KR20000068414A - Matrix Metalloproteinase Inhibitors and their Therapeutic Uses - Google Patents

Abstract

The present invention relates to a method for inhibiting matrix metalloproteinases using a compound which is a dibenzofuran sulfonamide derivative having formula (I). More particularly, the present invention relates to multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulcer, burns, pressure sores, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis or leukocytes The present invention relates to a method for treating a disease involving matrix metalloproteinases such as other autoimmune or inflammatory diseases following tissue invasion.

<Formula I>

Description

Matrix Metalloproteinase Inhibitors and Their Therapeutic Uses

<Field of invention>

The present invention relates to a method for inhibiting matrix metalloproteinases using compounds which are dibenzofuran sulfonamide derivatives. More particularly, the present invention relates to multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulcer, burns, pressure sores, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis or leukocytes The present invention relates to a method for treating a disease involving matrix metalloproteinases such as other autoimmune or inflammatory diseases following tissue invasion.

〈Background of the invention〉

Compounds of the invention are inhibitors of matrix metalloproteinases such as stromelysin-1 and gelatinase A (72 kDa gelatinase).

Tromelilysin-1 and gelatinase A are members of the matrix metalloproteinases (MMPs). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrylysine, collagenase 3 , Membrane-bound matrix metalloproteinases have been newly discovered [Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994; 370: 61-65.

Tromelilysin-1 is also known as MMP03 and gelatinase A is known as MMP02. In addition, several other matrix metalloproteinases are known:

MMP01-fibroblast collagenase;

MMP07-matrylysine;

MMP09 gelatinase B; And

MMP13-collagenase-3.

Catalytic zinc in matrix metalloproteinases is typically the focal point in inhibitor design. Modifications of substrates with chelating groups resulted in potent inhibitors such as peptidehydroxyxamate and thiol-containing peptides. Peptide hydroxamates and natural endogenous inhibitors of MMPs (TIMPs) have been successfully used to treat animal models of cancer and inflammation.

The ability of matrix metalloproteinases to degrade the various components of connective tissue is what makes them possible targets for controlling pathological progression. For example, rupture of atherosclerotic plaques is the most common cause of coronary thrombosis. Destabilization and disruption of these plaques around the extracellular matrix by MMPs have been proposed as a cause of plaque fissures. Regions of foam cell accumulation in the atherosclerotic plaques of the shoulder and humans show locally increased expression of gelatinase B, stromelysin-1 and interstitial collagenase. Zymography of these tissues shows increased gelatinization and caseinolytic activity [Galla ZS, Sukhova GK, Lark MW, and Libby P., "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 messages have been found to locally collect in each cell in atherosclerotic plaques removed from heart transplant patients during surgery [Henney AM, Wakeley PR, Davies MJ, Foster K., Hembry. R., Murphy G., and Humphries S., "Localization of stromelysin gene expression in artherosclerotic plaque by in situ hybridization," Proc. Nat'l. Acad. Sci., 1991; 88: 8154-8158.

Inhibitors of matrix metalloproteinases will have utility in the treatment of degenerative aortic diseases associated with thinning of the aortic wall. Increased levels of proteolytic activity of MMPs have been identified in patients with aortic aneurysms and aortic stenosis [Vine N. and Powell J.T., "Metalloproteinases in degenerative aortic diseases," Clin. Sci., 1991; 81: 233-239.

Heart failure is due to a variety of etiologies, but a common feature is aortic dilatation that has been identified as an independent risk factor for death [Lee TH, Hamilton MA, Stevenson LW, Moriguchi JD, Fonarow GC, Child JS, Laks H., and Walden JA, "Impact of left ventricular size on the survival in advanced heart failure," Am. J. Cardiol., 1993; 72: 672-676. This alteration of the insufficiency heart appears to be involved in the destruction of the extracellular matrix. Matrix metalloproteinases are increased in both 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 cardiomyopathy,” Clin. Res., 1993; 41: 660 A; Tyagi S.C., Reddy H.K., Voelker D., Tjara I.E., and Weber K.T., "Myocardial collagenase in failing human heart," Clin, Res., 1993; 41: 681A]. Animal models of heart failure have shown that induction of gelatinase is very important for cardiac dilatation [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 that cardiac expansion leads to major defects in heart function [Sabbah HN, Kono T., Stein PD, Mancini GB, and Goldstein S., "Left ventricular shape changes during the course of evolving heart failure, "Am. J. Physiol., 1992; 263: H266-H270. Renal endothelial hyperplasia that causes restenosis often develops after coronary angiogenesis. Migration of vascular smooth muscle cells (VSMC) from the intima to the renal artery is a major event in the development and progression of various vascular diseases and is a very predictable consequence of mechanical trauma to the blood vessels [Bendeck MP, Zempo N., Clowes AW, Galardy]. RE, and Reidy M., "Smooth muscle cell migration and matrix matalloproteinase expression after arterial injury in the rat," Circulation Research, 1994; 75: 539-545]. Northern blotting and zymographic analysis indicated that gelatinase A is the major MMP expressed and is secreted by these cells. In addition, antisera that can selectively neutralize gelatinase A activity also inhibited VSMC migration through the basement membrane barrier. After vascular trauma, gelatinase A activity increased more than 20-fold compared to VSCM undergoing a transition from a resting state to a proliferative, motility phenotype [Pauly RR, Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gluzband YA, Smith L., Weinstein C., Lakatta E., and Crow MT, "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 activity is shown in fibroblasts isolated from infected gums (Uitto VJ, Applegren R., and Robinson PJ, "Collagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva," J. Periodontal Res., 1981; 16: 417-424], enzyme levels correlated with severity of gum disease [Overall CM, Wiebkin OW, and Thonard JC, "Demonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva, J. Periodontal Res., 1987; 22: 81-88. Proteolytic breakdown of the extracellular matrix has been observed in corneal ulcers following alkali burns [Brown S.I., Weller C.A., and Wasserman H.E., “Collagenolytic activity of alkali burned corneas,” Arch. Opthalmol., 1969; 81: 370-373. Thiol-containing peptides inhibit collagenase isolated from alkaline-burn rabbit corneas [Burns F.R., Stack M.S., Gray R.D., and Paterson C.A., Invest. Opththamol., 1989; 30: 1569-1575.

