and R4a are hydrogen or at least one of R3, R^a r4, or R4a js fluorine; and corresponding isomersthereof; or a pharmaceutically acceptable sait thereof. 011584 -96-

Typical compounds from this class that are routinely utilized to treatatherosclerosis include: 4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;4-(4'-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 5 4-(4'-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)-butyric acid; 4-(4'-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;(±)-4-(4'-.Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid;4-(4'-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;(±)-4-(4'-Chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid; 10 4-(2',4'-Dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4-(2',4'-Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;(±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3- phenylpropyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(2- 15 phenylethyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3- phthalimidopropyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2- (phenylthiomethyl)-butyric acid; 20 4-(4'-Chloro-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid;4-(4'-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid;(±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-(l,3-dioxo-l,3-dihydro- isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; 25 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(lH-indol- 3-yl)methyl-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-methyl-butyric acid; (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-2-fluoro-6-phenyl-hexanoic acid; 30 -9Ί- 011584 (±)-4-(4'-Chloro-biphenyI-4-yl)-2-fluoro-2-[2-(l,3-dioxo-l,3-dihydro-benzo[F]isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-(l,3-dioxo- l,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid; 5 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-[2-(phenyl- ethylcarbamoyl)-ethyl]-butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-3,3-difluoro-4-hydroxyimino-butyric acid;(±)-4-(4'-Chloro-biphenyl-4-yl)-3,3-dimethyl-2-fluoro-4-hydroxyimino- butyric acid; 10 (±)-4-(4'-Chloro-biphenyl-4-yl)-2,2-dimethyl-3-fluoro-4-hydroxyimino- butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid;and 4-(4'-Chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric 15 acid. A compound selected from the group consisting of:4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;4-(4'-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid;4-(4'-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)-butyric acid ; 20 4-(4'-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid;4-(4'-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;(±)-4-(4'-Chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid;4-(2',4'-Dichloro-biphenyl-4-yl)-4-hydroxyimino7butyric acid; 25 ‘ 4-(2',4'-Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3- phenylpropyl)-butyric acid; (+)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(2-phenylethyl)-butyric acid; 30 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3- phthalimidopropyl)-butyric acid; 011584 -98- (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoFo-2-(phenylthiomethyl)-butyric acid; 4-(4'-Chloro-2'-fhioro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;4-Hydroxyimino-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid; 5 4-(4'-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-( 1,3 -dioxo-1,3 -dihydro- isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(lH-indol- 3-yl)methyl-butyric acid;· 10 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-methyl- butyric acid; (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-2-fluoro-6-phenyl-hexanoic acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-(l,3-dioxo-l,3-dihydro-15 benzo[F]isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-(l,3-dioxo- l,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-[2-(phenyl-ethylcarbamoyl)-ethyl]-butyric acid; 20 4-(4'-Chloro-biphenyl-4-yl)-3,3-difluoro-4-hydroxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-3,3-dimethyl-2-fluoro-4-hydroxyimino- butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2,2-dimethyl-3 -fluoro-4-hydroxyi mino-butyric acid; 25 4-(4'-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; and 4-(4'-Chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric acid.

Biphenyl sulfonamides are also particularly good in the présent method. 30 Such compounds include those of the formula: -99- 01158«

R

wherein: R1 is Ci-Cg alkyl, halo, nitro, NR4R5, cyano, OR4, and COOR4; R^ is CpCg alkyl, optionally substituted by phenyl, substituted phenyl, NR4R6,

NH OR6, carboxy, carboxamido, H2N-C-NH-, thio, methylthio, indole,imidazole, phthalimido, phenyl, and substituted phenyl; R3 is OH, OCpCg alkyl, orNHOH; 10 R4 is hydrogen, Cj-Cg alkyl, or CpCg alkanoyl; R5 is hydrogen or CpCg alkyl; and R6 is hydrogen, Cj-Cg alkyl, Cj-Cg alkanoyl, phenyl, or substituted phenyl.

Spécifie compounds which can be employed include a compound of the above formula wherein Rl is at the 4' position.

Another class of matrix metalloproteinase inhibitors usefùl in the présent method are the heterocyclic substituted phenyl butyric acid dérivatives, forexample those defined by the formula:

Ar-Ύ

(W) R- 20

Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR6 wherein R6 is hydrogen or alkyl,CN, CO2R6 wherein R6 is as defined above, 25 -100- 011584 SC^R-5 wherein R$ is as defined above, CHO, COR^ wherein R$ is as defined above, CONHR5 wherein R$ is as defined above, or 5 · NHCOR5 wherein R$ is as defined above, 2-naphthyl, orheteroaryl;

Rl is selected from hydrogen,methyl, 10 ethyl, NO2, halogen, ORS wherein R5 is as defined above, CN, 15 CO2R5 wherein R$ is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R^ is as defined above; R^ and R^ are the same or different and independently selected from hydrogen, 20 alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5,-(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above,-(CH2)p-X-(CH2)q-aryl wherein X is O or S and p and q is each 25 zéro or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as definedabove, 10 -101- 011584 -(CH2)tNR6R6a, wherein t is zéro or an integer of from 1 to 9 endR6 and R^a are each the same or different and are asdefined above for R^, -(CH2)vSR5, wherein v and R$ are as definedabove, -(CH2)vC02R5, wherein v and R$ are as defîned above, or -(CH2)vCONR^R^a, wherein R^ and R^a are the same or differentand are as defîned above for R$ and v is as defîned above; R^ is additionally -(CH2)rR^ wherein r is an integer from 1 to 5 and R^ is l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl, or l,3,-dihydro-l,3-dioxo-benzo[f]isoindol-2-yl; Y is CH or N;

.OH Z is 15 20 wherein R^ is as defîned above for R^ and R^, and is independently the

same or different from R^ and R^ provided that whenXOH Z is , then R4 must be OH,

Rlü C=O, C=NOR5 wherein R$ is as defîned above, or C=N-NR6R6a wherein R^ and R^a are the same or different and are asdefîned above for R^; W is -CHR5 wherein R^ is as defîned above; n is zéro or an integer.of 1; R4 is OH, NRÔpjôa wherein R^ and R^a are the same or different and are as defînedabove for R^, when R4 is NR^R^a then Z must be C=O or NHOR^ wherein R^ is hydrogen, alkyl, or benzyl; and corresponding isomers thereof; or a pharmâceutically acceptable sait thereof. 25 -102- 011584

Especially preferred MMP inhibitors hâve the formula ·

Ar is selected from phenyl, phenyl substituted with 5 alkyl, NO2, halogen, OR5 wherein R$ is hydrogen or alkyl, CN, 10 CO2r5 wherein R$ is as defined above, SO3R5 wherein R$ is as defined above, CHO, COR^ wherein R^ is as defined above,CONHR.5 wherein R$ is as defined above, or 15 NHCOR5 wherein R$ is as defined above, 2-naphthyl, orheteroaryl;

Rl is selected from hydrogen,methyl, 20 ethyl, NO2, halogen, ORS wherein R^ is as defined above, CN, 25 CO2r5 wherein R^ is as defined above, SO3R5 wherein R^ is as defined above, CHO, or 10 15 20 25 -103- CORS wherein is as defined above; 01 1 5 8 4 R^ and R^ are the same or different and independently selected from hydrogen,alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5,-(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above,-(CH2)p-X-(CH2)q-aryl wherein X is O or S and p and q is each zéro or an integer of 1 to 5, and the sum of p +q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are asdefined above, -(CH2)tNR^R^a, wherein t is zéro or an integer of from 1 to 9 and R^ and R^a are each the same or differentand are as defined above for R$, -(CH2)vSR5, wherein v and R$ are asdefined above, -(CH2)vCO2R5, wherein v and R$ are as defined above, or -(CH2)vCONR^R^a, wherein R^ and R^a are the same or- different and are as defined above for R$ and v is asdefined above; R^ is additionally -(CH2)rR^ wherein r is an integer from 1 to 5 and is l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl, or l,3,-dihydro-l,3-dioxo-• benzo[f]isoindol-2-yl; Y is CH or N;

Z is C

/OH ^R1O· wherein R^ is as defined above for R^ and R^, and is independently thesame or different from R^ and R^ provided that when -104- 011584

OH Z is , then R4 must be OH,

Riu c=o, C=NOR.5 wherein r4 is as defrned above, or C=N-NR^R^a wherein R^ and R^a are the same or different and are as 5 defined above for R$; W is -CHR5 wherein R^ is as defined above;n is zéro or an integer of 1 ; R4 is OH, NRÔRÔa. wherein R*> and R^a are the same or different and are as defined 10· above for R^, when R4 is NR^R^a then Z must be C=O or NHOR9 wherein R^ is hydrogen, alkyl, or benzyl; and corresponding isomers thereof; or a pharmaceutically acceptable sait thereof.Preferred compounds to be employed include:4-Oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; 15 4-Oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid, potassium sait; N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyramide;E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid;E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; 20 4-Oxo-4-[4-(4-phenyl-piperazin-l-yl)-phenyl]-butyric acid; (±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-l-yl)-phenyl]-pentanoic acid;4-Oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid;4-Oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid, potassium sait;N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyramide; 25 E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; 4-Oxo-4-[4-(4-phenyl-piperazin-l-yl)-phenyl]-butyric acid; and(±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-l-yl)-phenyl]-pentanoic acid. -105- 011584 A compound which is 4-oxo-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid.

Similar compounds which are sulfonamide dérivatives hâve the formula:

O O y— r"

Ar—(CH2)-Y^ N-^ λ—(ÇH)—

R

R 1 Ra 0 R2 10 15 20 25 wherein:

Ar is selected from phenyl; phenyl substituted with alkyl, -NO-2, halogen, -OR5, -CN, -CO2R5, -SO3R5, -CHO, -COR5, -CONHR5, -NHR5, or -NHCOR5;heteroaryl; or 2-naphthyl; - R1 is hydrogen, methyl, -NO2, -Cl, -NH2, -NHCO2CH3, -OH, or -CO2H; R2 and R5 are the same or different and are independently selected from hydrogen, alkyl, -(CH2)v-aryl, -(CH2)v-heteroaryl, -(CH2)v-cycloalkyl,-(CH2)p-X-(CH2)q-aryl, -(CH2)p-X-(CH2)q-heteroaryl, -(CH2)tNR6R6a,-(CH2)vR7, -(CH2)vCO2R5, -(CH2)vCONR6R6a Or-(CH2)VSR5; miszeroorl; Y is CH or N; provided that when m = 1, Y does not = N; z is zéro or 1; W is -CHR8; n is zéro or 1 ; R4 is -OH, -NR6R6a or -NHOR9; R5 is hydrogen or alkyl; v is 1 to 5; X is O or S; p and q are independently 1 to 5, provided that p + q is not greater than 5;t is 1 to 9;. r6 and R^a are each the same or different and are hydrogen or alkyl; -106- 011584 R7 is l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl, or l,3-dihydro-l,3-dioxo-benzo[f]isoindol-2-yl; R8 is hydrogen or alkyl; and R^ is hydrogen, alkyl, or benzyl; or5 a pharmaceutically acceptable sait thereof.

Spécifie sulfonamide dérivatives to be employed in the présent methodinclude: [4-(4-Phenyl-piperidin-l-yl)-benzenesulfonylamino]-acetic acid;N-Hydroxy-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- 10 acetamide; 3-[4-(4-Phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid; -107- 011584 (R) -4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; (S) -4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; 5 (S)-3 -Phenyl-2-[4-(4-phenyl-piperidin-1 -yl)-benzenesulfonylamino]- propionic acid; (R) -3-Phenyl-2-[4-(4-phenyl-pipéridin-l-yl)-benzenesulfonylamino]-propionic acid; (S) -3-(1 H-Indol-3-yl)-2-[4-(4-pheny l-piperidin-1-yl)-10 benzenesulfonylamino]-propionic acid; (±)-5-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; [4-(4-Phenyl-piperazin-l-yl)-benzene-sulfonylamino]-acetic acid;{Isobutyl-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonyl]amino}-acetic 15 acid; (S)-4-Phenyl-2- [4-(4-phenyl-piperidin-1 -y l)-benzenesulfonylamino]-butyric acid; (R) -2- [4-(4-Phenyl-p iperidin-1 -y l)-b enzenesul fo nylamino] -3 -tritylsulfanyl-propionic acid, sodium sait; 20 (R)-3 -( 1 H-Indol-3 -yl)-2-[4-(4-pheny l-piperidin-1 -yl)- benzenesulfonylaminoj-propionic acid, disodium sait, monohydrate; (S) -2-{4-[-4-(4-Hydroxy-phenyl)-piperazin-l-yl]-behzenesulfonylamino}-3-phenyl-propionic acid; (S)-2-{4-[-4-(4-Chloro-phenyl)-piperazin-l-yl]-25 benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride; (R) -3-Mercapto-2-[4-(4-phenyl-piperidin-l -yl)-benzenesulfonylamino]-propionic acid, trifluoracetic acid sait; (S) -2-[4-(4-Benzyl-piperidin-l-yl)-benzenesulfonylamino]-3-phenyl-propionic acid; 30 (S)-3-(4-Benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-l-yl)- benzenesulfonylamino]-propionic acid; -108- 011584 ( S)-3 -(4-Hydroxy-phenyl)-2-[4-(4-pheny 1-piperidin-1 -y 1)-benzenesulfonylamino]-propionic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperazin-l-yl)-benzenesulfonylamino]-propionic acid; 5 (S)-2-{4-[-4-(3-Methoxy-phenyl)-piperazin-l-yl]-benzenesulfonylamino} 3-phenyl-propionic acid; (S)-2-{4-[-4-(3-Hydroxy-phenyl)-piperazin-l-yl]-benzenesulfonylamino)3-phenyl-propionic acid hydrobromide; (S)-2-{4-[-4-(4-Methoxy-phenyl)-piperazin-l-yl]-benzenesulfonylamino}10 3-phenyl-propionic acid; (R) -4-Methyl-2-[4-(4-phenyl-piperidin-l -yl)-benzenesulfonylamino]-pentanoic acid; (S) -4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; 15 (S)-3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- propionic acid; (R) -3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid; (S) -3-(lH-Indol-3-yl)-2-[4-(4-phenyl-piperidin-l-yl)- ' 20 benzenesulfonylamino]-propionic acid; [4-(4-Phenyl-piperidin-l-yl)-benzenesulfonylamino]-acetic acid;N-Hydroxy-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- acetamide; 3-[4-(4-Phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid; 25 (R)-4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- pentanoic acid; (S)-4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- 30 propionic acid; (R)-3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- propionic acid; -109- 011584 (S)-3-(lH-Indol-3-yl)-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylaminoj-propionic acid; (±)-5-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; 5 [4-(4-Phenyl-piperazin-l-yl)-benzene-sulfonylamino]-acetic acid; {Isobutyl-[4-(4-phenyl-piperidin-1 -yl)-benzenesulfonyl]amino} -acetic acid; (S)-4-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-butyric acid; 10 (R)-2-[4-(4-Phenyl-piperidin-l-yl)-benzenesulfonylamino]-3- tritylsulfanyl-propionic acid, sodium sait; (R) -3-(lH-Indol-3-yl)-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylaminoj-propionic acid, disodium sait, monohydrate; (S) -2-{4-[-4-(4-Hydroxy-phenyl)-piperazin-l-yl]-15 benzenesulfonylamino}-3-phenyl-propionic acid; (S)-2-{4-[-4-(4-Chloro-phenyl)-piperazin-l-yl]-benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride; (R) -3-Mercapto-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid, trifluoracetic acid sait; 20 (S)-2-[4-(4-Benzyl-piperidin-l-yl)-benzenesulfonylamino]-3-phenyl- propionic acid; (S) -3-(4-Benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid; (S)-3 -(4-Hydroxy-phenyl)-2-[4-(4-phenyl-piperidin-1 -yl)-25 benzenesulfonylamino]-propionic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperazin-l-yl)-benzenesulfonylamino]-propionic acid; (S)-2- {4-[-4-(3-Methoxy-phenyl)-piperazin-l -yl]-benzenesulfonylamino}3-phenyl-propionic acid; 3θ (S)-2-{4-[-4-(3-Hydroxy-phenyl)-piperazin-l-yl]-benzenesulfonylamino) 3-phenyl-propionic acid hydrobromide; -110- 011584 (S)-2- {4-[-4-(4-Methoxy-phenyl)-piperazin-1 -yl]-benzenesulfonylamino} -3-phenyl-propionic acid; (R) -4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-pentanoic acid; 5 (S)-4-Methyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]- pentanoic acid; (S) -3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonytamino]-propionic acid; (R) -3-Phenyl-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-10 propionic acid; and (S) -3-(lH-Indol-3-yl)-2-[4-(4-phenyl-piperidin-l-yl)-benzenesulfonylamino]-propionic acid.

Additional spécifie compounds which can be used include: 2- (Dibenzofuran-2-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid; 15 2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid; 3- (4-tert-Butoxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acid; (Dibenzofuran-2-sulfonylamino)-phenyl-acetic acid;3-tert-Butoxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid; 20 2-(Dibenzofuran-2-sulfonylamino)-3-(lH-imidazol-4-yl)-propionic acid; 2- (Dibenzofuran-2-sulfonylamino)-3-hydroxy-propionic acid; 3- Benzyloxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid;6-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid; 25 5-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoic acid; (Dibenzofuran-2-sulfonylamino)-(4-methoxy-phenyl)-acetic acid;3-Chloro-2-(dibenzofuran-2-sulfonylamino)-propionic acid;3-(4-Benzyloxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic 30 acid; 2-(Dibenzofuran-2-sulfonylamino)-5-p-tolyl-sulfanylamino-pentanoic acid; 2-(Dibenzofuran-2-sulfonylamino)-4-mercapto-butyric acid; -111- 011584 3-(4-Bromo-phenyl)-2-(dibenzofuran-2-sulfonyl-amino)-propionic acid; 2- (Dibenzofuran-2-sulfonylamino)-butyric acid; 1- (Dibenzofuran-2-sulfonylamino)-cyclopropane-carboxylic acid; 3- (4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonyl-amino)-propionic acid; 2- (Dibenzofuran-2-sulfonylamino)-3-(lH-indol-3-yl)-propionic acid;2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-fluoro- benzenesul fonyl amino)-hexanoic-aci d ; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-methoxy- benzenesulfonylamino)-hexanoic acid; 6-(4-Bromo-benzérièsulfonylamino)-2-(4'-bromo-biphenyl-4- sulfonylamino)-hexanoic-acid; 6-(2-Acetylamino-thiazole-5-sulfonylamino)-2-(4'-bromo-biphenyl- 4-sulfonylamino)-hexanoic-acid; 6-(4-Acétylamino-benzenesulfonylamino)-2-(4'-bromo-biphenyl- 4-sulfonylamino)-hexanoic-acid; 6-Benzenesulfonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(pentane-l-sulfonylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-2-sulfonylamino)- hexanoic-acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-l- sulfonylamino)-hexanoic-acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenyl- ethenesulfonylamino)-hexanoic-acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-phenyl-acetylamino-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfbnylamino)-6-[2-(4-chloro-phenoxy)-acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-hexanoic acid; -"2- 011584 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(pyridin-4-ylsulfanyl)-acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-acetylaminoj-hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-thiophen-2-yl- acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(3-phenyl-acryloylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(7-phenyl-heptanoylamino)-10 hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenoxy-butyrylamino)-hexanoic acid; 15 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenyl-sulfanyl- acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenoxy-acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(3,4-dimethoxy-phenyl)-20 acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy)-acetylamino] -hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionylamino]-hexanoic acid; 25 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent-l-enyl- acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen-l-yloxy)-30 acetylaminoj-hexanoic acid; -i'3- 011584 2-(4/-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-acetylaminoj-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl-phenoxy)-butyrylamino]-hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl)- propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-hexanoic acid; 6-(2-Benzo[l,3]dioxol-5-yl-acetyiamino)-2-(4'-bromo-biphenyl-4-10 sulfonylamino)-hexanoic acid; 2-(4'-Brorno-biphenyl-4-sulfonylamino)-6-(2-pyridin-2-yl-acetylarnino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy)-acetylamino]-hexanoic acid; 15 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)- propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfony lamino)-6-(2-cyclopent-1 -enyl-acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-20 acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen-l-yloxy)-acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-acetylamino]-hexanoic acid; 25 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl- phenoxy)-butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl)-propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-30 hexanoic acid; -114- 01 1 584' 6-(2-Benzo[l,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfbnylamino)-6-(2-pyridin-2-yl-acetylamino)-hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-nitro-phenyl)- butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy)-acetylaminoj-hexanoic acid; 2-(4'-Bromo-bipbcnyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-10 propionylaminoj-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent-1 -enyl-acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-acetylaminoj-hexanoic acid; 15 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-phenyl-butyrylamino)- hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl-phenoxy)-butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenyl)-20 propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylatnino)-6-[3-(4-methoxy-phenyl)-propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-hexanoic acid; 25 6-(2-Benzo[l,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4- sulfonylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-naphthalen-l-yl-acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenoxy)-30 propionylamino]-hexanoic acid; -115- 011584 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(6-phenyl-hexanoylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2,4,6-triisopropyl- benzoylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-isobutoxycarbonylamino-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(9H-fluoren-9-10 ylmethoxycarbonylamino)-hexanoic acid; 6-(Adamantan-1 -yloxycarbonylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid; and 6-Allyloxycarbonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid. 15 Numerous succinamide MMP inhibitors are known and can be utilized in the method of this invention. Typical succinamides include: 2S,N^-Dihydroxy-3R-isobutyl-N4-{lS-[2-(2-methoxy-ethoxymethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide; 2S-Allyl-N1-hydroxy-3R-isobutyl-N4-{ lS-[2-(2-methoxy-20 ethoxymethoxy)ethylcarbamoyl]-2-phenyl-ethyl}-succinamide; 2S-Allyl-Nl-hydroxy-3R-isobutyl-N4-{lS-[2-(2-methoxy-ethoxymethoxy)ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide; 2S-Allyl-N1-hydroxy-3R-isobutyl-N4-(lS-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide; 25 2S-Allyl-N4-{ 1 S-[2,2-di-(methoxymethyl)-propylcarbamoyl}-2,2- dimethyl-propyl]-Nl-hydroxy-3R-isobutyl-succinamide; 2S-Allyl-N4-{lS-[2,2-di-(methoxymethyl)-butylcarbamoyl]-2,2-dimethylpropyl} -N1 -hydroxy-3R-isobutyl-succinamide; N4-Hydroxy-2R-isobutyl-N1 - {1 S-[2-(2-methoxy-ethoxy)- 30 ethylcarbàmoyl]-2,2-dimethyl-propyl}-3S-(thiophen-2-yl-sulfanylmethyl)- succinamide; -116- 011584 N^-Hydroxy-2R-isobutyl-N^ -(1 S-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylcarbamoyl}-2,2-dimethyl-propyl)-3S-(thiophen-2-yl-sulfanylmethyl)-succinamide;

Nl-{ 1 S-[2,2-Di-(methoxymethyl)-propylcarbamoyl]-2,2-dimethyl-5 propyl}-N4-hydroxy-3R-isobutyl-3S-(thiophen-2-yl-sulfanylmethyl)- succinamide; N4-Hydroxy-2R-isobutyl-N1 - {1 S-[2-(2-methoxy-ethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl}-3S-propyl-succinamide; N^-(lS-Cyclobutylcarbamoyl-2,2-dimethyl-propyl)-2S,N^-dihydroxy-3R-10 isobutyl-succinamide; N^-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2 S,N1 -dihydroxy-3R-isobutyl-succinamide; N^-(lS-Cyclopentylcarbamoyl-2,2-dimethyl-propyl)-2S,Nl-dihydroxy- 3R-isobutyl-succinamide; 15 Ν^-ζΙ S-Cyclohexylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1 -dihydroxy-3R- isobutyl-succinamide; N4-(lS-Cycloheptylcarbamoyl-2,2-dimethyl-propyl)-2S,Nl-dihydroxy- 3R-isobutyl-succinamide; N^-(l S-Cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-2S,N -20 dihydroxy-3R-isobutyl-succinamide; n4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1 -dihydroxy-3R-(3-phenyl-propenyl)-succinamide; N^-( 1 S-Cyclopropylcarbamoy l-2,2-dimethyl-propyl)-2 S ,N 1 -dihydroxy-3R-(3-phenyl-propyl)-succinamide; 25 N^-[2,2-Dimethyl-1 S-(2-phenyl-cyclopropylcarbamoyl)-propyl]-2S,N 1 - dihydroxy-3R-isobutyl-succinamide; 2S-Allyl-N^-( 1 -cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N 1 -hydroxy-3R-isobutyl-succinamide; 2S-Allyl-N^-(lS-cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-N^- 30 hydroxy-3R-isobutyl-succinamide; -117- 011584 N4-(lS-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N^-hydroxy-3R- isobutyl-2S-(thiophen-2-ylsulfanylmethyl)-succinamide; N4-(lS-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N^-hydroxy-2S-(4-hydroxy-phenylsulfanyImethyl)-3R-isobutyl-succinamide; and 5 N4-(lS-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S-(l,3-dioxo- l,3-dihydro-isoindol-2-ylmethyl)-N^-hydroxy-3R-isobutyl-succinamide.

