HRP20010055A2 - Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions - Google Patents

Description

Previous knowledge

Enzymes known as natural matrix metalloproteinases are a class of natural compounds found in most mammals. These are zinc proteases that hydrolyze collagen, proteoglycans and glycoproteins. The group includes gelatinase A and B, stromelysin-1, fibroplast collagenase, neutrophil collagenase, metalloelastase, and interstitial collagenase. These enzymes are associated with numerous diseases that occur due to the destruction of connective tissue, such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, and even tumor in metastasis. MMP expression in atherosclerosis is reviewed in White A., Bocan T. M. A., Boxer P. A., Peterson, J. T., Schrier D. There is a need to develop therapeutic properties of second-generation matrix metalloproteinase inhibitors Curr, Pharm. Design 3:45-58 (1997). To date, neither matrix metalloproteinase inhibitors have been used with ACAT inhibitors.

U.S. Patent Application 08/987167 filed December 1997 discloses MMP inhibitors and their preparation and is therefore incorporated herein by reference.

Compounds that inhibit acetyl-coenzyme A:cholesterol acyltransferase are known as ACAT inhibitors. Some ACAT inhibitors and methods of their preparation are disclosed in U.S. Pat. Patent 5,491,172 and its subset 5,633,287, which are incorporated herein by reference.

U.S. Patent 5,756,545 covers MMP inhibitors, particularly 2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid. That patent is incorporated herein by reference.

U.S. Patent 5,441,97 discloses ACAT inhibitors, particularly N-(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, 5,693,567, and 5,366,987 are incorporated herein by reference.

Summary of the invention

This invention relates to the simultaneous administration of ACAT and MMP inhibitors to reduce macrophages and smooth muscle cell components of atherosclerotic lesions in mammals, particularly humans. Lesions are directly reduced, therefore the expression of existing lesions and the development of new ones are prevented.

Some ACAT inhibitors and some MMP inhibitors are suitable for simultaneous administration.

Pharmaceutical preparations of inhibitors are also included in the invention.

Detailed description of the invention

Simultaneous administration of a bioavailable ACAT inhibitor with a matrix metalloproteinase (MMP) inhibitor can inhibit the development of atherosclerotic lesions and promote the development of a stable plaque morphology. ACAT inhibitors have been shown to reduce the accumulation of monocyte-macrophages with atherosclerotic lesions in rabbits. In addition, monocyte macrophages have been shown to secrete such metalloproteinases as MMP-7 and -9, while smooth muscle secretes MMP-1, -2, and -3. Inhibition of ACAT while directly reducing the accumulation of lipid-laden monocyte macrophages will reduce the source of MMPs. Inhibition of MMPs will also limit the development of atherosclerotic lesions by reducing smooth muscle and mirating monocytes into the developed intima by inhibiting remodeling of the extra-cellular matrix. Simultaneous administration of the agents will limit the development of lesions by preventing matrix remodeling and reducing the number of lipid-filled monocytic macrophages, which are the source of MMP-7 and -9.

The present invention is a method of treatment and/or prevention of atherosclerotic lesions comprising the simultaneous administration of one or more MMP inhibitors and one or more ACAT inhibitors.

The invention is also a method of preventing plaque rupture and promoting lesion regression by administering a combination of ACAT inhibitors and MMP inhibitors.

The method is performed by administering a compound that effectively inhibits biologically active metalloproteinases such as collagenase, stromelysin, gelatinase or elastase. A number of compounds known as matrix metalloproteinase inhibitors are useful in the practice of this invention.

The method is performed by administering a compound that inhibits acyl-coenzyme A: cholesterol acyltransferase. A number of compounds known as ACAT inhibitors are useful in the practice of this invention.

As used herein, "matrix metalloproteinase inhibitor" is used to mean any compound that inhibits the hydrolytic activity of at least five percent of at least one naturally occurring mammalian metalloproteinase. Such compounds are also referred to herein as "MMP inhibitors". A number of matrix metalloproteinase inhibitors are known and useful in the method of this invention. For example, 4-biarylbutyric acid derivatives are described in U.S. Patent Application 339,846 filed Nov. 15, 1994, which is incorporated herein by reference. Compounds are generally defined as (T)X-α-B-D-E-G. Over 400 specific compounds have been named, and each is incorporated herein and may be used in this invention. Particularly preferred compounds are sedentary:

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-(2-methylpropyl)-γ-oxo-, (S)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-(2-methylpropyl)-γ-oxo-, (R)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-β-(2-methylpropyl)-γ-oxo-, (S)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-β-(2-methylpropyl)-γ-oxo-, (R)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-bromo-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-fluoro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 2'-fluoro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 2'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 2',4'-dichloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 3'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, α-(2-methyl-propyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-bromo-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-fluoro-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-ethyl-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 2'-fluoro-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 2'-chloro-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-methoxy-α-(2-methylpropyl)-γ-oxo-;

[1,1 '-biphenyl]-4-butyric acid, 2',4'-difluoro-α-(2-methylpropyl)-γ-oxo-;

[1,1 '-biphenyl]-4-butyric acid, 4'-methyl-α-(2-methylpropyl)-γ-oxo-;

[1,1 J-biphenyl]-4-butyric acid,-α-(2-methylpropyl)-γ-oxo-4'-pentyl-;

[1,1 '-biphenyl]-4-butyric acid, 4'-chloro-α-methylene-γ-oxo-;

[1,1 '-biphenyl]-4-butyric acid, 2'-chloro-α-methylene-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-methyl-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-pentyl-;

benzenebutyric acid, 4'-methyl-α-(2-methylpropyl)-γ-oxo-;

benzenebutyric acid, 4-methyl-α-methylene-γ-oxo-;

2-butyric acid, 4-(4'-chloro[1,1'-biphenyl]-4-yl)-4-oxo-.(E)-;

2-butyric acid, 4-[4-(4-chlorophenoxy)-phenyl]-4-oxo-. (E)-;

[1,1'-biphenyl]-4-butyric acid, 4'-hydroxy-α-(2-methylpropyl)-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-β-methylene-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-hydroxy-α-(2-methylpropyl)-

2(3H)-furanone, 5-(4'-chloro[1,1'-biphenyl-4-yl)dihydro-3-(2-methylpropyl)-;

2(3H)-furanone, 5-(4'-chloro[1,1'-biphenyl-4-yl)dihydro-3-(2-methylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 3',4'-dichloro-γ-oxo-α-(3-phenylpropyl)-

[1,1'-biphenyl]-4-butyric acid, 3',5'-dichloro-γ-oxo-α-(3-phenylpropyl)-

[1,1'-biphenyl]-4-butyric acid, 4'-(acetoxy)-γ-oxo-α-(3-phenylpropyl)-

benzenepentanoic acid, α-[2-[4-(5-chloro-2-thienyl)phenyl]-2-oxoethyl]-;

2-furancarboxylic acid, 5-[4-(3-carboxy-1-oxo-6-phenylhexyl)phenyl]-;

benzenepentanoic acid, α-[2-oxo-2-[4-(3-pyridinyl)phenyl]ethyl]-;

benzenepentanoic acid, α-[2-oxo-2-[6-(pentyloxy)-3-pyridinyl]-phenyl]ethyl]-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(phenylethyl)-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-methoxy-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 3'-chloro-4'-fluoro-y-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenylJ-4-butyric acid, 4'-ethoxy-γ-oxo-α-(3-phenylpropyl)-;

benzenepentanoic acid, α-[2-oxo-2-[4-(3-thienyl)phenyl]ethyl]-;

[1,1'-biphenyl]-4-butyric acid, 2',4'-dichloro-γ-oxo-α-(3-phenylpropyl)-

[1,1'-biphenyl]-4-butyric acid, 4'-formyl-γ-oxo-α-(3-phenylpropyl)-

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(3-phenylpropyl)-3',5'-bis-(trifluoromethyl)-;

benzenepentanoic acid, α-[2-oxo-2-[4-(2-thienyl)phenyl]ethyl]-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(3-phenylpropyl)-3'-(trifluoromethyl)-;

[1,1'-biphenyl]-4-butyric acid, 2'-formyl-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4-hydroxy-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(3-phenylpropyl)-4'-propoxy;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(pentyloxy)-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(pentyloxy)-α-(3-phenylpropyl)-, (S)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(pentyloxy)-α-(3-phenylpropyl)-, (R)-;

[1,1'-biphenyl]-butyric acid, 4'-(hexyloxy)-γ-oxo-α-(3-phenylpropyl)-, (S)-;

[1,1'-biphenyl]-4-butyric acid, 4'-butoxy-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(3-phenylpropoxy)-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(1-methylethoxy)-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-butyric acid, 4'-(heptyloxy)-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(cyclohexyl-methylethoxy-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(2-methyl-propoxy)-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-butyric acid, γ-oxo-α-(3-phenylpropyl)-4'-(2-propenyloxy)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-heptyl-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-decyl-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-nitro-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-cyano-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-(2-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-butyric acid, 4'-chloro-α-[2-(3-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-(4-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-butyric acid, 4'-chloro-α-[2-(3,5-jdiemethoxyphenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-phenyl-;

[1,1'-biphenyl]-butyric acid, 4'-chloro-γ-oxo-α-(phenylmethyl)-;

[1,1'-biphenyl]-butyric acid, 4'-chloro-γ-oxo-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-[(trimethylsilyl)-methyl]-;

[1,1'-biphenyl]-4-butyric acid, 4'-bromo-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-amino-γ-oxo-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-butyric acid, γ-oxo-α-(2-phenylmethyl)-4'-[[(phenylmethoxy)-carbonyl]amino]-;

[1,1'-biphenyl]-4-butyric acid, 4'-[[(1,1-dimethylethoxy)carbonyl]amino]-γ-oxo-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(acetylamino)-γ-oxo-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-butyric acid, γ-oxo-4'-[(1-oxopentyl)amino]-carbonyl]amino]-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-[(3,3-dimethyl-1-oxobutyl)amino]-γ-oxo-α-(2-phenylmethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[2-(methoxycarbonyl)phenyl]-ethyl]-γ-oxo-;

[1,1'-biphenyl]-butyric acid, α-[2-(2-carboxyphenyl)ethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[2-(diethylamino)carbonyl]phenyl]ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[3-(diethylamino)carbonyl]-phenyl]ethyl]-γ-oxo-, (S)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[3-(diethylamino)carbonyl]-phenyl]ethyl]-γ-oxo-, (R)-;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

benzoic acid, 3-methyl-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl]-4-yl)-carbonylcyclopentyl-methyl ester, (1α,2β,5β)-;

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

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

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

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

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

cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-5-[(1,3-dihydro-4-nitro-1,3-dioxo-2H-isoindole -2-yl)methyl]-, (1α,2β,5β)-;

cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1 '-biphenyl]-4-yl)carbonyl]-5-[(1,3-dihydro-5-nitro-1,3-dioxo-2H-isoindole -2-yl)methyl]-, (1α,2β,5β)-;

2H-Benz[f]isoindole-2-butyric acid, α-[2-(4'-ethoxy[1,1'-biphenyl]-4-yl)-2-oxoethyl]-1,3-dihydro-1, 3-dioxo-;

[1,1'-biphenyl]-4-butyric acid, α-(acetylamino)-4'-chloro-γ-oxo-;

2H-Benz[f]isoindole-2-hexanoic acid, α-[2-(4'-ethoxy[1,1'-biphenyl]-4-yl)-2-oxoethyl]-1,3-dihydro-1, 3-dioxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[[3-(methoxycarbonyl)phenyl]thio]-methyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[2,6-(dimethylphenyl)thio]methyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[[4-fluoro-2-(methoxycarbonyl)-phenyl]thio]-methyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[[3-(diethylamino)carbonyl]-phenyl]thio]-methyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[[2-(diethylamino)carbonyl]-phenyl]thio]-methyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[[[3-(diethylamino)carbonyl]-phenyl]thio]-methyl]-γ-oxo-;

bicyclo[2.2.1]hept-5-ene-2-carboxylic acid 3-[[4'-(pentyloxy)[1,1'-biphenyl]-4-yl]carbonyl]-, (2-endo,3- exo)-;

1-cyclopentane-1-carboxylic acid 5-[(4'-chloro[1,1'-biphenyl]-4-yl]carbonyl]-,

cyclopentanecarboxylic acid 2-[(4'-chloro[1,1'-biphenyl]-4-yl]carbonyl]-5-[(phenylmethyl)thio]-, (1α,2β,5β)-;

cyclopentanecarboxylic acid 2-[(4'-chloro[1,1'-biphenyl]-4-yl]carbonyl]-5-[(phenylmethyl)thio]-, (1α,2β,5β)-;

1-cyclopentane-1-carboxylic acid 5-[[4'-(pentyloxy)[1,1'-biphenyl]-4-yl]carbonyl]-,

1-cyclopentane-1-carboxylic acid 5-[[4'-(hexyloxy)[1,1'-biphenyl]-4-yl]carbonyl]-,

[1,1'-biphenyl]-4-butyric acid, 4'-hydroxy-γ-oxo-α-[(phenylthio)-methyl]-;

[1,1'-biphenyl]-4-butyric acid, α-[2-[2-(butylamino)carbonyl]-phenyl]tethyl]-chloro-γ-oxo-;

[1,1'-biphenyl]-butyric acid, α-[2-(3-carboxyphenyl)ethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[3-[(diethylamino)carbonyl]-phenyl]tethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, α-[2-[3-[(butylamino)carbonyl]phenyl]ethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[4-[(diethylamino)carbonyl]-phenyl]tethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, α-[2-[4-[(butylamino)carbonyl]-phenyl]tethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, α-[2-(4-carboxyphenyl)ethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-methoxy-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-hydroxy-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-ethoxy-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(2-phenylethyl)-4'-propoxy-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-(pentyloxy)-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(hexyloxy)-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-butoxy-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(2-phenylethyl)-4'-(phenylmethoxy)-;

[1,1'-biphenyl]-4-butyric acid, α-[2-(3-iodophenyl)ethyl]-γ-oxo-4'-(pentyloxy)-;

[1,1'-biphenyl]-4-butyric acid, α-[2-(3-iodophenyl)ethyl]-γ-oxo-4'-(phenylmethoxy)-;

[1,1'-biphenyl]-4-butyric acid, α-[2-[3-[(diethylamino)carbonyl]phenyl]ethyl]-γ-oxo-4'-(pentyloxy)-;

[1,1'-biphenyl]-4-butyric acid, α-[2-[3-[(diethylamino)carbonyl]phenyl]ethyl]-γ-oxo-4'-(phenylmethoxy)-;

1,2-pyrrolidinedicarboxylic acid, [(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-, 1-(phenylmethyl) ester, (2S-trans)-;

1,2-pyrrolidinedicarboxylic acid, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-, 1-(phenylmethyl) ester, (2'Rtrans)-;

L-proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-[[(phenylmethyl)amino]-carbonyl]-,trans-;

L-proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(1-oxo-3-phenylpropyl)-, trans-;

L-proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(phenylacetyl)-, trans-;

L-proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(3,3-dimethyl-1-oxobutyl)-, trans-:

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-heptyl-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-decyl-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-nitro-γ-oxo-α-(2-phenylethene)-;

[1,1'-biphenyl]-4-butyric acid, 4'-cyano-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-(2-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-(3-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4J-chloro-α-[2-(4-iodophenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-(3,5-dimethoxyphenyl)ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-phenyl-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-(phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-γ-oxo-α-[(trimethylsilyl)methyl]-;

[1,1'-biphenyl]-4-butyric acid, 4'-bromo-γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(3-phenylpropyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-bromo-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-α-(2-phenylethyl)-4'-[[(phenylmethoxy)carbonyl]amino]-;

[1,1'-biphenyl]-4-butyric acid, 4'-[[(1,1-diethylethoxy)carbonyl]amino]-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-(acetylamino)-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, γ-oxo-4'-[(1-oxypentyl)amino]-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-[(3,3-dimethyl-1-oxobutyl)amino]-γ-oxo-α-(2-phenylethyl)-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[2-(methoxycarbonyl)phenyl]-ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, α-[2-(2-carbonylphenyl)ethyl]-4'-chloro-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[2-(dimethylamino)carbonyl]-phenyl]ethyl]-γ-oxo-;

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[3-(dimethylamino)carbonyl]-phenyl]ethyl]-γ-oxo-, (S); you

[1,1'-biphenyl]-4-butyric acid, 4'-chloro-α-[2-[3-(dimethylamino)carbonyl]-phenyl]ethyl]-γ-oxo-, (R).

Fenbufen and compounds related to fenbutene can be used. Such compounds are described in U.S. Patent No. 3,784,701 and by Child, et al., J. Pharm. Sci., 1977;66:466-476, and Arzneim-Forsch, 1080;30(4A):685-702, all of which are incorporated herein by reference.

Preferred compounds from the phenbutene series in this invention have the formula

[image]

where R is O-CCH2CH2COOH (phenbutene), COCH=CHCOOH, SO2NH2, COCH2CH(CH3)COOH,

[image]

COCH2CH2CONHOH, C(=NOH)CH2CH2COOH, and

COCH2SCH2COOH.

Numerous peptides are known that are metalloproteinase inhibitors. Typical ones are described in U.S. Patent No. 5,3000,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289, and WO 96/11209, all of which are incorporated herein by reference. Such compounds are illustrated by the formula

[image]

wherein each variable group may include hydrogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, carboxy and the like.

Preferred compounds within this group can be used in the method of this invention and include the following:

N-[2,3-bis-acetylmercaptoproanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-3-methoxycarbonylproanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-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;

N-[2-acetylmercapto-4-phtaimidobutanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-6-phtamidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2,3-bis-mercaptoproanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-3-methoxycarbonylproanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-methoxycarbonylpetanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-4-phtaimidobutanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-phtaimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-phtamidohexanoyl]-L-leucyl-L-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;

N-[2-acetylmercapto-6-methoxycarbonylhexanoyl]-L-vainyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-tryptophan N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-valinyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-leucyl-L-tryptophan N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-leucyl-L-[(3-(4-thiazolyl)alanine N-methylamide;

N-[2-acetylmercapto-5-methylamidopentanoyl O-L-leucyl-L-[(3-(2-pyridyl)alanine N-methylamide;

N-[2-acetylmercapto-5-phtaimidopentanoyl]-L-leucyl-L-gutamic acid N-methylamide;

N-[2-Acetylmercapto-5-ftamidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-2-(3-phthalimido)phenylacetyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-methoxycarbonylpentanoyl]-L-phenylalanine N-methylamide;

N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-tryptophan-N-methylamide;

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-(4-thiazolyl)alanine N-methylamide;

N-[2-mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[13-(2-pyridyl)alanine N-methylamide;

N-[2-mercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-lutamic acid N-methylamide;

N-[2-mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[N-mercaptoacetyl]-L-leucyl]-L-phenylalanine N-methylamide;

N-[acethiomercaptoacyl]-L-leucyl-L-phenylalanine N-methylamide;

(RS)-2-(acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(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;

(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 N-methylamide;

N-(acetylmercaptoacyl)-L-leucyl-L-tryptophan N-methylamide;

(RS)-2-mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-2-mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide;

(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-phenylalanine N-methylamide;

(RS)-2-mercapto-3-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide;

N-[N-(mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide;

N-[N-(mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide;

[4-(N-hydroxyamino)-2R-cyclohexylmethylsuccinyl]-L-β-cyclohexylalanine-N-2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-p-cyclohexylalanine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-β-cyclohexylalanine-N-(2-N,N-dimethylamino]ethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-β-cyclohexylalanine-N-[2-(p-sulfonamidophenyl)ethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-β-cyclohexylalanine-N-[2-(p-sulfonylphenyl)ethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-β-cyclohexylalanine-N-[2-(2-pyridyl)ethyl]amide;

[4-(N-hydroxyamino)-2R-pentylsuccinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-isoamylsuccinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-phenylbutylsuccinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl-L-β-cyclohexylalanine-N-[3-(4-morpholinyl)propyl]amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl-L-β-cyclohexylalanine-N-[β-alanine]amide;

[4-(N-hydroxyamino)-2R-isobutysuccinyl]-L-β-cyclohexylalanine amide;

[4-(N-hydroxyamino)-2R-(3-phenylpropyl)succinyl]-L-β-cyclohexylalanineamide;

[4-(N-hydroxyamino)-2R-(3-phenylpropyl)succinyl]-L-β-cyclohexylalanine amide;

[4-(N-hydroxyamino)-2R4enylethylsuccinyl]-L-leucine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-leucine-N-(2-phenylethyl)amide;

[4-(N-hydroxyamino)-2R-isobutysuccinyl]-L-tryptophan amide;

[4'(N-hydroxyamino)-2R-isobutysuccinyl]-L-valinamide;

[3-phosphono-2R,S-phenylpropyl-1-oxopropyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)-amide dimethyl ester;

[3-phosphono-2R-phenylpropyl-1-oxopropyl-L-β-cyclohexylalanine-N-(2-phenylethyl)-amide;

[3-phosphono-2S-phenylpropyl-1-oxopropyl]-L-β-cyclohexylalanine-palanine;

[3-phosphono-2R-phenylpropyl-1-oxopropyl]-L-β-cyclohexylalanine;

[3-phosphono-2R-phenylpropyl-1-oxopropyl]-L-β-cyclohexylalanine-β-alanine, methyl ester;

[3-phosphono-2R,S-(4-methylphenyl)propyl-1-oxopropyl]-L-β-cyclohexylalanine-N-[4-(3-aminopropyl)morpholine]amide, bromide salt;

[3-phosphono-2R,S-(4-methylphenyl)propyl-1-oxopropyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)-amide;

4-t-butoxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)-amide;

4-hydroxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-β-cyclohexanalanine-N-(2-phenylethyl)-amide;

4-(N-hydroxyamino)-2(R)-[3-(2-phenoxyethyl)succinyl]-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

{4-hydroxy-2(R)-[3-(4-pyridinium)propyl]succinyl}-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

{4-(N-hydroxyamino)-2(R)-[3-(4-pyridinium)propyl]succinyl}-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

{4-(N-hydroxyamino)-2(R)-[3-(N-methyl-4-pyridinium)propyl]succinyl}-L-β-cyclohexylalanine-N-(2-phenylethyl)amide;

{4-hydroxy-2(R)-[3-(4-methylphenyl)propyl]succinyl}-L-β-cyclohexylalanine-N-[(2-morpholine-sulfonylamino)ethyl]amide;

{4-(N-hydroxyamino)-2(R)-[3-(4-methylphenyl)propyl]succinyl}-L-β-cyclohexyl-alanine-N-[(2-morpholine-sulfonylamino)ethyl] amide;

{4-(N-hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-β-cyclohexyl-alanine-N-[(2-morpholine-sulfonylamino)ethyl] amide;

{4-(N-hydroxyamino)-2(R)-[3-(4-methylphenyl)propyl]succinyl}-L-β-cyclohexyl-alanine-N-[(2-dimethyl-sulfonylamino)ethyl] 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-(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)-penicylaminosulfone]-N-methylamide;

{4-(N-hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-[S-(methyl)-penicylaminosulfoxide]-N-methylamide;

{4-(N-hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-penicillamine-N-methylamide;

[4-(N-hydroxyamino)-2(R)-[3-(2-methylpropyl)succinyl]-L-[S-(methyl)penicylamino-sulfone]-N-methylamide;

N4-hydroxy-N1-(1(S)-carbomoyl-2,2-dimethylpropyl)-2R-4-(chlorophenylpropyl)-succinamide;

N4-hydroxy-N1-(1(S)-carbomoyl-2,2-dimethylpropyl)-2R-(4-methylphenylpropyl)-succinamide;

N4-hydroxy-N1-(1(S)-carbomoyl-2,2-dimethylpropyl)-2R-(4-methoxyphenylpropyl)-succinamide;

N4-hydroxy-N1-(1(S)-carbomoyl-2,2-dimethylpropyl)-2R-(4-trifluoromethylphenyl-propyl)succinamide;

N4-hydroxy-N1-(1(S)-carbomoyl-2,2-dimethylpropyl)-2R-(4-chloromethylphenylpropyl)-succinamide;

N-[N-(mercaptoacetyl)-L-leucyl]-L-phenylalanine methylamide;

N-(acetomercaptoacyl)-L-leucyl-L-phenylalanine methylamide;

(RS)-2-(acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(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;

(RS)-2-(acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-2-(acetylthio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide;

N-(acetomercaptoacyl)-L-threonyl-L-phenylalanine methylamide;

N-(acetomercaptoacyl)-L-leucyl-L-tryptophan methylamide;

(RS)-2-mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-2-mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide;

(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-phenylalanine N-methylamide;

(RS)-2-mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide;

N-[N-(mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide;

N-[N-(mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide;

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-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;

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-phenylalanine N-methylamide;

N-[2,3-bis-mercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-4-phthalimidobutanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-phthalimidohexanoyl]-L-leucyl-L-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;

N-[2-acetylmercapto-6-methoxycarbonylhexanoyl]-L-vainyl-L-phenylalanine N-methylamide;

N-[2-acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-tryptophan N-methylamide;

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-leucyl-L-tryptophan N-methylamide;

N-[2-acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-[β-(4-thiazolyl)]alanyl N-methylamide;

N-[2-acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-[β-(2-pyridyl)]alanyl N-methylamide;

N-[2-acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-glutamic acid N-methylamide;

N-[2-acetylmercapto-5-phthalimidopentanoH]-L-leucH-L-phenylalanine-N-methylamide;

N-[2-acetylmercapto-2-(3-phthalimido)phenylacetyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-tryptophan N-methylamide;

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-[β-(4-thiazolyl)]alanyl N-methylamide;

N-[2-mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[β-(2-pyridyl)]alanyl N-methylamide;

N-[2-mercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-gutamic acid N-methylamide;

N-[2-mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methyl-butanamide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-cyclohexyl-acetamide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-4-methylpentane-amide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanamide hydrochloride;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methyl-butanamide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-2-cyclohexyl-acetamide;

N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)-(4-picolyl)amino]-2-(2-tetrahydro-furanyl)acetamide;

N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutane-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyoxyphenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiophenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-thiobenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-isopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thiacetate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thioisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(2-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(3-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(4-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thio-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methoxybenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthiophenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-(methylthio-2-thienyl)succinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylacetate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylisopentanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthioacetate-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthioisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthio-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(3-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiophenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-thienyl)succinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylacetate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthioacetate-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthioisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthio-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthiobenzylsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-(methylthio-2-thienyl)fsuccinyl]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylacetate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-tert-butanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthioacetate-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthioisopropanoate]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthio-tert-butanoate]-N2-S-perazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(2-pyridyl)]N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(3-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N2-S-piperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S-4'(S/R)-benzylpiperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S-45'(S/R)-benzylpiperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S-6'(S/R)-benzylpiperazine acid N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-S-[5',6']benzo-piperazine acid N-methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-heptylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-octylicine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethoxyphenyl]-α-(S)-hexylglycine-(S)-N 2-piperazine acid methylamide;

N-[1(R)-carboxy-ethoxyphenyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-ethoxyphenyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxy-4-(β-toluenesulfonyl)butyl]-α-(S)-phenethylglycyl-(S)-N2-piperazine acid methylamide;

N-[1(R)-carboxyethyl]-α-[2-(4-phenylphenoxy)ethyl]-glycyl-(S)-N2-piperazine acid methylamide;

2-[2(R)-[2-[1,1'-biphenyl)yl]ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[1,1'-biphenyl)yl]ethyl]-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[1,1'-biphenyl)yl]propyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-(4-propylphenyl)ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-(4-butylphenyl)ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-(4-t-butylphenyl)ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-n-octyl-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methylamino-carbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl hexahydropyridazine;

2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methyl-aminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4S-carboxy-1-oxo-butyl]-3(S)-methylaminocarbonyl- hexahydropyridazine;

2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4S-carboxy-1-oxo-butyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4-butyl-4S-carboxy-1-oxo-butyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4-methyl-4S-carboxy-1-oxo-butyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4-4-(3-phenylpropyl)-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-butyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-methyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-4-(3-phenylpropyl)-4S-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;

HS(CH2)2-(S-D-Leu)-Phe-NHMe;

HS(S)CHMeCH2-(S-D-Leu)-Phe-NHMe;

HS(S)CH(PhtNBu)CH2-(S-D-Leu)-Phe-NHMe;

HS(S)CH(PhtNEt)CH2-(S-D-Leu)-Phe-NHMe;

HS(1,2-cyclopentyl)(S-D-Leu)-Phe-NHMe;

MeS(NH)2-(CH2-DL-Leu)-Trp-NHMn;

n-Bu-S(NH)2-(CH2-DL-Leu)-Trp-NHMn;

n-Bu-S(NH)2-(CH2-DL-TyrOCH3)-Trp-NHMn;

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 6

HONH-CO-CH2CH(CH2CH(CH3)2)-CO-Nal-Pro-NH2 HONH-CO-CH(CH3CH(CH2)-CH(CH3)2)-CO-Nal-Ala-NH2

[image]

where Pa is 3-pyridylalanine

[image]