Stromelicin is produced by basal epidermal cells in various chronic ulcers [Saarialho-Kere UK, Ulpu K., Pentland AP, Birkedal-Hansen H., Parks WC, Welgus HG, "Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds, "J. Clin. Invest., 1994; 94: 79-88.

Tromelilysin-1 mRNA and protein are preferably detected in terminal but adjacent basal epidermal cells from the wound edges indicating the site of the proliferating epidermis. Thus, stromelysin-1 can interfere with the healing of the epidermis. Davies et al. Cancer Res., 1993; 53: 2087-2091 show that peptide hydroxamate, BB-94, reduces tumor burden and prolongs survival of mice containing human ovarian carcinoma xenografts. Has been reported. Peptides of the conservative MMP propeptide sequence are weak inhibitors of gelatinase A and inhibit human tumor cell invasion through layers of the reconstituted basement membrane [Melchiori A., Albili A., Ray JM, and Stetler-Stevenson WG, Cancer Res., 1992; 52: 2353-2356], natural tissue inhibitors of metalloproteinase-2 (TIMP-2) also showed blocking of tumor cell invasion in an in vitro model [DeClerck YA, Perez N., Shimada H., Boone TC, Langley KE, and Taylor SM, Cancer Res., 1992; 52: 701-708. Studies in human cancer have shown that gelatinase A is activated on invasive tumor cell surfaces (Strongin AY, Marmer BL, Grant GA, and Goldberg GI, J. Biol Chem., 1993; 268: 14033-14039). Interactions with both molecules indicated that they stayed there [Monsky WL, Kelly T., Lin C.-Y., Yeh Y., Stetler-Stevenson WG, Mueller SC, and Chen W.-T., Cancer Res , 1993; 53: 3159-3164. Inhibitors of MMP have been shown to be active in models of tumor angiogenesis [Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown PD, and Giavazzi R., Journal of the National Cancer Institute, 1995; 87: 293; and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W.G., Santi L., and Albini A., Oncology Research, 1994; 6: 251-257].

Several investigators have demonstrated a consistent increase in stromelysine and collagenase in synovial fluid from patients with rheumatoid and osteoarthritis compared with controls [Walakovits LA, Moore VL, Bhardwaj N., Gallick GS, and Lark MW, "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 M., Pelletier J.P., Cloutier J.M., and Marcel-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 interfere with the formation of collagen fragments from the degeneration of both the nose and pig articular cartilage models of arthritis cows, but do not interfere with the proteoglycan fragments, whereas synthetic peptide hydroxamate prevents the formation of two fragments. Andrew HJ., Plumpton TA, Harper GP, and Cawston TE, 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 reported that GM6001, a peptide hydroxyxamate, inhibits the onset or reversed clinical manifestation of experimental allergic encephalomyelitis (EAE) in a dose dependent manner, It is described that the use of MMP inhibitors in the treatment of immune inflammatory diseases. A recent study by Madrid revealed the role of gelatinase A in the hemostasis of T-cells from the blood stream during inflammation [Ramanic A.M. and Madri J.A., "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 migration through the endothelial cell layer correlates with the induction of gelatinase A and is mediated by binding to vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is damaged, edema and inflammation are produced in the CNS. Leukocyte migration through the cerebrovascular barrier is known to be associated with an inflammatory response in EAE. Inhibition of metalloproteinase gelatinase A may block the degeneration of the extracellular matrix by activated T-cells required for CNS passage.

These studies have shown that inhibitors of stromelysin-1 and / or gelatinase A may cause inflammation of the extracellular matrix resulting in lymphatic infiltration, metastasis, or inflammation due to improper migration of active cells or loss of structural integrity necessary for organ function. It provided the basis for the belief that it treats diseases including destruction.

We believe that the tricyclic aromatic sulfonamide compounds are inhibitors of matrix metalloproteinases, in particular stromelysin-1 and gelatinase A, and thus multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysms, heart failure, It has been shown to be a useful drug for the treatment of periodontal disease, corneal ulcers, burns, pressure ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis or other autoimmune or inflammatory diseases following tissue invasion by leukocytes.

<Summary of invention>

The present invention relates to a matrix metalloprotein, comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of inhibition of matrix metalloproteinases. It is to provide a method of suppressing an agent.

Where M is a structure Natural (L) alpha amino acid derivative having;

X is O, S, S (O) n, CH ₂ , CO or NR ^Q , wherein R ^Q is hydrogen, C ₁ -C ₆ alkyl or —C ₁ -C ₆ alkyl-phenyl;

R is the side chain of the 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 , -SO ₃ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ ,-(CH ₂ ) nNR 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 To 2).

In one embodiment of the invention X in formula (I) is O.

In another embodiment of the invention X in formula (I) is S.

In another embodiment of the invention X in formula (I) is CH ₂ .

In another embodiment of the invention X in formula (I) is NR ^Q.

In another embodiment of the invention X in formula (I) is O and R ² and R ⁴ are hydrogen.

In another embodiment of the invention X in formula (I) is CO.

In another embodiment of the invention X in formula (I) is S (O) n.

In another embodiment of the invention R ¹ in formula (I) is hydroxy, C ₁ -C ₅ alkoxy, —NHOH or —NHObenzyl.

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

In another embodiment, the present invention relates to administering a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt, ester, amide or prodrug thereof to a patient in need of matrix metalloproteinase inhibition. It provides a method for suppressing a matrix metalloproteinase comprising.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid.

In a preferred embodiment of the method comprising formula (II), The group is located at the 2-position of the phenyl ring.

In another preferred embodiment of the method comprising formula (II), The group is located at the 3-position of the phenyl ring.

Matrix metalloproteins comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (III), a pharmaceutically acceptable salt, ester, amide or prodrug thereof Provided is a method of suppressing an agent.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid.

Matrix metalloproteins comprising administering a therapeutically effective amount of a compound of formula (IV), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Provided is a method of suppressing an agent.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid.