Another especially preferred group of MMP inhibitors to be utilized in themethod of this invention are the sulfonated amino acid dérivatives described inWO 97/27174, incorporated herein by reference. Those compounds hâve the 10 general structure 15 14 13 -SOj-b

COY 15 20 25 where R^ 1 is substituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroaryl, or substituted or unsubstituted heteroaryl alkyl; R12 is hydrogen, or a group as defined for R^1 ;

Rl3 is a single bond, substituted or unsubstituted arylene, or substituted orunsubstituted heteroarylene; R14 is a single bond, -(CH2)i or 2'» -CH=CH-, -C=C-, -CO-, -CONH-, -N=N-,NH, N-alkyl, -NHCONH-, -NHCO-, -O-, -S-, -SO2NH-, -SO2NH-N=CH-,or tetrazoldiyl;

Rl 5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, orsubstituted or unsubstituted non-aromatic heterocyclic group; and

YisNHOHorOH.

Especially preferred compounds to be employed in the method of thisinvention hâve the above formula wherein Rl3 is phenylene or substitutedphenylene. Typical of such compounds that can be employed hâve the formula -118- 011584

where RJ 1 and R.12 are as defined above, and RJ? is substituted or unsubstitutedaryl or substituted or unsubstituted heteroaryl.

Especially preferred are compounds of the formula R18 SCkNIT^COOH5 2 wherein R11 and Rl8 are as follows:

-119- 011584

-120- 011584

(CH3)2CH—

(CH3)2CH—

\ // -c=c

// CH — (CH3)2CH—

The following patents and applications covering MMP inhibitors areincorporated herein by reference: United States 5,753,653; WO 96/16027; WO 97/20824; WO 98/50348; WO 98/43963; WO 9832748; WO 98/17643; and 5 EP 0780386. These include compounds such as shown below. 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-3-cyclohexylpropionylaminojbenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-methyl-butyrylaminoj-benzoic acid methyl ester; -121- 01 1 5 8 zî 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 5 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl- butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-5-methyl-valerylamino)-3,3-dimethyl-butyrylaminoj-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-2-10 cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-4-methyl-valerylamino]-benzoic acid methyl ester; 4- [2-(2-Carboxymethyl-5-phenyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 15 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-3-(lH-indol-3-yl)- propionylamino-benzoic acid methyl ester; 5- Methyl-3-(9-oxo-l,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca-12(19),13,15,17-tetraen-10-ylcarbamoyl)-hexanoic acid ; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-methyl-20 butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-2-cyclohexylpropionylamino]-benzoic acid methyl ester benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-valerylamino)-4-methyl-valerylaminoj-benzoic acid methyl ester; 25 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino)-3- cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino)-3-cyclohexylpropionylamino]benzoic acid methyl ester; 4- [2-(2-Hydroxaminocarbonylmethyl-5-phenyl-valerylamino)-3,3-30 dimethyl-butyrylaminoj-benzoic acid methyl ester; 5- Methyl-3-(9-oxo-l,8-diaza-tricyclo[10.6.1.0 13,18]nonadeca-12(19), 13,15,17-tetraen-10-ylcarbamoyl)-l-hexylhydroxamic acid; -122- 011584 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)-3-(lH-indol-3-yl)-propionylamino]-benzoic acid methyl ester; 3 -[2-(4-Methoxy-benzylsulfany l)-2-methyl-1 -phenylcarbamoy 1-propylcarbamoyl]-5-methyl-hexanoic acid; 5 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-l-phenylcarbamoyl- propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxyamide; 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylaminoj-benzoic acid methyl ester; 2-(Phenyl-2-ethyl)benzoic acid N-hydroxy amide; 10 4-[2-(2-Acylhyrdazinomethyl-4-methyl-pentanoylamino)-3-(lH-indol-3- yl)-propionylamino]-benzoic acid methyl ester; 2-(Propylthio)-pyridine-3 -N-(hydroxy)carboxamide;4-[2-(2-Carboxymethyl-5-phenyl-pentanoylamino)-2- cyclohexylacetylamino]benzoic acid methyl ester; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-((thien-2-ylthio)methyl)succinyl]- L-phenylalanine-N-methylamide; N-Hydroxy-5-phenylpentanamide; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 20 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-4-pentenoyl)amino)-4- methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-4-pentenoyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester, trifluoroacetate sait; 2-(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide; 25 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl- 30 valeroyljaminobenzoic acid methyl ester; 2-[3-(3-Hydroxy-phenyl)-propylJ-benzohydroxamic acid; 2-(Thiobenzyl)benzoic acid N-hydroxy amide; 1 -(3-Phenyl-propyl)-pyrrolidine-2-hydroxamic acid; .,23. 01 1 5 84 4-[2-(2-Carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(N'-methylureido)valeroyl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 5 4-[2-(2-Carboxymethyl-5-(triflouroacetamido)valeroyl)amino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-phenylacetylamino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-2-phenylacetylamino)-4-methyl-10 valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylaminoj-benzoic acid methyl ester; 2-[3-(3-Amino-phenyl)-propylJ-benzohydroxamic acid;cis-4-Benzyloxy-pyrrolidine-2-carboxylic acid; 15 4-[2-(2-Carboxymethyl-5-(3-amino-4-(trifluoromethyl)phenyl)- valeroyl)amino)-4-methyl-valeroyl]aminobenzôic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(methanesulfamido)valeroyl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; N-Cbz-L-Tyrosine; 20 N-Boc-L-Tryptophan; 4-[2-(Carboxy-2-o-tolyl-propionylamino-4-methyl-pentanoylaminoJ- benzoic acid methyl ester; 4-[2-(Carboxymethyl-hepanoylamino)-4-methyl-pentanoylamino]-benzoicacid methyl ester; 25 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-4-pentenoyl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(2-thienyl)acetyIamino)-4-methyl-30 valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(3-aminophenyl)-butyryl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; -124- 011584 4-[2-(2-Carboxymethyl-5-(biphen-4-yl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; cis-4-Benzylsulfanyl-pyrrolidine-2-carboxylic acid; 2- Cyclohexylmethyl sulfonyl-benzoic acid; 5 Pyrrolidine-l-carbothioic acid phenethyl-amide; 3- (2-Methyl-thiazol-4-yl)-N-phenethyl-propionamide;N-Phenyl-3-[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-4-yl]- propionamide; 3 -(3H-Imidazol-4-yl)-N-phenethyl-propionamide; 10 4-[2-(2-Carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 2- Cyclohexylmethyl sulfonyl-benzohydroxamic acid; [2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid; 4- [2-(2-Carboxymethyl-5-(fluoren-2-yl)valeroyl)amino)-4-methyl-15 valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(3-thienyl)acetylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Benzylthio-3-carboxy-propionylamino)-4-methylpentanoylamino]-benzoic acid methyl ester; 20 4-[2-(2-Carboxymethyl-4-(2-indolyl)butyrylamino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 1- Allyl-3-(2-hydroxyethyl)-2-thiourea; 3- (l-Hydroxyimino-propyl)-6-phenyl-hexanoic acid; 2- (3H-Imidazol-4-ylmethyl)-N 1,N 4-diphenethyl-succinamide; 25 3-(2-Hydroxymethyl-3H-imidazol-4-yl)-N-phenethyl-propionamide; 6-Phenyl-3 -propionyl-hexanoic acid ; 4- {2-([2-Hydroxyamino-2-hydroxyimino-ethyl]-5-phenyl-pcntanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 4-[2-(2-(2-Phenylcyclopropyl)succinylamino)-4-methyl-30 valeroyl]aminobenzoic acid methyl ester; 6-Biphenyl-4-yl-[2,2-dimethyl-l-(pyridin-4-ylcarbamoyl)-propylcarbamoylj-hexanoic acid trifluoroacetate sait; -125- 011584 3- (1-(5,6-Dichloro-lH-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5-methyl-hexanoic acid; 6-Biphenyl-4-yl-3-[l-(5,6-dichloro-lH-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5-methyl-hexanoic acid; 5 2-Carboxymethyl-heptanoyl-2-(N-methylcarboxamide)piperidine; 4- (2-(2-(2 -Phenylcyclopropyl)succinylamino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 2-Carboxymethyl-heptanoyl-3-(N-methylcarboxamide)- hexahydropyridazine; 10 6-Biphenyl-4-yl-3-[l-[3-(3-hydroxy-ethyl)-phenylcarbamoyl]-2,2- dimethyl-propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5-methyl3 S-hexyl)succinamide; 6-Biphenyl-4-yl-3-[l-[3-(2-aminoethyl)-phenylcarbamoyl]-2,2-dimethyl-15 propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl)-N-(diphenylmethyl)succinamide;2R-(3-(4-Biphenyl)propyl)-N-(phenylmethyl)succinamide;2-(2-Oxo-imidazolidin-4-ylmethyl)-5-phenyl-pentanoic acid; 2-(3 -Biphenyl-4-yl-propyl)-N 1 -[ 1 -(5,6-dichloro-1 H-benzoimidazol-2-y 1)- 20 3-methyl-butyl]-N4-hydroxy-succinamide hexanoic acid; 6-Biphenyl-4-yl-[2,2-dimethyl-1 -(pyridin-4-ylcarbamoyl)- propylcarbamoyl]-hexanoic acid, N-hydroxyamide; 2R-(3 -(4-Biphenyl)propyl)-N-(( 1 -hydroxy-1 -methylethyl)phenylmethyl)- succinamide; 25 6-Biphenyl-4-yl-3-(l-phenylcarbamoyl-2-(4-cyano-benzylsulfanyl)-2- methyl-propylcarbamoylj-hexanoic acid; 4-{2-(2-Carboxymethyl-5-(4'-hydroxy-biphenyl-4-yl)-pentanoylamino]-4methyl-pentanoylamino}-benzoic acid methyl ester; l-(N-Methyl-N-phenethylthiocarbomyl)-pyrrolidine-2-carboxylic acid; 30 6-Biphenyl-4-yl-3-({cyclohexyl-[2-(4-sulfanoyl-phenyl)-ethylcarbamoyl] methyl }-carbamoyl)-hexanoic acid; 3R(6-(4-Biphenyl)-3-(N-benzylcarbamoyl))-hexanoic acid N-hydroxyamide; ·126· 011584 [3-(3-Biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3-yl]-acetic acid; 2-Benzylsulfonyl-cyclopent-l-ene-carboxylic acid hydroxamide;[2-Oxo-3-(3-phenyl-propyl)-pyrrolidin-3-yl]-acetic acid;[3-(3-Naphthalen-2-yl-propyl)-2-oxo-pyrrolidin-3-yl]-acetic acid; 5 2-Benzylsulfonyl-cyclohex-l-enecarboxylic acid hydroxy amide; 6-Benzylsulfonyl-cyclohex-l-enecarboxylic acid hydroxy amide; 2R-(3 -(4-Biphenyl)propyl)-N-(3 -methy lpyridine)succinamide; {3-[3-(3-Hydroxy-phenyl)-propy 1]-2-oxo-pyrrolidin-3-yl}-acetic acid;6-Biphenyl-4-yl- {[cyclohexyl-(3 -morpholin-4-yl-propylcarbamoyl)- 10 methyl]-carbamoyl}hexanoic acid; [2-Oxo-3-(3-biphenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid;4-[2-(2-Thioamidomethyl-5-phenyl-valerylamino)-4-methyl- valeroylamino]-benzoic acid methyl ester; 4-[2-(2-Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino)-4-methyl- 15 valeroylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfamoyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(2-hydroxyethylsulfamoyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 20 l-(N-Hydroxy)-3-(2-bibenzyl)urea; 4-(2-{5-[7-(2-Amino-acetylamino)-9H-fluoren-2-yl]-2-carboxymethyl- pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester TFA sait;3R-(6-(4-Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoic acid N-hydroxy amide; 25 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)- phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid, trifluoroacetate sait; 4-(2- {2-Carboxymethyl-5-[4-( 1 H-tetrazol-5-yl)-phenyl]-pentanoylamino) - 30 4-methyl-pentanoylamino)-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-ethyl)-phenyl)-pentanoylamino)- 4-methyl-pentanoylaminoj-benzoic acid methyl ester; -127- 011584 4-(2-([5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester; 5 -Hydroxyamino-3 -(3 -pheny l-propyl)-3,4-dihy dro-2-H-pyrrole-3 -Cdrboxylic acid(2-cyclohexyl-l-methylcarbamoyl-ethyl)amide; 5 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-(3-morpholin-4-yl-sulfamoyl)- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfanyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfonyl-phenylcarbamoyl)-10 propylcarbamoyl]-hexanoic acid; 4- [2-(5-Biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-pent-4-enoylaminoj-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfmyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 15 4-(2-( [5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3- carbonyl]-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester; 5- Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3-carboxylicacid(2-cyclohexy 1-1 -methy lcarbamoyl-ethyl)amide; 6- Biphenyl-4-yl-[2,2-dimethyl-l-(pyridin-4-ylcarbamoyl)-20 propyicarbamoylj-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-cyano-biphenyl-4-yl)-pentanoylamino)-4-methyl-pentanoylaminoj-benzoic acid methyl ester; acid; 25 acid; hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-pyridin-4-yl-phenyl)-pentanoylamino)-4- 30 methyl-pentanoylaminojbenzoic acid methyl ester; 6-Biphenyl-4-yl(2-hydroxy-2-methyl-1 -phenylcarbamoyl- propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-l-(S)-phenyl-ethylcarbamoyl)-hexanoic 3-(R)-(l-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic 6-B iphenyl-4-yl-3 -(R)-(2-hydroxy-1 -hydroxymethy 1-ethylcarbomy 1)- -128- 011584 6-Biphenyl-4-yl(2-hydroxy-2-methyl-1 -phenylcarbamoyl-propylcarbamoyl)-hexanoic acid; 3- {2-Allylsufamyl-2-methyl-l-[2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-propylcarbamoyl} -6-biphenyl-4-y 1-hexanoic acid ; 5 4-[2-(5-Biphenyl-4yl-2-carboxymethyl-pentanoylamino)-4,5-dihydroxy- pentanoylaminoj-benzoic acid methyl ester; 4- (2- {5-[4'-(2-Amino-ethoxy)-biphenyl-4-yl]-2-carboxymethyl-pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-l-(S)-phenyl-ethylcarbamoyl)-10 hexanehydroxamic acid; 3- (R)-(l-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl-hexanehydroxamic acid; N-[5-(Biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl]-tert-leucine, N-(pyrid-4-yl)amide; 15 [3-(3-Naphthalen-2-yl-propyl)-2-oxo-tetrahydro-fùran-3-yl]-acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-l-hydroxymethyl-ethylcarbomyl)- hexanehydroxamic acid; 4- [2-(2-Carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 20 3-[2,2-Dimethyl-l-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-5-methyl- hexanoicacid; N1 -[2,2-Dimethyl-1 -(pyridin-4-ylcarbamoyl)-propyl]-N4-hydroxy-2-isobutyl-succinamide; 4-{2-[2-Carboxymethyl-5-(2-fluoro-biphenyl-4-yl)-pentanoylamino]-4-25 methyl-pentanoylamino}-benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(l(S)-hyroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid; 4- {2-[5-Biphen-4-yl-2-( 1 -carboxy-ethylamino)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 30 6-Biphenyl-4-yl-3(R)-(l(S)-hyroxymethyl-2,2-dimethyl- propylcarbamoyl)-hexanehydroxamic acid; -129- 011584 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfinyl-phenylcarbamoyl)-propylcarbamoylj-hexanoic acid; 2-(Biphenyl-4-ylsulfonyl)-cyclohex-l-enecarboxylic acid hydroxyamide;6-(Biphenyl-4-ylsulfonyl)-cyclohex-l-enecarboxylic acid hydroxyamide; 5 2-Phenethylsulfanyl-cyclohex-l-enecarboxylic acid hydroxyamide; 6-(4'-cyano-biphenyl-4-yl)-3-[2-hydroxy-l-(4-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1 - {1 - [ 1 -(4-Methoxycarbonyl-phenylcarbamoy l)-3 -methy l- butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; 10 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4S-methylsulfinyl-phenylcarbamoyl)- propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-3,3,3-trifluoropropyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 2- Bènzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 15 l-{ l-[l-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl- butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid;trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide;4-[2-(2-Carboxymethyl-5-(4-(2-methylthiazol-4- yl)phenyl)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 20 1 - {1 -[ 1 -(4-Methoxycarbony 1-pheny lcarbamoyl)-3 -methyl- butylcarbamoyl]-3-methyl-butylthiocarbamoyl}-pyrrolidine-2-carboxylic acid; 3- [(Cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl)-méthyl)-carbamoyl]-6-(4-pyridin-4-yl-phenyl)-hexanoic acid trifluoroacetate sait; trans-2-(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acid25 hydroxamide; 6-Biphenyl-4-yl-3-(l-hydroxymethyl-2,2-dimethyl-but-3-enylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3 -( 1 -hy droxymethy l-2,2-dimethyl-but-3-enylcarbamoyl)-hexanoic acid; 30 6-B iphenyl-4-yl-3 -(R)-( 1 -hydroxymethyl-2-(S)-( lH-imidazol-4-y 1)- ethylcarbamoyl)-hexanoic acid; -130- 01 1 584 3- (R)-(2-(R)-Benzyloxy-l-(S)-hydroxymethyl-propylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 4- [4-Methyl-2-(2-nitromethyl-5-phenyl-pentanoylamino)-pentanoylaminoj-benzoic acid methyl ester; 5 6-Biphenyl-4-yl-3-[3-methyl-l-(4-(2-hydroxyethylsulfamoyl)- phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-(l-hydroxymethyl-2-phenyl-ethylcarbamoyl)-hexanoic acid; NI -( 1 -Benzyl-2-hy droxy-ethy 1)-2-(3 -biphenyl-4-yl-propyl)-N4-hydroxy-10 succinamide; 6-Biphenyl-4-yl-3-(R)-(l-hydroxymethyl-2-(S)-(lH-imidazol-4-yl)-ethylcarbamoyl)-hexanehydroxamic acid; N-Hydroxy-2-[2-Oxo-3 -(3 -pheny l-propyl)-tetrahydro-furan-3 -y 1] -a; etamide; 15 4-[2-(2-Carboxymethyl-5-(2-hydroxy-biphen-4-yl)-valeroylamino)-4- methyl-valeroylaminoj-benzoic acid methyl ester;

