MXPA00005034A - Statin-matrix metalloproteinase inhibitor combinations - Google Patents

Abstract

The invention is a pharmaceutical composition comprising an MMP inhibitor and a statin, said composition being useful for treating vascular diseases.

Description

COMBINATIONS OF STATIN - INHIBITORS OF THE METALOPROTEINASE MATRIX FIELD OF THE INVENTION This invention concerns a combination of a statin compound, known to cause a reduction in the plasma levels of low density lipoprotein (LDL) cholesterol, and of an MMP inhibitor, which reduces the breakdown of connective tissues. . The combination is useful for the treatment of vascular disorders and the prevention of cardiac insufficiencies.

BACKGROUND OF THE INVENTION Various clinical studies have established that the decrease of certain forms of cholesterol in a mammal is an effective way to treat and prevent heart attacks, sudden death and angina, in subjects who have circulating cholesterol levels higher than normal, as well as those who have normal cholesterol levels. The decrease of LDL, the harmful form of cholesterol, is now one of the main objectives of physicians who treat patients who have, or who have a high risk to develop cardiovascular diseases such as coronary heart disease, atherosclerosis, myocardial infarction , attack, cerebral infarction and even restenosis followed by balloon angioplasty. Many doctors are now using agents that lower cholesterol purely as a prophylactic treatment in healthy subjects whose cholesterol levels are normal, thus protecting them against the development of cardiovascular diseases. The agents most commonly used in cholesterol reduction are statins, which are compounds that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme responsible for catalyzing the conversion of HMG- CoA to mevalonate, which is an initial stage limiting the speed in the biosynthetic path of cholesterol. Compounds that inhibit the enzymes that mediate the breakdown of connective tissues are useful in the treatment of heart failure and associated ventricular dilation. Such enzymes are known as native matrix metalloproteinases (MMPs), which are naturally occurring classes of enzymes found in most mammals. They are zinc proteases that hydrolyze collagens, proteoglycans, and glycoproteins. Classes include gelatinase A and B, stromelysin-1 and -2, fibroblast collagenase, neutrophil collagenase, matrilysin, metalloelastase, and interstitial collagenase. These enzymes are involved in a number of diseases resulting from the breakdown of connective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, and even tumor metastasis. It has now been discovered that the treatment and prevention of vascular diseases can be affected by the administration of a combination of a statin with an MMP inhibitor.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for treating and preventing heart failure and other vascular diseases in a mammal comprising administering an effective amount of a matrix metalloproteinase inhibitor together with a statin. The invention also provides a method for the treatment and prevention of ventricular dilation comprising the administration of an effective amount of a matrix metalloproteinase inhibitor together with a statin. The methods can be practiced by the administration of any statin in combination with an MMP inhibitor, for example any chemical compound that is effective in inhibiting the biological activity of a metalloproteinase matrix such as collagenase, stromelysin, gelatinase or Elastase Numerous compounds are known to be inhibitors of the metalloproteinase matrix, and any such compound can be used in the method of this invention. In a preferred embodiment, the metalloproteinase matrix inhibitor to be used is a substituted bicyclic compound of the formula where: / \ A is phenyl or Y N where Y is CH or N: \ / R1 is a substituent such as alkyl, aryl, halo, amino, substituted and disubstituted amino, and alkoxy; R 2 is carboxyalkyl ketone or oxime, or a carboxyalkylsulfonamide such as. -S02NHCHCOOH where R3 is alkyl, substituted alkyl, amino, substituted and disubstituted amino, and aryl. Preferred alkyl and alkoxy groups are C 1 -C 10 alkyl and alkoxy C1-C10, which may be straight or branched chain, and optionally substituted by halo, amino, nitrogen, carboxy, hydroxy, aryl, and heteroaryl. A particularly preferred embodiment is a method for treating and preventing heart failure and ventricular dilatation by administering a statin together with a biphenylsulfonamide (compounds of the above formula when A is phenyl) such as which is also known as CI-1026 and PD 166793. In another embodiment, CHF and ventricular dilatation is treated or prevented by administering a statin together with a metalloproteinase matrix which is a substituted fused tricyclic compound of the formula. where R1 and R2 are as defined above, T is O, CH2, SQ (O) 0, 1O2, C = O, NR3, or -NR3C-, and W, W1, Z and Z1 are each the same or different and Or each is CR3, where R3 is alkyl, halogen, alkoxy, acyl, and aryl. A preferred method uses dibenzofurans and fluorenos of the above formula, for example compounds such as where R is, for example, OH I -C-CH2-CH-COOH, or -SO2NH-CH-COOH. I I R3 R * Especially preferred MMP inhibitors to be used are (S) -2- (dibenzofuran-3-sulfonylamino) -3-methyl-butyl acid and (S) -2- (dibenzofuran-3-sulfonylamino) -succinic acid. All inhibitors of the metalloproteinase matrix for use in the method of this invention are known or readily obtainable from common synthetic processes. Typical statins to be used in combination with the MMP inhibitor include atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, lovastatin, dalvastatin, and fluindostatin. The statins can be used as pharmaceutically acceptable salts. A particularly preferred composition of this invention uses an MMP inhibitor of biphenylsulfonamide together with a statin chosen from calcium atorvastatin, pravastatin sodium, simbastatin, lovastatin, and cerivastatin. The most preferred composition employs calcium atorvastatin together with the inhibitor 2- (4'-bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid inhibitor. Methods for treating vascular diseases such as peripheral vascular disease, coronary heart disease, stroke and restenosis are also provided by the invention.

DETAILED DESCRIPTION OF THE INVENTION It has been discovered that the combination of a statin with an MMP inhibitor provides a surprisingly effective composition for the treatment and prevention of vascular diseases. As noted above, MMP inhibitors and statins are known in the art and are readily available. The compounds can be the free acid, a salt form, or the tetrazolyl or aldehyde analog. The term "statin" when used in the specification and the appended claims is synonymous with the terms "inhibitor of 3-hydroxy-3-methyl-giltaryl-coenzyme A reductase" and "inhibitor of HMG-CoA reductase". These three terms are used interchangeably through the specification and the appended claims. As the synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and as such, are effective in lowering the level of cholesterol in the blood plasma. Statins and pharmaceutically acceptable salts thereof are particularly useful in lowering the low density lipoprotein (LDL-C) cholesterol levels in mammals and particularly in humans. The HMG-CoA reductase inhibitors available for use herein include, but are not limited to, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin.; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, or the pharmaceutically acceptable salts thereof. However, it should be noted that calcium atorvastatin is a particularly preferred statin for use in the present combinations. See U.S. Patent 5,273,995 incorporated herein by reference. The statins described herein are prepared by methods well known to those skilled in the art. Specifically, simvastatin can be prepared according to the method described in U.S. Patent 4,444,784, which is incorporated herein by reference. Pravastatin can be prepared according to the method described in U.S. Patent 4,346,227, which is incorporated herein by reference. The cerivastatin can be prepared according to the method described in US Pat. No. 5,502,199, which is incorporated herein by reference. The cerivastatin can be prepared alternatively according to the method described in European Patent Application Publication No. EP917019. Mevastatin can be prepared according to the method described in US Patent No. 3,983,140, which is incorporated herein by reference. Velostatin can be prepared according to the methods described in U.S. Patent No. 4,448,784 and U.S. Patent No. 4,450,171, both of which are incorporated herein by reference. Fluvastatin can be prepared according to the method described in U.S. Patent 4,739,073, which is incorporated herein by reference. Compactin can be prepared according to the method described in US Pat. No. 4,804,770, which is incorporated herein by reference. Lovastatin can be prepared according to the method described in U.S. Patent No. 4,231,938, which is incorporated herein by reference. Dalvastatin can be prepared according to the method described in European Patent Application Publication No. 738510 A2. Fluindostatin can be prepared according to the method described in European Patent Application Publication No. 363934 A1. Dihydrocompactin can be prepared according to the method described in U.S. Patent No. 4,450,171, which is incorporated herein by reference.

It will be recognized that some of the above statins contain a free carboxylic acid group or a free amino group as part of the chemical structure. In addition, some statins within the scope of this invention contain lactone molecules, which exist in equilibrium with the free carboxylic acid form. These lactones can be maintained as carboxylates by preparing pharmaceutically acceptable salts of the lactone. Thus, this invention includes pharmaceutically acceptable salts of the carboxylic or amino acid groups. The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The term "pharmaceutically acceptable cationic salts" is intended to define but is not limited to salts such as the alkali metal salts, (eg sodium and potassium), alkaline earth metal salts (eg, calcium and magnesium), aluminum salts, salts of ammonium, and salts with organic amines such as benzathine (N, N'-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglunine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino- 2-hydroxymethyl-1,3-propanediol) and procaine. The term "pharmaceutically acceptable addition salts" is intended to define but is not limited to salts such as the hydrochloride salt, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate). The pharmaceutically acceptable cationic salts of the statins contain free carboxylic acids which can be easily prepared by reacting the free acid form of the statin with an appropriate base, usually an equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine, and tromethamine. The salt is isolated by concentrating it to dryness or by the addition of a non-solvent. In many cases, the salts are preferably prepared by mixing a solution of the acid with a solution of a salt other than the cation (sodium or potassium ethylhexanoate, magnesium oleate), using a solvent (for example ethylacetate) from which the desired cationic salts precipitate. , or it can be isolated in another way by the concentration and / or addition of a non-solvent. The pharmaceutically acceptable acid addition salts or statins contain free amino groups which can be easily prepared by reacting the free base form of the statin with the appropriate acid. When the salt is of a monobasic acid (for example the hydrochloride, hydrobromide, p-toluenesulfonate, acetate), the hydrogenated form of a dibasic acid (for example, hydrogen sulfate, succinate), or the dihydrogenated form of a tribasic acid (eg, dihydrogen phosphate, citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However, when such salts as sulfate, N-succinate, hydrogen phosphate or phosphate are desired, the appropriate and exact chemical equivalents of the acid are generally used. The free base and the acid are generally combined in a co-solvent which precipitates the desired salt, or can otherwise be aided by concentration and / or addition of a non-solvent. In addition, the MMP inhibitors and the pharmaceutically acceptable acid addition salts thereof may be presented as hydrates or solvates. In addition, the statins of the current invention and the pharmaceutically acceptable salts of the statins of the present invention can be presented as hydrates or solvates. Hydrates and solvates are also within the scope of the invention. A "matrix metalloproteinase inhibitor" as used herein is any chemical compound that inhibits at least 5% of the hydrolytic activity of at least one enzyme of the metalloproteinase matrix that is naturally present in a mammal. Such compounds are also referred to as "MMP inhibitors". Numerous matrix metalloproteinase inhibitors are known, and all are useful in the method of this invention. For example, 4-biarylbutyric acid and 5-biarylpentanoic acid derivatives are described in WO 96/15096, which is incorporated herein by reference. The compounds are generally defined as (T) XA-B-D-E-G. More than 400 specific compounds are mentioned and each is incorporated herein and may be employed in this invention. Especially preferred compounds to be used include the following: [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- (2-methylpropyl) -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- (2-methylpropi!) -? - oxo-, (S) - [1,1'-biphenyl-4-butanoic acid, 4'-chloro-α- (2-methylpropyl) -α-oxo-, [1,1-biphenyl] -4-butanoic acid, 4'-cyoro-β- (2-methylpropyl) -α-oxo -, (S); [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-β- (2-methyl-propyl-α-oxo-, (R) -; V-biphenyl] -4-butanoic acid, 4'- cORO -? - oxo-; 1'-bifeni l] -4-butanoic acid, 4'-bromo-? -oxo-; 1'-bifeni-l] -4-butanoic acid, 4'-flour-o-oxo-; 1'-bifeni l] -4-butanoic acid, 2'-floúr -? - oxo-; 1'-bifeni l] -4-butanoic acid, 2'-chloro-? - oxo-, 1'-bifeni acid l] -4-butanoic acid, 2 ', 4'-difluoro-β-oxo-; 1'-biphenyl-1-butanoic acid, 3'-chloro-β-oxo-; - butane ico, a- (2-methylpropyl) -? - oxo; [1, 1'-biphenyl] -4-butanoic acid, 4'-bromo-a- (2-methylpropyl) -? - oxo- Acid [1] , 1 '-biphenyl] -4-butanoic, 4'-flour-a- (2-methylpropyl) -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid 4'-ethyl-a- ( 2-methylpropyl) -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid, 2'-flour-a- (2-methylpropyl) -? - oxo-; [1, 1'-biphenyl] ] -4-butanoic acid, 2'-chloro-a- (2-methylpropyl) -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-methoxy-a- (2-methylpropyl) -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid, 2 ', 4'-difiuoro-a- (2-methylpropyl) -? -oxo-; [1, 1 '-biphenyl] -4-butanoic acid, 4'-methyl-a- (2-methylpropyl) -α-oxo- acid; [1,1-biphenyl] -4-butanoic acid, 4'-methyl-a- (2-methyl-propyl) -α-oxo- acid; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a-methylene-α-oxo- acid; [1, 1'-biphenyl] -4-butanoic acid, 2'-chloro-a-methylene-α-oxo acid; [1, 1'-bi phenyl] -4 -butanoic acid, 4'-chloro-a-methyl-1-oxo-acid [1,1'-biphenyl] -4-butanoic acid, 4'-chloro-? -oxo-a-pentyl-; Benzenebutanoic acid 4-chloro-a- (2-methylpropyl) -α-oxo-benzoic acid nobutanoic acid, 4-methyl-a-methylene-α-oxo 2-Butenoic acid 4- (4-chloro [1,1 '- bifeniI-4-yl) -4-oxo- (E) - 2-Butenoic acid 4- [4- (4-chlorophenoxy) -phenyl] -4-oxo, (E) - [1, 1'-biphenyl] acid -4-butanoic, 4'-hydroxy-a- (2-methylpropyl) -α-oxo-; [1, 1'-biphenyl]] -4-butanoic acid, 4-chloro-β-methylene-α-oxo- acid; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-β-hydroxy-a- (2-methylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro -? - hydroxy- (2-methylpropyl) 2 (3H) -Furanone, 5- (4-chloro [1,1'-biphenyl] -4-yl) dihydro-3- (2-methylpropyl) -; 2 (3H) -Furanone, 5- (4'-chloro [1,1, -biphenyl] -4-yl) dihydro-3- (2-methylpropyl) -; [1,1-biphenyl] -4-butanoic acid, 3 ', 4'-dichloro-β-oxo-α- (3-phenylpropyl) -; [1,1-biphenyl] 4-butanoic acid, 3 ', 5'-dichloro-β-oxo- (3-phenylpropyl) -; [1,1-biphenyl] -4-butanoic acid, 4 '- (acetyloxy) -? - oxo-a- (3-phenylpropyl) -; Benzene-pentanoic acid, a - [- 2-4- (5-chloro-2-thienyl) phenyl] -2-oxoethyl] -; Furancarboxylic acid, 5- [4- (3-carboxy-1 -oxo-6-phenylexyl) phenyl] -; Benzene-pentanoic acid, α- [2-oxo-2- [4- (3-pyridinyl) phenyl] ethyl-; Benzene-pentanoic acid, α- [2-oxo-2- [4- [6- (pentyloxy) -3-pyridinyl] phenyl] ethyl] -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-4 '- (pentylthio) -a- (3-phenylpropyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-methoxy-? - oxo-a- (3-phenylpropyl) -; [1,1-biphenyl] -4-butanoic acid, 3'-chloro-4'-fIuoro-β-oxo-a- (3-phenylpropyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-ethoxy-α-oxo-a- (3-phenyl-yl-propyl) -; Benzene-pentanoic acid, α-12-oxo-2- [4- (3-thienyl) phenyl] ethyl] -; [1, 1 '-biphenyl] -4-butanoic acid, 2', 4'-dichloro-β-oxo-α- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-fonnyl-α-oxo-a- (3-phenylpropyl) -; [1,1-biphenyl] -4-butanoic acid,? -oxo-a- (3-f eni I propyl) -3 ', 5'-bis (trifluoromethyl) -; Benzene-pentanoic acid, α- [2-oxo-2- [4- (2-thienyl) phenyl] ethyl] -; [1, 1'-biphenyl] 4-butanoic acid,? -oxo-a- (3-phenylpropyl) -3 '- (trifluoromethyl) -; [1,1-biphenyl] -4-butanoic acid, 2'-formyl-β-oxo-a- (3-phenylpropyl) -; [1,1-biphenyl] -4-butanoic acid, 4-hydroxy-β-oxo-a- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-a- (3-phenylpropyl) -4'-propoxy- acid; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-4 '- (pentyloxy) -a- (3-phenpropi-1) -; - [1,1-biphenyl] -4-butanoic acid ,? -oxo-4 '- (pentyloxy) -a- (3-phenylpropyl) -, (S) -; - [1,1-biphenyl] -4-butanoic acid,? -oxo-4' - (pentyloxy) ) -a- (3-phenylpropyl) -, (R) -; [1,1-biphenyl] -4-butanoic acid, 4 '- (hexyloxy) -? - oxo-a- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-butoxy-α-oxo-α- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-4 '- (3-phenylpropoxy) -a- (3-phenylpropyl) -; Acid [1,1'-biphenyl nyl] -4-butanoic, 4 '- (1-methylethoxy) -? - oxo-a- (3-phenylpropyl) -; - Acid [1,1'-biphenyl] .4- butanoic, 4 '- (heptyloxy) -? - oxo-a- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (cyclohexyl-methoxy) -? - oxo-a- (3-phenylpropyl) -; - [1,1-biphenyl] -4-butanoic acid, 4 '- (2-methyl-propoxy) -α-oxo-α- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-a- (3-phenylpropyl) -4 '- (2-propenyloxy) -; Acid [1,1'-biphenyl] -4-butanoic, 4'-chloro-a-heptyl-α-oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a-decyl-α-oxo- acid; [1, 1'-bifeni] -4-b uta noic acid, 4'-nitro-β-oxo-a- (2-phenylethyl) -; [1,1'-biphenyl nyl] -4-buta-noic acid, 4'-cyano-β-oxo-a- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (2-iodophenyl) ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (3-iodophenyl) ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (4-iodophenyl) ethyl] -α-oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (3,5-dimethoxyphenyl) ethyl] -α-oxo-; [1, 1'-Biophenyl] -4-butanoic acid, 4'-chloro-a- [2- (3-iodophenyl) ethyl] -α-oxo-; [1,1-biphenyl] -4-butanoic acid, 4-chloro-a- [2- (4-iodophenyl) ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (3,5-dimethoxyphenyl) ethyl] -? - oxo -; - [1,1'-biphenyl] - acid 4-butanoic, 4'-chloro-α-oxo-α-phenyl-; [1,1'-biphenyl] -4-butanoic acid, 4'-chloro-β-oxo-a- (phenylmethyl) -; [1, 1'-bif eni l] -4-buta-noic acid, 4'-chloro-β-oxo-a- (2-phenylmethyl) -; [1,1'-bi-phenyl] -4-butanoic acid, 4'-chloro-β-oxo-a- [(trimethylsilyl) methyl] -; [1,1-biphenyl] -4-butanoic acid 4'-bromo-β-oxo-a- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid, -? - oxo-a- (3-phenylpropyl) -; [1,1'-Biphenyl] -4-butanoic acid, 4'-amino-α-oxo-α- (2-phenylethyl) -; 4'-amino-α-oxo-α- (2-phenylethyl) -; [1,1'-Biphenyl] -4-butanoic acid? -oxo-a- (2-phenylethyl) -4 '- [[(phenylmethoxy) carbonyl) amino] -; Acid [1,1'-bipheni] -4-butanoic, 4 '- [[(1,1-dimethylethoxy) carbonyl] amino] -α-oxo-α- (2-phenylethyl) -; Acid [1,1'-bife n i I] 3 -4 -butanoic, 4 '- (acetylamino) -? - oxo-a- (2-phenylethyl) -; [1, 1'-b] phenyl] -4-butanoic acid,? -oxo-4 '- [(1-oxopentyl) amino] -a- (2-phenylethyl) -; [1, 1'-bif eni l] -4-buta-noic acid, 4'- [(3, 3-di-methyl-1-oxo-butyl) amino] -α-oxo-α- (2-phenylethyl) -; [1,1'-Biphenyl] -butanoic acid, 4'-chloro- [2-2- (methoxycarbonyl) phenyl] -ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, a- [2-2-carboxyphenyl) ethyl] - 4'-chloro -? - oxo-; [1, 1'-bifeni I] -4-b uta noic acid, 4'-chloro-a- [2- [2- [(diethylamino) carbony]] phenyl] etl] -? - oxo-; [1,1'-Biphenyl] -4-butanoic acid, 4'-chloro-a- [2- [3 - [(diethylamino) carbonyl] phenyl] ethyl] -? - oxo-, (S) -; Acid [1,1 '-bifenyl-butanoic, 4'-chloro-a- [2- [3- (diethylamino-carbonyl] phenyl] ethyl] -? - oxo-, (R) -; Cyclopentanecarboxylic acid, 2- [ (4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenylmethoxy) methyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2 - [(4'- chloro [1,1'-biphenyl] -4-iI) carbonyl] -5- (phenoxymethyl) -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2 - [(benzoyloxy) -methyl] -5 - [( 4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (1a, 2ß, 5ß) -; 1-2-benzenedicarboxylic acid, 1 - [[- 2-carboxy-3 - [( 4'-chloro [1,1'-biphenyl] -4-yl] carbonyl] cyclophenyl] -methyl] -2-methyl ester, (1a, 2β, 3a) -; cyclopentanecarboxylic acid, 2 - [(4 ') -chloro [1, 1 '-biphenyl] -4-yl] carbonyl] -5 - [(2-thienylthio) methyl], (1a, 2ß, 5ß) -; Cyclopentanecarboxylic acid, 2 - [(benzoylamino) methyI] -5 - [(4'-chloro [1,1'-biphenyl] -4-yl] carbonyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [[(2-methoxyethoxy) methoxy] methyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2 - [(4'-chloro [1, 1'-biphenyl] -4-yl) carbonyl] -5 - [[(phenylmethyl) thio] methyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2- [(4'-chloro [1,1] -bipheni] -4-yl) carbonyl] -5 - [(phenylthio) methyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2 - [(4 ' -chloro [1, 1 '-biphenyl] 4-yl) carbonyl] -5 - [(propylthio) methyl] -, (1a, 2ß, 5ß) -; cyclopentanecarboxylic acid, 2 - [(2-benzothiazolylthio) methyl] - 5- [4'-chloro [1,1] -biphenyl] -4-yl) carbonyl] -, (1a, 2β, 5β) -; Benzoic acid, 2 - [[[2-carboxy-3 - [(4'-chloro [1,1'-bifcnill-4-yl] -carbonyl] cyclopentyl] methyl] thio] -, 1-methyl ester, (1a , 2ß, 3a) -; Cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-bifeni I] -l) carbonyl] -5 - [[[(phenylmethoxy) carbonyl] -amino] methyl] -, (1a, 2β, 5β ) -; Benzoic acid, 2-methyl-, [2-carboxy-3 - [(4'-chloro [1, 1'-biphenyl] -4-yl) carbonyl] cyclopentyl-methyl ester, (1a, 2β, 3a) -; Benzoic acid, 3-methyl-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (1a, 2β, 3a) -; Benzoic acid, 4-methyl-, (2-carboxy-3 - [(4'-cyoro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (1a, 2β, 3a) -; Benzoic acid, 2-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (1a, 2β, 3a) -; Benzoic acid, 3-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (1a, 2ß, 3a) -; Benzoic acid, 4-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] 4-yl) carbonyl] cyclopentyl] methyl ester, (1a, 2β, 3a) -; Cyclopentanecarboxylic acid, 2 - [(2-benzoxazolylthio) methyl] -5 - [(4'-chloro [1,1'-biphenyl] 4-yl) carbonyl] -, (la, 2β, 5β) -; Cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-bifen i I] -4-yl) carbonyl] -5 - [(1,3-dihydro-4-nitro-1,3-dioxo-2H -isoindol-2-yl) -methyl] -, (la, 2β, 5β) -; Cyclopentanecarboxylic acid, 2-4- (4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [- 1,3-dihydro-5-nitro-1,3-dioxo-2H- isoindol-2-yl) methyl] -, (la, 2ß, 5ß-; 2H-benz [f] isol-2-butanoic acid, a- [2- (4'-ethoxy [1,1'-biphenyl] ] -4-yl) -2-oxoethyl] -1,3-dihydro-1,3-dioxo-; [1, 1'-biphenyl] -butanoic acid, a- (acetylamino) -4'-chloro-? -oxo-; 2 / - / - lsoindol-2-hexanoic acid, a- [2- (4'-chloro [1,1'-biphenyl] -4-yl) -2-oxoethyl] -1,3-dihydro -1,3-dioxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[[3- (methoxycarbonyl) phenyl] thio] methyl] -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[(2,6- (dimethyl-n-nyl) thio] methyl] -α-oxo-; acid [1, 1 '- biphenyl] -4-butanoic, 4'-cORO-a - [[[4-fluoro-2- (methoxycarbonyl) phenyl] thio] methyl] -? - oxo-; acid [1,1'-biphenyl] -4- butanoic, 4'-chloro-a - [[[3- [(diethylamino (carbonyl] phenyl] thio] methyl] -? - oxo-; [1, 1'-biphenyl] -4-butane-ico acid, 4'- cORO-a - [[[2- [(dimethylamino) carbonyl] phenyl] thio] methyl] -? - oxo-; [1,1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[ [3- (dimethylaminocarbonyl] phenyl] thio.] Methyl] -? - oxo-; bicyclo [2.2.1] hept-5-ene-2-carboxylic acid, 3 - [[4 '- (pentyloxy) [ 1,1'-biphenyl] 4-yl] carbonyl] -, (2-endo, 3-exo) -; 1-cyclopentene-1-carboxylic acid, 5 - [(4'-chloro [1,1'-bipheni] ] 4-yl) -carbonyl] -; cyclopentanecarboxylic acid, 2 - [(4'-chloro [1, 1'-bifeni I] -4-yl) carbonyl] -5 - [(phenylmethyl) thio] -, (the , 2ß, 5ß) -; Cyclopentanecarboxylic acid, 2- [4'-chloro [1,1] -biphenyl] -4-yl) carbonyl] -5 - [(phenylmethyl) thio] -, (la, 2ß, 5ß) -; 1-cyclopentene-1-carboxylic acid, 5 - [[4 '- (pentyloxy) [[1,1'-bifeni] l] -4-yl) -carbonyl] -; 1-Cyclopentene-1-carboxylic acid, 5 - [[4 '- (hexyloxy) [1,1'-biphenyl] -4-yl) lcarbonyl] -; [1,1-biphenyl] -4-butanoic acid, 4'-hydroxy-4-α-oxo-a - [(phenylthio) methyl] -; [1,1-biphenyl] -4-butanoic acid, a- [2- [2- [(butylamino) carbonyl] phenyl] ethyl] -4'-chloro-β-oxo; [1,1-biphenyl] -4-butanoic acid, a- [2- (3-carboxyphenyl) ethyl] -4'-chloro-β-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- [3- [(diethylamino) -carbonyl] phenyl] ethyl] -4-? -oxo-; [1, 1'-biphenyl] -4-butanoic acid, a- [2- [3- [(butylamino) carbonyl] phenyl] ethyl] -4'-chloro-4-α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a-4 [2- [4 - [(diethylamino) carbonyl] phenyl] ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, a- [2- [4- [(butylamino) carbonyl] phenyl] ethyl] -4'-chloro-β-oxo-; [1,1-biphenyl] -4-butanoic acid, a- [2- (4-carboxyphenyl) ethyl] -4'-chloro-β-oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-methoxy-α-oxo-a- (2-phenylethyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-hydroxy-α-oxo-α- (2-phenylethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-ethoxy-? - oxo-a- (2-phenylethyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-a - (- 2-phenylethyl) -4'-propoxy-; [1, 1'-biphenyl] -4-butanoic acid, y-oxo-4 '- (pentyloxy) -a- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4 '- (hexyloxy) -? - oxo-a- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-butoxy-α-oxo-α- (2-phenylethyl) -; [[1, 1'-biphenyl] -4-butanoic acid,? -oxo-a- (2-phenylethyl) -4'- (phenylmethoxy) -; [1,1-biphenyl] -4-butanoic acid, a- [2- (3-iodophenyl) ethyl] -α-oxo-4 '- (pentyloxy) -; [1,1-biphenyl] -4-butanoic acid, a- [2- (3-iodophenyl) ethyl] -α-oxo-4 '- (phenylmethoxy) -; [1, 1'-biphenyl] -4-butanoic acid, a- [2- (3- [(diethylamino) carbonyl] -phenyl] etl] -4 -? - oxo-4 '- (pente) lox) -; [1, 1'-biphenyl] -4-butanoic acid, a- [2- (3- [(diethylamino) carbonyl] -phenyl] ethyl] -4 -? - oxo-4, - (phenylmethoxy) ) - 1, 2-pyrrolidinedicarboxylic acid, 3 - [(4'-chloro [1,1'-bipheni] 4-yl) carbonyl] -, 1 - (phenylmethyl) ester, (2S-trans) -; , 2-pyrrolidinedicarboxylic acid, 3 - [(4'-chloro [1,1'-biphenyl] 4-yl) carbonyl] -, 1- (phenylmethyl) ester, (2'R-trans) -; L-Proline, 3 - [(4'-chloro [1,1] -bifeniI] -4-yl) carboniI] -1 - [[(phenylmethyl) -amino] carbonyl] -, trans-; L-Proline, 3 - [(4 ' -chloro [1, 1 '-biphenyl] -4-yl) carbonyl] -1 - (1 -3-phenylpropyl) -, trans-; L-Proline, 3 - [(4'-chloro [1, 1' - biphenyl] -4-yl) carbonyl] -1 - (phenylacetyl) -, trans-L-Proline, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -1- ( 3,3-dimethyl-1-oxobutyl) -, trans-; [1, 1'-biphenyl] -4-butanoic acid, chloro-a-heptyl-β-oxo-, acid [1,1 '-biphenyl] - 4-butanoic, chloro-a-decyl-α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-nitro-β-oxo-a- (2-phenyl) ethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-cyano-β-oxo-a- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (2-iodophenyl) ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (3-iodophenyl) ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (4-iodophenyl) ethyl] -α-oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- (3,5-dimethoxyphenyl) ethyl] -α-oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-β-oxo-α-phenyl- acid; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-β-oxo-a- (phenylmethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-β-oxo-a- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-β-oxo-a- [(trimethylsilyl) methyl] -; [1,1-biphenyl] -4-butanoic acid, 4'-bromo-β-oxo-α- (3-phenylpropyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-a- (3-phenylpropyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-amino-α-oxo-α- (2-phenylethyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-a- (2-phenylethyl) -4 '- [[(phenylmethoxy) carbonyl] amino] -; [1, 1'-Biphenyl] -4-butanoic acid, 4 '- [[(1,1-dimethylethoxy) carboniI] amino] -α-oxo-α- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4 '- (acetylamino) -? - oxo-a- (2-phenylethyl) -; [1, 1'-biphenyl] -4-butanoic acid,? -oxo-4 '- [(1 -oxopentyl) amino] -a- (2-phenylethyl) -; [1,1'-Biphenyl] -4-butanoic acid, 4 '- [(3,3-dimethyl-1-oxobutyl) amino] -α-oxo-α- (2-phenylethyl) -; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- [2-methoxycarbonyl) phenyl] ethyl] -α-oxo-; [1, 1'-biphenyl] -4-butanoic acid, a- [2- (2-carboxyphenyl) ethyl] -4'-chloro-? -oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-cioro-a- [2 - [- 2- [(diethylamino) carbonyl) phenyl] ethyl] -? - oxo-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- [3- [(diethylamino) carbonyl]} phenyl] ethyl] -? - oxo-, (S) -; and [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a- [2- [3 (diethylamino) carbonyl) phenyl] ethyl] -? - oxo-, (R) -. Fenbufen and compounds related to fenbufen can be used. Such compounds are described in U.S. Patent No. 3,784,701 and by Child, et al., L. Pharm. Sci .. 1997; 466-476, and Arzneim-Forsch, 1980; 30 (4A): 695-702, all of which are incorporated herein by reference. The preferred compounds of the fenbufen series for use in this invention have the formula OR S CCH2CH2COOH (fenbufen), COCH = CHCOOH, S02NH2, COCIbCHCOOlI, COC.I2CII-.COOH. COCÍ HCl bS03N;?, I CH3 CH (OH) CH2CH2COOH, COCH2CHCOOH, COCH2CH2CONHOH, i OH C (= NOH) CH2CH2COOH, and COCH2SCH2COOH.

