MXPA99002254A - Use of matrix metalloproteinase inhibitors for treating neurological disorders and promoting wound healing - Google Patents

Abstract

Matrix metalloproteinase inhibitors are useful for preventing and treating neurological disorders and in promoting wound healing.

Description

USE OF METALOPROTEINASE INHIBITORS MATRIX TO TREAT NEUROLOGICAL DISORDERS AND PROMOTE WOUND HEALING FIELD OF THE INVENTION This invention provides a method for treating and preventing neurological disorders such as Alzheimer's disease and for promoting wound healing, comprising administering a compound characterized as being a matrix metalloproteinase inhibitor.

BACKGROUND OF THE INVENTION The formation of amyloid plaque is found in a number of diseases, including Alzheimer's disease, scrapings, bovine spongiform encephalopathy, Gerstmann-Straussler Syndrome and the like. Amyloid plaques comprise proteins coupled in a fibrous matrix. Amyloidosis is the general name given to diseases and conditions characterized by the presence of amyloid protein. A number of different types of amyloid protein are known, and all types are considered pathological, since amyloids of natural occurrence are not known. According to the above, the presence of amyloid protein in a host is an indication of the abnormal formation of fibrils and plaques. Amyloidosis has been clinically observed in a number of disease states, including certain mental illnesses, neurological diseases and collagenoses. In fact, brains diagnosed with Alzheimer's disease have one thing in common, mainly an abundance of amyloid in the form of plaques and knots.

Alzheimer's disease is a degenerative disorder of the brain characterized clinically by the progressive loss of memory, perception, reasoning, judgment and emotional stability that gradually leads to mental deterioration and ultimately death. Only two clinically approved treatments are available, one being tracrine hydrochloride (Cognex®, from the Parke-Davis Division of Warner-Lambert Company). Because Alzheimer's disease and related brain-degenerative disorders are an important issue for an elderly population, the need for new treatments and methods to diagnose disorders are needed.

We have now discovered that compounds that inhibit the enzymes that mediate the breakdown of connective tissues are useful for treating neurological disorders and wound healing. These enzymes are known as native matrix metalloproteinases, 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, collagenase fibroblast, neutrophil collagenase, matrilysin, metalloelastase and intersitial collagenase. These enzymes are involved with a number of diseases resulting from the breakdown of connective tissues, such as rheumatic arthritis, osteoarthritis, osteoporosis, multiple sclerosis and even tumor metastasis. To date, matrix metalloproteinase inhibitors have not been used to treat or prevent neurological disorders such as Alzheimer's disease and Parkinson's disease, or to promote wound healing. An objective of this invention is to provide a method for treating and preventing neurological disorders and promoting wound healing with metalloproteinase inhibitor.

SUMMARY OF THE INVENTION This invention provides a method for treating and preventing neurological disorders and promoting wound healing by administering an effective amount of a matrix metalloproteinase inhibitor.

The method can be practiced by administering any chemical compound that is effective in inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase or elastase. Numerous compounds are known to be inhibitors of matrix metalloproteinase and any of said compounds can be used in the method of this invention.

In a preferred specimen, the matrix metalloproteinase inhibitor to be used is a substituted bicyclic compound of the formula where: G? - and N - A is phenyl or, wherein Y is CH or N; R1 is a substitute such as alkyl, aryl, halo, amino, substituted amino and alkoxy; R2 is carboxyalkyl ketone or oxime or a carboxyalkyl sulfonamide such as SO2NHCHCOO RJ wherein R3 is alkyl, substituted alkyl, amino, substituted amino and disubstituted aryl.

A particularly preferred specimen is a method for treating and preventing neurological disorders and wound healing by administering a biphenylsulfonamide as it is In another example, neurological disorders and wound healing are treated or prevented by the administration of a matrix metalloproteinase which is a substituted tricyclic fused compound of the formula wherein R1 and R2 are as defined above, T is O, CH2, SQ (O) 0 > or 2, C = O, NR3 or - NR3C -, and W, W1, Z, and Z1 are each the same or different and each is CR3, II or wherein R3 is alkyl, halo, alkoxy, acyl and aryl. A preferred method uses dibenzofurans and fluorenos of the above formula, for example compounds such as wherein R2 is, for example, NOH II - C - CH2 - CH - COOH, or - SO2NH - CH - COOH. R3 R3 All of these matrix metalloproteinase inhibitors to be used in the method of this invention are known or readily available by common synthetic processes.

DETAILED DESCRIPTION OF THE INVENTION All that is required to practice this invention is to administer to a mammal suffering from a neurological disorder or suspected of developing a neurological disorder or in need of wound healing an effective amount of a matrix metalloproteinase inhibitor.

A "matrix metalloproteinase inhibitor" as used herein is any chemical compound that inhibits by at least five percent the hydrolytic activity of at least one matrix metalloproteinase enzyme that occurs naturally in one of this invention. For example, the 4-biarylbutyric 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 named, and each is incorporated herein and may be employed in this invention.

The matrix metalloproteinases (MMPs) (Table 1) represent a zinc-dependent subset of the protease enzymes. MMP-dependent remodeling of the extracellular matrix has been implicated in a variety of human diseases, but is also involved in the change and development of normal tissue. The activity of the compounds results from the binding to the enzymes in several bags, such as the bag Pl 'and the bag P3 \ MMP compounds in clinical development include batimastat (2) for the treatment of malignant pleural effusion, and marimastat (1) for the treatment of pancreatic cancer. Galardin (3) is for the treatment of corneal ulcers and a specific MMP-1 inhibitor is RO 31-9790 (4).

CLINICAL DEVELOPMENT COMPOUNDS TABLE 1. MMP Nomenclature Succinamides Most MMP inhibitors with the succinic acid template are potent and are not selective, particularly with a zinc binding group. However, it is possible to achieve selectivity with this half (Table 2). The series of compounds (5-10) are potent against MMP-8 and certain examples (9, 10) are very potent inhibitors of MMP-9. The selectivity for MMP-3 and MMP-1 can be obtained in this series with the ligand Pl '. The alcohol (5) is selective for MMP-1 more than MMP-3. The amides (6, 7) and the ether benzyl (8) are selective for MMP-3 more than MMP-1. The compound (9) is a potent inhibitor of MMPs - 1, 3, 8 and 9. The selectivity for MMP-2 and MMP-3 can be obtained on MMP-1 and MMP-7, when the substitute Pl 'is a long alkyl chain group (11) in a series related to a zinc carboxylate ligand. The selectivity can be explained by the size of the bag. In addition exquisite selectivity can be obtained for MMP-2 when the length of the chain is extended. The compound (12) is very selective for MMP-2 instead of MMP-1, 3 and 7.

TABLE 2. MMP Selectivity Selective Succinate MMP Inhibitors (8) (CH2) 3OCH2Ph (9) (CH2) 3OCH Ph (10) (CH2) 4OPh " (13) 'Bu (14) lBu (23) lBu The combination of a small Pl 'ligand and a pyrazyl-N-methyl / N-methyl amide in P2-P3' produces selectivity in one hundred for MMP-1 over MMP-3 (13). With tert - butyl in P2 'the selectivity for MMP - 1 and 3 on MMP - 2 is obtained with N - Me amides in P3' (14). The potency of MMP-2 is restored with P3'N-phenyl substitutes. The selective compounds for MMP-7 on MMP-1 and 3 have been obtained with a crude P3 'substitute and a small substitute for Pl' (15). The selectivity of MMP can be attenuated - 7 and MMP - 1 with cyclohexyl in Pl '(16).

The compounds with selectivity in one hundred for MMP-2 on-2 and the selectivity in 10,000 for MMP-2 on one have been reported by Celltech (17). A compound (18) in this series also potentially inhibits MMP-13. The corresponding carboxylates (19, 20) also retain this specific profile. These compounds all contain a cyclohexyl in P2 'and a phenethyl amide, or sulfonamide in P3'.

A modest selectivity can be obtained for MMP-1, 2 and 8 on MMP-3 and 7 with the analogue contained in the P2 '-P2' region (21).

Significant selectivity is observed for MMP-1 over MMP-2 and 3 with the quinolone analogue (22). these compounds are likely to bind in the same manner as compound (33), in which the hetero amide group is postulated to occupy Pl 'via a conformational expansion of the pouch.

A modest selectivity is obtained for MMP-1 over MMP-1 and 3 with phenyl-substituted amides in P3 '(23). a- Aminocarboxylates The a-aminocarboxylates are potent inhibitors of MMP. A long chain substitute in Pl 'produces selectivity for MMP-3 and -2 on MMP-1, with a methyl group in Pl (24). A phenethyl moiety substituted with small alkyl groups also compounds that are selective for MMP-3 and -2 against MMP-1 (25, 26). Interestingly, the 100-fold selectivity over MMP-3 over -1 and 10-fold over MMP-2 can be achieved with a phthalimidobutyl group in P21 (27). A related series of aminocarboxylates developed in Glaxo has selectivity for MMP-1 and 9 on MMP -3. These compounds contain extensive naphthylamide groups on the non-prime side. The selectivity on MMP-3 can be attenuated by substitution in the naphthalimide chain (28, 29). A variety of amino acid replacements were tolerated in P2 'by MMP-1 and -9 but a good activity for MMP-3 was only found with an aryl side chain. The selectivity for MMP-3 could also be obtained with a non-peptoid substitute at P2 '. The substitution of phenethyl eliminates the MMP-3 activity while the substitution of benzoic acid retains it in (30, 31).

In related glutamic acids, the selectivity for MMP-3 and -2 on MMP-1 is reached with substitutes 4- alkylphenethyl in Pl '(32).

Compounds Containing Phosphorus / Sulfur An intriguing series of compounds in terms of selectivity was published by Glaxo in which an acetamide functionality was postulated occupying Pl \ The thiol compound (33) showed selectivity for MMP-1 over 9 as a result of interactions favorable of trifluoroacetamide in Pl '. The corresponding acetamide (34) did not inhibit MMP-1 presumably since it lacks the ability to form a fluorine-hydrogen bond. The bulk increased with the phenethyl amide (35) reversed the selectivity for MMP-9 over MMP-1. However, the benzotriazole (36) that would not be expected to occur in Pl 'of MMP-1 was an inhibitor of MMP-1. This observation was reported with phenyleletics and Pl ', where it was postulated that arg 214 leaves the path and allows stacking or-or between an electron-rich phenolic chain and an electron-deficient guanidinium chain. A conformational adjustment has recently been reported in the P2'-P3 'region by accommodating hydrophobic inhibitors of MMP-3 and matrilysin crystal structures have shown that the Pl' bag can be expanded to accommodate large substitutes Pl \ This flexibility of the Enzymes is not surprising given that several of the MMP enzymes can divide many different natural substrates.

Selective Peptide MMP Inhibitors (31) 'i? U Ph-4-CO, H (39)' Bu Phosphonic acid (37) resembles the selectivity of MMP-2 over MMP-1 and 3 found with the analogous succinamide. This selectivity can be reversed for the compound (38) with a substitute Pl and N-phenyl amide in P3'- The crude Pl substitutes and a P2'-P3 'region contained as exemplified in (39), give rise to the MMP-1 on MMP-3.

Non Peptide Inhibitors Ciba Geigy presented a series of sulfonamides of which CGS27023A (40) shows a 20-fold selectivity for MMP-3 over MMP-1. In vivo the compound blocks the separation when dosed orally at 30 mg / kg in rabbits injected with stromelisin and is effective in the guinea pig model of osteoarthritis. The related sulfonamides (41) have been presented by British Biotech in which the aryl group has been replaced by a long alkyl chain and Pfizer has replaced the picolinyl group with a methylene amide functionality (42). Bayer has presented a series of aryl succinic acids in which the 2 amino acid residues have been replaced by one aryl moiety. Compounds with phenylalkyl substituents alpha to acid (43) inhibit MMP-3 and MMP-2 selectivity on MMP-9. Inhibition of MMP-9 can also be obtained with a phthalimidoalkyl group at carboxylic acid (44). This MMP-9 profile is similar to that observed with a-aminocarboxylates (28-31), thus the phthalimido group presumably occupies the non-primed side. Both compounds (43, 44) were active in the guinea pig model of osteoarthritis. In these two series, as with the peptide SAR, most of the activity resides in a stereoisomer, which suggests a similar mode of binding. The analogues contained around the zinc binding region do not increase the potency. In vivo, the compound (44) was antimetastatic in both models of tail vein metastasis and in the spontaneous metastasis model. Both 43 and 44 were effective in the guinea pig model of osteoarthritis inhibiting femoral injuries 37.8 and 53% respectively.

Phytoenone derivatives, exemplified by compound 45 have been shown to weakly inhibit MMPs 1, 3 and 9, with modest selectivity for MMP-3. These compounds are considered to bind on the non-primed side (by the overlap models with award) Tetracycline antibiotics, exemplified by aranciamycin (46), are weak inhibitors of MMPs. The activity has been distinguished from the antibiotic activity that produces submicromolar MMP-1 inhibitors with the monosaccharide chain eliminated (47). The anthracene carboxylic acids (48) have also been reported as inhibitors of MMP-1 suggesting that the D-tetracycline chain is not required for MMP activity.

The coumarin derivatives (49) have been shown to be weak inhibitors of MMP-1.

Recent crystallographic publications have provided exquisite approaches within the mode of action of peptide inhibitors with MMPs. The actual situation is more complex than the X-ray / homology models would suggest. It has been noted that the Pl 'bags of the enzymes MMP-3 and MMP-7 are flexible and can breathe or change conformation. The foregoing is not surprising given that these enzymes, particularly MMP-3 can degrade many natural substrates. Peptide inhibitors take 2 hydrogen bonds per amide, and conformationally these dominate along with the Zn coordination. In the case of non-peptide inhibitors or simplified peptides that have the propensity to interact hydrophobically, the enzyme may be more perceptive without being contained in a framework with rigid peptide H linkage.

The hydrophobic effects would also be amplified with a weaker zinc linkage group. Thus expanding the Pl 'pocket or changing the conformation to take advantage of the hydrophobic interactions, seems more likely with a non-peptide inhibitor and can possibly produce unique selectivities not observed with the peptide inhibitors.

NON-PEPTIDE MMP INHIBITORS Metalloproteinases Matrix in Neurological Disorders Inflammatory diseases can affect the central nervous system (CNS) (brain and spinal cord); The best characterized of these disorders are multiple sclerosis (MS) and various forms of meningitis and encephalitis. A common feature of these diseases in a breakdown of the blood-brain barrier (BBB) followed by inflammatory perivascular infiltration and eventual demyelination and astrogliosis. MMPs play a key role in allowing inflammatory cells access to the CNS. Both MMP-2 and MMP-9 are found in the CSF of patients with MS and MMP-9 immunoreactivity can be detected in active MS lesions. Similarly, using increased levels of zymography, MMP-9 can be found in the cerebrospinal fluid (CSF) of animals with experimental autoimmune encephalitis (EAE). In this commonly used animal model of neuroinflammatory diseases, animals are immunized with myelin basic protein or the active epitope of this protein. Increased stimulation with pertussis toxin or endotoxin produces behavioral symptomology ranging from numb tails to complete paralysis. It can be shown that most animals and humans have activated T cells that recognize MBP and other proteins in the myelin sheath, but these cells do not appear to cross the BBB. Direct evidence that MMPs can degrade the BBB and allow infiltration of T cells comes from studies in which MMP-2 has been injected directly into the brain in experimental animals.

The most convincing evidence of the involvement of MMPs in the contribution to the breakdown of the BBB and the safe inflammation is the ability of the hydroxamate inhibitors of MMPs to reduce the clinical symptomology of EAE. Both galarin (GM 6001) and RO 31-9790 have been examined in EAE models and were found to prevent and / or delay clinical signs. It is clear that the actions of these drugs occur after the induction of T cells, given that RP 31-9790 has also shown that it protects in a model of EAE adoptively transferred splenocytes sensitized MBP.

In addition to the role of MMP2 in the BBB breakdown contribution, there is good evidence that MMPs can also directly degrade the myelin basic protein, which leads to characteristic demyelination of MS. Using the MMPs expressed in Chinese hamster ovarian cells, it has been shown that MMP-2 has the highest activity in digesting MBP, but MMP-9 has also been shown to degrade MBP in EAE model. The foregoing indicates that MMPs play a critical role in two key processes in the pathophysiology of MS; mainly the breaking of the BBB and demyelination. The foregoing provides strong rationing for the development of systematically active inhibitors of MMP-2 and / or MMP-9 in the treatment of multiple sclerosis.

MMPs also play a role in other neurological disorders, which are not considered to be generally inflammatory in nature. For example, MMPs are probably responsible for the opening of the BBB in focal ischemia and the hemorrhagic lesion of the brain that leads to the secondary lesion of vasogenic edema. In post mortem brain tissue with Alzheimer 's disease both MMP - 2 and MMP - 9 were detected and using zymography the activity of MMP - 9 was about 4 as compared to that seen in control brains. The α-amyloid is a potent stimulator of both MMP-2 and MMP-9 in cortical cultures and TIMP spots were found to be co-distributed with neuritic lesions and the amyloid precursor protein in Alzheimer's brains. Increased amounts of MMP-9 were also observed in the regions of motor cortex, thoracic, and lumbar spine of patients suffering from amyotrophic lateral sclerosis. Taken together these results suggest that MMPs play a more general role in the degradation of the extracellular matrix in a variety of chronic neurodegenerative disorders.

Wound Healing Wound healing is characterized by the biosynthesis of normal connective tissue composed of appropriate extracellular and vascular organization and functions. This process is dynamic and involves the regulated remodeling of near ECM by MMPs. Regardless of the wound site, the balance between MMP activity and its endogenous inhibitors is responsible for the establishment of a stable extracellular matrix architecture. However, MMP profiles vary depending on the nature of the lesion, the site of the wound, and the species. The proteolytic activity within the wound environment is also an important determinant of the chronicity of the wound. In general, excess MMP activity is observed in chronic wounds. Moreover, the wound fluid obtained from chronic wounds contains high levels of degradation products of vitronectin and fibronectin. The specific factors for each wound class are described below.

Acute Healing Wounds The activity of collagenase is critical for the development and restructuring of matrix components during wound repair, and this process appears to be critical for cellular movement in the extracellular matrix. The elevation of collagenolytic activity has been reported in association with wound healing. Many cell types have the potential to produce intersitial collagenase, including fibroblasts, macrophages, endothelial cells and neutrophils. Keratinocytes have collagenolytic activity when cultured in certain matrices and in migrating cells during the early phase at the edge of the wound. The disruption of the lower membrane seems to be a primary stimulus for the induction of MMP-1 expression in keratinocytes. In in vitro systems, keratinocytes that migrate in collagen express enhanced collagenolytic activity, where contact with laminin does not stimulate collagenolysis. In normal skin, keratinocytes are in contact with laminin and thus are not exposed to collagen. The consistent discovery of MMP-1 expression in the wound edge epithelium and its close association with keratinocyte migration and reepithelialization suggests a distinct and temporal role of MMP-1 in wound healing. It seems that MMP-1 contributes to the effective healing of acute wounds. In fact, external sources of MMP-1 have been used as a therapeutic approach to promote wound healing.

MMP-2 and 9 are present in wound healing. The expression of MMP-2 is stable during the first week in wound healing, with an apparent maximum on days 4 to 6. The same time that the collagenolytic influences on the wound decrease. Active latent and multiple forms of the active enzyme are present in the wound fluid with the two lower molecular weight forms appearing at the end of the first week. This temporal sequence is consistent with the appearance of fibroblasts and a decrease in macrophages at the site of the wound. Fibroblasts accumulate newly formed capillary cycles where cell division and fibrillar collagen deposition occur. Collagen remodeling is a prominent feature during this period and the capillaries appear in the wound along with the fibroblasts. Capillar endothelial cells are also a potential source of MMP-2. MMP-9 has also been observed in tissues and wound fluids during the early stages of wound repair. MMP-9 is expressed by infiltrating neutrophils, granulation tissue, a few basal layers of the migrating epithelial sheet and in basal layers in the non-injured area. Most of the enzyme is in its latent form. However, the active enzyme is also present in most cases.

An important consideration regarding the involvement of MMPs in wound healing is the level of endogenous inhibitor present during the healing process. Several studies have shown that the inhibitory activity of MMP increases rapidly during the healing process. The levels usually peak within the first few days and decline afterwards. Presumably, high levels are required during the early phase of wound healing to temper healing during a period of matrix deposition.

Chronic Wounds Compared to acute wound fluid, total but inactive levels of collagenases are higher in chronic ulcers. Analyzed by immunoblotting / western immunoreactivities for MMP-1 and MMP-8 are both present. Studies with the MMP-1 inhibitor doxycycline suggest that the dominant enzyme appears to be of the MMP type - Although MMP-1 plays an important role in wound healing, only a few matrix proteins, mainly collagen types 1 and 3 , they are divided by the enzyme in an environment of wound healing.

For the division of other connective tissue components, including laminin, fibronectin, type IV collagen and glycosaminoglycans, additional proteinase activity is required. MMP-3 and stromelysin -2 (MMP-10) are other metalloproteinases involved in proteolysis and tissue remodeling. MMP-3 is prominently expressed by dermal cells and keratinocytes within chronic wounds. In the dermis, fibroblasts are a major source of the enzyme. In the epidermis, the basal cells that are distant at the edge of the wound, and distinct from those cells that produce MMP-1, produce MMP-3. It is likely that the cells that express MMP-3 are those that proliferate and become migrating cells, suggesting that these keratinocytes have different roles in tissue remodeling. Because the keratinocytes (which do not express MMP-3) and the positive keratinocytes MMP-3 are in contact with the lower membrane, the stimulus for the enzymatic expression is probably due to an interaction with a soluble factor. Estromelisin -2 has a unique pattern of expression in wound healing that is produced by basal keratinocytes at the leading edge of migrating cells (the same cells that make MMP -1). In contrast to MMP-3, however, a signal for stromelysin -2 is not detected within the dermis. Because stromelysin -2 and MMP-1 are expressed in keratinocytes on the migratory front, contact with the dermal matrix (eg, collagen) can stimulate the release of both enzymes. In addition, stromelysin -2 is not expressed in cells attached to the lower membrane, suggesting that altered cell-matrix interactions may stimulate its expression.

Although gelatinase levels rise in acute wounds, these enzymes are found in much larger amounts in wounds and chronic ulcers. MMP-2 levels rise by approximately 3 to 5 points in chronic wounds, and MMP-9 levels are from 5 to 25 higher. In addition, the local gelatinase profile is not common for all patients and the profiles are much more complex than in the fluid of acute wounds. Several smaller molecular weight bands are detectable in chronic wound fluid consistent with cleavage to smaller activated forms.

The distinct location of MMP-1, MMP-3 and stromelysin-2 in chronic wounds suggests that the enzymes have different functions. In the dermis, MMP-1 and MMP-3 and gelatinases affect tissue repair and scar tissue resolution. In the epidermis, MMP-1 seems to promote the migration of keratinocytes and promotes the remodeling of the dermal connective tissue. Estromelisin -2 can also facilitate the migration of keratinocytes by degrading the non-collagenous matrix or by removing damaged lower membrane. Estromelisin -2 activates secreted procollagenase but it is not clear whether the enzyme performs this function in vivo or not. MMP-3 can be useful for restructuring the newly formed lower membrane. Although the overproduction of MMPs can contribute to chronic wound healing, it is also clear that the activity of these enzymes is ultimately beneficial. Therefore, strategies developed for the treatment of chronic wounds with MMP inhibitors should be carefully focused to moderate those mechanisms that prevent healing. The reduction in TIMP-1 and TIMP-2 levels observed in chronic wounds, however, suggests that it may be productive to restore the balance of inhibitory and degrading influences within a chronic wound.