Nl-(2-Benzyloxy-l-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl-propyl)- N^-hydroxy-succinamide; trans-2-(4-Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acid20 hydroxamide; 2-(4-Indol-l-yl-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide;6-Biphenyl-4-yl-3-[2-hydroxy-2-methyl-l-(4S-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3 -(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3 - 25 ylcarbamoyl)-hexanoic acid; 5- Biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic acid{l-[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl-butyl}-amide; 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-Nl-(2,4,5-trihydroxy-6- hydroxymethyl-tetrahydro-pyran-3 -yl)-succinamide; 30 6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3- yharbamoyl)-hexanoic acid; -131- 011584 N-[2,2-Dimethyl-lS-(pyridin-4-ylcarbamoyl)-propyl]-3R-thiophen-3-yl-succinamic acid; 4-[2S-(2R-(3-Biphenyl-4-yl-pyrrol-l-yl)-3-carboxy-propionylamido)-4-methyl-pentanoylaminoj-benzoic acid methyl ester; 5 3-(R)-(2-Benzyloxy-phenyl)-l-(S)-hydroxymethyl-ethylcarbamoyl)-6- b ohenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-l-(S)-(4-hydroxy-benzyl)-ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(l-hydroxyimino-ethyl)-hexanoic acid; 10 N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxopentanoyl)-L-t-leucine, N' 4-(methylthio)phenyl amide; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-l-(S)-(4-hydroxy-benzyl)-ethylcarbamoyl)-hexanehydroxamic acid; 4-{2-[2-carboxymethyl-5-(4'-sulfamoyl-biphenyl-4-yl)-pentanoylamino]-15 4-methyl-pentanoylamino}-benzoic acid methyl ester; 2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acidhydroxy amide; 3 - Acetyl-6-biphenyl-4-yl-3 -hexanoic acid ; N-[5-(Biphen-4-yl)-2-( 1 -carboxy-2-hydroxybut-1 -yl)pentanoyl]-t-L-20 leucine, N'-(4-methylthiophenyl)amide; 6-Biphenyl-4-yl-3-(2-hydroxy-cyclohexylcarbamoyl)-hexanoic acid;2-(3-Biphenyl-4-yl-propyl)-N^-hydroxy-Nl-(2-hydroxy-cyclohexyl)- svïcinamide; - 6-Biphenyl-4-yl-3-(l-hydroxyimino-ethyl)-hexanoic acid hydroxamide. 25 6-Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyI)-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(pyridin-4-ylcarbamoyl)- propylcarbamoyl]-hexanoic acid ethyl ester; 2-(3 -Biphenyl-4-yl-pyrrol-1 -y 1 )-3 -carboxy-N-( 1 -hydroxy-3 -phenyl-prop- 2-yl)-propionamide; 3 0 N-[5-(Biphen-4-yl)-2-( 1 -carboxy-2-hydroxyethyl)pentanoyl]-L-t-leucine, N'-(4-methylthiophenyl)amide; -132- 01 1 584 3 -(R)-(2-Hydroxy-1 -(S)-( 1 H-imidazol-4-yl)-ethy lcarbamoy 1)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanoic acid; 3 -(R)-(2-Hydroxy-1 -(S)-( 1 H-imidazol-4-yl)-ethy lcarbamoy 1)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid; 5 5-Biphenyl-4-yl-2-(l-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)- pentanoic acid; 2- (3-Biphenyl-4-yl-propyl)-N-hydroxy-N'-(l-hydroxymethyl-3-methylsulfanyl-propyl)malonamide; 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-1 -carbonyl)-hexanoic acid; 10 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-l-carbonyl)-hexanoic acidhydroxyamide; 1 -(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxyamide; l-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid 15 h zdroxyamide; N-( 1 -Benzyl-2-methoxy-ethyl)-3 -(3 -bipheny 1-4-yl-pyrrol-1 -yl)-succinamic acid; N-( 1 -Benzyl-2-methoxy-ethyl)-3 -(3 -biphenyl-4-y 1-pyrrol-1 -y l)-succinamichydroxamic acid; 20 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(l(S)-hydroxymethyl-2,2-dimethyl- propylcarbamoyl)-hexanoic acid; 3- (l-Benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid;Nl-(l-benzyl-2-hydroxy-ethyl)-N^-hydroxy-2-isobutyl-succinamide;6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(l(S)-hydroxymethyl-2,2-dimethyl- 25 propylcarbamoyl)-hexanoic hydroxamic acid; l-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid;6-Biphenyl-4-yl-3-(2-hydroxy-1 -hydroxmethyl-propylcarbamoyl)- hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-cyclohexyl-l-(S)-carbamoyl)-hexanoic acid; 30 6-Biphenyl-4-yl-3-(2-hydroxy-l-hydroxmethyl-propylcarbamoyl)- hexanoichydroxamic acid; -133- 011584 2S-[(lS-Benzyl-2-hydroxyethylcarbamoyl)-3R-bipnenyl-4-yl-pyrrol-l-yl-methyl]-pentanoic acid; 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-(2R-hydroxy-cyciohexyl-lR-yl)-succinamic acid; 2-(3-Biphenyl-4-yl-pyrrol-1 -y l)-3 -carboxamate-N-( 1 -hydroxy-3 -phenyl-prop-2-yl)-propionamide; trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid;trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acidhydroxyamide; 6-Biphenyl-4-yl-3-(R)-(l-(S)-hydroxymethyl-2-(3-pyridyl)-ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-2-(S)-hydroxy-3-(R)-(l-hydroxymethyl-2-(S)-(lH-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid; l-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; l-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; l-(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide;6-Biphenyl-4-yl-2S-hydroxy-3R-(lS-hydroxymethyl-3-methylsulfanyl- propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(l-(S)-hydroxymethyl-2-(3-pyridyl)- ethylcarbamoyl)-hexanehydroxamic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R-(lS-hydroxymethyl-3-methylsulfanyl- propylcarbamoyl)-hexanoic hydroxamic acid; l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl)- piperazine-2-carboxylic acidhydroxyamide; l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperazine-2-carboxylic acidhydroxyamide; 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-[2-hydroxy-lS-(lH-imidazol-4-yl-methyl)-ethyl]-succinamic acid trifluoroacetate; 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-[lS-(methoxy-methylcarbamoyl)-3-methyl-butylj-succinamic acid; N-( 1 -Acetyl-3 -methyl-butyl)-3-(3-bipheny 1-4-yl-pyrrol-1 -yl)-succinamic acid; -134- 011584 6-B ip heny 1-4-y 1 -3 -(R)-(2-oxo-1 -tetrahydrofuran-3 -(S)-ylcarbamoyl)-hexanoic acid; 3- [2,2-Dimethyl-l-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-2-hydroxy- 5-methyl-hexanoic acid-hydrochloride sait; 5 N^-(2,2-Dimethyl-1 -methylcarbamoyl-propyl)-2,N 1 -dihydroxy-3 - isobutyl-succinamide; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanoic acid;N-(l-Benzyl-2-hydroxy-ethyl)-3-(4-biphenyl-4-yl-pyrazol-l-yl)- succinamic acid; 10 N-(8-Oxo-4-oxa-l,7-diaza-tricyclo[9.6.1.012,17]octadeca- 11(18),12(17),13,15 -tetraen-9R-yl)-3 S-(3 -phenyl-pyrrol-1 -yl)-succinamic acid; 4- Acetyl-1 -[4-phenoxy-benzenesulfonyl] -piperazine-2-carboxylic acid,N-hydroxyamide; l-(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide; 15 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-[3S-(2RS-hydroxy-5-methyl)-hexyl]- Süçcinamic acid; N-(l-(S)-Benzyl-2-hydroxy-ethyl)-3’(R)-(2-biphenyl-4-yl-cyclopropylmethyl)-succinamic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-l-tetrahydrofuran-3-(S)"-ylcarbamoyl)-20 hexanehydroxamic acid; l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; 4-(4-Methoxy-benzenesulfony l)-thiomorpholine-3 -carboxylicacidhydroxyamide; 25 3-(Diphenylphosphinic)-propanoic acid; 3- (Diphenylphosphinic)-propanoic acid hydroxyamide; 4- [2-(2-Carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; l-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-4-(N- 30 methylcarbamoyl)piperazine-2-carboxamide; 4-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; -135- 011584 3 -(3 -B ipheny 1 -4-y 1-py rrol-1 -yl)-N-(2,2-dimethyl-1 -methylcarbamoyl-propyl)-succinamic acid; 1 -[4-Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid,N-hydroxyamide; 5 4[4-Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; 3 -[2-Biphenyl-4-yl-ethyl sul fany 1 ]-tetrahydro-pyran—4-carboxy lie acidN-hydroxyamide; 6-Biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid; 10 1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]piperdine-2-amidoxime; 2-(3 -Biphenylnitrile-4-yl-pyrrol-1 -yl)-3 -carboxy-N-( 1 -hydroxy-3 -phenyl-prop-2-yl)-propionamide; {3 -[3 -(3-Amino-phenyl)-propyl]-2-oxo-tetrahydro-furan-3 -yl} -acetic acid ;6-Biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid; 15 5-Biphenylvaleric acid; l-[4-(Methoxy)-benzenesulfonyl]piperdine-2-amidoxime; 1- [4-Phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acidN-hydroxyamide; {3 -(3 -(3-Methylamino-phenyl)-propyl)-2-oxo-tetrahydro-furan-3 -yl} -20 acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanehydroxamic acid; 4-(lH-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 25 lR-[4-Bromo-phenoxy)-benzenesulfonyl)-N-amino-piperidine-2- carboxamide; 2- (3-Biphenyl-4-yI-propyl)-3, N-4-dihydroxy-N^-(l(S)-hydroxymethyl-3-methanesulfinyl-propyl)-succinamide; N-(l-Benzyl-2-hydroxy-ethyl)-3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-30 l-yl]-succinamic acid; l-(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acidhydroxamide; -136- 011 584 4-(4-(4-Chlorophenoxy)benzenesulfonyl)-N-hydroxy-morpholine-3R- carboxamide; 2 S-[ lR-(3-(4'-Cyano-biphenyl-4-yl)-pyrrol-1 -yl)-N-(2,2-dimethyl-1S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; 5 2(S,R)-{ 1 S-Benzyl-2-hydroxyethylcarbamoyl-[3R-(4'-cyano-biphenyl-4- yl)-pyrrol-1 -yl]-methyl}pentanoic acid; 2S-[3-(Biphenyl-4-yl)-pyrrol-lR-yl-(lS-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; 1- (l,3-Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid10 hydroxamide; 3- [3-(4'-Carbamoyl-biphenyl-4-yl]-pyrrol-l-yl)-N-(l-hydroxymethyl-2,2-dimethyl-propyl)-succinamic acid; 4- Methyl-1 -(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochloride; 15 1 -[4-Chlorophenoxybenzenesulfonyl]-N-hydroxy-2R- piperazinecarboxamide; 2- (3-Phenyl-propylsulfonyl)-cyclohexane carboxylic acid hydroxamide; 1 -(Pyrolidine-1 -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide;l-(Piperidine-l-sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 20 4-[4-Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; l-[4-(4-Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperdine-2-carboxylicacid hydroxyamide; l-[4-(4-Nitrile-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-25 piperazine-2-carboxylic acid N-hydroxyamide; 2 S-[3 -(Biphenyl-4-yl)-pyrrol-1 R-yl-( 1 S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-methyl]-pent-4-enoic acid; 6-Oxo-3-(4-phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4- carboxylic acid hydroxamate; 30 4-(t-Butoxycabonyl)-l-(4-(pyridin-2-yl)oxybenzensulfonyl)-N-hydroxj- piperazine-2-carboxamide; -137- 01 1 5 84 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid-N-hydroxyamide; 4-[4-(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; N-(2,2-Dimethyl-lS-hydroxymethyl-propyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1 -yl]-succinamic acid; N-(lS-Benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl)-succinamic acid; 4-(4-Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 4-(4-Butoxy-benzenesulfonyl)-l-oxothiomorpholine-3-carboxylic acidhydroxyamide; l-[4-(4-Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl)-2R-piperazine-2-carboxylic acid hydroxyamide; 1 -((4-(4-Chlorophenyl)-piperazine)-1 -sulfonyl)-piperidine-2-carboxylicacid hydroxamide; cis-2-Phenethylsulfanyl-cyclohexanecarboxylic acid hydroxyamide;N-(2-Hydroxy-lS-phenyl-ethyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l- yl]-succinamic acid; l-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochoride; l-(Diphenylphosphinic)-pyrolidine-2-(R)-carboxylic acid-hydroxyamide;N,N-{(Diphenylphosphinic)-(acetic açid-sodium salt)}-hydrazide; N-( 1 -Benzyl-2-hy droxy-ethy l)-3 -( 1 -biphenyl-4-yl-1 H-pyrrol-3 -yl)- succinamic acid; trans-2-Phenethylsulfonyl-cyclohexanecarboxylic acid hydroxyamide; 1 -[4-(4-Fluorophenyl)-piperazine-1 -sulfonyl]-piperidine-2-carboxylic acid hydroxamide; l-[4-(4-Fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylicacid hydroxyamide; 4-[4-(Bromo-phenoxy)-benzenesulfonyl]-2,2-dimethyl-1 -oxo-thiomorpholine-3-carboxylic acid hydroxyamide; -138- 011584 N-(2,2-Dimethyl-1 S-methylcarbamoyl-propyl)-3R-(3 -phenyl-pyrrol-1 -yl)-succinamic acid; 3R-(3-Biphenyl-4-yl)-N-(2-hydroxy-lS-hydroxymethyl-2-methyl-propyl)-succinamic acid; 5 l-(Pyrrolidine-l-carbonyl)-pyrrolidine-2(R)-carboxylic acid; l-(Pyrrolidine-l-carbonyl)-pyrrolidine-2(R)-carboxylic acid hyroxyamide;l-Phenethylcarbamoyl-pyrrolidine-2(R)-carboxylic acid; R-4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylic acid hydroxyamide; 10 4-(Ethoxycarbonyl)methyl-l-(4-(4-chlorophenyl)benzenesulforiyl)-N- hydroxy-2R-piperazinecarboxamidehydrochloride; N-(2R-Hydroxy-indan-lR-yl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[3-(4-pyridin-4-yl- 15 phenyl)-pyrrol-1 -yl]-succinamic acid; N-(2,2-Dimethyl-lS-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4-yl- phenyl-4-yl)-pyrrol-1 -yl]-succinamic acid; 1 -Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acid hydroxyamide;N-(2,2-Dimethyl-lS-methyl carbamoyl-propyl)-3R-[3-(4-propyl-phenyl)- 20 pyrrol-l-yl]-succinamic acid; l-(4-Benzyl-piperazine-l-sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 3(S)-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H- l,4-thiazine-3-carboxamide; 25 2(R)-4-Methyl-l-(4-(4-fluorophenyl)benzenesulfonyl)-N-hydroxy- piperazine-2-carboxamide; N-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-3-(5-biphenyl-4-yl-furan-2-yl)-succinamic acid; N-(2J2-Dimethyl-lS-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl-pyrrol- 30 l-yl)-succinamic acid; 1 -((2-Pyridyl)-4-piperazine-1 -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; -139- 011584 1- [4-(Pyridin-4-ylsulfamyl)-benzenesulfbnyl]-piperdine-2-carboxylic acidhydroxyamide; N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine;N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 5 N-(8-oxo-4-oxa-l,7-tricyclo[9.6.1.012,17]octadeca-ll(18),12(17),13,15- tetraen-9-yl)-3-[4-(4-pyridyl)-3-phenyl-pyrrol-l-yl)-succinamic acid; 3-[3 -(4-Pyridyl)phenyl-4-yl-pyrrol-1 -yl]-N-[2,2-dimethyl-1 -(4-pyridyl)carbamoyl-propyl]-succinamic acid; 2,2-Dimethyl-4-[4-(pyridin-2-yloxy)-benzenesulfonyl]-thio-morpholine-3-10 carboxylic acid hydroxyamide; N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine; N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 2- [2-(N'-Acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl-pentanoic acid; 15 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl- tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride; 2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-butyric acid; 2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino)-N-hydroxy-3,3-20 dimethyl-butyramide; 3(R)-N-Hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H- l,4-thiazine-3-carboxamide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine, 25 N-hydroxyamide; 2-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino]-3,3-dimethyl butyric acid;2-[4-(Pyridm-2-yl-oxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl butyramide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine; 30 3-[3-(4'-Carbamoyl-biphenyl-4-yl)-pyrrol-l-yl]-N-(2,2-dimethyl-l- methylcarbamoyl-propyl)-succinamic acid; -140- 01 1 584 3-[3-(4'-Cyano-biphenyl-4-yl)-pyrrol-l-y]-N-(2,2-dimethyl-l- methylcarbamoyl-propyl)-succinamic acid; 2- (2-Biphenyl-4-yl-ethylsulfonyl)-cyclohex-1 -ene-carboxy lie acidhydroxyamide; 5 6-(2-Biphenyl-4-yl-ethyl sufonyl)-cyclohex-l-ene-carboxylic acid hydroxyamide; N-(4-Pyridin-4-yl-oxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine; 3- [3-4'-Carbamoyl-biphenyl-4-yl)-pyrrol-l-yl]-N-[2,2-dimethyl-l-10 (pyridin-4-yl-carbamoyl)-propyl]-succinamicacid; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine, N-hydroxyamide; l-(4-Phenoxy-piperdine- l-sulfonyl)-piperdine-2-carboxylic acidhydroxyamide; 15 3(R)-4-[4-(4-Bromo)phenoxybenzenesulfonyl]-2,2-dimethyl-tetrahydro- 2H-1,4-thiazine-3 -carboxylic acid; N-(4-[4-Chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)- D-cysteine; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethÿl-S-(methylthio)-20 D-cysteine, N-hydroxyamide; N-(4-[4-Chlorophenoxy]-benzenesulfbnyl)-3,3-dimethyl-S-(methylsulfoxy)-D-cysteine, N-hydroxyamide; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 2- ylsulfanyl)-butyric acid; 25 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 3- ylsulfanyl)-butyric acid; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 4- ylsulfanyl)-butyric acid; cis-2-(2-Phenyl-ethanesulfonyl)-cycloheaxanecarboxylic acid30 hydroxyamide; 3 (R)-N-Hydroxy-4-(4-(imidaz-1 -yl)phenoxybenzenesulfony 1)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; -141- 011584 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl·-tetrahydro-2H-1,4-thiazine-3 -carboxamide; 4-[2-(2-Hydroxycabamoylmethyl-5-phenyl-pentanoylamino)-4-methyl-pentanoyl-benzoic acid methyl ester; 5 trans-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid; 2-[4-(4-Chlorophenyl)-piperazine-l-sulfonylamino]-3-methyl-3-(pyridin- 2-ylmethylsulfanyl)-butyric acid; 10 3R-[3-(4'-Cyano-biphenyl-4-yl)pyrrol-l-yl]-N-[2,2-dimethyl-lS-(pyridin 4-ylcarbamoyl)-propyl]-succinamic acid; 3.3- Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid,N-hydroxyamide; N-(2,2-dimethyl-l-methylcarbamoyl-propyl)-3-[l-(4-fluorophenyl)-lH-15 pyrrol-3-yl]-succinamic acid; 2(R)-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridi-2-ylsulfanyl)-butyric acid; 2-(2-Biphenyl-4-yl-ethanesulfonyl)-cyclohexanecarboxylic acidhydroxamate; 20 2-[4-(4-Chlorophenyl)-piperazine-l-sulfonylamino]-3-methyl-3-(pyridin· 2-ylmethylsulfanyl)-butyric acid, N-hydroxyamide; 3.3- Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid, N-hydroxyamide; 25 3-tert-Butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro- phenôxy)benzenesulfonylamino)-3-methyl-butyric acid; 1 -(4-Phenylsulfanyl-piperidine-1 -sulfonyl)-piperidine-2-carboxylic acidhydroxyamide; l-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-5-oxo-30 piperazine-2-carboxylic acid; N-(4-[4-Fluorophenoxy]-benzenesulfonylamino)-3-methyl-3-(l-benzyl-imidazole-2-yl-sulfanyl)-butyric acid; -142- 011584 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi n-2-yl-sulfanyl)-butyric acid, hydroxyamide; 3(R)-N-Hydroxy-4-(4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3 -carboxamide; 5 l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-4-(l-methyl-lH-imidazole-4- sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-Dimethyl-l S-methylcarbamoyl-propyl)-3R-[ 1 -(4'-cyanobiphenyl- 4-yl)-lH-pyrrol-3-yl]-succinamic acid; 3 -Carboxymethylsulfanyl-2-(4-(4-fluoro-phenoxy)-10 benzenesulfonylamino)-3-methyl-butyric acid; 2.2- Dimethyl-1-oxo-4-[4-(pyridin-4yloxy)-benzenesulfonyl]-1S14-thiomorpholine-3-carboxylic acid hydroamide; l-[4-(Pyridin-2-ylsulfanyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide; 15 2(R)-[4-(4-(fur-3-yl)-phenoxy)-benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfanyl)-butyric acid; 2.2- Dimethyl-1 -oxo-4-[4-(pyridin-4yloxy)-benzenesulfonyl]-1S14-thiomorpholine-3-carboxylic acid hydroamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-hÿdroxÿcarbamoyl-20 1,1 -dimethyl-ethylsulfanyl} -acetic acid tert-butyl ester; l-[4-(Pyridin-4-ylsulfanyl)-piperidine-l-sulfbnyl]-piperidine-2-carboxylicacid hydroxyamide; 2(R)-[4-(4-Bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfanyl)-butyric acid, hydroxyamide; 25 trans-2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexanecarboxylic acid hydroxyamide; N-[lS-(lH-Imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid formate; N-Methyl-3-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid; 30 N(4)-(2,2-Dimethyl-lS-hydroxymethyl-propyl)-N(l)-hydroxy-3R-[3-(4- pyridin-4-yl-phenyl)-pyrrol-1 -yl]-succindiamide; -143- 011584 {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-1,1 -dimethyl-ethylsulfanyl}-acetic acid; 1- [4[(4-Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl -5-oxo-piperazine-2-carboxylic acid hydroxyamide; 5 N-(4-[4-Bromophenoxy]-benzenesulfonylamino)-3-methyl-3-(l -benzyl- imidazole-2-yl-sulfanyl)-butyric acid; 3R-[3-(4'-Cyanobiphenyl-4-yl)-pyrrol-l-yl]-N-(2,2-dimethyl-lS-hydroxymethyl-propyl)-succinamic acid; 2- (R)-[4-(4-Iodophenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-2-10 yl-sulfanyl)-butyric acid; □ 3R-[3-(4-Cyano-phenyl)-pyrrol-l-yl]-N-(2,2-dimethyl-lS-hydroxymethyl-P' opyl)-succinamic acid; 2(R)-[4-(4-Iodo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-15 sulfonyl)butyric acid, hydroxyamide; 2(R)-[4-(4-Nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfonyl)butyric acid; 2-[4-(4-Fluoro-phenoxy)-benzene sulfonylamino]-3,3-dimethyl-pent-4-enoic acid; 20 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl- isoxazole-3-ylmethylsulfanyl)-butyric acid; 2-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoazole-3-ylmethylsulfanyl)-butyric acid; .. ... 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3-25 (5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3- (5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-(carbomethoxyethylsulfanyl)-butyric acid; 30 1 -[2-(Benzothiazol-2-ylsulfanyl)-piperidine-1 -sulfony 1]-p ip eridine-2- carboxylic acid hydroxyamide; -144- 011584 3R-[3-(4-Cyano-phenyl)-pyrrol-l-yl]-N-(2,2-dimethyl-l.S-methylcarbamoyl-propyl)-succinamic acid; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-(hydroxyethylsulfanyl)-butyric acid; 5 [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)- butyric acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[l-(4'-cyanobiphenyl-4-yl)-lH-pyrrol-3-yl]-succinamic acid; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-10 (amidoethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5-phenyl-pent-4-enoic acid; 15 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-4,5,6,7-tetrahydro-3H- imidazole[4,5,-c]pyridine-6-carboxylic acid hydroxyamide 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfonyl)butyric acid; 3(S)-4-(4-((Pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-20 l,4-thiazine-3-carboxylic acid; l-[4-(Pyridin-4-ylsulfanyl)-piperidine-l-sulfanyl]-piperidine-2-carboxylicacid hydroxyamide; N-[l-(lH-imidazol-2-yl)-3-methyl-butyl]-3-[l-(4'-cyanobiphenyl-4-yl)-lH-pyrrol-3-yl]-succinamic acid; 25 3R-{ 3 -[(4-Cyano-phenyl)-acetyl]-pyrrol-1 -yl }-N-(2,2-dimethyl-1S- methylcarbamoyl-propyl)-succinamic acid; 1 -[4-(4-Methoxy-phenylsulfamyl)-piperidine-1 -sulfonyl] -piperidine-2-carboxylic acid hydroxamide; 3R-[3 -(4-Cyano-phenyl)-pyrrol-1 -yl]-N-(2,2-dimethyl-1S- 30 methylcarbamoyl-propyl)-succinamic acid methyl ester; 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n- yl-sulfonyl)butyric acid, hydroxyamide; -·45- 01 1 584 1- [4-(4-Methyl-phenylsulfamyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid; 5 4-4(-Methoxy-benzenesulfbnyl)-2,2-dimethyl-thiomorpholine-3- carboxylic acid hydroxyamide; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine- 3-carboxylic acid; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-10 3-carboxylic acid hydroxyamide; 2(R)-[4-(4-bromo-phenoxy)benzenesulfbxylamino]-3-methyl-3-(pyridi-n-yl-sulfuroxide)butyric acid, hydroxyamide; 4-(4-Methoxy-bezensulfonyl)-2,2-dimethyl-l-oxo-thiomorpholine-3-ci rboxylic acid hydroxyamide; 15 2,2-Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]thiomorpholin-3-ol; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy-1-oxo- thiomorpholine-3-carboxylic acid hydroxyamide; 2- (R)-3-Methyl-3-(pyridin-2-yl-sulfanyl)-[4-(4-trifluoromethylphenoxy)-benzenesulfonylamino]-butyric acid; 20 3(R)-4-(4-(Pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H- 1,4-thiazine-3-carboxamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-yl·oxy)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3 -methyl-3 -[(5 -methyl-isoxazol-3 -yl)methylsulfanyl]-[4-25 (pyridin-4-yl-oxy)-benzenesulfonylamino]-butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3-hydroxy-3-methyl-butyricacid; .. 3(S)-2,2-Dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide; 30 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-yl sv!fanyl)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4- (pyridin-4-yl-sulfanyl)-benzenesulfonylamino]-butyramide; -146- 011584 3.3- Dimethyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidine-l-sulfonylamino]-butyric acid; 3.3- Dimethyl-N-hydroxy-2R-[4-(pyridin-4-ylsulfanyl)-piperidine-l-sulfonylamino]-butyramide; 5 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3- [( -methyl-imidazol-2-yl)methylsulfanyl]-butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3-methyl-3-[(l-methyl-imidazol-2-yl)methylsulfanyl]-butyric acid; N-Hydroxy-2-[(4-methylbenzenesulfonyl)amino]acetamide; 10 1 -[4-(4-Imidazol-l -yl-phenoxy)-piperidine-1 -sulfonyl]-piperidme-2- carboxylic acid hydroxyamide; 1 -[4-(4-Imidazol-1 -yl-phenylsulfanyl)-piperidine- l.-sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 2(R)-[4-(4-Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-l-carboxylic15 acid hydroxyamide; l(R)-[4-(4-Chloro-benzoyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylicacid amide; l(R)-(4-Pyridin-2-yl-piperazine-l-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide; 20 1 (R)- [4-(4-Imidazol-1 -yl-phenoxy)-piperidine-1 -sulfonyl]-piperidine-2- carboxylic acid; 1 (R)-[4-(4-Imidazol-1 -yl-phenoxy)-piperidine-1 -sulfonyl]- piperidine-2-c.'-rboxylic acid hydroxyamide; N-Hydroxy-3,3-dimethyl-2R-[4-(morpholine-4-carbonyl)piperidine-l-25 sulfonylaminojbutyramide; N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl)-2R-[4- (pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide; 4-(4'-Chloro-biphenyl-4-yl)-2RS-[2-( 1,3 -dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid; 30 4-(4'-Chloro-biphenyl-4-yl)-2R-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)- ethyl]-4-oxo-butyric acid; -147- 011584 N-Hydroxy-2R-[4-(4-imidazol-1 -yl-phenoxy)-piperidine-1 -sulfonylamino]-3,3-dimethyl-butyramide; 2R-[4-(4-Chloro-benzoyl)-piperazine-l-sulfonylamino]-N-hydroxy-3- methyl-3-methylsulfanyl-butyramide; 5 N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4-ylsulfanyl)- piperidine-l-sulfonylamino]-butyramide; 4-(Pyridin-4-yloxy)benzenesulfonîc acid;4-(Pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride;(3S)-2,2-Dimethyl-3-thiomorpholine carboxylic acid; 10 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl- 1,1 -dioxo-tetrahydro-2H-1,4-thiazine-3-carboxamide; 1R-3 S-2,2-Dimethyl-1 -oxo-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1 -thiomorpholine-3-carboxylic acid amide; 1 S-3S-2,2-Dimethy 1-1 -oxo-4-[4-(pyridin-4-y loxy)-benzenesulfonyl]-1 - 15 tl?i.omorpholine-3-carboxylic acid amide; and 4-[4-(l-Hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic acid amide.

