CZ2001126A3 - Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions - Google Patents

Abstract

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

Description

Technical field

Enzymes known as natural matrix metalloproteinases (MMPs) are classes of natural enzymes found in mammals. They are zinc proteases that hydrolyze collagens, proteoglycans and glycoproteins. Classes include gelatinases A and B, stromelysin-1 and -2, fibroblast collagenases, neurophilic collagenases, matrilysin, metalloelastase, and interstitial collagenase. These enzymes are associated with a number of diseases resulting from connective tissue disorders such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis and even tumor metastasis.

BACKGROUND OF THE INVENTION

The term MMP in relation to atherosclerosis is discussed in White A., Bocan T. M. A., Boxer P. A., Peterson J. T., Schrier D .: Emerging therapeutic advances for the development of second generation matrix metalloproteinase inhibitors, Curr. Pharm. Design 3 (1997), pp. 45-58. To date, matrix metalloproteinase inhibitors have not been used with ACAT inhibitors.

US Patent Application No. 08 / -987167, filed Dec. 8, 1997, discloses MMP inhibitors and their preparation, and the present invention is referred to.

Acyl coenzyme A inhibiting compounds: cholesterol

acyltransferase are referred to as ACAT inhibitors. Some ACAT inhibitors and methods for their preparation are described in U.S. Patent 5,491,172 and its 5,633,287, to which this invention is referred.

U.S. Patent 5,756,545 discloses MMP inhibitors, in particular

2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid and this invention is referred to.

U.S. Pat. No. 5,441,975 discloses ACAT inhibitors, particularly N- (2,6-diisopropylphenyl) -2- (2-dodecyl-2H-tetrazol-5-yl) phenyl acetamide. On this and related patents 5,646,170;

693 657 and 5 366 987, the present invention is also referred to.

SUMMARY OF THE INVENTION

The present invention relates to the interaction of ACAT and MMP inhibitors to reduce components of atherosclerotic lesions in macrophage and smooth muscle cells of mammals, especially humans. Lesions are reduced immediately, so that the spread of existing lesions and the development of new lesions are significantly reduced.

The invention includes certain ACAT inhibitors and certain MMP inhibitors suitable for co-action, as well as their pharmaceutical composition.

The interaction of a bioactive ACAT inhibitor with a matrix metalloproteinase (MMP) inhibitor may dull the development of atherosclerotic lesions and promote plaque stabilization. ACAT inhibitors have been shown to be a suitable reducing agent for accumulated monocyte-macrophages in atheroslerotic lesions in rabbits. In addition, it is clear that monocyte-macrophages report secretion of matrix metalloproteinases such as MMP-7 and MMP-9, while smooth muscle cells signal the secretion of MMP-1, MMP-2 and MMP-3. ACAT Inhibition, (aterfin1.doc)

which immediately reduces accumulated fat monocyte-macrophages leads to a decrease in MMP sources. Inhibition of MMP, in turn, limits the development of atherosclerotic lesions by reducing the migration of smooth muscle cell and monocyte to intima development by reshaping the extracellular matrix. The interaction of both agents limits the development of new lesions by inhibiting cellular accumulation and stabilizing previously developed lesions by preventing both matrix reformation and loss of the fat monocyte-macrophages that are the source of MMP-7 and MMP-9.

The present invention is a method of treating and preventing, optionally only preventing atherosclerotic lesions, comprising co-acting with one or more MMP inhibitors and one or more ACAT inhibitors.

Further, the present invention is a method of preventing plaque rupture and lesion reduction by administering a combination of an ACAT inhibitor and an MMP inhibitor.

The method is practiced by administering a chemical effectively inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase or elastase. A number of known matrix metalloproteinase inhibiting compounds are utilized in the practical part of the present invention.

The method is practiced by administering a chemical inhibitor of the enzyme acyl-coemzyme A: cholesterol acyltransferase. A number of compounds known as ACAT inhibitors are used in the practical part of the present invention.

The matrix metalloproteinase inhibitor used in the present invention is any chemical compound that inhibits at least 5 percent of the hydrolytic activity of at least one matrix metalloproteinase enzyme that occurs naturally in mammals. These compounds are also referred to as "MMP inhibitors." A variety of (aterfin1.doc) matrix metalloproteinase inhibitors and all are known

are utilized in the present invention. For example, 4-diaryl-butanoic derivatives a

4-diarylpentanoic acids are disclosed in U.S. patent application Ser. No. 339846 filed Nov. 15, 1994, to which the present invention refers.

Compounds are generally defined as (T) _X ABDEG.

About 400 compounds are reported each of which is used in the present invention and is also referred to.

The most prominent compounds used in the present invention are [1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-, (S) -;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-, (R) -;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-, (S) -;

[1,1'-biphenyl] -4-butane methylpropyl) -? -? -, (R) -;

[1,1'-biphenyl] -4-butano [1,1'-biphenyl] -4-butano [1,1'-biphenyl] -4-butano [1,1'-biphenyl] -4-butano [1 1,1'-biphenyl] -4-butanoic acid [1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α- (2-

acid, 4'-chloro-α- (2- acid, 4'-chloro-α- (2- acid, 4'-chloro-β- (2- acid, 4'-chloro-β- (2- acid, 4'-chloro-γ-oxo-; acid, 4'-bromo-γ-οχο-; acid, 4'-fluoro-γ-οχο-; acid, 2'-fluoro-γ-oxo-; acid, 2'-chloro-γ-oxo-; acid, 2 ', 4'-difluoro-γ-

oxo-;

[1,1'-biphenyl] -4-butanoic [1,1'-biphenyl] -4-butanoic y-oxo;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butane methylpropyl) -yloxy-;

acid, acid, 3'-chloro-γ-οχο-; α- (2-methylpropyl) acid, 4'-Bromo-α- (2- acid, 4'-fluoro-α- (2-

(aterfin1.doc) • φ

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butane methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butanoic (2-methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butanoic γ-ηχ-4'-pentyl-;

[1,1'-biphenyl] -4-butane methylene-γ-οχο-;

[1,1'-biphenyl] -4-butane methylene-γ-οχο-;

[1,1'-biphenyl] -4-butane γ-οχο-;

[1,1'-biphenyl] -4-butane pentyl-;

acid, 4'-Ethyl-α- (2- acid, 2'-fluoro-α- (2- acid, 2'-chloro-α- (2- acid, 4'-Methoxy-α- (2- acid, 2 ', 4'-difluoro-α- acid, α- (2-methylpropyl) acid, 4'-chloro-a- acid, 2'-chloro-a- acid, 4'-chloro-α-methyl acid, 4'-chloro-γ-οχο-α

Benzenbutanoic acid, 4-chloro-α- (2-methylpropyl) -γ-οχο-;

Benzenebutanoic acid, 4-methyl-α-methylene-γ-οχο-;

2-butenoic acid, 4- (4'-chloro [1,1'-biphenyl] -4-yl) -

4-OXO-, (E) -;

2-butenoic acid, 4- [4- (4-chlorophenyloxy) -phenyl] -40XO-, (E) -;

[1,1'-biphenyl] -4-butanoic acid, methylpropyl) -γ-οχο-;

[1,1'-biphenyl] -4-butanoic acid, methylene-γ-οχο-;

[1,1'-biphenyl] -4-butanoic acid,

4'-hydroxy-α- (24'-chloro-β 4'-chloro-γ-hydroxy-α- (2-methylpropyl) -;

(aterfin1.doc)

(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-butanoic acid, 3 ', 4'-dichloro-γοχο-α- (3-phenylpropyl) [1,1'-biphenyl] -4-butanoic acid, 3', 5 ' -dichloro- γοχο-α- (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4 '- (acetyloxy) -? -? -? - (3-phenylpropyl) -;

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

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

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

benzenpentanoic acid, α- [2-oxo-2- [4- [6- (pentyloxy) 3-pyridinyl] phenyl] ethyl] -;

[1,1'-biphenyl] -4-butanoic acid, γ-οχο -4 '(pentylthio) -α- (3-phenylpropyl) [1,1'-biphenyl] -4-butanoic acid, 4-methoxy-γ -οχο-α (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid, 3'-chloro-4 'fluoro-γ-6-α- (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid,

4'-ethoxy-γ-οχο-α (3-phenylpropyl) -;

benzenpentanoic acid, α- [2-oxo-2- [4- (3-thienyl) phenyl] ethyl] [1,1'-biphenyl] -4-butanoic acid, 2 ', 4'-dichloro-γοχο-α- ( 3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4'-formyl-γ-οχο-α16 (aterfin1.doc)

(3-phenylpropyl) -;

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

Benzenpentanoic acid, α- [2-oxo-2- [4- (2-thienyl) phenyl] ethyl] [1,1'-biphenyl] -4-butanoic acid, γ-οχο-α- (3-phenylpropyl) -3 '- ( trifluoromethyl) [1,1'-biphenyl] -4-butanoic acid, 2'-formyl-γ-οχο-α (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butane acid, 4-Hydroxy-γ-oxo-α- (3-Phenylpropyl) [1,1'-biphenyl] -4-butane acid, γ-οχο -ot- phenylpropyl) -4'-propoxy-; [1,1'-biphenyl] -4-butane acid, γ-οχο -4'- (pentyloxy) -α- (3-phenylpropyl) -; [1,1'-biphenyl] -4-butane acid, γ-οχο -4'- (pentyloxy) -α- (3-phenylpropyl) -, (WITH)-; [1,1'-biphenyl] -4-butane acid, γ-οχο -4'- (pentyloxy) -α- (3-phenylpropyl) -, (AND)-; [1,1'-biphenyl] -4-butane acid, 4 '- (hexyloxy) -γ-οχο ———— (3-Phenylpropyl) -; [1,1'-biphenyl] -4-butane acid, 4'-butoxy-γ-oxo-α- (3-Phenylpropyl) [1,1'-biphenyl] -4-butane acid, γ-οχο -4'- (3- phenylpropoxy) -a- (3-phenylpropyl) ”R [1,1'-biphenyl] -4-butane acid, 4 '- (1-methyloxy) -γ- oxo-α- (3-phenylpropyl) -; [1,1'-biphenyl] -4-butane acid, 4 '- (heptyloxy) -γ-

oxo-α- (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4 '- (cyclohexylmethoxy) -? -? -? - (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4 '- (2-methyl-16 (atherin ).doc .doc 9', 4'-propoxy) -γ-η-α- (3-phenylpropyl) -;

[1,1'-biphenyl] -4-butane acid, γ-οχο -α- (i 3- phenylpropyl) -4 '- (2-propenyloxy) ~~ ř [1,1'-biphenyl] -4-butane acid, 4'-chloro- and- heptyl-γ-οχο-; [1,1'-biphenyl] -4-butane acid, 4'-chloro- a-decyl- γ-οχο-; [1,1'-biphenyl] -4-butane acid, 4 '-nitro-γ- -oxo -a- (2-phenylethyl) -; [1,1'-biphenyl] -4-butane acid, 4'-cyano-γ- -oxo -a- (2-phenylethyl) -; [1,1'-biphenyl] -4-butane acid, 4'-chloro- a- [2- (2- iodophenyl) ethyl] -γ-οχο-; [1,1'-biphenyl] -4-butane acid, 4'-chloro- α- [2- (3- iodophenyl) ethyl] -γ-οχο-; [1,1'-biphenyl] -4-butane acid, 4'-chloro- a- [2— (4— iodophenyl) ethyl] -γ-οχο-; [1,1'-biphenyl] -4-butanoic acid acid, 4'-chloro- a- [2-

(3,5-dimethoxyphenyl) ethyl] -? -? -;

[1,1'-biphenyl] -4-butane acid, 4'-chloro-γ-oxo -a- phenyl-; [1,1'-biphenyl] -4-butane acid, 4'-chloro-γ-oxo -a- (phenylmethyl) -; [1,1'-biphenyl] -4-butane acid, 4'-Chloro-γ-οχο -a- (2-phenylethyl) -; [1,1'-biphenyl] -4-butane acid, 4'-chloro-γ-oxo -a- [(trimethylsilyl) methyl] -; [1,1'-biphenyl] -4-butane acid, 4'-Bromo-γ-oxo -a- (3-phenylpropyl) -; [1,1'-biphenyl] -4-butane acid, γ-οχο -α- (3- phenylpropyl) -; [1,1'-biphenyl] -4-butane acid, 4'-amino-γ-οχο -α

(2-phenylethyl) (aterfin1.doc)

• 4 4 * 4 ♦ * 4 * ft 4 W ♦ 4 • 4 4 4 and 4 44 4 4 * 4 r 44 4 4 4 4 4 • 4 »» 4 • 4 4 • 4 · · 4 4 4 4 4 4 4 »3 ··· • 4 • k • 4 »44

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

[1,1'-biphenyl] -4-butanoic acid, 4 '- [[(1,1-dimethylethoxy) carbonyl] amino] -? -? -? - (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4 ^of - (acetylamino) -γ-α-α- (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic acid, γ-οχο-4'- [(1 oxopentyl) amino] -α- (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4 ^of - [(3,3-dimethyl

1-oxobutyl) amino] -? -? -? - (2-phenylethyl) -;

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

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

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

[1,1'-biphenyl] -4-butanoic acid, 4 ^from -chloro- α- [2- [3 [(diethylamino) carbonyl] phenyl] ethyl] -γ-χχ-, (S) -;

[1,1'-biphenyl] -4-butanoic acid, 4 ^from -chloro-α- [2- [3 [(diethylamino) carbonyl] phenyl] ethyl] -γ-χχ-, (2 R) -;

cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenylmethoxy) methyl] -, (1a,

2β, 5β) -;

cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5- (phenoxymethyl) -, (Ια, 2β, 5β) -; cyclopentanecarboxylic acid, 2 - [(benzoyloxy) methyl] -5 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (1a,

2β, 5β) -;

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

cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(2-thienylthio) methyl] -, (1a, (aterfin1.doc)) · · · · · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2β, 5β) -;

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

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

cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenylthio) methyl] -, (Ια, 2β,

5β) -;

cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(propylthio) methyl] -, (Ια, 2β,

5β) -;

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

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

1-methyl ester, (Ια, 2β, 3a) -;

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

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

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

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

benzoic acid, 2-methoxy-, [2-carboxy-3 - [(4'chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] (atherfin.doc) •

methyl ester, (Ια, 2β, 3α) -;

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

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

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

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

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

2 H -benzo [R] isoindole-2-butanoic acid, α- [2- (4 ^of ethoxy [1,1'-biphenyl] -4-yl) -2-oxoethyl] -1,3-dihydro-1,3-dioxo -;

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

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

[1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α - [[[3 (methoxycarbonyl) -phenyl] thio] methyl] -? -? -;

[1,1'-biphenyl] -4-butanoic acid, 4 ^from -chloro-α - [[2,6 (dimethylphenyl) thio] methyl] -? -? -;

[1,1'-biphenyl] -4-butanoic acid, 4 ^from -chloro-α - [[[4-fluoro-2- (methoxycarbonyl) -phenyl] thio] methyl] -γ-οχο-;

[1,1'-biphenyl] -4-butanoic acid, 4 ^from -chloro-α - [[[3 [(diethylamino) carbonyl] phenyl] thio] methyl] -γ-οχο-;

[1,1'-biphenyl] -4-butanoic acid, 4 ^of -chloro-α - [[[2 [(dimethylamino) carbonyl] phenyl] thio] methyl] -? -? -;

(aterfin1.doc) •

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

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

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

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

1-Cyclopentene-1-carboxylic acid, 5 - [[4 (hexyloxy) [1,1'-biphenyl] -4-yl] carbonyl] [1,1'-biphenyl] -4-butanoic acid, 4'-hydroxy γ-οχοα - [(phenylthio) -methyl] -;

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

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

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

[1,1'-biphenyl] -4-butanoic acid, a- [2- [3 - [(butylamino) carbonyl] phenyl] ethyl] ^{-4-chloro-a-oxo-y;}

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

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

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

(aterfin1.doc) [1,1'-biphenyl] -4-butane α- (2-phenylethyl) -;

[1,1'-biphenyl] -4-butane α- (2-phenylethyl) [1,1'-biphenyl] -4-butane (2-phenylethyl) -;

[1,1'-biphenyl] -4-butane phenylethyl) -4'-propoxy-;

[1,1'-biphenyl] -4-butane (pentyloxy) -α- (2-phenylethyl) [1,1'-biphenyl] -4-butane oxo-α- (2-phenylethyl) [1,1'- biphenyl] -4-butane (2-phenylethyl) [1,1'-biphenyl] -4-butane

acid, 4'-methoxy- γ-οχο- acid, 4'-hydroxy- γ-οχο- acid, 4'-ethoxy-γ-oxo-α- acid, γ-οχο -α- (2- acid, γ-οχο- 4'- F acid, 4 '- (hexyloxy) - γ- acid, 4'-butoxy- γ-οχο-α- acid, γ-οχο -α- (2-

phenylethyl) -4 '- (phenylmethoxy) -;

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

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

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

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

1,2-pyrrolidinedicarboxylic [1,1'-biphenyl] -4-yl) carbonyl] -, (2'R-trans) -;

L-proline, 3 - [(4'-chloro [1,1 '] acid, [(4'-chloro

1- (phenylmethyl) ester, acid, [(4'-chloro

1- (phenylmethyl) ester,

-biphenyl] -4-yl) carbonyl] -1 (atherfin) [[(phenylmethyl) amino] carbonyl] -, trans-;

• ·

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

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

L-proline, 3 - [(4'-chloro [1 (3,3-dimethyl-1-oxobutyl) -, [1,1'-biphenyl] -4-butane] heptyl-γ-οχο-;

[1,1'-biphenyl] -4-butane γ-οχο-;

[1,1'-biphenyl] -4-butanoic (2-phenylethyl) -;

[1,1'-biphenyl] -4-butane (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic (phenylphenyl) ethyl] -? -? -;

[1,1'-biphenyl] -4-butane iodophenyl) ethyl] -? -? -;

[1,1'-biphenyl] -4-butanoic (phenylphenyl) ethyl] -? -? -;

[1,1'-biphenyl] -4-butane (3,5-dimethoxyphenyl) ethyl] -γ- [1,1'-biphenyl] -4-butane phenyl-;

[1,1'-biphenyl] -4-butane (phenylmethyl) -;

[1,1'-biphenyl] -4-butane (2-phenylethyl) -;

[1,1'-biphenyl] -4-butano [(trimethylsilyl) methyl] -;

[1,1'-biphenyl] -4-butanoic (3-phenylpropyl) -;

1'-Biphenyl] -4-ylcarbonyl] -1- F 1'-Biphenyl] -4-yl) carbonyl] -1- 1'-Biphenyl] -4-yl) carbonyl] -1- : rans-; acid, 4'-chloro-a- acid, 4'-chloro-a-decyl- acid, 4'-nitro- γ-οχο-α- acid, 4'-Cyano- γ-οχο-α- acid, 4'-chloro-α- [2- (2- acid, 4'-chloro-α- [2- (3-) acid, 4'-chloro-α- [2- (4- acid, 4'-chloro-α- [2- oxo-; acid, 4'-chloro-γ-οχο-α- acid, 4'-chloro-γ-οχο-α- acid, 4'-chloro-γ-οχο-α- acid, 4'-chloro-γ-οχο-α- acid, 4'-bromo-γ-οχο-α-

(aterfin1.doc) •

Φ · [1,1'-biphenyl] -4-butanoic acid, γ-οχο-α- (3-acid, acid,

4'-amino-γ-οχο-αγ-οχο-α- (24 '- (acetylamino) -γγ-οχο-4' - [(14 '- [(3,3-dimethylphenylpropyl) -;

[1,1'-biphenyl] -4-butane (2-phenylethyl) -;

[1,1'-biphenyl] -4-butane phenylethyl) -4 '- [[(phenylmethoxy) carbonyl] amino] -;

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

[1,1'-biphenyl] -4-butanoic acid, oxopentyl) amino] -? - (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic acid,

1-oxobutyl) amino] -? -? -? - (2-phenylethyl) -;

[1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α [(2-methoxycarbonyl) phenyl] ethyl] -? -? -;

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

[1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α [(diethylamino) carbonyl] phenyl] ethyl] -? -? -;

[1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α [(diethylamino) carbonyl] phenyl] ethyl] -? -? -, (S) -;

[1,1'-biphenyl] -4-butanoic acid, 4'-chloro-α [(diethylamino) carbonyl] phenyl] ethyl] -? -? -, (R) -.

[2 [2- [2 [2- [3 [2- [3]] Fenbufen and related compounds described in U.S. Pat. No. 3,784,701 and Child, et al., J. Pharm. Sci., 66 (1977), pp. 466-476, as well as ArzneimForsch: J. Pharm. Sci., 30 (4A) (1980), pp. 695-702, to which this patent refers. Significant compounds of the fenbufen family used in the present invention have the formula (aterfin1.doc). ·· ···

where R j e

O

AND

CCH ₂ CH ₂ COOH (fenbufen), COCH = CHCOOH, SO ₂ NH ₂ , COCH ₂ CHCOOH, I ch ₃

COCH ₂ CH — COOH

COCH ₂ CH ₂ SO ₃ Na, CH (OH) CH ₂ CH ₂ COOH, COCH ₂ CHCOOH,

AND

OH coch ₂ ch ₂ conhoh;

C (= NOH) CH ₂ CH ₂ COOH, and COCH ₂ SCH ₂ COOH.

Many peptides are known inhibitors of matrix metalloproteinase. Typical examples of such peptides are described in US Patent Nos. 5,333,501; 5,455,258; No. 5,552,419, as well as world patents WO 95/13289 and WO 96/11209. Each of said patents is referred to by the present invention. Said compounds are represented by the formula

wherein each of the variable groups may include hydrogen, alkyl, aryl, heteroaryl, alkenyl, carboxy, and others.

(aterfin1.doc) ·

• · »· · · · · · · · · ·

The most important compounds of this group that have been used in the method of the present invention are as follows:

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

N- [2-acetylmercapto-3-methoxycarbonylpropanoyl] -Lleucyl-L-phenylalanine N-methylamide;

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

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

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

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

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

N- [2-acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine 77-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-4-methoxycarbonylpentanoyl] -L-leucyl-L-phenylalanine N-methylamide;

N- [2-mercapto-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-L16 (aterfin1.doc) • phenylalanine N-methylamide;

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

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

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

N- [2-acetylmercapto-6-methoxycarbonylhexanoyl] -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-Ltrypropane N-methylamide;

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

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

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

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

N- [2-acetylmercapto-2- (3-phthalimido) phenylacetyl] -leucyl-L-phenyl] alanine 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-leucyl-Ltryptophan N-methylamide

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

(aterfin1.doc) 4 4 · · 4 4 a 4 a 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · · · · · · · · ·

N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-Ltryptophan 7,7-methylamide;

N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [beta- (4-thiazolyl)] alanine N-methylamide;

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

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

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

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

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

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

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

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

(aterfin1.doc) · ♦ β β β β β β β β β β β β β β β β β β a a a a 4 (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;

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

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

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

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

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

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

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

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

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

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

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

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

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

(aterfin1.doc)

« 4 * • «· • 9 «« • Φ • 4 • · ·· • · • • * ·· • · • i • £ i • · • · ·· ··· « • 4 * 4 9 · ··

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

[4- (2H-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-β-cyclohexylalanine amide;

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

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

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

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

[4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-tryptophanamide;

[4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-valine amide;

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

[3-phosphono-2R, 5-phenylpropyl-1-oxopropyl] -L-β-cyclohexylalanine -N- (2-phenylethyl) amide;

[3-phosphono-2R, 5-phenylpropyl-1-oxopropyl] -L-β-cyclohexylalanine-β-alanine;

[3-phosphono-2R, 5-phenylpropyl-1-oxopropyl] -L-β-cyclohexylalanine;

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

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

[3-Phosphono-2R, S- (4-methylphenyl) propyl-1-oxopropyl] -Lβ-cyclohexylalanine-N- (2-phenylethyl) amide diethyl ester;

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

4-t-butoxy-2 (R) - [3- (2-phenoxyethyl) succinyl] -L-β16 (aterfin1.doc) · · · · · · · · · · · · · · · · Cyclohexylalanine-N- (2-phenylethyl) amide;

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

4- (N-hydroxyamino) -2 (R) - [3- (2-phenoxyethyl) succinyl] -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} -1H-cyclohexylalanine -N- (2-phenylethyl) amide;

{4- (N-Hydroxyamino) -2 (R) - [3- (N-methyl-4-pyridinium) propyl] succinyl} -1H-cyclohexylalanine -N- (2-phenylethyl) amide;

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

{4- (N-hydroxyamino) -2 (R) - [3- (4-methylphenyl) propyl] succinyl} -1H-cyclohexylalanine -N - [(2-morpholinesulfonylamino) ethyl] amide;

{4- (N-hydroxyamino) -2 (R) - [3- (4-chlorophenyl) propyl] succinyl} -L-p-cyclohexylalanine -N - [(2-morpholinesulfonylamino) ethyl] amide;

{4- (N-hydroxyamino) -2 (R) - [3- (4-methylphenyl) propyl] succinyl} -1H-cyclohexylalanine -N - [(2-dimethylsulfonylamino) propyl] amide;

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

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

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

(aterfin1.doc) {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) penicillamine] -N-methylamide;

N ⁴ -hydroxy-N ¹ - (1- (S) -carbamoyl-2,2-dimethylpropyl) -2 (R) -4- (chlorophenylpropyl) succinamide;

N ⁴ -hydroxy-N ¹ - (1- (S) -carbamoyl-2,2-dimethylpropyl) -2 (R) - (4-methylphenylpropyl) succinamide;

N ⁴ -hydroxy-N ¹ - (1- (S) -carbamoyl-2,2-dimethylpropyl) -2 (R) - (4-methoxyfenylpropyl) succinamide;

N ⁴ -hydroxy-N ¹ - (1- (S) -carbamoyl-2,2-dimethylpropyl) -2 (R) - (4-trifluormethylfenylpropyl) succinamide;

N ⁴ -hydroxy-N ¹ - (1- (S) -carbamoyl-2,2-dimethylpropyl) -2 (R) - (4-chlormethylfenylpropyl) 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 met´met hylamide;

(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 methylamide;

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

(aterfin1.doc) (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 AZ-methylamide;

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

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

N- [2,3-bis-acetylmercaptopropanoyl] -1-L-leucyl-L-phenylalanine N-methylamide;

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

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

N- [2-acetylmercapto-5-methoxycarbonylpentanoyl] -leucyl-L-phenylalanine-4-methylamide;

N- [2-acetylmercapto-6-methoxycarbonylhexanoyl] -Lleucyl-L-phenylalanine-4-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;

(aterfin1.doc) ···· ············································

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-mercapto-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] -leucyl-L-phenylalanine N-methylamide;

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

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

N- [2-acetylmercapto-6-methoxycarbonylhexanoyl] -Lleucyl-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-Ltryptophan N-methylamide;

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

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

N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-516 (aterfin1.doc) • 9 · 9 · 9 99

9 9 9 9 9 9 99

9999 99 99 99999 methyl-L-glutamic acid N-methylamide;

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

N- [2-acetylmercapto-2- (3-phthalimido) phenylacetyl] -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-Ltryptophan N-methylamide;

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

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

N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [beta- (4-thiazolyl)] alanine N-methylamide;

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

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

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

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

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

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

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

N-hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] - (316 (aterin-1.doc));

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

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

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

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

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

[4- (N-hydroxyamino) -2R-isobutyl-3S- methoxyfenylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-thiophenylsuccinyl] -N- (S) -piperazineic acid N-methylamide;

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

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

[4- (N-hydroxyamino) -2R-isobutyl-3S-methyl acetate] -N ^2- (S) -piperazic acid N-methylamide;

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

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

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylthioacetate] N ² - (S) -piperazineic acid N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylthioisopropanoate] -N ² - (S) -piperazineic acid, N-methylamide;

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

(aterfin1.doc) ·· ······································ [4- (N-hydroxyamino) -2R-isobutyl-3S-methyl- (3-pyridyl)] - N - (S) -piperazine acid, N-methylamide;

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

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

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

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

[4- (N-hydroxyamino) -2R-isobutyl-3S-methoxyfenylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methoxybenzylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylthiofenylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-hexyl-3S-methylthiobenzylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-hexyl-3S- (methylthio-2-thienyl) succinyl] -N @ ² - (S) -piperazic acid Nmethylamid;

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

[4- (N-hydroxyamino) -2R-hexyl-3S-methyl acetate] -N ² - (S) piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-hexyl-3S-methylisopropanoat] -N ² - (S) -piperazic acid N-methylamide;

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

[4- (N-hydroxyamino) -2R-hexyl-3S-methylthioacetate] -N ^2- (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-hexyl-3S-methylthioisopropanoat] -N ² - (S) -piperazic acid N-methylamide;

(aterfin1.doc) * · · ♦ ♦ «« «a a a a a a a a a a a a a a a 999 [4- (N-hydroxyamino) -2R-hexyl-3S-methylthio-tert-butanoate] -N ² - (S) -piperazine acid, N-methylamide;

[4- (N-Hydroxyamino) -2R-hexyl-3S-methyl- (2-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-Hydroxyamino) -2R-hexyl-3S-methyl- (3-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-Hydroxyamino) -2R-hexyl-3S-methyl- (4-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methylsuccinyl] -N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-benzylsuccinyl] -N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methoxyfenylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methoxybenzylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methylthiofenylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methylthiobenzylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

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

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-benzylsuccinyl] -N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-mehylacetatl] -N ² (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-ethylphenyl-3S-methylisopropanoate]

-N ² - (S) -piperazine acid, N-methylamide;

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

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

(aterfin1.doc) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· φφφ [4- (N-hydroxyamino) -2R-ethylphenyl-3S-mehylthioisopropanoat] -Ν ² - (S) -piperazic acid N-methylamide;

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

[4- (N-hydroxyamino) -2R-octyl-3S-mehylsukcinyl] -N ² - (S) piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S-methylthiophenylsuccinyl]

-N ² - (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S-mehylthiobenzylsukcinyl] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S- (mehylthio-2-thienyl) succinyl] -N @ ² - (S) -piperazic acid N-methylamide;

[4- (2V-hydroxyamino) -2R-octyl-3S-methyl acetate,] -N ² - (S) piperazic acid 2V-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S-mehylisopropanoat] -N ² (S) -piperazic acid N-methylamide;

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

[4- (N-hydroxyamino) -2R-octyl-3S-mehylthioacetat] -N ² (S) -piperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S-methylthioisopropanoate]

-N ² - (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-octyl-3S-methylthio-tercbutanoat] -N ² - (S) -piperazic acid N-methylamide;

[4- (N-Hydroxyamino) -2R-octyl-3S-methyl- (2-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-Hydroxyamino) -2R-octyl-3S-methyl- (3-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-Hydroxyamino) -2R-octyl-3S-methyl- (4-pyridyl)] - N ²

- (S) -piperazine acid, N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N ^2- (S) -4 ^(S / R) benzylpiperazic acid N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N ² 16 (aterfin1.doc) • 9 4 9 · 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 99

9 9 9 9 9 9 9 9999 99 99 99 999 (S) -5 '(S / R) -benzylpiperazineic acid, N-methylamide;

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

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

N- [1 (R) -carboxy-ethyl] -α- (S) -isobutylglycine- (S) -N ² piperazineic acid, methylamide;

N - [1 (R) -carboxy-ethyl] - N - (S) -hexylglycine- (S) -N ² piperazineic acid amide;

N- [1 (R) -carboxy-ethyl] -α- (S) -heptylglycine- (S) -N ² piperazineic acid, methylamide;

Μ- [1 (R) -carboxy-ethyl] -α- (S) -octylglycine- (S) -N ² piperazinic acid, γ methylamide;

N- [1 (R) -carboxy-ethyl] -α- (S) -ethylphenylglycine- (S) -N ² piperazineic acid, methylamide;

N- [1 (R) -carboxy-ethyl] -α- (S) -propylphenylglycine- (S) -N ² piperazinic acid methylamide;

N- [1 (R) -Carboxy-ethylthiobenzyl] -a- (S) -isobutylglycin (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -carboxy-ethylthiobenzyl] -α- (S) -hexylglycine- (S) N ² -piperazineic acid, methylamide;

N- [1 (R) -Carboxy-ethylthiobenzyl] -a- (S) ethylfenylglycin- (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -Carboxy-ethylthiobenzyl] -a- (S) propylfenylglycin- (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -Carboxy-ethyloxybenzyl] -a- (S) -isobutylglycin (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -Carboxy-ethyloxybenzyl] -a- (S) -hexylglycin- (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -Carboxy-ethyloxybenzyl] -a- (S) -ethylfenylglycin (S) -N ² - Piperazine acid methylamide;

N- [1 (R) -carboxy-ethyloxybenzyl] -α- (S) -propylphenyl16 (atherfin ).doc Glycine (S) -N ² -piperazineic acid amide;

N- [1 (R) -carboxy-4- (p-toluenesulfonyl) butyl] -α- (S) - (2-phenylethyl) glycyl- (S) -N ² -piperazineic acid, methylamide;

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

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

2- [2 (R) - [2 - [(1,1'-Biphenyl) yl] ethyl] -4-methyl-4 (S) carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

2- [2 (R) - [2 - [(1,1'-Biphenyl) yl] propyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

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

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

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

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

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

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

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

2- [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4-methyl-4 (S) -16 (aterfin1.doc)

• • 4 * • · 4 · 4 4 • 44 • • • 4 • 4 · 4 4 4 • • • 4 4 4 4 4 4 4 • 4 4 4 4 * 4 4 4 4 4 4 • 4 • •• 4 44 44 44 . «4 4

carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

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

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

2- [2 (R) - [2 - [(4-oxazoyl) phenyl] ethyl] -4-butyl-4 (S) carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

2- [2 (R) - [2 - [(4-oxazoyl) phenyl] ethyl] -4-methyl-4 (S) carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

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

2- [2 (R) - [2 - [(4-Oxazoyl) phenyl] ethyl] -4- (3-phenylpropyl) -4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

2- [2 (R) - [2- [4- (dimethylamino) methylphenyl] ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

2- [2 (R) - [2- [4- (dimethylamino) methylphenyl] ethyl] -4-methyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

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

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

(aterfin1.doc) • · ··························· · ·· ·· ·· ···

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

2- [2 (R) - [2 - [(4-imidazolyl) phenyl] ethyl] -4-methyl-4 (S) carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine;

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

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

MS (CH ₂ ) 2 - (SD-Leu) -Phe-NHMe;

HS (S) CHMeCH ₂ - (SD-Leu) -Phe-NHMe;

MS (S) CH (PhtNBu) CH ₂ - (SD-Leu) -phenylalanine-NHMe;

MS (S) CH (PhtNEt) CH ₂ - (SD-Leu) -phenylalanine-NHMe;

MS (1,2-cyclopentyl) (S-D-Leu) -phenylalanine-NHMe;

Me-S (NH) ₂ - (CH ₂ -DL-Leu) - Trp-NHBn;

n-Bu-S (NH) ₂ - (CH ₂ -DL-TyrOCH ₃ ) - Trp-NHBn;

Me-RS-SO (NH) - (CH ₂ -L-Leu) -Phe-Ala-NH ₂ ; n-Bu-RS-SO (NH) - (CH ₂ -L-Leu) -Phe-Ala-NH ₂ ;

HONH-C-CH ₂ CH (CH ₂ CH (CH ₃ ) ₂ ) -CO-Nal-Ala-NH ₂ ;

AND

HO-NH-CO-CH ₂ -CH- (CH ₂ -CH (CH ₃ ) ₂ -CO-Nal-Pro-NH ₂ ;

HO-NH-CO-CH (CH ₃ -CH (CH ₂ ) -CH (CH ₃ ) ₂ ) -CO-Nal-Ala-NH ₂ ;

i r

HON-COCH 2 -C-CO-Pal-Ala-NH ₂ , where Pal is

3-pyridylalanine;

(aterfin1.doc)

Η

HON-COCH ₂

AND

-C-CO-Nal (CH ₂ S) Ala-NH _2;

HO-NH-CO-CH 2 -CH (CH ₂ CH (CH ₃ ) ₂ ) -CO-Nal- (CH ₂ NH) -Ala-NH ₂ ;

0 II 0 II II HONHCO-CH ₂ - -CHC— ₂ -N-CH ₂ SCHCONH rr II | ch ₂ I ^{z H} ch ₂ ch ₃ CH JL _{(CH3) 2} 0

(aterfin1.doc)

—Conh ₂

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

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

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

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(4- hydroxy-2-methyl-2H-pyrimidine-516 (atherfin ).doc) methyl] amino] carbonyl] butyl] amino] butanoic acid;

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[[1- (1H-Tetrazol-5-yl) ethyl] amino] carbonyl] butyl] amino] butanoic acid;

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

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

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

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

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[(3) -sulfamoyl-phenyl) amino] (aterfin1.doc)

9 9 9 · · · · · · · · · · · karb · karb · karb · karb · karb karb] karb karb] karb ] butanoic acid;