Matrix metalloproteins comprising administering a therapeutically effective amount of a compound of formula (V), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Provided is a method of suppressing an agent.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid.

Matrix metalloproteins comprising administering a therapeutically effective amount of a compound of formula (VI), a pharmaceutically acceptable salt, ester, amide or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Provide a method of suppressing an offer.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid;

n is 0 to 2;

Matrix metalloproteins, which also include administering to a patient in need of a matrix metalloproteinase inhibition a therapeutically effective amount of a compound of formula (VII), a pharmaceutically acceptable salt, ester, amide or prodrug thereof Provided is a method of suppressing an agent.

In which Z is a structure Natural (L) amino acid derivatives having;

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 ) nNR 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 To 2);

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl;

R ^b is the side chain of the natural alpha amino acid.

In a most preferred embodiment, the compounds of formulas (I) to (VIII) are one of the following:

(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-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-sulfonylamino) -acetic acid tert-butyl ester;

(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-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-sulfonylamino) -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-5λ ⁶ -dibenzothiophene-3-sulfonylamino) -3-methyl-butyric acid;

(L) -2- (dibenzothiophen-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-sulfonylamino) -butyric acid; And

2- (9H-Carbazole-3-sulfonylamino) -3-methyl-butyric acid.

Also provided by the present invention is a method of treating multiple sclerosis comprising administering to a patient with multiple sclerosis a therapeutically effective amount of a compound of formulas (I) to (VIII).

Also provided by the present invention is a method for treating atherosclerotic plaque rupture comprising administering a therapeutically effective amount of a compound of formulas (I) to (VIII) to a patient at risk of atherosclerotic plaque rupture.

Also provided by the present invention is a method of treating and preventing stenosis comprising administering a therapeutically effective amount of a compound of Formulas (I) to (VIII) to a patient with or at risk of restenosis.

Also provided by the present invention are methods of treating aortic aneurysm comprising administering to aortic aneurysms a therapeutically effective amount of a compound of Formulas (I) to (VIII).

Also provided by the present invention is a method of treating heart failure comprising administering to a patient with a therapeutically effective amount of a compound of formulas (I) to (VIII).

Also provided by the present invention is a method of treating periodontal disease comprising administering a therapeutically effective amount of a compound of Formulas (I) to (VIII) to a patient with periodontal disease.

Also provided by the present invention are methods of treating corneal ulcers comprising administering to a patient a corneal ulcer a therapeutically effective amount of a compound of formulas (I) to (VIII).

Also provided by the present invention are methods of treating burns comprising administering to a burn patient a therapeutically effective amount of a compound of formulas (I) to (VIII).

Also provided by the present invention is a method of treating pressure ulcers comprising administering a therapeutically effective amount of a compound of Formulas (I) to (VIII) to a patient with pressure ulcers.

Also provided by the present invention are methods of treating chronic ulcers or wounds comprising administering a therapeutically effective amount of a compound of Formulas (I) to (VIII) to a chronic ulcer or wound patient.

Also provided by the present invention is a method of treating cancer metastasis comprising administering to a cancer metastatic patient a therapeutically effective amount of a compound of formulas (I) to (VIII).

Also provided by the present invention are methods of treating tumor angiogenesis comprising administering to a tumor angiogenesis patient a therapeutically effective amount of a compound of Formulas (I) to (VIII).

Also provided by the present invention is a method of treating arthritis comprising administering to a patient with arthritis a therapeutically effective amount of a compound of formulas (I) to (VIII).

In addition, treatment of autoimmune or inflammatory diseases following tissue invasion by leukocytes comprising administering a therapeutically effective amount of a compound of formula (I) to (VIII) to a patient with autoimmune or inflammatory disease following tissue invasion by leukocytes The method is provided by the present invention.

The present invention also provides a compound of formula (I), a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

<Formula I>

Where M is a structure Natural (L) alpha amino acid derivative having;

X is S, S (O) n, CH ₂ , CO or NR ^Q , wherein R ^Q is hydrogen, C ₁ -C ₆ alkyl or —C ₁ -C ₆ alkyl-phenyl;

R ^b is the side chain of the natural alpha amino acid;

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 , -SO ₃ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ ,-(CH ₂ ) nNR 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 To 2).

The present invention provides a compound of formula (VIII), a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

Where M is a structure Natural (L) alpha amino acid derivative having;

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 each R ⁵ and R ⁶ is independently hydrogen or C ₁ -C ₅ alkyl, and n is 0 to 2);

R ^b is the side chain of the natural alpha amino acid;

R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ⁵ .

<Detailed Description of the Invention>

The present invention comprises administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, ester, amide or prodrug to a patient in need of matrix metalloproteinase inhibition. It is to provide a method for suppressing naase.

<Formula I>

Where M is a structure Natural (L) alpha amino acid derivative having;

X is O, S, S (O) n, CH ₂ , CO or NR ^Q ;

R is the side chain of the 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 , -SO ₃ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ ,-(CH ₂ ) nNR 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 To 2).

The term "alkyl" refers to a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, secondary-butyl, pentyl and hexyl.

The term "alkoxy" means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups are methoxy, ethoxy, tert-butoxy, propoxy and isopropoxy.

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

The term "phenyl" also includes substituted phenyl in which one or more hydrogens on the phenyl ring are replaced with organic radicals. Examples of suitable substituents include 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 Including but not limited to.

The symbol "-" means a bond.

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

Natural alpha amino acids are amino acids found in living organisms. 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.

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, hydroxy groups can be converted to ethers or esters, and thiol groups can be converted to thioethers or thioesters.

The compounds of formulas (I) to (VIII) may be administered to the patient alone or as part of a pharmaceutically acceptable composition. The composition is oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), subretinal, intravaginal, intraperitoneal, in bladder, topical (powder, ointment or drops), or oral to patients such as humans and animals. Or intranasal sprays.

Compositions suitable for parenteral injection may comprise sterile powders for reconstitution into physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg olive oil) and ethyl oleate. Injectable organic esters. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, or by the maintenance of the required particle size and surfactant in the case of dispersions.