Especially preferred are the MMP inhibitors currently in clinical development, for example batimastat (2). 20 MMP compounds in clinical development include batimastat (2) for the treatment of malignant pleural effusion, and marimastat (1) for the treatment ofpancreatic cancer. Galardin (3) is for the treatment of corneal ulcers, and aspécifie MMP-1 inhibitor is RO 31-9790 (4). -14*' 011584

Compounds in Clinical Development

Ail that is required to practice the présent invention is to administer to amammal suffering from atherosclerosis, an effective amount of a matrix 5 metalloproteinase inhibitor and an ACAT inhibitor. Compounds winch can inhibitthe actions of matrix metalloproteinase enzymes can be identified utilizing routinein vitro and in vivo assays. Several compounds from within the foregoing classeshâve been evaluated in such standard assays and determined to be potent matrixmetalloproteinase inhibitors. The assays measure the amount by which a test 10 compound reduces the hydrolysis of a thiopeptolide substrate caused by a matrix metalloproteinase enzyme. Such assays are described in detail by Ye, et al., inBiochemistry, Vol. 31, No 45, 1992, (11231-11235), which is incorporated hereinby reference.

Thiopeptolide substrates show virtually no décomposition or hydrolysis in 15 the absence of a matrix metalloproteinase enzyme. A typical thiopeptolide substrate commonly utilized for assays is Ac-Pro-Leu-Gly-thioester-Leu-Leu-

Gly-0 Et. A 100 pL assay mixture will contain 50 mM of 2-morpholinoethane sulfonic acid monohydrate (MES, pH 6.0) 10 mM CaC^, 100 pM thiopeptolide -149- 011584 substrate, and 1 mM 5,5'-dithio-bis-(2-nitro-benzoic acid) (DTNB). Thethiopeptolide substrate concentration is varied from 10 to 800 μΜ to obtain Kmand Kcat values. The change iri absorbance at 405 nm is monitored on a ThermoMax microplate reader (molecular Devices, Menlo Park, CA) at room température(22°C). The calculation of the amount of hydrolysis of the thiopeptolide substrateis based on E412 = 13600 irH cm"l for the DTNB-derived product 3-carboxy-4-nitrothiophenoxide. Assays are carried out with and without matrixmetalloproteinase inhibitor compounds, and the amount of hydrolysis is comparedfor a détermination of inhibitory activity of the test compounds.

Several représentative compounds hâve been evaluated for their ability toinhibit various matrix metalloproteinase enzymes. Table I below présentsinhibitory activity for compounds from various classes. In the table, MMP-1 refers,to interstitial collagénase; MMP-2 refers to Gélatinase A; MMP-3 refers tostromelysin; MMP-7 refers to matrilysin; and MMP-9 refers to Gélatinase B. Testcompounds were evaluated at various concentrations in order to détermine theirrespective IC50 values, the micromolar concentration of compound required tocause a 50% inhibition of the hydrolytic activity of the respective enzyme.

As noted above, any matrix metalloproteinase inhibitor can be used to treator prevent atherosclerotic lésions according to this invention. ACAT inhibitors useful in the practice of the instant invention are those ofFormulai C |' R·,—x—s—n—c—y—r2

O R or a pharmaceutically acceptable sait thereof wherein: X and Y are selected from oxygen, sulfur and (CR'R")n wherein n is an integer offrom 1 to 4 and R' and R' are each independently hydrogen, alkyl, alkoxy,halogen, hydroxy, acyloxy, cycloalkyl, phenyl optionally substituted or R'and R" together form a spirocycloalkyl or a carbonyl; R is hydrogen, a straight or branched alkyl of from 1 to 8 carbon atoms or benzyl; -150- 011584

Rl and R2 are each independently selected from (a) phenyl or phenoxy each of which is unsubstituted or is substitutedwith 1 to 5 substituents selected from phenyl, 5 an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atôms and< which is straight or branched; phenoxy, 10 hydroxy, fluorine,chlorine,bromine,nitro, 15 trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms andis straight or branched, -(CH2)pNR3R4 wherein p is zéro or on'e, and each of 20 R3 and R4 is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms; (b) 1- or 2-naphthyl unsubstituted or substituted with from 1 to3 substituents selected from phenyl, 25 an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atoms andwhich is straight or branched; hydroxy, 30 phenoxy, fluorine,chlorine, -151- 10 15 20 25 bromine, 01 1 5 84 nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms andis straight or branched, -(CH2)pNR3R4 wherein p, R3 and R4 hâve the meaningsdefined above; (c) arylalkyl; (d) a straight or branched alkyl chain having from 1 to 20 carbonatoms and which is saturated or contains from 1 to 3 double bonds;or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety hasfrom 3 to 6 carbon atoms.

Preferred compounds of the instant invention are those of Formula I:wherein Rj is phenyl or is phenyl disubstituted in the 2,6-positions, wherein R2 is phenyl or is phenyl disubstituted in the 2,6-positions,wherein each of Rj and R2 is phenyl, wherein each phenyl is disubstituted in the 2,6-position, wherein Rj is phenyl disubstituted in the 2,6-positions and R2 is phenyl trisubstituted in the 2,4,6-positions, whereinRi is2,6-bis(l-methylethyl)phenylandR2is2,6-bis(l- methylethyl)phenyl or 2,4,6-tris(l-methylethyl)phenyl,wherein one of Rj and R2 is the group R5 than 5; -(CH2)t-C-(CH2)w-R7, 30 wherein t is zéro or 1 to 4; w is zéro or 1 to 4 with the proviso that the sum of t and w is not greater -152- 011584 I<5 and are each independently selected from hydrogen or alkyl havingfrom 1 to 6 carbon atoms, or when R5 is hydrogen, Rg can be selected from thegroups defined for R7; and R7 is phenyl or phenyl substituted with from 1 to 3 substituents selected5 from a straight or branched alkyl group having from 1 to 6 carbon atoms, straight or branched alkoxy group having from 1 to 6 carbon atoms, phenoxy, hydroxy,fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl whereinalkyl has from 1 to 4 carbon atoms, or -(CH2)pNR3R4 wherein P, R3 andR4 hâve the meanings defined above.

10 Also preferred compounds of the instant invention are those of Formula I wherein X is oxygen, sulfur or (CR'R")n; Y is oxygen, sulfur or (CR'R")n, with the proviso that at least one of X or Y is (CR'R")n wherein n is an integer of from 1 to 4 and R' and R” are each15 independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy,cycloalkyl, or R' and R" taken together form a carbonyl or aspirocycloalkyl group of from 3 to 10 carbons; R is hydrogen; 20 Rj is phenyl optionally substituted, straight or branched alkyl of from 1 to10 carbon atoms, cycloalkyl of from 3 to 10 carbon atoms; R2 is phenyl optionally substituted, straight or branched alkyl of from 1 to10 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenoxyoptionally substituted with the proviso that only if X is (CR'R")n can 25 R] be optionally substituted phenoxy and only if Y is (CR'R")n can R2 be optionally substituted phenoxy, and with the further proviso that at leastone of Rj and R2 is optionally substituted phenyl or phenoxy.

More preferred compounds of the instant invention are those of Formula I wherein 30 X is oxygen; -153- 01 1 584 Y is (CR'R")n wherein n is an integer of from 1 to 2; R is hydrogen;

Rj is optionally substituted phenyl; R2 is optionally substituted phenyl or phenoxy, straight or branched alkyl of from1 to 10 carbons, or cycloalkyl of from 3 to 10 carbons; and R' and R" are each independently hydrogen, straight or branched alkyl of from1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy,acyloxy, cycloalkyl, or R' and R” taken together form a carbonyl or aspirocycloalkyl.

Preferred compounds of Formula I include, but are not limited to thefolio wing:

Sulfamic acid (phenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid[[2,4,6-tri s( 1 -methylethyl)phenyl]acetyl-2,6-b is( 1 -methyl- ethyl)phenyl ester,

Sulfamic acid[[2,6-bis(l-methylethyl)phenyl]acetyl]-2,6-bis(l-methyl-ethyl)phenyl ester,

Sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl-2,4,6-tris(l-methyl-ethyl)phenyl ester,

Sulfamic acid[[2,6-bis(l-methylethyl)phenyl]acetyl]-2,4,6-tris(l -methyl-ethyl)phenyl ester,

Sulfamic acid[adamantaneacetyl]-2,6-bis[l-methylethyl)phenyl ester,Sulfamic acid[[2,6-bis(l-methylethyl)phenyl]acetyl]-2,6-bis(l-methyl- ethyl)phenyl ester-sodium sait,

Sulfamic acid[[2,4,6-tris(l-methylethyl)phenyl]acetyl]-2,6-bis(l-methyl-ethiyl)phenyl ester-sodium sait,

Sulfamic acid (decanoyl)-2,6-bis-(l-methylethyl)phenyl ester,

Sulfamic acid (dodecanoyl)-2,6-bis-(l-methylethyl)phenyl ester, 2,6-Bis(l-methylethyl)-N-[[[2,4,6-tris(l-methylethyl)phenyl]methyl]- sulfonyl]benzeneacetamide, 2,6-Bis(l-methylethyl)-N-[[[2,4,6-tris(l-methylethyl)phenyl]methyl]-sulfonyl]benzeneacetamide-sodium sait, -154- 011584 2,6-Bis(l-methylethyl)phenyl[[[2,4,6-tris(l-methylethyl)phenyl]methyl]- sulfonyljcarbamate, 2,6-Bis(l-methylethyl)phenyl[[[2,4,6-tris(l-methylethyl)phenyl]methyl]-sulfonyljcarbamate-sodium sait, 5 Sulfamic acid (l-oxo-3,3-diphenylpropyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl 10 ester,

Sulfamic acid trans-[(2-phenylcyclopropyl)carbonyl]-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, 15 Sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(l- methylethyl)phenyl ester,

Sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(l-methylèthyl)phenyl ester,20 Sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid (oxophenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,Sulfamic acid [2-trifluoromethylphenyl(acetyl)]-2,6-bis(l- 25 methylethyl)phenyl ester,

Sulfamic acid (l-oxo-2-phenylpropyl)-2,6-bis(l-methylethyl)phenyl ester,Sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(l -methylethyl)phenyl eser,

Sulfamic acid (cyclohexylacetyl)-2,6-bis(l-methylethyl)phenyl ester, 30 Sulfamic acid (diphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid (triphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [(l-phenylcyclopentyl)carbonyl]-2,6-bis(l- methylethyl)phenyl ester, -155- 011584

Sulfamic acid (3-methyl-l-oxo-2-phenylpentyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid (l-oxo-2-phenylbutyl)-2,6-bis(l-methylethyl)phenyl ester,Sulfamic acid (cyclohexylphenylacetyl)-2,6-bis(l-methylethyl)phenyl 5 ester,

Sulfamic acid ( 1 -oxo-2,2-diphenylpropyl)-2,6-bis( 1 -methylethyl)phenyl ester,

Sulfamic acid [(9H-fluoren-9-yl)carbonyl]-2,6-bis(l-methylethyl)phenyl ester, 1θ Sulfamic acid (l-oxo-3-phenylpropyl)-2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [l-oxo-3-[2,4,6-tris(l-methylethyl)phenyl]-2-propenyl]- 2,6-bis(l-methylethyl)phenyl ester,

Sulfamic acid [l-oxo-3-[2,4,6-tris(l-methylethyl)phenyl]propyl]- 2,6-bis(l-methylethyl)phenyl ester, 15 Sulfamic acid [(acetyloxy)[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis(l-methylethyl)phenyl ester,

Sulfamic acid [hydroxy[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis( 1 -methylethyl)phenyl ester,

Sulfamic acid [fluoro[2,4,6-tris(l-methylethyl)phenyl]acetyl]-20 2,5-bis(l-methylethyl)phenyl ester,

Sulfamic acid (3-methyl-l-oxo-2-phenylpentyl)-2,6-bis(l-methylethyl)phenyl ester sodium sait,

Sulfamic acid [[2,4,6-tris(l-methylethyl)phenoxy]acetyl]-2,6-bis(l-methylethyl)phenyl ester, 25 Sulfamic acid [[2,6-bis(l-methylethyl)phenoxy]açetyl]-2,6-bis(l- methylethyl)phenyl ester, and

Sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis(phenyl)phenyl ester.

Other ACAT inhibitors useful in the practice of this invention are selected 30 from: 4-Hexadecylamino-benzoic acid monosodium sait; 3,5-Dimethyl-l-[5-(l,4,5-triphenyl-2H-imidazol-2-ylsulfanyl)-pentyl]-lH- pyrazole monosodium sait; -156- 011584 8- (1,4,5-Triphenyl-2H-imidazol-2-yloxy)-octanoic acid;, 9- Bromo-6,ll-dihydro-dibenzo[b,e]oxepine-ll-carboxylic acid (2,6-diisopropyl-phenyl)-amide; 5-((3,5-Di-tert-butyl-4-hydroxy-phenylamino)-{[4-(2,2-dimethyl-propyl)-5 benzyl]-hexyl-amino}-methylene)-2,2-dimethyl-[l,3]dioxane-4,6-dione; 3 -(2,4-Difluoro-pheny 1)-1 -[4-(2,2-dimethyl-propyl)-benzyl] -1 -heptyl-urea;1 -Heptyl-1 -[4-(3-methyl-butyl)-benzyl]-3-(2,4,6-trifluoro-phenyl)-urea; 3 -(2,4-Difluoro-phenyl)-1 -[5-(4,5-diphenyl- lH-imidazol-2-ylsulfanyl)- pentyl]-1 -heptyl-urea; 10 l-Butyl-3-{2-[3-(5-ethyl-4-phenyl-imidazol-l-yl)-propoxy]-6-inethyl- phenyl}-urea; 1- (2-{2-[4-(2,2-Dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)- 3-heptyl-urea;

Octadeca-9,12-dienoic acid (l-phenyl-ethyl)-amide; 15 3-(lH-Indol-3-yl)-2-octadec-9-enoylamino-propionic acid ethyl ester; 3 -(Dimethyl-nonyl-silanyl)-N-( 1 -phenyl-2-p-tolyl-ethyl)-propionamide;(R)2-Hexyl-decanoic acid (6-methyl-2,4-bis-methylsulfanyl-pyridin-3-yl)- amide; N-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-ethyl]-4-flu'oro-20 benzenesulfonamide; 2- (2-Ethoxy-ethylsulfanyl)-4,5-diphenyl-lH-imidazole; 4-Cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl- 4,5-dihydro-3H-imidazol-4-yl]-N-methyl-benzamide; 1 - {3 -[3 -( 1 -Methyl-1 H-imidazol-2-y l)-2-phenethyl-2H-chromen-6-y loxy]- 25 propyl}-cyclopentanecarboxylic acid ethyl ester; l-[4-(2-Chloro-phenyl)-2-ethyl-thieno[2,3-b]pyridin-5-yl]-3-(2,4-difluoro- phenyl)-urea; l-(2-Cyclohexyl-[l,3]dithiolan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl)- u:;?a; 30 1 -Cycloheptyl-1 -(2,3-dihydro-benzo[ 1,4]dioxin-5-ylmethyl)- 3-(2,4,6-trimethyl-phenyl)-urea; 1 - {2-[4-( 1,2-Dimethoxy-ethoxy)-phenyl] -ethyl} -3 -(2,4-dimethoxy-phenyl)-1-heptyl-urea; -157- 01 1 584 2- (4-( 2- [3 -(2,4-Dimethoxy-pheny 1)-1 -heptyl-ureido]-ethyl} -phenoxy)- 2-methyl-propionic acid; 3- (2,4-Difluoro-phenyl)-1 -octyl-1 -(2,3,4,5-tetrahydro-benzo[b]oxepin- 5-yl)-urea; 5 N-(2,6-Diisopropyl-phenyl)-2-octadecylsulfanyl-acetamide; 2-Bromo-6,l l-dihydro-dibenzo[b,e]oxepine-ll-carboxylic acid (2,6-diisopropyl-phenyl)-amide; (±)N-(l,2-Diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide;2,2-Dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl)-amide; 10 (Z) 1 -(6,7-Dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-octadec-9-en- 1-one; (Z)2,2,5,5-Tetramethyl-[l,3]dioxane-4-carboxylic acid [2-(2-octadec-9-enoylamino-ethylcarbamoyl)-ethyl]-amide; 1- Bënzyl-l-(5-methyl-3-phenyl-benzofuran-2-ylmethyl)-3-(2,4,6-trifluoro 15 phenyl)-urea; 5-Chloro-3-o-tolyl-benzofuran-2-carboxylic acid (2,6-diisopropyl-phenyl) amide; 2- (2,4a-Dimethyl-4a,5-dihydro-naphthalen-l-ylsulfanyl)-N-(2-((6,6-dimethyl-hepta-2,4-diynyl)-pentyl-amino]-ethyl}-acetamide; 20 (Z)Octadec-9-enoic acid [2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-l-phenyl eïiylj-amide; N-(4-Dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl)-4-(phenyl- propyl-amino)-butyramide; (Z) 1 -(6,7-Dimethoxy-3 -phenyl-3,4-dihydro-1 H-isoquinolin-2-yl)-octadec-25 9-en-l-one; (trans)l,4-Bis-(4-methoxy-phenyl)-3-(3-phenyl-propyl)-azetidin-2-one; l-Butyl-3-(2-dimethylamino-6-[3-(4-phenyl-imidazol-l-yl)-propoxy]- phenyl}-urea; 1 - (2-Dimethylamino-6-[3 -(4-phenyl-imidazol-1 -yl)-propoxy]-phenyl} -30 3-pentyl-urea; l-(2-Dimethylamino-6-(3-(5-methyl-4-phenyl-imidazol-l-yl)-propoxy]-pheny 1}-3 -pentyl-urea; -158- 011584 l-(2-{2-[4-(2,2-Dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)- 3- heptyl-urea; (4S-trans)6-(4,5-Diphenyl-1 H-imidazol-2-ylsulfanylmethyl)-4-hydroxy- 4- methyl-tetrahydro-pyran-2-one; 5 2-(3-[l,3]Dioxan-2-yl-propylsulfanyl)-4,5-diphenyl-lH-imidazole;

Hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester;

Acetiçacid l-(ll-hydroxy-4-methoxy-9-methyl-5-oxo-5H,7H-6,12-dioxa- dibenzo[a,d]cycloocten-3-yl)-3-methyl-butyl ester; 10-Hydroxy-2,4a,6a,6b,9,10,12a-heptamethyl-4-octadecanoyloxy- 10 1,2,3,4,4a,5,6,6a, 6b,7,8,8a,9,10, 11,12,12a, 12b, 13,14b-eicosahydro-picene- 2-carboxylic acid; 3-[(2,2,5,5-Tetramethyl-[l,3]dioxane-4-carbonyl)-amino]-propionic acid2;:[3-(2,2-dimethyl-propyl)-3-nonyl-ureido]-cyclohexyl ester; l-(2,6-Diisopropyl-phenyl)-3-(2-p-tolyI-heptyl)-urea; 15 1 -[4-(2-Chloro-phenyl)-6,8-dimethyl-quinolin-3 -yl] -3 -(2,4-difluoro- phenyl)-urea; . l-[4-(2-Chloro-phenyl)-l,6,7-trimethyl-2-oxo-l,2-dihydro-quinolin-3-yl]-3 -(2,4-difluoro-pheny l)-urea; 1- [4-(2-Chloro-phenyl)-6,7-dimethyl-2-oxo-2H-chromen-3-yl]- 20 3-(2,4-difluoro-phenyl)-urea; (S)l-[6-Bromo-5-(2-chloro-phenyl)-l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[e][ 1,4] diazepin-7-yl] -3 -(2-hydroxy-1 -hydroxymethyl-1 -methyl-ethyl)-urea; 3-(4,5-Diphenyl-lH-imidazol-2-ylsulfanylmethyl)-l-methyl-piperidine; 2- (5,5-Dimethyl-[l,3]dioxan-2-yl)-4,5-diphenyl-lH-imidazole; 25 2,2-Dimethyl-5-[3-(l-methyl-lH-imidazol-2-yl)-2-propyl-chroman- 6-yloxy]-pentanoic acid ethyl ester; N-(4-Hexadecylamino-benzoyl)-4-methyl-benzenesulfonamide; 2-(4-Chloro-phenyl)-6-cyclohexyl-4-(2-oxo-2-phenyl-ethyl)-6,7-dihydro- 4H-l,4,6,8a-tetraaza-s-indacene-5,8-dione; 3 0 [2-(3 -tert-Butyl-4-hydroxy-naphthalen-1 -yl)-1 -(diethoxy-phosphory 1)- vinyl]-phosphonic acid diethyl ester; -159- 01 1 5 8 4 5-[l-(acetyloxy)-3-methylbutyl]-2'-(hydroxymethyl)-4-methoxy-4'- methylspiro[benzofuran-2(3H),l'-cyclohexa-2',4'-diene]-3,6'-dione; 5-[l-(acetyloxy)-3-methylbutyl]-4-methoxy-4'-methyl- 3,6-dioxospiro[benzofuran-2(3H),l'-cyclohexa-2',4'-diene]-2'-carboxaldehyde;(3 □ ,4 □, 22 □, 24 □ )-3 -hydroxy-22-[( 1 -oxooctadecy l)oxy]-24-norolean- 12-en-29-oic acid; l-[5-(4,5-Diphenyl-lH-imidazoIe-2-sulfinyl)-pentyl]-3,5-dimethyl-lH-pyrazole; and 10 N-butyl-3-[[(4-decyloxyphenyI)carbonyl]amino]-4-(methylthio)- benzamide;

15

The compounds, both ACAT and MMP inhibitors, include ail possiblestereoisomers. 011584 -160-

METHODS

The direct antiatherosclerotic potential of ACAT and MMP inhibitors isevaluated in a model of atherosclerotic lésion régression. Male New ZealandWhite rabbits (Kuiper Farms, Gary, Indiana) weighing 1.2 to 1.5 kg are meal-fed a