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[2-morpholin-4-ylethyl)amino] carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[methyl-amino]carbonyl]butyl]amino] - butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1H-imidazol-2-ylmethyl)amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1H-tetrazol-5-ylmethyl)amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[(2-(phenyl)-ethyl] amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(pyridin-3-ylmethyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2-methyl-2H-tetrazo-5 -ylmethyl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-hydroxy-2-methyl-pyrimidine -5-ylmethyl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[2-pyridin-3-yl)ethio ]amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1H-tetrazol-5-ylethio]amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(5-amino-4H-[1, 2,4]-triazol-3-ylmethyl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[1-(6-oxo-1, 6-dihydro-pyridazin-3-yl)ethyl]amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(phenyl)-amino]carbonyl]butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(benzyl)-amino]carbonyl]butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(pyridin-4-ylmethyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[2-(1H-imidazol-4- yl)ethyl]amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(pyridin-2-ylmethyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-sulfamoyl-phenyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-sulfamoyl-phenyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-dimethylamino-benzyl)amino]carbonyl ]butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[(S)-phenyl-ethyl]amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1,1-dioxo-tetrahydro-thiophene -3-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-sulfamoyl-benzyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[1R-phenyl-ethyl]amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-fluorobenzyl)amino]carbonyl]butyl ]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(furan-2-yl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1-methyl-1H-tetrazol-5 -ylmethyl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1,2,3,4-tetrahydro -naphthalen-1-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2,4-difluoro-benzyl)amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-nitrobenzyl)amino]carbonyl]butyl ]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-nitrobenzyl)amino]carbonyl]butyl ]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-methanesulfonylamino-benzyl)amino]carbonyl ] butyl]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-methanesulfonylamino-benzyl)amino]carbonyl ] butyl]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3,4-difluoro-benzyl)amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-trifluoro-benzyl)amino]carbonyl ]butyl]amino]butyric acid;

4-[2S-[1R-carboxy-3-(1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-yl)-propylamino-4-methyl-pentanoylamino-methyl)-benzoic acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2-hydroxy-1,1-bis -hydroxymethyl-ethyl)amino]carbonyl]butyl]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3,5-difluoro-benzyl)amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[benzylmethyl-amino]carbonyl]butyl]amino] - butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2-dimethylaminoethyl)methylamino]carbonyl]butyl ] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1-azabicyclo[2.2.2]oct -3(R)-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1-azabicyclo[2.2.2]oct -3(S)-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3R-4-(S)-5 -(R)-6-tetrahydroxy-tetrahydra-pyran-2R-ylmethyl)amino]carbonyl]-butyl]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(N,N'-dimethyl-hydrazino) carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(methylmethoxy)amino]carbonyl]butyl]amino ]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(dimethyl)-amino]carbonyl]butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2-oxo-tetrahydro-thiophene-3R -yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(2-oxo-tetrahydro-thiophene-3S -yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3R-acetylamino-4S-5-( S)-dihydroxy-6-(R)-hydroxymethyl-tetrahydro-pyran-2-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[benzyl(2-hydroxyethyl)amino]carbonyl] butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[3,4-dihydro-1H-isoquinoin-2 -carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[4-methypiperazine-1-carbonyl]butyl]amino ]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[1-oxo-[1,4]thiazinan- 4-carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[morpholine-4-carbonyl]butyl]amino]- butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[4-(2,3-dihydroxy-propyl- piperazine-1-carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[3,4,5,6-tetrahydro-H -[2,3]bipyridine-1-carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1-methyl-8-oxo-1 ,7-azacyclotridec-9-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[methyl-(1-methyl-piperidin-4 -yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(4-hydroxy-1,1-dioxo -tetrahydro-thiophen-3-yl)amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-(4-ethoxycarbonylmethyl-piperazine-1-carbonyl)butyl ]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(1,1-diosco-tetrahydro-thiophene -3-yl)methyl-amino]carbonyl]butyl]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[2R-(pyridin-3-yl)-pyrrolidinecarbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[2S-(pyridin-3-yl)-pyrrolidinecarbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[3-oxo-2R-phenyl-piperazine-1 -carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[3-oxo-2S-phenyl-piperazine-1 -carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[(pyridine-3-carbonyl-hydrazino)carbonyl] butyl] amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(benzenesulfonyl)amino]carbonyl]butyl ]amino]-butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(3-amino-benzyl)amino]carbonyl ]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[4-(trifluoromethanesulfonylamino)benzyl] amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[2-hydroxy-(R)-bicyclo [4.3.0]non-3,6-(1)-diene]amino]carbonyl]butyl]amino]butyric acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[[2-hydroxy-(S)-bicyclo [4.3.0]nona-3,6-(l)-diene]

amino]carbonyl]butyl]amino] acid;

4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[[(N-methyl-pyrrolidine)methyl-amino ]carbonyl]butyl]amino]butyric acid;

4-(1,3dihydro-1,3dioxo-2H-benz[f]isoindol-2-yl)-2R-[[3-methyl-1S-[N(-ethoxy-carbonylmethyl-piperazine)-1-carbonyl]butyl ] amino]-butyric acid;

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-propoxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-phenyl-1,3-dioxo-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(Benznamino)-carbonyl-3-methylbutylamino]-4-(5-methanesulfonylamino-1,3-dioxo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-benzenesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid

2R-[1S-(benzylamino)-carbonyl-3-methylbutylamino]-4-(5-hydroxy-1,3-dioxo-1,3-dihydro-rzophndol-2-yl)-masphaic acid

2R-[[3-methyl-1S-[[(pyridin-3-ylmethyl)amino]carbonyl]butyl]amino]-4-(1,3,5,7-tetraoxo-3,5,6-tetrahydro-1H -pyrrolo[3,4-f]isoindol-2-yl)-butyric acid

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

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

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

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

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

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;

MeNHCONOH-CH2CH(iBu)-CO-L-Aia(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;

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;

NHOHCOCH2CH(iBu)-CO-L-TrpNHMe;

HONHCONHCH2CH(iBu)-CONHCH(R4)COOH, or

ROOCCH2CH(iBu)-CONHCH(R4)COOH, or

N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2'-naphthyl)-alanyl-L-alanine, 2.(amino)ethylamide;

N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethylamide;

4S-[3-hydroxyaminocarbonyl-2(R)-(2-methylpropyl)propanoyl]amino-1,2,3,4,5-tetrahydro-3H-2-benzazepin-3-one;

[4-(N-hydroxyamino-(2R)-isobutyl-3-methylsuccinyl]-L-phenyllycine-N-methylamide;

4S-[2(R)-[1(R)-hydroxycarbamoyl-2-morpholineethyl]-4-methylvaleryl]amino-1,2,3,4,5-tetrahydro-3H-2-benzazepin-3-one;

(1R,4S)-4-[(2R)-hydroxycarbamoylmethyl-4-methylvaleryl]amino-3-oxo-1,2,3,4,5-tetrahydro-3H-2-benzazepine-1-carboxylic acid;

3-[2-(N-methylcarbamoyl)ethylsulfonyl]-5-methylhexanohydroxamic acid; N-[(2-thenoylmercapto-3-methyl)-butanoyl] homocysteinethiolactone;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-isoeucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)-glycine-(L)-serine-O-benzyl ether, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)hycine-(L)-tryptophan, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)hycine-α-(S)-(2-phenylethyl)hycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)hycine-(L)-valine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-serine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-asparagine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide hydrochloride;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)-glycine-(L)-glutamic acid, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride;

N-[1(R)-carboxy-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N -phenylamide;

N-[1(R)-carboxy-5-(1,-oxo-isoindolin-2-yl)pentyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N- phenylamide hydrochloride;

N-[1(R)-carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-α-(S)-(2-phenyl-ethyl)hycine-(L)-larinine, N-phenylamide ;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(4-hydroxyphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(2'-thienyl)ethyl)glycine-(S)-leucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(4-ethylphenyl)ethyl)glycine-(S)-leucine, N-phenylamide;

N-[1(R)-carboxy-5-(1,-oxo-isoindolin-2-yl)pentyl]-α-(S)-(2-(4-propylphenyl)ethyl)hycine-(L)-leucine , N-phenylamide

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-leucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-(2-cyclohexyl-ethyl)glycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-(cyclohexyl)glycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-(cyclohexylmethyl)glycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-β-(naphthylalanine, N-phenylamide);

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-α-(naphthylalanine, N-phenylamide);

N-[1 (R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)-glycine-[(L)-gutamic acid, α,β-bis-N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-cyclohexylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-(4-hydroxyphenyl-ethyl)glycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide;

N-[1 (R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid, Nδ-benzylamide, Nα-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)hycine-(L)-ornithine, N-phenylamide;

N-[(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)-glycine-(L)-arginine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-(3-phenylpropyl)glycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-α-(S)-n-octylglycine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-carboxyphenyl)-amide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-trifluoromethylphenyl)-amide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl)-amide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-arginine, N-phenylamide;

N-[1(R)-carboxy-ethyl]-α-(S)-(2-(3,4-dimethylphenyl-ethyl)glycine-(L)-leucine, N-phenylamide;

(2-(((4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl)-hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide;

(2-(((4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)butyl)-hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide;

(2-(((4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)butyl)(2-methyl-1-(1-oxopropyoxy)-propoxy)phosphinyl)methyl)-4 -phenylbutanoyl)-L-leucine, N-phenylamide;

(2-((hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-phenylamide;

[[hydroxy[1(R)-[N-[(N-acetyl-L-propyl-L-alanyl)-amino]-ethyl]-phosphinyl]-methylH phenyl-butanoyl-L-leucyl, N-phenylamide;

[hydroxy-[N-(N-(benzoyl)-L-propyl)aminobutyl]phosphinyl]methyl]-4-phenyl-butanoyl-L-leucyl, N-phenylamide;

[hydroxy-[2-methylpropyloxycarbonyl-aminobutyl]phosphinyl]methyl]-4-phenyl-butanoyl-L-leucyl, N-phenylamide;

[hydroxy-[1-methylethylaminocarbonyl-aminobutyl]phosphinyl]methyl]-4-phenyl-butanoyl-leucyl, N-phenylamide;

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)-leucine, N-phenylalanilamide;

N-(2-thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine, N-phenylamide;

N-(2-thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine, N-benzylamide;

N-(2-thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine-alanine;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(L-leucine, N-(phenyl-amide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(2(S)-t-butyl)glycine, N-(phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(2(S)-t-butyl)glycine, N-(4-pyridylamide)amide ;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(L-arginine, N-methylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(2(S)-tert-butyl)glycine, N-phenylamide) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(2(S)-(4-thiazolylmethyl)glycine, N-phenylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(2(S)-(3-pyridylmethyl)glycine, N-phenylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyselin 1-(L-leucine, N-(4-pyridyl)amide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(2(S)-(2-pyridylmethyl)glycine, N-phenylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(L-arginine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(L-phenylalanine, N-4-pyridylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(1-(4-(N-(2-oxoisoindolinyl))butyl)-1,5-pentanedioxyline 1- (L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(4-fluorophenyl)ethyl)-4-methyl-1,5-pentanedioxyselin 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(phenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(4-Methoxyphenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(4-methyleneyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyselin 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(4-Hydroxy-n-butyl)phenyl)ethyl)-4-methyl-pentanedioxyline 1-(S-leucine, phenylamide)amide;

2(R),4S-(2-(4-(3-Hydroxy-n-propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioxyselin 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-phenylethyl)-4-methyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)-amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(L-leucine, N-ethylamide)-amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(L-leucine, N-isopropyl-amide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-(2(S)-tert-butyl-glycine, N-4-pyridylamide)amide;

2(R)-(3-(4-(1-n-propyl)phenyl)ethyl)-1,3-pentanedioxyline 1-(L-leucine, N-phenyl-amide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-hexyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-butyl-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(3-methylbenzyl)-1,5-pentanedioxyline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-(2-benzimidazolyl)butyl)-1,5-pentanedi-acid 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-(2-benzthiazolyl)butyl)-1,5-pentanedioxyline 1-(L-leucine, N- phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-(2-benzoxazolyl)butyl)-1,5-pentane-diciline 1-(L-leucine, N-phenylamide)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxyline 1-(L-leucine, N-phenylamide)amide 9-piperidinamide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxyline 1-(L-leucine, N-methylmid)amide 9-phenylamide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxyline 1-(L-leucine, N-methylamide)amide 9-tert-butylamide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxyline 1-(L-leucine, N-methylmid)amide 9-benzylamide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxyline 1-(L-leucine, N-methylimide)amide 9-morphoinimide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide 9-(1(R )-phenylethyl)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide 9-(1(S )-phenylethyl)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide 9-(N-methyl -N-phenyl)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide 9-(N'- methylpiperazine)amide trifluoroacetate;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide 9-(3-pyridyl) amide;

2(R)-(2-(4-(1-propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioxylin 1-(L-leucine, N-methylmid)amide;

2(R)-(2-(4-(1-propyl)phenyl)ethyl)-1,5-pentanedioxyline 1-((R)-(S-p-methoxy-benzyl)penicillamine, N-phenylamide)amide;

2(R)-(2-(4-(1-propyl)phenyl)ethyl)-1,5-pentanedioxyselin-1-((R)-(S-p-methoxy-benzyl)penicillamine sulfone, N-phenylamide)amide;

2-(2-(4-(1-propyl)phenyl)ethyl)-4-(1-(4-(2-phthalimido))butyl)-1,5-pentanedioxyline 1-(L-eucine, N-methylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-benzoylamino-1-butyl)-1,5-pentane-diciline 1-(L-leucine, N -methylmid)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-pivaloyl-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-phenylsulfonylamino-1-butyl)-1,5-pentane-diciline 1-(L-leucine, N -methylmid)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-N'-uredio-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylmid)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-phenyloxycarbonylamino-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-N'-benzyloxycarbonylamino-L-propyl-amino-1-butyl)-1,5-pentanedioxyline 1 -(L-leucine, N-methylmid)amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-cyclopentylamino-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylamide ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-carboxylbenzoylamino-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylimide) ) amide;

2(R)-(2-(4-(1-n-propyl)phenyl)ethyl)-4-(4-cyano-1-butyl)-1,5-pentanedioxyline 1-(L-leucine, N-methylimide) ) amide;

N-[1(R)-carboxyethyl]-α-(S)-(9-amino-n-nonyl)]glycine-(L)-leucine, N-phenylamide;

N-[1(R)-carboxyethyl]-α-(S)-(n-octyl)]glycine-(L)-leucine, N-phenylamide;

N-[1(R)-carboxyethyl]-α-(S)-(n-octyl)]glycine-(L)-arginine, N-phenylamide;

N-[1(R)-carboxyethyl]-α-(S)-(9-amino-n-nonyl)]glycine-(L)-arginine, N-phenylamide;

N-[1(R)-carboxyethyl]-α-(S)-(n-decyl)]glycine-(L)-leucine, N-phenylamide;

1-(2-(4-propylphenyl)ethyl)cyclopentane-1,3-dicarboxylic acid 1-(L-leucine, N-phenylamide)amide;

1-(2-(4-propylphenyl)ethyl)cyclohexane-1,3-dicarboxylic acid 1-(L-leucine, N-phenylamide)amide;

N-[1(R)-carboxyethyl]-α-(S)-2-(4-fluorobiphenyl)-glycyl-(S)-2-(tert-butyl)glycine, N-phenylamide;

3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydro-carbostriryl;

3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-3,4-dihydrocarbostriryl;

3S-[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostriryl;

3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostriryl;

1-carboxymethyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostriryl;

3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethoxymethyl-3,4-dihydrocarbostriryl;

3S-[4-(N-Hydroxyamino)-2R-heptylsuccinyl]amino-1-methoxy-3,4-dihydro-carbostriryl;

7-chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostriryl;

3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-3,4-dihydrocarbostriryl;

3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostriryl;

3R-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostriryl;

2R-N-hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-oxo-propyl)amino]-3-methyl-butylramide;

2R-2-[(2-benzylcarbamoylethyl)(4-methoxy-benzenesulfonyl)-amino]-N-hydroxy-3 methylbutyramide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl)(2-[(pyridin-3-ylmethyl)-carbamoyl]ethyl)amino)-3-methyl-butylramide;

2R-N-hydroxy-2-([4-methoxybenzenesulfonyl]-[2-(methylpyridin-3-ylmethyl-carbamoyl]ethyl]amino)-3-methyl-butylramide;

4-(3-[1R-1-hydroxycarbamoyl-2-methylpropyl)-(4-methoxybenzenesulfonyl)amino]propionyl)piperazine-1-carboxylic acid, tert-butyl ester;

2R-N-hydroxy-2-[(4-methoxybenzenesulfonyl) (3-oxo-3-piperazin-1-ylpropyl)amino]-3-methylbutylramide hydrochloride;

2R-2-[(4-benzylcarbamoylethyl) (3-methoxy-benzenesulfonyl)amino]-N-hydroxy-3-methylbutylramide;

2R-N-hydroxy-2-[(4-methoxybenzenesulfonyl] [(2-morpholin-4-ylethylcarbamoyl)methyl]amino]-3-methylbutylramide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl) ([(pyridyl-3-ylmethyl)carbamoyl]methyl)amino)-3-methylbutylramide;

2R-3,3,3-trifluoro-N-hydroxy-2-[(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]propionamide;

2R-N-hydroxy-2-((4-phenoxybenzenesulfonyl)[methylpyridine-4H'1methylcarbamoyl)-ether]amino]-3-methylbutylramide;

4-[4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-1-methylpiperidine-4-carboxylic acid hydroxyamide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl)[3-(4-methylpiperazin-1-yl)-3-oxopropyl]amino]-3-methylbutylramide;

2R-2-[(carboxyethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;

2-[(carboxyethyl)(3,4-dimethoxybenzenesulfonyl)amino]-N-hydroxyacetamide;

2R-2-[(carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;

2R,3R-3,N-dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperidin-1-ylpropyl)amino]butyramide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl)(3-methylpyridin-3-ylmethyl-carbamoyl)propyl]amino]-3-methylbutyramide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl)[2-(methylcarboxymethylcarbamoyl)ethyl]amino)-3-methylbutyramide;

2R-N-hydroxy-2-((4-methoxybenzenesulfonyl)[(1-methylpyridin-4-ylcarbamoyl)-methyl]amino])-3-methylbutyramide;

2R-N-cyclohexyl-N-hydroxy-2-((4-methoxybenzenesulfonyl)[3-(4-methyl-piperazin-1-yl)-3-oxopropyl]amino]-acetamide;

2R-N-hydroxy-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-ylmethyl-(3-oxo-propyl)amino]-4-(morpholin-4-yl)butyramide;

[4-(N-benzyloxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl ester

[4-(N-benzyloxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminolaurolactam;

Na-[4-(N-benzyloxyamino)-2(R)-isobutylsuccinyl]-Ne-(N-benzyloxycarbonyl-glycyl)-L-lysyl-L-alanine ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine isopentylams

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-vaylglycine ethylamide;

[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl[-L-leuucylglycine ethylamide;

Na-[4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-N-tert-butoxycarbonyl-L-lysylglycine ethylamide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-tyrosylglycine ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-tyrosylglycine ethylamide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycinisopentyl ester;

[4-(N-hydroxyamino)-2(RS)-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 ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylsarcosine ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-proyne ethyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-alanine isopropyl ester;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-2-oxopropylamide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-2-methoxyethylamide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-2,2-dimethoxyethyl-amide;

Na-[4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-N-glycyl-L-lysylnmethylamide;

Na-[4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-N-(4-carboxybenzyl)-L-lysyl-L-alanine ethyl ester;

Na-[4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-(4-carboxybenzyl)-L-lysyl-L-alanine;

[4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminooctahydro-2H-azonin-2-one;

[4-(N-hydroxyamino)-2(S)-methyl-2(R)-isobutylsuccinyl]-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-(methylcarbamoyl)butyl]carbamoyl]pentyl](1,8-naphthalenedicarboximidomethyl)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-[1-(benzyloxo)carbonyl]-L-prolyl]-L-leucyl]amino]-methyl]hydroxyphosphinyl]-methyl]- 4-methylvaeryl]-L-leucyl]-L-alanine;

[[1,4-dihydro-2,4-dioxo-3(2H)-quinazolyl]-methyl][[(R or S)-4-methyl-2-[[(R or S)-2-oxo- 3-azacyclodecyl]carbamoyl]pentyl]phystic acid;

N2-[(R)-hydroxycarbamoylmethyl]-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

N2-[2(R or S)-[[[(5-bromo-2,3-dihydro-6-hydroxy)-1,3-dioxo-1H-benz[d,e]isoquinol-2-yl)methyl ]-[(hydroxy)phosphinyl]methyl]-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

N2-[2(R or S)-[[(R)-(amino)[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz[d,e]isoquinol -2-yl)methyl]-[(hydroxy)phosphinyl]methyl]-4-methylvaleryl]-N3,1-dimethyl-L-valinamide hydrobromide;

N2-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

N2-[2(R)-[1(R or S)-(hydrocarbamoyl)-4-(methoxycarbonyl)butyl]]-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

N2-[2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenyl-butyl-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

N2-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-succinimidoethyl]-4-methylvaleryl]-N1,3-dimethyl-L-valinamide;

4-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]morpholine;

4-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-tetrahydro-1,4-thiazine;

1-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinol;

1-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)ethyl]- 4-methylvaleryl]piperidine;

4-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3-methyl-2,5-dioxo-1-imidazoinidine)-ethyl]-4-methylvaleryl]tetrahydro-1,4 '-thiazine;

hexahydro-2-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-phthalimidoethyl]-4-methyl-valeryl]-N-methyl-3(S)-piperazinecarboxamide;

1-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4 -piperidinol;

[4-(N-hydroxyamino)-2(R or S)-heptylsuccinyl]-L-leucyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(R or S)-nonylsuccinyl]-L-leucyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(R or S)-heptyl-3(S)-methylsuccinyl]-L-leucyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(R)-heptyl-3(RylS)-(phthalimidomethyl)succinyl]-L-leucyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(RS)-nonylsuccinyl]-L-tert-butylglycinemethylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanine methylamide;

[4-(N-Hydroxyamino)-2(R)-heptyl-3(RylS)phthalimidomethyl)succinyl]-L-tert-butylglycine methylamide;

[4-(N-Hydroxyamino)-2(R)-heptyl-3(RylS)-(3-phenylpropyl)-succinyl]-L-tert-butylglycine methylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucine methylamide;

[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucinepentylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-alanyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-(N-phtaoyl)lysyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(RS)-undecylsuccini1]-L-leucyl-L-leucineethylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanyl-L-leucineethylamide;

[4-(N-Hydroxyamino)-2(RS)-heptylsuccini1]-L-nonaine-L-leucineethylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-phenylalanine tert-butylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-tert-butylglycine methylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-neopentylglycine methylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-homophenylalanyl-L-leucine ethylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-cyclohexylalanine methylamide;

[4-(N-hydroxyamino)-2(RS)-isooctylsuccinyl]-L-phenylalanine methylamide;

[4-(N-hydroxyamino)-2(RS)-heptylsuccinyl]-L-neopentylglycine methylamide;

[4-(N-hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-β,β-dimethylphenylalanine methylamide;

[4-(N-hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-threo-β-methylphenylalanine methylamide;

[4-(N-hydroxyamino)-2(R)-heptylsuccinyl]-DL-erythro-p-methylphenylalanine methylamide;

[4-(N-hydroxyamino)-2(R)-heptyl3(R or S)-[(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl]succinyl]-L-leucyl-L-leucine ethylamide ;

N2-[3-cyclobutyl-2(R or S)-(hydrocarbamoyl)-methyl]propionyl]-N1,3-dimethyl-L-valinamide;

N2-[3-cyclopropyl-2(R or S)-(hydrocarbamoyl)-methyl]propionyl]-N1,3-dimethyl-L-valinamide;

N2-[3-cyclopentyl-2(R or S)-(hydrocarbamoyl)-methyl]propionyl]-N1,3-dimethyl-L-valinamide;

N2-[3-cyclopropyl-2(R)-[1 (R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- N1,3-dimethyl-L-valinamide;

N2-[3-cyclopropyl-2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenylbutyl)]propionyl]-N1,3-dimethyl-L-valinamide;

N2-[3-Cyclobutyl2(R)-[1(R or S)-(Hydrocarbamoyl)-4-phenylbutyl]propionyl]-N1,3-Imethyl-L-valinamide;

N2-[3-cycloprentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenylbutyl)]propionyl]-N1,3-dimethyl-L-valinamide;

1-[3-cyclopropyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine

1-[3-cyclopropyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 4-piperidinol;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 4-piperidinol;

1-[3-cyclopentyl-2(R)-[1 (R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine

1-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 4-piperidinol;

3-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 3-azabicyclo[3.2.2]nonane;

3-[3-cyclopropyl-2(R)-[1 (R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 3-azabicyclo[3.2.2]nonane;

3-[3-cyclopentyl-2(R)-[1 (R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 3-azabicyclo[3.2.2]nonane;

1-[3-cyclohexyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine ;

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro -1,4-thiazine;

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro -1,4-thiazine S-S-dioxide;

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro -1,4-thiazine;

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 5,5-dimethyl-N-propyl-[4R-thiazolidinecarboxamide;

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine ;

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- N,5,5-trimethyl-[4R-thiazolidinecarboxamide;

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 4-phenylpiperazine;

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine ;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]pyrrolidine ;

8-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 1,4-dioxa-8-azaspiro[4,5]decane;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- 4-methoxypiperidine;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl] octahydroazocine ;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-ioxazolidinyl)ethyl]propionyl]piperidine;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepine ;

1-[3-cyclobutyl-2(R)-[(hexahydro-1,3-dioxo-pyrazolo[1,2a][1,2,4]-triazol-2-yl)-1(R or S)- (hydroxycarbamoyl)ethyl]propionyl]piperidine;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydrocarbamoyl)-2-(phthalimidoethyl]propionyl]-piperidine;

2-[2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenylbutyl]nonanoyl]hexahydro-N-methyl-3(S)-pyridazinecarboxamide;

N-cyclohexyl-hexahydro-2-[2(R)-[1(RS)-(hydrocarbamoyl)-4-phenylbutyl]-nonanoyl]hexahydro-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R)-[1(RS)-(hydrocarbamoyl)-4-phenylbutyl]nonanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)- pyridazinecarboxamide;

1-[2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenylbutyl]-nonanoyl]piperidine;

N2-[2(R)-[1(RS)-hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazol-idinyl)ethyl]nonanoyl]-N1-methyl-L -prolinamide;

1-[2(R)-[1(R or S)-hydrocarbamoyl)2-(3,4,4-trimethyl-2,5-dioxo-1-imidazol-idinyl)ethyl]nonanoyl]piperidine;

hexahydro-2-[2(R)-[1(R or S)-(hydrocarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]nonanoyl]-N- methyl-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)-3-phenylpropyl]undecanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)-3-phenylpropyl]undecanoyl]-N-methoxy-N-methyl-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)-3-phenylpropyl]undecanoyl]-N-(1,2,2,6,6-pentamethyl-4-piperidinyl-3( S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)ethyl]undecanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)3-phenylpropyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)ethyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;

1-[2(R or S)-[1(S)-(hydrocarbamoyl)ethyl]undecanoyl]piperidine;

1-[2(R or S)-[1(S)-(hydrocarbamoyl)-3-phenylpropyl]undecanoyl]piperidine;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)3-phenylpropyl]undecanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S) -pyridazinecarboxamide;

hexahydro-2-[2(R or S)-[1(S)-(hydrocarbamoyl)ethyl]undecanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide ;

1-[2(R or S)-[1(S)-(hydrocarbamoyl)-4-phenylbutyl]undecanoyl]piperidine;

4-[2(R or S)-[1(S)-(hydrocarbamoyl)-4-phenylbutyl]undecanoyl]morpholine;

1-(Benzyloxycarbonyl)-hexahydro-2-[2(R)-[1(R or S)-(hydrocarbamoyl)-4-phenylbutyl]nonanoyl]-N-(a(S)-methiobenzyl-3(S)- pyridazinecarboxamide;

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;

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]-6(RS)-6-(hydroxy)heptanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(hydroxy)-heptanoyl]-amino-3,3 -dimethylbutyric acid N-methylamide;

(2S)-N-2-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)-hexane-oyl]amino-3, 3-dimethylbutyric acid N-methylamide;

N-[(2'R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(4'-oxobutylamino)-hexanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-(propyl-amino) hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

N-[(2R)-2-[(1'S)-1'-(methyl)-2'-(hydroxyamino)-2l-(oxo)ethyl]-6-(phenyl-methoxy)hexanoyl]-L-phenylalanine N -methylamide;

N-[(2R)-2-[(1'S)-1'-(methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-(propyl-amino) hexanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2-[(2'R)-[(1"R)-1"-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-2" -(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl)amino-3,3-dimethylbutyric 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'-[(1''S)-1''-(methyl)-2"-(hydroxyamino)-2-"-(oxo)ethyl] -6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-2-phenylethylamide;

(2S)-N-2-[(2'R)-2' –[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6' -(oxo)-6-'propylamino)hexanoyl]amino-3,3-dimethylbutyric acid N-2-phenylethylamide;

(2S)-N-[(2'R)-2'-[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-( oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutyric acid N-2-(4'-sulfamoyl)-phenylethylamide;

(2S)-N-2-[(2'R)-2''-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3-cyclohexyl-propionic 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-methoxy)-phenoxy] hexanoyl]amino-3,3-dimethylbutyric 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-dimethylbutyric acid N-2-(4'-sulfamoyl)phenylethylamide;