Thus, this invention provides a method for treating neurological disorders and promoting wound healing by administering an effective amount of an MMP inhibitor. Especially preferred compounds to be used include the following. [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- (2-methyl-propyl) -? - oxo-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- (2-methyl-propyl) -? - oxo -, (S) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a- (2-methyl-propyl) -? - oxo - , (R) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-β- (2-methyl-propyl) -? - oxo -, (S); [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-β- (2-methyl-propyl) -? - oxo -, (R); [1-Biphenyl] -4-butanoic acid, 4'-chloro-? - oxo; [1-Biphenyl] -4-butanoic acid, 4'-bromo-? - oxo; [1-Biphenyl] -4-butanoic acid, 4'-fluoro-? - oxo; [1-Biphenyl] -4-butanoic acid, 2'-fluoro-? - oxo; [1-Biphenyl] -4-butanoic acid, 2'-chloro-? - oxo; [1-Biphenyl] -4-butanoic acid, 2 ', 4'-difluoro-? - oxo; [1-Biphenyl] -4-butanoic acid, 3'-chloro-? - oxo; [1-Biphenyl] -4-butanoic acid, a - (2-methyl-propyl) -? - oxo; [1'-Biphenyl] -4-butanoic acid, 4'-bromo-a- (2-methyl-propyl) -? oxo; [1'-Biphenyl] -4-butanoic acid, 4'-fluoro-a- (2-methyl-propyl) -? - oxo; [1'-Biphenyl] -4-butanoic acid, 4'-ethyl-a- (2-methyl-propyl) -? - oxo; [1'-Biphenyl] -4-butanoic acid, 2'-fluoro-a- (2-methyl-propyl) -? - oxo; [1'-Biphenyl] -4-butanoic acid, 2'-chloro-a- (2-methyl-propyl) -? - oxo; [1-Biphenyl] -4-butanoic acid, 4'-methoxy - (2-methyl-propyl) -? -oxo; [1, 1'-biphenyl] -4-butanoic acid, 2 ', 4'-difluoro-a- (2-methyl-propyl) -? • oxo; [1,1-biphenyl] -4-butanoic acid, 4'-methyl-a- (2-methyl-propyl) -? - oxo; [1, 1-biphenyl] -4-butanoic acid, a - (2-methyl-propyl) -? oxo-4'-pentyl-; [1,1-biphenyl] -4-butanoic acid, 4'-chloro-a-methylene-? - oxo -; [1,1-biphenyl] -4-butanoic acid, 2'-chloro-a-methylene -? - oxo -; [1, 1-biphenyl] -4-butanoic acid, 4'-chloro-a-methyl-? - oxo -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? oxo-a-pentyl; Benzene-butanoic acid, 4-chloro-a - (2-methyl-propyl) -? - oxo -; Benzene - butanoic acid, 4 - methyl - - methylene -? - oxo -; 2-butenoic acid, 4 - (4'-chloro [1,1'-biphenyl] -4-yl) -4-oxo-, (E) -; 2-butenoic acid, 4 - [4 - (4-chloro-phenoxy) -phenyl] -4-yl) -4-oxo-, (E) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-hydroxy-a - (2-methyl-propyl) -? -oxo; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-β-methylene -? - oxo -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - hydroxy-a - (2-methyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - hydroxy-a - (2-methyl-propyl) -; 2 (3H) -furanone, 5- (4'-chloro [1,1'-biphenyl] -4-yl) dihydro-3 - (2-methyl-propyl) -; 2 (3H) -furanone, 5- (4'-chloro [1,1'-biphenyl] -4-yl) dihydro-3 - (2-methyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 3 ', 4'-dichloro -? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 3 ', 5'-dichloro -? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (acetyloxy) -? - oxo-a - (3-phenyl-propyl) -; Benzene-pentanoic acid, a - [2 - [4 - (5-chloro-2-thienyl) phenyl] -2-oxo-ethyl] -; 2-furan-carboxylic acid, 5 - [4 - (3-carboxy-1-oxo-6-phenyl-hexyl) phenyl] -; Benzene-pentanoic acid, α- [2-oxo-2 - [4- (3-pyridinyl) phenyl] -ethyl] -; Benzene-pentanoic acid, a - [2-oxo-2 - [4 - [6 - (pentyloxy) -3-pyridinyl] phenyl] -ethyl] -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (pentthylthio) - a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-methoxy -? - oxo - - (3-phenyl-propyl) [1, 1'-biphenyl] -4-butanoic acid, 3'-chloro-4'-fluoro-? - oxo-a - (3-.phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-ethoxy -? - oxo-a - (3-phenyl-propyl) -; Benzene-pentanoic acid, a - [2-oxo-2 - [4 - (3-thienyl) phenyl] -ethyl] -; [1, 1'-biphenyl] -4-butanoic acid, 2 ', 4'-dichloro-? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-formyl -? - oxo - a - (3 - phenyl - propyl) [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (3-phenyl-propyl) -3 ', 5'-bis (trifluoromethyl) -; Benzene-pentanoic acid, a - [2-oxo-2 - [4 - (2-thienyl) phenyl] -ethyl] -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (3-phenyl-propyl) -3 '(trifluoromethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 2'-formyl -? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4-hydroxy -? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo - a - (3 - phenyl - propyl) - 4 'propoxy [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (pentyloxy) - a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (pentyloxy) - a - (3-phenyl-propyl) - (S) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (pentyloxy) - a - (3-phenyl-propyl) - (R) -; [1, 1'-Biphenyl] -4-butanoic acid, 4 '- (hexyloxy) -? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-butoxy -? - oxo - a - (3 - phenyl - propyl) [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (3-phenyl-propoxy) - a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (1-methyl-ethoxy) -? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (heptyloxy) -? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (cyclohexyl-methoxy) -? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4 '- (2-methyl-propoxy) -? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (3-phenyl-p-phenyl) -4' - (2 -propenyloxy) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a-heptyl-? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a-decyl-? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-nitro -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-cyano -? - oxo-a - (2-phenyl-ethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (2-iodo-phenyl) ethyl] -? oxo [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (3-iodo-phenyl) ethyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (4-iodo-phenyl) ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (3,5-dimethoxy-phenyl) ethyl] -? - oxo -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a-phenyl-; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? oxo-a- (phenyl-methyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a - [(trimethyl-silyl) methyl] -; [1, 1'-biphenyl] -4-butanoic acid, 4'-bromo-? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-amino-? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (2-phenyl-ethyl) -4 '- [[(phenyl-methoxy) carbonyl] amino] -; [1, 1'-Biphenyl] -4-butanoic acid, 4 '- [[(1,1-dimethyl-ethoxy) carbonyl] amino] -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4' - (acetylamino) -? - oxo - a - (2 - phenyl) - ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- [(1-oxo-pentyl) -amino] - a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- [(3,3-dimethyl-1-oxo-butyl) -amino]? - oxo- a - (2-phenyl-ethyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - [2 - (methoxy-carbonyl) phenyl] ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - (2-carboxy-phenyl) ethyl] -4'-chloro-? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-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) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - [3 - [(diethylamino) -carbonyl] phenyl] ethyl] -? - oxo -, (R) -; Cyclopentanecarboxylic acid, 2 - [(4-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenyl-methoxy) methyl] -, (la, 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(4"-chloro [1, 1'-biphenyl] -4-yl) carbonyl] -5- (phenoxy-methyl) -, (la, 2ß, 5ß) -; cyclopentane-acid carboxylic acid, 2 - [(benzyloxy) -methyl] -5 - [(4X-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (la, 2ß, 5ß) -; benzene dicarboxylic, 1 - [[2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] -methyl] -2-methyl ester, (la, 2ß, 3a) - Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(2-thienylthio) -methyl] -, (the , 2ß, 5ß) - Cyclopentane carboxylic acid, 2 - [(benzyl-amino) -methyl] -5 - [(4-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (the , 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] - 5 - [[(2-methoxy-ethoxy) methoxy] methyl] ] -, (la, 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [[(phenyl-methyl)] thio] methyl] -, ( la, 2ß, 5ß) - Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenyl-thio) methyl] -, ( la, 2ß, 5ß) -; Cyclopentane carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(propylthio) methyl] -, (la, 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(2-benzothiazolyl-thio) methyl] -5 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (la, 2ß, 5ß) -; Benzoic acid, 2 - [[[2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl] thio] -, 1-methyl ester, ( la, 2ß, 3a) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [[[(phenyl-methoxy) carbonyl] -amino] methyl] -, (the , 2ß, 5ß) -; Benzoic acid, 2-methyl-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2β, 3a) -; Benzoic acid, 3-methyl-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2β, 3a) -; Benzoic acid, 4-methyl-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2ß, 3a) -; Benzoic acid, 2-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2ß, 3a) -; Benzoic acid, 3-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2β, 3a) -; Benzoic acid, 4-methoxy-, [2-carboxy-3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] cyclopentyl] methyl ester, (la, 2β, 3a) -; Cyclopentane-carboxylic acid, 2 - [(2-benzoxazolyl-thio) methyl] -5 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, (la, 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(1,3-dihydro-4-nitro-1,3-dioxo-2H isoindol-2-yl) methyl] -, (la, 2ß, 5ß) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(1,3-dihydro-5-nitro-1, 3-dioxo-2H isoindol-2-yl) methyl] -, (la, 2β, 5β; 2H-Benz [f] isoindole-2-butanoic acid, a - [2 - (4'-ethoxy [1,1'-biphenyl] -4-yl) -2-oxo-ethyl] -1,3-dihydro- 1,3-dioxo -; [1, 1'-biphenyl] -4-butanoic acid, a - (acetylamino) -4'-chloro-? - oxo -; 2H-Isoindole-2-hexanoic acid, a - [2 - (4'-chloro [1, 1'-biphenyl] -4-yl) -2-oxo-ethyl] -1,3-dihydro-1,3- dioxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [[[3- (methoxy-carbonyl) phenyl] thio] methyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[(2,6- (dimethyl-phenyl) thio] methyl] -α-oxo-; [1, 1 '-] acid biphenyl] -4-butanoic, 4'-chloro-a - [[[4-fluoro-2 - (methoxy-carbonyl) phenyl] thio] methyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [[[3 - [(diethylamino) -carbonyl] phenyl] thio] methyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[[2 - [(dimethylamino) -carbonyl] phenyl] thio] methyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [[[3 - [(dimethylamino) -carbonyl] 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'-biphenyl] -4-yl) carbonyl] -; Cyclopentanecarboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenyl-methyl) thio] -, (la, 2ß, 5a) -; Cyclopentane-carboxylic acid, 2 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -5 - [(phenylmethyl) thio] -, (la, 2β, 5β) -; 1-Cyclopentene-1-carboxylic acid, 5 - [[4 '- (pentyloxy) [1,1'-biphenyl] -4-yl] carbonyl] -; 1-Cyclopentene-1-carboxylic acid, 5 - [[4 '- (hexyloxy) [1,1'-biphenyl] -4-yl] carbonyl] -; [1, 1'-biphenyl] -4-butanoic acid, 4'-hydroxy -? - oxo - a - [(phenylthio) methyl] [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - [2 - [(butylamino) carbonyl] phenyl] ethyl] -4'-chloro-? - oxo -; [1, Y-biphenyl] -4-butanoic acid, a - [2 - (3-carboxy-phenyl) ethyl] -4'-chloro-? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - [3 - [(diethylamino) carbonyl] -phenyl] ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - [3 - [(butylamino) carbonyl] -phenyl] ethyl] 4'-chloro-? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - [4 - [(diethylamino) carbonyl] -phenyl] ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - [4 - [(butylamino) carbonyl] -phenyl] ethyl] -4'-chloro-? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, - a - [2 - (4-carboxy-phenyl) ethyl] -4'-chloro -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-methoxy -? - oxo-a - (2-phenyl-ethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-hydroxy -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-ethoxy -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (2-phenyl-ethyl) -4'-propoxy-; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- (pentyloxy) - a - (2-phenyl-ethyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4 '- (hexyloxy) -? - oxo - a - (2-phenyl-ethyl) [1, 1 '- biphenyl] -4-butanoic acid, 4'-butoxy -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (2-phenyl-ethyl) -4 '- (phenyl-methoxy) -; [1, 1'-biphenyl] -4-butanoic acid, a - [2 - (3-iodo-phenyl) ethyl]? - oxo-4 '- (pentyloxy) -; [1, 1'-biphenyl] -4-butanoic acid, a - [2 - (3-iodo-phenyl) ethyl]? - oxo-4'- (phenyl-methoxy) -; [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - (3 - [(diethylamino) carbonyl] phenyl] ethyl] -? - oxo-4'- (pentyloxy) -; Acid [1 , 1'-biphenyl] -4-butanoic, a - [2 - (3 - [(diethylamino) carbonyl] phenyl] ethyl] -? - oxo-4'- (phenyl-methoxy) -; Acid 1, 2 - pyrrolidine-dicarboxylic acid, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, 1 - (phenyl-methyl) ester, (2S-trans) -; 1,2-Acid - pyrrolidine-dicarboxylic acid, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -, 1 - (phenyl-methyl) ester, (2'R-trans) -; L- proline, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -1 - [[(phenylmethyl) amino] carbonyl] -, trans -; L - proline, 3 - [(4'-chloro [1, 1'-biphenyl] -4-yl) carbonyl] -1- (1-oxo-3-phenyl-propyl) -, trans-; L-proline, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -1- (phenyl-acetyl) -, trans-; L-proline, 3 - [(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -1- (3, 3-dimethyl-1-oxo-butyl) -, trans-; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a-heptyl-? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a-decyl-? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-nitro -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-cyano -? - oxo-a - (2-phenyl-ethyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (2-iodo-phenyl) ethyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (3-iodo-phenyl) ethyl] -? - oxo -; [1, 1'-biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (4-iodo-phenyl) ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - (3,5-dimethoxy-phenyl) ethyl] -? - oxo -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a-phenyl-; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? oxo-a- (phenyl-methyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4'-chloro-? - oxo-a - [(trimethyl-silyl) methyl] -; [1, 1'-biphenyl] -4-butanoic acid, 4'-bromo-? - oxo-a - (3-phenyl-propyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (3-phenyl-propyl) -; [1, 1'-biphenyl] -4-butanoic acid, 4'-amino-? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-a - (2-phenyl-ethyl) -4 '- [[(phenyl-methoxy) carbonyl] amino] -; [1, 1'-Biphenyl] -4-butanoic acid, 4 '- [[(1,1-dimethyl-ethoxy) carbonyl] amino] -? - oxo-a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid, 4' - (acetylamino) -? - oxo - a - (2 - phenyl) - ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- [(1-oxo-pentyl) -amino] - a - (2-phenyl-ethyl) -; [1, 1 '- biphenyl] -4-butanoic acid,? - oxo-4 '- [(3,3-dimethyl-1-oxo-butyl) -amino]? - oxo- a - (2-phenyl-ethyl) -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-a - [2 - [2 - (methoxy-carbonyl) phenyl] ethyl] -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, a - [2 - (2-carboxy-phenyl) ethyl] -4'-chloro -? - oxo -; [1, 1'-Biphenyl] -4-butanoic acid, 4'-chloro-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) -; [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., J. Pharm. Sci., 66, 466-476 (1977), and Arzneim-Forsch, 1980, 30 (4a): 695-702, all of which are incorporated herein by reference. The preferred compounds of the fenbufen series which are used in this invention have the formula: OH?) - opdeR is OR II CCH2CH2COOH (fenbufen), COCH = CHCOOH, SO2NH2, COCH2CHCOOH, CH3COOH, COCH2CH2SO3Na, CH (OH) CH2CH2COOH, COCH2CHCOOH, COCH2CH2CONHOH, C (= NOH) CH2CH2COOH, OH and COCH2SCH2COOH.

Numerous peptides are known inhibitors of matrix metalloproteinase. Typical peptides are those described in U.S. Patent Number ,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. Said compounds are illustrated by the formula: Where each of the variable groups may include alkyl hydrogen, aryl, heteroaryl, alkenyl, alkynyl, carboxy 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-acetyl-mercapto-propanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-acetyl-mercapto-3-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-4-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-4-ptalimido-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-ptalimido-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-ptalimido-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2, 3-bis-mercapto-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-3-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-4-methoxy-carbonyl-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-4-phallimido-butanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-5-phallimido-butanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-6-phallimido-butanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-acetyl-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-valinyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L -triptophan N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-valinyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-tryptophan N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (4-thiazolyl)] alanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (2-pyridyl)] alanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-5-methyl-L-glutamic acid N-methyl-amide; N - [2-acetyl-mercapto-6-phallimido-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-2, (3-ptalimido) phenyl-acetyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-5-methoxy-carbonyl-hexanoyl] -L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-tryptophan N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-tryptophan N -methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (4-thiazolyl)] alanine N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (2-pyridyl)] alanine N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-5-methyl-L-glutamic acid N-methyl-amide; N - [2-mercapto-6-phallimido-hexanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [N-mercapto-acetyl) -L-leucyl] -L-phenylalanine N-methyl-amide; N - [aceto-mercapto-acyl) -L-leucyl] -L-phenylalanine methyl amide; (RS) -2- (acetylthio) pentanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2- (acetylthio) propanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2- (acetylthio) -3-methyl-butanoyl-L-leucyl-L-phenylalanine N -methyl-amide; (RS) -2- (acetylthio) -2-phenyl-acetyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2- (acetylthio) -3-phenyl-propanoyl-L-leucyl-L-phenylalanine N -methyl-amide; (RS) -2- (acetylthio) -4-phenyl-butanoyl-L-leucyl-L-phenylalanine N -methyl-amide; N - (acetyl mercapto-acyl) -L-threonyl-L-phenylalanine methyl amide; N - (acetyl mercapto-acyl) -L-leucyl-L-tryptophan methyl amide; (RS) -2-mercapto-pentanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-propanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-3-methyl-butanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-2-phenyl-acetyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-3-phenyl-propanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-4-phenyl-butanoyl-L-leucyl-L-phenylalanine N-methyl-amide; N - [N - (mercapto-acetyl) -L-threonyl] -L-phenylalanine methyl amide; and N - [N - (mercapto-acetyl) -L-leucyl] -L-tryptophan methyl amide.