5 · chow diet (Purina 5321) supplemented with 0.5% cholestérol (C), 3% peanut(PNO) oil, and 3% coconut (CNO) oil diet for a total of 9 weeks followed by a0% C, 3% PNO, and 3% CNO diet (chow/fat diet) for 6 weeks prior to an 8-weekadministration of the ACAT inhibitor, for example, sulfamic acid[[2,4,6-tris-(l-methylethyl)phenyl]acetyl-2,6-bis(l -methylethyl)phenyl ester, the HMG-Co A 10 reductase inhibitor, for example, simvastatin, either alone or together. The dietaryregimen consiste of feeding 30 g for the first week, 40 g for 2 weeks, 50 g for2 weeks, 60 g for 4 weeks, 70 g for the next 6 weeks, and 80 g for the final8 weeks. After 1 week of diet initiation, a chronic endothélial injury is induced inthe abdominal aorta and fémoral artery by surgically inserting a stérile, 15 indwelling, 18-cm nylon monofilament with a diameter of 200 DM into the lumen of the right fémoral artery. After the initial 15-week lésion induction phase, wbichconsiste of both a hypercholesterolemic and plasma cholestérol normalizationstage, the animais are randomized on the basis of their 24-hour postmeal plasmatotal cholestérol values into groups which are not statistically different. A group of 20 animais, termed the time zéro control (n = 16), ïs necropsied prior to drug administration while a second group, termed the progression control (n = 16), ismaintained on the chow/fat diet for the remaining 8 weeks of the study. Additionalgroups of animais are administered either ACAT inhibitors, MMP inhibitors, orcoadministered both compounds. 25 Other ACAT inhibitors useful in the practice of the instant invention are those of Formula 1 below

wherein n is zéro, one or two;wherein Rj is selected from -161- 011584 (a) phenyl which is unsubstituted or is substituted with from one tothree substituents selected from: alkyl having from 1 to 4 carbon atoms and which is straight or branched,alkoxy having from 1 to 3 carbon atoms and which is straight or branched, 5 alkylthio having from 1 to 3 carbon atoms and which is straight or : branched, hydroxy, phenyl, fluorine, 10 chlorine, bromine,nitro,cyano, trifluoromethyl, 15 -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which isstraight or branched, "(CH2)mNR5R6 wherein m is zéro or one, and each of R5 and Rg is hydrogen or a straight or branched alkyl group having 1 to 4 carbon 20 atoms; (b) 1- or 2-naphthyl which is unsubstituted or substituted with 1 to3 substituents selected from: is alkyl having from 1 to 4 carbon atoms and which is straight or branched,alkoxy having from 1 to 3 carbon atoms and which is straight or branched, 25 hydroxy, fluorine,chlorine,bromine,nitro, 30 cyano, trifluoromethyl, -COOH, -162- 011584 -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight orbranched, -(CH2)mNR5R6 wherein m, R5, and R5 hâve the meanings defined above; (c) the group

wherein R7 is a lower alkyl group having from 1 to 3 carbon atoms and isstraight or branched; (d) the group

I \R10 10 wherein Rg and R9 are straight or branched alkyl having from 1 to 4 carbon atoms or phenyl, and Rjq is a straight or branchedhydrocarbon group having from 1 to 18 carbon atoms which issaturated or is unsaturated containing one double bond or twononadjacent double bonds; phenyl; phenyl substituted with from 15 one to three substituents selected from straight or branched alkyl having 1 to 4 carbon atoms, straight or branched alkoxy havingfrom 1 to 3 carbon atoms, hydroxy, fluorine, chlorine, bromine,nitro, cyano, trifluoromethyl, -COOH, -COOalkyl wherein alkylhas from 1 to 4 carbon atoms and is straight or branched or 20 -(CH2)mNR5R<5 wherein m, R5, and Rg are as defined above; or a heterocyclic group selected from 2-, 3-, or 4-pyridyl, 2-, 4-, or5-pyrimidinyl, 2- or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyi, e«· 1 4 pyridazinyl and the N-oxides thereof; (e) the group -163- 011584 (f) the group

10 (g) (h)(0 G) a straight or branched hydrocarbon group having from 1 to 18 carbonatoms which is saturated or is unsaturated containing one double bond ortwo nonadjacent double bonds; a cycloalkyl group having from 3 to 8 carbon atoms; a heteroaromatic group selected from 2-, 3-, or 4-pyridyl which isunsubstituted or substituted with an alkyl group having from 1 to 4 carbonatoms or 2-, 4-, or 5-pyrimidinyl, and the N-oxides thereof; the group

15 wherein — dénotés a single or double bond; Y and Z are each independently hydrogen, a straight or branched alkyl group of 1 to4 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or halo; X is oxygen or two hydrogen atoms;

Rl J is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, and n' is zéro or one; or -164- 011584 10 15

wherein R42, R13, R14, and R45 are each independently hydrogen, halo, astraight or branched alkyl group of 1 to 4 carbon atoms, an alkoxygroup of 1 to 3 carbon atoms, and alkylthio group of 1 to 3 carbonatoms, cycloaklylthio of five to seven carbon atoms,phenylalkylthio in which alkyl is 1 to 4 carbon atoms, substitutedphenylthio, heteroarylthio, or heteroaryloxy; and B, D, E, and Gare nitrogen or carbon where one or more of B, D, and E isnitrogen; with the proviso that when G = nitrogen the group isattached to the nitrogen atom of Formula I at the 4- or 5-position ofthe pyrimidine ring (a and b); wherein R2 and R3 are the same or different and are selected from: (a) hydrogen, halo or one of R2 or R3 is hydroxy; (b) a straight or branched alkyl group having ffom 1 to 12 carbon atoms, or acycloalkyl group having from 3 to 8 carbon atoms; (c) a phenyl or phenylalkyl group where alkyl is from 1 to 4 carbon atoms andwhich the phenyl ring unsubstituted or substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbonatoms, alkythio, straight or branched having 1 to 4 carbon atoms, hydroxy,fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro, phenyl, or(CH2)mNR5R6 wherein m, R5, and Rg hâve the meanings defined above; (d) a straight or branched alkenyl group having from 2 to 6 carbon atoms; or 20 -165- 011584 (e) R-2 and R3 taken together with the carbon atom to which they are attached form an alkylidene group of 1 to 4 carbon atoms, a benzylidene or aspiroalkyl group having front 3 to 7 carbon atoms; or (f) when R2 is hydrogen, F, alkyl of (442 atoms, R3 is a heteroaryl selectedfrom a 5- or 6-membered monocyclic or iused bicyclic heterocyclic groupcontaining at least 1 to 4 heteroatoms in at least one ring, said heteroatomsbeing nitrogen, oxygen, or sulfur and combinations thereof, saidheterocyclic group being unsubstituted or substituted with an alkyl grouphaving from 1 to 4 carbon atoms and the N-oxides thereof; (g) 1- or 2-naphthyl which is unsubstituted or substituted with 1 to3 substituents selected from: alkyl having from 1 to 4 carbon atoms and which is straight or branched,alkoxy having from 1 to 3 carbon atoms and which is straight or branched, wherein R4 is a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and is saturated or is unsaturated and has 1 double bond or has2 nonadjacent double bonds or is alkylthio having 1 to 20 carbon atoms and issaturated; or a pharmaceutically acceptable sait or individual enantiomeric isomerthereof.

Specifically,the following compounds are useful in the instant invention: N-[2,6-Bis( 1 -methylethyl)phenyl]-2-dodecyl-2H-tetrazole-5-acetamide; - 2-Dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tétrazole-5-acetamide; N-(2,4-Difluorophenyl)-2-dodecyl-2H-tetrazole-5-acetamide; 2-Tetradecyl-N-(2,4,6-tri-methoxyphenyl)-2H-tetrazole-5-acetamide; N-(4,6-Dimethoxy-5-pyrimidinyl)-2-dodecyl-2H-tetrazole-5-acetamide; N-(4,6-Dimethoxy-5-pyrimidinyl)-2-dodecyl-lH-tetrazole-5-acetamide; 2-Dodecyl-N-(3-methyl-2-pyridinyl)-2H-tetrazole-5-acetamide; 2-Dodecyl-N-(l,3,5-trimethyl-lH-pyrazol-4-yl)-2H-tetrazole-5-acetamide; 1 -Dodecy l-N-( 1,3,5 -trimethy 1-1 H-pyrazol-4-y 1)-1 H-tetr azole- 5 -acetami de; (±) 2-Dodecyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; (±) 2-Dodecyl-N,a-diphenyl-2H-tetrazole-5-acetamide; 011584 -166- (±)-N-[2,6-bis( 1 -Methylethyl)phenyl]-2-dodecyl-a-phenyl-2H-tetrazole-5-acetamide; (±)-N-(2,4-Difluorophenyl)-2-dodecyl-a-phenyl-2H-tetrazole- 5-acetamide; 5 (±)-2-Octyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; (±)-2-Hexadecyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-t’etrazole- 5-acetamide; (±)-N-(4,6-Dimethoxy-5-pyrimidinyl)-2-dodecyl-a-phenyl-2H-tetrazole- 10 5-acetamide; (±)-N-(5,7-Dimethyl-l,8-naphthyridine-2-yl)-2-dodecyl-a-phenyl-2H- tetrazole-5-acetamide; (±)-2-Dodecyl-a-phenyl-N-( 1,3,5-trimethyl-1 H-pyrazol-4-yl)-2H-tetrazole-5-acetamide; 15 (±)-N-Cyclopropyl-2-dodecyl-a-phenyl-2H-tetrazole-5 -acetamide; (±)-2-Dodecyl-a-phenyl-N-2-pyridinyl-2H-tetrazole-5-acetamide; (±)-2-Dodecyl-N-(3-methyl-2-pyridinyl)-a-phenyl-2H-tetrazole- 5-acetamide; (±)-2-Dodecyl-N-(3-methyl-2-pyridinyl)-2-phenyl-2H-tetrazole- 20 5-acetamide, N-oxide; (+)-N-( 1,1 -Dimethylethyl)-2-dodecyl-a-phenyl-2H-tetrazole-5-acetamide;(±)-2-Dodecyl-a-(2-pyridyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; (±)-N-[2,6-Bis(l-methylethyl)phenyl]-2-dodecyl-a-2-pyridinyl-2H- 25 tetrazole-5-acetamide; 2-Dodecyl-a,a-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide; 2-Dodecyl-a,a'-(2-propenyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; 30 l-(2-Dodecyl-2H-tetrazol-5-yl)-N-(2,4,6-trimethoxyphenyl)- yclopentanecarboxamide; Οι 1534 -167- 2-Tridecyl-a,a-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; 2-Dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-propanamide; N-(2,6-bis(l-Methylethyl)phenyl)-2-dodecyl-2H-tetrazole-5-propanamide; 5 N-(2,4-Difluorophenyl)-2-dodecyl-2H-tetrazole-5-propanamide; l-Dodecyl-N-(2,4,6-trimethoxyphenyl)-lH-tetrazole-5-propanamide;(±)-n-(2,4-Difluorophenyl)-l-dodecyl-a-phenyl-lH-tetrazole-5-acetamide;(±)-N-[2,6-bis(l -Methylethyl)phenyl]-1 -dodecyl-a-phenyl-1 H-tetrazole- 5-acetamide; 10 (±)-2-Dodecyl-a-methyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H- tetrazole-5-acetamide; (±)-2-Dodecyl-a-(4-fluorophenyl)-N-(2,4,6-trimethoxyphenyl)-2H- tetrazole-5-acetamide; (±)-2-Dodecyl-a-2-naphthalenyl-N-(2,4,6-trimethoxyphenyl)-2H- 15 tetrazole-5-acetamide; (±)-a-([l,r-Biphenyl]-4-yl)-2-dodecyl-N-(2,4,6-trimethoxy-phenyl)-2H- tetrazole-5-acetamide; (±)-2-Dodecyl-D-methyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole- 5-acetamide; 20 (±)-2-DodecyÎ-a-phenylmethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 5-acetamide; (±)-2-Dodecyl-a-cyclohexyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole- 5-acetamide; (-)-2-Dodecyl-a-phenyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole- 25 5-acetamide [a]jy = -58° (1% in CH3OH); (+)-2-Dodecyl-a-phenyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole-5-acetamide [a]j) = +55.1° (1% in CH3OH); (±)-N-[2,6-Bis(l-Methylethyl)phenyl]-2-dodecyl-a-fluoro-a-phenyl-2H- tetrazole-5-acetamide; 30 (±)-2-Dodecyl-a-fluoro-a-phenyl-N-(2,4,6-trimethoxy phenyl)-2H- tetrazole-5-acetamide; -168- 1 584 N-[2,6-bis(l-Methylethyl)phenyl]-5-decyl-2H-tetrazole-2-acetamide;N-[2,6-bis(l-Methylethyl)phenyl-5-dodecyl-2H-tetrazole-2-acetamide;(±)-N-[2,6-bis(l-Methylethyl)phenyl]-5-dodecyl-a-phenyl-2H-tetrazole- 2-acetamide; 5 (±)-N-[2,6-bis(l-Methylethyl)phenyl]-5-dodecyl-a-pentyl-2H-tetrazole- 2-acetamide; (±)-N-[2,6-bis(l-Methylethyl)phenyl-5-(dodecylthio)-a-phenyl-2H- tetrazole-2-acetamide; (±)-5-Decyl-a,-phenyl-N-(2,4,6-trimethoxyphenyl-2H-tetrazole-10 2-acetamide; 5-Dodecyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole-2-acetamide; (+)-5-Dodecyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 2-acetamide; (+)-5-Dodecyl-a-pentyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-15 2-acetamide; (±)-N-(2,4-Difluorophenyl-5-dodecyl-a-phenyl-2H-tetrazole-2-acetamide; 5-Dodecyl-oc,a-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole- 2 acetamide; (±)-5-(Dodecylthio)-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-20 2-acetamide; or (±)-5-(Dodecylsulfinyl)-a-phenyl-N-(2,4,6)-trimethoxyphenyl)-2H- tetrazole-2-acetamide.

The compounds to be employed in the présent invention can be preparedand administered in a wide variety of oral and parentéral dosage forms for treating 25 and preventing atherosclerosis. The compounds can be administered by injection,that is, intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally. Also, the compounds can be administered byinhalation, for example, intranasally. Additionally, the compounds can beadministered transdermally. It will be obvious to those skilled in the art that the 30 following dosage forms may comprise as the active component, either a compound as a free base, acid, or a corresponding pharmaceutically acceptable -169- 011584 sait of such compound. The active compound generally is présent in aconcentration of about 5% to about 95% by weight ofthe formulation.

For preparing pharmaceutical compositions from the compounds of theprésent invention, pharmaceuticaüy acceptable carriers can be either sc-lid or 5 liquid. Solid form préparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. A solid carrier can be one or moresubstances which may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material. 10 In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted in the shapeand size desired. 15 The powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnésium carbonate, magnésiumstéarate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “préparation” is intended to include the formulation 20 of the active compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers, issurrounded by a carrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges canbe used as solid dosage forms suitable for oral administration. 25 For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component isdispersed homogeneously therein, as by stirring. The molten homogenous mixtureis-hen poured into convenient sized molds, allowed to cool, and thereby tosolidify. 30 Liquid form préparations include solutions, suspensions, and émulsions, for example, water or water propylene glycol solutions. For parentéral injection, liquid préparations can be formulated in solution in aqueous polyethylene glycol solution. -170- 011584

Aqueous solutions suitable for oral use can be prepared by dissolving theactive component in water and adding suitable colorants, flavors, stabilizing, andtiiickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the5 finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, andother well-known suspending agents.

Also included are solid form préparations which are intended to beconverted, shortly before use, to liquid form préparations for oral administration. 10 Such liquid forms include solutions, suspensions, and émulsions. Thesé préparations may contain, in addition to the active component, colorants, flavors,stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners,solubilizing agents, and the like.

The pharmaceutical préparation is preferably in unit dosage form. In such 15 form, the préparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packagedpréparation, the package containing discrète quantities of préparation, such aspacketed tablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the 20 appropriate number of any of these in packaged form.

The quantity of active component in a unit-dose préparation may be varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mg according to the particularapplication and the potency of the active component. The composition can, ifdesired, also contain other compatible therapeutic agents. 25 The compounds utilized in the pharmaceutical method of this invention are administered at a dose that is effective to inhibit the hydrolytic activity of one ormore matrix metalloproteinase enzymes. Such effective amounts are thus thosewhich prevent or treat CHF and ventricular dilatation. The compounds can also beused prophalactically at the same dose levels. The initial dosage of about 1 mg to 30 about 100 mg per kilogram daily will be effective to prevent and treat heart failure. A daily dose range of about 5 to about 75 mg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. 011584 -171-

Determination of the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages which are less thanthe optimum dose of the compound. Thereafter, the dosage is increased by smallincréments until the optimum effect under the circumstance is reached. For 5 convenience, the total daily dosage may be divided and administered in portionsduring the day if desired. Typical dosages will be from about 0.1 to about500 mg/kg, and ideally about 25 to about 250 mg/kg.

The following examples illustrate typical formulations that can be utilizedin the invention. 10 Tablet Formulation

Ingrédient Amount (mg) 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methyl- 25 butyric acid ACAT Compound Lactose 50 Corn starch (for mix) 10 Corn starch (paste) 10 Magnésium stéarate (1%) 5 Total 100

The biphenylsulfonamide, lactose, and corn starch (for mix) are blended touniformity. The corn starch (for paste) is suspended in 200 mL of water andheated with stirring to form a paste. The paste is used to granulate the mixed 15 powders. The wet granules are passed through a No. 8 hand screen and dried at80°C. The dry granules are lubricated with the 1% magnésium stéarate andpressed into a tablet. Such tablets can be administered to a human from one to fourtimes a day for treatment of atherosclerosis and arthritis. -172- 011584

Préparation for Oral Solution

Ingrédient Amount (R)-2-(4'-Cyanobiphenyl-4-sulfonylamino)-3-phenyl- 400 mg propionic acid sodium sait AC AT Compound Sorbitol solution (70% N.F.) . 40 mL Sodium benzoate 20 mg Saccharin 5 mg Red dye 10 mg Cherry flavor 20 mg Distilled water q.s. 100 mL

The sorbitol solution is added to 40 mL of distilled water, and thebiphenylsulfonamide is dissolved therein. The saccharin, sodium benzoate, flavor, 5 and dye are added and dissolved. The volume is adjusted to 100 mL with distilledwater. Each milliliter of syrup contains 4 mg of invention compound.

Parentéral Solution

In a solution of 700 mL of propylene glycol and 200 mL of water forinjection is suspended 20 g of (S)-2-(4'-amino-biphenyl-4-sulfonylamino)- 10 3-(3-ethoxyphenyl)-propionic acid. After suspension is complété, the pH is adjusted to 6.5 with IN sodium hydroxide, and the volume is made up to 1000 mLwith water for injection. The formulation is sterilized, filled into 5.0 mL ampouleseach containing 2.0 mL, and sealed under nitrogen.

Claims (4)

011584 • -173-CLAIMS

1 -Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acidhydroxyamide; 5 N-(2,2-Dimethyl-lS-methyl carbamoyl-propyl)-3R-[3-(4-propyl- phenyl)-pyrrol-1 -yl]-succinamic acid; l-(4-Benzyl-piperazine-l-sulfonyl)-piperdine-2-carboxylic acidhydroxyamide; 3(S)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-10 dimethyl-tetrahydro-2H-l,4-thiazine-3-carboxamide; 2(R)-4-Methyl-1 -(4-(4-fïuorophenyl)benzenesulfony l)-N-hy droxypiperazine-2-carboxamide; N-(2,2-Dimethyl-l-methylcarbamoyl-propyl)-3-(5-biphenyl-4-yl-furan-2-yl)-succinamic acid; 15 N-(2,2-Dimethyl-1 S-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl pyrrol-l-yl)-succinamic acid; l-((2-Pyridyl)-4-piperazine-l-sulfonyl)-piperdine-2-carboxylicacid hydroxyamide; l-[4-(Pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperdine-2-20 carboxylic acid hydroxyamide; N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine;N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine,N-hydroxyamide;N-(8-oxo-4-oxa-l ,7-tricyclo[9,6.1.0,12,17]octadeca- 11(18), 12(17), 13,15-tetraen-9-yl)-3-[4-(4-pyridyl)-3-phenyl~pyrrol- 1-yl)-25 succinamic acid; 3-[3-(4-Pyridyl)phenyl-4-yl-pyrrol-l-yl]-N-[2,2-dimethyl-l-(4-pyridy l)carbamoy 1-propyl]-succinamic aci d ; 2,2-Dimethy 1-4- [4-(pyridin-2-y loxy)-benzenesulfonyl] -thio- morpholine-3-carboxylic acid hydroxyamide; 30 N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine; N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; -214- 011584 2-[2-(N'-Acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl-pentanoic acid; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-l,4-thiazine-3-carboxamide hydrochloride; 5 2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl- butyric acid; 2- [4-(4-Chloro-phenoxy)-benzenesulfonylamino)-N-hydroxy-3,3 -dimethyl-butyramide; 3(R)-N-Hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2-10 dimethyl-tetrahydro-2H-l,4-thiazine-3-carboxamide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D- cysteine; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine, N-hydroxyamide; 15 2-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino] -3,3 -dimethy 1 butyric acid; 2- [4-(Pyridin-2-yl-oxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl butyramide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-20 cysteine; 3- [3-(4'-Carbamoyl-biphenyl-4-yl)-pyrrol-l-yl]-N-(2,2-dimethyl-l-methylcarbamoyl-propyl)-succinamic acid; 3-[3-(4'-Cyano-biphenyl-4-yl)-pyrrol-l-y]-N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-succinamic acid; 25 2-(2-Biphenyl-4-yl-ethylsulfonyl)-cyclohex-l-ene-carboxylic acid hydroxyamide; 6-(2-Biphenyl-4-yl-ethyl sufonyl)-cyclohex-l-ene-carboxylic acidhydroxyamide; N-(4-Pyridin-4-yl-oxy-benzenesulfbnyl)-3,3-dimethyl-S- 30 (benzylthio)-D-cysteine; 3-[3-4'-Carbamoyl-biphenyl-4-yl)-pyrrol-l-yl]-N-[2,2-dimethyl-l- (pyridin-4-yl-carbamoyl)-propyl]-succinamic acid; -215- 011584 N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine, N-hydroxyamide; l-(4-Phenoxy-piperdine-l-sulfonyl)-piperdine-2-carboxylic acidhydroxyamide; 5 3(R)-4-[4-(4-Bromo)phenoxybenzenesulfonyl]-2,2-dimethyl- tetrahydro-2H-1,4-thiazine-3 -carboxy lie acid ; N-(4-[4-Chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S- (methylthio)-D-cysteine; N-(4-[4-Chlorophenoxy] -benzenesulfonyl)-3,3 -dimethyl-S-10 (methylthio)-D-cysteine, N-hydroxyamide; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylsulfoxy)-D-cysteine, N-hydroxyamide; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 15 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3- (pyridin-3-ylsulfanyl)-butyric acid; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-4-ylsulfanyl)-butyric acid; cis-2-(2-Phenyl-ethanesulfonyl)-cycloheaxanecarboxylic acid20 hydroxyamide; 3(R)-N-Hydroxy-4-(4-(imidaz-l-yl)phenoxybenzenesulfonyl)-2,2dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 3(R)-N-Hydroxy-4-(4-(pyridin-4-jl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 25 4-[2-(2-Hydroxycabamoylmethyl-5-pheny.l-pentanoylamino)-4- methyl-pentanoyl-benzoic acid methyl ester; trans-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid ·hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid;30 2-[4-(4-Chlorophenyl)-piperazine-l-sulfonylamino]-3-methyl-3- (pyridin-2-ylmethylsulfanyl)-butyric acid; -216- 011584 3R-[3-(4'-Cyano-biphenyl-4-yl)pyrrol-l-yl]-N-[2,2-dimethyl-lS-(pyridin-4-ylcarbamoyl)-propyl]-succinamic acid; 3,3 -Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid,N-hydroxyamide; 5 N-(2,2-dimethyl-l-methylcarbamoyl-propyl)-3-[l-(4- fluorophenyl)-lH-pyrrol-3-yl]-succinamic acid; . 2(R)-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridi-n-2-ylsulfanyl)-butyric acid; 2-(2-Biphenyl-4-yl-ethanesulfonyl)-cyclohexanecarboxylic acid10 hydroxamate; 2- [4-(4-Chlorophenyl)-piperazine-1 -sulfonylamino] -3 -methyl-3 -(pyridin-2ylmethylsulfanyl)-butyric acid, N-hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid, 15 N-hydroxyamide; 3- tert-Butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro-phenoxy)benzenesulfonylamino)-3-methyl-butyric acid; l-(4-Phenylsulfanyl-piperidine-l-sulfonyl)-piperidine-2-carboxylicacid hydroxyamide; 20 1 -[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-5-oxo- piperazine-2-carboxylic acid; N-(4-[4-Fluorophenoxy]-benzenesulfbnylamino)-3 -methyl-3 -( 1 -benzyl-imidazole-2-yl-sulfanyl)-butyricacid; 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3-25 (pyridi-n-2-yl sulfanyl)-butyric acid, hydroxyamide; 3(R)-N-Hydroxy-4-(4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)- 2,2-dimethyl-tetrahydro-2H-l,4-thiazine-3-carboxamide; l-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-4-(l-methyl-lH-imidazole-4-sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-Dimethyl-lS-methylcarbamoyl-propyl)-3R-[l-(4'-cyanobiphenyl-4-yl)- lH-pyrrol-3-yl]-succinamic acid; 30 -zi?- 011584