Numerous peptide inhibitors of the metalloproteinase matrix are known. Typical of such peptides are those described in U.S. Patent Number 5,300,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289; and WO 96/11209, all of which are incorporated herein by reference. Such compounds are illustrated by the formula. wherein each of the variable groups can include hydrogen alkyl, aryl, heteroaryl, alkenyl, alkynyl, caboxy, and the like. Preferred compounds within this class that can be used in the method of this invention include the following: N- [2,3-bis-Acetylmercaptopropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-3-methoxycarbonylpropanoyl] -L-Ieucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-4-methoxycarbonylbutanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetyl mercapto-5-methyl toxic rbonylpentanyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-4-phthalimidobutanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2,3-bis-mercaptopropanoi I-L-leucyl-L-phenlalanine N-methylamide; N - [2- rcapto-3-m-ethoxy carbon i I pro-pacil] -L-leucyl-L-phenylalanine N-methylamide; N- [2-mercapto-4-methoxycarbonylbutanol] -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-phen i I-alan ina N-methylamide; N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N - [- 4-mercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-5-methoxycarbonylpentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-6-methoxycarbonylhexanioI] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-6-methoxycarbonylhexaniol] -L-vaiinyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-6-methoxycarbonylhexaniol] -L-leuciI-L-tryptophan N-methylamide; N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-vaIinyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L- [β- (4-thiazolyl)] alaine N-methylamide; N- [2-acetylmereapto-5-phthalimidopentanoyl] -L-leucyl-L- (β- (2-pyridyl) alanine N-methylamide; N- [2-acetylmereapto-5-phthalimidopentanoyl] -L-leucyl-5- acid methyl-L-glutamic N-methylamide; N- [2-acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-acetylmercapto-2- (3-phthalimido) phenylacetyl] - L-leucyl-L-phenylalanine N-methylamide; N- [2-mercapto-5-methoxycarbonylpentanoyl] -L-phenylalanine N-methylamide; N- [2-mercapto-6-methoxycarbonylhexaniol] -L-leucyl-L-phenylalanine N -methylamide; N- [2-mercapto-6-methoxycarbonylhexaniol] -L-leuciI-L-trptophan N-methylamide; N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenyl-alanine N-methylamide; N- [2-mercaplo-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [β- (4-thiazolyl) alanine N-methylamide; N- [2-mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [β-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-phenyl-alanine N-methylamide; N- [N-mercaptoacetyl] -L-leucyl] -L-phenylalanine N-methylamide; N- [acetomercaptoacyl] -L-leucyl-L-phenylalanine methylamide; (RS) -2- (acetylthio-pentanoyl-L-leuciI-L-phenylalanine N-methylamide; (RS) -2- (acetylthio) propanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS) -2- (acetylthio) -3-methylbutanoyl-L-leucyl-L-phenollanine N-methylamide; (RS) -2- (acetylthio) -2-phenylacetyl-L-leucyl-phenylalanine N-methylamide; ) -2- (acetylthio) -3-phenylimopnoyl-L-leucyl-4-phenyl-alanine N-methylamide; [RS) -2- (acetylthio) -4-phenylbutanoyl-L-leucyl-L-phen i lalanine N-methylamide; N- (acetyl mercaptoacid) -L-threonyl-L-phenylalanine methylamide; N- (acetyl mercapto acyl) -L-Ieucyl-L-tryptophan methylamide; (RS) -2-mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS) -2-mercaptopropanoyl-L-Ieucyl-L-phenylalanine N-methylamide; (RS) -2-mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS) -2-mercapto-2-phen i lacetil-L-leucyl-L-phen i lalanine N-methylamide; (RS) -2-mercapto-3-pheni I propanoyl-L-leucyl-L-phenollanine N-methylamide; (RS) -2-mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; N- [N- (mercaptoacetyl) -L-threonyl] -L-phen i lalanine methylamide; and N- [N- (mercaptoacetyl) -L-leucyl] -L-tryptophan methylamide. The additional metalloproteinase (MMP) matrix inhibitors, which can be used to prevent and treat heart attack and ventricular dilation, include the following: [4- (N-Hydroxyamino) -2 (R) - cyclohexylmethylsuccinyl] -L-β-cyclohexylalanine-N- (2-phenylethyl) amide; [4-N- (Hydroxyamino) -2R-isobutylsuccinyl] -L-β-cyclohexyl-alanine-N- (2-phenylethyl) amide; [4- (N-hydroxyamino) -2R-phenylpropyl-1-yl] -L-β-cyclohexylalanine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2R-phenolpropyl succinyl] -L-β-cyclohexylalanine-N- [2- (N, N-dimethylamino] ethyl) amide; [4- (N-Hydroxyamino) -2R-phenylpropylsuccinyl] -L-β-cyclohexylalanine-N- [2-p-sulfonamidophenyl) ethyl) a mide; [4- (N-Hydroxyamino) -2R-phenypropyl-succinyl] -L-β-cyclohexylalanine-N [2- (p-sulfonylphenyl) ethyl) amide; [4- (N-Hydroxyamino) -2R-phenylpropylsuccinyl] -L-β-cyclohexylalanine-N- [2- (2-pyridyl) ethyl] amide; [4- (N-Hydroxyamino) -2R-pentylsuccinyl] -L-β-cyclohexyl-alanine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2R-isoamylsuccinyl] -L-β-cyclohexyl-alanine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2R-phenylbutylsuccinyl] -L-β-cyclohexylalanine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2R-phenylpropylsuccinyl] -L-β-cyclohexylalanine-N- [3- (4-morfoinyl-propyl] amide; [4- (N-Hydroxyamino) -2R-phenylpropyl succinyl] - L-ß-cyclohexylalanine-N - [- 4-alanine] amide; [4 (N-Hydroxyamino) -2R-isobutylsuccinyl] -L-β-cyclohexyl-alanine amide; [4- (N-Hydroxyamino) -2R- (3-f eni I propyl) succinyl] -L-β-cyclohexylalanine amide; [4 (N-Hydroxyamino) -2R- (3-phenylbutyl) succinyl] -L-β-cyclohexylalanine amide; [4-N- (Hydroxyamino) -2R-phenylethylsuccinyl] -L-leucine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2R-phenylpropyl-succinyl] -L-leucine-N- (2-phenylethyl) amide; [4- (N-Hydroxyamino) -2 (R) -isobutylsuccinyl] -L-tryptophan amide; [4- (N-Hydroxyamino) -2 (R) -isobutylsuccinyl] -L-valine amide; [3-Fophone-2R, S-f in ilpropyl-1-oxo propyl] -L-4-β-cyclo or -hexylalanine-N- (2-phenylethyl) amide, dimethyl ester; [3-Phosphono-2R-pheni I propyl-1-oxo propyl] -L-β-cyclohexyl-alan-na- (2-phenylethyl) amide; [3-Phosphono-2S-phenylpropyl-1] -oxopropyl] -L-ß-cyclohexyl-alanine-ß-alanine; [3-Phosphono-2 R-pheni I propyl-1-oxopropyl] -L-ß-cyclohexyl-alanine; [3-Fosf ono-2S-f enyl propi I-1-oxopropyl] -L-β-cyclohexyl-alanine-β-alanine, methyl ester; [3-Phosphono-2R, S-phenylpropyl-1-oxopropyI] -L-β-cyclohexyl-alanine-N- [4 (3-aminopropyl) morpholine] amlda, bromine salt; [3-Phonophone-2R, S- (4-methylphenyl) propyl-1-oxopropyl] -L-cyclohexylala n ina-N- (2-f in ileyl) amide, diethyl ester; [3-Phonophone-2R, S- (4-methylphenyl) propyl-1-oxopropyl] -L-β-cyclohexylalanine-N- (2-phenylethyl) -amide; 4-t-Butoxy-2 (R) - [3- (2-phenoxyethyl) succinyl] -L-β-cyclohexyl-alanine-N- (2-phenylethyl) amide; 4-Hydroxy-2 (R) - [3- (2-phenoxyethyl) succinyl] -L-β-cyclohexyl-alanine-N- (2-phenylethyl) amide; 4- (N-Hydroxyamino-2 (R) - [3- (2-phenoxyethyl) succinyl] -L-β-cyclohexylalan ina-N- (2-f in ileyl) amide; .4-4-Hydroxy- 2 (R) - [3- (4-pyridinium) propyl] succinyl.}. -L-β-cyclohexylalanine-N- (2-phenylethyl) amide;. {4- (N-Hydroxyamino) -2 (R) - [- 3- (4-pyridinium) proyl] succinyl.] - L-β-cyclohexylalanine-N- (2-phenylethyl) amide; {4- (N-Hydroxyamino) -2 (R) - [3 - (N-methyl-4-pyridinium) propyl] -succinyl.} - L-β-cyclohexylalanine-N- (2-phenylethyl) amide; .4-Hydroxy-2- (R) - [3- ( 4-methylphenyl) propyl] succinyl.}. -L-β-cyclohexylalanine-N - [(2-morpholine-sulfonylamino) ethyl] amide;. {4- (N-Hydroxyamino) -2- (R) - [3 - (4-methylphenyl) propyl] -succinyl.} - L-β-cyclohexylalanine-N - [(2-morpholin-sulfonylamino) -ethyl] -amide; . { 4- (N-Hydroxyamino) -2- (R) - [3- (4-chlorophenyl) propyl] -succinyl} -L-ß-cyclohexylalanine-N - [(2-morpholinesulfonylamino) ethyl] -amide; . { 4-N-Hydroxyamino) -2- (R) - [3- (4-methylphenyl) propyl] -succinyl} -L-ß-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) penicillaminesulfone] -N-methylamide; . { 4- (N-Hydroxyamino) -2 (R) - [3- (4-chlorophenyl) propyl] -succinyl} -L- [S (methyI) penicillaminesulfoxida] -N-methylamide; . { 4- (N-Hydroxyamino) -2 (R) - [3- (4-chlorophenyl) propyl] -succinyl) -L-penicillamine-N-met-lamide; [4- (N-Hydroxyamino) -2 (R) -3- (2-methylpropyl) succinol] -L- [S-methyl) penicillamine] -N-methylamide; N 4 -hydroxy-N 1 - (1- (S) -carbamoyl-2,2-d-methylpropyl) -2- (R) -4- (chlorophenylpropyl) succinamide; N4-H-droxy-N1- (1 - (S) -carbamoyl-2, 2-d-methylpropi I) -2- (R) - (4-methylphenylpropyl) succinamide; N4-Hydroxy-N1- (1- (S) -carbamoyl-2,2-dimethylpropyl) -2- (R) - (4-methoxyphenylpropyl) succinamide; N4-H id roxy-N1- (1 - (S) -carbamoyl-2,2-di methyl propyl) -2- (R) - (4-trifluoromethylphenylpropyl) succinamide; N4-Hydroxy-N1- (1- (S) -carbamoyl-2,2-dimethylpropyl) -2- (R) - (4-chloromethylpheniylpropyl) succinamide; N- [N- (Mercaptoacetyl) -L-leucyl] -L-phen i lalanine 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-phen i lalanine N-methylamide; (RS) -2- (Acetylthio) -3-methylbutanoyl-L-leucyl-L-phen i lalanin N-methylamide; (RS) -2- (Acetylthio) -2-phen i-lacetyl-L-leucyl-L-phenollanine N-methylamide; (RS) -2- (Acetylthio) -3-phenylpropanoyl-L-leucyl-L-phenyl-alanine 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; (RS) -2-Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS) -2-Mercaptopropanoyl-L-leucyl-L-phen Halanyl N-methylamide; (RS) -2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS) -2-Mercapto-2-phen i lacetil-L-leucl-L-phenylalanine N-methylamide; (RS) -2-Mercapto-3-phenylpropanoyl-L-leucyl-L-phen Halan ina N-methylamide; (RS) -2-Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; N- [N- (Mercaptoaceti I) -L-threonyl] -L-phen i lalanine methylamide; N- [N- (MercaptoacetiI) -L-leucyl] -L-tryptophan methylamide; N- [2,3-bis-Acetylmercaptopropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-3-methoxycarbonylpropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-4-methoxycarbonylbutanoyl] -L-leucyl-L-4-phenylalanine N-methylamide; N- [2-Acetyl mercapto-5-me toxic rbonylpentanyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercaptomethyl-rbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-4-phthalimidobutanoiI] -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-O / s-Mercaptopropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-3-methoxycarbonylpropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-4-methoxycarbonylbutanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-5-methoxycarbonylpentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-4-phthalimidobutanoyl] -L-leucyl-L-phenyl-alanine N-4-methylamide; N-4-2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenyl-alanine N-methylamide; N- [2-Mercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-5-methoxycarbonylpentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N [2-Acetyl-mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-6-methoxycarbonylhexanoyl] -L-valinyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-vaIinyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L- [β- (4-thiazolyl)] alanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L- [β- (2-pyridyl) alanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-5-methyl-L-glutamic acid N-methylamide; N- [2-AcetHmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Acetylmercapto-2- (3-phthalimido) phenylacetyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2- React pto-5-methoxycarbonylpentanoyl] -L- leu-cy-L-phenylalanine N-methylamide; N- [2-Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenyl-alanine N-methylamide; N- [2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [2-Mcrcapto-5-phthalimidopentanoyl} -L-Ieucyl-LL- (ß- (4-thiazolyl) alanine N-methylamide; N- [2-Mercapto-5-phthalimidopentanoyl] -L-leuciI-L- [β- (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-phenyl- alanine N-methylamide; N-Hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] - (3-picolyl) -amino] -3methylbutanamide; N-Hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] -3- picoIil) -amino] -2-cycloexilacetamda; N-Hydroxy-2 (R) - [[4-methoxybenzensulfonyl] - (benzyl) -amino] -4-methylpentanamide; N -H id roxy-2 (R) - [[4-m-ethoxy-benzensulfon-1] - (benzyl) -amino] -6 - [(N, N-dimethylglycyl) amino] hexanamide hydrochloride; N-H idroxy-2 (R) - [[4-methoxy benzensulfon I] (3-picol i I) -amino] -3-methylbutanamide; N-Hydroxy-2 (R) - [[4-methoxybenzenesulfonyl] - (4-picolyl) -amino] -2-clohexylacetamide; NH id roxi-2 (R) - [(4-methoxy benzensulfon i I) - (4- peak I i I) -amino] -2- (2-tetrahydrofuranyl) acetamide; N-Hydroxy-2 (R) - [ [4-methoxybenzensulfonyl] - (3-picolyl) -amino] -3-methylbutanamide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N2- (S) -piperazoic acid N-methyl amide; Acid [4- (N-Hydroxyamino) -2R-isobutyl-3S-benzyl-succinyl] 3-N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S- acid] methoxyphenyl-succinyl] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methoxybenzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; Acid [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylthiophenol-succinyl] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylthiobenzyl acid; -succinyl] -N2- (S) -piperáz¡co N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S- (methylthio-2-thienyl) -succinyl] -N2- (S) acid -piperazic N-methyl amide; Acid [4- (N-H id roxia mino) -2R-isobutyl-3S-methylamide to] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylisopropane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl-tert-butane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylthio-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylthioisopropane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methyl- (2-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutH-3S-methyl- (3-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutii-3S-methyl- (4-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylthio-tert-butane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylsuccinyl] -N2- (S) -piperazoic acid N-methyl amide; Acid [4- (NH-dideoxyamino] -2R-hexyI-3S-benzylsuccinyl] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methoxyphenyl-succinyl acid; ] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methoxybenzyl succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylthiophenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methyltiobenzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S- (methylthio-2-thienyl) -succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-benzylsuccinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methyl acetate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylisopropa-noato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methyl-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylthioacetate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylthioisopropanoate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methylthio-tert-butane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexp-3S-methy1- (2-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methyl- (3-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-hexyl-3S-methyl- (4-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methylsuccinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methoxyphenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methoxybenzyl succinyl] -N2- (S) -piperazoic acid N-methyl amide; Acid [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methylthiophenyl-succinyl] -N2- (S) -piperazyl N-methyl amide; Acid [4- (N-Hydroxyamino) -2R-ethylpheni-3S-methylthiobenzyl-succinyl] -N2- (S-piperazic N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S- (methylthio -2-thienyl) -succinyl] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-benzyl-succinyl] -N2- (S) - acid piperazic N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methyl-azetato] -N2- (S) -piperazoic acid N-methyl amide; [4- (NH4droxyamino)] -2R-ethylphenol-3S-methylisopropanoate] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methyl-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylpheni-3S-methytthio-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methylthioisopropanoate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-ethylphenyl-3S-methylthio-tert-butane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylsuccinyl] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylthiophenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; Acid (4- (N-Hydroxyamino) -2R-octyl-3S-methylthiobenzyl succinyl] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylthio -2-thienyl) -succinyl] -N1- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methyl acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 (N-Hydroxyamino) -R-octyl-3S-methylisopropane-ato] -N2- (S) -piperazoic acid N-methyl amide; Acid [4- (N-H idroxy mino) -2R-octy I -3 S-methyl-te r-butanoate] -N2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylthioacetate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylthioisopropanoate] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methylthio-tert-butane-ato] -N2- (S) -piperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-octyl-3S-methy1- (2-pyridyl)] - N2- (S) -piperazoic acid N-methyl amide; Acid [4 (N-Hdroxyamino) -2R-octii-3S-methy1- (3-pyridyl) l-N2- (S) -piperazoic N-methyl amide; Acid [4- (N-H idroxyamino) -2R-octyl-3S-methyl-4-pyrid OJN2- (S) -piperazoic N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N2- (S) -4 '(S / R) -benzylpiperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N2- (S) -5 '(S / R) -benzylpiperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccininyl] -N2- (S) -6 '(S / R) -benzylpiperazoic acid N-methyl amide; [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -N2- (S) - [5 ', 6'] - benzopyperidic acid N-methyl amide; N- [1 (R) -carboxy-ethyl] -a- (S) -isobutylglycine- (S) -N2-piperazoic acid methyl amide; N- [1 (R) -carboxy-ethyl] -a- (S) -hexylglycine- (S) -N2-piperazoic acid methyl amide; N- [1 (R) -carboxy-ethyl] -a- (S) -heptyl-glycine- (S) -N2-piperazic acid amide; N- [1 (R) -carboxy-ethyl] -a- (S) -octylglycine- (S) -N2-piperazoic acid amide; N- [1 (R) -carboxy-ethyl] -a- (S) -ethylphenylglycine- (S) -N2-piperazoic acid methyl amide; N- [1 (R) -Calboxi-etl) -a- (S) -propylphenylcyanic acid (S) -N2-piperazoic acid methyl amide; N- [1 (R) -carboxy-ethylthiobenzyl] -a- (S) -isobutyl-glycine- (S) -N2-piperazoic acid amide; N- [1 (R) -carboxy-ethylthiobenzyl] -a- (S) -hexylglycine- (S) -N2-piperazoic acid amide; N- [1 (R) -carboxy-ethylthiobenzyl] -a- (S) -ethylphenyl-glycine- (S) -N2-piperazic acid amide; N- [1 (R) carboxy-ethylthiobenzyl] -a- (S) -propylphenyl-glycine- (S) -N2-piperazoic acid amide; N- [1 (R) carboxy-ethyloxybenzyl] -a- (S) -isobutylglycine- (S) -N2-piperazoic acid methyl amide; N- [1 (R) carboxy-ethyloxybenzyl] -a- (S) -hexylglycine- (S) -N2-piperazoic acid methyl amide; N- [1 (R) -carboxy-ethyloxybenzyl] -a- (S) -ethylphenyl-glycine- (S) -N2-piperazic acid! amide; N- [1 (R) -carboxy-ethyloxy-benzyl] -a- (S) -propylphenyl-glycine- (S) -N2-piperazic acid amide; N- [1 (R) -carboxy-4- (p-toluenesulfonyl) butyl] -a- (S) -phenethylglycyl- (S) N2-piperazoic acid amide; N- [1 (R) -carboxytyl] -a- [2- (4-phenylphenoxy) ethyl] -glycyl (S) -N2-piperazoic acid amide; 2- [2 (R) - [2- [1,1'-bipheni I) il] ethyl] -4-butyI-4 (S) -carboxy-1-oxobutyl] 3 (S) -methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2- [1,1'-biphenyl) il] etiI] -4-methyl-4 (S) -carboxy-1-oxobutyl] 3 (S) -methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2- [1,1'-biphenyl) il] propyl-4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methaminocarbonyl-hexahydropyridazine; 2- [2 (R) - [2- (4-Propylphenyl) ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methalaminocarbonyl-hexahydropyridazine; 2- [2 (R) - [2- (4-Butylphenyl) ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) methylaminocarbonyl-hexahydropyridazine; 2- [2 (R) - [2- (4-t-Butylphenyl) ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2- [4- (4-fluorophenyl] phenyl] ethyl] 4-butyl-4- (S) -carboxy-1-oxobutyl] -3 (S) -met -laminocarbonyl- hexahydropyridazine; 2- [2 (R) - [2- [4- (4-fluorophenyl) phenyl] ethyl] 4-methyl-4- (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl-hexahydropyr Ridazin; 2- [2 (R) - [2-n-Octyl-4-methyl-4- (S) -carboxy-1-oxobutyl] -3 (S) methylaminocarbonyl-hexahydropyridaz Na; 2- [2 (R) - [2 - [(4-tiazolyl) phenol] etii] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4-methyl-4 (S) -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-Oxazolyl) pheny] ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) - Methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2 - [(4-Oxazoip) phenyl] etiI] -4-methyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl-hexahydropyridazine; 2- [2 (R) [2 - [(4-Oxazolyl-phenp) ethyl] 4- [3- (phenylsuiphenyl) propyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl-hexahydropyridazine; 2- [2 (R) [2 - [(4-Oxazole i-phenyl] ethyl] 4- [3- (phenylpropyl) -4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl-hexahydropyridazine; 2- [2 (R) - [2- [4- (dimethylamino) methylphenyl] ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl -hexahydropyridazine; 2- [2 (R) - [2- [4- (dimethylamino) metpphenyl] etp] -4-metp-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) methyl] phenyl] ethyl] -4- [3-phenylpropyl) -4 (S) -carboxy- 1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2 - [(4-lmidazolyl) phenyl] ethyl] -4-butyl-4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonylhexahydropyridazine; 2- [2 (R) - [2 - [(lmidazolyl) phenyl] ethyl] -4-methyl-4 (S) -carboxy-1-oxobutp] -3 (S) -methylaminocarbonyl-hexahydropyridazine; 2- [2 (R) - [2 - [(4-lmidazolyl) phenp] ethyl] -4- [3- (phenylsulfonyl) -propyl-4 (S) -carboxy-1-oxobutyl] -3 (S) - Methylaminocarbonylhexahydro-pyridazine; 2- [2 (R) - [2 - [(4-lmidazole) -phenyl] ethyl] -4- [3- (phenylpropyl) -4 (S) -carboxy-1-oxobutyl] -3 (S) -methylaminocarbonyl -hexahyd ropyridazine; HS (CH2) 2- (S-D-Leu) -Phe-NHMe; HS (S) CHMeCH2- (S-D-Leu) -Phe-NHMe; HS (S) CH (PhtNBu) CH2- (S-D-Leu) -Phe-NHMe; HS (S) CH (PhtNEt) CH2- (S-D-Leu) -Phe-NHMe; HS (1,2-Cyclopentyl) (S-D-Leu) -Phe-NHMe Me-S (NH) 2- (CH2-DL-Leu) -Trp-NHBn; n-Bu-S (NH) 2- (CH2-DL-Leu) -Trp-NHBn; n-Bu-S (NH) 2- (CH2-DL-TyrOCH3) -Trp-NHBn; Me-RS-SO (NH) - (C2-L-Leu) -Phe-Ala-NH2; n-Bu-RS-SO (NH) - (C2-L-Leu) -Phe-Ala-NH2; HONH-C-CH2CII (CH2CH (CH3) 2) CO-Nal? La-NÍH; O UO NFI-CO-CH2.CII- (CH2-CII (CH) 2-C () Nal-P? -NH2; HO-Np-CO-CH (CH3.CH (CIl2) -CH (CH3b) CO- Nal-Ala-NH2; H I HON-C? CH2-CH-CO Pal Ala-NH2 wherein Pal is 3-pyridylamanine; (CH2S) Ala NH2 HO- NH- CO- CH2.CH (CH2CH (CH3) 2) CONal- (CH2NH) -? Ia-NH2; H 2 4- (1,3-Dihydro-1,3-dioxo-2H-benz [] isoindol-2-yl) -2- (R) - [[3-metiI - [(S) - [[(2- morpholin-4-ylethyl) amino] carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [] isoindol-2-yl) -2- (R) - [[3-metiI-1- (S) - [[methylamino or ] carbonyl] butyl] amin or] -butanoic; 4- (1,3-dihydro-1,3-d-oxo-2 H-benz [f] i soindoI-2-i I) -2- (R) - [[[3-methyl-1-] (S) - [[(1 H -midazoI-2-methylmethyl) amino] carbonyl] -butyl] amin or] -butanoic acid; 4- (1,3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [[(1 H -tetrazol-5-ylmethyl) amino] carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-i I) -2- (R) - [[3-methyl-1 - [(S)] - [[[(2- (phenyl) ethyl] amino] carbonyl] butyl] amino] -butanoic acid; 4- (1,3-dihydro-1,3-dioxo-2H-benz [torreindol-2-yl] - 2- (R) - [[3-methyl-1- (S) - [[(pyridin-3-ylmethyl) amino] carbonyl] butyl] -amino] -butanoic acid 4- (1,3-dihydro-1) , 3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[(2-methyl-2H-tetrazo-5-ylmethyl amino] -carbonyl] butyl] amino] -butanoic acid 4- (1,3-dihydro-1,3-dioxo-2H-benz [fjisoindol-2-yl] -2- (R) - [[3- methyl-1- (S) - [[- 4-hydroxy-2-methyl-pyrimidin-5-ylmethyl) amino] -carbonyl] butyl] amino] butanoic; 4- (1, 3-dihydro-1,3-dioxo-2H-benz [soindol-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-benz [f] sondole-2-yl) -2- (R) - [[3-metiI-1 (S) - [ [1- (1H-tetrazol-5-yl) ethyl] amino] carbonyl] butyl] -amin or] -butanoic acid; 4- (1, 3-dihydro-1,3-dioxo-2H-benz [] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [ [(5-amino-4H- [1,2,4] -triazol-3-ylmethyl) amino] -carbonyl] butyl] amino] butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f | isoindol-2-yl) -2- (R) - [[3-metH-1- (S) - [[[ 1- (6-oxo-1,6-dihydro-pyridazin-3-yl) ethyl] -amin or] carbonyl] butyl] amin or] -butanoic acid; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[( phenyl) amino] carbonyl] butyl] amino] -butanoic; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [f | isondol-2-yl) -2- (R) - [[3-methyl-1- (S) - [ [(benzyl) amino] carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [flisoindol-2-yl] -2- (R) - [[3-methyl-1- (S) - [[(pyridin- 4-ylmethyl) amino] carbonyl] butyl] -amino] -butanoic acid; 4- (1, 3-dihydro- 1, 3-di oxo-2H-benz [r] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] -buti I] amino] -butanoic; 4- (1, 3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-metii-1- (S) - [ [(pyridin-2-ylmethyl) -amino] carbonyl] butyl] -amino] -butanoic acid; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[(4-sulfamoyl-phenyl) -amino] carbonyl] butyl] -amino] -buta-noic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f] isol-2-yl) -2- (R) - [[3-methyl-1- (S) - [ [(3-sulfamoyl-phenyl) -amino] carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-met il-1- (S) - [[ (4-dimethylamino-benzyl) -amino] -carbonyl] -butyl] -amino] -buta-noic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-metiI-1- (S) - [[[ 1- (S) -phenyl-eti] amino] carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - [[( 1,1-dioxo-tetrahydro-thiophen-3-yl) amino] -carbonyl] butyl] -amin or] -butanoic acid; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz []! Soindol-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-benz [f] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - [[[ 1- (R) -phenyl-ethyl] amino] carbonyl] butyl] -amino] -butanoic; 4-, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - (3-fluorobenzyl) amino] acid] carbonyl] butyl] -amino] -butanoic; 4-, 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-, 3-Dihydro-1, 3-dioxo-2H-benz [] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - (methyl-1 H- tetrazol-5-ylmethyl] amino] carboniI] -butyl] -amino] -butanoi? o; 4 * -, 3-dihydro-1,3-dioxo-2H-benz [f] isoindoI-2-yl) -2 acid - (R) - [[3-methyl-1- (S) - (1, 2,3,4-tetrahydro-naphthalen-1-yl) amino] -carbonyl] butyl] -aminobutanoic acid; 4-, 3-dihydro-1,3-d-oxo-2H-benz [soindol-2-I | ). 2- (R) - [[3-methyl-1- (S) - (2,4-d.fluoro-benzyl) amino] carbonH] butyl] -amino] -butanoic; 4-, 3-Dihydro-1,3-dioxo-2H-benz [f | isoindol-2-yl] -2- (R) - [[3-methyl-1- (S) - (3-nitrobenzyl) acid] amino] carbonyl] butyl] -amino] -butanoic acid; 4-, 3-Dihydro-1,3-di-oxo-2 H-benz [f] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - (4- n-benzyl) amino] carbonyl] butyl] -amino] -butanoic acid; 4-, 3-Dihydro-1,3-d-oxo-2H-benz [f] isol-2-yl) -2- (R) - [[3-methyl-1- (S) - ( 4-methanesulfonylamino-benzyl) amino] -carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [[(3-methanesulfonylamino-benzyl) amino] -carbonyl] butyl] -amino] -butane; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [soindol-2-yl] -2- (R) - [[3-methyl-1- (S) - [[(3, 4-difluoro-benzyl) amino] -carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-Dihydro-1,3-d-ioxo-2H-benz [f | isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [ [(3-trifluoromethyl-benzyi) amino] carbonyl] -butyl] -amino] -butanoic acid; 4- [2- (S) - [1- (R) -carboxy-3- (1,3-dioxo-1,3-dihydro-benzo [] isoindol-2-yl) -propylamino] -4-methyl acid phenylamino-methyl) -benzoic acid; 4- (1,3-Dihydro-1,3-d-ioxo-2 H-benz - [/] isoi ndol-2-yl) -2- (R) - [[3-metp-1- (S ) - [[(2-hydroxy-1,1-bis-hydroxymethyl-ethyl) amino] -carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [((3, S-difluoro-benzyl) -animate] carbonyl] -butyl] amin or] -butanoic acid: 4- (1,3-dihydro-1,3-d-oxo-2H -be nz [/] isoindol -2-i I) -2- (R) - [[3-methyl-1- (S) - [[benzylmethyl-amino] carbanyl] butyl] amino] -butanoic acid 4- (1,3-dihydro) - 1,3-d ioxo-2 H-benz [/] isoi ndol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[(2-dimethylaminoethyl) -methyl] -amino] carbonyl] -butyl] amino] -buta noico; 4- (1,3-dihydro-1,3-dioxo-2H-benz [/] iso indo 1-2- i I) -2- (R) - [[3-methyl-1- (S ) - [[(1-azabicyclo [2.2.2] -oct-3 (R) -amino] -carbonyl] butyl] amin or] -butanoic acid: 4- (1,3-dihydro-1,3-dioxo- 2H-benz [/] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - (1-azabicyclo [2.2.2] oct-3- (S) -yl) amino] -carbonyl] butyl] amino] -butanoic acid 4- (1,3-dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[ 3-methyl-1- (S) - [[(3- (R) -4- (S) -5- (R) -6-tetrahydrox-tetra-hydra-pyran-2- (R) -ylmethyl) amino ] -carbonyl] butyl] -butanoic acid; 4- (1,3-Dihydro-1,3-d-oxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [ [(N, N'-dimethyl-hydrazino) carbonyl] butyl] -amino] -butanoic; 4- (1, 3-dihydro-1,3-d-ioxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [(metpmethoxy) amino] carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - [[( dimethyl) amino] carbonyl] butyl] amino] -butanoic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3-metiI-1- (S) - [[(2-oxo-tetrahydro-thiophen-3- (R) -yl) amino] -carbonyl] butyl] amin or] -butanoic acid 4- (1,3-dihydro-1,3-dioxo-2H-benz [/] 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-d-oxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3- methyl-1- (S) - [[(3- (R) -acetylamino-4- (S) -5- (S) -dih¡drox¡-6- (R) -hydroxymethyl-tetra hydro -pira n- 2-yl) amino] carbonyl] butyl] amin or] -butanoic acid; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] ¡soindol-2-yl) -2- (R) - [[3-methyl-1- (S)] - [[[(2-hydroxyethyl] amino] carbonyl] butyl] -aminoj-butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [1,3-dihydro-1 H-isoquinoline-2-carbonyl] butyl] -amino] -butanoic acid; 4- (1, 3-dihydro-1,3-dioxo-2H-benz [/] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - [4- methylpiperazine-1-carbonyl] butyl] amino] -butanoic acid; 4- (1, 3-dihydro-1,3-d-ioxo-2H-benz [/] isoindol-2-i I) -2- (R) - [[3-methyl-1- (S) - [1-oxo- [1,4] thiazine-4-carbonyl] butyl] amino] -butanoic; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1 - (S) - [morpholine] na-4-carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [4- (2-3-dihydroxy-propyl) -piperazine-1-carbonyl] butyl] -amino] -butanoic acid; 4- (1,3-dihydro-1,3-dioxo-2 H-benz [/] isoi ndol-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 [/] isoindol-2-yl) -2- (R) - [[3-metiI-1- (S) - [[( 1-methyl-8-oxo-1, 7-diazacyclotide-9-yl) -amin or] carbonyl] butyl] amin or] -butanoic acid; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [[methyl] -1-methyI-piperidin-4-yl) -amino] -carbonyl] butyl] amin or] -butanoic acid; 4- (1,3-Hydro-1,3-d-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S)] ) - [[(4-hydroxy-1,1-d-oxo-tetrahydro-thiophen-3-H) -amino] carbonyl] butyl] amin or] -butanoic acid; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - (4- ethoxycarbonylmethyl-piperazine-1-carbonyl] -butyl] amin or] -butanoic acid 4- (1,3-dihydro-1,3-di oxo-2 H-benz [/] isoi ndol-2-i I) -2- (R) - [[3-methyl-1- (S) - [[(1,1-dioxo-tetrahydro-thiophen-3-yl) methyl-amino] carbonyl] butyl] amino] -butanoic; 4- (1,3-Dihydro-1,3-dioxo-2 H-benz [/] isoin dol-2-i I) -2- (R) - [[3-methyl-1- ( S) - [2- (R) - (pyridin-3-yl) -pyrrolidincarbonyl) butyl] -amino] -butanoic acid; 4- (1,3-dydro-1,3-dioxo- 2H-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [2- (S) -pyridin-3-yl) -pyrrolidinecarbonyl] butyl] - amino] carbonyl] butyl] amin or] -butanoic; 4- (1,3-Dihydro-1,3-d-ioxo-2 H-benz [/] isoi ndol-2-yl) -2- (R) - [[3-m ethyl- 1- (S ) - [3-oxo-2- (R) -f eni lp i-pe razi na- 1 -carbon i I] -butyl] amino] -buta noico; 4- (1, 3-Dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-meti 1-1 - (S) - [3 -oxo-2- (S) -phenyl-pi-perazine-1-carbon] I] -butyl] amin or] -butanoic acid; 4- (1, 3-dihydro-1,3-d-ioxo-2H-benz [/] isoindol-2-H) -2- (R) - [[3-methyl-1- (S) - [ (pyridine-3-carbonyl-hydrazino) carbonyl] -butyl] amino] -buta-noic acid; 4- (1, 3-dihydro-1,3-dioxo-2 H-benz [/] isoi ndol-2-yl) -2- (R) - [[3-methyl-1- (S)] - [[(benzensulfonyl) amino] carbonyl] butyl] amino] -butanoic; 4- (1,3-dihydro-1,3-d-oxo-2H-benz [/] isoindol-2-H) -2- (R) - [[3-methyl-1- (S)] - [[(3-aminobenzyl) amino] carbonyl] butyl] amino] -butanoic; 4- (1, 3-dihydro-1,3-dioxo-2H-benz [/] isoindol-2-yl) -2- (R) - [[3-meti 1-1 - (S) - [[ [4- (Trifluoro-methanesulfonyl] -lamino] benzyl] -amino] carbonyl] butyl] amino] -buta-noic acid; 4- (1,3-dihydro-1,3-dioxo-2H-benz [/] isoindol-2) -il) -2- (R) - [[3-methyl-1- (S) - [[[2-hydroxy- (R) -bicyclo [4.3.0] nona-3,6 (1) -diene] amin or] carbonyl] butyl] amin or] -butanoic acid 4- (1,3-dihydro-1,3-dioxo-2H-benz [/] 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-benz [/] isoindol-2-yl) -2- (R) - [[3-methyl-1- (S) - [ [(N-methyl-pyrrolidine) -methyl-amino] carbonyl] -butyl] amino] -butanoic; 4- (1,3-dihydro-1,3-d-dioxo-2H -be nz [/] so indo l-2-i I) -2- (R) - [[3-methyl-1- (S) - [(N-ethoxycarbonylmethyl-piperazine) -1-carbonyl] -butyl] amino] -butanoic acid; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutylamino] -4- (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2) acid -yl) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amin or] -4- (5-propoxy-1,3-di-oxo-1,3-dihydro-isoindol-2-acid -il) -buta noico; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2) acid -yl) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) acid ) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-methyl-1,3-di-oxo-1,3-dihydro-isoindol-2- il) -buta noico; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-methoxy-1,3-dioxo-1,3-dihydro-iisoindole -2 acid -i I) - butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbu ti I-amino] -4- (5-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol- 2-yl) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-phenyl-1,3-di-oxo-1,3-dihydro-isoindol) acid 2- i I) - butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (1,3-di-oxo-1,3-dihydro-isoindol-2-yl) -buta acid noico; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-methanesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-acid -yl) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-benzensulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) acid ) -butanoic; 2- (R) - [1- (S) - (Benzylamino) carbonyl-3-methylbutyl-amino] -4- (5-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2- il) -butanoic; Acid 2- (R) - [[3-meti 1-1 - (S) - [[(pyridi n-3-ylmethyl) am no] -carbonyl] butyl] amino] -4- (1, 3 , 5,7-tetraoxo-3,5,6-tetrahydro-1 H -pyrolo [3,4-f] isoindo I-2-yl] -butanoic acid, EtONHCONMe-CH 2 CH (iBu) -CO-L-Trp NHEt; EtCONOH -CH2CH (iBu) -CO-L-Trp-NHEt; n-PrCONOEt-CH2CH (iBu) -CO-L-Trp-NHEt; EtNHCONOMe-CH2CH (iBu) -CO-L-Trp-NHEt; MeNHCONOH-CH2CH ( iBu) -CO-L-Trp-NHEt; EtONHCONMe-CH2CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt; EtCONOH-CH2CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt; n-PrCONOEt-CH2CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt; EtNHCONOMe-CH2CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt; MeNHCONOH-CH2CH (iBu) - CO-L-Ala (2-naphthyl) -NHEt; HONHCONHCH2CH (iBu) -CO-L-TrpNHMe; HONHCONHCH2CH2CH (iBu) -CO-L-TrpNHMe; HONHCONHCH (Bu) -CO-L-TrpNHMe; H2NCON (OH) CH (Bu) -CO-L-TrpNHMe; N (OH) CH2CH (iBu) -CO-L-TrpNHMe; H2NCON (OH) CH2CH2CH (iBu) -CO-L-TrpNHMe; C3CON (OH) CH (iBu) -CO-L-TrpNHMe; C3CON (OH) CH2CH (iBu) -CO-L-TrpNHMe; C3CON (OH) CH2CH2CH (iBu) -CO-L-TrpNHMe; NHOHCOCH2CH (i-Bu) CO-L-Trp-NHMe; HONHCONHCH2CH (i-Bu) CONHCHCOOH R4 ROOCCH2CH (i-Bu) CONHCHCOOH or; R4 N-. { D, L-2- (Hydroxy-aminocarbonyl) methyl-4-methylpentanoyl} -L-3- (2'-naphthyl) alanyl-L-alanine, 2- (amino) ethyl amide; N-D, L-2- (Hydroxyaminocarbonyl) methyl-4-methy1pentanoyl} -L-3-amino-2-dimethylbutanoiI-L-alanine, 2- (amino) ethylamide; 4 (S) - [3-Hydroxy-aminocarbonyl-2 (R) - (2-methylpropyl) propanoyl] amino-1, 2,3,4,5-tetrahydro-3H-2-benzazepin-3-one; [4- (N-Hydroxyamino) - (2R) -isobutyl-3-methylsuccinyl] -L-phenylglycine-N-methylamide; 4 (S) - [2 (R) - [1 (R) -Hydroxycarbamoyl-2-morpholinoethyl] -4-methylvaeryl] amino-1,2,4,5-tetrahydro-3H-2-benzacepin-3 ona; Acid (1R, 4S) -4 - [(2R) -Hydroxycarbamoylmethyl-4-methyl-valeryl] amino-3-oxo1, 2,4,5-tetrahydro-3H-2-benzazepine-1-carboxylic acid; 3- [2- (N-Methylcarbamoyl) etllsulfinyl] -5-methyloxane-hydroxamic acid; N - [(2-Tenoylmercapto-3-methyl) -butanoyl] -homocysteine thiolactone; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenylethyl) glycine- (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -isoleuccin, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -ala nina, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -phenylalanine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -serine-na-O-benzyl ether, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -triptofan, N-phenylamide; N- [1 (R) -carboxy-ethyl] -α- (S) - (2-phenyl-ethyl) -glycine-a- (S) - (2-phenyl-ethyl) glycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -norleucine, N-phenylamide; N- [1 (R) -carboxy-etyl] -α- (S) - (2-phenyl-ethyl) glycine- (L) -valin, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -serine, N-phenylamide hydrochloride; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- phenyl-ethyl) glycine- (L) -asparagine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -treonine, N-phenylamide hydrochloride N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -lysine N-phenylamide; N- [1 ( R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -glutamic, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) ) - (2-phenyl-ethyl) glycine- (L) -tyrosine, N-phenylamide hydrochloride; N- [1 (R) -carboxy-5- (1,3-dioxo-isoindolin-2-yl) pentyl] α- (S) - (2-phenylethyl) glycine- (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-5- (1-oxo-isoindo-Iin-2-yl) pentyl] - a- (S) - (2-phenyl-ethyl) glycine- (S) -leucine, N-phenylamide hydrochloride; N- [1 (R) -carboxy-5- (1-oxo-iso-indolin-2-) il) pentyl] -a- (S) - (2-phenyl-ethyl) glycine- (S) -arginine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) ) - (2- (3-hydroxyphenyl) -ethyl) Glycine- (S) -leucine, N-phenylamide hydrochloride; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- (4-methylphenyl) -ethyl-glycine- (S) -Ieucine, N-phenylamide hydrochloride; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- (2'-thienyl) ethyl) glycine- (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- (4-ethylphenyl) ethyl) glycine- (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-5- (1-oxo-iso-indolin-2-yl) pentyl] -a- (S) - (2- (4-propylphenyl) ethyl) glycine- (L) - leucine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -α- (S) - (2- (4-chlorophenyl) ethyl) glycine- (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) -glycine-a- (S) - (2-cyclohexyl-ethyl) glycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl-glycine-a- (S) - (cyclohexyl) glycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine-a- (S) - (cyclohexylmethyl) glycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -β-naphthylalanine, N-phenylamide; N- [1 (R) -carboxy-ethyl] - a- (S) - (2-phenyl-ethyl) glycine- (L) -a-naphthylalanine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- phenyl-ethyl) glycine - [(L) -glutamate, a, d-bis-N-phenylamide; N- [1 (R) -carboxy-etiI] -a- (S) - (2-phenyl-ethyl) glycine - (L) -leucine, N-cyclohexylamide, N-4- (1 (R) -carboxy-etp)] - a- (S) - (2-phenylethyl) glycine-a- (S) - ( 4-hydroxyphenylethyl) glycine, N-phenylamide; N- [1 (R) -carboxy-etiI] -a- (S) - (2-phenyl-ethyl) glycine- (L) -phenylglycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) -glycine- (L) -glutamic acid, Nd-benzylamide, Na-phenylamide; N- [1 (R) carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -ornithine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -4- (S) - (2-phenyl-ethyl) glycine- (L) -arginine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) -4-2-phenH-ethyl) glycine-a- (S) - (3-phenylpropyl) glycine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) -n-octylglicica, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -leucine, N- (4-carboxyphenyl) amide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -leucine, N- (4-trifluoromethylphenyl) amide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phenyl-ethyl) glycine- (L) -leucine, N- (3-pyridyl) amide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-phene-ethyl) glycine- (L) -leucine, N- (benzothiazol-2-yl) amide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2- (4-n-propylphenyl) ethyl) glycine - (L) -leucine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (S) - (2-4-propylphenol) etl) glycine- (L) -arginine, N-phenylamide; N- [1 (R) -carboxy-ethyl] -a- (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-Di hydro-1-oxo-2 H-isoindol-2-H) butyl) -hydroxyphosphinyl) methyl) 4-phenylbutanoyl) -L-leucine, N-phenylamide; (((4- (1,3-Dihydro-1-oxo-2H-isoindol-2-yl) butyl) (2-methyl-1- (1-oxo-propoxy) propoxy) phosphinyl) methyl) -4-phenylbutanoyl) - L-leucine, N-phenylamide; (2 - ((Hydroxy (meth!) Phosphinyl) methyl) -4-phenolbutane oil) -L-leucine, N-phenylamide; [[Hydroxy [1 (R)] - [N- (N-Acetyl-L-propyl-L-alanyl) -amino] -ethyl] phosphinyl] -methyl] -4-phenyl-butanoyl-L-leucyl, N-phenylamide; [Hydroxy- [N- ( N- (benzoyl) -L-propyl) aminobutyl] -phosphinyl] methyl] -4-phenyl-butanoyl-L-leucine, N-phenylamide; [Hydroxy- [2-Methopropyloxycarbonyl-aminobutyl] -phosphinyl] methyl] -4-phenylbutanoyl-L-leucine, N-phenylamide; [Hydroxy-1-Methylaminocarbonyl-aminobutyl] -phospholinyl] methyl] -4-phenylbutanoyl-L-leucine, N-phenylamide N- (2-thiomethyl-4-phenylbutanoyl) - (L) -leucinamide; N- (2-Tiomethyl-4-phenylbutanoyl) - (L) -Ieucine, N-phenylamide; N- (2-Tiomethyl-4-phenylbutanoyl) - (L) -leucine, N -benzyl-amide; N- (2-Tiometl-4-phenylbutanoi) - (L) -leucine, N- (2-phenylethyl) amide; N- (2-Tiomethyl-4-phenylbutanoyl) - (L) -phenylalaninamide; N- (2-T-methyl-4-phenylbutanoyl) - (L) -phenylalanine N-phenylamide; N- (2-Tiomethyl-4-phenylbutanoyl) - (L) -phenylalanine N-benzylamide; N- (2-Tiomethyl-4-phenylbutanoyl) - (L) -phenylalanine-b-alanine; 2 (R) - (2- (4 (1-n-Propyl) phenyl) ethyl) -1,5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4 (1-n-Propyl) phenyI) ethyl) -1,5-pentanedioic 1- (2 (S _) - t-butyl) glycine, N-phenylamide) amide; Acid 2 () - (2- (4 (1-n-Propyl) phenyl) ethyl) -1,5-pentanedioic 1- (L-leucine, N- (4-pridylamide) amide; Acid 2 (R) - ( 2- (4 (1-n-Propyl) phenyl) etl) -1,5-pentanedioic 1- (L-arginine, N-methylamide) amide; Acid 2 (R) - (2- (4 (1-n-Pro? Il) phenyl) ethyl) -4-methyl-1,5-pentanedioic 1- (L-leucine, N-phenylamide) amide Acid 2 (R) - (2- (4 (1-n-Propyl) f-enyl) eti I) -4-methylo-1,5-pentanedioic 1- (2 (S _) - t-butyl) glycine, N-phenylamide )amide; Acid 2 (R) - (2- (4 (1-n-Propyl) phenH) etl) -4-methyl-1,5-pentanedioic 1 - (2 (S _) - (4-thiazolylmethyl) glycine, N phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-methyl-l, 5-pentanedioic 1- (2 (S _) - (3-pyridylmethyl) glycine, N- phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-methyl-l, 5-pentanedioic 1- (L-leucine, N- (4-pyridyl) amide) amide ); Acid 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-methyl-l, 5-pentanedioic 1- (2 (S _) - (2-pyridylmethyl) glyc na, N-phenylamide) amide; 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-methylene-l, 5-pentanedioic acid 1- (L-arginine, N-phenylamide) amide; 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4-methyl-l, 5-pentanedioic acid 1- (L-phenylalanine, N-4-pyridylamide) amide; Acid 2 (R) - (2- (4- (1-n-Propyl) phenyI) ethyl) -4- (1- (4- (N- (2-oxo-sol-indolyl)) -butyl)) -1, 5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-Propyl) phenyl) ethyl) -4- (1- (4- (N- (2-oxoisoindolinyl)) - but-2-enyl)) - 1,5-pentanedioic 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (4-fluorophenyl) phenyI) ethyl) -4-methyl-1,5-pentanedioic 1- (L-leucine, N-phenylamide) amide; 2 (R) - (2- (4- (phenyl) phenyl) ethyl) -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; Acid 2 (R) - (2- (4- (4-methyl-phenyl) -f-enyl) -eti I) -4-methyl-1, 5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide; 2 (R) - (2- (4- (4-Hydroxy-n-butyl) -phenyl) -ethyl) -4-methylpentanedioic acid 1- (S-leucine, N-phenylamide) amide; Acid 2 (R), 4 (a) - (2- (4- (3-hydroxy-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic 1- (L-leucine, N-phenylamide )amide; 2 (R) - (2-phenylethyl) -4-methyl-1,5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyI) phenyl) ethyl) -1,5-pentanedioic acid 1 - . 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; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) propyl) -1, 5- tadarioic pen 1- (2 (S _) - ig? -butyl-glycine, 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-1,5-pentanedioic acid 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) etiI) -4- (3-methylbenzyl) -1,5-pentanedioic acid 1 - (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4- (2-benz-midazolyl) butyl) -1,5-pentanedioic acid 1 - (L-leucine) , N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) 4- (4- (2-benzthiazolyl) butyl) -1,5-pentanedioic 1- (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) 4- (4- (2-benzo-xazolyl) butyl) -1,5-pentanedioic acid 1 - (L-leucine, N-phenylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) etH) -4-carboxy-1,9-nonanedioic acid 1 - (L-leucine, N-phenylalande) amide 9-piperidinamide; Acid 2 (R) - (2- (4- (1-propyl) f-enyl) eti I) -4-carboxy-1,9-nonanedioic 1- (L-leucine, N-methylamide) amide 9-phenylamide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic 1- (L-leucine, N-methylamide) amide 9-ig? I -butylamide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethi) 4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methylamide) amide 9-benzylamide; 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1- (L-leucine, N-methylamide) amide 9-morpholineamide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic 1- (L-leucine, N-methylamide) amide 9- (1 (R) -phenylethyl) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanodioic 1- (L-leucine, N-methylamide) amide 9- ( 1 (S) -phenylethyl) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanodioic 1- (L-leucine, N-methylamide) amide 9- (N- methyl-N-phenyl) amlda; 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid salt 1 - (L-leucine, N-methylamide) amide 9 - (N'-methylpiperazin) tri-fluoroacetic amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4-carboxy-1,9-nonanodioic 1- (L-leucine, N-methylamide) amide 9- (3- pyridyl) amide; 2 (R) - (2- (4- (1-Propyl) phenyl) ethyl) -4-carboxy-1,9-nonanodioic acid 1- (L-leucine, N-methylamide) amide; Acid 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 1 - ((R) - (S-p-methoxybenzyl) penicillamine sulfone, N-phenylamide) amide; 2- (2- (4- (1-propyl) phenyl) ethyl) -4- (1- (4- (2-phthalimido)) -bu ti I) -1,5-pentanedioic acid 1- (L leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-benzoyl-amino-1-butyl) -1,5-pentanedioic 1- (L-leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-pivaloyl-amino-1-butyl) -1,5-pentanedioic 1 - (L- leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-phenylsulfo-nylamino-1-butyl) -1,5-pentanedioic 1- (L-Ieucine, N-methylamide) amide; 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) 4- (4- (N'-phenyl-ureido) -1-butyl) -1,5-pentanedioic acid 1 - ( L-leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyI) ethyl) -4- (4-phenyloxycarbonylamino-1 -buti I) - 1,5-pentanedioic acid 1 - (L-leucine) , N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-N'-benzyloxycarbonylamino-L-propylamino) -1-butyl) -1, 5- pentanedioic 1- (L-leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) pheny1) ethyl) -4- (4-cyclopentyl-amino-1 -bu ti I) -1,5-pentanedioic 1- ( L-leucine, N-methylamide) amide; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4- (2-carboxy-benzoylamino) -1 buty I) - 1,5-pentanedioic acid 1 - (L-leucine, N-methylamide) anude; Acid 2 (R) - (2- (4- (1-n-propyl) phenyl) ethyl) -4- (4-cyano-1-butyl) -1,5-pentanedioic 1- (L-leucine, N- phenylamide) amide; N- [1 (R) -Carboxyethyl] -a- (S) - (9-amino-n-nonyl)] glycine- (L) -leucine, N-phenylamide; N- [1 (R) -Carboxyethyl] -a- (S) - (n-octyl)] glycine- (L) -leucine, N-phenylamide; N- [1 (R) -Carboxyethyl] -a- (S) - (n-octyl)] glycine- (L) -arginine, N-phenylamide; N- [1 (R) -Carboxyethyl] -a- (S) - (9-amino-n-nonyl)] glycine- (L) -arginine, N-phenylamide; N- [1 (R) -Carboxyethyl] -a- (S) - (n-decyl)] glycine- (L) -leucine, N-phenylamide; 1- (2- (4-propylphenyl) ethyl) cyclopentane-1,3-dicarboxylic acid 1- (L-Ieucine, N-phenylamide) amide; 1- (2- (4-propylphenyl) ethyl) cyclohexane-1,3-dicarboxylic acid 1- (L-leucine, N-phenylamide) amide; N- [1 (R) -Carboxyethyl] -a- (S) -2- (4-fluorobiphenyl) -glycyl- (S) -2- (e-butyl) glycine, N-phenylamide; 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril; 3S- [4- (N-hydroxamino) -2R-isobutyl-3S-acetylthio-methylsuccinyl] 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-h id roxy mino) -2 R-isobutyl I-3 S -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-1-amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril; 2- (R) -N-hydroxy-2 - [(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-oxopropyl) amino] -3-methyl-butyramide; 2- (R) -2 - [(2-Benzylcarbamoylethyl) (4-methoxy-benzenesulfonyl) 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 - ([- methoxybenzenesulfonyl] - [2- (methy1-pyridin-3-ylmethylcarbamoyl) ethyl] amino) -3-methylbutyramide; 4- (3- [1 - (R) -1-Hydro-xicarbamoyl-2-methylp-pil) (4-methoxy-benzenesulfonyl) -amino] -propionyl) -piperazine-1-arboxylic acid, tert-butyl ester; 2- (R) -N-Hydroxy-2 - [(4-methoxybenzenesulfonyl) (3-oxo-3-piperazin-1-ylpropyl) amino) -3-methylbutyramide hydrochloride; 2- (R) -2 - [(Benzylcarbamoylethyl) (4-methoxy-benzenesulfonyl) 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 - [(methoxy-benzenesulfon i I) (3-morpholin-4-yl-3-oxopropyl) ami no] propionamide; 2- (R) -N-hydroxy-2 - ((4-phenoxybenzenesulfonyl) [2-methyl-pyridin-4-ylmethylcarbamoyl) ether] amino) -3-methylbutyramide; 4- [4-Methoxybenzenesulfonyl) (3-morpholin-4-yl-3-oxopropyl) amino] -1-methylpiperidene-4-carboxylic acid hydroxyamide; 2- (R) -N-h id roxy-2 - ((4-m ethoxy benzenes ulfon i I) - [3- (4-methy1-piperazin-1-yl) -3-oxopropyl] amino) -3-methylbutyramide; 2- (R) -2 - [(2-Carboxyethyl) (4-methoxybenzene-sulfo nyl) amin or] -N-hydroxy-3-methylbutyramide; [(2-Carboxyethyl) (3,4-dimethoxybenzenesulfonyl) amino] -N-hydroxyacetamide; 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-h id rox¡-2- ((4-methoxy-benzenesulfon i I) [3- (methylpyridin-3-ylmethylcarbamoyl) propyl] amino) -3-methylbutyramide; 2- (R) -N-h id roxy-2 - ((4-methoxybenzenesulfonyl) [2- (methylcarboxymethylcarbamoyl) ethyl] amino) -3-methyl-butyramide; 2- (R) -N-hydroxy-2 - ((4-methoxybenzenesulfonyl) [(1-methylpiperi din-4-ylcarbamoyl) methyl] -3-methylbutyramide; 2- (R) -N-Cyclohexyl-N-hydroxy-2 - ((4-methoxy-benzenesulfonyl) - [3- (4-methylpiperazin-1-yl) -3-oxopropyl] amino) -acetamide; 2- (R) -Nh id roxy-2 - [(methoxy benzenesulfon i I) (3 ~ molfol in-4-yl- [3-oxopropyl) amino] -4- (morpholin-4-yl) but Ramida [4-N-Benzyloxyamino) -2 (R) -isobutylsuccinyl] -L-leucyl-L-alanine ethyl ester; [4-N-Benzyloxyamino) -2 (R) -isobutylsuccinyl] -3 (RS) -aminolau rola ct ama; Na- [4- (N-Benzyloxyamino) -2 (R) -isobutylsuccinyl] -Ne- (N-benzyloxycarbonylglycyl) -L-lysyl-L-alanine ethyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucylglycine eti ester; [4- (N -hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucylglycine isopentylamide; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-valiglycine ethylamide; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinI] -L-leucylglycine ethylamide; Na- [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -Ne-tert.butoxycarbonyl-L-lysylglycine ethylamide; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -O-methyl-L-tyrosine n i I glycol ethyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -O-methyl-L-ti rosini Iglycine ethylamide; [4- (N -hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucyl-L-alanine ethyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucylglycine isopentyl ester; [4- (N-hydroxyamino) -2 (R) -propylsuccinyl] -L-leucylglycine ethyl ester; [4- (N-hydroxyamino) -2 (RS) -sec.butylsuccinyl] -L-leucylglycine ethyl ester; [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -L-leucyl-L-alanine; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucylglycine methyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsucciniI] -L-leucylsarcosine ethyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucyl-L-proline ethyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucine-L-alanine isopropyl ester; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucine-2-oxopropylamide; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucine-2-methoxyethylamide; [4- (N-hydroxyamino) -2 (RS) -isobutylsuccinyl] -L-leucine-2,2-dimethoxyethylamide; Na- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -N-glycyl-L-lysine methylamide; Na- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -Ne- (4-carboxybenzoyl) -L-lysyl-L-alanine ethyl ester; Na- [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -Ne- (4-carboxybenzoyl) -L-lysyl-L-aline; [4- (N-hydroxyamino) -2 (R) -isobutylsuccinyl] -3 (RS) -aminooctahydro-2H-azonin-2-one; [4- (N-hydroxyamino) -3 (S) -metl-2 (R) -isobutyl-succinyl] -L-leucylglycine ethyl ester; [(3-Aminophthalimido) methyl] [(RS) -4-metii-2 - [[(S) 3-methyl-1- (methylcarbamoyl) butyI] carbamoyl] pentyl] phosphinic acid: Acid [(RS) -4- MetiI-2 - [[(S) -3-methyl-1- (methyl-carbamoyl) -butyl] carbamoyl] pentyl] (1,8-naphthalenedi-carboximidomethyl) phosphinic; [(R or S) -4-Methyl-2 - [[(R or S) -2-oxo-3-azacyclo-tridecyl] carbamoyl] pentyl] (1,8-naphthalene-carboxymethyl-methyl) -phosphinic acid; N- [N - [(R or S) -2 [[[[[N- [1- (Benzyloxy) carbonyl] -L-prolyl] -L-leucyl] amino] methyl] hydroxyphosphine] -methyl ] -4-methylvaleryl] -L-leucyl] -L-alanine; [[1,4-Dih id ro-2,4-d ioxo-3 (2 H) -quinazol i nil] -methyl] [[(R or S) -4-methyl-2 - [[(R or S ) -2-oxo-3-azacyclotyldecyl] carbamoyl] pentyl] -phosphinic; N2 - [(R) -hydroxycarbamopmetyl] 4-methylvaleryl] -N1,3-dimethyl-L-valinamide; N2- [2 (R or S) - [[[(5-Bromo-2,3-dihydro-6-hydroxy) -1,3-dioxo-1H-benz [d, e] isoquinol-2-yl) methyl ] - [(hydroxy) phosphinyl] methyl] -4-m ethyl val eri I] - N1, 3-di met i l-va I was measured; N2 - [(R or S) - [[(R) - (Amino) [(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo-1H-benz [d, e] isoquinol- 2-yl) methyl] (hydroxy) phosphinyl] methyl] -4-methylvaleryl] -N3,1-dimethyl-L-valinamide hydrobromide; N2- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl-4-methylvaleryl] -N1,3-dimethylvalinemide; N2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -N1,3-dimethyl-L-valinamide; N2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4- (methoxy-carbonyl) butyl] -4-methyl-valeryl] -N1,3-dimethyl-L-valinamide; M2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4-phenyl-butyl] -4-methylvaleryl] -N1,3-dimethyl-L-valnamide; N2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-succinimidoethyl] -4-methylvaleriI] -N1,3-dimethyl-L-valinamide; 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleri I] 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-piperidinoI; 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-di oxo-1, 2,4-triazolidin-4-yl) ethyl] -4-methylvaleryl] pperidine; 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyI-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methyIvaleryl] 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-amydazolidinyl) ethyl] -4-methylvaleryl] - 4-piperidonol; [4- (N-hydroxyamino) -2 (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (R or S) -nonylsucciniI] -L-leucyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (R or S) -heptyl-3 (S) -methyl-succinyl] -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) -nonyl-succinyl] -L-tert.butylglycine methylamide; [4- (N-hydroxyamino) -2 (RS) -heptyl-succinyl] -L-phenylalanine methylamide; [4- (N-hydroxyamino) -2 (R) -heptiI-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] -L-leucine methylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-leucine neopentylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-alanyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L- (Ne-phthaloyl) -lysyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -undecyl succinyl] -L-Ieucyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-phenylalanyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-nonalyl-L-leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -phenylalanine tert-butylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-tert-butylglycine methylamide; [4- (N-hydroxyamino) -2 (Rs) -1-heptylsuccinyl] -L-neopentylglycine methylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-homophen Halan il-L -leucine ethylamide; [4- (N-hydroxyamino) -2 (RS) -heptylsuccinyl] -L-cyclohexylalanine methylamide; [4- (N-hydroxyamino) -2 (RS) -sooctylsuccinyl] -L-phenylalanine methylamide; [4- (N-hydroxyamino) -2 (R) -heptiIsuccinyl] -L-neonpentylglycine methylamide; [4- (N-hydroxyamino) -2 (R) -heptylsuccinyl] - (D or L) -β, β-dimethylphenylalanine methylamide; [4- (N-hydroxyamino) -2 (R) -heptylsuccinyl] 3- (D or L) -treo-β-methylphenylalanine methylamide; [4- (N-hydroxyamino) -2 (R) -heptylsuccinyl] -DL-ertro-β-methylphenylalanine methylamide; [4- (N-hydroxyamino) -2 (R) -heptii-3 (R or S) - [(3-methyl-2,5-dioxo-1-imidazole id i nyl) methyl] succinyl] -L-leucyl -L-leucine ethylamide; N2- [3-Cyclobutyl-2 (R or S) -l (hydroxycarbamoyl) -methyl] -propionyl] N1, 3-dimethyl-L-valinamide; N2- [3-Cyclopropyl-2 (R or S) - [(hydroxycarbamoyl) -methyl] -propionp] N1,3-dimethyl-L-valinamide; N2- [3-Cyclopentyl-2 (R or S) - [(hydroxycarbamoyl) -methyl] -propionyl] -N1, 3-dimethyl-L-valinamide; N2- [3-Cyclopropyl-2 (R) - [1 (R or S) - [(hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl] -N1, 3-dimethyl-L-valinamide; N2- [3-Cyclopropyl-2 (R) - [1 (R or S) - [(hydroxy-carbamoyl) -4-phenyl] -butyl) propionyl] -N1, 3-dimethyl-L-valinamide; N2- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -4-phenylbutyl] propionyl] -N1, 3-dimethyl-L-valinamide; N2- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -4-phenylbutylpropionyl] -N1, 3-dimethyl-L-valinamide; 1- [3-Cyclopropyl-2 (R) - [1 (R or S - (hydro xy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl propionyljpiperidine; 1- [3-Cyclopropyl-2 (R) - [1 (R or S - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl propionyl] - 4-piperidinol; 1- [3-Cyclobutyl-2 (R) - [1 (R or S - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-l, 2,5-dioxo-1-imidazole idinyl) ethyl propionyl] piperidine; 1- [3-Cyclobutyl-2 (R) - [1 (R or S - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl) ethyl propionyl] -4-piperidinol; 1- [3-Cyclopentyl-2 (R) - [1 (R or S - (hydroxy-carbamoyl) -2- (3,4,4-trimeti-1 2,5-dioxo-1-imidazole id i nil) eti I propionyl] -4-piperidinol; 1- [3-Cyclopentyl-2 (R) - [1 (R or S - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-d-oxo-1-imidazolidinyl) ethyl propionyl] piperidine; 3- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) ) -2 (3,4,4-trimethyl-2,5-dioxo-1-imidazoIidinyl) etl) propionyl] -3-azabicyclo [3.2.2] nonane; 3- [3-Cyclopropyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-tri-methyl-2,5-d-xoxo-1-imidazole id inil ) ethyl] propy on il] -3-azabicicio [3.2.2] nonane; 3- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-amidazolidinyl) ethyl] propionyl] -3-azabicyclo [3.2.2] nonane; 1- [3-Cyclohexyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-4-4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] piperidine; 4- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl ] propionyl] tetrahydro-1,4-thiazine; 4- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) etp] propionyl] tetrahydro -1,4-thiazine S, S-dioxide; 4- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) etl. ] pro pió ni I] tetra h id ro-1, 4-thiazine; 3- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) et L] propionp] -5,5-dimethyl-N-propyl- [4 (R) -thiazolidine carboxamide; 4- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl] morpholine; 3- [3-Cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] nyl] -N, 5,5-trimethyl-4 (R) -thiazolidinecarboxamide; 4- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-d-oxo-1) -imidazolidinyl) ethyl] propionyl] -4-phenylpiperazine; 4- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethoxy-2,5-dioxo-1-imidazolidinyl) ethyl) propionyl] morpholine; 1- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimeti 1-2, 5-dioxo-1-imidazole din. ) ethyl] propion i I] pyrro I id i na; 8- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-l-2,5-dioxo-1-imidazole id in i I) ethyl] propionyl] -1,4-dioxo-8-azaspiro [4,5] decane; 1- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionium ] -4-methoxypiperidine; 1- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3j4j4-trimethyl-2,5-dioxo-1-imid azo lid inyl) ethyl] own nil] octah id roazocina; 1- [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (5,5-dimethyl-2,4-dioxo-3-oxazolidinyl) ethyl] propionyl] piperidine; 1- [3-CyclobutyI-2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl] hexahydroazepine; 1- [3-Cyclobutyl-2 (R) - [2- (hexahydro-1,3-dioxo-pyrazolo [1, 2a] [1, 2,4] triazol-2-yl) -1 (R or S) - (hydroxycarbamoyl) -ethyl] propionyl] piperidine; 1- [3-Cyclobutyl-2 (R) - [1 (R or S) - (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) - (hydroxy-carbamoyl) 4-phen i I butyl] nonanoyl] -3 (S) -pyridazo ñeca rboxam da; Hexahydro-2- [2 (R) - [1 (RS) - (hydroxycarbamoyl) 4-phenyl] butyl] Nanoyl] N- (2,2,6,6-tetramethyl-piperidinyl) -3 (S) -pyridazi ñeca rboxam da; 1- [2 (R) - [1 (R or S) -hydroxycarbamoyl) -4-phenylimbutyl] -nonanoyl] piperidine; N2- [2 (R) - [1 (RS) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-amidazolidinyl) eti l] nonanoyl] -N 1 -methyl-prolinemide; 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-d-oxo-1-imldazolidinyl) ) ethyl] nonanoyl] piperidine; Hexahydro-2- [2 (R) -1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-l-2,5-dioxo-1-imidazole idinyl) eti I] nonanoi l] -N-methyI-3 (S) -pyrid azi naca rboxam id a; 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-N-methyl-3 (S) -pyridazi ñeca rboxam id a; Hexahydro-2- [2 (R or S) - [(1 (S) - (hydroxycarbamoyl) -3-faith nilpropyl] undecanyl] -N- (1, 2,2,6,6-penta methyl -4- Pipe RI Dinil) -3 (S) -pi Rite azi ñeca rboxam ida; Hexahydro-2- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) ethyl] -undecanoI) 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; 1- [2- (R or S) - [1 (S) - (hydroxycarbamoyl) -3-phenylpropyl] unde-canoiljpiperidine; 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; - [2 (R or S) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] unde-canoyl] -piperidine; 4- [2 (R or S) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] undecanyl] morpholine; 1- (Benzyloxycarbonyl) -hexahydro-2- [2 (R) - [(R or S) - (hydroxycarbamoyl) -4-phenylbutyl] nonanoyl] -N- (a (S) -methylbenzyl) -3 (S ) -pyridazinecarboxamide; N - [(2R) -2- [2 '- (hyd roxy mi no) -2' - (oxo) ethyl] -5 (ca rboxi) pen-tanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 (phenylmethoxy) -hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (propylamino) -6- (oxo) hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] - (6RS) -6- (hydroxy) heptanoyl] -L-phenylalanine N-methylamide; (2S) -N 2 - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - (hydroxy) hexanoyl] amino-3,3- dimethylbutanoic N-methylamide; (2S) -N-2 - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - (phenylmethoxy) hexane] amino] 3,3-amino -dimet and Ibutanoic N-methylamide; N - [(2'R) -2- [2 '- (hydroxyamino) -. 2"- (oxo) ethyl] -6- (4'-oxobutylamino) hexanoyl] -L-phenollanine N-methylamide; Acid 2 (S) -N-2 - [(2'R) -2 '- [2 *' - (hydroxyamino) -2"- (oxo) ethyl] -6 '- (oxo) -6' (propylamino) hexanoyl] amino-3,3-dimethylbutanoic N-methylamide; N - [(2R) -2 - [(1'S) -1 '- (MetiI) -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-phen i lalanine N-methylamide; Acid (2S) -N-2 [(2'R) -4- (1"R) -1" - (1,3-Dihydro-1,3-dioxo-2H-isoindoi-2-yl) methyI-2"- (hydroxyamino) -2" - (oxo) ethyl] -6'- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbuta noico N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (oxo) -6- (propylamino) hexanoyl] -L-phenylalanine N-2-phenylethyl lamide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (Methyl) -2"- (hydroxy-amino) -2" - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino-3,3-di methyl butanoic N-2-phen i let i l amide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (MetiI) -2"- (hydroxy-amino) -2" - (oxo) ethyl] 6 '- (oxo) -6' - (propylamino) hexanoyl] amino-3,3-dimethylbuta-noic N-2-phenyl-ethylamide; Acid (2S) -N-2-4- (2'R) -2 '- [(1"S) -1" - (MetiI) -2"- (hydroxy-amino) -2" - (oxo) ethyl ] -6 '- (oxo) -6' - (propylamino) hexanoyl] amino-3,3-dimethylbuta noico N -2- (4 '-suIamoamoyl) phenyl ethylamide; Acid (2S) -N - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - (phenylmethoxy) hexanoyl] amino-3-cyclohexylpropionic N-2 - (4'-sulfamoyl) phenylethylamide; N- [2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 '- (phenylmethyl) hexanoyl] -L- (3,5-dimethyl I) f in lalanine N-2- (4'-sulfamoyl) phenyl-ethylamide; 9. 4 Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(4-methoxy) phenoxy] hexanoiI] amino-3,3-dimethylbutanoic N-2- (4'sulfamoyl) phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(4-meth I) phenoxy] hexanoyl] amino-3,3-dimeti I butanoic N-2- (4'-sulfamoyl) phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(1-oxo) butylamino] hexanoyl] amino-3-cyclohexylpropionic N-2- (4'-sulfamoyl I) -phenolyl lamide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (Methyl) -2"- (hydroxyamino) -2" (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid N-methylamide; Acid (2S) -N-2 - [(2 'R) -2' - [(1"S) -1" - (2-Methyl-propyl) -2"- (hydroxyamino) -2" (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (phenoxy) hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- (phenoxy) heptanoyl] -L-phen i lalanine N-methylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '(f in I-methoxy) hexanoyl] amino- 3, 3-di methyl butanoic N-2-phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- (phenylmethoxy) hexanoyl] amino-3,3 -dimethylbutanoic N-2- (4'-sulfamoyl) phenylethylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5- (phenylmethoxy) pentanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- (phenylmethoxy) heptanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (phenyloxy) hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- [(phenyloxy) heptanoyl] -L-phenylalanine N-methylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(2-phenethylamino) -6' - (oxo) hexanoyl] amino-3,3-dimethylbutanoic N methylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(4-methylphenoxy) hexanoyl] amino- 3, 3-di methyl butanoic N-methylamide; Acid (2S) -N-2, - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - [(4-chlorophenoxy) hexanoyl] amino- 3,3-d-methyl butanoic N-methylamide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(3-methylphenoxy) hexanoyl] amino-3 acid, 3-di methyl butanoic N-methylamide; (2S) -N-2 '- [(2'R) -2' - (carboxymethyl] -6 '- (3-methyloxy) hexanoyl] amino-3,3-dimethylbuta noic acid Nm ethylamide; (2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5- (carboxy) pentanoiI] -L-phen Halan ina N-methylamide; N - [(2R) -2- [ 2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] -L-phenylalanine N-methylamide; Nl (2R) -2- [2 '- (hydroxyamino) -2' - ( oxo) ethyl] -6- (propylamino) -6- (oxo) hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl ] - (6RS) -6- (hydroxy) heptanoyl] -L-phenylalanine N-methylamide; (2S) -N-2 - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- (hydroxy) hexanoyl] amino-3,3-dimethylbutanoic N-methylamide; (2S) -N-2 - [(2'R) -2' - [2 ', - ( hydroxyamino) -2"- (oxo) etiI] -6 '- (phenylmethoxy) hexanoyl] am i non-3,3-d-methyl butanoic N-methylamide; N - [(2'R) -2- [2, - (hydroxyamino) -2 '- (oxo) etI) -6- (4'-oxobutylamino) hexanoyl] -L-phen Halan ina N-methylamide; Acid 2 (S) -N-2 - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - (oxo) -6 '- (propylamino) hexanoyl] amin or-3,3-dimethylbutanoic N-methylamide; N - [(2R) -2 - [(1'S) -1 '- (Methyl) -2' - (hydroxyamino) -2 '- (oxo) etiI] -6- (phen i I methoxy) hexanoyl] -L- fen Halan ina N-methylamide; N - [(2 R) -2-t (l'S) -1 '- (Methyl) -2' - (hyd roxyamino) -2 '- (oxo) eti I] -6- (oxo) -6- (propylamino ) hexanoyl] -L-phenylalanine N-methylamide; Acid (2S) -N-2 [(2 R) - [(1 R) -1 '- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl-2"- ( hydroxyamino) -2"- (oxo) ethyl] -6 '- (phen i I methoxy) hexanoyl] amino-3,3-d-methyl butanoic N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (oxo) -6- (propylamino) hexanoyl] -L-phenylalanine N-2-phenylethylamide; Acid (2S) -N-2 - [(2 'R) -2' - [(1"S) -1" - (Methyl) -2"- (hyd roxy-amino) -2" (oxo) ethyl] -6- (phenolomethoxy) hexanoyl] amino-3,3-dimethylbutanoic acid N-2-phenylethylamide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (Methyl) -2"- (hydroxyamino) -2" (oxo) etl ] -6 '- (oxo) -6' - (propylamino) hexanoyl] -amino-3,3-dimethylbutanoic N-2-phen i I ethylamide; Acid (2S) -N-2 - [(2 'R) -2' - [(1"S) -1" - (Methyl) -2"- (h id roxi-amino) -2" (oxo) et L] -6 '- (oxo) -6' - (propylamino) hexanoyl] amino-3,3-dimethylbutanoic N-2- (4'-sulfamoyl) phenylethylamide; Acid (2S) -N - [(2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) etiI] - 6' - (phenylmethoxy) hexanoyl] amino-3-cyclohexylpropionic N- 2- (4'-sulfamoyl) phenylethylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6 '- (phen i lmethoxy) hexanoyl] -L- (3,5-dimeti I) phenylalanine N -2-4-4'-sulfamoyl) phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) etII] -6 '- [(4-methoxy) phenoxy] hexanoyl] amino- 3,3-dimethylbutanoic N-2- (4'sulfamoyl) -fen i let i lamida; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6 '- [(4-methyl) phenoxy] hexanoyl] amino- 3,3-dimeti I butanoic N-2- (4'-sulfamoi I) phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (1) idroxyamino) -2" - (oxo) ethyl] -6 '- [(1-oxo) buty-amino] hexanoyl] amino-3-cyclohexylpropionic N-2- (4'-sulfamoyl) -phenylethylamide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (Methyl) -2"- (hydroxy-amino) -2" (oxo) etl ] -6- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic N-methylamide; Acid (2S) -N-2 - [(2'R) -2 '- [(1"S) -1" - (2-Methylpropyl) -2"- (hydroxyamino) -2" (oxo) ethyl ] -4- (phenylmethoxy) hexanoyl] amino-3,3-dimethylbutanoic Nmethylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -4- (phenoxy) hexanoyl] -L-phen Hala nina N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- (phenoxy) heptanoyl] -L-phenylalanine N-methylamide; (2S) -N-2 '- [(2'R) -2'-l-2"- (hydroxyamino) -2" - (oxo) ethyl] -6' - (phenylmethoxy) hexanoyl] amino-3 acid , 3-di methyl butanoic N-2-phenylethylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) -ethyl] -6 '- (f in i I methoxy) hexanoyl] amino-3, 3-di methyl butanoic N-2- (4'-suIamoamoyl) phenylethylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -5- (phenylmethoxy) pentanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- (phenylimethoxy) heptanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -6- (phenyloxy) hexanoyl] -L-phenylalanine N-methylamide; N - [(2R) -2- [2 '- (hydroxyamino) -2' - (oxo) ethyl] -7- [(phenyloxy) heptanoyl] L-phenylalanine N-methylamide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) ethyl] -6, - [(2-phenylamino) -6 '- (oxo) acid ) hexanoyl] amino-3,3-dimethylbutanoic N-methylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) -ethyl] -6 '- [(4-methylphenoxy) hexanoiI] amino -3,3-dimethylbutanoic N-methylamide; Acid (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxyamino) -2" - (oxo) -ethyl] -6 '- [(4-chlorophenoxy) hexanoyl] me not 3, 3-di methyl butanoic N-methylamide; Acid (2S) -N-2'-4- (2'R) -2 '- [2"- (hydroxyamino) -2" - (oxo) -ethyl] -6' - [(3-methyl-fa-noxy) hexanoyl] amino-3,3-dimethylbuta noico N-methylamide; Acid (2S) -N-2 '- [(2'R) -2' - (Carboxymethyl) -6 '- (3-methyl-phenoxy) -hexane-1] amino-3,3-dimethylbutanoic N-methylamide; 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; (3R, 10S) -? / - hydroxy-5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14,16-tetraen- 10-ylcarbamoyl) hexanamide; (3 R, 11 S) -? / - hydroxy-5-methyl-3- (10-0X0-1,9-diazatriciclo [11.6.1.0] ei thing- 13-20), 14 (19), 15.17 -tet raen- 11-Hcarbamoyl) hexanamide; Acid (3R, 95) -5-Methyl-3- (8-oxo-1,7-diazatricyclo [9.6.l.0] -octadeca-11 (18), 12 (17), 13,15-tetraen -9-ylcarbamoyl) hexanoic; (3R, 9S) -? / - hydroxy-5-methyl-3- (8-oxo-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12 (17), 13,15-tetraen- 9-ylcarbamoyl) hexanamide; Acid (10S) - [4-Methyl-2- (9-oxo-1, 8-diazatricyclo- [10.6.1.0] nonadeca12 (19), 13 (18), 14,16-tetraen-IO-ylcarbamoyl) pentyl] - (quinolin-2-ylthiomethyl) phosphinic; (3R, 10S) -N-hydroxy-5-methyl-2-methoxycarbonyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), [3 (18), [4 , 16-tetraen-10-ylcarbamoyl) hexanamide; N- (4-Methyl-2-carboxymethylpentanoyl) -L-leucine-N '- (4-methoxycarbonylpheni) carboxamide; N- (4-Methyl-2 - (? / "- hydroxycarbamoyl) methylpentanoyl) -L-leucine -? /, - (4-methoxycarbonylphenyl) carboxamide; N- (4-Methyl-2 - (? /" - hydroxycarbamoyl) methylpentanoyl) -L-leucine-N '- (4-carboxy phenyl) carboxamide; N- (4-Methyl-2 - (/ V "-h id roxycarbamyl) methyl pen tan oil) -L-tri-pheno-N '- (4-carboxyphene) Ca -boxamide; N- (4-Methoxy) -2- (N "-hydro xicarh amoyl) methylpen tanoyl) -L.cyclohexylglycine-N '- (4-n-ethoxycarbonyl phenyl) carboxamide; N- (4-Methyl-2- (N "-hydroxy carbamoyl) met ilpenta noyl) -Lt-leucine-N '(4-methoxycarbonylphenyl) carboxamide; Acid (3R, 70S) -6-Biphenyl4-iI) -3- (9-oxo-1, 8-diazatricyclo- [10.6.1.0] onadeca-12 (19), [3 (18), 14,16-tetraen-10-ylcarbamoyl) hexanoic acid (3R, 70SJ-3- ( ° -oxo-1,8-diazatricyclo [10.6.1.0] nona-deca-12 (19), 13 (18), 14,16-tetraen-10-ylcarbamoyl) -5- (thiophen-2-yl) pentanoic acid; Acid (3R, IOS) -3-Cyclopentyl-3- (9-oxo-1,8-diazatri-cyclo [10.6.1] nonadeca [2 (19), 13 (18), [4,16-tetraen-10] -ilcarbamoyl) propionic acid (3R, • / 0S) -4-Cyclopentyl-3- (9-oxo-1, 8-diazatrici-clo [10.6.0] nonadeca [2 (19), [3 (18), [4,16-tetraen-10-ylcarbamoyl] butanoic acid (3R, os) 4-cyclopropyl-3- (9-oxo-1, 8-diazatricyclo- [10.6.1.0] nonadeca [2 (19), [3 (18), 14,16-tetraen-10-ylcarbamoyl) butanoic acid (3R, 10S) -5-Methyl-3- (9-oxo-1,8-diazatricyclo [-10.6.1.0] nonadeca [2 (19) ), [3 (18), 14,16-tetraen-10-Hcarbamoyl) hexanoic; Acid (3R, 10S) -N-hydroxy-5-methyl-3- (9-oxo-1, 8-diazatriciclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14,16-tetraen- 1 Oilcarbamoyl) hexanamide; Acid (3R, 11S) -Nh id roxi-5-meti I -3- (10-oxo-1,9-diazatriciclo [11.6.1.0] eicosa- [3 (20), [4 (19), 15, 17-tetraen-1 1-ylcarbamoyl) hncxanamide; Acid (3R, 9S) -N-5-Methyl-3- (8-oxo-1,7-diazatricyclo- [9.6.1.0] octadeca-11 (18), [2 (17), [3,15-tetraen -9-ylcarbamoyl) hexanoic; (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 -carbamoyl) hexanamide; (10S) -2-Mercaptomethyl-4-methyl-N- (9-oxo-1, 8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (78), 14,16-tetraen- 10- Lcarbamoyl) pentanamide; (10S) -2-Acetylthiomethyl-4-methyl-N- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-l2 (19), [3 ('18), [4,16-tetraen- 10-ylcarbamoyl) pentanamide; Acid (3R, • 0S) -2- (Methanesulfonamidomethyl) -5-methyl-3- (9-oxo-1, 8-diazatricyclo [10.6.1.0] nonadeca- 12 (19), 13 (18), 14, 16-tetraen-ylcarbamoyl) hexanoic; (3R, 10S) -2- (3-Ethylureidomethyl) -5-methyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-l2 (19), 13 (18), 14,16 -tetraen-10-ylcarbamoyl) hexanoic; (3R, 9S) -N-hydroxy-2-hydroxy-5-methyl-3- (8-oxo-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12 (17), [4, 16-tetraen-9-ylcarbamoyl) hexanamide or its (2S, 3R, 9S) stereoisomer; (3R, 10S) -N-hydroxy-5-methyl-2-methoxycarbonyl-3- (9-oxo-1,8-diazatricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), [4, 16-tetraen-1 O-ylcarbamoyl) hexanamide; Acid (3R, 9S) -5-Methyl-3- (8-oxo-4-oxa-1, 7-diazatricyclo- [9.6.1.0] octadeca11 (18), 12,14,16-tetraen-9-lcarbamoyl -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- ilcarbamoyl) succinate; 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-Icarbamoyl) 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-1, 7-diazatricyclo [9.6.1.0] - octadeca-11- (18), 12,14,16-tetraen-9-ylcarbamoyl) pentanoic ethyl ester: Acid (3R, 9S) -6- (4-hydroxy-phenyl) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12, 14,16 -tetraen-9-ylcarbamoyl) hexanoic; (3R, 9S) -3- (8-Oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] -octadeca-11 (18), 12,14,16-tetraen-9-iCarbamoyl) - 6-pyridin-4-yl-hexanoic acid; 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; Acid (3R, 9S) -3- (8-Oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] -octadecal 1 (18), 12,14,16-tetraen-9-ylcarbamoyl) -6- [4- (2-pyrrolidin-1-yl-ethoxyphenyl] hexanoic acid: (3R, 9S) -6- (4-Methoxy-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-Methoxy-toxy) -phenyl] -3 - (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16-tetraen-9-ylcarbamoyl) hexanoic acid; Acid (3R, 9S) -3- (8-Oxo-4-oxa-1, 7-diazatricyclo [9.6.1.0] -octadeca11 (18), 12,14,16-tetraen-9-Hcarbamoyl) -5-phenyl -pentanoic; Acid (3R, 9S) -3- (8-Oxo4-oxa-1, 7-diazatricyclo [9.6.1.0] -octadeca11 (18), 12,14,16-tetraen-9-ylcarbamoyl) -6-phenyl-hexanoic acid; Acid (3R, 9S) -6- (3-hydroxy-phenyl) -3- (8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.01 octadeca-11 (18), 12, 14,16- tetraen-9-carbamoyl) 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-pipendin-1-iI-propoxy) phenyl] hexanoic; Acid (3R, 9S) -6- [4- (3-Dimethylamino-propoxy) -phenyl] -3- (8-oxo-4-oxa-1,7-diazatricicio [9.6.1.0] octadeca-11 (18) .12, 14, 16-tetraen-9-ylcarbamoyl) hexanoic; Acid (3R19S) -6- [4- (2-Dimethylamino-ethoxy) -phenyl] -3- (8-oxo-4-oxa-1, 7-diaza tricyclo [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) -4-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-oxa-1,7-diazatricyclo [9.6. 1. 0] octadeca11 (18), 412,14,16-tetraen-9-Hcarbamo I) -6- (4-pyrrol-1-yl) hexanoic acid; Acid (3R, 9S) -6- (4-hydroxy-3-methyl-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-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; Acid (3R, 9S) -6- [4- (4-Aminobutoxy-phenyl) -1-3- (8-oxo-4-oxa-1, 7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12 , [4,16-tetraen-9-ylcarbamoyl) hexanoic acid; Acid (3R, 9S) -5- (4-Methoxy-phenyl) -3- (8-oxo4-oxa-1,7-diazatricyclo [9.6.1.0] octadeca-11 (18), 12,14,16-tetraen -9-ylcarbamoyl) pentanoic; Acid (3R, 9S) -6- (4-Amino-phenyl) -3- (8-oxo-4-oxa-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), [2, [4,16-tetraen-9-ylcarbamoyl) -6- [4- (pyridin-4-ylmethoxy) phenyl] hexanoic acid; Acid (3R, 9S) -6- (Acetylamino-phenyl) -3- (8-oxo-4-oxa-1,7-diaza tricyclo [9.6.1.0] octadeca-11 (18), 12,14,16- tetraen-9-ylcarbamoii) hexanoic; Na - [[3- (N-hydroxycarbamoyl) -4-methylthio-2-propoxymethyl] butyl] N, O-dimethylstylamine amide; Na - [[3- (N-hydroxycarbamoyl) -4-isopropylthio-2-propoxymethyl] butyl] -N, 0-dimethyltirosine amide; Na-4- [3- (N-hydroxycarbamoyl) -2-propylthio) butyl] -N, O-dimethylstylamine amide; N- [N- (1-Phosphono-3-phenylepropyl) - (S) -Ieucyl] - (S) -phenylalanine-N-methylamide; N- [N- (1-Phosphono-3- (4-bromo-1, 8-naphthalene-dicarboximido) propi I) (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-m ethylamide; N- [N- (1-Phosphono-3- (methylsulfonyl) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methylamide; N- [N- (1-Phosphono-3- (1, 8-naphthalenedicarboximido) propyl) - (S) -leuci] - (S) -triptofan-N-m ethylamide; N- [N- (1-Phosphono-3- (1,8-naphthalenedicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N-methylamide; N- [N- (1-Phosphono-3- (1,8-n-afta I in od i carboxymethyl) 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) -isine-N- (ethyl-N-methylpiperazine) amide; N- [N- (1-Phosphono-3- [8- [7,9-dioxo-8-azaspiro [4,5] decl]] propyl) - (S) -leucyl] - (S) -phenylalanine -N-methylamide; and N- [N- (1-Phosphono-3- [8- [7,9-dioxo-8-azaspiro [4.5] decyl)] propyl) - (S) -leucyl] - (S) -lysin- N-methylamide.