(2S)-N-2'-[(2'R)-2'-[2''-(hydroxyamino)-2''-(oxo)ethyl]-6'-[(1-oxo)butyl-amino ]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)phenylethylamide;

(2S)-N-2-[(2'R)-2'-[(1''S)-1''-(methyl)-2''-(hydroxyamino)-2''-(oxo)( phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2-[(2'R)-2'-[(1"S)-1''-(2-methylpropyl)-2-''-hydroxyamino-2''-(oxo)ethyl -6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid 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;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2''-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]amino-3, 3-dimethylbutyric acid N-2-phenylethylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]amino-3,3 -dimethylbutyric acid N-2-phenylethylamide;

N-[(2R)-2-[2'-(hydroxyamino)-21-(oxo)ethyl]-5-(phenylmethoxy)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;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(2-phenethylamino)-6'-( oxo)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-methylphenoxy)-hexanoyl]amino- 3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-chlorophenoxy)-hexanoyl]amino- 3,3-Dimethylrnaic acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(3methylphenoxy)-hexanoyl]amino-3, 3-dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

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;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(propylamino)-(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-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(hydroxy)-hexanoyl]-amino-3,3 -dimethylbutyric acid

N-methylamide;

(2S)-N-2-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]amino-3,3- dimethylbutyric acid N-methylamide;

N-[(2'R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(4'-oxobutylamino)-hexanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl] amino-3,3-dimethylbutyric acid N-methylamide;

N-[(2R)-2-[(1'S)-1'-(methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(phenylmethoxy)-hexanoyl]-L-phenylalanine N -methylamide;

N-[(2R)-2-[(1'S)-1'-(methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-(propylamino)hexanoyl] -L-phenylalanine N-methylamide;

(2S)-N-2-[(2'R)-[(1"R)-1"-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-2" -(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric 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'-[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6- (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2-[(2'R)-2'-[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6' -(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutyric acid N-2-phenylethylamide;

(2S)-N-2-[(2'R)-2'-[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6' -(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutyric 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;

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-methoxy)-phenoxy]-hexanoyl ]amino-3,3-dimethylbutyric 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-dimethylbutyric acid N-2-(4'-sulfamoyl)phenylethylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(1-oxo)-butylamino]hexanoyl] amino-3,3-dimethylbutyric acid N-2-(4'-sulfamoyl)phenylethylamide;

(2S)-N-2-[(2'R)-2'-[(1"S)-1"-(methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]-6- (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2-[(2'R)-2'-[(1"S)-1"-(2-methylpropyl)-2"-(hydroxyamino)-2"-(oxo)ethyl]- 6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutyric acid 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;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]amino-3,3 -dimethylbutyric acid N-phenylethylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)-hexanoyl]amino-3,3 -dimethylbutyric acid N-2-(4'-sulfamoyl)phenylethylamide;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-5-(phenimethoxy)pentanoyl]-L-phenylalanine N-methylamide;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-7-(phenimethoxy)heptanoyl]-L-phenylalanine N-methylamide;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(phenyloxy)hexanoyl]-L-phenylalanine N-methylamide;

N-[(2R)-2-[2'-(hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]-L-phenylalanine N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(2-phenylethylamino)-6'-( oxo)hexanoyl]amino-3,3-dimethylbutyric acid N-2-(4'-sulfamoyl)-phenylethylamide;

(2S)-N-2'-[(2'R)-21-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-methylphenoxy)-hexanoyl]amino-3 ,3-Dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-chlorophenoxy)-hexanoyl]amino- 3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-[2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-[(3-methylphenoxy)-hexanoyl]amino- 3,3-dimethylbutyric acid N-methylamide;

(2S)-N-2'-[(2'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl]amino-3,3-dimethylbutyric acid N-methylamide;

(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraene-10-carbamoyl)hexane acid;

(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]-nonadeca-12(19), 13(18), 14,16-tetraen- 10-ylcarbamoyl)hexamide;

(3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.0]-eicosa-13(20), 14(19), 15,17-tetraene- 11-ylcarbamoyl)hexamide;

(3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexane acid;

(3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]octadeca-11 (18), 12(17), 13,15-tetraen-9-ylcarbamoyl)hexamide ;

(10S)-[4-methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)pentyl] -(quinoline-2-thiomethyl)phosphinic acid;

(3R,10S)-N-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.0]nonadeca-12(19), 13(18), 14,16- tetraen-10-ylcarbamoyl)hexamide;

N-(4-methyl-2-carboxymethylpentanoyl)-L-leucine-N'-(4-methoxycarbonyl-enyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl-L-leucine-N'-(4-methoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl-L-leucine-N'-(4-carboxy-phenyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl-L-tryptophan-N'-(4-carboxyphenyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl-L-cyclohexylglycine-N'-(4-methoxycarbonyl-enyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl-L-Meucin-N'-(4-methoxycarbonyl-enyl)carboxamide;

(3R,10S)-6-biphenyl-4-i)-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraene- 10-ylcarbamoyl)hexanoic acid;

(3R,10S)-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)-5-thiophene- 2-yl)pentanoic acid;

(3R,10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)- 5-thiophen-2-yl)propionic acid;

(3R,10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18), 14,16-tetraen-10-ylcarbamoyl)- 5-thiophen-2-yl)butyric acid;

(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca-12(19), 13(18),14,16-tetraen-10-ylcarbamoyl)- 5-thiophen-2-yl)hexanoic acid;

(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]-nonadeca-12(19),13(18),14,16-tetraen- (10-ylcarbamoyl)-5-thiophen-2-yl)hexanamide;

(3R,11S)-N-hydroxy-5-methyl-3-(9-oxo-1,9-diazatricyclo[11.6.1.0]eicosa-13(20),14(19),15,17-tetraene-11 -ylcarbamoyl)hexanamide;

(3R,9S)-N-methyl-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12(17), 13,15-tetraen- 9-ylcarbamoyl)hexanoic acid;

(3R,9S)-N-methyl-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12(17), 13,15-tetraen- 9-ylcarbamoyl)hexanamide;

(10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0]-nonadeca-12(19), 13(18), 14,16-tetraene-10- ylcarbamoyl)pentanamide;

(10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0]-nonadeca-12(19), 13(18), 14,16-tetraene-10- ylcarbamoyl)pentanamide;

(3R,10S)-2-(methanesulfonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.0]-nonadeca-12(19), 13(18), 14,16 -tetraen-10-ylcarbamoyl)-hexanoic acid;

(3R,10S)-2-(3-ethylurediomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.0]nonadeca-12(19), 13(18), 14, 16-tetraen-10-ylcarbamoyl)hexanoic acid;

(3R,9S)-N-hydroxy-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18),12(17),13, 15-tetraen-9-ylcarbamoyl)hexanamide or its (2S,3R,9S) stereoisomer;

(3R,10S)-N-hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.0]nonadeca-12(19),13(18),14, 16-tetraen-10-ylcarbamoyl)hexanamide;

(3R,9S)-5-methyl-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-cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl )succinamic acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-5- phenoxy-pentanoic acid;

(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraene -9-ylcarbamoyl)pentanoic acid;

(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18),12,14,16-tetraene -9-ylcarbamoyl) pentanoic acid ethyl ester;

(3R,9S)-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid ethyl ester;

(3R,9S)-6-(4-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraene -9-ylcarbamoyl)hexanoic acid

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6- pyridin-4-yl-hexanoic acid;

(3H,9S)-6-[4-(3-hydroxy-propoxyphenyl]-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-1,7-diazatricyclo[9.6.1.0]octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid;

(3fl,9S)-6-[4-(2-hydroxyethoxy)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-1,7-diazatricyclo[9.6.1.0]-octadeca-11(18), 12,14,16-tetraen-9-ylcarbamoyl)-6- [4-(2-pyrrolidin-1-yloxyphenylhexanoic acid;

(3R,9S)-6-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraene -9-ylcarbamoyl)hexanoic acid;

(3R,9S)-6-[4-(2-methoxyethoxy)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-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18),12,14,16-tetraen-9-ylcarbamoyl)-5- phenyl-pentanoic acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)-6- phenyl-hexanoic acid;

(3R,9S)-6-(3-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraene -9-ylcarbamoyl)hexanoic acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)-6- [4-(3-piperidin-1-ylpropoxy)phenyl]hexanoic acid;

((3R,9S)-6-[4-(3-dimethylamino-propoxy)phenyl]-3-(8-oxo-4-oxo-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18) , 12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;

(3R,9S)-6-[4-(2-dimethylaminoethoxy)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)-6-(4-cyanophenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraene -9-ylcarbamoyl)hexanoic acid;

(3R,9S)-6-naphthalen-2-yl-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraene -9-ylcarbamoyl)hexanoic acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-octadeca-11 (18),12,14,16-tetraen-9-ylcarbamoyl)-6- (4-pyrro-1-yl)hexanoic acid;

(3R9S)-6-(4-hydroxy-3-methylphenyl)-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)-6-(4-benzyloxy-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)-6-[4-(4-aminobutoxyphenyl)]-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)-5-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo-[9.6.1.0]-octadeca-11 (18), 12,14,16- tetraen-9-ylcarbamoyl)pentanoic acid;

(3R,9S)-6-(4-aminophenyl)-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-1,7-diazatricyclo-[9.6.1.0]-octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl)-6 -[4-(pyridine-4-imethoxy)phenyl]hexanoic acid;

(3R,9S)-6-(4-acetylamino-phenyl)-3-(8-oxo-4-oxa-17-diazatricyclo-[9.6.1.0]-octadeca-11 (18), 12,14,16- tetraen-9-ylcarbamoyl)hexanoic acid;

Nα-[[3-(N-hydroxycarbamoyl)-4-methylthio-2-propoxymethyl]butylyl]-N,O-dimethyltyrosine amide;

Nα-[[3-(N-hydroxycarbamoyl)-4-isopropylthio-2-propoxymethyl]butylyl]-N,O-dimethyltyrosine amide;

Nα-[[3-(N-hydroxycarbamoyl)-2-propylthio]butylyl]-N,O-dimethyltyrosinamide;

N-[N-(1-phosphono-3-phenylpropyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide;

N-[N-(1-phosphono-3-(4-bromo-1,8-naphthalene-dicarboxyimido)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide;

N-[N-(1-phosphono-3-(benzyloxycarbonylamino)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide;

N-[N-(1-phosphono-3-(2-hydroxyphenyl)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide;

N-[N-(1-phosphono-3-(methylmercapto)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methylamide;

N-[N-(1-phosphono-3-(methylsulfinyl)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methyl;

N-[N-(1-phosphono-3-(methylsulfonyl)propyl)-(S)-leucyl]-(S)-phenylalanine-N-methyl

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-(S)-leucyl]-(S)-tryptophan-N-methylamide;

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-(S)-leucyl]-(S)-lysine-N-methylamide;

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-(S)-leucyl]-(-)-amino-azacycloreodecan-2-one;

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-S)-leucyl]-(S)-lysine-N-(aminoethyl)amide;

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-(S)-leucyl]-(S)-lysine-N-(ethylpyrrolidine)amide;

N-[N-(1-phosphono-3-(1,8-naphthalenedicarboxyimido)propyl)-(S)-leucyl]-(ethyl-N-methylpiperazine)amide;

N-[N-(1-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S)-leucyl]-(S)-phenylalanine-N -methylamide; you

N-[N-(1-phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S)-leucyl]-(S)-lysine-N -methylamide;

As indicated above, numerous inhibitors of matrix metalloproteinases are known. A large number of inhibitors are derivatives with the basic structure of hydroxamic acid and/or carboxylic acid. Typical such compounds are described in the following references, all of which are incorporated herein by reference, as all such compounds can be used according to the method of this invention.

US 4,599,361 (Searle)

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)

US 5,453,438 (British Biotechnology)

US 5,239,078 (Glycomed)

US 5,183,900 (Glycomed)

US 5,270,326 (Glycomed)

WO 92/17460 (Smith-Kine Beecham)

US 5,300,501 (Celltech)

US 5,304,549 (Roche)

US 5,256,657 (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 (Vamanouchi)

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 (Shinogi)

Particularly preferred groups of compounds for use in this method are described in WO 95/35275 and WO 95/35276, both of which are incorporated herein by reference. Typical compounds used from these groups are:

N-hydroxy-2-[[(2-(4-methoxy-phenoxy)-ethyl-1-(toluene-4-sulfonyl)-amino]-acetamide:

N-hydroxy-2-[(4-phenoxy-ethyl)-toluene-4-sulfonyl)amino]-acetamide;

N-hydroxy-2-[(4-methoxy-benzenefonyl)-nonyl-amino]-acetamide;

2-[decyl-(toluene-4-sulfonyl)-amino]-N-hydroxy-acetamide;

2-benzyl-(octane-1-sulfonyl-9)-amino]-N-hydroxy-acetamide;

N-hydroxy-2-[(2-methoxy-benzyl)-(octane-1-sulfonyl)-amino]-acetamide;

2-[(2-ethoxy-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;

N-hydroxy-2-[(naphthalen-2-yl-methyl-(octane-1-sulfonyl)-amino]-acetamide;

2-[(4-chloro-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide; and corresponding salts, solvates and hydrates.

The next group of matrix metalloproteinase inhibitors are aryl sulfonamides of the formula:

[image]

wherein Ar is carbocyclic or heterocyclic aryl and R, R1 and R2 include hydrogen, alkyl, aryl, heteroaryl, amino, substituted or disubstituted amino. These compounds are included in European Patent no. 0606046, and here they are made with cutato. Specific compounds used in this method include:

N-hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)amino]acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](cyclohexylmethyl)amino]acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](cyclohexyl)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;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](4-methylbenzyl)amino]acetamide;

4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[dimethylaminoacetyl]-piperidine hydrochloride;

4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[3-picolyl-piperidinedihydrochloride;

4-[N-hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[carbomethoxymethyl]-piperidine hydrochloride;

4-[N-hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-piperidine trifluoroacetate

4-[N-hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[t-butoxycarbonyl-piperidine;

4-[N-hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[methylsulfonyl]-piperidine;

N-hydroxycarbamoyl-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[4-picolyl]-piperidine hydrochloride;

N-hydroxycarbamoyl-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[morpholino-carbonyl-piperidine hydrochloride; you

N-(t-butoxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]acetamide;

The following compounds are prepared similarly to Example 7:

N-hydroxy-2-[[4-methoxybenzenesulphoethyl]acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-picoyl)-amino]-2-[2-(4-morpholino)-ethylacetamide dihydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](3-picol)-amino]-2-[2-(4-morpholine ethylacetamide dihydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-methyl-thiazol-4-methyl)-amino]-2-[2-(4-morpholino)ethyl]acetamide dihydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[2-(4-thio-morpholino)ethyl]acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[2-(4-methyl-thioazol-4-ylmethyl]acetamide dihydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[(6-chloro-piperonyl]acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[(1-pyrazolyl)-methylacetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-2-[3-picolyl]-acetamide;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamide hydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)-amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamide hydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamide hydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-picolyl)-amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamide hydrochloride;

N-hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)-amino](-methylthiazol-4-ylmethyl)amino-2-[(1-methyl-4-imidazolyl)methyl] cetamide hydrochloride;

The next group of small peptides, which are inhibitors of matrix metalloproteinases, is described in US Patent no. 5,270,326, 5,530,161, 5,525,629, and 5,304,604 (herein incorporated by reference). Hydroxamic acid compounds are defined by formulas

[image]

wherein R1, R2, R3, and R4 can be hydrogen or alkyl, and X is OR5 or NHR5, wherein R5 includes hydrogen, alkyl, and aryl, A includes alkyl, and n is from 0 to 2. Typical compounds used in this method are as follows:

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-N-methyl-L-tryptophan methylamide;

N-[2-isobutyl-3-(N-hydroxycarbonylamino)-propanoyl]-3-(2-naphthyl)-alanine methylamide;

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophan-2-hydroxyethylamide;

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophanamylamide;

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophan piperidinamide;

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophandodecylamide;

N-[2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophan(S)-methylbenzylamide;

N-[L-2-isobutyl-3-(N'-hydroxycarbonylamino)-propanoyl]-L-tryptophan(6-phenyl-methoxycarbonyl-amino-hexyl-1)amide;

2S-hydroxy-3R-[1S-(3-methoxy-2,2-dimethyl-propylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-6-(4-chloro)-phenyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-octane-hydroxamic acid;

2S-hydroxy-3R-[1S-(pyridin-2-ylmethylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(pyridin-3-ylmethylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5 methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(pyridin-4-ylmethylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-4-methoxy-butanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-4-benzyloxy-butanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-4-benzylthio-butanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-buten-3-ylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(tert-butylcarbamoyl)-2,-dimethyl-propylcarbamoyl]-5-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(N,N-dimethyl-carbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(3-hydroxy-2,2-dimethyl-propylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanehydroxamic acid;

2S-hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-butylcarbamoyl]-5-methyl-hexanehydroxamic acid;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-hydroxyethyl)-amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-proline;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-hydroxyethyl)-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-D-prolinol;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-L-prolinol;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(5-N-methyl-pentylcarboxamide)amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-ethylthioethyl)-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(methoxyethyl)-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccini1]-L-phenylalanine-N-(2-N-acetylethyl)-amide

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)-propyl)amide;

[4-(N-hydroxyamino)-2RH'isobutylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)-propyl)amide sodium salt;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-acetoxy-ethyl)amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)-propyl)amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylaniline-N-methyl-N-(2-hydroxyethyl)amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-N-(2-hydroxyethyl)amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-D-prolinol;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-N-(3-(2-pyrrolidone)-propyl)amide sodium salt;

[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 n'eovasol;

N2-[4-(N-hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-N6-tert-butoxycarbonyl-L-lysine-N1-methylamide;

N2-[4-(N-hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-N6-tert-butoxycarbonyl-N6-(4-hydroxyphenylthiomethyl)-L-lysine-N1-methylamide;

N2-[4-(N-hydroxyamino)-3S-(2-thienylthiomethyl)-2R-isobutylsuccini1]-N6-tert-butoxycarbonyl-L-lysine-N1-methylamide;

N2-[4-(N-hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-O-tert-butyl-L-threonine-N1-methylamide;

N2-[4-(N-hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-L-utamine-N1,N5-dimethylamide;

N2-[4-(N-hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-isobutylsuccinyl]-N6-acetyl-L-lysine-N1-methylamide;

3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl)-5-methyl-2S-2-propenyl-hexanehydroxamic acid;

3R-(1S-methoxycarbonyl-2-thienyl-2-yl-ethylcarbamoyl)-5-methyl-2S-2-propenyl-hexanehydroxamic acid;

3R-(3-methyl-1S-methoxycarbonyl-butylcarbamoyl)-5-methyl-2S-2-propenyl-hexanehydroxamic acid;

3R-(1S-methoxycarbonyl-2-oxadiazo-5-yl-ethylcarbamoyl)-5-methyl-2S-2-propenyl-hexanehydroxamic acid;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxylic acid)phenylalanine-N-(2-methoxyethyl)-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxyl-N-methylamide)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxyl-β-alanine)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxylglycine)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxyl-N-benzylamide)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-cyano)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-acetamido)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxamide)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)succinyl]-L-(4-N-acetylamino)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)succinyl]-L-(4-N-methylsuccinylamide)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)succinyl]-L-(4-N-methylsuccinylamide)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)succinyl]-L-(4-N-(4-(4-oxobutyric acid)aminophenylalanine-N-methylamide);

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)succinyl]-L-(4-N-methylsucciniamido)phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)succinyl]-L-(4-N-(4-(4-oxobutyric acid)aminophenylalanine-N-methylamide);

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)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-(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-oxymethyl-carboxyglycyl methyl ester)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-(4-oxymethyl-carboxyglycine)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylnitrile)-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-3-(1-(2-methoxycarbonyl)-ethyl)-4-methoxyphenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-3-(hydroxymethyl)-4-methoxy-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-3-methyl-4-methoxyphenylalanine-N-methylamide;

2-[benzyl-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;

N-hydroxy-2-[(2-methoxybenzyl)-(octane-1-sulfonyl)-amino]-acetamide;

2-[(2-ethoxy-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;

N-hydroxy-2-[(2-naphthalen-2-yl-methyl)-(octan-1-sulfonyl)-amino]-acetamide;

2-[(4-chloro-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;

N2-[3S-hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-leucine-N1-methylamide;

N2-[3S-hydroxy-4-(N-hydroxyamino)-2RH'isobutylsuccinyl]-5-methyl-L-leucine-N1-methylamide;

N2-[3S-hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N1-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(phenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;

2S-(4-methoxyphenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(3-chlorophenylsulfanylmethyl)-3R-(2-phenn-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(phenylsulfanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(3-methylphenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(thien-2-ylsulfanylmethyl)-3R-(2-(4-carboxymethoxyphenyl)-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(thien-2-ylsulfanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxy7enylsulfanylmethyl)-3R-(2-phenyl-1S-(pyrid-3-ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(thien-2-ylsulfanylmethyl)-3R-(2-naphth-2-yl-1S-(methylcarbamoyl-ethylcarbam methyl-hexanehydroxamic acid);

2S-(4-hydroxyphenylsulfanylmethyl)-3R-(2R-hydroxy-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxyphenylsulfanylmethyl)-3R-(5-acetamido-1S-methylcarbamoyl-pentylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxyphenylsulfanylmethyl)-3R-(3-[1,1-dimethylethoxycarbonyl]-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(thien-2-ylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(2-[4-acetamido-phenyl]-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-phthalimido-butyl)-3R-(3-methyl-1S-ethoxycarbonylmethylcarbamoyl-butylcarbamoyl)-5-methyl-hexanehydroxamic acid;

3R-(2-[4-methoxy-phenyl]-1S-methylcarbamoyl-ethylcarbamoyl)-2S,5-dimethyl-hexanehydroxamic acid;

3R-(2-phenyl-1S-[2-oxo-pyrrolid-1-yl][-propylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanehydroxamic acid;

3R-(2-[4-methoxy-phenyl]-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexane-hydroxamic acid;

3R-(2-phenyl-1S-[pyrid-3-ylmethylcarbamoyl]-ethylcarbamoyl)-5-methyl-hexane-hydroxamic acid;

3R-(2,2-dimethyl-1S-methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexane-hydroxamic acid;

isobutylmalonyl-L-alanine furfurylamide hydroxamate;

2-isobutyl-3-carbonyl-3'-(4-acetylaniline)propionic acid;

N-benzyloxycarbonyl-α-phosphonoicyl-L-alaninefurfurylamide;

[4-(N-hydroxyamino)-2RH'isobutyl-3S-(phenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-methoxyphenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)succinyl]-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)succinyl]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(3-chlorophenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(3-methylphenylthiomethyl)succinyl]-L-phenyl-alanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-(N-acetyl)-aminophenylthiomethyl)-succinol]-L-phenylalanine-N-methylamide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-phenylsufinylmethylsuccinyl]-L-phenylalanine-N-methylamide;

3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-2S-phenylsulfanylmethyl-hexanehydroxamic acid;

3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-2S-(thien-2-ylsulfanylmethyl)-hexanehydroxamic acid;

2S-(4-methoxy-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-amino-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(ethylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propyl-cabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(acetylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propyl-cabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(benzylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propyl-cabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(tert-butylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propyl-cabamoyl)-5-methyl-hexanehydroxamic acid;

2S-thiomethyl-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxy-phenylsulfanylmethyl)-3R-(2-tert-butoxycarbonyl-1S-methyl-carbamoyl-ethylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxy-phenylsulfinylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

2S-(4-hydroxy-phenylsulfonylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-propylcabamoyl)-5-methyl-hexanehydroxamic acid;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[1-(2-aminoethyl)-pyrrolidineamide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[1-(3-aminopropyl)-2(RS)-methylpiperidin]amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[2-(2-aminoethyl)-1-methylpyrrole]amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-aminomethyl-pyridine)amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-aminomethyl-pyridine)amide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-(4-aminomethyl-pyridine)amide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-(1-(3-amino-propyl)-imidazole)amide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-(2-aminomethyl-benzimidazol)amide;

[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)-morpholinoamide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-[2-(2-aminoethyl)-pyridine]amide;

[4-(N-hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-[4-(2-amino-propyl)-pyridine]amide;

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-aminomethyl-pyridine)amide hydrochloride; you

[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[4-(2-aminoethyl)-morpholine]amide hydrochloride.

In a preferred embodiment, tricyclic derivatives of butyric acid are used in this invention, which are inhibitors of matrix metalloproteinases. The preferred group of tricyclic derivatives of butyric acid is defined by the formula:

[image]

where

[image]

X is O,

NOR6, where R6 is hydrogen,

-(CH2)n-aryl where n is zero or an integer from 1 to 5 alkyl, or

-(CH 2 ) n -cycloalkyl wherein n is as defined above, or N-N-R 6 , and R 6 and R 6a are the same or different as defined above for R 6 |

R6a

R and Ra are the same or different are hydrogen,

-(CH2)n aryl, where n is as defined above,

-(CH2)n heteroaryl, where n is as defined above,

-(CH2)p-R7-(CH2)q-aryl, where R7 is O or S, p and q are zero or an integer from 1 to 5, and the sum of p+q is equal to the integer 5, cycloalkyl,

-(CH2)p-R7-(CH2)q-heteroaryl, wherein p, q and R7 are as defined above, alkyl,

-(CH2)n-cycloalkyl, where n is as defined above,

-(CH2)rNH2, where r is an integer from 1 to 9;

a is zero or v is an integer from 1 to 3;

R5 is OH,

OR6, wherein R6 is as defined above,

N-R6, and R6 and R6a, are the same or different as defined above for R6, or

|

R6a

NH-OR6, wherein R6 is as defined above;

R3 and R4 are the same or different are hydrogen,

alkyl,

NO2,

halogen,

OR6, wherein R6 is as defined above,

CN,

CO2R6, wherein R6 is as defined above,

SO3R6, wherein R6 is as defined above,

CHO,

ON

||

C-R where R is as defined above,

ON

||

C-N-R6 wherein R6 and R6a are the same or different as R6 above, or

|

R6a

-(CH2)n-N-R6 wherein R6 and R6a are the same or different as R6 above;

|

R6a

W, W1, Z and Z1 are the same or different are CR3, where R3 is as defined above, or

N with the fact that only one of W and W1 is N and/or only one of Z and Z1 is N, and

Y is -N- where R is as defined above,

|

R

-ON-,

-S-(O)m where m is zero or an integer from 1 to 2,

-CH2-,

-C-,

|

ON

-C- wherein R6 is as defined above,

|

N-OR6

-CH- wherein R6 is as defined above,

|

OR6

-C- wherein R6 and R6a are the same or different as defined above for R6,

|

N-N-R6

|

R69

-C-N- wherein R 6 is as defined above,

|| |

About the R6

-N-C- wherein R 6 is as defined above,

| ||

R6 Oh

-C-O-

||

ON

-O-C-,

||

ON

-CH2-O-,

-O-CH2-,

-CH2-S-(O)m where m is as defined above,

-S-(O)m-CH2- where m is as defined above,

-CH2-N- wherein R6 is as defined above,

|

R6

-N-CH2-wherein R6 is as defined above,

|

R6

-CH=N-, or

-N=CH-;

with the limitation that when X is O and R5 is not NH-OR6, at least one of R or Ra is not hydrogen, and the corresponding isomers or pharmaceutically acceptable salts.

Typical compounds from this category include:

4-dibenzofuran-2-ii-4-hydroxyimino-masiac acid;

2-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-4-methyl-pentanoic acid;

2-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-phenyl-pentanoic acid;

4-dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid;

5-(4-Corphenyl)-2-(2-dibenzofuran-2-yl2-hydroxyiminoethyl)-pentanoic acid;

2-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-(4-fluorophenyl)-pentanoic acid;

2-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-(4-methoxyphenyl)-pentanoic acid;

2-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-p-toylpentanoic acid;

3-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-methyl-hexanoic acid;

3-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-6-phenyl-hexanoic acid;

3-(2-dibenzofuran-2-yl-2-hydroxyiminoethyl)-5-phenyl-pentanoic acid;

6-(4-chlorophenyl)-3-(2-dibenzofuran-2-yl-2-hydroxyiminomethyl)-hexanoic acid;

3-(dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-chlorophenyl)-hexanoic acid;

3-(dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxyphenyl)-hexanoic acid; you

3-(dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoic acid; and their respective isomers or pharmaceutically acceptable salts.

