JP2000517341A - Matrix metalloproteinase inhibitors and their therapeutic use - Google Patents

Abstract

(57) Summary The present invention relates to a method for inhibiting matrix metalloproteinases using a compound that is a dibenzofuran sulfonamide derivative having formula (I). In particular, the present invention relates to diseases involving matrix metalloproteinases, such as multiple sclerosis, destruction of atherosclerotic plaque, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, pressure ulcers, chronic It relates to a method of treating ulcer or trauma, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune disease or inflammatory disease due to leukocyte tissue invasion.

Description

DETAILED DESCRIPTION OF THE INVENTION               Matrix metalloproteinase inhibitors and               Their therapeutic use Field of the invention   The present invention provides a method for preparing a matrix using a compound that is a dibenzofuran sulfonamide derivative. The present invention relates to a method for inhibiting a metalloproteinase. In particular, the present invention Diseases associated with xus metalloproteinases, such as multiple sclerosis, atheroma Atherosclerotic plaque destruction, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulcer Burns, burns, pressure ulcers, chronic ulcers or trauma, cancer metastasis, tumor angiogenesis, arthritis, Treats other autoimmune or inflammatory diseases caused by leukocyte invasion About the method. Background of the Invention   The compounds of the present invention can be used as matrix metalloproteinases, e.g. And inhibitors of gelatin-1 and gelatinase A (72 kDa gelatinase).   Stromelysin-1 and gelatinase A are available as matrix metalloproteiners. He is a member of MSE. Other members include fibroblast collagenase, Neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin- 2, stromelysin-3, matrilysin, collagenase 3 and new A newly discovered membrane-related matrix metalloproteinase (Sato H, Takano T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M. , Nature, 1994; 370: 61-65).   Stromelysin-1 is also known as MMP03, and gelatinase A Also known as MP02. In addition, some other matrix metalloproteins Nase is known.   MMP01 Fibroblast collagenase   MMP07 Matrilysin   MMP09 gelatinase B, and   MMP13 collagenase-3   Zinc, a catalyst in matrix metalloproteinases, is A typical center for. Modification of the substrate by introducing a chelating group is strongly Peptides containing potent inhibitors such as peptide hydroxamates and thiols Generate a code. Natural endogenous nature of peptide hydroxamates and MMPs (TIMPs) Inhibitors have been used successfully to treat animal models of cancer and inflammation.   The ability of matrix metalloproteinases to degrade various components of connective tissue More likely, these proteinases are potential targets for controlling pathological processes. Become a target. For example, destruction of atherosclerotic plaque can lead to coronary thrombosis This is the most common event that happens. Extracellular surrounding these plaques by MMPs Matrix instability and degradation are proposed as causes of plaque cracking Have been. Shoulder of foam cell accumulation in human atherosclerotic plaque And the region are parts of gelatinase B, stromelysin-1, and stromal collagenase. Shows differentially increased expression. In the system, the zymography of this tissue is increased Exhibiting gelatin-degrading and casein-degrading activities (Galla Z.S., Sukhova G .K., Lark M.W., and Libby P., “Increased expression of matrix metallo-p roteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques ", J. Clin. Invest., 1994; 94: 2494-2503). High levels of stromelysin RNA messages indicate that heart transplant patients may In atherosclerotic plaque removed from It has been found to be localized to individual cells (Henney A.M., Wakeley P.R. , Davies M.J., Foster K., Hembry R., Murphy G., and Humphries S., “Local ization of stromelysingene expression in atheroscle rotic plaques by in situ hybridization ", Proc. Nat'1. Acad. Sci., 1991; 88: 8154-8158).   Matrix metalloproteinase inhibitors thin the central aortic wall. It may be effective in treating degenerative aortic disease associated with. MMPs are growing Levels of proteolytic activity have been identified in patients with aortic aneurysms and aortic stenosis (Vine N. and Powell J.T., "Metalloproteinases in degenerative aortic di seases ", Clin. Sci., 1991; 81: 233-239).   Although heart failure results from a variety of different etiologies, a common feature is the independent risk to mortality. Cardiac hypertrophy has been identified as a stout factor (Lee T.H., Hamilton M.A., Steven son L.W., Moriguchi J.D., Fonarow G.C., Child J.S., Laks H, and Walden J .A., “Impact of left ventricular size on the survival in advanced heart  failure ”, Am. J. Cardiol., 1993; 72: 672-676). This may be related to the destruction of the extracellular matrix. Matrix meta Loproteinase is increased in patients with idiopathic and ischemic heart failure (Reddy  H.K., Tyagi S.C., Tjaha I.E., Voelker D.J., Campbell S.E., and Weber K. T., “Activated myocardial collagenase in idiopathic dilated cardiomyopa thy ”, Clin. Res., 1993; 41: 660A; Tyagi S.C., Reddy H.K., Voelker D., Tja ra I.E., and Weber K.T., “Myocardial collagenase in failing human heart Clin. Res., 1993; 41: 681A). An animal model of heart failure is the induction of gelatinase. Is important for cardiac hypertrophy (Armstrong P.W., Moe G.W., Howard R.J., Grima) E.A., and Cruz T.F., “Structural remodeling in heart failure: gelatinase induction ”. Can. J. Cardiol., 1994; 10: 214-220), and heart Hypertrophy precedes a serious defect in cardiac function (Sabbah H.N., Kono T., Stein P.D., Mancini G.B., and Goldstein S., “Left ventricular shape changes d uring the course of evolving heart failure ”. Am. J. Physiol., 1992; 263. : H266-H270). Neointimal proliferation leads to restenosis after coronary angioplasty Often happens. Migration of vascular smooth muscle cells (VSMCs) from the media to the neointima is Is important in the development and progression of vascular disease in the Predictable results (Bendeck M.P., Zempo N., Clowes A.W., Galardy R.E., and Reidy M., “Smooth muscle cell migration and matrix metalloproteinas e expression after arterial injury in the rat ”, Circulation Research, 1 994; 75: 539-545). Northern blot and zymographic analysis are Shows that Aase A is the major MMP expressed and excreted by these cells did. Further, an antiserum that can selectively neutralize gelatinase A activity, It also inhibited VSMC migration across the basement membrane barrier. After vascular injury, 20 VSMCs Gelatinase A activity, which is more than doubled, has a motile phenotype that grows from rest. (Pauly R.R., Passaniti A., Bilato C., Monticone R., Chen g L., Papadopoulos N., Gluzband Y.A., Smith L., Weinstein C., Lakatta E. , And Crow M.T., “Migration of cultured vascular smooth muscle cells th rough a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation ”. Circulation Research, 1 994; 75: 41-54).   Collagenase and stromelysin activities are fibroblasts isolated from inflamed gingiva (Uitto V.J., Applegren R., and Robinson P.J., “Collagenase a nd neutral metalloproteinase activity in extracts from inflamed human gingiva ”, J. Periodontal Res., 1981; 16: 417-424), Enzyme levels correlate with the severity of gum disease (Overall C.M., Wiebkin O.W. , And Thonard J.C., “Demonstrations of tissue collagenase activity in v ivo and its relationship to inflammation severity in human gingiva ”, J . Periodontal Res., 1987; 22: 81-88). Proteolysis of extracellular matrix It is observed in corneal ulceration following Lucari burn (Brown S.I., Weller C.A., and Wass erman H.E., "Collagenolytic activity of alkali burned corneas". Arch. O pthalmol., 1969; 81: 370-373). Thiol-containing peptides are alkaline burned rabbits Inhibits collagenase isolated from the cornea of humans (Burns F.R., Stack M.S., Gray  R.D., and Paterson C.A., Invest. Opththamol., 1989; 30: 1569-1575).   Stromelysin is produced by basic keratinocytes in various chronic ulcers (Saarialho-Kere U.K., Ulpu K., Pentland A.P., Birkedal-Hansen H, Parks W.C., Welgus H.G., "Distinct populations of basal keratinocytes ex press stromelysin-1 and stromelysin-2 in chronic wounds ", J. Clin. Inves t., 1994; 94: 79-88).   