As noted above, numerous inhibitors of the metalloproteinase matrix are known. A large number of inhibitors is characterized as hydroxamic acid and / or acid-carboxylic acid based compounds. Typical of such compounds are those described in the following references, all of which are incorporated herein by reference, since all of the described compounds can be used in the method of this invention. US 4599361 (Searle) EP-A-2321081 (ICI) EP-A-0236872 (Rocbe) EP-A-0274453 (Bellon) WO 90/05716 (British Biotechnology) WO 90/05719 (British Biotechnology) WO 91/02716 ( British Biotechnology) WO 92/09563 (Glycomed) US 5183900 (Glycomed) US 5270326 (Glycomed) WO 92/17460 (Smith-Kline Beecham) EP-A-0489577 (Celltech) EP-A-0489579 (Celltech) EP-A- 0497192 (Roche) US 5256657 (Sterling Winthrop) WO 92/13831 (British Biotechnology) WO 92/22523 (Research Corporation Technologies) WO 93/09090 (Yamanouchi) WO 93/09097 (Sankyo) WO 93/20047 (British Biotechnology) WO 93/24449 (Celltech) WO 93/244 (Celltech) EP-A-0574758 (Roche) WO 94/02447 (British Biotechnology) WO 94/02446 (British Biotechnology) WO 97/27174 (Shionogi) An especially preferred group of compounds for use in the present method are those described in WO 95/35275 and WO 95/35276, both of which are incorporated herein by reference. Typical compounds within these groups to be employed include: N-hydroxy-2 - [[2- (4-methoxy-phenoxy) et] - (toluene-4-sulfonyl) -amino] -acetamide; N-hydroxy-2 - [(4-phenoxy-ethyl) -toluene-4-sulfonyl) amino] -acetamide; N-hydroxy-2 - [(4-methoxy-benzenesulfonyl) nonyl-amino] -acetamide; 2 - [- Decyl- (toluene-4-sulfonyl) amino-N-hydroxy acetamide; 2-benzyl- (achane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(2-methoxy-benzyl) - (octan-1-sulfonyl) -amino] -acetamide; 2 - [(2-ethoxy-benzyl) - (octan-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(naphthalen-2-yl-methyl) - (octan-1-sulfonyl) -amino] -acetamide; 2 - [(4-chloro-benzyl) - (octan-1-sulfonyl) -amino] -N-hydroxy-acetamide, and salts, solvates, or hydrates thereof. Another class of matrix metalloproteinase inhibitors are the arylsulfonamides of the formula where Ar is a carbocyclic or heterocyclic aryl, and R, R1, and R2 include hydrogen, alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. These compounds are described in European Patent Number 0606046, incorporated herein by reference. Specific compounds for use in the present method include: N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (isobutyl) -amino] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (cyclohexylmethyl) -amino] acetamide; N-hydroxy-2 - [[4-m-ethoxy benzenesulfon I]] (cid o -hexy I) -amino] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (pheneti I) -aminojacetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (3-methyl I butyl I) -aminojacetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (sec-butyl) amino] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (tert-butyl) amino] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (4-fluorobenzyl) amino] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (4-chlorobenzyl) amino] acetamide; N-h id roxy-2 - [[4-methoxy benzenes ulfon il] (i so propi I) -aminojacetamide; N -h id roxy-2 - [[4-m ethoxy benzenes ulfon i I] (4-methylbenzyl) amino] acetamide; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl] (benzp) -amino] -1- [dimethylaminoacetyl] -piperidine hydrochloride; 4-N-hydroxycarbamoH] -4 - [[4-methoxybenzenesulfonyl (benzyl) -amino] -1- [3-picolyl] -piperidine dihydrochloride; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) -amino] -1- [carbomethoxymethyl] -piperidine hydrochloride; 4-N-hydroxy-carbamoyl trifluroacetate] -4 - [[4-m-ethoxy-benzene-s] -phonyl (benzyl) -am] - 1 -piperidine; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1- [t-butoxycarbonyl] -piperidine; 4-N-hydroxy-carbamoH] -4 - [[4-methoxybenzenesulfonyl (benzyl) -amino] -1- [methylsulfonyl] -piperidine; N-hydroxycarbamoyl hydrochloride] -4 - [[4-methoxybenzenesulfonyl (benzyl) -amino] -1- [4-picolyl-p-peridine; N-hydroxycarbamoyl] -4 - [[4-methoxybenzenesulfonyl (benzyl) amino] -1-morpholinocarbonyl] -piperidine hydrochloride; N- (t-Butyloxy) -2 - [[4-methoxybenzenesulfonyl (benzyl) amino] -2- (2- (4-morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (isobutyl) - amino-2- (2- (4-morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-picoli) -amino-2- (2 - [(4-morpholino ) ethyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -2- [2 - [(4-morpholino) ethyl] acetamide dihydrochloride; N-hydroxydihydrochloride; 2 - [[4-methoxybenzenesulfonyl] (2-methyI-thiazol-4-ylmethyl) amino] -2- [2- (4-morfoIino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] ] benzyl) amino] -2- [2- (4-thiomorpholino] etiI] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (benzyl) amino] -2- [2- (4- methylthiazol-4-ylmethyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (benzyl) amino] -2 - [(6-chloro pipe ronyl] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] ] (benzyl) amino] -2- [(1-pyrazolyl) methyl] acetamide; Nh id rox i -2- [[4- methoxybenzenesulfonyl] (3-picol i I) amino] -2- [3-picolyl] ] acetamide; N-hydroxy-2 - [[4-methoxybenzenesulfonyl- (benzyl) -amino] -2 - [(1-methyl-4-imidazolyl) methyl] acetamidate hydrochloride; N-hydroxy-2 - [[4-methoxybenzenesulfonyl- (isobutyl) -amino] -2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (3-picolyl) amino] -2 - [(1-methyl-4-imidazole) methyl] acetamide hydrochloride; N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-picolyl) amino] -2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride; Y N-hydroxy-2 - [[4-methoxybenzenesulfonyl] (2-methylthiazole-4-pmethyl) amino-2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride. Another group of small peptide metalloproteinase matrix inhibitors are described in U.S. Patent Nos. 5,270,326, 5,530,161, 5,525,629, and 5,304,604 (incorporated herein by reference). The compounds are hydroxamic acids, for example compounds of the formula R2 OR R3 R4 R ^ On-A-CH-CH-C-NH-CH-C-N-R5 CONHOH O where R1, R2, R3, R4 and R5 can be alkyl, A includes a hydrocarbon chain and n is 0 to 2. Typical compounds for use in the current method include the following: N- [2-lsobutyl-3- (N'-hydroxycarbonylamido) -propanoyl] -D-tryptophan methylamide; N- [2- i sobutyl-3- (N '-hydroxy carbon and the m id o) -p clothing noyl] -N-methyl-L-tryptophan methylamide; N- [2-lsobutyl-3- (N-hydroxycarbonylamido) -propanoyl] -L-3- (2-naphthyl) -alanine methylamide; N- [2-Isobutyl-3- (N'-hydroxycarbonylamido) -propanoyl] -L-tryptophan 2-hydroxyethylamide; N- [2-lsobutyl-3- (N'-hydroxycarbonylamido) -propanoyl] -L-tryptophan amylamide; N- [2-lsobutyl-3- (N'-hydroxycarbonylamido) -propanoyl] -L-tryptophan piperidinamide; N- [2-lsobutyl-3- (N'-hydroxycarbonylamido) -propanoyl-L-tryptophan dodecylamide; N- [2-lsobutyl-3- (N'-hydroxycarbonyl) amido) -propanoyl] -L-triflucan (S) -methylbenzylamide; N- [2-lsobutyl-3- (N'-hydroxycarbonylamido) -propanoyl] -L-tryptophan (6-phenylmethoxycarbonyl-amino-hexyl-1) amide; 2S-Hydroxy-3R- [1 S- (3-methoxy-2,2-dimethyl-p-ro-pyl-carb-amyl) -2,2-dimet-I-pro-p-p-amyl] -5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R- [1 S- (methylcarbamoyl) -2,2-dimethyl-propylammonium] -6- (4-chloro) phenol-hexahydroxamic acid; 2S-hydroxy-3R- [1 S- (methylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -octanohydroxamic acid; 2S-Hydroxy-3R- [1 S- (pyridin-2-ylmethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -5-meth yl-hexanohydroxamic acid; 2S-Hydroxy-3R- [1 S- (pyridin-3-ylmethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -5-meth yl-hexanohydroxamic acid; 2S-Hydroxy-3R- [1 S- (pyridin-4-ylmethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R- [1S- (Methylcarbamoyl-2,2-dimethyl-propylea rbamoyl] -4-methoxy-butanoh idroxamic acid; 2S-hydroxy-3R- [1S- (methylcarbamoyl-2,2-dimethyl -propylcarbamoyl] -4-benzyloxy-butanohydroxamic acid; 2S-hydroxy-3R- [1S- (methylcarbamoyl-2,2-dimethyl-propylcarbamoyl] -4-benzylthio-butanamide hydroxyand 2S-hydroxy-3R acid - [1 S- (methylcarbamoyl-2,2-dimethyl-bu te-3-ylcarbamoyl] -5-methyl-hexanohydroxamic acid; 2S-hydroxy-3R- [1S- (tert-butylcarbamoyl) -2,2- dimethyl-propylcarbamoyl] -5-methyl-hexanohydroxamic acid; 2S-hydroxy-3R- [1S- (N, N-dimethyl-carbamoyl) -2,2-d, methyl-propylcarbamoyl] -5-methyl acid -hexanohyd roxamic; 2S-hydroxy-3R- [1 S- (3-hydroxy-2,2-dimethyl-propylcarbamoyl) -2,2-dimethyl-1-propylcarbanoyl] -5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R- [1 S- (metpcarbamoH) -2,2-dimethyl-propyl-carbanoyl] -6-phenyl-hexanohydroxamic acid; 2S-hydroxy-3R- [1 S- (methylcarbamoyl) -2,2-dimethyl-butylcarbamoyl] -5-methyl-hexanohydroxamic acid; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-hydroxyethyl) amide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalaninyl-proline; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (2-hydroxyethyl) -N-methylamide; [4- (N-hydroxyamino) -2R-isobutyJsuccinyl] -L-phenylalaninyl-D-prolinol; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenpalaninyl-L-prolinol; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine- N- (5-N-methyl-pentiI carb oxa mide) 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; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) -amide sodium salt; [4- (N-h-idroxyamino) -2R-isobutylsucl and l] -L-phen Halan ina-N- (2-acetoxyethyl) amide; [4- (N-hydroxyamino) -2R-isubutyl-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-isobuyl-3S-methylisuccinyl] -L-phen Halan i-N- (2-hydroxyethyl) a mide; [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalaninyl-D-prolinol; [4-. { 4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide sodium salt; [4- (N-H-dioxamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide; [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] -L-phenylalanine-N- (3- (2-pyrrolidone) propyl) amide or a salt thereof; N2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -N6-tert-butyloxycarbonyl-L-lysine-N1-methylamide; N2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -N6-y-butyloxycarbonyl-N6- (4-hydroxyphenylthiometp) -L-lysine-N1- methylamide; N2- [4- (N-hydroxyamino) -3S- (2-thieny-thiomethyl) -2R-isobutylsuccinyl] -N6-ε-t-butyloxycarbonyl-L-lysine-N 1 -methylamide; N2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R-isobutylsuccinyl] -O-fer-butyl-L-threonine-N1-methylamide; N2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylthiomethyl) -2R isobutylsuccini I] -L-gluta min e-N1, N5-dimethylamide; N2- [4- (N-hydroxyamino) -3S- (4-hydroxyphenylsulfonylmethyl) -2R-isobutylsuccinyl] -N6-acetyl-L-lysine-N1-methylamide; 3-R- (3-Methoxycarbon-1-S-met-rbamoyl-propylcarbamoyl) -5-methyl-2S-2-propenyl-hexanohydroxamic acid; 3R- (1S-Methalocarbamoyl-2-t-ene-2-yl-ethylcarbamoyl) -5-methyl-2S-2-propionyl hexanohydroxamic acid; 3R- (3-etl-1S-methyIcanbamoyl-butylcarbamoyl) -5-methyl-2-S-2-propenyl-hexanohydixamic acid; 2S- (1 S-Methylcarbamoyl-2-oxadiazol-5-yl-ethylcarbamoyl) -5-methyl-2S-2-propenyl-hexanohydroxamic acid; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-oxymethylcarboxylic acid) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-oxymethylcarboxy-N-methylamide) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-oxymethylcarboxy-beta-alanine) phenylalanine, -N-methylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-oxymethylcarboxyglycine) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L- (4-oxymethylcarboxy-N-benzylamide) phenylalanine-N-m ethylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinH] -L- (4-cyano) phenylalanine-N-m ethylamide; [4- (N-hydroxyamino) -2R-isobulylsuccinyl] -L- (4-acetamido) phenylalanine-N-m ethylamide; [4- (N-h id roxia mino) -2R-isobut i Isu cornyl] -L- (4-oxymethylcarboxamide) -henylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- [2-thienhylthiomethylsuccinyl] -L- (4N-acetylamino) -henylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienhylthiomethylsuccinyl) -L- (4-N-methylsuccinylidene) phenylalanine-N-methylamide; [4- (Nh-d roxy mi no) -2R- Sobutil-3S- (4-am mofen i I-thiometp) succinyl] -L- (4-N- (methylsuccinylamide) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- ( 4-aminophenium-thiomethylsuccinyl] -L- (4-N- (4- (4-oxobutanoic acid) aminophenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- (4-hydroxyphenylthio -methyl) succinyl] -L- (4-N-methylsuccinylalide) phenylalanine-N-methylamide; [4 (N-hydroxyamino) -2R-isobutyl-3S- [4-hydroxyphenylthio-methyl) succinyl] -L- (4-N- (4- (4-oxabutanoic acid) aminophenylalanine-N-methylamide; [4- ( N-hydroxyamino) -2R-isobutyl-3S- (2-thienythiomethyl) -succinyl] -L- (4-oxymethylcarboxymethyl) phenylalanine-N-methylamide; [4 (N-hydroxyamino) -2R-is-thi-3S - (2-thienyltiomethyl) -succinyl] -L (4-N- (acetoxymethylcarboxylic) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) -succinyl] -L-4-oximemethylcarboxyglycyl methyl ester) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) -succinyl ] -L-Oxymethylcarboxyglycine) phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S-methyl-succinyl] -L-4- (oxymethylcarboxyglycyl methyl ester) -phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S-methyl) -succinyl] -L-4- (oxymethylcarboxyglycine) -phenylalanine-N-methylamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-4-oxymethylnitrile) phenylalanine-N-methamide; [4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-3- (1- (2-methylaxycarbonyl) -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.-methylamide; 2- [Benzyl- (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(2-methoxy-benzyl) - (octane-1-sulfonyl) -amino] -acetamide; 2 - [(2-Ethoxy-benzyl) - (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(naphthalen-4-H-methyl) - (octane-1 -sulfo n i I) -aminojacetamide; 2 - [(4-Chloro-benzyl) - (octane-1-sulfonyl) -amino-J-N-hydroxy-acetamide; N2- [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl] -L-leucine-N1-m ethylamide; N2- [3S-hydroxy4- (N-hydroxyamino) -2R-isobutyl-succinyl)] - S-methyl-L-glutamic acid N1-methylamide; N2- [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutylsuccinyl) J-L-phenylalamide-N1-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S- (t-indolimethyl) succinyl i IJ-L-phen Halan i-N-methylamide; [4- (N-hydroxyamino) -2R-isobutyl-3S-phenylthiomethyl] -succinyl] -L-phenylalanine-N-methylamide; 2S- (4-Methoxyphenylsulfanylmethyl) -3R- (2-phenyl-1S-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (3-Chlorophenylsulfanylmethyl) -3R- (2-phenyll-1S-methylcarbamoylethylcarbamoyl) 5-methyl-exanohydroxamic acid; 2S- (Fenpsulfanylmethyl) -3R- (2-phenyl-1S- (pyrid-3-ylmethylcarbamoyl) -ethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (3-Metpphenylsulfanylmethyl) -3R- (2-phenyl-1S-metpcarbamoylethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (Thien-2-ylsulfanylmetp) -3R- (2- (4-carboxymethoxyphenyl) -1 S-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (T-ene-2-ylsulfanylmethyl) -3R- (2-phenyl-1 S- (pyrid-3-ylmethylcarbamoyl) -etylcarbamoyl) -5-meth yl-hexanohydroxamic acid; 2S- (4-Hydroxyphen and Isulfanylmethyl) -3R- (2-phenyl) -1S- (pyrid-3-ylmethylcarbamoyl) -ethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (2-thien-2-ylsulfanylmethyl) -3R- (2-naph-2-yl-1S-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanoh idroxamic acid; 2S- (4-hydroxyphenylsulfanylmethyl) -3R- (2R-hydroxy-1S-methylcarbamoyl-propylcarbamoyl) -5-methylhexanehydroxamic acid; 2S- (4-hydroxyphenylsulfanylmethyl) -3R- (5-acetamido-1S-metpcarbamoyl-pentylcarbamoyl) -5-methyl-hexanoh idroxamic acid; 2S- (4-hydroxyphenylsulfanylmethyl) -3R- (3- [1,1-dimethylethoxycarbonylJ-1S-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexahydroxy aminide; 2S- (Tien-2-lysulfonylmethyl) -3R- (2-phenyl-1 S -methylcarbamoylethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 3S- (2- [4-Acetamido-phenyl] -1 S-methylcarbamoyl-ethylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (4-Phthalimido-butyl) -3R- (3-methyl-1S-ethoxycarbo-nylmethylcarbamoyl-butylcarbamoyl) -5-methyl-hexanohydroxamic acid; 3R - (- 4- [4-Methoxy-phenyl] -1S-methylcarbamoyl-ethylcarbamoyl) -2S, 5-dimethyl-he xa-n-hydroxamic acid; 3R- (2-Phenyl-1 S- [2-oxo-pyridol-1-HJ-propylcarba-moylethylcarbamoyl) -5-methyl-hexanehydroxamic acid; 3R- (2- [4-Methoxy-pheny [3-1 S-methylcarbamoyl-ethylcarbamoy I) -5-methyl-hexonobid-oxoamidohydroxamic acid; 3R- (2-Phenyl-1 S- [pyrid-3-ylmethylcarbamoyl] -ethylcarbamyl) i-5-methyl-hexahydroxamic acid; 3R- (2,2-Dimethyl-1S-metpcarbamoyl-propylcarbamoyl) -5-methylhexanohydroxamic acid; Isobuti I malonoyl-L-alanine-furfuri lamida hydroxamate; 2-lsobutyl-3-carbonyl-3 '- (4-acetyl aniline-propionic acid; N-benzyloxycarbonyl-a-phosphonoglycyl-L-alanine furfurylamide; [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-h id roxia mino) -2R-isobu ti l-3S- (4-hydroxyphenylthiometp) succiniI] -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) succini] 3-L-phenylalanine-N-methylamide; [41 N-Hydrioxyamino) -2R-isobutyl-3S- (3-chlorophenthiomethyl) succinyl] -L-phen Hala nina-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-h id roxia mi no) -2R-iso buty I-3S-phenylsulfinylmethyl) succinyl] -L-phenylalanine-N-methylamide; 3R- (3-Methoxycarbonyl-1S-methylcarbamoyl-propyl-carbamoyl) -5-methyl-2S-phenylsulfanyl-1-methylhexanoyl idroxyacid; 3R- (3-Methoxycarbonyl-1S-methylcarbamoyl-propyl-carbamoyl) -5-methyl-2S- (thien-2-ylsulfanylmethyl) -hexanehydroxamic acid; 2S- (4-Methoxyphen-ylsulfanylmethyl) -3R- (3-methoxycarbonyl-1 S -methylcarbamoyl-propylcarbamoyl) -5-methylene-hexanohydroxamic acid; 2S - (- 4-Amlno-phenylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-pro-pilbabamoyl) -5-methyo-hexanahydroxamic acid; 2S- (Ethylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoypropylcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (Acetylsulfanylmethyl) -3R- (3-methoxycarbonyl-1 S -methyl) carbamoylpropylcarbamoyl) -5-methyl-hexanahydroxamic acid; 2S- (Benzyl-sulfinylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-proppcarbamoyl) -5-methyl-hexanohydroxamic acid; 2S- (Ier-Butylsulfanylmethyl) -3R- (3-methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl I) -5-methyl-hexa-hydroxylhydroxamic acid; 2S-Thiomethyl-3R- (3-methoxycarbonyl-1S-methylcarbamoyl-hexanohydroxamic acid; 2S- (4-Hydroxy-phenylsulfanylmethyl) -3R- (2-ene-butoxycarbonyl-1S-methylcarbamoyl-ethylcarbamoyl) -5-methyl ester; 1-Hexanohydroxamic; 2S- (4-Hydroxy-phenylsulfinylmethyl) -3R- (3-methoxycarbonyl-1-Smethylcarbamyl-pro-pilca-r-amoyl) -5-methyl-hexanohydroxamic acid; 2S- (4-Hydroxy-phenylsulfonylmethyl) -3R- (3-methoxycarbonyl-IS-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexanohydroxamic; [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; [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) -morph or lina] amide; [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -L-phenhalan I-N- (3-aminomethylpyridin) aminide hydrochloride; and [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] -L-penylalanine-N- [4- (2-aminoethyl) -morph or lina] amide hydrochloride. In a preferred embodiment, tricyclic butyric acid derivatives which are inhibitors of the metalloproteinase matrix are used to treat or prevent heart failure and ventricular dilatation according to this invention. A preferred group of tricyclic butyric acid derivatives is defined by the formula: X where one of R1 or R2 is -C-CH-ICHJa-C-R5 RR where X is O, N-OR6 wherein R6 is hydrogen, - (CH2) n-aryl wherein n is zero or an integer from 1 to 5, alkyl or - (CH2) n-cycloalkyl or wherein n is as defined above, or NN-R6 wherein R6 and R6a are each the same or different and each is as defined R6a above for R6; R and Ra are each the same or different and each is hydrogen - (CH2) n-aryl wherein n is as defined above, - (CH2) n-heteroaryl wherein n is as defined above, - (CH2) p-R7- (CH2) q-aryl wherein R7 is O or S and p and p are each zero or an integer from 1 to 5 and the sum of p + q is equal to an integer of 5, - (CH2) p-R7- (CH2) q-heteroaryl wherein p, q, and R7 are as defined above, alkyl, - (CH2) n-cycloalkyl wherein n is as defined above, or - (CH 2) r-NH 2 wherein r is an integer from 1 to 9; a is zero or an integer from 1 to 3; R5 is OH, OR6 where R6 is as defined above, NR6 where R6 and R6a are each the same or different and are as defined above for R6, or R6a NH-OR6 wherein R6 is as defined above; R3 and R4 are each the same or different and each is hydrogen, alkyl, NO2, halogen, OR6 wherein R6 is as defined above, CN, C02R6 wherein R6 is as defined above, SO3R6 wherein R6 is as was previously defined, CHO, O -C-R where R is as defined above, OR -CN-R6 wherein R6 and R6a are each the same or different and are as R6a as defined above for R6, or - (CH2) nN-R6 where R6 and R6a are each the same or different are as define R6a above for R6; W, W1, Z and Z1 are each the same or different and each is CR3 where R3 is as defined above, or N provides only one of W or W1 is N and / or only one of Z or Z1 is N and Y is -N- where R is as defined above, R -O-, -S- (0) m- where m is zero or an integer of 1 or -CH2- C-, OR -C- where R is as defined above, N-OR6 -CH- where R6 is as defined above, OR6 -C- where R6 and R6a are the same or different and are as defined above for R6, R6a -C-N- where R6 is as defined above, O Rf -N-C- R60 wherein R6 is as defined above, -C-O-, O -O-C-, O -CH2-0-, -O-CH2-, -CH2-S (O) m- where m is as defined above, -S (0) m -CH2- where m is as defined above, - CH2-N- where R6 is as defined above, Rb -N-CH2- wherein R6 is as defined above, R6 -CH = N-, or -N = CH-; with the proviso that when X is O and R5 is not NH-OR6, at least one of R or Ra is not hydrogen; and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Typical compounds of this class include: 4-Dibenzofuran-2-yl-hydroxyimino-butyric acid; 2- (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -methylpentanoic acid; 2- (2-Di-benzofuran-2-y1- 1-2 -hydroxy-1-yl) -5-phenyl-pentanoic acid; 4-Dibenzofuran-2-yl-4-hydroxy-2-phenethyl-butyric acid; 5- (4-Chloro-phenyl) -2- (2-dibenzofuran-2-yl-2-hydroxyimino-ethyl) pentanoic acid; 2- (2-Dibenzofuran-2-yl-2-hydroxyimino-etiI) -5- (4-fluoro-phenyl) pentanoic acid; 2- (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5- (4-methoxy-phenyl) pentanoic acid; 2- (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5-p-tolyl-pentanoic acid; 3- (D 2 -benzofuran-2-yl-hydroxy-1-yl-methy1) -5-methy1-hexanoic acid; 3- (Dibenzofuran-2-yl-hydroxyimino-methyl) -6-phenyl-hexanoic acid; 3- (Dibenzofuran-2-yl-hydroxy-amino-methyl) -5-phenyl-pentaanoic acid; 6- (4-Chloro-phenyl) -3- (dibenzofuran-2-yl-hydroxy-methyl) hexanoic acid; 3- (Dibenzofuran-2-yl-hydroxyimino-methyl) -6- (4-fluoro-phenyl) hexanoic acid; 3- (Dibenzofuran-2-yl-hydroxyimino-methyl) -6-4-4-methoxyphenyl) hexanoic acid; and 3- (Dibenzofuran-2-yl-hydroxyimino-methyl) -6-p-tolyl-hexanoic acid; and and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. The tricyclicbutyric acids have an a-amino substituent which are defined by the formula: wherein X is O, NOR9, S, OH, SH, or; / R7 N- -N \ R7 are independently 7a hydrogen, C -? - C2o alkyl or substituted C? -C2o alkyl, aryl of (CH2) 0-6, heteroaryl of (CH2) 0-6, or cycloalkyl from (CH2) 0-6; R 1 and R 2 independently are hydrogen, C 1 -C 20 alkyl or substituted C 1 -C 20 alkyl, halo, CN 2 NO, CHO, COR 6, COOR 6, SO 3 R 6, OR 6, CONR 4 R 5, aryl of (CH 2) 0 6, heteroaryl (CH2) 0-6, or cycloalkyl of (CH2) oe; Re is hydrogen, C 1 -C 2 alkyl or substituted C 1 -C 20 alkyl; aryl is phenyl or substituted phenyl; R 3 is hydroxy, C 1 -C 2 0 -alkyl or C 1 -C 20 -O-substituted alkyl aryl of O- (CH 2)? -3, or NHOR 6; R 4 and R 5 independently are hydrogen, C 1 -C 20 alkyl or substituted C 1 -C 2 alkyl, (CH 2) 0 6 -aryl, (CH 2) or 6-heteroaryl; or one of R4 and R5 is hydrogen and the other is: COR8, CONRsRg, CSNRsRg, COOR8. COSR8, COCHR8, NRiRz, CON-CONRsRg, Ri CON-COORß, Ri CON-COSRß, or Ri CON-S02NR8R9; Ri CON-SO3R8; Ri Y is -N-, Ri O-, -S (0) or, 1 or 2, • CH2-, C-, OR C-, NOR8 -CH-, 10 OR8 -C-, fifteen - . 15 -C-N-, OR R8 N-C-, -CO, O -CH2-0-, -0-CH2-. -CH2S (O) 0, 1 or 2, -S (0) or, 1 or 2-CH2- -CH2-N-.