Tricyclic butyric acids that have an a-amino substituent are defined by the form:

[image]

where

X is O, NOR9, S, OH, SH or

[image]

R7 and R7a are independently hydrogen,

C1-C20 alkyl or C1-C20 substituted alkyl,

(CH2)0-6 aryl,

(CH2)0-6 heteroaryl,

(CH2)0-6 cycloalkyl,

R1 R2 are independently hydrogen,

C1-C20 alkyl or C1-C20 substituted alkyl,

halogen,

NO2,

CN,

CHO,

COR6,

COOR6,

SO3R6,

OR6,

CONR4R5,

(CH2)0-6aryl,

(CH2)0-6 heteroaryl, or

(CH2)0-6 cycloalkyl,

R6 is hydrogen,

C1-C20 alkyl or C1-C20 substituted alkyl,

aryl is phenyl or substituted phenyl,

R3 is hydroxy,

O-C1-C20 alkyl or O-C1-C20 substituted alkyl,

O-(CH2)1-3 aryl, or

NHOR6,

R4 and R5 are independent

C1-C20 alkyl or C1-C20 substituted alkyl,

C2-C20 alkenyl or C2-C20 substituted alkenyl,

(CH2)0-6 aryl,

(CH2)0-6 heteroaryl,

(CH2)0-6-(O or S)-heteroaryl,

or one of R4 or R5 is hydrogen and the other is:

COR8,

CSR8,

CONR8R9,

COOR8

COSR8

[image]

S(O)1 or 2-C1-C20 alkyl or substituted alkyl,

S(O)1 or 2-aryl

S(O)1 or 2-heteroaryl or

S(O)1 or 2-cycloalkyl;

Y is

[image]

-O-, S(O)0,1 or 2,

-CH2-,

[image]

[image]

-CH2-O-,

-O-CH2-,

-CH2S(O)0,1 or 2

-S(O)0,1 or 2-CH2-,

[image]

-CH=N, or

-N=CH-,

R8 and R9 are independently hydrogen,

C1-C20 alkyl or C1-C20 substituted alkyl,

C1-C20 alkenyl or C1-C20 substituted alkenyl,

(CH2)0-6-(O or S)0-1 aryl,

(CH2)0-6-(O or S)0-1 heteroaryl, or

(CH2)0-6-(O or S)0-1-cycloalkyl,

W, W1, Z and Z1 are independent of CR1 or N,

and pharmaceutically acceptable salts, isomers, stereomers and solvates.

The specific compounds used in this method are:

(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 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-dibenzofuran-2-yl-2-[3-(2,6-diisopropyl-phenyl)-uredio]-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-(dodecanoylamino)-butyric acid;

(S)-4-dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid;

(S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric 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-dibenzofuran-2-yl-[3-(2,6-diisopropyl-phenyl)-uredio]-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; you

(S)-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid.

Tricyclic sulfonamides that are inhibitors of amtric metalloproteinases include:

[image]

where M is a natural (L) alpha amino acid having the structure,

[image]

X is O, S, S(O)n, CH2, CO or NH,

R is the side chain of a natural alpha amino acid,

R 1 is C 1 -C 5 oxy, hydroxy or -NHOR 5 ;

R2 and R4 are independently hydrogen, C1-C5 alkyl, NO2, halogen, -OR5, -CN, -CO2R5, -SO3R5, -CHO, -COR5, -CONR5R6, -(CH2)nNR5R6, -CF3 or -NHCOR5,

each of R 5 and R 6 is independently hydrogen or C 1 -C 5 alkyl, etc

n is 0 to 2,

and corresponding pharmaceutically acceptable salts, esters, amides and prodrugs.

Specific compounds from this class that are used include:

(L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-phenyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;

(dibenzofuran-2-sulfonylamino)-acetic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-succinic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxamide;

(L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-phenyl-pentanoic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;

(dibenzofuran-2-sulfonylamino)-acetic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-succinic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid;

(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxamide;

Additional cyclic sulfonamides defined by the formula:

[image]

where Q is a synthetic amino acid,

Specific examples of 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, and

2(S)-3-[-(dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid.

The next general class of matrix metalloproteinase inhibitors useful for the treatment and prevention of heart failure and ventricular dilatation are biphenylbutyric acid derivatives that include compounds of the formula:

[image]

in which R and R1 are the same or different are hydrogen, acyl,

halogen, nitro, cyano, trifluoromethyl,

-OR6 where R6 is hydrogen, alkyl, aryl,

arylalkyl, heteroaryl, or cycloalkyl;

N-R6, and R6 and R6a, are the same or different as defined above for R6,

|

R6a

ON

||

-O-C-R6 wherein R6 is as defined above,

ON

||

-NH-C-R6 wherein R6 is as defined above,

ON

||

-S-C-R6 wherein R6 is as defined above,

-SR6 where R6 is as defined above,

ON

||

-C-R6 wherein R6 is as defined above,

-CH2-OR6 where R6 is as defined above,

-CH2-N-R6 where R6 and R6a are the same or different as defined for R6,

|

R6a

ON

||

-C-N-R6 where R6 and R6a are the same or different as defined for R6,

|

R6a

ON

||

-S-R6 where R6 is as defined above,

||

ON

cycloalkyl, or

heteroaryl, with the restriction that R and R 1 are not both hydrogen.

R 2 is -OR 6 where R 6 is as defined above, or

N-R6, and R6 and R6a, are the same or different as defined above for R6,

|

R6a,

R3, R3a, R4 are the same or different are hydrogen, fluoro, alkyl,

-(CH2)n-aryl where n is an integer from 1 to 6,

-(CH2)n-heteroaryl where n is as defined above,

-(CH2)n-cycloalkyl where n is as defined above,

-(CH2)p-X-(CH2)q-aryl, where X is O, or S, SO, SO2 or NH, and p and q are zero or an integer from 1 to 6, and the sum of p+q is not greater than six,

-(CH2)p-X-(CH2)q-heteroaryl, wherein X, p and q are as defined above, or

-(CH2)P-R7 where R7 is:

N-phthalimido,

N-2,3-naphthylimido,

-OR6 where R6 is as defined above,

N-R6, and R6 and R6a, are the same or different as defined for R6,

|

R6a.

-SR6 where R6 is as defined above,

ON

||

-S-R6 where R6 is as defined above,

||

ON

ON

||

-O-C-R6 where R6 is as defined above,

ON

||

N-C-R6, and R6 and R6a, are the same or different as defined for R6,

|

R6a;

ON

||

-S-C-R6 where R6 is as defined above,

ON

||

-C-R6 where R6 is as defined above,

ON

||

-C-OR6 where R6 is as defined above, or

ON

||

-C-N-R6 and R6 and R6a are the same or different as defined for R6,

|

R6a;

n is as defined above;

R 5 is OH or SH; with the restriction that R3, R3a, R4 and R4a are hydrogen or at least one of R3, R3a, R4 or R4a is fluorine,

and corresponding isomers or pharmaceutically acceptable salts.

Typical compounds of this class that are routinely used for the treatment of atherosclerosis include:

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;

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-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-phenylethyl)-butyric acid;

(±)-4-(4'-chloro-biphenyl-4-yl)-4-hydroxylamino-2-fluoro-2-(3-phthalimidopropyl)-butyric acid;

(±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxylamino-2-fluoro-2-(phenylthiomethyl)-butyric acid;

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-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-ethyl]-4 -hydroxyimino-butyric acid;

(±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxylamino-2-fluoro-2-(1H-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;

(±)-4-(4'-chloro-biphenyl-4H1)-2-fluoro-2-[2-(1,3-dioxo-1,3-dihydrobenzo[F]-isoindol-2-yl)ethyl] -4-hydroxyimino-butyric acid;

(±)-2-[2-(4'-chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2 -fluorohexanoic acid;

(±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxylamino-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)-2,2-dimethyl-2-fluoro-4-hydroxyimino-butyric acid;

(±)-4-(4'-chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; you

(±)-4-(4'-chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric acid;

Compounds 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;

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-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-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;

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-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-ethyl]-4 -hydroxyimino-butyric acid;

(±)-4-(4'-chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(1H-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;

(±)-4-(4'-chloro-biphenyl-4-yl)-2-fluoro-2-[2-(1,3-dioxo-1,3-dihydrobenzo[F]-isoindol-2-yl) ethyl]-4-hydroxyimino-butyric acid;

(±)-2-[2-(4'-chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2 -fluorohexanoic acid;

(±)-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)-2,2-dimethyl-2-fluoro-4-hydroxyimino-butyric acid;

(±)-4-(4'-chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; you

(±)-4-(4'-chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric acid;

Biphenyl sulfonamides are particularly good in this method. Such compounds include those having the formula:

[image]

where

R1 is C1-C6 alkyl, halogen, nitro, NR4R5, cyano, OR4 or COOR4;

R2 is C1-C6 alkyl, which may be substituted by phenyl, substituted by phenyl,

NH

|

NR4R5, OR6, carboxy, H2N-C-NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl and

substituted phenyl; or COOR4;

R 3 is OH, O C 1 -C 6 alkyl or NHOH;

R4 is hydrogen, O C1-C6 alkyl or C1-C6 alkynyl;

R 5 is hydrogen or O C 1 -C 6 alkyl; you

R 6 is hydrogen, O C 1 -C 6 alkyl, C 1 -C 6 alkyanyl, phenyl or substituted phenyl.

Specific compounds which can be used include a compound of the above formula wherein R 4 is in the 4' position.

The next class of matrix metalloproteinase inhibitors useful in this method are heterocyclic substituted derivatives of phenylbutyric acid, for example those defined by the formula:

[image]

Ar is selected from phenyl,

phenyl substituted with

alkyl,

NO2,

halogen,

OR5, where R5 is hydrogen or alkyl,

CN,

CO2R5, where R5 is as defined above,

SO3R5 where R5 is as defined above,

CHO,

COR5 where R5 is as defined above,

CONHR5 where R5 is as defined above,

NHCOR5 where R5 is as defined above,

2-naphthyl or heteroaryl;

R1 is selected from: hydrogen, methyl, ethyl, NO2, halogen,

OR5 where R5 is as defined above,

CN,

CO2R5 where R5 is as defined above,

SO 3 R 5 where R 5 is as defined above, CHO or

COR5 where R5 is as defined above; R2 and R3 are the same or different: hydrogen, alkyl

-(CH2)V aryl where 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 where X is O or S, and p and q can each be zero or an integer from 1 to 5, and the sum of p+q is not greater than the integer 5

-(CH2)p-X-(CH2)q heteroaryl wherein X, p and q are as defined above,

-(CH2)tNR6R6a, aryl wherein t is an integer from 1 to 9 and R6 and R6a are the same or different as defined above for R5

-(CH2)VSR5 wherein v and R5 are as defined above,

-(CH2)vCONR6R6a and R6 and R6a are the same or different as defined above

for R 5 and v is as defined above, R 3 is further -(CH 2 ) r R 7 aryl wherein R 7 is 1 to 7 and R 7 is 1,3-dihydro-1,3-dioxo-2H-isoindole-2 -yl or 1,3-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;

Y is CH or N;

Z is [image]

; wherein R 10 is as defined above for R 2 and R 3 and are independently the same or different as R 2 and R 3 , provided that when

Z is[image] ; then R4 must be OH,

C=NOR5 where R5 is as defined above,

C=N-NR6R6a, wherein R6 and R6a are the same or different as defined above for R5;

W is -CHR5 wherein R5 is as defined above;

n is zero or the integer 1;

R4 is OH,

NR6R6a, wherein R6 and R6a are the same or different as defined above for R5, when R4 is NR6R6a then Z must be C=O or NHOR9, wherein R9 is hydrogen, alkyl or benzyl; or releasing isomers or releasing pharmaceutically acceptable salts.

Particularly preferred are MMP inhibitors having the formula

[image]

Ar is selected from phenyl, phenyl substituted with alkyl), NO2, halogen,

OR5, where R5 is hydrogen or alkyl, CN,

CO2R5, where R5 is as defined above,

SO3R5 where R5 is as defined above,

CHO,

COR5 where R5 is as defined above,

CONHR5 where R5 is as defined above,

NHCOR5 wherein R5 is as defined above, 2-naphthyl or heteroaryl; R1 is hydrogen, methyl, ethyl, NO2, halogen,

OR5 where R5 is as defined above, CN,

CO2R5 where R5 is as defined above,

SO 3 R 5 where R 5 is as defined above, CHO or

COR5 where R5 is as defined above; R2 and R3 are the same or different: hydrogen, alkyl

-(CH2)V aryl where 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 where X is O or S, and p and q can each be zero or an integer from 1 to 5, and the sum of p+q is not greater than the integer 5

-(CH2)p-X-(CH2)q heteroaryl wherein X, p and q are as defined above,

-(CH2)tNR6R6a, aryl wherein t is an integer from 1 to 9 and R6 and R6a are the same or different as defined above for R5

-(CH2)VSR5 wherein v and R5 are as defined above,

-(CH2)vCONR6R6a and R6 and R6a are the same or different as defined above

for R5 and v is as defined above,

R3 is further -(CH2)rR7 aryl wherein the integer is from 1 to 7, and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl or 1,3-dihydro-1, 3-dioxo-benzo[f]isoindol-2-yl;

Y is CH or N;

Z is[image] ;

wherein R 10 is as defined above for R 2 and R 3 and is independently the same or different from R 2 and R 3 provided that when

Z is[image] ; then R4 must be OH,

C=O,

C=NOR5 where R5 is as defined above,

C=N-NR6R6a, wherein R6 and R6a are the same or different as defined above

for R5;

W is -CHR5 wherein R5 is as defined above;

n is zero or the integer 1; R4 is OH,

NR6R6a, wherein R6 and R6a are the same or different as defined above for

R6, when R4 is NR6R6a then Z must be C=O or

NHOR9, wherein R9 is hydrogen, acyl or benzyl; or releasing isomers or releasing pharmaceutically acceptable salts.

Preferred compounds used include the following:

4-oxo-4-[-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

4-oxo-4-[-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;

N-hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

E/Z-4-hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

E/Z-4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

4-oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid;

(±)-3-methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid;

4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;

N-hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;

E/Z-4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

E/Z-4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;

4-oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid;

and (±)-3-methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid;

A compound which is 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid.

Similar compounds that are sulfonamide derivatives having the formula:

[image]

where

Ar is phenyl,

phenyl substituted alkyl, NO2, halogen, OR5, CN, CO2R5, SO3R5, CHO, COR5, CONHR5, or NHCOR5,

heteroaryl or 2-naphthyl;

R1 is hydrogen, methyl, NO2, Cl, -NH2, -NHCO2CH3, -OH or CO2H;

R2 and R3 are the same or different independently: 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)VCO2R65 -(CH2)vCONR6R6a or (CH2)VSR5,

m is zero or 1;

Y is CH or N; provided that when m=1, Y is not N;

z is zero or 1; W is -CHR8; n is zero or 1;

R4 is OH, NR6R6a, or NHOR9;

R 5 is hydrogen or acyl;

v is from 1 to 5; X is O or S;

p and Q are independently from 1 to 5, with the fact that the sum of p+q is not greater than 5;

t is from 1 to 9;

R 6 and R 61 , the same or different, are hydrogen or alkyl;

R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl or 1,3-dihydro-1,3-dioxy-nenzo[f]isoindol-2-yl;

R8 is hydrogen or alkyl; and R9 is hydrogen, alkyl or benzyl, or corresponding pharmaceutically acceptable salts.

The specific sulfonamide derivatives used in this method are as follows:

[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid;

N-hydroxy-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetamide;

[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(R)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(S)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(R)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(R)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(±)-5-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

[4-(4-phenyl-piperazin-1-yl)-benzenesulfonylamino]-acetic acid;

{isobutyl-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino}-acetic acid;

(S)-4-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-butyric acid;

(R)-2-[4-(4-phenyl-piperidin-1H1)-benzenesulfonylamino]-3-tritylsulfanyl-propionic acid, sodium salt;

(R)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid, disodium salt monohydrate;

(S)-2-{4-[4-(4-hydroxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(S)-2-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride;

(R)-3-mercapto-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-3-tritylsulfanyl-propionic acid, trifluoroacetate;

(S)-2-[4-(4-benzyl-piperidin-1-yl)-benzenesulfonylamino]-3-phenyl-propionic acid;

(S)-3-(4-Benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-(4-hydroxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-phenyl-2-[4-(4-phenyl-piperazin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-2-{4-[4-(3-Methoxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(S)-2-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid hydrobromide;

(S)-2-{4-[4-(4-Methoxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(R)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(S)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(R)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid;

N-hydroxy-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetamide;

3-[4-(4.phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(R)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(S)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(S)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(R)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(±)-5-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid;

{isobutyl-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino}-acetic acid;

(S)-4-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-butyric acid;

(R)-2-[4-(4-phenyl-piperidin-1-ol)-benzenesulfonylamino]-3-tritylsulfanyl-propionic acid, sodium salt;

(R)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid, disodium salt monohydrate;

(S)-2-{4-[4-(4-hydroxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(S)-2-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride;

(R)-3-mercapto-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-3-tritylsulfanyl-propionic acid, trifluoroacetate;

(S)-2-[4-(4-benzyl-piperidin-1-yl)-benzenesulfonylamino]-3-phenyl-propionic acid;

(S)-3-(4-benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-(4-hydroxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-phenyl-2-[4-(4-phenyl-piperazin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-2-{-[4-(3-methoxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(S)-2-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid hydrobromide;

(S)-2-{4-[4-(4-Methoxyphenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid;

(R)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(S)-4-methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-pentanoic acid;

(R)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;

(S)-3-phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid; you

(S)-3-(1H-indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid.

Further specific compounds used in the invention are:

2-(dibenzofuran-2-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid;

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;

2-(dibenzofuran-2-sulfonylamino)-3-(1H-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;

5-benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoic acid;

2-(dibenzofuran-2-sulfonylamino)-(4-methoxy-phenyl)-acetic acid;

3-(4-benzyloxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

2-(dibenzofuran-2-sulfonylamino)-5-p-tolyl-sulfanylamino-pentanoic acid;

2-(dibenzofuran-2-sulfonylamino)-4-mercaptobutyric acid;

3-(4-bromo-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

(dibenzofuran-2-sulfonylamino)-masic acid;

1-(dibenzofuran-2-sulfonylamino)-cyclopropane-carboxylic acid;

3-(4-chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

2-(dibenzofuran-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(4-fluoro-benzenesulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(4-methoxy-benzenesulfonylamino)-hexanoic acid;

6-(4-bromo-benzenesulfonylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid;

6-(2-acetylamino-thiazole-5-sulfonylamino)-2-(4'-bromo-biphenyl-4-sulfonyl-aminohexanoic acid;

6-(2-acetylamino-benzenesulfonylamino)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-hexanoic acid;

6-benzenesulfonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(pentane-1-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-2-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-1-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-phenylethanesulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-phenyl-acetylamino-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-pentoxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-phenoxy)-2-methyl-propionyl-amino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(pyridin-4-ylsulfanyl)-acetylaminohexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-thiophen-2-ylacetylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(3-phenyl-acryloylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(7-phenyl-heptanoylamino)-hexanoic acid;

2-(4'-bromo-btphenyl-4-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-phenoxy-butyrylamino)-hexanoic acid;

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)-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)-acetylamino]-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)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen-1-yloxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-acetnamino]-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-methoxy-phenyl)-propionylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-pyridyl-3-yl-acetylamino)-hexanoic acid;

6-(2-benzo[1,3]dioxo-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-pyridyl-2-yl-acetylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[3-(4-tert-butyl-phenoxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionyl-amino]-hexanoic acid;

2-(4'-bromo-biTenyl-4-sulfonylamino)-6-(2-cyclopent-1-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-1-yloxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl-phenoxy)-butyrylamhexanoic 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)-hexanoic acid;

6-(2-benzo[1,3]dioxo-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-pyridyl-2-yl-acetylamino)-hexanoic acid;

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)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-pyridyl-2-yl-acetylamino)-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)-acetylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(4-phenyl-butyrylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[4-(4-4-chloro-3-methyl)-phenoxy)-butyrylamino]-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenyl)-propionylamino]-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)-hexanoic acid;

6-(2-benzo[1,3]dioxo-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2-naphthaen-1-yl-acetylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenoxy)-propionylamino]-hexanoic acid;

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;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(2,4,6-triisopropyl-benzoylamino)-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-isobutylcarbonylamino-hexanoic acid;

2-(4'-bromo-biphenyl-4-sulfonylamino)-6-(9H-fluorene-9-imethoxycarbonylamino)-hexanoic acid;

6-(adamantan-1-yloxycarbonylamino)-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid; you

6-Allyloxycarbonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-hexanoic acid.

A number of MMP inhibitors that are succinamides are known and can be used in the method of this invention. Typical succinamides are:

2S,N1-dihydroxy-3R-isobutyl-N4-{1S-[2-(2-methoxy-ethoxymethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl)-succinamide;

2S-allyl-N1-hydroxy-3R-isobutyl-N4-{1S-[2-(2-methoxy-ethoxymethoxy)-ethylcarbamoyl]-2-phenyl-ethyl}-succinamide;

2S-allyl-N1-hydroxy-3R-isobutyl-N4-{1S-[2-(2-methoxy-ethoxymethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide;

2S-allyl-N1-hydroxy-3R-isobutyl-N4-(1S-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide;

2S-allyl-N4-{1S-[2,2-di-(methoxy-methyl)-propylcarbamoyl]-2,2-dimethyl-propyl}-N1-hydroxy-3R-isobutyl-succinamide;

2S-allyl-N4-{1S-[2,2-di-(methoxy-methyl)-butylcarbamoyl]-2,2-dimethyl-propyl}-N1-hydroxy-3R-isobutyl-succinamide;

N4-hydroxy-2R-isobutyl-N1-{1S-[2-(2-methoxy-ethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl}-3S-(thiophen-2-yl-sulfanylmethyl)-succinamide;

N4-hydroxy-2R-isobutyl-N1-(1S-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl-carbamoyl}-2,2-dimethyl-propyl)-3S-(thiophene-2 -yl-sulfanylmethyl)-succinamide

N1-{1S-[2,2-di-(methoxy-methyl)-propylcarbamoyl]-2,2-dimethyl-propyl}-N4-hydroxy-3R-isobutyl-3S-(thiophen-2-yl-sulfanylmethyl)- succinamide;

N4-hydroxy-2R-isobutyl-N1-{1S-[2-(2-methoxy-ethoxy)-ethylcarbamoyl]-2,2-dimethyl-propyl}-3S-propyl-succinamide;

N4-(1S-cyclobutylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cyclopentylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cyclohexylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cycloheptylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-2S,N1-dihydroxy-3R-isobutyl-succinamide;

N4-(1S-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S,N1-dihydroxy-3R-(3-phenyl-propenyl)-succinamide;

N4-[2,2-dimethyl-1S-(2-phenyl-cyclopropylcarbamoyl)-propyl]-2S,N1-dihydroxy-3R-isobutyl-succinamide;

2S-allyl-N4-(1-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N1-hydroxy-3R-isobutyl-succinamide;

2S-allyl-N4-(1-cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-N1-hydroxy-3R-isobutyl-succinamide;

N4-(1-cyclopropylcarbamoH-2,2-dimethyl-propyl)-N1-hydroxy-3R-isobutyl-2S-(thiophene-2-isosulfanylmethyl)-succinamide;

N4-(1-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N1-hydroxy-3S-(4-hydroxy-phenylsulfanylmethyl)-3R-isobutyl-succinamide; you

N4-(1-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N1-hydroxy-3R-isobutyl-succinamide.

The next particularly preferred group of MMP inhibitor compounds used in the method of this invention are the sulfonated amino acid derivatives described in WO 97/27174, incorporated herein by reference. These compounds have a general structure

[image]

wherein R 11 is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalkyl;

R 12 is hydrogen or a group as defined for R 11 ;

R 13 is a single bond, substituted or unsubstituted arylene or substituted or unsubstituted heteroaryl;

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 tetrazolidyl;

R15 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group, and

Y is NHOH or OH.

Particularly preferred compounds for use in the method of the present invention having the above formula are those wherein R 13 is phenylene or substituted phenylene. Typical such compounds which may be used have the formula

[image]

wherein R 11 and R 12 are as defined above and R 17 is substituted or unsubstituted heteroaryl.

Particularly preferred are compounds of the formula

[image]

in which R11 and R18 are as follows:

[image] [image]

The following patent applications disclose MMP inhibitors, which are incorporated herein by reference. US 5,753,653; WO 96/16027; WO 97/20824; WO 98/50348; WO 98/43963; WO 9832748; WO 98/17643; and EP 0780386. They include the compounds listed below:

4-[2-(2-carboxymethyl-4-phenyl-butylamino)-3-cyclohexylpropionylamino]-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-3-methyl-butyrylamino]benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester;

4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylaminobenzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester;

4-[2-(2-hydroxyaminocarbonylmethyl-5-methyl-valerylamino)-3,3-dimethyl-butyrylamino]benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-2-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-butynamino]-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-methyl-pentanoylamino)-3-(1H-indol-3-yl)-propionyl-amino]-benzoic acid methyl ester;

5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca12(19),13,15,-17-tetraen-10-ylcarbamoyl)-hexanoic acid;

4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyryl-amino]benzoic acid methyl ester;

4-[2-(2-Hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-2-cyclohexylpropionyl-amino]-benzoic acid methyl ester;

4-[2-(2-Hydroxyaminocarbonylmethyl-4-methyl-valerylamino)-4-methyl-valeryl-aminoj-benzoic acid methyl ester;

4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3-cyclohexylpropionyl-amino]-benzoic acid methyl ester;

4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3-cyclohexylpropionyl-amino]-benzoic acid methyl ester;

4-[2-(2-hydroxyaminocarbonylmethyl-5-phenyl-valerylamino)-3,3-dimethyl-butyryl-amino]-benzoic acid methyl ester;

5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca12(19),13,15,17-tetraen-10-ylcarbamoyl)-1-hexylhydroxamic acid;

4-[2-(2-hydroxyaminocarbonylmethyl-4-methyl-valerylamino)-3-(1H-indol-3-yl)-propionylamino]-benzoic acid methyl ester;

3-[2-(4-Methoxy-benzylsulfanyl-2-methyl-1-phenylcarbamoyl)-propylcarbamoyl]-5-methyl-hexanoic acid;

3-[2-(4-Methoxy-benzylsulfanyl-2-methyl-1-phenylcarbamoyl)propylcarbamoyl]-5-methyl-hexanoic acid-n.hydroxamide;

4-[2-(2-hydroxyaminocarbonylmethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylamino]-benzoic acid methyl ester;

2-(phenyl-2-ethyl)benzoic acid N-hydroxamide;

4-[2-(2-acylhydroazinomethyl-4-methyl-pentanoylamino)-3-(1H-indol-3-yl)-propionylamino]-benzoic acid methyl ester;

2-(propylthio)-pyridine-3-N-(hydroxy)carboxamide;

4-[2-(2-carboxymethyl-5-phenyl-pentanoylamino)-2-cyclohexyl-acetylamino]-benzoic acid methyl ester;

[4-(N-hydroxyamino)-2R-isobutyl-3S-((thien-2-thio)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;

4-[2-(2-carboxymethyl-5-(3-hydroxyphenyl)-pentenoyl)amino)-4-methyl-valeroyl]-aminobenzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(3-aminophenyl)-pentenoyl)amino)-4-methyl-valeroyl]-aminobenzoic acid methyl ester, trifluoroacetate;

2-(phenyl-2-ethyl)pyridine-3N-hydroxycaroxamide;

4-[2-(2-carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(3-aminophenyl)-acetyl)amino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

2-[3-(3-hydroxy-phenyl)-propyl]-benzhydroxamic acid;

2-(thiobenzium)benzoic acid N-hydroxamide;

1-(3-phenyl-propyl)-pyrrolidine-2-hydroxamic acid;

4-[2-(2-carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(N'-methyluredio)valeroyl)amino)-methyl-valeroyl]-aminobenzoic acid methyl ester;

442-(2-carboxymethyl-5-(trifluoroacetamido)valeroyl)amino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-2-phenylacetylamino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-hydroxyaminocarbonylmethyl-2-phenylacetylamino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylamino]-benzoic acid methyl ester;

2-[3-(3-amino-phenyl)-propyl]-benzhydroxamic acid;

cis-4-benzyloxy-pyrrolidine-2-carboxylic acid;

4-[2-(2-carboxymethyl-5-(3-amino-4-(trifluoromethyl)phenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(methanesulamido)valeroyl)amino)-4-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;

4-[2-(carboxymethyl-heptanonylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(4-n-butylphenyl)-4-pentanoyl)amino)-4-methyl-valeroyl]-aminobenzoic 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]amino-4-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-5-(biphen-4yl)-valeroyl)amino)-4-methyl-valeroyl]amino benzoic acid methyl ester;

cis-4-benzylsulfanyl-pyrrolidine-2-carboxylic acid;

2-cyclohexylmethyl sulfonyl-benzoic acid;

pyridine-1-carbothionic acid phenylethyl-amide;

3-(2-methyl-thiazol-4-yl)-N-phenethyl-propionamide;

N-phenyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-propionamide;

3-(3H-imidazol-4-yl]-N-phenethyl-propionamide;

4-[2-(2-carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl-valeroyl]-amino-benzoic acid methyl ester;

2-cyclohexylmethyl sulfonyl-benzenehydroxamic acid;

[2-oxo-3-(3-phenyl-propyl)-tetrahydrouran-3-yl]-acetic acid

4-[2-(2-carboxymethyl-5-(fuoren-2-yl)-valeroyl)amino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

4-[2-(2-Carthoxymethyl-2-(3-thienyl)acetylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

4-[2-(2-benzylthio-3-carboxy-propionylamino)-4-methylpentanoylamino]-benzoic acid methyl ester;

4-[2-(2-carboxymethyl-4-(f2-indolyl)butyrylamino)-4-methyl-valeroyl]amino-benzoic acid methyl ester;

1-allyl-3-(2-hydroxyethyl)-2-thiourea;

3-(1-hydroxyimino-propyl)-6-phenyl-hexanoic acid;