Additional inhibitors of matrix metalloproteinases (MMPs) that can be used to prevent and treat heart failures include the following: [4 - (N-hydroxy-amino) -2 (R) -cyclohexyl-methyl-succinyl] -L - ß-cyclohexyl-alanine - N - (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-β-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- (2-phenyl-ethyl) -amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- [2 - (N, N-dimethylamino] ethyl) amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-ß-cyclohexyl-alanine-N- (2 - (p-sulfonamido-phenyl) -ethyl) -amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- (2 - (p-sulfonyl-phenyl) -ethyl) -amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- [2- (2-pyridyl) -ethyl] -amide; [4 - (N-hydroxy-amino) -2R-pentyl-succinyl] -L-β-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isoamyl-succinyl] -L-β-cyclohexyl-alanine-N - (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-phenyl-butyl-succinyl] -L-β-cyclohexyl-alanine-N- (2-phenyl-ethyl) -amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- [3- (4-morpholinyl) propyl] amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-β-cyclohexyl-alanine-N- [β-alanine] amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-β-cyclohexyl-alanine-amide; [4 - (N-hydroxy-amino) -2R- (3-phenyl-propyl) -succinyl] -L-β-cyclohexyl-alanine-amide; [4 - (N-hydroxy-amino) -2R- (3-phenyl-butyl) -succinyl] -L-β-cyclohexyl-alanine-amide; [4 - (N-hydroxy-amino) -2R-phenyl-ethyl-succinyl] -L-leucine N - (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-phenyl-propyl-succinyl] -L-leucine N- (2-phenyl-ethyl) amide; [4 - (N-hydroxy-amino) -2 (R) -isobutyl-succinyl] -L-tryptophan amide; [4 - (N-hydroxy-amino) -2 (R) -isobutyl-succinyl] -L-valine amide; [3-phosphono-2R, S-phenyl-propyl-1-oxo-propyl] -L-ß-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide, dimethyl-ester; [3-phosphono-2R-phenyl-propyl-1-oxo-propyl] -L-ß-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide, dimethyl ester; [3-phosphono-2S-phenyl-propyl-1-oxo-propyl] -L-ß-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide, dimethyl ester; [3-phosphono-2R-phenyl-propyl-1-oxo-propyl] -L-β-cyclohexyl-alanine; [3-phosphono-2R-phenyl-propyl-1-oxo-propyl] -L-β-cyclohexyl-alanine-β-alanine, methyl ester; [3-phosphono-2R, S-phenyl-propyl-1-oxo-propyl] -L-β-cyclohexyl-alanine-N- [4 (3-amino-propyl) morpholine] amide, bromine salt; [3-phosphono-2R, S - (4-methyl-phenyl) -propyl-1-oxo-propyl] -L-ß-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide, diethyl ester; [3-phosphono-2R, S - (4-methyl-phenyl) -propyl-1-oxo-propyl] -L-β-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide; 4-t-Butoxy-2 (R) - [3 - (2-phenoxy-ethyl) succinyl] - L - ß - cyclohexyl - alanine - N - (2-phenyl-ethyl) amide; 4-hydroxy-2 (R) - [3 - (2-phenoxy-ethyl) succinyl] -L-β-cyclohexyl-alanine-N - (2-phenyl-ethyl) amide; 4 - (N-hydroxy-amino) -2 (R) - [3 - (2-phenoxy-ethyl) succinyl] -L-ß-cyclohexyl-alanine-N- (2-phenyl-ethyl) amide; . { 4-hydroxy-2 (R) - [3- (4-pyridinium) propyl] succinyl} - L - ß - cyclohexyl - alanine - N - (2 - phenyl - ethyl) amide; . { 4 - (N-hydroxy-amino) 2 (R) - [3 - (4-pyridinium) propyl] succinyl} - L - ß - cyclohexyl - alanine - N - (2 - phenyl - ethyl) amide; . { 4 - (N-hydroxy-amino) 2 (R) - [3 - (N-methyl-4-pyridinium) propyl] succinyl} - L - ß - cyclohexyl - alanine - N - (2 - phenyl - ethyl) amide; . { 4-hydroxy-2 (R) - [3- (4-pyridinium) propyl] succinyl} - L - ß - cyclohexyl - alanine - N - (2 - morpholino - sulfonyl - amino) ethyl] amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-methyl-phenyl) propyl] succinyl} - L - ß - cyclohexyl-alanine-N- (2-morpholino-sulfonyl-amino) ethyl] amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-chloro-phenyl) propyl] succinyl} - L - ß - cyclohexyl-alanine-N- (2-morpholino-sulfonyl-amino) ethyl] amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-methyl-phenyl) propyl] succinyl} - L - ß - cyclohexyl-alanine - N - (2-dimethyl-sulfonyl-amino) propyl] amide; [4 - (N-hydroxy-amino) -2 (R) - [3 - (4-chloro-phenyl) propyl] succinyl] - L - [S - (methyl) penicyl-amine] - N -methyl-amide; [4 - (N-hydroxy-amino) -2 (R) - [3 - (4-chloro-phenyl) -propyl] -succinyl] -L- [S- (methyl) penicyl-amine] -amide; [4 - (N-hydroxy-amino) -2 (R) - [3- (4-chloro-phenyl) propyl] succinyl] -L-penicyl-amine amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-chloro-phenyl) propyl] succinyl} - L - [S - (methyl) penicil-amine-sulfone] -N-methyl-amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-chloro-phenyl) propyl] succinyl} - L - [S - (methyl) penicyl-amine sulfoxide] - N-methyl-amide; . { 4 - (N-hydroxy-amino) -2 (R) - [3- (4-chloro-phenyl) propyl] succinyl} - L -penicyl-amine-N-methyl-amide; [4 - (N-hydroxy-amino) -2 (R) - [3 - (2-methyl-propyl) succinyl] -L - [S - (methyl) penicyl-amine] -N-methyl-amide; N 4 -hydroxy-N 1 - (1 - (S) -carbamoyl-2, 2-dimethyl-propyl) -2- (R) -4- (chloro-phenyl-propyl) succinamide; N 4 -hydroxy-N 1 - (1 - (S) -carbamoyl-2, 2-dimethyl-propyl) -2- (R) - (4-methyl-phenyl-propyl) succinamide; N 4 -hydroxy-N 1 - (1 - (S) -carbamoyl-2, 2-dimethyl-propyl) -2- (R) - (4-methoxy-phenyl-propyl) succinamide; N 4 -hydroxy-N 1 - (1 - (S) -carbamoyl-2, 2-dimethyl-propyl) -2- (R) - (4-trifluoro-methyl-phenyl-propyl) succinamide; N 4 -hydroxy-N 1 - (1 - (S) -carbamoyl-2, 2-dimethyl-propyl) -2- (R) - (4-chloro-methyl-phenyl-propyl) succinamide; N - [N - (mercapto-acetyl) -L-leucyl] -L-phenylalanine methyl amide; N - (aceto-mercapto-acyl) -L-leucyl] -L-phenylalanine methyl amide; (RS) -2- (acetylthio) pentanoyl-L-leucyl-L-phenylalanine-N-methyl-amide; (RS) -2- (acetylthio) propanoyl-L-leucyl-L-phenylalanine-N-methyl-amide; (RS) -2- (Acetylthio) -3-methyl-butanoyl-L-leucyl-L-phenylalanine-N-methyl-amide; (RS) -2- (acetylthio) -2-phenyl-acetyl-L-leucyl-L-phenylalanine-N-methyl - amide; (RS) -2- (acetylthio) -3-phenyl-propanoyl-L-leucyl-L-phenylalanine-N-methyl-amide; (RS) -2- (acetylthio) -4-phenyl-butanoyl-L-leucyl-L-phenylalanine-N-methyl-amide; N - (acetyl mercapto-acyl) -L-threonyl-L-phenyl-alanine methyl amide; N - (acetyl mercapto-acyl) -L-leucyl-L-tryptophan methyl amide; (RS) -2-mercapto-pentanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-propanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-3-methyl-butanoyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-2-phenyl-acetyl-L-leucyl-L-phenylalanine N-methyl-amide; (RS) -2-mercapto-3-phenyl-propanoyl-L-leucyl-L-phenylalanine N-methyl - amide; (RS) -2-mercapto-4-phenyl-butanoyl-L-leucyl-L-phenylalanine N-methyl-amide; N - [N - (mercapto-acetyl) -L-threonyl] -L-phenylalanine methyl amide; N - [N - (mercapto-acetyl) -L-leucyl] -L-tryptophan methyl amide; N - [2, 3-bis-acetyl-mercapto-propanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-acetyl-mercapto-3-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-4-methoxy-carbonyl-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-4-ptalimido-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-ptalimido-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-ptalimido-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2, 3-bis-mercapto-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-3-methoxy-carbonyl-propanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-4-methoxy-carbonyl-butanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-4-phallimido-butanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-6-phalimido-hexanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-acetyl-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-valinyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L -triptophan N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-valinyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-5-ptalimido-pentanoyl] -L-leucyl-L-tryptophan N - methyl amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (4-thiazolyl)] alanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (2-pyridyl)] alanine N-methyl-amide; N - [2-acetyl-mercapto-5-phallimido-pentanoyl] -L-leucyl-5-methyl-L-glutamic acid N-methyl-amide; N - [2-acetyl-mercapto-6-phallimido-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-acetyl-mercapto-2 - (3-ptalimido) -phenyl-acetyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-5-methoxy-carbonyl-pentanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-phenylalanine N-methyl-amide; N - [2-mercapto-6-methoxy-carbonyl-hexanoyl] -L-leucyl-L-tryptophan N - methyl amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L-tryptophan N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (4-thiazolyl) alanine N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-L - [β - (2-pyridyl) alanine N-methyl-amide; N - [2-mercapto-5-phallimido-pentanoyl] -L-leucyl-5-methyl-L-glutamic acid N-methyl-amide; N - [2-mercapto-6-phallimido-hexanoyl] -L-leucyl-L-phenylalanine N -methyl-amide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (3-picolyl) amino] -3-methyl-butanamide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (3-picolyl) amino] -2-cyclohexyl-acetamide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (benzyl) amino] -4-methyl-pentanamide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (benzyl) amino] -6 - [(N, N-dimethyl-glycyl) amino] hexanamide hydrochloride; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (3-picolyl) amino] -3-methyl-butanamide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (4-picolyl) amino] -2-cyclohexyl-acetamide; N-hydroxy-2 (R) - [[4-methoxy-benzenesulfonyl] - (4-picolyl) amino] -2- (2-tetrahydro-furanyl) acetamide; N-hydroxy-2 (R) - [[4-methoxy-benzene-sulfonyl] - (3-picolyl) amino] -3-methyl-butanamide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-benzyl-succinyl] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methoxy-phenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methoxy-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-thio-phenyl-succinyl] - N2 - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-thio-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (methyl-thio-2-thienyl) succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-isopropanoate] -N2 acid - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-tert-butanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-thio-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-thio-isopropanoate] - N2 - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3 S -methyl- (2-pyridyl)] - N 2 - (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl- (3-pyridyl)] - N2 - (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3 S -methyl- (4-pyridyl)] - N 2 - (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-thio-tert-butanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methoxy-phenyl-succinyl] -N2 acid - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methoxy-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-thio-phenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-thio-benzyl-succinyl] - N2 - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S- (methyl-thio-2-thienyl) -succinyl] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-isopropanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-thio-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-thio-isopropanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl-thio-tert-butanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl- (2-pyridyl)] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3 S -methyl- (3-pyridyl)] - N 2 - (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-hexyl-3S-methyl- (4-pyridyl)] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methoxy-phenyl-succinyl] - N2 - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methoxy-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-thio-phenyl-succinyl] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-thio-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S- (methyl-thio-2-thienyl) -succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-benzyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-acetate] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-isopropanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-thio-acetate] - N2 acid - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-thio-isopropanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-ethyl-phenyl-3S-methyl-thio-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-thio-phenyl-succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-thio-benzyl-succinyl acid] - N2 - (S) - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S- (methyl-thio-2-thienyl) -succinyl] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-acetate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-isopropanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-tert-butanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-thio-acetate] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-thio-isopropanoate] -N2- (S) -piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl-thio-tert-butanoate] -N2- (S) -pyrazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl- (2-pyridyl)] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl- (3-pyridyl)] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-octyl-3S-methyl- (4-pyridyl)] - N2 - (S) acid - piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] - N2 - (S) acid - 4 '(S / R) - benzyl-piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] - N2 - (S) acid - 5 '(S / R) - benzyl-piperazic N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -N2- (S) -6 '(S / R) -benzyl-piperazoic acid N-methyl amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] - N2 - (S) acid - [5 ', 6'] (S / R) - benzo-piperazic N-methyl amide; N- [1 (R) -carboxy-ethyl] -α- (S) -isobutyl-glycine - (S) -N 2 -piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyl] - a - (S) -hexyl-glycine - (S) -N2-piperazoic acid, methyl amide; N - [1 (R) -carboxy-ethyl] - a - (S) -heptyl-glycine - (S) -N2-piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyl] - a - (S) -octyl-glycine - (S) -N2-piperazoic acid, methyl amide; N - [1 (R) -carboxy-ethyl] -α- (S) -ethyl-phenyl-glycine - (S) -N 2 -piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyl] -α- (S) -propyl-phenyl-glycine - (S) -N 2 -piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyl-thio-benzyl] -α- (S) -isobutyl-glycine - (S) -N2-piperazoic acid, methyl amide; N - [1 (R) -carboxy-ethyl-thio-benzyl] - a - (S) -hexyl-glycine - (S) -N2 acid - piperazic, methyl amide; N - [1 (R) -carboxy-ethyl-thio-benzyl] - a - (S) -ethyl-phenyl-glycine acid - (S) - N2 - piperazic, methyl amide; N - [1 (R) -carboxy-ethyl-thio-benzyl] -α- (S) -propyl-phenyl-glycine - (S) -N2-piperazoic acid, methyl amide; N - [1 (R) -carboxy-ethyloxy-benzyl] - a - (S) -isobutyl-glycine - (S) -N2-piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyloxy-benzyl] -α- (S) -hexyl-glycine - (S) -N 2 -piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyloxy-benzyl] -α- (S) -ethyl-phenyl-glycine - (S) -N2-piperazoic acid, methyl amide; N - [1 (R) -carboxy-ethyloxy-benzyl] - a - (S) -propyl-phenyl-glycine - (S) acid - N2 - piperazic, methyl amide; N- [1 (R) -carboxy-4 - (p-toluene-sulfonyl) butyl] -α- (S) -phenethyl-glycyl- (S) -N2-piperazoic acid, methyl amide; N- [1 (R) -carboxy-ethyl] - a - [2 - (4-phenyl-phenoxy) ethyl] -glycyl- (S) -N2-piperazoic acid, methyl amide; 2 - [2 (R) - [2 - [1, 1'-biphenyl) il] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino- carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [1, 1'-biphenyl) il] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino- carbonyl-hexahydro-pyridazine; 2 - . 2 - . 2 - [2 (R) - [2 - [1, 1 '- biphenyl) il] propyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino- carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - (4-propyl-phenyl) ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl-hexahydro - pyridazine; 2 - [2 (R) - [2 - (4-Butyl-phenyl) ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] - 3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - (4-1-Butyl-phenyl) ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl - hexahydro-pyridazine; 2 - [2 (R) - [2 - [4 - (4-Fluoro-phenyl) phenyl] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl- amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [4 - (4-Fluoro-phenyl) phenyl] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] - 3 (S) -methyl- amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2-n-octyl-4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl- hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl- hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4 - [3 - (phenyl-sulfonyl) propyl-4 - (S) -carboxy-1-oxobutyl] -3 (S ) - methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-thiazolyl) phenyl] ethyl] -4- [3 - (phenyl-propyl) -4 - (S) -carboxy - 1-oxobutyl] -3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-oxazolyl) phenyl] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl- hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-oxazolyl) phenyl] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl- hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-oxazolyl) phenyl] ethyl] -4 - [3 - (phenyl-sulfonyl) propyl-4 - (S) - carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-oxazolyl) phenyl] ethyl] -4 - [3 - (phenyl-propyl) -4- (S) -carboxy-1-oxobutyl] -3 (S) - Methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [4 - (Dimethyl-amino) methyl-phenyl] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl- amino - carbonyl - hexahydro - pyridazine; 2 - [2 (R) - [2 - [4 - (dimethyl-amino) methyl-phenyl] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl- amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [4 - (dimethyl-amino) methyl-phenyl] ethyl] -4 - [3 - (phenyl-sulfonyl) propyl-4 - (S) -carboxy-1-oxobutyl] - 3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [4 - (dimethyl-amino) methyl-phenyl] ethyl] -4 - [3 - (phenyl-propyl) -4 - (S) -carboxy-1-oxobutyl] - 3 (S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-imidazolyl) -phenyl] ethyl] -4-butyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl - hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-imidazolyl) -phenyl] ethyl] -4-methyl-4 - (S) -carboxy-1-oxobutyl] -3 (S) -methyl-amino-carbonyl - hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-imidazolyl) -phenyl] ethyl] -4 - [3 - (phenyl-sulfonyl) propyl-4 - (S) -carboxy-1-oxobutyl] -3 ( S) -methyl-amino-carbonyl-hexahydro-pyridazine; 2 - [2 (R) - [2 - [(4-imidazolyl) -phenyl] ethyl] -4 - [3 - (phenyl-propyl) -4- (S) -carboxy-1-oxobutyl] -3 (S ) - methyl-amino-carbonyl-hexahydro-pyridazine; HS (CH2) 2 - (S-D-Leu) -Phe-NHMe; HS (S) CH Me CH2 - (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) -Tf-NHBn; N-Bu-S (NH) 2 - (CH2-DL-TyrOCH) - Trp-NHBn; Me - RS - SO (NH) - (CH2 - L - Leu) - Phe - Ala - NH2; N-Bu-RS-SO (NH) - (CH2) -L-Leu) -Phe-Ala-NH2; HONH - C - CH2CH (CH2CH (CH3) 2) - CO - Nal - Ala - NH2; OR HO-NH-CO-CH2-CH- (CH2-CH (CH3) 2) -CO-Nal-Pro-NH2; HO - NH - CO - CH (CH3 - CH (CH2) - CH (CH3) 2) - CO - Nal - Ala - NH2; H HON - COCH2 r- CO - Pal - Ala - NH2, Where Pal is 3-pyridyl-alanine; H HON - COCH2 r- CO - Nal (CH2S) Ala - NH2, HO - NH - CO - CH2 - CH (CH2 CH (CH3) 2) - CONal - (CH2NH) - Ala - NH2; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) [[3-methyl-1 - (S) - [[(2)] acid - morpholin-4-yl-ethyl) amino] carbonyl] butyl] amino] butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) [[3-methyl-1 - (S) - [[(methyl)] amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3 - dihydro - 1, 3 - dioxo - 2H - benz [f] isoindol - 2 - yl) - 2 - (R) [[3-methyl-1 - (S) - [[(1H-imidazol-2-yl-methyl) -amino] carbonyl] butyl] amino] butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) [[3-methyl-1 - (S) - [[(1H)] acid - tetrazol-5-yl-methyl) -amino] carbonyl] butyl] amino] butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ (2 - (phenyl) ethyl] amino] carbonyl] butyl] amino] -butanoic acid 4 - (1,3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[(pyridin-3-yl-methyl) amino] carbonyl] butyl] amino] -butanoic acid 4 - (1,3-dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2- (R) - [[3-methyl-1 - (S) - [[(2-methyl-2H-terrazzo-5-yl- methyl) -amino] carbonyl] butyl] amino] -butanoic acid 4 - (1, 3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [ [3-methyl-1 - (S) - [[(4-hydroxy-2-methyl-pyrimidin-5-yl-methyl) -amino] carbonyl] butyl] amino] -butanoic acid 4 - (1, 3 - dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[2- (2-pyridine-3 - il) ethyl] -amino] carbonyl] butyl] amino] -butanoic acid 4 - (1, 3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[1- (1H-tetrazole- 5-yl) ethyl] -amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 5-amino-4H - [1, 2, 4] -triazol-3-yl-methyl) -amino] carbonyl] butyl] amino] -butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 1 - (6-oxo-1,6-dihydro-pyridazin-3-yl) ethyl] amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( phenyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( benzyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( pyridin-4-yl-methyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 2 - (1H-imidazol-4-yl) ethyl] amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( pyridin-2-yl-methyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f | isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-sulfamoyl-phenyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-sulfamoyl-phenyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-dimethyl-amino-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 1- (S) -phenyl-ethyl] amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1,1-dioxo-tetrahydro-thiophen-3-yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-sulfamoyl-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 1 - (R) -phenyl-ethyl] amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-fluoro-benzyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( fyran-2-yl-methyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1-methyl-1H-tetrazol-5-yl-methyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1, 2, 3, 4-tetrahydro-naphthalen-1-yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 2,4-difluoro-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-nitro-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-nitro-benzyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-methanesulfonyl-amino-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-methanesulfonyl-amino-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3,4-difluoro-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-trifluoro-methyl-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - [2 - (S) - [1 - (R) -carboxy-3 - (1,3-dioxo-1,3-dihydro-benzoic acid) [f] isoindol-2-yl) -propyl-amino] -4-methyl-pentanoylamino-methyl) -benzoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 2-hydroxy-1,1-bis-hydroxy-methyl-ethyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3, 5-difluoro-benzyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[benzyl] acid - methyl-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-dimethyl-amino-ethyl) -methyl-amino] carbonyl] butyl] amino] - butanóico; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1-azabicyclo [2.2.2] - oct-3 (R) -amino] carbonyl] butyl] amino] -butanoic acid 4 - (1,3-dihydro-1,3-dioxo-2H-benz [f] isoindole) - 2 - yl) - 2 - (R) - [[3-methyl-1 - (S) - [[(1-azabicyclo [2.2.2.] - oct-3 (S) -amino] carbonyl] butyl] amino] - butanoic; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3 - (R) -4- (S) -5- (R) -6-Tetrahydroxy-tetrahydro-pyran-2 - (R) -yl-methyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( N, N-dimethyl-hydrazino) carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( methyl-methoxy) 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) - [[( dimethyl) 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-oxo-tetrahydro-thiophen-3 - (R) -yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 2-oxo-tetrahydro-thiophen-3 - (S) -yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3 - (R) -acetyl-amino-4 - (S) -5- (S) -dihydroxy-6 - (R) -hydroxy-methyl-tetrahydro-pyran-2-yl) amino] carbonyl] butyl] amino] - butanóico; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ benzyl (2-hydroxy-ethyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [3, 4-dihydro-1H-isoquinoline-2-carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [4 -] acid. methyl-piperazine-1-carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [1 -] oxo- [1,4] -thiazine-4-carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [morpholino- 4-carbonyl] butyl] amino] -butanoic; 4 - (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [4 -] acid. (2 -3-dihydroxy-propyl) -piperazine-1-carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [3, 4, 5, 6 - tetrahydro - H - [2, 3] bipyridinyl] carbonyl] butyl] amino] - butanóico; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1-methyl-8-oxo-1,7-diazacyclotide-9-yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3 - Dihydro - 1, 3 - dioxo - 2 H - benz [f] isoindol - 2 - yl) - 2 - (R) - [[3-methyl-1 - (S) - [[methyl] - 1-methyl-piperidin-4-yl) amino] carbonyl] butyl] amino] - butanóico; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 4-hydroxy-1,1-dioxo-tetrahydro-thiophen-3-yl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - (4 -) acid ethoxy-carbonyl-methyl-piperazine-1-carbonyl) butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 1,1-dioxo-tetrahydro-thiophen-3-yl) -methyl-amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [2 -] - acid (R) - (pyridin-3-yl) -pyrrolidine-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 -] - acid (S) - (pyridin-3-yl) -pyrrolidine-carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [3 -] - acid oxo-2 - (R) -phenyl-piperazine-1-carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [3 -] - acid oxo-2 - (S) -phenyl-piperazine-1-carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [(pyridine - 