Rf N-CH2-, R8 -CH = N, or -N = CH-; - Re and Rg independently are hydrogen C1-C20 alkyl or substituted C1-C20 alkyl, (CH) o-6-aryIo, (CH2) o -6-heteroaryl, or (CH2) o -6-cycloalkyl; W, W1, Z, and Z1 independently are CR1 or N; and the pharmaceutically acceptable salts, isomers, stereoisomers and solvates thereof. Specific examples of the compounds to be employed in the present method include: (S) -4-dibenzofuran-2-yl-4-oxo-2- (2,2,2-trifluoroacetylamino) -butyric acid; (R) -Dibenzofuran-2-yl-4-oxo-2- (2,2,2-trifluoroacetylamino) -butyric acid; (S) -2-amino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) 4-Dibenzofuran-2-yl-2- [3- (2,6-d¡¡-propyl-phenyl) -ureido] -4-oxobutyric acid; (S) -2-Benzoylamino-dibenzofuran-2-yl-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (3-phenyl-propionylamino) -butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (7-pheny-heptanoylamino) -butyric acid; (S) -2 - [(Biphenyl-4-carbonyl) -amino] -4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-H-4-oxo-2- (octanoylamino) -butyric acid and; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (dodecanoyl-amino) -butyric acid; (S) 4-Dibenzofuran-2-H-4-oxo-2- (2,2,2-trifluoroacetylamino) -butyric acid; (R) -4-Dibenzofuran-2-yl-4-oxo-2- (2,2,2-trifluoroacetylaminobutyric acid; (S) -2-amino-4-dibenzofuran-2-H-4-oxo-butyric acid; (S) -2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-d.benzofuran-2-yl-2- [3- (2,6-diisopropyl-phenyl) -ureido] -4-oxobutyric acid; (S) -2-Benzoylamino-4-dibenzofuran-2-H-4-oxo-butyric acid; Acid (S) -4-d i benzofura n-2-yl-4-oxo-2-f eni laceti my non-butyric my; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (3-phenyl-propionyl-amino) -butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (7-phenyl-heptanoyl-amino) -butyric acid; Acid (S) -2 - [(b-phenyl-4-carbonyl) -amino] -4-dibenzofuran-2-yl-4-oxo-butyric acid (S) -4-dibenzofuran-2-H4-oxo -2- (octanoylamino) -butyric; and (S) -4-d-benzofura n-2-yl-4-oxo-2- (dodecanoyl-amino) -butyric acid. Metalloproteinase matrix inhibitors include the compounds of the formula where M is an amino acid derivative alpha (L) that has the structure X is O, S, S (0) ", CH2, CO, or NH; R is a side chain of a natural alpha amino acid; R1 is C1-C5 alkoxy, hydroxy, or -NHOR5; R2 and R4 are independently hydrogen, C?-C5 alkyl, -N02, halogen, OR5, -CN, -C02R5, -SO3R5, -CHO, -COR5, CONR5R6, - (CH2) nNR5R6, -CF3, or -NHCOR5; Each of R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides, and prodrugs thereof. Specific compounds of this class to be employed include: (L) -2- (d.benzofuran-2-sulfonylamino) -4-methylpentanoic acid; Acid (L) -2- (dibenzofuran-2-sulfonyl! Amino) -3-methylpentanoic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-phenylpropionic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -propionic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid; Acid (dibenzofuran-2-sulfonylamino); acetic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -succinic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-tritylsulfanyl-propionic acid; Acid; (L) -2- (dibenzofuran-2-sulfonylamino) -3- mercapto-propionic; Acid; (L) -2- (dibenzofuran-2-sulfonylamino) -3-methylpentanoic acid hydroxamide; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-pentanoic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-phenyl-propionic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -propionic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid; Acid (dibenzofuran-2-sulfonylamino) -acetic; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -succinic acid; Acid (L) -2- (dibenzofuran-2-sulfonylamino) -3-tritylsul-fanyl-propionic acid; Acid (L) -2- (dibenzofuran-2-sulfonyllamino) -3-mercapto-propionic acid; and Acid; (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic, hydroxyamide.