3-(3H-imidazol-4-ylmethyl]-N1,N4-diphenethyl-succinamide;

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-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-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-hexanoic acid trifluoroacetate;

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

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

2-carboxymethyl-heptanoyl-2-[N-methylcarboxamide)piperidine;

4-[2-(2-(2-phenylcyclopropyl)succinylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester;

2-carboxymethyl-heptanoyl-3-(N-methylcarboxamide)hexahydropridazine;

6-biphenyl-4-yl-3-[1-[3-(3-hydroxy-ethyl)-phenylcarbamoyl]-2,2-dimethyl-propylcarbamoyl]-hexanoic acid;

2R-(3-(4-biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5-methyl-3S-hexyl)-succinamide;

6-biphenyl-4-yl-3-[3-(2-aminoethyl)-phenylcarbamoyl]-2,2-dimethyl-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-methyl-pentanoic acid;

2-(3-biphenyl-4-yl-propyl)-N1-[1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-methyl-butyl-carbamoyl]-N4-hydroxy-succinamide- hexanoic acid;

6-biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamic acid, N-hydroxamide;

2R-(3-(4-biphenyl)propyl)-N-((1-hydroxy-1-methylethyl)phenylmethyl)succinamide;

6-biphenyl-4-yl-3-[1-phenylcarbamoyl)-2-(4-cyano-benzenesulfanyl)-2-methyl-propyl-carbamoyl]-hexanoic acid;

4-{2-[2-carboxymethyl-5-(4'-hydroxy-biphenyl-4-yl)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester;

1-(N-methyl-N-phenethylthiocarbamoyl)-pyrrolidine-2-carboxylic acid;

6-Birenyl-4-yl-3-({cyclohexyl-[2-(4-sulfamoyl-phenol)-ethylcarbamoyl]-methyl}-carbamoyl)hexanoic acid;

2R-(6-(4-biphenyl)propyl)-3-(N-benzylcarbamoyl))hexanoic acid N-hydroxamide;

[3-(3-biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3-y]-acetic acid;

2-benzenesulfonyl-cyclopent-1-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-y]-acetic acid;

2-benzenesulfonyl-cyclohex-1-encarboxylic acid hydroxamide;

6-benzenesulfonyl-cyclohex-1-enecarboxylic acid hydroxamide;

2R-(3-(4-biphenyl)propyl)-N-(3-methylpyridine)succinamide;

{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;

[2-oxo-3-(3-biphenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid

4-[2-(2-thioamidomethyl-5-phenyl-valeramino)-4-methyl-valeroylamino]-benzoic acid methyl ester;

4-[2-(2-amino-2-hydroxylamino-ethyl-5-phenyl-valeramino)-4-methyl-valeroyl-amino]-benzoic acid methyl ester;

6-biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfamoylphenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

6-biphenyl-4-yl-3-[2,2-dimethyl-1-(2-hydroxyethylsulfamoyl-phenylcarbamoyl)-propyl-carbamoyl]-hexanoic acid;

1-(N-hydroxy)-3-(2-bibenzyl)urea;

4-(2-{5-[7-(2-amino-acetylamino)-9H-fluoren-2-yl]-2-carboxymethyl-pentanoyl-amino}-4-methyl-pentanoylamino]-benzoic acid methyl ester TFA salt ;

2R-(6-(4-biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoic acid N-hydroxamide;

6-biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl)-methyl-carbamoyl}-hexanoic acid;

6-biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl)-methylcarbamoyl}-hexanoic acid trifluoroacetate salt;

4-(2-{2-carboxymethyl-5-[4-(1H-tetrazol-5-yl)-phenyl-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-hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino]-benzoic acid methyl ester ;

5-hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2H-pyrrole-3-carboxylic acid-(2-cyclohexyl-1-methylcarbamoyl-ethyl) amide;

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

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

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

4-[2-(5-biphenyl-4-yl-2-carboxyethyl-pentanoylamino)-pent-4-enoylamino]-benzoic acid methyl ester;

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

4-(2-{[5-hydroxyamino-3-(3-pentyl)-3,4-dihydro-2H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino]-benzoic acid methyl ester;

5-hydroxyamino-3-(3-pentyl)-3,4-dihydro-2H-pyrrole-3-carboxylic acid-(2-cyclohexyl-1-methylcarbamoyl-ethyl)amide;

6-biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

4-[2-(2-carboxymethyl5-(4-cyano-biphenyl-4-yl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester;

6-biphenyl-4-yl-3R-(2-hydroxy-1S-phenyl-ethylcarbamoyl)-hexanoic acid;

3R-(1R-benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-ylhexanoic acid;

6-biphenyl-4-yl-3R-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-hexanoic acid;

4-[2-(2-carboxymethyl-5-(4-pyridin-4-i-phenyl)-pentanoylamino)-4-methyl-pentanoyl-amino]-benzoic acid methyl ester;

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

3-{2-allylsulamyl-2-methyl-1-[2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-propylcarbamoyl}-6-biphenyl-4-yl-hexanoic acid;

4-[2-(5-biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-4,5-dihydroxy-pentanoyl-amino]-benzoic acid methyl ester;

4-(2-{5-[4'-(2-amino-ethoxy)-biphenyl-4-i]-2-carboxymethyl-pentanoylamino}-4-methyl-pentanoylamino]-benzoic acid methyl ester;

6-biphenyl-4-yl-3R-(2-hydroxy-1S-phenyl-ethylcarbamoyl)-hexanehydroxamic acid;

3R-(1R-benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-i-hexanehydroxamic acid;

N-[5-(biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl)-terf-leucine, N-(pyrid-4-yl)amide;

[3-(3-naphthalen-2-yl-propyl)-2-oxo-tetrahydrofuran-3-yl]-acetic acid;

6-biphenyl-4-yl-3R-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-hexanehydroxamic acid;

4-[2-(2-carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4-methyl-pentanoylamino-benzoic acid methyl ester;

3-[2,2-dimethyl-1-(pyridin-4ylcarbamoyl)-propylcarbamoyl]-5-methyl-hexanoic acid;

N1-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propyl]-N-hydroxy-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-3R-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid;

4-{2-[5-biphen-4-yl-2-(1-carboxy-ethylamino)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester;

6-biphenyl-4-yl-3R-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamic acid;

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

2-(biphenyl-4-sulfonyl)-cyclohex-1-enecarboxylic acid hydroxamide;

2-(biphenyl-4-sulfonyl)-cyclohex-1-enecarboxylic acid hydroxamide;

2-phenethylsulfanyl-cyclohex-1-enecarboxylic acid hydroxamide;

6-(4'-Cyano-biphenyl-4-yl)-3-[2-hydroxy-1-(4-methylsufinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid;

6-biphenyl-4-yl-3-[2,2-dimethyl-1-(4S-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

4-[2-(2-carboxymethyl-5-(4-hydroxy-3,3,3,-trifluoropropyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester;

2-benzylsulfanyl-cyclohexanecarboxylic acid hydroxamide;

1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid;

trans-2-benzylsulfanyl-cyclohexanecarboxylic acid hydroxamide;

4-[2-(2-carboxymethyl-5-(4-(2-methylthiazol-4-yl)phenyl)valeroyl]amino-benzoic acid methyl ester;

1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl-butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid;

3-[(cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl)-methyl)carbamoyl]-6-(4-pyridin-4-yl-phenyl)-hexanoic acid trifluoroacetate salt;

trans-2-(biphenyl-4-yl-methylsulfanyl)-cyclohexanecarboxylic acid hydroxamide;

6-biphenyl4-yl-3-(1-hydroxymethyl-2,2-dimethyl-but-3-enylcarbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3R-(1-hydroxymethyl-2S-(1H-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid;

3R-(2R-benzyloxy-1S-hydroxymethyl-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-1-(4-(2-hydroxyethylsulfamoyl)-phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid;

6-biphenyl-4-yl-3-(1-hydroxymethyl-2-phenyl-ethylcarbamoyl)-hexanoic acid;

N1-(1-benzyl-2-hydroxy-ethyl)-2-(3-biphenyl-4-yl-propyl)-N4-hydroxy-succinamide;

6-biphenyl-4-yl-3R-(1-hydroxymethyl-2S-(1H-imidazol-4-yl)-ethylcarbamoyl)-hexanehydroxamic acid;

N-hydroxy-2-[2-oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetamide;

4-[2-(2-carboxymethyl-5-(4-(2-hydroxy-biphenyl-4-yl)-valeroylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester;

N1-(2-benzyloxo-1-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl-propyl)-N4-hydroxy-succinamide;

trans-2-(4-phenoxy-benzylsulfanyl)-cyclohexanecarboxylic acid hydroxamide;

2-(4-indol-1-yl-benzylsulfanyl)-cyclohexanecarboxylic acid hydroxamide;

6-biphenyl-4-yl-3-[2-hydroxy-2-methyl-1-(4S-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;

6-biphenyl-4-yl-3-[2,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-3-ylcarbamoyl)-hexanoic acid;

5-biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic acid {1-[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl-butyl}-amide;

2-(3-biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-3-yl)-succinamide;

6-biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-3-ylcarbamoyl)-hexanoic acid;

N-[2,2-dimethyl-1S-pyridin-4-ylcarbamoyl)-propyl]-3R-thiophen-3-yl-succinic acid;

4-[2S-(2R-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-propionylamido)-4-methyl-pentanoylamino-benzoic acid methyl ester;

3R-(2-benzyloxo-phenyl)-1S-hydroxymethyl-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid;

6-biphenyl-4-yl-3R-(2-hydroxy-1S-(4-hydroxy-benzyl)-ethylcarbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid;

N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxo-pentanoyl)-L-t-leucine, N'-4-(methylthio)phenyl amide;

6-biphenyl-4-yl-3R-(2-hydroxy-1S-(4-hydroxy-benzyl)-ethylcarbamoyl)-hexanehydroxamic acid;

4-{2-[2-carboxymethyl-5-(4'-sulfamyl-biphenyl-4-yl)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester;

2-(2-biphenyl-4-yl-ethylsulfanyl)-cyclohexanecarboxylic acid hydroxamide;

3-acetyl-6-biphenyl-4-yl-3-hexanoic acid;

N-[5-(biphenyl-4-yl)-2-(1-carboxy-2-hydroxybut-1-yl)pentanoyl]-tert-leucine, N'-4-(methylthiophenyl) amide;

6-biphenyl-4-yl-3-(2-hydroxy-cyclohexylcarbamoyl)-hexanoic acid;

2-(2-biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2-hydroxy-cyclohexyl)-succinamide; and

6-biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid hydroxamide;

6-biphenyl-4-yl-3-(2-hydroxy-cyclohexylcarbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3-[2,2-dimethyl-1-(pyridin-4ylcarbamoyl)-propylcarbamoyl)-hexanoic acid ethyl ester;

2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl-propyl-2-yl) propionamide;

N-[5-(biphenyl-4-yl)-2-(1-carboxy-2-hydroxyethyl)pentanoyl]-L-tert-leucine, N'-(4-methylthiophenyl)amide;

3R-(2-hydroxy-1S-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-triazol-4-yl)-phenyl)-hexanoic acid;

3R-(2-hydroxy-1S-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid;

5-biphenyl-4-yl-2-(1-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-pentanoic acid;

2-(3-biphenyl-4-yl-propyl)-N-hydroxy-N(1-hydroxymethyl-3-methylsulfanyl-propyl)-maonamide;

6-biphenyl-4-yl-3-(3-hydroxy-piperidin-1-carbonyl)-hexanoic acid;

6-biphenyl-4-yl-3-(3-hydroxy-piperidin-1-carbonyl)-hexanoic acid hydroxamide;

1-(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;

N-(1-benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinic acid;

N-(1-benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinamic-hydroxamic acid;

6-biphenyl-4-yl-3R-2S-hydroxy-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid;

3-(1-benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid;

N1-(1-benzyl-2-hydroxy-ethyl)-N4-hydroxy-2-isobutyl-succinamide;

6-biphenyl-4-yl-3R-2S-hydroxy-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamic acid;

1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;

6-biphenyl-4-yl-3-(2-hydroxy-1-hydroxymethyl-propylcarbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3R-(2-oxo-cyclohexyl-1S-carbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3-(2-hydroxy-1-hydroxymethyl-propylcarbamoyl)-hexanehydroxamic acid;

2S-[(1S-benzyl-2-hydroxy-ethylcarbamoyl)-3R-biphenyl-4-yl-pyrrol-1-yl-methyl]-pentanoic acid;

3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-(2R-hydroxy-cyclohexyl-1R-yl)-succinic acid;

2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxamate-N-(1-hydroxy-3-phenyl-prop-2-yl)-propionamide;

trans-2-(3-biphenyl-4-yl-propyl)-cyclohexanecarboxylic acid;

frans-2-(3-biphenyl-4-yl-propyl)-cyclohexanecarboxylic acid hydroxamide;

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

6-biphenyl-4-yl-2S-hydroxy-3R-(1-hydroxymethyl-2S-(1H-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid;

1-[4-biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid;

1-[4-biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1-(4-phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide;

6-biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanoic acid;

6-biphenyl-4-yl-3R-(1S-hydroxymethyl-2-(3-pyridyl)-ethylcarbamoyl)-hexanehydroxamic acid;

6-biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanehydroxamic acid;

1-[4-(4-Bromo-phenoxy)enesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acid hydroxamide;

1-[4-(4-Bromo-phenoxy)enesulfonyl]-4-piperazine-2-carboxylic acid hydroxamide;

3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[2-hydroxy-1S-(1H-imidazol-4-yl)-methyl)-ethyl]-succinic acid trifluoroacetate;

3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[1S-(methoxy-methylcarbamoyl)-3-methyl)-butyl]-succinic acid;

N-(acetyl-3-methyl-butyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinic acid;

6-biphenyl-4-yl-3R-(2-oxo-tetrahydrofuran-3S-ylcarbamoyl)-hexanoic acid;

3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl)-2-hydroxy-5-methyl-hexanoic acid hydrochloride;

N4-(2,2-dimethyl-1-methylarbamoyl-propyl)-2,N1-dihydroxy-3-isobutyl-succinamide;

6-biphenyl-4-yl-3R-(2-oxo-azepan-3S-ylcarbamoyl)-hexanoic acid;

N-(1-benzyl-2-hydroxy-ethyl)-3-(4-biphenyl-4-yl-pyrazol-1-yl)-succinamide;

N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.0,12,17]octadeca11(18), 12(17), 13,15-tetraen-9R-yl)-3S- (3-phenyl-pyrdol-1-yl)-succinic acid;

4-acetyl-1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxamide;

1-(Diphenylphosphine)-piperidine-2-carboxylic acid hydroxamide;

3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[3S-(2RS-hydroxy-5-methyl)-hexyl]-succibamide;

N-(1S-benzyl-2-hydroxy-ethyl)-3R-(2-biphenyl-4-yl-cyclopropylmethyl)-succinamide;

6-biphenyl-4-yl-3R-(2-oxo-1-tetrahydrofuran-3S-ylcarbamoyl)-hexanehydroxamic acid;

1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxamide;

4-(4-Methoxy-benzenesulfonyl)-trimorpholine-3-carboxylic acid hydroxamide;

3-(diphenylphosphine)-propionic acid;

3-(diphenylphosphine)-propionic acid hydroxamide;

4-[2-(2-carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester;

1-[4-(4-chloro-phenoxy)-benzenesulfonyl]-N-hydroxy-4-(N-methylcarbamoyl)-piperazine-2-carboxamide;

1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxamide;

3-(3-biphenyl-4-yl-pyrrol-1-yl)-N-(2,2-dimethyl-1-methylcarbamoyl-propyl)succinic acid;

1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid N-hydroxamide;

4-[4-phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxamide;

3R-[2-biphenyl-4-yl-ethylsulfanyl]-tetrahydropyran-4-carboxylic acid N-hydroxamide;

6-biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid

1-[4-(4-bromo-phenoxy)-benzenesulfonyl]-piperidine-2-amidoxime;

2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl-prop-2-yl)propionamide;

{3-[3-(3-amino-phenyl)-propyl]-2-oxo-tetrahydrofuran-3-yl}-acetic acid;

6-biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid 5-biphenylvaleric xylene;

1-[4-(methoxy)-benzenesulfonyl]piperidine-2-amidoxime;

1-[4-phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxamide;

{3-[3-(3-methylamino-phenyl)-propyl]-2-oxo-tetrahydrofuran-3-yl}-acetic acid;

6-biphenyl-4-yl-3R-(2-oxo-azepan-3S-ylcarbamoyl)-hexanehydroxamic acid;

4-(1H-indole-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxamide;

1R-[4-bromo-phenoxy)-benzenesulfonyl]-N-amino-piperidine-2-carboxamide;

2-(3-biphenyl-4-i-propyl)-3,N-dihydroxy-N1-(1S-hydroxymethyl-3-methanesulfinyl-propyl)-succinamide;

N-(1-benzyl-2-hydroxy-ethyl)-3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-1-y]-succinic acid;

1-(methyl-phenylphosphine)-piperidine-2R-carboxylic acid hydroxamide;

4-(4-(4-chlorophenoxy)benzenesulfonyl-N-hydroxy-morpholine-3R-carbocamide;

2S-[1R-(3-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl)-N-(2,2-dimethyl-1S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid;

2SR-{1S-benzyl-2-hydroxyethylpropylcarbamoyl-[3R-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl]-methyl}-pentanoic acid;

2S-[3-(biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid;

1-(1,3-dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

3-[3-(4'-carbamoyl-biphenyl-4-yl]-pyrrol-1-yl)-N-(1-hydroxymethyl-2,2-dimethyl-propyl)succinic acid;

4-methyl-1-(4-(4-chlorophenylbenzenesulfonyl-N-hydroxy-2R-piperazinecarbocamide hydrochloride);

1-[4-chlorophenoxybenzenesulfonyl-N-hydroxy-2R-piperazinecarbocamide;

2-(3-phenyl-propylsulfonyl)-cyclohexane carboxylic acid hydroxamide;

1-(pyrrolidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1-(piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

4-[4-bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid N-hydroxamide;

1-[4-(4-Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylic acid N-hydroxamide;

1-[4-(4-nitrile-phenyl)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acid N-hydroxamide;

2S-[3-(biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2-dimethyl-propionylcarbamoyl)-methyl]-pent-4-enoic acid;

6-oxo-3-(4-phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4-carboxylic acid hydroxamate;

4-(t-butoxycarbonyl)-1-(4-(pyridin-2-yl)oxybenzenesulfonyl)-N-hydroxy-piperazine-2-carboxamide;

4-[(4-fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxamide;

4-[4-(Fluorophenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid N-hydroxamide;

N-(2,2-dimethyl-1S-hydroxymethyl-propyl)-3-R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)]-succinic acid;

N-(1S-benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl)-succinic acid;

4-(butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acid quilseine hydroxamide;

4-(butoxy-benzenesulfonyl)-1-oxothiomorpholine-3-carboxylic acid hydroxamide;

1-[4-(4-fluorophenyl)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-2R-piperazine-2-carboxylic acid hydroxamide;

1-((4-(4-chlorophenyl)-piperazine)-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

cis-2-phenethylsulfanyl-cyclohexanecarboxylic acid hydroxamide;

N-(2-hydroxy-1S-phenyl-ethyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)]-succinic acid;

1-[4-(4-fluorophenyl)-benzenesulfonyl]-N-hydroxy-2R-piperazinecarboxamide hydrochloride;

1-(diphenylphosphine)-pyrrolidine-2R-carboxylic acid hydroxamide;

N,N-{(diphenylphosphine)-(acetic acid-sodium salt)}-hydrazide;

N-(1-benzyl-2-hydroxy-ethyl)-3-(1-biphenyl-4-i-1H-pyrrol-3-yl)-succinic acid;

trans-2-phenylsulfonyl-cyclohexanecarboxylic acid hydroxamide;

1-[4-(4-fluorophenyl)-piperazine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

1-[4-(4-fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxamide;

4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylic acid hydroxamide;

N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-phenyl-pyrrol-1-yl)-succinic acid;

3R-(3-biphenyl-4-yl)-N-(2-hydroxy-1S-hydroxymethyl-2-methyl-propyl)-succinic acid;

1-(pyrrolidine-1-carbonyl)-pyrrolidine-2R-carboxylic acid;

1-(pyrrolidine-1-carbonyl)-pyrrolidine-2R-carboxylic acid hydroxamide;

1-phenethylcarbamoyl-pyrrolidine-2R-carboxylic acid;

R-4-[4-(bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylic acid hydroxamide;

4-(ethoxycarbonyl)methyl-1-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochloride;

N-(2R-hydroxy-indan-1R-yl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid;

N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid;

N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid;

1-phenylethylcarbamoyl-pyrrolidine-2R-carboxylic acid hydrocamide;

N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-[3-(4-propyl-phenyl)-pyrrol-1-yl]-succinic acid;

1-(4-benzyl-piperazine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

3S-N-hydroxy-4-(4-pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

2R-4-methyl-1-4-(4-fluorophenyl)benzenesulfonyl)-N-hydroxy-piperazine-2-carboxamide;

N-(2,2-dimethyl-methylcarbamoyl)-propyl-3-(5-biphenyl-4-furan-2-yl)-succinic acid;

N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl-pyrrol-1-yl]-succinic acid;

1-((2-pyridyl)-4-piperazine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1-[4-(pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxamide;

N-(4-phenoxy-benzenesulfonyl)-D-tert-leucine;

N-(4-phenoxy-benzenesulfonyl)-D-tert-leucine N-hydroxamide;

N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.0,12,17]octadeca11(18),12(17)],13,15-tetraen-9R-yl)-3 -[4-(pyridol-1-yl)-succinic acid;

3-[3-(4-pyridyl)phenyl-4-yl-pyrdol-1-yl]-N-[2,2-dimethyl-1-(4-pyridyl)carbamoyl-propyl]-succinic acid;

2,2-dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamide;

N-[4-(4-fluorophenoxy)benzenesulfonyl)-D-tert-leucine;

N-[4-(4-fluorophenoxy)benzenesulfonyl)-D-tert-leucine N-hydroxamide;

2-[2-(N1-acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl-pentanoic acid;

3R-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride;

2-[4-(4-chloro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-butyric acid;

2-[4-(4-chloro-phenoxy)-benzenesulfonyl]-N-hydroxy-3,3-dimethyl-butyramide;

3R-N-hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-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 hydroxamide;

2-[4-(pyridin-2-yloxy)-benzenesulfonylamino]-3,3-dimethyl-butyric acid;

2-[4-(pyridin-2-yloxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl-butyramide;

N-(4-phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine;

3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1-methylcarbam propyl)-succinic acid;

3-[3-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-succinic acid;

2-(2-biphenyl-4-yl-ethylsulfonyl)-cyclohex-1-ene-carboxylic acid hydroxamide;

6-(2-biphenyl-4-yl-ethylsulfonyl)-cyclohex-1-ene-carboxylic acid hydroxamide;

N-(4-pyridin-4-yl-oxo-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine;

3-[3-(4'-carbamoyl-biphenyl-4-yl)-propyl-1-yl]-N-[2,2dimethyl-1-pyridin-4-ylcarbamoyl)-propyl]-succinic acid;

N-(4-phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine N-hydroxamide;

1-(4-phenoxy-piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

3R-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-chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine N-hydroxamide;

N-(4-[4-chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylsulfoxy)-D-cysteine N-hydroxamide;

2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid;

2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-3-ylsulfanyl)-butyric acid;

2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-4-ylsulfanobutyric acid);

cis-2-(2-phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamide;

2R-N-hydroxy-4-(4-(imidaz-1-yl)phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

2R-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

4-[2-(2-hydroxycarbamoylmethyl-5-phenyl-pentanoylamino)-4-methyl-pentanoyl-benzoic acid methyl ester;

trans-2-(2-phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamide;

3,3-dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid;

2-[4-(4-chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin-4-ylmethyl-sulfanyl)-butyric acid;

3R-[3-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-(pyridin-4-ylcarbamoyl-propyl)-succinic acid;

3,3-dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid N-hydroxamide;

N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-3-[1-(4-fluorophenyl)-1H-pyrrol-3-y]-succinic acid;

2R-[4-(4-bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid;

2-(2-biphenyl-4-yl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamate;

2-[4-(4-chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin-4-ylmethyl-sulfanyl)-butyric acid N-hydroxamide;

3,3-dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid;

3,3-dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid N-hydroxamide;

3-tert-butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-butyric acid;

1-(4-phenylsulfanyl-piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1-[4-(4-fluoro-phenoxy)-benzenesulfonyl)-3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid;

N-(4-[4-fluorophenoxy)]-benzenesulfonyl)-3-methyl-3-(1-benzyl-imidazol-2-yl-sulfanyl)-butyric acid;

2R-[4-(4-fluoro-phenoxy)benzenesulfonyl)amino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide;

3R-N-hydroxy-4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

1-[4-(4-chloro-phenoxy)-benzenesulfonyl)-4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazine-2-carboxylic acid hydroxamide;

N-(2,2-dimethyl-1S-methylylcarbamoyl-propyl)-3R-[1-(4'-cyanobiphenyl-4-yl)-pyrrol-1-yl]-1H-pyrrol-3-yl]-succinic acid ;

3-carboxymethylsulfanyl-2-(4-fluoro-phenoxy)-benzenesulfonyl)-3-methyl-butyric acid;

2,2-dimethyl-1-oxo-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1S14-thiomorpholine-3-carboxylic acid hydroxamide;

1-[4-(pyridin-2-ylsulfanyl)-piperidin-1-sulfonyl]-piperidine-2-carboxylacid hydroxamide;

3R-[4-(4-(fur-3-yl)phenoxy)-benzenesulfonylamino]-3-methyl-(pyridin-2-ylsulfanyl)-butyric acid;

2,2-dimethyl-1-oxo-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1S14-thiomerophone carboxylic acid hydroxamide;

{2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-1,1-dimethyl-ethylsulfani}3-acetic acid tert-butyl ester;

1-[4-(pyridin-2-ylsulfanyl)-piperidin-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

2R-[4-(4-bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide;

trans-2-(2-biphenyl-4-ylethylsulfanyl)-cyclohexanecarboxylic acid hydrocamide;

N-[1S-(imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-i-phenyl-)-pyrrol-1-yl]-succinic acid formate;

N-methyl-3-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)-succinic acid

N4-(2,2-dimethyl-1S-hydroxymethyl-propyl)-N1-hydroxy-3R-[1-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinamide;

{2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-1,1-dimethyl-ethylsulfani}3-acetic acid;

1-[4-[(4-fluoro-phenoxy)benzenesulfonyl)]-3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid hydroxamide;

N-(4-[4-bromo-phenoxy]benzenesulfonylamino)-3-methyl-3-(1-benzyl-imidazol-2-ylsulfanyl)-butyric acid;

3R-[3-(4'-cyanobiphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-(pyridin-4-ylcarbamoyl-propyl)succinic acid;

2R-[4-(4-iodophenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid;

3R-[3-(4-cyano-phenyl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-hydroxymethyl-propyl-succinic acid;

2R-[4-(4-iodo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide;

2R-[4-(4-nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid;

2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-pent-4-enoic acid;

2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyric acid;

2-[4-(4-bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyric acid;

2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyramide;

2-[4-(4-bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyramide;

2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(carbomethoxyethyl-sulfanyl)-butyric acid;

1-[2-(Benzothiazol-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

3R-[3-(4-cyano-phenyl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-succinic acid;

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-tetrahydrofuran-2S-yl)-3R-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinic acid;

2-[4-(4-fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-(aminoethylsulfanyl)-butyric acid;

[4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid;

2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5-phenyl-pent-4-enoic acid;

5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-34,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridine-6-carboxylic acid hydroxamide;

2R-[4-(4-methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid;

2S-4-(4-((pyrid-4-yl)oxo)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid;

1-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfanyl]-piperidine-2-carboxylic acid hydroxamide;

N-[1-(1H-imidazol-2-yl)-3-methyl-butyl]-3-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinic acid;

3R-{3-[(4-cyanophenyl)-acetyl]-pyrrol-1-yl}-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-succinic 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-methylcarbamoyl-propyl)-succinic acid methyl ester;

2R-[4-(4-methylphenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfonyl)-butyric acid hydroxamide;

1-[4-(4-Methoxy-phenylsulfamyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid;

4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid hydroxamide;

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid;

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid hydroxamide;

2R-[4-(4-bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid hydroxamide;

4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-1-oxo-3-thiomorpholine-3-carboxylic acid hydroxamide;

2,2-dimethyl-4-[4-pyridin-4-yloxo)-benzenesulfonyl]thiomorpholin-3-ol;

4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-3-thiomorpholine-3-carboxylic acid hydroxamide;

2R-3-methyl-3-(pyridin-2-yl-sulfanyl)-[4-(4-trifluoromethylphenoxy)-benzenesulfonyl-amino]-butyric acid;

3R-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-yloxy)-benzenesulfonylamino-butyric acid;

2R-N-hydroxy-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-4-(pyridin-4-yloxy)-benzenesulfonylamino]-butyramide;

2R-[4-(4-bromophenoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-butyric acid;

3S-2,2-dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]thiomorpholine-3-carboxylic acid hydroxamide;

2R-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-ylsulfanyl-benzenesulfonylamino]-butyric acid;

2R-N-hydroxy-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-4[4-(pyridin-4-ylsulfanyl-benzenesulfonylamino]-butyramide;

3,3-dimethyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino] butyric acid;

3,3-dimethyl-N-hydroxy-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino]butyramide;

2R-[4-(4-bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-[(1-methyl-imidazol-2-yl)methylsulfanyl]-butyramide;

2R-[4-(4-bromophenoxy)-benzenesulfonylamino]-3-methyl-[(1-methyl-imidazol-2-yl)methylsulfanyl]-butyric acid;

N-hydroxy-2-[(4-methylbenzenesulfonyl)amino]acetamide;

1-[4-(imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

1-[4-(imidazol-1-yl-phenylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

2R-[4-(4-chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-1-carboxylic acid hydroxamide;

2R-[4-(4-chloro-benzoyl)-piperidine-1-sulfonyl]-piperidine-1-carboxamide;

1R-(4-pyridin-2-yl-piperazin-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide;

1R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid;

1R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide;

N-hydroxy-3,3-dimethyl-2R-[4-morpholine-4-carbonyl)piperidine-1-sulfonylamino]butyramide;

N-hydroxy-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino]-butyramide;

4-(4'-chloro-biphenyl-4-yl)-2RS-[2-(1,3-dioxy-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid;

4-(4'-chloro-biphenyl-4-yl)-2R42-(1,3-dioxy-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid;

N-hydroxy-2R-[4-(imidazol-1-yl-phenoxy)-piperidine-1-sulfonylamino]-3,3-dimethyl-butyramide;

2R-[4-(4-chloro-benzoyl)-piperazine-1-sulfonylamino]-N-hydroxy-3-methyl-methyl-sulfanyl-butryamide;

N-hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino-butyramide;

4-(pyridin-4-yloxy)benzenesulfonic acid;

4-(pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride;

3S-2,2-dimethyl-3-thiomorpholine-carboxylic acid;

3R-N-hydroxy-4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-1,1-dioxo-tetrahydro-2H-1,4-thiazine-3-carboxamide;

1R-3S-2,2-dimethyl-1-oxo-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1-thiomorpholine-3-carboxamide; you

4-[4-(1-hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxamide.