3-carbonyl-hydrazino) carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( benzene-sulfonyl) amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( 3-amino-benzyl) amino] carbonyl] butyl] amino] -butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 4-trifluoro-methanesulfonyl-amino) benzyl] amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 2-hydroxy - (R) -bicyclo [4.3.O.] nona-3, 6 (1) -diene] amino] carbonyl] butyl] amino] -butanoic; 4 - (1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[[ 2-hydroxy- (S) -bicyclo [4.3.0] nona-3, 6 (1) -diene] amino] carbonyl] butyl] amino] -butanoic acid; 4 - (1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl) -2 - (R) - [[3-methyl-1 - (S) - [[( N-methyl-pyrrolidine) -methyl-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) - [(N)] acid - ethoxy-carbonyl-methyl-piperazine) -1-carbonyl] butyl] amino] -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-propoxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4- (5-amino-1,3-dioxo-1,3-dihydro-isoindole) acid - 2 - il) - butanoic; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-Benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-phenyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-methano-sulfonyl-amino-1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [1 - (S) - (Benzyl-amino) carbonyl-3-methyl-butyl-amino] -4 acid - (5-hydroxy-1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -butanoic acid; 2 - (R) - [[3-Methyl-1 - (S) - [[(pyridin-3-yl-methyl) amino] carbonyl] -butyl] amino] -4- (1, 3, 5, 7 acid - tetraoxo-3, 5, 6-tetrahydro-1H-pyrolo [3,4-f] isoindol-2-yl) butanoic; EtONHCONMe - CH2CH (iBu) - CO - L - Trp - NHEt; EtCONOH - CH 2 CH (iBu) - CO - L - Trp - NHEt; N - PrCONOEt - CH2CH (iBu) - CO - L - Trp - NHEt; EtHCONOMe - CH2 CH (iBu) - CO - L - Trp - NHEt; MeNHCONOH - CH2 CH (iBu) - CO - L - Trp - NHEt; EtONHCONMe - CH2 CH (iBu) - CO - L - Ala (2 - naphthyl) - NHEt; EtCONOH-CH2CH (iBu) -CO-L-Ala (2-naphthyl) -NHEt; N - PrCONOEt - CH 2 CH (Ibu) - CO - L - Ala (2 - naphthyl) - NHEt; EtNHCONOMe - CH2 CH (iBu) - CO - L - Ala (2 - naphthyl) - NHEt; MeNHCONOH - CH2 CH (iBu) - CO - L - Ala (2 - naphthyl) - NHEt; HONHCONHCH2 CH (iBu) -CO-L - TrpNHMe; HONHCONHCH2 CH2CH (iBu) -CO-L -TfNHMe; HONHCONHCH (iBu) -CO-L - TfNHMe; H2NCON (OH) CH (iBu) -CO-L-TfNHMe; N (OH) CH2 (iBu) -CO-L -TfNHMe; H2NCON (OH) CH2CH2CH (iBu) -CO-L -TfNHMe; CH3CON (OH) CH (iBu) -CO-L-TfNHMe; CH3CON (OH) CH2CH (iBu) -CO-L -TrpNHMe; CH3CON (OH) CH2CH2CH (i-Bu) -CO-L-TfNHMe; NHOHCOCH2CH (i -Bu) CO -L-Tf -NHMe; HONHCONHCH2 CH (i -Bu) CONHCHCOOHo ROOCH2 CH (i - Bu) CONHCHCOOH ±;. I R4 N -. { D, L-2 - (hydroxy-amino-carbonyl) methyl-4-methyl-pentanoyl} - L-3 - (2'-naphthyl) alanyl-L-alanine, 2- (amino) ethyl amide; N -. { D, L-2 - (hydroxy-amino-carbonyl) methyl-4-methyl-pentanoyl} - L-3-amino-2-dimethyl-butanoyl-L-alanine, 2- (amino) ethyl amide; 4 (S) - [3-hydroxy-amino-carbonyl-2 (R) - (2-methyl-propyl) propanoyl] amino-1, 2, 3, 4, 5-tetrahydro-3H-2-benzazepin-3- ona; [4 - (N-hydroxy-amino) - (2R) -isobutyl-3-methyl-succinyl] -L-phenyl-glycine-N-methyl-amide; 4 (S) - [2 (R) - [1 (R) -hydroxy-carbamoyl-2-morpholino-ethyl] -4-methyl -valeryl] amino-1, 2, 4, 5-tetrahydro-3H-2- benzazepine-3-one; (IR, 4S) - 4 - [(2R) -hydroxy-carbamoyl-methyl-4-methyl-valeryl] amino-3 -oxo-1, 2,4,5,5-tetrahydro-3H-2-benzazepine-3-one; 3 - [2 - (N-Methyl-carbamoyl) -ethyl-sulfinyl] -5-methyl-hexane-hydroxamic acid; N - [(2-Tenoyl-mercapto-3-methyl) -butanoyl] -homocysteine thio-lactone; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -isoleucine, N - phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -lanine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -phenylalanine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -serine-O -benzyl ether, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -tryptophan, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a- (S) - (2-phenyl) ethyl) glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -norleucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -valin, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine hydrochloride - (L) - serine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -asparagine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine hydrochloride - (L) threonine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -lysine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -glutamic acid, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] -α- (S) - (2-phenyl-ethyl) -glycine - (L) -tyrosine, N-phenyl-amide hydrochloride; N - [1 (R) -carboxy-5 - (1,3-dioxo-isoindolin-2-yl) pentyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-5 - (1-oxo-isoindolin-2-yl) pentyl] - a - (S) - (2-phenyl-ethyl) -glycine - (S) -leucine hydrochloride, N-phenyl-amide; N - [1 (R) -carboxy-5 - (1-oxo-isoindolin-2-yl) pentyl] - a - (S) - (2-phenyl) - ethyl) - glycine - (L) - arginine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (3-hydroxy-phenyl) -ethyl hydrochloride) - glycine - (S) - leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] -α- (S) - (2 - (4-methyl-phenyl) -ethyl) -glycine - (S) -leucine, N-phenyl-amide hydrochloride; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (2'-thienyl) -ethyl) -glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (4-ethyl-phenyl) -ethyl) -glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-5 - (1-oxo-isoindolin-2-yl) pentyl] - a - (S) - (2 - (4-propyl-phenyl) -ethyl) -glycine - (L ) - leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (4-chloro-phenyl) -ethyl) -glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a - (S) - (2-cyclohexyl-ethyl) glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a- (S) - (cyclohexyl) glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a - (S) - (cyclohexyl-methyl) glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -β-naphthyl-alanine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -α-naphthyl-alanine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - [(L) -glutamic acid, to L-bis-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -leucine, N -cyclohexyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a- (S) - (4-hydroxy-phenyl-ethyl) glycine, N-phenyl- amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -phenyl-glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -glutamic acid, NL-benzyl-amide, Na-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) - ornithine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -arginine, N - phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a - (S) - (3-phenyl) propyl) glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine-a- (S) -n-octyl - glycine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -leucine, N - (4-carboxy-phenyl) amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2-phenyl-ethyl) -glycine - (L) -leucine, N - (4-trifluoromethyl-phenyl) 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-phenyl-ethyl) -glycine - (L) -leucine, N - (benzothiazol-2-yl) amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (4-n-propyl-phenyl-ethyl) -glycine - (L) -leucine, N-phenyl-amide; N- [ 1 (R) -carboxy-ethyl] - a - (S) - (2 - 4-propyl-phenyl) -ethyl) -glycine - (L) -arginine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (2 - (3, 4-dimethyl-phenyl-ethyl) -glycine - (L) -leucine, N-phenyl-amide; (((4 - (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -butyl) -hydroxy-phosphinyl) methyl) -4-phenyl-butanoyl) -L-leucine, N- phenyl-amide; (2 - (((4 - (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) -butyl) -hydroxy-phosphinyl) methyl) -4-phenyl-butanoyl) -L-leucine, N - phenyl-amide; (2 - (((4 - (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) -butyl) (2-methyl-1- (1-oxo-propoxy) propoxy) phosphinyl) methyl) 4-phenyl-butanoyl) -L-leucine, N-phenyl-amide; (2 - ((Hydroxy (methyl) phosphinyl) methyl-4-phenyl-butanoyl) -L-leucine, N-phenyl-amide; [[Hydroxy [1 (R) - [N- (N-acetyl-L-prolyl - L-alanyl) -amino] -ethyl] -phosphinyl] -methyl] -4-phenyl-butanoyl-L-leucyl, N-phenyl-amide; [Hydroxy - [N - (N-benzoyl) -L-prolyl) amino - butyl] phosphinyl] methyl] - 4 - phenyl - butanoyl-L-leucine, N-phenyl-amide; [Hydroxy - [2-methyl-propyloxy-carbonyl-amino-butyl] -phosphinyl] methyl] -4-phenyl-butanoyl-L-leucine, N-phenyl-amide; [Hydroxy - [2-methyl-propyloxy-carbonyl-amino-butyl] -phosphinyl] methyl] -4-phenyl-butanoyl-L-leucine, N-phenyl-amide; [Hydroxy - [1-methyl-propyloxy-carbonyl-amino-butyl] -phosphinyl] methyl] -4-phenyl-butanoyl-L-leucine, N-phenyl-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -leucinamide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -leucine, N-phenyl-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -leucine, N-benzyl-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -leucine, N - (2-phenyl-ethyl) amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -phenyl-alanine-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -phenyl-alanine-N-phenyl-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -phenyl-alanine-N-benzyl-amide; N - (2-thio-methyl-4-phenyl-butanoyl) - (L) -phenyl-alanine-b-alanine; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1 - (2 (S)) - 1 - butyl) glycine, N - (phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1 - (2 (S)) - 1 - butyl) glycine, N - (4-pyridyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1- (L-arginine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - . 1 - . 1 - . 1 - . 1 - . 1 - . 1 - (L-leucine, N-phenylamide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1- (2 (S) -1-butyl) glycine, N- phenyl amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (2 (S) - (4-thiazolyl-methyl) glycine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (2 (S) - (3-pyridyl-methyl) glycine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (L-leucine, N - (4-pyridyl) amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (2 (S) - (2-pyridyl-methyl) glycine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1- (L-arginine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (l-n-propyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (L-phenylalanine, N-4-pyridyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (1 - (4 - (N - (2-oxo-isoindolinyl)) -butyl)) -1, 5-pentanedioic, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (1 - (4 - (N - (2-oxo-isoindolinyl)) - but-2-enyl) acid ) - 1, 5 - pentanedioic, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (4-Fluoro-phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (phenyl) phenyl) ethyl) -4-methyl-1,5-pentanedioic acid 1 - (L -leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (4-methoxy-phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (L-leucine, phenyl-amide) amide; 2 (R) - (2 - (4 - (4-methyl-phenyl) ethyl) -4-methyl-1,5-pentanedioic acid, 1- (L-leucine, phenyl-amide) amide; 2 (R) acid - (2 - (4 - (4-hydroxy-n-butyl) -phenyl) -ethyl) -4-methyl-pentanedioic, 1 - (S-leucine, phenyl-amide) amide; 2 (R) -acid, 4 ( S) - (2 - (4 - (3-hydroxy-n-propyl) -phenyl) ethyl) -4-methyl-1, 5 - pentanedioic, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2-phenyl-ethyl) -4-methyl-1,5-pentanedioic acid, 1 - (L-leucine, N phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1 - (L -leucine, N-ethyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -1,5-pentanedioic acid, 1- (L-leucine, N-isopropyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) propyl) -1,5-pentanedioic acid, 1 - (2 (S) -tert-butyl-glycine, N-4-pyridyl) amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) propyl) -1,3-pentanedioic acid, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-hexyl-1,5-pentanedioic acid, 1 - . 1 - (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-butyl-1,5-pentanedioic acid, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (3-methyl-benzyl) -1,5-pentanedioic acid, 1 - (L-leucine, N-phenyl) amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4 - (2-benzimidazole) butyl) -1,5-pentanedioic acid, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4 - (2-benzothiazolyl) butyl) -1,5-pentanedioic acid, 1 - (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1 - n - propyl) phenyl) ethyl) - 4 - (4 - (2-benzoxazolyl) butyl) acid - 1, 5 - pentanedioic, 1- (L-leucine, N-phenyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1- (L-leucine, N-methyl-amide) amide 9-piperidine - amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9-tert - butyl amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1- (L-leucine, N-methyl-amide) amide 9-benzyl - amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1- (L-leucine, N-methyl-amide) amide 9-morpholino - amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9 - ( 1 - (R) -phenyl-ethyl) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9 - ( 1 - (S) -phenyl-ethyl) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9 - ( N-methyl-N-phenyl) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9 - ( N'-methyl-piperazine) amide trifluoroacetic acid salt; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 9 - ( 3-pyridyl) amide; 2 (R) - (2 - (4 - (1-propyl) phenyl) ethyl) -4-carboxy-1, 9-nonanedioic acid 1 - (L-leucine, N-methyl-amide) amide 2 (R) - (2 - (4 - (1-propyl) phenyl) ethyl) -1,5-pentanedioic acid 1 - ((R) - (S-) p-methoxy-benzyl) penicil-amine, N-methyl-amide) amide 2 (R) - (2 - (4 - (1-propyl) phenyl) ethyl) -1,5-pentanedioic acid 1 - ((R) - (S-p-methoxy-benzyl) penicil-amine sulfone, N-methyl-amide) amide 2 - (2 - (4 - (1-propyl) phenyl) ethyl) -4- (1- (4 - (2 - phalimido)) butyl) -1,5-pentanedioic 1 - (L-leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4-benzoyl-amino-1-butyl) -1,5-pentanedioic acid, 1 - (L-leucine) , N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4-pivaloyl-amino-1-butyl) -1,5-pentanedioic acid, 1- (L-leucine) , N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4-phenyl-sulfonyl-amino-1-butyl) -1,5-pentanedioic acid, 1 - (L - leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4 - (N'-phenyl-ureido) -1 acid - butyl) - 1,5-pentanedioic, 1- (L-leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4- (4-phenyloxycarbonyl-amino-1-butyl) -1,5-pentanedioic acid, 1 - (L - leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (4-N'-benzyloxycarbonyl-amino-L-prolyl-amino) -1-butyl) acid 1, 5-pentanedioic, 1- (L-leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (4-cyclopentyl-amino-1) acid - butyl) - 1,5-pentanedioic, 1- (L-leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (4 - (2-carboxy-benzoyl-amino) -1-butyl) -1,5-pentanedioic acid, 1 - (L-leucine, N-methyl-amide) amide; 2 (R) - (2 - (4 - (1-n-propyl) phenyl) ethyl) -4 - (4-cyano-1-butyl) -1,5 acid - pentanedioic, 1- (L-leucine, N-methyl-amide) amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (9-amino-n-nonyl)] glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (n-octyl)] glycine - (L) -leucine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (n-octyl)] glycine - (L) -arginine, N-phenyl - amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (9-amino-n-nonyl)] glycine - (L) -arginine, N-phenyl-amide; N - [1 (R) -carboxy-ethyl] - a - (S) - (n-decyl)] glycine - (L) -leucine, N-phenyl-amide; 1 - (2 - (4-propyl-phenyl) -ethyl) -cyclopentane-1,3-dicarboxylic acid 1 - (L -leucine, N-phenyl-amide) amide; 1 - (2 - (4-propyl-phenyl) ethyl) cydohexane-1,3-dicarboxylic acid 1 - (L -leucine, N-phenyl-amide) amide; N - [1 (R) -carboxy-ethyl] - a - (S) -2- (4-fluoro-biphenyl) -glycyl- (S) -2- (tert-butyl) glycine, N-phenyl-amide; 3 S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-3, 4 - dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-3S-acetyl-thio-methyl-succinyl] amino-3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] amino-1-methoxy-3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-methyl-3,4-dihydro-carbostyril; 1-carboxymethyl-3S- [4-N-hydroxy-amino) -2R-isobutyl-3 S -methyl-succinyl] amino-3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-ethoxy-methyl-3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-heptyl-succinyl] amino-1-methoxy-3,4-dihydro-carbostyril; 7-chloro-3 S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-methyl-3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-ethyl - 3,4-dihydro-carbostyril; 3S - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-ethyl - 6,7-methylene-dioxy-3,4-dihydro-carbostyril; 3R - [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] amino-1-methoxy-ethyl - 6,7-methylene-dioxy-3,4-dihydro-carbostyril; 2 - (R) - N -hydroxy-2 - [(4-methoxy-benzene-sulfonyl) (3-morpholin-4-yl) - 3-oxo-propyl) amino] -3-methyl-butyramide; 2 - (R) -2 - [(2-benzyl-carbamoyl-ethyl) (4-methoxy-benzene-sulfonyl) amino] -N-hydroxy-3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzene-sulfonyl) (2 - [(pyridin-3-ylmethyl) carbamoyl] ethyl) amino) -3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - ([4-methoxy-benzenesulfonyl] [2 - (methyl-pyridin-3-yl-methyl-carbamoyl) ethyl] amino) -3-methyl-butyramide; 4 - (3 - [1 - (R) -1-Hydroxy-carbamoyl-2-methyl-propyl) - (4-methoxy) benzene sulfonyl) amino] propionyl) piperazine-1-carboxylic acid, tert-butyl ether; 2 - (R) -N-Hydroxy-2 - [(4-methoxy-benzene-sulfonyl) (3 -oxo-3-piperazin-1-yl-propyl) amino] -3-methyl-butyramide hydrochloride; 2 - (R) -2 - [(benzyl-carbamoyl-ethyl) (4-methoxy-benzene-sulfonyl) amino] N - hydroxy-3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - [(4-methoxy-benzene-sulfonyl] [(2-morpholin-4-yl) ethyl-carbamoyl) methyl] amino] -3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzenesulfonyl) [(3-pyridin-yl-methyl) carbamoyl] methyl) amino) -3-methyl-butyramide; 2 - (R) -3,3,3-trifluoro-N-hydroxy-2 - [(methoxy-benzene-sulfonyl) (3-morpholin-4-yl-3-oxo-propyl) amino] propionamide; 2 - (R) - N -hydroxy-2 - ((4-phenoxy-benzene-sulfonyl) [2-methyl-pyridine-4] - il-methyl-carbamoyl) ether] amino) -3-methyl-butyramide; 4 - [4-methoxy-benzene-sulfonyl) (3-morpholin-4-yl-3-oxo-propyl) amino] -1-methyl-piperidine-4-carboxylic acid hydroxamide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzenesulfonyl) [3 - (4-methyl-piperazin-1-yl) -3-oxo-propyl] amino) -3-methyl- Butyramide; 2 - (R) -2 - [(2-carboxy-ethyl) (4-methoxy-benzene-sulfonyl) amino] -N-hydroxy-3-methyl-butyramide; [(2-carboxy-ethyl) (3,4-dimethoxy-benzene-sulfonyl) amino] -N-hydroxy-acetamide; 2 - (R) -2 - [(2-carbamoyl-ethyl) (4-methoxy-benzene-sulfonyl) amino] -N-hydroxy-3-methyl-butyramide; 2 - (R), 3 - (R) -3, N-dihydroxy-2 - [(4-methoxy-benzene-sulfonyl) (3-oxo - 3-piperidin-1-yl-propyl) amino] -butyramide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzenesulfonyl) [3 - (methyl-pyridin-3-yl-methyl-carbamoyl) propyl] amino) -3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzene-sulfonyl) [2 - (methyl-carboxy-methyl-carbamoyl) ethyl] amino) -3-methyl-butyramide; 2 - (R) - N -hydroxy-2 - ((4-methoxy-benzenesulfonyl) [(1-methyl-piperidin-4-yl-carbamoyl) methyl] amino) -3-methyl-butyramide; 2 - (R) - N -cyclohexyl-N-hydroxy-2 - ((4-methoxy-benzene-sulfonyl) [3 - (4-methyl-piperazin-1-yl) -3-oxo-propyl] amino) - acetamide; 2 - (R) - N -hydroxy-2 - [(methoxy-benzene-sulfonyl) (3-morpholin-4-yl- [3 - oxo-propyl) amino] -4- (morpholin-4-yl) butyramide; [4 - (N-benzyloxy-amino) -2- (R) -isobutyl-succinyl] -L-leucyl-L-alanine ethyl ester; [4 - (N-benzyloxy-amino) -2- (R) -isobutyl-succinyl] -3- (RS) -amino-lauro-lactam; Na - [4 - (N-benzyloxy-amino) -2- (R) -isobutyl-succinyl] - Ne- (N -benzyloxycarbonyl-glycyl) -L-lysyl-L-alanine ethyl ester; [4 - (N-hydroxy-amino) -2 - (RS) -isobutyl-succinyl] -L-leucyl-glycine ethyl - ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-glycine isopentyl-amide; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-valyl-glycine ethyl-amide; [4 - (N-hydroxy-amino) -2 - (RS) -isobutyl-succinyl] -L-leucyl-glycine ethyl - amide; Na - [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -N6-tert. butoxycarbonyl-L-lysyl-glycine ethyl amide; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -O-methyl-L-tyrosinyl-glycine ethyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -O-methyl-L-tyrosinyl-glycine ethyl amide; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-L-alanine ethyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-glycine isopentyl ester; [4 - (N-hydroxy-amino) -2- (R) -propyl-succinyl] -L-leucyl-glycine ethyl ester; [4 - (N-hydroxy-amino) -2- (RS) - sec.butyl-succinyl] -L-leucyl-glycine ethyl ester; [4 - (N-hydroxy-amino) -2- (R) -isobutyl-succinyl] -L-leucyl-L-alanine; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-glycine methyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-sarconsin ethyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucyl-L-proline ethyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucine-L-alanine isopropyl ester; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucine-2-oxo-propyl-amide; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucine-2-methoxy-ethyl-amide; [4 - (N-hydroxy-amino) -2- (RS) -isobutyl-succinyl] -L-leucine-2,2-dimethoxy-ethyl-amide; Na - [4 - (N-hydroxy-amino) -2- (R) -isobutyl-succinyl] -N6-glycyl-L -lysine-methyl-amide; Na - [4 - (N-hydroxy-amino) -2- (R) -isobutyl-succinyl] -N6- (4-carboxy-benzoyl) -L-lysyl-L-alanine ethyl ester; Na - [4 - (N-hydroxy-amino) -2- (R) -isobutyl-succinyl] -Ne- (4-carboxy-benzoyl) -L-lysyl-L-alanine; [4 - (N-hydroxy-amino) -2- (R) -isobutyl-succinyl] -L3 (RS) -amino-octahydro-2H-azonin-2-one; [4 - (N-hydroxy-amino) -3 (S) -methyl-2 (R) -isobutyl-succinyl] -L-leucyl-glycine ethyl ester; [(RS) -4-Methyl-2 - [[(S) -3-methyl-1 - (methyl-carbamoyl) butyl] carbamoyl] -pentyl] (1,8-naphthalene-dicarboximido-methyl) -phosphinic acid; [(R or S) -4-methyl-2 - [[(R or S) -2-oxo-3-azacyclo-tridecyl] carbamoyl] -pentyl] (1,8-naphthalene-dicarboximido-methyl) -phosphinic acid; N - [N - [(R or S) - 2 [[[[[N - [1 - (benzyloxy) carbonyl] -L-prolyl] -L-leucyl] amino] methyl] hydroxy-phosphinyl] -methyl-4 - methyl-valeryl] -L-leucyl] L-alanine; [[1,4-Dihydro-2,4-dioxo-3 (2H) -quinazolinyl] -methyl] [[(R or S) -4-methyl-2 - [[(R or S) -2-oxo]] - 3 - azacyclo-tridecyl] carbamoyl] pentyl] phosphinic; N2 - [(R) -hydroxy-carbamoyl-methyl] -4-methyl-valeryl] -N1, 3-dimethyl-L-valinamide; N2 - [2 (R or S) - [[[(5-bromo-2,3-dihydro-6-hydroxy) -1,3-dioxo-1 H -benz [d, e] isoquinol-2-yl) methyl ] - [(hydroxy) phosphinyl] methyl] -4-methyl-valeryl] - N 1, 3-dimethyl-L-valinamide; N2 - [(R or S) - [[(R) - (amino) [(5-bromo-2,3-dihydro-6-hydroxy-1, 3-dioxo-1H-benz [d, e]] Hydrochloride isoquinol-2-yl) methyl] (hydroxy) -phosphinyl] methyl] - 4-methyl-valeryl] - N3, 1-dimethyl-L-valinamide; N 2 - [2 (R or S) - [1 - (S) - (hydroxy-carbamoyl) ethyl-4-methyl-valeryl] - N 1, 3 -dimethyl-valinamide; N2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2-phalimid-ethyl] -4-methyl-valeryl] - N1, 3-dimethyl-valinamide; N2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -4 - (methoxy-carbonyl) butyl] -4 - methyl-valeryl] - N1, 3-dimethyl-valinamide; M2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -4-phenyl-butyl] -4-methyl -valeryl] - N1, 3-dimethyl-valinamide; N2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2-succinimido-ethyl] -4-methyl-valeryl] - N1, 3-dimethyl-valinamide; N2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2-phalimid-ethyl] -4-methyl-valeryl] - N1, 3-dimethyl-valinamide; N2 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2-phalimid-ethyl] -4-methyl -valeryl] -tetrahydro-1,4-thiazine; 1 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2-ptalimido-ethyl] -4-methyl -valeryl] -4-piperidinol; 1 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2- (1, 2-dimethyl-3,5-dioxo-1, 2,4-triazolidin-4-yl) ethyl] -4-methyl-valeryl] -4-piperidine; 4 - [2 (R) - [1 - (R or S) - (hydroxy-carbamoyl) -2- (3-methyl-2, 5-dioxo-1-imidazolidinyl) ethyl] -4-methyl-valeryl] tetrahydro - 1, 4 - thiazine; Hexahydro-2 - [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2-ptalimido-ethyl] -4-methyl-valeryl] - N -methyl-3 (S) -pyridazine-carboxamide; 1 - [2 (R) - (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolinyl) ethyl] -4-methyl-valeryl] - 4 - piperidinol; [4 - (N-hydroxy-amino) -2 (R or S) -heptyl-succinyl] -L-leucyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (R or S) -nonyl-succinyl] -L-leucyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (R or S) -heptyl-3 (S) -methyl-succinyl] -L-leucyl-L-leucine-ethyl-amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-3 (R or S) - (phalimido-methyl) -succinyl] -L-leucyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -nonyl-succinyl] -L-tert.butyl-glycine methyl - amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-phenylalanine methyl-amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-3 - (R or S) -ptalimido-methyl) -succinyl] -L-tert-butyl-glycine-methyl-amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-3 - (R or S) - (3-phenyl-propyl) -succinyl] -L-leucyl-L-leucine-ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-leucine methyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-leucine neopentyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-alanyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L- (Ne-ptaloyl) -lysyl-L - leucine ethyl amide; [4 - (N-hydroxy-amino) -2 (RS) -decyl-succinyl] -L-leucyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-phenyl-alanyl-L-leucine-ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-nonanyl-L-leucine ethyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -phenylalanine tert.butyl-amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-tert.butyl-glycine methyl amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-neopentyl-glycine methyl amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-homophenyl-alanyl-L - leucine ethyl amide; [4 - (N-hydroxy-amino) -2 (RS) -heptyl-succinyl] -L-cyclohexyl-alanine methyl amide; [4 - (N-hydroxy-amino) -2 (RS) -isooctyl-succinyl] -L-phenylalanine methyl-amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-succinyl] -L-neon-pentyl-glycine methyl amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-succinyl] - (D or L) -β, β-dimethyl-phenyl-alanine methyl amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-succinyl] - (D or L) -threo-β-methyl-phenyl-alanine methyl amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-succinyl] -DL-threo-β-methyl-phenyl-alanine methyl amide; [4 - (N-hydroxy-amino) -2 (R) -heptyl-3 - (R or S) - [(3-methyl-2, 5-dioxo-1-imidazolidinyl) methyl] succinyl] -L-leucyl - L - leucine ethyl amide; N2 - [3-Cyclobutyl-2 (R or S) - [hydroxy-carbamoyl) -methyl] -propionyl] -N I, 3-dimethyl-L-valinamide; N2 - [3-cyclopropyl-2 (R or S) - [hydroxy-carbamoyl) -methyl] -propionyl] -N I, 3-dimethyl-L-valinamide; N2 - [3-cyclopentyl-2 (R or S) - [hydroxy-carbamoyl) -methyl] -propionyl] - N I, 3 - . 