Tricyclic sulfonamides are defined by the formula: wherein Q is an unnatural amino acid: X is O, S, S (0) n, CH2, CO or NH; R2 and R4 are independently hydrogen, C1-C5 alkyl, -NO2, halogen, -OR5, -CN, -CO2R5, -SO3R5, -CHO, -COR5, -CONR5R6, - (CH) nNR5R6, -CF3, or - NHCOR5; Each of R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides, and prodrugs thereof. Specific compounds of such compounds include: (S) -2- (dibenzofuran-2-sulfonylamino) -4-phenyl-butyric acid; 2 (S) -3 - [(dibenzofuran-2-sulfonylamino) -methyl] -5-methyl-hexanoic acid; Acid (S) -2- (d i benzofura n-2-s ulfon i la mino) -4-f eni I-butyric; and 2 (S) -3 - [(dibenzofuran-2-sulfonylamino) -methyl] -5-methyl-hexanoic acid. Another general class of metalloproteinase matrix inhibitors, which are useful for combining with statins to treat and prevent heart failure and ventricular dilatation, are the biphenylbutyric acid derivatives, including the compounds of the formula: wherein R and R1 are the same or different and are hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, -OR6 wherein R6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl, -N-R6 wherein R6 and R6a are the same or R 6a different and are as defined in the above for R, O • O-C-R6 where R6 is as defined in the above, -NH-C-R where R is as defined in the above, OR -S-C-R6 wherein R6 is as defined in the above, -SR6 wherein R6 is as defined in the above, OR -C-R6 wherein R6 is as defined above, -CH2-OR6 where R6 is as defined above, • CH2-N-Rb where Rb and Rba are the same or different and are as defined in the above for R6 O • C-N-Rb where R and R a are the same or R 6a different and they are as defined in the above Re O S-R6 where R6 is as defined in the above, O Cycloalkyl, or heteroaryl, with the proviso that R and R1 are both hydrogen; R2 is -OR6 where R6 is as defined above, or N-RD where RD and D R6oaa are the same or R 6a different and they are as defined in the above for R6; R, R, R, and R are the same or different and are hydrogen, fluorine, alkyl, - (CH2) p-aryl where n is an integer from 1 to 6, - (CH2) n-heteroaryl where n is as defined in the above, • (CH2) n-cycloalkyl where n is as defined in the above, - (CH2) pX- (CH2) q-aryl where X is O, S, SO, S02, or NH, ypyq are they are zero or an enetero of 1 to 6, and the sum of p + q is not greater than six, - (CH2) pX- (CH2) q-heteroaryl wherein X, p, and q are as defined above, or - (CH2) n-R7 where R7 is N-phthalimido, N-2,3-naftilimido, -OR6 where R6 is as defined above, -N-R6 where R6 and R6a are the same or R 6a different and are as defined in the above for R6, -SR6 where R6 is as defined in the above, OR S-R6 where R6 is as defined in the above, OR S-R6 where R6 is as defined in the above, OR OR O-C-R6 where R6 is as defined in the above, OR • N-C-R0 where R 6b, y, D R6oaa are the same R 6a or different and they are as defined in the above for R6, O • S-C-R6 where R6 is as defined above, OR • C-OR where R is as defined in the above, OR -C-N-R where R6 is as defined in the above, OR -C-N-Rb where Rb and R 6aa are the same R 6a or different and they are as defined in the above for Rf n is as defined in the above; R5 is OH or SH; with the proviso that R3, R3a, R4, and R4a are hydrogen or at least one of R3, R3a, R4, or R4a is fluorine; and correspondingly isomers thereof; or a pharmaceutically acceptable salt thereof. Typically, compounds of this class are routinely used in combination with a statin to treat and prevent a cardiac deficiency including: 4- (4-chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4- (4'-Bromo-bi faith nyl-4-yl) 4-hydroxyimino-butyric acid; 4- (4'-Chloro-biphenyl-4-yl) -4- (dimethylhydrazono) -butyric acid; 4- (4'-Fluoro-biphenyl-p) -4-hydroxyimino-butyric acid; (±) -4- (4l-Chloro-biphenyl-4-yl) -4-hydroxy-butyric acid; Acid (4, -bromo-2, -fiuoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; Acid (±) -4- (4 '(chloro-b-phenyl-4-yl) -3-fluoro-4-oxo-butyric acid; 4- (2 \ 4-d, chloro-biphenyl-4) -yl) -4-hydroxy-butyric acid: 4- (2 ', 4'-difluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; acid (±) -4- (4-chloro) -biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phenylpropyl) -butyric acid (±) -4- (4l-chloro-biphenyl-4-yl) -4-hydroxyimino-2 -fluoro-2- (2-phenylethyl) -butyric Acid (±) -4- (4'-chloro-bipheni-4-yl) -4-hydroxyimino-2-fIuoro-2- (3-phthalimidopropyl) -butyric Acid (±) -4- (4'-Chloro-biphenyl-4-yl) 4-hydroxyimino-2-fluoro-2- (phenylthiomethyl) -butyric acid: 4- (4'-chloro-2'-f I or oro-bif in i I -4- i I) -4-hydroxy-butyric acid; 4-hydroxyimino-4- (4, -trifluoromethyl-biphenyl-4-yl) -butyric acid; 4- (4, -chloro-biphenyl-4-yl) -4-methoxyimino-butyl; acid (+) - 4,4'-cioro-biphenyl-4-H) -2-fluoro-2- [2- (1,3-dioxo-1,3-dihydroeisoindol-2-yl-ethyl] -4-hydroxyimino-butyric; (±) -4- (4, -chloro-bipheni-4-yl) -4-hydroxyimino-2-fluoro-2- (1 H -indol-3-yl) methyl-butyric acid; Acid (±) -4- (4, -chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methylbutyric acid; (+) -2- [2- (4, -chloro-biphenyl-4-yl) -2-hydroxyiminoethyl] -2-fluoro-6-phenyl-hexanoic acid; Acid (+) -4- (4, -chloro-biphenyl-4-yl) -2-fluoo-2- [2- (1, 3-dioxo-l, 3-di h id robenzo [F] ¡soindol- 2-H) -ethyl] -4-h id roxii my non-butyric; Acid (+) -2- [2- (4, -chloro-biphenyl-4-yl) -2-hydroxyiminoethyl] -6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) - 2-fluorohexaenoic; (±) -4- (4, -chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- [2- (phenetepcarbamoyl) -ethyl] -butyric acid; 4- (4, -chlorobiphenyl-4-yl) -3,3-difluoro-4-hydroxyimino-butyric acid; (+) - (4, -chloro-biphenyl-1-yl) -3,3-dimethyl-2-fluoro-4-h idroxylmino-butyric acid; (+) - (4'-Chloro-biphenyl-4-yl) -2,2-dimethyl-3-fluoro-4-hydroxyimino-butyric acid; 4 (4'-Chlorobiphenyl-yl) -2,2-difluoro-4-hydroxyimino-butyric acid; and Acid; 4- (4'-Chloro-biphenyl-4-yl) -2,2,3,3-tetrafluoro-4-h idroxy-non-butyric acid; A compound selected from the group consisting of: 4- (4'-chloro-biphen-l-4-yl) -4-hydroxy-im-butyric acid; 4- (4I-bromo-biphenyl-4-yl] -4-hydroxyimino-butyric acid; 4- (4'-Cl-oro-bifenyl-4-i) -4- (di-methyl-id-reason) - Butyric; 4- (4, -flour-biphenyl-4-yl) -4-hydroxyimino-butyric acid; (+.) - 4- (4'-Chloro-biphenyl-4-yl) -4-hydroxy-butyric acid; 4- (4'-bromo-2'-fluoo-bifen and I-4-yl-h idroxy-non-butyric acid; acid (±) -4-4'-chloro-biphenyl-4-yl) -3 acid; -fluoro-4-oxo-butyric; 4- (2,, 4'-dichloro-biphen-4-yl) -4-hydroxyimino-butyric acid; 4- (2l, 4'-dichloro-biphenyl) -4-yl) -4-hydroxyimino-butyric acid; (±) -4- (4, -chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phenylpropyl) butyric acid; (±) -4- (4, -chloro-bifenp-4-yl) -4-hydroxyimino-2-fluoro-2- (2-phenylethyl) -butyric acid: (+) -4- (4, -chloro- biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2- (3-phtha-1-imidopropi-butyric acid; (+.) - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino- 2-fIuoro-2- (phenylthiomethyl) -butyric acid; 4- (4'-chloro-2'-f-Iooro-bif eni 1-4-i) -4-h idroxy-butyric acid; 4-Hydroxyimino-4- (4, -trifluoromethyl-biphenyl-4-yl) -butyric acid; 4- (4'-Cioro-biphenyl-4-H) -4-methoxyimino-butyric acid; Acid (+) -4- (4'-chloro-biphenyl-4-yl) -2-fIuoro-2- [2- (1,3-di-oxo-1,3-dihydro-isoindol-2-) i I) -ethyl] -4-h id roxii my non-butyric; Acid (±) -4- (4'-4-chloro-bif eni l-4-yl) -4-h id roxii m ino-2-fluoro-2- (1H-indol-3-H) methyl-butyric; (±) -4- (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methylbutyric acid; Acid (±) -2- [2- (4'-C-loro-biphenyl-4-yl) -2-hydroxyiminoethyl] -2-fluoro-6-phenyl-hexanoic acid; (+) -4- (4, -chloro-biphenyl-4-yl) -2-fluoro-2- [2- (1,3-dioxo-1,3-dihydrobenzo [F] isoindoI-2-yl) -ethyl] -4-hydroxyimino-butyric; Acid (±) -2- [2-4-4, .- cORO-biphenyl-4-yl) -2-hydroxyiminoethyl] -6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2-fluoro-hexanoic; (±) -4- (4l-Chloro-biphenl-4-yl) -4-hydroxyimino-2-fluoro-2- [2- (phenyl-etpcarbamoyl) -ethyl] -butyric acid; 4- (4'-Chloro-biphenyl-4-yl) -3,3-difluoro-4-hydroxyimino-butyric acid; (+) -4- (4'-Chloro-biphenyl-4-yl) -3,3-dimethyl-2-fluoro-4-hydroxyimino-butyric acid; Acid (±) -4-4, -chloro-biphenyl-4-H) -2,2-dimethyl-3-fluoro-4-hid roxii my no-butyric; 4- (4'-Chloro-bife nyl-2-yl) -2,2-difluoro-hydroxyimino-butyric acid and 4- (4'-chloro-biphenyl-4-yl) -2,2,3 , 3-tetrafluoro-4-hydroxyimino-butyric acid. The biphenyl sulfonamides are also particularly good in the present method. Such compounds include those of the formula: wherein: R1 is C6-C6 alkyl, halo, nitro, NR4R5, cyano, OR4, and COOR4; R 2 is C 1 -C 2 alkyl, optionally substituted by phenyl, substituted phenyl, NR 4 R 5, OR 6, NH carboxy, carboxamido, H2N-C-NH-, thio, methylthio, indole, imidazole, phthalamido, phenyl, and substituted phenyl; R3 is OH, C? -C6 alkyl, or NHOH; R4 is hydrogen, Ci-Cß alkyl, or C-t-Cß alkanoyl; R 5 is hydrogen or C 1 -C 2 alkyl; and R6 is hydrogen, Ci-Cß alkyl, Ci-Cß alkanoyl, phenyl or substituted phenyl.

