MXPA00012948A - Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases - Google Patents

Abstract

Tricyclic sulfonamide compounds and derivatives are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A, collagenase-3, and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion diseases, myasthenia gravis, and Duchenne's muscular dystrophy.

Description

SULFONAMIDAS TRICICLICAS AND ITS DERIVATIVES AS INHIBITORS OF METALOPROTEINASAS MATRIZ BACKGROUND OF THE INVENTION The present invention relates to novel tricyclic sulfonamide compounds and their derivatives useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions including these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are inhibitors of matrix metalloproteins, for example, gelatinase A (MMP-2), collagenase-3 (MMP-13), and stromelysin-1 (MMP-3). More particularly, the novel compounds of the present invention are useful in the treatment of atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilatation, restenosis, periodontal disease, corneal ulcer, treatment of burns, decubital ulcers, repair of wounds, cancer, inflammation, pain, arthritis, osteoporosis, multiple sclerosis, kidney disease, and other autoimmune or inflammatory disorders dependent on the invasion of leukocytes into the tissue or other activated migrating cells. Additionally, the compounds of the present invention are useful in the treatment of acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion diseases, myasthenia gravis, and Duchenne muscular dystrophy. Gelatinase A and stromelysin-1 are members of the matrix metalloproteinase family (MMP) (Woessner J.F., FASEB J., 1991; 5: 2145-2154). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (gelatinase 92 kDa), stromelysin-2, stromelysin-3, matrilysin, collagenase 3 (Freije JM, Diez-ltza I., Balbin M., Sánchez LM, Blasco R., Tolivia J., and Lopez-Otin C, J. Biol. Chem., 1994; 269: 16766-16773), and the matrix metalloproteinases associated with newly discovered membranes (Sato H., Takino T., Okada Y., Cao J ., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994; 370: 61-65). The catalytic zinc in the matrix metalloproteinases is a focal point for the design of inhibitors. Modifying substrates by introducing chelating groups has generated potent inhibitors such as peptide hydroxymates and thiol-containing peptides. Peptide hydroxylates 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 various connective tissue components makes them potential targets to control pathological processes. For example, rupture of an atherosclerotic plaque is the most common event that initiates coronary thrombosis. The destabilization and degradation of the extracellular matrix surrounding these plates by the MMP has been proposed as a cause of plate fissure. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase. The in situ zymography of this tissue reveals increased gelatinol and caseinolytic activity. (Galis Z.S., Sukhova G.K., Lark M.W., and Libby P., "Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques," J. Clin. Invesi., 1994; 94: 2494-2503). In addition, high RNA message levels for stromelysin have been found located in individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney AM, Wakeley PR, Davies MJ, Foster K., Hembry R. , Murphy G., and Humphries S., "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization," Proc. Nat'l. Acad Sci., 1991; 88: 8154-8158).

Matrix metalloprotein inhibitors will be useful in treating degenerative aortic disease associated with thinning of the middle aortic wall. Increased levels of proteolytic activities 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 arises from a number of different etiologies, but a common characteristic is cardiac dilation, which has been identified as an independent risk factor for mortality. (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 remodeling of heart failure seems to involve the breakdown of the extracellular matrix. Matrix metalloproteinases are increased in patients with idiopathic and ischemic heart failure. (Reddy HK, Tyagi SC, Tjaha IE, Voelker DJ, Campbell SE, and Weber KT, "Activated myocardial collagenase in idiopathic dilated cardiomyopathy," Clin. Res., 1993; 41: 660A; Tyagi SC, Reddy HK, Voelker D. , Tjara IE, and Weber KT, "Myocardial collagenase in failing human heart," Cline Res., 1993; 41: 681A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong PW, Moe GW, Howard RJ, Grima EA, and Cruz TF, "Structural remodeling in heart failure: gelatins. J. Cardiol., 1994; 10: 214-220), and cardiac dilation precedes deep deficits in cardiac 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: H266-270). Neointima proliferation, which leads to restenosis, frequently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel (Bendeck MP, Zempo N., Clowes AW, Galardy RE, and Reidy M., "Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat," Circulation Research, 1994; 75: 539-545). Northern and cyminographic tinsion analyzes indicate that gelatinase A was the primary MMP expressed and excreted by these cells. Additionally, antisera capable of selectively neutralizing gelatinase A activity also inhibits the migration of VSMC through the basement membrane barrier. After the wound to the vessel, the activity of gelatinase A increased more than 20 times as VSMC underwent the transition from a quiescent state to one of proliferating mobile phenotype (Pauly RR, aniti 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, "Circ? Lation Research, 1994; 75: 41-54). The activities of collagenase and stromelysin have been demonstrated in isolated fibroblasts of inflamed gingiva (Uitto VJ, Applegren R., and Robinson PJ, "Collagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva," J. Periodontal Res., 1981; : 417-424), and enzyme levels have been correlated to the 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 degradation of the extracellular matrix has been observed in ulceration of the cornea after alkali burns (Brown SI, Weller CA, and Wasserman HE, "Collagenolytic activity of alkali burned corneas," Arch. Ophthalmol., 1969; 81: 370-373). Thiol-containing peptides inhibit collagenase isolated from alkali-burned rabbit corneas (Burns F.R., Stack M.S.>, Gray R.D., and Paterson C.A., Invest. Ophthalmol., 1989; 30: 1569-1575).

Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere UK, Ulpu K., Pentland AP, Birkedal-Hansen H., Parks W.C '., And Welgus HG, "Distinct Populations of Basal Keratinocytes Express Stromelysin-1 and Stromelysin-2 in Chronic Wounds, "J. Clin Invest., 1994; 94: 79-88). Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent but distal to the edge of the lesion in what probably represents the sites of the proliferating epidermis. Stromelysin-1 can thus prevent the healing of the epidermis. Davies et al., (Cancer Res., 1993; 53: 2087-2091) reports that a peptide hydroximate, BB-94, decreased tumor burn and prolonged the survival of mice carrying human ovarian carcinoma genografts. A peptide from the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited the invasion of human tumor cells through a layer of reconstituted base membrane (Melchiori A., Albili A., Ray JM, and Stetler-Stevenson WG , Cancer Res., 1992; 52: 2353-2356). The natural tissue inhibitor metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models. (DeClerck Y. A., Perez N., Shimada H., Boone T.C., Langley K.E., and Taylor S.M., Cancer Res:, 1992; 52: 701-708). Studies of human cancers have shown that gelatinase A is activated on the surfaces of invasive tumor cells (Strongin AY, Marmer BL, Grant GA, and Goldberg GI, J. Biol Chem., 1993; 268: 14033-14039) and it is retained there through interaction with a receptor-like molecule (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 MMPs have shown activity 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 researchers have demonstrated the consistent elevation of stromelysin and collagenase in synovial fluids of patients with osteoarthritis and rheumatoid arthritis as compared to 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 JP, Cloutier JM, and Marcel-Pelletier J.," Elevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthrilic synovia, "J. Rheumatol., 1993; 20: 693-697). TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not fragments of proteoglycan in cartilage models -agt _ »- ?. articular pig and bovine nasal arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews HJ, Plumpton TA, Harper GP, and Cawston TE, Agents Actions, 1992; 37: 147-154; Ellis AJ, Curry VA, Powell EK, and Cawston TE, Biochem. Biophys, Res. Commun., 1994,201: 94-101). Gijbels et al., (J. Clin. Invest., 1994; 94: 2177-2182) recently described a peptide hydroxamate, GM6001, which suppressed the development or reversed the chemical expression and experimental autoimmune encephalomyelitis (EAE) in a the dose, suggesting the use of MMP inhibitors in the treatment of autoimmune inflammatory disorders such as multiple sclerosis. A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T cells from the bloodstream during inflation (Ramanic AM, and Macri JA, "The Induction of 72-kDa Gelatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent, "J. Cell Biology, 1994; 125: 1165-1178). This transmigration that passes the endothelial cell layer is coordinated with the induction of gelatinase A and mediated by binding to the vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is compromised, edema and inflation occur in the CNS. Also, it is known that leukocyte migration through the brain-blood barrier is associated with the inflammatory response in EAE. Inhibition of the metalloprotein to gelatinase A would block the degradation of the extracellular matrix by activated T cells that are necessary for CNS penetration. These studies provide the basis for the expectation that an effective inhibitor of gelatinase A and / or stromelysin-1 would have value in the treatment of diseases that involve disorganization of the extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function. Neuroinflammatory mechanisms are implicated in a wide range of acute and chronic neurodegerative disorders, including stroke, head trauma, multiple sclerosis, and Alzheimer's disease, to name a few (McGeer EG and McGeer PL, "Neurodegeneration and the immune system" In: Calne DB, ed., Neurodegenerative Diseases, W, B. Saunders, 1994: 277-300). Other disorders that may involve neuroinflammatory mechanisms include amyotrophic lateral sclerosis (Leigh PN, "Pathogenic mechanims in amyotrophic lateral sclerosis and other motor neuron disorders" In: Calne DB, ed., Neurodegenerative Diseases, WB Saunders, 1994: 473-88), angiopathy cerebral amyloid (Mandybur Tl and Balko G., "Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment," Clin. Neuropharm., 1992; 15: 241-7), AIDS (Gendelman HE and Tardieu M., "Macrophages / microglia and the pathophysiology of CNS injuries in AIDS," J. Leukocyte Bio!., 1994; 56: 387-8), Parkinson's disease. , Huntington's disease, prion diseases and certain disorders that involve the peripheral nervous system, such as myasthenia gravis and Duchenne muscular dystrophy. Neuroinflammation, which occurs in response to brain injury or autoimmune disorders, has been shown to be the cause of healthy