Particularly preferred MMP inhibitors are currently in clinical research, for example batimastat (2).

MMP compounds in clinical research include batimastat (2) for the treatment of malignant pulmonary effusion and marimastat (1) for the treatment of pancreatic cancer, alardin (3) is for the treatment of colon ulcers, and the specific MMP-1 inhibitor is RO 31-9790(4). .

Compounds in clinical research

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All practitioners of the present invention will administer to mammals suffering from atherosclerosis an effective amount of a matrix metalloproteinase inhibitor and an ACAT inhibitor. Compounds that may exhibit activity against matrix metalloproteinase enzymes can be identified using in vitro and/or in vivo assays. Several compounds from the previously shown classes have been evaluated in such standard assays and found to be able to inhibit matrix metalloproteinases. The assay measures the amount by which the test compound reduces the hydrolysis of the substrate thiopeptoylide caused by the enzyme matrix metalloproteinase. Such assays are described in detail by Ye et al., in Biochemistry, vol. 31, no. 45, 1992 (11231-11235) which is incorporated herein by reference.

Thiopeptolide substrates show no elaboration or hydrolysis in the absence of matrix metalloproteinases. The tric tripeptolide substrate commonly used for the assay is Ac-Pro-Leu-ly-thioester-Leu-Leu-ly-OEt. 100 μL of the assay mixture will contain 50 mM 2-morphoinoethanesulfonic acid monohydrate (MES, pH 6.0), 10 mM CaCl2, 100 μM thiopeptoid substrate and 1 mM 5,5'-dithio-bis-(2-nitro-benzoic acid) ) (DTNB). The concentration of the tripeptoid substrate was varied from 10 to 800 μM to obtain Km and Kcat values. The change in absorbance at 405 nm was monitored with a Thermo Max reader (Molecular Devices, Menlo Park, CA) at room temperature (22 °C). Measurement of the amount of hydrolysis of the thiopeptoid substrate was based on E412=13600 m-1 cm-1 for the DTNB-derived product, 3-carboxy-4-nitro-phenoxide. The test was performed with or without compounds that are inhibitors of matrix metaloproteinases, and the amount of hydrolysis was compared to determine the inhibitory potential of the tested compounds.

Some representatives of the compounds were evaluated for their ability to inhibit various metalloproteinase enzymes. Table 1 below shows the inhibitory activity of compounds from different classes. In the table, MMP-1 refers to interstinal collagenase, MMP-2 refers to gelatinase A, MMP-3 refers to stromelysin, MMP-7 refers to matrilysin, MMP-9 refers to gelatinase B. The tested compounds were evaluated at at different concentrations, and in order to determine the acceptable IC50 value, a micromolar concentration of the compound is required to inhibit the hydrolytic activity of the enzyme by 50%.

As indicated above, according to the present invention, matrix metalloproteinase inhibitors can be used for the treatment and prevention of atherosclerotic lesions.

ACAT inhibitors useful in the practice of this invention are those of formula 1 or a corresponding pharmaceutically acceptable salt thereof

[image]

X and Y are independently: oxygen, sulfur and (CR'R")n, where n is an integer from 1 to 4, and R' and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl , phenyl which may be substituted or R1 and R" together form spiroalkyl or carbonyl;

R is hydrogen, straight or branched alkyl of 1 to 8 carbon atoms or benzyl;

R1 and R2 are independent

(a) phenyl or phenoxy which may be unsubstituted or substituted with 1 to 5 substituents which are:

phenyl,

an acyl group having from 1 to 6 carbon atoms, which is straight or branched,

an alkyl group having from 1 to 6 carbon atoms, which is straight or branched,

phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl,

-COOH,

-COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched,

-(CH2)pNR3R4 where p is zero or one, and each R3 and R4 is hydrogen or a straight or branched alkyl group having from 1 to 4 carbon atoms;

(b) 1- or 2-naphthyl which may be unsubstituted or substituted with 1 to 3 substituents which are:

phenyl, an acyl group having from 1 to 6 carbon atoms, which is straight or branched,

an alkyl group having from 1 to 6 carbon atoms, which is straight or branched,

hydroxy, phenoxy, fluorine, chlorine,

bromine,

nitro,

trifluoromethyl,

-COOH,

-COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched,

-(CH 2 )PNR 3 R 4 where p, R 3 and R 4 are as defined above;

(c) arylalkyl;

(d) a straight or branched alkyl chain having from 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or

(e) an adamantyl or cycloalkyl group and wherein the cycloalkyl radical has from 3 to 6 carbon atoms.

Preferred compounds of this invention are those of Formula I in which R1 is phenyl or phenyl disubstituted in the 2,6-positions,

where R2 is phenyl or phenyl disubstituted in 2,6-positions,

where R1 and R2 are phenyl,

where each phenyl is disubstituted in the 2,6-positions,

where R1 is phenyl disubstituted in 2,6-positions and R2 is phenyl trisubstituted in 2,4,6-positions,

where R1 is 2,6-bis(1-methylethyl)phenyl, and R2 is 2,6-bis(1-methylethyl)phenyl or 2,4,6-tris(1-methylethyl)phenyl.

where R1 and R2 are the following group:

[image]

in which t is zero or 1, with the restriction that the sum of t and w is not greater than 5;

R 5 and R 6 are each independently selected from hydrogen or alkyl having 1 to 6 carbon atoms, or when R 5 is hydrogen R 6 may be selected from the group defined for R 7 ; you

R7 is phenyl or phenyl substituted with from 1 to 3 substituents which are straight or branched chains of an alkyl group having from 1 to 6 carbon atoms, straight or branched chains of an alkyl group having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COO alkyl wherein the alkyl has from 1 to 4 carbon atoms, or -(CH2)PNR3R4, where P, R3 and R4 have the meanings defined above.

Also preferred are the compounds of the present invention of the formula I in which: X is oxygen, sulfur or (CR'R')n.

Y is oxygen, sulfur or (CR'R")n with the restriction that at least one of X or Y is (CR'R")n where n is an integer from 1 to 4 and R' and R" are each independently hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, phenyl which may be substituted, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" taken together form a carbonyl or spiroalkyl group of 3 to 10 carbon atoms;

R is hydrogen;

R1 is phenyl which may be substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms;

R2 is phenyl which may be substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenoxy which may be substituted, with the limitation that only if X is (CR'R")n R1 can be substituted phenoxy and only if Y is (CR'RM)n R 2 may be substituted phenoxy, and with the further Limitation that at least one of R 1 and R 2 may be substituted phenyl or phenoxy.

More preferred compounds of the present invention of formula 1 in which:

X is oxygen,

Y is (CR'R'')n where n is an integer from 1 to 2;

R is hydrogen;

R 1 is phenyl which may be substituted;

R2 is phenyl or phenoxy which may be substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms;

R' and R" are each independently hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, phenyl which may be substituted, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" taken together form carbopnyl or spirocycloalkyl.

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

sulfamic acid (phenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl) phenyl

ester,

sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)-phenyl ester,

sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)phenyl ester,

sulfamic acid [adamantaneacetyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester sodium salt,

sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)-phenyl ester sodium salt,

sulfamic acid (decanoyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (dodecanoyl)-2,6-bis(1-methylethyl)phenyl ester,

2,6-bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]benzene-acetamide,

2,6-bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]benzene-acetamide-sodium salt,

2,6-bis(1-methylethyl) [[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]carbamate,

2,6-bis(1-methylethyl) [[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]carbamate sodium salt,

sulfamic acid (1-oxo-3,3-diphenylpropyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid trans-[2-phenylcyclopropyl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (oxophenylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [2-trifluoromethylphenyl(acet)]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (1-oxo-2-phenylpropyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (cyclohexylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (diphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (triphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [(1-phenylcyclopentyl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (-oxo-2-phenylbutyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester,

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

sulfamic acid [(9H-fuoren-9-yl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid (1-oxo-3-phenylpropyl)-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [1-oxo-3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [1-oxo-3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl]-2,6-bis(1-methylethyl)phenyl ester,

sulfamic acid [(acetyloxy)[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester,

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

sulfamic acid [fluoro[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)-phenyl ester,

sulfamic acid (3-methyl-1-oxo-2-phenylpentyl)-2,6-bis(1-methylethyl)phenyl ester sodium salt,

sulfamic acid [[2,4,6-tris(1-methylethyl)phenoxy]acetyl]-2,6-bis(1-methylethyl)-phenyl ester,

sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester, and

sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester,

Other AC AT inhibitors useful in the application of this invention are:

4-hexanedecylamino-benzoic acid minisodium salt;

3,5-dimethyl-1-[5-(1,4,5-triphenyl-2H-imidazol-2-ylsulfanyl)pentyl]-1H-pyrazole monosodium salt;

8-(1,4,5-triphenyl-2H-imidazol-2-yloxy)-octanoic acid;

9-bromo-6,11-dihydro-dibenzo[b,e]oxepine-11-carboxylic acid (2,6-diisopropyl-phenyl)-amide;

5-((3,5-di-tert-butyl-4-hydroxy-phenyamino)-{[4-(2,2-dimethyl-propyl)-benzi]-hexyl-amino}-methylene)-2,2- dimethyl-[1,3]dioxane-4,6-dione;

3-(2,4-difluoro-phenyl)-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-1H-imidazol-2-ylsulfanyl)-pentyl]-1-heptyl-urea;

1-butyl-3-{2-[3-(5-ethyl-4-phenyl-imidazol-1-yl)-propoxy]-6-methyl-phenyl}-urea;

1-(2-{2-[4-(2,2-dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)-3-heptyl-urea;

octadeca-9,12-dienoic acid (1-phenyl-ethyl)-amide;

3-(1H-indol-3-yl)-2-octadeca-9-enoyamino-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-fluoro-benzenesulfonamide;

2-(2-ethoxy-ethylsulfanyl)-4,5-diphenyl-1H-imidazole;

4-cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl-4,5-dihydro-3H-imidazol-4-y]-N-methyl-benzamide;

1-{3-[3-(1-methyl-1H-imidazol-2-yl)-2-phenethyl-2H-chromen-6-ioxy]-propyl}-cyclopentanecarboxylic acid ethyl ester;

1-[4-(2-chloro-phenyl)-2-ethyl-thieno[2,3-b]pyridin-5-yl]-3-(2,4-difluorophenyl)-urea;

1-(2-cyclohexyl-[1,3]-dithiolan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl)-urea;

1-(2-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;

1-(4-{2-[3-(2,4-dimethoxy-phenyl)-1-heptyl-uredio]-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;

N-(2,6-diisopropyl-phenyl)-2-octadeecysulfanyl-acetamide;

2-bromo-6,11-dihydro-dibenzo[b,e]oxepin-11-carboxylic acid (2,6-diisopropylphenyl)-amide;

(±)N-(1,2-diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide;

2,2-dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl)-amide;

(Z) 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octadeca-9-en-1-one;

(Z)2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [2-(2-octadeca-9-enoylamino-ethylcarbamoyl)-ethyl]-amide;

1-benzyl-1-(5-methyl-3-phenyl-benzofuran-2-ylmethyl)-3-(2,4,6-trifluorophenyl)-urea;

5-chloro-3-o-toyl.benzofuran-2-carboxylic acid (2,6-diisopropyl-phenyl)-amide;

2-(2,4a-dimethyl-4a,5-dihydro-naphthalen-1-ylsulfanyl)-N-{2-[(6,6-dimethyl-hepta-2,4-diinyl)-pentyl-amino]-ethyl )-acetamide;

(Z)octadeca-9-enoic acid [2-(1,4-dioxa-8-azaspiro[4,5]-dec-8-yl)-1-phenyl-ethyl]-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-1H-isoquinolin-2-yl)-octadeca-9-en-1-one;

trans-1,4-bis-(4-methoxy-phenyl)-3-(3-phenyl-propy)-azetidin-2-one;

1-butyl-3-{2-dimethylamino-6-[3-(4-phenyl-imidazol-1-yl)-propoxy]-phenylurea;

H2-dimethylamino-6-[3-(4-phenyl-imidazol-1-yl)-propoxy]-phenyl}-3-pentyl-urea;

1-{2-dimethylamino-6-[3-(5-methyl-4-phenyl-imidazol-1-ii)-propoxy]-phenyl}-3-pentyl-urea;

1-(2-{2-[4-(2,2-dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)-3-heptyl-urea;

(4S-trans)-6-(4,5-diphenyl-1H-imidazol-2-ylsulfanimethyl)-4-hydroxy-4-methyl-tetrahydro-pyran-2-one;

2-(3-[1,3]dioxan-2-i-propylsulfanyl)-4,5-diphenyl-1H-imidazole;

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

acetic acid 1-(11-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-octadecanoyl-1,2,3,4,43,5,6,63,65,7,8,83,9, 10,11,12,12a, 12b, 13,14b-eicosahydro-picene-2-xcarboxylic acid;

3-[3-(2,2,5,5-tetramethyl-[1,3]dioxane-4-carbonyl)-3mino]-propionic acid 2-[3-(2,2-dimethyl-propyl)-3- nonyl-uredio]-cyclohexyl ester;

1-(2,6-diisopropyl-phenyl)-3-(2-p-tolyl-heptyl)-urea;

1-[4-(2-chloro-phenyl)-6,8-dimethyl-quinolin-3-yl]-3-(2,4-difluoro-phenyl)-urea;

1-[4-(2-chloro-phenyl)-1,6,7-trimethyl-2-oxo-1,2-dihydro-quinolin-3-y]-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;

(S)1-[6-bromo-5-(2-chloro-phenyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-7 -yl]-3-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-urea;

3-(4,5-diphenyl-1H-imidazol-2-ylsulfanylmethyl)-1-methyl-piperidine;

2-(5,5-dimethyl-[1,3]-dioxan-2-yl)-4,5-diphenyl-1H-imidazole;

2,2-dimethyl-5-[3-(1-methyl-1H-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-osco-2-phenyl-ethyl)-6,7-dihydro-4H-1,4,6,8a-tetraza-s-indacene- 5,8-dione;

[2-(3-tert-butyl-4-hydroxy-naphthylene-1-yl)-1-(diethoxy-phosphory)-vinyl]-phosphoric acid diethyl ester;

5-[1-(acetoxy-3-methylbutyl]-2'-(hydroxymethyl)-4-methoxy-4'-methylspiro[benzofuran-2(3H),1'-cyclohexa-2',4'-diene]- 3,6'-dione;

5-[1-(acetoxy)-3-methylbutyl]-4-methoxy-4'-methyl-3,6-dioxospiro[benzofuran-2(3H),1'-cyclohexa-2'4'-diene]-2 '-carboxaldehyde;

(3α,4α,22α,24α)-3-hydroxy-22-[(1-oxooctadecyl)oxy]-24-norolean-12-ene-29-ic acid

1-[5-(4,5-diphenyl-1H-imidazol-2-sufynyl)-pentyl]-3,5-dimethyl-1H-pyrazole; and N-butyl-3-[[(4-decyloxyphenyl)carbonyl]amino]-4-(methylthio)-benzamide;

[image]

ACAt and MMP inhibitor compounds include all possible stereoisomers.

METHODS

The direct antisclerotic potential of ACAT and MMP inhibitors was evaluated according to the reduction of atherosclerotic lesions in the model. Male New Zealand White rabbits (Kuiper Farms, Gary, Indiana) weighing 1.2 to 1.5 kg were fed a special diet (Purina 5321) supplemented with 0.5% cholesterol (C), 5% peanut oil (PNO) and 5% coconut oil (CNO ) for a total of 9 weeks, followed by a fat-enriched diet supplemented with 0% C, 3% PNO and 3% CNO for 6 weeks, and before an eight-week administration of an ACAT inhibitor, for example sulfamic acid [[2,4,6-tris-(1- methylethyl)phenyl]acetyl-2,6-bis(1-methylethyl)phenyl ester, HM-CoA reductase inhibitor, for example simavastin individually or together. The diet regimen consists of giving 30 g in the first week, 40 g in 2 weeks, 50 g in 2 weeks, 60 g in 4 weeks, 70 g in the next 6 weeks and 80 g in the last 8 weeks. One week after the start of the diet, chronic endothelial injury was induced in the abdominal aorta and femoral artery by surgically inserting a sterile 18 cm thin needle with a diameter of 200 μM into the lumen of the right femoral artery. After the initial 15 weeks of the induction phase of the lesion, which consisted of hypercholesterolemic normalization and plasma cholesterol normalization, the animals were divided into statistically identical groups based on plasma cholesterol levels 24 hours after the meal. A group of null control animals (n=16) were necropsied before drug administration, while another group was designated as a progression control (n=16) and was maintained on a high-fat diet for the next 8 weeks of the study. Additional groups of animals were given either ACAT inhibitors, MMP inhibitors, or a combination of both compounds.

Other ACAT inhibitors useful in the practice of this invention are those of formula I below

[image]

where n is zero, one or two; where R-i is selected from the following:

(a) phenyl which is unsubstituted or substituted with one to three substituents selected from the following:

alkyl having from 1 to 4 carbon atoms, which is straight or branched,

alkoxy having from 1 to 3 carbon atoms, which is straight or branched,

alkylthio having from 1 to 4 carbon atoms, which is straight or branched,

hydroxy,

phenyl,

fluorine,

chlorine,

bromine,

nitro,

cyan,

trifluoromethyl,

-COOH,

-COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched,

-(CH2)mNR5R6 where p is zero or one and each rs and R6 is hydrogen or a straight or branched alkyl group having from 1 to 4 carbon atoms;

(b) 1- or 2-naphthyl which may be unsubstituted or substituted with 1 to 3 substituents which are: an acyl group having from 1 to 4 carbon atoms, which is straight or

a branched, alkyl group having from 1 to 3 carbon atoms, which is straight or

branched, hydroxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl,

-COOH,

-COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched,

-(CH2)pNR5R6 where p, R5 and R6 are as defined above;

(c) group

[image]

in which R7 is a lower alkyl group having from 1 to 3 carbon atoms and is straight or branched;

(d) group

[image]

in which R s and R 9 are straight or branched alkyl having 1 to 4 carbon atoms or phenyl, and R 10 is a straight or branched hydrocarbon having 1 to 18 carbon atoms that is saturated or unsaturated and contains one or two non-contiguous double bonds, phenyl , phenyl substituted with from one to three substituents which are: straight or branched alkyl having from 1 to 4 carbon atoms, hydroxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, -COOH, -COO alkyl where alkyl has from 1 of up to 4 carbon atoms, which is straight or branched, -(CH2)pNR5R6 where p, R5 and R6 are as defined above, or a heterocyclic group selected from 2-, 3- or 4-pyridyl, 2-, 4- , or 5-pyrimidines, 2- or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl or 3-or 4-pyradizinyl and the corresponding N-oxides;

(e) group

[image]

(f) group

[image]

(g) straight or branched hydrocarbon having from 1 to 18 carbon atoms that is saturated or unsaturated and contains one or two non-contiguous double bonds,

(h) a cycloalkyl group having 3 to 8 carbon atoms;

(i) a heteroaromatic group selected from 2-, 3- or 4-pyridyl which is

unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms or 2-, 4-, 5-pyrimidyl and the corresponding N-oxides;

(j) group

[image]

wherein ------ represents a single or double bond, Y and Z are each independently hydrogen, a straight or branched alkyne group of 1 to 4 carbon atoms, an alkyl group of 1 to 3 carbon atoms, or a halogen;

X is oxygen or two hydrogen atoms;

R11 is hydrogen or a straight or branched alkyl group having from 1 to 4 carbon atoms and n is zero or one, or

(k) is selected from the group:

[image]

in which R12, R13, R14 and R15 are each independently hydrogen, halogen, straight or branched alkyne group of 1 to 4 carbon atoms, alkyl group of 1 to 3 carbon atoms, alkylthio group of 1 to 4 carbon atoms, heteroarylthio or heteroaryloxy, and B, D, E and G are nitrogen with the restriction that when G=nitrogen the group of Formula I is attached to a nitrogen atom in the 4- or 5-positions of the pyrimidine portene (a and b);

where R2 and R3 are the same or different:

(a) hydrogen, halogen or one of R2 or R3 is hydroxy;

(b) a straight or branched alkyl group having from 1 to 12 carbon atoms or a cycloalkyl group having from 3 to 8 carbon atoms;

(c) phenyl or phenylalkyl group in which the alkyl has from 1 to 4 carbon atoms in which the phenyl ring is unsubstituted or substituted by d 1 to three substituents which can be a straight or branched alkyne group from 1 to 4 carbon atoms, a straight or branched alkyl group from 1 to 4 carbon atoms, straight or branched alkylthio from 1 to 4 carbon atoms, hydroxy, fluorine, chlorine, bromine, trifluorophenyl, cyano, nitro, phenyl or -(CH2)mNR5R6 where m, R5 and R6 have the previously defined meanings,

(d) a straight or branched alkenyl group having from 2 to 6 carbon atoms or;

(e) R 2 and R 3 taken together with the carbon atoms to which they are attached form an alkylidene group of 1 to 4 carbon atoms, a benzylidene or a spiroalkyl group of 3 to 7 carbon atoms; or

(f) when R2 is hydrogen, F, alkyl of C1-12 atoms, R3 is heleroaryl which can be a five- or six-membered monocyclic or fused bicyclic helerocyclic group consisting of at least 1 to 4 heteroatoms and at least one ring, said heterocyclic the group is unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms and corresponding N-oxides;

(g) 1- or 2-naphthyl which can be unsubstituted or substituted with 1 to 3 substituents which are:

alkyl which has from 1 to 4 carbon atoms, and which is straight or branched,

an alkyl group having from 1 to 3 carbon atoms, which is straight or branched,

in which R4 is a straight or branched hydrocarbon having from 1 to 20 carbon atoms which is saturated or unsaturated and contains one or two non-contiguous double bonds or is alkylthio having from 1 to 20 carbon atoms and is saturated, or pharmaceutically acceptable salts or the corresponding individual enantiomeric isomers

The following compounds are useful in this invention:

N-[2,6-bis(1-methylethyl)phenyl]-2-dodecyl-2H-tetrazole-5-acetamide;

2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

N-(2,4-difluorophenyl)-2-dodecyl-2H-tetrazole-5-acetamide;

2-tetradecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

N-(4,6-dimethoxy-5-pyrimidinyl)-2-dodecyl-2H-tetrazole-5-acetamide;

N-(4,6-dimethoxy-5-pyrimidinyl)-2-dodecyl-1H-tetrazole-5-acetamide;

2-dodecyl-N-(3-methyl-2-pyridinyl)-2H-tetrazole-5-acetamide;

2-dodecyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2H-tetrazol-5-acetamide;

1-dodecyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-tetrazol-5-acetamide;

(±)-2-dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-N,α-diphenyl-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis(1-methylethyl)phenyl]-2-dodecyl-2H-tetrazole-5-acetamide;

(±)-N-(2,4-difluorophenyl)-2-dodecyl-2H-tetrazole-5-acetamide;

(±)-2-octyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-hexadecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-N-(4,6-dimethoxy-5-pyrimidinyl)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-N-(5,7-dimethyl-1,8-naphthydrin-2-yl)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-phenyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2H-tetrazol-5-acetamide;

(±)-cyclopropyl-2-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-phenyl-N-2-pyridinyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-N-(3-methyl-2-pyridinyl)-α-phenyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-N-(3-methyl-2-pyridinyl)-2-phenyl-2H-tetrazole-5-acetamide N-oxide;

(±)-N-(1,1-dimethylethyl)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-(2-pyridyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis(1-methylethyl)phenyl]-2-dodecyl-α-2-pyridinyl-2H-tetrazole-5-acetamide;

2-dodecyl-α,α-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

2-dodecyl-α,α-(2-propenyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

1-(2-dodecyl-2H-tetrazol-5-yl)-N-(2,4,6-trimethoxyphenyl)-cyclopentanecarboxamide;

2-tridecyl-α,α-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-propionamide;

N-[2,6-bis(1-methylethyl)phenyl]-2-dodecyl-2H-tetrazole-5-propionamide;

N-(2,4-difluorophenyl)-2-dodecyl-2H-tetrazole-5-propionamide;

1-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-propionamide;

(±)-N-(2,4-difluorophenyl)-1-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis-(1-methylethyl)phenyl)]-1-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-methyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-(4-fluorophenyl)-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-2-naphthalenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-α-([1,1'-biphenyl]-4-yl)-2-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazol-5-acetamide;

(±)-2-dodecyl-α-methyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-phenylmethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(±)-2-dodecyl-α-cyclohexyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide;

(-)-2-dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide [α]D=-58°(1% in CH3OH);

(+)-2-dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide [α]D=+55.1° (1% in CH3OH);

(±)-N-[2,6-bis-(1-methylethyl)phenyl)]-2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetamide;

N-[2,6-bis-(1-methylethyl)phenyl)]-5-decyl-2H-tetrazole-5-acetamide;

N-[2,6-bis-(1-methylethyl)phenyl)]-5-dodecyl-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis-(1-methylethyl)phenyl)]-5-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis-(1-methylethyl)phenyl)]-5-dodecyl-α-pentyl-2H-tetrazole-5-acetamide;

(±)-N-[2,6-bis-(1-methylethyl)phenyl)]-5-(dodecylthio)-α-phenyl-2H-tetrazole-5-acetamide;

(±)-5-decyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide;

5-dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide;

(±)-5-dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide;

(±)-5-dodecyl-α-pentyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide;

(±)-N-(2,4-difluorophenyl)-5-dodecyl-α-phenyl-2H-tetrazole-2-acetamide;

2-dodecyl-α,α-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide;

(±)-5-(dodecylthio)-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide; or

(±)-5-(dodecylsulfinyl)-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-2-acetamide.

The compounds of this invention can be prepared and administered in a wide variety of oral and parenteral dosage forms for the treatment and prevention of atherosclerosis. The compounds can be administered by injection, which is intravenous, intramuscular, intracutaneous, subcutaneous, intraduodenal or intraperitoneal. The compounds of this invention can also be administered by inhalation, for example intranasally. Furthermore, the compounds can be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may have the active ingredient as the free acid or free base, or a corresponding pharmaceutically acceptable salt. The active compound is generally present in a concentration of from about 5% to about 95% by weight of the formulation.

For the preparation of the pharmaceutical compositions of this invention, the pharmaceutically acceptable carriers may be solid or liquid. Solid forms of preparations include powders, tablets, pills, capsules, sachets, suppositories or dispersible granules. The solid carrier may be one or more substances that also act as diluents, flavor enhancers, binders, preservatives, tablet disintegrants, or encapsulating agents.

In powders, the carrier is a finely divided solid that is mixed with a finely divided active component.

In tablets, the active component is mixed with a carrier that necessarily has binder properties, in a suitable ratio, and pressed into the desired shape and size.

Powders and tablets preferably contain from 5% or 10% to about 70% of the active substance. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, butter, and the like. The term "preparation" includes the formulation of an active substance with an encapsulating substance such that a capsule is obtained in which the active component with or without a carrier is surrounded by, and therefore associated with, a carrier. It is similarly included in sachets and lozenges. Tablets, powders, capsules, pills, sachets and lozenges can be used as solid dosage forms suitable for oral administration.