3 - . 3 - . 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] - N 1, 3-dimethyl-L-valinamide; N2 - [3-cyclopropyl-2 (R) - [1 (R or S) - [hydroxy-carbamoyl) -4-phenyl-butyl)] propionyl] -N 1, 3-dimethyl-L-valinamide; N2 - [3-cyclobutyl-2 (R) - [1 (R or S) - [hydroxy-carbamoyl) -4-phenyl-butyl)] propionyl] -N 1, 3-dimethyl-L-valinamide; N2 - [3-cyclopentyl-2 (R) - [1 (R or S) - [hydroxy-carbamoyl) -4-phenyl-butyl)] propionyl] -N 1, 3-dimethyl-L-valinamide; 1 - [3-Cyclopropyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] piperidine; 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-2,5-dioxo-1-imidazolidinyl) 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-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-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] piperidine; 3 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 3 - azabicyclo [3.2.2.] Nonane; 3 - [3-cyclopropyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 3 - azabicyclo [3.2.2.] Nonane; 3 - [3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 3 - azabicyclo [3.2.2.] Nonane; 1 - [3-cyclohexyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] propionyl ] piperidine; 4 - [3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -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) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] tetrahydro-1,4-thiazine S, S-dioxide; 4 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] propionyl ] tetrahydro-1,4-thiazine; 3 - [3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 5, 5-dimethyl-N-propyl - [4 (R) thiazolidine carboxamide; 4 - [3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] morpholino; 3 - [3-cyclopentyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 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-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 4-phenyl-piperazine; 4 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] morpholino; 1 - . 1 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] pyrrolidino; 8 - [5-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 1, 4-dioxa-8-azaspiro [4, 5] decane; 1 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] - 4-methoxy-piperidine; 1 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3,4,4 -trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ] octahydro-azocine; 1 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (5,5-dimethyl-2,4-dioxo-3-oxazolidinyl) 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 ] hexahydro-azepine; 1 - [3-Cyclobutyl-2 (R) - [2 - (hexahydro-1, 3-dioxo-pyrazolo [1,2-a] [1, 2,4] -triazol-2-yl) -1 (R or S) - (hydroxy-carbamoyl) ethyl] propionyl] piperidine; 1 - [3-Cyclobutyl-2 (R) - [1 (R or S) - (hydroxy-carbamoyl) 2-phalimido-ethyl] propionyl] piperidine; 2 - [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -4-phenyl-butyl] nonanoyl] -hexahydro-N-methyl-3 (S) -pyridazine-carboximide; N-cyclohexyl-hexahydro-2 - [2 (R) - [1 (RS) - (hydroxy-carbamoyl) -4-phenyl - butyl] nonanoyl] -3 (S) -pyridazine-carboximide; Hexahydro-2 - [2 (R) - [1 (RS) - (hydroxy-carbamoyl) -4-phenyl-butyl] nonanoyl] - N - (2, 2, 6, 6-tetramethyl-4-piperidinyl) -3 (S) -Pyridazine-carboxamide; 1 - [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -4-phenyl-butyl] nonanoyl] -piperidine; N2 - [2 (R) - [1 (RS) - (hydroxy-carbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo) - 1-imidazolidinyl) ethyl] nonanoyl] - NI-methyl-L-prolinamide; 1 - [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) -2- (3, 4, 4, -trimethyl-2, 5-dioxo - 1-imidazolidinyl) ethyl] nonanoyl] -piperidine; Hexahydro-2 - [2 (R) -1 (R or S) - (hydroxy-carbamoyl) -2 - (3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] nonanoyl] - N-methyl-3 (S) -pyridazinecarboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] undecanoyl] -N-methyl-3 (S) -pyridazine-carboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] undecanoyl] -N-methoxy-N-methyl-3 (S) -pyridazine-carboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] -undecanoyl] - N - (1, 2, 2, 6, 6 - pentamethyl-4 - piperidinyl) - 3 (S) -pyridazinecarboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) ethyl] undecanoyl] - N -methyl-3 (S) -pyridazine-carboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] nonanoyl] -N-methyl-3 (S) -pyridazine-carboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) ethyl] nonanoyl] - N -methyl-3 (S) -pyridazine-carboxamide; 1 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) ethyl] undecanoyl] piperidine; 1 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] undecanoyl] piperidine; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -3-phenyl-propyl] undecanoyl] - N - (2, 2, 6, 6-tetramethyl-4-piperidinyl) - 3 (S) - pyridazine -carboxamide; Hexahydro-2 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -ethyl] undecanoyl] - N - (2, 2, 6, 6-tetramethyl-4-piperidinyl) -3 (S ) - pyridazine-carboxamide; 1 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -4-phenyl-butyl] undecanoyl] piperidine; 4 - [2 (R or S) - [1 (S) - (hydroxy-carbamoyl) -4-phenyl-butyl] undecanoyl] morpholino; 1 - (benzyloxycarbonyl) -hexahydro-2 - [2 (R) - [2 (R) - [(R or S) - (hydroxycarbamoyl) -4-phenyl-butyl] nonanoyl] -N- (a (S) -methyl-benzyl) -3- (S) -pyridazine-carboxamide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -5- (carboxy) pentanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [T - (hydroxy-amino) -T- (oxo) ethyl] -6- (phenyl-methoxy) hexanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (propyl-amino) 6 - (oxo) hexanoyl] -L-phenyl-alanine N- methyl amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] - (6RS) -6- (hydroxy) heptanoyl] -L-phenyl-alanine N-methyl-amide; (2S) -N-2 - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6' - (hydroxy) hexanoyl] amino-3 acid, 3-dimethyl-butanoic N-methyl-amide; (2S) - N - 2 - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6' - (phenylmethoxy) hexanoyl] amino acid 3, 3-dimethyl-butanoic N-methyl-amide; N - [(2'R) -2 - [- (hydroxy-amino) -2 '- (oxo) ethyl] -6- (4'-oxo-butyl-amino) hexanoyl] -L-phenyl-alanine N- methyl amide; (2S) -N-2 - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6' - (oxo) -6 '(propyl) acid amino) hexanoyl] amino-3, 3-dimethyl-butanoic N-methyl-amide; N - [(2R) -2 - [(l'S) -1 '- (methyl) -2' - (hydroxy-amino) -2 '- (oxo) ethyl] -6- (phenyl-methoxy) hexanoyl] -L phenyl-alanine N-methyl-amide; N - [(2R) -2 - [(l'S) -1 '- (methyl) -2' - (hydroxy-amino) -2 '- (oxo) ethyl] -6- (oxo) -6- (propyl- amino) hexanoyl] -L-phenyl-alanine N-methyl-amide; (2S) - N - 2 - [(2'R) - [(1"R) -1" - (1,3-Dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-2 acid "- (hydroxy-amino) -2" - (oxo) ethyl] -6 '- (phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic N-methyl-amide; N - [(2R) -2 - [- (hydroxy-amino) -2 '- (oxo) ethyl] -6- (oxo) -6- (propyl-amino) hexanoyl] -L-phenyl-alanine N-methyl - amide; (2S) - N - 2 - [(2'R) - [(1"S) -1" - (Methyl) -2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6 - acid (phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic N-2-phenyl - ethyl amide; (2S) - N - 2 - [(2'R) - [(1"S) -1" - (methyl) -2"- (hydroxy-amino) -2" acid - (oxo) ethyl] -6 '- (oxo) -6'- (propyl-amino) hexanoyl] amino-3, 3-dimethyl-butanoic N-2-phenyl-ethyl-amide; (2S) - N - 2 - [(2'R) - [(1"S) -1" - (methyl) -2"- (hydroxy-amino) -2" acid - (oxo) ethyl] -6 '- (oxo) -6'- (propyl-amino) hexanoyl] amino-3, 3-dimethyl-butanoic N-2 - (4-sulfamoyl) phenyl-ethyl-amide; (2S) - N - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6' - (phenyl-methoxy) hexanoyl] amino-3 - acid cyclohexyl-propionic, N-2 - (4'-sulfamoyl) -phenyl-ethyl-amide; N - [(2R) -2 - [- (hydroxy-amino) -2 '- (oxo) ethyl] -6' (phenyl-methoxy) hexanoyl] - L - (3,5-dimethyl) phenyl-alanine N- 2 - (4'-sulfamoyl) phenyl-ethyl-amide; (2S) - N - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6' - [(4) - methoxy) phenoxy] hexanoyl] amino-3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) -phenyl-ethyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '- [(4-methyl) phenoxy] acid] hexanoyl] amino-3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) -phenyl-ethyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '- [(1-oxo) butyl) acid amino] hexanoyl] amino-3-cyclohexyl-propionic, N-2 - (4'-sulphamoyl) -phenyl-ethyl-amide; (2S) - N - 2 - [(2'R) -2 '- [(1"S) -1" - (methyl) -2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6 '- (phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N -methyl-amide; (2S) - N - 2 - [(2'R) -2 '- [(1"S) -1 - (2-methyl-propyl) -2" - (hydroxy) acid amino) -2"- (oxo) ethyl] -6- (phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; N - [(2R) -2- [2 ' - (hydroxy-amino) -2 '- (oxo) ethyl] -6 (phenoxy) hexanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2 - [- (hydroxy-amino) - 2 '- (oxo) ethyl] - 7 (phenoxy) heptanoyl] - L phenyl-alanine N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino acid 3, 3-dimethyl-butanoic, N-2-phenyl-ethyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6- (phenylmethoxy) hexanoyl] amino acid 3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) -phenyl-ethyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -5- (phenyl-methoxy) pentanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -7- (phenyl-methoxy) heptanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (phenyloxy) hexanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2 - [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -7 - [(phenyloxy) heptanoyl] - L-phenyl-alanine N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 - [(2-phenethyl-amino) - 6 - (oxo) hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) - N - 2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6 - [(4-methyl-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) - N - 2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6 - [(4-chloro-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) - N - 2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] - 6 - [(3-methyl-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) - N - 2 '- [(2'R) -2'-carboxymethyl) -6' (3-methyl-phenoxy) hexanoyl] amino-3, 3-dimethyl-butanoic acid, N-methyl- amide; N - [(2R) -2 - [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -5 - [(carboxy) pentanoyl] - L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6 - [(phenyl-methoxy) hexanoyl] -L-phenyl-alanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (propyl-amino) -6- (oxo) hexanoyl] -L-phenyl-alanine N - methyl amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] - (6RS) -6- (hydroxy) heptanoyl] -L-phenyl-alanine N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"-hydroxy-amino) -2" - (oxo) ethyl] -6 '(hydroxy) hexanoyl] amino-3 (3) acid - dimethyl-butanoic, N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"-hydroxy-amino) -2" - (oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino-3 acid , 3-dimethyl-butanoic, N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (4'-oxo-butyl-amino) hexanoyl] -L-phenyl-alanine N- methyl amide; (2S) - N - 2 - [(2'R) -2 '- [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6' (oxo) -4 '- (propyl) acid amino) hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; N - [(2R) -2 - [(l'S) -1 '- (methyl) -T- (hydroxy-amino) -2' - (oxo) ethyl] -6- (phenyl-methoxy) hexanoyl] - L- phenyl-alanine N-methyl-amide; N - [(2R) -2 - [(l'S) -1 '- (methyl) -2' - (hydroxy-amino) -2 '- (oxo) ethyl] -6- (oxo) - (propylamino) hexanoyl] -L-phenyl-alanine N-methyl-amide; (2S) - N - 2 - [(2'R) - [(1"R) -1" - (1, 3-dioxo-2H-isoindol-yl) methyl-2"- (hydroxy-amino) - acid 2"- (oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (oxo) -6- (propyl-amino) hexanoyl] -L-phenyl-alanine N - 2-phenyl-ethyl-amide; (2S) -N-2 - [(2'R) - [(1"S) -1" - (methyl) -2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 'acid (phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N-phenyl-ethyl - amide; (2S) -N-2 - [(2'R) - [(1"S) -1" - (methyl) -2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 'acid (oxo) -6 '- (propyl-amino) hexanoyl] amino-3, 3-dimethyl-butanoic, N-2-phenyl-ethyl-amide; (2S) -N- 2 - [(2'R) - [(1"S) -1 - (Methyl) -2" - (hydroxy-amino) -2"- (oxo) ethyl] -6 'acid (oxo) -6 '- (propyl-amino) hexanoyl] amino-3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) phenyl-ethyl-amide; (2S) -N-2 - [(2'R) - [(1"S) -1 - (Methyl) -2" - (oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino acid 3-cyclohexyl-propionic, N-2 - (4'-sulfamoyl) phenyl-ethyl-amide; N - [(2R) -2 - [2 '- (hydroxy-amino) -2' - (oxo) ethyl] - 6 '- (phenyl-methoxy) hexanoyl] -L - (3,5-dimethyl) -phenyl-alanine N-2 - (4'-sulfamoyl) -phenyl-ethyl-amide; (2S) -N-2' acid - [(2'R) -2 '- [2"- (oxo) ethyl] -6' [(4-methoxy) phenoxy] hexanoyl] amino-3, 3-dimethyl-butanoic, N-2 - (4 ' Sulfamoyl) phenyl ethyl amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '[(4-methyl) phenoxy] hexanoyl acid ] amino-3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) phenyl-ethyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '[(1-oxo) butyl-amino acid ] hexanoyl] amino-3-cyclohexyl-propionic, N-2 - (4 '-sulfamoyl) phenyl-ethyl-amide; (2S) - N - 2 - [(2'R) -2 '- [(1"S) -1 - (Methyl) -2" - (hydroxy-amino) -2"- (oxo) ethyl] acid] - 6 '(phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N -methyl-amide; (2S) - N - 2 - [(2'R) -2 '- [(1"S) -1" - (2-methyl-propyl) -2"- (hydroxy-amino) -2" - ( oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; N - [(2R) -2 - [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (phenoxy) hexanoyl] -L-phenylalanine N-methyl-amide; N - [(2R) -2 - [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -7- (phenoxy) heptanoyl] -L-phenylalanine N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino acid 3, 3-dimethyl-butanoic, N-2-phenyl-ethyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '(phenyl-methoxy) hexanoyl] amino acid 3, 3-dimethyl-butanoic, N-2 - (4'-sulfamoyl) phenyl-ethyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -5- (phenyl-methoxy) pentanoyl] -L-phenylalanine N-methyl-amide; N - [(2R) -2 - [- (hydroxy-amino) -2 '- (oxo) ethyl] -7- (phenyl-methoxy) heptanoyl] -L-phenylalanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -6- (phenyl-methoxy) hexanoyl] -L-phenylalanine N-methyl-amide; N - [(2R) -2- [2 '- (hydroxy-amino) -2' - (oxo) ethyl] -7- (phenyloxy) heptanoyl] -L-phenylalanine N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '(2) acid phenethyl-amino) -6 '- (oxo) -hexanoyl] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '[(4-methyl-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) - N - 2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '[(4-chloro-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) -N-2 '- [(2'R) -2' - [2"- (hydroxy-amino) -2" - (oxo) ethyl] -6 '[(3-methyl-phenoxy) hexanoyl) acid ] amino-3, 3-dimethyl-butanoic, N-methyl-amide; (2S) -N-2 '- [(2'R) -2' (carboxymethyl) -6 '[(3-methyl-phenoxy) hexanoyl] amino-3, 3-dimethyl-butanoic acid, N-methyl - amide; Acid (3R, IOS) - 5 - methyl - 3 - (9 - oxo - 1, 8 - diaza - tricyclo [10.6.1.0] nonadeca - 12 (19), 13 (18), 14, 16 - tetra - 10 - il-carbamoyl) hexanoic; Acid (3R, IOS) N-hydroxy-5-methyl-3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0] nonadeca - 12 (19), 13 (18), 14, 16 -tetraen - 10 - yl-carbamoyl) hexanoic; Acid (3R, IOS) N-hydroxy-5-methyl-3 - (10-oxo-1, 9-diaza-tricyclo [11.6.1.0.] Eicosa-13 (20), 14 (19), 15, 17- tetraen-11-yl-carbamoyl) hexanoic; Acid (3R, 9S) - 5 - methyl - 3 - (8 - oxo - 1, 7 - diaza - tricyclo [9.6.1.0] octadeca - 11 (18), 12 (17), 13, 15-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) N-hydroxy-5-methyl-3 - (8-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca-11 (18), 12 (17), 13, 15-tetraen-9-yl-carbamoyl) hexanoic; (IOS) - [4-methyl-2 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14, 16-tetraen-10-yl- carbamoyl) pentyl] - (quinolin-2-ylthio-methyl) phosphinic; (3R, IOS) N-hydroxy-5-methyl-2-methoxy-carbonyl-3 - (9-oxo-1,8-diaza-tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18) , 14, 16-tetraen-10-yl-carbamoyl) hexanamide; N - (4-methyl-2-carboxy-methyl-pentanoyl) -L-leucine-N '- (4-methoxy-carbonyl-phenyl) carboxamide; N - (4-methyl-2 - (N "-hydroxy-carbamoyl) methyl-pentanoyl) -L-leucine-N '- (4-methoxy-carbonyl-phenyl) -carboxamide; N - (4-methyl-2 - (N "-hydroxy-carbamoyl) methyl-pentanoyl) -L-leucine-N '- (4-carboxy-phenyl) carboxamide; N- (4-methyl-2 - (N' '-hydroxy-carbamoyl) methyl-pentanoyl) -L-tryptophan-N' - (4-carboxy-phenyl) -carboxamide; N- (4-methyl-2 - (N "-hydroxy-carbamoyl) methyl-pentanoyl) -L - cyclohexyl-glycine-N '- (4-carboxy-phenyl) carboxamide; N - (4-methyl-2 - (N "-hydroxy-carbamoyl) methyl-pentanoyl) -L-1-leucine-N '- (4-carboxy-phenyl) carboxamide; (3R, IOS) -6-biphenyl - 4 - il) - 3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0.] Nonadeca - 12 (19), 13 (18), 14, 16 -tetraen-10-yl-carbamoyl) hexanoic; Acid (3R, IOS) - 3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0.] Nonadeca - 12 (19), 13 (18), 14, 16 -tetraen-10-yl-carbamoyl) -5- (thiophen-2-yl) pentanoic acid; Acid (3R, IOS) -3-cyclopentyl-3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18), 14, 16-tetraen-10 - il-carbamoyl) propionic; Acid (3R, IOS) - 4 - cyclopentyl - 3 - (9 - oxo - 1, 8 - diaza - tricyclo [10.6.1.0] nonadeca - 12 (19), 13 (18), 14, 16 - tetraen - 10 - butanoic il-carbamoyl); Acid (3R, IOS) -4-cyclopropyl-3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18), 14, 16-tetraen-10 - il-carbamoyl) butanoic; Acid (3R, IOS) - 5 - methyl - 3 - (9 - oxo - 1, 8 - diaza - tricyclo [10.6.1.0] nonadeca - 12 (19), 13 (18), 14, 16 - tetraen - 10 - il-carbamoyl) hexanoic; (3R, IOS) N-hydroxy-5-methyl-3 - (9-oxo-1, 8-diaza-tricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14, 16-tetraen- 10-yl-carbamoyl) hexanamide; (3R, US) N-hydroxy-5-methyl-3 - (10-oxo-1, 9-diaza-tricyclo [11.6.1.0] eicosa-13 (20), 14 (19), 15, 17 -tetraen- 11-yl-carbamoyl) hexanamide; (3R, 9S) N-5-methyl-3 - (8-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca - 11 (18), 12 (17), 13, 15 - tetraen - 9 - il-carbamoyl) hexanamide; (3R, 9S) N-hydroxy-5-methyl-3 - (8-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca - 11 (18), 12 (17), 13, 15 - tetraen - 9-yl-carbamoyl) hexanamide; (3R, 9S) N-hydroxy-5-methyl-3 - (8-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca - 11 (18), 12 (17), 13, 15 - tetraen - 9-yl-carbamoyl) hexanamide; (IOS) - 2 - mercapto - methyl - 4 - methyl - N - (9 - oxo - 1, 8 - diaza - tricyclo [10.6.1.0.] Nonadeca - 12 (19), 13 (18), 14, 16 -tetraen-10-yl-carbamoyl) pentanamide; (IOS) - 2 - acetyl thio - methyl - 4 - methyl - N - (9 - oxo - 1, 8 - diaza - tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18), 14, 16-tetraen-10-yl-carbamoyl) pentanamide; Acid (3R, IOS) -2- (methanesulfonamido-methyl) -5-methyl-3 - (9-oxo-1, 8 -. 8-diaza-tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18), 14, 16-tetraen-10-yl -carbamoyl) hexanoic; Acid (3R, IOS) -2- (3-ethyl-ureido-methyl) -5-methyl-3 - (9-oxo-1, 8 -diaza-tricyclo [10.6.1.0.] Nonadeca-12 (19), 13 (18), 14, 16-tetraen-10-yl-carbamoyl) hexanoic; (3R, 9S) N-hydroxy-2-hydroxy-5-methyl-3 - (8-oxo-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12 (17), 13, 15-tetraen-9-yl-carbamoyl) hexanamide or its stereoisomer (2S, 3R, 9S); (3R, IOS) N-hydroxy-5-methyl-2-methoxy-carbonyl-3 - (9-oxo-1,8-diaza-tricyclo [10.6.1.0] nonadeca-12 (19), 13 (18), 14, 16-tetraen-10-ylcarbamoyl) hexanamide; Acid (3R, 9S) -5-methyl-3 - (8-oxo-4-oxo-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen- 9-yl-carbamoyl) hexanoic; Acid (3R, 9S) - 3 - cyclobutyl - N - (8 - oxo - 4 - oxo - 1, 7 - diaza - tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) succinamic; Acid (3R, 9S) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) ) - 5 - phenoxy - pentanoic; Acid (3R, 9S) 5 - (4-chloro-phenoxy) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14 , 16-tetraen-9-yl-carbamoyl) -pentanoic; Acid (3R, 9S) 5 - (4-chloro-phenoxy) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0] octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) -pentanoic acid ester; Acid (3R, 9S) -3- (8-oxo-4-oxo-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12,14,16-tetraen-9-yl- carbamoyl) - pentanoic ethyl ester; Acid (3R, 9S) -6- (4-hydroxy-phenyl) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16 -tetraen-9-yl-carbamoyl) -hexanoic; Acid (3R, 9S) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca -11 (18), 12, 14, 16 -tetraen-9-yl- carbamoyl) -6-pyridin-4-yl-hexanoic acid; Acid (3R, 9S) -6- [4 - (3-hydroxy-propoxy) -phenyl] -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca - 11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca -11 (18), 12, 14, 16 -tetraen-9-yl- carbamoyl) - 5 - (4-phenoxy-phenyl) pentanoic; Acid (3R, 9S) -6- [4 - (3-hydroxy-ethoxy) -phenyl] -3- (8-oxo-4-oxo-1, 7 -. 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -3- (8-oxo-4-oxo-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca -11 (18), 12, 14, 16 -tetraen-9-yl- carbamoyl) - 6 - [4 - (2-pyrrolidin-1-yl-ethoxy-phenyl] -pentanoic acid (3R, 9S) -6- (4-methoxy-phenyl) -3- (8-oxo-4-oxa - 1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic acid (3R, 9S) - 6 - [4 - ( 2-methoxy-ethoxy) -phenyl] -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9 - il - carbamoyl) hexanoic acid (3R, 9S) - 3 - (8 - oxo - 4 - oxa - 1, 7 - diaza - tricyclo [9.6.1.0.] octadeca - 11 (18), 12, 14, 16 - tetraen-9-yl-carbamoyl) -5-phenyl-pentanoic acid (3R, 9S) -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] octadeca -11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) -6-phenyl-pentanoic acid (3R, 9S) -6- (3-hydroxy-phenyl) -3- (8-oxo-4) - oxa - 1, 7 - diaza -trip [9.6.1.0.] octadeca - 11 (18), 12, 14, 16 -tetraen-9-yl-carbamoyl) hexanoic; (3R, 9S) - 3 - (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0] octadeca -11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) ) - 6 - [4 - (3-piperidin-1-yl-propoxy) phenyl] -hexanoic; Acid (3R, 9S) -6- [4- (3-dimethyl-amino-propoxy) -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- (2-dimethyl-amino-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-diaza-tricyclo [9.6.1.0] octadeca-11 (18), 12, 14 , 16 - tetraen - 9 - yl - carbamoyl) hexanoic; Acid (3R, 9S) -6-naphthalen-2-yl-3 - (8-oxo-4-oxa-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16 -tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca -11 (18), 12, 14, 16-tetraen-9-yl- carbamoyl) - 6 - (4-pyrrol-1-yl) hexanoic; Acid (3R, 9S) -6- (4-hydroxy-3-methyl-phenyl) -3- (8-oxo-4-oxa-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18 ), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -6- (4-benzyloxy-phenyl) -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -6- [4 - (4-amino-butoxy-phenyl)] - 3 - (8-oxo-4-oxa-1, 7 - diaza - tricyclo [9.6.1.0.] octadeca - 11 (18), 12, 14, 16 - tetraen - 9 - yl - carbamoyl) hexanoic; Acid (3R, 9S) -5- (4-methoxy-phenyl) -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16 -tetraen-9-yl-carbamoyl) pentanoic; (3R, 9S) -6- (4-Amino-phenyl) -3- (8-oxo-4-oxa-1, 7-diazatricide [9.6.1.0.]] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Acid (3R, 9S) -3- (8-oxo-4-oxa-1, 7-diaza-tricyclo [9.6.1.0.] Octadeca -11 (18), 12, 14, 16 -tetraen-9-yl- carbamoyl) - 6 - [4 - (pyridin-4-yl-methoxy) phenyl] hexanoic; Acid (3R, 9S) -6- (4-acetylamino-phenyl) -3- (8-oxo-4-oxa-1,7-diaza-tricyclo [9.6.1.0.] Octadeca-11 (18), 12, 14, 16-tetraen-9-yl-carbamoyl) hexanoic; Na - [[3 - (N-hydroxy-carbamoyl) -4-methyl-thio-2-propoxy-methyl] butyl-lyl] -N, O-dimethyl-tyrosine-amide; N ™ - [[3 - (N-hydroxy-carbamoyl) -4-isopropyl-thio-2-propoxy-methyl] butyl - il] - N, O - dimethyl-tyrosine-amide; N - [[3 - (N-hydroxy-carbamoyl) -2-propyl-thio] butyl-yl] -N, O-dimethyl-tyrosine-amide; N - [N - (1-phosphono-3-phenyl-propyl) - (S) -leucyl] - (S) -phenylalanine-N -methyl-amide; N - [N - (1-phosphono-3 - (4-bromo-1,8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (benzyloxy-carbonyl-amino) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (2-hydroxy-phenyl) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (methyl mercapto) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (methyl-sulfinyl) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (methyl-sulfonyl) propyl) - (S) -leucyl] - (S) -phenylalanine-N-methyl-amide; N - [N - (1-phosphono-3 - (1, 8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) -tryptophan-N-methyl-amide; N - [N - (1-phosphono-3 - (1,8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N-methyl-amide; N - [N - (1-phosphono-3 - (1,8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (-) - amino-azacyclo-tridecan-2-one; N - [N - (1-phosphono-3 - (1,8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) - lysine - N - (amino-ethyl) -amide; N - [N - (1-phosphono-3 - (1,8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) - lysine - N - (ethyl-pyrrolidine) -amide; N - [N - (1-phosphono-3- (1, 8-naphthalene-dicarboximido) propyl) - (S) -leucyl] - (S) -lysine-N- (ethyl-methyl-piperazine) -amide; N - [N - (1-phosphono-3 - [8 - (7,9-dioxo-8-azaspiro [4, 5] decyl)] propyl) - (S) -leucyl] - (S) -phenylalanine - N - methyl amide; and N - [N - (1-phosphono-3 - [8 - (7,9-dioxo-8-azaspiro [4,5] decyl)] propyl) - (S) -leucyl] - (S) -lysine - N-methyl-amide.