Stromelysin-1 mRNA and protein damage to the growing epidermis, trauma Detected in basal keratinocytes adjacent but distal to the end of the keratinocyte. Follow Thus, stromelysin-1 may interfere with epidermal healing. Davies et al. (Cancer  Res., 1993; 53: 2087-2091) shows that peptide hydroxamate, BB-94, Reduce the load and improve the survival of mice receiving xenografts of human ovarian tumors Reported to extend. Peptides with a conserved MMP propeptide sequence A weak inhibitor of gelatinase A and humans through the reconstituted basement membrane layer Inhibits tumor cell invasion (Melchiori A., Albili A., Ray J.M., and Stet1ler-Ste venson W.G., Cancer Res., 1992; 52: 2353-2356), the nature of metalloproteinase-2 (TIMP-2) Tissue inhibitors have also been shown to block tumor cell invasion in in vitro models (DeClerck Y.A., Perez N., Shimada H, Boone T.C., Langley K.E., and Taylo r S.M., Cancer Res., 1992; 52: 701-708). Human cancer research shows that gelatin ZeA is activated on the surface of invasive tumor cells (Strongin A.Y., Marmer B.L., Grant  G.A., and Goldberg G.I., J. Biol. Chem., 1993; 268: 14033-14039), and It is maintained there through interaction with receptor-like molecules (Monsky W.L., Kelly T., Lin C.-Y., Yeh Y., Stettler-Stevenson W.G., Mueller S.C., and Chen W. -T., Cancer Res., 1993; 53: 3159-3164). MMPs inhibitors are tumor Active in models of angiogenesis (Taraboletti G., Garofalo A., Belotti D. , Drudis T., Borsotti P., Scanziani E., Brown P.D., and Giavazzi R., Jou rnal of the National Cancer Institute, 1995; 87: 293, and Benelli R., Ad atia R., Ensoli B., Stettler-Stevenson W.G., Santi L., and Albini A., Onc ology Research, 1994; 6: 251-257).   Some studies have compared rheumatic patients with osteoarthritis compared to controls. Showed a stable increase in stromelysin and collagenase in synovial fluid from the elderly (Walak ovits L.A., Moore V.L., Bhardwaj N., Gal1ick G.S., and Lark M.W., "Dete ction of stromelysin and collagenase in synovial fluid fromr patients wi th rheumatoid arthritis and post-traumatic knee injury ”, Arthritis Rheu m., 1992; 35: 35-42; Zafarullah M., Pelletier J.P., Cloutier J.M., and Mar cel-Pelletier J., “Elevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia ”. J. Rheumatol. , 1993; 20: 693-697). TIMP-1 and TIMP-2 are used in cattle nose and pig joint softness for arthritis. Both bone models Degradation of collagen prevents the formation of collagen fragments, but proteoglycan Does not interfere with On the other hand, synthetic peptide hydroxamates use both fragments. (H.J., Plumpton T.A., Harper G.P. , And Cawston T.E., Agents Actions, 1992; 37: 147-154; Ellis A.J., Curry V A., Powell E.K., and Cawston T.E., Biochem. Biophys. Res. Commun., 1994 ; 201: 94-101).   Gijbels et al. (J. Clin. Invest., 1994; 94: 2177-2182) recently described multiple sclerosis. Suggests the use of MMP inhibitors in the treatment of autoimmune inflammatory diseases such as Control the development or clinical manifestation of experimental allergic encephalomyelitis (EAE) A peptide hydroxamate, GM6001, which antagonizes PEG was described. Recent by Madri Studies have shown a role for gelatinase A in the exudation of T-cells from the bloodstream during inflammation (Ramanic A.M. and Madri J.A., “The Induction of 72-kD Gelatin ase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent ” . J. Cell Biology, 1994; 125: 1165-1178). This movement across the endothelial cell layer Cooperates with the introduction of gelatinase A and binds to vascular cell adhesion molecule-1 (VCAM-1). And is mediated by Edema and inflammation occur in the CNS once its barrier is weakened . Leukocyte migration across the blood-brain barrier is known to be involved in the inflammatory response of EAE I have. T-cell activated by inhibition of metalloproteinase gelatinase A Vesicles prevent extracellular matrix degradation required for CNS penetration You.   These studies indicate that stromelysin-1 and / or gelatinase A are blocked. The harmful agent may cause lymphocyte infiltration, metastasis or improper migration of activated cells, or Is an extracellular matrix that causes inflammation due to loss of structural integrity required for organ function The idea of treating diseases involving rupture of Rix The basis was provided.   We have discovered that matrix metalloproteinases, in particular stromelysin-1 And inhibitors of gelatinase A, and therefore multiple sclerosis, atherosclerosis Destruction of sclerosis plaque, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, fire Wound, pressure sore, chronic ulcer or trauma, cancer metastasis, tumor angiogenesis, arthritis, or leukemia Useful as a therapeutic agent for other autoimmune diseases or inflammatory diseases caused by infiltration of spheres into tissues A series of tricyclic aromatic sulfonamide compounds has been identified. Summary of the Invention   The present invention provides compounds of formula I (Where M is a structure A natural (L) α amino acid derivative having   X is O, S, S (O)_n, CH_Two, CO, or NR^QAnd   R^QIs hydrogen, C₁~ C₆Alkyl, or C₁~ C₆Alkyl-phenyl,   R is the side chain of a natural α-amino acid;   R¹Is C₁~ C_FiveAlkoxy, hydroxy, or -NHOR^FiveAnd   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_Three,Also Is -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Matrix metalloproteiner comprising administering to a patient a therapeutically effective amount of For inhibiting matrix metalloproteinases in patients in need thereof I will provide a.   In certain embodiments 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_TwoIt is.   In another embodiment of the invention of formula I, X is NR^QIt is.   In a preferred embodiment of the invention of formula I, X is O, R^TwoAnd R^FourIs 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)_nIt is.   In another preferred embodiment of the invention of formula I, R¹Is hydroxy, C₁~ C_FiveAlkoxy , -NHOH or -NHO benzyl.   In a further preferred embodiment, R is a natural alpha amino acid, glycine, alanine, Valine, leucine, isoleucine, cysteine, aspartic acid or phenyl It is the side chain of lualanine.   In another embodiment, the present invention requires matrix metalloproteinase inhibition. For inhibiting matrix metalloproteinase in a patient having (Where Z is a structure A natural (L) α amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF^ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In a preferred embodiment of the process comprising Formula II, Is located at the 2-position of the phenyl ring.   In another preferred embodiment of the process comprising Formula II, Is located at the 3-position of the phenyl ring.   In addition, the matrix of patients requiring matrix metalloproteinase inhibition A method of inhibiting a metalloproteinase, i.e. formula III (Where Z is a structure A natural (L) amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In addition, the matrix of patients requiring matrix metalloproteinase inhibition Methods for inhibiting smetalloproteinases, i.e. formula IV (Where Z is a structure A natural (L) amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C₆Alkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In addition, the matrix of patients requiring matrix metalloproteinase inhibition A method for inhibiting a metalloproteinase, ie, a formula V (Where Z is a structure A natural (L) amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In addition, the matrix of patients requiring matrix metalloproteinase inhibition A method for inhibiting a metalloproteinase, i.e., formula VI(Where Z is a structure A natural (L) amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   n is 0 to 2,   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In addition, the matrix of patients requiring matrix metalloproteinase inhibition A method of inhibiting a metalloproteinase, i.e. formula VII (Where Z is a structureA natural (L) amino acid derivative having   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^cAnd   R^QIs hydrogen, C₁~ C₆Alkyl or C₁~ C₆Alkyl-phenyl,   R^bIs the side chain of a natural α-amino acid,   