For the preparation of suppositories, a low-melting wax, such as a mixture of glycerides of fatty acids or butter, is first melted, and the active component is added with mixing. The melted homogeneous mixture is then placed in molds of a suitable size, and left to cool, whereupon it hardens.

Liquid preparations include solutions, suspensions and emulsions, for example water or solutions of propylene glycol in water and/or any additive considered safe. For parenteral injections, the liquid preparation can be formulated as a solution in an aqueous solution of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and optionally adding a suitable color, flavor, stabilizer and thickener.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with a viscous material, such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspension agents.

Also included here are solid preparations that are converted into liquid preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions and emulsions. These preparations, in addition to the active component, may contain coloring and flavoring agents, stabilizers, buffers, thickeners, solubilizers and the like.

Pharmaceutical preparations are preferably in unit doses. In such a form, the preparation is divided into dosage units containing the appropriate amount of the active component. The dosage unit form may be a packaged preparation, wherein the package contains discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the dosage unit form may be a capsule, tablet, sachet, or lozenge itself, or may be an appropriate number of each of these packaged dosage forms.

Determining the appropriate dose in a given situation is within the scope of the profession. In general, treatment is initiated at a lower dose than the optimal dose of the compound. Then the dose is increased little by little until the optimal effect is achieved under the given conditions. For convenience, the total daily dose can be divided and given in meals during the day if desired. A typical dosage will be from about 0.1 to about 500 mg/kg, ideally from about 25 to about 250 mg/kg.

Tablet formulation

[image]

Biphenylsulfonamide, lactose and corn starch (for mixing) are uniformly mixed. Corn starch (for the paste) was suspended in 200 mL of water and heated with stirring until a paste was formed. The paste was used for granulating the mixed powders. Wet granules passed through hand sieve no. 8 and dried at 80 °C. The dry granules were lubricated with 1% magnesium stearate and pressed into tablets. Such tablets can be given to people one to four times a day for the treatment of atherosclerosis and arthritis.

Preparation of oral solution

[image]

The sorbitol solution was added to 10 mL of distilled water, and biphenylsulfonamide was dissolved in it. Saccharin, sodium benzoate, flavor and color were added and dissolved. The volume was adjusted to 100 mL by adding distilled water. Each milliliter of syrup contains 4 mg of the compound of the invention.

Parenteral solution

20 g of (S)-2-(4'-amino-biphenyl-4-sulfonylamino)-3-(3-ethoxyphenyl)-propionic acid was suspended in a solution of 700 mL of propylene glycol and 200 mL of water for injection. After the suspension was prepared, the pH was adjusted to 6.5 with 1 M sodium hydroxide, and the volume was made up to 1000 mL by adding water for injection. The formulation was sterilized, filled into 2.0 mL ampoules, each containing 2.0 mL, and sealed under nitrogen.

Claims (35)