Such compositions may also include adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of microbial action can be ensured by various antibacterial and antifungal reagents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic reagents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved using reagents that delay absorption, such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, pills, powders, and granules. In such solid dosage forms the active compound is at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol and seals Lactic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) curb agents, such as glycerol, (d) disintegrants, eg For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution papermaking agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds (g) wetting agents, such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate Oh acrylate, solid polyethylene glycols, sodium is referred to us mixed with sulfate or mixtures thereof. For capsules, tablets and pills, the dosage form may also include buffering agents.

Solid compositions of a similar type may be used in soft and hard gelatin capsules using excipients such as high molecular weight polyethylene glycols as well as lactose or lactose as filler.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with enteric coatings and other coatings and shells as are known in the art. Solid dosage forms can contain a milky agent, such that the composition can release the active compound (s) in a delayed manner at a specific site in the intestine. Examples of containment compositions that can be used are polymeric substances and waxes. The active compound may also be in micro-encapsulated form with one or more of the aforementioned excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms can be used inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corneye oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, Fatty acid esters of polyethylene glycol and sorbitan, mixtures of these materials, and the like.

In addition to these inert diluents, the compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and fragrances.

Suspensions in addition to the active compounds may be suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or such Mixtures of materials, and the like.

The composition for rectal administration preferably contains a suitable non-magnetic compound such as cocoa butter, polyethylene glycol or suppository wax (solid at normal temperature but liquid at body temperature so that it melts in the rectum or vagina and releases the active ingredient). Suppositories that can be prepared by mixing with polar excipients or carriers.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and inhalants. The active ingredient may be mixed under sterile conditions with a physiologically acceptable carrier and with any preservatives, buffers, or gunpowder that may be required. Eye drops, eye ointments, powders and solutions are also contemplated within the scope of this invention.

The compound of the present invention may be administered to a patient in a dosage range of about 0.1 to about 1,000 mg per day. For average human adults having a body weight of about 70 kg, a dosage range of about 0.01 to about 100 mg / kg body weight per day is preferred. However, the specific dosage used may vary. For example, the dosage will vary depending on a number of factors including the needs of the patient, the severity of the condition to be treated and the pharmacological activity of the compound to be used. Determination of the optimal dosage for a particular patient is known to those skilled in the art. The term "patient" includes humans and animals.

As used herein, the term “pharmaceutically acceptable salts, esters, amides or prodrugs” refers to the tissue of a patient at an appropriate gain / loss ratio, without improper toxicity, irritation, allergic reactions, etc., within the scope of intact medical judgment. Carboxides, amino acid addition salts, esters, amides and prodrugs of the compounds of the invention that are suitable for use in contact with and effective for the intended use, as well as the zwitterionic forms of the compounds of the invention, where possible. The term "salt" means a relatively nontoxic, inorganic and organic acid addition salt of a compound of the invention. Such salts may be prepared during the final separation and purification of the compound or by reacting the purified compound with a suitable organic or inorganic acid in free base form and separating the salts formed. Representative salts are hydrobromide, hydrochloride, sulfate, sulfite, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosyl Acid salts, citrate, maleate, fumarate, succinate, tartrate, naphthyl acid, mesylate, glucoheptanoate, lactobionic acid salts and lauryl sulfonate salts. These include ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, as well as cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like. Non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to, and the like (see, eg, SM Berge, et al., "Pharmaceutical Salts, J. Pharm. Sci., 1977: 66 (1-19)].

Examples of pharmaceutically acceptable nontoxic esters of the compounds of the invention include C ₁ to C ₆ alkyl esters, wherein the alkyl group is straight or branched chain. Acceptable esters also include arylalkyl esters such as, but not limited to, C ₅ to C ₇ cycloalkyl esters. Preference is given to C ₁ to C ₄ alkyl esters. Esters of the compounds of the present invention can be prepared according to conventional methods.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention are derived from ammonia, primary C ₁ to C ₆ alkyl amines and secondary C ₁ to C ₆ dialkyl amines, wherein the alkyl group is straight or branched chain Amides. For secondary amines, the amine may be in the form of a five or six membered heterocycle containing one nitrogen atom. Preferred are amides derived from ammonia, C ₁ to C ₃ alkyl primary amines and C ₁ to C ₂ dialkyl secondary amines. Amides of the compounds of the present invention can be prepared according to conventional methods.

The term "prodrug" refers to a compound which is rapidly converted in vivo, eg, hydrolyzed in blood to give the parent compound of the above-described formula. Both thorough discussions have been made by T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S., both incorporated herein by reference. Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In addition, the compounds of the present invention may exist in unsolvated forms 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 patients in need of matrix metalloproteinase inhibition. In general, a patient in need of matrix metalloproteinase inhibition is a patient with a disease or condition in which the matrix proteinase plays a role. Examples of such diseases include multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulcer, burns, pressure sores, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis or leukocytes. Other autoimmune or inflammatory diseases following tissue invasion by, but are not limited to.

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

A "therapeutically effective amount" is the amount of a compound of formulas (I) to (VIII) when the compound of formulas (I) to (VIII) can be administered to a patient having a disease that can treat the symptoms of the disease. . A therapeutically effective amount of a compound of formula (I) to (VIII) is readily determined by one skilled in the art by administering to a patient a compound of formula (I) to (VIII) and observing the results.

The following examples illustrate certain embodiments of the invention and do not in any way limit the scope of the specification, including the claims.