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

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

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

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

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

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

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(4- nitrobenzyl) amino] carbonyl] (aterfin1.doc)

butyl] amino] butanoic acid;

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

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

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

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

- [2- (S) - [1- (R) -carboxy-3- (1,3-dioxo-1,3-dihydrobenz [f] isoindol-2-yl) propylamino] -4-methylpentanoylaminomethyl) benzoic acid acid;

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(2- hydroxy-1,1-bis (hydroxymethylethyl) amino] carbonyl] butyl] amino] butanoic acid;

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(1- azabicyclo [2.2.2] -oct-3 (S) 16 (aterfin1.doc) • 4 44 44 44 44

4 4 4 «φ ** 445

4444 44

444 4445 44 4

4444 44 44 44 44 4 amino] carbonyl] butyl] amino] butanoic acid;

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(N, N ' -dimethylhydrazino) carbonyl] butyl] amino] butanoic acid;

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(3- (R) -Acetylamino-4- (S) -5- (S) dihydroxy-β- (R) -hydroxymethyl-tetrahydropyran-2-yl) amino] carbonyl] butyl] amino] butanoic acid;

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

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

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

(aterfin1.doc)

9 99 99 99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9

9999 99 99 99 999

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [3,4, 5,6-tetrahydro-H- [2,3] bipyridinyl

1-carbonyl] butyl] amino] butanoic acid;

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

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

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [2- (S)] ) - (pyridin-3-yl) pyrrolidine16 (aterfin1.doc) φ · · · · · · · φ φ · φ φ φ φ φ φ φ φ φ

Carbonyl] butyl] amino] butanoic acid;

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

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

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

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

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

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

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

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

4- (1,3-dihydro-1,3-dioxo-2H-benzo [f] isoindol-2-yl) -2 (R) - [[3-methyl-1- (S) - [[(N- methylpyrrolidine) methylamino] carbonyl] butyl] amino] butanoic acid;

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

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-bromo-1,3-dioxo-1,3-dihydroisoindol-2-yl) butane (atherfin ).doc )

ΦΦ · · φ • • • kyselina φ kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina kyselina

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-propoxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-amino-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-methoxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-benzyloxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-phenyl-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-methanesulfonylamino-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-benzenesulfonylamino-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] 4- (5-hydroxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) butanoic acid;

2- (R) - [[3-Methyl-1- (S) - [[(pyridin-3-ylmethyl) amino] carbonyl] butyl] amino] -4- (1,3,5,7-tetraoxo-3) 5,6-tetrahydrol-1 H -pyrrolo [3,4- f] isoindol-2-yl) butanoic acid;

(aterfin1.doc) • 4 ·· 44 44 44

9444 4444 444

4,444 4 4

444 4445 44 4

4444 44 44 44 ···

EtONHCONMe-CH ₂ CH (iBu) -CO-L-Trp-NHEt;

EtCONOH-CH ₂ CH (iBu) -CO-L-Trp-NHEt;

n-PrCONOEt-CH ₂ CH (iBu) -CO-L-Trp-NHEt;

EtNHCONOMe-CH ₂ CH (iBu) -CO-L-Trp-NHEt;

MeNHCONOH-CH ₂ CH (iBu) -CO-L-Trp-NHEt;

EtNHCONMe-CH ₂ CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt;

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

MeNHCONOH-CH ₂ CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt;

HONHCONHCH ₂ CH (iBu) -CO-L-Trp-NHMe;

HONHCONHCH ₂ CH ₂ CH (iBu) -CO-L-Trp-NHMe;

HONHCONHCH (iBu) -CO-L-Trp-NHMe;

H ₂ NCON (OH) CH (iBu) -CO-L-Trp-NHMe;

N (OH) CH ₂ CH (iBu) -CO-L-Trp-NHMe;

H ₂ NCON (OH) CH ₂ CH ₂ CH (iBu) -CO-L-Trp-NHMe;

CH 3 CON (OH) CH (iBu) -CO-L-Trp-NHMe;

CH ₃ CON (OH) CH ₂ CH (iBu) -CO-L-Trp-NHMe;

CH ₃ CON (OH) CH ₂ CH ₂ CH (iBu) -CO-L-Trp-NHMe;

NHOHCO CH ₂ CH (iBu) -CO-L-Trp-NHMe;

HONHCONH CH ₂ CH (iBu) CONHCHCOOH or

ROOCCH ₂ CH (iBu) CONHCHCOOH;

IR ⁴

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;

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

(aterfin1.doc) ·· * 4 44 Μ »· * • 4 9 4 4 4 4 4 4> 4 4 • 4 · 44 444 4 · · 4 4 * 4 44 4 · 4 44 * 44 44 * 4 4 »*

4 * 4 ** 4 44 4 * * 4 * »[4- (N-hydroxyamino) - (2R) -isobutyl-3-methylsuccinyl] -phenylglycine-N-methylamide;

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

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

3- [2- (N-methylcarbamoyl) ethylsulfinyl] -5-methylhexanohydroxamic acid;

N - [(2- (phenoylmercapto-3-methyl) butanoyl] -homocysteine thioacetone;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) isoleucine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) alanine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) phenylalanine, N-phenylamide;

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

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) tryptophan, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- and (S) - (2-phenylethyl) glycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) norleucine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) valine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) serine, N-phenylamide hydrochloride;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) asparagine, N-phenylamide;

(aterfin1.doc)

* « «Fc 9 * « • • c • • · • ♦ • · • • • * <· • • • • • • • 3 • • ·· 9 9 • Λ • · *>

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) threonine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) lysine, N-phenylamide;

N- [1 (R) -carboxyethyl] - [alpha] - (S) - (2-phenylethyl) glycine- (L) glutamic acid, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) tyrosine, N-phenylamide hydrochloride;

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

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

N- [1 (R) -carboxy-5- (1-oxo-isoindolin-2-yl) pentyl] -α- (S) (2-phenylethyl) glycine- (S) -arginine, N-phenylamide;

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

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

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

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

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

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

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- and (S) - (2-cyclohexylethyl) glycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- and (S) - (cyclohexyl) glycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- and (S) - (cyclohexylmethyl) glycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) -β16 (aterfin1.doc) ♦ · · · · * · · <W <w w w w w w w w w w w w w w w w w w w w w w w w Naphthylalanine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) α-naphthylalanine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) glutamic acid, α, δ-bis-N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N-cyclohexylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine-α- (S) (4-hydroxyphenylethyl) glycine, N-phenylamide;

N- [1 (R) -carboxyethyl] - N - (S) - (2-phenylethyl) glycine- (L) phenylglycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) glutamic acid, N ₅ -benzylamide, Na-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) ornithine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) arginine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (3-phenylpropyl) glycine- (L) arginine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine-α- (S) n-octylglycine, N-phenylamide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N- (4-carboxyphenyl) amide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N- (4-trifluoromethylphenyl) amide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N- (3-pyridyl) amide;

N- [1 (R) -carboxyethyl] -α- (S) - (2-phenylethyl) glycine- (L) leucine, N- (benzothiazol-2-yl) amide;

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

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

(aterfin1.doc) •

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

N- [1 (R) -carboxyethyl] -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-2yl) 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-oxopropoxy) propoxy) phosphinyl) methyl) -4-phenylbutanoyl) -L-leucine, N-phenylamide;

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

[[hydroxy [1 (R) - [N- (N-acetyl-L-prolyl-L-alanyl) amino] ethyl] phosphinyl] methyl] -4-phenylbutanoyl-L-leucyl, N-phenylamide;

[hydroxy [N- (N- (benzoyl) -L-prolyl) aminobutyl] phosphinyl] methyl] -4-phenylbutanoyl-L-leucine, N-phenylamide;

[hydroxy [2-methylpropyloxycarbonyl-aminobutyl] phosphinyl] methyl] -4-phenylbutanoyl-L-leucine, N-phenylamide;

[hydroxy [2-methylethylaminocarbonylaminobutyl] phosphinyl] methyl] -4-phenylbutanoyl-L-leucine, 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) -phenylalaninamide;

N- (2-thiomethyl-4-phenylbutanoyl) - (L) -phenylalanine, N16 (aterfin1.doc) •

phenylamide;

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

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

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

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

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

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

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

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

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

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

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid 1- (L-leucine, N- (4-pyridylamide) amide);

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

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

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid 1- (L-phenylalanine, N-4-pyridylamide) (aterfin1.doc)

amide;

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (1- (4- (N- (2-oxoisoindolinyl)) butyl)) -1,5-pentanedioic acid 1- (Lleucine, N-phenylamide) amide;

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (1- (4- (N- (2-oxoisoindolinyl)) but-2-enyl)) -1, 5-pentanedioic acid 1- (Lleucine, N-phenylamide) amide;

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

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

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

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

2 (R) - (2- (4- (4-hydroxy-n-butyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid 1- (S-leucine, phenylamide) amide;

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

2 (R) - (2-Phenylethyl) -4-methyl-1,5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide;

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

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

2 (R) - (2- (4- (1-n-propyl) phenyl) propyl) -1,5-pentanedioic acid 1- (2 (S) -tert-butylglycine, N-4-pyridyl) amide) amide ;

2 (R) - (3- (4- (1-n-propyl) phenyl) propyl) -1,3-pentanedioic acid 1- (L-leucine, N-phenylamide) amide;

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

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-butyl-1,516 (atherfin ).doc • pentanedioic acid 1- (L-leucine, N- phenylamide) amide;

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

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

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

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

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

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

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

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

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid 9-morpholinamide 1- (L-leucine, N-methylamide) amide;

9- (1 (R) 1- (L-Leucine, N-methylamide) amide 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid Phenylethyl) amide;

2- (4-) 1- (L-Leucine, N-methylamide) amide 9- (1 (S) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid Phenylethyl) amide;

(aterfin1.doc)

52 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid 9- (N-methyl-) - (L-leucine, N-methylamide) amide N-phenyl) amide;

2- (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid 9- (me-methylpiperazine) 1- (L-leucine, N-methylamide) amide amide, trifluoroacetic acid salt;

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

2 (R) - (2- (4- (1-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanedioic acid 1- (L-leucine, N-methylamide) amide;

2 (R) - (2- (4- (1-propyl) phenyl) ethyl) -1,5-pentanedioic acid 1 - ((R) - (S-p-methoxybenzyl) penicillamine, N-phenylamide) amide;

2 (R) - (2- (4- (1-propyl) phenyl) ethyl) -1,5-pentanedioic acid 1 - ((R) - (S-p-methoxybenzyl) penicillamine sulfone, N-phenylamide) amide;

2- (2- (4- (1-propyl) phenyl) ethyl) -4- (1- (4- (2-phthalimido) butyl) -1,5-pentanedioic acid) 1- (L-leucine, N-methylamide) ) amide;

2- (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-benzoylamino-

1-butyl) -1,5-pentanedioic acid 1- (L-leucine, N-methylamide) amide;

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

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

2- (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4- (4'-phenylureido) -1-butyl) -1,5-pentanedioic acid 1- (L- leucine, N-methylamide) amide;

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-phenyloxy16 (aterfin ).doc) ·· ········· J j j j j j j j ony ony -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1) 5-pentanedioic acid 1- (L-leucine,

N-methylamide) amide;

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-p-benzyloxycarbonylamino-L-prolylamino) -1-butyl) -1,5-pentanedioic acid 1- (L-leucine, N-methylamide) amide;

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

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

2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-cyano-1-butyl) -1,5-pentanedioic acid 1- (L-leucine, N-methylamide) 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] - N - (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-dihydrocarbostyril;

3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetyl16 (aterfin1.doc) ··· · · · · · · · · · · · · · · · · · · · · · · · Thiomethylsuccinyl] amino-3,4-dihydrocarbostyril;

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

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

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

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

3S- [4- (N-hydroxyamino) -2R-heptylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril;

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

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

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

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

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

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

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

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

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

2- (R) -N-hydroxy-2 - [(4-methoxybenzenesulfonyl) (3-oxo-316 (atherfin ).doc) piperazin-1-ylpropyl) amino] -3-methylbutyramide hydrochloride;

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

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

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

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

2- (R) -N-hydroxy-2 - ((4-phenoxybenzenesulfonyl) [2-methylpyridin-4-ylmethylcarbamoyl) ether] amino) -3-methylbutyramide;

4 - [(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-propyl) amino] -1-methylpiperidene-4-carboxylic acid hydroxylamide;

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

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

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

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

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

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

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

2- (R) - N -hydroxy-2 - ((4-methoxybenzenesulfonyl) [(116 (aterfin1.doc)) 9 9 99 99) 9 9 9 9 999

999 9999 99 9 9999 (methylpiperidin-4-ylcarbamoyl) methyl] amino) -3-methylbutyramide;

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

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

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

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

Μ ^3- [4- (N-benzyloxyamino) -2 (R) -isobutylsuccinyl] -N- (N-benzyloxycarbonylglycyl) -1-lysyl-L-alanine ethyl ester;

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

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -Lleucylglycine isopentylamide;

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

[4- (AZ-hydroxyamino) -2 (RS) -isobutylsuccinyl] -Leucylglycine ethylamide;

N ^3- [4- (N -hydroxyamino) -2 (RS) -isobutylsuccinyl] - N - tert -butylcarbonyl-L-lysylglycine ethylamide;

[4- (N-Hydroxyamino) -2 (RS) -isobutylsuccinyl] -O-methyl-Ltyrosinylglycine ethyl ester;

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

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

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

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

(aterfin1.doc) • φ · φ · ♦ · φ · φ · φ · φ · · · · 9 9 ·· 9 * [4- (N-hydroxyamino) -2 (RS) -sec-butylsuccinyl] -Leucylglycine ethyl ester;

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

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -Lleucylglycine methyl ester;

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -Leucyl-sarconsine ethyl ester;

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

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

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

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

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -leucine-2,2-dimethoxyethylamide;

N ^3- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -4-glycyl-L-lysine methylamide;

N ^3- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] N - (4-carboxybenzoyl) -L-lysyl-L-alanine ethyl ester;

N ^3- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] β- (4-carboxybenzoyl) -L-lysyl-L-alanine;

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

[4- (N-hydroxyamino) -3 (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-naphthalene dicarboximidomethyl) phosphinic acid;

[(RS) -4-methyl-2 - [[(S) -3-methyl-1- (methylcarbamoyl) butyl] carbamoyl] pentyl] (1,8-naphthalene dicarboximidomethyl) phosphinic acid;

N - [N - [(R or S) -2 - [[[[[N - [1- (Benzyloxy) carbonyl] -L-prolyl] -L-leucyl] amino] methyl] hydroxyphosphinyl] methyl] -4- methylvaleryl] -L-leucyl] L-alanine;

[[1,4-dihydro-2,4-dioxo-3 (2H) -quinazolinyl] methyl] [[(R or S) -4-methyl-2 - [[(R or S) -2-oxo]

3-azacyclotridecyl] carbamoyl] pentyl] phosphinic acid;

N ² - [(R) -hydroxycarbamoylmethyl] -4-methylvaleryl] -N ¹ _, 3-dimethyl-L-valinamide;

N ² - [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] -N ^1, 3-dimethyl-L-valinamide;

N 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] -N ^3, 1-dimethyl-L-valinamide hydrobromide;

N ² - [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl 4methylvaleryl] -N ^1, 3-dimethyl-valinamide;

N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2ftalimidoethyl] -4-methylvaleryl] -N ^1, 3-dimethyl-Lvalinamid;

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

· * * * ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** * ** * * * * * *

Μ ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4-phenyl-butyl] -4-methylvaleryl] -N ^1, 3-dimethyl-Lvalinamid;

N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-succinimidoethyl] -4-methylvaleryl] -N 1,3-dimethyl- ^L -valinamide;

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

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

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

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

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

Hexahydro-2- [2 (R) - [1 (R or S (hydroxycarbamoyl) -

2-phthalimidoethyl] -4-methylvaleryl] -N-methyl-3 (S) pyridazinecarboxamide;

1- [2 (R) - (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methyl-valeryl] -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 (R or S) (phthalimidomethyl) succinyl] -L-leucyl-L-leucine ethylamide;

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

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

[4- (N-hydroxyamino) -2 (R) -heptyl-3 (R or S) (phthalimidomethyl) succinyl] -L- tert -butylglycine methylamide;

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

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

[4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -Lleucine neopentylamide;

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

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

[4- (N-hydroxyamino) -2 (RS) -undecylsuccinyl] -Lleucyl-L-leucine ethylamide;

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

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

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

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

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

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

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

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

[4- (N-Hydroxyamino) -2 (R) -heptylsuccinyl] -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-4-methylphenylalanine methylamide;

[4- (N-Hydroxyamino) -2 (R) -heptylsuccinyl] - (DL) -thyrr-4-methylphenylalanine methylamide;

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

N ² - [3-cyclobutyl-2 (R or S) - [(hydroxycarbamoyl) -methyl] -propionyl] - N ^1, 3-dimethyl-L-valinamide;

N ² - [3-cyclopropyl-2 (R or S) - [hydroxycarbamoyl) -methyl] -propionyl] -N ^1, 3-dimethyl-L-valinamide;

N ² - [3-cyclopentyl-2 (R or S) - [hydroxycarbamoyl) -methyl] -propionyl] -N ^1, 3-dimethyl-L-valinamide;

N ² - [3-cyclopropyl-2 (R) - [1- (R or S) - [hydroxycarbamoyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] - N ^1, 3-dimethyl-Lvalinamid;

N ² - [3-cyclopropyl-2 (R) - [1 (R or S) - [(hydroxycarbamoyl) -4-phenylbutyl)] propionyl] - N ^1, 3-dimethyl-Lvalinamid;

N ² - [3-cyclobutyl-2 (R) - [1 (R or S) - [(hydroxycarbamoyl) -4-phenylbutyl)] propionyl] - N ^1, 3-dimethyl-Lvalinamid;

«·« * * * * * * * * * * * * * * * * * * * * * *

N ² - [3-cyclopentyl-2 (R) - [1 (R or S) - [Hydroxycarbamoyl) -4-phenylbutyl)] propionyl] - N ^1, 3-dimethyl-Lvalinamid;

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

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

1- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] piperidine;

1- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] -4 - piperidinol;

1- [3-Cyclopentyl-2 (R) - [1- (R or S) (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] -4- piperidinol;

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

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

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

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

n • 9 · * • · · · 9 • • 9 and 9 • · • · · and and and a and and • i · · and and á · and aa and λ λ · and a · and a • a and a

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

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

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

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

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

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

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

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

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

·· ·· • tr • • «· • • • • • • ·· • · ♦ • • ·· • • • • • • • • • • • ···· ·· ·· · ♦

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

8- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] -1 4-dioxa-8-azaspiro [4,5] dean;

1- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] propionyl] -4 -methoxypiperidine;

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

1- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2- (5,5-dimethyl-2,4-dioxo-3-oxazolidinyl) ethyl] propionyl] piperidine;

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

1- [3-Cyclobutyl-2 (R) - [2- (hexahydro-1,3-dioxopyrazolo [1,2- a] [1,2,4] (R) -triazol-2-yl) -1 - (R or

S) - (hydroxycarbamoyl) ethyl] propionyl] piperidine;

1- [3-Cyclobutyl-2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] propionyl] piperidine;

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

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

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

• · • ·

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

N ² - [2 (R) - [1 (RS) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] nonanoyl] -N-methyl-L-prolinamide ;

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

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

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

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

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

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

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

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

1- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl] undecanoyl] piperidine;

• ·

- - · · - - 66. ········· * · · ··· * · ·· ·········

1- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) -3-phenylpropyl] undecanoyl] piperidine;

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

hexahydro-2- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl] undecanoyl] -N- (2,2,6,6-tetramethyl-4-piperidinyl) -3 (S) -pyridazinecarboxamide;

1- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] undecanoyl] piperidine;

4- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] undecanoyl] morpholine;

1- (benzyloxycarbonyl) -hexahydro-2- [2 (R) - [(R or S) - (hydroxycarbamoyl) -4-phenylbutyl] nonanoyl] -N (a (S) -methylbenzyl) -3 (S) -pyridazinecarboxamide;

N- [2 (R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5 (carboxy) pentanoyl] -L-phenylalanine-N-methylamide;

N- [2 (R) -2- [2 (hydroxyamino) -2 '- (oxo) ethyl] -6 (phenylmethoxy) hexanoyl] -L-phenylalanine-N-methylamide;

N- [2 (R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (propylamino) -6- (oxo) hexanoyl] -L-phenylalanine-N-methylamide;

N- [2 (R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] (6RS) -6- (hydroxy) heptanoyl] -L-phenylalanine-N-methylamide;

(2S) -N-2 - [(2 ^Z R) -2 ^z - [2 ^zz - (hydroxyamino) -2 ^zz (oxo) ethyl] -6 '- (hydroxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N -methylamide;

(2S) -N-2 - [(R 2 ^Z) -2' ^[from 2 - (hydroxyamino) -2 ^ZZ (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoate acid N -methylamide;

• • •

N - [(R 2 ^Z) -2- [2- (hydroxyamino) -2 '- (oxo) ethyl] -6- (4'-oxobutylamino) hexanoyl] -L-phenylalanine Wmethylamid;

2 (S) -N-2 - [(2 R ^a) 2 ' [2 ^Z '- (hydroxyamino) -2 ^ZZ (oxo) ethyl] -6' - (oxo) - 6 '- (propylamino) hexanoyl amino-3,3-dimethylbutanoic acid, N-methylamide;

N - [(2R) -2 - [(1'S) -1 ^z - (methyl) -2 ^z - (hydroxyamino) -2 '- (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] -L-phenylalanine-N-methylamide ;

N - [(2R) -2 - [(1'S) -1 '- (methyl) -2' - (hydroxyamino) -2 ^z - (oxo) ethyl] -6- (oxo) -6- (propylamino) hexanoyl] -L-phenylalanine-N-methylamide;

(2S) -N-2 - [(2 ^Z R) - ^[(Z L ^Z R) -1 ^Zz - (1,3-dihydro-l, 3dioxo-2H-isoindol-2-yl) methyl-2 ' - (hydroxyamino) 2 ^zz - (oxo) ethyl] -6 (phenylmethoxy) hexanoyl] amino-

3,3-dimethylbutanoic acid, N-methylamide;

N - [(2R) -2- [2 ^of - (hydroxyamino) -2 '- (oxo) ethyl] -6 (oxo) -6- (propylamino) hexanoyl] -L-phenylalanine-N-2-phenylethylamide;

2 (S) -N-2 - [(2 ^Z R) -2 ^Z - [(1 ^{Z Z} ) -1 ^{Z z} - (methyl) -2 ^zz (hydroxyamino) -2 '' - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-2-phenylamide;

2 (S) -N-2 - [(2 R ^Z) -2 ^Z - ^[(Z L ^Z) -1 ^Z '- (methyl) -2 ^z' (hydroxyamino) -2 '- (oxo) ethyl ] ^from -6 - (oxo) -6 ^of (propylamino) hexanoyl] amino-3,3-dimethylbutanoic acid N-2-phenylamide;

2 (S) -N-2 - [(2 ^Z R) -2 ^Z - [(1 ^{Z Z} ) -1 ^{Z z} - (methyl) -2 ^zz (hydroxyamino) -2 '' - (oxo) ethyl] -6 '- (oxo) -6' (propylamino) hexanoyl] amino-3,3-dimethylbutanoic acid N-2- (4 ^of sulfamoyl) phenylethylamide;

2 (S) -N - [(2 R ^Z) -2 ^z - [2- (hydroxyamino) -2 (oxo) ethyl] -6 ^of - (phenylmethoxy) hexanoyl] amino-368

cyclohexylpropanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] 6 '- (phenylmethoxy) hexanoyl] -1- (3,5-dimethyl) phenylalanine, N-2- ( 4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(4-methoxy) phenoxy] hexanoyl ] amino-

3,3-dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(4-methyl) phenoxy] hexanoyl ] amino-

3,3-dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(1-oxo) butylamino] hexanoyl ] amino-

3-cyclohexylpropanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

(S) -N-2 - [(2 'R) -2' - [(1S) -1 '' - (methyl) -2 '' (hydroxyamino) -2 '' - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 - [(2'R) -2'- [(1''S) -1 '' - (2-methylpropyl) -2 '' - (hydroxyamino) -2 '' - ( oxo) ethyl] -6 (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (phenoxy) hexanoyl] -L-phenylalanine, N-methylamide;

N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7 (phenoxy) heptanoyl] -L-phenylalanine, N-methylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - (phenylmethoxy) hexanoyl] amino-3, 3dimethylbutanoic acid, N-2-phenylethylamide;

(S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoate acid, N-2- (4'-sulfamoyl) phenylethylamide;

N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5 (phenylmethoxy) pentanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7 (phenylmethoxy) heptanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (phenyloxy) hexanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7 (phenyloxy) heptanoyl] -L-phenylalanine, N-methylamide;

(S) -N-2 '- [(2' R) -2 '- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(2-phenethylamino) -6'- (oxo) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(4-methylphenoxy) hexanoyl] amino -

3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(4-chlorophenoxy) hexanoyl] amino -3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2'- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(3-methylphenoxy) hexanoyl] amino -

3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2' - (carboxymethyl) -6 '- (3-methylphenoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5 (carboxy) pentanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (phenylmethoxy) hexanoyl] -L-phenylalanine, N-methyl amide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (propylamino) -6- (oxo) hexanoyl] -L-phenylalanine,

N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] (6RS) -6- (hydroxy) heptanoyl] -L-phenylalanine,

N-methylamide;

2 (S) -N-2 - [(2'R) -2'- [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- (hydroxy) hexanoyl] amino-3,3-dimethylbutanoate acid, N-methylamide;

2 (S) -N-2 - [(2'R) -2'- [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoate acid, N-methylamide;

N - [(2'R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] 6- (4'-oxobutylamino) hexanoyl] -L-phenylalanine, W-methylamide;

2 (S) -N-2 - [(2'R) -2'- [2 '(hydroxyamino) -2' '(oxo) ethyl] -6' - (oxo) -6 '- (propylamino) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

N - [(2R) -2 - [(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;

(S) -N-2 - [(2'R) - [(1R) -1 '' - (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl-2 '' - ( hydroxyamino) 2 '' - (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-

3,3-dimethylbutanoic acid, N-methylamide;

N - [(2'R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] 6- (oxo) -6- (propylamino) hexanoyl] -L-phenylalanine, N-2-phenylethylamide ;

(S) -N-2 - [(2'R) - [(1S) -1- (methyl) -2 (hydroxyamino) -2 '' - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino- 3,3-dimethylbutanoic acid, N-2-phenylethylamide;

• (S) -N-2 - [(2'R) -2 '- [(1S) -1- (methyl) -2' '(hydroxyamino) -2' '- (oxo) ethyl] -6' (oxo) -6 '- (propylamino) hexanoyl] amino-3,3-dimethylbutanoic acid, N-2-phenylethylamide;

(S) -N-2 - [(2'R) -2 '- [(1S) -1' (methyl) -2 '' (hydroxyamino) -2 '' - (oxo) ethyl] -6 '- ( oxo) -6 '- (propylamino) hexanoyl] amino-3,3-dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

2 (S) -N - [(2'R) -2 '- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6 (oxo) -6' - (phenylmethoxy) hexanoyl] amino- 3,3-cyclohexylpropanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] 6 '- (phenylmethoxy) hexanoyl] -1- (3,5-dimethyl) phenylalanine, N-2- ( 4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- [(4-methoxy) -phenoxy] hexanoyl] amino-

3,3-dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- [(4-methyl) -phenoxy] hexanoyl] amino-

3,3-dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- [(1-oxo) butylamino] hexanoyl] amino-3-cyclohexylpropanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

(S) -N-2 - [(2'R) -2 '- [(1' 'S) -1- (methyl) -2' '(hydroxyamino) -2' '- (oxo) ethyl] -6 - (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 - [(2'R) -2 '- [(1S) -1- (2-methylpropyl) -2' '- (hydroxyamino) -2' '- (oxo) ethyl] -672 (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

N - [(2 R) -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;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-3, 3-dimethylbutanoic phenyl acid, N-2-phenylethylamide;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-3, 3dimethylbutanoic acid, N-2- (4'-sulfamoyl) phenylethylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5 (phenylmethoxy) pentanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7 (phenylmethoxy) heptanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (phenyloxy) hexanoyl] -L-phenylalanine, N-methylamide;

N - [(2 R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7 [(phenyloxy) heptanoyl] -L-phenylalanine, N-methylamide;

2 (S) -N-2 '- [(2' R) -2 '- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(2-phenethylamino) -6 ' (oxo) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- [(4-methylphenoxy) hexanoyl] amino -3,3-dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 [(2'R) -2 '- [2' '- (hydroxyamino) -2' '(oxo) ethyl] -6' - [(4-chlorophenoxy) hexanoyl] amino-3 3dimethylbutanoic acid, N-methylamide;

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2 (S) -N-2 '- [(2R) -2' - [2 '' - (hydroxyamino) -2 '' (oxo) ethyl] -6 '- [(3-methylphenoxy) hexanoyl] amino-3 3dimethylbutanoic acid, N-methylamide;

2 (S) -N-2 '- [(2'R) -2' - (carboxymethyl) -6 '- [(3-methylphenoxy) hexanoyl] amino-3,3-dimethylbutanoic acid, N-methylamide;

(3R, 10S) -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) -N-hydroxy-5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (18),

14,16-tetraen-10-ylcarbamoyl) hexanamide;

(3R, 11S) -N-hydroxy-5-methyl-3- (10-oxo-1,9-diazatricyclo [11.6.1.0] -eicose-13 (20), 14 (19), 15,17-tetra-11-ylcarbamoyl) hexanamide;

(3R, 9S) -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-hydroxy-5-methyl-3- (8-oxo-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12 (17),

13,15-tetraen-9-ylcarbamoyl) hexanamide;

(10S) - [4-Methyl-2- (9-oxo-1,8-diazatricyclo [10.6.1.0] - nonadeca-12 (19), 13 (18), 14,16-tetraen-10-ylcarbamoyl) pentyl] - (quinolin-2-ylthiomethyl) phosphinic acid;

(3R, 10S) -N-hydroxy-5-methyl-2-methoxycarbonyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] - nonadeca- (19), 3 (18), 14,16-tetraene -10-ylcarbamoyl) hexanamide;

N- (4-methyl-2-carboxymethylpentanoyl) -L-leucine-N '- (4-methoxycarbonylphenyl) carboxamide;

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N- (4-methyl-2- (4'-hydroxycarbamoyl) methylpentanoyl) -L-leucine-N '- (4-methoxycarbonylphenyl) carboxamide;

N- (4-methyl-2- (4'-hydroxycarbamoyl) methylpentanoyl) -L-leucine-N '- (4-carboxyphenyl) carboxamide;

N- (4-methyl-2- (4'-hydroxycarbamoyl) methylpentanoyl) -L-tryptophan-N '- (4-carboxyphenyl) carboxamide;

N- (4-methyl-2- (4'-hydroxycarbamoyl) methylpentanoyl) -L-cyclohexylglycine-N '- (4-methoxycarbonylphenyl) carboxamide;

N- (4-methyl-2- (4'-hydroxycarbamoyl) methylpentanoyl) -L-1-leucine-N '- (4-methoxycarbonylphenyl) carboxamide;

(3R, 10S) - (6-Biphenyl-4-yl) -3- (9-oxo-1,8-diazatricyclo [10.6.1.0] - nonadeca-12 (19), 13 (18),

14,16-tetraen-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) -propanoic acid ;

(3R, 10S) -4-Cyclopentyl-3- (9-oxo-1,8-diazatricyclo [10.3.1.0] nonadeca-12 (19), 13 (18), 14,16-tetraen-10-ylcarbamoyl 1-butanoic acid;

(3R, 10S) -4-Cyclopropyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14,16-tetraen-10-ylcarbamoyl) -butanoic 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) -hexanoic acid ;

(3R, 10S) -N-hydroxy-5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6. 1.0] nonadeka-12 (18), 13 (19),

14,16-tetraen-10-ylcarbamoyl) -hexanamide;

(3R, 11S) -N-hydroxy-5-methyl-3- (10-oxo-1,9-diazatricyclo [11.6.1.0] -eicose-13 (20), 14 (19), 15,17-tetraen-11-ylcarbamoyl) hexanamide;

(3R, 9S) -N-5-methyl-3- (8-oxo-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12 (17), 13,15-tetra-9-ylcarbamoyl) hexanoic acid;

(3R, 9S) -N-hydroxy-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-tetraen-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-tetraen-10-ylcarbamoyl) pentanamide;

(3R, 10S) -2- (methanesulfonamidomethyl) -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-ethylureidomethyl) -5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14,16-tetraene- 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-

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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-tetrahydro-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-tetraen-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-tetraen-9-ylcarbamoyl pentanoic acid, ethyl ester;

(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 ethyl ester;

(3R, 9S) -6- (4-hydroxyphenyl) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16tetraene-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-pyridine- 4-yl-hexanoic acid;

(3R, 9S) -6- [4- (3-hydroxy-propoxy) -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- (4-Phenoxy-phenyl) -pentanoic acid;

(3R, 9S) -6- [4- (2-hydroxy-ethoxy) phenyl] -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14, 16-tetraen-9-ylcarbamoyl) hexanoic acid;

(3R, 9S) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl) -6- [ 4- (2-pyrrolidin-1-yl) -ethoxyphenyl] hexanoic acid;

(3R _of 9S) -6- (4-methoxyphenyl) -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- (2-methoxy-ethoxy) phenyl] -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14 , 16-tetraen-9-ylcarbamoyl) hexanoic acid;

(3R, 9S) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl) -5-phenylpentane 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-phenylhexane acid;

(3R, 9S) -6- (3-hydroxyphenyl) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16tetraene-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-yl) propoxyphenyl] hexanoic acid;

(3R, 9S) -6- [4- (3-dimethylamino-propoxy) phenyl] 3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca · · · · · · · · · · · · · · · · · · · ·

11 (18), 12,14,16-tetraen-9-ylcarbamoyl) hexanoic acid;

(3R, 9S) -6- [4- (2-dimethylamino-ethoxy) phenyl] -3 (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14 , 16-tetraen-9-ylcarbamoyl) hexanoic acid;

(3R, 9S) -6- (4-cyano-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-Naphthalen-2-yl-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 -pyrrol-1-yl) hexanoic acid;

(3R, 9S) -6- (4-hydroxy-3-methylphenyl) -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-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-Methoxy-phenyl) -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-tetraene-9-

ylcarbamoyl) -6- [4- (pyridin-4-ylmethoxy) phenyl] hexanoic acid;

(3R, 9S) -6- (4-Acetylaminophenyl) -3- (8-oxo-4-oxa-

1,7-diazatricyclo [9.6.1.0] - octadeca-11 (18), 12,

14,16-tetraen-9-ylcarbamoyl) hexanoic acid;

N ⁰¹ - [[3- (N-hydroxycarbamoyl) -4-methylthio-2-propoxymethyl] butylyl] -N, O-dimethyltyrosine amide;

N ⁰¹ - [[3- (N-hydroxycarbamoyl) -4-isopropylthio-2-propoxymethyl] butylyl] -N, O-dimethyltyrosine amide;

N '- [[3- (N-hydroxycarbamoyl) -2-propylthio] butylyl] -N, O-dimethyltyrosine amide;

N- [N- (1-phosphono-3-phenylpropyl) - (S) -leucyl] - (S) phenylalanine-N-methylamide;

N- [N- (1-phosphono-3- (4-bromo-1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -phenylalanine methylamide;

N- [N- (1-phosphono-3- (benzyloxycarbonylamino) propyl) - (S) -leucyl] - (S) -phenylalanine methylamide;

N- [N- (1-phosphono-3- (2-hydroxyphenyl) propyl) - (S) leucyl] - (S) -phenylalanine 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-methylamide;

N- [N- (1-phosphono-3- (methylsulfonyl) propyl) - (S) leucyl] - (S) -phenylalanine-N-methylamide;

N- [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -tryptophan-N-methylamide;

N- [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N-methylamide;

N- [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (-) - aminoazacyclotridecan-2-one;

N - [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N- (aminoethyl) amide;

N- [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N (ethylpyrrolidine) amide;

N- [N- (1-phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N- (ethyl-N-methylpiperazine) amide;

N- [N- (1-phosphono-3- [8- (7,9-dioxo-8-azaspiro [4.5] decyl) propyl) - (S) -leucyl] - (S) -phenylalanine-W-methylamide; and

N- [N- (1-phosphono-3- [8- (7,9-dioxo-8-azaspiro [4.5] decyl)] propyl) - (S) -leucyl] - (S) -lysine-N-methyl amide.

It is clear from the above list that many matrix metalloproteinase inhibitors are known.

A large number of inhibitors are hydroxamic or carboxylic acid compounds, or both.