1 - Al ly 1-3 -(2-hydroxyethyl)-2-thiourea; 10 3-(l-Hydroxyimino-propyl)-6-phenyl-hexanoic acid; 2- (3H-Imidazol-4-ylmethyl)-Nl ,N4-diphenethyl-succinamide; 3- (2-Hydroxymethyl-3H-imidazol-4-yl)-N-‘phenethyl-propionamide;

6-Phenyl-3 -propionyl-hexanoic acid; 15 4-{2-([2-Hydroxyamino-2-hydroxyimino-ethyl]-5-phenyl- pentanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 4- [2-(2-(2-Phenylcyclopropyl)succinylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

6-Biphenyl-4-yl-[2,2-dimethyl-l-(pyridin-4-ylcarbamoyl)-20 propylcarbamoyl]-hexanoic acid trifluoroacetate sait; 3- [l-(5,6-Dichloro-lH-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5-methyl-hexanoic acid;

6-Biphenyl-4-yl-3-[ 1 -(5,6-dichloro-1 H-benzoimidazol-2-yl)-3 -methyl-butylcarbamoyl]-5-methyl-hexanoic acid;

1 -Butyl-3 - {2-dimethylamino-6-[3-(4-phenyl-imidazol-1 -yl)-25 propoxy]-phenyl}-urea; l-{2-Dimethylamino-6-[3-(4-phenyl-imidazol-l-yl)-propoxy]-pheny 1} -3 -pentyl-urea; 1 - {2-Dimethylamino-6-[3 -(5-methyl-4-phenyl-imidazol-1 -yl)-propoxy] -pheny 1} -3 -pentyl-urea; l-(2-{2-[4-(2,2-Dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)-3-heptyl-urea; 30 -,93- 01 1 584 (4S-trans)6-(4,5-Diphenyl-lH-imidazol-2-ylsulfanylmethyl)- 4-hydroxy-4-methyl-tetrahydro-pyran-2-one; 2- (3-[l,3]Dioxan-2-yl-propylsulfanyl)-4,5-diphenyl-lH-imidazole;Hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester; 5 Acetic acid 1-(1 l-hydroxy-4-methoxy-9-methyl-5-oxo-5H,7H- 6,12-dioxa-dibenzo[a,d]-cycloocten-3-yl)-3-methyl-butyl ester;

10-Hydroxy-2,4a,6a,6b,9,10,12a-heptamethyl-4-octadecanoyloxy-1,2,3,4,4a,5,6, 6a,6b,7,8,8a,9,10, 11,12,12a, 12b, 13,14b-eicosahydro-picene-2-carboxylic acid; 10 3-[(2,2,5,5-Tetramethyl-[l,3]dioxane-4-carbonyl)-amino]- propionic acid 2-[3-(2,2-dimethyl-propyl)-3-nonyl-ureido]-cyclohexylester; l-(2,6-Diisopropyl-phenyl)-3-(2-p-tolyl-heptyl)-urea; l-[4-(2-Chloro-phenyl)-6,8-dimethyl-quinolin-3-yl]-3-(2,4- 15 difluoro-phenyl)-urea; l-[4-(2-Chloro-phenyl)-l,6,7-trimethyl-2-oxo-l,2-dihydro- quinolin-3-yl]-3-(2,4-difluoro-phenyl)-urea; 1- [4-(2-Chloro-phenyl)-6,7-dimethyl-2-oxo-2H-chromen-3-yl]- 3-(2,4-difluoro-phenyl)-urea; 20 (S) 1 -[6-Bromo-5-(2-chloro-phenyl)-1,3 -dimethy 1-2-oxo- 2,3-dihydro-lH-benzo[e][l,4]-diazepin-7-yl]-3-(2-hydroxy-1 -hydroxymethyl-1 -methyl-ethyl)-urea; 3- (4,5-Diphenyl-lH-imidazol-2-ylsulfanylmethyl)-l-methyl-piperidine; 25 2-(5,5-Dimethyl-[l,3]dioxan-2-yl)-4,5-dip.henyl-lH-imidazole; 2,2-Dimethyl-5-[3-(l-methyl-lH-imidazol-2-yl)-2-propyl- chroman-6-yloxy]-pentanoic acid ethyl ester; N-(4-Hexadecylamino-benzoyl)-4-methyl-benzenesulfonamide; 2- (4-Chloro-phenyl)-6-cyclohexyl-4-(2-oxo-2-phenyl-ethyl)- 30 6,7-dihydro-4H-l,4,6,8a-tetraaza-s-indacene-5,8-dione; [2-(3 -tert-Butyl-4-hydroxy-naphthalen-1 -yl)-1 -(diethoxy- phosphoryl)-vinyl]-phosphonic acid diethyl ester; -iw- 011584 5 -[ 1 -(acetyloxy)-3 -methylbutyl]-2'-(hydroxymethyl)-4-methoxy-4'-methylspiro[benzofuran-2(3H),l'-cyclohexa-2',4'-diene]-3,6'-dione; 5-[ 1 -(acetyloxy)-3 -methylbutyl]-4-methoxy-4'-methyl- 3,6-dioxospiro[benzofuran-2(3H), 1 '-cyclohexa-2',4'-diene]-2'- 5 carboxaldehyde; (3a,4a,22a,24a)-3-hydroxy-22-[(l-oxooctadecyl)oxy]-24-norolean-12-en-29-oic acid; l_[5-(4,5-Diphenyl-lH-imidazole-2-sulfinyl)-pentyl]-3,5-dimethyl-ΙΗ-pyrazole; and ..... 10 N-butyl-3-[[(4-decyloxyphenyl)carbonyl]-amino]'4-(methylthio)- benzamide.

36. Use according to Claim 1 wherein the MMP inhibitor is selected from: 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-3-cyclohexyl propionylaminojbenzoic acid methyl ester; 15 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-methyl- butyrylaminoj-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-20 dimethyl-butyrylaminoj-benzoic acid methyl ester; 4~[2-(2-Carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl-butyrylaminoj-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-5-methyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 25 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-2- cyclohexylpropionylaminojbenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-4-methyl-valerylaminoj-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-phenyl-valerylamino)-3,3-dimethyl-30 butyryîaminol-benzoic acid methyl ester; -195- 011584 4- [2-(2-Carboxymethyl-4-methyl-pentanoylamino)-3 -( 1 H-indol-3-yl)-propionylamino-benzoic acid methyl ester;

5- Methyl-3-(9-oxo-l,8-diaza-tricyclo[10.6.1.0 13,18]nonadeca-12(19),13,15,17-tetraen-10-ylcarbamoy l)-hexanoic acid ; 5 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3- methyl-butyrylaminoj-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-2-cyclohexylpropionylaminoj-benzoic acid methyl ester benzoic acid methylester; 10 4-[2-(2-Hydroxaminocarbonylmethy 1-4-methyl-valery lamino)-4- methyl-valerylaminoj-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino)-3-cyclohexylpropionylaminojbenzoic acid methyl ester; - 4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino)-3-15 cyclohexylpropionylamino]benzoic acid methyl ester; 4- [2-(2-Hydroxaminocarbonylmethyl-5-phenyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester;

5- Methyl-3-(9-oxo-1,8-diaza-tricyclo[l 0.6.1.0,13,18]nonadeca-12( 19), 13,15,17-tetraen-10-ylcarbamoyl)-1 -hexylhydroxamic acid; 20 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)- 3-(lH-indol-3-yl)-propionylamino-benzoic acid methyl ester; 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-l-phenylcarbamoyl- propylcarbamoyl]-5-methyl-hexanoiç.açid; 3- [2-(4-Methoxy-benzylsulfanyl)-2-methyl-l -phenylcarbamoyl- 25 propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxyamide; 4- [2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)- 2-cyclohexyl-acetylamino]-benzoic acid methyl ester; 2-(Phenyl-2-ethyl)benzoic acid N-hydroxy amide; 4-[2-(2-Acylhyrdazinomethyl-4-methyl-pentanoylamino)-3-(lH- 30 indol-3-yl)-propionylamino]-benzoic acid methyl ester; 2-(Propylthio)-pyridine-3-N-(hydroxy)carboxamide; 4-[2-(2-Carboxymethyl-5-phenyl-pentanoylamino)-2- cyclohexylacetylaminojbenzoic acid methyl ester; -196- 01 1 584 [4-(N-Hydroxyamino)-2R-isobutyl-3S-((thien-2-4 ylthio)methyl)succinyl]-L-phenylalanine-N-methylamide; N-Hydroxy-5-phenylpentanamide; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-valeroyl)amino)-4-5 methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-4-pentenoyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-4-pentenoyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester, trifluoroacetate sait; 10 2-(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4- methyl-valeroyljaminobenzoic acid methyl ester; . 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 15 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 2-[3-(3-Hydroxy-phenyl)-propyl]-benzohydroxamic acid;2-(Thiobenzyl)benzoic acid N-hydroxy amide; 1- (3-Phenyl-propyl)-pyrrolidine-2-hydroxamic'acid; 20 4-[2-(2-Carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(N'-methylureido)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(triflouroacetamido)valeroyl)amino)-4-25 methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-phenylacetylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-2-phenylacetylamino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 30 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl- acetylamino]-benzoic acid methyl ester; 2- [3-(3-Amino-phenyl)-propyl]-benzohydroxamic acid; -197- 011584 cis-4-Benzyloxy-pyrrolidine-2-carboxylic acid;4-[2-(2-Carboxymethyl-5-(3-amino-4-(triflouromethyl)phenyl)- valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(methanesulfamido)valeroyl)amino)-4- 5 methyl-valeroyl]aminobenzoic acid methyl ester; N-Cbz-L-Tyrosine; N-Boc-L-Tryptophan; 4-[2-(Carboxy-2-o-tolyl-propionylamino-4-methyl-pentanoylamino]-benzoic acid methyl ester; 10 4-[2-(Carboxymethyl-hepanoylamino)-4-methyl-pentanoylamino]- benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4-methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-4-pentenoyl)amino)-4 15 methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(2-thienyl)acetylamino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(3-aminophenyl)-butyryl)amino)-4- methyl-valeroyl]aminobenzoic acid methyl ester; 20 4-[2-(2-Carboxymethyl-5-(biphen-4-yl)-valeroyl)amino)-4-methyl valeroyljaminobenzoic acid methyl ester; cis-4-Benzylsulfanyl-pyrrolidine-2-carboxylic acid;

1- Butyl-3-{2-[3-(5-ethyl-4-phenyl-imidazol-l-yl)-propoxy]-6-methyl-phenyl} -urea; 5 1-(2-(2-(4-(2,2-Dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro- phenyl)-3 -heptyl-urea; Octadeca-9,12-dienoic acid (l-phenyl-ethyl)-amide; 3- (lH-Indol-3-yl)-2-octadec-9-enoylamino-propionic acid ethyl ester; 10 3 -(Dimethyl-nony 1-sil anyl)-N-( 1 -phenyl-2-p-tolyl-ethyl)- propionamide; (R)2-Hexyl-decanoic acid (6-methyl-2,4-bis-methylsulfanyl-pyridin-3 -yl)-amide; - N-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-ethyl]-4-fluoro-15 benzenesulfonamide; 2- (2-Ethoxy-ethylsulfanyl)-4,5-diphenyl- IH-imidazole;

4- Cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl-4,5-dihydro-3H-imidazol-4-yl]-N-methyl-benzamide; 1-(3-(3-(1 -Methyl-1 H-imidazol-2-yl)-2-phenethyl-2H-chromen-20 6-yloxy]-propyl}-cyclopentanecarboxylic acid ethyl ester; l-[4-(2-Chloro-phenyl)-2-ethyl-thieno(2,3-b]pyridin-5-yl]-3 -(2,4-difluoro-pheny l)-urea; 1- (2-Cyclohexyl-[l,3]dithiolan-27ylmethyl)-3-(2,6-diisopropyl-phenyl)-urea; 25 l-Cycloheptyl-l-(2,3-dihydro-benzo(l,4]dioxin-5-ylmethyl)- 3- (2,4,6-trimethyl-phenyl)-urea; 1 -(2-(4-(1 ,2-Dimethoxy-ethoxy)-phenyl]-ethyl} -3 -(2,4-dimethoxy-phenyl)-1 -heptyl-urea; 2- (4-(2-(3-(2,4-Dimethoxy-phenyl)-l -heptyl-ureido]-ethyl} - 30 phenoxy)-2-methyl-propionic acid; 3 -(2,4-Difluoro-phenyl)-1 -octyl-1-(2,3,4,5-tetrahydro- benzo [b] oxepin-5-y l)-urea; N-(2,6-Diisopropyl-phenyl)-2-octadecylsulfanyl-acetamide; -192- 011584

1. Use of an ACAT inhibitor with a MMP inhibitor in the manufacture of amédicament for the treatment and/or prévention of atherosclerotic lésionsin a mammal.

2- Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 1 - {1-[ 1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl- 15 butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide;4-[2-(2-Carboxymethyl-5-(4-(2-methylthiazol-4-yl)phenyl)- valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 1 - {1 - [ 1 -(4-Methoxycarbonyl-phenylcarbamoyl)-3 -methy 1- 20 butylcarbamoyl]-3-methyl-butylthiocarbamoyl}-pyrrolidine-2-carboxylic acid; 3- [(Cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl)-methyl)-carbamoyl]-6-(4-pyridin-4-ylrphenyl)-hexanoic acidtrifluoroacetate sait; 25 trans-2-(Biphenyl-4-yl-methylsulfanyl)-cy.clohexancarboxylic acid hydroxamide;

6-Biphenyl-4-yl-3-(l-hydroxymethyl-2,2-dimethyl-but-3-enylcarbamoyl)-hexanoic acid;

6-Biphenyl-4-yl-3-(l-hydroxymethyl-2,2-dimethyl-but-3- .30 enylcarbamoyl)-hexanoic acid;

6-Biphenyl-4-yl-3-(R)-(l-hydroxymethyl-2-(S)-(lH-imidazol-4- yl)-ethylcarbamoyl)-hexanoic acid; -204- 011584 3 -(R)-(2-(R)-B enzyloxy-1 -(S)-hydroxy methyl-propylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 4- [4-Methyl-2-(2-nitromethyl-5-phenyl-pentanoylamino)-pentanoylamino]-benzoic acid methyl ester;

6-Biphenyl-4-yl-3-[3 -methyl- l-(4-(2-hydroxyethylsulfamoyl)- phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid;

6-Biphenyl-4-yl-3-(l-hydroxymethyl-2-phenyl-ethylcarbamoyl)-hexanoic acid; N1-(l-Benzyl-2-hydroxy-ethyl)-2-(3-biphenyl-4-yl-propyl)-N^-10 hydroxy-succinamide;

6-Biphenyl-4-yl-3-(R)-(l-hydroxymethyl-2-(S)-(lH-imidazol-4-yl)-ethylcarbamoyl)-hexanehydroxamic acid; N-Hydroxy-2-[2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]- acetamide; 15 4-[2-(2-Carboxymethyl-5-(2-hydroxy-biphen-4-yl)- valeroylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester; N1-(2-Benzyloxy-l-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl- propyty-N^-hydroxy-succinamide; trans-2-(4-Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acid20 hydroxamide; 2-(4-Indol-1 -yl-benzylsulfanyl)-cyclohexancarboXylic acidhydroxamide;

6-Biphenyl-4-yl-3-[2-hydroxy-2-methyl-l-(4S-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3 -ylcarbamoyl)-hexanoic acid;

5- Biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoicacid{l-[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl-butyl}-amide; 30 2-(3-Biphenyl-4-yl-propyl)-N^-h vdroxy-N 1 -(? A 5 -trihydroxy-6- byd· exymethyi-tetrahydro-pyran-3-yl)-succinamide; -205- 011584

6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro·pyran-3-ylcarbamoyl)-hexanoic acid; N-[2,2-Dimethyl-lS-(pyridin-4-ylcarbamoyl)-propyl]-3R-thiophen-3-yl-succinamic acid; 5 4-[2S-(2R-(3-Biphenyl-4-yl-pyrrol-l-yl)-3-carboxy- propionylamido)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 3- (R)-(2-Benzyloxy-phenyl)-l-(S)-hydroxymethyl-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid ;

6-Biphenyl-4-yl-3-(R)-(2-hydroxy-l-(S)-(4-hydroxy-benzyl)-10 ethyl carbamoyl)-hexanoic acid;

6-Biphenyl-4-yl-3-(l-hydroxyimino-ethyl)-hexanoic acid;N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxopentanoyl)-L-t- leucine, N'-4-(methylthio)phenyl amide;

6-Biphenyl-4-yl-3-(R)-(2-hydroxy-l-(S)-(4-hydroxy-benzyl)- 15 ethylcarbamoyl)-hexanehydroxamic acid; 4- {2-[2-carboxymethyl-5-(4'-sulfamoyl-biphenyl-4-yl)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acidhydroxyamide;

3-Acetyl-6-biphenyl-4-yl-3-hexanoic acid; N-[5-(Biphen-4-yl)-2-(l-carboxy-2-hydroxybut-l-yl)pentanoyl]-t L-leucine, N'-(4-methylthiophenyl)amide;

6-Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 25 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-Nl-(2-hydroxy- cÿclohexyl)-succinamide;

6-Biphenyl-4-yl-3-(l-hydroxyimino-ethyl)-hexanoic acidhydroxamide;

6-Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyl)-hexanoic .30 acid;

6-Biphenyl-4-yl-3-[2,2-dimethyl-1 -(pyridin-4-ylcarbamoyl)- propylcarbamoyl]-hexanoic acid ethyl ester; -206- 10 15 20 25 011584 2-(3-Biphenyl-4-yl-pyrrol-l-yl)-3-carboxy-N-(l-hydroxy-3- phenyl-prop-2-yl)-propionamide; N-[5-(Biphen-4-yl)-2-(l-carboxy-2-hydroxyethyl)pentanoyl]-L-t-leucine, N'-(4-methylthiophenyl)amide; 3 -(R)-(2-Hydroxy-1 -(S)-( 1 H-imidazol-4-yl)-ethylcarbamôyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanoic acid; 3 -(R)-(2-Hydroxy-1 -(S)-( 1 H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid;

5- Biphenyl-4-yl-2-(l-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N-hydroxy-N'-(l-hydroxymethyl-3- methylsulfanyl-propyl)malonamide;

6- Biphenyl-4-yl-3-(3-hydroxy-piperidine-l-carbonyl)-hexanoic acid;

6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-l-carbonyl)-hexanoic acid-hydroxyamide; l-(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; l-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxyamide; N-( 1 -Benzy l-2-methoxy-ethyl)-3 -(3 -biphenyl-4-yl-pyrrol-1 -yl)-succinamic acid; N-( 1 -Benzy l-2-methoxy-ethyl)-3 -(3 -biphenyl-4-y 1-pyrrol-1 -yl)-succinamichydroxamic acid;

6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(l(S)-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid; 3 -(1 -Benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid;Nl-(l-benzyl-2-hydroxy-ethyl)-N^-hydroxy-2-isobutyl- succinamide; ^'5 -Λ ri Vit VITlCtliy 1"2 2“ dimethyl-propylcarbamoyl)-hexanoic hydroxamic acid; -m- 011584 1- [4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid;

6-Biphenyl-4-yl-3-(2-hydroxy-l-hydroxmethyl-propylcarbamoyl)-hexanoic acid;

6-Biphenyl-4-yl-3-(R)-(2-oxo-cyclohexyl-l-(S)-carbamoyl)- hexanoic acid;

6-Biphenyl-4-yl-3-(2-hydroxy-l-hydroxmethyl-propylcarbamoyl)-hexanoichydroxamic acid; 2S-[(lS-Benzyl-2-hydroxyethylcarbamoyl)-3R-biphenyl-4-yl-10 pyrrol-l-yl-methyl]-pentanoic acid; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-(2R-hydroxy-cyclohexyl-1R-yl)-succinamic acid; 2- (3-Biphenyl-4-yl-pyrrol-1 -yl)-3 -carboxamate-N-(l-hydroxy-3 -phehyl-prop-2-yl)-propionamide; 15 trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid; trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid hydroxyamide;

6-Bipheny 1-4-y 1-3 -(R)-( 1 -(S)-hydroxymethyl-2-(3 -pyridyl)-ethylcarbamoyl)-hexanoic acid;

6-Biphenyl-4-yl-2-(S)-hydroxy-3-(R)-(l-hydroxymethyl-2-(S)- (lH-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid; l-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; l-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic25 acidhydroxamide; l-(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide;

6-Biphenyl-4-yl-2S-hydroxy-3R-(lS-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanoic acid; 3 0 6-Biphenyl-4-yl-3 -(R)-( 1 -(S)-hydroxymethy 1-2-(3 -pyridy 1)- ethylcarbamoyl)-hexanehydroxamic acid;

6-Biphenyl-4-yl-2S-hydroxy-3R-(lS-hydroxymethyl-3- methylsulfanyl-propylcarbamoyl)-hexanoic hydroxmic acid; -208- 01 1 584 l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acidhydroxyamide; l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperazine-2-carboxylic acidhydroxyamide; 5 3R-(3-Biphenyl-4-yl-pyrrol-1 -yl)-N-[2-hydroxy-1 S-( lH-imidazol- 4-yl-methyl)-ethyl]-succinamic acid trifluoroacetate; . 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-[lS-(methoxy- 'methylcarbamoyl)-3-methyl-butyl]-succinamic acid; N-( 1 - Acetyl-3 -methyl-butyl)-3 -(3 -bipheny l-4-yl-pyrrol-1 -yl)-10 succinamic acid;

6-B iphenyl-4-yl-3-(R)-(2-oxo-1 -tetrahydrofuran-3-(S)-ylcarbamoyl)-hexanoic acid; 3 -[2,2-Dimethyl-1 -(pyridin-4-ylcarbamoyl)-propylcarbamoy 1] -2-hydroxy-5-methyl-hexanoic acid-hydrochloride sait; 15 N^-(2,2-Dimethyl-1 -methylcarbamoyl-propyl)-2, N1 -dihydroxy-3 - isobutyl-succinamide;

6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanoic acid; N-(l-Benzyl-2-hydroxy-ethyl)-3-(4-biphenyl-4-yl-pyrazol-l-yl)-20 succinamic acid; N-(8-Oxo-4-oxa-l,7-diaza-tricyclo[9.6.1.0 12,17]octadeca-11(18),12(17),13,15-tetraen-9R-yl)-3 S-(3 -pheny 1-pyrrol-1 -yl)-succinamicacid;