General Synthesis of Dibenzofuran Sulfonamide

Compounds of the invention can be synthesized using a number of different synthetic routes. In a general synthetic scheme, a typical starting material is sulfonyl chloride (1). It is readily synthesized by those skilled in the art by sulfonation of the parent heterocycle. The typical process is as follows. For dibenzofuran (1, X = O) and dibenzothiophene (1, X = S), Bassin, et al., (Phosphorus, Sulfur and Silicon, 1992; 72: 157-170) The sulfonation is carried out in 2-position using 1 equivalent of chlorosulfonic acid in chloroform at 0 ° C. according to the method. The sulfonic acid is then treated with phosphorus pentachloride at 170-180 ° C. to convert to the corresponding sulfonyl chloride (1, X = 0, S). For carbazole (1, X = NH), sulfonation of the parent heterocycle in the 3-position with sulfuric acid at 100 ° C. and neutralization with barium carbonate gave Loza et al., Sb. Mater. Nauch.-Tekh. Konf. Ukrain. Zaoch. Poitekh. Inst. Vith, Kharkov, 1966: 202-205 to obtain the corresponding barium salt of sulfonic acid. The sulfonic acid is then treated with phosphorus pentachloride at 170-180 ° C. or reacted with phosphoryl chloride, thionyl chloride or oxalyl chloride to convert to the corresponding sulfonyl chloride (1, X = NH). For fluorene (1, X = CH ₂ ) mocha according to Chrzaszczewska et al., (Lodz. Tow. Nauk., Wydz. 3, Acta Chim., 1966; 11: 143-155). The bicycle is sulfonated at 2-position with 1 equivalent of chlorosulfonic acid in chloroform at 0 ° C. and neutralized with potassium hydroxide to give the potassium salt of the corresponding sulfonic acid. This fluorene derivative is then oxidized with aqueous potassium permanganate at 80 ° C. to give the corresponding fluorene derivative (1, X = CO). The sulfonate is then treated with phosphoryl chloride in phosphorus pentachloride and chloroform to convert to the corresponding sulfonyl chloride (1, X = CH ₂ , CO).

In Method A, sulfonyl chloride (1) is a preferred compound by direct condensation with natural amino acids using a base such as triethylamine (TEA) in a mixture of tetrahydrofuran (THF) and water (3: 5) at 10 ° C. (2) is obtained. The corresponding hydroxyxamic acid (5) is O-protected (usually benzyl) hydroxy with acid (2) using dicyclohexylcarbodiimide (DCC) as a coupling agent in dichloromethane at-(10) to 0 ° C. It can be easily prepared by coupling with an amine. The protecting group can be removed from compound (4) by catalytic hydrogenolysis with Pd / BaSO ₄ in hydrogen gas and aqueous methanol at 50 psi to give hydroxyxamic acid derivative (5).

In method B, sulfonyl chloride (1) is condensed with a suitably C-protected (usually tertiary butyl ester) amino acid at 0 ° C. using a base such as N-methylmorpholine (NMM) in a solvent such as dichloromethane. To yield compound (3). The protecting group can be removed from the carboxylic acid by treatment with trifluoroacetic acid in dichloromethane using anisol as a carboion scavenger at 25-35 ° C. to obtain (2).

Example Prepared by Method A

<Example 1>

(L) -2- (dibenzofuran-2-sulfonylamino) -4-methyl-pentanoic acid

Step (a) (L) -2- (Dibenzofuran-2-sulfonylamino) -4-methyl-pentanoic acid, tert-butyl ester

Dibenzofuran in 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. Dichloromethane solution (10 ml) of -2-sulfonyl chloride (1.0 g, 0.00375 moles) was added with stirring. The resulting solution was stirred at 0 ° C. for 4 h and partitioned with water (30 ml). The organic layer was separated and washed with water (2 x 30 ml) and brine (2 x 30 ml). It 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%) eluted with 20% ethyl acetate / hexanes; Melting point = 106-109 ° C .;

Step (b) (L) -2- (Dibenzofuran-2-sulfonylamino) -4-methyl-pentanoic acid, (Example 1)

Trifluoroacetic acid (5 ml) was added to the material (0.5 g, 0.00119 mol) and anisol (0.5 ml) of dichloromethane solution (5 ml) obtained in step (a) with stirring at room temperature. The resulting solution was stirred at rt for 24 h and concentrated in vacuo. The residue was treated with ethyl acetate / hexanes to give the title compound (0.14 g, 33%); Melting point = 75-80 ° C.

¹ H NMR (CDCl ₃ ): δ 8.4 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4-7.6 (m, 4H), 5.0 (d, 1H), 3.9 (m, 1H), 1.8 (m, 1H), 1.4 (m, 2H), 0.9 (d, 3H), 0.8 (d, 3H) ppm.

According to the general method of Example 1, the following compounds were obtained:

<Example 2>

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid

¹ H NMR (DMSO-D ₆ ): δ 8.6 (s, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.8-7.9 (m, 3H), 7.6 (tr, 1H), 7.5 ( tr, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 1.7 (m, 1H), 1.1-1.4 (m, 2H), 0.75-0.85 (m, 6H) ppm.

<Example 3>

(L) -2- (dibenzofuran-2-sulfonylamino) -3-phenyl-propionic acid; Melting point = 196-198 ° C.

Example Prepared by Method B

<Example 4>

(L) -2- (dibenzofuran-2-sulfonylamino) -propionic acid

Dibenzofuran-2-sulfonyl chloride (1.0 g, in a THF / water (5: 3, 8 ml) solution of (L) -alanine (0.3 g, 0.0034 mol) and triethylamine (1 ml) at 10 ° C. 0.00375 mol) was added with stirring at one time. The resulting solution was stirred at rt for 24 h. The solution was then concentrated in vacuo and the residue was redissolved in water (10 ml). This solution was cooled in an ice bath and acidified with 1N HCl. The precipitated white solid was filtered off and washed with water. This solid was recrystallized from aqueous ethanol to give the title compound (0.6 g, 50%); Melting point = 158-163 ° C .;

According to the general method of Example 4, the following compounds were obtained:

<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-trisulfanyl-propionic acid

¹ H NMR (DMSO-D ₆ ): δ 8.5 (s, 1H), 8.2 (m, 2H), 7.1-7.9 (m, 19H), 3.6 (m, 1H), 3.5 (m, 1H), 2.3 ( d, 2H) ppm.