Typical compounds of this type also describe the following patents, all of which are incorporated by reference in the present invention, since all of the novel compounds disclosed therein may

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 Real name of Smith-Kline Beecham is Smith US 4,304,549 Roche) US 5,256,657 Real name of Sterling Winthrop is Sterling Winthrop US 5,300,674; US 5,412,145 (British Biotechnology) US 5,387,610; US 5,616,605 Research Technology companies) US 5,442,110; US 5,473,100 (Yamanouchi) US 5,643,908 (Sankyo) US 5,525,629 (British Biotechnology) US 5,569,665 (Celltech) US 5,530,128 (Celltech) US 4,318,964; US 5,447,929 (Roche) US 5,643,964; US 5,700,838 (British Biotechnology) WO 97/27174 (Shionogi)

The most commonly used class of compounds is described in WO 95/35275 and WO 95/35276, which are also incorporated herein by reference. Typical compounds from this group are:

N-hydroxy-2 - [(2- (4-methoxyphenoxy) ethyl- (toluene-4-sulfonyl) amino] acetamide;

N-hydroxy-2 - [(2- (4-methoxybenzenesulfonyl) nonylamino) acetamide;

2- [decyl- (toluene-4-sulfonyl) amino] -N-hydroxyacetamide;

2- [benzyl- (octane-1-sulfonyl) amino] -N-hydroxyacetamide;

N-hydroxy-2 - [(2-methoxybenzyl) - (octane-1-sulfonyl) amino] acetamide;

2 - [(2-ethoxy-benzyl) - (octane-1-sulfonyl) amino] N-hydroxyacetamide;

• ··

N-hydroxy-2 - [(naphthalen-2-ylmethyl) - (octane-1-sulfonyl) amino] acetamide;

2 - [(4-chlorobenzyl) - (octane-1-sulfonyl) amino] -N-hydroxyacetamide and salts, solvates or hydrates thereof.

Another group of matrix metalloproteinase inhibitors are the aryl sulfonamides of the formula

OR ¹ O

Ar-S-N- C-C-NHOH

II I ₂

O CH ² R ² wherein Ar is carbocyclic or heterocyclic aryl and R, R ¹ , R ² represent hydrogen, alkyl, aryl, heteroaryl, amino, optionally substituted once or twice. These compounds are disclosed in European patent EP 0606046, which is also incorporated by reference into the present invention.

Characteristic compounds used in the cited patent are:

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] (secbutyl) amino] acetamide;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (tert-butyl) amino] acetamide;

4 44 44 44 44

4444 4444 · · ··

4 «44 * 44

4,444 44,444 4 4

444 4444 44 4 * 444 44 44 ·· 444

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-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [dimethylaminoacetyl] piperidine hydrochloride;

4-N-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [3-picolyl] piperidine dihydrochloride;

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-methoxybenzene sulfonyl (benzyl) amino] -1- [t-butoxycarbonyl] piperidine;

4-N-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [methylsulfonyl] piperidine;

4-N-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [4-picolyl] piperidine hydrochloride;

4-N-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [morpholinecarbonyl] piperidine hydrochloride; φφ φφφφ φφ φφ φφ φφφ

Ν- (t-butyloxy) -2 - [[4-methoxybenzenesulfonyl (benzyl) amino] -2- [2- (4-morpholine) ethyl] acetamide.

The following compounds were prepared as in Example 7:

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (isobutyl) amino-2- (2- (4-morpholine) ethyl) acetamide;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-picoly) amino-2- (2- (4-morpholine) ethyl) acetamide dihydrochloride;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -2 - [(2- (4-morpholine) ethyl] acetamide dihydrochloride);

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-methylthiazol-4-ylmethyl) amino] -2- [2- (4-morpholine) ethyl] acetamide dihydrochloride;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] benzyl) amino] -2- [2- (4-thiomorpholine) ethyl] acetamide;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] benzyl) amino] -2- [2- (4-methylthiazol-4-ylmethyl) acetamide;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] benzyl) amino] -2 - [(6-chloropiperonyl) acetamide;

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] benzyl) amino] -2 - [(1-pyrazolyl) methyl] acetamide;

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;

• · ·

• <· · Φ · Φ · Φ · φ · φ · φ · φ · φ · φ · φ ·

Φ φ Φ «Φ · Φ ΦΦ ΦΦ« ΦΦ

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 and

N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-methylthiazol-4-ylmethyl) amino] -2 - [(1-methyl-4imidazolyl) methyl] acetamide hydrochloride.

Another group of small peptide matrix metalloproteinase inhibitors are described in US Patents 5,270,326; 5,530,161; 5,525,629 and 5,304,604 (also cited herein). These are hydroxamic acid compounds of the formula

O

II

HONHCCH - CH - CN - CHCOX

wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen or alkyl and X is OR ⁵ or NHR ⁵ wherein R ⁵ is hydrogen, alkyl and aryl, A is alkyl and n is 0 to 2. Typical compounds of this group are:

N- [2-isobutyl-3- (4'-hydroxycarbonylamido) propanoyl] -D-tryptophan methylamide;

N- [2-isobutyl-3- (4'-hydroxycarbonylamido) propanoyl] -N-methyl-L-tryptophan methylamide;

4

N- [2-isobutyl-3- (N-hydroxycarbonylamido) propanoyl] -L-3- (2-naphthyl) alanine methylamide;

N- [2-isobutyl-3- (N-hydroxycarbonylamido) propanoyl] -L-tryptophan 2-hydroxyethylamide;

N- [2-isobutyl-3- (4'-hydroxycarbonylamido) propanoyl] -L-tryptophan amylamide;

N- [2-isobutyl-3- (N-hydroxycarbonylamido) propanoyl] -L-tryptophan piperidinamide;

N- [2-isobutyl-3- (4'-hydroxycarbonylamido) propanoyl] -L-tryptophan dodecylamide;

N- [2-isobutyl-3- (4'-hydroxycarbonylamido) propanoyl] -L-tryptophan (S) methylbenzylamide;

N- [L-2-isobutyl-3- (N-hydroxycarbonylamido) propanoyl] -L-tryptophan (6-phenylmethoxycarbonylaminohexyl-1) amide;

2S-hydroxy-3R- [1S- (3-methoxy-2,2-dimethylpropylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -5-methyl-hexanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -6- (4-chloro) phenylhexanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] octanhydroxamic acid;

2S-hydroxy-3R- [1S- (pyridin-2-ylmethylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -5-methylhexanhydroxamic acid;

2S-hydroxy-3R- [1S- (pyridin-3-ylmethylcarbamoyl) -

2,2-dimethylpropylcarbamoyl] -5-methylhexanhydroxamic acid;

2S-hydroxy-3R- [1S- (pyridin-4-ylmethylcarbamoyl) -

2,2-dimethyl-propylcarbamoyl] -5-methyl-hexanhydroxamic acid;

this to it to it to it to it to it

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -4-methoxybutanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -4-benzyloxy-butanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -4-benzylthio-butanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylbuten-3-ylcarbamoyl] -5-methylhexanhydroxamic acid;

2S-hydroxy-3R- [1S- (tert-butylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -5-methyl-hexanhydroxamic acid;

2S-hydroxy-3R- [1S- (N, N-dimethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -5-methyl-hexanhydroxamic acid;

2S-hydroxy-3R- [1S- (3-hydroxy-2,2-dimethylpropylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -5-methyl-hexanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylpropylcarbamoyl] -β-phenyl-hexanhydroxamic acid;

2S-hydroxy-3R- [1S- (methylcarbamoyl) -2,2-dimethylbutylcarbamoyl] -5-methylhexanhydroxamic 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-phenylalaninyl-D-prolinol;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalaninyl-L-prolinol;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (5-N-methylpentylcarboxamide) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-ethylthioethyl) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-methoxyethyl) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-N-acetylethyl) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide;

Sodium [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -phenylalanine-N- (3- (2-pyrrolidone) propyl) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-acetoxyethyl) amide;

[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-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-phenylalaninyl-D-prolinol;

Sodium [4- (N-hydroxyamino) -2R-isobutyl-3-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide;

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

89 '[4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide or a salt thereof;

N ^2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -N-tert-butyloxycarbonyl-L-lysine-N ^1- methylamide;

N ² - [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] - N - tert -butyloxycarbonyl-L-lysine-N ⁶ - (4-hydroxyphenylthiomethyl) -L-lysine-N ¹ methylamide;

N ² - [4- (N-hydroxyamino) -3 S - (2-thienylthiomethyl) 2 R -isobutylsuccinyl] -N ⁶ -tert-butyloxycarbonyl-Llysine-N ^1- methylamide;

N ^2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -O-tert-butyl-L-threonine-N ^1- methylamide;

N ^2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -L-glutamine-N ¹ , N ⁵ -dimethylamide;

N ^2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylsulfonylmethyl) -2R-isobutylsuccinyl] -N-acetyl-Llysine-N ^1- methylamide;

3R- (3-methoxycarbonyl-1S-methylcarbamoylpropylcarbamoyl) -5-methyl-2S-2-propenylhexanhydroxamic acid;

3R- (1S-Methylcarbamoyl-2-thien-2-ylethylcarbamoyl) -5-methyl-2S-2-propenylhexanhydroxamic acid;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylcarboxylic acid) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylcarboxy-N) (methylamide) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylcarboxy-beta-alanine) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylcarboxyglycine) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylcarboxy-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-methoxymethylcarboxamide) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethylsuccinyl) -L- (4-N-acetylamino) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethylsuccinyl) -L- (4-N-methylsuccinylamide) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (4-aminophenylthiomethyl) succinyl] -L- (4-N-methylsuccinylamide) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (4-aminophenylthiomethyl) succinyl] -L- (4-N- (4- (4-oxobutanoic acid) aminophenylalanine-N-methylamide);

[4- (N-hydroxyamino) -2R-isobutyl-3S- (4-hydroxyphenylthiomethyl) succinyl] -L- (4-N-methylsuccinylamido) phenylalanine-N-methylamide;

• [4- (N-hydroxyamino) -2R-isobutyl-3S- (4-hydroxyphenylthiomethyl) succinyl] -L- (4-N- (4- (4-oxobutanoic acid) aminophenylalanine-N-methylamide);

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl] -L- (4-oxymethylcarboxymethyl) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl] -L- (4-N- (oxymethylcarboxylic acid) phenylalanine-N-methylamide);

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl] -L- (4-oxymethylcarboxyglycyl methyl ester) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl] -L- (4-oxymethylcarboxyglycine) phenylalanine-N-methylamide;

Phenylalanine-N-methylamide [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L- (4-oxymethylcarboxyglycyl methyl ester);

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

[4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -L- (4-methoxymethylnitrile) phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-3- (1- (2-methyloxycarbonyl) ethyl) -4-methoxyphenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-3 (hydroxymethyl) -4-methoxyphenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-3-methyl-4-methoxyphenylalanine-N-methylamide;

2- [benzyl- (octane-1-sulfonyl) amino] -N-hydroxyacetamide;

·· · · 9 9 9 999

9 9 9 9 9 9 9 * * 9

9 9 9 99 99

9 9 9 9 9 9 99

9999 99 99 99999

N-hydroxy-2 - [(2-methoxybenzyl) - (octane-1-sulfonyl) amino] acetamide;

2 - [(2-ethoxybenzyl) - (octane-1-sulfonyl) amino] -N-hydroxyacetamide;

N-hydroxy-2 - [(naphthalen-2-ylmethyl) - (octane-1-sulfonyl) amino] acetamide;

2 - [(4-chlorobenzyl) - (octane-1-sulfonyl) amino] -N-hydroxyacetamide;

N ² - [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-leucine-N ¹ -methylamide;

N ² - [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl] -5-methyl-L-glutamic acid -N ¹ methylamide;

N ² - [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine -N ¹ -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-1-methylcarbamoyl-ethylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (3-chlorophenylsulfanylmethyl) -3R- (2-phenyl-1-methylcarbamoyl-ethylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (phenylsulfanylmethyl) -3R- (2-phenyl-1S- (pyrid-3-ylmethylcarbamoyl) ethylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (3-methylphenylsulfanylmethyl) -3R- (2-phenyl-1-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexane hydroxamic acid;

Φ Φ · · · φ · · · · · · · · · · ·

Φ · φφφφ φφ φφ φφ φφφ

2S- (thien-2-ylsulfanylmethyl) -3R- (2- (4-carboxymethoxyphenyl) -1S-methylcarbamoylethylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (thien-2-ylsulfanylmethyl) -3R- (2-phenyl-1S (pyrid-3-ylmethylcarbamoyl) ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-Hydroxyphenylsulfanylmethyl) -3R- (2-phenyl-1S (pyrid-3-ylmethylcarbamoyl) ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (thien-2-ylsulfanylmethyl) -3R- (2-naphth-2-yl-1-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-hydroxyphenylsulfanylmethyl) -3R- (2R-hydroxy1S-methylcarbamoyl-propylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (4-hydroxyphenylsulfanylmethyl) -3R- (5-acetamido-1S-methylcarbamoyl-pentylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-hydroxyphenylsulfanylmethyl) -3R- (3- [1,1-dimethylethoxycarbonyl] -1S-methylcarbamoylpropylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (thien-2-ylsulfonylmethyl) -3R- (2-phenyl-1-methylcarbamoyl-ethylcarbamoyl) -5-methylhexanhydroxamic acid;

3S- (2- [4-acetamidophenyl] -1S-methylcarbamoylethylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (4-phthalimidobutyl) -3R- (3-methyl-1-methoxycarbonylmethylcarbamoyl-butylcarbamoyl) -5-methyl-hexanhydroxamic acid;

3R- (2- [4-methoxyphenyl] -1S-methylcarbamoylethylcarbamoyl) -2S, 5-dimethylhexanhydroxamic acid;

··························································· ·· ···

3R- (2-phenyl-1S- [2-oxo-pyrrolid-1-yl] propylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

3R- (2- [4-methoxyphenyl] -1S-methylcarbamoylethylcarbamoyl) -5-methylhexanhydroxamic acid;

3R- (2-phenyl-1S- [pyrid-3-ylmethylcarbamoyl] ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

3R- (2,2-dimethyl-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanhydroxamic acid;

isobutylmalonoyl-L-alanine furfurylamide hydroxamate;

2-isobutyl-3-carbonyl-3 '- (4-acetylaniline) propanoic acid;

N-benzyloxycarbonyl-α-phosphonoglycyl-L-alanine, firfurylamide;

[4- (N-hydroxyamino) -2R-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-phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S- (4- (N-acetyl) aminophenylthiomethyl) succinyl] -L-phenylalanine-N-methylamide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-phenylsulphinylmethylsuccinyl] -L-phenylalanine-N-methylamide;

3R- (3-methoxycarbonyl-1S-methylcarbamoylpropylcarbamoyl) -5-methyl-2S-phenylsulfanylmethylhexanhydroxamic acid;

3R- (3-methoxycarbonyl-1S-methylcarbamoylpropylcarbamoyl) -5-methyl-2S- (thien-2-ylsulfanylmethyl-hexanhydroxamic acid);

2S- (4-methoxy-phenylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-Amino-phenylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (ethylsulfanylmethyl) -3R- (3-methoxycarbonyl) -5-methylcarbamoyl-propylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (acetylsulfanylmethyl) -3R- (3-methoxycarbonyl) -5-methylcarbamoyl-propylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (benzylsulfanylmethyl) -3R- (3-methoxycarbonyl) -5-methylcarbamoyl-propylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (tert-butylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanhydroxamic acid;

• 9 9 9 j j:. :;. ··. . ; j:

9 9 · ···

9999 99 99 99 999

2S-thiomethyl-3R- (3-methoxycarbonyl-1-methylcarbamoyl-propylcarbamoyl) -5-methylhexanhydroxamic acid;

2S- (4-Hydroxy-phenylsulfanylmethyl) -3R- (2-tert-butoxycarbonyl-1S-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-Hydroxy-phenylsulfinylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanhydroxamic acid;

2S- (4-Hydroxy-phenylsulfonylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl) -

5-methyl-hexanhydroxamic acid;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- [1- (2-aminoethyl) -pyrrolidine] amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- [1- (3-aminopropyl) -2 (RS) -methylpiperidine] amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- [2- (2-aminoethyl) -1-methylpyrrole] amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (3-aminomethylpyridine) amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-aminomethylpyridine) amide;

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-phenylalanine-N- (4-aminomethylpyridine) amide;

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-phenylalanine-N- (1- (3-aminopropyl) -imidazole) amide;

[4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-phenylalanine-N- (2-aminomethylbenzimidazole) amide;

[4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- [4- (2-aminoethyl) morpholino] amide;

9 · · 9 9 * ·· »• • 9; ,; _# · \. · *;

9 9 9 9 9 9

9999 99 ·· ·· 999 [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- [4- (2-aminoethyl) morpholine] amide;

[4- (N-hydroxyamino) -2 (R, S) -isobutylsuccinyl] -L-phenylalanine-N- [2- (2-aminoethyl) -pyridine] amide;

[4- (N-hydroxyamino) -2 (R, S) -isobutylsuccinyl] -L-phenylalanine-N- [4- (2-aminopropyl) morpholine] amide;

[4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (3-aminomethylpyridine) amide, hydrochloride and [4- (2H-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- [4- (2 (aminoethyl) morpholine] amide hydrochloride.

In particular, tricyclic butyric acid derivatives which are matrix metalloproteinase inhibitors are used in the present invention. The group of tricyclic butyric acid derivatives is defined by the formula:

w ‘ X 7 at AND ~ ^ R ² < ⁴

O X

II II wherein one of R ¹ or R ² is-C-CH- (CH) _and -CR ⁵ ,

RR ^and where X is 0,

N-OR ⁶ where R ⁶ is hydrogen,

- (CH 2) _n - aryl, wherein n is 0 or an integer of 1 to 5, alkyl or

- (CH ₂ ) n -cycloalkyl, wherein n is as defined above, or

4 * «4« · «·· <

9 · ♦ 9 ♦ 9 * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 44 44 44

NNR ⁶ , wherein R ⁶ and R ^6a are the same or different

AND

R 6a substituents defined above as R ⁶ ;

R and R ^a are the same or different substituents and represent hydrogen,

- (CH _{2) n} -aryl wherein n is as defined above, ~ _(CH2) n ^_ heteroaryl, wherein n is as defined above,

- (CH ₂ ) _p -R ⁷ - (CH ₂ ) q -aryl, wherein R ⁷ is O or S and p, q are 0 or an integer from 1 to 5, wherein p + q is 5,

- (CH ₂ ) _p -R ⁷ - (CH ₂ ) q -heteroaryl, wherein R ⁷ , p and q are as defined above, alkyl, ^- (CH ₂ ) _n -cycloalkyl, or

- (CH ₂ ) _r -NH ₂ wherein r is an integer from 1 to 9;

a is zero or an integer of 1 to 3; R ⁵ is OH,

-OR ⁶ where R ⁶ is as defined above,

-NR ⁶ wherein R ⁶ and R ^6a are the same or different _R e _and substituents defined as R ^6;

NH-OR ⁶ wherein R ⁶ is as defined above;

R ³ and R ⁴ are the same or different substituents selected from hydrogen, alkyl,

NO ₂ , halogen,

OR ⁶ , wherein R ⁶ is as defined above,

CN,

CO ₂ R ⁶ , where R ⁶ is as defined above,

SO ³ R ⁶ , wherein R ⁶ is as defined above,

# 9 AT * O 99 • 9 9 · 9 * 9 • 9 9 9 9 99 • 9 9 »» 9 • 9 9 9 9 • 9 • O 9 9 9 ' «· * 9 9999 9 9 ·· 99 * 9

CHO,

O

-C-R, wherein R is as defined above,

O

II _{6 6 6}

-CNR ⁵ wherein R and R ^a are the same or different

L

R ⁵ substituents already defined as R ⁶ , or

- (CH ₂ ) _n -NR ⁶ wherein R ⁶ and R ^6a are the same or

R ^6a different substituents defined as R ⁶ ;

l / LWSz and Z1 ^* are the same or different CR ³ substituents, wherein R ³ is as defined above, or is N such that one of W or W ¹ is N, or one of Z or Z ¹ is N, or both, and

Y is -N-, wherein R is as defined above,

AND

R

-O-,

-S- (0) _m , where m is zero or an integer of 1 or 2,

-CH ₂ -,

-C-,

I o

-C-, wherein R ⁶ is as defined above,

N-OR ⁵

-CH-, wherein R ⁶ is as defined above,

OR ⁶

-C-, wherein R ⁶ and R ^6a are the same or different

I ₆

NNR ⁵

AND.

R ^6a substituents defined as R ⁵ ;

• · • ·

100 ALIGN!

-C- N-, wherein R ⁶ is as defined above, i L

OR ⁶

-N- C-, wherein R ⁶ is as defined above, i ₆ L

R ⁶ O

-C- 0-,

II o

-About what

-CH2-0-,

-O- CH2-,

-CH ₂ -S (O) _m -, wherein m is as defined above,

-S (O) _{m -CH2} - wherein m is as defined above,

-CH ₂ -N-, wherein R ⁶ is as defined above,

-N-CH ₂ -, wherein R ⁶ is as defined above,

-CH = N-, or

-N = CH-;

in case X is O and R ⁵ is not ^NH-OR6, at least one of R and R ^a is not hydrogen;

as well as the corresponding isomers of these compounds or their pharmaceutically usable salts.

Typical representatives of this group are:

2- (2-dibenzofuran-2-yl-2-hydroxyiminoethyl) -4-methylpentanoic acid;

2- (2-dibenzofuran-2-yl-2-hydroxyiminoethyl) -5-phenylpentanoic acid;

4-dibenzofuran-2-yl-4-hydroxyimino-2-phenethylbutyric acid;

101

5- (4-chlorophenyl) -2- (2-dibenzofuran-2-yl-2-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) -5β-tolylpentanoic acid;

3- (dibenzofuran-2-yl-hydroxyiminomethyl) -5-methylhexanoic acid;

3- (dibenzofuran-2-yl-hydroxyiminomethyl) -6-phenylhexanoic acid;

3- (dibenzofuran-2-yl-hydroxyiminomethyl) -5-phenylpentanoic acid;

6- (4-chlorophenyl) -3- (dibenzofuran-2-ylhydroxyiminomethyl) hexanoic acid;

3- (dibenzofuran-2-yl-hydroxyiminomethyl) -6- (4-fluorophenyl) hexanoic acid;

3- (dibenzofuran-2-yl-hydroxyiminomethyl) -6- (4-methoxyphenyl) hexanoic acid; and

3- (dibenzofuran-2-yl-2-hydroxyiminomethyl) -6-ptolylhexanoic acid, as well as the corresponding isomers of these compounds, or a pharmaceutically acceptable salt thereof.

Tricyclic butyric acids containing an α-amino substituent are defined by the formula

About NR4R5

II I

C-CH 2 CHCOR3 · · · · · ·

102 where

X is O, NOR ₉ , S, OH, SH or. ^R 7 —N —N <

R _7a

R ₇ and R _7a are independently hydrogen

C 1 -C 20 alkyl or substituted C 1 -C 20 alkyl, (CH ₂ ) 0-6 aryl, (CH ₂ ) 0-6 heteroaryl, or (CH ₂ ) 0-6 cycloalkyl;

Ri and _R2 are independently hydrogen,

C 1 -C 20 alkyl or substituted C 1 -C ₂₀ alkyl, halogen,

NO ₂ ,

CN,

CHO,

COR ₆ , Coor ₆ ,

SO ₃ R _6, OR @ _6, CONR ₄ R _5, (CH ₂₎ o-6 aryl, _(CH2) -6 heteroaryl, or (CH ₂₎ o -C 6 cycloalkyl;

Ré is hydrogen,

Ci-C ₂ o alkyl or substitued _Ci-C20 alkyl;

aryl is phenyl or substituted phenyl;

R ₃ is hydroxy,

O-C 1 -C ₂ alkyl or substituted O-C 1 -C 20 alkyl,

O- (CH ₂ ) _1-3 aryl, or

NHOR ₆ ;

R ₄ and R ₅ are independently hydrogen,

103 · ······························· · ·

C1-C20 alkyl or substitued Ci-C ₂ o alkyl, _(CH2) o-6 aryl, _(CH2) -6 heteroaryl, or one of R

R ₄ and R ₅ are hydrogen and the other is:

CORg,

CSRg,

CONRgRg,

CSNRgRg,

COORg,

COSRg,

COCHRg,

AND

NRiR ₂

CON-CONRgRg

AND

Ri

CON-COORg

AND

Ri

CON-COSRg, or

Ri

CON-SO ₂ NR ₈ R ₉

AND

Ri

CON-SO ₃ R _8;

AND

Ri

Y is -N-,

AND

Ri

-0-,

-S (O) 0, 1 or 21

-ch ₂ -,

104

-C-,

II o

-c-, II

NORg

-CH-,

ORg

-C-,

II

N-N-Rg Rg

-C- N-,

II I

O Rg

-N- C-, II

Rs O

-WHAT-,

O-CH ₂ -O,

-O-CH2-,

CH2S (O) 0, 1 or 2, - S (O) 0, 1 or 2 ^- 0¾ ^- ,

-CH 2 -N,

AND

Rs

-N-CH 2 -, I

Rs

-CH = N, or

-N = CH-;

R 8 and R 8 are independently hydrogen,

C 1 -C 20 alkyl or substituted C 1 -C 20 alkyl;

_(CH2) o-6 aryl, _(CH2) 6-heteroaryl, or (CH ₂₎ o- ₆ cycloalkyl;

W, W ¹ , Z and Z ¹ are independently CR 1 or N;

and pharmaceutically usable salts, isomers, stereoisomers and solvates thereof.

Typical compounds used in the method are, for example:

(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-oxobutyric acid (S) -4-Dibenzofuran-2-yl-2- [3- (2,6-diisopropylphenyl) -ureido] -4-oxo- butyric acid;

(S) -2-Benzoylamino-4-dibenzofuran-2-yl-4-oxobutyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylaminobutyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2- (3-phenylpropionylamino) butyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2- (7-phenylheptanoylamino) 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;

44 · ·· 44 ·· • 4 * 4 · ♦ · * · 4 ιοβ i: * · · í:

444 (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-oxobutyric acid;

(S) -4-Dibenzofuran-2-yl-2- [3- (2,6-diisopropyl-phenyl) -ureido] -4-oxo-butyric acid;

(S) -2-Benzoylamino-4-dibenzofuran-2-yl-4-oxobutyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylaminobutyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2- (3-phenylpropionylamino) butyric acid;

(S) -4-Dibenzofuran-2-yl-4-oxo-2- (7-phenylheptanoylamino) 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;

(S) -4-Dibenzofuran-2-yl-4-oxo-2- (dodecanoylamino) butyric acid.

Trycyclic sulfonamide matrix metalloproteinase inhibitors include compounds of the formula:

where M is a derivative of the natural (L) -a-amino acid structure * * ♦ * · · · · · · · · · · ·

107 ··· · · · · · · ················

X is O, S, S (O) _n , CH ₂ , co, or NH;

R is a side chain of a natural α-amino acid;

R ¹ is Οχ-C ₅ alkoxy, hydroxy or NHOR ⁵ ;

R ² and R ⁴ are independently hydrogen, -C 1 -C 5 alkyl, NO 2, halogen, -OR ⁵ , -CN, -CO ₂ R ⁵ , -SO ³ R ⁵ , -CHO, COR ⁵ , -CONR ⁵ R ⁵ , - ( CH 2) n NR ⁵ R ⁶ , -CF 3, or -NHCOR ⁵ ;

R ⁵ and R ⁶ are each independently hydrogen or -C 1 -C 5 alkyl;

n is 0 to 2;

as well as pharmaceutically usable salts, esters, amides, and medicament-acceptable derivatives thereof.

Characteristic compounds of this group are:

(L) -2- (dibenzofuran-2-sulfonylamino) -4-methylpentanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methylpentanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-phenylpropanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) propionic acid;

(L) -2- (Dibenzofuran-2-sulfonylamino) -3-methylbutyric acid;

(dibenzofuran-2-sulfonylamino) -acetic acid;

(L) -2- (Dibenzofuran-2-sulfonylamino) succinic acid;

(L) -2- (Dibenzofuran-2-sulfonylamino) -3-tritylsulfanyl-propionic acid;

• · · · t · t · t · • · • · • · t · t · t · tt 9 ··· · ♦ ···

108 (L) -2- (Dibenzofuran-2-sulfonylamino) -3-mercaptopropionic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methylpentanoic acid, hydroxyamide;

(L) -2- (dibenzofuran-2-sulfonylamino) -4-methylpentanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methylpentanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-phenylpropanoic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) propionic acid;

(L) -2- (Dibenzofuran-2-sulfonylamino) -3-methylbutyric 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-mercaptopropionic acid;

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methylpentanoic acid, hydroxyamide;

Other tricyclic sulfonamides are defined by the formula

wherein Q is a synthetic amino acid;

X is O, S, S (O) n / CH 2, CO or NH;

• · φ Φ φ φ φ φ φ

2.09 φ · * 4 φ φ 4 φ 4 · 4

R ² and R ⁴ are independently hydrogen, -C 1 -C 5 alkyl, NO 2, halogen, -OR ⁵ , -CN,

-CO 2 R ⁵ , -SO ³ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ , - (CH ₂ ) _n NR ⁵ R ⁶ ,

-CF 3, or

-NHCOR ⁵ ;

R ⁵ and R ⁶ are each independently hydrogen or -C 1 -C 5 alkyl;

n is 0 to 2;

as well as pharmaceutically usable salts, esters, amides, and medicament-acceptable derivatives thereof.

Typical examples of these compounds are:

(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, a

2 (S) -3 - [(Dibenzofuran-2-sulfonylamino) -methyl] -5-methyl-hexanoic acid.

Another general class of matrix metalloproteinase inhibitors that are used to treat and prevent heart failure and ventricular dilatation are biphenyl butyric acid derivatives comprising compounds of the formula:

·· ·· # · ·· ··

4 * ·· <· ♦ ♦ · ·

9 9 · · 99 9 9

9 9 9 9 9

9 9 9 99 9 9 9 · ·

110

wherein R and R ¹ are either the following, or other substituents hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, -OR ⁶ , wherein R ⁶ is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or cycloalkyl,

-NR ⁶ wherein R ⁶ and R ^6a are the same or different

AND

R ^6a substituents already defined for R ⁶ ,

O ^II ₆

-O-C-R, where R is as defined above,

O

II ₆

-NH-C-R, wherein R is as defined above,

O ¹¹ ₆

-S-C-R, where R is as defined above,

-SR ⁶ , wherein R ⁶ is as defined above,

111 o

II -CR ⁶ , wherein R ⁶ is as defined above,

-CH 2 -OR ⁶ , wherein R ⁶ is as defined above,

-CH ₂ -NR ⁶ wherein R ⁶ and R ^6a are the same or different _R 6a substituents defined for R ⁶ ,

O

II _{6 6 6}

-CNR where R ^b and R ^5a are the same or different _{16 R} 6a substituents defined as R ⁶ ,

-SR ⁶ , wherein R ⁶ is as defined above,

II o

cycloalkyl or heteroaryl, with the proviso that R ¹ and R ¹ are not both hydrogen atoms;

6 6

R is -OR, wherein R is as defined above, or

-NR ⁶ wherein R ⁶ and R ^6a are the same or different

R ^6a substituents already defined for R ⁶ ,

R ² , R ^3a , R ⁴ and R ^4a are the same or different substituents from the group of hydrogen, fluoro, alkyl, - (CH ₂ ) _n - aryl, wherein n is from 1 to 6,

- (CH ₂₎ n -heteroaryl, wherein n is the interval defined above,

- (CH ₂ ) _n - cycloalkyl, wherein n is from the interval defined above,

99 ·· 99 * 9 · * ·· 9 9 9 9 ···

9 · 9 9 99 · ·

112 • 9 9 9 9 9 · 99 9

9999 99 ·· 99 9 ··

- (CH ₂ ) p X - (CH ₂ ) q -aryl, wherein X is O, S, SO, SO ₂ or NH and p, q are 0 or a value from 1 to 6, wherein p + q is not greater than 6,

- (CH ₂ ) _p -X- (CH ₂ ) q -heteroaryl, wherein X, p and q are as defined above, or

-CH ₂ ) _n -R ⁷ wherein R ⁷ is

N-phthalimido,

N-2,3-naphthylimido,

-OR ⁶ , wherein R ⁶ is as defined above,

-NR ⁶ wherein R ⁶ and R ^6a are the same or different

Ø ^6a substituents already defined as R ⁶ ,

-SR ⁶ , wherein R ⁶ is as defined above,

-SR ^6, wherein R ⁶ is as defined above, ¹ ₆

-S-R, wherein R is as defined above, II o o

-OCR ⁶ , wherein R ⁶ is as defined above,

O

-NCR ⁶ wherein R ⁶ and R ^6a are the same or different

R ^6a substituents defined as R ⁶ ,

-SCR ⁶ , wherein R ⁶ is as defined above,

-CR ⁶ , wherein R ⁶ is as defined above,

113 ¢ 4 · 44 · 44 ♦ * 444 4 444 4 444 4 4 4 4 4444 • 4 · 4 4 44 444 4 44 44444

O ¹ ₆

-C-OR, wherein R is as defined above, or

-CNR ⁶ wherein R ⁶ and R ^6a are the same or different

_R 6a is a substituent already defined as R ⁶ , and n is as defined above;

R ⁵ is OH or SH, provided that R ³ , R ^3a , R ⁴ and R ^4a are hydrogen or at least one of R ³ , R ^3a , R ⁴ and R ^4a is fluorine, as well as the corresponding isomers of said compounds, or a pharmaceutically acceptable salt thereof. Typical compounds of this class that are commonly used to treat atherosclerosis are:

4- (4'-chlorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

4- (4'-Bromobiphenyl-4-yl) -4-hydroxyimino butyric acid;

4- (4'-chlorobiphenyl-4-yl) -4- (domethylhydrazono) butyric acid;

4- (4'-Fluorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

(±) -4- (4'-chlorobiphenyl-4-yl) -4-hydroxybutyric acid;

4- (4'-Bromo-2'-fluorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

(±) -4- (4'-chlorobiphenyl-4-yl) -3-fluoro-4-oxobutyric acid;

4- (2 ', 4'-dichlorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

4- (2 ', 4'-Difluorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phenylpropyl) butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (2-phenylethyl) butyric acid;

«« ♦ · w w w 44 44 444 ·

114 t 4 · · · · ♦ ··

4 (±) -4- (4'-chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phthalimidopropyl) butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 (phenylthiomethyl) butyric acid;

4- (4'-chloro-2'-fluorobiphenyl-4-yl) -4-hydroxyiminobutyric acid;

4-hydroxyimino-4- (4'-trifluoromethyl-biphenyl-4-yl) butyric acid;

4- (4-chlorobiphenyl-4-yl) -4-methoxyimino butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -2-fluoro-2- [2- (1,3-dioxo-

1,3-dihydro-isoindol-2-yl) ethyl] -4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 (1H-indol-3-yl) methyl butyric acid;

(±) -4- (4'-chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methylbutyric acid;

(±) -2- [2- (4'-chlorobiphenyl-4-yl) -2-hydroxyiminoethyl] -2-fluoro-6-phenyl hexanoic acid;

(+) - 4- (4'-Chlorobiphenyl-4-yl) -2-fluoro-2- [2- (1,3-dioxo-

1,3-dihydro-benzo [F] isoindol-2-yl) -ethyl] -4-hydroxyiminobutyric acid;

(±) -2- [2- (4-chlorobiphenyl-4-yl) -2-hydroxyiminoethyl] -6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -2-fluoro- hexanoic acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- [2- (phenylethylcarbamoyl) ethyl] butyric acid;

4- (4 ^of -Chlorobiphenyl-4-yl) -3,3-difluoro-4-hydroxyiminomáselná acid;

(±) -4- (4-Chlorobiphenyl-4-yl) -3,3-dimethyl-2-fluoro-4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -2,2-dimethyl-3-fluoro-4-hydroxyimino-butyric acid;

115> · · · · · · · · · · · · · · · · · · · · · · · · ·

4- (4'-chlorobiphenyl-4-yl) -2,2-difluoro-4-hydroxyiminobutyric acid;

and

- (4'-chlorobiphenyl-4-yl) -2,2,3,3-tetrafluoro-4-hydroxyimino butyric acid.