As noted above, several inhibitors of matrix metalloproteinases are known. A large number of inhibitors are characterized as hydroxamic acid base and / or carboxylic acid base compounds. Typical such compounds are those described in the following references, all of which are incorporated herein by reference, since all disclosed compounds can be used in the method of this invention.

US 4599361 (Searle) EP-A-2321081 (ICI) EP-A-0236872 (Roche) EP-A-0274453 (Bellon) WO 90/05716 (British Technology) WO 90/05719 (British Technology) WO 91/02716 ( British Technology) 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- 1497192 (Roche) US 5256657 (Sterling Winthrop) WO 92/13831 (British Technology) WO 92/22523 (Research Coforation Technologies) WO 93/09090 (Yamanouchi) WO 93/09097 (Sankyo) WO 93/20047 (British Technology) WO 93/24449 (Celltech) WO 93/24475 (Celltech) EP-A-0574758 (Roche) WO 94/02447 (British Technology) WO 94/02446 (British Technology).

A particularly preferred group of compounds to be employed in the present method are those described in WO 95/35275 and WO 95/35276, both of which are hereby incorporated by reference. Typical compounds that fall within these groups to be employed include: N-hydroxy-2 - [[(2 - (4-methoxy-phenoxy) -ethyl- (toluene-4-sulfonyl) -amino] -acetamide; N-hydroxy-2 - [(4-phenoxy-ethyl) -toluene-4-sulfonyl) -amino] -acetamide; N-hydroxy-2 - [(4-methoxy-benzene-sulfonyl) -nonyl-amino] -acetamide; 2 - . 2 - [decyl - (toluene-4-sulfonyl) -amino] -N-hydroxy-acetamide; 2-benzyl- (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [[(2 - (2-methoxy-benzyl) - (octane-1-sulfonyl) -amino] -acetamide; 2 - [(2-ethoxy-benzyl) -octane-1-sulfonyl) amino] ] - N-hydroxy-acetamide; N-hydroxy-2 - [(naphthalen-2-yl-methyl) -octane-1-sulfonyl) -amino] -acetamide; 2 - [(4-chloro-benzyl) - (octane-1-sulfonyl) amino] -N-hydroxy-acetamide; and salts, solvates or hydrates thereof.

Another class of matrix metalloproteinase inhibitors are aryl sulfonamides of the formula: Where Ar is carbocyclic or heterocyclic aryl, and R, R1 and R2 include hydrogen, alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. These compounds are disclosed in European Patent Number 0606046, hereby incorporated by reference. Specific compounds to be employed in the present method include: N-hydroxy-2 - [[4-methoxy-benzenesulfonyl] (isobutyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (cyclohexyl-methyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (cyclohexyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (phenethyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (3-methyl-butyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (sec-butyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (tert-butyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (4-fluoro-benzyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (4-chloro-benzyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (isopropyl) amino] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (4-methyl-benzyl) amino] acetamide; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl] hydrochloride (benzyl) -amino] -1- [dimethylamino-acetyl] -piperidine; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] -1- [3-picolyl] -piperidine hydrochloride; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl] hydrochloride (benzyl) -amino] -1- [carbomethoxy-methyl] -piperidine; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] - 1-piperidine trifluoro-acetate; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] - 1 - [t -butoxycarbonyl] -piperidine; 4-N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] - 1 - [Methyl-sulfonyl] -piperidine; N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] -1- [4-picolyl] -piperidine hydrochloride; N-hydroxy-carbamoyl] -4 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] -1 - [morpholino-carbonyl] -piperidine hydrochloride; and N - (t-butoxy) -2 - [[4-methoxy-benzene-sulfonyl (benzyl) -amino] -2- [2- (4-morpholino) -ethyl] -acetamide.

The following compounds are prepared in a manner similar to Example 7: N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (isobutyl) -amino-2 - (2 - (4 - morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (2-picolyl) -amino-2 - (2 - (4-morpholino) ethyl] acetamide dihydrochloride; N-hydroxy-2 - [[ 4-methoxy-benzene-sulfonyl] (3-picolyl) -amino] -2- (2 - (4-morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] dihydrochloride ( 2-methyl-thiazol-4-yl-methyl) amino] -2- [2 - (4-morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (benzyl) amino] -2- [2 - (4-thio-morpholino) ethyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (benzyl) amino] -2- [2 - (4-methyl-thiazol-4-yl-methyl] acetamide; N-hydroxy-2 - [[ 4-methoxy-benzene-sulfonyl] (benzyl) amino] -2 - [(6-chloro-piperonyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (benzyl) amino] -2- [(1-pyrazolyl) methyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (3-picolyl) amino] -2- [3-picolyl] acetamide; N-hydroxy-2-hydrochloride - [[4-methoxy-benzene-sulfonyl] (benzyl) amino] - 2 - [(1-methyl-4-imidazolyl) methyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (isobutyl) amino] hydrochloride] - 2 - [(1-methyl-4-imidazolyl) methyl] acetamide; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (3-picolyl) amino] -2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride; N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (2-picolyl) amino] -2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride; and N-hydroxy-2 - [[4-methoxy-benzene-sulfonyl] (2-methyl-thiazol-4-yl-methyl) amino-2 - [(1-methyl-4-imidazolyl) methyl] acetamide hydrochloride.

Another group of small inhibitor peptides of the matrix metalloproteinase 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 defined by the formula: O O II II HONHCCH-CH-CN-CHCOX I I I I R1 R2 R3 R wherein R1, R2, R3 and R4 can be hydrogen or alkyl and X is OR5 or NHR5, where R5 includes hydrogen, alkyl and aryl. A, includes alkyl and n is 0 or 2. Typical compounds to be employed in the present method include the following: N - [2-isobutyl-3 - (N'-hydroxycarbonyl-amido) -propanoyl] - D -tryptophan methyl amide; N - [2-isobutyl-3 - (N '-hydroxycarbonyl-amido) -propanoyl] -N-methyl-L-tryptophan methyl amide; N - [2-isobutyl-3 - (N-hydroxycarbonyl-amido) -propanoyl] -L-3 - (2 -naphthyl) -lanine methyl amide; N - [2-isobutyl-3 - (N '-hydroxy-carbonyl-amido) -propanoyl] -L -triptophan-2-hydroxy-ethyl-amide; N - [2-isobutyl-3 - (N '-hydroxycarbonyl-amido) -propanoyl] -L -triptophan amyl-amide; N - [2-isobutyl-3 - (N '-hydroxycarbonyl-amido) -propanoyl] -L -triptophan piperidine-amide; N - [2-isobutyl-3 - (N '-hydroxy-carbonyl-amido) -propanoyl] -L -triptophan dodecylamide; N - [2-isobutyl-3 - (N '-hydroxycarbonyl-amido) -propanoyl] -L -triptophan (S) -methyl-benzyl-amide; N - [2-isobutyl-3 - (N '-hydroxycarbonyl-amido) -propanoyl] -L -tryptophan (6-phenyl-methoxy-carbonyl-amino-hexyl-1) amide; 2S-Hydroxy-3R- [1 S - (3-methoxy-2,2-dimethyl-propyl-carbamoyl) -2, 2-dimethyl-propyl-carbamoyl] -5-hexane-hydroxamic acid; 2S-hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -6- (4-chloro) phenyl-hexane-hydroxamic acid; 2S-Hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-propylcarbamoyl] octane-hydroxamic acid; 2S-Hydroxy-3R - [IS - (pyridin-2-yl-methyl-carbamoyl) -2,2-dimethyl acid - propyl-carbamoyl] -5-methyl-hexane-hydroxamic; 2S-Hydroxy-3R - [IS - (pyridin-3-yl-methyl-carbamoyl) -2,2-dimethyl acid - propyl-carbamoyl] -5-methyl-hexane-hydroxamic; 2S-hydroxy-3R- [1 S - (pyridin-4-yl-methyl-carbamoyl) -2,2-dimethyl acid - propyl-carbamoyl] -5-methyl-hexane-hydroxamic; 2S-hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -4-methoxy-butane-hydroxamic acid; 2S-hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -4-benzyloxy-butane-hydroxamic acid; 2S-Hydroxy-3R - [IS - (methyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -4-benzyl-thio-butane-hydroxamic acid; 2S-hydroxy-3R - [1 S - (methyl-carbamoyl) -2,2-dimethyl-buten-3-yl acid - carbamoyl] -5-methyl-hexane-hydroxamic; 2S-hydroxy-3R- [1 S - (tert-butyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -5-methyl-hexane-hydroxamic acid; 2S-Hydroxy-3R- [IS - (N, N-dimethyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -5-methyl-hexane-hydroxamic acid; 2S-Hydroxy-3R- [IS - (3-hydroxy-2,2-dimethyl-propyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -5-methyl-hexane-hydroxamic acid; 2S-hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-propyl-carbamoyl] -6-phenyl-hexane-hydroxamic acid; 2S-hydroxy-3R- [IS - (methyl-carbamoyl) -2,2-dimethyl-butylcarbamoyl] -5-methyl-hexane-hydroxamic acid; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (2-hydroxy-ethyl) -amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanyl-proline; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (2-hydroxy-ethyl) -N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanyl-D -prolinol; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanyl-L-prolinol; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine - N - (5-N) methyl-pentylcarboxamide) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (2-ethyl-thio-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (2-methoxy-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine - N - (2-N) - acetyl-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (3 - (2-pyrrolidone) propyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (3 - (2-pyrrolidone) propyl) amide, sodium salt; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (2-acetoxy-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N - (3 - (2-pyrrolidone) propyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N-methyl-N- (2-hydroxy-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N - (2-hydroxy-ethyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanyl-D-prolinol; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine-N- (3 - (2-pyrrolidone) propyl) amide, sodium salt; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N - (3 - (2-pyrrolidone) propyl) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N - (3 - (2-pyrrolidone) propyl) amide or a salt thereof; N2 - [4 - (N-hydroxy-amino) -3S- (4-hydroxy-phenyl-thio-methyl) -2R-isobutyl-succinyl] -N6-tert-butyloxy-carbonyl-L-lysine-N1-methyl- amide; N2 - [4 - (N-hydroxy-amino) -3S- (4-hydroxy-phenyl-thio-methyl) -2R-isobutyl-succinyl] -N6-tert-butyloxy-carbonyl-N6- (4-hydroxy-phenyl) thio-methyl) L-lysine-N 1 -methyl-amide; N2 - [4 - (N-hydroxy-amino) -3S- (2-thienyl-thio-methyl) -2R-isobutyl-succinyl] -N6-tert-butyloxy-carbonyl-L-lysine-N1-methyl-amide; N2 - [4 - (N-hydroxy-amino) -3S- (4-hydroxy-phenyl-thio-methyl) -2R-isobutyl-succinyl] -O-tert-butyl-L-threonine-N1-methyl-amide; N2 - [4 - (N-hydroxy-amino) -3S- (4-hydroxy-phenyl-thio-methyl) -2R-isobutyl-succinyl] -L-glutamine-N1, N5-dimethyl-amide; N2 - [4 - (N-hydroxy-amino) -3S- (4-hydroxy-phenyl-sulfonyl-methyl) -2R-isobutyl-succinyl] -N6-acetyl-L-lysine-N1-methyl-amide; 3R - (3-methoxycarbonyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-2S-2-propenyl-hexane-hydroxamic acid; 3R - (ÍS-methyl-carbamoyl-2-thien-2-yl-ethyl-carbamoyl) -5-methyl acid 2S-2-propenyl-hexane-hydroxamic; 3R - (3-Methyl-IS-methyl-carbamoyl-butyl-carbamoyl) -5-methyl-2S acid - 2 - propenyl - hexane - hydroxamic; 2S - (1 S -methyl-carbamoyl-2-oxadiazol-5-yl-ethyl-carbamoyl) -5-methyl-2S-2-propenyl-hexane-hydroxamic acid; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxylic acid) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxy-N-methyl-amide) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxy-beta-alanine) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxy-glycine) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxy-N-benzyl-amide) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-cyano) phenylalanine - N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-acetamido) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L- (4-oxymethyl-carboxamide) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2-thienyl-thio-methyl-succinyl) - L - (4-N-acetylamino) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2-thienyl-thio-methyl-succinyl) - L - (4-N-methyl-succinyl-amide) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-amino-phenyl-thio-methyl) -succinyl] -L- (4-N (methyl-succinyl-amide) phenylalanine-N-methyl) - amide: [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-amino-phenyl-thio-methyl-succinyl] - L - (4 - N - (4 - (4 - oxo - butanoic) amino-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-hydroxy-phenyl-thio-methyl) -succinyl] -L- (4-N) - methyl-succinyl-amido) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-hydroxy-phenyl-thio-methyl) -succinyl] -L- (4-N- (4 - (4-oxa-butanoic acid) amino-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2-thienyl-thio-methyl) -succinyl] -L- (4-oxymethyl-carbonyl-methyl) ) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2-thienyl-thio-methyl) -succinyl] - L - (4 - N - (oxymethylcarboxylic acid) phenylalanine - N - methyl - amide; [4 - (N - hydroxy - amino) - 2R - isobutyl - 3S - (2 - thienylthio - methyl) - succinyl ] - L - (4- (oxymethyl-carboxy-glycyl methyl ester) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2-thienyl-thio-methyl) - succinyl] - L - (4- (oxymethyl-carboxy-glycine) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-4 - (oxymethyl) - carboxy-glycyl methyl ester) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-4 - (oxymethyl-nitrile) phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-3 - (1- (2-methyloxy -carbonyl) -ethyl) -4-methoxy-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-3 - (hydroxymethyl) -4 - methoxy-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-3-methyl-4-methoxy-phenylalanine-N-methyl-amide; 2 - [benzyl- (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(2-methoxy-benzyl) - (octane-1-sulfonyl) -amino] -acetamide; 2 - . 2 - [(2-Ethoxy-benzyl) - (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N-hydroxy-2 - [(naphthalen-2-yl-methyl) - (octane-1-sulfonyl) -amino] -acetamide; 2 - [(4-chloro-benzyl) - (octane-1-sulfonyl) -amino] -N-hydroxy-acetamide; N2 - [3S-hydroxy-4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L -leucine-N1-methyl-amide; N2 - [3S-hydroxy-4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -5-methyl-L-glutamic acid-N1-methyl-amide; N2 - [3S-hydroxy-4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N1-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (thienyl-thio-methyl) succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3 S- (phenyl-thio-methyl) succinyl] -L-phenylalanine-N-methyl-amide; 2S - (4-methoxy-phenyl-sulfanyl-methyl) -3R- (2-phenyl-IS-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (3-chloro-phenyl-sulfanyl-methyl) -3R- (2-phenyl-IS-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Phenyl-Sulfanyl-methyl) -3R- (2-phenyl-IS- (pyrid-3-yl-methyl-carbamoyl) -ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (3-Methyl-phenyl-sulfanyl-methyl) -3R- (2-phenyl-IS-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Thien-2-yl-sulfanyl-methyl) -3R- (2 - (4-carboxy-methoxy-phenyl) acid) 1 S-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S - (Thien-2-yl-sulfanyl-methyl) -3R- (2-phenyl-1 S - (pyrid-3-yl-methyl-carbamoyl) -ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (4-Hydroxy-phenyl-sulfanyl-methyl) -3R- (2-phenyl-1 S- (pyrid-3) acid - il-methyl-carbamoyl) -ethyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S - (Thien-2-yl-sulfanyl-methyl) -3R- (2-naph-2-yl-IS-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (4-Hydroxy-phenyl-sulfanyl-methyl) -3R- (2R-hydroxy-1 S -methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (4-hydroxy-phenyl-sulfanyl-methyl) -3R- (5-acetamido-IS-methyl) acid carbamoyl-pentyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S - (4-Hydroxy-phenyl-sulfanyl-methyl) -3R - (3 - [1,1-dimethyl-ethoxy-carbonyl] - IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Thien-2-sulfanyl-methyl) -3R- (2-phenyl-IS-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 3R - (2 - [4 - acetamido - phenyl] - IS - methyl carbamoyl ethyl carbamoyl) - 5-methyl-hexane-hydroxamic; 2S - (4-Ptalimido-butyl) -3R- (3-methyl-IS-ethoxy-carbamoyl-methyl) acid carbamoyl) -5-methyl-hexane-hydroxamic; 3R - (2 - [4-methoxy-phenyl] -IS-methyl-carbamoyl-ethyl-carbamoyl) -2S, 5-dimethyl-hexane-hydroxamic acid; 3R - (2-phenyl-1 S - [2-oxo-pyrolid-yl] -propyl-carbamoyl-ethyl-carbamoyl) -5-dimethyl-hexane-hydroxamic acid; 3R - (2 - [4-methoxy-phenyl] -IS-methyl-carbamoyl-ethyl-carbamoyl) -5 acid - methyl-hexane-hydroxamic; 3R - (2-phenyl-ÍS - [pyrid-3-yl-methyl-carbamoyl] -ethyl-carbamoyl) -5 acid - dimethyl-hexane-hydroxamic; 3R - (2,2-Dimethyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-dimethyl-hexane-hydroxamic acid; Isobutyl-malonoyl-L-alanine-furfuryl-amide hydroxamate; 2-Isobutyl-3-carbonyl-3 '- (4-acetyl-aniline) propionic acid; N-benzyloxy-carbonyl-a-phosphono-glycyl-L-alanine furfuryl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (phenyl-thio-methyl) succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-methoxy-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4-hydroxy-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (2,4-dimethyl-phenyl-thio-methyl) succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (3-bromo-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (3-chloro-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (3-methyl-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S- (4 - (N-acetyl) -amino-phenyl-thio-methyl) -succinyl] -L-phenylalanine-N-methyl-amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-phenyl-sulfinyl-methyl-succinyl] -L-phenylalanine-N-methyl-amide; 3R - (3-methoxycarbonyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-2S-phenyl-sulfanyl-methyl-hexane-hydroxamic acid; 3R - (3-Methoxy-carbonyl-1 S-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-2S- (thien-2-yl-sulfanyl-methyl) -hexane-hydroxamic acid; 2S - (4-methoxy-phenyl-sulfanyl-methyl) -3R- (3-methoxy-carbonyl) - S - methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2 S - (4-Amino-phenyl-sulfanyl-methyl) -3R- (3-methoxy-carbonyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Ethyl-sulfanyl-methyl) -3R- (3-methoxy-carbonyl-1 S -methylcarbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Acetylsulfanylmethyl) -3R- (3-methoxycarbonyl-IS-methylcarbamoyl-propylcarbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (Benzyl-sulfanyl-methyl) -3R- (3-methoxy-carbonyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (tert -butyl-sulfanyl-methyl) -3R- (3-methoxy-carbonyl-IS-methyl) acid carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S-thio-methyl-3R- (3-methoxy-carbonyl-IS-methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic acid; 2S - (4-hydroxy-phenyl-sulfanyl-methyl) -3R- (2-tert-butoxy-carbonyl) acid 1 S-methyl-carbamoyl-ethyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S - (4-Hydroxy-phenyl-sulfinyl-methyl) -3R- (3-methoxy-carbonyl) - S - methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic; 2S - (4-Hydroxy-phenyl-sulfonyl-methyl) -3R- (3-methoxy-carbonyl) - S - methyl-carbamoyl-propyl-carbamoyl) -5-methyl-hexane-hydroxamic; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- [1 - (2-amino-ethyl) -pyrrolidine] -amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine - N - [1 - (3-amino-propyl) -2 (RS) -methyl-piperidine] -amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- [2 - (2-amino-ethyl) -1-methyl-pyrroline] -amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (3-amino-methyl-pyridine) amide; [4 - (N-hydroxy-amino) -2 (RS) -isobutyl-succinyl] -L-phenylalanine - N - (4 amino-methyl-pyridine) amide; [4 - (N-hydroxy-amino) -2 (RS) -isobutyl-succinyl] -L-phenylalanine - N - (1 - (3-amino-propyl) -imidazole) amide; [4 - (N-hydroxy-amino) -2 (RS) -isobutyl-succinyl] -L-phenylalanine - N - (2 amino-methyl-benzimidazole) amide; [4 - (N-hydroxy-amino) -2R-isobutyl-3S-methyl-succinyl] -L-phenylalanine - N - [4 - (2-amino-ethyl) -morpholino] amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- [4 - (2-amino-ethyl) -morpholino] amide; [4 - (N-hydroxy-amino) -2 (R, S) -isobutyl-succinyl] -L-phenylalanine - N - [2 - (2-amino-ethyl) -pyridine] amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine - N - [4 - (2 amino-propyl) -morpholino] amide; [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- (3-amino-methyl-pyridine) amide hydrochloride; and [4 - (N-hydroxy-amino) -2R-isobutyl-succinyl] -L-phenylalanine-N- [4 - (2-amino-methyl) -morpholino] amide hydrochloride.