<Example 9>

(L) -2- (dibenzofuran-2-sulfonylamino) -3-mercapto-propionic acid

Trifluoro in dichloromethane solution (10 ml) of (L) -2- (dibenzofuran-2-sulfonylamino) -3-trisulfanyl-propionic acid (Example 8, 1.0 g, 0.00168 mol) at room temperature Acetic acid (10 ml) was added. A dark red / orange solution was produced. When triethylsilane (0.33 ml, 0.00202 mol) was added to this solution, the color disappeared immediately, and the resulting clear solution was stirred at room temperature for 3 hours. The solution was then concentrated in vacuo and the residue was redissolved in ether (10 ml) and concentrated in vacuo. This process was repeated three times. The residue was recrystallized from ethyl acetate / hexanes (1: 1) to give the title compound (0.23 g, 39%). Melting point = 164-166 ° C .;

<Example 10>

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid hydroxyamide

Step (a) (L) -2- (Dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid benzyloxy-amide

(L) -2- (dibenzofuran-2-sulfonylamino) -3-methyl-pentanoic acid (Example 2, 0.55 g, 0.0015 mol) and carbonyldiimidazole (0.26 g) at room temperature under an inert nitrogen atmosphere O-benzylhydroxyamine (0.23 g, 0.0018 mol) was added in one portion to a THF solution (50 ml). This solution was then heated to reflux for 72 hours and stirred at room temperature for 24 hours. The mixture was then concentrated in vacuo and flash chromatography eluting with ethyl acetate / hexanes (1: 4) on silica gel 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)

A THF (2 ml) / methanol (10 ml) solution of the material (0.037 g, 0.0000793 mol) obtained in step (a) described above was hydrolyzed with Pd / BaSO ₄ for 1 hour at room temperature using hydrogen gas at 50 psi. Bovine digestion. The catalyst was filtered off and the solution was concentrated in vacuo. The residue was treated with ether to give the title compound (0.022 g, 74%).

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

<Example 11>

(L) -2- (dibenzofuran-3-sulfonylamino) -3-methyl-butyric acid

Step (a) (dibenzofuran-3-sulfonyl chloride)

3-aminodibenzofuran (10 g, 54.6 mol) was diazotized by dissolving in 180 ml of glacial acetic acid, 50 ml of water and 14 ml of concentrated hydrochloric acid at 0 ° C., and 15 ml of 5.5 M aqueous sodium nitrite solution was added. 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 saturated with sulfur dioxide and glacial acetic acid. This mixture was allowed to warm up to room temperature and stirred for 16 h. 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 ° C .;

Step (b)

According to the method of Example 1, dibenzofuran-3- instead of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester Sulfonyl chloride was used to yield the title compound; Melting point = 197-200 ° C.

<Example 12>

(L) -2- (9H-fluorene-2-sulfonylamino) -3-methyl-butyric acid

According to the method of Example 1, 9H-fluorene-2 instead of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester Sulfonyl chloride was used to yield the title compound.

<Example 13>

(L) -2- (5,5-dioxo-5H-5λ ⁶ -dibenzothiophene-3-sulfonylamino) -3-methyl-butyric acid

According to the method of example 1, 5,5-dioxo instead of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester -5H-5λ ⁶ -dibenzothiophen-3-sulfonyl chloride was used to give the title compound; Melting point = 85-90 ° C .;

<Example 14>

(L) -2- (dibenzothiophene-2-sulfonylamino) -3-methyl-butyric acid

According to the method of Example 1, dibenzothiophene-2 instead of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester Sulfonyl chloride was used to give the title compound; Melting point = 150-155 ° C.

<Example 15>

(L) -2- (5,5-dioxo-5H-5λ ⁶ -dibenzothiophene-2-sulfonylamino) -3-methyl-butyric acid

Example 14 To a solution of glacial acetic acid (30 ml) of the material obtained in step (a) (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, stirred for 16 hours and filtered to give the crude product as a white solid. This solid was washed with water and boiling ether to give the title compound; Melting point 216-218 ° C.

<Example 16>

(L) -2- (7-Bromo-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid

Step (a) 3-bromo-dibenzofuran

3-amino-dibenzofuran (15 g, 81.9 mmol) was added to a suspension of copper (II) bromide (21.9 g, 98.2 mmol) and tert-butyl nitrite (12.66 g, 122.8 mmol) in 350 ml of acetonitrile at once. Added. The mixture was heated to reflux for 2 hours and stirred at room temperature for 16 hours. The reaction was partitioned between 1 M HCl 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 (b) 7-bromo-dibenzofuran-2-sulfonyl chloride

Chlorosulfonic acid (3.75 ml, 56 mmol) was added dropwise to a solution of 3-bromo-dibenzofuran (9.21 g, 37.3 mmol) in 150 ml of chloroform at room temperature. The reaction was stirred for 5 hours, cooled to 0 ° C. and filtered to wash the solid with cold dichloromethane. This solid (6.12 g, 18.7 mmol) was mixed with phosphorus pentachloride (12.9 g, 61.7 mmol) and the mixture was heated to 110 ° C for 4 h. The mixture was cooled to rt and quenched with ice water. The resulting suspension was filtered to afford the title compound as a white solid.

Step (c) (L) -2- (7-Bromo-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid

According to Example 1, 7-bromo-dibenzofuran in place of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester 2-sulfonyl chloride was used to give the title compound; Melting point = 191-193 ° C.

<Example 17>

(L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylamino) -butyric acid

Step (a) (L) -2- (7-Bromo-dibenzofuran-2-sulfonylamino) -butyric acid, tert-butyl ester

Example 1 According to step (a), 7-bromo instead of (L) -valine, tert-butyl ester, dibenzofuran-2-sulfonyl chloride instead of (L) -leucine, tert-butyl ester -Dibenzofuran-2-sulfonyl chloride was used to give the title compound.

Step (b) (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylamino) -butyric acid, tert-butyl ester

(L) -2- (7-bromo-dibenzofuran-2-sulfonylamino) -3-methyl-butyric acid, tert-butyl ester (1.0 g, 2.0 mmol) and phenyl boronic acid (0.3 g, 2.5 Mmol) was mixed with 10 ml of toluene, 5 ml of water and 0.5 g of sodium carbonate. Tetrakis (triphenylphosphine) palladium (0) (0.15 g, 0.1 mmol) was added and the resulting mixture was heated to reflux for 6 hours. Further 0.15 g of palladium catalyst was added and reflux was continued for 16 hours. The reaction was cooled to rt and partitioned between 1 M HCl and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white solid.