Compound from the group consisting of:

4- (4'-chlorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

4- (4'-Bromobiphenyl-4-yl) -4-hydroxyimino butyric acid;

4- (4'-chlorobiphenyl-4-yl) -4- (dimethylhydrazono) butyric acid;

4- (4'-Fluorobiphenyl-4-yl) -4-hydroxyimino butyric acid;

(±) -4- (4'-chlorobiphenyl-4-yl) -4-hydroxybutyric acid;

4- (4'-Bromo-2'-fluorobiphenyl-4-yl) -4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -3-fluoro-4-oxo-butyric acid

4- (2 ', 4'-dichlorobiphenyl-4-yl) -4-hydroxyimino-butyric acid;

4- (2 ', 4'-difluorobiphenyl-4-yl) -4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phenylpropyl) butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (2-phenylethyl) butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phthalimidopropyl) butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (phenylthiomethyl) butyric acid;

4- (4'-chloro-2'-fluorobiphenyl-4-yl) -4-hydroxyiminobutyric acid;

116

·· ♦ · • • • · • • • · • • • · • • € • • · « E • • • • • • «· • • · ♦ ·· ·· • a ·· ·· Λ ·

4-hydroxyimino-4- (4'-trifluoromethyl-biphenyl-4-yl) butyric acid;

4- (4'-chlorobiphenyl-4-yl) -4-methoxyimino butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -2-fluoro-2- [2- (1,3-dioxo-

1,3-dihydro-isoindol-2-yl) ethyl] -4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 (1H-indol-3-yl) methyl butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methylbutyric acid;

(±) -2- [2- (4'-Chlorobiphenyl-4-yl) -2-hydroxyiminoethyl] -2-fluoro-6-phenyl hexanoic acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -2-fluoro-2- [2- (1,3-dioxo-

1,3-dihydro-benzo [F] isoindol-2-yl) -ethyl] -isoindol-2-yl) -ethyl] -4-hydroxyimino-butyric acid;

(±) -2- [2- (4'-Chlorobiphenyl-4-yl) -2-hydroxyiminoethyl] -6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-fluoro- hexanoic acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- [2- (phenylethylcarbamoyl) ethyl] butyric acid;

4- (4'-chlorobiphenyl-4-yl) -3,3-difluoro-4-hydroxyiminobutyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -3,3-dimethyl-2-fluoro-4-hydroxyimino-butyric acid;

(±) -4- (4'-Chlorobiphenyl-4-yl) -2,2-dimethyl-3-fluoro-4-hydroxyimino-butyric acid;

4- (4'-chlorobiphenyl-4-yl) -2,2-difluoro-4-hydroxyiminobutyric acid;

and

4- (4'-Chlorobiphenyl-4-yl) -2,2,3,3-tetrafluoro-4-hydroxyimino butyric acid.

117

For this method, there are also 4 · 4 · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ···········································.

very suitable biphenyl sulfonamides having the formula

N - <- - COR ^{3 H} i?

where:

R ¹ is C 1 -C ₆ alkyl, halogen, nitro, NR ⁴ R ⁵ , cyano, OR ⁴ and COOR ⁴ ;

R ² is C 1 -C ₆ alkyl, optionally substituted with phenyl, substituted phenyl, NR ⁴ R ⁵ , OR ⁶ , carboxy,

NH

I carboxamido, H ₂ NC (NH) -NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl and substituted phenyl;

R ³ is OH, 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 or C 1 to C 4 alkyl; and

R ⁶ is hydrogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkanoyl, phenyl or substituted phenyl.

The characteristic compounds to be used have the R ¹ in the 4 'position in the above formula.

Another group of matrix metalloproteinase inhibitors used in the present invention are heterocyclic substituted phenylbutyric acid derivatives having, for example, the formula:

Ar can be phenyl, phenyl substituted

alkyl,

NO ₂ , halogen,

OR ⁵ , wherein R ⁵ is hydrogen or alkyl,

CN,

CO ₂ R ⁵ , where R ⁵ is as defined above,

SO ₃ R ⁵ , where R ⁵ is as defined above,

CHO,

COR ⁵ where R ⁵ is as defined above, CONHR ⁵ where R ⁵ is as defined above, or NHCOR ⁵ where R ⁵ is as defined above,

2-naphthyl or heteroaryl;

R ¹ can be hydrogen, methyl, ethyl,

NO ₂ , halogen,

OR ⁵ , wherein R ⁵ is as defined above,

CN, CO ₂ R ⁵ , wherein R ⁵ is as defined above, SO ³ R ⁵ , wherein R ⁵ is as defined above, CHO, or

COR ⁵ , wherein R ⁵ is as defined above;

R ² and R ³ are the same or different substituents which may independently be hydrogen, alkyl,

- (CH ₂₎ -aryl wherein v is an číslol to 5,

- (CH ₂ ) _v - heteroaryl, wherein v is as defined above,

- (CH ₂ ) _v -cycloalkyl, wherein v is as defined above,

- (CH ₂ ) _p -X- (CH ₂ ) _q -aryl, wherein X is O or S and p and q are each 0 or an integer from 1 to 5, with p + q not greater than 5,

119

- _(CH2) pX- _(CH2) q-heteroaryl wherein X, p and q are as defined above,

- (CH ₂ ) _t NR ⁶ R ^6a , wherein t is 0 or an integer from 1 to and R ⁶ and R ^6a are the same or different substituents defined as R ⁵ ,

- (CH ₂ ) _in SR ⁵ , where v and R ⁵ are as defined above,

- (CH ₂ ) in CO ₂ R ⁵ where and in R ⁵ are as defined above,

- (CH ₂ ) _in CONR ⁶ R ^6a where R ⁶ and R ^6a are the same or different substituents defined as R ⁵ and v is as defined above;

R ³ is additionally - (CH 2) r R ⁷ where r is from 1 to 5 and R ⁷ 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

O

wherein R ¹⁰ is defined above as R ² and R ³ and is arbitrarily the same as or different from R ² and R ³ , wherein when Z is

R ¹⁰ then R ⁴ must be OH,

C = 0,

C = NOR ⁵ , where R ⁵ is as defined above,

C = N-NR ⁶ R ^5, wherein R ⁶ and R ^6a are the same or different substituents as defined above for R ^5;

W is -CHR ⁵ , wherein R ⁵ is as defined above;

n is 0 or 1;

R ⁴ is OH,

NR ⁶ R ^6a where R ⁶ and R ^6a are the same or different substituents defined above as R ⁵ , and if R ⁴ is NR ⁶ R ^6a , then Z must be C = O or NHOR ⁹ where R ⁹ is hydrogen, alkyl or benzyl, and the corresponding isomers of said compounds or their useful salts.

• · • ·

Particularly preferred MMP inhibitors have the formula

120

Ar can be phenyl, phenyl substituted with alkyl,

NO ₂ , halogen,

OR ⁵ , wherein R ⁵ is hydrogen or alkyl,

CN,

CO ₂ R ⁵ , where R ⁵ is as defined above,

SO ³ R ⁵ , wherein R ⁵ is as defined above,

CHO,

COR ⁵ where R ⁵ is as defined above, CONHR ⁵ where R ⁵ is as defined above, or NHCOR ⁵ where R ⁵ is as defined above,

2-naphthyl or heteroaryl;

R ¹ can be hydrogen, methyl, ethyl,

NO ₂ , halogen,

OR ⁵ , wherein R ⁵ is as defined above,

CN, CO ₂ R ⁵ , wherein R ⁵ is as defined above, SO ³ R ⁵ , wherein R ⁵ is as defined above, CHO, or

COR ⁵ , wherein R ⁵ is as defined above;

R ² and R ³ are the same or different substituents which may independently be hydrogen, • • · ·

alkyl,

- (CH ₂ ) v -aryl, wherein v is an integer of 1 to 5,

- (CH ₂ ) v - heteroaryl, wherein v is as defined above,

- (CH ₂ ) v -cycloalkyl, wherein v is as defined above,

- (CH ₂ ) _p -X- (CH ₂ ) _q -aryl, wherein X is O or S and p and q are each 0 or an integer from 1 to 5, with p + q not greater than 5,

- (CH ₂ ) _p -X- (CH ₂ ) q -heteroaryl, wherein X, p and q are as defined above,

- (CH ₂ ) _t NR ⁶ R ^6a , wherein t is 0 or an integer from 1 to and R ⁶ and R ^6a are the same or different substituents defined as R ⁵ ,

- (CH ₂ ) _In SR ⁵ , where in and R ⁵ are as defined above,

- (CH ₂ ) _in CO ₂ R ⁵ where and in R ⁵ are as defined above,

- (CH ₂ ) _in CONR ⁶ R ^6a where R ⁶ and R ^6a are the same or different substituents defined as R ⁵ and v is as defined above;

R ³ is additionally - (CH ₂ ) _r R ⁷ , where r is from 1 to 5 and R ⁷ 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

O

wherein R ¹⁰ is defined above as R ² and R ³ and is arbitrarily the same as or different from R ² and R ³ , wherein when Z is

O

then R ⁴ must be OH,

C = 0,

C = NOR ⁵ , where R ⁵ is as defined above,

122

C = N-NR ⁶ R ^6a , wherein R ⁶ and R ^6a are the same or different substituents as defined above as R ⁵ ;

W is CHR ⁵ , wherein R ⁵ is as defined above;

n is 0 or 1;

R ⁴ is OH,

NR ⁶ R ^6a where R ⁶ and R ^6a are the same or different substituents defined above as R ⁵ , and if R ⁴ is NR ⁶ R ^6a , then Z must be C = O or NHOR ⁹ where R ⁹ is hydrogen, alkyl or benzyl, and the corresponding isomers of said compounds or their useful salts.

Preferred compounds used in this invention include:

4- [4- (4- (4-Phenylpiperidin-1-yl) phenyl) butyric acid;

4-oxo-4- [4- (4-phenylpiperidin-1-yl) -phenyl] butyric acid potassium salt;

N-hydroxy-4-oxo-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyramide;

E / Z-4-hydroxyimino-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyric acid;

E / Z-4-benzyloxyimino-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyric acid;

4- [4- (4- (4-phenylpiperazin-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-ΟΧΟ-4- [4- (4-phenylpiperidin-1-yl) -phenyl] butyric acid, potassium salt;

N-hydroxy-4-oxo-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyramide;

123

E / Z-4-hydroxyimino-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyric acid;

E / Z-4-benzyloxyimino-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyric acid;

4-oxo-4- [4- (4-phenylpiperazin-1-yl) phenyl] butyric acid; and, (±) 3-methyl-5-oxo-5- [4- (4-phenylpiperidin-1-yl) phenyl] pentanoic acid.

A compound that is 4-oxo-4- [4- (4-phenylpiperidin-1-yl) phenyl] butyric acid.

Similar compounds that are sulfonamide derivatives have the formula:

Ar- (CH _{2) m} -

(CH) _Z - SN - (W) '

R ^and OR ²

Ar may be phenyl;

phenyl substituted with alkyl, NO ₂ , halogen, -OR ⁵ , -CN, -CO ² R ⁵ , -SO ³ R ⁵ , -CHO, -COR ⁵ , -CONHR ⁵ , -NHR ⁵ , or -NHCOR ⁵ ;

heteroaryl; or

2-naphthyl;

R ¹ is hydrogen, methyl, -NO ₂ , -Cl, -NH ₂ , -NHCO ₂ CH ₃ , -OH, or CO ₂ H;

R ² and R ³ are the same or different substituents each independently hydrogen, alkyl,

- (CH ₂ ) _v -aryl, - (CH ₂ ) _v -heteroaryl, - (CH ₂ ) _v -cycloalkyl,

- _(CH2) pX- _(CH2) q-aryl, - _{(CH2) p} -X- (CH _{2) q} -heteroaryl, (CH _{2) t} NR ⁶ R ^6a, - (CH 2) v R ^7, - (CH 2) _in CO ₂ R ⁵ ,

- (CH ₂ ) in CONR ⁶ R ^6a or - (CH ₂ ) _V SR ⁵ ;

m is 0 or 1;

Y is CH or N; when m = 1, Y is not N;

Z is 0 or 1;

W is -CHR ⁸ ;

99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 99 9 9 η is Ο or 1;

R ⁴ is -OH, -NR ⁶ R ^6a or -NHOR ⁹ ;

R ⁵ is hydrogen or alkyl;

v is 1 to 5;

X is O or S;

p and q are independently 1 to 5, wherein p + q is not more than 5;

t is 1 to 9;

R and R are the same or different substituents formed by hydrogen or alkyl;

R ⁷ is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl or 1,3-dihydro-1,3-dioxo-benzo [f] isoindol-2-yl;

R ⁸ is hydrogen or alkyl; and

R ⁹ is hydrogen, alkyl or benzyl; or a pharmaceutically acceptable salt thereof.

Typical sulfonamide derivatives include the following compounds:

[4- (4-Phenyl-piperidin-1-yl) -benzenesulfonylamino] -acetamide; N-hydroxy-2- [4- (4-phenylpiperidin-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-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid;

(±) -5-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -pentanoic acid;

• ♦

125 · 9 9 «9 * * * · · · · ·« «« «« «« «« «9 [4- (4-phenylpiperazin-1-yl) -benzenesulfonylamino] -acetic acid;

{isobutyl- [4- (4-phenylpiperidin-1-yl) benzenesulfonyl] amino [acetic acid;

(S) -4-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -butyric acid;

(R) -2- [4- (4-Phenylpiperidin-1-yl) -benzenesulfonylamino] -3-tritylsulfanyl-propionic acid, sodium salt;

(R) -3- (1H-indol-3-yl) -2- [4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid, disodium salt, monohydrate;

(S) -2- (4- [4- (4-hydroxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid;

(S) -2- {4- [4- (4-chloro-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid hydrochloride;

(R) -3-mercapto-2- [4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid, trifluoroacetic acid salt;

(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-methoxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid;

(S) -2- {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl] -benzesulfonylamino} -3-phenyl-propionic acid hydrobromide;

(S) -2- {4- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -benzesulfonylamino} -3-phenyl-propionic acid;

126 ··············· 44 44

4 44 44 444

4,444 44,444 4 4

444 4445 44 4

4444 44 (44) (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] -pentanoic acid;

(S) -3- (1H-indol-3-yl) -2- [4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid;

[4- (4-Phenylpiperidin-1-yl) -benzenesulfonylamino] -acetic acid;

N-hydroxy-2- [4- (4-phenylpiperidin-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-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid;

(±) -5-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -pentanoic acid;

[4- (4-Phenylpiperazin-1-yl) -benzenesulfonylamino] -acetic acid;

{isobutyl- [4- (4-phenylpiperidin-1-yl) benzenesulfonyl] amino) acetic acid;

(S) -4-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -butyric acid;

·· ·· ·· · ♦ ·· · · · · · · · · φ · φ ·

127 (R) -2- [4- (4-Phenylpiperidin-1-yl) -benzenesulfonylamino] -3-tritylsulfanyl-propionic acid, sodium salt;

(R) -3- (1H-indol-3-yl) -2- [4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid, disodium salt, monohydrate;

(S) -2- {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid;

(S) -2- {4- [4- (3-chloro-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid hydrochloride;

(R) -3-mercapto-2- [4- (4-phenylpiperidin-1-yl) -benzenesulfonylamino] propionic acid, trifluoroacetic acid salt;

(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-methoxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid;

(S) -2- {4- [4- (3-hydroxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid hydrobromide;

S) -2- {4- [4- (4-methoxy-phenyl) -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;

(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; and

ΦΦ φ · · · · · · · · · ·

128 (S) -3- (1H-indol-3-yl) -2- [4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] propionic acid.

Other characteristic compounds that have been used are:

2- (dibenzofuran-2-sulfonylamino) -3- (4-fluorophenyl) propionic acid;

2- (dibenzofuran-2-sulfonylamino) -3-phenylpropionic acid;

3- (4-tert-butoxyphenyl) -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-hydroxypropionic acid;

3-Benzyloxy-2- (dibenzofuran-2-sulfonylamino) -propionic acid;

6-benzyloxycarbonylamino-2- (dibenzofuran-2-sulfonyl-amino) -hexanoic acid;

5-benzyloxycarbonylamino-2- (dibenzofuran-2-sulfonyl-amino) -pentanoic acid;

(dibenzofuran-2-sulfonylamino) - (4-methoxyphenyl) acetic acid;

3-chloro-2- (dibenzofuran-2-sulfonylamino) -propionic acid;

3- (4-Benzyloxy-phenyl) -2- (dibenzofuran-2-sulfonylamino) -propionic acid;

2- (dibenzofuran-2-sulfonylamino) -5-p-tolylsulfanylaminopentanoic acid;

2- (dibenzofuran-2-sulfonylamino) -4-mercapto-butyric acid;

ΦΦΦΦ · ♦ ·· • φ · Φ Φ Φ * Φ 9 9 9

Φ Φ Φ ΦΦ

129

«Φ · Φ · Φ Φ

ΦΦ ΦΦΦΦ * · Φ * ·· ΦΦΦ

3- (4-bromophenyl) -2- (dibenzofuran-2-sulfonylamino) propionic acid;

2- (dibenzofuran-2-sulfonylamino) -butyric acid;

1- (dibenzofuran-2-sulfonylamino) -cyclopropane-carboxylic acid;

3- (4-chlorophenyl) -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-fluorobenzenesulfonylamino) -hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (4-methoxybenzenesulfonylamino) -hexanoic acid;

2- (4-bromobenzenesulfonylamino) -2- (4'-bromobiphenyl-4-sulfonylamino) -hexanoic acid;

6- (4-Acetylamino-benzenesulfonylamino) -2- (4'-bromobiphenyl-

4-sulfonyl-amino) -hexanoic acid;

6-benzenesulfonylamino) -2- (4'-bromobiphenyl-4-sulfonylamino) -hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (pentane-1-sulfonylamino) hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (naphthalene-2sulfonylamino) hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (naphthalene-1-sulfonylamino) hexanoic acid;

-4-sulfonylamino) -6- (2-phenylhexanoic acid);

(4-sulfonylamino) -6-phenyl-acetylamino

2- (4'-Bromo-biphenyl-ethylenesulfonyl-amino)

2- (4'-bromobiphenyl hexanoic acid);

2- (4'-Bromo-biphenyl-acetylamino] -hexane

2- (4'-Bromobiphenyl)

-4-sulfonylamino) -6- [2- (4-chlorophenoxy) acid;

-4-sulfonylamino) -6- [2- (4-chlorophenoxy) 2-methylpropionylamino] hexanoic acid;

130

* · • Λ • • # • · • • * • • • • ·· • · · « • • « • • · • • • • • • · • • • · ·· ·· • · ·· t ·

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [2- (pyridin-4-ylsulfanyl) -acetylamino] -hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (2- (2,4-dichlorophenoxy) acetylamino] hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-thiophen-2-ylacetylamino) -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (3-phenylacryloylamino) -hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (7-phenylheptanoylamino) hexanoic acid;

- (4'-Bromobiphenyl-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-sulfanylacetylamino) -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) -propionylamino] -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-cyclopent-lenyl-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'-Bromobiphenyl-4-sulfonylamino) -6- [2- (4-nitrophenoxy) acetylamino] -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [4- (4-chloro-3-methyl-phenoxy) -butyrylamino] -hexanoic acid;

131

W 9 · * • 9 «· 9 ♦ • · ♦ « • · • • • 9 • · • · • W * »· 9 9 «* 44 ·· 99 Λ9 • »

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [3- (4-methoxy-phenyl) -propionylamino] -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-pyridin-3-ylacetylamino) -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-pyridin-2-ylacetylamino) -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-cyclopent-lenyl-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'-Bromobiphenyl-4-sulfonylamino) -6- [2- (4-nitrophenoxy) acetylamino] -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-pyridin-3-ylacetylamino) -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-pyridin-2-ylacetylamino) -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [4- (4-nitrophenyl) -butyrylamino] -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [2- (4-tert-butyl-phenoxy) -acetylamino] -hexanoic acid;

ΦΦ ΦΦ • ΦΦ Φ ·

Φ Φ ΦΦ

132

Φφ • · * ·

Φ Φ Φ

* * *

Φ Φ Φ

Φ · ΦΦ

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [3- (3,4-dimethoxy-phenyl) -propionylamino] -hexanoic acid;

2- (4'-bromobiphenyl-4-sulfonylamino) -6- (2-cyclopent-1-enylacetylamino) 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-chloro-3-methyl-phenoxy) -butyrylamino] -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [3- (4-chloro-phenyl) -propiony-1-amino] -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-ylacetylamino) -hexanoic acid;

6- (2-Benzo [1,3] dioxo-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonylamino) -hexanoic acid;

2- (4-bromobiphenyl-4-sulfonylamino) -6- (2-naphthalen-1-ylacetylamino) -hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [3- (4-chloro-phenoxy) -propionyl-amino] -hexanoic acid;

2- (4'-Bromobiphenyl-4-sulfonylamino) -6- (6-phenylhexanoylamino) -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-isobutoxycarbonylamino-hexanoic acid;

2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (9H-fluoren-9-ylmethoxycarbonylamino) -hexanoic acid;

6- (adamantan-1-yloxycarbonylamino) -2- (4'-bromobiphenyl-4-sulfonylamino) -hexanoic acid; and · to · to · 133 · 133 · 133 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

6-Allyloxycarbonylamino-2- (4'-bromobiphenyl-4-sulfonylamino) -hexanoic acid.

Many succinamide-based MMP inhibitors are known and can be used in the method described herein. Typical succinamides are:

2S, N ¹ -dihydroxy-3R-isobutyl-N ⁴ - {1S- [2- (2-methoxy-ethoxymethoxy) -ethylcarbamoyl] -2,2-dimethylpropyl} -succinamide;

N-allyl-1H-hydroxy-SR-isobutyl-N ⁴ - {1S- [2- (2-methoxyethoxymethoxy) ethylcarbamoyl] -2-phenyl-ethyl} succinamide;

2S-allyl-N ¹ -hydroxy-3R-isobutyl-N ⁴ - {1S- [2- (2-methoxyethoxymethoxy) ethylcarbamoyl] -2,2-dimethylpropyl} succinamide;

2S-allyl-N ¹ -hydroxy-3R-isobutyl-N ⁴ - (1S- {2- [2- (2-methoxyethoxy) ethoxy] ethylcarbamoyl) -2,2-dimethylpropyl} succinamide;

2S-allyl-N ⁴ - {1S- [2,2-bis (methoxymethyl) -propylcarbamoyl] 2,2-dimethylpropyl} -N ¹ -hydroxy-3R-isobutyl-succinamide;

2S-allyl-N ⁴ - {1S- [2,2-bis (methoxymethyl) -butylcarbamoyl] 2,2-dimethylpropyl} -N ¹ -hydroxy-3R-isobutyl-succinamide; N ⁴ -hydroxy-2R-isobutyl-N ¹ - {1S- [2- (2-methoxy-ethoxy) ethylcarbamoyl] -2,2-dimethylpropyl} -3S- (thiophen-2-ylsulfanylmethyl) succinamide;

N ⁴ -hydroxy-2R-isobutyl-N ¹ - (1S- {2- [2- (2-methoxyethoxy) ethoxy] ethylcarbamoyl} -2,2-dimethylpropyl-3S- (thiophen-2-ylsulfanylmethyl) - succinamide;

N ¹ - {1S- [2,2-bis (methoxymethyl) -propylcarbamoyl] -2,2-dimethylpropyl} - N ⁴ -hydroxy-3R-isobutyl-3S- (thiophen-2-ylsulfanylmethyl) -succinamide;

N ⁴ -hydroxy-2R-isobutyl-N ¹ - {1S- [2- (2-methoxyethoxy) ethylcarbamoyl] -2,2-dimethylpropyl} -3S-propylsuccinamide;

N ^4- (1S-cyclobutylcarbamoyl-2,2-dimethylpropyl) -2S, N ¹ dihydroxy-3R-isobutylsuccinamide;

N ^4- (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -2S, N ¹ dihydroxy-3R-isobutylsuccinamide;

N ⁴ - (S-Cyclopentylcarbamoyl-2,2-dimethylpropyl) -Σβ, Ν ¹ -dihydroxy-3R-isobutyl-succinamide;

N ^4- (1S-cyclohexylcarbamoyl-2,2-dimethylpropyl) -2S, N ¹ dihydroxy-3R-isobutylsuccinamide;

N ^4- (1S-cycloheptylcarbamoyl-2,2-dimethylpropyl) -2S, N ^X dihydroxy-3R-isobutylsuccinamide;

N ⁴ - (1S-cyclopropylcarbamoyl-2-mercapto-2-methylpropyl) 2 S, N ¹ -dihydroxy-3R-isobutylsuccinamide;

N ^4- (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -2S, N ¹ dihydroxy-3R- (3-phenylpropenyl) succinamide;

N ^4- (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -2S, N ¹ dihydroxy-3R- (3-phenylpropyl) succinamide;

N ^4- [2,2-dimethyl-1S- (2-phenyl-cycloheptylcarbamoyl) propyl] -2S, N ¹ -dihydroxy-3R-isobutyl-succinamide;

2S-allyl-N ⁴ - (1-cyclopropylcarbamoyl-2,2-dimethylpropyl) -N ¹ -hydroxy-3R-isobutylsuccinamide;

2S-allyl-N ⁴ - (1S-cyclopropylcarbamoyl-2-mercapto-2-methylpropyl) -N ¹ -hydroxy-3R-isobutyl-succinamide;

N ^4- (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -N ¹ hydroxy-3R-isobutyl-2S- (thiophen-2-ylsulfaylmethyl) succinamide;

N ⁴ - (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -N ¹ hydroxy-2S- (4-hydroxyphenylsulfanylmethyl) -3R-isobutylsuccinamide; and

N ^4- (1S-cyclopropylcarbamoyl-2,2-dimethylpropyl) -2S- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -N ¹ -hydroxy-3R-isobutylsuccinamide.

Another important group of MMP inhibitors used in the present invention are the sulfonated amino acid derivatives described in WO 97/27174, to which this invention is referred. The basic structure of these compounds is illustrated

COY

wherein R ¹¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted heteroaryl alkyl;

R ¹² is hydrogen or a group defined above as R ¹¹ ;

R ¹³ is a single bond, substituted or unsubstituted arylene, optionally substituted or unsubstituted heteroarylene;

R ¹⁴ is a single bond, - (CH ₂ ) i or -CH = CH-, -C = C-, -CO-, -CONH-, -Ν = Ν-, NH, N-alkyl, -NHCONH-, -O-, -S-, SO ₂ NH-,

SO ₂ NH-N = CH- or tetrazoldiyl;

R ¹⁵ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted non-aromatic heterocyclic group; and

Y is NHOH or OH.

Of particular interest for use herein are compounds wherein R ¹³ in the above formula is phenylene or substituted phenylene. Typical compounds of this kind that can be used have the formula

wherein R ¹¹ and R ¹² are as defined above and R ¹⁷ is substituted or unsubstituted aryl or unsubstituted heteroaryl.

substituted or

Particularly important are the compounds of the formula

R

R ¹⁸ SO ₂ N

COOH where R ¹¹ and R ¹⁸ are the following substituents:

_{(CH3) 2} CH-,

(CH ₃ ) ₂ CH

The following patents and applications relating to MMP inhibitors are cited in the present invention: US 5,753,653; WO 96/16027; WO 97/20824; WO 98/50348; WO 98/43963; WO 98/32748; WO 98/17643; and EP 0780386. The compounds disclosed in these references are:

4- [2- (2-Carboxymethyl-4-phenyl-butylamino) -3-cyclohexyl-propionylamino] -benzoic acid methyl ester;

4- [2- (2-Carboxymethyl-4-phenyl-butyrylamino) -

3,3-methyl-butyrylamino] -benzoic acid;

4- [2- (2-Carboxymethyl-4-phenyl-butyrylamino) -

3,3-dimethyl-butyrylamino] -benzoic acid;

4- [2- (2-Hydroxaminocarbonylmethyl-4-phenylbutyrylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester;

4- [2- (2-Carboxymethyl-4-methyl-valerylamino) -

3,3-dimethyl-butyrylamino] -benzoic acid;

4- [2- (2-Hydroxaminocarbonylmethyl-5-methylvalerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester;

4- [2- (2-Carboxymethyl-4-phenyl-butylamino) -2-cyclohexyl-propionyl-amino] -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;

4- [2- (2-Carboxymethyl-4-methylpentanoylamino) -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] nonadeca-12 (19), 13,15,17-tetraen-10-ylcarbamoyl) -hexanoic acid;

4- [2- (2-Hydroxaminocarbonylmethyl-4-phenylbutyrylamino) -3,3-methyl-butyrylamino] -benzoic acid methyl ester;

4- [2- (2-Hydroxaminocarbonylmethyl-4-phenylbutyrylamino) -2-cyclohexylpropionylamino] -benzoic acid methyl ester;

4- [2- (2-Hydroxaminocarbonylmethyl-4-methylvalerylamino) -4-methyl-valerylamino] -benzoic acid methyl ester;

4- [2- (2-Hydroxaminocarbonylmethyl-4-phenylbutylamino) -3-cyclohexylpropionylamino] -benzoic acid methyl ester;

4- [2- (2-methoxyaminocarbonylmethyl-4-phenylbutylamino) -3-cyclohexylpropionylamino] -benzoic acid methyl ester;

4- [2- (2-Hydroxaminocarbonylmethyl-5-phenylvalerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester;

• 9 ·· 99 99 99

99 9 9 9 9 9 9 9

9 9 9 · 9 · 9 · 14δ · · · · · * · «·« «« «« ««

5-methyl-3- (9-oxo-1,8-diaza-tricyclo [10.6.1.0,13,18] nonadeca-12 (19), 13,15,17-tetraen-10-ylcarbamoyl) -1-hexylhydroxamic acid acid;

4- [2- (2-Hydroxaminocarbonylmethyl-4-methylpentanoylamino) -3- (1H-indol-3-yl) propionylamino] -benzoic acid methyl ester;

3- [2- (4-methoxy-benzylsulfanyl) -2-methyl-1-phenylcarbamoyl-propylcarbamoyl] -5-methylhexanoic acid;

3- [2- (4-methoxy-benzylsulfanyl) -2-methyl-1-phenylcarbamoylpropylcarbamoyl] -5-methylhexanoic acid, N-hydroxyamide;

4- [2- (2-Hydroxaminocarbonylmethyl-4-methylpentanoylamino) -2-cyclohexyl-acetylamino] -benzoic acid methyl ester;

2- (phenyl-2-ethyl) benzoic acid N-hydroxyamide;

4- [2- (2-Acylhydrazinomethyl-4-methylpentanoylamino) -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-ylthio) methyl) succinyl] -L-phenylalanine-N-methylamide;

N-hydroxy-5-phenylpentanamide;

4- [2- (2-Carboxymethyl-5- (3-hydroxyphenyl) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

4- [2- (2-Carboxymethyl-5- (3-hydroxyphenyl) -4-pentenoyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

4- [2- (2-Carboxymethyl-5- (3-aminophenyl) -4-pentenoyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester trifluoroacetate;

2- (phenyl-2-ethyl) -pyridine-3- N- (hydroxy) carboxamide;

4- [2- (2-Carboxymethyl-5- (3-aminophenyl) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

· 99 · 9 9 · 9 9 99999 • 14? 9 9999 99 4- [2- (2-Carboxymethyl-5- (3-aminophenyl) acetyl) amino) -4-methyl-valeroyl methyl ester ] -aminobenzoic acids;

2- [3- (3-hydroxyphenyl) propyl] -benzohydroxamic acid;

2- (thiobenzyl) benzoic acid, N-hydroxyamide;

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-methylureido) 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] -aminobenzoic acid methyl ester;

4- [2- (2-Hydroxyaminocarbonylmethyl-2-phenylacetylamino) -4-methyl-valeroyl] -aminobenzoic acid methyl ester;

4- [2- (2-Carboxymethyl-4-methylpentanoylamino) -2-cyclohexylacetylamino] -benzoic acid methyl ester;

2- [3- (3-Aminophenyl) -propyl] -benzohydroxamic acid; cis -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- (methanesulfamido) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

N-Cbz-tyrosine;

N-Boc-tryptophan;

4- [2- (Carboxy-2-o-tolyl-propionylamino-4-methyl-pentanoylamino) -benzoic acid methyl ester;

4- [2- (carboxymethyl-heptanoylamino) -4-methylpentanoylamino] -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-pentenoyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

• 9

9 9 9 9

9 9 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 sulfonylbenzoic acid; pyrrolidine-1-carbothioic acid, phenethylamide;

3- (2-methylthiazol-4-yl) -N-phenethylpropionamide;

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-cyclohexylmethylsulfonylbenzohydroxamic acid;

[2-oxo-3- (3-phenylpropyl) -tetrahydrofuran-3-yl] -acetic acid;

4- [2- (2-Carboxymethyl-5- (fluoren-2-yl) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

4- [2- (2-Carboxymethyl-2- (3-thienyl) acetylamino) -4-methyl-valeroyl] aminobenzoic acid methyl ester;

4- [2- (2-Benzylthio-3-carboxy-propionylamino) -4-methylpentanoylamino] -benzoic acid methyl ester;

4- [2- (2-Carboxymethyl-4- (2-indolyl) butyrylamino) -4-methyl-valeroyl] -aminobenzoic acid methyl ester;

1-allyl-3- (2-hydroxyethyl) -2-thiourea;

3- (1-hydroxyimino-propyl) -6-phenylhexanoic acid,

2- (3H-imidazol-4-ylmethyl) -N 1, N, 4-diphenethylsuccinamide;

3- (2-hydroxymethyl-3H-imidazol-4-yl) -N-phenethylpropionamide;

6-phenyl-3-propionylhexanoic acid;

9 ♦ · # ·· ·· ··· · »· 9 9 9 9 9 999

9 9 9 9 9 143 143 4 - {2 - ([2-hydroxyamino-2-hydroxyimino] methyl ester -ethyl] -

5-phenyl-pentanoylamino] -4-methyl-pentanoylamino} -benzoic acid;

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-benzimidazol-2-yl) -3-methylbutylcarbamoyl] -5-methylhexanoic acid;

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

2R- (3- (4-Biphenyl) propyl-N- (2R-hydroxy-3- (2-hydroxyphenyl)) -

5-methyl-3S-hexyl) succinamide;

6-Biphenyl-4-yl-3- [1- [3- (2-amino-ethyl) -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-phenylpentanoic acid;

2- (3-Biphenyl-4-yl-propyl) -NI- [1- (5,6-dichloro-1H-benzimidazol-2-yl) -3-methyl-butyl] -N4-hydroxy-succinamide hexanoic acid;

6-Biphenyl-4-yl- [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) propylcarbamoyl] hexanoic acid, N-hydroxyamide;

2R- (3- (4-biphenyl) propyl-N - ((1-hydroxy-1-methylethyl) phenylmethyl) succinamide;

99

9 9 9

9 9 * ·

6-Biphenyl-4-yl-3- [1-phenylcarbamoyl-2- (4-cyanobenzylsulfanyl) -2-methylpropylcarbamoyl] hexanoic acid;

4- {2- [2-Carboxymethyl-5- (4'-hydroxy-biphenyl-4-yl) -pentanoylamino] -4-methyl-pentanoylamino} -benzoic acid methyl ester;

1- (N-methyl-N-phenethylthiocarbonyl) -pyrrolidine-2-carboxylic acid;

6-Biphenyl-4-yl-3 - ({cyclohexyl- [2- (4-sulfanoyl-phenyl) -ethylcarbamoyl] -methyl} -carbamoyl) -hexanoic acid;

3R (6- (4-Biphenyl) -3- (N-benzylcarbamoyl)) hexanoic acid, N-hydroxyamide;

[3- (3-Biphenyl-4-yl-propyl) -2-oxo-pyrrolidin-3-yl] -acetic acid;

2-Benzylsulfonyl-cyclopent-1-enecarboxylic acid hydroxamide;

[2-oxo-3- (3-phenyl-propyl) -pyrrolidin-3-yl] -acetic acid;

[3- (3-Naphthalen-2-yl-propyl) -2-oxo-pyrrolidin-3-yl] -acetic acid;

2-benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxamide;

6-benzylsulfonyl-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) -tetrahydrofuran-3-yl] -acetic acid;

4- [2- (2-Thioamidomethyl-5-phenyl-valerylamino) -4-methyl-valeroylamino] -benzoic acid methyl ester;

4- [2- (2-Amino-2-hydroxyimino-ethyl-5-phenylvalerylamino) -4-methyl-valeroylamino] -benzoic acid methyl ester;

• · ·

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

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

1- (N-hydroxy) -3- (2-bis (benzyl)) urea;

4- (2- {5- [7- (2-Amino-acetylamino) -9H-fluorene-] methyl ester

2-yl] -2-carboxymethylpentanoylamino} -4-methylpentanoylamino) benzoic acid, TFA salt;

3R- (6- (4-Biphenyl) propyl-N- (3-methylpyridinecarbamoyl) hexanoic acid, N-hydroxyamide);

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

6-biphenyl-4-yl-3- [cyclohexyl- (4- (2-dimethylaminoethylsulfamoyl) -phenylcarbamoyl) methylcarbamoyl] hexanoic acid, trifluoroacetate;

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-yl-3- [2,2-dimethyl-1- (4- (3-morpholin-4-ylsulfamoyl) -phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid;

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

• ·· ·· ·· · • • • • · • • • · • • • • 11 • • • ·· • • · ·· • • • ·

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

4- [2- (5-Biphenyl-4-yl-2-carboxymethylpentanoylamino) -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-3- [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-3- (R) - (2-hydroxy-1- (S) -phenylethylcarbamoyl) -hexanoic acid;

3- (R) - (1- (R) -Benzyl-2-hydroxy-ethylcarbamoyl) -6-biphenyl-

4-yl-hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -hexanoic acid;

4- [2- (2-Carboxymethyl-5- (4-pyridin-4-yl-phenyl) -pentanoylamino) -4-methyl-pentanoylamino] -benzoic acid methyl ester;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-2-methyl-1-phenylcarbamoyl-propylcarbamoyl) -hexanoic acid;

β-Biphenyl-4-yl- (2-hydroxy-2-methyl-1-phenylcarbamoylpropylcarbamoyl) hexanoic acid;