In a preferred example, the tricyclic butyric acid derivatives which are inhibitors of the matrix metalloproteinases are used to treat neurological disorders and to promote wound healing according to this invention. A preferred group of tricyclic butyric acid derivatives is defined by the formula: O X where one of the R1 or R2 is C - CH - (CH) a -C - R5 I I R Ra where X is O, N - OR6 where R6 is hydrogen, - (CH2) n - aryl where n is zero or an integer from 1 to 5, alkyl or - (CH2) n - cycloalkyl where n is as defined above or N - N - R6 where R6 and R6a are each the same or different and are as R6a defined above for R; R and Ra are the same or different and each one is hydrogen, - (CH2) n - aryl where n is as defined above, - (CH2) n-cycloalkyl where n is as defined above, - CH2) P - R7 - (CH2) q - aril where R7 is O or S and p or q is 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 where p, q and R7 are as defined above, I rent, - (CH2) n-cycloalkyl where n is as defined above, or - (CH2 - NH2 where 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, NRb R '6a where R and R a are each the same or different and are as defined above for R6, or NH-OR6 where R6 is as defined above; R3 and R4 are each the same or different and each is hydrogen, alkyl, NO2, halogen, OR6 where R6 is as defined above, CN, CO2R6 where R6 is as defined above, SO3R6 where R6 is as defined above, CHO, O II - C - R - where R is as defined above, OR C-N-R0 R 6'a where R6 and R6a are each the same or different and are as defined above for R6, or (CH2) "- N-R6 R '6a where R6 and R6a are each the same or different and are as defined above stop; W, W1, Z and Z1 are each the same or different and each one is CR3 where R3 is as defined above or, N supplies only one of W or W1 is N and / or only one of Z or Z1 is N; Y And it is - N - where R is as defined above, R -O- - S - (O) m - where m is zero or an integer of 1 or 2, - CH2 -, -C- O -C- N - OR6 where R6 is as defined above -CH¬ OR6 where R6 is as defined above, -C- N-N-R6 R where R? 6. Y. R, 6a are the same or different and are as defined above for R6, • C-N- OR R6 where R6 is as defined above, -N-C I II R6 O where R is as defined above, -C-O I O -O-C O - CH2 - O -, - O - CH2 -, - CH2 - S (O) m - where m is as defined above, - S (O) m- CH2 - where m is as defined above, -CH2- N- R6 where R6 is as defined above, - N - CH2 - I R6 where R6 is as defined above, -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-Dibenzo-furan-2-yl-4-hydroxyimino-butyric acid; 2 - (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -4-methyl-pentanoic acid; 2 - (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5-phenyl-pentanoic acid; 4-Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid; 5 - (4-Chloro-phenyl) -2- (2-dibenzofuran-2-yl-2-hydroxyimino-ethyl) -pentanoic acid; 2 - (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5- (4-fluoro-phenyl) -pentanoic acid; 2 - (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5- (4-methoxy-phenyl) -pentanoic acid; 2 - (2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl) -5-p-tolyl-pentanoic acid; 3 - (Dibenzo-furan-2-yl-hydroxyimino-methyl) -5-methyl-hexanoic acid; 3 - (Dibenzo-furan-2-yl-hydroxyimino-methyl) -6-phenyl-hexanoic acid; 3 - (Dibenzo-furan-2-yl-hydroxyimino-methyl) -5-phenyl-pentanoic acid; 6 - (4-Chloro-phenyl) -3- (dibenzo-furan-2-yl-hydroxyimino-methyl) -hexanoic acid; 3 - (Dibenzo-furan-2-yl-hydroxyimino-methyl) -6- (4-fluoro-phenyl) acid - hexanoic; 3 - (Dibenzo-füran-2-yl-hydroxyimino-methyl) -6- (4-methoxy-phenyl) acid - hexanoic; and 3 - (dibe? zo-furan-2-yl-hydroxyimino-methyl) -6-p-tolyl-hexanoic acid; and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.

Tricyclic butyric acids having an α-amino substituent are defined by the formula: ' where: Rv X is O, NOR9, S, OH, SH, or N N R7a R7 and R7a independently are: hydrogen, Ci-C20 alkyl or C? - C Q substituted alkyl, (CH2) or -6 aryl, (CH2) or -6-heteroaryl, or (CH2) or -6-cycloalkyl; and R2 independently are hydrogen, Ci-C20 alkyl or C1-C20 substituted alkyl, halo, NO2, CN, CHO, COR *, COOR *, SO3R *, ORO, CONR4R5, (CH2) 0-6-aryl, (CH2) or -6-heteroaryl, or (CH2) or -6-cycloalkyl; R6 is hydrogen, C 1 -C 20 alkyl or C 1 -C 20 substituted alkyl; aryl is phenyl or substituted phenyl; R3 is hydroxy, O-Ci-C20 alkyl or Ci-C20 substituted alkyl; O - (CH2)? - 3 - aryl, or NHOR ^; R4 and R5 are independently hydrogen, Ci-C20 alkyl or Ci-C20 substituted alkyl; (CH2) or -6-aryl, (CH2) or -6-heteroaryl; or one of the R and R5 is hydrogen and the other is: CORs, CSRg, CONR «R9, CSNRsR9, COORg, COSRg, COCHR », I NRÍRJ, CON - CONRsRg, R! CON - COORg, Ri CON - COSRs, or Ri Ri; Yes-N- Ri, -O-, - S (O) or, l or 2, - CH2 -, -C-, O -c-, - C -, OR8 -C-, N-N-RsR9 C-N-, OR R * -N-C-, Rs O C-O-, OR CH2 - O -, O - CH2 -, - CH2S (O) o. 2, CH2-N-, Rs -N-CH2-, Rs -CH = N, or -N-CH-; Rs and R9 independently are: Hydrogen, Ci-C20 alkyl or Ci-C20 substituted alkyl, (CH) 0-6-aryl, (CH2) 0-6-heteroaryl, or (CH2) or -6-cycloalkyl; W, W1, Z and Z1 independently are CRt 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-trifluoro-acetyl-amino) -butyric acid; (R) -4-Dibenzofuran-2-yl-4-oxo- (2,2,2-trifluoro-acetyl-amino) -butyric acid; (S) -2-amino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-2 - [3- (2,6-diisopropyl-phenyl) -ureido] -4-oxo-butyric acid; (S) -2-Benzoyl-amino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2-phenyl-acetyl-amino-butyric acid; (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; (S) -2 - [(Biphenyl-4-carbonyl) -amino] -4-dibenzo-furan-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2 - (dodecanoyl-amino) -butyric acid; (R) -4-Dibenzofuran-2-yl-4-oxo-2 - (dodecanoyl-amino) -butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2- (2, 2, 2-trifluoro-acetyl-amino) -butyric acid; (R) -4-Dibenzofyran-2-yl-4-oxo-2- (2, 2, 2-trifluoro-acetyl-amino) -butyric acid; (S) -2-amino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-2 - [3- (2,6-diisopropyl-phenyl) -ureido] -4-oxo-butyric acid; (S) -2-Benzoyl-amino-4-dibenzofttran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2-phenyl-acetyl-amino-butyric acid; (S) -4-Dibenzofyran-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; (S) -2 - [(Biphenyl-4-carbonyl) -amino] -4-dibenzofuran-2-yl-4-oxo-butyric acid; (S) -4-Dibenzofuran-2-yl-4-oxo-2 - (octanoylamino) -butyric acid; and (S) -4-dibenzofuran-2-yl-4-oxo-2 - (dodecanoyl-amino) -butyric acid.

The tricyclic sulfonamide inhibitors of the matrix metalloproteinase include compounds of the formula: Where M is a natural alpha (L) amino acid derivative having the structure COR1 R X is O, S (O) n, CH 2, CO, or NH; R is a side chain of a natural alpha amino acid; R1 is Ci-C5 alkoxy, hydroxy, or -NHOR5; R2 and R4 are independently hydrogen, - Ci. C5 alkyl, - NO2, halogen, - OR5, - CN, - CO2R5, - SO3R5, - CHO, - COR5, - CONR5R6, - (CH2) "NR5R6, - CF3, or - NHCOR5; each R5 and R6 are independently hydrogen or Ci-C5 alkyl; and n is 0 to 2 and pharmaceutically acceptable salts, esters, amides and prodrugs thereof Specific compounds of this class to be employed include (L) -2- (dibenzo-furan-2-sulfonyl-amino) -4-methyl-petanoic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-methyl-petanoic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-phenyl-propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-methyl-butyric acid; Acid (dibenzo-furan-2-sulfonyl-amino) acetic; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -succinic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-tritylsulfanyl-propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-mercapto-propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-methyl-pentanoic acid hydroxy-amide. (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -4-methyl-petanoic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-methyl-petanoic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-phenyl-propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-methyl-butyric acid; Acid (dibenzo-furan-2-sulfonyl-amino) acetic; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -succinic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-tritylsulfanyl-propionic acid; (L) -2- (Dibenzo-furan-2-sulfonyl-amino) -3-mercapto-propionic acid; acid (L) -2- (dibenzo-furan-2-sulfonyl-amino) -3-methyl-pentanoic hydroxy-amide.

Additional inhibitors of matrix metalloproteinases are defined by the formula: Where R and R1 are the same or different and are: Hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, - OR6 where R6 is hydrogen, alkyl, aryl, aryl-alkyl, heteroaryl or cycloalkyl, - N - R6 R6a where R6 and R6 are the same or different and are as defined above for R6, O - O - C - R6 where R6 is as defined above, O - NH - C - R6 where R6 is as defined define above, OC - R6 where R6 is as defined above. SR »6 where R is as defined above, OR C-R6 where R6 is as defined above, -CH2-OR6 where R6 is as defined above, -CH2- -N-R6 RR6a where R and R 6a are the same or different and are as defined above for R6, O C-N-R6 R, 6a where R and R, 6a are the same or different and are as defined above for R6, OR S-R6 OR where R6 is as defined above, Cycloalkyl, or Heteroaryl, with the proviso that R and R1 are not both hydrogen; R2 is -OR6 where R6 is as defined above, or -N-R6 R6a where R6 and R6a are the same or different and are as defined above for R6; R3, R3a, and R4a are the same or different and are: Hydrogen, fluoro, alkyl, - (CH2) n - aryl where n is an integer from 1 to 6, - (CH2) n - heteroaryl where n is as defined above, - (CH2) n - cycloalkyl where n is as defined above, - (CH2) P - X (CH2) q - aryl where X is O, S, SO, SO2 or NH ypyq are each zero or an integer from 1 to 6, and the sum of p + q is not greater than 6, - (CH2) P - X - (CH2) q - heteroaryl where X, p and q are as defined above, or - (CH2) " R7 wherein R7 is N-ptalimido, N-2, 3-naphthimido, -OR6 where R6 is as defined above, -N-R6 R6a where R and R 16a are the same or different and are as defined above for R6; -SR6 where R is as defined above, OR -S-R6 where R is as defined above, OR II 6 -S-R6 II OR where R is as defined above, O -O -C-R6 where R is as defined above, OR N-C-Rb R 6 * a where R) 6 and R, 6a are the same or different and are as defined above for R O - S - C 11 - R 6 where R is as defined above, OR II - C - R6 where R6 is as defined above, OR - C 11 - R 6 where R is as defined above, or OR II - C - N - R6 R6 where R6 and R6a are the same or different and are as defined above for R6; and n is as defined above; R5 is OH or SH; with the proviso that R3, R3, R4 and R4a are hydrogen or at least one of R3, R3a, R4 and R4a is fluoro; and the corresponding isomers thereof; or a salt pharmaceutically acceptable thereof.

Typical compounds of this class that are routinely used in the present method include: 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (4'-Bromo-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -4- (dimethyl-hydrazono) -butyric acid; 4 - (4'-Fluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxy-butyric acid; 4 - (4'-Bromo-2'-fluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -3-fluoro-4-oxo-butyric acid; 4 - (2'-4'-Dichloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (2'-4'-difluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (3 phenyl-propyl) -butyric; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (2-phenyl-ethyl) -butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (3 - phalimido-propyl) -butyric; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (phenyl-thio-methyl) -butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4-Hydroxyimino-4- (4'-trifluoromethyl-biphenyl-4-yl) -butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -4-methoxyimino-butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -2-fluoro-2 - [2 - (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -ethyl ] - 4-hydroxyimino-butyric; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (1H-indol-3-yl) methyl-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methyl-butyric acid; (+) - 2 - [2 - (4'-Chloro-biphenyl-4-yl) -2-hydroxyimino-ethyl] -2-fluoro-6-phenyl-hexanoic acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -2-fluoro-2 - [2 - (1, 3-dioxo-1,3-dihydro-benzo [F] isoindol-2- il) -ethyl] -4-hydroxyimino-butyric; Acid (±) - 2 - [2 - (4'-chloro-biphenyl-4-yl) -2-hydroxyimino-ethyl] -6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) ) - 2 - fluoro-hexanoic; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - [2 - (phenyl-ethyl-carbamoyl) -ethyl] -butyric; 4 - (4'-Chloro-biphenyl-4-yl) -3,3-difluoro-4-hydroxyimino-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -3,3-dimethyl-2-fluoro-4-hydroxyimino-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -2,2-dimethyl-3-fluoro-4-hydroxyimino-butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -2,2-difluoro-4-hydroxyimino-butyric acid; and 4 - (4'-Chloro-biphenyl-4-yl) -2,2,3,3-tetrafluoro-4-hydroxyimino-butyric acid.

A compound selected from the group consisting of: 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (4'-Bromo-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -4- (dimethyl-hydrazono) -butyric acid; 4 - (4'-Fluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; (±) - 4 - (4'-Fluoro-biphenyl-4-yl) -4-hydroxy-butyric acid; 4 - (4'-Bromo-2'-fluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; (+) - 4 - (4'-Chloro-biphenyl-4-yl) -3-fluoro-4-oxo-butyric acid; 4 - (2 ', 4'-Dichloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4 - (2 4'-difluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (3-phenyl-propyl) -butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (2 phenyl-ethyl) -butyric; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (3 - phalimido-propyl) -butyric; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (phenyl-thio-methyl) -butyric acid; 4 - (4'-Chloro-2'-fluoro-biphenyl-4-yl) -4-hydroxyimino-butyric acid; 4-Hydroxyimino-4- (4'-trifluoromethyl-biphenyl-4-yl) -butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -4-methoxyimino-butyric acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -2-fluoro-2 - [2 - (1, 3-dioxo-1, 3 - . 3-dihydro-isoindol-2-yl) -ethyl] -4-hydroxyimino-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - (1H-indol-3-yl) methyl-butyric acid; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-methyl-butyric acid; (+) - 2 - [2 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2-fluoro-6-phenyl-hexanoic acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -2-fluoro-2 - [2 - (1, 3-dioxo-1,3-dihydro-benzo [F] isoindol-2- il) -ethyl] -4-hydroxyimino-butyric; Acid (±) - 2 - [2 - (4'-chloro-biphenyl-4-yl) -2-hydroxyimino-ethyl] - 6 - (1, 3 - dioxo-1,3-dihydro-isoindol-2-yl) -2-fluoro-hexanoic acid; Acid (±) - 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-2-fluoro-2 - [2 - (phenyl-ethyl-carbamoyl) -ethyl] -butyric; 4 - (4'-Chloro-biphenyl-4-yl) -3,3-difluoro-4-methoxyimino-butyric acid; - - - - - - -, - - - - - methoxyimino-butyric; (±) - 4 - (4'-Chloro-biphenyl-4-yl) -2,2-dimethyl-3-fluoro-4-hydroxyimino-butyric acid; 4 - (4'-Chloro-biphenyl-4-yl) -2,2-difluoro-4-hydroxyimino-butyric acid; and 4 - (4'-Chloro-biphenyl-4-yl) -2,2,3,3-tetrafluoro-4-hydroxyimino acid - Butyric The biphenyl sulfonamides are also particularly good in the present method.

Said compounds include those of the formula: wherein: R1 is Ci-C6 alkyl, halo, nitro, NR4R5, cyano, OR4 and COOR4; R2 is Ci-C6 alkyl, optionally substituted by phenyl, substituted phenyl, NR4R5, OR6, NH II carboxy, carboxamide, H2N-C-NH-, thio, methylthio, indole, imidazole, ptalimido, phenyl and substituted phenyl; R3 is OH, OC, -C6 alkyl, or NHON; , i-6, i-6 R5 is hydrogen or Ci-Cg alkyl; and R6 is hydrogen, C? - C6 alkyl, or Ci-C6 alkanoyl, phenyl, or substituted phenyl.

Specific compounds that can be employed include a compound of the above formula wherein R1 is in the 4 'position.

Another class of matrix metalloproteinase inhibitors useful in the present method are substituted phenyl heterocyclic butyric acid derivatives, for example those defined by the formula: Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR5 where R5 is hydrogen or alkyl, CN, C02R5 where R5 is as defined above, S03R5 where R5 is as defined above, CHO, COR5 where R5 is as is defined above, CONHR5 where R5 is as defined above, or NHCOR5 where R5 is as defined above, 2-naphthyl, or heteroaryl; R1 is selected from hydrogen, methyl, ethyl, N02, halogen, OR5 where R5 is as defined above, CN, CO2R where R is as defined above, SO3R5 where R5 is as defined above, CHO, COR5 where R5 is as defined above, R2 and R3 are the same or different and independently selected from hydrogen, alkyl, - (CH2) V - aril where v is an integer from 1 to 5, - (CH2) V - heteroaryl where v is as defined above, - (CH2) V - cycloalkyl where v is as defined above, - (CH2) - X - (CH2) q - aril where X is O or S and p and q are each zero or an integer from 1 to 5 and the sum of p + q is not greater than an integer of 5, - (CH2) P - X - (CH2) q - heteroaryl 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 are each same or different and they are as defined above for R5, - (CH2) VSR5, where v and R5 are as defined above, - (CH2) vC? 2R5, where v and R5 are as defined above, or - (CH2) vCONR6R6a, where R6 and R6a are the same or different and are as defined up for R5 and v is as defined above; R3 is additionally -. (CH2) 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; OH Z is, C R 10 n e as and in arr a for y, and is n epen emen e same or different from R and R so that: when Z is C R10 then R4 must be OH, C = 0 C = NORD where RD is as defined above, or C = N - NR R a where R6 and R a are the same or different and are as defined up for R5; W is - CHR5 where R5 is as defined above; n is zero or an integer of 1; R4 is OH, NR6R6a where R and R a are the same or different and are as defined above for R5, when R4 is NR6R6a, then Z must be C = O or NHOR where R is hydrogen, alkyl or benzyl; and the corresponding isomers of the same; or a pharmaceutically acceptable salt thereof.

Especially preferred matrix metalloproteinase inhibitors have the formula: Ar is selected from phenyl, phenyl substituted with alkyl, N02, halogen, OR3, where R5 is hydrogen or alkyl, CN, CO2R5, where R5 is as defined above, SO3R5. where R is as defined above, CHO, COR5, where R5 is as defined above, CONHR5, where R5 is as defined above, or NHCOR5, where R5 is as defined above, 2-naphthyl, or heteroaryl; R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5, where R is as defined above, CH, CO2R5, where R5 is as defined above, SO3R5, where R5 is as defined above, CHO, or COR5 where R5 is as defined above; R and R are the same or different and independently selected from hydrogen, alkyl, - (CH2) V-aryl, where v is an integer from 1 to 5, - (CH2) V-heteroaryl, where v is as defined above, - (CH 2) V - cycloalkyl, where v is as defined above, - (CH 2) P - X - (CH 2) q - aryl, where X is O, or S and p and q are each zero or an integer from 1 to 5 and the sum of p + q is not greater than an integer of 5, - (CH2) q - X - (CH2) q heteroaril, 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 are each the same or different and are as defined above for R5, - (CH2) VR5, where v and R5 are as defined above, - (CH2) vC? 2R5, where v and R5 are as defined above, - (CH2) vCONR6R6a, where R6 and R6a are the same or different and are as define above for R5 and v is as defined above; R3 is additionally -. (CH2) 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 [i] isoindol - 2 - . 2 - il; And it is CH or N; OH Z is, C R 10 where R10 is as defined above for R2 and R3, and is independently what same or different from R2 and R3 so that: when _- OH Z is C R10 then R4 must be OH, C = O C = ÑOR5 where R5 is as defined above, or C = N - NR6R6a where R6 and R6a are the same or different and are as defined up for R5; W is - CHR5 where R5 is as defined above; n is zero or an integer of 1; R4 is OH, NR6R6a where R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6, then Z must be C = O, or NHOR9 where 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-phenyl-piperidin-1-yl) -phenyl] -butyramide; E / Z - 4-hydroxyimino-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; E / Z-4-Benzyloxyimino-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; 4-Oxo-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; and (+) 3-Methyl-5-oxo-5 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -pentanoic acid.

A compound which is 4-oxo-4 - [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid.

A compound according to Claim 5 which is selected from the group consisting of: 4-Oxo-4 - [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid. - - - - - - - - - -, potassium; N-hydroxy-4-oxo-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyramide; E / Z - 4-hydroxyimino-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; E / Z-4-Benzyloxyimino-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; 4-Oxo-4 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid; and (+) 3-Methyl-5-oxo-5 - [4 - (4-phenyl-piperidin-1-yl) -phenyl] -pentanoic acid.

A compound which is 4-oxo-4 - [4- (4-phenyl-piperidin-1-yl) -phenyl] -butyric acid.

Similar compounds that are derivatives of sulfonamides have the formula: where: Ar is selected from phenyl; Phenyl substituted with alkyl, - NO2, halogen, - OR5, - CN, - CO2R5, - CHO, - COR5, - CONHR5, - NHR5, or NHCOR5; heteroaryl; or 2-naphthyl; R1 is hydrogen, methyl, - NO2, - Cl, - NH2, - NHCO2CH3, - OH, or - CO2H; R and R are the same or different and are independently selected from hydrogen, alkyl, - (CH2) V-aryl, - (CH) V-heteroaryl, - (CH2) V-cycloalkyl, - (CH2) P-X - ( CH2) q - aryl, - (CH2) P - X - (CH2) q - heteroaryl, - (CH2) t NR6R6a, - (CH2) VR7, (CH2) V CO2R5, - (CH2) vCONR6R6a, or (CH2) VSR5 m is zero or 1; And it is CH or N; supplied so that when m = 1, Y is not = N; z is zero or 1; z is zero or 1; W is - CHR8; n is zero or 1; R4 is OH, NR6R6a, NHOR9, R5 is hydrogen or alkyl; v is 1 to 5; X is O or S; p and q are independently 1 to 5, supplied such that p + q is not greater than 5; t is 1 to 9; R6 and R a are each the same or different and are hydrogen or alkyl; 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 to be employed in the present method include: [4- (4-Phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -acetic acid; N-hydroxy-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -acetamide; 3 - [4 - (4-Phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid; (R) -4-Methyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -4-Methyl-2 - [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -3-phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (R) -3-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (S) -3 - (1 H indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid; (±) - 5-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; [4 - (4-Phenyl-piperazin-1-yl) -benzene-sulfonyl-amino] -acetic acid; Acid { isobutyl - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl] amino} -acetic; (S) -4-phenyl-2 - [4- (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -butyric acid; (R) -2- [4 - (4-Phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -3 acid - trityl-sulfanyl-propionic, sodium salt; (R) -3- (1H-Indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid, disodium salt, monohydrate; Acid (S) -2 -. { 4 - [4 - (4-Hydroxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid hydrochloride (S) - 2 -. { 4 - [4 - (4-Chloro-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; (R) -3-Mercapto-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid, trifluoroacetic acid salt; (S) -2 - [4 - (4-Benzyl-piperidin-1-yl) -benzenesulfonyl-amino] -3-phenyl-propionic acid; (S) -3- (4-Benzyloxy-phenyl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -3-phenyl-propionic acid; (S) -3- (4-Hydroxy-phenyl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -3-phenyl-propionic acid; (S) -3-phenyl-2 - [4 - (4-phenyl-piperazin-1-yl) -benzenesulfonyl-amino] -propionic acid; Acid (S) -2 -. { 4 - [4 - (3-methoxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid Bromhydrate (S) - 2 -. { 4 - [4 - (3-hydroxy-phenyl) -piperazin-1-yl] benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid (S) -2 -. { 4 - [4 - (4-methoxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; (R) -4-Methyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -4-Methyl-2 - [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -3-phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (R) -3-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (S) -3 - (1H-Indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; [4 - (4-Phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -acetic acid; N-hydroxy-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -acetamide; 3 - [4 - (4-Phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid; (R) -4-Methyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -4-Methyl-2 - [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -3-phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (R) -3-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (S) -3 - (1H-Indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid; (+) - 5-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -pentanoic acid; [4 - (4-Phenyl-piperazin-1-yl) -benzene-sulfonyl-amino] -acetic acid; Acid { isobutyl - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino} -acetic acid (S) -4-phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -butyric acid; (R) -2- [4 - (4-Phenyl-piperidin-1-yl) -benzene-sulfonyl-amyl] -3 acid - trityl-sulfanyl-propionic, sodium salt; (R) -3- (1H-Indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid, disodium salt, monohydrate; Acid (S) -2 -. { 4 - [4 - (4-Hydroxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid hydrochloride (S) - 2 -. { 4 - [4 - (4-Chloro-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; (R) -3-Mercapto-2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid, trifluoroacetic acid salt; (S) -2 - [4 - (4-Benzyl-piperidin-1-yl) -benzenesulfonyl-amino] -3-phenyl-propionic acid; (S) -3- (4-Benzyloxy-phenyl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (S) -3- (4-Hydroxy-phenyl) -2 - [4 - (4-phenyl-piperidin-1-yl) benzene sulfonyl-amino] -propionic; (S) -3-phenyl-2 - [4 - (4-phenyl-piperazin-1-yl) benzenesulfonyl-amino] -propionic acid; Acid (S) -2 -. { 4 - [4 - (3-methoxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid Bromhydrate (S) - 2 -. { 4 - [4 - (3-hydroxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; Acid (S) -2 -. { 4 - [4 - (4-methoxy-phenyl) -piperazin-1-yl] -benzene-sulfonyl-amino} - 3-phenyl-propionic; (R) -4-Methyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -4-Methyl-2 - [4- (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -pentanoic acid; (S) -3-phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; (R) -3-Phenyl-2 - [4 - (4-phenyl-piperidin-1-yl) -benzenesulfonyl-amino] -propionic acid; and (R) -3 - (1H-Indol-3-yl) -2 - [4 - (4-phenyl-piperidin-1-yl) -benzene-sulfonyl-amino] -propionic acid.