Step (c) (L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylamino) -butyric acid

(L) -3-methyl-2- (7-phenyl-dibenzofuran-2-sulfonylamino) -butyric acid, tert-butyl ester (0.94 g, mmol) was dissolved in concentrated trifluoroacetic acid, 2 Stir for hours. Concentrate in vacuo and treat the residue with diethyl ether to afford the title compound as an off-white solid; Melting point = 254-255 ° C .;

<Repression Research>

Experiments were performed showing the efficacy of the compounds of formulas (I) and (II) as effective inhibitors of stromelysin-1 and gelatinase A. Experiments showed that the catalytic domain (ie Table 1 shows the activity of the examples for both stromelysin-1 and gelatinase A, GCD (recombinant gelatinase A catalytic domain); SCD (stromelisin-1 catalytic) Domains). IC ₅₀ values were calculated from the thiopeptolide substrate, Ac-Pro-Leu-Gly-thioester, Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson LL, Hupe DJ, and Baragi V., “Purification and Characterization of the Human Stromelysin Catalytic Domain Expressed in Escherichia coli, "Biochemistry, 1992; 31: 11231-11235). MMP01, MMP07, MMP09 and MMP13 activities were analyzed in a similar way to MMP02 and MMP03 (SCD and GCD). MMP01 and MMP09 can be obtained from Washington University School of Medicine (St. Louis, Missouri). MMP07 is described in Ye QZ, Johnson LL, and Baragi V., "Gene Syntheses and Expression in E. coli for PUMP, a Human Matrix Metalloproteinase" Biochem. and Biophys. Res. Comm., 1992; 186: 143-149. MMP13 is described in Freije JMP, et al., “Molecular Cloning and Expression of Collagenase-3, a Novel Human Matrix Metalloproteinase Produced by Breast Carcinomas” J. Bio. Chem., 1994; 269: 16766-16773.

<Thiopeptolide analysis>

Hydrolysis of the thiopeptide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Bachem), is used as the first screen for measuring IC ₅₀ values for MMP inhibitors. 100 μl reaction contains 1 mM 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB), 100 μM substrate, 0.1% Brij, enzyme and inhibitor in a suitable reaction buffer. Activated full length enzymes were analyzed at 5 nM, stromelysin catalytic domain (SCD) at 10 nM and gelatinase A catalytic domain (GaCD) at 1 nM. Inhibitors were screened from 100 μM to 1 nM. Full length enzymes include 50 mM HEPES, 10 mM CaCl ₂ , pH 7.0; SCD in 50 mM MES, 10 mM CaCl ₂ , pH 6.0; And GaCD in 50 mM MOPS; 10 mM CaCl ₂ , 10 μM ZnCl ₂ , pH 7.0. Absorbance change at 405 nm was monitored on a ThermoMax microplate reader for 20 min continuously at room temperature.

HEPES is 4- (2-hydroxyethyl) -piperazine-1-ethane sulfonic acid;

MES is 2-morpholinoethane sulfonic acid monohydrate;

Ac is acetyl;

Pro is proline;

Leu is leucine;

Gly is glycine;

Et is ethyl;

MOPS is 3-morpholinopropane sulfonic acid.

Soluble Proteoglycan Analysis (Stromelisin Natural Substrate Analysis) SCD (PG)

Dissolved proteoglycan substrates are described in Nagase and Woessner in Anal. Biochem., 1980; 107: 385-392, to prepare from bovine cartilage powder (Sigma). 100 μL reactant contains 10 μg / mL proteoglycans, enzymes, and inhibitors in 50 mM MES, 10 mM CaCl ₂ , pH 6.0. Activated full length stromelysin or stromelysin catalytic domain (SCD) is analyzed at 100 nM. Inhibitors are screened from 100 μM to 1 nM. The reaction is incubated at 37 ° C. for 3 hours and stopped at a final concentration of 1 mM by addition of 1,10-phenanthroline. The reaction product is separated from the undegraded substrate using ultrafree-MC polysulfone microcone with 300,000 molecular weight cut-off membrane (Millipore) and described by Farndale, Sayers, and Barrett in Connective Tissue Research, 1982 ; 9 :: 247-248 to quantify using the modified 1,9-dimethylene blue (DMB) assay described. Absorbance is measured at 518 nm using 32 μg / mL DMB in 1 mL reaction. Standard curves are prepared from 0-100 μg shark cartilage chondroitin sulfate C (Sigma).

Gelatin Analysis (Gelatin Natural Substrate Analysis) (Gel)

Rat tail I collagen (Sigma) was denatured by heating at 95 ° C. for 20 minutes to prepare a gelatin matrix. The 50 μL reaction contains 80 μg / mL soy trypsin inhibitor as 1.12 mg / mL substrate, enzyme, inhibitor and inert internal standard in 50 mM MOPS, 10 mM CaCl ₂ , 10 μM ZnCl ₂ , pH 7.0. Activated full length gelatinase A is analyzed at 1 nM and gelatinase A catalytic domain (GaCD) at 10 nM. Inhibitors are screened from 100 μM to 1 nM. The reaction is incubated at 37 ° C. for 30 minutes and stopped at 50 μL in 2 × Tricine gel loading buffer (Novex). The reaction product is separated from undegraded substrates by electrophoresis on Tricin-SDS 10-20% polyacrylamide gradient gel (Novex). Protein bands are stained with Coomassie Brilliant Blue R and quantified using a Bio Image densitometer (Millipore). IC ₅₀ values are calculated from the disappearance of the substrate using the sum of the top three bands of each reactant after normalization with an internal standard.