3- {2-allylsulfamyl-2-methyl-1- [2- (4-sulfamoyl-phenyl) -ethylcarbamoyl] -propylcarbamoyl} -6-biphenyl-4-yl-hexanoic acid;

»* 99 Λ9 99 • · · · ·

4- [2- (5-Biphenyl-4-yl-2-carboxymethylpentanoylamino) -4,5-dihydroxy-pentanoylamino] -benzoic acid methyl ester;

4- (2- {5- [4 '- (2-Amino-ethoxy) -biphenyl-4-yl] -) -

2-carboxymethylpentanoylamino} -4-methylpentanoylamino) benzoic acid;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) -phenyl-ethylcarbamoyl) -hexane-hydroxamic acid;

3- (R) - (1- (R) -Benzyl-2-hydroxy-ethylcarbamoyl) -6-biphenyl-

4-yl hexane-hydroxamic 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-tetrahydro-furan-3-yl] -acetic acid;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -hexane-hydroxamic acid;

4- [2- (2-Carboxymethyl-5-naphthalen-2-ylpentanoylamino) -4-methylpentanoylamino] -benzoic acid methyl ester;

3- [2,2-Dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -5-methylhexanoic acid;

N 1 - [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propyl] -N 4 -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-3 (R) - (1 (S) -hydroxymethyl-2,2-dimethylpropylcarbamoyl) -hexanoic acid;

4- {2- [5-Bifen-4-yl-2- (1-carboxy-ethylamino) -pentanoylamino] -4-methyl-pentanoylamino [benzoic acid methyl ester;

6-Biphenyl-4-yl-3 (R) - (1 (S) -Hydroxymethyl-2,2-dimethylpropylcarbamoyl) -hexanhydroxamic acid;

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

φ ♦ · · · · Φ φ φ • • · · φ φ

2- (Biphenyl-4-ylsulfonyl) -cyclohex-1-enecarboxylic acid hydroxamide;

6- (biphenyl-4-ylsulfonyl) -cyclohex-1-enecarboxylic acid hydroxamide;

2-phenethylsulfanyl-cyclohex-1-enecarboxylic acid, hydroxamide;

6- (4'-Cyano-biphenyl-4-yl) -3- [2-hydroxy-1- (4-methylsulfinyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid;

1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -3-methyl-butylcarbamoyl} -pyrrolidine-2-carboxylic acid;

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

4- [2- (2-Carboxymethyl-5- (4- (2-hydroxy-3,3,3-trifluoropropyl) -phenyl-pentanoylamino) -4-methyl-pentanoylamino] -benzoic acid methyl ester;

2-Benzylsulfanyl-cyclohexanecarboxylic acid, hydroxamide;

1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -3-methyl-butylcarbamoyl} -pyrrolidine-2-carboxylic acid;

trans-2-benzylsulfanyl-cyclohexanecarboxylic acid, hydroxamide;

4- [2- (2-carboxymethyl-5- (4- (2-methylthiazole-) methyl ester))

4-yl) phenyl) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid;

1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -3-methyl-butylthiocarbamoyl} -pyrrolidine-2-carboxylic acid;

3 - [(cyclohexyl- (4- (2-hydroxy-ethylsulfamoyl) -phenylcarbamoyl) -methyl) -carbamoyl] -6- (4-pyridin-4-yl-phenyl) hexanoic acid, trifluoroacetate;

· · 4 4 4 4 4 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 Trans-2- (Biphenyl-4-ylmethylsulfanyl) -cyclohexanecarboxylic acid hydroxamide;

6-Biphenyl-4-yl-3- (1-hydroxymethyl-2,2-dimethyl-but-3-phenylcarbamoyl) -hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2- (S) - (1H-imidazole-

4-yl) ethylcarbamoyl) hexanoic acid;

3- (R) - (2- (R) -Benzyloxy-1- (S) -hydroxymethyl-propylcarbamoyl) -6-biphenyl-4-yl-hexanoic acid;

4- [4-Methyl-2- (2-nitromethyl-5-phenylpentanoylamino) -pentanoylamino] -benzoic acid methyl ester;

6-Biphenyl-4-yl-3- [3-methyl-1- (4- (2-hydroxy-ethylsulfamoyl) -phenylcarbamoyl) -butylcarbamoyl] -hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2-phenyl-ethylcarbamoyl) -hexanoic acid;

N 1 - (1-benzyl-2-hydroxy-ethyl) -2- (3-biphenyl-4-yl-propyl) N 4 -hydroxy-succinamide;

6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2- (S) - (1H-imidazole-

4-yl) ethylcarbamoyl) hexanoic acid;

N-hydroxy-2- [2-oxo-3- (3-phenyl-propyl) -tetrahydrofuran-3-yl] acetamide;

4- [2- (2-Carboxymethyl-5- (2-hydroxy-biphen-4-yl) -valeroylamino) -4-methyl-valeroylamino] -benzoic acid methyl ester;

N 1 - (1-benzyloxy-1-hydroxymethyl-propyl) - N ⁴ -hydroxysuccinamide;

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-tetrahydro-pyran-3-ylcarbamoyl) -hexanoic acid;

• J φ · · · · ·

6-Biphenyl-4-yl-2 - [(formyl-hydroxyamino) -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-tetrahydro-pyran-3-ylcarbamoyl) -hexanoic acid;

N- [2,2-dimethyl-1S- (pyridin-4-ylcarbamoyl) -propyl] -3R-thiophen-3-yl-succinamic acid;

4- [2S- (2R- (3-Biphenyl-4-yl-pyrrol-1-yl) -3-carboxy-propionylamido) -4-methyl-pentanoylamino] -benzoic acid methyl ester;

3- (R) - (2-Benzyloxy-phenyl) -1- (S) -hydroxymethyl-ethylcarbamoyl) -6-biphenyl-4-yl-hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) - (4-hydroxybenzyl) ethylcarbamoyl) hexanoic acid;

6-Biphenyl-4-yl-3- (1-hydroxyimino-ethyl) -hexanoic acid;

N- [2- (3- (4-Biphenyl) propyl) -5,5-difluoro-4-oxopentanoyl] -L-t-leucine, N'-4- (methylthio) phenylamide;

6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) - (4-hydroxybenzyl) ethylcarbamoyl) hexanhydroxamic 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- (biphen-4-yl) -2- (1-carboxy-2-hydroxybut-1-yl) pentanoyl] -1-t-leucine, N'-4- (methylthiophenyl) amide;

6-Biphenyl-4-yl-3- (2-hydroxy-cyclohexylcarbamoyl) -hexanoic acid;

2- (3-biphenyl-4-yl-propyl) -N ⁴ -hydroxy-Nl- (2-hydroxycyclohexyl) - succinamide;

** ** ·· 9008 9

9 0 9 9 9 9 0 O O90 ♦ <ΐ · 9 9 9 90 0 90

OJ 19 9 9 9 9 0 9 0 0 ·· • * O 0 0 9 9 0 00

9090 99 09 »· ···

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-4-ylcarbamoyl) -propylcarbamoyl] -hexanoic acid ethyl ester;

2- (3-Biphenyl-4-yl-pyrrol-1-yl) -3-carboxy-N- (1-hydroxy-3-phenyl-prop-2-yl) -propionamide;

N- [5- (biphen-4-yl) -2- (1-carboxy-2-hydroxyethyl) pentanoyl] L-1-leucine, N (4-methylthiophenyl) amide;

3- (R) - (2-Hydroxy-1- (S) - (1H-imidazol-4-yl) -ethylcarbamoyl) -6- (4- (2-methyl-thiazol-4-yl) -phenyl) - hexanoic acid;

3- (R) - (2-Hydroxy-1- (S) - (1H-imidazol-4-yl) -ethylcarbamoyl) -6- (4- (2-methyl-thiazol-4-yl) -phenyl) - hexanhydroxamic 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) -malonamide;

6-Biphenyl-4-yl-3- (3-hydroxy-piperidine-1-carbonyl) -hexanoic acid;

β-Biphenyl-4-yl-3- (3-hydroxy-piperidine-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-yl-pyrrol-1-yl) -succinamic acid;

N- (1-benzyl-2-methoxy-ethyl) -3- (3-biphenyl-4-yl-pyrrol-1-yl) -succinic-hydroxamic acid;

6-Biphenyl-4-yl-3 (R) -2 (S) -hydroxy- (1 (S) -hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexanoic acid, ·········· ···· ·· · i S? ··· ···· ··· ^x · · · · · · · · ·· ·· ···

3- (1-Benzyl-2-hydroxy-ethylcarbamoyl) -5-methyl-hexanoic acid;

N ¹ - (1-benzyl-2-hydroxy-ethyl) - N ⁴ -hydroxy-2-isobutylsuccinamide;

6-Biphenyl-4-yl-3 (R) -2 (S) -hydroxy- (1 (S) -hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexane-hydroxamic acid,

1 - [(4-bromo-phenoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid;

6-Biphenyl-4-yl-3- (2-hydroxy-1-hydroxymethyl-propylcarbamoyl) -hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (2-oxo-cyclohexyl-1- (S) -carbamoyl) -hexanoic acid;

6-Biphenyl-4-yl-3- (2-hydroxy-1-hydroxymethyl-propylcarbamoyl) -hexane-hydroxamic acid;

2S - [(1S-Benzyl-2-hydroxyethylcarbamoyl) -3R-biphenyl-4-yl-pyrrol-1-ylmethyl] -pentanoic acid;

3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- (2R-hydroxy-cyclohexyl-1R-yl) -succinamic acid;

2- (3-Biphenyl-4-yl-pyrrol-1-yl) -3-carboxamate-N- (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-3- (R) - (1- (S) -hydroxymethyl-2- (3-pyridyl) ethylcarbamoyl) -hexanoic acid;

6-Biphenyl-4-yl-2- (S) -hydroxy-3- (R) - (1-hydroxymethyl-2 (S) - (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;

• · · · · φ · · · · · · · · φ ·

153 ··· ··· «· · · · · · · · · ·

6-Biphenyl-4-yl-2S-hydroxy-3R- (1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl) -hexanoic acid;

6-Biphenyl-4-yl-3- (R) - (1- (S) -hydroxymethyl-2- (3-pyridyl) ethylcarbamoyl) hexanhydroxamic acid;

6-biphenyl-4-yl-2S-hydroxy-3R- (1S-hydroxymethyl-methylsulfanyl-propylcarbamoyl) -hexane-hydroxamic acid;

1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -4- (tert-butylcarbamoyl) -piperazine-2-carboxylic acid hydroxamide;

1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -piperazine-2-carboxylic acid hydroxamide;

3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [2-hydroxy-cyclohexyl-1- (1H-imidazol-4-ylmethyl) -ethyl] -succinamic acid trifluoroacetate;

3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [1S- (methoxymethylcarbamoyl) -3-methyl-butyl] succinamic acid;

N- (1-acetyl-3-methyl-butyl) -3- (3-biphenyl-4-yl-pyrrol-1-yl) -succinamic acid;

6-Biphenyl-4-yl-3- (R) - (2-oxo-1-tetrahydrofuran-3- (S) ylcarbamoyl) -hexanoic acid;

3- [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -2-hydroxy-5-methylhexanoic acid hydrochloride;

N ^4- (2,2-dimethyl-1-methylcarbamoyl-propyl) -2, N ^X dihydroxy-3-isobutyl-succinamide;

6-Biphenyl-4-yl-3- (R) - (2-oxo-1-azepan-3- (S) -ylcarbamoyl) hexanoic acid;

N- (1-Benzyl-2-hydroxy-ethyl) -3- (4-biphenyl-4-yl-pyrazol-1-yl) -succinamic acid;

N- (8-oxo-4-oxa-1,7-diaza-tricyclo [9.6.1.0 12.17] octadeca-11 (18), 12 (17), 13,15-tetraen-9R-yl) -3S - (3-phenylpyrrol-1-yl) -succinamic acid;

4-acetyl-1- [4-phenoxy-benzenesulfonyl] -piperazine-2-carboxylic acid, N-hydroxamide;

1- (diphenylphosphine) -piperidine-2-carboxylic acid hydroxamide;

························

154

3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [3S- (2RS-hydroxy-5-methyl) -hexyl] -succinamic acid;

N- (1- (S) -benzyl-2-hydroxy-ethyl) -3- (R) - (2-biphenyl-4-yl-cyclopropylmethyl) -succinamic acid;

6-Biphenyl-4-yl-3- (R) - (2-oxo-1-tetrahydrofuran-3- (S) ylcarbamoyl) hexanhydroxamic acid;

1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -4-methyl-piperazine-

2-carboxylic acid, N-hydroxamide;

4- (4-Methoxy-benzenesulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide;

1- (diphenylphosphine) -propanoic acid;

1- (diphenylphosphine) -propanoic acid, hydroxamide;

4- [2- (2-Carboxymethyl-5- (4- (3-hydroxypropyl) phenyl) -pentanoylamino) -4-methylpentanoylamino] benzoic acid methyl ester;

1- (4- (4-chlorophenoxy) benzenesulfonyl) -N-hydroxy-4- (N-methylcarbamoyl) -piperazine-2-carboxamide;

4- [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) -succinamic acid;

1- [4-Phenoxy-benzenesulfonyl] -piperazine-2-carboxylic acid, N-hydroxamide;

4- [4-Phenoxy-benzenesulfonyl] -thiomorpholine-3-carboxylic acid, N-hydroxamide;

3- [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-amido oxime;

2- (3-Biphenylnitrile-4-yl-pyrrol-1-yl) -3-carboxy-N- (1-hydroxy-3-phenyl-prop-2-yl) -propionamide;

········ · · · ··· · ···· · ·

155 {3- [3- (3-Aminophenyl) -propyl] -2-oxo-tetrahydrofuran-3-yl} -acetic acid;

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

5-biphenylvaleric acid;

1- [4- (methoxy) -benzenesulfonyl] -piperidin-2-amidoxime;

1- [4-Phenoxy-benzenesulfonyl] -4-methyl-piperazine-2-carboxylic acid, N-hydroxamide;

{3- [3- (3-Methyl-aminophenyl) -propyl] -2-oxo-tetrahydrofuran-3-yl} -acetic acid;

6-Biphenyl-4-yl-3- (R) - (2-oxo-azepan-3- (S) -ylcarbamoyl) hexanhydroxamic acid;

4- (1H-indole-2-sulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide;

IR - [(4-bromo-phenoxy) -benzenesulfonyl] -N-amino-piperidine-2-carboxamide;

2- (3-biphenyl-4-yl-propyl) -3, N4-dihydroxy-N ¹ - (1 (S) hydroxymethyl-3-methanesulfinyl-propyl) -succinamide;

N- (1-benzyl-2-hydroxy-ethyl) -3- [3- (4'-carbamoyl-biphenyl-

4-yl) -pyrrol-1-yl] -succinamic acid;

1- (methylphenylphosphinic) -piperidine-2- (R) -carboxylic acid hydroxamide;

4- (4- (4-chlorophenoxy) benzenesulfonyl) -N-hydroxy-morpholine-3R-carboxamide;

2S- [IR- (3- (4'-Cyano-biphenyl-4-yl) -pyrrol-1-yl) -N- (2,2-dimethyl-1S-hydroxymethyl-propylcarbamoyl) -methyl] -pentanoic acid;

2 (S, R) - {1S-Benzyl-2-hydroxy-ethylcarbamoyl- [3R- (4'-cyanobiphenyl-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;

• 4 ·· · 4 Φ ·· * 4 * 4 4 ··· ·· · * 444444

156 • 4,444,444

4444 44 44 H * 444

3- [3- (4'-Carbamoyl-biphenyl-4-yl] -pyrrol-1-yl) -N- (1-hydroxymethyl-2,2-dimethyl-propyl) -succinamic acid;

4-methyl-1- (4- (4-chlorophenyl) benzenesulfonyl) -N-hydroxy-2R-piperazinecarboxamide hydrochloride;

1- [4-chlorophenoxybenzenesulfonyl] -2,7-hydroxy-2R-piperazinecarboxamide;

2- (3-phenyl-propylsulfonyl) -cyclohexanecarboxylic 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, hydroxamide;

1- [4- (4-nitrile-phenoxy) -benzenesulfonyl] -4- (tert-butylcarbamoyl) -piperazine-2-carboxylic acid, N-hydroxyamide;

2S- [3- (Biphenyl-4-yl) -pyrrol-1R-yl- (1S-hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -methyl] -pent 4-enoic acid;

6-ΟΧΟ-3- (4-phenoxy-benzenesulfonyl) -hexahydro-pyrimidine-4-carboxylic acid hydroxamate;

4- (t-butoxycarbonyl) -1- (4- (pyridin-2-yl) oxybenzenesulfonyl) - N 7 -hydroxy-piperazine-2-carboxamide;

4 - [(4-fluorophenoxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid, N-hydroxamide;

4 - [(4-fluoro-phenoxy) -benzenesulfonyl] -oxothiomorpholine-3-carboxylic acid, N-hydroxamide;

N- (2,2-dimethyl-1S-hydroxymethyl-propyl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid;

N- (1S-benzyl-2-hydroxy-ethyl) -3S- (5-biphenyl-4-yl-furan-2-yl) -succinamic acid;

······················

157 • · · ♦ ·· ··························

4- (4-butoxy-benzenesulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide;

4- (4-butoxybenzenesulfonyl) -1-oxothiomorpholine-3-carboxylic acid hydroxamide;

1- [4- (4-Fluorophenyl) -benzenesulfonyl] -4- (tert-butoxycarboxylic) -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-ylphenyl) -pyrrol-1-yl] -succinamic acid;

1- [4- (4-Fluorophenyl) -benzenesulfonyl] -N-hydroxy-2-piperazinecarboxamide hydrochloride;

1- (diphenylphosphinic) -pyrrolidine-2- (R) -carboxylic acid hydroxamide;

N, N - {(diphenylphosphine) - (sodium acetate)} hydrazide;

N- (1-Benzyl-2-hydroxy-ethyl) -3- (1-biphenyl-4-yl) -1H-pyrrole-

3-yl) succinamic acid;

trans-2-phenethylsulfonyl-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- (bromo-phenoxy) -benzenesulfonyl] -2,2-dimethyl-loxothiomorpholine-3-carboxylic acid hydroxamide;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- (3-phenylpyrrol-1-yl) succinamic acid;

3R- (3-Biphenyl-4-yl) -N- (2-hydroxy-1S-hydroxymethyl-2-methyl-propyl) -succinamic acid;

1- (pyrrolidine-1-carbonyl) -pyrrolidine-2 (R) -carboxylic acid;

ΦΦ φ φ · · φ φ φ φ φ φ φ · · ·

158 φ · · · φ · · · · · · ·

1- (pyrrolidine-1-carbonyl) -pyrrolidine-2 (R) -carboxylic acid hydroxamide;

1-phenethylcarbamoyl-pyrrolidine-2 (R) -carboxylic acid; R-4- [4- (Bromophenoxy) -benzenesulfonyl] -2,2-dimethyl-loxothiomorpholine-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] -succinamic acid;

N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid;

1-phenethylcarbamoyl-pyrrolidine-2- (R) -carboxylic acid hydroxamide;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [3- (4-propyl-phenyl) -pyrrol-1-yl] -succinamic acid;

1- (4-Benzyl-piperazine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide;

3 (S) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -

2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

2 (R) -4-methyl-1- 4- (4-fluorophenyl) benzenesulfonyl) -N-hydroxy-piperazine-2-carboxamide;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3- (5-biphenyl-4-yl-furan-2-yl) -succinamic acid;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- (3-pyridin-4-yl-pyrrol-1-yl) -succinamic acid;

1 - ((2-pyridyl) -4-piperazine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide;

1- [4- (pyridin-4-ylsulfanyl) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxamide;

N- (4-phenoxy-benzenesulfonyl) -D-tert-leucine;

N- (4-phenoxy-benzenesulfonyl) -D-tert-leucine, N-hydroxamide;

·· ·· ·· ·· ··

9 ··· · · · · · · · ····· ·

159 • · · · · · · · · · · · · · · · · · · · · · · · · ·

Ν- (8-oxo-4-oxa-1,7-tricyclo [9.6.1.0 12.17] octadeca-11 (18), 12 (17), 13,15-tetraen-9-yl) -3- [4- (4-Pyridyl) -3-phenylpyrrol-1-yl) succinamic acid;

3- [3- (4-pyridyl) -phenyl-4-yl-pyrrol-1-yl] -N- [2,2-dimethyl-1- (4-pyridyl) carbamoyl-propyl] -succinamic acid;

2,2-dimethyl-4- [4- (pyridin-2-yloxy) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxamide;

N- [4- (4-fluorophenoxy) -benzenesulfonyl] -D-tert-leucine;

N- [4- (4-fluorophenoxy) -benzenesulfonyl] -D-tert-leucine, N-hydroxyamide;

2- [2-N'-acetyl-hydrazino) -2-oxo-ethyl] -5-biphenyl-4-ylpentanoic acid;

3 (R) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -

2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride;

2- [4- (4-chlorophenoxy) -benzenesulfonylamino] -3,3-dimethyl-. butyric acid;

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

3,3-dimethyl-butyramide;

3 (R) -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, N-hydroxamide;

2- [4- (pyridin-2-yloxy) -benzenesulfonylamino] -3,3-dimethylbutyric 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) -succinamic acid;

160

• 9 ·· 9 · t · 9 9 • 9 • 9 9 9 9 9 • 9 • · • · • 9 9 9 9 9 9 • · 9 9 AND 9 » 9 • ·· ···· • 9 • A 9 9 9 9

3- [3- (4'-Cyano-biphenyl-4-yl] -pyrrol-1-yl] -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic 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-oxy-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-yl-carbamoyl) -propyl] -succinamic acid;

N- (4-phenoxy-benzenesulfonyl) -3,3-dimethyl-S- (methylthio) D-cysteine, N-hydroxamide;

1- (4-Phenoxy-piperidine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide;

3 (R) -4- [4- (4-Bromo) phenoxybenzenesulfonyl] -2,2-dimethyltetrahydro-2H-1,4-thiazine-3-carboxylic acid;

N- (4- [4-chloro-phenoxy] -benzenesulfonyl) -3,3-dimethyl-S (methylthio) -D-cysteine;

N- (4- [4-chlorophenoxy] -benzenesulfonyl) -3,3-dimethyl-S (methylthio) -D-cysteine, N-hydroxamide;

N- (4- [4-chlorophenoxy] -benzenesulfonyl) -3,3-dimethyl-S (methylsulfoxy) -D-cysteine, N-hydroxamide;

2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-2-ylsulfanyl) -butyric acid;

2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-3-ylsulfanyl) -butyric acid;

2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-4-ylsulfanyl) -butyric acid;

cis-2- (2-phenyl-ethanesulfonyl) -cyclohexanecarboxylic acid, hydroxamide;

3 (R) -N-hydroxy-4- (4- (imidaz-1-yl) phenoxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

4 4 · 99 • 9 9 9 • 9 9 9 *

161 • · ················

3 (R) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 4- [2- (2-Hydroxycarbamoylmethyl-5-phenylpentanoylamino) -4-methylpentanoyl] -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-2-ylmethylsulfanyl) -butyric acid;

3R- [3- (4'-Cyano-biphenyl-4-yl) -pyrrol-1-yl] -N- [2,2-dimethyl-1S- (pyridin-4-ylcarbamoyl) -propyl] -succinamic 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-yl] succinamic acid;

2 (R) - [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-2-ylmethylsulfanyl) -butyric acid, N-hydroxyamide;

3,3-dimethyl-2- (4-phenoxy-phenylsulfonylmethyl) -butyric acid;

3,3-dimethyl-2- (4-phenoxy-phenylsulfonylmethyl) -butyric acid, N-hydroxamide;

3- tert -butoxycarbonylmethylsulfanyl-2- (4- (4-fluorophenoxy) benzenesulfonylamino] -3-methylbutyric 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;

162

«4 9 « »4 • • ♦ • 4 4 • · 44 • • • • 4 • · • 4 • • • • · • 4 ·· • •• 4 • 4 44 ··

N- (4- [4-fluorophenoxy] -benzenesulfonylamino) -3-methyl-3- (1-benzyl-imidazol-2-yl-sulfanyl) -butyric acid;

2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-2-yl-sulfanyl) -butyric acid, hydroxamide;

(R) -N-hydroxy-4- (4 - ((pyridin-4-yl) methyl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

1- [4- (4-chlorophenoxy) -benzenesulfonyl] -4- (1-methyl-1H-imidazole-4-sulfonyl) -piperazine-2-carboxylic acid hydroxamide;

N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [1- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] succinamic acid;

3-carboxymethylsulfanyl-2- (4- (4-fluorophenoxy) benzenesulfonylamino) -3-methylbutyric acid;

2,2-dimethyl-1-oxo-4- [4- (pyridin-4-yloxy) benzenesulfonyl] -1S14-thiomorpholine-3-carboxylic acid hydroxamide;

1- [4- (pyridin-2-ylsulfanyl) -piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxamide;

2 (R) - [4- (4- (Fur-3-yl) -phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfanyl) -butyric acid;

2,2-dimethyl-1-oxo-4- [4- (pyridin-4-yloxy) -benzenesulfonyl] -1S14-thiomorpholine-3-carboxylic acid hydroxamide;

{2- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -2-hydroxy-carbamoyl-1,1-dimethylethylsulfanyl} -acetic acid tert-butyl ester;

1- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxamide;

2 (R) - [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfanyl) -butyric acid, hydroxamide;

trans-2- (2-Biphenyl-4-yl-ethylsulfanyl) -cyclohexanecarboxylic acid hydroxamide;

N- [1H- (1H-imidazol-2-yl) -3-methyl-butyl] -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid, format ;

163 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ·· ···

N-methyl-3- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid;

N (4) - (2,2-Dimethyl-1S-hydroxymethyl-propyl) -N (1) -hydroxy-3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamide;

{2- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -2-hydroxycarbamoyl-1,1-dimethyl-ethylsulfanyl} -acetic acid;

1- [4 - [(4-Fluoro-phenoxy) -benzenesulfonyl]] -3,3-dimethyl-

5-oxo-piperazine-2-carboxylic acid hydroxamide;

N- (4- [4-Bromo-phenoxy] -benzenesulfonylamino) -3-methyl-3- (1-benzyl-imidazol-2-yl-sulfanyl) -butyric acid;

3R- [3- (4'-Cyanobiphenyl-4-yl) -pyrrol-1-yl] -N- (2,2-dimethyl-1S-hydroxymethyl-propyl) -succinamic acid;

2- (R) - [4- (4-Iodophenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-2-yl-sulfanyl) -butyric acid;

3R- [3- (4-Cyanophenyl) -pyrrol-1-yl] -N- (2,2-dimethyl-1-hydroxymethyl-propyl) -succinamic acid;

2- (R) - [4- (4-Iodo-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid hydroxamide;

2- (R) - [4- (4-Nitrile-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-yl-sulfonyl) -butyric acid;

2- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -3,3-dimethylpent-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-isoazol-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-fluorophenoxy) -benzenesulfonylamino] -3-methyl-3- (carbomethoxyethylsulfanyl) -butyric acid;

1- [2- (Benzothiazol-2-ylsulfanyl) -piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxamide;

9 9 9 9 9 9 9 10 11 12 13 14 15 16 17

164

3R- [3- (4-Cyanophenyl) -pyrrol-1-yl] -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic acid;

2- [4- (4-fluorophenoxy) -benzenesulfonylamino] -3-methyl-3- (hydroxyethylsulfanyl) -butyric acid;

[4-Methoxy-benzenesulfonylamino] -3-methyl-3- (pyridin-2-ylsulfanyl) -butyric acid;

N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl) -3R- [1- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] succinamic acid;

2- [4- (4-fluorophenoxy) -benzenesulfonylamino] -3-methyl-3- (amidoethylsulfanyl) -butyric acid;

[4-Methoxy-benzenesulfonylamino] -3-methyl-3- (pyridin-2-ylsulfanyl) -butyric acid;

2- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3,3-dimethyl-

5-phenyl-pent-4-enoic acid;

5- [4- (4-fluorophenoxy) -benzenesulfonyl] -4,5,6,7-tetrahydro-3H-imidazole [4,5, -c] pyridine-6-carboxylic acid hydroxamide;

2- (R) - [4- (4-Methyl-phenoxy) -benzenesulfonylamino] -3-methyl-

3- (pyridin-yl-sulfonyl) -butyric acid;

3 (S) -4- (4 - ((pyrid-4-yl) oxy) benzenesulfonyl) -2,2-dimethyltetrahydro-2H-1,4-thiazine-3-carboxylic acid;

1- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfanyl] piperidine-2-carboxylic acid hydroxamide;

N- [1- (lH-imidazol-2-yl) -3-methyl-butyl] -3- [l- (4-cyanobiphenyl ^of 4-yl) -lH-pyrrol-3-yl] succinamic acid;

3R- {3 - [(4-cyano-phenyl) -acetyl] -pyrrol-1-yl} -N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -succinamic acid;

1- [4- (4-Methoxy-phenylsulfamyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid hydroxamide;

3R- [3- (4-Cyano-phenyl) -pyrrol-1-yl] -N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -succinamic acid methyl ester;

2 (R) - [4- (4-Methyl-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid, hydroxamide;

·· ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

165 · · ·············································

1- [4- (4-Methyl-phenylsulfamyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid hydroxamide;

4- (4-Methoxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid;

4- (4-Methoxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxamide;

4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid;

4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxamide;

2 (R) - [4- (4-Bromo-phenoxy) -benzenesulfoxyamino] -3-methyl-3 (pyridin-yl-sulfuroxide) -butyric acid, hydroxamide;

4- (4-Methoxy-benzenesulfonyl) -2,2-dimethyl-1-oxothiomorpholine-3-carboxylic acid hydroxamide;

2,2-dimethyl) -4- [4- (pyridin-4-yloxy) -benzenesulfonyl] -thiomorpholin-3-ol;

4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethoxy-10-oxo-thiomorpholine-3-carboxylic acid hydroxamide;

2- (R) -3-Methyl-3- (pyridin-2-yl-sulfanyl) - [4- (4-trifluoromethyl-phenoxy) -benzenesulfonylamino] -butyric acid;

3 (R) -4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyltetrahydro-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) benzenesulfonylamino] -3-hydroxy-3-methylbutyric acid;

3 (S) -2,2-Dimethyl-4- [4- (pyridin-4-ylsulfanyl) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxamide;

2R- N -hydroxy-3-methyl-3 - [(5-methyl-isoxazol-3-yl) methylsulfanyl] - [4- (pyridin-4-ylsulfanyl) -benzenesulfonylamino] -butyramide;

Fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc

166 ··· ···················

3,3-dimethyl-2R- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonylamino] -butyric acid;

3,3-dimethyl-N-hydroxy-2R- [4- (pyridin-4-ylsulfanyl) piperidine-1-sulfonylamino] butyramide;

2R- [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -N-hydroxy-3-methyl-3 - [(1-methyl-imidazol-2-yl) -methylsulfanyl] -butyramide;

2R- [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl-3 [(1-methyl-imidazol-2-yl) methylsulfanyl] -butyric acid;

N-hydroxy-2 - [(4-methylbenzenesulfonyl) amino] acetamide;

1- [4- (4-Imidazol-1-yl-phenylsulfanyl) -piperidine-1sulfonyl] -piperidine-2-carboxylic acid hydroxamide;

2 (R) - [4- (4-Chloro-benzoyl) -cyclohexanesulfonyl] -piperidine-1-carboxylic acid hydroxamide;

1 (R) - [4- (4-Chloro-benzoyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid amide;

1 (R) - (4-Pyridin-2-yl-piperazine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide;

1 (R) - [4- (4-Imidazol-1-yl-phenoxy) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid;

1 (R) - [4- (4-Imidazol-1-yl-phenoxy) -piperidine-1-sulfonyl] -piperidine-2-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-yl) methylsulfanyl] -2R- [4- (pyridin-4-ylsulfanyl) -piperidinesulfonylamino] -butyramide;

- (4'-chloro-biphenyl-4-yl) -2RS- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) ethyl] -4-oxo-butyric acid;

4- (4'-chloro-biphenyl-4-yl) -2R- [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) ethyl] -4-oxo-butyric acid;

N-hydroxy-2R- [4- (4-imidazol-1-yl-phenoxy) -piperidine-1-sulfonylamino] -3,3-dymethyl-butyramide;

2R- [4- (4-chloro-benzoyl) -piperazine-1-sulfonylamino] -Nhydroxy-3-methyl-3-methylsulfanyl-butyramide;

167 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

N-hydroxy-3-methyl-3-methylsulfanyl-2R- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonylamino] -3,3-dymethylbutyramide;

4- (pyridin-4-yloxy) benzenesulfonic acid;

4- (pyridin-4-yloxy) benzenesulfonyl chloride hydrochloride;

(3S) -2,2-dimethyl-3-thiomorpholine carboxylic acid;

(R) -N-Hydroxy-4- (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-carboxylic acid amide;

4- [4- (1-hydroxy-pyridin-4-yloxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid amide;

Priority are MMP inhibitors that are currently under clinical investigation, such as batimastat (2).

Clinically investigated MMP inhibitors contain batimastat (2) for the treatment of malignant pleural effusion and marimastat (1) for the treatment of pancreatic cancer. Galardin (3) is suitable for the treatment of corneal ulcers and RO 31-9790 (4) is a specific MMP-1 inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

Clinically investigated compounds

168

Practical application of the present invention is directed to atherosclerotic diseases in mammals, an effective amount of a matrix metalloproteinase inhibitor, and an ACAT inhibitor. Compounds that inhibit the activity of matrix metalloproteinase enzymes are determined by conventional tube and living organism assays. Some compounds of the above classes have been investigated and evaluated as potential inhibitors of matrix metaoproteinase by these methods. Assays measure the amount at which the test compound reduces the hydrolysis of the thiopeptolide substrate caused by the matrix metalloproteinase enzyme. Their procedures are described in detail by Ye et al. in Biochemistry, 31 (45), 1992, pp. 11231-11235, to which the present invention refers.

In the absence of the matrix metalloproteinase enzyme, the thiopeptolide substrate practically does not decompose or hydrolyze. A typical thiopeptolide substrate to be used in the laboratory assay is Ac-Pro-Leu-thioesterLeu-Leu-Gly-0 Et. 100 μΐ of the test mixture contains 50 mM 2-morpholinoethane-sulfonic acid, monohydrate (MES, pH 6 6.0), 10 mM CaCl 2, 100 μΜ of thiopeptolide substrate and 1 mM 5,5'-dithio-bis (2-nitrobenzoic acid), ). For determination of Km and Kcat values, the concentration of thiopeptolide substrate ranges from 10 to 800 100 μΜ. The change in absorbance at 405 nm is measured on a Thermo Max microplate reader (Molecular Instruments, Menlo Park, CA) at room temperature (22 ° C). The calculation of the degree of hydrolysis of the thiopeptolide substrate is based on E ₄ i ₂ = 13 600 m ^-1 cm ^-1 for the DTNB derivative, 3-carboxy-4-nitrothiophenoxide. Assays are performed with or without matrix metalloproteinase inhibitors, and the degree of hydrolysis then corresponds to the inhibitory activity of the test compound.

Some compounds of interest have the ability to inhibit various matrix metalloproteinase enzymes. Table I (see below) lists inhibitory activities of compounds from different chemical species

169 groups. MMP-1 in the table represents interstitial collagenase, MMP-2 Gelatinase

Gelatinase Concentrations / Concentrations (In Suppression)

How

A, MMP-3 stromelysin, MMP-7 matrilysin and MMPS compounds tested in various were able to determine the IC 50 value of a given compound, which is required for 50% of the activity of the respective enzyme.

above, according to the present invention, a matrix metalloproteinase inhibitor can be used

Β.

that pmol) hydrolytic is said to be any for the treatment or prevention of atherosclerotic lesions.

The ACAT inhibitors used in this invention are compounds of Formula I

OO

IIII

R, - XSNCYR ₂

III

OR or a pharmaceutically acceptable salt thereof, wherein:

X and Y are oxygen, sulfur or (CR ^z R ^zz ) _n , wherein n is an integer from to 4 and R 'and R ^z ' are independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, optionally substituted phenyl, optionally R ^z and R ' ^z together form spirocycloalkyl or carbonyl;

R is hydrogen, straight or branched chain alkyl of up to 8 carbon atoms, or benzyl;

R 1 and R ₂ are independently (a) phenyl or phenoxy, each of which may be substituted with 1 to 5 substituents from phenyl, an alkyl group having 1 to 6 carbon atoms (straight or branched;

(1-6C) alkoxy

170

straight and branched chain atoms;

phenoxy, hydroxy, fluoro, chloro, bromo, nitro, trifluoromethyl,

-COOH,

-COOalkyl, wherein the alkyl contains 1 to 6 carbon atoms (straight or branched),

- (CH ₂ ) _p NR ₃ R ₄ , wherein p is 0 or 1, and each of R ₃ and R ₄ may be hydrogen or (C 1 -C 4) alkyl (straight or branched chain);

(b) 1- or 2-naphthyl unsubstituted or substituted with up to 3 substituents of phenyl, (C 1 -C 6) alkyl (straight or branched chain;

(C 1 -C 6) alkoxy (straight or branched;

phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl,

171 • 9 • 9

9 9 9 9 9

9999 99 99 99 999

-COOH,

-COOalkyl, wherein the alkyl contains 1 to 6 carbon atoms (straight or branched),

- (CH ₂ ) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are as defined above;

(c) arylalkyl;

(d) a straight or branched alkyl chain having 1 to 20 carbon atoms, saturated or having 1 to 3 double bonds, or (e) an adamantyl or cycloalkyl group, wherein the half of the cycle contains from 3 to 6 carbon atoms.