Specific compounds which may be employed include a compound of the above formula wherein R 1 is in the 4 'position. Another class of metalloproteinase matrix inhibitors useful in the present method are the substituted heterocyclic derivatives of phenylbutyric acid, for example those defined by the formula: Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 where R5 is as defined above, NHCOR5 where R5 is as defined above, 2-naphthyl or heteroaryl; R1 is selected from hydrogen, methyl, ethyl, N02, halogen, OR5 wherein R5 is as defined above, CN, C0 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above; R2 and R3 are the same or different and independently selected from hydrogen, alkyl, - (CH2) v-aryl wherein v is an integer from 1 to 5, - (CH2) v-heteroaryl wherein v is as defined in the above, - (CH2) pX- (CH2) q -aril where X is O or S ypyq is each zero or an integer from 1 to 5, and the sum of p + q is not greater than an integer of 5, - (CH2) pX- (CH2) q -heteroaryl wherein X, p, and q are as defined above, - (CH2) tNR6R6a, where t is zero or an integer from 1 to 9 and R6 and R6a each is the same or different and are as defined above for R5, - (CH2) VSR5, wherein v and R5 are as defined above, - (CH2) vC? 2R5, where v and R5 are as defined above, or - (CH2) vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above; R3 is additionally - (CH2) rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindoI-2-yl, or 1,3-dihydro-1 , 3-dioxo-benzo [f] isoindol-2-yl; And it is CH or N; 0 where R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 with the proviso that When Z is then R4 must be OH, 0 c = o, C = NOR5 where R5 is as defined above, or C = N-NR6R6a where R6 and R6a are the same or different and are as defined above for R5; W is -CHR5 wherein R5 is as defined above; N is zero or an integer of 1; R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C = 0 or NHOR9 wherein R9 is hydrogen, alkyl or benzyl; and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Especially preferred MMP inhibitors have the formula Ar is selected from phenyl, phenyl substituted with alkyl, N02, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 where R5 is as defined above, NHCOR5 wherein R5 is as defined above, 2-naphthyl or heteroaryl; R1 is selected from hydrogen, methyl, ethyl, N02, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above; R2 and R3 are the same or different and independently selected from hydrogen, alkyl, - (CH2) v-aryl wherein v is an integer from 1 to 5, - (CH2) v-heteroaryl wherein v is as defined above , - (CH2) v-cycloalkyl wherein v is as defined above, - (CH2) pX- (CH2) q-aryl wherein X is O or S and p and p is each zero or an integer from 1 to 5, and the sum of p + q is not greater than an integer of 5, - (CH2) pX- (CH2) q-heteroary where X, p, and q are as defined above, - (CH2) tNR6R6a, where t is zero or an integer from 1 to 9 and R6 and R6a each is the same or different and are as defined above for R5, - (CH2) VSR5, where v and R5 are as defined above, - (CH2KCO2R5 , wherein v and R5 are as defined above, or - (CH2) vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above; R3 is additionally - (CH 2) rR7 where r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo- benzo [f] isoindol-2-yl; And it is CH or N; 0 where R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 with the proviso that, OH when Z is C then R must be OH,, 10 c = o, C = NOR5 where R5 is as defined above, C = N-NR? 6 ° nR6aa where R ° and R 6baa are the same or different and are as defined above for R5; W is -CHR5 wherein R5 is as defined above; n is zero or an integer of 1; R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C = 0 or NHOR9 wherein R9 is hydrogen, alkyl or benzyl; and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred compounds to be employed include: 4-Oxo-4- [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; 4-Oxo-4- [4- (4-phenyl] -piperidin-1-yl) -phenyl] -butyric acid; potassium salt; N-Hydroxy-4-oxo-4-4- (4-pheny1-piperidin-1-yl) -phenyl] -butyramide; E / Z-4-hydroxyimino4-4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; Acid E / Z-4-benzyloxy-amino-4-4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid 4-Oxo-4- [4 - (- pheny1-piperazin-1-yl) ) -phenyl] -butyric; Acid (i?) - 3-metp-5-oxo-5- [4- (4-phenyl-piperidin-1-yl) -phenyl] -pentanoic acid; 4-Oxo-4- [4- (4-phenyl-p-pyridin-1-yl) -phenyl] -butyric acid; 4-Oxo-4- [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; potassium salt; N-Hydroxy-4-oxo-4- [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyramide; E / Z-4-hydroxyimino-4- [4- (4-phenyl-piperidin-1-H) -phenyl] -butyric acid; Acid E / Z-4-Benzyloxyimino-4- [4- (4-phenyl-piperidin-1-yl) -phenyl-butyric acid 4-Oxo-4- [4- (4-phenyl-piperazin-1-yl) phenyl] -butyric; Y Acid (±) 3-metp-5-oxo-5- [4- (4-phenyl-piperidin-1-yl) -phenyl] -pentanoic acid; A compound which is 4-oxo-4- [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid. The similar compounds which are derivatives of the sulfonamide have the formula Ar- (CH2) where: Ar is selected from phenyl; phenyl substituted with alkyl, -N02, halogen, -OR5, -CN, -C02R5, -SO3R5, -CHO, -COR5, -CONHR5, -SO3R5, -CHO, -COR5, -CONHR5, -NHR5, or -NHCOR5; heteroaryl; or 2-naphthyl; R1 is hydrogen, methyl, -N02, -Cl, -NH2, -NHC02CH3, -OH, or -C02H; R2 and R3 are the same or different and are independently selected from hydrogen, alkyl, aryl of - (CH2) V, heteroaryl of - (CH2) V, cycloalkyl of - (CH2) V, aryl of - (CH2) PX- ( CH2) q? heteroaryl of - (CH2) p-X- (CH2) q, - (CH2) tNR6R6a, - (CH2) VR7, - (CH2) vC02R5, - (CH2) vCONR6R6a, or - (CH2) VSR5; m is zero or 1; And it is CH or N; with the proviso that when m = 1, Y is not N; z is zero or 1: W is -CHR8; n is zero or 1; R4 is -OH, -NR6R6a, or -NHOR9; R5 is hydrogen or alkyl; v is 1 to 5; X is O or S; p and q are independently 1 to 5, with the proviso that p + q is not greater than 5; t is 1 to 9; R6 and R6a are each the same or different and are hydrogen or alkyl; R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo-benzo [f] isoindol-2-yl; R8 is hydrogen or alkyl; and R9 is hydrogen, alkyl, or benzyl; or a pharmaceutically acceptable salt thereof. Specific sulfonamide derivatives for use in the present method include: [4- (4-phenylapiperidin-1-yl) -benzenesulfonylamino] -acetic acid; N-Hydroxy-2- [4- (4-phenyl-p-peridin-1-yl) -benzenesulfonyl-amino] acetamide; 3- [4-4-phenyl-p.peridin-1-yl) -benzenesulfonyl] -propionic acid; (R) -4-Methyl-2- [4- (4-phenyl-p-piperidin-1-yl) -benzenesulfonylamino or] -pentanoic acid; (S) -4-methyl-2- [4- (4-phenH-piperidin-1-yl) -benzenesulfonylamino or] -pentanoic acid; (S) -3-phenyl-2- [4- (4-phenyl-p-peridin-1-yl) -benzenesulfonyl-amino or] -propionic acid; (R) -3-phenyl-2- [4- (4-phenyl-piperidin-1-H) -benzenesulfonylamino or] -propionic acid; (S) -3- (1H-Indol-3-yl) -2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -propionic acid; (+.) - 5-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -pentanoic acid; [4- (4-Phenyl-piperazin-1-yl) -benzenesulfonylamino] -acetic acid; Acid { [lsobutyl- [4- (4-phenyl-piperidin-1-yl) -benzenesul-fonyl] amino} -acetic; (S) -4-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesul-phonylamino] -butyric acid; (R) -2- [4- (4-Phenyl-piperidin-1-yl) -benzenesul-phonylamino] -3-tritylsulfanyl-propionic acid, sodium salt; (R) -3- (1H-Indol-3-yl) -2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -propionic acid; sodium salt, monohydrate; Acid (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; hydrochloride; (R) -3-mercapto-2- [4- (4-phenyl-piperidin-1-H) -benzenesulfonylamino] -propionic acid, trifluoroacetic acid salt; (S) -2- [4- (4-Benzyl-p -peridin-1-yl) -benzenesul-fonylamino] -3-phenyl-propionic acid; (S) -3- (4-Benzyloxy-phenyl) -2- [4- (4-phenyl-piperidin-1-yl) benzenesulphonylamino or] -propionic acid; (S) -3- (4-Hydroxy-phenyl) -2- [4- (4-phenyl-piperidin-1-yl) benzenesulfonilamin or] -propionic acid; (S) -3-phenyl-2- [4- (4-phenyl] -piperazin-1-H) -benzenesulfonylamino or] -propionic acid; Acid; (S) -2-. { 4 - [4- (3-methoxy-phenyl) -piperazin-1-yl] -benzenesulfonic acid} -3-phenol-proponic; Acid (S) -2-. { 4 - [- 4- (3-Hydroxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic; bromohydride; Acid (S) -2-. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl [3-benzenesulfonylamino} -3-phenyl-propionic; (R) -4-Methylene-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl] -amino] -pentanoic acid (S) -4-methyl-2- [4- (4-phenyl-piperidin-1-yl) -benzene-sulfonylamino-pentanoic acid; (S) -3-phenyI-2- [4 - (- 4-phenyl-piperidin-1-yl) -benzenesulfonylamino or] -propionic acid; Acid; (R) -3-phenyl-2- [4- (4-phenyl-piperidin-1-H) -benzene-sulfonylamino-propionic acid; (S) -3- (1H-indol-3-yl) -2- [4- (4-phenyl-piperidin-1-yl) benzenesulfonyl-amino or] -propionic acid; 4- (4-Phenyl-piperidin-1-yl) -benzenesulfonylamino] -acetic acid; N-hydroxy-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -acetamide acid; 3- [4- (4-Phenyl] -piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (R) -4-Methylene-2- [4- (4-phenyl] -piperidin-1-H) -benzenesulfonylamino] -pentanoic acid; (S) -4-Methyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -pentanoic acid; (S) -3-phenyl-2- [4- (4-phenyl-pipendin-1-yl) -benzenesulfonylamino or] -propionic acid; (R) -3-phenyl-2- [4- (4-phenyl-piperidin-1-H) -benzenesulfonylamino or] -propionic acid; (S) -3- (1H-Indol-3-yl) -2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -propionic acid; Acid; () -5-Fenp-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl aminol pentanoic; [4- (4-f in yl-piperazin-1-yl) -benzenesulfonyl] -acetic acid; Acid [isobutyl- [4- (4-phenyl-piperidin-1-yl) -benzene-suphonyl] amino} -3-acetic; (S) -4-Phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzene-none-sulfonylamino or] -butyric acid; (R) -2- [4- (4-Phenyl-piperidin-1-yl) -benzenesul-fonylamino] -3-tritylsulfanyl-propionic acid; sodium salt; (R) -3- (1H-indol-3-yl) -2-14- (4-phenyl-piperidin-1H) benzenesulfonylamino] -propionic acid; sodium salt, monohydrate; Acid, (S) -2-. { 4 - [- 4- (4-hydroxy-phenyl) -piperazin-1-H] -benzenesulfonylamino} -3-phenyl-proponic; Acid (S) -2-. { 4 - [4- (4-Chloro-phenyl) -piperazin-1-yl] -benzenesulfonylamino) -3-phenyl-propionic acid;, hydrochloride; (R) -3-mercapto-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -propionic acid; trifluoroacetic acid salt; Acid (S) -2- [4- (4-benzyl-p -peridin-1-yl) -benzene-s-ulfon-lamino] -3-phen-1-propionic acid; (S) -3- (4-Benzyloxy-phenyl) -2- [4- (4-phenyl-piperidin-1-yl) -benzenesulfonylamino] -propionic acid; (S) -3- (4-Hydroxy-f-enyl) -2- [4- (4-f-1-pipendin-1H) -benzenesulfonic-amino] -propionic acid; (S) -3-phenyl-2- [4- (4-phenyl-piperazin-1-yl) -benzenesulfonylamino or] -propionic acid; Acid (S) -2-. { 4 - [- 4- (3-methoxy-phenyl) -piperazin-1-yl] -ben cenu os Ifon i lamino} -3-phenylpropionic; Acid (S) -2-. { 4- [4- (3-Hydroxy-phenyl) -piperazin-1-yl] -benzene sulphonium} -3-phen i-propion ico; bromine hydrate; Acid (S) -2-. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -benzenesulfonylamino} 3-phenyl-proponic; (R) -4-Methyl-2- [4- (4-phenyl-pipendin-1-yl) -benzenesulfonylamino] -pentanoic acid (S) -4-methyl-2- [4- (4-phenyl) acid -piperidin-1-H) -benzene-sulfonylamino-pentanoic acid; (S) -3-phenyl-2- [4- (4-phenyl-piperidin-1-yl) -benzenesulphonylamino or] -propionic acid; J r Acid (R) -3-phenyl-2- [4- (4-phenyl-p-peridin-1-yl) -benzene-su-phenylamino] -propionic acid; and (S) -3- (1 H -indol-3-yl) -2- [4- (4-phenyl] -piperidin-1-yl) -benzenesu-f-phenylamino] -propionic acid. Additional specific compounds that may be used include: 2- (Dibenzofuran-2-sulfonylamino) -3- (4-fluoro-phenyl) -propionic acid; 2- (Dibenzofuran-2-sulfonylamino) -3-phenyl-pro-pionic acid; 3- (4-tert-Butoxy-pheny1) -2-dibenzofuran-2-sulfonyl-amino) -pro-pionic acid; Acid (dibenzofuran-2-sulfonylamino) -phenyl-acetic acid; 3-tert-butoxy-2- (dibenzofuran-2-sulfonylamino) -propionic acid; Acid (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-sulfonylamino) hexanoic acid; Acid 5- be nciloxicarbo or mi no-2- (di benzofura n-2-sulfonylamino) -penta noico; Acid (dibenzofuran-2-sulfonylamino) - (4-methoxy-pheny1) -acetic; 3-Chloro-2- (dibenzofuran-2-sulfonylamino) -propionic acid; 3- (4-Benzyloxy-phenyl) -2- (dibenzofuran-2-sulfonylamino) -pro-pionic acid; 2- (Dibenzofuran-2-sulfonylamino) -5-p-tolyl-sulfanylamino-pentanoic acid; 2- (Dibenzofuran-2-sulfonylamino) -4-mercapto-butyric acid; 3- (4-b-romo-nyl) -2- (dibenzofuran-2-sulfonyl-amino) -propionic acid; 2- (Dibenzofuran-2-sulfonylamino) -butyric acid; 1- (dibenzofuran-2-sulfonylamino) -cyclopropane-carboxylic acid; 3- (4-chlorophenyl) -2- (di-benzofura n-2 -s-ulfon-1-amino) -propionic acid; 2- (Dibenzofuran-2-sulfonylamino) -3- (1 H -indol-3-yl) -propionic acid; 2- (4'-Bromo-biphenp-4-sulfonylamino) -6- (4-fluorobenzenesulfonylamino) -hexanoic acid; 2- (4'-Bromo-b-phenyl-4-sulfonylamino) -6- (4-methoxybenzenesulfonylamino) -hexanoic acid; 6- (4-Bromo-benzenesulfonyl-amino) -2- (4'-bromo-bife-n-sulphonylamino) -hexanoic acid; 6- (2-Acetylamino-thiazole-5-sulfonylamino) -2- (4'-bromo-biphenyl-4-sulfonylamino) -hexa-noic acid; 6- (4-Acetylaminobenzenesulfonylamino) -2- (4'-bromo-biphenyi-4-sulfonylamino) -hexanoic acid; 6-Benzenesulfonylamino-2- (4, -bromo-biphenyl-4-sulfonylamino) hexanoic acid; 2- (4 * -bromo-bife nyl-4-sulphonyl amino) -6- (pen tano-1-suphillylamino) hexanoic acid; 2- (4'-bromo-bife nyl-4-sulfo nylamino) -6- (naft-2-sulfonylamino) -hexanoic acid; 2- (4, -Bromo-b-phenyl-4-sulfonylamino) -6- (naphthalene-1-sulfonylamino) -hexanoic acid; 2- (4-bromo-biphenyl-4-sulfonylamino) -6- (2-phenyl-ethenesulfonamino) -hexanoic acid 2- (4'-bromo-biphenyl-4-sulphonamino) -6 acid phenyl-acetylamino-hexanoic acid; 2- (4'-Bromo-b-phenyl-4-sulfonylamino) -6- [2- (4-chloro-phenoxy) -acetylamino] -hexanoic acid; 2- (4'-bromo-bife nyl-sulfo nylamino) -6- [2- (4-chloro-phenoxy) -2-methyl-propionylamino] -hexanoic acid; 2- (4'-b-romifene-n-4-sulfonylamino) -6- [2 - (pyridin-4-psulfanyl) -acetylamino] -hexa-noic acid; 2- (4'-b-rome-bife nyl-4-sulated nylamino) -6- [2- (2,4-dichloro-phenoxy) acetylamino] -hexanoic acid; 2- (4, -Bromo-b-phenyl-4-suphionilasnino) -6- (2-thiophen-2-yl-acetylamino) -hexanoic acid; 2- (4, -Bromo-b-phenyl-4-sulfonylamino) -6- (3-phenyl-acryloylamino) -hexanoic acid; 2- (4-Bromo-biphenyl-4-sulfonylamino) -6- (7-phenyl-heptanoylamino) -hexanoic acid; 2- (4'-b-romifene-n-4-sulfo-nylamino) -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'-b-rome-bife nyl-4-su-phenylamino) -6- (fexy-acetylamino) -hexanoic acid; 2- (4'-b-romifene-4-sulfo-nylamine) -6- [2- (3, 4-dimethoxy-phenyl) -acetylamino] -hexanoic acid; 2- (4, -Bromo-biphenyl-4-su-phonyl-amino) -6- [2- (4-tert-butyl-phenoxy) -acetylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfo-nylamino) -6- [3- (3, 4-dimethoxy-phenyI) -propionylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfo-nylamino) -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-solphonylamino) -6- [2- (naphthalen-1-yloxy) -acetylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [2- (4-nitro-phenoxy) -acetylamino] -hexanoic acid; 2- (4, -Bromo-b-phenyl-4-sulfonylamino) -6- [4- (4-cyoro-3-methyl-phenoxy) -butyrylamino] -hexanoic acid; 2- (4'-bromo-bife nyl-4-sulphonyl) -6- [3- (4-methoxy-phenyl) -propionylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulphonyl) -6- (2-pyridin-3-yl-acetylamino) -hexanoic acid; 6- (2-Benzo [1,3] dioxol-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonylamino) -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-pyridin-2-yl-acetylamino) hexanoic acid; 2- (4'-Bromo-biphenp-4-sulfonylamino) -6- [2- (4-tert-butyl-phenoxy) -acetylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfonylamino) -6- [3- (3,4-dimethoxy-phenyl) -propionylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-cyclopen-1-enyl-acetylamino) -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [2- (4-methoxy-phenoxy) -acetylamino] -hexanoic acid; 2- (4'-Bromo-b-phenyl-4-sulfonyl-lane) -6- [2- (naphthalen-1-yloxy) acetylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [2- (4-nitro-phenoxy) acetylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [4- (chloro-3-methyl-phenoxy) -butyrylamino] -hexanoic acid; 2- (4-Bromo-biphenyl-4-sulfonylamino) -6- [3- (4-methoxy-phenyl) -propionylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfo-nylamino) -6- (2-pyridin-3-yl-acetylamino) hexanoic acid; 6- (2-Benzo- [1, 3] dioxol-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonylamino) -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (2-pyridin-2-yl-acetylamino) hexanoic acid; 2- (4, -Bromo-biphenyl-4-sulfonylamino) -6- [4- (4-nitro-phen i) -butyl-amino] -hexane-ico acid; 2- (4, -bromo-biphenyl-4-sulfonylamino) -6- [2- (4-tert-butyl-phenoxy) -acetylamine] -hexane acid; 2- (4'-bromo-bife nyl-4-sulfonylamino) -6- [3- (3, 4-dimethoxy-phenyl) -propionylamino] -hexanoic acid; 2- (4'-bromo-bife nyl-4-sulfonylamino) -6- (2-cyclopent-1-enylacetylamino) -hexanoic acid; 2- (4'-b-rome-biphenyl-4-sulfonylamino) -6- [2- (4-methoxy-phenoxy) -acetylamino] -hexa-noic acid; 2- (4'-Bromo-b-phenyl-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'-b-rome-bife-nyl-4-sulphonyl) -6- [3- (4-chloromethyl) propionylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- [3- (4-methoxy-phenyl) propylamino] -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfo-nylamino) -6- (2-pi-ri-din-3-yl-acetylamino) hexanoic acid; 6- (2-Benzo [1,3] dioxol-5-yl-acetylamino) -2- (4'-b-rome-n-4-sulfonylamino) -hexanoic acid; 2- (4-Bromo-biphenyl-4-sulfonylamino) -6- (2-naphthalen-1-yl-acetylamino) -hexa-noic acid; 2- (4'-Bromo-biphenyl-4-suphillylamino) -6- [3- (4-chloro-phenoxy) propionylamino] -hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (6-phenyl-hexanoylamino) hexanoic acid; 2- (4'-Bromo-biphenyl-4-sulfonylamino) -6- (4-thiophen-2-yl-butyrylamino) -hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulphonyl) -6- (2,4,6-triisopropyl-benzoylamino) -hexanoic acid; 2- (4 * -Bromo-bife nyl -4-sulphonyl amino) -6-isobutoxy-carbonylamino-hexanoic acid; 2- (4'-b-rome-bife nyl-4-sulfo-nylamino) -6- (9H-fluoren-9-ylmethoxycarbonylamino) -hexane acid; 6- (Adamantan-1-yloxycarbonylamino) -2- (4'-bromo-biphenyl-4-sulfonylamino) -hexanoic acid; and 6-allyloxycarbonylamino-2- (4'-bromo-biphenyl-4-sulfonylamino) hexanoic acid; MMP inhibitors of numerous succinamide are known and can be used in the method of this invention. It typically includes succinamides: 2S, N1-Dihydroxy-3R-isobutyl-N4-. { 1S- [2- (2-methoxy-ethoxymethoxy) ethylcarbamoyl] -2,2-dimethyl-propyl} -succinamide; 2S-Allyl-N 1 -hydroxy-3R-isobutyl-N 4 -. { 1S- [2- (2-methoxy-ethoxymethoxy) ethylcarbamoyl] -2-phenyl-ethyl} -succinamide; 2S-AIH-N1-hydroxy-3R -sobutp-N4-. { 1S- [2- (2-methoxy-ethoxymethoxy) ethylcarbamoyl] -2,2-dimethyl-propyl} -succinamide; 2S-Allyl-N1-hydroxy-3R-isobutyl-N4-. { 1S-. { 2- [2- (2-methoxy-ethoxy) -ethoxy] -ethylcarbamoyl] -2,2-dimethyl-propyl} -succinamide; 2S-Alil-N4-. { 1S- [2,2-di- (methoxymethyl) -propylcarbamoyl} - 2,2-dimethyl-propyl] -N1-hydroxy-3R-isobutyl-succinamide; 2S-AH l-N -. { 1S- [2,2-d - (methoxymethyl) -butylcarbamoyl] -2,2-dimethylpropyl} -N 1 -hydroxy-3R-isobutyl succinamide; N4-Hydroxy-2R-isobutyl-N1-. { 1S- [2- (2-methoxy-ethoxy) -ethylcarbamoyl] -2,2-dimethyl-propyl} -3S- (thiophen-2-yl-suIf indigo methyl) -succinamide; N4-Hydroxy-2R-isobutyl-N1-. { 1S- [2- (2-methoxy-ethoxy) -ethoxy] -ethylcarbamoyl} -2,2-dimethyl-propyl) -3S- (thiophen-2-yl-sulfanylmethyl) -succinamide; N1-. { 1S- [2,2-Di- (methoxymethyl) -propylcarbamoyl] -2,2-dimethyl-propyl} -N4-hydroxy-3R-isobutyl-3S- (thiophen-2-yl-sulfanylmethyl) succinamide; N4-Hydroxy-2R-isobutyl-N1-. { 1S- [2- (2-methoxy-ethoxy) ethylcarbamoyl] -2,2-dimethyl-propyl} -3S-propyl-succinamide; N 4 - (1 S-Cyclobutylcarbamoyl-2,2-d, methyl-propyl) -2 S, N 1 -dihydroxy-3 R -isobutyl-succinamide; N 4 - (1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl) -2 S, N 1 -dihydroxy-3R-isobutyl succinamide; N 4 - (1 S-Cicl open til ca rba mo-l-2,2-dimethyl-p ropil) -2 S, N 1 -dihydroxy-3R-isobutyl succinamide; N 4 - (1 S-Cyclohexylcarbamoyl-2,2-d-methyl-propyl) -2 S, N 1 -dihydroxy-3R-isobutyl-succinamide; N 4 - (1 S-C hepti le rba moil-2,2-d, methyl-propyl) -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; N 4 - (1 S-Cycloprop Hcarbamoyl-2-mercapto-2-methyl-1-propyl) -2 S, N 1 -dihydroxy-3R-isobutyl succinamide; N 4 - (1 S-Cyclopropylcarbamoyl-2,2-d, methyl-propyl) -2 S, N 1 -dihydroxy-3R- (3-phenyl-propenyl) -succinamide; N 4 - (1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl) -2 S, N 1 -dihydroxy-3R- (3-phenyl-propyl) -succinamide; N 4 - [2,2-Dimethyl-1 S- (2-f-enyl-cid or pro-pilcar-bamoyl) -pro pil] -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; 2S-Allyl-N 4 - (1-cyclopropylcarbamoyl-2,2-dimethyl-propyl) -N 1 -hydroxy-3R-isobutyl-succinamide; 2S-Allyl-N4- (1S-cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl) -N1-hydroxy-3R-isobutyl-succinamide; N 4 - (1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl) -N 1 -hydroxy-3R-isobutp-2 S- (thiophen-2-yl-sulphamylmethyl) -succinamide; N 4 - (1 S-Cyclopropylcarbamop-2,2-dimethyl-propyl) -N 1 -hydroxy-2 S- (4-hydroxy-phenylsulfanylmethyl) -3R-isobutyl-succinamide; and N 4 - (1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl) 2 S- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -N 1 -hydroxy-3R-isobutyl-succinamide. Another especially preferred group of MMP inhibitors to be used in combination with a statin according to the method of this invention are the sulfonated amino acid derivatives described in WO 97/27174, incorporated herein by reference. These compounds have the general structure R 11 R- 15_.R1L_R1J S0 / COY R, 1J2 wherein R 11 is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl; R 12 is hydrogen, or a group as defined by R 11; R 13 is a single bond, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; R14 is a single bond, - (CH2)? OR 2-, -CH = CH-, CC-, -CO-, -CONH-, N = N-, NH, N-alkyl, -NHCONH-, -NHCO-, -O-, -S-, -SO2NH -, -S02NH-N = CH-, or tetrazoldiyl; R15 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group; and Y is NHOH or OH. Especially preferred compounds for use in the method of this invention have the above formula wherein R 13 is phenylene or substituted phenyl. Typical of such compounds that may be employed have the formula R11 wherein R11 and R12 are as defined above, and R17 is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Especially preferred are the compounds of the formula , 11 R18 S02NH- ^ "COOH wherein R > 11 and D R18 are as follows: Rll Rl8 CF3CH2- \ ^ // \\ /) R'I Rl « R > 1 R18 Especially preferred are the MMP inhibitors currently in clinical development, for example batimastat (2). MMP compounds in clinical development include batimastat (2) for the treatment of malignant pleural effusion, and marimastat (1) for the treatment of pancreatic cancer. The award (3) is for the treatment of corneal ulcers and a specific inhibitor of MMP-1 is RO 31-9790 (4).