R^cIs hydrogen, C₁~ C_FiveAlkyl or -CH_TwoPhenyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof Administering to a patient a therapeutically effective amount of   In a most preferred embodiment, the compound of Formulas I-VIII is   (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-penta Acid,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-penta Acid,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-phenyl-pro Pionic 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-sulfonylamino) -3-tritylsulf Anilyl-propionic acid,   (L) -2- (Dibenzofuran-2-sulfonylamino) -3-mercaptop Ropionic acid,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-penta Acid hydroxyamide,   (L) -2- (dibenzofuran-2-sulfonylamino) -tert-butyl acetate Steal,   (L) -2- (dibenzofuran-2-sulfonylamino) -propionic acid tert- Butyl ester,   (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl- Pentanoic acid tert-butyl ester,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-penta Acid tert-butyl ester,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-penta Benzyloxyamide acid,   (L) -2- (dibenzofuran-2-sulfonylamino) -3-phenyl-pro Pionic acid tert-butyl ester,   (L) -2- (dibenzofuran-3-sulfonylamino) -3-methyl-butyric acid,   3-methyl-2- (9-methyl-9H-carbazole-3-sulfonylamino ) -Butyric acid,   2- (9-benzyl-9H-carbazole-3-sulfonylamino) -3-me Tyl-butyric acid,   (L) -2- (9H-fluorene-2-sulfonylamino) -3-methyl-butyric acid ,   (L) -2- (5,5-dioxo-5H-5λ⁶-Dibenzothiophene-3-sulfo Nylamino) -3-methyl-butyric acid,   (L) -2- (dibenzothiophene-2-sulfonylamino) -3-methyl-butyric acid,   (L) -2- (7-bromo-dibenzofuran-2-sulfonylamino) -3-meth Tyl-butyric acid,   (L) -3-methyl-2- (7-phenyldibenzofuran-2-sulfonylamido G) -butyric acid, and   2- (9H-carbazole-3-sulfonylamino) -3-methyl-butyric acid It is.   The present invention also relates to a method for treating multiple sclerosis, i.e., for patients with multiple sclerosis. There is provided a method comprising administering a therapeutically effective amount of a compound of Formulas I-VIII.   The present invention also provides a method of treating atherosclerotic plaque destruction, Therapeutically effective in patients at risk of atherosclerotic plaque destruction A method comprising administering an effective amount of a compound of Formulas I-VIII.   The present invention also relates to a method for treating or preventing restenosis, i.e. Administers a therapeutically effective amount of a compound of Formulas I-VIII to a patient at risk for restenosis Providing a method comprising:   The present invention also provides a method of treating an aortic aneurysm, ie, a therapeutically useful method for a patient with an aortic aneurysm. There is provided a method comprising administering an effective amount of a compound of Formulas I-VIII.   The present invention also provides a method for treating heart failure, i.e., a therapeutically effective treatment for patients with heart failure. Providing a method comprising administering an amount of a compound of Formulas I-VIII.   Also, the present invention provides a method for treating periodontal disease, that is There is provided a method comprising administering an effective amount of a compound of Formulas I-VIII.   The present invention also provides a method for treating corneal ulceration, that is, a method for treating corneal ulcer patients. There is provided a method comprising administering an effective amount of a compound of Formulas I-VIII.   The present invention also provides a method of treating burns, i.e., a therapeutically effective treatment for burned patients. Providing a method comprising administering an amount of a compound of Formulas I-VIII.   In addition, the present invention provides a method for treating pressure ulcers, A method comprising administering an effective amount of a compound of Formulas I-VIII.   The invention also relates to a method for treating chronic ulcers or trauma, i.e. Administering to a trauma patient a therapeutically effective amount of a compound of Formulas I-VIII I will provide a.   The present invention also provides a method for treating cancer metastasis, that is, a method for treating cancer metastasis in patients. There is provided a method comprising administering an effective amount of a compound of Formulas I-VIII.   The invention also relates to a method of treating tumor angiogenesis, i.e. a patient with tumor angiogenesis. Administering a therapeutically effective amount of a compound of Formulas I-VIII to the subject. .   The present invention also provides a method of treating arthritis, i.e., a therapeutically effective treatment for patients with arthritis. Providing a method comprising administering an amount of a compound of Formulas I-VIII.   Further, the present invention treats an autoimmune disease or an inflammatory disease caused by leukocyte invasion of a tissue. Of autoimmune diseases or inflammatory diseases caused by infiltration of leukocytes into tissues Administering to a subject a therapeutically effective amount of a compound of Formulas I-VIII. You.   The present invention also provides compounds of formula I (Where M is a structure A natural (L) α amino acid derivative having   X is O, S, S (O)_n, CH_Two, CO, or NR^QAnd   R^bIs the side chain of a natural α-amino acid,   R^QIs hydrogen, C₁~ C₆Alkyl or C₁~ C₆Alkyl-phenyl,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^FiveAnd   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof I will provide a.   The present invention also provides a compound of formula VIII (Where M is a structure A natural (L) α amino acid derivative having   R^bIs the side chain of a natural α-amino acid,   R^aIs C₁~ C_FiveAlkoxy, hydroxy or -NHOR^FiveAnd   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl,   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prodrugs thereof I will provide a. DETAILED DESCRIPTION OF THE INVENTION   The present invention provides compounds of formula I(Where M is a structure A natural (L) α amino acid derivative having   X is O, S, S (O)_n, CH_Two, CO or NRQ,   R is the side chain of a natural α-amino acid;   R¹Is C₁~ C_FiveAlkoxy, hydroxy or -NHOR^FiveAnd   R^TwoAnd R^FourIs independently hydrogen, -C₁~ C_FiveAlkyl, phenyl-NO_Two, Halogen, -O R^Five, -CN, -CO_TwoR^Five, -SO_ThreeR^Five, -CHO, -COR^Five, -CONR^FiveR⁶,-(CH_Two)_nNR^FiveR⁶, -CF_ThreeOr -NHCOR^FiveAnd   R^FiveAnd R⁶Are each independently hydrogen or C₁~ C_FiveAlkyl, and   n is 0 to 2) And pharmaceutically acceptable salts, esters, amides and prod thereof Matrix metallopro comprising administering to a patient a therapeutically effective amount of rug Inhibits matrix metalloproteinases in patients in need of proteinase inhibition Provide a way to   The term "alkyl" means a straight or branched chain hydrocarbon. Archi Representative examples of methyl groups include methyl, ethyl, propyl, isopropyl, Butyl, tert-butyl, sec-butyl, pentyl and hexyl.   The term "alkoxy" refers to an alkyl group attached to an oxygen atom. A Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, And oxy and isobutoxy.   The term "halogen" includes chlorine, fluorine, bromine and iodine.   The term "phenyl" also means that one or more water And substituted phenyl, in which the element is substituted by an organic group. Examples of suitable substituents include Halogen, C₁~ C₆Alkoxy, -CF_Three, -NO_Two, -NH_Two, -NH (C₁~ C₆Alkyl) or- N (C₁~ C₆Alkyl)_TwoBut not limited thereto.   The sign "-" means binding.   The term "side chain of a natural alpha amino acid" refers to a compound of the formula H_TwoNatural amino of N-CH (Q) -COOH Means the group Q in the acid. Examples of natural α-amino acid side chains include alanine, Guinine, asparagine, aspartic acid, cysteine, glutamic acid, glycine , Histidine, isoleucine, leucine, lysine, methionine, phenylalanine , Proline, serine, threonine, tryptophan, tyrosine and valine And side chains.   Naturally occurring alpha amino acids are amino acids found in living organisms. Examples of such amino acids Glycine, alanine, valine, leucine, isoleucine, Phenylalanine, proline, serine, threonine, tyrosine, asparagine, Glutamine, lysine, arginine, tryptophan, histidine, cysteine, Methionine, aspartic acid and glutamic acid.   