4-Acetyl-l-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic25 acid, N-hydroxyamide; l-(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide; 3R-(3-Biphenyl-4-yl-pyrrol-l-yl)-N-[3S-(2RS-hydroxy-5-methyl)-hexyl]-succinamic acid; N-( 1 -(S)-Benzyl-2-hydroxy-ethyl)-3 -(R)-(2-biphenyl-4-yl-30 cyclopropylmethyl)-succinamic acid;

6-Biphenyl-4-yl-3 -(R)-(2-oxo-1 -tetrahydrofuran-3 -(S)-ylcarbamoyl)-hexanehydroxamic acid; -209- 011584 l-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; 4-(4-Methoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 5 3-(Diphenylphosphinic)-propanoic acid; 3- (Diphenylphosphinic)-propanoic acid hydroxyamide; 4- [2-(2-Carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; l-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-4-(N-10 methylcarbamoyl)piperazine-2-carboxamide; 4- [4-(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorphoIine-3-carboxylic acid N-hydroxyamide; 3 -(3 -Biphenyl-4-yl-pyrrol-1 -yl)-N-(2,2-dimethy 1-1 -methylcarbamoyl-propyl)-succinamic acid; 15 l-[4-Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; 4[4-Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acidN-hydroxyamide; 3-[2-Biphenyl-4-yl-ethylsulfanyl]-tetrahydro-pyran—4-carboxylic20 acid N-hydroxyamide;

6-Biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid; 1- [4-(4-Bromo-phenoxy)-benzenesulfonyl]piperdine-2-amidoxime; 2- (3-Biphenylnitrile-4-yl-pyrrol-1-yl)-3-carboxy-N-(l-hydroxy-3-phenyl-prop-2-yl)-propionamide; 25 {3 -[3 -(3 - Amino-phenyl)-propyl]-2-oxo-tetrahydro-furan-3 -y 1} - acetic acid;

6-Biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid;

5- Biphenylvaleric acid; l-[4-(Methoxy)-benzenesulfonylJpiperdine-2-amidoxime; 30 l-[4-Phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; {3 -(3 -(3-Methylamino-phenyl)-propyl)-2-oxo-tetrahydro-furan-3 - yl}-acetic acid; -21θ- 011584

6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanehydroxamic acid; 4-(lH-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 5 1 R-[4-Bromo-phenoxy)-benzenesulfonyl)-N-amino-piperidine-2- carboxamide; . 2-(3-Biphenyl-4-yl-propyl)-3, N-4-dihydroxy-N1-(l(S)-hydroxymethyl-3-methanesulfinyl-propyl)-succinamide; N-(l-Benzyl-2-hydroxy-ethyl)-3-[3-(4'-carbamoyl-biphenyl-4-yl)-10 pyrrol-l-yl]-succinamic acid; l-(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acidhydroxamide; 4-(4-(4-Chlorophenoxy)benzenesulfonyl)-N-hydroxy-morpholine- 3R-carboxamide; 15 2S-[lR-(3-(4'-Cyano-biphenyl-4-yl)-pyrrol-l -yl)-N-(2,2-dimethyl- 1 S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; 2(S,R)-{lS-Benzyl-2-hydroxyethylcarbamoyl-[3R-(4'-cyano-biphenyl-4-yl)-pyrrol-l-yl]-methyl}pentanoic acid; 2S-[3-(Biphenyl-4-yl)-pynol-lR-yl-(lS-hydroxymethyl-2,2-20 dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; l-(l,3-Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acidhydroxamide; 3 -[3 -(4'-Carbamoyl-biphenyl-4-yl]-pyrrol-1 -yl)-N-( 1 -hydroxymethyl-2,2-dimethyl-propyl)-succinamic acid;

4-Methyl-l-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R- piperazinecarboxamide hydrochloride; 1- [4-Chlorophenoxybenzenesulfonyl]-N-hydroxy-2R-piperazinecarboxamide; 2- (3-Phenyl-propylsulfonyl)-cyclohexane carboxylic acid 30 hydroxamide; l-(Pyrolidine-l-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide; 10 15 20 25 30 -211- 011584 1 -(Piperidine-1 -sulfonyl)-piperidine-2-carboxylic acidhydroxyamide; 4-[4-Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; l-[4-(4-Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperdine-2-carboxylic acid hydroxyamide; l-[4-(4-Nitrile-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acid N-hydroxyamide; 2S-[3-(Biphenyl-4-yl)-pyrrol-lR-yl-(lS-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-methyl]-pent-4-enoic acid;

6-Oxo-3-(4-phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4-carboxylic acid hydroxamate; 4-(t-Butoxycabonyl)-l-(4-(pyridin-2-yl)oxybenzensulfonyl)-N- hydroxy-piperazine-2-carboxamide; 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid-N-hydroxyamide; 4-[4-(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; N-(2,2-Dimethyl-lS-hydroxymethyl-propyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1 -yl]-succinamic acid; N-(lS-Benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl)-succinamic acid; 4-(4-Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 4-(4-Butoxy-benzenesulfonyl)-l-oxothiomorpholine-3-carboxylicacid hydroxyamide; l-[4-(4-Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl)-2R-piperazine-2-carboxylic acid hydroxyamide; l-((4-(4-Chlorophenyl)-piperazine)-l-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; cis-2-Phenethylsulfanyl-cyclohexanecarboxylic acidhydroxyamide; -212- 011584 N-(2-Hydroxy-lS-phenyl-ethyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid; l-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochoride; 5 l-(Diphenylphosphinic)-pyrolidine-2-(R)-carboxylic acid- hydroxyamide; . N,N-{(Diphenylphosphinic)-(acetic acid-sodium salt)'}-hydrazide;N-( 1 -Benzyl-2-hydroxy-ethyl)-3 -( 1 -biphenyl-4-y 1-1 H-pyrrol-3 -yl)- succinamic acid; 10 trans-2-Phenethylsulfonyl-cyclohexanecarboxylic acid hydroxyamide; l-[4-(4-Flourophenyl)-piperazine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; l-[4-(4-Fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-15 carboxylic acid hydroxyamide; 4-[4-(Bromo-phenoxy)-benzenesulfonyl] -2,2-dimethyl-1 -oxo-thiomorpholine-3-carboxylic acid hydroxyamide; N-(2,2-Dimethyl-1 S-methylcarbamoyl-prôpyl)-3R-(3-phenyl-pyrrol-l-yl)-succinamic acid; 20 3R-(3 -Biphenyl-4-yl)-N-(2-hydroxy-1 S-hydroxymethyl-2-methyl- propyl)-succinamic acid; l-(Pyrrolidine-l-carbonyl)-pyrrolidine-2(R)-carboxylic acid;l-(Pyrrolidine-l-carbonyl)-pyrrolidine-2(R)-carboxylic acid hyroxyamide; 25 l-Phenethylcarbamoyl-pyrrolidine-2(R)-carboxylic acid; R-4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1 -oxo- thiomorpholine-3-carboxylic acid hydroxyamide; 4-(Ethoxycarbonyl)methyl-l-(4-(4-chlorophenyl)benzenesulfonyl)- N-hydroxy-2R-piperazinecarboxamide hydrochloride; 30 N-(2R-Hydroxy-indan-lR-yl)-3R-[3-(4-pyridin-4-yl-phenyl)- pyrrol-l-yl]-succinamic acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[3-(4-pyridin- 4-yl-phenyl)-pyrrol-1 -yl]-succinamic acid; -213- 011584 N-(2,2-Dimethyl-lS-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4yl-phenyl-4-yl)-pyrrol-l-yl]-succinamic acid;

2-Phenethylsulfanyl-cyclohex-l-enecarboxylic acid hydroxyamide; 6-(4'-cyano-biphenyl-4-yl)-3-[2-hydroxy-l-(4-methylsulfinyl-5 phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1 - {1 -[ 1 -(4-Methoxycarbonyl-phenylcarbamoyl)-3 -methyl-butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid;

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4S-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1θ 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-3,3,3-trifluoropropyl)- phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methylester;

2-Benzylsulfonyl-cyclohex-l-enecarboxylic acid hydroxy amide;

6-Benzylsulfonyl-cyclohex-l-enecarboxylic acid hydroxy amide; 2R-(3-(4-Biphenyl)propyl)-N-(3-methylpyridine)succinamide; -200- 011584 {3-[3-(3-Hydroxy-phenyl)-propyl]-2-oxo-pyrrolidin-3-yl}-acetic acid;

6-Biphenyl-4-yl-{[cyclohexyl-(3-morpholin-4-yl-propylcarbamoyl)-methyl]-carbamoyl}hexanoic acid; 5 [2-Oxo-3 -(3 -biphenyl-propyl)-tetrahydro-furan-3 -yl]-acetic acid; 4-[2-(2-Thioamidomethyl-5-phenyl-valerylamino)-4-methyl-valeroylaminoj-benzoic acid methyl ester; 4-[2-(2-Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester;

6-Biphenyl-4-yl-3-[2,2-dimethyl-1 -(4-methylsulfamoyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(2-hydroxyethylsulfamoyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1 -(N-Hydroxy)-3-(2-bibenzyl)urea; 15 4-(2- {5-[7-(2-Amino-acetylamino)-9H-fluoren-2-yl]-2- carboxymethyl-pentanoylamino}-4-methyl-pentanoylaminô)-benzoic acidmethyl ester TFA sait; 3R-(6-(4-Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoic acid N-hydroxy amide;

6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)- phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid;

6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid,trifluoroacetate sait; 25 4-(2-{2-Carboxymethyl-5-[4-(lH-tetrazol-5-yl)-phenyl]- pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-ethyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 4-(2-{[5-Hydrcxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H- 30 pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester;

5 -Hydroxyamino-3 -(3 -pheny l-propyl)-3,4-dihydro-2-H-pyrrole-3 - carboxylic acid(2-cyclohexyl-l-methylcarbamoyl-ethyl)amide; -2θ1- 0115 8 4

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-(3-morpholin-4-yl- sulfamoyl)-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;6-Biphenyl-4-yl-3-[2,2-dimethyl-1 -(4-methylsulfanyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfonyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-[2-(5-Biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-pent-4- enoylaminoj-benzoic acid methyl ester;

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfmyl- 10 phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4- (2-{[5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester;

5- Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3-carboxylic acid(2-cyclohexyl-l-methylcarbamoyl-ethyl)amide;

6-Biphenyl-4-yl-[2,2-dimethyl-l-(pyridin-4-ylcarbamoyl)- propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-cyano-biphenyl-4-yl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester;

6- Biphenyl-4-y-3-(R)-(2-hydroxy-l-(S)-phenyl-ethylcarbamoyl)- 20 hexanoic acid; 3-(R)-(l-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid;

6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1 -hydroxymethyl-ethylcarbomyl)-hexanoic acid; 25 4-[2-(2-Carboxymethyl-5-(4-pyridin-4-yl-phenyl)- pentanoylamino)-4-methyl-pentanoylamino]benzoic acid methyl ester;

6-Biphenyl-4-yl(2-hydroxy-2-methyl-1-phenylcarbamoyl-propylcarbamoyl)-hexanoic acid;

6-Biphenyl-4-yl(2-hydroxy-2-methyl-1 -phenylcarbamoyl- 30 propylcarbamoyl)-hexanoic acid; 3-{2-Allylsufamyl-2-methyl-l-[2-(4-sulfamoyl-phenyl)- ethylcarbamoyl]-propyIcarbamoyl}-6-biphenyl-4-yl-hexanoic acid; -202- 011584 4-[2-(5-Biphenyl-4yl-2-carboxymethyl-pentanoylamino)-4,5-dihydroxy-pentanoylaminoj-benzoic acid methyl ester; 4-(2-{5-[4'-(2-Amino-ethoxy)-biphenyl-4-yl]-2-carboxymethyl-pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester;

6-Biphenyl-4-y-3-(R)-(2-hydroxy-l-(S)-phenyl-ethylcarbamoyl)- hexanehydroxamic acid; . 3-(R)-(l-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl-hexanehydroxamic acid; N-[5-(Biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl]-10 tert-leucine, N-(pyrid-4-yl)amide; [3 -(3 -Naphthalen-2-yl-propyl)-2-oxo-tetrahydro-furan-3 -yl] -acetic acid;

6-Biphenyl-4-yl-3 -(R)-(2-hydroxy-1 -hydroxymethyl-ethylcarbomy l)-hexanehy droxamic acid ; 15 4-[2-(2-Carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4- methyl-pentanoylamino]-benzoic acid methyl ester; 3- [2,2-Dimethyl-l-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-5-methyl-hexanoicacid; Nl-[2,2-Dimethyl-l-(pyridin-4-ylcarbamoyl)-propyl]-N4-hydroxy-20 2-isobutyl-succinamide; 4- {2-[2-Carboxymethyl-5-(2-fluoro-biphenyl-4-yl)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester;

6-Biphenyl-4-yl-3(R)-(l(S)-hyroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid; 25 4-{2-[5-Biphen-4-yl-2-(l-carboxy-ethylamino)-pentanoylamino]- 4-methyl-pentanoylamino}-benzoic acid methyl ester;

6-Biphenyl-4-yl-3(R)-(l(S)-hyroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamic acid;

6-Biphenyl-4-yl-3-[2,2-dimethyl-l-(4-methylsulfinyl-30 phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 2 ' /lôUÎiunyij-vyciohex-l-enccaiboxylic acid hydroxyamide; -203* 01 1 5 8 4 6-(Biphenyl-4-ylsulfonyl)-cyclohex-l-enecarboxylic acidhydroxyamide;

2- Benzylsulfonyl-cyclopent-l-ene-carboxylic acid hydroxamide;[2-Oxo-3-(3-phenyl-propyl)-pyrrolidin-3-yl]-acetic acid; [3 -(3 -Naphthalen-2-yl-propyl)-2-oxo-pyrrolidin-3 -yl]-acetic acid;

2-Carboxymethyl-heptanoyl-3 -(N-methylcarboxamide)-hexahydropyridazine;

6-Biphenyl-4-yl-3-[l-[3-(3-hydroxy~ethyl)-phenylcarbamoyl]-2,2- Ij-hvxaiKnc acid; -199- 011584 2R-(3-(4-Biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5- methyl-3S-hexyl)succinamide;

6-Biphenyl-4-yl-3-[l-[3-(2-aminoethyl)-phenylcarbamoyl]-2,2-dimethyl-propylcarbamoyl]-hexanoic acid; 5 2R-(3-(4-Biphenyl)propyl)-N-(diphenylmethyl)succinamide; 2R-(3-(4-Biphenyl)propyl)-N-(phenylmethyl)succinamide; 2-(2-Oxo-imidazolidin-4-ylmethyl)-5-phenyl-pentanoic acid;2-(3-Biphenyl-4-yl-propyl)-N^-[l-(5,6-dichloro-lH- benzoimidazol-2-yl)-3-methyl-butyl]-N4-hydiOxy-succinamide hexanoic 10 acid;

6-Biphenyl-4-yl-[2,2-dimethyl-1 -(pyridin-4-ylcarbamoyl)-propylcarbamoylj-hexanoic acid, N-hydroxyamide; 2R-(3-(4-Bipheny l)propyl)-N-(( 1-hydroxy-1-methylethyl)phenylmethyl)succinamide;

6-Biphenyl-4-yl-3-[ 1 -phenylcarbamoyl-2-(4-cyano- benzylsulfanyl)-2-methyl-propylcarbamoyl]-hexanoic acid; 4-{2-[2-Carboxymethyl-5-(4'-hydroxy-biphenyl-4-yl)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 1- (N-Methyl-N-phenethylthiocarbomyl)-pyrrolidine-2-carboxylic 20 acid;

6-Biphenyl-4-yl-3-({cyclohexyl-[2-(4-sulfanoyl-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-hexanoic acid; 3R(6-(4-Biphenyl)-3-(N-benzylearbamoyl))-hexanoic acidN-hydroxyamide; 25 [3-(3-Biphenyl-4-yl-propyl)-2-oxo-pyrrolrdin-3-yl]-acetic acid;

2-Carboxymethyl-heptanoyl-2-(N-methylcarboxamide)piperidine; 4- [2-(2-(2-Phenylcyclopropyl)succinylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

2-Cyclohexylmethyl sulfonyl-benzohydroxamic acid; [2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid; -198- 011584 4-[2-(2-Carboxymethyl-5-(fluoren-2-yl)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(3-thienyl)acetylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 5 4-[2-(2-Benzylthio-3-carboxy-propionylamino)-4- methylpentanoylaminoj-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(2-indolyl)butyrylamino)-4-methyl-valeroyljaminobenzoic acid methyl ester;

2- Cyclohexylmethyl sulfonyl-benzoic acid; Pyrrolidine-1 -carbothioic acid phenethyl-amide; 25 3-(2-Methyl-thiazol-4-yl)-N-phenethyl-propionamide; N-Phenyl-3-[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-4- yl]-propionamide; 3- (3H-Imidazol-4-yl)-N-phenethyl-propionamide; 4- [2-(2-Carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl- 30 valeroyl]aminobenzoic acid methyl ester;

2-Bromo-6,l l-dihydro-dibenzo[b,e]oxepine-l 1-carboxylic acid(2,6-diisopropyl-phenyl)-arnide; (±)N-(l,2-Diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide;2,2-Dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl)- 5 amide; (Z) 1 -(6,7-Dimethoxy-3,4-dihydro-1 H-isoquinolin-2-yl)-octadec-9-en-l-one; (Z)2,2,5,5-Tetramethyl-[l,3]dioxane-4-carboxylic acid[2-(2-octadec-9-enoylamino-ethylcarbamoyl)-ethyl]-amide; 10 l-Benzyl-l-(5-methyl-3-phenyl-benzoiùran-2-ylmethylj- 3- (2,4,6-trifluoro-phenyl)-urea;

5-Chloro-3-o-tolyl-benzofuran-2-carboxylic acid (2,6-diisopropyl-phenyl)-amide; 2-(2,4a-Dimethyl-4a,5-dihydro-naphthalen-l-ylsulfanyl)-N-15 {2-[(6,6-dimethyl-hepta-2,4-diyny l)-pentyl-amino] -ethyl} -acetamide; (Z)Octadec-9-enoic acid [2-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)- 1- phenyl-ethyl]-amide; N-(4-Dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl)- 4- (phenyl-propyl-amino)-butyramide; 20 (Z)l-(6,7-Dimethoxy-3-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)- octadec-9-en-1-one; (trans) 1,4-Bis-(4-methoxy-phenyl)-3 -(3 -pheny l-propyl)-azetidin- 2- one;

2. Use of an ACAT inhibitor with a MMP inhibitor in the manufacture of a médicament for preventing plaque rupture and promoting lésion régressionin a mammal..

3. Use according to Claim 1 wherein the MMP inhibitor is a compound of theformula 10

wherein: 15 20 A is a bond, CONH, or —, where Y is CH or N; RJ is alkyl, aryl, halo, amino, substituted or disubstituted amino, oralkoxy; Rp is carboxy alkyl ketone or oxime, carboxyalkylsulfonamide, or-SO2-NHCHCOOH; and R3 is alkyl, substituted alkyl, amino, substituted or disubstituted amino, oraryl, and pharmaceutically acceptable salts thereof.

4. Use according to Claim 3 wherein the compound is of the formula

5. Use according to Claim 1 wherein the MMP inhibitor is a compound of theformula -174- 011584 r1-O~CK3^-rî wherein: ; RÎ is alkyl, aryl, halo, amino, substituted or disubstituted amino, or alkoxy; 5 R2 is carboxyalkyl ketone or oxime, carboxyalkylsulfonamide, or -SO2-NHCHCOOH; and R3 R3 is alkyl, substituted alkyl, amino, substituted or disubstituted amino, or10 aryl, and pharmaceutically acceptable salts thereof.

6. Use according to Claim 1 wherein the MMP inhibitor is a compound of the formula

15 R1 is Cj-Cg alkyl, halo, nitro, NR4R$, cyano, OR4, and COOR4; R^ is CpCg alkyl, optionally substituted by phenyl, substituted phenyl, NH I NR4R5, ΟΚΟ, carboxy, carboxamido, H2N-C-NH-, thio, 20 methylthio, indole, imidazole, phthalimido, phenyl, and substituted phenyl; R3 is OH, OC!-C6 alkyl, orNHOH; R4 is hydrogen, Cj-Cg alkyl, or CpCg alkanoyl; R5 is hydrogen or Cj-Cg alkyl; and -175- 011584 R.6 is hydrogen, Cj-Cg alkyl, Cj-Cg alkanoyl, phenyl, or substitutedphenyl. Use according to Claim 6 wherein the compound is of the formula

Use according to Claim 6 wherein the compound is 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methyl-butyric acid. Use according to Claim 2 wherein the MMP inhibitor is a compound of theformula

10 . wherein R and Rl are the same or different and are hydrogen,alkyl,halogen,nitro, 15 cyano, trifluoromethyl, OR6 wherein R6 is hydrogen,alkyl,aryl, 20 arylalkyl, heteroaryl, orcycloalkyl, 10 15 20 25 30 35 -176- 011584 -N-R6 wherein R^ and R^a are the same or different and areR6a as defined above for R^, O -O-C-R6 wherein R6 is as defined above, O ' Il -NH-C-R6 wherein R6 is as defined above, O II -S-C-R6 wherein R6 is as defmed above, -SR^ wherein R^ is as defmed above, O II -C-R6 wherein R6 is as defmed above, -CH2-OR6 wherein R6 is as defmed above, -CH2-N-R6 wherein R6 and R^a are the same or different I Rôa and are as defmed above for R6, O 11 -C-N-R6 wherein R6 and r6&amp; are the same or different andRôa are as defmed above for R6, O II -S-R6 wherein R6 is as defmed above, II 0 cycloalkyl, or heteroaryl, with the proviso that R and Rl are not both hydrogen;R2 is -OR6 wherein R6 is as defmed above, or -177- 01 1 584 -N-R.6 wherein and R^a are the same or different and are I R6a as defined above for R^; 5 R3, R3a, R4, and R4aarethe same or different and are hydrogen, fluorine,alkyl, -(CH2)n-aryl wherein n is an integer from 1 to 6,-(CH2)n-heteroaryl wherein n is as defined above, 10 -(CH2)n-cycloalkyl wherein n is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O, S, SO, SO2, or NH, and p and q are each zéro or an integer of 1 to 6, and the sum ofp + q is not greater than six, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined 15 above, or -(CH2)n-R7 wherein R? is N-phthalimido, N-2,3-naphthyimido, -OR6 wherein R^ is as defined above, 20 -N-RO wherein R^ and R^a are the same or different and I R6a are as defmed above for R^, -SR6 where R^ is as defmed above, 25 O II. -S-RO wherein R^ is as defmed above, O II .30 -S-R6 wherein R6 is as defmed above, -178- 011584 ο . -O-C-R6 wherein R^ is as defined above, O 5 II -N-C-R6 wherein R^ and R^a are the same or different I Rôa and are as defined above for R^, 10 O -I - -S-C-R6 wherein R^ is as defined above, O II 15 -C-R6 wherein R^ is as defined above, O II -C-OR6 wherein R^ is as defined above, orO 20 || -C-N-R6 wherein R^ and R^a are the same or different I R6a and are as defined above for R^, and25 n is as defined above; R^ is OH or SH; with the proviso that R3, R^a r4, and R4a are hydrogen or at least one of R3, R3a, R4, or R4a is fluorine; and corresponding isomers thereof; or a pharmaceutically acceptablesait thereof.