1. Use of a therapeutically effective amount of an ACAT inhibitor with a therapeutically effective amount of an MMP inhibitor for the production of a pharmaceutical composition, indicated in that it is for the treatment and/or prevention of atherosclerotic lesions in mammals. 2. The use of a therapeutically effective amount of an ACAT inhibitor with a therapeutically effective amount of an MMP inhibitor for the production of a pharmaceutical preparation, indicated to be for the prevention of plaque rupture and reduction of the spread of lesions in mammals. 3. Use according to claim 1, characterized in that the MMP inhibitor has the formula [image] where And it is a connection, CONH or [image] where Y is CH or N, R1 is alkyl, aryl, halogen, amino, substituted or disubstituted amino or alkoxy; R 2 is carboxyalkyl ketone or oxime, carboxyalkylsulfonamide or [image] R3 is alkyl, substituted alkyl, amino, substituted or disubstituted amino or aryl, or a corresponding pharmaceutically acceptable salt. 4. The use of claim 3, characterized in that the compound is of the formula [image] 5. Use according to claim 3, characterized in that the compound is of the formula [image] wherein R1 and R2 are as defined in claim 3. 6. Use according to patent claim 3, characterized in that the compound is of the formula [image] where R1 is C1-C6 alkyl, halogen, nitro, NR4R5, cyano, OR4 and COOR4; R2 is C1-C6 alkyl which can be substituted with phenyl, substituted phenyl, NR4R5, OR6, carboxy, NH | carboxyamido, H2N-C-NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl and substituted phenyl; R3 is OH, O C1-C6 alkyl, or NHOH; R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkanoyl; R 5 is hydrogen, C 1 -C 6 alkyl; you R6 is hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, phenyl or substituted phenyl. 7. Use according to claim 5, characterized in that the compound is of the formula [image] 8. Use according to claim 6, characterized in that the compound is 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutyric acid. 9. Use according to claim 2, characterized in that the MMP inhibitor has the formula [image] in where R and R1 are the same or different: hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, OR6, where R6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl, -N-R6 wherein R6 and R6a are the same or different as defined for R6 | R6a ON || -O-C-R6, wherein R6 is as defined above, ON || -NH-C-R6, wherein R6 is as defined above, ON || -S-C-R6, wherein R6 is as defined above, -SR6, where R6 is defined above, ON || -C-R6, wherein R6 is as defined above, -CH2-OR6, wherein R6 is as defined above, -CH2-N-R6, wherein R6 and R6a, the same or different, are as above | R6a defined for R6 ON || -C-N-R6, wherein R6 and R6a, the same or different, are as above | R6a defined for R6 ON || -S-R6 where R6 is as defined above, || ON cycloalkyl, or heteroaryl, with the restriction that R and R 1 are not both hydrogen; R 2 is -OR 6 where R 6 is as defined above, or N-R6, and R6 and R6a, are the same or different as defined above for R6, | R6a; R3, R3a, R4 are the same or different: hydrogen, fluorine, alkyl, -(CH2)n-aryl where n is an integer from 1 to 6, -(CH2)n-heteroaryl where n is as defined above, -(CH2)n-cycloalkyl where n is as defined above, -(CH2)p-X-(CH2)q-aryl, where X is O, or S, SO, SO2 or NH, and p and q are zero or an integer from 1 to 6, and the sum of p+q is not greater than six, - (CH2)p-X-(CH2)q-heteroaryl, wherein X, p and q are as defined above, or -(CH2)P-R7 wherein R7 is: N-phthalimido, N-2,3-naphthylimido, - OR6 where R6 is as defined above, N-R6, and R6 and R6a, are the same or different as defined for R6, | R6a; -SR6 where R6 is as defined above, ON || -S-R6 where R6 is as defined above, || ON ON || -O-C-R6 where R6 is as defined above, ON || N-C-R6, and R6 and R6a are the same or different as defined for R6, | R6a; ON || -S-C-R6 where R6 is as defined above, ON || -C-R6 where R6 is as defined above, ON || -C-OR6 where R6 is as defined above, or ON || -C-N-R6a R6 and R6a are the same or different as defined for R6, | R6a; n is as defined above; R 5 is OH or SH; with the restriction that R3, R3a, R4 and R4a are hydrogen or at least one of R3, R3a, R4 or R4a is fluorine, and corresponding isomers or pharmaceutically acceptable salts. 10. Use according to patent claim 9, characterized in that it is a compound of the formula [image] 11. Use according to claim 1, characterized in that the compound is 4-(4'-chlorophenyl-4-yl)-4-hydroxyimino-butyric acid. 12. Use according to patent claim 1, characterized in that the Inhibitor MMP has the formula [image] where X is oxygen or -C-CH2-, NOH || R2 is -C-CH2-CH-COOH or SO2NH-CH-COOH; you | | R3; R3 R 3 is acyl, halogen, alkoxy, aci or aryl. 13. Use according to patent claim 11, characterized in that it is a compound of the formula [image] 14. Use according to claim 12, characterized in that (S)-2-(9H-fluorene-2-sulfonylamino)-4-phenyl-butyric acid is used. 15. Use according to patent claim 12, characterized in that it is a compound of the formula [image] 16. Use according to claim 1, characterized in that the MMP inhibitor has the formula [image] where ON || R1 is C1-C6 alkyl, halogen, nitro, (CH2)0-4-NR4R5, cyano, OR4, CH, CF3; ON || CNR4R5 and COOR4; R2 is hydrogen or C1-C6 alkyl which can be substituted with phenyl, substituted with the following groups: phenyl, substituted phenyl, phenoxy, substituted ON || phenoxy, NR4R5, OR6, carboxy, carboxyamido, H2N-C-NH-, thio, methylthio, indole, imidazole and phthalimido; R 3 is OH, O, OC 1 -C 6 alkyl, or NHOH; R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkanoyl; R 5 is hydrogen, C 1 -C 6 alkyl; you R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, phenyl or substituted phenyl, or corresponding pharmaceutically acceptable salts and solvates. 17. Use according to claim 1, characterized in that the MMP inhibitor is selected from the following group: (S)-2-(4'-chloro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-3-methyl-2-(4'-nitro-biphenyl-4-sulfonylamino)-butyric acid; (S)-2-(41-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 salt; (S)-2-(3'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-bromo-2'-fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (R)-2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-propionic acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-4-methyl-pentanoic 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; (S)-3-methyl-2-(4'-trifluoromethyl-biphenyl-4-sulfonylamino)-butyric acid; 2-(4'-formyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 4'-(1-carboxy-2-methyl-propylsuphamoyl)-biphenyl-4-carboxylic acid; 2-(4'-hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 2-(4'-aminomethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)3-phenyl-propionic acid; (S)-2-(4'-isopropyl-biphenyl-4-sulfonylamino)3-phenyl-propionic acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)3-methyl-butyric acid; you (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)3-methyl-butyric acid tert-butyl ester: 18. Use according to patent claim 1, characterized in that the inhibitor AC AT is a compound of the formula [image] or a corresponding pharmaceutically acceptable salt, X and Y are: oxygen, sulfur or (CR'R")n, where n is an integer from 1 to 4, and R' and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, phenyl which may be substituted or R' and R" together form spiroalkyl or carbonyl; R is hydrogen, straight or branched alkyl of 1 to 8 carbon atoms or benzyl; R1 and R2 are independently: (a) phenyl or phenoxy which may be unsubstituted or substituted with 1 to 5 substituents which are: phenyl, an acyl group having from 1 to 6 carbon atoms, which is straight or branched, an alkyl group having from 1 to 6 carbon atoms , which is straight or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromelyl, -COOH, -COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched, -(CH2)PNR3R4 where p is zero or one, and each R3 and R4 is hydrogen or a straight or branched alkyl group having from 1 to 4 carbon atoms; (b) 1- or 2-naphthyl which may be unsubstituted or substituted with 1 to 3 substituents which are: phenyl, an acyl group having from 1 to 6 carbon atoms, which is straight or branched, an alkyl group having from 1 to 6 carbon atoms, which is straight or branched, hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COO alkyl where the alkyl has from 1 to 4 carbon atoms, and which is straight or branched, -(CH 2 )PNR 3 R 4 where p, R 3 and R 4 are as defined above; (c) arylalkyl; (d) a straight or branched alkyl chain having from 1 to 20 carbon atoms and which is saturated or contains 1 to 3 double bonds; or (e) an adamantyl or cycloalkyl group where the cycloalkyl radical has from 3 to 6 carbon atoms. 19. The use of claim 18, characterized in that R 1 is phenyl. 20. The use of claim 18, characterized in that R1 is phenyl disubstituted in the 2,6-positions. 21. The use of claim 18, characterized in that R 2 is phenyl. 22. The use of claim 18, characterized in that R2 is phenyl disubstituted in the 2,6-positions. 23. The use of claim 18, wherein R1 and R2 are phenyl. 24. The use of claim 23, wherein each phenyl is disubstituted in the 2,6-positions. 25. Use of patent claim 23, characterized in that R1 is phenyl disubstituted in 2,6-positions, and R2 is phenyl trisubstituted in 2,4,6-positions. 26. The use of claim 23, characterized in that R1 is 2,6-bis(1-methylethyl)phenyl and R2 is 2,6-bis(1-methylethyl)phenyl or 2,4,6-tris(1-methylethyl ) phenyl. 27. The use of claim 18, characterized in that R1 is phenyl or isophenyl disubstituted in the 2,6-positions, wherein R2 is phenyl or phenyl disubstituted in the 2,6-positions, wherein each R1 and R2 is phenyl, wherein each phenyl is disubstituted in 2,6-positions, where R1 is phenyl disubstituted in 2,6-positions and R2 is phenyl trisubstituted in 2,4,6-positions, where R1 is 2,6-bis(1-methylethyl)phenyl and R2 is 2,6-bis(1-methylethyl)phenyl or 2,4,6-tris(1-methylethyl)phenyl, where one of R1 or R2 is a group [image] where t is zero or from 1 to 4; w is zero or from 1 to 4; with the restriction that the sum of t and w is not greater than 5; R 5 and R 6 are each independently selected from hydrogen or alkyl having 1 to 6 carbon atoms, or when R 5 is hydrogen R 6 may be selected from the group defined for R 7 , and R 7 is phenyl or phenyl substituted with 1 to 3 substituents which are straight or branched chains of alkyl groups having from 1 to 6 carbon atoms, straight or branched chains of alkoxy groups having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COO alkyl where alkyl has from 1 to 4 carbon atoms, or -(CH 2 )PNR 3 R 4 , where p is p, R 3 and R 4 have the meanings defined above. 28. Use of patent claim 27, characterized in that X is oxygen, sulfur or (CR'R")n Y is oxygen, sulfur or (CR'R")n with the restriction that at least one of X or Y is (CR'R")n where n is an integer from 1 to 4 and R' and R" are each independently hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, phenyl which may be substituted, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" taken together form a carbonyl or spiroalkyl group of 3 to 10 carbon atoms; R is hydrogen; R1 is phenyl which may be substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms; R2 is phenyl which can be substituted, straight or branched alkyl! from 1 to 10 carbon atoms, cycloalkyl from 3 to 8 carbon atoms, phenoxy which may be substituted. 29. Use of patent claim 27, characterized in that X is oxygen, Y is (CR'R")n where n is an integer from 1 to 2; R is hydrogen; R 1 is phenyl which may be substituted; R2 is phenyl or phenoxy which may be substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms; R' and R" are each independently hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, phenyl which may be substituted, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl or R' and R" taken together form carbonyl or spirocycloalkyl. 30. Use of patent claim 26, characterized in that the compound is sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl-2,6-bis(1-methylethyl)phenyl ester 31. The use of claim 18, characterized in that the compound is selected from the following group; sulfamic acid (phenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)phenyl ester, sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)phenyl ester, sulfamic acid [adamantaneacetyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl ester sodium salt, sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,4,6-tris(1-methylethyl)phenyl ester sodium salt, sulfamic acid (decanoyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (dodecanoyl)-2,6-bis(1-methylethyl)phenyl ester, 2,6-bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]-benzeneacetamide, 2,6-bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl]sulfonyl]-benzeneacetamide sodium salt, 2,6-bis(1-methylethyl) [[[2,4,6-trans(1-methylethyl)phenyl]methyl]sulfonyl]carbamate, 2,6-bis(1-methylethyl) [[[2,4,6-trans(1-methylethyl)phenyl]methyl]sulfonyl]carbamate sodium salt, sulfamic acid (1-oxo-3,3-diphenylpropyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid trans-[2-phenylcyclopropyl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2,6-dimethoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid trans-[(2-phenylcyclopropyl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (oxophenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [2-trifluoromethylphenyl(acet)]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (1-oxo-2-phenylpropyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (cyclohexylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (diphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (triphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [(1-phenylcyclopentyl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (3-methyl-1-oxo-2-phenylbutyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid (1-oxo-2-phenylbutyl)-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,4,6-tris(1-methylethyl)phenoxy]acetyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,6-bis(1-methylethyl)phenoxy]acetyl]-2,6-bis(1-methylethyl)phenyl ester, sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(phenyl)phenyl ester. 32. Use according to claim 1, characterized in that the MMP inhibitor is selected from [image] and the ACAT inhibitor is [(2,4,6-triisopropyl-phenyl)-acetyl]sulfamic acid 2,6-diisopropyl ester or N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazole) -5-yl)-2-phenylacetamide. 33. Pharmaceutical preparation for the treatment and/or prevention of atherosclerotic lesions, characterized in that it contains a therapeutically effective amount of ACAT inhibitor and MMP inhibitor. 34. Use according to claim 1, characterized in that the inhibitor AC AT is selected from: 4-hexanedecylamino-benzoic acid monosodium salt; 3,5-dimethyl-1-[5-(1,4,5-triphenyl-2H-imidazol-2-ylsulfanyl)pentyl]-1H-pyrazole monosodium salt; 8-(1,4,5-triphenyl-2H-imidazol-2-yloxy)-octanoic acid; 9-bromo-6,11-dihydro-dibenzo[b,e]oxepine-11-carboxylic acid (2,6-diisopropyl-phenyl)-amide; 5-((3,5-di-tert-butyl-4-hydroxy-phenyamino)-{[4-(2,2-dimethyl-propyl)-benzi]-hexyl-amino}-methylene)-2,2- dimethyl-[1,3]dioxane-4,6-dione; 3-(2,4-difluoro-phenyl)-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-1H-imidazol-2-ylsulfanyl)-pentyl]-1-heptyl-urea; 1-butyl-3-{2-[3-(5-ethyl-4-phenyl-imidazol-1-yl)-propoxy]-6-methyl-phenyl}-urea; 1-(2-{2-[4-(2,2-dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)-3-heptyl-urea; octadeca-9,12-dienoic acid (1-phenyl-ethyl)-amide; 3-(1H-indol-3-yl)-2-octadeca-9-enoyamino-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-fluoro-benzenesulfonamide; 2-(2-ethoxy-ethylsulfanyl)-4,5-diphenyl-1H-imidazole; 4-cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl-4,5-dihydro-3H-imidazol-4-y]-N-methyl-benzamide; 1-{3-[3-(1-methyl-1H-imidazol-2-yl)-2-phenethyl-2H-chromen-6-ioxy]-propyl}-cyclopentanecarboxylic acid ethyl ester; 1-[4-(2-chloro-phenyl)-2-ethyl-thieno[2,3-b]pyridin-5-yl]-3-(2,4-difluorophenyl)-urea; 1-(2-cyclohexyl-[1,3]-dithiolan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl)-urea; 1-(2-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; 2-(4-{2-[3-(2,4-dimethoxy-phenyl)-1-heptyl-uredio]-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; N-(2,6-diisopropyl-phenyl)-2-octadeecysulfanyl-acetamide; 2-bromo-6,11-dihydro-dibenzo[b,e]oxepin-11-carboxylic acid (2,6-diisopropylphenyl)-amide; (±)N-(1,2-diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide; 2,2-dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl)-amide; (Z) 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octadeca-9-en-1-one; (Z)2,2,5,5-tetramethyl-[1,3]dioxane-4-carboxylic acid [2-(2-octadeca-9-enoylamino-ethylcarbamoyl)-ethyl]-amide; 1-benzyl-1-(5-methyl-3-phenyl-benzofuran-2-ylmethyl)-3-(2,4,6-trifluorophenyl)-uea; 5-chloro-3-o-toyl-benzofuran-2-carboxylic acid (2,6-diisopropyl-phenyl)-amide; 2-(2,4a-dimethyl-4a,5-dihydro-naphthalen-1-ylsulfanyl)-N-{2-[(6,6-dimethyl-hepta-2,4-diinyl)-pentyl-amino]-ethyl }-acetamide; (Z)octadeca-9-enoic acid [2-(1,4-dioxa-8-azaspiro[4,5]-dec-8-yl)-1-phenyl-ethyl]-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-1H-isoquinolin-2-yl)-octadeca-9-en-1-one; trans-1,4-bis-(4-methoxy-phenyl)-3-(3-phenyl-propy)-azetidin-2-one; 1-butyl-3-{2-dimethylamino-6-[3-(4-phenyl-imidazol-1-yl)-propoxy]-phenyl}-urea; 1-{2-dimethylamino-6-[3-(4-phenyl-imidazol-1-yl)-propoxy]-phenyl}-3-pentyl urea; 1-{2-dimethylamino-6-[3-(5-methyl-4-phenyl-imidazol-1-yl)-propoxy]-phenyl}-3-pentyl-urea; 1-(2-{2-[4-(2,2-dimethyl-propyl)-phenyl]-ethyl}-4,6-difluoro-phenyl)-3-heptyl-urea; (4S-trans)-6-(4,5-diphenyl-1H-imidazol-2-ylsulfanimethyl)-4-hydroxy-4-methyl-tetrahydro-pyran-2-one; 2-(3-[1,3]dioxan-2-i-propylsulfanyl)-4,5-diphenyl-1H-imidazole; hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester; acetic acid 1-(11-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-octadecanoyl-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-[3-(2,2,5,5-tetramethyl-[1,3]dioxane-4-carbonyl)-amino]-propionic acid 2-[3-(2,2-dimethyl-propyl)-3- nonyl-uredio]-cyclohexyl ester; 1-(2,6-diisopropyl-phenyl)-3-(2-p-tolyl-heptyl)-urea; 1-[4-(2-chloro-phenyl)-6,8-dimethyl-quinolin-3-yl]-3-(2,4-difluoro-phenyl)-urea; 1-[4-(2-chloro-phenyl)-1,6,7-trimethyl-2-oxo-1,2-dihydro-quinolin-3-y]-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; (S)1-[6-bromo-5-(2-chloro-phenyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-7 -yl]-3-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-urea; 3-(4,5-diphenyl-1H-imidazol-2-ylsulfanylmethyl)-1-methyl-piperidine; 2-(5,5-dimethyl-[1,3]-dioxan-2-yl)-4,5-diphenyl-1H-imidazole; 2,2-dimethyl-5-[3-(1-methyl-1H-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-osco-2-phenyl-ethyl)-6,7-dihydro-4H-1,4,6,8a-tetraza-s-indacene-5 ,8-dione; [2-(3-tert-butyl-4-hydroxy-naphthalene-1-yl)-1-(diethoxy-phosphory)-vinyl]-phosphoric acid diethyl ester; 5-[1-(acetoxy-3-methylbutyl]-2'-(hydroxymethyl)-4-methoxy-4'-methylspiro-[benzofuran-2(3H),1'-cyclohexa-2'.4'-diene] -3,6'-dione; 5-[1-(acetoxy)-3-methylbutyl]-4-methoxy-4'-methyl-3,6-dioxospiro-[benzofuran-2(3H), 1'-cyclohexa-2',4'-diene[ -2-carboxaldehyde; (3α,4α,22αa,24α)-3-hydroxy-22-[(1-oxooctadecyl)oxy]-24-norolean-12-ene-29-ic acid 1-[5-(4,5-diphenyl-1H-imidazol-2-sufynyl)-pentyl]-3,5-dimethyl-1H-pyrazole; you N-butyl-3-[[(4-decyloxyphenyl)carbonyl]amino]-4-(methylthio)-benzamide; 35. Use according to claim 1, characterized in that the MMP inhibitor is selected from: 4-[2-(2-carboxymethyl-4-phenyl-butylamino)-3-cyclohexylpropionylamino]-benzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-3-methyl-butyrylamino]benzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino]benzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-5-methyl-valerylamino)-3,3-dimethyl-butyrylamino]benzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-phenyl-butyrylamino)-2-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; 4-[2-(2-carboxymethyl-4-methyl-pentanoylamino)-3-(1H-indol-3-yl)-propionylamino]-benzoic acid methyl ester; 5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca12(19),13,15,17-tetraen-10-ylcarbamoyl)-hexanoic acid; 4-[2-(2-Hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-dimethyl-butyrylamino] benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-2-cyclohexylpropionylamino]-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-4-methyl-valerylamino)-4-methyl-valerylamino]-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3-cyclohexylpropionylamino]-benzoic acid methyl ester; 4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butyrylamino)-3-cyclohexylpropionylamino]-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-5-phenyl-valerylamino)-3,3-dimethyl-butyrylamino]-benzoic acid methyl ester; 5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca12(19),13,15,17-tetraen-10-ylcarbamoyl)-1-hexylhydroxamic acid; 4-[2-(2-hydroxyaminocarbonylmethyl-4-methyl-valerylamino)-3-(1H-indol-3-yl)-propionylamino]-benzoic acid methyl ester; 3-[2-(4-Methoxy-benzylsulfanyl-2-methyl-1-phenylcarbamoyl)-propylcarbamoyl]-5-methyl-hexanoic acid; 3-[2-(4-Methoxy-benzylsulfanyl-2-methyl-1-phenylcarbamoyl)propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxamide; 4-[2-(2-hydroxyaminocarbonylmethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylamino]-benzoic acid methyl ester; 2-(phenyl-2-ethyl)benzoic acid N-hydroxamide; 4-[2-(2-acylhydroazinomethyl-4-methyl-pentanoylamino)-3-(1H-indol-3-yl)-propionylamino]-benzoic acid methyl ester; 2-(propylthio)-pyridine-3-N-(hydroxy)carboxamide; 4-[2-(2-carboxymethyl-5-phenyl-pentanoylamino)-2-cyclohexyl-acetylaminoj-benzoic acid methyl ester; [4-(N-hydroxyamino)-2R-isobutyl-3S-((thien-2-thio)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; 4-[2-(2-carboxymethyl-5-(3-hydroxyphenyl)-pentenoyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(3-aminophenyl)-pentenoyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester, trifluoroacetate; 2-(phenyl-2-ethyl)pyridine-3N-hydroxycaroxamide; 4-[2-(2-carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(3-aminophenyl)-acetyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 2-[3-(3-hydroxy-phenyl)-propyl]-benzhydroxamic acid; 2-(thiobenzium)benzoic acid N-hydroxamide; 1-(3-phenyl-propyl)-pyrrolidine-2-hydroxamic acid; 4-[2-(2-carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(N'-methyluredio)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(trifluoroacetamido)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-2-phenylacetylamino)-4-methyl-valeroyl]amino-benzoic acid methyl ester; 4-[2-(2-hydroxyaminocarbonylmethyl-2-phenylacetylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl-acetylamino]benzoic acid methyl ester; 2-[3-(3-amino-phenyl)-propyl]-benzhydroxamic acid; cis-4-benzyloxy-pyrrolidine-2-carboxylic acid; 4-[2-(2-carboxymethyl-5-(3-amino-4-(trifluoromethyl)phenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(methanesulamido)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; N-Cbz-L-tyrosine; N-Boc-L-tryptophan; 4-[2-(Carboxy-2-otolyl-propionylamino-4-methyl-pentanoylamino]-benzoic acid methyl ester; 4-[2-(Carboxymethyl-heptanonylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 4 -[2-(2-carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-carboxymethyl-5-(4-n-butylphenyl)-4-pentanoyl)amino)-4-methyl-valeroyl]aminobenzoic 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; 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; pyridine-1-carbothionic acid phenylethyl-amide; 3-(2-methyl-thiazol-4-yl)-N-phenethyl-propionamide; N-phenyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-propionamide; 3-(3H-imidazol-4-yl]-N-phenethyl-propionamide; 4-[2-(2-carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl-valeroyl]-aminobenzoic acid methyl ester; 2-cyclohexylmethyl sulfonyl-benzenehydroxamic acid; [2-oxo-3-(3-phenyl-propyl)-tetrahydrouran-3-yl]-acetic acid 4-[2-(2-carboxymethyl-5-(fuoren-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; 4-[2-(2-benzylthio-3-carboxy-propionylamino)-4-methylpentanoylamino]-benzoic acid methyl ester; 4-[2-(2-carboxymethyl-4-(f2-indolyl)butyrylamino)-4-methyl-valeroyl]amino-benzoic acid methyl ester; 1-allyl-3-(2-hydroxyethyl)-2-thiourea; 3-(1-hydroxyimino-propyl)-6-phenyl-hexanoic acid; 3-(3H-imidazol-4-ylmethyl]-N1,N4-diphenethyl-succinamide; 3-(2-hydroxymethyl-3H-imidazol-4-yl-N-phenethyl-propionamide; 6-phenyl-3-propionyl-hexane) acid; 4-{2-([2-hydroxyamino-2-hydroxylamino-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-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-hexanoic acid trifluoroacetate; 3- [1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5-methyl-hexanoic acid;6-biphenyl-4-yl-3-[1-(5,6 -dichloro-1H-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5-methyl-hexanoic acid; 2-carboxymethyl-heptanoyl-2-[N-methylcarboxamide)piperidine; 4-[2-(2-( 2-phenylcyclopropyl)succinylamino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 2-carboxymethyl-heptanoyl-3-(N-methylcarboxamide)hexahydropyridazine; 6-biphenyl-4-yl-3-[1-[3-( 3-hydroxy-ethyl)-phenylcarbamoyl]-2,2-dimethyl-propylcarbamoyl]-hexane k Eselin; 2R-(3-(4-biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5-methyl-3S-hexyl)succinamide; 6-biphenyl-4-yl-3-[1- [3-(2-aminoethyl)-phenylcarbamoyl]-2,2-dimethyl-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-methyl-pentanoic acid; 2-(3-biphenyl-4-yl-propyl)-N1- [1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-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; 6 -biphenyl-4-yl-3-[1-phenylcarbamoyl)-2-(4-cyano-benzenesulfanyl)-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-phenethylthiocarbamoyl)-pyrrolidine-2-carboxylic acid; 6-biphenyl-4-yl-3-({cyclohexyl-[2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)hexanoic acid; 2R-(6-(4-biphenyl)propyl)-3-(N-benzylcarbamoyl))hexanoic acid N-hydroxamide; [3-(3-biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3-y]-acetic acid; 2-benzenesulfonyl-cyclopent-1-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-y]- acetic acid; 2-benzenesulfonyl-cyclohex-1-enecarboxylic acid hydroxamide; 6-benzenesulfonyl-cyclohex-1-enecarboxylic acid hydroxamide; 2R-(3-(4-biphenyl)propyl)-N-(3-methylpyridine)succinamide; {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; [2-oxo-3-(3-biphenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid 4-[2-(2-thioamidomethyl-5-phenyl-valeriamino)-4-methyl-valeroylamino]- benzoic acid methyl ester; 4-[2-(2-amino-2-hydroxyimino-ethyl-5-phenyl-valeramino)-4-methyl-valeroylamino]-benzoic acid methyl ester; 6-biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsuphamoylphenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-biphenyl-4-yl-3-[2,2-dimethyl-1-(2-hydroxyethylsuphamoyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1-(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 salt; 2R -(6-(4-biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoic acid N-hydroxamide; 6-biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsuphamoyl)- phenylcarbamoyl)-methylcarbamoyl}-hexanoic acid; 6-biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino-ethylsuphamoyl)-phenylcarbamoyl)-methylcarbamoyl}-hexanoic acid trifluoroacetate salt; 4-(2-{ 2-carboxymethyl-5-[4-(1H-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-hydroxyamino-3-(3-phenyl-propyl)-3 ,4-dihydro-2H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino]-benzoic acid methyl ester; 5-hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2H -pyrrole-3-carboxylic acid-(2-cyclohexyl-1-methylcarbamoyl-ethyl)amide; 6-biphenyl-4-i 1-3-[2,2-dimethyl-1-(4-(3-morpholin-4-i-suphamoyl)-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-1-(4-methylsulfonyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-[2-(5-biphenyl-4-yl-2-carboxyethyl-pentanoylamino)-pent-4-enoylamino]-benzoic acid methyl ester; 6-biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl-hexanoic acid; 4-(2-{[5-hydroxyamino-3-(3-pentyl)-3,4-dihydro-2H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino]-benzoic acid methyl ester; 5 -hydroxyamino-3-(3-pentyl)-3,4-dihydro-2H-pyrrole-3-carboxylic acid-(2-cyclohexyl-1-methylcarbamoyl-ethyl)amide; 6-biphenyl-4-yl-[2, 2-dimethyl-1-(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-yl-3R-(2-hydroxy-1S-phenyl-ethylcarbamoyl)-hexanoic acid; 3R-(1R-benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl -4-ylhexanoic acid; 6-biphenyl-4-yl-3R-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-hexanoic acid; 4-[2-(2-carboxymethyl-5-(4-pyridine-4- i-phenyl)-pentanoylamino)-4-methyl-pentanoylamino-benzoic acid methyl ester; 6-biphenyl-4-yl(2-hydroxy-2-methyl-1-phenylcarbamoyl)-propylcarbamoyl}-hexanoic acid; 3-{2 -allylsulamyl-2-methyl-1-[2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-propylcarbamoyl}-6-biphenyl-4-yl-hexane and acid; 4-[2-(5-biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-4,5-dihydroxy-pent-anoylamino-benzoic acid methyl ester; 4-(2-{5-[4'-(2-amino-ethoxy)-biphenyl-4-i]-2-carboxymethyl-pentanoylamino}-4-methyl-pentanoylamino]-benzoic acid methyl ester; 6-biphenyl- 4-yl-3R-(2-hydroxy-1S-phenyl-ethylcarbamoyl)-hexanehydroxamic acid; 3R-(1R-benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-i-hexanehydroxamic acid; N-[5 -(biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl)-tert-leucine, N-(pyrid-4-yl)amide; [3-(3-naphthalen-2-yl-propyl)-2-oxo-tetrahydrofuran-3-yl]-acetic acid; 6-biphenyl-4-yl-3R-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-hexanehydroxamic acid; 4-[2-(2-carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-5-methyl-hexanoic acid; N1-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propyl]-N-hydroxy-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-3R-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid; 4-{2-[5-biphen-4-yl-2-(1-carboxy-ethylamino)-pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 6-biphenyl-4-yl-3R-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamic acid; 6-biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfinyl-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 2-(biphenyl-4-sulfonyl)-cyclohex-1-enecarboxylic acid hydroxamide; 2-(biphenyl-4-sulfonyl)-cyclohex-1-enecarboxylic acid hydroxamide; 2-phenethylsulfanyl-cyclohex-1-enecarboxylic acid hydroxamide; N-hydroxy-2-[2-oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetamide; 4-[2-(2-carboxymethyl-5-(4-(2-hydroxy-biphenyl-4-yl)-valeroylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester; N1-(2-benzyloxo-1 -hydroxymethyl-propyl)-2-(3-biphenyl-4-yl-propyl)-N4-hydroxy-succinamide; trans-2-(4-phenoxy-benzylsulfanyl)-cyclohexanecarboxylic acid hydroxamide; 2-(4-indole-1 -yl-benzylsulfanyl)-cyclohexanecarboxylic acid hydroxamide; 6-biphenyl-4-yl-3-[2-hydroxy-2-me propylcarbamoyl]-hexanoic acid; 6-biphenyl-4-yl-3-[2,4,5 -trihydroxy-6-hydroxymethyl-tetrahydropyran-3-ylcarbamoyl)-hexanoic acid; 5-biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic acid {1-[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl-butyl}-amide; 2-(3-biphenyl-4-yl-propyl)-N4-hydroxy-N1(2,4,5-trihydroxy-6-hydroxy tetrahydropyran-3-yl)-succinamide; 6-biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-3-ylcarbamoyl)-hexanoic acid; N-[2,2-dimethyl-1S-(pyridin-4-ylcarbamoyl)-propyl]-3R-thiophen-3-yl-succinic acid; 4-[2S-(2R-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-propionylamido)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 3R-(2-benzyloxo-phenyl)-1S-hydroxymethyl-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 6-biphenyl-4-yl-3R-(2-hydroxy-1S-(4-hydroxy-benzyl)-ethylcarbamoyl)-hexanoic acid; 6-biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid; N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxo-pentanoyl)-L-Meucine, N'-4-(methylthio)phenyl amide; 6-biphenyl-4-yl-3R-(2-hydroxy-1S-(4-hydroxy-benzyl)-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)-cyclohexanecarboxylic acid hydroxamide; 3-acetyl-6-biphenyl-4-yl-3-hexanoic acid; N-[5-(biphenyl-4-yl)-2-(1-carboxy-2-hydroxybut-1-yl)pentanoyl]-tert-L-leucine, N'-4-(methylthiophenyl) amide; 6-biphenyl-4-yl-3-(2-hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 2-(2-biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2-hydroxy-cyclohexyl)-succinamide; and 6-biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexane hydroxamide acid; 6-biphenyl-4-yl-3-(2-hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 6-biphenyl-4-yl-3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl)-hexanoic acid ethyl ester; 2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl-propyl-2-yl)-propionamide; N-[5-(biphenyl-4-yl)-2-(1-carboxy-2-hydroxyethyl)pentanoyl]-L-tert-leucine, N'-(4-methylthiophenyl)amide; 3R-(2-hydroxy-1S-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanoic acid; 3R-(2-hydroxy-1S-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid; 5-biphenyl-4-yl-2-(1-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-pentanoic acid; 2-(3-biphenyl-4-yl-propyl)-N-hydroxy-N'-(1-hydroxymethyl-3-methylsulfanyl-propyl)-maonamide; 6-biphenyl-4-yl-3-(3-hydroxy-piperidin-1-carbonyl)-hexanoic acid; 6-biphenyl-4-yl-3-(3-hydroxy-piperidin-1-carbonyl)-hexanoic acid hydroxamide; 1-(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; N-(1-benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinic acid; N-(1-benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinamic-hydroxamic acid; 6-biphenyl-4-yl-3R-2S-hydroxy-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoic acid; 3-(1-benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid; N1-(1-benzyl-2-hydroxy-ethyl)-N4-hydroxy-2-isobutyl-succinamide; 6-biphenyl-4-yl-3R-2S-hydroxy-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamic acid; 1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; 6-biphenyl-4-yl-3-(2-hydroxy-1-hydroxymethyl-propylcarbamoyl)-hexanoic acid; 6-biphenyl-4-yl-3R-(2-oxo-cyclohexyl-1S-carbamoyl)-hexanoic acid; 6-biphenyl-4-yl-3-(2-hydroxy-1-hydroxymethyl-propylcarbamoyl)-hexanehydroxamic acid; 2S-[(1S-benzyl-2-hydroxy-ethylcarbamoyl)-3R-biphenyl-4-yl-pyrrol-1-yl-methyl]-pentanoic acid; 3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-(2R-hydroxy-cyclohexyl-1R-yl)-succinic acid; 2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxamate-N-(1-hydroxy-3-phenyl-prop-2-yl)-propionamide; trans-2-(3-biphenyl-4-yl-propyl)-cyclohexanecarboxylic acid; trans-2-(3-biphenyl-4-yl-propyl)-cyclohexanecarboxylic acid hydroxamide; 6-biphenyl-4-yl-3R-(1S-hydroxymethyl-2-(3-pyridyl)-ethylcarbamoyl)-hexanoic acid; 6-biphenyl-4-yl-2S-hydroxy-3R-(1-hydroxymethyl-2S-(1H-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid; 1-[4-biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 1-[4-biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1-(4-phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; 6-biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanoic acid; 6-biphenyl-4-yl-3R-(1S-hydroxymethyl-2-(3-pyridyl)-ethylcarbamoyl)-hexanehydroxamic acid; 6-biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanehydroxamic acid; 1-[4-(4-Bromo-phenoxy)enesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acid hydroxamide; 1-[4-(4-Bromo-phenoxy)enesulfonyl]-4-piperazine-2-carboxylic acid hydroxamide; 3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[2-hydroxy-1S-(1H-imidazol-4-yl)-methyl)-ethyl]-succinic acid trifluoroacetate; 3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[1S-(methoxy-methylcarbamoyl)-3-methyl)-butyl]-succinic acid; N-(acetyl-3-methyl-butyl)-3-(3-biphenyl-4-i-pyrrol-1-yl)-succinic acid; 6-biphenyl-4-yl-3R-(2-oxo-tetrahydrofuran-3S-ylcarbamoyl)-hexanoic acid; 3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl)-2-hydroxy-5-methyl-hexanoic acid hydrochloride; N4-(2,2-dimethyl-1-methylarbamoyl-propyl)-2,N1-dihydroxy-3-isobutyl-succinamide; 6-biphenyl-4-yl-3R-(2-oxo-azepan-3S-ylcarbamoyl)-hexanoic acid; N-(1-benzyl-2-hydroxy-ethyl)-3-(4-biphenyl-4-yl-pyrazol-1-yl)-succinamide; N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.0,12,17]octadeca11(18),12(17),13,15-tetraen-9R-yl)-3S- (3-phenyl-pyrdol-1-yl)-succinic acid; 4-acetyl-1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxamide; 1-(Diphenylphosphine)-piperidine-2-carboxylic acid hydroxamide; 3R-(3-biphenyl-4-yl-pyrrol-1-yl)-N-[3S-(2RS-hydroxy-5-methyl)-hexyl]-succinamide; N-(1S-benzyl-2-hydroxy-ethyl)-3R-(2-biphenyl-4-yl-cyclopropylmethyl)-succinamide; 6-biphenyl-4-yl-3R-(2-oxo-1-tetrahydrofuran-3S-ylcarbamoyl)-hexanehydroxamic acid; 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-trimorpholine-3-carboxylic acid hydroxamide; 3-(diphenylphosphine)-propionic acid; 3-(diphenylphosphine)-propionic acid hydroxamide; 4-[2-(2-carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 1-[4-(4-chloro-phenoxy)-benzenesulfonyl]-N-hydroxy-4-(N-methylcarbamoyl)-piperazine-2-carboxamide; 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxamide; 3-(3-biphenyl-4-yl-pyrrol-1-yl)-N-(212-dimethyl-1-methylcarbamoyl-propyl)succinic acid; 1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid N-hydroxamide; 4-[4-phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxamide; 3R-[2-biphenyl-4-yl-ethylsulfanyl]-tetrahydropyran-4-carboxylic acid N-hydroxamide; 6-biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid 1-[4-(4-bromo-phenoxy)-benzenesulfonyl]-piperidine-2-amidoxime; 2-(3-biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl-prop-2-yl)propionamide; {3-[3-(3-amino-phenyl)-propyl]-2-oxo-tetrahydrofuran-3-yl}-acetic acid; 6-biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid 5-biphenylvaleric xylene; 1-[4-(methoxy)-benzenesulfonyl]piperidine-2-amidoxime; 1-[4-phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxamide; {3-[3-(3-Methylamino-phenyl)-propyl]-2-oxo-tetrahydrofuran-3-yl}-acetic acid; 6-biphenyl-4-yl-3R-(2-oxo-azepan-3S-ylcarbamoyl)-hexanehydroxamic acid; 4-(1H-indole-2-sulfonyl)-thiomorph! in-3-carboxylic acid hydroxamide; 1R-[4-bromo-phenoxy)-benzenesulfonyl]-N-amino-piperidine-2-carboxamide; 2-(3-biphenyl-4-i-propyl)-3,N-dihydroxy-N1-(1S-hydroxymethyl-3-methanesulfinyl-propyl)-succinamide; N-(1-benzyl-2-hydroxy-ethyl)-3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-1-y]-butanic acid; 1-(methyl-phenylphosphine)-piperidine-2R-carboxylic acid hydroxamide; 4-(4-(4-Chlorophenoxy)benzenesulfonyl-N-hydroxy-morpholine-3R-carboxamide; 2S-[1R-(3-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl)- N-(2,2-dimethyl-1S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; 2SR-{1S-benzyl-2-hydroxyethylpropylcarbamoyl-[3R-(4'-cyano-biphenyl-4-yl!)-pyrrol-1-yl]-methyl}-pentanoic acid; 2S-[3-(biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; 1-(1,3-dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 3-[3-(4'-carbamoyl-biphenyl-4-yl]-pyrrol-1-yl)-N-(1-hydroxymethyl-2,2-dimethyl-propyl)succinic acid; 4-Methyl-1-(4-(4-Chlorophenylbenzenesulfonyl-N-hydroxy-2R-piperazinecarbamide hydrochloride; 1-[4-Chlorophenoxybenzenesulfonyl-N-hydroxy-2R-piperazinecarbamide; 2-(3-Phenyl-propylsulfonyl)-cyclohexane carboxyl acid hydroxamide; 1-(pyrrolidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1-(piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 4-[4-bromo-phenoxy-benzenesulfonyl] -oxothiomorpholine-3-carboxylic acid N-hydroxamide; 1-[4-(4-methoxy-phenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylic acid N-hydroxamide; 1-[4-(4-nitrile-phenyl)- benzenesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylic acid N-hydroxyamide;2S-[3-(biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2-dimethyl -propionylcarbamoyl)-methyl]-pent-4-enoic acid; 6-oxo-3-(4-phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4-carboxylic acid hydroxamate; 4-(t-butoxycarbonyl)-1-(4 -(pyridin-2-yl)oxybenzenesulfonyl)-N-hydroxy-piperazine-2-carboxamide; 4-[(4-fluorophenoxy)-benzenesulfonyl ]-thiomorpholine-3-carboxylic acid N-hydroxamide; 4-[4-(Fluorophenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid N-hydroxamide; N-(2,2-dimethyl-1S-hydroxymethyl-propyl)-3-R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)]-succinic acid; N-(1S-benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl)-succinic acid; 4-(butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acid hydroxamide; 4-(butoxy-benzenesulfonyl)-1-oxothiomorpholine-3-carboxylic acid hydroxamide; 1-[4-(4-fluorophenyl)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-2R-piperazine-2-carboxylic acid hydroxamide; 1-((4-(4-chlorophenyl)-piperazine)-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; c/s-2-phenethylsulfanyl-cyclohexanecarboxylic acid hydroxamide; N-(2-hydroxy-1S-phenyl -ethyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)]-succinic acid; 1-[4-(4-fluorophenyl)-benzenesulfonyl]-N-hydroxy-2R-piperazinecarboxamide hydrochloride; 1-(diphenylphosphine)-pyrrolidine-2R-carboxylic acid hydroxamide; N,N-{(diphenylphosphine)-(acetic acid-sodium salt)}-hydrazide; N-(1-benzyl-2-hydroxy-ethyl)-3-(1-biphenyl-4-i-1H-pyrrol-3-yl)-succinic acid; trans-2-phenylsulfonyl-cyclohexanecarboxylic acid hydroxamide; 1-[4-(4-fluorophenyl)-piperazine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 1-[4-(4-fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxamide; 4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylic acid hydroxamide; N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-phenyl-pyrrol-1-yl)-succinic acid; 3R-(3-biphenyl-4-yl)-N-(2-hydroxy-1S-hydroxymethyl-2-methyl-propyl)-succinic acid; 1-(pyrrolidine-1-carbonyl)-pyrrolidine-2R-carboxylic acid; 1-(pyrrolidine-1-carbonyl)-pyrrolidine-2R-carboxylic acid hydroxamide; 1-phenethylcarbamoyl-pyrrolidine-2R-carboxylic acid; R-4-[4-(bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylic acid hydroxamide; 4-(ethoxycarbonyl)methyl-1-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochloride; N-(2R-hydroxy-indan-1R-yl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid; N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid; N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinic acid; 1-phenylethylcarbamoyl-pyrrolidine-2R-carboxylic acid hydrocamide; N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-[3-(4-propyl-phenyl)-pyrrol-1-yl]-succinic acid; 1-(4-benzyl-piperazine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 3S-N-hydroxy-4-(4-pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 2R-4-methyl-1-4-(4-fluorophenyl)benzenesulfonyl)-N-hydroxy-piperazine-2-carboxamide; N-(2,2-dimethyl-methylcarbamoyl-propyl)-3-(5-biphenyl-4-yl-furan-2-yl)-succinic acid; N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-pyridin-4H1-pyrrol-1-yl]-succinic acid; 1-((2-pyridyl)-4-piperazine-1- sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1-[4-(pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxamide; N-(4-phenoxy-benzenesulfonyl)-D-tert-leucine ; N-(4-phenoxy-benzenesulfonyl)-D-tert-leucine N-hydroxamide; N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.0,12,17]octadeca11 (18 ), 12(17), 13,15-tetraen-9R-yl)-3-[4-(pyridyl)-3-phenyl-pyrdol-1-yl)-succinic acid; 3-[3-(4-pyridyl)phenyl-4-yl-pyrdol-1-yl]-N-H2,-dimethyl-1-(4-pyridi)carbamoyl-propyl]-succinic acid; 2,2-Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamide; N-[4-(4-fluorophenoxy)benzenesulfonyl)-D-tert-leucine; N-[4-(4-fluorophenoxy)benzenesulfonyl)-D-tert-leucine N-hydroxamide; 2-[2-(N'-acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl-pentanoic acid; 3R-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride; 2-[4-(4-chloro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-butyric acid; 2-[4-(4-chloro-phenoxy)-benzenesulfonyl]-N-hydroxy-3,3-dimethyl-butyramide; 3R-N-hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2-dirnethyl-tetrahydro-2H-1,4-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 hydroxamide; 2-[4-(pyridin-2-yloxy)-benzenesulfonylamino]-3,3-dimethyl-butyric acid; 2-[4-(pyridin-2-yloxy-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl-butyramide; N-(4-phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D -cysteine; 3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-succinic acid; 3-[ 3-(4'-cyano-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1-methylcarbampropyl)-succinic acid; 2-(2-biphenyl-4-yl) -ethylsulfonyl)-cyclohex-1-ene-carboxylic acid hydroxamide; 6-(2-biphenyl-4-yl-ethylsulfonyl)-cyclohex-1-ene-carboxylic acid hydroxamide; N-(4-pyridin-4-yl-oxo -benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine;3-[3-(4'-carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-[2, 2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propyl]-succinic acid; N-(4-phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine N-hydroxyamide; 1 -(4-phenoxy-piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 3R-4-[4-(4-bromo)phenoxybenzenesulfonyl]-2,2-dimethyl-tetrahydro-2H-1,4- thiazine-3-carboxylic acid; N-(4-[4-chloro-phenoxy]-benzenesulfonyl)-3,3-d imethyl-S-(methylthio)-D-cysteine; N-(4-[4-chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine N-hydroxamide; N-(4-[4-chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylsulfoxy)-D-cysteine N-hydroxamide; 2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-3-ylsulfanyl)-butyric acid; 2R-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-4-ylsulfanyl)-butyric acid; cis-2-(2-phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamide; 2R-N-hydroxy-4-(4-(imidaz-1-yl)phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 2R-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 4-[2-(2-hydroxycarbamoylmethyl-5-phenyl-pentanoylamino)-4-methyl-pentanoyl-benzoic acid methyl ester; trans-2-(2-phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamide; 3,3-dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid; 2-[4-(4-chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin-4-ylmethylsulfanyl)-butyric acid; 3R-[3-(4'-cyano-biphenyl-4-yl)-propyl-1-yl]-N-(2,2-dimethyl-1S-(pyridin-4-ylcarbamoyl-propyl)-succinic acid; 3 ,3-dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid N-hydroxyamide; N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-3-[1-(4-fluorophenyl)-1H- pyrrole-succinic acid; 2R-[4-(4-bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 2-(2-biphenyl-4-yl-ethanesulfonyl) )-cyclohexanecarboxylic acid hydroxamate; 2-[4-(4-chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin-4-ylmethylsulfanyl)-butyric acid N-hydroxamide; 3,3-dimethyl- 2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid N-hydroxamide; 3-tert-butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro -phenoxy)-benzenesulfonylamino]-3-methyl-butyric acid; 1-(4-phenylsulfanyl-piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1-[4-(4-fluoro-phenoxy)-benzenesulfonyl )-3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid; N-(4-[ 4-fluorophenoxy)]-benzenesulfonyl)-3-methyl-3-(1-benzyl-imidazol-2-yl-sulfanyl)-butyric acid; 2R-[4-(4-fluoro-phenoxy)benzenesulfonyl)amino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide; 3R-N-hydroxy-4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 1-[4-(4-chloro-phenoxy)-benzenesulfonyl)-4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-dimethyl-1S-methylylcarbamoyl-propyl)-3R-[1-(4'-cyanobiphenypyrrol-1-yl]-1H-pyrrol-3-yl]-succinic acid; 3-carboxymethylsulfanyl-2 -(4-Fluoro-phenoxy)-benzenesulfonyl)-3-methyl-butyric acid; 2,2-dimethyl-1-oxo-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1S14-thiomorpholine-3-carboxylic acid hydroxamide; 1-[4-(pyridin-2-ylsulfanyl)-piperidin-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 3R.[4-(4-(fur-3-yl)phenoxy)-benzenesulfonylamino]-3-methyl-(pyridin-2-ylsulfanyl)-butyric acid; 2,2-dimethyl-1-oxo-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1S14-thiomerofoline-3-carboxylic acid hydroxamide; {2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl-1,1-dimethyl-ethylsulfani}3-acetic acid tert-butyl ester; 1-[4-(pyridine-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 2R-[4-(4-bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide; trans-2-(2-biphenyl-4-ylethylsulfanyl)-cyclohexanecarboxylic acid hydrocamide; N-[1S-(1H-imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-i-phenyl)-propyl-1-i]-succinic acid formate; N-methyl-3-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl)-butaneic acid N4-(2,2-dimethyl-1S-hydroxymethyl-propyl)-N1-hydroxy- 3R[1-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succinamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbanoyl-1,1-dimethyl-ethylsulfani}3-acetic acid; 1-[4-[(4-fluoro-phenoxy)benzenesulfonyl)]-3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid hydroxamide; N-(4-[4-bromo-phenoxy]benzenesulfonylamino)-3-methyl-3-(1-benzyl-imidazol-2-ylsulfanyl)-butyric acid; 3R-[3-(4'cyanobiphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-(pyridin-4-ylcarbamoyl-propyl)succinic acid; 2R-[4- (4-Iodophenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid;3R-[3-(4-cyano-phenyl)-pyrrol-1-yl]-N-(2, 2-dimethyl-1S-hydroxymethyl-propyl-succinic acid; 2R-[4-(4-iodo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid hydroxamide; 2R-[4 -(4-nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl)-butyric acid; 2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl- pent-4-enoic acid; 2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyric acid; 2-[4-( 4-bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyric acid; 2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy -3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-butyramide; 2-[4-(4-bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3-(5-methyl -isoxazol-3-ylmes tilsulfanyl)-butyramide; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(carbomethoxyethyl-sulfanyl)-butyric acid; 1-[2-(Benzothiazol-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 3R-[3-(4-cyano-phenyl)-pyrrol-1-yl]-N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-succinic acid; 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-tetrahydrofuran-2S-yl)-3R-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinic acid; 2-[4-(4-fluorophenoxy)-benzenesulfonylamino]-3-methyl-3-(aminoethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid; 2-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5-phenyl-pent-4-enoic acid; 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-34,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridine-6-carboxylic acid hydroxamide; 2R-[4-(4-methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid; 2S-4-(4-((pyrid-4-yl)oxo)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid; 1-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfanyl]-piperidine-2-carboxylic acid hydroxamide; N-[1-(1H-imidazol-2-yl)-3-methyl-butyl]-3-[1-(4-'cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinic acid; 3R-{3-[(4-cyanophenyl)-acetyl]-pyrrol-1-yl}-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1S-methylcarbamoyl-propyl)-succinic 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-methylcarbamoyl-propyl)-succinic acid methyl ester; 2R-[4-(4-methylphenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfonyl)-butyric acid hydroxamide; 1-[4-(4-Methoxy-phenylsulfamyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid hydroxamide; 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-3-thiomorpholine-3-carboxylic acid hydroxamide; 2R-[4-(4-bromo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl)-butyric acid hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-1-oxo-3-thiomorpholine-3-carboxylic acid hydroxamide; 2,2-dimethyl-4-[4-pyridin-4-yloxo)-benzenesulfonyl]thiomorpholin-3-ol; 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-3-thiomorpholine-3-carboxylic acid hydroxamide; 2R-3-methyl-3-(pyridin-2-yl-sulfanyl)-[4-(4-trifluoromethylphenoxy)-benzenesulfonylamino]-butyric acid; 3R-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-yloxy)-benzenesulfonylamino-butyric acid; 2R-N-hydroxy-3-methan-3-[(5-methyl 4-yloxy)-benzenesulfonylamino]-butyramide; 2R-[4-(4-bromophenoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-butyric acid; 3S-2,2-dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]thiomorpholine-3-carboxylic acid hydroxamide; 2R-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-ylsulfanyl benzenesulfonylamino]-butyric acid; 2R-N-hydroxy-3-methyl-3- [(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-ylsulfanyl-benzenesulfonylamino]-butyramide; 3,3-dimethyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidine -1-sulfonylamino] butyric acid; 3,3-dimethyl-N-hydroxy-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino] butyramide; 2R-[4-(4-bromophenoxy)- benzenesulfonylamino]-N-hydroxy-3-methyl-[(1-methyl-imidazol-2-yl)methylsulfanyl]-butyramide;2R-[4-(4-bromophenoxy)-benzenesulfonylamino]-3-methyl-[(1- methyl-imidazol-2-yl)methylsulfanyl]-butyric acid; N-hydroxy-2-[(4-methylbenzenesulfony)amino]acetamide; 1-[4-(imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl ]-piperidine-2-carboxylic acid hydroxamide; 1-[4-(imidazol-1-yl-phenylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 2R-[4-(4-chloro- benzoyl)-cyclohexanesulfonyl]-piperidine-1-carboxylic acid hydroxamide; 2R-[4-(4-chloro-benzoyl )-piperidine-1-sulfonyl]-piperidine-1-carboxamide; 1R-(4-pyridin-2-yl-piperazin-1-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 1R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid; 1R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; N-hydroxy-3,3-dimethyl-2R-[4-(morpholine-4-carbonyl)piperidine-1-sulfonylamino]butyramide; N-hydroxy-3-methyl-3-(5-methyl-isoxazol-3-ylmethylsulfanyl)-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino]-butyramide; 4-(4'-chloro-biphenyl-4-yl)-2-RS-[2-(1,3-dioxy-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid acid; 4-(4'-chloro-biphenyl-4-yl)-2R-[2-(1,3-dioxy-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid; N-hydroxy-2R-[4-(imidazol-1-yl-phenoxy)-piperidine-1-sulfonylamino]-3,3-dimethyl-butyramide; 2R-[4-(4-chloro-benzoyl)-piperazine-1-sulfonylamino]-N-hydroxy-3-methyl-methylsulfanyl-butryamide; N-hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidin-1-sulfonylamino-butyramide; 4-(pyridin-4-yloxy)benzenesulfonic acid; 4-(pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride; 3S-2,2-dimethyl-3-thiomorpholine-carboxylic acid; 3R-N-hydroxy-4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-1,1-dioxo-tetrahydro-2H-1,4-thiazine-3-carboxamide; 1R-3S-2,2-dimethyl-1-oxo-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-1-thiomorpholine-3-carboxamide; and 4-[4-(1-hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxamide.