AU735013B2

AU735013B2 - Matrix metalloproteinase inhibitors and their therapeutic uses

Info

Publication number: AU735013B2
Application number: AU41595/97A
Authority: AU
Inventors: Patrick Michael O'brien; Joseph Armand Picard; Drago Robert Sliskovic; Andrew David White
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1996-09-04
Filing date: 1997-08-22
Publication date: 2001-06-28
Anticipated expiration: 2017-08-22
Also published as: BR9711988A; AU4159597A; JP2000517341A; NZ333063A; WO1998009934A1; EP0931045A1; CA2256716A1; KR20000068414A

Description

-1- MATRIX METALLOPROTEINASE INHIBITORS AND THEIR THERAPEUTIC USES FIELD OF THE INVENTION The present invention relates to a method of inhibiting matrix metalloproteinases using compounds that are dibenzofuran sulfonamide derivatives. More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, coreal ulceration, Sbums, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion 10 by leukocytes.

BACKGROUND OF THE INVENTION S" Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

The compounds of the present invention are inhibitors of matrix metalloproteinases, stromelysin-1 and gelatinase A (72 kDa gelatinase).

Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3, and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino Okada Cao Shinagawa Yamamoto and Seiki Nature 1994;370:61-65).

-la- Stromelysin-1 is also known as MMPO3 and gelatinase A is known as MMPO2. In addition, several other matrix metalloproteinases are known: MPO1 Fibroblast collagenase; MMPO7 Matrilysin; MMP-09 Gelatinase B; and MMP13 Collagenase-3.

The catalytic zinx in matrix metalloproteinases is typically the focal point for :inhibitor design. The modification of substrates by introducing chelating groups has generated potent inhibitors such as peptidehyroxamates and thiol-containing peptides.

10 Peptide hydroxamates and the natural endogenous inhibitors 0 WO 98/09934 PCT/US97/14859 -2of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.

The ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Sukhova Lark and Libby "Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques", J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney Wakeley Davies Foster K., Hembry Murphy and Humphries "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization," Proc. Nat'l. Acad.

Sci., 1991;88:8154-8158).

Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall.

Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine N. and Powell J.T., "Metalloproteinases in degenerative aortic diseases," Clin. Sci., 1991;81:233-239).

Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee Hamilton Stevenson Moriguchi J.D., Fonarow Child Laks and Walden "Impact of left ventricular size on the survival in advanced heart failure," Am. J. Cardiol., 1993;72:672-676).

This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both WO 98/09934 PCT/US97/14859 -3idiopathic and ischemic heart failure (Reddy Tyagi Tjaha I.E., Voelker Campbell and Weber "Activated myocardial collagenase in idiopathic dilated cardiomyopathy," Clin. Res., 1993;41:660A; Tyagi S.C., Reddy Voelker Tjara and Weber "Myocardial collagenase in failing human heart," Clin. Res., 1993;41:681A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong Moe Howard Grima and Cruz T.F., "Structural remodeling in heart failure: gelatinase induction," Can. J. Cardiol., 1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (Sabbah Kono Stein Mancini and Goldstein S., "Left ventricular shape changes during the course of evolving heart failure," Am. J. Physiol., 1992;263:H266-H270). Neointimal proliferation, leading to restenosis, frequently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel (Bendeck Zempo Clowes Galardy and Reidy "Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat," Circulation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSCMs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly Passaniti Bilato Monticone R., Cheng Papadopoulos Gluzband Smith Weinstein Lakatta E., and Crow "Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation," Circulation Research, 1994;75:41-54).

Collagenase and stromelysin activities have been demonstrated in fibroblasts isolated from inflamed gingiva (Uitto Applegren and Robinson "Collagenase and neutral metalloproteinase activity in extracts WO 98/09934 PCT/US97/14859 -4from inflamed human gingiva," J. Periodontal Res., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C.M., Wiebkin and Thonard "Demonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva," J. Periodontal Res., 1987;22:81-88). Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burs (Brown S.I., Weller and Wasserman "Collagenolytic activity of alkali burned corneas," Arch. Opthalmol., 1969;81:370-373). Thiol-containing peptides inhibit the collagenase isolated from alkali-burned rabbit corneas (Burs F.R., Stack Gray and Paterson Invest. Opththamol., 1989;30:1569-1575).

Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere Ulpu Pentland Birkedal-Hansen H., Parks Welgus "Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds," J. Clin. Invest., 1994;94:79-88).

Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. Stromelysin-1 may thus prevent the epidermis from healing. Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxamate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing human ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement membrane (Melchiori Albili Ray and Stetler-Stevenson Cancer Res., 1992;52:2353-2356), and the natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Perez Shimada Boone Langley and Taylor Cancer Res., 1992;52:701-708). Studies of human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (Strongin Marmer Grant and Goldberg J. Biol Chem., 1993;268:14033-14039) and is retained there through interaction with a WO 98/09934 PCT/US97/14859 receptor-like molecule (Monsky Kelly Lin Yeh Y., Stetler-Stevenson Mueller and Chen Cancer Res., 1993;53:3159-3164). Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti Garofalo Belotti Drudis Borsotti P., Scanziani Brown and Giavazzi Journal of the National Cancer Institute, 1995;87:293; and Benelli Adatia Ensoli B., Stetler-Stevenson Santi and Albini Oncology Research, 1994;6:251-257).

Several investigators have demonstrated consistent elevation of stromelysin and collagenase in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls (Walakovits Moore Bhardwaj N., Gallick and Lark "Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury," Arthritis Rheum., 1992;35:35-42; Zafarullah Pelletier J.P., Cloutier and Marcel-Pelletier "Elevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia," J. Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews Plumpton Harper and Cawston Agents Actions, 1992;37:147-154; Ellis Curry Powell and Cawston T.E., Biochem. Biophys. Res. Commun., 1994;201:94-101).

Gijbels, et al., Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental allergic encephalomyelitis (EAE) in a dose dependent manner, suggesting the use of MMP inhibitors in the treatment of autoimmune inflammatory disorders such as multiple sclerosis. A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (Ramanic A.M. and Madri "The Induction of 72-kD Gelatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent," J. Cell Biology, 1994;125:1165-1178). This transmigration WO 98/09934 PCT/US97/14859 -6past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by binding to the vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is compromised, edema and inflammation are produced in the CNS.

Leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.

These studies provided the basis for the belief that an inhibitor of stromelysin-1 and/or gelatinase A will treat diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.

We have identified a series of tricyclic aromatic sulfonamide compounds that are inhibitors of matrix metalloproteinases, particularly stromelysin-1 and gelatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, bums, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.

SUMMARY OF THE INVENTION The present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition comprising administering to the patient a therapeutically effective amount of a compound of Formula I 0 R2S WO 98/09934 PCT/US97/14859 -7wherein M is a natural alpha amino acid derivative having the structure

COR

1

-H

H

X is O, S, S(O)n, CH 2 CO, or NRQ; RQ is hydrogen, C 1

-C

6 alkyl, or -Ci-C 6 alkyl-phenyl; R is a side chain of a natural alpha amino acid;

R

1 is Ci-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C -C 5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.

In one embodiment of the invention of Formula I, X is O.

In another embodiment of the invention of Formula I, X is S.

In another embodiment of the invention of Formula I, X is CH 2 In another embodiment of the invention of Formula I, X is NR

Q

In a preferred embodiment of the invention of Formula I, X is O and R 2 and R 4 are hydrogen.

In another embodiment of the invention of Formula I, X is CO.

In another embodiment of the invention of Formula I, X is S(O)n.

In another preferred embodiment of the invention of Formula I, R 1 is hydroxy, C 1

-C

5 alkoxy, -NHOH, or -NHObenzyl.

In still another preferred embodiment, R is the side chain of the natural alpha amino acid glycine, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, or phenylalanine.

WO 98/09934 PCT/US97/14859 -8- In another embodiment, the present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula II

R

2

S=

O

O II

R

wherein Z is a natural amino acid derivative having the structure CORa

H

Rb

R

2 and R 4 are independently hydrogen, -C -C 5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl;

R

a is C 1

-C

5 alkoxy, hydroxy, or -NHORc; Rb is a side chain of a natural alpha amino acid; and

R

c is hydrogen, C 1

-C

5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

In a preferred embodiment of the method comprising Formula II, the group 0

I

is located at the 2-position of the phenyl ring.

Z

WO 98/09934 PCT/US97/14859 -9- In another preferred embodiment of the method comprising Formula II, the

O

1I group -S=0 is located at the 3-position of the phenyl ring.

Z

Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula III 0O 2 II R S=O S III 4 wherein Z is a natural amino acid derivative having the structure CORa

H

Rb

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl;

R

a is C 1

-C

R

c is hydrogen, C 1

-C

WO 98/09934 PCT/US97/14859 Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula IV.

R

S=O

IV

CH Z 2 4 wherein Z is a natural amino acid derivative having the structure

COR

a -N H

H

Rb

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -N0 2 halogen,

-OR

5 -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C -C 5 alkyl;

R

a is C -C 5 alkoxy, hydroxy, or -NHORC; Rb is a side chain of a natural alpha amino acid; and

R

c is hydrogen, C 1

-C

Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula V WO 98/09934 PCT/US97/14859 -11- III R 4 0

O

wherein Z is a natural amino acid derivative having the structure CORa Rb

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C -C 5 alkyl;

R

a is C 1

-C

5 alkoxy, hydroxy, or -NHORc; Rb is a side chain of a natural alpha amino acid; and RC is hydrogen, C -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VI WO 98/09934 PCT/US97/14859 -12wherein Z is a natural amino acid derivative having the structure CORa

-N--H

H

Rb

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -C0 2

R

5

-SO

3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl;

R

a is C -C 5 alkoxy, hydroxy, or -NHORC; n is 0 to 2; Rb is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1

-C

Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VII 0O

R

2 I S=O 1

VII

wherein Z is a natural amino acid derivative having the structure 13- CORa -N H

H

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -CO 2

R

5

-SO

3

R

5 -CHO, -CORs, -CONRR 6

-(CH

2 )nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; S* Ra is CI-C 5 alkoxy, hydroxy, or -NHORc;

R

Q is hydrogen, Ci-C 6 alkyl, or C 1

-C

6 alkyl-phenyl;

R

b is a side chain of a natural alpha amino acid; and Rc is hydrogen, C -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

There is also provided a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VIII 2 o

M

wherein M is a natural aplha amino acid derivative having the structure CORa -N -H

H

13a- Ris Cj-C 5 alkoxy, hydroxy, or -NHOR R is a side chain of a natural alpha amino acid;

R

2 and R 4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 5 5 5 5566 halogen, -OR5, -CN, -CO 2 R' ,SOR -CHO, -COR ,-CONR5RI (CH 2 )nMN. R

CF

3 ,or -NI{COR 5 each R 5and R 6are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

In a most preferred embodiment, thle compound of Formula I-VI is: (L)-2-(dibenzoturan-2-sulfonlylamino)-4-methy1-pentanoic acid; (L)-2-(dibenzofuran-2-sulfonlylamnino)-3 -methyl-pentanoic acid; (L)-2-(dibenzofuran-2-sulfonlylamino)-3-phenyl- propionic acid; (L)-2-(dibenzofuran-2-sulfonlylaniino)-propionic acid; (L)-2-(dibenzofuran-2-sulfonlylamino)-3- methyl-butyric acid; 15 (L)-2-(dibenzofuran-2-sulfonlylaniino)-acetic acid; (L)-2-(dibenzofuran-2-sulfonlylamino)-succinic acid; (L)-2-(dibenzofuran-2-sulfonlylaniino)-3-tritylsulfanyl-propionic acid; (L)-2-(dibenzofuran-2-sulfonlylamino)-3-mercapto-propionic acid; (L)-2-(dibenzofur an-2-sulfonlylamino)-3-methyl-pentanoic acid hydroxyamide; (L)-2-(dibenzofuran-2-sulfonlylanino)-acetic acid tert-butyl. ester; (L)-2-(dibenzofuran-2-sulfonlylamino)-propionic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonlylamino)-propionic acid tert-butyl. ester; WO 98/09934 WO 9809934PCTIUS97/14859 -14- (L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid tert-butyl ester; (L)-2-(dibenzofiiran-2-sulfonylamino)-3-methyl-pentanoic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid benzyloxyamide; (L)-2-(dibenzofuran-2-sulfonylamino)-3 -phenyl-propionic acid tert-butyl ester; (L)-2-(dibenzofuran-3-sulfonylamino)-3-methyl-butyric acid; 3 -Methyl-2-(9-methyl-9H-carbazole-3 -sulfonylamnino)-butyric acid; 2 -(9-Benzyl-9H-carbazole-3-sulfonylamino)-3-methyl-butyric acid; (L)-2-(9H-Fluorene-2-sulfonylamino)-3 -methyl-butyric acid; (L)-2-(5,5-Dioxo-5H-5X 6 -dibenzothiophene-3-sulfonylamino)-3 -methylbutyric acid; (L)-2-(Dibenzothiophene-2-sulfonylamino)-3-methyl-butyric acid; (L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-3 -methyl-butyric acid; (L)-3-Methyl-2-(7-phenyl dibenzofuran-2-sulfonylamnino)-butyric acid; and 2-(9H-Carbazole-3-sulfonylaniino)-3-methyl-butyric acid.

Also provided by the present invention is a method of treating multiple sclerosis, the method comprising administering to a patient having multiple sclerosis a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating atherosclerotic plaque rupture, the method comprising administering to a patient having an atherosclerotic plaque at risk for rupture a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I-VIII.

WO 98/09934 PCT/US97/14859 Also provided by the present invention is a method of treating aortic aneurism, the method comprising administering to a patient having aortic aneurism a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating heart failure, the method comprising administering to a patient having heart failure a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating periodontal disease, the method comprising administering to a patient having periodontal disease a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating corneal ulceration, the method comprising administering to a patient having corneal ulceration a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating bums, the method comprising administering to a patient having bums a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating decubital ulcers, the method comprising administering to a patient having decubital ulcers a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating chronic ulcers or wounds, the method comprising administering to a patient having chronic ulcers or wounds a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating cancer metastasis, the method comprising administering to a patient having cancer metastasis a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating tumor angiogenesis, the method comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of Formula I-VIII.

Also provided by the present invention is a method of treating arthritis, the method comprising administering to a patient having arthritis a therapeutically effective amount of a compound of Formula I-VIII.

-16- Also provided by the present invention is a method of treating autoimmine or inflammatory diseases dependent upon tissue invasion by leukocytes, the method comprising administering to a patient having autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes a therapeutically effective amount of a compound of Formula I-VII.

In another aspect, there is provided compounds of Formula I as follows:

O

i: R2 O I

M

wherein M is a natural alpha amino acid derivative having the structure CORa N -H

H

X is S, S(O)n, CH2, CO, or NRQ; Rb is a side chain of a natural alpha amino acid;

R

Q is hydrogen, C 1

-C

6 alkyl, or -Ci-C 6 alkyl-phenyl; Ra is C 1

-C

5 alkoxy, hydroxy, or -NHOR

S

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 CN, -CO 2

R

5

-SO

3 R -CHO, -COR 5

-CONRR

6

-(CH

2 )nNRR 6

-CF

3 or

NHCOR;

each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, with the proviso that the compound is other than N-2o0 fluorenesulfonylmethionine, N-2-fluorenesulfonylphenylalanine, N-2- -16afluorenesulfonylalanine, N-2-fluorenesulfonylvaline,N-2-fluorenesulfonylleucine, dibenzofuran-2-sulfonylalanine, dibenzofuran-2-sulfonylvaline, dibenzofuran-2sulfonylleucine, dibenzofuran-2-sulfonylphenylalanine, dibenzofuran-2-sulfonyserine, dibenzofuran-2-sulfonyltyrosine, dibenzofuran-2-sulfonylpro line, dibenzofuran-2sulfonytryptophan,dibenzofuran-2-sulfonyhmethione, dibenzofuran-2sulfonylglutaniine,7-nitrodibenzofuran-2-sulfonylalanine, 7-nitrodibenzofuran-2sulfonylvaline, 7-nitrodibenzofuran-.2-sulfonylleucine, 7-nitrodibenzofuran-2sufnlhnyaaie 7-irdbnoua-**loytrsn,7ritoiezfrn sulfonenyllnine, 7-nitrodibenzofuran-2-sulfonyltyoner 7-nitrodibenzofuran-2- 1.sulfonylgiutamiine, or a methyl ester of any one of N-2-fluorenesulfonylphenylalanine, N-2-fluorenesulfonylalanine, N-2-fluorenesulfonylvaline,N-2-fluorenesulfonylleucine, dibenzofuran-2-sulfonylaianine, dibenzofuran-2-sulfonylvaline, dibenzofuran-2sulfonylleucine, dibenzofuran-2-sulfonylphenylalanine, dibenzofuran-2-sulfonyltyrosine, dibenzofuran-2-sulfonylproline, dibenzofuran-2-sulfonylglutamine,7-nitrodibenzofuran- 2-sulfonylalanine, 7-nitrodibenzofuran-2-sulfonylvaline, 7-nitrodibenzofuran-2sufnlluie irdbnoaa--ufnlhnllnn,7ntoiezfrn2 sulfonylleucine, 7-nitrodibenzofuran-2-sulfonylpenlanine, 7-nitrodibenzofuran-2sulfonyltryptophan, and 7-nitrodibenzofuran-2-sulfonylglutamine.

In a further aspect, there is provided compounds of Formula VII as follows: R 04 0 xrM

R

M

wherein M is a natural apiha amino acid derivative having the structure 17

-H

H

Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5 Ris a side chain of a natural alpha amino acid;

R

2 and R' are independently hydrogen, -C I-C 5 ailkyl, phenyl. -NO 2 halogen, -OR, -CN, C0 2

R

5 -S0 3

R

5 -CHO, -COR 5 -CONR 5 R 6

-(CH

2

).NR-

5 R 6

-CF

3 or -NHCOR 1 each R 5 and RU6 are independently hydrogen or C I-C 5 alkyl; and *See 0n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The present invention also provides use of a compound of Formula I 0 x wherein M is a natural alpha amino acid derivative having the structure -N -H

H

X is S, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid; RQ is hydrogen, C I-C 6 alkyl, or C I-C 6 alkyl-phenyl; Ris C I-C 5 alkoxy, hydroxy, or -NHOR 5 R2 and R are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -CN, -C0 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6

-(CH

2

)N

5

R

6

-CF

3 or -NHCOR 5 -17aeach R 5 an dR 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase.

The present invention also provides use of a compound of Formula I wherein X is O.

The present invention also provides use of a compound of Formula I wherein X is S.

The present invention also provides use of a compound of Formula I wherein X is CH2.

10 The present invention also provides use of a compound of Formula I wherein XisNR

Q

The present invention also provides use of a compound of Formula I wherein R 2 and R 4 are hydrogen.

o SThe present invention also provides use of a compound of Formula I wherein X is CO.

The present invention also provides use of a compound of Formula I wherein X is The present invention also provides use of a compound of Formula I wherein R is hydroxy or Ci-C 5 alkoxy or -NHOH or -NHObenzyl.

The present invention also provides use of a compound of Formula I wherein R is the side chain of the natural alpha amino acid, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, phenylalanine, or glycine.

-17b- The present invention also provides use of a compound of Formula II 0 2f2 SO R2 O =O z wherein Z is a natural amino acid derivative having the structure CORa -N H

H

R

5 R2 and R4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR 5

-CN,

-CO

2

R

5

-SO

3

R

5 -CHO, -CORS, -CONRR 6

-(CH

2 )nNR 5

R

6

-CF

3 or -NHCOR; each R 5 and R 6 are independently hydrogen or C -C 5 alkyl; R" is CI-C 5 alkoxy, hydroxy, or -NHORC;

R

b is a side chain of a natural alpha amino acid; and S 10 R is hydrogen, C 1

-C

5 alkyl, or -CH 2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase.

The present invention also provides use of a compound of Formula II wherein the

O

II

group S= O is located at the 2-position of the phenyl ring.

Z

-17c- The present invention also provides use of a compound of Formula II wherein the

O

group -S-O is located at the 3-position of the phenylring.

z

Z

The present invention also provides use of a compound of Formula II 0 2 II R j S=O CORa N H

H

Rb o: R 2 andR 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5

-CN,

-CO

2 R -SO 3

R

S

-CHO, -COR 5 -CONR5 R, -(CH 2

),NRSR

6 -CF3, or -NHCOR; each R 5 and R 6 are independently hydrogen or Cl-C 5 alkyl; Ra is C 1

-C

5 alkoxy, hydroxy, or -NHORC;

R

b is a side chain of a natural alpha amino acid; and RC is hydrogen, C 1

-C

-17d- The present invention also provides use of a compound of Formula IV

O

I I C I S=O IV

CH

2 41 wherein Z is a natural amino acid derivative having the structure CORa -N H

H

R2 and R 4 are independently hydrogen, -C 1 alkyl, phenyl -NO 2 halogen, -OR s

-CN,

-CO

2

R

s

-SO

3 R, -CHO, -COR 5

-CONRR

6

-(CH

2

)INRSR

6

-CF

3 or -NHCORS; Rb is a side chain of a natural alpha amino acid; and 10 R is hydrogen, C 1

-C

The present invention also provides use of a compound of Formula V

O

R2 SO

V

-17ewherein Z is a natural amino acid derivative having the structure CORa -N

H

b

R

2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR 5

-CN,

-CO

2

R

5 -SO3R 5 -CHO, -COR 5

-CONRR

6

-(CH

2

NR

5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHORc; R is a side chain of a natural alpha amino acid; and R is hydrogen, Ci-C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the .manufacture of a medicament for inhibiting a matrix metalloproteinase.

The present invention also provides use of a compound of Formula VI o o 0

S"II

R S=O VI S(O)n R 4 wherein Z is a natural amino acid derivative having the structure CORa

H

R'

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR s

-CN,

-CO

2

R

5

-SO

3

R

5 -CHO, -CORS, -CONRR 6

-(CH

2

)NRR

6

-CF

3 or -NHCOR; AZ each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; 17f- Ra is C 1

-C

5 alkoxy, hydroxy, or -NHORC; n is 0 to 2; Rb is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1

-C

5 alkyl, or -CH2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase.

The present invention also provides use of a compound of Formula VII 0

II

10 wherein Z is a natural amino acid derivative having the structure CORa -N H RQ is bydrogen, C-C6 alkyl, or C1-C6 alkyl-phenyl; ee is a a side cha in o a natural alpha amino acid; and Ra is C 1

-C

5 alkoxy, hydroxy, or -NHOR; RC is hydrogen, C 1

-C

5 alyl, or -CH2 phenyl; and n is -0to-2, n is 0 to 2, -17gor the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase.

The present invention also provides use of a compound of Formula I wherein the compound is 5(L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid; -1 7h- 2 -{dibenzofuan2-sulfonylarnjno)..3-phenyi..prpionic acid; 2 -(dibenzofiran-2-sulfonYlamnino)..propionic acid; (L)-2-(dibenzofuran-2-sufonyamino)3methyI.buryic acid; (L)-2-(dibenzofuran-2-sulfonylamino>..acetic acid; 2 -(dibenzofuran-2-sulfonylarnino).succjnic acid; 2 (dibelzofian2sufonylaminoy..3.titysulfanyi..prwpionj acid; 2 -(dibenzofizra-2-sulfonylaminoy..3.mercapto-prpionic acid, 2 -(dibenzofiiran-2-sulfonyI~ino)-3.methy..pentanoic acid hydroxyamide; (L)-2-(dibenzofuran-2-sulfonylamino)-atcetic acid tert-butyl ester; (L)-2-(dibenzofuan-2-sulfonylamino)-propionic acid tert-butyl ester; (L)-2-(dibenzofuan2-sulfonyiamino)-propionic acid tert-butyl 2 -(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid tert-butyl -ester; (L)-2-(dibenzofuran-2-sulfonylamino)-3-methylbpentanoic acid tert-butyl ester, 20 2 -(dibenzofuran-2-sulfonylamino)-3-methyl.pentanoic acid benzyloxy-amide; (L)-2-(dibenzGfuran-2-sulfonylamnino)-3-phenyl.propionic acid tertbutyl ester; (L)'-2-(dibenzofuran-3-sulfonylamino)-3-methyl.buridc acid;, (L)-2-(9H-Fluorene-2-sulfonyammino).3-methyl.buyric acid; (L)-2-(5,5-Dioxo-SH-5X 6 dbenzothiophene-3.sulfonylamino).

3-methyl-butyric acid; (L)-2-(Dibenzothiophene-2-sulfonylamino)3-methyl.butyric acid; (L)-2-(7-Bromo-dibenzofura2sufonylanino)3-methy..butyric acid;.

-17i (L)-3-Methyl-2-(7-phenyl dibenzofuran-2-sulfonylarnino)-butyric acid; 3-Methyl-2-(9-methyl-9H-carbazole-3-sulfonylamino)-butyric acid; 2-(9-Benzyl-9H-carbazole-3-sulfonylamino)-3-methyl-butyric acid; and 2-(9H-Carbazole-3-sulfonylaniino)-3-methyl-butyric acid.

I n another aspect there is provided the use of a compound of Formula I 0 R S~O I wherein M is a natural alpha amino aciddeiavehintesruue

COW

N -H

H

X is S, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, CI-C 6 ailkyl, or C 1

-C

6 alkyl-phenyl; Rais CI-C 5 alkoxy, hydroxy, or -NHOR 5 R2 and R4 are independently hydrogen, -C I-C 5 ailkyl, phenyl -NO 2 halogen, -CN, -C0 2 R 5 -S0 3 R 5 _CHO, -COR 5 -CONR R6, -(CH 2 ),,NkR6, -CF 3 or -NIICOR; each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in the manufacture of a medicament for the treatment of multiple sclerosis.

ii ii-mnrv-/AC.W -17j- In still another aspect there is provided use of a compound of Formula I

O

x II X R4 1 1

M

wherein M is a natural alpha amino acid derivative having the structure CORa -N H

H

b 5 X is S, S(O)n, CH 2 CO, or NRQ;

R

b is a side chain of a natural alpha amino acid; i" R Q is hydrogen, Ci-C 6 alkyl, or C 1

-C

6 alkyl-phenyl; Ra is C1-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 S 10 -CN, -CO 2 R, -S0 3

R

5 -CHO, -COR', -CONRSR 6

-(CH

2

)NRSR

6

-CF

3 or -NHCOR 5 6 each R 5 and R are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of atherosclerotic plaque rupture.

In yet another aspect there is provided use of a compound of Formula I

O

R I I X

R

41 iiq? mrV-/A CWV -17kwherein M is a natural alpha amino acid derivative having the structure CORa -N H

H

R

X is S, S(0)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid;

R

Q is hydrogen, C 1

-C

6 alkyl, or CI-C 6 alkyl-phenyl;

R

a is Ci-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5 S-CN, -CO 2 R, -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6

-(CH

2

),NRR

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for treating or preventing restenosis.

:In a further aspect there is provided use of a compound of Formula I 2

II

XR4

M

H

R

X is S, S(O)n, CH 2 CO, or NRQ;

R

b is a side chain of a natural alpha amino acid; tZ\ R

Q

is hydrogen, Ci-C 6 alkyl, or Cl-C 6 alkyl-phenyl; -171- Ra is Ci-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -CO 2

R

5 -SO3R 5 -CHO, -COR 5

-CONR

5

R

6

-(CH

2 )nNRSR 6

-CF

3 or -NHCOR 5 each R 5 and R 6 areindependently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacure of a medicament for the treatment of aortic aneurism.

In a still further aspect there is provided use of a compound of Formula I 0 2 II

*S-O

R4~M

M

wherein M is a natural alpha amino acid derivative hfavig the structure CORa N H

H

R

X is S, S(O)n, CH2, CO, or NRQ; e Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, CI-C 6 alkyl, or CI-C 6 alkyl-phenyl; Ra is C 1 -C alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -CL-C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -C0 2 R, -SO 3 R, -CHO, -CORs, -CONRR 6

-(CH

2 )nNRSR 6

-CF

3 or -NHCOR; each Rs and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of heart failure.

/A rW 17m- In another aspect there is provided use of a compound of Formula I

O

R

2 I

I

M

wherein M is a natural alpha amino acid derivative having the structure CORa -N -H

H

R

5 X is S, S(O)n, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid;

R

Q is hydrogen, Ci-C 6 alkyl, or C 1

-C

6 alkyl-phenyl; Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -Cl-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 o* o. 10 -CN, -CO 2

R

5 -S0 3 R, -CHO, -COR 5

-CONR

5

R

6

-(CH

2 )nNRR 6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, for the manufacture of a medicament for the treatment of periodontal disease.

In yet another aspect there is provided use of a compound of Formula I S I II-o S 71T7nn Mnnr/ACW -Nw 17nwherein M is a natural alpha amino acid derivative having the structure CORa -N H

H

R'

X is S, S(O)n, CH 2 CO, or NRQ;

R

b is a side chain of a natural alpha amino acid;

R

Q is hydrogen, C 1

-C

6 alkyl, or C 1

-C

6 alkyl-phenyl; Ra is C 1

-C

5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5 S. -CN, -CO 2

R

5

-SO

3

R

5 -CHO, -CORS, -CONRSR 6

-(CH

2 )NR R 6

-CF

3 or -NHCOR; each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of corneal ulceration.

.In a further aspect there is provided use of a compound of Formula I

O

X 4

M

H

R

X is S, S(O)n, CH 2 CO, or NRQ;

R

b is a side chain of a natural alpha amino acid; R is hydrogen, C 1

-C

6 alkyl, or C 1

-C

6 alkyl-phenyl; 71 nn~ no/A CW -17o- Ra is C 1

-C

5 alkoxy, hydroxy, or -NHOR;

R

5

-SO

3 R -CHO, -COR 5

-CONR

5

R

6

-(CH

2 )nNRR 6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of bums.

In yet another aspect there is provided use of a compound of Formula I i 0 0 x 4o

M

wherein M is a natural alpha amino acid derivative having the structure

COR

a -N

H

X is S, S(O)n, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid;

R

Q is hydrogen, C 1

-C

6 alkyl, or CI-C 6 alkyl-phenyl;

R

a is C 1

-C

5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONRSR

6

-(CH

2 )nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of decubital ulcers.

i ii-_nr-/A r/C -17p- In another aspect there is provided use of a compound of Formula I 0 2 II X 4 1

M

wherein M is a natural alpha amino acid derivative having the structure

COR

a -N H

H

5 X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; R is hydrogen; C 1

-C

6 alkyl, or C 1

-C

6 alkyl-phenyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5 10 -CN, -CO 2 R, -SO 3

R

S

-CHO, -COR -CONR5R 6

-(CH

2 )NR5R 6

-CF

3 or -NHCOR; ease each R 5 and R 6 are independently hydrogen or C -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of chronic ulcers or wounds.

In still another aspect there is provided use of a compound of Formula I

O

R 15X

M

~~jy NnAC/A('x 17q wherein M is a natural alpha amino acid derivative having the structure N -H

H

X is S, CH 2 CO, or NRO; Rb is a side chain of a natural alpha amino a cid; RQ is hydrogen, CI-C 6 ailkyl, or C 1

-C

6 alkyl-phenyl; Ra is C I-C 5 alkoxy, hydroxy, or -NE{0R 5 R and R are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -C0 2

R

5 -S0 3

R

5 -CHO,- -COR 5

-CONR

5

R

6

-(CH

2

)"NR

5

R

6

-CF

3 or -NHCOR 5 0 0:00 each R5 and R6 are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the S. manufacture of a medicament for the treatment of cancer metastasis.

In a still further aspect there is provided use of a compound of Formula I 0 41 X R M wherein M is a natural alpha amino acid derivative having the structure

-N-H

H

R

X is S, S(O)n, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1

-C

6 alkyl, or CIrC 6 alkcyl-phenyl; 21532

O.D~OC/ACVT

17r- Ra is Ci-C 5 alkoxy, hydroxy, or -NHORS;

R

2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2

R

5

-SO

3

R

5 -CHO, -COR 5

-CONRSR

6

-(CH

2 )nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of tumor angiogenesis.

In a further aspect there is provided use of a compound of Formula I

O

S 4 II R2 2.

X R4

M

wherein M is a natural alpha amino acid derivative having the structure CORa -N

H

N

.H

b Ra is CI-C 5 alkoxy, hydroxy, or -NHORS;

R

2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -CO2R 5 -S0 3

R

5 -CHO, -COR 5

-CONRSR

6

-(CH

2

),NRR

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of arthritis.

,I i. rw. r/A CW -17s- In yet another aspect there is provided use of a compound of Formula I

O

4

M

H

Rb 5 X is S, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid;

R

Q is hydrogen, C 1

-C

6 alkyl, or CI-C 6 alkyl-phenyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen, -OR 5 S* 10 -CN, -CO 2

R

5

-SO

3

R

5 -CHO, -COR 5

-CONR

5

R

6

-(CH

2 )nNR 5

R

6

-CF

3 or -NHCOR 5 *o each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of autoimmune or inflammatory disease dependent upon tissue invasion by leukocytes.

Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

21532-00.DOc/ACW -17t- DETAILED DESCRIPTION OF THE INVENTION As indicated above, the present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition comprising administering to the patient a therapeutically effective amount of a compound of Formula I 99 9 9 9 999 9 *.99 9* 9 9 9 9 999 9 9 9999*9 9 9.9.

9 *999 99999 9 *9.9 0 9 9 9 999 9 .999 9 9 9.99 9 *9**99 9 .999 9 9 9 9 9999 21532-oo.Doc/ACVI WO 98/09934 PCT/US97/14859 -18wherein M is a natural alpha amino acid derivative having the structure

COR

1

H

X is 0, S, S(O)n, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid;

R

1 is C 1

-C

5 alkoxy, hydroxy, or -NHOR 5

R

2 and R 4 are independently hydrogen, -C 1

-C

5 alkyl, phenyl -NO 2 halogen,

-OR

5 -CN, -CO 2

R

5 -S0 3

R

5 -CHO, -COR 5

-CONR

5

R

6 -(CH2)nNR 5

R

6

-CF

3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The term "alkyl" means a straight or branched chain hydrocarbon.

Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term "alkoxy" means an alkyl group attached to an oxygen atom.

Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.

The term "halogen" includes chlorine, fluorine, bromine, and iodine.

The term "phenyl" also includes substituted phenyl wherein one or more hydrogen on the phenyl ring is replaced with an organic radical. Examples of WO 98/09934 PCT/US97/14859 -19suitable substituents include, but are not limited to, halogen, C 1

-C

6 alkoxy, -CF 3

-NO

2

-NH

2

-NH(C

1

-C

6 alkyl), or -N(C 1

-C

6 alkyl) 2 The symbol means a bond.

The term "side chain of a natural alpha amino acid" means the group Q in a natural amino acid of formula H 2 N-CH(Q)-COOH. Examples of side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

A natural alpha amino acid is an amino acid found in a living organism.

Examples of such amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, asparagine, glutamine, lysine, arginine, tryptophan, histidine, cysteine, methionine, aspartic acid, and glutamic acid.

The functional groups in the amino acid side chains can be protected. For example, carboxyl groups can be esterified, amino groups can be converted to amides or carbamates, hydroxyl groups can be converted to ethers or esters, and thiol groups can be converted to thioethers or thioesters.

The compounds of Formula I-VIII can be administered to a patient either alone or as part of a pharmaceutically acceptable composition. The compositions can be administered to patients such as humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as WO 98/09934 PCT/US97/14859 ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, humectants, as for example, glycerol, disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, solution retarders, as for example paraffin, absorption accelerators, as for example, quaternary ammonium compounds, wetting agents, as for example, cetyl alcohol and glycerol monostearate, adsorbents, as for example, kaolin and bentonite, and lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others wellknown in the art. They may contain opacifying agents, and can also be of such WO 98/09934 PCT/US97/14859 -21composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic WO 98/09934 PCT/US97/14859 -22formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg/kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The term "patient" includes humans and animal.

The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.

These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for WO 98/09934 PCT/US97/14859 -23example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66(1-19) which is incorporated herein by reference.) Examples of pharmaceutically acceptable, nontoxic esters of the compounds of this invention include C 1 to C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5 to C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1 to C 4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary

C

1 to C 6 alkyl amines, and secondary C 1 to C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 to C 3 alkyl primary amines and

C

1 to C 2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.

Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The compounds of the present invention are administered to a patient in need of matrix metalloproteinase inhibition. In general, patients in need of matrix metalloproteinase inhibition are those patients having a disease or condition in which a matrix metalloproteinase plays a role. Examples of such diseases include, WO 98/09934 PCTIUS97/14859 -24but are not limited to, multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, bums, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.

In a preferred embodiment, the matrix metalloproteinase is stromelysin-1 or gelatinase-A.

A "therapeutically effective amount" is an amount of a compound of Formula I-VIII that when administered to a patient having a disease that can be treated with a compound of Formula I-VIII ameliorates a symptom of the disease.

A therapeutically effective amount of a compound of Formula I-VIII is readily determined by one skilled in the art by administering a compound of Formula I-VIII to a patient and observing the results.

The following examples illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the Claims, in any manner.

EXAMPLES

General Dibenzofuran Sulfonamide Synthesis The compounds of the present invention can be synthesized using a number of different synthetic routes. Referring to the General Synthetic Scheme, the common starting materials are the sulfonyl chlorides These are easily synthesized by one skilled in the art by sulfonation of the parent heterocycle. Some representative procedures are as follows. For dibenzofuran X=O) and dibenzothiophene the parent heterocycle is sulfonated at the 2-position using one equivalent of chlorosulfonic acid in chloroform at o0C according to the method of Bassin, et al., (Phosphorus, Sulfur and Silicon, 1992;72:157-170). The sulfonic acid is then converted to the corresponding sulfonyl chloride X=O,S) by treatment with phosphorus pentachloride at 170-180 0 C. For carbazole X=NH), the parent heterocycle is sulfonated at the 3-position using sulfuric WO 98/09934 PCT/US97/14859 acid at 100 0 C followed by neutralization with barium carbonate to yield the barium salt of the corresponding sulfonic acid according to the method of Loza, et al., (Sb. Mater. Nauch.-Tekh. Konf. Ukrain. Zaoch. Poitekh. Inst. Vith, Kharkov, 1966:202-205). The sulfonic acid is then converted to the corresponding sulfonyl chloride X=NH) by treatment with phosphorus pentachloride at 170-180 0 C or reaction with either phosphoryl chloride, thionyl chloride, or oxalyl chloride. For fluorene X=CH 2 according to the method of Chrzaszczewska et al., (Lodz. Tow. Nauk., Wydz. 3, Acta Chim., 1966;11:143-155) the parent carbocycle is sulfonated at the 2-position using one equivalent of chlorosulfonic acid in chloroform at 0°C followed by neutralization with potassium hydroxide to give the potassium salt of the corresponding sulfonic acid. This fluorene derivative can then be oxidized using aqueous potassium permanganate at 80 0 C to the corresponding fluorenone derivative X=CO). The sulfonic acid salts are then converted to the corresponding sulfonyl chloride X=CH 2 ,CO) by treatment with phosphorus pentachloride and phosphoryl chloride in chloroform.

In Method A, the sulfonyl chloride is condensed directly with a natural amino acid using a base such as triethylamine (TEA) in a mixture of tetrahydrofuran (THF) and water at 10 0 C to yield the desired compound The corresponding hydroxamic acid can be conveniently prepared by coupling the acid with an O-protected (usually benzyl) hydroxylamine using dicyclohexylcarbodiimide (DCC) as the coupling agent in dichloromethane at temperatures ranging from to 0 C. The protecting group can be removed from compound by catalytic hydrogenolysis using hydrogen gas at 50 psi and Pd/BaSO 4 in aqueous methanol to yield the hydroxamic acid derivative In Method B, the sulfonyl chloride is condensed with a suitably C-protected (usually tertiary butyl ester) amino acid using a base such as N-methylmorpholine (NMM) in a solvent such as dichloromethane at 0°C to yield compound The protecting group can be removed from the carboxylic acid by treatment with trifluoroacetic acid in dichloromethane at 25-35 0 C using anisole as a carbocation scavenger to yield General Synthetic Scheme

IOC

X 0, CH, GO, NH

R

C0 2

H

TEA, THF-H- 2 0 Method A 0 R R2-C s 11 11 NKC02H 0 H R4

TFA

anisole 14 2 N "kCO 2

C(CH

3 3 Method B IDCC, CH 2

CI

2 BzONH 2 0 R 2

I_

R 1 N CO C(CH 3 R4 IPd/BaSO 4 MeOH/H 2 0

H

2 R R 1

R

2 0 H~ CONHOH Bz benzyl DCC dicyclohexylcarbodiirnide NMM N-methylmorpholine THF tetrahydrofuran TEA =tfiethylamine MeOH methanol WO 98/09934 PCT/US97/14859 -27- Examples Prepared by Method A EXAMPLE 1 (L)-2-(Dibenzofuran-2-sulfonvlamino)-4-methyl-pentanoic acid Step (L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid, tert.-butyl ester To a dichloromethane solution (20 mL) of (L)-leucine, tert.-butyl ester (2.1 g, 0.0099 mol) and N-methylmorpholine (2.2 mL, 0.0199 mol) at 0°C under an inert nitrogen atmosphere was added a dichloromethane solution (10 mL) of dibenzofuran-2-sulfonyl chloride (1.0 g, 0.00375 mol) with stirring. The resulting solution was stirred at 0°C for 4 hours and then partitioned with water (30 mL).

The organic layer was separated and washed with water (2 x 30 mL) and brine (2 x 30 mL). This was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was then flash chromatographed on silica gel and the title product (1.0 g, 64%) was eluted with 20% ethyl acetate/hexane; melting point 106-109 0

C.

Step (L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid (Example 1) To a dichloromethane solution (5 mL) of the material obtained in step (a) g, 0.00119 mol) and anisole (0.5 mL) at room temperature with stirring was added trifluoroacetic acid (5 mL). The resulting solution was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was triturated with a mixture of ethyl acetate/hexane to yield the title compound (0.14 g, melting point 75-80°C.

1 H NMR (CDC1 3 8 8.4 1H), 8.0 1H), 7.9 1H), 7.4-7.6 4H), 5.0 (d, 1H), 3.9 1H), 1.8 1H), 1.4 2H), 0.9 3H), 0.8 3H) ppm.

Following the general procedure of Example 1, the following compounds were obtained: WO 98/09934 WO 9809934PCT/US97/14859 -28- EXAMPLE 2 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-12entanoic acid I1H NMR (DMSO-D 6 8 8.6 I 8.3 I 8.1 I1H), 7.8-7.9 (in, 3H), 7.6 (tr, I 7.5 (tr, I1H), 3.7 (in, I1H), 3.4 11H), 1.7 (in, I1H), 1. 1- 1.4 (in, 2H), 0.75-0.85 (in, 6H) ppm.

EXAMPLE 3 (L)-2-(Dibenzofuran-2-sulfonvylamino)-3-1phenyl-propionic acid; melting point 196-198'C.

Examples prepared by Method B EXAMPLE 4 (L)-2-(Dibenzofuran-2-sulfonvlajnino)-propionic acid To a THF/water 8 mL) solution of (L)-alanine (0.3 g, 0.0034 mol) and triethylamine (I mL) at 1 0 0 C was added dibenzofuran-2-sulfonyl chloride g, 0.003 75 mol) in one portion with stirring. The resulting solution was stirred at room temperature for 24 hours. The solution was then concentrated in vacuo and the residue redissolved in water (10 mL). This solution was cooled in an ice bath and then acidified with IN HCl. A white solid was deposited which was then filtered and washed with water. This solid was recrystallized from aqueous ethanol to give the title product (0.6 g, melting point =158-163'C.

Following the general procedure of Examnple 4, the following compounds were obtained: EXAMPLE (L)-2-(Dibenzofuran-2-sulfonvylanino)-3 -iethyl-butyric acid; melting point 163-165'C EXAMPLE 6 (Dibenzofuran-2-sulfonylainino)-acetic acid; melting point 208-21 0"C WO 98/09934 WO 9809934PCTIUS97/14859 -29- EXAMPLE 7 (L)-2-(Dibenzofuran-2-sulfonvlamino)-succinic acid; melting point =165-168 0

C

EXAMPLE 8 (L)-2-(Dibenzofuran-2-sulfonlylamino)-3-tritvlsulfanyl-propionic acid 1 NMR (DMSO-D 6 8 8.5 11H), 8.2 (in, 2H), 7.1-7.9 (in, 19H), 3.6 (in, I1H), (in, I 2.3 2H1) ppm.

EXAMPLE 9 (L)-2-(Dibenzofiiran-2-sulfonvlamino)-3-mercapto-propionic acid To a dichioroinethane solution (10 inL) of (L)-2-(Dibenzofuran- 2-sulfonylamino)-3-tritylsulfanyl-propionic acid (Example 8, 1.0 g, 0.00168 mol) at room temperature was added trifluoroacetic acid (10 mL). A deep red/orange solution resulted. To this solution was added triethylsilane (0.33 mL, 0.00202 mol), the color was immediately discharged, and the resulting clear solution was stirred at room temperature for 3 hours. The solution was then concentrated in vacuo and the residue redis solved in ether (10 mL) which was then removed in vacuo. This procedure was repeated three times. The residue was recrystallized from ethyl acetate/hexane 1) to yield the title compound (0.23 g, melting point 164-166'C.

EXAMPLE (L)-2-(Dibenzofuran-2-sulfonvlamino)-3-methvl-pentanoic acid-hydroxyamide SteD2 (L)-2-(D~ibenzofuran-2-sulfonylamino)-3-methvl-pentanoic acid benzloxy-amnide To a TI-IF solution (50 mL) of (L)-2-(Dibenzofuran-2-sulfonylamino)- 3-methyl-pentanoic acid (Example 2, 0.55 g, 0.00 15 mol) and carbonyldiiinidazole (0.26 g, 0.00 16 mol) at room temperature under an inert nitrogen atmosphere was added O-benzylhydroxylamine (0.23 g, 0.00 18 mol) in one portion. This solution was then heated to reflux for 72 hours and then allowed to stir at room temperature for 24 hours. The mixture was then concentrated in vacuo and flash WO 98/09934 PCT/US97/14859 chromatographed on silica gel eluting with ethyl acetate/hexane to yield the title compound (0.27 g, melting point 207-209 0

C.

Step (L)-2-(Dibenzofuran-2-sulfonvlamino)-3-methyl-pentanoic acid hydroxvamide (Example A THF (2 mL)/methanol (10 mL) solution of the material obtained above in step (0.037 g, 0.0000793 mol) was hydrogenolyzed using hydrogen gas at psi with a Pd/BaSO 4 catalyst at room temperature for 1 hour. The catalyst was removed by filtration and the solution concentrated in vacuo. The residue was triturated with ether to yield the title compound (0.022 g, 74%).

1 H NMR (CDCl 3 6 8.6-7.2 8H), 5.1 1H), 4.1 1H), 1.9-1.2 3H), 0.9 3H), 0.85 3H) ppm.

EXAMPLE 11 (L)-2-(dibenzofuran-3-sulfonvlamino)-3-methvl-butvric acid Step (Dibenzofuran-3-sulfonvl chloride) 3-Aminodibenzofuran (10 g, 54.6 mol) was diazotized by dissolving in 180 mL glacial acetic acid, 50 mL water, and 14 mL concentrated hydrochloric acid at 0 C and adding 15 mL of a 5.5 M aqueous solution of sodium nitrite. The resulting mixture was stirred for 1 hour before pouring into a solution of copper(II)chloride (2.0 g, 14.9 mmol) in 240 mL of a 1:1 mixture of benzene and glacial acetic acid saturated with sulfur dioxide. This mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was partitioned between water and chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellowish solid; melting point 142-144 0

C.

Step (b) Using the procedure of Example 1, (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced WO 98/09934 WO 9809934PCT/US97/14859 -31with dibenzofuran-3-sulfonyl chloride, the title compound is obtained; melting point 1 97-200*C.

EXAMPLE 12 (L)-2-(9H-Fluorene-2-sulfonylamino)-3 -methyl-butyric acid When in the procedure of EXAMPLE 1, (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced with 9H-fluorene-2-sulfonyl chloride, the title compound is obtained.

EXAMPLE 13 (L)-2-(5,5-Dioxo-5H-5 X 6 -dibenzothiophene-3-sulfonylamino)-3 -methyl-butyric acid When in the procedure of EXAMPLE 1, (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced with 5,5-dioxo-5H-5X% 6 -dibenzothiophene-3-sulfonyl chloride, the title compound is obtained; melting point 85-906C.

EXAMPLE 14 (L)-2-(Dibenzothiophene-2-sulfonylamino)-3-mehyl-butyric acid When in the procedure of EXAMPLE 1, (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced with dibenzothiophene-2-sulfonyl chloride, the title compound is obtained; melting point 150-155'C.

EXAMPLE (L)-2-(5,5-Dioxo-5H-5X 6 -dibenzothiohene-2-sulfonylamino)-3-mehyl-butyric acid To a glacial acetic acid (30 mL) solution of the material obtained in EXAMPLE 14 Step (1.5 g, 0.0036 mol) was added 10 mL of 30% hydrogen peroxide. The resulting solution was heated to reflux for 2.5 hours, cooled to room temperature and stirred for 16 hours and then filtered to give the crude product as WO 98/09934 PCT/US97/14859 -32a white solid. The solid was washed with water and boiling ether to yield the title compound; melting point 216-218°C.

EXAMPLE 16 (L)-2-(7-Bromo-dibenzofuran-2-sulfonvlamino)-3-methyl-butric acid Step 3-Bromo-dibenzofuran 3-Amino-dibenzofuran (15 g, 81.9 mmoles) was added in portions to a suspension of cupric bromide (21.9 g, 98.2 mmoles) and tert.-butyl nitrite (12.66 g, 122.8 mmoles) in 350 mL of acetonitrile. This mixture was heated to reflux for 2 hours and then stirred for 16 hours at room temperature. The reaction was partitioned between 1 M HC1 and diethyl ether. The diethyl ether layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography gave the title compound as a yellowish solid.

Step 7-Bromo-dibenzofuran-2-sulfonyl chloride Chlorosulfonic acid (3.75 mL, 56 mmoles) was added dropwise to a solution of 3-bromo-dibenzofuran (9.21 g, 37.3 mmoles) in 150 mL of chloroform at room temperature. The reaction was stirred for 5 hours, cooled to 0°C, filtered, and washed the solid with cold dichloromethane. This solid (6.12 g, 18.7 mmoles) was mixed with phosphorous pentachloride (12.9 g, 61.7 mmoles) and the mixture was heated to 110 0 C for 4 hours. The mixture was cooled to room temperature and quenched with ice water. Filtered the resulting suspension to give the title compound as a white solid.

Step (L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid When in the procedure of EXAMPLE 1, (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced with 7-bromo-dibenzofuran-2-sulfonyl chloride, the title compound is obtained; melting point 191-193 0

C.

WO 98/09934 WO 9809934PCTIUS97/14859 -33- EXAMPLE 17 (L)-3-Methvl-2-(7-phenyl-dibenzofiiran-2-sulfonvylamino)-butyric acid Step (L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-butyric acid, tert.butyl ester When in the procedure of EXAMPLE 1, Step (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofuran-2-sulfonyl chloride is replaced with 7-bromo-dibenzofuran-2-sulfonyl chloride, the title compound is obtained.

Step (1b) (L)-3-Methvl-2-(7-phenyl-dibenzofiiran-2-sulfonylamino)-butyric acid, tert.-butvl ester (L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid, tert.-butyl ester (1.0 g, 2.0 mmoles) and phenyl boronic acid (0.3 g, 2.5 mmoles) were mixed with 10 mL toluene with 5 mL water the 0. 5 g sodium carbonate.

Tetrakis(triphenylphosphine) palladium 15 g, 0. 1 mmoles) was added and the resulting mixture was heated to reflux for 6 hours. Another 0. 15 g of the palladium catalyst was added and reflux was continued for 16 hours. The reaction was cooled to room temperature and partitioned between 1 M HC1 and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white solid.

Step (L)-3-Methyl-2-(7-phenyl-dibenzoduran-2-sulfonylamino)-butyic acid (L)-3-Methyl-2-(7-phenyl-dibenzofuran-2-sulfonylamino)-butyric acid, tert.-butyl ester (0.94 g, mmoles) was dissolved in concentrated trifluoroacetic acid and stirred for 2 hours. Concentrated in vacuo and triturated the residue with diethyl ether to give the title compound as an off-white solid; melting point 254-255 0

C.

WO 98/09934 PCT/US97/14859 -34- INHIBITION STUDIES Experiments were carried out which demonstrate the efficacy of compounds of Formula I and II as potent inhibitors of stromelysin-1 and gelatinase A. Experiments were carried out with the catalytic domains, i.e., Table 1 shows the activity of the Examples with respect to both stromelysin-1 and gelatinase A, GCD (recombinant gelatinase A catalytic domain); SCD (stromelysin-1 catalytic domain). IC 5 0 values were determined using a thiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Johnson Hupe and Baragi "Purification and Characterization of the Human Stromelysin Catalytic Domain Expressed in Escherichia coli," Biochemistry, 1992;31:11231-11235). MMP01, MMP07, MMP09, and MMP13 activity was assayed in a method similar to MMP02 and MMP03 (SCD and GCD). MMP01 and MMP09 can be obtained from Washington University School of Medicine, St. Louis, Missouri. MMP07 can be obtained in accordance with the known procedure set forth by Ye Q-Z, Johnson and Baragi "Gene Syntheses and Expression in E. coli for PUMP, a Human Matrix Metalloproteinase" Biochem. and Biophys. Res. Comm., 1992; 186:143-149.

MMP 13 can be obtained in accordance with the known procedure set forth by Freije et al., "Molecular Cloning and Expression of Collegenase-3, a Novel Human Matrix Metalloproteinase Produced by Breast Carcinomas" J. Bio.

Chem., 1994;269:16766-16773.

Thiopeptolide Assay Hydrolysis of the thiopeptolide substrate Ac-Pro-Leu-Gly-thioester-Leu- Leu-Gly-OEt (Bachem) is used as the primary screen to determine IC 5 0 values for MMP inhibitors. A 100 gpL reaction contains 1 mM 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), 100 pgM substrate, 0.1% Brij, enzyme, and inhibitor in the appropriate reaction buffer. Activated full-length enzymes are assayed at 5 nM, Stromelysin Catalytic Domain (SCD) at 10 nM, and Gelatinase A Catalytic Domain (GaCD) at 1 nM. Inhibitors are screened from 100 gM to 1 nM.

WO 98/09934 PCT/US97/14859 Full-length enzymes are assayed in 50 mM HEPES, 10 mM CaCl 2 pH 7.0; SCD in 50 mM MES, 10 mM CaC12, pH 6.0; and GaCD in 50 mM MOPS, 10 mM CaCl 2 10 pgM ZnCl 2 pH 7.0. The change in absorbance at 405 nm is monitored on a ThermoMax microplate reader at room temperature continuously for 20 minutes.

HEPES is 4-(2-hydroxylethyl)-piperazine- -ethane sulfonic acid; MES is 2-morpholinoethane sulfonic acid menohydrate; Ac is acetyl; Pro is proline; Leu is leucine; Gly is glycine; Et is ethyl; and MOPS is 3-morpholinopropane sulfonic acid.

Soluble Proteoglvcan Assay (stromelvsin natural substrate assay) SCD (PG) Solubilized proteoglycan substrate is prepared from bovine cartilage powder (Sigma) using the method described by Nagase and Woessner in Anal.

Biochem., 1980;107:385-392. A 100 gL reaction contains 10 gg/mL proteoglycan, enzyme, and inhibitor in 50 mM MES, 10 mM CaCl 2 pH 6.0. Activated fulllength stromelysin or stromelysin catalytic domain (SCD) is assayed at 100 nM.

Inhibitors are screened from 100 lpM to 1 nM. The reaction is incubated at 37 0

C

for 3 hours then stopped with the addition of 1,10-phenanthroline at a final concentration of 1 mM. Reaction products are separated from undigested substrate using ultrafree-MC polysulfone microcons with a 300,000 molecular weight cutoff membrane (Millipore) and quantified using a modified 1,9-dimethylene blue (DMB) assay described by Famdale, Sayers, and Barrett in Connective Tissue Research, 1982;9:247-248. Absorbance is measured at 518 nm using 32 pg/mL DMB in a 1 mL reaction. The standard curve is constructed from 0 to 100 pg shark cartilage chondroitin sulfate C (Sigma).

WO 98/09934 PCT/US97/14859 -36- Gelatin Assay (gelatinase natural substrate assay) (Gel) Rat tail Type I collagen (Sigma) is denatured by heating at 95°C for minutes to prepare the gelatin substrate. A 50 pL reaction contains 1.12 mg/mL substrate, enzyme, inhibitor, and 80 pg/mL soy bean trypsin inhibitor as an inert internal standard in 50 mM MOPS, 10 mM CaCl 2 10 gM ZnCI 2 pH Activated full-length gelatinase A is assayed at 1 nM and gelatinase A catalytic domain (GaCD) at 10 nM. Inhibitors are screened from 100 RpM to 1 nM. The reactions are incubated at 37 0 C for 30 minutes then stopped with 50 jtL at 2X Tricine gel loading buffer (Novex). Reaction products are separated from undigested substrate by electrophoresis on Tricine-SDS 10-20% polyacrylamide gradient gels (Novex). Protein bands are stained with Coomassie Brilliant Blue R and quantified using a Bio Image densitometer (Millipore). IC 5 0 values are calculated from the disappearance of substrate using the sum of the top three bands of each reaction after normalization with the internal standard.

MMP Inhibitor Bioassay Animals are dosed by gavage with either vehicle or compound at 2, 10, or mg/kg. Blood samples are collected from 3 to 4 animals from each dosing group at 1, 2, 4, 6, and 24 hour postdose, centrifuged, and the plasma immediately frozen at -20 0 C. Plasma protein is precipitated with an equal volume of acetonitrile and separated by centrifugation at room temperature. The supernate is evaporated to dryness and reconstituted to the original plasma volume with mM Tris, pH 7.6. Ten-fold serial dilutions of the reconstituted plasma samples are prepared in 50 mM Tris, pH 7.6 for dose response assays using the appropriate thiopeptolide assay. The concentration of plasma which yields 50% inhibition of enzyme is determined and used to calculate the inhibitor plasma level from the known IC 50 value. To demonstrate that the compound can be quantitatively extracted from plasma as active inhibitor, controls for each inhibitor include normal rat plasma, normal rat plasma spiked with compound, and buffer dilutions WO 98/09934 WO 9809934PCTIUS97/14859 -37of compound. All control samples are subjected to acetonitrile precipitation and analyzed with the thiopeptolide assay.

TABLE 1 Example- MMPO I (GCD) (S CD) MMP07 MMP09 MMP 13 Number MMP02 MMP03 1 66 0.32 1.18 100 2 100 2.3 1.5 100 3 100 0.9 0.72 100 4 1.7 5.4 19 0.084 0.23 100 6 100 0.73 4.8 100 7 1.2 1.0 8 9.4 14.4 9 4.5 0.69 35 100 11 1.8 0.0045 0.015 5.0 0.047 12 32.3 0.049 0.185 10.8 100 0.34 13 14 100 0.61 0.69 27 2.6 100 100 100 100 100 16 0.47 0.75 17 100 0.36 0.062 6 0.69 WO 98/09934 WO 9809934PCTIUS97/14859 -38- TABLE2 2- SCD (IC 50 SCD (PG) (IC 5 0 GCD (IC 50 Gel (IC 5 0 Example 0.233 p.M 8.9 p.M 0.084 p.M 0.58 p.M Bioassay (50 mg/kg) Peak 24 Hours 82 p.M 0.18 p.M

Claims

1. A method of inhibiting a matrix metalloproteinase in a patient- in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a co mpound of Formula I 0 X V. *4 4 wherein M is a natural alpha amino acid derivative having the structure CORI -N H R* ishdoeCI-6akl r-a C ly-hnl R isasd hi fantua lh mn cd RIi I-5akoy ydoy r R4 A 04 .1 rorgstero WO 98/09934 PCT/US97/14859

2. The method of Claim 1 wherein X is O.

3. The method of Claim 1 wherein X is S.

4. The method of Claim 1 wherein X is CH 2 The method of Claim 1 wherein X is NRQ.

6. The method of Claim 2 wherein R 2 and R 4 are hydrogen.

7. The method of Claim 1 wherein X is CO.

8. The method of Claim 1 wherein X is S(O)n.

9. The method of Claim 1 wherein R 1 is hydroxy or C 1 -C 5 alkoxy or -NHOH or -NHObenzyl.

10. The method of Claim 1 wherein R is the side chain of the natural alpha amino acid, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, phenylalanine, or glycine.

11. A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula II O II z Z WO 98/09934 PCT/US97/14859 -41- wherein Z is a natural amino acid derivative having the structure CORa -N--H H Rb R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C -C 5 alkyl; R a is C 1 -C 5 alkoxy, hydroxy, or -NHORc; Rb is a side chain of a natural alpha amino acid; and R c is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

12. The method of Claim 11 wherein the group O -S=O is located at the 2-position of the phenyl ring. I Z

13. The method of Claim 11 wherein the group O II -S=0 is located at the 3-position of the phenyl ring. I Z

14. A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering WO 98/09934 PCT/US97/14859 -42- to the patient a therapeutically effective amount of a compound of Formula III 0O R 2 S=O SZ III R4 wherein Z is a natural amino acid derivative having the structure CORa H H Rb R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -SO 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; Ra is C -C 5 alkoxy, hydroxy, or -NHORC; Rb is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. WO 98/09934 PCT/US97/14859 -43- A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula IV R S=O 1 IV CH, Z 2 4 wherein Z is a natural amino acid derivative having the structure CORa -NH H H Rb R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; R a is C -C 5 alkoxy, hydroxy, or -NHORC; Rb is a side chain of a natural alpha amino acid; and RC is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

16. A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering WO 98/09934 PCT/US97/14859 -44- to the patient a therapeutically effective amount of a compound of Formula V II V C Z II R4 wherein Z is a natural amino acid derivative having the structure CORa -NH H Rb R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; Ra is C -C 5 alkoxy, hydroxy, or -NHORC; Rb is a side chain of a natural alpha amino acid; and R c is hydrogen, Ci-C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. WO 98/09934 PCT/US97/14859

17. A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula VI O R 2 I S O S(O)n Z VI R 4 wherein Z is a natural amino acid derivative having the structure CORa -NH H H Rb R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; R a is C 1 -C 5 alkoxy, hydroxy, or -NHORC; n is 0 to 2; Rb is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

18. A method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering WO 98/09934 WO 9809934PCTIUS,97/14859 -46- to the patient a therapeutically effective amount of a compound of Formula VII 0 2~ 11 R S=0 N L I wherein Z is a natural amino acid derivative having the structure CORa -N--H H Rb R 2 and R 4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 I-C 5 alkyl; Ra is C 1 I-C 5 alkoxy, hydroxy, or -NHORC; RQ is hydrogen, C 1 I-C 6 alkyl, or C 1 I-C 6 alkyl-phenyl; Rb is a side chain of a natural alpha amnino acid; and Rc is hydrogen, C 1 I-C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

19. The method of Claim I wherein the compound: (L)-2-(dibenzofuran-2-sulfonylanino)-4-methyl-pentanoic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid; WO 98/09934 WO 9809934PCTIUS97/14859 -47- (L)-2-(dibenzofuran-2-sulfonylamino)-3 -phenyl-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamnino)-3 -methyl-butyric acid; (L)-2-(dibenzofuran-2-sulfonylamino)-acetic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-succinic acid; (L)-2-(dibenzofuiran-2-sulfonylaxnino)-3 -tritylsulfanyl-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3 -mercapto-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3 -methyl-pentanoic acid hydroxyamide; (L)-2-(dibenzofuran-2-sulfonylamnino)-acetic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylaxnino)-propionic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid tert-butyl ester; (L)-2-(dibenzofiiran-2-sulfonylamino)-3-methyl-pentanoic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-3 -methyl-pentanoic acid benzyloxy-amide; (L)-2-(dibenzofuran-2-sulfonylamnino)-3-phenyl-propionic acid tert- butyl ester; (L)-2-(dibenzofuran-3-sulfonylamnino)-3-methyl-butyric acid; (L)-2-(91--Fluorene-2-sulfonylamino)-3-methyl-butyric acid; ,5-Dioxo-5H-5X 6 -dibenzothiophene-3-sulfonylamino)- 3-methyl-butyric acid; (L)-2-(Dibenzothiophene-2-sulfonylamino)-3-methyl-butyric acid; (L)-2-(7-Bromo-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid; 48 (L)-3-Methyl-2-(7-phenyl dibenzofuran-2-sulfonylamino)-butyric acid; 3 -Methyl-2-(9-methyl-9H-carbazole-3 -sulfonylamino)-butyric acid; 2-(9-Benzyl-9H-carbazole-3-sulfonylamino)-3-methyl-butyric acid; and 2-(9H-Carbazole-3-sulfonylamino)-3-methyl-butyric acid. A method of treating multiple sclerosis, the method comprising administering to a patient having multiple sclerosis a therapeutically effective amount of a compound of Formual I R* S 0 0 V 00V -4 x R6 00 eg*. 1 heei Mi anaurl(L aph mio ci ervaiv avngth trc0r 4.. -NH g X is S, CH 2 CO, or NRQ; fee. R is a side chain of a natural alpha amino acid; RQ is hydrogen, C I-C 6 alkyl, or C I-C 6 alkyl-phenyl; R a is C 1 I-C 5 alkoxy, hydroxy, or -NF0R 5 2 45 R and R4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -C0 2 R 5 _S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNR 5 R 6 or -NHCOR 5 each R 5and R 6are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

21532-OO.Doc/ACW -49- 21. A method of treating atherosclerotic plaque rupture, the method comprising administering to a patient having an atherosclerotic plaque at risk of rupture a therapeutically effective amount of a compound of Formula I 0 R S=O S 4 O I M wherein M is a natural alpha amino acid derivative having the structure CORa N--H H 0 b X is S, S(O)n, CH 2 CO, or NRQ; owe* R b is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 -C 6 alkyl, or CI-C 6 alkyl-phenyl; 50 S 10 Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONRSR 6 -(CH 2 )nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 22. A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I 21532-O0.DO/ACW O XI M wherein M is a natural alpha amino acid derivative having the structure COR a -N H H b R b is a side chain of a natural alpha amino acid; RQ is hydrogen, CI-C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHORS; 2 4 R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONRR 6 -(CH 2 )nNR R 6 -CF3, or each R and R are independendtly hydrogen or C-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 23. A method of treating aortic aneurism, the method comprising administering to a patient having aortic aneurism a therapeutically effective amount of a compound of Formula I O 4 wherein M is a natural alpha amino acid derivative having the structure M wherein M is a natural alpha amino acid derivative having the structure 21532-OO.Doc/ACW -51 COR a -N H H Rb X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; RQ is hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkyl-phenyl; R a is C 1 -C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -COR 5 -CONR5R 6 -(CH 2 )nNR R 6 -CF 3 or -NHCORS; 5 6 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. o 24. A method of treating heart failure, the method comprising administering to a patient having heart failure a therapeutically effective amount of a compound of Formula I R S O R2X R4 M- O M wherein M is a natural alpha amino acid derivative having the structure CORa -N H H Rb X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; 21532-OO.Doc/ACW 52 RQ is hydrogen, C 1 -C 6 alkyl, or CI-C 6 alkyl-phenyl; R a is C I-C 5 alkoxy, hydroxy, or -NHOR 5 R and R4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -CN, -CO 2 R 5 _S0 3 R 5 _CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNR 5 R 6 -CF 3 or -NHCOR each R 5 and R 6 are independently hydrogen or C I-C 5 alkyl; and n isO0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. A method of treating periodontal disease, the method comprising administering to a patient having periodontal disease a therapeutically effective amount of a compound of Formula I 0 wherein M is a natural alpha amino acid derivative having the structure N -H H X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; R a is C I-C 5 alkoxy, hydroxy, or -NI0R 5 R2 and R4 are independently hydrogen, -Cl-C 5 alkyl, phenyl -NO 2 halogen, -CN, -C0 2 R 5 -S0 3 -CHO, -COR 5 -CONR 5 -(CH 2 )~nR 5 -CF 3 or-NHFCOR 5 21 532-OODoc/AC\V -53- each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 26. A method of treating corneal ulceration, the method comprising administering to a patient having corneal ulceration a therapeutically effective amount of a compound of Formula I II 20 R S O M wherein M is a natural alpha amino acid derivative having the structure CORa N *H H H X is S, S(O)n, CH 2 CO, or NR Q Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkyl-phenyl; Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -CORS, -CONRSR 6 -(CH 2 )nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 21532-OO.Doc/ACW -54- 27. A method of treating bums, the method comprising administering to a patient having burns a therapeutically effective amount of a compound of Formula I O R2 I 4 X R i M wherein M is a natural alpha amino acid derivative having the structure CORa N--H R S 0 X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHORS; 10 R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R S -S0 3 R 5 -CHO, -COR 5 -CONRSR 6 -(CH2)nNR 5 R 6 -CF 3 or -NHCOR 5 5 6 each R and R 6 are independently hydrogen or C -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 28. A method of treating decubital ulcers, the method comprising administering to a patient having decubital ulcers a therapeutically effective amount of a compound of Formula I 21532-OO.Doc/ACW R2 R I S O R M wherein M is a natural alpha amino acid derivative having the structure CORa H H b R X is S, S(O)n, CH 2 CO, or NR R b is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1 -C 6 alkyl, or Ci-C 6 alkyl-phenyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHOR 5 2 45 R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )NR 5 R 6 -CF 3 or -NHCOR 5 10 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, S* or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 29. A method of treating chronic ulcers or wounds, the method comprising administering to a patient having chronic ulcers or wounds a therapeutically effective amount of a compound of Formula I O 2 N II R- IIo s o wn x R M wherein M is a natural alpha amino acid derivative having the structure 21532-00.DOc/ACW 56- CORa -N -H H X is S, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1 -C 6 alkyl, or CI-C 6 alkyl-phenyl; Ra is C I-C 5 alkoxy, hydroxy, or -NHOR 5 R: 2 and R are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, :.CN-CR 5 -0R,-CHO, -COR 5 -CONR 5 -(CH )NR 5 R 6 or -NHCOR'; oeach R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 30. A method of treating cancer metastasis, the method comprising administering to a patient having cancer metastasis a therapeutically effective amount of a compound of 0000 Formula I 0 -4R wherein M is a natural alpha amino acid derivative having the structure COW N -H H X is S, CH 2 CO, or NRQ; 21532-00 DocIACW' -57- Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 -C 6 alkyl, or Ci-C 6 alkyl-phenyl; Ra is C1-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONRR 6 -(CH 2 )NR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, S* or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 10 31. A method of treating tumor angiogenesis, the method comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of Formula I 0e* -4 *c N -H H X is S, CH2, CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, Ct-C6 alkyl, or C-Cs alkyl-phenyl; Ra is C-Cs alkoxy, hydroxy, or -NHOR 2 0 oo*• wherein M is a natural alpha amino acid derivative having the structure CORa R X is S, S(O)n, CH 2 CO, or NRQ; R is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHOR 5 21532-00.DOc/ACW -58- R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -COR 5 -CONRsR 6 -(CH 2 )NR5R 6 -CF 3 or -NHCORS; each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 32. A method of treating arthritis, the method comprising administering to a patient having arthritis a therapeutically effective amount of a compound of Formula I R2 S O R:X R4 S M wherein M is a natural alpha amino acid derivative having the structure CORa O C N H H R b is a side chain of a natural alpha amino acid; R Q is hydrogen, C1-C6 alkyl, or CI-C6 alkyl-phenyl; R a is CI-C alkoxy, hydroxy, or -NHORS; R 2 and R 4 are independently hydrogen, -C1-C5 alkyl, phenyl -NO2, halogen, -OR' -CN, -CO2RS, -SO3 R S -CHO, -COR 5 -CONR5R 6 -(CH2)NR5R 6 -CF3, or-NHCORS n is 0 to 2, 0or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof ^i is ^20 or a pharmaceutically acceptable salt, ester, amnide, or prodrug thereof. 21532-OO.DOc/ACW -59- 33. A method of treating autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes, the method comprising administering to a patient having autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes a therapeutically effective amount of a compound of Formula I O R2 o M wherein M is a natural alpha amino acid derivative having the structure CORa -N H H X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; 10 R Q is hydrogen, CI-C 6 alkyl, or CI-C 6 alkyl-phenyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNRSR 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 21532-o.Doc/ACW 34. A compound of Formula I 0 R4M wherein M is a natural alpha amino acid derivative having the structure N -H H i CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ris C I-C 5 alkoxy, hydroxy, or -NHOR; R 2 and R 4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -O -CN, 10 -C0 2 R 5 -S0 3 R 5 -CHO, -COR -CONR R -(CH 2 )nNR R, -CF 3 or -NHCOR; 5 6 each R and R are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, with the proviso that the compound is other than N-2-fluorenesulfonylmethionine, N-2- fluorenesulfonyiphenylalanine, N-2-fluorenesulfonylalanine, N-2- fl'uorenesulfonylvaline,N-2-fluorenesulfonylleucine, dibenzofuran-2-sulfonylalamne, dibenzofuran-2-sulfonylvaline, dibenzofuran-2-sulfonylleucine, dibenzofuran-2- sulfonylphenylalanine, dibenzofuran-2-sulfonyserine, dibenzofuran-2-sulfonyltyrosine, dibenzofuiran-2-sulfonylproline, dibenzofuran-2-sulfonytryptophan,dibenzofuran-2- 21 532-OODoc/AC\V -61- sulfonylmethione, dibenzofuran-2-sulfonylglutamine,7-nitrodibenzofuran-2- sulfonylalanine, 7-nitrodibenzofuran-2-sulfonylvaline, 7-nitrodibenzofuran-2- sulfonylleucine, 7-nitrodibenzofuran-2-sulfonylphenylalanine, 7-nitrodibenzofuran-2- sulfonyltyrosine, 7-nitrodibenzofuran-2-sulfonylproline, 7-nitrodibenzofuran-2- sulfonyltryptophan or 7-nitrodibenzofuran-2-sulfonylglutamnine, or a methyl ester of any one of N-2-fluorenesulfonylphenylalanine, N-2-fluorenesulfonylalanine, N-2- fluorenesulfonylvaline,N-2-fluorenesulfonylleucine, dibenzofuran-2-sulfonylalanine, dibenzofuran-2-sulfonylvaline, dibenzofuran-2-sulfonylleucine, dibenzofuran-2- *sulfonyiphenylalanine, dibenzofuran-2-sulfonyltyrosine, dibenzofuran-2-sulfonylproline, 10 dibenzofuran-2-sulfonylglutamnine,7-nitrodibenzofuran-2-sulfonylalanine, 7- nitrodibenzofuran-2-sulfonylvaline, 7-nitrodibenzofuiran-2-sulfonylleucine, 7- nitrodibenzofiiran-2-sulfonylphenylalanine, 7-nitrodibenzofuran-2-sulfonyltyrosine, 7- nitrodibenzofuran-2-sulfonylproline, 7-nitrodibenzofiiran-2-sulfonyltryptophan and 7- nitrodibenzofuran-2-sulfonylglutamine. .15 35. A compound of Formula VIII *fee CO 0 VIII 0 4 S// M wherein M is a natural aplha amino acid derivative having the structure N H H R a is C 1 I-C 5 alkoxy, hydroxy, or -NI0R 5 M 4 20 R is a side chain of a natural alpha amino acid; 21532-00 Doc/ACW -62- R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR s -CN, -CO 2 R 5 -SO 3 R S -CHO, -COR 5 -CONRSR 6 -(CH 2 )nNRR 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrugs thereof. 36. Use of a compound of Formula I 0 2 R S=O 0 R4M 4M wherein M is a natural alpha amino acid derivative having the structure COR a N- H H Rb S •10 X is S, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 alkyl, or C,-C 6 alkyl-phenyl; R a is C 1 -Cs alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -C 1 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -SO 3 R s -CHO, -COR 5 -CONR 5 R 6 -(CH 2 NR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, in the manufacture of a medicament for the treatment of multiple sclerosis. 21532-00.doc/ACW -63- 37. Use according to claim 36 wherein X is 0. 38. Use according to claim 36 wherein X is S. 39. Use according to claim 36 wherein X is CH 2 Use according to claim 36 wherein X is NR Q r 41. Use according to claim 37 wherein R 2 and R 4 are hydrogen. 42. Use according to claim 36 wherein X is CO. 43. Use according to claim 36 wherein X is S(O)n. 44. Use according to claim 36 wherein R' is hydroxy or Ci-C 5 alkoxy or -NHOH or -NHObenzyl. Use according to claim 36 wherein R is the side chain of the natural alpha amino acid, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, phenylalanine, or glycine. 46. Use of a compound of Formula II 0 O II -s=o z 21532-00.DOC/ACW -64- wherein Z is a natural amino acid derivative having the structure CORa H H k R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -COR -CONRSR 6 -(CH 2 )nNR R 6 -CF 3 or -NHCORS; each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHORC; R b is a side chain of a natural alpha amino acid; and Rc is hydrogen, CI-C 5 alkyl, or -CH 2 phenyl; and Sn is 0 to 2, 10 or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase. o; 47. Use according to claim 46 wherein the group 0 -S=O is located at the 2-position of the phenyl ring. Z 48. Use according to claim 46 wherein the group O S= O is located at the 3-position of the phenyl ring. Z 21532-00.DOc/ACW 49. Use of a compound of Formula III O R R =O zIII 4 1 wherein Z is a natural amino acid derivative having the structure CORa -N H H Rb R2 and R4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -CO 2 R 5 -SO3R 5 -CHO, -COR 5 -CONRR 6 -(CH 2 )NR R 6 -CF 3 or -NHCORS; 6 each R and R are independently hydrogen or C 1 -C 5 alkyl; Ra is CI-C 5 alkoxy, hydroxy, or -NHORc; R b is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase. 50. Use of a compound of Formula IV 0 2eZ at2 4 wherein Z is a natural amino acid derivative having the structure wherein Z is a natural amino acid derivative having the structure 21532-00.Doc/ACW -66- CORa N- H R' R 2 and R 4 are independently hydrogen, -Ci-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNRR 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; R" is Ci-C 5 alkoxy, hydroxy, or -NHORc; R b is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and o n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the 10 manufacture of a medicament for inhibiting a matrix metalloproteinase. 