Of particular interest to the present invention are compounds of formula I wherein

R 1 is phenyl or phenyl double substituted at the 2,6-position, wherein R ₂ is phenyl or phenyl double substituted at the 2,6-position, wherein both R _x and R ₂ are phenyl, wherein each phenyl is double substituted at the 2-position

2,6 wherein R 1 is phenyl double substituted at the positions

2,6 and R ₂ is phenyl three-substituted at the 2,4,6-position, wherein R 1 is 2,6-bis (1-methylethyl) phenyl and R ₂ is 2,6-bis (1-methylethyl) phenyl or 2,4, 6-tris (1-methylethyl) phenyl wherein one of R ₁ and R ₂ is a group

R ⁵

- (CH ₂ ) _t - C - (CH ₂ ) _w —R ₇

R ⁶ wherein t is 0 or the number 1 to 4;

172 Φ Φ Φ φ · • • • • • φ φ φ • · · φ φ φ φ φ φ φ φ φ φ · · · · · · · · · · · · · · · · · · w w · not more than 5;

R ₅ and R ₆ are independently hydrogen or alkyl of 1 to 6 carbon atoms, optionally when R ₅ is hydrogen, then R 6 may be one of the groups defined as R ₇ ; and

R ₇ is phenyl or phenyl substituted with 1 to 3 substituents which may be a straight or branched alkyl chain of 1 to 6 carbon atoms, a straight or branched alkoxy chain of 1 to 6 carbon atoms, phenoxy, hydroxy, fluoro, chloro, bromo, nitro , -COOH, -COOalkyl, wherein the alkyl contains 1 to 4 carbon atoms, or - (CH 2) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are as defined above;

Other important compounds are those compounds of formula I wherein

X is oxygen, sulfur or (CR'R '') _n ;

Y is oxygen, sulfur or (CR'R '') _n provided that at least one of X and Y is (CR'R '') _n , where n is an integer from 1 to 4 and R'a R '' are independently hydrogen, straight or branched alkyl containing 1 to 6 carbon atoms, optionally substituted phenyl, halo, hydroxy, alkoxy, acyloxy, cycloalkyl, or R 'and R ^Z' together form a carbonyl or a spirocycloalkyl containing 3-10 carbon atoms;

R is hydrogen;

R 1 is phenyl optionally substituted, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms;

R 2 is phenyl optionally substituted, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, phenoxy optionally substituted provided that only when X is (CR ^of R ^zz ) _{n /} R 1 can be arbitrarily a substituted phenoxy group and only if Y is φφφφ φφφφφ ΦΦφφφφφ♦ · φφφφφ φφ

173 φφφ φφφφ φφ φ φφ φφφφ φφ · φ φφ φφφ (CR'R '') _n, R 2 may be optionally substituted phenoxy, with the further proviso that at least one of R and R2 is lobovolně substituted phenyl or phenoxy.

Even more important compounds used in this

of the invention are compounds of formula I wherein X Yippee oxygen; Y Yippee (CR'R) _n , where n is whole number from 1 to 2; R Yippee hydrogen; Ri Yippee arbitrarily substituted phenyl; R2 Yippee arbitrarily substituted phenyl or a phenoxy group, direct

or a branched alkyl chain of 1 to 10 carbon atoms or a cycloalkyl of 3 to 10 carbon atoms; and

R 'and R' 'are independently hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, optionally R' and R '' together form carbonyl or spirocycloalkyl.

Preferred compounds of formula I are, inter alia, the following compounds:

sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, [ Sulfamic acid [2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,4 6- (tris (1-methylethyl) phenyl sulfamic acid), [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,4,6-tris (1-methylethyl) phenyl sulfamic acid, [adamantanacetyl] -2,6- sulfamic acid bis (1-methylethyl) phenyl ester,

174 Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, sodium salt, (decanoyl) -2,6-bis (1-methylethyl) phenyl ester sulfamic acid, (dodecanoyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid ester,

2,6-bis (1-methylethyl) -N - [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide,

2,6-bis (1-methylethyl) phenyl-N - [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, sodium salt,

2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate,

2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, (1-oxo-3,3-diphenylpropyl) -2,6- sulfamic acid bis (1-methylethyl) phenyl ester, [2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [(2-phenylcyclopropyl) carbonyl] -2,6-bis ( Sulfamic acid 1-methylethyl) phenyl ester, [2,5-dimethoxyphenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [2,4,6-trimethoxyphenyl (acetyl)] - 2,6- sulfamic acid bis (1-methylethyl) phenyl ester, [2,4,6-trimethylphenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [2-thiophenyl (acetyl)] - 2,6- sulfamic acid bis (1-methylethyl) phenyl ester, [3-thiophenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [2-methoxyphenyl (acetyl)] - 2,6-bis (1- methylethyl) phenyl sulfamic acid ester,

175 Sulfamic acid (oxophenylacetyl) 2,6-bis (1-methylethyl) phenyl ester, [2-trifluoromethylphenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, (1-oxo-2-phenylpropyl) ) - 2,6-bis (1-methylethyl) phenyl sulfamic acid, (cyclopentylphenylacetyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid, (cyclohexylacetyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid acid, (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, [(1-phenylcyclopentyl) carbonyl] -2,6 - sulfamic acid bis (1-methylethyl) phenyl ester, (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester, (1-oxo-2-phenylbutyl) -2 , 6-bis (1-methylethyl) phenyl sulfamic acid ester, (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (1-oxo-2,2-diphenylpropyl) -2,6-bis (1 -methylethyl) phenyl sulfamic acid ester, [(9H-fluoren-9-yl) carbonyl] -2, Sulfamic acid 6- bis (1-methylethyl) phenyl ester, (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [1-oxo-3- [2,4,6- tris (1-methylethyl) phenyl] -2-propenyl] -

Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester, [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] propyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid ester , Sulfamic acid [(acetyloxy) [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester,

··· 9 • ·

176 * [Sulfamic acid hydroxy [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, [fluoro [ Sulfamic acid 2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1 sulfamic acid methyl ester, sodium salt, [[2,4,6-tris (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [[2,6-bis (1-methylethyl) phenyl] -methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, and [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (phenyl) phenyl sulfamic ester acid.

Other ACAT inhibitors useful in the present invention include:

4-hexadecylaminobenzoic acid, sodium salt;

3,5-dimethyl-1- [5- (1,4,5-triphenyl-2H-imidazol-2-ylsulfanyl) -pentyl] -4-pyrazole, sodium 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-bis (tert-butyl) -4-hydroxy-phenylamino) - {[4- (2,2-dimethyl-propyl) benzyl] -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-trifluorophenylurea);

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-phenylethyl) amide;

177 99 W 9 9 Ethyl 3- (1H-indole-3-) ethyl ester yl) -2-octadec-9-enoylaminopropionic acid;

3- (dimethyl-nonyl-silanyl) -N- (1-phenyl-2-p-tolyl-ethyl) -propionamide;

(R) 2-Hexyldecanoic acid (6-methyl-2,4-bis (methylsulfanyl) -pyridin-3-yl) -amide;

N- [2- (3,5-bis (tert-butyl) -4-hydroxyphenyl) ethyl] -4-fluorobenzenesulfonamide;

2- (2-ethoxy-ethylsulfanyl) -4,5-diphenyl-1H-imidazole;

4-cyano-N- [2- (4-cyanophenyl) -3-methyl-5,5-bis (trifluoromethyl) -4,5-dihydro-3H-imidazol-4-yl] -N-methylbenzamide;

1- (3- [3- (1-Methyl-1H-imidazol-2-yl) -2-phenethyl-2H-chromen-6-yloxy] -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-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-ureido] -ethyl} -phenoxy) -2-methyl-propionic acid;

3- (2,4-Difluoro-phenyl) -1-octyl-1- (2,3,4,5-tetrahydro-benzo [b] oxepin-5-yl) -urea;

N- (2,6-diisopropyl-phenyl) -2-octadecylsulfanyl-acetamide;

2-bromo-6,11-dihydro-dibenzo [b, e] oxepine-11-carboxylic acid, (2, β-diisopropyl-phenyl) amide;

(±) N- (1,2-Diphenyl-ethyl) -3- (2-heptyloxy-phenyl) -propionamide;

2,2-dimethyl-dodecanoic acid, (7-methoxy-4-oxochroman-8-yl) amide;

178 ♦ · «* * * 178 178 (Z) 1- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) octadec-9-ene -l he;

(Z) 2,2,5,5-tetramethyl- [1,3] dioxane-4-carboxylic acid- [2- (2-octadec-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-tolyl-benzofuran-2-carboxylic acid, (2,6-diisopropyl-phenyl) amide;

2- (2,4α-dimethyl-4α, 5-dihydronaphthalen-1-ylsulfanyl) -N- {2 - [(6,6-dimethyl-hepta-2,4-diynyl) -pentyl-amino] -ethyl} -acetamide ;

(Z) octadec-9-enoic acid, [1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -1-phenyl-ethyl] amide;

N- (4-dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl) -4- (phenyl-propylamino) -butyramide;

(Z) 1- (6,7-Dimethoxy-3-phenyl-3,4-dihydro-1H-isoquinolin-2-yl) -octadec-9-en-1-one;

(trans) 1,4-Bis (4-methoxyphenyl) -3- (3-phenylpropyl) 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-imidazol-1-yl) -propoxy] -phenyl} -3-pentyl-urea;

1- (2- (2- [4- (2,2-Dimethyl-propyl) -phenyl] -ethyl} -4,6-difluorophenyl) -3-heptyl-urea;

(4S-trans) 6- (4,5-Diphenyl-1H-imidazol-2-ylsulfanylmethyl) -

4-hydroxy-4-methyl-tetrahydropyran-2-one;

2- (3- [1,3] dioxan-2-yl-propylsulfanyl) -4,5-diphenyl-1H-imidazole;

Hydroxy-phenylacetic acid 3,3,5-trimethyl-cyclohexyl ester;

179

·· • v • 4 • 4 • * • 4 4 • 4 4 4 4 • 4 • • • 4 * • 4 4 4 • • 4 4 • • 4 4 4 44 4 * 44 4 * • 4 «4 * 4

Acetic acid 1- (11-hydroxy-4-methoxy-9-methyl-5-oxo-5H, 7H-6,12-dioxadibenzo [a, d] cycloocten-3-yl) -3-methylbutyl ester;

10-hydroxy-2,4a, 6a, 6b, 9,10,12a-heptamethyl-4-octadecanoyloxy-1,2,3,4,4a, 5,6,6a, 6b, 7,8,8a, 9, 10,11,12,12a, 12b, 13,14bicosahydro-picene-2-carboxylic acid;

3 - ((2,2,5,5-tetramethyl- [1,3] dioxane-4-carbonyl) amino] -propionic acid 2- (3- (2,2-dimethyl-propyl) -3-nonyl-ureido] 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-difluorophenyl) -urea;

1- [4- (2-Chloro-phenyl) -1,6,7-trimethyl-2-oxo-1,2-dihydro-quinolin-3-yl] -3- (2,4-difluorophenyl) -urea;

1- [4- (2-Chloro-phenyl) -6,7-dimethyl-2-oxo-2H-chromen-3-yl] -

3- (2,4-Difluorophenyl) -urea;

(S) 1- [6-Bromo-5- (2-chloro-phenyl) -1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diazepin-7-yl] - 3- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl) -urea;

3- (4,5-diphenyl-1H-imidazol-2-ylsulfanylmethyl) -1-methylpiperidine;

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-chlorophenyl) -6-cyclohexyl-4- (2-oxo-2-phenyl-ethyl) -

6,7-dihydro-4H-1,4,6,8a-tetraaza-s-indacene-5,8-dione;

[2- (3-tert-Butyl-4-hydroxy-naphthalen-1-yl) -1 (diethoxy-phosphoryl) -vinyl] -phosphonic acid diethyl ester;

5- [1- (acetyloxy) -3-methylbutyl] -2 '- (hydroxymethyl) -4-methoxy-4'-methylspiro [benzofuran-2- (3H), 1'-cyclohexa-2', 4'-diene] - 3,6'-dione;

·· ♦ · · » ·· • 4 • · • · · · • · • · · • · • · · ·· • 4 180 • · • 4 • · · » • · 4 • 4 4 4 · • 4 4 4 • 4 • •• 44 44 i · 4

5- [1- (acetyloxy) -3-methylbutyl] -4-methoxy-4'-methyl-3,6-dioxospiro [benzofuran-2- (3H), 1'-cyclohexa-2 ', 4'-diene] - 2'carboxaldehyde;

(3α, 4a, 22a, 24a) -3-hydroxy-22 - [(1-oxooctadecyl) oxy] -24-norolean-12-ene-29-acid;

1- [5- (4,5-diphenyl-1H-imidazole-2-sulfinyl) -pentyl] -3,5-dimethyl-1H-pyrazole; and

N-butyl-3 - [[(4-decyloxyphenyl) carbonyl] amino] -4- (methylthio) -benzamide;

Bay 02752

181

H ₃ C) ₂ N

N _{(CH3) 2}

YM-17E

RP73163

Both ACAT and MMP inhibitors include all existing stereoisomers of these compounds.

METHODS

The anti-atherosclerotic potential of ACAT and MMP inhibitors is evaluated directly from model atherosclerotic lesion regression. Male New Zealand white rabbits (Kuiper farms, Gary, Indiana) weighing 1.2 to 1.5 kg are fed with cereal crumb (Purina 5321) supplemented with 0.5% cholesterol (C), 3% peanut oil (PNO) 3% coconut oil (CNO) for 9 weeks followed by a diet containing 0% C, 3% PNO and 3% CNO (fat diet) for 6 weeks. This diet precedes the 8-week application of an ACAT inhibitor, such as [[2,4,6-tris (1182)] 9 9 · 9 · 9 · 9 · 9 · 9 99 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 99 9 9 9 9 9 9 9 9 9 9 methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl amidosulfurate and HMG-CoA reductase inhibitor, for example simvastatin, both administered separately or together . The diet consists of 30 g for the first week, 40 g for the next two weeks, 50 g for the next two weeks, 60 g for 4 weeks, 70 g for the next 6 weeks and 80 g for the last 8 weeks. After the first week of initiation of the diet, chronic endothelial damage to the abdominal aorta and thigh artery is induced by surgically inserting an 18 cm nylon fiber of 200 µm diameter into the passage of the right thigh artery. After an initial 15-week lesion-inducing phase, in which both hypercholesterolemic and plasma cholesterol are stabilized, the animals are divided into numbers of the same groups based on the amount of total plasma cholesterol 24 hours after feeding. The group of animals with no resistance (n = 16) dies before drug administration, while the second, progressive group (n = 16) survives on the fat diet for the remaining 8 weeks of the experiment. Other groups of animals are given either ACAT and MMP inhibitors, or a combination of both.

Other ACAT inhibitors useful in the present invention are compounds of Formula 1,

R4 wherein n is 0, 1 or 2;

wherein R 1 is from group (a) phenyl unsubstituted or substituted with one to three substituents from:

straight or branched chain alkyl having 1 to 4 carbon atoms, straight or branched chain alkoxy having up to 3 carbon atoms,

183 straight or branched chain alkylthio group containing 1 to 3 carbon atoms, hydroxy group, phenyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl,

-COOH,

-COOalkyl- straight or branched chain containing up to 4 carbon atoms,

- (CH ₂ ) _m NR ₅ R 6, wherein m is zero or one, and each of R ₅ and R ₆ is hydrogen or a straight or branched alkyl chain having 1 to 4 carbon atoms;

(b) 1- or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents selected from:

straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkoxy of up to 3 carbon atoms, hydroxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl,

-COOH,

-COOalkyl- straight or branched chain containing 1 to 4 carbon

- (CH ₂ ) _m NR ₅ R 6, wherein m, atoms,

R ₅ and R 8 are as defined above;

184 (c)

wherein R ₇ is straight or branched lower alkyl having 1 to 3 carbon atoms;

(d) group

Rs

wherein R 8 and R ₉ are straight or branched lower alkyl having 1 to 4 carbon atoms or phenyl and R ₁₀ is a straight or branched hydrocarbon chain having 1 to 18 carbon atoms, saturated or unsaturated, containing one or two non-accumulated double bonds; phenyl; phenyl substituted with 1 to 3 substituents which may be straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 3) alkoxy, hydroxy, fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, -COOH, Straight or branched chain C 1 -C 4 alkyl, - (CH ₂ ) _m NR ₅ R ₆ , wherein m, R ₅ and R ₆ are as defined above; or a heterocyclic group which may be 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2 or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7 or 8-quinolinyl, or 3- or 4-pyridazinyl and their N-oxides;

(e) group • · · · · · φ φ φ φ φ

185 • ΦΦ «······ ·· φ · ·· ·· φφ φφφ

(f) group

(g) a straight or branched chain hydrocarbon containing from 1 to 18 carbon atoms, saturated or unsaturated, containing one or two non-accumulated double bonds;

(h) cycloalkyl having 3 to 8 carbon atoms;

(i) a heteroaromatic group which may be 2-, 3- or

4-pyridyl unsubstituted or substituted by C 1 -C 4 alkyl; or

2-, 4- or 5-pyrimidinyl, as well as the N-oxides thereof;

(j) group

wherein ----- represents a single or double bond; Y and Z are independently hydrogen, straight or branched chain alkyl of 1 to 4

186 ·· 99 · Φ ·· · ···· · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · ΦΦ φφ φφ φφφ carbon atoms, an alkoxy group of 1 to 3 carbon atoms or halogen;

X is oxygen or two hydrogen atoms;

R ₁ is hydrogen or straight or branched alkyl having 1 to 4 carbon atoms and n 'is zero or one; or (k) is from the group

R14

wherein R12, Ri3, R14 and _R15 are independently hydrogen, halogen, straight or branched alkyl containing 1 to 4 carbon atoms, alkoxy of from 1 to carbon atoms, alkylthio of from 1 to 3 carbon atoms, cycloalkylthio of 5 to phenylthio, carbon atoms wherein alkyl is 1 to 4 carbon atoms, substituted phenylthio, heteroarylthio or heteroaryloxy; and B, D, E and G are nitrogen or carbon wherein one or more of B, D, and E is nitrogen; provided that G = nitrogen, the group binds to the nitrogen atom in Formula 1 at the 4- or 5-position of the pyrimidine ring (a and b);

187 ··············································· ··· ··· ···· ·· ·· ·· »» »· R ₂ and R 3 are identical or different radicals from the group:

(a) hydrogen, halogen, or one of R ₂ and R ₃ is hydroxy;

(b) straight or branched alkyl having 1 to 12 carbon atoms, or cycloalkyl having from 3 to 8 carbon atoms;

(c) phenyl or phenylalkyl wherein the alkyl is 1 to 4 carbon atoms, and the phenyl ring is unsubstituted or substituted with 1 to 3 substituents, which may be straight or branched alkyl of 1 to 4 carbon atoms, straight or branched alkoxy of 1 to 4 carbon atoms Straight or branched chain alkylthio of 1 to 4 carbon atoms, hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, phenyl or - (CH ₂ ) _m NR 5 R 6 wherein m, R 5 and R 6 are as defined above;

(d) straight or branched alkenyl having 2 to 6 carbon atoms; or (e) R ₂ and R ₃ are bonded through carbon to form a C 1 -C 4 alkylidene, a benzylidene or a C 3 -C 7 spiroalkyl; or (f) when R ₂ is hydrogen, fluoro, C1-C12 alkyl, R3 is a heteroaryl group of a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 heteroatoms in at least one ring, wherein the heteroatoms can be nitrogen, oxygen or sulfur, or combinations thereof. Heterocycles may be unsubstituted or substituted with from 1 to 4 carbon atoms. This group also includes the N-oxides of said compounds.

188 * * · 188 188 188 * * * * * (G) 1- or 2-naphthyl, unsubstituted or substituted with up to 3 substituents from the group:

straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkoxy of 1 to 3 carbon atoms, wherein R4 is a straight or branched hydrocarbon of 1 to 20 carbon atoms, saturated or unsaturated with one or two unconjugated double bonds, or a saturated alkylthio group having 1 to 20 carbon atoms, including pharmaceutically acceptable salts and individual enantiomers of said compounds.

The following compounds are particularly suitable for use in the present invention:

N- [2,6-bis (1-methylethyl) phenyl] -2-dodecyl-2H-tetrazole-5-acetamide;

2-dodecyl-N- (2,4, β-trimethoxyphenyl) -2H-tetrazole-5-acetamide;

N- (2,4-difluorophenyl) -2-dodecyl-2H-tetrazole-5-acetamide;

2-tetradecyl-N- (2,4, β-trimethoxyphenyl) -2-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-tetrazole-5-acetamide;

1-dodecyl-N- (1,3,5-trimethyl-1H-pyrazol-4-yl) 1H-tetrazole-5-acetamide;

189 • 9 ♦ ♦ f f f f 4 4 4 4 4 4 4 4 9 9 9 9 9 9 9 9 9 9 9 9 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-phenyl-2H-tetrazole-5-acetamide;

(±) - N - (2,4-Difluorophenyl) -2-dodecyl-α-phenyl-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-dodecylphenyl-2H-tetrazole-5-acetamide;

(+) - N - (5,7-Dimethyl-1,8-naphthyridin-2-yl) -2-dodecyl-α-phenyl-2H-tetrazole-5-acetamide;

(±) -2-dodecyl-1'-phenyl-N- (1,3,5-trimethyl-1H-pyrazol-4-yl) -2H-tetrazole-5-acetamide;

(±) - N -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) -α-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;

190 · to · to · to · to · to · to · to · to · to · to · to · to · to · to

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) -2-tetrazole-5-propanamide;

N- (2,6-bis (1-methylethyl) phenyl) -2-dodecyl-2H-tetrazole-5-propanamide;

N- (2,4-difluorophenyl) -2-dodecyl-2H-tetrazole-5-propanamide;

1-dodecyl-N- (2,4,6-trimethoxyphenyl) -1H-tetrazole-5-propanamide;

(±) - N - (2,4-difluorophenyl) -1-dodecyl-α-phenyl-1 H -tetrazole-5-acetamide;

(±) - N - [2,6-Bis (1-methylethyl) phenyl] -1-dodecylphenyl-1H-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;

(±) -? - ([1,1'-Biphenyl] -4-yl) -2-dodecyl-N- (2,4,6-trimethoxyphenyl) -2H-tetrazole-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;

191 (-) - 2-dodecyl-α-phenyl-N- (2,4,6-trimethoxyphenyl) 2H-tetrazole-5-acetamide, [α] _D -58 ° (1% in CH ₃ OH);

(+) - 2-dodecyl-α-phenyl-N- (2,4,6-trimethoxyphenyl) 2H-tetrazole-5-acetamide, [α] _D = + 55.1 ° (1% in CH 3 OH);

(±) - N - [2,6-Bis (1-methylethyl) phenyl] -2-dodecyl-afluoro-α-phenyl-2H-tetrazole-5-acetamide;

(±) -2-dodecyl-α-fluoro-α-phenyl-N- (2,4,6-trimethoxyphenyl) -2H-tetrazole-5-acetamide;

N- [2,6-bis (1-methylethyl) phenyl] -5-decyl-2H-tetrazole-2-acetamide;

N- [2,6-bis (1-methylethyl) phenyl] -5-decyl-2H-tetrazole-2-acetamide;

N- [2,6-bis (1-methylethyl) phenyl] -5-dodecyl-2H-tetrazole-2-acetamide;

(±) - N - [2,6-Bis (1-methylethyl) phenyl] -5-dodecylphenyl-2H-tetrazole-2-acetamide;

(±) - N - [2,6-Bis (1-methylethyl) phenyl] -5-dodecyl-apentyl-2H-tetrazole-2-acetamide;

(±) - N - [2,6-Bis (1-methylethyl) phenyl] -5 (dodecylthio) -? - phenyl-2H-tetrazole-2-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;

5-dodecyl-α, α-dimethyl-N- (2,4,6-trimethoxyphenyl) -2-tetrazole-2-acetamide;

(±) -5- (dodecylthio) - α-phenyl-N- (2,4,6-trimethoxyphenyl) -2H-tetrazole-2-acetamide; or

192 (±) -5- (Dodecylsulphinyl) - α-phenyl-N- (2,4,6-trimethoxyphenyl) -2H-tetrazole-2-acetamide.

The compounds utilized in this invention are prepared in a variety of forms suitable for oral and parenteral administration in therapy

The compounds are administered in intramuscular, intracutaneous (subcutaneous), intraduodenal and prevention of atherosclerosis.

intravenous, (dermal), subcutaneous (duodenal) and intraperitoneal (peritoneal) injections. The compounds may also be administered in the form of inhalations, for example nasal.

In addition, they can be administered transdermally. It will be appreciated that said forms of administration of the medicaments comprise the active ingredient in the form of the free base, acid, or corresponding pharmaceutically acceptable salt thereof. The active ingredient usually comprises from 5 to 95% by weight of the preparation.

Solid or liquid, pharmaceutically acceptable carriers are used to prepare pharmaceutical preparations from the compounds of the invention. The solid form includes powders, tablets, pills, capsules, capsules, suppositories, and degradable granules. The solid carrier may be one or more substances, and may be solvents, flavoring agents, diluents, lubricants, suspensions, binders, preservatives, tablet disintegrating agents, or a coating material.

For powders, the carrier is a fine-grained solid which is mixed with the fine-grained active ingredient.

In the case of tablets, the active ingredient is admixed with a carrier which is sufficiently cohesive to maintain the desired shape and size.

The powders and tablets usually contain from 5% to about 70% active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, goat, methylcellulose, low-solid waxes, cocoa butter, and others. By "preparation" is meant the association of the active ingredient with the coating material such as

193 • a carrier to form capsules in which the active ingredient is pure or in association with other carriers, it is encased in a carrier which is tightly coupled thereto. Similarly, capsules and lozenges are prepared. Tablets, powders, capsules, pills, capsules, and lozenges can be used as a solid dosage form of a medicament suitable for oral administration.

In preparing suppositories, a low-setting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and then the homogeneously active ingredient is mixed into the melt. The homogeneous melt is then divided into batches of the desired shape and size and allowed to solidify in the cold.

The preparation of liquid preparations includes solutions, suspensions and emulsions, for example, aqueous solutions or water-diluted propylene glycol solutions. The basis of the injectable solutions is a dilute polyethylene glycol solution.

Aqueous solutions suitable for oral administration are prepared by dissolving the active ingredient in water followed by the addition of a suitable colorant, flavoring and, if desired, stabilizing and thickening agents.

Aqueous suspensions suitable for oral administration can be prepared by dispersing fine active ingredient particles in water containing viscous material, such as natural or synthetic resins, rubbers, methylcellulose, sodium carboxymethylcellulose, and other readily suspending agents.

Solid preparations are also prepared which are shortly before application to a liquid form suitable for oral administration. This group includes solutions, suspensions and emulsions. Corresponding formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, natural and artificial sweeteners, dispersants, thickeners, solvents and others.

The pharmaceutical preparations are generally prepared in unit dosage form. That is, the preparation is divided into unit doses containing the appropriate amount of active ingredient. Certain preparations of the preparation are prepared, each of which is prepared.

The 194 pack contains separate amounts of the drug in the form of tablets, capsules, powder in vials or ampoules. A single dose may take the form of a single capsule, tablet, capsule or lozenge, or a plurality of such compositions may be provided in a single package.

The amount of active ingredient in the formulation ranges from about 1 to about 1000 mg, but is typically about 10 to about 100 mg depending on the mode of administration and the strength of the agent. The medicament may also contain other active ingredients as desired.

The compounds used in the pharmaceutical methods of the invention are administered in dosages such that the hydrolytic activity of one or more matrix metalloproteinase enzymes is effectively reduced. An effective amount of such compounds is an amount that will prevent or treat CHF and ventricular dilatation. The substances can also be used prophylactically at the same dosage. An initial dose of about 1 to 100 mg per kilogram of weight per day is effective for the prevention and treatment of heart failure, with a range of 5 to 75 mg being best. However, the dosage may be adjusted according to the individual requirements of the patient, the severity of the disease and the active ingredients used. Obviously, it is envisaged to determine the appropriate dose for each individual case. Treatment is generally initiated at lower doses that contain less active ingredients than is optimal. Thereafter, the doses are gradually and slowly increased until an optimum effect is obtained. It is advantageous to divide the daily dose and to administer it several times a day as needed. The usual dose is from 0.1 to 500 mg / kg, ideally from 25 to 250 mg / kg.

The following examples illustrate typical preparations used in the present invention.

9 9

195

9

9 ·

Component

Quantity (mg)

Tablets

2- (4'-Bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid

ACAT component lactose maize starch (mixed) maize starch (paste) magnesium stearate (1%) total

100 mixes) the heating is used

The biphenylsulfonamide, lactose and corn starch are mixed in a homogeneous mixture. Corn (paste) is suspended in 200 ml of water to form a paste, not a mixture. Wet with stirring until powdered powder is passed through No. 8 hand sieve for granulation and dried at (k starch and then

The paste (to be granules ° C. The dry to the granules are compressed until then rubbed with 1% magnesium stearate and

tablet. For the treatment of atherosclerosis and administered 1 to 4 tablets daily. arthritis in humans with Oral solution Component Amount (R) -2- (4'-Cyanobiphenyl-4-sulfonylamino) -3-phenyl- 400 mg propionic acid, sodium salt ACAT folder Sorbitol solution (70% N.F.) 40 ml sodium benzoate 20 mg saccharin 5 mg red dye 10 mg Cherry flavor 20 mg Distilled water 100 ml

»« ·· ·· ·· ···· · · · · ·

The sorbitol solution is added to 40 ml of distilled water and the biphenylsulfonamide is dissolved in the resulting solution. Then other soluble components - saccharin, sodium benzoate, flavoring and coloring agent - are added. After dissolution, make up to 100 ml with distilled water. 1 ml of syrup contains 4 mg of a compound of the invention.

Parenteral solution

20 g of (S) -2- (4'-aminobiphenyl-4-sulfonylamino) -3- (3-ethoxyphenyl) propionic acid are suspended in a solution of 700 ml of propylene glycol and 200 ml of water. After formation of the suspension, the pH is adjusted to 6.5 by addition of 1α sodium hydroxide and the volume of the suspension is made up to 1000 ml with water for injection. The preparation is sterilized and dosed into 5 ml ampoules, each ampoule containing 2 ml of the preparation. Finally, the vials are sealed in a nitrogen atmosphere.

197 ··· ··· ··· ·· ·· ···

Claims (4)