Compounds in Clinical Development All that is required to practice the present invention is to administer to a mammal suffering from vascular disorder, including heart failure or ventricular dilation, or at risk of developing any such vascular disorder, an effective amount of the metalloproteinase matrix inhibitor in combination. with an effective amount of a statin. Compounds that can inhibit the actions of metalloproteinase matrix enzymes can be used using routine in vitro and in vivo assays. Various compounds within the above classes have been evaluated in such standard tests and have been determined to be potent inhibitors of metalloproteinase matrix. The assays measure the amount by which a test compound reduces the hydrolysis of a thiopeptolide substrate caused by a matrix enzyme of the metalloproteinase. Such assays are described in detail by Ye, et al., In Biochemistry. vol 31, No. 45, 1992, (11231-11235), which is incorporated herein by reference. Thiopeptolide substrates have virtually no decomposition or hydrolysis in the absence of the metalloproteinase matrix enzyme. A typical thiopeptide substrate commonly used for assays is Ac-Pro-Leu-Gly-thioester-Leu-Gly-OEt. A 100 μL assay mixture will contain 50 mM of 2-morpholinoethanesulfonic acid monohydrate (MES, pH 6.0) 10 mM CaCl, 100 μM of thiopeptolide substrate, and 1 mM of 5,5'-dithio-bis- (2- nitro-benzoic) (DTNB). The concentration of thiopeptolide substrate varies from 10 to 800 μM to obtain the Km and Kcat values. The change in absorbance at 405 nm is monitored on a Thermo Max microplate reader (Molecular Apparatus, Menlo Park, CA) at room temperature (22 ° C). The calculation of the hydrolysis amount of the thiopeptolide substrate is based on E4? = 13600 m "1 for the DTNB 3-carboxy-4-nitrothiophenoxide derivative The tests are carried out with and without metalloproteinase matrix inhibitor compounds and the amount of hydrolysis is compared for a determination of the inhibitory activity of the compounds Several representative compounds have been evaluated for their ability to inhibit various metalloproteinase matrix enzymes Table I below presents the inhibitory activity of compounds of various classes In Table, MMP-1 refers to interstitial collagenase MMP-2 refers to gelatinase A, MMP-3 refers to stromelysin, MMP-7 refers to matrilysin, and MMP-9 refers to Gelatinase B. Test compounds were evaluated at various concentrations for determining their respective IC50 values, the micromolar concentration of the compound required to cause a 50% inhibition of the hydrolytic activity of the respective enzyme.

TA-BLA I (IC50 μM) MMP1 MMP2 MMP3 MMP7 MP9 Batimastat is N4-hydroxy-N1- [2- 0.005 0.004 0.02 (m ethylamin) -2-oxo-1 - (phenylmethyl) eti I)] - 2- (2-methylpropyl) -3 - [(2-thienylthio ) methyl] -butandiamide CDP-845 (Celltech) 0.303 0.0015 0.01 CGS 27023A (Ciba-Giegy) 0.033 0.01 0.01 0.008 Galardin is N4-hydroxy-N1- [2- 0.0004 0.0005 27 0.0002 (methylamine) -2-oxo-1 (3-indoylmethyl) ethyl] -2- (2-methyl) I propyl) -butand amide U24522 (Merck) 0.05 0.02 RO-31-9790 (Roche) 0.0055 0.006 0.47 4-Oxo -4- [4- (4-fe nyl-piperidin-1-yl) - 1.3 0.14 phenyl acid ] -butyric N-hydroxy-4-oxo-4- [4- (4-phenyl-piperidin-1- 0.04 0.02 il) -phenyl] butyramide 4-0X0-4- [4- (4-phenyl-pipe-razin -1- 1.6 0.25 il) phenyl] -butyric acid [4- (4-phenyl-piperidin-1-yl) - 0.21 0.02 benzenesulfonylamino-acetic acid N-hydroxy-2- [4- (4-phenyl-piperidine- 1- 0.81 0.019 il) benzenesulfonyl amine] -a ceta mide Acid (S) -3-phenyl-2- [4- (4-phenyl-piperidin-0.22 0.014 1-yl) -benzene-sulfonylamino] -pro pionic TABLE I (IC50 μM) (continued) MMP1 MMP2 MMP3 MMP7 MMP9 Acid (S) -2- [4- (4-benzyl-piperidin-1-yl) - 0.088 0.021 benzenesulfonyl-amino] -3-phenyl-propionic acid (S) -2-. { 4- [4- (4-methoxy-phenyl) -0.033 0.014 piperazin-1-yl] -benzenesulfonylamino} -3-phenyl-propionic acid (S) -2- (4'-bromo-biphenyl-4- 3.24 0.025 0.012 sulfonylamino) -3-methyl-butyric acid (S) -3-methyl-2- (4'-nitro) -biphenyl-4- 0.013 0.10 sulfonylamino) -butyric; Acid (S) -2- (4'-am i no-bife n il-4-su Ifonil) - 0.044 0.067 3-methyl-butyric Acid (S) -2- (4'-bromo-biphenyl-4- 0.026 0.026 sulfonylamino) -3-phenyl-pro pionic acid 4- (4'-Chloro-b-phenyl-4-yl) -4- 0.39 0.12 hydroxyiminobutyric acid 4- (4'-bromo-bif in i I -4- i I) -4- 0.058 0.11 hydroxyiminobutyric acid 4- (4'-chloro-biphenyl-4-M) -4- 0.73 0.93 (dimethylhydrazono) -butyric acid (±) -4- (4'- chloro-biphenyl-4-yl) -hydroxy- 0.15 0.28 butyric Acid (S) -2- (dibenzofuran-2- 0.265 0.46 sulfon i lam i) -4-phen i I-butyric TABLE I (IC5o μM) (continued) MMP1 MP2 MMP3 MMP7 MMP9 Acid (L) -2-diberczcAjnan-2-sulfhnylami? X) H-metapentanci (co 0.32 1.18 Acid (L) -2-diber? Zejran-2-sulfonylfernro ^ 0.89 0.72 Acid (L) -2 ^ dibenzcft? rarh2-sulfonilamiro ^ 0.084 0.23 Acid (L) -2- (dibenzoftjran-2-suli nylamino) -3-tritylsuifanil- 9.4 14.4 propionic acid (L) -2- < d¡ber? zcájrarh2-sulfonilamir? o) -3 -mercapto- 4.45 0.69 propionic Acid (SH-dibenzofura? 2 4-oxo-2- { 2,2> 2- 0.72 1.33 triflu Oacetylamino) -butyroic Acid (S) -2-amir? > 4-dibenzcájfan-2-iM-oxo-butírico 3.8 33.0 Acido (S) -2- ^ cetilamino -dibenz? Jran-2-il-4-oxo rico 0.16 1.55 Acid (S) -4-diber_zofura? 2-il-4-oxo-2-fTn¡l ^ 0.084 0.33 Acid (S) -diber? Zo. { URIh2- (3-phenyl-propionyl-a) -butyric 0.096 0.28 All the pharmaceutical combinations and methods of this invention are adapted for therapeutic use as agents in the prevention and treatment of arteriosclerosis, angina pectoris, and a condition characterized by the presence of hypertension and hyperlipidemia in mammals, particularly humans. Additionally, since these diseases and conditions are closely related to the development of heart disease and adverse cardiac conditions, these combinations and methods, by virtue of their action as antiarthrosclerotic, antianginal, antihypertensive, and antihyperlipidemic, are useful in the management of cardiac risk in subjects at risk of developing adverse cardiac conditions and in subjects at risk of suffering cardiac adverse events and heart failure such as CHF and ventricular dilation. The utility of the compositions of the present invention as medical agents in the treatment of vascular disorders such as arteriosclerosis and CHF in mammals (for example humans) is demonstrated by the activity of the compounds of this invention in conventional assays and in protocol clinical as described below. The following examples are illustrative only, and do not attempt to limit the invention in any way.