51. Use of a compound of Formula V 0 R S=O R Z O wherein Z is a natural amino acid derivative having the structure CORa -N -H H Rb R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, .s -CO 2 R 5 -SO 3 R 5 -CHO, -COR -CONRSR 6 -(CH 2 )nNR R 6 -CF 3 or -NHCOR 5 21532-OO.Doc/ACW -67- each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHORC; R b is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase. 52. Use of a compound of Formula VI O Ra COR S=O VI 10 Ra is C-C alkoxy, hydroxy, or -NHOR a n is 0 to 2; Rb is a side chain of a natural alpha amino acid; and H and R are independently hydrogen, -CC--C alkyl, or -CH phenyl -NO, halogen, -ORand, -CN, -CO -S 3 R, -CHO, -COR, -CONR -(H 2 )NRR 6 -CF 3 or -NHCOR2, each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHORc; n is 0 to 2; R b is a side chain of a natural alpha amino acid; and Rc is hydrogen, C 1 -C 5 alkyl, or -CH 2 phenyl; and s 20 nisOto2, 21532-00ODOI/ACW -68- or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase. 53. Use of a compound of Formula VII O R2 =O VII N 41 R wherein Z is a natural amino acid derivative having the structure 09'CORa SN H H R b* R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -CO 2 R -S0 3 R 5 -CHO, -COR -CONR5R 6 -(CH 2 )nNR R 6 -CF 3 or -NHCORS; 10 each R 5 and R 6 are independently hydrogen or C -C 5 alkyl; SRa is C 1 -C 5 alkoxy, hydroxy, or -NHORC; R Q is hydrogen, CI-C 6 alkyl, or CI-C 6 alkyl-phenyl; *b R is a side chain of a natural alpha amino acid; and Rc is hydrogen, CI-C 5 alkyl, or -CH 2 phenyl; and n is 0 to 2, or the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, in the manufacture of a medicament for inhibiting a matrix metalloproteinase. 54. Use according to claim 36 wherein the compound is (L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid; 21532-00.DOC/ACW 69 (L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid; (L)-2-(dibenzofuran-2-sulfonylamino)-acetic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-succinic acid; (L)-2-(dibenzofuran-2-sulfonylamnino)-3-tritylsulfanyl-propionic acid; (L)-2-(dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid; ~.(L)-2-(dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide; 10()2(ienoua--uloyaio-cei cdtrtbtletr 10(L)-2-(dibenzofuran-2-sulfonylamnino)-acetiic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-propionic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylwmino)-propionpeanic acid tert-butyl ester; (L)-2-(dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid tert-butyl ester; 15 0L--dbnoua--ufnlmn)3mty-etni cdbnyoyaie (L)-2-(dibenzofuran-2-sulfonylamnino)-3-meyl-pentanoic acid tert-butyl ester; 15 (L)-2-(dibenzofuiran-2-sulfonylamino)-3-methyl-pentanic acidbnyoyaie (L)-2-(Dibenzofurane-2-sulfonylamino)-3-enyl-propioic acid;r-uyletr :(L)-2-(7B-dibenzofiran-2-sulfonylamino)-3-methy -butyric acid; (L)-3Mty-2-(7-ol-dibenzofuran-2-sulfonylamino)ty-butyric acid; 3 -Methyl-2-(9-methyl-9H-carbazole-3-sulfonylamino)-butyric acid;' 21 532-00. Doc/ACWM 70 2-(9-Benzyl-9H-carbazole-3-sulfonylamino)-3-methyl-butyric acid; and 2-(9H-Carbazole-3-sulfonylamino)-3 -methyl-butyric acid. Use of a compound of Formula I 0 R S-0 -41 X R M wherein M is a natural alpha amino acid derivative having the structure cow H X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, CI-C 6 alkyl, or CI-C 6 alkyl-phenyl; Ra is CI-C 5 alkoxy, hydroxy, or -NHOR; 2 4 R2 and R4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -OR -CO 2 R -S0 3 R 5 -CHO, -COR 5 -CONR5 R 6, -(CH ),,NR5 R 6, -CF, or each R 5 and R 6 are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of multiple sclerosis. 21532-00 Doc/ACW -71 56. Use of a compound of Formula I 0 I I X R I M wherein M is a natural alpha amino acid derivative having the structure CORa -N H H Rb 5 X is S, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, Ci-C 6 alkyl, or Ci-C 6 alkyl-phenyl; .:Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 10 -CN, -CO 2 R 5 -SO 3 R S -CHO, -CORS, -CONRSR 6 -(CH 2 )nNR R 6 -CF 3 or -NHCOR 5 5 6 S. each R and R are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of atherosclerotic plaque rupture. 57. Use of a compound of Formula I O 21532-o0.DOc/ACW -72- wherein M is a natural alpha amino acid derivative having the structure CORa -N H H b R X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; R Q is hydrogen, alkyl, or C 1 alkyl-phenyl; R a is C 1 -Cs alkoxy, hydroxy, or -NHORS; .R 2 and R 4 are independently hydrogen, -C,-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -SO 3 -CHO, -COR 5 -CONR'R 6 -(CH 2 ),NRR 6 -CF 3 or -NHCOR 5 *0 each R s and R 6 are independently hydrogen or C 1 -C 5 alkyl; and o 10 n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for treating or preventing restenosis. *0 0 *0 58. Use of a compound of Formula I R2 S=O I X R 4 M M wherein M is a natural alpha amino acid derivative having the structure CORa -N H H Rb X is S, S(O)n CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; 21532-00.DOC/ACW 73 RQ is hydrogen, CI-C 6 alkyl, or C 1 -C 6 alkyl-phenyl; R a is C 1 -C 5 alkoxy, hydroxy, or -NIHOR 2 R and R 4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 (CH 2 5 R 6 -CF 3 or -NHCOR each R 5and R6 are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of aortic aneurism. 59. Use of a compound of Formula I 00 *0 0 -4 wherein M is a natural alpha amino acid derivative having the structure COW N -H H X is S, S(OL, CH 2 CO, or NO~; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, C I-C 6 alkyl, or C I-C 6 alkyl-phenyl; Ra is C I-C 5 alkoxy, hydroxy, or -NI0R 5 2 45 R and R4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -CO 2 R 5, _SO 3 R 5, -CHO, -COR 5, -CONRR R, -(CH 2 )nNR R6, -CF 3 or each R 5and R6 are independently hydrogen or C I-C 5 alkyl; and 21 532-OO.DocACMI -74- n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of heart failure. Use of a compound of Formula I O co N I X is S, S(O). CH2, CO, or NRQ; X R4 M wherein M is a natural alpha amino acid derivative having the structure -N H i" X is S, CH2, CO, or NR R b is a side chain of a natural alpha amino acid; 10 RQ is hydrogen, Ci-C, alkyl, or alkyl-phenyl; R a is C-Cs alkoxy, hydroxy, or -NHORS; -CN, -CO2R 5 -S03R S -CHO, -COR 5 -CONRR 6 -(CH2)NRSR 6 -CF3, or each R 5 and R 6 are independently hydrogen or Ci-C5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of periodontal disease. 21532-00 DOC/ACW 75 61. Use of a compound of Formula I 0 wherein M is a natural alpha amino acid derivative having the structure N -H H 5X is S, S(O)n, CH 2 CO, or NRQ; Rb is a side chain of a natural alpha amino acid; RQ is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is C I-C 5 alkoxy, hydroxy, or -NHOR; 2 45 R and R4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR 10 -N C 2 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 (CH 2 ),NR 5 R 6 or -NHCOR'; io 4N -02 Le 4,0 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the 4 manufacture of a medicament for the treatment of corneal ulceration. 62. Use of a compound of Formula I 0 2 S 0 R 3 S1 0 21 532-OO.Doc/ACW -76- wherein M is a natural alpha amino acid derivative having the structure COR a N H H b X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; R Q is hydrogen, Ci-C 6 alkyl, or CI-C 6 alkyl-phenyl; R a is Ci-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -COR 5 -CONRSR 6 -(CH 2 )NRR 6 -CF3, or -NHCOR 5 each R and R 6 are independently hydrogen or CI-C 5 alkyl; and S 10 n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of bums. W a 63. Use of a compound of Formula I O R2 -s I IIIIs S 4 *R S- 0 X R4 M wherein M is a natural alpha amino acid derivative having the structure CORa -N H H R X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; 21532-00.DOc/ACW 77 RQ is hydrogen, CI-C 6 alkyl, or C 1 6 alkyl-phenyl; Ra is C I-C 5 alkoxy, hydroxy, or -NHOR 2 4 R2 and R4 are independently hydrogen, -C I-C 5 alkyl, phenyl -NO 2 halogen, -OR -CN, -C0 2 R 5 -S0 3 R 5 -CHO, -COR', -CONR 5 R 6 -(CH 2 )"NR 5 R 6 -CF 3 or -NI{COR each R 5and R 6are independently hydrogen or C I-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of decubital ulcers. 64. Use of a compound of Formula I 0600 S-0 *ses whri santrl()6lh mn cddrvtiehvn h tutr 5 cow R~ H~ wrin M siscan a natural alpha amino acid;rvtv ain h tutr shdogn IC lkl rC-6 lyShnl Ra s C-C5alkxyhydoxy orCOHRa 05 R2 anS r neednl yrgn CI_5akl hnl-0,hlgn O -C0 -C2 CN5R ,-C2nRR6 C, each~- H n r neednl hdoe rCI-5akl n 21532.O.Doc/ACW 78- n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of chronic ulcers or wounds. Use of a compound of Formula I O X R4 11 M wherein M is a natural alpha amino acid derivative having the structure CORa H R b is a side chain of a natural alpha amino acid; R is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is C 1 -C 5 alkoxy, hydroxy, or -NHOR; R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR, -CN, -C0 2 R -S0 3 R s -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )NR 5 R 6 -CF 3 or -NHCOR each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer metastasis. 21532-00 Doc/ACW -79- 66. Use of a compound of Formula I O R2 s--O I N-4 M wherein M is a natural alpha amino acid derivative having the structure COR a -N H H R 5 X is S, S(0)n, CH 2 CO, or NR Q R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 10 -CN, -CO 2 R S -SO 3 R 5 -CHO, -COR 5 -CONRSR 6 -(CH 2 )NR 5 R 6 -CF 3 or -NHCOR; each R and R are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of tumor angiogenesis. 67. Use of a compound of Formula I 0 o S R2 -O II 1(2 I S4- O 21 532-O.DOc/ACW wherein M is a natural alpha amino acid derivative having the structure CORa -N H H Rb X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; R Q is hydrogen, C 1 -C 6 alkyl, or Ci-C 6 alkyl-phenyl; Ra is Ci-C 5 alkoxy, hydroxy, or -NHOR 5 S.R 2 and R 4 are independently hydrogen, -CI-C 5 alkyl, phenyl -NO 2 halogen, -OR 5 S* -CN, -CO 2 R 5 -SO 3 R 5 -CHO, -COR 5 -CONRSR 6 -(CH 2 )nNRR 6 -CF 3 or -NHCOR; each R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of arthritis. 68. Use of a compound of Formula I oooSo0 x I 4 X R M wherein M is a natural alpha amino acid derivative having the structure CORa N H H b R X is S, S(O)n, CH 2 CO, or NRQ; R b is a side chain of a natural alpha amino acid; 21532-OO.D c/ACW -81 R Q is hydrogen, CI-C 6 alkyl, or C 1 -C 6 alkyl-phenyl; Ra is CI-C 5 alkoxy, hydroxy, or -NHOR 5 R 2 and R 4 are independently hydrogen, -C 1 -C 5 alkyl, phenyl -NO 2 halogen, -OR 5 -CN, -CO 2 R 5 -S0 3 R 5 -CHO, -COR 5 -CONR 5 R 6 -(CH 2 )nNR 5 R 6 -CF 3 or -NHCOR 5 each R 5 and R 6 are independently hydrogen or Ci-C 5 alkyl; and n is 0 to 2, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in the manufacture of a medicament for the treatment of autoimmune or inflammatory disease dependent upon tissue invasion by leukocytes. 10 69. A method of inhibiting a matrix metalloproteinase comprising administering to a *patient a therapeutically effective amount of a compound of any one of Formula I to Formula VIII, substantially as herein described with reference to any one of the examples. 15 70. A method of treating multiple sclerosis comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 71. A method of treating atherosclerotic plaque rupture comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 21532-00.Doc/ACW -82- 72. A method of treating or preventing restenosis comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 73. A method of treating aortic aneurism comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. i:' 10 74. A method of treating heart failure comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. S. 75. A method of treating periodontal disease comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein 15 described with reference to any one of the examples. 76. A method of treating comeal ulceration comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 77. A method of treating bums comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 21532-O.DocACW -83- 78. A method of treating decubital ulcers comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 79. A method of treating chronic ulcers or wounds comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. ,o 80. A method of treating cancer metastasis comprising administering to a patient a 10 therapeutically effective amount of a compound of Formula I, substantially as herein 66 described with reference to any one of the examples. 81. A method of treating tumor angiogenesis comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein *6 6 15 described with reference to any one of the examples. .6 6 82. A method of treating arthritis comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 83. A method of treating autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes comprising administering to a patient a therapeutically effective amount of a compound of Formula I, substantially as herein described with reference to any one of the examples. 21532-00.Doc/ACW 84- 86. Use of a compound of Formual I in the manufacture of a medicament for administration to a patient, substantially as herein described with reference to any one of the examples. DATED this 1 st Day of May, 2001 WARNER-LAMBERT COMPANY Attorney: DAVID A. ADAMTHWAITE Fellow Institute of Patent and Trade Mark Attorneys of Australia of BALDWIN SHELSTON WATERS 21532-OO.Doc/ACW