PATENT CLAIMS 1 (R) - [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; ΦΦ «Φ ·· 09 • · Φ · ΦΦΦΦ · · · · · · · TC1 · · φ · · · · · · · · φ · φ · φ · N-hydroxy-3-methyl-3- (5-methyl-isoxazol-3-yl) methylsulfanyl] -2R- [4- (pyridin-4-ylsulfanyl) piperidine-sulfonylamino] -butyramide; 4- (4'-chloro-biphenyl-4-yl) -2RS- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) ethyl] -4-oxo-butyric acid; 4- (4'-chloro-biphenyl-4-yl) -2R- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) ethyl] -4-oxo-butyric acid; N-hydroxy-2R- [4- (4-imidazol-1-yl-phenoxy) -piperidine-1-sulfonylamino] -3,3-dymethyl-butyramide; 2R- [4- (4-chloro-benzoyl) -piperazine-1-sulfonylamino] -N-hydroxy-3-methyl-3-methylsulfanyl-butyramide; N-Hydroxy-3-methyl-3-methylsulfanyl-2R- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonylamino] -3,3-methyl-butyramide; 4- (pyridin-4-yloxy) benzenesulfonic acid; 4- (pyridin-4-yloxy) benzenesulfonyl chloride hydrochloride; (3S) -2,2-dimethyl-3-thiomorpholine carboxylic acid; 1 (R) - [4- (4-Imidazol-1-yl-phenoxy) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid; 1 (R) - (4-Pyridin-2-yl-piperazine-1-sulfonyl) piperidine-2-carboxylic acid hydroxamide; 1 (R) - [4- (4-Chloro-benzoyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid amide; 1- [4- (4-Imidazol-1-yl-phenylsulfanyl) -piperidine-1sulfonyl] -piperidine-2-carboxylic acid hydroxamide; 1-sulfonylamino] -butyric acid; 1- [4- (4-Methyl-phenylsulfamyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid hydroxamide; 4- (4-Methoxy-benzenesulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid; 4- (4-methoxybenzenesulfonyl) -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxamide; 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid; 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethylthiomorpholine-3-carboxylic acid hydroxamide; 1- [4- (4-Methoxy-phenylsulfamyl) -piperidine-1sulfonyl] -piperidine-2-carboxylic acid hydroxamide; 3R- [3- (4-Cyano-phenyl) -pyrrol-1-yl] -N (2,2-dimethyl-1S-methylcarbamoyl-propyl) -succinamic acid methyl ester; 1- [4- (pyridin-4-ylsulfanyl) -piperidine-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] succinamic acid; 3R- {3 - [(4-Cyano-phenyl) -acetyl] -pyrrol-1-yl} -N (2,2-dimethyl-1S-methylcarbamoyl-propyl) -succinamic acid; 1- [2- (Benzothiazol-2-ylsulfanyl) -piperidine-1-sulfonyl] -piperidine-2-carboxylic acid hydroxamide; 3R- [3- (4-Cyanophenyl) -pyrrol-1-yl] -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic 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-yl-sulfanyl) -butyric acid; 247 99 · « 99 99 • · 9 · 9 9 9 9 9 9 • · • · • 9 9 99 9 · ♦ 9 • 9 9 9 9 • · 99 9999 99 9 9 ·· 9 9 3R- [3- (4'-Cyanobiphenyl-4-yl) -pyrrol-1-yl] -N- (2,2-dimethyl-1S-hydroxymethyl-propyl) -succinamic acid; 1- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxamide; 1- [4- (pyridin-2-ylsulfanyl) -piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxamide; 1- [4- (4-chlorophenoxy) -benzenesulfonyl] -4- (1-methyl-1H-imidazole-4-sulfonyl) -piperazine-2-carboxylic acid hydroxamide; N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [1- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] succinamic acid; 1- [4- (4-Fluoro-phenoxy) -benzenesulfonyl] -3,3-dimethyl-5-oxo-piperazine-2-carboxylic acid; N- (4- [4-fluorophenoxy] -benzenesulfonylamino) -3-methyl- 1- (4-Phenylsulfanyl-piperidine-1-sulfonyl) -piperidine- 1- (4-Phenoxy-piperidine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1- [4- (pyridin-4-ylsulfanyl) -benzenesulfonyl] piperidine-2-carboxylic acid hydroxamide; N- (4-phenoxy-benzenesulfonyl) -D-tert-leucine; N- (4-phenoxy-benzenesulfonyl) -D-tert-leucine, N-hydroxyamide; N- (8-oxo-4-oxa-1,7-tricyclo [9.6.1.0 12.17] octadeca-11 (18), 12 (17), 13,15-tetraen-9-yl) -3- [4- (4-Pyridyl) -3-phenyl-pyrrol-1-yl) -succinamic acid; 1 - ((2-pyridyl) -4-piperazine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1- (4-Benzyl-piperazine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1-Phenethylcarbamoyl-pyrrolidine-2- (R) -carboxylic acid hydroxamide; N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [3- (4-propyl-phenyl) -pyrrol-1-yl] -succinamic acid; 1- (pyrrolidine-1-carbonyl) -pyrrolidine-2 (R) -carboxylic acid hydroxamide; 1-phenethylcarbamoyl-pyrrolidine-2 (R) -carboxylic acid; R-4- [4- (bromophenoxy) -benzenesulfonyl] -2,2-dimethyl-loxothiomorpholine-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-ylphenyl) -pyrrol-1-yl] -succinamic acid; N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid; N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid; 1- (pyrrolidine-1-carbonyl) -pyrrolidine-2 (R) -carboxylic acid; 1- [4- (4-Fluorophenylsulfanyl) -benzenesulfonyl] piperidine-2-carboxylic acid hydroxamide; 4- [4- (bromo-phenoxy) -benzenesulfonyl] -2,2-dimethyl-loxothiomorpholine-3-carboxylic acid hydroxamide; 241 «« · t t t t * t * * * * * * * * 241 241 241 · · ···· · · · · · · · N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- (3-phenyl-pyrrol-1-yl) -succinamic acid; 3R- (3-Biphenyl-4-yl) -N- (2-hydroxy-1S-hydroxymethyl-2-methyl-propyl) -succinamic acid; 1- [4- (4-Fluorophenyl) -piperazine-1-sulfonyl] -piperidine- 1- (diphenylphosphinic) -pyrrolidine-2- (R) -carboxylic acid hydroxamide; N, N - {(diphenylphosphine) - (sodium acetate)} hydrazide; N- (1-benzyl-2-hydroxy-ethyl) -3- (1-biphenyl-4-yl-1H-pyrrol-3-yl) -succinamic acid; trans-2-phenethylsulfonyl-cyclohexanecarboxylic acid, hydroxamide; 1- [4- (4-Fluorophenyl) -benzenesulfonyl] -N-hydroxy-2-piperazinecarboxamide hydrochloride; 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-ylphenyl) -pyrrol-1-yl] -succinamic acid; 1- [4- (4-Fluorophenyl) -benzenesulfonyl] -4- (tert-butoxycarboxylic) -2R-piperazine-2-carboxylic acid hydroxamide; 1- [4- (4-nitrile-phenoxy) -benzenesulfonyl] -4- (tert-butylcarbamoyl) -piperazine-2-carboxylic acid, Ν-hydroxamide; 2S- [3- (Biphenyl-4-yl) -pyrrol-1R-yl- (1S-hydroxymethyl- 1- [4- (4-Methoxy-phenylsulfanyl) -benzenesulfonyl] -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- (pyrrolidine-1-sulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1- [4-chlorophenoxybenzenesulfonyl] -N-hydroxy-2R-piperazine-carboxamide; 1- (1,3-dihydro-isoindole-2-sulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1- (methylphenylphosphinic) -piperidine-2- (R) carboxylic acid hydroxamide; 4- (4- (4-chlorophenoxy) benzenesulfonyl) -N-hydroxymorpholine-3R-carboxamide; 2S- [1R- (3- (4'-Cyano-biphenyl-4-yl) -pyrrol-1-yl) -N (2,2-dimethyl-1S-hydroxymethyl-propylcarbamoyl) -methyl] -pentanoic acid; 1- [4-Phenoxy-benzenesulfonyl] -4-methyl-piperazine-2-carboxylic acid, N-hydroxamide; 1- [4- (methoxy) -benzenesulfonyl] -piperidin-2-amidoxime; 1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -piperidine-2-amido oxime; 1- [4-Phenoxy-benzenesulfonyl] -piperazine-2-carboxylic acid, N-hydroxamide; 4- [4-Phenoxy-benzenesulfonyl] -thiomorpholine-3-carboxylic acid, N-hydroxamide; 1- [4- (4-chlorophenoxy) -benzenesulfonyl] -N-hydroxy-4- (N-methylcarbamoyl) -piperazine-2-carboxamide; 4- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -thiomorpholine- 1- (diphenylphosphine) -propanoic acid, hydroxamide; 4- [2- (2-Carboxymethyl-5- (4- (3-hydroxypropyl) phenyl) -pentanoylamino) -4-methylpentanoylamino] benzoic acid methyl ester; 1- (diphenylphosphine) -propanoic acid; 1- [4- (4-bromo-phenoxy) -benzenesulfonyl] -4-methylpiperazine-2-carboxylic acid, N-hydroxamide; 4- (4-Methoxy-benzenesulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide; 1- (diphenylphosphine) -piperidine-2-carboxylic acid hydroxamide; 3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [3S- (2RS-hydroxy- 5-methyl-hexyl] -succinamic acid; N- (1- (S) -benzyl-2-hydroxy-ethyl) -3- (R) - (2-biphenyl-4-yl-cyclopropylmethyl) -succinamic acid; 6-Biphenyl-4-yl-3- (R) - (2-oxo-1-tetrahydrofuran-3- (S) ylcarbamoyl) hexanhydroxamic acid; 1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -piperazine-2-carboxylic acid hydroxamide; 3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [2-hydroxycyclohexyl-1S- (1H-imidazol-4-ylmethyl) -ethyl] -succinamic acid trifluoroacetate; 3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- [1S- (methoxymethylcarbamoyl) -3-methyl-butyl] succinamic acid; N- (1-acetyl-3-methyl-butyl) -3- (3-biphenyl-4-yl-pyrrol-1-yl) -succinamic acid; 6-Biphenyl-4-yl-3- (R) - (2-oxo-1-tetrahydrofuran-3- (S) ylcarbamoyl) -hexanoic acid; 1- [4- (4-Bromo-phenoxy) -benzenesulfonyl] -4- (tert-butylcarbamoyl) -piperazine-2-carboxylic acid hydroxamide; 1- (4-Phenoxy-benzenesulfonyl) -piperidine-2-carboxylic acid hydroxamide; 236 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 6-Biphenyl-4-yl-2S-hydroxy-3R- (1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl) -hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (1- (S) -hydroxymethyl-2- (3-pyridyl) -ethylcarbamoyl) -hexanhydroxamic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R- (1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl) -hexane-hydroxamic acid; 1- [4-Biphenyl-4-yloxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxamide; 1- [4-Biphenyl-4-yloxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; 1 - [(4-bromo-phenoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid; 6-Biphenyl-4-yl-3- (2-hydroxy-1-hydroxymethyl-propylcarbamoyl) -hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (2-oxo-cyclohexyl-1- (S) carbamoyl) -hexanoic acid; 6-Biphenyl-4-yl-3- (2-hydroxy-1-hydroxymethyl-propylcarbamoyl) -hexane-hydroxamic acid; 2S - [(1S-Benzyl-2-hydroxyethylcarbamoyl) -3R-biphenyl- 4-yl-pyrrol-1-yl-methyl] -pentanoic acid; 3R- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- (2R-hydroxycyclohexyl-1R-yl) -succinamic acid; 1 - [(4-bromo-phenoxy) -benzenesulfonyl] -piperidine-2-carboxylic acid hydroxamide; N- (1-Benzyl-2-methoxy-ethyl) -3- (3-biphenyl-4-yl-pyrrol-1-yl) -succinamic acid; N- (1-benzyl-2-methoxy-ethyl) -3- (3-biphenyl-4-yl-pyrrol-1-yl) -succinic-hydroxamic acid; 6-Biphenyl-4-yl-3 (R) -2 (S) -hydroxy- (1 (S) hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexanoic acid, 1- (4-Methoxy-benzenesulfonyl) -piperidine-2-carboxylic acid hydroxamide; 1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -3-methyl-butylthiocarbamoyl} -pyrrolidine- 1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -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) -4-methylvaleroyl] aminobenzoic acid methyl ester; 1- {1- [1- (4-Methoxycarbonyl-phenylcarbamoyl) -3-methyl-butylcarbamoyl] -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- (2-hydroxy- 1- (N-hydroxy) -3- (2-bis (benzyl)) urea; 4- (2- {5- [7- (2-Amino-acetylamino) -9H-fluoren-2-yl] -2-carboxymethyl-pentanoylamino} -4-methylpentanoylamino) -benzoic acid methyl ester, TFA salt; 3R- (6- (4-Biphenyl) propyl-N- (3-methylpyridinecarbamoyl) -hexanoic acid, N-hydroxyamide); 228 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· 6-Biphenyl-4-yl-3- [cyclohexyl- (4- (2-hydroxy-ethylsulfamoyl) -phenylcarbamoyl) -methylcarbamoyl] -hexanoic acid; 6-Biphenyl-4-yl-3- [cyclohexyl- (4- (2-dimethylaminoethylsulfamoyl) -phenylcarbamoyl) methylcarbamoyl] hexanoic acid, trifluoroacetate; 4- (2- {2-carboxymethyl-5- [4- (1H-tetrazole) methyl ester) 5-yl) -phenyl] -pentanoylamino} -4-methylpentanoylamino) benzoic acid; 4- [2- (2-Carboxymethyl-5- (4- (2-hydroxyethyl) phenyl) -pentanoylamino) -4-methylpentanoylamino] benzoic acid methyl ester; 4- (2 - ([5-hydroxyamino-3- (3-phenylpropyl) -3,4-dihydro-2H-pyrrole-3-carbonyl] amino} -4-methylpentanoylamino) 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-yl-sulfamoyl) -phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (4-methylsulfanyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (4-methylsulfonyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 4- [2- (5-Biphenyl-4-yl-2-carboxymethylpentanoylamino) -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-methylpentanoylamino) benzoic acid methyl ester; 229 ·· · φ · φ · · • · • · • · · · · · · · · · · · · · • · 5-hydroxyamino-3- (3-pentyl) -3,4-dihydro-2H-pyrrole-3-carboxylic acid, (2-cyclohexyl-1-methylcarbamoylethyl) amide; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 4- [2- (2-Carboxymethyl-5- (4-cyanobiphenyl-4-yl) -pentanoylamino) -4-methylpentanoylamino] benzoic acid methyl ester; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) -phenylethylcarbamoyl) -hexanoic acid; 1- (N-methyl-N-phenethylthiocarbonyl) -pyrrolidine-2-carboxylic acid; 6-Biphenyl-4-yl-3 - ({cyclohexyl- [2- (4-sulfanoyl-phenyl) -ethylcarbamoyl] -methyl} -carbamoyl) -hexanoic acid; 3R (6- (4-Biphenyl) -3- (N-benzylcarbamoyl)) hexanoic acid, N-hydroxyamide; 1-allyl-3- (2-hydroxyethyl) -2-thiourea; 1- (3-Phenyl-propyl) -pyrrolidine-2-hydroxamic acid; 4- [2- (2-Carboxymethyl-5- (5-hydroxy-valeroyl) -amino) -4-methyl-valeroyl] -aminobenzoic acid methyl ester; 223 4- [2- (2-Carboxymethyl-5- (t-methylureido) 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] -aminobenzoic acid methyl ester; 4- [2- (2-Hydroxyaminocarbonylmethyl-2-phenylacetylamino) -4-methyl-valeroyl] -aminobenzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-methylpentanoylamino) -2-cyclohexylacetylamino] -benzoic acid methyl ester; 1- [5- (4,5-Diphenyl-1H-imidazole-2-sulfinyl) -pentyl] - 1-hydroxymethyl-1-methyl-ethyl) -urea; 1- [4- (2-Chloro-phenyl) -6,7-dimethyl-2-oxo-2H-chromen-3-yl] -3- (2,4-difluorophenyl) -urea; (S) 1- [6-Bromo-5- (2-chloro-phenyl) -1,3-dimethyl-2-oxo- 1- [4- (2-Chloro-phenyl) -1,6,7-trimethyl-2-oxo-1,2-dihydro-quinolin-3-yl] -3- (2,4-difluorophenyl) -urea; • »φφ · * ΦΦ φ # φ φ 9 · ♦ φ Φ · · · * 219 φ Φ φ • · · · 1- [4- (2-Chloro-phenyl) -6,8-dimethyl-quinolin-3-yl] -3 (2,4-difluoro-phenyl) -urea; 1- (2,6-diisopropyl-phenyl) -3- (2-p-tolyl-heptyl) -urea; 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-octadecanoyloxy-1,2,3,4,4a, 5,6,6a, 6b, 7,8,8a, 9, 10, 11,12,12a, 12b, 13,14b-eicosahydro-picene-2-carboxylic acid; 1- (2- (2- [4- (2,2-Dimethyl-propyl) -phenyl] -ethyl} -4,6-difluorophenyl) -3-heptyl-urea; (4S-trans) 6- (4,5-diphenyl-1H-imidazol-2-ylsulfanylmethyl) -4-hydroxy-4-methyl-tetrahydropyran-2-one; 1- {2-Dimethylamino-6- [3- (4-phenyl-imidazol-1-yl) -propoxy] -phenyl} -3-pentyl-urea; 1- {2-dimethylamino-6- [3- (5-methyl-imidazol-1-yl) -propoxy] -phenyl} -3-pentyl-urea; 1-Benzyl-1- (5-methyl-3-phenyl-benzofuran-2-ylmethyl) - 1- {2- [4- (1,2-dimethoxy-ethoxy) -phenyl] -ethyl} -3- (2,4-dimethoxy-phenyl) -1-heptyl-urea; 1-Cycloheptyl-1- (2,3-dihydro-benzo [1,4] dioxin-5-ylmethyl) -3- (2,4,6-trimethyl-phenyl) -urea; 1- (2-Cyclohexyl- [1,3] dithiolan-2-ylmethyl) -3- (2,6-diisopropyl-phenyl) -urea; φ · φΦ φΦ φΦ • Φ 217 • φ φ φ φ φ φ φ Φ Φ φ φ φ φ φ φ φ φ φ 1- [4- (2-Chloro-phenyl) -2-ethyl-thieno [2,3-b] pyridin-5-yl] -3- (2,4-difluorophenyl) -urea; 1- (2- {2- [4- (2,2-Dimethyl-propyl) -phenyl] -ethyl} -4,6-difluoro-phenyl) -3-heptyl-urea; octadeca-9,12-dienoic acid, (1-phenylethyl) amide; 3- (1H-Indol-3-yl) -2-octadec-9-enoylaminopropionic acid ethyl ester; 1-heptyl-1- [4- (3-methyl-butyl) benzyl] -3- (2,4,6-trifluorophenylurea); An ACAT inhibitor together with an MMP inhibitor for use in treating and / or preventing atherosclerotic lesions in a mammal. 2 (R) - [4- (4-Chloro-benzoyl) -cyclohexanesulfonyl] -piperidine-1-carboxylic acid hydroxamide; 2- (R) -3-Methyl-3- (pyridin-2-yl-sulfanyl) - [4- (4-trifluoromethyl-phenoxy) -benzenesulfonylamino] -butyric acid; (R) -4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 2R-3-methyl-3 - [(5-methyl-isoxazol-3-yl) methylsulfanyl] - [4- (pyridin-4-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-Bromo-phenoxy) -benzenesulfonylamino] -3-hydroxy-3-methyl-butyric acid; 250 ♦ · 99 9 ΦΦ Φ · ΦΦΦΦ ♦ Φ · »♦ Φ Φ Φ · · · · · · · 4 4 4 4 ΦΦ φφφφ φφ φφ · φ φ 2,2-dimethyl) -4- [4- (pyridin-4-yloxy) benzenesulfonyl] thiomorpholin-3-ol; 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -2,2-dimethoxy-1-oxo-thiomorpholine-3-carboxylic acid hydroxamide; 2 (R) - [4- (4-Bromo-phenoxy) -benzenesulfoxyamino] -3-methyl-3- (pyridin-yl-sulfuroxide) -butyric acid, hydroxamide; 4- (4-Methoxy-benzenesulfonyl) -2,2-dimethyl-1-oxothiomorpholine-3-carboxylic acid hydroxamide; 2 (R) - [4- (4-Methyl-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid hydroxamide; · · · · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 249 9 9 9 9 9 9999 99 99 99 999 2- (R) - [4- (4-Methyl-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid; 2- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -3,3-dimethyl-5-phenyl-pent-4-enoic acid; 5- [4- (4-fluorophenoxy) -benzenesulfonyl] -4,5,6,7-tetrahydro-3H-imidazole [4,5, -c] pyridine-6-carboxylic acid hydroxamide; 2-yl-sulfanyl) -butyric acid; 248 * « · ♦ • Φ ·· · • • • · • • · • • • · • • • • • · « • • • • ♦ • • « • · • • ·· ·· · · • » 4 · • · • · · N- (4,4-dimethyl-2-oxo-tetrahydrofuran-3S-yl) -3R- [1- (4'-cyanobiphenyl-4-yl) -1H-pyrrol-3-yl] succinamic acid; - [4- (4-Fluorophenoxy) -benzenesulfonylamino] -3-methyl- 2- [4- (4-Fluorophenoxy) -benzenesulfonylamino] -3-methyl- 2- [4- (4-Fluorophenoxy) -benzenesulfonylamino] -3-methyl- 2- [4- (4-bromo-phenoxy) -benzenesulfonylamino] -Nhydroxy-3-methyl-3- (5-methyl-isoxazol-3-ylmethylsulfanyl) -butyramide; 2- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -N-hydroxy-3-methyl-3- (5-methyl-isoxazol-3-ylmethylsulfanyl) -butyramide; 2- [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl- 2- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-3- (5-methyl-isoxazol-3-ylmethylsulfanyl) -butyric acid; 2- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -3,3-dimethyl-pent-4-enoic acid; 2- (R) - [4- (4-Nitrile-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid; 2- (R) - [4- (4-Iodo-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfonyl) -butyric acid hydroxamide; 2- (R) - [4- (4-Iodophenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-2-yl-sulfanyl) -butyric acid; 3R- [3- (4-Cyanophenyl) -pyrrol-1-yl] -N- (2,2-dimethyl-5-hydroxymethyl-propyl) -succinamic acid; {2- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -2-hydroxycarbamoyl-1,1-dimethyl-ethylsulfanyl} -acetic acid; 2 (R) - [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfanyl) -butyric acid, hydroxamide; trans-2- (2-Biphenyl-4-yl-ethylsulfanyl) -cyclohexanecarboxylic acid hydroxamide; N- [1S- (1H-imidazol-2-yl) -3-methyl-butyl] -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid format; N-methyl-3- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid; N (4) - (2,2-dimethyl-1S-hydroxymethyl-propyl) -N (1) hydroxy-3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] succinamide; 2,2-dimethyl-1-oxo-4- [4- (pyridin-4-yloxy) -benzenesulfonyl] -1S14-thiomorpholine-3-carboxylic acid hydroxamide; {2- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -2-hydroxy-carbamoyl-1,1-dimethylethylsulfanyl} -acetic acid tert-butyl ester; 2 (R) - [4- (4- (Fur-3-yl) -phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-yl-sulfanyl) -butyric acid; 2,2-dimethyl-1-oxo-4- [4- (pyridin-4-yloxy) benzenesulfonyl] -1S14-thiomorpholine-3-carboxylic acid hydroxamide; 246 • · 2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-2-yl-sulfanyl) -butyric acid, hydroxamide; 2-carboxylic acid, hydroxamide; 2- [4- (4-chlorophenyl) -piperazine-1-sulfonylamino] -3-methyl-3- (pyridin-2-ylmethylsulfanyl) -butyric acid, N-hydroxamide; 2- (2-Biphenyl-4-yl-ethanesulfonyl) -cyclohexanecarboxylic acid hydroxamate; 2 (R) - [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-2-ylsulfanyl) -butyric acid; 245 • 9 • 9 99 • 9 9 · • 9 9 9 9 9 9 9 • • • 9 • 9 9 9 9 ♦ 9 « 9 • • 9 • 9 9 9 9 • • 9 • 999 99 9 · ·· • · 2- [4- (4-chlorophenyl) -piperazine-1-sulfonylamino] -3-methyl-3- (pyridin-2-ylmethylsulfanyl) -butyric acid; 3R- [3- (4'-Cyano-biphenyl-4-yl) -pyrrol-1-yl] -N- [2,2-dimethyl-1S- (pyridin-4-ylcarbamoyl) -propyl] -succinamic acid; 2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-4-ylsulfanyl) -butyric acid; cis-2- (2-phenyl-ethanesulfonyl) -cyclohexanecarboxylic acid, hydroxamide; 2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-3-ylsulfanyl) -butyric acid; 2 (R) - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -3-methyl-3- (pyridin-2-ylsulfanyl) -butyric 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-oxy-benzenesulfonyl) -3,3-dimethyl-S- (benzylthio) -D-cysteine; 2- [4- (pyridin-2-yloxy) -benzenesulfonylamino] -Nhydroxy-3,3-dimethyl-butyramide; N- (4-phenoxy-benzenesulfonyl) -3,3-dimethyl-S (methylthio) -D-cysteine; 2- [4- (pyridin-2-yloxy) -benzenesulfonylamino] -3,3-dimethylbutyric acid; 2- [4- (4-chlorophenoxy) -benzenesulfonylamino] -Nhydroxy-3,3-dimethyl-butyramide; 2- [4- (4-chlorophenoxy) -benzenesulfonylamino] -3,3-dimethylbutyric acid; 2- [2-N'-acetyl-hydrazino) -2-oxo-ethyl] -5-biphenyl-4-yl-pentanoic acid; 2,2-dimethyl-4- [4- (pyridin-2-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 (R) -4-methyl-1- 4- (4-fluorophenyl) benzenesulfonyl) -N-hydroxy-piperazine-2-carboxamide; N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3- (5-biphenyl-4-yl-furan-2-yl) -succinamic acid; ·· ·· 99 99 99 ················· <9 9 9 242 ·· «9 ··· · · ··· 9 ··· ·· ·· N- (2,2-dimethyl-1S-methylcarbamoyl-propyl) -3R- (3-pyridin-4-yl-pyrrol-1-yl) -succinamic acid; 2-carboxylic acid, hydroxamide; 2,2-Dimethyl-propylcarbamoyl) -methyl] -pent 4-enoic acid; 6-oxo-3- (4-phenoxy-benzenesulfonyl) -hexahydropyrimidine-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; 240 4 - [(4-fluoro-phenoxy) -benzenesulfonyl] oxothiomorpholine-3-carboxylic acid, N-hydroxamide; N- (2,2-dimethyl-1S-hydroxymethyl-propyl) -3R- [3- (4-pyridin-4-yl-phenyl) -pyrrol-1-yl] -succinamic acid; N- (1S-benzyl-2-hydroxy-ethyl) -3S- (5-biphenyl-4-yl-furan-2-yl) -succinamic acid; 4- (4-butoxy-benzenesulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide; 4- (4-butoxybenzenesulfonyl) -1-oxothiomorpholine-3-carboxylic acid hydroxamide; 2- (3-phenyl-propylsulfonyl) -cyclohexanecarboxylic acid, hydroxamide; -2,2-dimethylpropylcarbamoyl) methyl] -5-hydroxypentanoic acid; 2 (S, R) - {1S-Benzyl-2-hydroxy-ethylcarbamoyl- [3R- (4'-cyano-biphenyl-4-yl) -pyrrol-1-yl] -methyl} -pentanoic acid; ·· ·· 99 99 ·· 9 9 9 9999 999 • 9 · · · ·· ·· 239 2S- [3- (Biphenyl-4-yl) -pyrrol-1R-yl] - (1S-hydroxymethyl) 2- (3-biphenyl-4-yl-propyl) -3, N4-dihydroxy-N ¹ - (1 (S) - hydroxymethyl-3-methansulfiny1-propyl) succinamide; N- (1-Benzyl-2-hydroxy-ethyl) -3- [3- (4'-carbamoylbiphenyl-4-yl) -pyrrol-1-yl] -succinamic acid; 2- (3-Biphenylnitrile-4-yl-pyrrol-1-yl) -3-carboxy-N- (1-hydroxy-3-phenyl-prop-2-yl) -propionamide; 2- (S) - (1H-Imidazol-4-yl) -ethylcarbamoyl) -hexanoic 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-3- (R) - (1- (S) -hydroxymethyl-2- (3-pyridyl) -ethylcarbamoyl) -hexanoic acid; 6-Biphenyl-4-yl-2- (S) -hydroxy-3- (R) - (1-hydroxymethyl- 2- (3-Biphenyl-4-yl-propyl) -N-hydroxy-N '- (1-hydroxymethyl-3-methylsulfanyl-propyl) -malonamide; 6-Biphenyl-4-yl-3- (3-hydroxy-piperidine-1-carbonyl) -hexanoic acid; 6-Biphenyl-4-yl-3- (3-hydroxy-piperidine-1-carbonyl) -hexanoic acid, hydroxamide; 2- (3-Biphenyl-4-yl-pyrrol-1-yl) -3-carboxy-N- (1-hydroxy-3-phenyl-prop-2-yl) -propionamide; N- [5- (biphen-4-yl) -2- (1-carboxy-2-hydroxyethyl) pentanoyl] -1-t-leucine, N '- (4-methylthiophenyl) amide; 2- (3-biphenyl-4-yl-propyl) -N ⁴ -hydroxy-Ni- (2-hydroxycyclohexyl) - succinamide; 6-Biphenyl-4-yl-3- (1-hydroxyimino-ethyl) -hexanoic acid, hydroxamide; 6-Biphenyl-4-yl-3- (2-hydroxy-cyclohexylcarbamoyl) -hexanoic acid; 9 »·· 9 · 9 9 234-9 4 9994 • 9 β-Biphenyl-4-yl-3- [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -hexanoic acid ethyl ester; 2- (2-Biphenyl-4-yl-ethylsulfanyl) -cyclohexanecarboxylic acid hydroxamide; 2- (3-biphenyl-4-yl-propyl) -N4-hydroxy-N- (2,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-3-yl) succinamide; 6-Biphenyl-4-yl-3- (2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl) -hexanoic acid; 233 • Φ φ φ φ φ φ φ φ • φ • • • • • • φ φ φ φ »» »φ φ φ φ φ φ N- [2,2-dimethyl-1S- (pyridin-4-ylcarbamoyl) -propyl] -3R-thiophen-3-yl-succinamic acid; 4- [2S- (2R- (3-Biphenyl-4-yl-pyrrol-1-yl) -) - 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-tetrahydro-pyran-3-ylcarbamoyl) -hexanoic acid; 6-Biphenyl-4-yl-2 - [(formyl-hydroxyamino) -methyl] pentanoic acid, {1- [4- (2-dimethylaminoethylsulfamoyl) -phenylcarbamoyl] -3-methyl-butyl} amide; 2-carboxylic acid; 2-Benzylsulfanyl-cyclohexanecarboxylic acid, hydroxamide; 2-phenethylsulfanyl-cyclohex-1-enecarboxylic acid, hydroxamide; 6- (4'-Cyano-biphenyl-4-yl) -3- [2-hydroxy-1- (4-methylsulfinyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 231 ΦΦΦΦ φ φ φ φ φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ 2- (Biphenyl-4-ylsulfonyl) -cyclohex-1-enecarboxylic acid hydroxamide; 6- (biphenyl-4-ylsulfonyl) -cyclohex-1-enecarboxylic acid hydroxamide; [2-oxo-3- (3-biphenyl-propyl) -tetrahydrofuran-3-yl] acetic acid; 4- [2- (2-Thioamidomethyl-5-phenyl-valerylamino) -4-methyl-valeroylamino] -benzoic acid methyl ester; 4- [2- (2-Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino) -4-methyl-valeroylamino] -benzoic acid methyl ester; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (4-methylsulfamoyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (2-hydroxyethylsulfamoyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; 2-benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxamide; 6-benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxamide; 2R- (3- (4-biphenyl) propyl-N- (3-methylpyridine) succinamide); 2-Benzylsulfonyl-cyclopent-1-enecarboxylic acid hydroxamide; 227 φφοφ φφφ · 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2;; 2;; 2- (3-Biphenyl-4-yl-propyl) -NI- [1- (5,6-dichloro-1H-benzimidazol-2-yl) -3-methyl-butyl] -N4-hydroxy-succinamide hexanoic acid; 6-Biphenyl-4-yl- [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -hexanoic acid, N-hydroxyamide; 2R- (3- (4-biphenyl) propyl-N- ((1-hydroxy-1-methylethyl) phenylmethyl) succinamide; 6-Biphenyl-4-yl-3- [1-phenylcarbamoyl-2- (4-cyanobenzylsulfanyl) -2-methylpropylcarbamoyl] hexanoic acid; 4- {2- [2-Carboxymethyl-5- (4'-hydroxybiphenyl-4-yl) -pentanoylamino] -4-methylpentanoylamino} benzoic acid methyl ester; 2- (2-oxo-imidazolidin-4-ylmethyl) -5-phenylpentanoic acid; 2-carboxymethyl-heptanoyl-3- (N-methylcarboxamide) hexahydropyridazine; 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); 9 9 9 9 9 9 226 ··· ···· · · ················· 6-Biphenyl-4-yl-3- [1- [3- (2-amino-ethyl) -phenylcarbamoyl] -2,2-dimethyl-propylcarbamoyl] -hexanoic acid; 2R- (3- (4-biphenyl) propyl) -N- (diphenylmethyl) succinamide; 2R- (3- (4-biphenyl) propyl) -N- (phenylmethyl) succinamide; 2-carboxymethyl-heptanoyl-2- (N-methylcarboxamide) piperidine; 4- [2- (2- (2-Phenylcyclopropyl) succinylamino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 2- (3H-imidazol-4-ylmethyl) -N 1, N, 4-diphenethylsuccinamide; [2-oxo-3- (3-phenylpropyl) -tetrahydrofuran-3-yl] acetic acid; 4- [2- (2-Carboxymethyl-5- (fluoren-2-yl) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 4- [2- (2-Carboxymethyl-2- (3-thienyl) acetylamino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 4- [2- (2-Benzylthio-3-carboxypropionylamino) -4-methylpentanoylamino] -benzoic acid methyl ester; 225 ···················································································· 225 225 225 225 225 225 [2- (2-carboxymethyl-4- (2-indolyl) butyrylamino) -4-methyl-valeroyl] aminobenzoic acid; 2-cyclohexylmethylsulfonylbenzohydroxamic acid; 2-cyclohexylmethyl sulfonylbenzoic acid; pyrrolidine-1-carbothioic acid, phenethylamide; 2- [3- (3-Aminophenyl) -propyl] -benzohydroxamic acid; cis-benzyloxy-pyrrolidine-2-carboxylic acid; 4- [2- (2-Carboxymethyl-5- (3-amino-4- (trifluoromethyl) phenyl-valeroyl) amino) -4-methylvaleroyl] aminobenzoic acid methyl ester; 4- [2- (2-Carboxymethyl-5- (methanesulfamido) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; N-Cbz-tyrosine; N-Boc-tryptophan; 4- [2- (carboxy-2-o-tolyl-propionylamino) - 4-Methyl-pentanoylamino] -benzoic acid; 4- [2- (Carboxymethyl-heptanoylamino) -4-methyl-pentanoylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-5- (4-n-butylphenyl) -valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; · · Φ φ · · · · · · · · · · · 224 4- [2- (2-Carboxymethyl-5- (4-tert-butylphenyl) -4-pentenoyl) amino methyl ester -4-methyl-valeroyl] aminobenzoic acid; 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- (thiobenzyl) benzoic acid, N-hydroxyamide; 2- [3- (3-hydroxyphenyl) propyl] -benzohydroxamic acid; 2- (phenyl-2-ethyl) -pyridine-3- N - (hydroxy) carboxamide; 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- (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-ylthio) methyl) succinyl] -L-phenylalanine-N-methylamide; N-hydroxy-5-phenylpentanamide; 4- [2- (2-Carboxymethyl-5- (3-hydroxyphenyl) -valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 4- [2- (2-Carboxymethyl-5- (3-hydroxyphenyl) -4-pentenoyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 4- [2- (2-Carboxymethyl-5- (3-aminophenyl)) - 4-pentenoyl) amino) -4-methyl-valeroyl] aminobenzoic acid trifluoroacetate; 2- (4-chlorophenyl) -6-cyclohexyl-4- (2-oxo-2-phenylethyl) -6,7-dihydro-4H-1,4,6,8a-tetraaza-s-indacene-5,8-dione; [2- (3-tert-Butyl-4-hydroxy-naphthalen-yl) -1- (diethoxy-phosphoryl) -vinyl] -phosphonic acid diethyl ester; 5- [1- (acetyloxy) -3-methylbutyl] -2 '- (hydroxymethyl) - 4-methoxy-4'-methylspiro [benzofuran-2- (3H), 1'-cyclohexa-2 ', 4'-diene] -3,6'-dione; 5- [1- (acetyloxy) -3-methylbutyl] -4-methoxy-4'-methyl- 2-yl) -2-propyl-chroman-6-yloxy] pentanoic acid; N- (4-hexadecylaminobenzoyl) -4-methylbenzenesulfonamide; 2- (5,5-dimethyl- [1,3] dioxan-2-yl) -4,5-diphenyl-1H-imidazole; 2,2-dimethyl-5- [3- (1-methyl-1H-imidazole-) ethyl ester 2,3-dihydro-1H-benzo [e] [1,4] diazepin-7-yl] -3- (2-hydroxy- 3 - [(2,2,5,5-tetramethyl- [1,3] dioxane-4-carbonyl) amino] -propionic acid 2- [3- (2,2-dimethyl-propyl) -3-nonyl-ureido] cyclohexyl ester ; 2- (3- [1,3] dioxan-2-yl-propylsulfanyl) -4,5-diphenyl-imidazole; 2- (2,4α-dimethyl-4α, 5-dihydronaphthalen-1-ylsulfanyl) N- {2 - [(6,6-dimethyl-hepta-2,4-diynyl) -pentyl-amino] ethyl} -acetamide; (Z) octadec-9-enoic acid, [1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -1-phenyl-ethyl] amide; N- (4-dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl) -4- (phenyl-propylamino) -butyramide; (Z) 1- (6,7-Dimethoxy-3-phenyl-3,4-dihydro-1H-isoquinolin-2-yl) -octadec-9-en-1-one; 218 * · • ♦ · · • · · ·· ·· • · ·· ·· • · • 4 • · • · · ·· ···· • · · · • · · · • · • · • · (trans) 1,4-Bis (4-methoxyphenyl) -3- (3-phenylpropyl) azetidin-2-one; 1-butyl-3- {2-dimethylamino-6- [3- (4-phenyl-imidazol-1-yl) -propoxy] -phenyl [-urea; 2,2-dimethyl-dodecanoic acid, (7-methoxy-4-oxochroman-8-yl) amide; (Z) 1- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -octadec-9-en-1-one; (Z) 2,2,5,5-tetramethyl- [1,3] dioxane-4-carboxylic acid- [2- (2-octadec-9-enoylamino-ethylcarbamoyl) -ethyl] -amide; 2-bromo-6,11-dihydro-dibenzo [b, e] oxepine-11-carboxylic acid, (2,6-diisopropyl-phenyl) amide; (±) N- (1,2-Diphenyl-ethyl) -3- (2-heptyloxy-phenyl) -propionamide; 2- (4- {2- [3- (2,4-dimethoxy-phenyl) -1-heptyl-ureido] ethyl} -phenoxy) -2-methyl-propionic acid; 2- (2-ethoxy-ethylsulfanyl) -4,5-diphenyl-1H-imidazole; 4-cyano-N- [2- (4-cyanophenyl) -3-methyl-5,5-bis (trifluoromethyl) -4,5-dihydro-3H-imidazol-4-yl] -N-methylbenzamide; 1- {3- [3- (1-Methyl-1H-imidazol-2-yl) -2-phenethyl-2H-chromen-6-yloxy] -propyl} -cyclopentanecarboxylic acid ethyl ester; 2-ylsulfanyl) pentyl] -1-heptyl-urea; 1-butyl-3- {2- [3- (5-ethyl-4-phenyl-imidazol-1-yl) -propoxy] -6-methyl-phenyl} -urea; Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester, [fluoro [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (3-methyl 1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid, sodium salt, [[2,4,6-tris (1-methylethyl) phenoxy] acetyl] -2,6-bis (1- sulfamic acid methylethyl) phenyl ester, [[2,6-bis (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) sulfamic acid phenyl ester, and [[2,4,6-tris (1-methylethyl)] phenyl] acetyl] -2,6bis (phenyl) phenyl sulfamic acid ester. 