tissue destruction (Martin R, MacFarland HF, and McFarlin DE, "Immunological aspects of demyelinating diseases," Annul Rev. Immunol. , 1992; 10: 153-87; Clark RK, Lee EV, Fish CJ, et al., "Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric sbudy," Brain Res. Bull., 1993; 31: 565-72; Giulian O. and Vaca K., "Inflammatory glia medíate delayed neuronal damage after schemia in the central nervous system," Stroke, 1993; 24 (Suppl 12): 184-90; Patterson PH, "Cytokines in Alzheimer's disease and multiple sclerosis, "Cur., Opinion Neurobiol., 1995; 5: 642-6; McGeer PL, Rogers J., and McGeer EG," Neuroimmune mechanisms in Alzheimer's disease pathogenesis, "Alzheimer Dis. Assoc. Disorders, 1994; 8: 149-58; Martin R. and McFarland HF, "Immunological aspects of experimental allergic enc ephalomyelitis and multiple sclerosie., "Crit. Rev. Clin. Lab. Sci., 1995; 32: 121-82; Rogers J., Webster S., L.L. L., et al., "Inflammation and Alzheimer's disease pathogenesis." In: Neurobiology of Aging, 1996; 17: 681-686; Rothwell N.J. and Relton J.K., "Involvement of cytokines, neurodegeneration in the CNS," Neurosci. Biobehav. Rev., 1993; 17: 217-27). The pathological profiles and clinical courses of these disorders differ widely, but all have in common the participation of immune / inflammatory elements in the disease process. In particular, many neurodegenerative disorders are characterized by large amounts of reactive microglial cells in postmortem brain samples, indicative of an active inflammatory process. (McGeer E.G. and McGeer P.L., supra., 1994). Increasing attention is being directed towards the inflammatory mechanisms in Alzheimer's disease. Several lines of evidence support the implication of neuroinflammation in Alzheimer's disease: 1) There is a significant increase in inflammatory markers in the Alzheimer's brain, which include acute phase reagents, cytokines, complementary proteins, and MHC molecules (McGeer et al., supra., 1994; Rogers et al., supra); 2) There is evidence that ß-amyloid induces neurodegenerative changes mainly through interactions with inflammatory molecules, and that inflation alone is sufficient to induce neurodegeneration (Rogers et al., Supra); and 3) increasing epidemiological data indicate that anti-inflammatory therapy can delay the onset and slow the progression of Alzheimer's disease (McGeer PL and Rogers J., "Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease," Neurology, 1992; 42: 447-9; Canadian Study of Health and Aging, "Risk factors for Alzheimer's Disease in Canada," Neurology, 1994; 44: 2073-80; Lucca U., Tettamarti M., Forloni G., and Spagnoli A., "Nonsteroidal antiinflammatory drug use in Alzheimer's disease," Biol. Psychiatry, 1994; 36: 854-66; Hampel H. and Müller N., "Inflammatory and immunological mechanisms in Alzheimer's disease," DN & P, 1995; 8: 599- 60B; Breitner JCS, Gau BA, Welsh KA, et al., "Inverse association of anti-inflammatory treatments and Alzheimer's disease: Initial results of a co-twin control smdy," Neurology, 1994; 44: 227-32; Breitner JCS , Welsh KA, Helms MJ, et al., "Delayed onset of Alzheimer's disease with nonsteroidal anli-inflammator and and histamine H2 blocking drugs, "Neurobiol. Aging, 1995; 16: 523-30; Andersen K., Launer L.J., Ott A., Hoes A.W., Breteler M.M.B., and Hofman A., "Do nonsteroidal anli-inflammatory drugs decrease the risk for Alzheimer's disease? The Rotterdam Study," Neurology, 1995; 45: 1441-5, Rich J.E., Rasmusson D.X., Folstein M.F., et al., "Nonsteroidal a ni i-inflammatory drugs in Alzheimer's disease," Neurology, 1995; 45: 51-5; Aisen P.S., "Anti-inflammatory therapy for Alzheimer's disease," Dementia, 1995,9: 173-82; Rogers et al., Y . * h 'above). He used chronic non-steroidal anti-inflammatory drugs (NSAIDs), most commonly for the treatment of rheumatoid arthritis, decreases the likelihood of developing Alzheimer's disease, and there is reason to believe that other anti-inflammatory ingredients may also be effective, although direct evidence is lacking for the efficiency of such treatments (Hamper and Müller, supra., 1995). In addition, virtually all currently available compounds, which include corticosteroids, NSAIDs, antimalarial drugs, and colchicine, have serious disadvantages that make them undesirable in the treatment of chronic disorders. Glucocorticoids, which are in wide clinical use as anli-inflammatory / immunosuppressive drugs, can be directly neurotoxic and are also toxic to systemic organs at two to moderate to high. NSAIDs have gastrointestinal and renal side effects that obviate long-term use in most people, and a few of them cross the blood-brain barrier in significant quantities. The toxic properties of the chloroquine and conchycin compounds are also known. An anti-inflammatory drug that is well tolerated by patients and that crosses the brain-blood barrier has significant advantages for the treatment of acute and chronic degenerative diseases of the central nervous system.