EXAMPLE 1 The following animal test establishes the ability of an MMP inhibitor together with a statin to treat vascular disorders. To four groups of white rabbits males of New Zeeland was fed a diet (Ralston Purina) that combined 2% cholesterol, 3% peanut oil, 3% coconut diet oil one week before administering the test compounds, and throughout the test. The water was available ad libitum. A group of 10 animals served as untreated controls. Ten milligrams per kilogram of PD166793 (CI-1026) was administered daily to a group of 10 animals for 8 weeks. Five milligrams per kilogram of calcium atorbastatin was administered daily to a group of 10 animals for 8 weeks. The combination of both agents was administered in the same dose to a group of 10 animals for 8 weeks. At necropsy, the blood was collected for plasma cholesterol measurements, the aortic arch was removed for morphological analysis, morphometric and biochemical. The extent of the thick surface of arteriosclerosis within the aortic arch, the lesion of the cross-sectional area and the macrophage-monocyte content were measured as antisclerotic activity indices. Biochemical methods. Triglyceride and total cholesterol levels in plasma were measured enzymatically through the Abbott VP Series II bicromatic analyzer (Chicago, IL), using the total cholesterol reagent from Boehringer-Mannheim (Indianapolis, IN) and the triglyceride reagent Abbott ( Chicago, IL). Lipid measurements were made monthly or biweekly through the study in plasma samples collected 24 hours after the meal. The aortic arch was analyzed for its content of cholesteryl ester (CE), free cholesterol and total phospholipids. The lipids were extracted in chloroform: methanol (2: 1 v / v) and 300-500 μL of an Internal standard, that is, 200 mg / mL of a solution of 44-hydroxy-cholesterol in ethyl acetate: acetone (2 : 1 v / v), was added to the extracts of the aortic samples. After extraction, the organic phase was dried under nitrogen and redissolved in isooctane / tetrahydrofuran (97: 3 v / v). The lipid content and composition of the aortic arch were measured using a method in HPLC. Cytochemical methods. For the isthological evaluation of the aortic arch lesions and for the quantification of the lesion of the cross-sectional area of the aortic arch, a 1 cm segment of the ascending aorta distal to the aortic valves was fixed at 10% neutral buffered formalin for 24 hours. The vessels were dehydrated, rinsed in xylene, and infiltrated with molten paraffin (<60EC) using a Tissue Tek VIP autoprocessor (Miles Scientific, Elkhart, Indiana). The tissue segments were embedded in paraffin and sectioned at 5 μm with a Reichert-Jung microtome (Baxter, McGraw Park, Illinois). To obtain a complete representation of the histological appearance of the aortic arch lesions, 3 strips of 20 sections each were cut. Each strip of sections was separated approximately 100 μm. Three pairs of sections, that is, one pair of each strip, was adhered to a clean carrier covered with 3-aminopropyltriethoxy-silane and stored until dyeing. The general histological character was evaluated in Verhoeff elastic stained sections. Morphometric methods. The gross extent of arteriosclerosis within the aortic arch was measured. The area of the aortic arch distal to the 1 cm segment taken for histological evaluation of the first intercostal ostia was removed from the animal, opened longitudinally, and the images of the vessel surface were assembled using a digital camera. The lesions were identified as elevated, opaque areas and their area was determined using Image Pro Plus image analysis software. The entire aortic arch area was also determined. The percentage of the aortic arch covered by arteriosclerotic lesions was calculated. The cross-sectional area and the macrophage content of lesions located distal to the aortic valve annulus were also measured. Sections of the aortic arch, a site of hypercholesterolemic induced lesions, were stained using the Verhoeff elastic procedure for the quantification of the transverse area of the lesion. The internal elastic lamina (IEL) was identified as a blue-black ring and the images of that region were gathered using a digital camera. The area within the IEL was quantified using Image Pro Plus image analysis software. The lumen area of the aortic arch was also quantified in a similar way. The area of the lesion is defined as the difference between the area circumscribed by the internal elastic lamina and the area of the lumen. The contiguous sections stained for monocyte-macrophages using antibodies specific for rabbit macrophages were used for the quantification of the macrophage area. Regions stained red or brown were identified within the lesions of the aortic arch, and the images were collected using a digital camera. Since the macrophages are darker than the area of the surrounding lesion, a grayscale histogram was used to identify a point of infection in the gray level intensities of the image which arbitrarily delineates the gray levels associated with the macrophages After the delineation of the macrophages, their area was identified using Image Pro Plus image analysis software. The data thus generated established that the MMP statin-inhibitor combinations are surprisingly useful for the treatment of vascular disorders.

EXAMPLE 2 Effect of the MMP Inhibitor and a Statin, Alone and in Combination in the Treatment of Arteriosclerosis This study is a randomized prospective evaluation of the effect of a combination of an MMP inhibitor or a pharmaceutically acceptable salt thereof and statin on the progression / regression of a carotid and coronary artery disease. The study is used to show that a combination of an MMP inhibitor, for example, 2- (4'-bromophenyl-4-sulphonyl) -3-methyl-butypic acid, or an acceptable acid addition salt, and statin , for example calcium atorvastatin, is effective in slowing or stopping the progression or causing regression of existing coronary artery disease (CAD) as evidenced by changes in coronary angiography or ultrasound of the carotid, in subjects with the established disease. This study is an angiographic documentation of coronary artery disease carried out as a double-blind placebo controlled trial with a minimum of approximately 500 subjects and preferably from approximately 780 to approximately 1200 subjects. It is especially preferred to study 1200 subjects in this study. Subjects are admitted into the study after satisfying certain entry criteria established later.

Entry criteria: The subjects accepted to enter this test must satisfy certain criteria. Thus, the subject must be an adult, male or female, from 18 to 80 years of age in which coronary angiography is clinically indicated. Subjects will have an angiographic presence of a significant focal lesion such as 30 to 50% upon subsequent evaluation by quantitative coronary artery bypass (QCA) in a minimum of one segment (without PTCA), without deviation, or vessel without MI) that is He judged that it probably does not require intervention for the next 3 years. It is required not to interfere with the segments that undergo the analysis. Since percutaneous transluminal cardiac angioplasty (PTCA) interferes with the segments by the insertion of a balloon catheter, non-PTCA segments are required for analysis. It is also required that the segments to be analyzed have not suffered a thrombotic event, such as a myocardial infarction (MI). Thus, the requirement for vessels without MI. The segments that will be analyzed include: Left main, proximal, and distal left anterior descending, first and second diagonal branch, distal and proximal left circumplejo, the first or larger marginal obtuse space, distal and medial right coronary artery. The subjects will have a fraction of expulsion greater than 30% determined by the catheterization or ventriculography of radionuclide or ECHO cardiogram at the time of qualification of the angiogram or within 3 months prior to acceptance of the qualification of the provided angiogram not intervening in events such as a thrombotic event or that a procedure such as PTCA has been presented. Generally, due to the number of patients and the physical limitations of any person, the study was carried out in multiple places. At the entrance of the study, subjects undergo quantitative coronary angiography as well as a B-mode carotid artery ultrasonography and a carotid arterial compliance assessment at the designated test centers. This establishes baselines for each subject. Once admitted to the test, subjects are randomly placed to receive the MMP inhibitor (200 mg) and a placebo or statin (the dose depends on the particular statin used, however, usually 80 mg will be used first) and a placebo or inhibitor of MMP (200 mg) and statin (80 mg). It will be recognized by a skilled person that the free base form or other salt form of the MMP inhibitors or the free base form or other salt statin forms can be used in this invention. The calculation of the amount of doses for this and other forms of statin and the MMP inhibitor making a simple relation relative to the molecular weights of the species involved. The amount of MMP inhibitor may vary as required. Usually, a subject will begin taking 200 mg and the amount will be dosed to not less than 50 mg as determined by the clinician. The amount of statin will similarly be dosed from 80 mg if determined by the doctor that is in the best interest of the subject. Subjects are monitored for a period of 1 to 3 years, with 3 years generally preferred. Ultrasound evaluation of carotid mode B of arteriosclerosis of the carotid artery and adaptability is carried out at regular intervals during the study. Generally, intervals of 6 months are adequate. Typically, this evaluation is carried out using a mode B ultrasound equipment. However, a person skilled in the art can use other methods to conduct this evaluation. Coronary angiography is conducted at the end of the treatment period of 1 to 3 years. Baseline and post-treatment angiograms and B-mode ultrasonograms of the operated carotid artery are evaluated for new lesions or progression of existing atherosclerotic lesions. Measurements of arterial compliance are evaluated for changes in the baseline and during 6-month evaluation periods. The main objective of this study is to show that the combination of the MMP inhibitor or a pharmaceutically acceptable acid addition salt and a statin reduces the progression of arteriosclerosis lesions as measured by quantitative coronary angiography (QCA) in subjects with clinical coronary artery disease. The QCA measures the opening in the lumen of the arteries measured.

The main endpoint of the study is the change in the average diameter of the middle segment of the coronary artery tree. Thus, the diameter of an artery segment is measured in several portions along the length of that segment. The average diameter of that segment is then determined. After the average segment diameter of many segments has been determined, the average of all segment averages is determined to arrive at the average mean segment diameter. The average diameter of the segment of subjects taking statin and an inhibitor of MMP or a pharmaceutically acceptable acid addition salt will decrease more slowly, either completely stop or there will be an increase in the average diameter of the segment. These results represent a decreased progression of arteriosclerosis, no change in the progression of arteriosclerosis, and regression of arteriosclerosis respectively. The secondary objective of this study is that the combination of the MMP inhibitor or a pharmaceutically acceptable addition salt and statin reduces the rate of progression of arteriosclerosis in the carotid arteries measured by the curve of medial-intimal maximum thickness measurements averaged over 12 separate wall segments (Media Max) as a function of time, more than the inhibitor does in MMP or a pharmaceutically acceptable acid addition salt or statin alone. The intimal-medial thickness of the subjects taking statin and an MMP inhibitor or a pharmaceutically acceptable salt thereof will increase more slowly, cease to increase or decrease. These results represent decreased progression of arteriosclerosis, arrested progression of arteriosclerosis and regression of arteriosclerosis, respectively. Additionally, these results can be used to facilitate the determination of the dose. The utility of the compounds of the present invention as medical agents in the treatment of angina pectoris in mammals (for example humans) is demonstrated by the activity in the compounds of this invention in conventional tests and the clinical protocol as described below.

EXAMPLE 3 Effect of the MMP and Statin Inhibitor, Single and in Combination, on Angina Treatment. This study is a randomized double-blind arm-parallel study to show the effectiveness of the inhibitor in MMP or a pharmaceutically acceptable acid addition salt thereof and a given statin in combination in the treatment of symptomatic angina. Entry Criteria: Subjects are men or women between 18 and 80 years of age with a history of typical chest pain associated with one of the following objective evidences of cardiac ischemia: (1) tension test of the segment elevation of approximately 1 mm or more of the ECG; (2) positive treadmill tension test; (3) abnormality to the ultrasound of the movement of the new wall; or (4) coronary angiogram with a significant qualified stenosis. Generally, a stenosis of approximately 30% to 50% is considered significant. Each subject was evaluated for approximately 10 to 32 weeks. At least 10 weeks are required to complete the study. Sufficient subjects are used in this selection to ensure that approximately 200 to 800 subjects and preferably approximately 400 subjects are evaluated to complete the study. The subjects are selected for the adaptability of the entry criterion, established in the following, during a run in the 4-week phase. After the selection criteria is met, the subjects are suspended their current anti-anginal medication and stabilized on a long-acting nitrate such as nitroglycerin, 5-isosorbide mononitrate or isosorbide dinitrate. The term "suspension" when used with reference to this selection means withdrawal of the current anti-anginal medication so that substantially all of the medication is removed from the subject's body. A period of 8 weeks is preferably allowed for the period of suspension and for the stabilization of the subject in a stable dose of nitrate. Subjects who have one or two angina attacks per week while in stable doses of long-acting nitrate are generally allowed to bypass the suspension phase. After that the subjects are stabilized in nitrates, the subjects enter the randomization phase with the condition that the subjects continue having one or two attacks of angina per week. In the randomization phase, the subjects are placed randomly in one of the four arms of the study established in the following. After completing the suspension phase, the subjects in the compliance with the entry criteria undergo a 24-hour ambulatory electrocardiogram (ECG) such as Holter monitoring, exercise stress test such as the treadmill, and evaluation of perfusion. of the myocardium using a photon emission tomography (PET) scan to establish a baseline for each subject. When performing an attention test, the speed of the treadmill and the gradient of the treadmill can be controlled by a technician. The speed of the treadmill and the angle of the gradient are generally increased during the test. The time intervals between each increase in velocity and gradient is generally determined using a modified Bruce Protocol. After the baseline of investigations has been completed, the subjects are initiated into one of the following four arms of the study: (1) placebo; (2) a statin (approximately 2.5 mg to approximately 160 mg); (3) MMP inhibitor (about 25 mg to about 200 mg); or (4) a combination of the above doses of MMP inhibitor and statin together. The subjects are then monitored for 2 to 4 weeks. It will be recognized by a skilled person that the free base form or other forms of salts of the MMP inhibitor or the free base form or other forms of statin salt can be used in this invention. The calculation of the dose amount for these other forms of statin and the MMP inhibitor is easily achieved by performing a simple relation relative to the molecular weights of the species involved. After the monitoring period is over, subjects will undergo the following investigations: (1) 24-hour outpatient ECG, such as Holter monitoring; (2) exercise stress test (for example the modified Bruce Protocol treadmill); and (3) assessment of myocardial perfusion using PET scanning. Patients keep a diary of painful ischemic events and nitroglycerin consumption. It is generally desirable to have an accurate record of the number of anginal attacks suffered by the patient during the duration of the test. Since a patient generally takes nitroglycerin to decrease the pain of an anginal attack, the number of times the patient administers nitroglycerin provides a reasonably accurate record of the number of anginal attacks. To demonstrate the effectiveness and dose of the drug combination of this invention, the person performing the test will evaluate the subject using the tests described. Successful treatment will produce few cases of ischemic events as detected by the SG, allow the subject to exercise longer or at a higher intensity level on the treadmill or exercise painlessly on the treadmill or produce better perfusion or fewer perfusion defects in the PET. The utility of the compounds of the present invention as medical agents in the treatment of hypertension and hyperlipidemia in mammals (for human examples) suffering from a combination of hypertension and hyperlipidemia is demonstrated by the activity of the compounds of this invention in the conventional tests and in the clinical protocol described in the following.

EXAMPLE 4 Effects of the MMP inhibitor and a statin. Alone and in combination, in the treatment of subjects who have hypertension and hyperlipidemia. This study is a randomized double-blind arm-parallel study to show the effectiveness of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof and a given statin in combination with the control of hypertension and hyperlipidemia in subjects who they have mild, moderate or severe hypertension and hyperlipidemia.

Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are used in this selection to ensure that approximately 400 to 800 subjects are evaluated to complete the study. Entry Criteria: The subjects are adult men or women between 18 and 80 years of age, having hyperlipidemia hypertension. The presence of hyperlipidemia is evidenced by the evaluation of the LDL cholesterol level of the subject in relation to certain positive risk factors. If the subject does not have coronary heart disease (CHD) and has less than two positive risk factors, then the subject is considered to have hyperlipidemia, which requires drug therapy if the subject's LDL is 190 mg / dL. If the subject does not have CHD and has two or more positive risk factors then the subject is considered to have hyperlipidemia, which requires drug therapy if the subject's LDL is 160 mg / dL. If the subject has CHD, then the subject is considered to have hyperlipidemia if the subject's LDL is 130 mg / dL. Positive risk factors include: (1) men above 45, (2) women above 55 where women do not experience hormone replacement therapy (HRT), (3) family history of premature cadiovascular disease, (4) the subject is a current smoker, (5) the subject has diabetes, (6) an HDL of less than 45 mg / dL, and (7) the subject has hypertension. An HDL of > 60 mg / dL is considered a negative risk factor and will compensate for one of the positive risk factors mentioned above. The presence of hypertension is evidenced by a set diastolic blood pressure (BP) of > 90 mmHg or systolic seated BP of > 140 mmHg. All blood pressures are generally determined as the average of the three measurements taken at 5 minutes interval. Subjects are selected for adaptability with the entry criteria established in the above. After all the selection criteria are met, the subjects are suspended their current lipid-lowering and antihypertensive medication and put on the NCEP ATP diet Stage 1. Stage 1 of NCEP ATP li of the diet (treatment panel of adult, 2nd revision) establishes the amount of unsaturated and saturated fat which can be consumed as a proportion of the total caloric intake. The term "suspension" when used in conjunction with this selection means withdrawal of the current lipid lowering and antihypertensive medication so that substantially all of the medication is removed from the subject's body. Recently diagnosed subjects usually remain untreated until the test begins. These subjects are also placed in Stage 1 of the NCEP diet. After the 4-week period of suspension and stabilization of the diet, subjects undergo the following baseline investigations: (1) blood pressure and (2) selection of lipid fasting. The selection of lipid fasting determines lipid levels of the baseline in the fasting state of a subject. Generally, the subject abstains from food for 12 hours, at which time the lipid levels are measured. After baseline investigations are performed, the subjects are initiated in one of the following: (1) a fixed dose of MMP inhibitor, generally 25 to 200 mg; (2) a fixed dose of statin, usually from 2.5 mg to approximately 160 mg; or (3) a combination of the above doses of MMP inhibitor and together with a statin. It will be recognized by an expert that the free base form or other salt forms of the MMP inhibitor of the free base form or other forms of the statin salt can be used in this invention. The calculation of the dose amount for these other forms of statin and the MMP inhibitor is easily achieved by making a simple relation relative to the molecular weights of the species involved. Subjects stay at these doses for a minimum of 6 weeks and generally for no more than 8 weeks. The subject returns to the test center at the end of 6 to 8 weeks so baseline assessments can be repeated. The blood pressure of the subject at the end of the study is compared with the blood pressure of the subject at entry. The lipid selection measurements of total cholesterol, cholesterol-LDL, cholesterol-HDL, triglycerides, apoB, very low density lipoprotein (VLDL) and other components of the lipid profile of the subject. The improvement in the values obtained after the treatment relative to the pretreatment values indicate the utility of the combination of drugs. The utility of the compounds of the present invention as medical agents in the management of cardiac risk in mammals (for example humans) at risk of an adverse cardiac event is demonstrated by the activity of the compounds of this invention in the conventional tests and in the clinical protocol described in the following.

EXAMPLE 5 Effects of an MMP and Statin Inhibitor, alone and in combination, in Subjects at Risk of Future Cardiovascular Events This study is a randomized, parallel-arm, double-blind study to demonstrate the effectiveness of a carboxyalkylether or a pharmaceutically acceptable acid addition salt and a given statin in combination to reduce the total calculated risk of events futures in subjects who are at risk of having future cardiovascular events. This risk is calculated using the Framingham Risk Equation. A subject is considered at risk of having a future cardiovascular event if the subject has more than one standard deviation above the mean as calculated by the Framingham Irrigation Equation. The study is used to evaluate the efficacy of a fixed combination of carboxyalkylether or a pharmaceutically acceptable acid addition salt and statin to control cardiovascular risk by controlling hyperlipidemia and hypertension in patients who have hyperlipidemia and mild to moderate hypertension. Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are recruited to ensure that approximately 400 to 800 subjects are evaluated to complete the study. Entry Criteria: The subjects included in the study are adult men or women between 18 and 80 years of age with a baseline of 5 years of risk, which is above the median for the sex and age of the subject, as defined by the Framingham Heart Study, which is a current prospective study of adult men and women showing that certain risk factors can be used to predict the development of coronary heart disease. Age, sex, diastolic and systolic blood pressure, smoking habit, the presence or absence of carbohydrate intolerance, the presence or absence of left ventricular hypertrophy, serum cholesterol, HDL of more than one standard deviation above the norm for the Framingham population they are all evaluated to determine if a patient is at risk of an adverse cardiac event. The values for the risk factors are inserted into the Framingham Risk Equation and calculated to determine if a subject is at risk of a future cardiovascular event.

Subjects are selected for adaptability with the entry criteria established above. After all the selection criteria have been met, patients are suspended their current medication for lipid and antihypertensive reduction and any other medication which would affect the results of the selection. The patients are then placed in Stage 1 of the NCEP AT II diet, as described above. Subjects recently diagnosed in general remain untreated until the test begins. These subjects are also placed in stage 1 of the NCEP AT II diet. After the 4-week period of suspension and stabilization of the diet, subjects undergo the following baseline investigations: (1) blood pressure; (2) fasting; (3) selection of lipids; (4) glucose tolerance test; (5) ECG; and (6) cardiac ultrasound. These tests were carried out using standard procedures well known to those skilled in the art. ECG and cardiac ultrasound are generally used to measure the presence or absence of left ventricular hypertrophy. After the baseline investigations are performed, patients are initiated in one of the following: (1) a fixed dose of MMP inhibitor (approximately 25 to 200 mg); (2) a fixed dose of statin (approximately 2.5 mg to approximately 160 mg); or (3) the combination of the above doses of MMP inhibitor and statin. Patients are kept on these doses and are asked to return in 6 to 8 weeks so baseline assessments can be repeated. At this time, the new values are inserted into the Framingham Risk Equation to determine if the subject has a lower, greater or no change in the risk of a future cardiovascular event. The above tests demonstrated the effectiveness of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof in the treatment of angina pectoris, arteriosclerosis, hypertension and hyperlipidemia together, and the management of cardiac risk, also provides a means by which The activities of the compounds of this invention can be compared with each other and with the activities of other known compounds. The results of these comparisons are useful for determining dose levels in mammals, including humans, for the treatment of such diseases. The following dose amounts and other dose amounts set forth elsewhere in this specification and in the appended claims are for an average human subject having a weight of about 65 kg up to about 70 kg. The skilled practitioner will easily be able to determine the amount of dose required for a subject whose weight falls outside the range of 65 to 70 kg, based on the medical history of the subject and the presence of diseases, for example diabetes in the subject. All doses set forth herein, and in the appended claims, are daily doses.

In general, according to this invention, the MMP inhibitor is generally administered in a dose of about 25 mg to about 500 mg. Preferably, the MMP inhibitor is administered in a dose of about 5 mg to about 100 mg. It will be recognized by a skilled person that the free base form or other forms of salts of the MMP inhibitor can be used in this invention. The calculation of the dose amount for these other forms of the free base form or other salt forms of the MMP inhibitor is easily achieved by performing a simple relation relative to the molecular weights of the species involved. In general, according to this invention, the above statin is administered in the following dosage amounts: Simvastatin, in general from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 40 mg; Pravastatin, generally from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 40 mg; Cerivastatin, generally from about 25 μg to about 5 mg and preferably from about 1 mg to about 3.2 mg; Fluvastatin, generally from about 2.5 mg to about 160 mg and preferably from about 20 mg to about 80 mg; Lovastatin, in general from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 80 mg; and Atorvastatin, in general from about 2.5 mg to about 160 mg and preferably from about 10 mg to about 80 mg. It will be recognized by an expert that the free base form or other salt forms of the above statins can be used in this invention. The calculation of the dose amount for these other forms of either the free base form or other forms of statin salt is easily achieved by making a simple relation relative to the molecular weights of the species involved. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable diluent or carrier. Thus, the MMP and statin inhibitors can be administered individually or together in any conventional oral, parenteral or transdermal dosage form. For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate are used together with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, laurylsodium sulfate, and talc are often very useful for the purpose of tableting. Solid compositions of a similar type are also used as fillers in gelatin soft and hard filling capsules. Preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents, and / or suspending agents, as well as diluents such as water, ethanol. , propylene glycol, glycerin, and various similar combinations thereof. The combinations of this invention can also be administered in a controlled release formulation such as a slow release formulation or a rapid release formulation. Such controlled release formulations of the combination of this invention can be prepared using methods well known to those skilled in the art. The method of administration will be determined by the attending physician or another person skilled in the art after an evaluation of the conditions and requirements of the subject. The generally preferred formulation of calcium atorvastatin is Lipitor as described in US Pat., 686.104 incorporated herein by reference. For parenteral administration purposes, solutions in peanut or sesame oil or aqueous propylene glycol as well as sterile aqueous solutions of the corresponding water soluble salts may be employed. Such aqueous solutions can be adequately stabilized, if necessary, and the diluent liquid first converted to isotonic with sufficient glucose or salt. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitonal injection purposes. In this connection, the sterile aqueous media used all are readily obtainable by standard techniques well known to those skilled in the art. Methods for preparing various pharmaceutical compositions with a certain amount of active ingredient, or will be apparent in the light of this disclosure, are known to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pennsylvania, 15th Edition (1975). The pharmaceutical compositions according to the invention may contain from 0.1% to 95% of the compounds of this invention, preferably from 1% to 70%. In any case, the composition or formulation to be administered will contain an amount of a compound or compounds according to the invention in an amount effective to prevent or treat the condition or disease of the subject being treated, i.e., a vascular disorder, including CHF . Since the present invention relates to the treatment of diseases and conditions with a combination of active ingredients which can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof, and a statin or a pharmaceutically acceptable salt thereof. The equipment includes the container means for containing the separate compositions such as a divided bottle or split corrugated package; however, the separate compositions may also be contained within a simple, undivided container. Typically, the equipment includes instructions for the administration of the separate components. The form of equipment is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), are administered at different dose intervals, or when the dosage of the individual components of the combination is desired by the medical prescription.

It should be understood that the invention is not limited to the particular embodiments described herein, but those various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined in the following claims.

Claims (28)

1. A pharmaceutical composition characterized in that it comprises: a. an amount of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof; b. an amount of a statin or a pharmaceutically acceptable salt thereof; and c. a pharmaceutically acceptable diluent or carrier.

2. The pharmaceutical composition according to claim 1, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, galvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, mevastatin, lovastatin, cerivastatin, or the pharmaceutically acceptable salts thereof.

4. The pharmaceutical composition according to claim 3, characterized in that it comprises: a. an amount of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof having the formula where: / \ A is phenyl or -and N- where Y is CH or N: R1 is a substituent such as alkyl, aryl, halo, amino, substituted and disubstituted amino, and alkoxy; R2 is carboxyalkyl ketone or oxime, or a carboxyalkylsulfonamide such as - SO2NHCHCOOH where R3 is alkyl, substituted alkyl, amino, substituted and disubstituted amino and aryl. Preferred alkyl and alkoxy groups are C 1 -C 10 alkyl and C 1 -C 0 alkoxy, which may be straight or branched chain, and optionally substituted by halo, amino, nitro, carboxy, hydroxy, aryl, and heteroaryl; b. an amount of a statin or a pharmaceutically acceptable salt thereof; and c. a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition according to claim 4, characterized in that it comprises calcium atorvastatin and 2- (4'-bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid.

6. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a hypolipidemic effect in a mammal suffering from hyperlipidemia, whose effects are greater than the sum of the hypolipidemic effects achieved by the administration of the first and second pharmaceutical compositions separately and that the second pharmaceutical composition comprises an amount of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable diluent or carrier, the first pharmaceutical composition is characterized in that it comprises an amount of a statin or a pharmaceutically acceptable salt of the same and a pharmaceutically acceptable diluent or carrier; with the proviso that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

The composition according to claim 6, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptable salt of sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin.

8. The composition according to claim 7, characterized in that the second pharmaceutical composition comprises 2- (4'-bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid.

A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a hypolipidemic effect in a mammal suffering from hyperlipidemia, whose effects are greater than the sum of the hypolipidemic effects achieved by the administration of the first and second pharmaceutical compositions separately and that the second pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, the first pharmaceutical composition is characterized in that it comprises an amount of a biphenyl MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.

The composition according to claim 9, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin, or lovastatin; or a pharmaceutically acceptable salt thereof.

11. A composition according to claim 10, characterized in that it comprises 2- (4'-bromobiphenyl-4-sulfonyllamino) -3-methylbutyric acid.

12. A first pharmaceutical composition for use with a second pharmaceutical composition for the management of cardiac risk in a mammal at risk of suffering an adverse cardiac event, whose effect is greater than the sum of the management of the effects of cardiac risk achieved by the administration of the first and second pharmaceutical compositions separately and whose second pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, the first pharmaceutical composition is characterized in that it comprises an amount of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable diluent or carrier.

The composition according to claim 12, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or a pharmaceutically acceptable salt of cinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin.

14. A composition according to claim 13, characterized in that it comprises the 2- (4'-b-romyl-bif-i-4-sulfonylamino) -3-methyl-butyric acid.

15. A kit for achieving a therapeutic effect in a mammal characterized in that it comprises: a. an amount of an MMP inhibitor or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable diluent or carrier in the form of a first dose unit; b. an amount of a statin or a pharmaceutically acceptable salt thereof and a diluent or carrier in the form of a second dose unit; and c. the container means for containing the first and second dosage forms; with the proviso that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

16. A kit according to claim 15, characterized in that the statin is atorvastatin, sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or a pharmaceutically acceptable salt of sinvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin.

17. The equipment according to claim 16, characterized in that it comprises an MMP inhibitor which is a diphenyl compound.

18. The equipment according to claim 17, characterized in that it employs 2- (4'-bromobiphenyl-4-sulfonylamino) -3-methylbutyric acid.

19. The equipment according to claim 15, characterized in that the therapeutic effect is a hyperlipidemia treatment.

20. The equipment according to claim 15, characterized in that the therapeutic effect is the treatment of angina pectoris.

21. The equipment according to claim 15, characterized in that the therapeutic effect is the treatment of cardiac irrigation.

22. The equipment according to claim 15, characterized in that the therapeutic effect is the treatment of arteriosclerosis.

23. The device according to claim 22, characterized in that the treatment of arteriosclerosis decreases the progression of the atherosclerotic plaques.

24. The equipment according to claim 23, characterized in that the progression of the atherosclerotic plaques is decreased in the coronary arteries.

25. The equipment according to claim 23, characterized in that the progression of the atherosclerotic plaques is decreased in the carotid arteries.

26. The equipment according to claim 23, characterized in that the progression of the atherosclerotic plaques is decreased in the peripheral arterial system.

27. The equipment according to claim 22, characterized in that the treatment of atherosclerosis causes the regression of the atherosclerotic plaques.

28. A device according to claim 27, characterized in that the regression of the atherosclerotic plaques occurs in the coronary arteries.