Functional groups in the amino acid side chains may be protected. For example, if the carboxyl group It may be esterified and the amino group is converted to an amide or carbamate. And the hydroxyl group may be converted to an ether or ester. And the thiol group may be converted to a thioether or thioester. No.   The compounds of Formulas I-VIII may be used alone or as part of a pharmaceutically acceptable composition. It may be administered to a patient. The composition can be administered to a patient, e.g., humans and animals. By mouth, rectally, parenterally (intravenously, intramuscularly or subcutaneously), into the cisternal, Intravaginally, intraperitoneally, intravesically, topically (powder, ointment or infusion), or oral It may be administered by spray or nasal spray.   Suitable compositions for parenteral injection include sterile physiologically acceptable aqueous or non-aqueous solutions Solutions, i.e. dispersions, suspensions or emulsions, and sterile injectable solutions or It may consist of a sterilized powder for dissolving in the dispersion. Proper aqueous solution Examples of non-aqueous carriers, diluents, solvents or vehicles are water, ethanol , Polyols (propylene glycol, polyethylene glycol, glycerol And appropriate mixtures thereof, vegetable oils (eg olive oil), and injections Organic esters such as ethyl oleate. Suitable fluidity, even if For example, by coating with lecithin, etc. Can be maintained by maintaining diameter and by using surfactants .   These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and preparations May be included. Prevention of the action of microorganisms includes various antibacterial and antifungal agents, For example, with paraben, chlorobutanol, phenol, sorbic acid, etc. Can be done. It is also desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. No. Prolonged absorption of injectable medicines may involve substances which delay the absorption, for example, monostearyl Obtained by use of aluminum phosphate and gelatin.   Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules Is mentioned. In the solid dosage form, the active compound comprises at least one It is mixed with an active common excipient (or carrier), for example, citric acid Sodium or dicalcium phosphate or (a) a filler or bulking agent, such as Starch, lactose, sucrose, glucose, mannitol and silicic acid, ( b) binders such as carboxymethylcellulose, alginate, gelatin, Ribyl pyrrolidone, sucrose and gum arabic, (c) wetting agents such as Serol, (d) disintegrants such as agar, calcium carbonate, potato starch or tapi Oka starch, alginic acid, certain complex silicates and sodium carbonate, (e) retarder solution Liquids such as paraffins, (f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, (h A) adsorbents such as kaolin and bentonite, and (i) lubricants such as tall , Calcium stearate, magnesium stearate, solid polyethylene glycol Recall, sodium lauryl sulfate, or a mixture thereof. capsule, In the case of tablets and pills, the dosage form may comprise a buffer.   Solid compositions of a similar type include lactose or milk sugar and Soft and hard using excipients such as It may be used as a filling in degelatin capsules.   Solid dosage forms such as tablets, dragees, capsules, pills and granules may be Coatings and shells, such as enteric coatings and other well-known techniques. It may be made. These may contain opacifiers and, in a delayed manner, A composition which releases the active compound or compounds in a part of the intestinal tract, Is also good. Examples of inclusion compositions that can be used are polymeric substances and waxes. The active compound, if appropriate, is prepared using one or more of the above-mentioned excipients. In microencapsulated form,   Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs are included. Liquid dosage form in addition to the active compound The form is an inert diluent commonly used in the art, such as water or other solvents, It may contain solubilizers and emulsifiers, such as ethyl alcohol, Pill alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid ben Jill, propylene glycol, 1,3-butylene glycol, dimethylformami Oil, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, Castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan or mixtures of these substances Compounds.   In addition to such inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents and the like. Suspensions, sweetening, flavoring and flavoring agents may also be included.   In addition to the active compound, suspensions can be prepared as suspending agents, for example, ethoxylated isostere. Allyl alcohol, polyoxyethylene sorbitol and sorby Tanester, microcrystalline cellulose, aluminum metahydroxide, vent Knight, agar and tragacanth, or mixtures of these substances You may.   Compositions for rectal administration are preferably suitable nonirritating excipients of the compounds of the invention. Agent or carrier, for example, cocoa butter, polyethylene glycol, Is a suppository that can be prepared by mixing with a suppository. Solid at temperature but liquid at body temperature, and therefore dissolved in the rectum or vaginal cavity, Releases active compound.   Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and And inhalants. A physiologically acceptable carrier in which the active ingredient is sterile and And any preservatives, buffers or propellants as may be required. Ophthalmic The formulations, i.e., ophthalmic ointments, powders and solutions, are intended to be within the scope of the present invention. It is intended.   The compounds of the present invention can be administered to a patient at a dosage level in the range of about 0.1 to about 1,000 mg per day. Can be administered. For a normal human adult weighing about 70 kg, per day Dosages in the range of about 0.01 to about 100 mg / kg (body weight) are preferred. However, used The particular dosage given can vary. For example, the dosage may be Various factors, including the severity of the condition being treated and the pharmacological activity of the compound used, It can depend on factors. Determination of the optimal dosage for a particular patient is well known to those of skill in the art. You. The term "patient" includes humans and animals.   As used herein, "pharmaceutically acceptable salts, esters, amides and pro- The term "drug" refers to their carboxylate salts, amino acid addition salts, Ter, amide and prodrugs of the compounds of the invention are meant, Excessive toxicity, irritation, allergies within the reach of medical judgment -No reaction, suitable for use in contact with patient's tissue, and reasonable benefit / Corresponds to risk ratios and is effective for their intended use; Thus, where possible, it is a zwitterionic form of the compound of the invention. The term "salt" Means relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts may be purified in-system during final isolation and purification of the compound, or The compounds are reacted separately with the appropriate organic or inorganic acids in free base form and And thus isolating the salt thus formed. Representative salt and Include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate , Valerate, oleate, palmitate, stearate, laurate, Borate, benzoate, lactate, phosphate, toluenesulfonate, citrate , Maleate, fumarate, succinate, tartrate, naphthylate, mesylate Salts, glucoheptonate, lactobionate and lauryl sulfonate No. These are alkali and alkaline earth metals such as sodium, Similarly non-toxic ammonia such as lithium, potassium, calcium, magnesium , Quaternary ammonium and amine cations, including but not limited to ammonia , Tetramethylammonium, tetraethylammonium, methylamine, Includes dimethylamine, trimethylamine, triethylamine, ethylamine, etc. (Eg, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. ., 1977: 66 (1-19), incorporated herein by reference).   Examples of pharmaceutically acceptable, non-toxic esters of compounds of the present invention include:₁~ C₆A And alkyl groups which are straight or branched. Tolerance Ester is also C_Five~ C₇Cycloalkyl esters, also arylalkyl Esters also include, but are not limited to, benzyl. C₁~ C_FourAlkyl esters are preferred. Esters of the compounds of the invention can be prepared in the usual way. Can be manufactured.   