<MMP Inhibitor Bioassay>

Animals are administered by gavage with vehicle or compound at 2, 10 or 50 mg / kg. Blood samples are taken from 3 to 4 animals from each dose group after 1, 2, 4, 6 and 24 hour administration, centrifuged and the plasma immediately frozen to -20 ° C. Plasma proteins are precipitated with equal volume of acetonitrile and separated by centrifugation at room temperature. The supernatant is dried to evaporate and reconstituted to the original plasma volume with 50 mM Tris, pH 7.6. Ten-fold serial dilutions of the reconstituted plasma samples are prepared at 50 mM, pH 7.6 for dose response analysis using the appropriate thiopeptolide assay. Plasma concentrations indicating 50% inhibition of the enzyme are measured and used to calculate inhibitor plasma levels from known IC ₅₀ values. To demonstrate that a compound can be quantitatively extracted from plasma as an active inhibitor, the control for each inhibitor includes normal rat plasma, normal rat plasma spiked with the compound, and a buffered dilution of the compound. All control samples were acetonitrile precipitated and analyzed by thiopeptolide assay.

Example number MMP01 (GCD) MMP02 (SCD) MMP03 MM--P07 MMP09 MMP13 One 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 - - - 5 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 - - - 10 - 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 15 100 100 100 100 - 100 16 - 0.47 0.75 - - - 17 100 0.36 0.062 6 - 0.69

Example 5 SCD (IC ₅₀ ) 0.233 μM SCD (PG) (IC ₅₀ ) 8.9 μM GCD (IC ₅₀ ) 0.084 μM Gel (IC ₅₀ ) 0.58 μM Biopsy (50 mg / kg) peak 82 μM 24 hours 0.18 μM

Claims (35)

Inhibition of matrix metalloproteinases comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, ester, amide or prodrug thereof Way. <Formula I> Where M is a structure Natural (L) alpha amino acid derivative having; X is O, S, S (O) n, CH ₂ , CO or NR ^Q , wherein R ^Q is hydrogen, C ₁ -C ₆ alkyl or —C ₁ -C ₆ alkyl-phenyl; R is the side chain of the 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 , -SO ₃ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ ,-(CH ₂ ) nNR 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 To 2). The method of claim 1 wherein X is O. The method of claim 1 wherein X is S. The method of claim 1 wherein X is CH ₂ . The method of claim 1 wherein X is NR ^Q. The method of claim 2, wherein R ² and R ⁴ are hydrogen. The method of claim 1 wherein X is CO. The method of claim 1 wherein X is S (O) n. The method of claim 1, wherein R ¹ is hydroxy, C ₁ -C ₅ alkoxy, —NHOH or —NHObenzyl. The method of claim 1, wherein R is a side chain of a natural alpha amino acid, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, phenylalanine or glycine. Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Method of suppression. <Formula II> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid. The method of claim 11, Wherein the group is located at the 2-position of the phenyl ring. The method of claim 11, Wherein the group is located at the 3-position of the phenyl ring. Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (III), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of inhibition of matrix metalloproteinases Method of suppression. <Formula III> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid. Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (IV), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Method of suppression. <Formula IV> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid. Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (V), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Method of suppression. <Formula V> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid. Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (VI), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Method of suppression. <Formula VI> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid; n is 0 to 2; Matrix metalloproteinases comprising administering a therapeutically effective amount of a compound of formula (VII), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a patient in need of matrix metalloproteinase inhibition Method of suppression. <Formula VII> In which Z is a structure Natural (L) amino acid derivatives having; 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 ) nNR 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 To 2); R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ^c , wherein R ^c is hydrogen, C ₁ -C ₅ alkyl or —CH ₂ phenyl; R ^b is the side chain of the natural alpha amino acid. The compound of claim 1 wherein 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-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-sulfonylamino) -acetic acid tert-butyl ester; (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-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-5λ ⁶ -dibenzothiophene-3-sulfonylamino) -3-methyl-butyric acid; (L) -2- (dibenzothiophen-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-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 comprising administering a therapeutically effective amount of a compound of claim 1 to a patient with multiple sclerosis. A method of treating atherosclerotic plaque rupture comprising administering a therapeutically effective amount of a compound of claim 1 to a patient at risk of atherosclerotic plaque rupture. A method of treating or preventing stenosis comprising administering a therapeutically effective amount of the compound of claim 1 to a patient at rest or at risk of restenosis. A method of treating aortic aneurysm comprising administering a therapeutically effective amount of the compound of claim 1 to a patient with an aortic aneurysm. A method of treating heart failure comprising administering a therapeutically effective amount of a compound of claim 1 to a heart failure patient. A method for treating periodontal disease, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient with the periodontal disease. A method of treating corneal ulceration comprising administering to a patient a corneal ulcer a therapeutically effective amount of the compound of claim 1. A method of treating burns, comprising administering a therapeutically effective amount of the compound of claim 1 to a burn patient. A method of treating pressure ulcers comprising administering a therapeutically effective amount of the compound of claim 1 to a pressure ulcer patient. A method of treating chronic ulcers or wounds comprising administering a therapeutically effective amount of a compound of claim 1 to a chronic ulcer or wound patient. A method of treating cancer metastasis comprising administering a therapeutically effective amount of the compound of claim 1 to a cancer metastasis patient. A method of treating tumor angiogenesis comprising administering a therapeutically effective amount of a compound of claim 1 to a tumor angiogenesis patient. A method of treating arthritis comprising administering a therapeutically effective amount of a compound of claim 1 to a sphincitis patient. A method of treating autoimmune or inflammatory disease following tissue invasion of white blood cells, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient with autoimmune or inflammatory disease following tissue invasion of white blood cells. Compounds of formula (I), pharmaceutically acceptable salts, esters, amides or prodrugs thereof. <Formula I> Where M is a structure Natural (L) alpha amino acid derivative having; X is O, S, S (O) n, CH ₂ , CO or NR ^Q , wherein R ^Q is hydrogen, C ₁ -C ₆ alkyl or —C ₁ -C ₆ alkyl-phenyl; R ^b is the side chain of the natural alpha amino acid; 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 , -SO ₃ R ⁵ , -CHO, -COR ⁵ , -CONR ⁵ R ⁶ ,-(CH ₂ ) nNR 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 To 2). Compounds of formula (VIII), pharmaceutically acceptable salts, esters, amides or prodrugs thereof. <Formula VIII> Where M is a structure Natural (L) alpha amino acid derivative having; 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 ) nNR 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 To 2); R ^b is the side chain of the natural alpha amino acid; R ^a is C ₁ -C ₅ alkoxy, hydroxy or —NHOR ⁵ .