Additional specific compounds that can be used include: 2- (Dibenzo-furan-2-sulfonyl-amino) -3- (4-fluoro-phenyl) -propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -3-phenyl-propionic acid; 3 - (4-tert-phenyl) -2- (dibenzo-furan-2-sulfonyl-amino) propionic acid; Acid (dibenzo-furan-2-sulfonyl-amino) -phenyl-acetic acid; 3-tert -butoxy-2 - (dibenzo-furan-2-sulfonyl-amino) -propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -3- (1H-imidazol-4-yl) propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -3-hydroxy-propionic acid; 3-Benzyloxy-2 - (dibenzo-furan-2-sulfonyl-amino) -propionic acid; 6-Benzyloxy-carbonyl-amino-2 - (dibenzo-furan-2-sulfonyl-amino) -hexanoic acid; 5-Benzyloxy-carbonyl-amino-2 - (dibenzo-furan-2-sulfonyl-amino) -pentanoic acid; Acid (dibenzo-furan-2-sulfonyl-amino) - (4-methoxy-phenyl) -acetic; 3-chloro-2 - (dibenzo-furan-2-sulfonyl-amino) -propionic acid; 3 - (4-Benzyloxy-phenyl) -2- (dibenzo-furan-2-sulfonyl-amino) propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -5-p-tolyl-sulfanyl-aminopentanoic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -4-mercapto-butyric acid; 3 - (4-Bromo-phenyl) -2- (dibenzo-furan-2-sulfonyl-amino) propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -butyric acid; 1 - (Dibenzo-furan-2-sulfonyl-amino) -cyclopropane-carboxylic acid; 3 - (4-Chloro-phenyl) -2- (dibenzo-furan-2-sulfonyl-amino) -propionic acid; 2 - (Dibenzo-furan-2-sulfonyl-amino) -3- (1H-indol-3-yl) -propionic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (4-fluoro-benzene-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (4-methoxy-benzene-sulfonyl-amino) -hexanoic acid; Acid-6 - (4-bromo-benzene-sulfonyl-amino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 6 - (2-Acetyl-amino-thiazole-5-sulfonyl-amino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 6 - (4-Acetyl-amino-benzene-sulfonyl-amino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 6-Benzene-sulfonyl-amino-2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -6- (pentane-1-sulfonyl) acid amino) -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (naphthalene-2-sulfonyl) acid amino) -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (naphthalene-1-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-phenyl-ethene-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6-phenyl-acetyl-amino-hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-chloro-phenoxy) acid) - acetyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-chloro-phenoxy) acid) - 2-methyl-propionyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (pyridin-4-yl-sulfanyl) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2- (2, 4-dichloro-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-thiophen-2-yl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (3-phenyl-acryloyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (7-phenyl-heptanoyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2- (2-trifluoro-methyl-phenyl) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-phenoxy-butyryl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-phenyl-sulfanyl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-phenoxy-acetyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2- (3-4-dimethoxy-phenyl) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-tert-butyl-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [3- (3, 4-dimethoxy-phenyl) -propionyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-cyclopentyl-1-enyl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-methoxy-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (naphthalen-1-yloxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-nitro-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [4 - (4-chloro-3-methyl-phenoxy) -butyryl-amino] -hexanoic acid; 2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -6- [3 - (4-methoxy-phenyl) acid) -propionyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-pyridin-3-yl-acetylamino) -hexanoic acid; 6 - (2-Benzo [1,3] dioxol-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-pyridin-2-yl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-tert-butyl-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [3- (3, 4-dimethoxy-phenyl) -propionyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-cyclopent-1-enyl) acid acetyl-amino) -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-methoxy-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (naphthalen-1-yloxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-nitro-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [4 - (4-chloro-3-methyl-phenoxy) -butyryl-amino] -hexanoic acid; 2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -6- [3 - (4-methoxy-phenyl) acid) - propionyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-pyridin-3-yl-acetylamino) -hexanoic acid; 6 - (2-Benzo [1,3] dioxol-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-pyridin-2-yl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [4 - (4-nitro-phenyl) -butyryl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-tert-butyl-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [3- (3, 4-dimethoxy-phenyl) -propionyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-cyclopent-1-enyl) acid acetyl-amino) -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [2 - (4-methoxy-phenoxy) -acetyl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (4-phenyl-butyryl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [4 - (4-chloro-3-methyl-phenoxy) -butyryl-amino] -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [3- (4-chloro-phenyl) -propionyl-amino] -hexanoic acid; 2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -6- [3 - (4-methoxy-phenyl) acid) - propionyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-pyridin-3-yl-acetylamino) -hexanoic acid; 6 - (2-Benzo [1,3] dioxol-5-yl-acetylamino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2-naphthalen-1-yl-acetylamino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- [3 - (4-chloro-phenoxy) acid) - propionyl-amino] -hexanoic; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (6-phenyl-hexanoyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (4-thiophen-2-yl-butyryl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (2,4,6-triisopropyl-benzoyl-amino) -hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6-isobutoxycarbonyl-amino-hexanoic acid; 2 - (4'-Bromo-biphenyl-4-sulfonyl-amino) -6- (9H-fluoren-9-yl-methoxy-carbonyl-amino) -hexanoic acid; 6 - (Adamantan-1-yloxy-carbonyl-amino) -2- (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid; and 6-Allyloxycarbonyl-amino-2 - (4'-bromo-biphenyl-4-sulfonyl-amino) -hexanoic acid.

Various inhibitors of the metalloproteinase matrix succinamide are known and can be used in the method of this invention. Typical succinamides include: 2S, N1-dihydroxy-3R-isobutyl-N4-. { 1 S - [2 - (2-methoxy-ethoxy-methoxy) ethyl-carbamoyl] -2,2-dimethyl-propyl} - succinamide; 2S-allyl-N1-hydroxy-3R-isobutyl-N4-. { ÍS - [2 - (2-methoxy-ethoxy-methoxy) ethyl-carbamoyl] -2-phenyl-ethyl} - succinamide; 2S-allyl-N1-hydroxy-3R-isobutyl-N4-. { ÍS - [2 - (2-methoxy-ethoxy-methoxy) ethyl-carbamoyl] -2,2-dimethyl-propyl} - succinamide; 2S-allyl-N 1 -hydroxy-3R-isobutyl-N 4 - (1 S -. {2 - [2 - (2-methoxy-ethoxy) -methoxy) ethyl-carbamoyl] -2,2-dimethyl-propyl} - succinamide; 2S - alyl - N4 -. { ÍS - [2, 2-di- (methoxy-methyl) -propyl-carbamoyl} 2, 2-dimethyl-propyl] -N1-hydroxy-3R-isobutyl-succinamide; 2S - alyl - N4 -. { ÍS - [2, 2-di- (methoxy-methyl) -butylcarbamoyl} 2, 2-dimethyl-propyl] -N1-hydroxy-3R-isobutyl-succinamide; N4-hydroxy-2R-iso-butyl-N, -. { 1 S - [2 - (2-methoxy-ethoxy) -ethylcarbamoyl] -2,2-dimethyl-propyl} - 3S - (thiophen-2-yl-sulfanyl-methyl) -succinamide; N 4 -hydroxy-2R-iso -butyl-N 1 - (1 S -. {2 - [2 - (2-methoxy-ethoxy) -ethoxy] -ethyl-carbamoyl.} - 2, 2-dimethyl-propyl) - 3S - (thiophen-2-yl-sulfanyl-methyl) -succinamide; N1 -. { ÍS - [2, 2-di- (methoxy-methyl) -propyl-carbamoyl] -2,2-dimethyl-propyl} - N 4 - hydroxy-3R-isobutyl-3 S - (thiophen-2-yl-sulfanyl-methyl) -succinamide; N4-hydroxy-2R-iso-butyl-N1-. { ÍS - [2 - (2-methoxy-ethoxy) -ethylcarbamoyl] -2,2-dimethyl-propyl} - 3S - propyl succinamide; N 4 - (1 S - cyclobutyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; N4 - (SS-cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N1-dihydroxy-3R-isobutyl-succinamide; N4 - (SS-cyclopentyl-carbamoyl-2,2-dimethyl-propyl) -2S, N1-dihydroxy-3R-isobutyl-succinamide; N 4 - (Í S - cyclohexyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; N 4 - (SS-cycloheptyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; N 4 - (1 S - cyclopropyl-carbamoyl-2-mercapto-2-methyl-propyl) -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; N4 - (SS-cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N1-dihydroxy-3R- (3-phenyl-propenyl) -succinamide; N4 - (ÍS-cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) -2S, N1-dihydroxy-3R- (3-phenyl-propyl) -succinamide; N 4 - [2, 2-dimethyl-1 S - (2-phenyl-cyclopropyl-carbamoyl) -propyl] -2S, N 1 -dihydroxy-3R-isobutyl-succinamide; 2S - allyl - N4 - (1-cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) - N1-hydroxy - 3R - isobutyl succinamide; 2S-allyl-N 4 - (1 S -cyclopropyl-carbamoyl-2-mercapto-2-dimethyl-propyl) -N 1 -hydroxy-3R-isobutyl-succinamide; N4 - (SS-cyclopropyl-carbamoyl-2,2-dimethyl-propyl) -N1-hydroxy-3R-iso-butyl-2S- (thiophen-2-yl-sulfanyl-methyl) -succinamide; N4 - (1 S - cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) -N1-hydroxy-2S- (4 - hydroxy-phenyl-sulfanyl-methyl) -3R-iso-butyl-succinamide; and N4 - (1 S - cyclopropyl-carbamoyl-2, 2-dimethyl-propyl) -2S- (1,3-dioxo, 1, 3 - . 3-dihydro-isoindol-2-yl-methyl) -N1-hydroxy-3R-iso-butyl-succinamide.

All that is required to practice the present invention is to administer to a mammal suffering from a neurological disorder or the development of a neurological disorder or wound is suspected of an effective amount of a matrix metalloproteinase inhibitor. Compounds that can inhibit the actions of matrix metalloproteinase enzymes can be identified using routine in vitro and in vivo experiments. Several compounds that are within the present classes have been evaluated in said standard experiments and determined to be potent inhibitors of matrix metalloproteinases. The experiment measures the amount by which a test compound reduces the hydrolysis of a thiopeptolide substrate caused by an enzyme of the matrix metalloproteinase. Said experiments are described in detail by Ye, et al. In Biochemistry, vol. 31, No. 45, 1992, (11231-11235), which is incorporated herein by reference.

The thiopeptolide substrates virtually show no decomposition or hydrolysis in the absence of an enzyme of the matrix metalloproteinase. A typical thio-peptide substrate commonly used for the experiments is Acid-Pro-Leu-Gly-thio-ester-Leu-Leu Gly-O. A mixture of 100 μL of the experiment will contain 50 mM of 2-morpholinoethane sulfonic acid monohydrate (MES) , pH 6.0), 10 mM of CaCl2, 100 μM of thiopeptolide substrate and 1 Mm of 5,5'ditio - bis - (2 - nitro - benzoic acid (DTNB) The concentration of thiopeptolide substrate varies from 10 to 800 μM. To obtain the Km and Kcta values, the change in absorbance at 405 nm is monitored in a Thermo Max microplatform reader (Molecular Devices, Menlo Park, California) at room temperature (22 ° C.) The calculation of the amount of hydrolysis of the Thiopeptolide substrate is based on E? 2 = 13600 m "'cm" for the DTNB 3 -carboxy-4-nitrothiophenoxide derivative The assays were carried out with and without matrix metalloproteinase inhibitor compounds, and the amount of hydrolysis is compared for a determination of a inhibitory activity of the test compounds.

Several representative compounds have been evaluated for their ability to inhibit several matrix metalloproteinase enzymes. In the table, MMP-1 refers to intersitial collagenase; MMP-2 refers to gelatinase A; MMP-3 refers to stromelysin; MMP-7 refers to matrilysin; and MMP-9 refers to Gelatinase B. The test compounds were evaluated in various concentrations to determine their respective IC 50 values, the micromolar concentration of the compound required to cause 50% inhibition. of the hydrolytic activity of the respective enzyme.

The compounds to be employed in the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms to treat and prevent heart failure. The compounds can be administered by injection, i.e., intravenous, intramuscular, intercutaneous, subcutaneous, intraduodenal or intraperitonally. Also, the compounds can be administered by inhalation, for example, intranasally. In addition, the compounds can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound such as a free base, acid or a pharmaceutically acceptable salt of said compound. The active compound is generally present in a concentration of about 5% to about 95% by weight of the formulation.

To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either liquid or solid. Solid form preparations include powders, tablets, pills, capsules, lozenges, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, bonds, preservatives, tablet disintegrating agents or an encapsulating material.

In the powders, the carrier is a finely divided solid in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in appropriate proportions and compacted to the desired shape and size.

The powders and tablets preferably contain from 5% or 10% up to about 70 percent of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier that provides a capsule in which the active component with or without other carriers, is surrounded with a carrier, which is thus in relation thereto. Similarly, the pills are included. The tablets, powders, capsules, pills and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melts first and the active component is dispersed homogeneously there, by stirring, the molten homogeneous mixture is then poured into molds of appropriate size, they are allowed to cool and therefore solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution with polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired.

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

Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

The pharmaceutical preparation is preferably in the dosage form per unit. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of preparation, such as tablets, capsules and powders packed in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, or tablet itself, or it may be the appropriate number of any of these in packaged form.

The amount of the active component in a unit dose preparation can be varied or adjusted from 1 to 1000 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

In therapeutic use as agents for the treatment of cardiac failures, the compounds used in the pharmaceutical method of this invention are administered in a dose that is effective to inhibit the hydrolytic activity of one or more matrix metalloproteinase enzymes. The compounds can also be used prophylactically at the same dosage levels. The initial dose of around 1 mg to about 100 mg per kilogram daily will be effective in preventing and treating heart failure. A daily dosage range of from about 25 to about 75 mg / kg is preferred. The doseHowever, they can be varied depending on the patient's requirements, the severity of the condition being treated and the compounds that are used. The determination of the appropriate dosage for a particular situation is within the knowledge of the art. In general, treatment starts with doses smaller than the optimal dose of the compound. Then, the dose is increased by small increments until the optimum effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day if desired. Typical doses will be from about 0.1 to about 500 mg / kg and ideally from about 2 to about 25 mg / kg.

The following examples illustrate typical formulations that can be used in the invention.

Formulation of Tablets Benzylsulfonamide, lactose and corn starch (for mixing) are beaten until they are uniform. The corn starch (paste) is suspended in 200 ml of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a manual filter of number 8 and dried at 80 ° C. The dried granules are lubricated with 1% magnesium stearate and pressed into a tablet. Said tablets can be administered to a human from one to four times a day for the treatment of atherosclerosis and arthritis.

Preparation for Oral Solution The sorbitol solution is added to 40 ml of distilled water and the biphenylsulfonamide dissolves there. Saccharin, sodium benzoate, flavoring and tincture are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each milliliter of syrup contains 4 mg of the compound of the invention.

Parenteral Solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20 g of (S) -2- (4'-amino-biphenyl-4-sulfonylamino) -3- (3-ethoxyphenyl) acid are suspended. - propionic. After the suspension is finished, the pH is adjusted to 6.5 with IN of sodium hydroxide, and the volume is brought to 1000 mL with water for injection. The formulation is sterilized, filled into 5.0 ml ampoules each having 2.0 mL and sealed under nitrogen.

Claims (14)

1. CLAIMS: 1. A method for treating and preventing a neurological disorder in a mammal comprising the administration of an effective amount of a matrix metalloproteinase inhibitor.
2. 2. The method of Claim 1 wherein the neurological disorder is Alzheimer's disease.
3. 3. The method of Claim 1 wherein the neurological disorder is Huntington's disease.
4. 4. The method of Claim 1 wherein- the neurological disorder is Parkinson's disease.
5. 5. The method of Claim 1 wherein the neurological disorder is amyotrophic lateral sclerosis.
6. 6. The method of Claim 1 wherein the MMP inhibitor used is a compound of the formula wherein R1 is C, -C6 alkyl, halo, nitro, NR4R5, cyano, OR4 and COOR4; R2 is Ci-C6 alkyl, optionally substituted by phenyl, substituted phenyl, NR4R5, OR6, carboxy, carboxamido, NH II H2N-C-NH-, thio, methylthio, nature, imidazole, phthalimido, phenyl and substituted phenyl; R3 is OH, O-C6 alkyl or NHOH; R4 is hydrogen, Ci-C6 alkyl or Ci-C6 alkanoyl; R5 is hydrogen or Ci-C6 alkyl; and R6 is hydrogen, d-C6 alkyl, Ci-C alkanoyl, phenyl or substituted phenyl.
7. 7. The method of the Claim employing (2 - (4'-bromobiphenyl-4-sulfonylamino) -3-methyl-butyric acid.
8. 8. The method of Claim 1 wherein the MMP inhibitor used is a compound 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 different and are as define before for R6, O -O-C-R6 where R6 is as defined above, OR II -NH-C-R0 where R ° is as defined above, OR -S-C-R0 where R ° is as defined above, -SR6 where R6 is as defined above, OR -C 11 -R 6 where R is as defined above, -CH2-OR where R is as defined above, -CH2-N-R6 where R6 and R6a are the same or different and are as R6a is defined before for R6, OR -C-N-R6 where R6 and R6a are the same or different and are as R6a is defined before for R6, Or -S-R6 wherein R6 is as defined above, II or cycloalkyl or heteroaryl, provided that R and R1 are not both hydrogen; R is OR where R is as defined above, or NR6 R6a where R6 and R6a are each the same or different and are as defined above for R6; R3, R3a, R4 and R4a are the same or different and are hydrogen, fluorine, alkyl, - (CH2) n-aryl wherein n is an integer from 1 to 6, - (CH2) n-heteroaryl wherein n is as define before; - (CH2) n-cycloalkyl wherein n is as defined above. - (CH2) pX- (CH2) q-aril where X is O, S, SO, SO2 or NH ypyq are each zero or an integer from 1 to 6, and the sum of p + q is not greater than six , - (CH2) -X- (CH2) q-heteroaryl wherein X, p and q are as defined above, or - (CH2) n-R7 wherein R7 is N-phthalimide, N-2,3-naphthiimido, -OR6 wherein R6 is as defined above, -N-R6 where R6 and R6a are the same or different R6a and they are as defined before, -SR6 where R6 is as defined above, OR -S-R6 where R6 is as defined above, OR -S-R where R is as defined above, OR OR -O-C-R6 where R6 is as defined above, O -N-C-R0 wherein R ° and Roa are the same or different R (6a and are as defined above for R6, OR -S-C-R6 where R6 is as defined above, OR II -C-R6 where R is as defined above, OR -C-OR6 where R6 is as defined above, or OR -C-N-R0 where R ° and Roa are the same or different and are as R6a define before for R6, and n is as defined above; R5 is OH or SH; provided that R3, R3a, and R4 and R4a are fluorine; and isomers corresponding thereto; or a pharmaceutically acceptable salt thereof.
9. 9. The method of Claim 8 wherein the MMP inhibitor employed is 4 - (4'-Chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid.
10. 10. A method to prevent the healing of wounds in a mammal that comprises the administration of an effective amount of a metalloproteinase inhibitor matrix.
11. 11. The method of Claim 10 wherein the MMP inhibitor used is a compound of the formula wherein: R1 is alkyl dC6, halo, nitro, NR4R5, cyano, OR4 and COOR4 ' R2 is C6-alkyl, optionally substituted by phenyl, substituted phenyl, NR4R5, OR6, carboxy, carboxamido, NH II H2N-C-NH-, thio, methylthio, Nature, imidazole, phthalimido, phenyl and substituted phenyl; R3 is OH, O-C6 alkyl or NHOH; R 4 is hydrogen, C 1 -C 6 alkyl or C 6 alkanoyl; R5 is hydrogen or Cj-C6 alkyl; and R6 is hydrogen, Ci-C6 alkyl, Ci-C6 alkanoyl, phenyl or substituted phenyl.
12. 12. The method of Claim 11 wherein the MMP inhibitor used is (2 - (4'-bromobiphenyl-4-sulfonylamino) -3-methyl-butyric acid.
13. 13. The method of Claim 10 wherein the MMP inhibitor used is a compound 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 different and are as R 6a define before for R6, OR II -O-C-R6 wherein R6 is as defined above, O -NH-C-R6 where R6 is as defined above, OR II -S-C-R6 wherein R6 is as defined above, -SR6 where R6 is as defined above. Or II -C-R6 where R6 is as defined above, -CH2-OR6 where R6 is as defined above, CH2-N-R > 6 e "" n don .dje-. R r > 6 y .. R D6a are the same or different and are like R 6a is defined before for R6, OR II? 6 .. r > 6a -C-N-R where R and R are the same or different and are like R6a is defined before for R6, OR II -S-R6 where R is as defined above, || OR cycloalkyl or heteroaryl, provided that R and R1 are not both hydrogen; R > 2 is OR where R is as defined above, or NR6 R6a where R6 and R6a are each the same or different and are as defined above for R6; R3, R3a, R4 and R4a are the same or different and are hydrogen, fluorine, alkyl, - (CH2) n-aryl wherein n is an integer from 1 to 6, - (CH2) n-heteroaryl wherein n is as defined above; - (CH2) n-cycloalkyl wherein n is as defined above. - (CH2) pX- (CH2) q-aril where X is O, S, SO, SO2 or NH ypyq are each zero or an integer from 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 wherein R7 is N-phthalimide, N-2,3-naphthiimido, -OR6 wherein R6 is as defined above, -N-R6 wherein R6 and R6a are the same or different R6a and they are as defined before, -SR where R is as defined above, OR -S-R6 where R6 is as defined above, OR -S-R6 where R6 is as defined above, II or or -O-C-R where R is as defined above, OR N-C-R where R and R, 6a are the same or different and they are as defined before for R6, OR -S-C-R6 where R6 is as defined above, OR -C-R6 where R6 is as defined above, OR -C-OR6 where R6 is as defined above, or O -C-N-R6 where R6 and R6a are the same or different and are as R 6a define before for R6, and n is as defined above; R5 is OH or SH; provided that R3, R3a, and R4 and R4a are fluorine; and isomers corresponding thereto; or a pharmaceutically acceptable salt thereof.
14. 14. The method of Claim 13 employing 4 - (4'-chloro-biphenyl-4-yl) -4-hydroxyimino-butyric acid. EXTRACT OF THE INVENTION Matrix metalloproteinase inhibitors are useful for preventing and treating neurological disorders and promoting wound healing.