Pharmaceutically acceptable, non-toxic amides of the compounds of the present invention include ammonia, primary C₁ ~ C₆Alkylamine and secondary C₁~ C₆Amides derived from dialkylamines And these alkyl groups are straight-chain or branched. Secondary amine site If the amine is in the form of a 5- or 6-membered heterocycle containing one nitrogen atom, Good. Ammonia, C₁~ C_ThreeAlkyl primary amine and C₁~ C_TwoDialkyl secondary Amides derived from amines are preferred. The amide of the compound of the present invention can be prepared by a conventional method. Can be manufactured.   The term “prodrug” is used to obtain the original compound of the above formula, for example, A compound that changes rapidly in vivo due to hydrolysis in the blood. Detailed discussion , T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,“ Vol  14 of the A.C.S. Symposium Series and Bioreversible Carriers in Drug  Design, ed. Edward B. Roche, American Pharmaceutical Association and Pe rgamon Press, 1987, both incorporated herein by reference.   In addition, the compounds of the present invention are also pharmaceutically acceptable in unsolvated form. Solvent, for example, water, ethanol, etc. You. In general, for the purposes of the present invention, a solvated form is an unsolvated form. It is considered the same as the shape.   Compounds of the invention can be used in patients requiring matrix metalloproteinase inhibition Is administered. Generally, patients who require matrix metalloproteinase inhibition Have diseases or conditions in which matrix metalloproteinases play a role I am a patient. Examples of such diseases include, but are not limited to, multiple sclerosis, Atherosclerotic plaque destruction, restenosis Stenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burn, pressure ulcer, chronic ulcer or Trauma, cancer metastasis, tumor angiogenesis, arthritis, or other self due to leukocyte tissue invasion Examples include an immune disease or an inflammatory disease.   In a preferred embodiment, the matrix metalloproteinase is stromelysin -1 or gelatinase-A.   "Therapeutically effective amount" refers to a disease that can be treated with a compound of Formulas I-VIII. The amount of a compound of Formulas I-VIII that, when administered to a patient, improves the symptoms of the disease. You. A therapeutically effective amount of a compound of Formulas I-VIII is obtained by administering the compound of Formulas I-VIII to a patient. And can be readily determined by one skilled in the art by observing the results.   The following examples illustrate particular embodiments of this invention, but do not include the claims, including the claims. Is not limited in any way. Example General dibenzofuran sulfonamide synthesis   The compounds of the present invention can be synthesized using several different synthetic routes . For the general synthetic scheme, a common starting material is sulfonyl chloride (1) . These are readily synthesized by those skilled in the art by sulfonation of the original heterocycle. Go Some typical procedures are as follows. Dibenzofuran (1, X = O) and di Benzothiophene (1, X = S) was prepared at 0 ° C by the method of Bassin et al. In roloform, using one equivalent of chlorosulfonic acid, the original heterocyclic ring is substituted at the 2-position. (Phosphorus, Sulfur and Silicon, 1992; 72: 157-170). afterwards The sulfonic acid is treated with phosphorus pentachloride at 170-180 ° C to give the corresponding sulfonyl chloride. (1, X = O, S). For carbazole (1, X = NH) According to the method of Loza et al., The original heterocycle is sulfonated at 3-position with sulfuric acid at 100 ° C. And Subsequent neutralization with barium carbonate produces the corresponding barium salt of sulfonic acid (S b. Mater. Nauch.-Tekh. Konf. Ukrain. Zaoch. Poitekh. Inst. Vith, Kharkov , 1966: 202-205). Then the sulfonic acid is treated with phosphorus pentachloride at 170-180 ° C Or either phosphoryl chloride, thionyl chloride or oxalyl chloride To convert to the corresponding sulfonyl chloride (1, X = NH). Fluorene (1 , X = CH_Two) By the method of Chrzaszczewska et al. (Lodz. Tow. Nauk., Wyd). z. 3, Acta Chim., 1966; 11: 143-155), and its original carbocycle is chloroform at 0 ° C. , Sulfonated in 2-position using one equivalent of chlorosulfonic acid followed by hydroxylation Neutralization with potassium gives the corresponding potassium salt of sulfonic acid. Then Of fluorene derivatives at 80 ° C using aqueous potassium permanganate solution It can be oxidized to a fluorene derivative (1, X = CO). The sulfonate is then Treatment with phosphorus pentachloride and phosphoryl chloride in Nil (1, X = CH_Two, CO).   In Method A, sulfonyl chloride (1) is added at 10 ° C. to tetrahydrofuran (THF ) And water (3: 5) using a base such as triethylamine (TEA) Condensation directly with the natural amino acid gives the desired compound (2). Corresponding hi Droxamic acid (5) is prepared by converting the acid (2) into dichloromethane in a temperature range of -10 to 0 ° C. Using dicyclohexylcarbodiimide (DCC) as a coupling agent, By coupling with protected (usually benzyl) hydroxylamine It can be manufactured conveniently. Protecting groups are hydrogen at 50 psi in aqueous methanol Gas and Pb / BaSO_FourTo remove from compound (4) by catalytic hydrogenation This gives the hydroxamic acid derivative (5).   In Method B, the sulfonyl chloride (1) is treated at 0 ° C. with dichloromethane. In a suitable solvent, use a base such as N-methylmorpholine (NMM) to properly Condensation with a protected (usually tert-butyl ester) amino acid gives compound (3) can get. Anisole as a carbocation scavenger Treated with trifluoroacetic acid in dichloromethane at 25-35 ° C. Removal from the acid gives (2). Example produced by method A Example 1 (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-pentane acid Step (a) (L) -2- (dibenzofuran-2-sulfonylamino) -methyl-pe Tantanic acid, tert-butyl ester   (L) -leucine, tert-butyl ester (2.1 g, 0.0099 mol) and N-methyl Inactive in a dichloromethane solution (20 mL) of ruphorin (2.2 mL, 0.0199 mol) at 0 ° C Under a nitrogen atmosphere, dibenzofuran-2-sulfonyl chloride (1.0 g, 0.00375 m ol) in dichloromethane (10 mL) was added with stirring. 0 ° C For 4 hours and then partitioned with water (30 mL). Separate the organic layer and add water (2 × 30 mL) And brine (2 × 30 mL). Then, add this to anhydrous magnesium sulfate , Filtered and the solvent was removed under reduced pressure. The residue is then silica gel Flash chromatography, and the title product (1.0 g, 64%) was eluted with 20% ethyl acetate. / Hexane. Melting point = 106-109 ° C Step (b) (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl -Pentanoic acid (Example 1)   Dichloromethane containing the substance (0.5 g, 0.00119 mol) obtained in step (a) and anisole (0.5 mL) While stirring at room temperature, trifluoroacetic acid (5 mL) was added to the dichloromethane solution (5 mL). I got it. The resulting solution was stirred at room temperature for 24 hours, then concentrated in vacuo. The residue was treated with acetate Trituration with a mixture of chill / hexane provided the title compound (0.14 g, 33%). Melting point = 75 ~ 80 ℃   The following compounds were obtained according to the general method of Example 1. Example 2 (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentane acid Example 3 (L) -2- (dibenzofuran-2-sulfonylamino) -3-phenyl-propyl On-acid Melting point = 196-198 ° C Example manufactured by method B Example 4 (L) -2- (dibenzofuran-2-sulfonylamino) -propionic acid   (L) -alanine (0.3 g, 0.0034 mol) and triethylamine (1 mL) in THF / water ( 5: 3, 8 mL) solution at 10 ° C. with dibenzofuran-2-sulfonyl chloride (1.0 mL). g, 0.00375 mol) were added all at once with stirring. Stir the resulting solution at room temperature for 24 hours did. Afterwards, the solution was concentrated in vacuo and the residue was redissolved in water (10 mL). this The solution was cooled in an ice bath and then acidified with 1N HCl. A white solid precipitates, then Filtered and washed with water. This solid was recrystallized from aqueous