32. The method of claim 1, wherein the MMP inhibitor a and an ACAT inhibitor selected from 2,6-diisopropyl-phenyl [(2,4,6-triisopropyl-phenyl) -acetyl] 215 sulfamic acid and N- (2,6-diisopropyl-phenyl) -2 (2-dodecyl-2H-tetrazol-5-yl) -2-phenyl acetamide. A pharmaceutical composition for treating and / or preventing atherosclerotic lesions, comprising a therapeutically effective amount of an ACAT inhibitor and an MMP inhibitor. An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using an MMP inhibitor selected from an ACAT inhibitor selected from [(2,4,6-triisopropylphenyl) -acetyl] sulfamic acid 2,6-diisopropyl phenyl ester and N- ( 2,6-Diisopropyl-phenyl) -2 (2-dodecyl-2H-tetrazol-5-yl) -2-phenyl-acetamide. An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using an ACAT inhibitor selected from 4-hexadecylaminobenzoic acid, sodium salt; Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester, [hydroxy [2,4,6-tris (1-methylethyl) phenyl] acetyl] - Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester, [(acetyloxy) [2,4,6-tris (1-methylethyl) phenyl] acetyl] - 2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, (1-oxo-3,3-diphenylpropyl) -2,6- sulfamic acid bis (1-methylethyl) phenyl ester, [2,6-dichlorophenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [(2-phenylcyclopropyl) carbonyl] -2,6-bis ( Sulfamic acid 1-methylethyl) phenyl ester, [2,5-dimethoxyphenyl (acetyl)] - 2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [2,4,6-trimethoxyphenyl (acetyl)] - 2,6-bis ( sulfamic acid lmethylethyl) phenyl ester, [2,4,6-trimethylphenyl (acetyl)] - 2,6-bis (lmethylethyl) sulfamic acid phenyl ester, 213 • Φ 9 »Φ Φ · Φ · Φ Sulfamic acid [2-thiophenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl ester, [3-thiophenyl (acetyl)] - 2,6-bis (1) i ΦΦ ♦ Φ Φ Φ (2-methoxyphenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl sulfamic acid, (oxophenylacetyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid, [2-methylethyl) phenyl ester, [2 -trifluoromethylphenyl (acetyl)] - 2,6-bis (1-methylethyl) phenyl sulfamic acid, (1-oxo-2-phenylpropyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid, (cyclopentylphenylacetyl) - 2,6 - bis (1-methylethyl) phenyl sulfamic acid, (cyclohexylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid, (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid, (triphenylacetyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid ester, [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (3-methyl-1-oxo-2-phenylpentyl) - Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester, (lo xo-2-phenylbutyl) 2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (cyclohexylphenylacetyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid ester, (1-oxo-2,2-diphenylpropyl) - 2,6-bis (1-methylethyl) phenyl sulfamic acid, [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid, (1-oxo-3-phenylpropyl) ) - 2,6-bis (1-methylethyl) phenyl sulfamic acid ester, 214 <9 9 »♦ · 99 9 9 9 9 9 9 9 9 99 999 «· 99 999 9999 999 • 9 99999 [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] -2-propenyl] -2,6-bis (1-methylethyl) Sulfamic acid phenyl ester, [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] propyl] - 2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] carbamate, 2,6-bis (1-methylethyl) phenyl-N - [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, sodium salt, 2,6-bis (1-methylethyl) -N - [[[2,4,6-tris (1-methylethyl) phenyl] methyl] sulfonyl] benzeneacetamide, Sulfamic acid 2,6-bis (1-methylethyl) phenyl ester. 31. The compound of claim 14 wherein the compound is selected from: sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester, [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) sulfamic acid phenyl ester, [ Sulfamic acid [2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, 212 Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,4,6tris (1-methylethyl) phenyl ester, [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,4,6-tris (1-methylethyl) phenyl sulfamic acid, [adamantanacetyl] -2,6-bis (1-methylethyl) phenyl sulfamic acid, [[2,4,6-tris (1-methylethyl) phenyl] acetyl ] -2,6-bis (1-methylethyl) phenyl sulfamic acid, sodium salt, (decanoyl) -2,6-bis (1-methylethyl) phenyl sulfamic acid, (dodecanoyl) -2,6-bis (1-methylethyl) phenyl ester sulfamic acids, 2,6-bis (1-methylethyl) phenyl and _R2 is 2,6-bis (methylethyl) phenyl or 2,4,6-tris (1-methylethyl) phenyl. 27 Mar: The compound of claim 14 wherein R ₁ is phenyl or isophenyl double substituted at the 2,6-position, and further characterized in that R ₂ is phenyl or isophenyl double substituted at the 2,6-position, and further characterized by: wherein each of R _x and R ₂ is phenyl, wherein each phenyl is double substituted at the 2,6-positions, and further characterized in that R _x is phenyl twice substituted at the 2,6-positions, and R ₂ is phenyl three-substituted at the _2- position; 2,4 and 6 positions, where _R is 2,6-bis (1-methylethyl) phenyl and _R2 is 2,6-bis (methylethyl) phenyl or 2,4,6-tris (1-methylethyl) phenyl, and furthermore characterized in that one of R ₁ and R ₂ is a group Rs AND - (CH ₂₎ Tc _(CH2) wR ₇ AND Re 210 • · ♦ ♦ • · · · • · · • · · • · · · · · • t · 9 • · · · 9 9 9 · 9 99 9 9 9 · • · · • · • · 9 9 · wherein t is 0 or 1 to 4; w is 0 or 1 to 4 with the proviso that the sum of t and w is not greater than 5 ; R5 a R 8 are independently hydrogen or alkyl containing 1 to 6 carbon atoms, or when R 5 is hydrogen, R 8 may be selected from the groups defined as R ₇ ; and R _{7 is} phenyl or phenyl substituted with 1 to 3 substituents from the group consisting of C 1 -C 6 straight and branched chain alkyl, C 1 -C 6 straight chained and branched alkoxy, phenoxy, hydroxy, fluoro, chloro, bromo, nitro, trifluoromethyl, -COOH, COOalkyl, wherein the alkyl contains 1 to 4 carbon atoms, or - (CH ₂ ) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are as defined above. 28. A compound according to claim 14, characterized in that or z / ixin; (CR'R) n proviso that the substituents X is (CR'R '') _n where n R 'j sum j ^e independently an integer from 1 each, to 4, and R 'a straight or carbon, alkyl containing substituted hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R '' together form a carbonyl or spirocycloalkyl group containing 3 to 10 carbons; branched arbitrarily to phenyl, halogen, Ri R ₂ is hydrogen; is phenyl optionally substituted, straight or branched alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms; is phenyl optionally substituted, straight or branched chain alkyl containing from 1 to 10 carbon atoms. 211, atoms, cycloalkyl of 3 to 8 carbon atoms, phenoxy optionally substituted. 29. The compound of claim 14, wherein: X is oxygen; Y is (CR'R '') _n , wherein n is an integer from 1 to 2; R is hydrogen; R 1 is optionally substituted phenyl; R ₂ is optionally substituted phenyl or phenoxy, straight or branched alkyl of 1 to 10 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms; R 'and R' 'are independently hydrogen, straight or branched (C 1 -C 6) alkyl, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy cycloalkyl or R' and R '' together form carbonyl or spiroalkyl. 30. A compound according to claim 14, which is [[2,4,6-tris (1-methylethyl) phenyl] acetyl] - 2- (4'-Aminomethyl-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-phenyl-propionic acid; (S) - (4'-Isopropyl-biphenyl-4-sulfonylamino) -3-phenyl-propionic acid; (S) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid; and target. (S) -2- (4'-Bromo-biphenyl-4sulfonylamino) -3-methyl-butyric acid butyl ester. An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using a compound of the formula O 0 Rx-X-S-N-C-Y-R2 AND Or a pharmaceutically acceptable salt thereof, wherein X and Y may be oxygen, sulfur and (CR'C '') _n , wherein n is an integer from 1 to 4 and R ^z and R '' are independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl , phenyl optionally substituted or R 'and R''together form spirocycloalkyl or carbonyl; R is hydrogen, straight or branched (C 1 -C 8) alkyl or benzyl; ·· · · · · · · · · · · · · · · · · · · · · · 207 R 1 and R ₂ are independently (a) phenyl or phenoxy, each unsubstituted or substituted with 1 to 5 substituents selected from phenyl, alkyl of 1 to 6 carbon atoms, straight or branched, alkoxy of 1 to 6 carbon atoms, with straight or branched chain, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, - _(CH2) pNR3R ₄ wherein p is 0 or 1 and each of R ₃ and R ₄ is hydrogen or from straight or branched alkyl containing 1 to 4 carbon atoms; (b) 1- or 2-naphthyl unsubstituted or substituted with 1 to 3 substituents from phenyl, alkyl of 1 to 6 carbon atoms and s direct or branched string; alkoxy containing 1 to 6 carbon atoms and s direct or branched string; hydroxy, • phenoxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl, wherein the alkyl contains 1 to 6 carbon atoms and is straight or branched chain, - (CH ₂ ) _p NR ₃ R ₄ , wherein p, as defined above; R ₃ and R ₄ are (c) arylalkyl; (d) a straight or branched alkyl chain containing 1 to 20 carbon atoms, saturated or containing 1 to 3 double bonds, or (e) an adamantyl or cycloalkyl group wherein the half of the cycle contains from 3 to 6 carbon atoms. 19. The compound of claim 14 wherein R1 is phenyl. The compound of claim 14, wherein R 1 is phenyl double substituted at positions 2 and 6. 21. A compound of Claim 14 wherein R ₂ is phenyl. 22. The compound of Claim 14 wherein R ₂ is phenyl disubstituted in positions 2 and 6. 209 • · · · · · · · · · · · · · · · · · · · · · · 23. The compound of claim 14 wherein each of R _and R2 is phenyl. 24. The compound of claim 16 wherein each phenyl is double substituted at positions 2 and 6. 25. The compound of Claim 14 wherein R _x is phenyl disubstituted in positions 2 and 6, and R ₂ is phenyl trisubstituted in the 2,4-position and the sixth 26. The compound of Claim 14 wherein R _x is 2- (4'-hydroxymethyl-biphenyl-4-sulfonylamino) -3-methylbutyric acid; 2- (4'-Formyl-biphenyl-4-sulfonylamino) -3-methylbutyric acid; 1- (1-carboxy-2-methyl-propylsulfamoyl) biphenyl-4-carboxylic acid; An ACAT inhibitor together with an MMP inhibitor for use in preventing plaque rupture and promoting lesion regression in mammals. 3 (R) -N-Hydroxy-4- (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-carboxylic acid amide; 3 - [(1-methyl-imidazol-2-yl) methylsulfanyl] butyric acid; N-hydroxy-2 - [(4-methylbenzenesulfonyl) amino] acetamide; 3,3-dimethyl-N-hydroxy-2R- [4- (pyridin-4-ylsulfanyl) -piperidine-1-sulfonylamino] -butyramide; 2R- [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -N-hydroxy-3-methyl-3 - [(1-methyl-imidazol-2-yl) methylsulfanyl] -butyramide; 2R- [4- (4-Bromo-phenoxy) -benzenesulfonylamino] -3-methyl- 3,3-Dimethyl-2R- [4- (pyridin-4-ylsulfanyl) -piperidine- 3 (S) -2,2-Dimethyl-4- [4- (pyridin-4-ylsulfanyl) -benzenesulfonyl] -thiomorpholine-3-carboxylic acid hydroxamide; 2R- N -hydroxy-3-methyl-3 - [(5-methyl-isoxazol-3-yl) methylsulfanyl] - [4- (pyridin-4-ylsulfanyl) -benzenesulfonylamino] -butyramide; 3 (S) -4- (4 - ((pyrid-4-yl) oxy) benzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid; 3- (amidoethylsulfanyl) -butyric acid; [4-methoxy-benzenesulfonylamino] -3-methyl-3- (pyridin-2-yl-sulfanyl) -butyric acid; 3- (hydroxyethylsulfanyl) -butyric acid; [4-Methoxy-benzenesulfonylamino] -3-methyl-3- (pyridine- 3- (carbomethoxyethylsulfanyl) -butyric acid; 3- (5-Methyl-isoazol-3-ylmethylsulfanyl) -butyric acid; 3-carboxymethylsulfanyl-2- (4- (4-fluorophenoxy) benzenesulfonylamino) -3-methylbutyric acid; 3 (R) -N-hydroxy-4- (4 - ((pyridin-4-yl) methyl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 3- (1-Benzyl-imidazol-2-yl-sulfanyl) -butyric acid; 3- tert -butoxycarbonylmethylsulfanyl-2- (4- (4-fluorophenoxy) benzenesulfonylamino] -3-methylbutyric acid; 3,3-dimethyl-2- (4-phenoxy-phenylsulfonylmethyl) butyric acid, N-hydroxamide; 3,3-dimethyl-2- (4-phenoxy-phenylsulfonylmethyl) butyric 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-yl] succinamic acid; 3,3-dimethyl-2- (4-phenoxy-phenylsulfanylmethyl) butyric acid; 3 (R) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 4- [2- (2-Hydroxycarbamoylmethyl-5-phenylpentanoylamino) -4-methylpentanoyl] -benzoic acid methyl ester; trans-2- (2-phenyl-ethanesulfonyl) cyclohexanecarboxylic acid, hydroxamide; 3 (R) -N-hydroxy-4- (4- (imidaz-1-yl) phenoxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 3 (R) -4- [4- (4-Bromo) phenoxybenzenesulfonyl] -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid; N- (4- [4-chloro-phenoxy] -benzenesulfonyl) -3,3-dimethyl-S- (methylthio) -D-cysteine; N- (4- [4-chlorophenoxy] -benzenesulfonyl) -3,3-dimethyl-S (methylthio) -D-cysteine, N-hydroxamide; 244 fcfc fcfc fcfcfcfc fcfcfcfc fcfc fcfc fcfc fcfc ···· N- (4- [4-chlorophenoxy] -benzenesulfonyl) -3,3-dimethyl-S (methylsulfoxy) -D-cysteine, N-hydroxamide; 3- [3- (4'-Carbamoyl-biphenyl-4-yl] -pyrrol-1-yl] -N- (2,2-dimethyl-1- (pyridin-4-yl-carbamoyl) -propyl] -succinamic acid; N- (4-phenoxy-benzenesulfonyl) -3,3-dimethyl-S (methylthio) -D-cysteine, N-hydroxamide; 3- [3- (4'-Cyano-biphenyl-4-yl] -pyrrol-1-yl] -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic acid; 3- [3- (4'-Carbamoyl-biphenyl-4-yl] -pyrrol-1-yl] -N (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic acid; 3 (R) -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; 243 Ν- (4-phenoxy-benzenesulfonyl) -3,3-dimethyl-S (benzylthio) -D-cysteine, N-hydroxamide; 3 (R) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4thiazine-3-carboxamide hydrochloride; 3- [3- (4-pyridyl) -phenyl-4-yl-pyrrol-1-yl] -N- [2,2-dimethyl-1- (4-pyridyl) carbamoyl-propyl] -succinamic acid; 3 (S) -N-hydroxy-4- (4- (pyridin-4-yl) oxybenzenesulfonyl) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 3- [3- (4'-Carbamoyl-biphenyl-4-yl] -pyrrol-1-yl) -N- (1-hydroxymethyl-2,2-dimethyl-propyl) -succinamic acid; 4-methyl-1- (4- (4-chlorophenyl) benzenesulfonyl) -Nhydroxy-2R-piperazinecarboxamide hydrochloride; {3- [3- (3-Methylamino-phenyl) -propyl] -2-oxo-tetrahydro-furan-3-yl} -acetic acid; 6-Biphenyl-4-yl-3- (R) - (2-oxo-azepan-3- (S) ylcarbamoyl) -hexanhydroxamic acid; 4- (1H-indole-2-sulfonyl) -thiomorpholine-3-carboxylic acid hydroxamide; IR - [(4-bromo-phenoxy) -benzenesulfonyl] -N-aminopiperidine-2-carboxamide; 3-yl} -acetic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R- (carboxylic acid) hexanoic acid; 5-biphenylvaleric acid; {3- [3- (3-Aminophenyl) -propyl] -2-oxo-tetrahydrofuran- 3- [2-Biphenyl-4-yl-ethylsulfanyl] -tetrahydropyran-4-carboxylic acid, N-hydroxamide; 6-Biphenyl-4-yl-3- (carboxylic acid) -hexanoic acid; • Φ Φ · φ • • • • • • 238 3- (3-Biphenyl-4-yl-pyrrol-1-yl) -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic acid; 3-carboxylic acid, N-hydroxamide; 3- [2,2-Dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -2-hydroxy-5-methylhexanoic acid hydrochloride; N ^4- (2,2-dimethyl-1-methylcarbamoyl-propyl) -2, N ^X dihydroxy-3-isobutyl-succinamide; 6-Biphenyl-4-yl-3- (R) - (2-oxo-1-azepan-3- (S) ylcarbamoyl) -hexanoic acid; N- (1-Benzyl-2-hydroxy-ethyl) -3- (4-biphenyl-4-yl-pyrazol-1-yl) -succinamic acid; N- (8-oxo-4-oxa-1,7-diaza-tricyclo [9.6.1.0 12.17] octadeca-11 (18), 12 (17), 13,15-tetraen-9R-yl) -3S - (3-phenylpyrrol-1-yl) -succinamic acid; 237 4-acetyl-1- [4-phenoxy-benzenesulfonyl] -piperazine-2-carboxylic acid, N-hydroxamide; 3- (1-Benzyl-2-hydroxy-ethylcarbamoyl) -5-methyl-hexanoic acid; 235 4 · 99 ve * 9 99 4 • • · • 9 9 9 9 9 99 • • • • • • 9 • 9 • 9 • • 9 Ó · 9 9 9 « ···· 9 « A · 99 N ¹ - (1-benzyl-2-hydroxy-ethyl) - N ⁴ -hydroxy- ² -isobutyl-succinamide; 6-Biphenyl-4-yl-3 (R) -2 (S) -hydroxy- (1 (S) -hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexanhydroxamic acid, 3- (R) - (2-Hydroxy-1- (S) - (1H-imidazol-4-yl) ethylcarbamoyl) -6- (4- (2-methyl-thiazol-4-yl) phenyl) hexanhydroxamic acid ; 5-Biphenyl-4-yl-2- (1-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl) -pentanoic acid; 3- (R) - (2-Hydroxy-1- (S) - (1H-imidazol-4-yl) ethylcarbamoyl) -6- (4- (2-methyl-thiazol-4-yl) phenyl) hexanoic acid ; 3-Acetyl-6-biphenyl-4-yl-3-hexanoic acid; N- [5- (biphen-4-yl) -2- (1-carboxy-2-hydroxybut-1-yl) pentanoyl] -1-t-leucine, N -4- (methylthiophenyl) amide; 6-Biphenyl-4-yl-3- (2-hydroxy-cyclohexylcarbamoyl) -hexanoic acid; 3- (R) - (2-Benzyloxy-phenyl) -1- (S) -hydroxymethyl-ethylcarbamoyl) -6-biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) - (4-hydroxybenzyl) ethylcarbamoyl) hexanoic acid; 6-Biphenyl-4-yl-3- (1-hydroxyimino-ethyl) -hexanoic acid; N- [2- (3- (4-Biphenyl) propyl) -5,5-difluoro-4-oxopentanoyl] -L-1-leucine, N '-4- (methylthio) phenylamide; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) - (4-hydroxybenzyl) ethylcarbamoyl) hexanhydroxamic acid; 4- {2- [2-Carboxymethyl-5- (4'-sulfamoyl-biphenyl-4-yl) -pentanoylamino] -4-methyl-pentanoylamino} -benzoic acid methyl ester; 3-carboxy-propionylamido) -4-methyl-pentanoylamino] -benzoic acid; 3- (R) - (2- (R) -Benzyloxy-1- (S) -hydroxymethyl-propylcarbamoyl) -6-biphenyl-4-yl-hexanoic acid; 4- [4-Methyl-2- (2-nitromethyl-5-phenylpentanoylamino) -pentanoylamino] -benzoic acid methyl ester; 232 Φ φ · · · · • • • • • • • • φ φ φ φ φ φ φ φ φ φ φ φ φ 6-Biphenyl-4-yl-3- [3-methyl-1- (4- (2-hydroxy-ethylsulfamoyl) -phenylcarbamoyl) -butylcarbamoyl] -hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2-phenylethylcarbamoyl) hexanoic acid; N 1 - (1-benzyl-2-hydroxyethyl) -2- (3-biphenyl-4-ylpropyl) -N 4 -hydroxysuccinamide; 6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2- (S) - (1H-imidazol-4-yl) -ethylcarbamoyl) -hexanoic acid; N-hydroxy-2- [2-oxo-3- (3-phenylpropyl) tetrahydrofuran-3-yl] acetamide; 4- [2- (2-Carboxymethyl-5- (2-hydroxybiphen-4-yl) valeroylamino) -4-methyl-valeroylamino] benzoic acid methyl ester; N 1 - (1-benzyloxy-1-hydroxymethyl-propyl) - N ⁴ -hydroxysuccinamide; trans-2- (4-phenoxy-benzylsulfanyl) -cyclohexanecarboxylic acid hydroxamide; 3-enylcarbamoyl) hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (1-hydroxymethyl-2- (S) - (1H-imidazol-4-yl) -ethylcarbamoyl) -hexanoic acid; 3 - [(cyclohexyl- (4- (2-hydroxy-ethylsulfamoyl) -phenylcarbamoyl) -methyl) -carbamoyl] -6- (4-pyridin-4-yl-phenyl) hexanoic acid, trifluoroacetate; trans-2- (biphenyl-4-ylmethylsulfanyl) -cyclohexanecarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3- (1-hydroxymethyl-2,2-dimethyl-but- 3,3,3-trifluoropropyl) -phenyl-pentanoylamino) -4-methylpentanoylamino] -benzoic acid; 3- [2,2-Dimethyl-1- (pyridin-4-ylcarbamoyl) -propylcarbamoyl] -5-methylhexanoic acid; N 1 - [2,2-dimethyl-1- (pyridin-4-ylcarbamoyl) -propyl] N 4 -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-3 (R) - (1 (S) -hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexanoic acid; 4- {2- [5-Bifen-4-yl-2- (1-carboxyethylamino) -pentanoylamino] -4-methyl-pentanoylamino} -benzoic acid methyl ester; 6-Biphenyl-4-yl-3 (R) - (1 (S) -hydroxymethyl-2,2-dimethyl-propylcarbamoyl) -hexanhydroxamic acid; 6-Biphenyl-4-yl-3- [2,2-dimethyl-1- (4-methylsulfinyl-phenylcarbamoyl) -propylcarbamoyl] -hexanoic acid; [3- (3-Naphthalen-2-yl-propyl) -2-oxo-tetrahydro-furan-3-yl] -acetic acid; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -hexane-hydroxamic acid; 4- [2- (2-Carboxymethyl-5-naphthalen-2-ylpentanoylamino) -4-methylpentanoylamino] -benzoic acid methyl ester; 3- (R) - (1- (R) -Benzyl-2-hydroxy-ethylcarbamoyl) -6-biphenyl-4-yl-hexane-hydroxamic acid; 230 ·········································· · ·· ··· N- [5- (Biphenyl-4-yl) -2- (N-hydroxy formamido) methylpentanoyl] -tert-leucine, N- (pyrid-4-yl) amide; 3- {2-allylsulfamyl-2-methyl-1- [2- (4-sulfamoyl-phenyl) -ethylcarbamoyl] -propylcarbamoyl} -6-biphenyl-4-yl-hexanoic acid; 4- [2- (5-Biphenyl-4-yl-2-carboxymethylpentanoylamino) -4,5-dihydroxy-pentanoylamino] -benzoic acid methyl ester; 4- (2- {5- [4 '- (2-Amino-ethoxy) -biphenyl-4-yl] -2-carboxymethyl-pentanoylamino} -4-methyl-pentanoylamino) -benzoic acid methyl ester; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1- (S) -phenyl-ethylcarbamoyl) -hexane-hydroxamic acid; 3- (R) - (1- (R) -Benzyl-2-hydroxy-ethylcarbamoyl) -6-biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -hexanoic acid; 4- [2- (2-Carboxymethyl-5- (4-pyridin-4-yl-phenyl) -pentanoylamino) -4-methyl-pentanoylamino] -benzoic acid methyl ester; 6-Biphenyl-4-yl-3- (R) - (2-hydroxy-2-methyl-1-phenylcarbamoyl-propylcarbamoyl) -hexanoic acid; 6-Biphenyl-4-yl- (2-hydroxy-2-methyl-1-phenylcarbamoylpropylcarbamoyl) hexanoic acid; {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; [3- (3-Naphthalen-2-yl-propyl) -2-oxo-pyrrolidin-3-yl] -acetic acid; [3- (3-Biphenyl-4-yl-propyl) -2-oxo-pyrrolidin-3-yl] -acetic acid; 3- [1- (5,6-dichloro-1H-benzoimidazol-2-yl) -3-methyl-butylcarbamoyl] -5-methylhexanoic acid; 6-Biphenyl-4-yl-3- [1- (5,6-dichloro-1H-benzimidazol-2-yl) -3-methyl-butylcarbamoyl] -5-methylhexanoic acid; 3- (2-hydroxymethyl-3H-imidazol-4-yl) -N-phenethylpropionamide; 6-phenyl-3-propionylhexanoic acid; 4- {2 - ([2-hydroxyamino-2-hydroxyiminoethyl] -5-phenylpentanoylamino] -4-methylpentanoylamino) 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-hydroxyimino-propyl) -6-phenylhexanoic acid, 3- (3H-Imidazol-4-yl) -N-phenethyl-propionamide; 4- [2- (2-Carboxymethyl-5- (formamido) valeroyl) amino) -4-methyl-valeroyl] aminobenzoic acid methyl ester; 3- (2-methylthiazol-4-yl) -N-phenethylpropionamide; N-phenyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-4-yl] -propionamide; 3- [2- (4-methoxy-benzylsulfanyl) -2-methyl-1-phenylcarbamoylpropylcarbamoyl] -5-methylhexanoic acid, N-hydroxyamide; 4- [2- (2-Hydroxaminocarbonylmethyl-4-methylpentanoylamino) -2-cyclohexyl-acetylamino] benzoic acid methyl ester; 2- (phenyl-2-ethyl) benzoic acid N-hydroxyamide; • · φ φ φ φφ φ · · 222 4- [2- (2-Acylhydrazinomethyl-4-methylpentanoylamino) -3- (1H-indole-3) methyl ester -yl) -propionylamino] benzoic acid; 3- [2- (4-methoxy-benzylsulfanyl) -2-methyl-1-phenylcarbamoyl-propylcarbamoyl] -5-methylhexanoic acid; 3,5-dimethyl-1H-pyrazole; and N-butyl-3 - [[(4-decyloxyphenyl) carbonyl] amino] -4- (methylthio) -benzamide; An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using an MMP inhibitor selected from 220 * · 4 4 »· 4« <1 * 4 • 9 9 ♦ · 9 9 ♦ · f · · 4 ·· · 99 9 · 9 999999994 9 9 9 9 9 9 9 99 • «4 · 4 · 9 <9 9 9 9 *. 4- [2- (2-Carboxymethyl-4-phenylbutylamino) -3-cyclohexyl-propionylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-phenylbutyrylamino) -3,3-methyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-phenylbutyrylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-methylvalerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-5-methyl-valerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-phenylbutylamino) -2-cyclohexylproionyl-amino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-methylvalerylamino) -4-methyl-valerylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-5-phenylvalerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Carboxymethyl-4-methylpentanoylamino) -3- (1H-indol-3-yl) propionylamino] benzoic acid methyl ester; 5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0,13,18] nonadeca-12 (19), 13,15,17 tetraen-10-ylcarbamoyl) -hexanoic acid; 222 h <· ·· * 9 · * * 9 9 4 9 9 9 9 9 9 99 99 99 99 99999 9,999,999,999 9,999,999,999,999 4- [2- (2-hydroxaminocarbonylmethyl-4-phenyl-butyrylamino) -3,3-methyl-butyrylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino) -2-cyclohexylpropionylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-4-methyl-valerylamino) -4-methyl-valerylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino) -3-cyclohexylpropionylamino] -benzoic acid methyl ester; 4- [2- (2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino) -3-cyclohexyl-propionylamino] -benzoic acid methyl ester; 4- [2- (2-Hydroxaminocarbonylmethyl-5-phenyl-valerylamino) -3,3-dimethyl-butyrylamino] -benzoic acid methyl ester; 5-Methyl-3- (9-oxo-1,8-diaza-tricyclo [10.6.1.0,13,18] nonadeca-12 (19), 13,15,17-tetraen-10-ylcarbamoyl) -1-hexyl-hydroxamic acid acid; 4- [2- (2-Hydroxaminocarbonylmethyl-4-methylpentanoylamino) -3- (1H-indol-3-yl) propionylamino] benzoic acid methyl ester; 3,6-dioxospiro [benzofuran-2 (3H), l-cyclohex-2 ', 4 ^Z diene] -2'-carboxaldehyde; (3a, 4a, 22a, 24a) -3-hydroxy-22 - [(1-oxooctadecyl) oxy] 24-norolean-12-ene-29-acid; 3- (4,5-diphenyl-1H-imidazol-2-ylsulfanylmethyl) -1-methylpiperidine; Hydroxy-phenylacetic acid 3,3,5-trimethyl-cyclohexyl ester; 3- (2,4,6-Trifluorophenyl) -urea; 5-chloro-3-o-tolyl-benzofuran-2-carboxylic acid, (2,6-diisopropyl-phenyl) amide; 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-octadecylsulfanylacetamide; 3- (dimethyl-nonyl-silanyl) -N- (1-phenyl-2-p-tolylethyl) -propionamide; (R) 2-Hexyldecanoic acid (6-methyl-2,4-bis (methylsulfanyl) -pyridin-3-yl) -amide; N- [2- (3,5-bis (tert-butyl) -4-hydroxyphenyl) ethyl] -4-fluorobenzenesulfonamide; 3- (2,4-Difluoro-phenyl) -1- [5- (4,5-diphenyl-1H-imidazole- 3- (2,4-Difluoro-phenyl) -1- [4- (2,2-dimethyl-propyl) -benzyl] -1-heptyl-urea; 3,5-dimethyl-1- [5- (1,4,5-triphenyl-2H-imidazol-2-ylsulfahyl) -pentyl] -4-pyrazole, sodium 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; 216 9 99 9 9999 99 99 99 999 5 - ((3,5-bis (tert-butyl) -4-hydroxy-phenylamino) - {[4- (2,2-dimethyl-propyl) benzyl] -hexylamino} -methylene) -2,2-dimethyl- [ 1,3] dioxane-4,6-dione; An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using a compound of the formula A is a bond, CONH or (Y-N N) wherein Y is CH or N; R ¹ is alkyl, aryl, halogen, amino, substituted or unsubstituted amino, or alkoxy; R ² is carboxyalkyl ketone or oxime, carboxyalkylsulfonamide, or -SO 2 -NHCHCOOH; and AND R ³ « R is alkyl, substituted alkyl, amino, substituted or unsubstituted amino, or aryl, and pharmaceutically acceptable salts thereof. • · 198 An ACAT inhibitor together with an MMP inhibitor for use according to claim 5 using a compound of the formula An ACAT inhibitor together with an MMP inhibitor for use according to claim 5 using a compound of the formula An ACAT inhibitor together with an MMP inhibitor for use according to claim 4 using a compound of the formula R ¹ is C 1 -C 6 alkyl, halogen, nitro, NR ⁴ R ⁵ , cyano, OR ⁴ and COOR ⁴ ; R ² is C 1 -C ₆ alkyl, optionally substituted by phenyl, substituted phenyl, NR ⁴ R ⁵ , OR ⁶ , carboxy, carboxamido, NH AND H ₂ NC-NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl and substituted phenyl; R ³ is OH, OC 1 -C 6 alkyl or NHOH; • · 199 R ⁴ is hydrogen, C 1 -C ₆ alkyl or C ₁ -C ₆ alkanoyl; R ⁵ is hydrogen or C 1 -C ₆ alkyl; and R ⁶ is hydrogen, C 1 -C 6 alkyl, C 1 -C ₆ alkanoyl, phenyl or substituted phenyl. An ACAT inhibitor together with an MMP inhibitor for use according to claim 5 using a compound of the formula The ACAT inhibitor together with the MMP inhibitor for use according to claim 6 using 2- (4'-bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid. The ACAT inhibitor together with the MMP inhibitor for use according to claim 2 using a compound of the formula wherein the substituents are hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, -OR ⁶ where R ⁶ is 200 99 99 9999 · «· fcfc ·· 9 999999 9 9 9 9 9 99 Hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or cycloalkyl, -NR ⁶ wherein R ⁶ and R ^6a are the same or different Even R63 substituents already defined for R ^6, O -OCR ⁶ , wherein R ⁶ is as defined above, O ¹ ₆ -NH-C-R, wherein R is as defined above, O ¹¹ ₆ -S-C-R, where R is as defined above, -SR ⁶ , wherein R ⁶ is as defined above, O -CR ⁶ wherein R ⁶ is as defined above, -CH ₂ -OR ⁶ , where R ⁶ is as defined above, -CH ₂ -NR ⁶ wherein R ⁶ and R ^6a are the same or different _R 6a is a substituent as defined for R ⁶ , O II -CNR ⁶ wherein R ⁶ and R ^6a are the same or different _R L substituents defined as R ⁶ , O -SR ⁶ , wherein R ⁶ is as defined above, II o cycloalkyl or ΦΦ φφ ·· ·· ·· • ♦ · Φ ΦΦΦΦ »φ Φ ΦΦ Φ ΦΦΦΦ ΦΦ 201 Φ Φ Φ φφφφ φφ φ ΦΦΦ ΦΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ heteroaryl, with the proviso that R ¹ and R ¹ are not both hydrogen atoms; R ² is -OR ⁶ , wherein R ⁶ is as defined above, or -NR ⁶ wherein R ⁶ and R ^6a are the same or different R ^6a substituents already defined for R ⁶ , R ³ , R ^3a , R ⁴ and R ^4a are the same or different substituents from hydrogen, fluoro, alkyl, ~ (CH ₂ ) _n -aryl, where n is from 1 to 6, "(CH ₂ ) n - heteroaryl, wherein n is from the above defined range, ~ (CH ₂ ) _n " cycloalkyl, wherein n is from the above defined range, - (CH ₂ ) p X - (CH ₂ ) q -aryl, wherein X is O, S, SO, SO ₂ or NH and p, q are 0 or a value from 1 to 6, wherein p + q is not greater than 6, - (CH ₂ ) p X - (CH ₂ ) q -heteroaryl, wherein X, p and q are as defined above or -CH ₂ ) _n -R ⁷ wherein R ⁷ is N-phthalimido, N-2,3-naphthylimido, -OR ⁶ , wherein R ⁶ is as defined above, -NR ⁶ wherein R ⁶ and R ^6a are the same or different R ^6a substituents already defined as R ⁶ , -SR ⁶ , wherein R ⁶ is as defined above, O ¹¹ ₆ -S-R, where R is as defined above, 202 ♦ · 9 9 ·· 99 ·· 9 * ♦ · 9 9 99 9 · 99 99 ·· 9 99 ·· «9« * * 9 99 99 999 9 9 • · 9 9 9 · 9 99 9 ··· · · · · Φ 99 « ₆ ι ₆ -S-R, where R is as defined above, II o O II ₆ -O-C-R, where R is as defined above, O II _{6 6 6} -N-C-R, where R and R are the same or different R ^6a substituents defined as R ⁶ , O I ₆ -S-C-R, where R is as defined above, O II ₆ -C-R, where R is as defined above, O “ ₆ -C-OR, wherein R ^b is as defined above, or O II _{e 6 6} -C-N-R where R and R are the same or different _R 6a substituents already defined as R 5 ^, and n are as defined above; R ⁵ is OH or SH, provided that R ³ , R ^3a , R ⁴ and R ^4a are hydrogen or at least one of R ³ , R ^3a , R ⁴ and R ^4a is fluorine, as well as the corresponding isomers of said compounds, or a pharmaceutically acceptable salt thereof. 203 An ACAT inhibitor together with an MMP inhibitor for use according to claim 8 using a compound of the formula C-CH ₂ CH ₂ CO An ACAT inhibitor together with an MMP inhibitor for use according to claim 9 using 4- (4'-chlorobiphenyl-4-yl) -4-hydroxyiminobutyric acid. An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using a compound of the formula wherein X is oxygen or -C-CH2NOH AND R ² is -C-CH ² CH-COOH or -SO ₂ NHCHCOOH; and R ³ R ³ R ³ is alkyl, halogen, alkoxy, acyl or aryl. An ACAT inhibitor together with an MMP inhibitor for use according to claim 11 using a compound of the formula 204 An ACAT inhibitor together with an MMP inhibitor for use according to claim 12 using (S) -2- (9H-fluorene-2-sulfonylamino) -4-phenylbutyric acid. The ACAT inhibitor together with claim 12 utilizing An MMP inhibitor for use of a compound of the formula 16. ACAT inhibitor together with An MMP inhibitor for use according to claim 1 using a compound of formula I O II S — N— (I) where: R ¹ is C 1 -C ₆ alkyl, halogen, nitro, (CH ₂ ) 0-4 NR ⁴ R ⁵ , cyano, 0 II i OR ^4, CH, CF _3, CNR ⁵ R ^4, and COOR ^4; R ² is hydrogen or C 1 -C 6 alkyl, optionally substituted with the following groups: phenyl, substituted phenyl, phenoxy, substituted phenoxy, NR ⁴ R ⁵ 'OR ⁶ , carboxy, carboxamido, O H 2 N-C-NH-, thio, methylthio, indole, imidazole and phthalimido; R ³ is OH, O, C 1 -C ₆ alkyl or C 1 -C ₆ alkanoyl; 205 • * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 999 999 99 99 R ⁴ is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 alkanoyl; R ⁵ is hydrogen or C 1 to C 8 alkyl; and R ⁶ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkanoyl, phenyl or substituted phenyl, and pharmaceutically usable salts and solvates thereof. An ACAT inhibitor together with an MMP inhibitor for use according to claim 1 using a compound selected from (S) -2- (4'-bromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (4'-Chloro-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -3-Methyl-2- (4'-nitro-biphenyl-4-sulfonylamino) -3-methyl-butyric acid; (S) -2- (4'-Cyano-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (3 ', 4'-dibromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid, sodium salt; (S) -2- (3'-Bromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (4'-Bromo-2'-fluoro-biphenyl-4sulfonylamino) -3-methyl-butyric acid; (R) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -propionic acid; (S) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -4-methylpentanoic acid; (S) -2- (4'-Methoxy-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (4'-Fluoro-biphenyl-4-sulfonylamino) -3-methylbutyric acid; (S) -2- (3'-Fluoro-biphenyl-4-sulfonylamino) -3-methylbutyric acid; 206 (S) -3-methyl-2- (4'-trifluoromethyl-biphenyl-4-sulfonylamino) -butyric acid; 4- [4- (1-Hydroxy-pyridin-4-yloxy) -benzenesulfonyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid amide;