10. Use according to Claim 9 wherein the compound is of the formula,OH R

)— c— ch2ch2c-oh 30 11. 12. -179- 011584 Use according to Claim 9 wherein the compound is 4-(4'-chlorobiphenyl-4-yl)-4-hydroxyimino-butyric acid. Use according to Claim 1 wherein the MMP inhibitor is a compound of theformula

10 15 13. wherein X is oxygen or -C-CH2-NOH I R2 is -C-CH2CH-COOH or -SO2NHCHCOOH; and I I R3 R3 R3 is alkyl, halo, alkoxy, acyl, or aryl. Use according to Claim 12 wherein the compound is of the formula

14. 15. Use according to Claim 12 wherein the-compound is (S)-2-(9H-fluorene-2-sulfonylamino)-4-phenyl-butyric acid. Use according to Claim 12 wherein the compound is of the formula 20 -180- 011584

CO2H

16. Use according to Claim 1 wherein the MMP inhibitor is a compound of theformula O Il H o - s—N-C—COR4 Il H O ,-,2

wherein: 5 R1 is CpCg alkyl, halo, nitro, (CH2)o-4-NR4R5, O O Il I cyano, OR4, CH, CF3, CNR4R5, and COOR4; R2 is hydrogen or CpCg alkyl, optionally substituted by the following 10 groups: phenyl, substituted phenyl, phenoxy, substituted phenoxy, O II NR4R5, OR6, carboxy, carboxamido, H2N-C-HN-, thio,methylthio, indole, imidazole, and phthalimido; 15 R3 is OH, O, C1 -C6 alkyl, or NHOH; R4 is hydrogen, Cj-Cg alkyl, or Cj-Cg alkanoyl; R5 is hydrogen or Cj-Cg alkyl; and R6 is hydrogen, Cj-Cg alkyl, Cj-Cg alkanoyl, phenyl, or substituted phenyl, and pharmaceutically acceptable salts and solvatés thereof.

17. Use according to claim 1 wherein th«* T iJ:;1; is selected from the group consisting of . -181- 011584 (S)-2-(4'-Br^mo-biphenyl-4-sulfonylamino)~3-methyl-butyric acid; (S)-2-(4'-Chloro-biphenyl-4-suIfonylamino)-3-methyl-butyric acid;(S)-3-Methyl-2-(4'-nitro-biphenyl-4-sulfonylamino)-butyric acid; 5 (S)-2-(4'-Amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-Cyano-biphenyl-4-sulfonylamino)-3-methyl-butyric acid;(S)-2-(3',4'-Dibromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, sodium sait; (S)-2-(3'-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 1 θ (S)-2-(4'-Bromo-2'-fluoro-biphenyl-4-sulfonylamino)-3 -methyl- butyric acid, (R) -2-(4'-Bromo-biphenyl-4-sulfbnylamino)-3-methyl-butyric acid; (S) -2-(4'-Bromo-biphenyl-4-sulfonylamino)-propionic acid;(S)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-4-methyl-pentanoic 15 acid; (S)-2-(4’-Methoxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-Fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid;(S)-2-(3'-Fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 20 (S)-3 -Methyl-2-(4'-trifluoromethyl-biphenyl-4-sulfonylamino)- butyric acid; 2-(4'-Formyl-biphenyl-4-sulfo_nylamino)-3-methyl-butyric acid;4'-( 1 -Carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-carboxylic acid; 25 2-(4'-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 2-(4'-AminomethYl-biphenyl-4-sulfbnvlamino)-3-methyl-butyric acid; (S)-2-(4'-Bromo-biphenyi-4-sulfonylamino)-3-phenyl-propionic 30 acid; -182- 011584 (S)-(4,-Isopropyl-biphenyl-4-sulfonylamino)-3-Phenyl-propionic acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid;and 5 (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert.-butyl ester.

18. Use according to Claim 1 wherein the AC AT inhibitor is a compound ofthe formula O O R<—X-S-N-C-Y-R2 Il I O R 10 or a pharmaceutically acceptable sait thereof wherein: X and Y are selected ffom oxygen, sulfur and (CR'R")n wherein n is an integer of from 1 to 4 and R' and R” are each independently15 hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, phenyl optionally substituted or R' and R" together form aspirocycloalkyl or a carbonyl; R is hydrogen, a straight or branched alkyl of from 1 to 8 carbon atoms orbenzyl; 20 R{ and R2 are each independently selected from (a) phenyl or phenoxy each of which is unsubstituted or is substitutedwith 1 to 5 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and whichis straight or branched, 25 10 15 20 25 -183- 01 1 584 an alkoxy group having from 1 to 6 carbon atoms andwhich is straight or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms andis straight or branched, -(CH2)pNR3R4 wherein p is zéro or one, and each of R3 and R4 is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms; (b) 1- or 2-naphthyl unsubstituted or substituted with from 1 to 3 substituents selected fromphenyl, an alkyl group having from 1 to 6 carbon atoms and whichis straight or branched, an alkoxy group having from 1 to 6 carbon atoms andwhich is straight or branched; hydroxy, - — phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms andis straight or branched, .30 -184- 011584 -(CH2)pNR.3R4 wherein ρ, R3 and R4 ha.ve the meaningsdefined above; (c) arylalkyl; (d) a straight or branched alkyl chain having from 1 to 20 carbon 5 atoms and which is saturated or contains from 1 to 3 double bonds; or (e) . adamantyl or a cycloalkyl group wherein the cycloalkÿl moiety has from 3 to 6 carbon atoms.

19. Use according to Claim 18 wherein Rj is phenyl.

20. Use according to Claim 18 wherein R| is phenyl disubstituted in the 2,6-positions.

21. Use according to Claim 18 wherein R2 is phenyl.

22. Use according to Claim 18 wherein R2 is phenyl disubstituted in the 2,6-positions.

23. Use according to Claim 18 wherein each of Rj and R2 is phenyl.

24. Use according to Claim 23 wherein each phenyl is disubstituted in the 2.6- positions.

25. Use according to Claim 18 wherein Rj is phenyl disubstituted in the 2.6- positions and R2 is phenyl trisubstituted in the 2,4,6-positions.

26. Use according to Claim 18 wherein R| is 2,6-bis(l-methylethyl)phenyl and R2 is 2,6-bis(l-methylethyl)phenyl or 2,4,6-tris(l-methylethyl)phenyl.

27. Use according to Claim 18 wherein Ri is phenyl or isophenyl disubstitutedin the 2,6-positions, wherein R2 is phenyl or is phenyl disubstituted in the -185- 011584 2,6-positions, wherein each of Rj and R2 is phenyl, wherein each phenylis disubstituted in the 2,6-position, wherein Rj is phenyl disubstituted inthe 2,6-positions and R2 is phenyl trisubstituted in the 2,4,6-positions,wherein R^ is 2,6-bis(l-methylethyl)phenyl and R2 is 2,6-bis(l- 5 methylethyl)phenyl or 2,4,6-tris(l-methylelthyl)phenyl, wherein one of Rj and R2 is the group R5! -(ch^-c-cch^ 10 R6 wherein t is zéro or 1 to 4; w is zéro or 1 to 4 with the proviso that the sumof t and w is not greater than 5; R5 and R5 are each independently selectedfrom hydrogen or alkyl having from 1 to 6 carbon atoms, or when R5 is 15 hydrogen, R^ can be selected from the groups defined for R7; and R7 is phenyl or phenyl substituted with from 1 to 3 substituents selected from astraight or branched alkyl group having from 1 to 6 carbon atoms, straightor branched alkoxy group having from 1 to 6 carbon atoms, phenoxy,hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, 20 COOalkÿl wherein alkyl has from 1 to 4 carbon atoms, or -(CH2)pNR3R4 wherein P, R3 and R4 hâve the meanings defined above.

28. Use according to Claim 18 whereinX is oxygen, sulfur or (CR'R")n; Y is oxygen, sulfur or (CR'R")n with the proviso that at least one of X or25 Y is (CR'R”)n wherein n is an integer of from 1 to 4 and R' and R" are each independently hydrogen, straight or branched alkyl offrom 1 to 6 carbons, optionally substituted phenyl, halogen,hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R” taken togetherform a carbonyl or a spirocycloalkyl group of from 3 to 10 carbons; 30 Ris hydrogen; -186- 011584 R] is phenyl optionally substituted, straight or branched .alkyl of from 1 to 10 carbon atoms, cÿcloalkyl of from 3 to 10 carbon atoms; R2 is phenyl optionally substituted, straight or branched alkyl of from 1 to 10 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenoxy5 optionally substituted.

29. Use according to Claim 18 whereinX is oxygen; Y is (CR'R")n wherein n is an integer of from 1 to 2; R is hydrogen; 10 Rj is optionally substituted phenyl; R2 is optionally substituted phenyl or phenoxy, straight or branched alkyl of from 1 to 10 carbons, or cycloalkyl of from 3 to 10 carbons; R' and R" are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, 15 hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R” taken together form a carbonyl or a spirocycloalkyl.

30. Use according to Claim 18 wherein the compound is sulfamicacid[[2,4,6-tris(l-methylethyl)phenyl]acetyl-2,6-bis(l-methylethyl)-phenyl ester.

31. Use according to Claim 18 wherein the compound is selected from the group consisting of Sulfamic acid (phenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,Sulfamic acid[[2,6-bis(l-methylethyl)phenyl]acetyl]-2,6- bis(l-methylethyl)phenyl ester, 25 Sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl-2,4,6- tris(l-methylethyl)phenyl ester, Sulfamic acid[[2,6-bis( 1 -methylethyl)phenvllacetvll-2,4,6-tris(l-methylethyl)phenyl ester, -187- 0115 84 Sulfamic acid[adamantaneacetyl]-2,6-bis[l-methylethyl)phenyl ester, Sulfamic acid[[2,6-bis( 1 -methylethyl)phenyl]acetyl]- 2,6-bis(l-methylethyl)phenyl ester-sodium sait, 5 Sulfamic acid[[2,4,6-tris(l -methylethyl)phenyl]acetyl]- 2,6-bis(l-methylethyl)phenyl ester-sodium sait, Sulfamic acid (decanoyl)-2,6-bis-(l-methylethyl)phenyl ester,Sulfamic acid (dodecanoyl)-2,6-bis-(l-methylethyl)phenyl ester, 2,6-Bis(l-methylethyl)-N-[[[2,4,6-tris(l-methylethyl)phenyl]- 10 methyl]sulfonyl]benzeneacetamide, 2.6- Bis(l-methylethyl)-N-[[[2,4,6-tris(l-methylethyl)phenyl]-methyl]sulfonyl]benzeneacetamide-sodium sait, 2.6- Bis(l-methylethyl)phenyl[[[2,4,6-tris(l-methylethyl)phenyl]-methy 1] sulfonyl ] carbamate, 15 2,6-Bis(l-methylethyl)phenyl[[[2,4,6-tris(l-methylethyl)phenyl]- methyl]sulfonyl]carbamate-sodium sait, Sulfamic acid (l-oxo-3,3-diphenylpropyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(l-20 methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid trans-[(2-phenylcyçlopropyl)carbonyl]-2,6-bis(l-methylethyl)phenyl ester, 25 Sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(l- methylethyl)phenyl ester, Sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(l-30 methylethyl)phenyl ester, Sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(l -methylethyl)phenyl ester, -188- 011584 Sulfamicacid [3-thiophenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, 5 Sulfamæ acid (oxophenylacetyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid [2-trifluoromethylphenyl(acetyl)]-2,6-bis(l-methylethyl)phenyl ester, Sr’faniîv acid (l-oxo-2-phenylpropyl)-2,6-bis(l- 10 methylethyl)phenyl ester, Sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(l- methylethyl)phenyl ester, Sulfamic acid (cyclohexylacetyl)-2,6-bis(l-methylethyl)phenyl ester, 15 Sulfamic acid (diphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (triphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,Sulfamic acid [(l-phenylcyclopentyl)carbonyl]-2,6-bis(l- methylethyl)phenyl ester, Sulfamic acid (3-methyl-l-oxo-2-phenylpentyl)-2,6-bis(l- 20 methylethyl)phenyl ester, Sulfamic acid (l-oxo-2-phenylbutyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (cyclohexylphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester, 25 Sulfamic acid (l-oxo-2,2-diphenylpropyl)-2,6-bis(l- methylethyl)phenyl ester, Sulfamic acid [(9H-fluoren-9-yl)carbonyl]-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (l -oxo-3-phenylpropyl)-2,6-bis(l- 30 methylethyl)phenyl ester, Sulfamic acid [l-oxo-3-[2,4,6-tris(l-methylethyl)phenyl]- 2-propenyl]-2,6-bis(l-metby!ethyl)phenyl ester, -189- 011584 Sulfamic acid [ 1 -oxo-3-[2,4,6-tris( 1 -methylethyl)phenyl]propyl]- 2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid [(acetyloxy)[2,4,6-tris(l-methylethyl)phenyl]acetyl] 2,6-bis(l-methylethyl)phenyl ester, 5 Sulfamic acid [hydroxy[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis(l-methylethyl)phenyl ester, Sulfamic acid [fluoro[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis( 1 -methylethyl)phenyl ester, Sulfamic acid (3-methyl-l-oxo-2-phenylpentyl)-2,6-bis(l-10 methylethyl)phenyl ester sodium sait, Sulfamic acid [[2,4,6-tris(l-methylethyl)phenoxy]acetyl]- 2.6- bi s( 1 -methylethyl)phenyl ester, Sulfamic acid [[2,6-bis(l-methylethyl)phenoxy]acetyl]-2,6-bis-(l-methylethyl)phenyl ester, and 15 Sulfamic acid [[2,4,6-tris(l-methylethyl)phenyl]acetyl]- 2.6- bis(phenyl)phenyl ester.

32. Use according to Claim 1 wherein the MMP inhibitor is selected from so2ni-k\c°2h 20 and

and the ACAT inhibitor is selected from [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester andN-(2,6-diisopropyl-phenyI)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- 25 acetamide. . -190- 011584

33. A pharmaceutical composition for treating and/or preventingatherosclerotic lésions comprising a therapeutically effective amount of anAC AT inhibitor and a MMP inhibitor.

34. Use according to Claim 1 whcrcin the MMP inhibitor is selected ffom

and the AC AT inhibitor is selected ffom [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester and 10 N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide are administered.

35. Use according to Claim 1 wherein the AC AT inhibitor is selected from:

4- Hexadecylamino-benzoic acid monosodium sait;3,5-Dimethyl-l-[5-(l,4,5-triphenyl-2H-imidazol-2-ylsulfanyl)- 15 pentyl]-lH-pyrazole monosodium sait; 8- (l,4,5-Triphenyl-2H-imidazol-2-yloxy)-octanoic acid;

9- Bromo-6,l l-dihydro-dibenzo[b,e]oxepine-l 1-carboxylic acid(2,6-diisopropyl-phenyl)-amide; 5- ((3,5-Di-tert-butyl-4-hydroxy-phenylamino)-{[4-(2,2-dimethyl- 20 propyl)-benzyl]-hexyl-amino}-methylene)-2,2-dimethyl-[l,3]dioxane- 4,6-dione; 3 -(2,4-Difluoro-phenyl)-1 -[4-(2,2-dimethyI-propyl)-benzy 1] - 1-heptyl-urea; l-Heptyl-l-[4-(3-methyl-butyl)-benzyll-3-f2.4.6-trifluoro-phenyl)- 25 ure»' -191- 011584 3-(2,4-Difluoro-phenyl)-l-[5-(4,5-diphenyl-lH-imidazol- 2- y lsulfany l)-pentyl]-1 -heptyl-urea,

3-Carboxymethylsulfanyl-2-(4-(4-fluoro-phenoxy)- benzenesulfonylamino)-3-methyl-butyric acid; 2,2-Dimethyl-1 -oxo-4-[4-(pyridin-4yloxy)-benzenesulfonyl]-1S14- thiomorpholine-3-carboxylic acid hydroamide; l-[4-(Pyridin-2-ylsulfanyl)-piperidine-l-sulfonyl]-piperidine-2- carboxylic acid hydroxyamide; 2(R)-[4-(4-(fur-3-yl)-phenoxy)-benzenesulfonylamino]-3-methyl- 3-(pyridi-n-yl-sulfanyl)-butyric acid; 2,2-Dimethyl-1 -oxo-4-[4-(pyridin-4yloxy)-benzenesulfony 1]-1S14-thiomorpholine-3-carboxylic acid hydroamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-l,l-dimethyl-ethylsulfanyl}-acetic acid tert-butyl ester; l-[4-(Pyridin-4-ylsulfanyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 2(R)-[4-(4-Bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfanyl)-butyric acid, hydroxyamide; trans-2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexanecarboxylicacid hydroxyamide; N-[lS-(lH-Imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid formate; N-Methyl-3-[3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succinamic acid; N(4)-(2,2-Dimethyl-lS-hydroxymethyl-propyl)-N(l)-hydroxy-3R- [3-(4-pyridin-4-yl-phenyl)-pyrrol-l-yl]-succindiamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-l,l-dimethyl-ethylsulfanyl}-acetic acid; l-[4[(4-Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid hydroxyamide; N-(4-[4-Bromophenoxy]-benzenesulfonylamino)-3-methyl-3-(l-benzyl-imidazole-2-yl-sulfanyl)-butyric acid; 3R-[3-(4'-Cyanobiphenyl-4-yl)-pyrrol-1 -yl]-N-(2,2-dimethyl-1S-hydroxymethyl-propyl)-succinamic acid; -218-. 011584 2-(R)-[4-(4-Iodophenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-2-yl-sulfanyl)-butyric acid; 3R-[3-(4-Cyano-phenyl)-pyrrol-l-yl]-N-(2,2-dimethyl-lS-hydroxymethyl-propyl)-succinamic acid; 5 2(R)-[4-(4-Iodo-phenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; . 2(R)-[4-(4-Nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfonyl)butyric acid; 2-[4-(-Fluoro-phenoxy)-benzene sulfonylamino]-3,3-dimethyl-10 pent-4-enoic acid; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyric acid; 2-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoazole-3-ylmethylsulfanyl)-butyric acid; 15 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-20 (carbomethoxyethylsulfanyl)-butyric acid; 1- [2-(Benzothiazol-2-ylsulfanyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-l-yl]-N-(2,2-dimethyl-lS-methylcarbamoyl-propyl)-succinamic acid; 25 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3- (hydroxyethylsulfanyl)-butyric acid;

[4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3 S-yl)-3R-[ 1 -(4 ' -30 cyanobiphenyl-4-yl)-lH-pyrrol-3-yl]-succinamic acid; 2- [4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-(amidoethylsulfanyl)-butyric acid; -219- 011584 [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5-phenyl-pent-4-enoic acid; 5 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-4,5,6,7-tetrahydro-3H- imidazole[4,5,-c]pyridine-6-carboxylic acid hydroxyamide 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl-sulfonyl)butyric acid; 3(S)-4-(4-((Pyrid-4-yI)oxy)benzenesulfbnyl)-2,2-dimethyl-10 tetrahydro-2H-l,4-thiazine-3-carboxylic acid; l-[4-(Pyridin-4-ylsulfanyl)-piperidine-l-sulfanyl]-piperidine-2-carboxylic acid hydroxyamide; N-[l-(lH-imidazol-2-yl)-3-methyl-butyl]-3-[l-(4'-cyanobiphenyl- 4-yl)·- lH-pyrrol-3-yl]-succinamic acid; 15 3R-{3-[(4-Cyano-phenyl)-acetyl]-pyrrol-1 -yl}-N-(2,2-dimethyl- lS-methylcarbamoyl-propyl)-succinamic acid; l-[4-(4-Methoxy-phenylsulfamyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-l-yl]-N-(2,2-dimethyl-lS-20 methylcarbamoyl-propyl)-succinamic acid methyl ester; 2(R)-[4-(4-Methylphenoxy)benzenesulfonÿlamino]-3-methyl-3-(pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; l-[4-(4-Methyl-phenylsulfamyl)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 25 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3- carboxylic acid; 4-4(-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-30 thiomorpholine-3-carboxylic acid; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; -220- 011584 2(R)-[4-(4-bromo-phenoxy)benzenesulfoxylamino]-3-methyl-3-(pyridi-n-yl-sulfuroxide)butyric acid, hydroxyamide; 4-(4-Methoxy-bezensulfonyl)-2,2-dimethyl-l-oxo-thiomorpholine- 3-carboxylic acid hydroxyamide; 5 2,2-Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]- thiomorpholin-3-ol; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy-l-oxo-thiomorpholîne-3-carboxylic acid hydroxyamide; 2-(R)-3-Methyl-3-(pyridin-2-yl-sulfanyl)-[4-(4- 10 trifluoromethylphenoxy)benzenesulfonylamino]-butyric acid; 3(R)-4-(4-(Pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl- tetrahydro-2H-l,4-thiazine-3-carboxamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4- (pyridin-4-yl-oxy)-benzenesulfonylamino] -butyric acid; 15 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3- yl)methylsulfanyl]-[4-(pyridin-4-yl-oxy)-benzenesulfonylamino]- butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3-hydroxy-3-methyl-butyric acid; 20 3(S)-2,2-Dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]- thiomorpholine-3-carboxylic acid hydroxyamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-yl-sulfanyl)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3- 25 yl)methylsulfanyl]-[4-(pyridin-4-yl-sulfanyl)-benzenesulfonylamino]- butyramide; 3.3- Dimethyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidine-l-sulfonylamino]-butyric acid; 3.3- Dimethyl-N-hydroxy-2R-[4-(pyridin-4-ylsulfanyl)-piperidine- 30 l-sulfonylamino]-butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-[(l-methyl-imidazol-2-yl)methylsulfanyl]-butyramide; -22 Ι- ΟΙ 1 584 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3-methyl-3-[(lmethyl-imidazol-2-yl)methylsulfanyl]-butyric acid; N-Hydroxy-2-[(4-methylbenzenesulfonyl)amino]acetamide; 1 -[4-(4-Imidazol-1 -yl-phenoxy)-piperidine-1 -sulfony 1 ]-piper idi ne 2-carboxylic acid hydroxyamide; l-[4-(4-Imidazol-l-yl-phenylsulfanyl)-piperidine-l-sulfonyl]- piperidine-2-carboxylic acid hydroxyamide; 2(R)-[4-(4-Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-l- carboxylic acid hydroxyamide; 10 1 (R)-[4-(4-Chloro-benzoyl)-piperidine-1 -sulfony 1] -piperidine-2- carboxylic acid amide; l(R)-(4-Pyridin-2-yl-piperazine-l -sulfony l)-piperidine-2-carboxylic acid hydroxyamide; - l(R)-[4-(4-Imidazol-l-yl-phenoxy)-piperidine-l-sulfonyl]-15 piperidine-2-carboxylic acid; l(R)-[4-(4-Imidazol-l-yl-phenoxy)-piperidine-l-sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; N-Hydroxy-3,3-dimethyl-2R-[4-(morpholine-4- carbonyl)piperidine-l-sulfonylamino]butyramide; 20 N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl)- 2R-[4-(pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide; 4-(4'-Chloro-biphenyl-4-yl)-2RS-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-2R-[2-( 1,3-dioxo-1,3-dihydro-25 isoindol-2-yl)-ethyl]-4-oxo-butyric acid; N-Hydroxy-2R-[4-(4-imidazol-l-yl-phenoxy)-piperidine-l-sulfonylamino]-3,3-dimethyl-butyramide; 2R-[4-(4-Chloro-benzoyl)-piperazine-1 -sulfonylamino]-N- hydroxy-3 -methyl-3 -methylsulfanyl-butyramide; 30 N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4- ylsulfanyl)-piperidine-l-sulfonylamino]-butyramide; 4-(Pyridin-4-yloxy)benzenesulfonic acid; J -222- 011584 4-(Pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride; (3 S)-2,2-Dimethy 1-3-thiomorpholine carboxylic acid;3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2- dimethyl-1,1 -dioxo-tetrahydro-2H-1,4-thiazine-3 -carboxamide; 5 lR-3S-2,2-Dimethyl-l-oxo-4-[4-(pyridin-4-yloxy)- benzenesulfonyl]-l-thiomorpholine-3-carboxylic acid amide; . 1S-3 S-2,2-Dimethyl-l-oxo-4- [4-(pyridin-4-yloxy)- ' benzenesulfonyl]-l-thiomorpholine-3 -carboxylic acid amide; and 4-[4-(l-Hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl 10 thiomorpholine-3-carboxylic acid amide.