ethanol to give the title product. The product (0.6 g, 50%) was obtained. Melting point = 158-163 ° C   Following the general procedure of Example 4 provided the following compound. Example 5 (L) -2- (Dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid Melting point = 163-165 ° C Example 6 (Dibenzofuran-2-sulfonylamino) -acetic acid Melting point = 208-210 ° C Example 7 (L) -2- (dibenzofuran-2-sulfonylamino) -succinic acid Melting point = 165-168 ° C Example 8 (L) -2- (dibenzofuran-2-sulfonylamino) -3-tritylsulfa Nyl-propionic acid Example 9 (L) -2- (dibenzofuran-2-sulfonylamino) -3-mercapto-pro Pionic acid   (L) -2- (dibenzofuran-2-sulfonylamino) -3-tritylsulf Anilyl-propionic acid (Example 8, 1.0 g, 0.00168 mol) in dichloromethane (10 ) was added trifluoroacetic acid (10 mL) at room temperature. A deep red / orange solution resulted. To this solution was added triethylsilane (0.33 mL, 0.00202 mol) and the color immediately disappeared. And the resulting clear solution was stirred at room temperature for 3 hours. Then the solution is Concentrate in the air, redissolve the residue in ether (10 mL), then remove the ether in vacuo did. This procedure was repeated three times. The residue was reconstituted from ethyl acetate / hexane (1: 1). Crystallize to give the title compound (0.23 g, 39%). Melting point = 164-166 ° C Example 10 (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentane Acid hydroxyamide Step (a) (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl -Pentanoic acid benzyloxy-amide   (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-penta Acid (Example 2, 0.55 g, 0.0015 mol) and carbonyldiimidazole (0.26 g, 0.1 0016 mol) in THF (50 mL) at room temperature under an inert nitrogen atmosphere under O-benzyl hydride. Roxylamine (0.23 g, 0.0018 mol) was added in one portion. Then, add this solution to 72 Heated to reflux for hours and then stirred at room temperature for 24 hours. The mixture is concentrated in vacuo and acetic acid Silica gel flash chromatography eluting with ethyl / hexane (1: 4) To give the title compound (0.27 g, 38%). Melting point = 207-209 ° C Step (b) (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl -Pentanoic acid hydroxyamide (Example 10)   The substance (0.037 g, 0.0000793 mol) obtained in the above step (a) in THF (2 mL) / meta A solution of phenol (10 mL) in hydrogen gas at 50 psi with Pd / BaS04 catalyst at room temperature for 1 hour And hydrogenated. The catalyst was removed by filtration and the solution was concentrated in vacuo. The residue Trituration with ether provided the title compound (0.022 g, 74%). Example 11 (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid Step (a) dibenzofuran-3-sulfonyl chloride   3-aminodibenzofuran (10 g, 54.6 mol) was added at 180C in 180 mL glacial acetic acid, 50 mL In water and 14 mL of concentrated hydrochloric acid, and add 15 mL of 5.5 M aqueous sodium nitrate solution. In addition, it was diazotized. The resulting mixture was stirred for 1 hour and then 240 mL of Copper (II) chloride in a 1: 1 mixture of benzene and glacial acetic acid saturated with au (2.0 g) , 14.9 mmol). The mixture is warmed to room temperature and stirred for 16 hours did. The reaction solution was partitioned between water and chloroform. Wash the chloroform layer with water, Dry over magnesium sulfate, filter, and concentrate to give the title compound as a yellow solid. I got it. Melting point = 142-144 ° C Step (b)   Using the procedure of Example 1, (L) -leucine, tert-butyl ester was converted to (L) Valine, replaced by tert-butyl ester, and dibenzofuran-2-sul Replacing phonyl chloride with dibenzofuran-3-sulfonyl chloride, The title compound was obtained. Melting point = 197 ~ 200 ℃ Example 12 (L) -2- (9H-fluorene-2-sulfonylamino) -3-methyl-butyric acid   In the procedure of Example 1, (L) -leucine, tert-butyl ester was replaced with (L) -ba Phosphorus, replaced by tert-butyl ester and dibenzofuran-2-sulfonate Replacing the chloride with 9H-fluorene-2-sulfonyl chloride, The title compound was obtained. Example 13 (L) -2- (5,5-dioxo-5H-5λ⁶-Dibenzothiophene-3-sulfoni Ruamino) -3-methyl-butyric acid   In the procedure of Example 1, (L) -leucine, tert-butyl ester was replaced with (L)- Valine, replaced by tert-butyl ester, and dibenzofuran-2-sulfo Nyl chloride is converted to 5,5-dioxo-5H-5λ⁶-Dibenzothiophen-3-sul Displacement with fonyl chloride provided the title compound. Melting point = 85-90 ° C Example 14 (L) -2- (dibenzothiophene-2-sulfonylamino) -3-methyl-butyric acid   In the procedure of Example 1, (L) -leucine, tert-butyl ester was replaced with (L) -ba Phosphorus, replaced by tert-butyl ester, and dibenzofuran-2-sulfo Replacing nil chloride with dibenzothiophene-2-sulfonyl chloride To give the title compound. Melting point = 150-155 ° C Example 15 (L) -2- (5,5-dioxo-5H-5λ⁶-Dibenzothiophene-2-sulfoni Ruamino) -3-methyl-butyric acid   A solution of the substance obtained in Example 14, step (a) (1.5 g, 0.0036 mol) in glacial acetic acid (30 mL) To this was added 10 mL of 30% hydrogen peroxide. The resulting solution is heated at reflux for 2.5 hours, room temperature And stirred for 16 h, then filtered to give the crude product as a white solid Obtained. The solid was washed with water and boiling ether to give the title compound. Melting point = 216-2 18 ℃ Example 16 (L) -2- (7-bromo-dibenzofuran-2-sulfonylamino) -3-methyl Ru-butyric acid Step (a) 3-bromo-dibenzofuran   3-Amino-dibenzofuran (15 g, 81.9 mmoles) was added to 350 mL of acetonitrile. Cupric bromide (21.9 g, 98.2 mmoles) and tert-butyl nitrate (12.66 g, 12 2.8 mmoles). The mixture is heated at reflux for 2 hours and then Stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and diethyl ether. The The ethyl ether layer was washed with brine, dried over magnesium sulfate, filtered, and filtered. And concentrated to an oily solid. Chromatography of the title compound as a yellow solid As obtained. Step (b) 7-bromo-dibenzofuran-2-sulfonyl chloride   Chlorosulfonic acid (3.75 mL, 56 mmoles) was dissolved in 150 mL of chloroform at room temperature in 3 mL. -Bromo-dibenzofuran (9.21 g, 37.3 mmoles) was added dropwise. Reaction solution for 5 hours Stir, cool to 0 ° C., filter, and wash the solid with cold dichloromethane . This solid (6.12 g, 18.7 mmoles) was mixed with phosphorus pentachloride (12.9 g, 61.7 mmoles), The mixture was heated to 110 C for 4 hours. Cool the mixture to room temperature and add ice water Quenched. The resulting suspension was filtered to give the title compound as a white solid. Step (c) (L) -2- (7-bromo-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid   In the procedure of Example 1, (L) -leucine, tert-butyl ester was replaced with (L) -ba Phosphorus, replaced by tert-butyl ester and dibenzofuran-2-sulfonate Chlorochloride with 7-bromo-dibenzofuran-2-sulfonyl chloride In turn, the title compound was obtained. Melting point = 191-193 ° C Example 17 (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylamido G) -butyric acid Step (a) (L) -2- (7-bromo-dibenzofuran-2-sulfonylamino ) -Butyl acid, tert-butyl ester   In the procedure of Example 1, step (a), (L) -leucine, tert-butyl ester Is replaced with (L) -valine, tert-butyl ester, and dibenzofuran-2 7-bromo-dibenzofuran-2-sulfonyl chloride Displacement with the id afforded the title compound. Step (b) (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sul (Honylamino) -butyric acid, tert-butyl ester   (L) -2- (7-bromo-dibenzofuran-2-sulfonylamino) -3-meth Tyl-butyric acid, tert-butyl ester (1.0 g, 2.0 mmoles) and phenylboron The acid (0.3 g, 2.5 mmoles) was combined with 10 mL of toluene, 5 mL of water, and 0.5 g of sodium carbonate. Mixed. Tetrakis (triphenylphosphine) palladium (0) (0.15 g, 0.1 mmoles) was added and the resulting mixture was heated to reflux for 6 hours. An additional 0.15g of palladium Catalyst was added and reflux continued for 16 hours. The reaction was cooled to room temperature and 1M H Partitioned between Cl and ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated, and The title compound was obtained as a white solid. Step (c) (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sul (Honylamino) -butyric acid   (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylua Mino) -butyric acid, tert-butyl ester (0.94 g) was dissolved in concentrated trifluoroacetic acid. And stirred for 2 hours. Concentrate in vacuo and triturate the residue with diethyl ether to give the title The compound was obtained as an off-white solid. Melting point = 254-255 ° C Inhibition studies   As potent inhibitors of stromelysin-1 and gelatinase A, compounds of formulas I and II Experiments were performed to show the efficacy of the compounds. Experiment with its catalytic domain Table 1 shows the results for both stromelysin-1 and gelatinase A. Example activities, GCD (recombinant gelatinase A catalytic domain), SCD (stromelysin- 1 catalytic domain). I c₅₀Values are thiopeptolide substrate, Ac-Pro-Leu-Gly- Oeester-Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson L.L., Hupe  D.J., and Baragi V., “Purification and Characterization of the Human S tromelysin Catalytic Domain Expressed in Escherichia coli, “Biochemistry , 1992; 31: 11231-11235). MMP01, MMP07, MMP09 and MMP13 activities And MMP03 (SCD and GCD). MMP01 and MMP09 are W ashington University School of Medicine, St. Louis, getting from Missouri Can be. MMP07 is based on Ye Q.-Z., Johnson L.L., and Baragi V., “Gene Synthes es and Expression in E. coli for PUMP, a Human Matrix Metalloproteinase "Biochem. And Biophys. Res. Comm., 1992; 186: 143-149. Can be obtained by the following procedure. MMP13 is available from Freiji J.M.P., et al., “Molecula r Cloning and Expression of Collegenase-3, a Novel Human Matrix Metallop roteinase Produced by Breast Carcinomas ”J. Bio. Chem., 1994; 269: 16766-1 It can be obtained by known procedures described in 6773. Thiopeptride assay   Thiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Bach em) by hydrolysis against MMP inhibitors₅₀A primary screen for measuring the value Used. 100 μL of the reaction solution is 1 mM 5,5′-dithiobis in a suitable reaction buffer. (2-nitrobenzoic acid) (DTNB), 100 μM substrate, 0.1% Brij, enzyme and Inhibitors included. Activated standard-length enzyme is 5 nM, and stromelysin-catalyzed Main (SCD) is 10nM, and gelatin Thease A catalytic domain (GaCD) was assayed at 1 nM. Inhibitor at 100 μM to 1 nM Screened. Standard length enzyme 50 mM HEPES, 10 mM CaCl_Two, PH 7.0, S CD is 50 mM MES, 10 mM CaCl_TwoPH 6.0, and GaCD 50 mM MOPS, 10 mM CaCl_Two,Ten μM ZnCl_TwoAssayed at pH 7.0. Change in absorbance at 405 nm continuously for 20 minutes at room temperature During that time, monitoring was performed using a ThermoMax microplate reader.   HEPES is 4- (2-hydroxylethyl) -piperazine-1-ethanesulfonic acid And   MES is 2-morpholinoethanesulfonic acid monohydrate,   Ac is acetyl,   Pro is proline,   Leu is leucine,   Gly is glycine,   Et is ethyl, and   MOPS is 3-morpholinopropanesulfonic acid. Soluble proteoglycan assay (stromelysin natural substrate assay) SCD (PG)   The solubilized proteoglycan substrate was obtained from Nagase and Woessner in Anal.Bioche. m., 1980; 107: 385-392, from bovine cartilage powder (Sigma). Built. 100 μL of the reaction solution was 50 mM MES, 10 mM CaCl_Two10 μg / mL in pH 6.0 Includes roteoglycans, enzymes and inhibitors. Activated standard length strobe Lysine or stromelysin catalytic domain (SCD) was assayed at 100 nM. Obstruction Pests were screened from 100 μM to 1 nM. Incubate the reaction at 37 ° C for 3 hours. Baits were then added and 1,10-phenanthroline was added and stopped at a final concentration of 1 mM. The reaction product is 300,000 Ultra-free-MC polysulfone mye with molecular weight cut-off membrane (Millipore) Separated from the undigested substrate using crocon and obtained from Farndale, Saysers , And Barrett's Connective Tissue Research, 1982; 9: 247-248, Quantification was performed using a modified 1,9-dimethylene blue (DMB) assay. Absorption is 1 The standard curve was determined at 518 nm using 32 μg / mL DMB in a mL reaction, Made from μg of shark cartilage chondroitin sulfate C (Sigma). Gelatin Assay (Gelatinase Natural Substrate Assay) (Gel)   Rat tail type I collagen (Sigma) was placed at 95 ° C to produce a gelatin matrix. For 20 minutes. 50 μL of the reaction solution is 50 mM MOPS, 10 mM Ca Cl_Two, 10μM ZnCl_Two1.12 mg / mL substrate, enzyme, inhibitor and inactive at pH 7.0 80 μg / mL soybean trypsin inhibitor as a good internal standard. Activated standard Gelatinase A of length 1 nM and the gelatinase A catalytic domain (GaCD) Was assayed at 10 nM. Inhibitors were screened from 100 μM to 1 nM. Anti The reaction solution was incubated at 37 ° C for 30 minutes, and then 2x Tricine gel low. Stopping with 50 μL of loading buffer (Novex). The reaction product was treated with Tricine-SDS 1 Digest by electrophoresis on a 0-20% polyacrylamide gradient gel (Novex) Separated from unsubstituted substrate. Coomassie Brilliant Blue R protein band And quantified using a BioImage densitometer (Millipore). I c₅₀Value After standardization, the sum of the three bands above each reaction was used to eliminate the substrate. Calculated from loss. MMP inhibitor bioassay   Animals received vehicle or compound at 2, 10, or 50 mg / kg, respectively. Administered by feeding. After administration of the blood sample 1, 2, 4, 6 and At 24 hours, 3-4 animals from each dose group were collected, centrifuged and blood The plasma was immediately frozen at -20 ° C. Plasma proteins are precipitated with an equal volume of acetonitrile and Separated by centrifugation at warm. The supernatant is evaporated to dryness and at 50 mM Tris, pH 7.6 It was returned to the original plasma volume. A reconstituted plasma sample of 10-fold serial dilution For a dose response assay using the appropriate thiopeptolide assay, 50 mM Tris , PH 7.6. The plasma concentration that gives 50% inhibition of the enzyme is measured and the known IC₅₀ The values were used to calculate inhibitor plasma levels. The compound is an active inhibitor For each inhibitor to show that it can be quantitatively extracted from plasma Controls include standard rat plasma, normal rat plasma with compound added, and And buffer dilution compounds. All control samples were acetonitrile And subjected to thiopeptolide assay.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 A61P 9/10 17/02 17/02 19/02 19/02 27/02 27/02 29 / 00 29/00 35/00 35/00 43/00 111 43/00 111 // C07D 209/88 C07D 209/88 307/91 307/91 333/76 333/76 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AL, AU, BA, BB, BG, BR, CA , CN, CZ, EE, GE, GH, HU, IL, IS, JP, KR, LC, LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU, ZW (72) Inventor White, Andrew David 48169, Michigan, USA. Pink knee. West Split Stone 10608

Claims (1)

[Claims] 1. Formula I (Where M is a structure Is a natural (L) alpha amino acid derivative having, X is O, S, S (O) n, CH 2, CO or NR ^Q,, R ^Q is hydrogen, C ₁ -C ₆ alkyl or C, ₁ -C ₆ alkyl - phenyl, R is the side chain of a natural α 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, -SO 3 R 5, -CHO, -COR 5, -CONR 5 R 6, - (CH ₂ ) _n NR ⁵ R ⁶ , —CF ₃ , or —NHCOR ⁵ , wherein R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₅ alkyl, and n is 0-2 A method of treating a patient in need of matrix metalloproteinase inhibition comprising administering to a patient a therapeutically effective amount of a compound of formula (I) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof. A method of inhibiting the scan metalloproteinases. 2. The method of claim 1, wherein X is O. 3. The method of claim 1, wherein X is S. 4. _2. The method of claim 1, wherein X is CH2. 5. The method of claim 1 wherein X is NR ^Q. 6. The method of claim 2 wherein R ² and R ⁴ are hydrogen. 7. 2. The method according to claim 1, wherein X is CO. 8. The method of claim 1, wherein X is S (O) _n . 9. R ¹ is hydroxy, C ₁ -C ₅ alkoxy The method of claim 1 wherein the -NHOH or -NHO benzyl. Ten. The method according to claim 1, wherein R is a side chain of a natural α-amino acid, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, phenylalanine or glycine. 11． Formula II (Where Z is a structure Wherein 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}} , -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ each independently is hydrogen or C ₁ -C ₅ alkyl and, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, R ^b is a side chain of a natural α amino acid, and R ^c hydrogen ,, a C ₁ -C ₅ alkyl or -CH ₂ phenyl, and n administration the compounds of 0-2) and pharmaceutically acceptable salts thereof, esters, a therapeutically effective amount of the amide and prodrug to a patient A method of inhibiting matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising: 12． Base Is located at the 2-position of the phenyl ring. 13. Base Is located at the 3-position of the phenyl ring. 14. Formula III (Where Z is a structure Wherein 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,}} -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ are each independently a Te hydrogen or C ₁ -C ₅ alkyl, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, R ^b is a side chain of a natural α amino acid, R ^c is hydrogen ,, C a ₁ -C ₅ alkyl or -CH ₂ phenyl, and n are administered compound of 0-2) and pharmaceutically acceptable salts thereof, esters, a therapeutically effective amount of the amide and prodrug to a patient A method of inhibiting matrix metalloproteinase in a patient in need thereof, the method comprising inhibiting matrix metalloproteinase. 15． Formula IV (Where Z is a structure Wherein 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,}} -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ are each independently a Te hydrogen or C ₁ -C ₅ alkyl, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, R ^b is a side chain of a natural α amino acid, R ^c is hydrogen ,, C a ₁ -C ₅ alkyl or -CH ₂ phenyl, and n are administered compound of 0-2) and pharmaceutically acceptable salts thereof, esters, a therapeutically effective amount of the amide and prodrug to a patient A method of inhibiting matrix metalloproteinase in a patient in need thereof, the method comprising inhibiting matrix metalloproteinase. 16． Equation V (Where Z is a structure Wherein 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,}} -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ are each independently a Te hydrogen or C ₁ -C ₅ alkyl, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, R ^b is a side chain of a natural α amino acid, R ^c is hydrogen, C ₁ -C ₅ alkyl or -CH ₂ phenyl, and n is administering a compound of 0-2) and pharmaceutically acceptable salts thereof, esters, a therapeutically effective amount of the amide and prodrug to a patient A method of inhibiting matrix metalloproteinase in a patient in need thereof, the method comprising inhibiting matrix metalloproteinase. 17． Formula VI (Where Z is a structure Wherein 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,}} -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ are each independently Te is hydrogen or C ₁ -C ₅ alkyl, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, n is 0 to 2, R ^b is the side chain of a natural α amino acid R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl, and n is 0 to 2) and pharmaceutically acceptable salts, esters, amides and prodrugs thereof. A method for inhibiting matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, comprising administering an effective amount to the patient. 18． Formula VII (Where Z is a structure Wherein 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,}} -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ are each independently a Te hydrogen or C ₁ -C ₅ alkyl, R ^a is C ₁ -C ₅ alkoxy, hydroxy, or -NHOR ^c, R ^Q is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl - phenyl R ^b is the side chain of a natural α-amino acid; R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; and n is 0-2). Matrix for patients in need of matrix metalloproteinase inhibition, comprising administering to the patient a therapeutically effective amount of an acceptable salt, ester, amide and prodrug A method of inhibiting the metalloproteinases. 19. When the compound is (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-pentanoic acid, (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid, (L)- 2- (dibenzofuran-2-sulfonylamino) -3-phenyl-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-sulfonylamino) -3-tritylsulfaniloopropionic acid, (L) -2- (dibenzofuran-2-sulfonylamino) -3-mercapto-propion Acid, (L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid hydroxyamide, (L) -2- (dibenzofuran-2-sulfonylamino) -acetic acid tert-butyl ester, (L) Tert-butyl 2- (dibenzofuran-2-sulfonylamino) -propionate, tert-butyl (L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-pentanoate, (L) -2 -(Dibenzofuran-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, (L) -2- (9H-fluorene-2-sulfonylamino) -3-methyl-butyric acid, (L) -2- (5,5-dioxo-5H) -5Ramuda 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, (L) -3-methyl-2- (7-phenyldibenzofuran-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-sulfonyl) Amino) -3-methyl - The method of claim 1 wherein the butyric acid. 20. A method of treating multiple sclerosis, comprising administering to a patient with multiple sclerosis a therapeutically effective amount of a compound of claim 1. twenty one. A method of treating atherosclerotic plaque destruction, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient at risk of destroying atherosclerotic plaque. twenty two. A method for treating or preventing restenosis comprising administering to a patient having restenosis or a patient at risk for restenosis a therapeutically effective amount of a compound according to claim 1. twenty three. A method of treating an aortic aneurysm comprising administering to a patient having an aortic aneurysm a therapeutically effective amount of a compound of claim 1. twenty four. A method for treating heart failure, comprising administering to a patient with heart failure a therapeutically effective amount of a compound of claim 1. twenty five. A method for treating periodontal disease, comprising administering to a patient with periodontal disease a therapeutically effective amount of a compound according to claim 1. 26. A method of treating corneal ulceration, comprising administering to a patient with corneal ulcer a therapeutically effective amount of a compound of claim 1. 27. A method for treating burns, comprising administering to a burned patient a therapeutically effective amount of a compound of claim 1. 28. A method of treating pressure ulcer comprising administering to a patient with pressure ulcer a therapeutically effective amount of the compound of claim 1. 29. A method for treating chronic ulcer or trauma comprising administering to a patient with chronic ulcer or trauma a therapeutically effective amount of a compound according to claim 1. 30. A method of treating cancer metastasis, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient who has metastasized. 31. A method of treating tumor angiogenesis comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of claim 1. 32. A method of treating arthritis, comprising administering to a patient with arthritis a therapeutically effective amount of a compound of claim 1. 33. A method for treating an autoimmune disease or an inflammatory disease caused by leukocyte tissue invasion, comprising administering a therapeutically effective amount of the compound according to claim 1 to a patient having an autoimmune disease or inflammatory disease caused by leukocyte tissue invasion. . 34. Formula I (Where M is a structure It is a natural (L) alpha amino acid derivative having, X is _{S, S (O) n,} CH 2, CO or NR ^Q, R ^b is a side chain of a natural alpha amino acid, R ^a is C ₁ -C ₅ alkoxy, hydroxy or -NHOR ^5, hydrogen R ² and R ⁴ are independently, -C ₁ -C ₅ alkyl, phenyl -NO _2, halogen, -OR ^5, -CN, -CO _{2 ^{R 5, -SO 3 R 5,}} -CHO, -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ⁵ and R ⁶ each independently hydrogen or C ₁ -C ₅ alkyl, and salts n is acceptable on the compounds and their pharmaceutical 0-2), esters, amides and prodrugs. 35. Formula VIII (Where M is a structure Wherein 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}} , -COR 5, -CONR 5 R 6, - (CH 2) n NR 5 R 6, are -CF ₃ or -NHCOR ^5, R ^b is a natural α amino acid R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ⁵ , R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₅ alkyl, and n is 0-2. And the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.