The normal function of the kidney is dependent on the maintenance of tissues constructed of differentiated and highly specialized renal cells which are in a dynamic equilibrium with their surrounding extracellular matrix (ECM) components (Davies M. et al., "Proteinases and glomerular matrix turnover, "Kidney Int., 1992; 41: 671-678). Effective glomerular filtration requires that a semipermeable glomerular base membrane (GBM) composed of collagens, fibronectin, enactin, laminin and proteoglycans be maintained. A structural equilibrium is achieved by balancing the continuous deposition of SM proteins with their degradation by specific metalloproteinases (MMPs). MMP belongs to a super-gene family of zinc endopeptidases (Woessner J.F., "Matrix metalloproteinases and their inhibitors in connective tissue remodeling," FASEB J., 1991; 5: 2145-2154). These proteins are first secreted as coenzymes and subsequently activated in the extracellular space. These proteins are in turn subject to counterbalancing regulation of their activity by naturally occurring inhibitors referred to as TIMP (tissue metalloproteinase inhibitors). Deficiency or defects in any component of the filtration barrier can have catastrophic consequences for kidney function over a longer period. For example, in hereditary nephretis or Alport type, associated with mutations in genes encoding ECM proteins, defects in collagen assembly lead to progressive renal failure associated with the division of GBM and eventual glomerular and interstitial fibrosis. In contrast, in inflammatory renal diseases such as glomerulonephritis, cellular proliferation of glomerulus components often precedes the obvious ultra structural alteration of the ECM matrix. Cytokines and growth factors involved in proliferative glomerulonephritis such as interleukin-1, tumor necrosis factor, and transforming growth factor β can upregulate the expression of metalloproteinase in cells of the message (Martin J. et al. , "Enhancement of glomerular mesangial cell neutral proteinase secretion by macrophages: role of interleukin 1," J. Immunol., 1986; 137: 525-529; Marti HP et al., "Homology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells, "Biochem J., 1993; 291: 441-146; Marti HP et al.," Transforming growth factor-b stimulates glomerular mesangial cell synthesis of the 72 kDa type IV collagenase, "Am J. Pathol., 1994; 144: 82-94). It is believed that these metalloproteinases are intimately involved in the aberrant tissue remodeling and cell proliferation characteristic of renal diseases, such as IgA nephropathy which can progress through a process of gradual glomerular fibrosis and loss of fusion of GBM up to the terminal stage of kidney disease. The expression of metalloproteins has already been well characterized in glomerulonephritis mediated by experimental immune complex such as the anti-Thy 1.1 rat model (Bagchus WM, Hoedemacker PJ, Rozing J., Bakker WW, "Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies : A sequential histological and ultrastructural study in the rat, "Lab. Invesf., 1986; 55: 680-687; Lovett DH, Johnson RJ, Martin HP, Martin J., Davies M., Couser WG," Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex mediated glomerulonephritis, "Am. J. Pathol., 1992; 141: 85-98). Unfortunately, in the present, there are very limited therapeutic strategies to modify the course of progressive kidney disease. Although many kidney diseases have an inflammatory component, their responses to standard immunosuppressive regimens are unpredictable and potentially dangerous to individual patients. Secondary consequences of gradual nephron insufficiency such as activation of the renin-angiotensin system accompanied by glomerular hyperfiltration of individual and renal hypertension, can be effectively treated with ACE inhibitors or angiotensin II receptor antagonists; but at most, these compounds can only reduce the rate of decline of CFR. A novel strategy to treat at least some kidney diseases has been suggested by recent observations of MMP behavior. A MMP cell from rat messaging (MMP-2) has been cloned which is regulated in a tissue-specific manner, and in contrast to other cellular sources such as tumor cell lines, is induced by cytokines. (Brown PD, Levy AT, Margulies I., Liotta LA, Stetler-Stevenson WG, "Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines," Cancer Res.1990; 50: 6184- 6191; Marti HP et al., "Homology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells," Biochem J., 1993; 291: 441-446). While MMP-2 may specifically degrade surrounding ECMs, it also affects the phenotype of adjacent messaging cells. Inhibition of MMP-2 by antisense oligonucleotides or transfection techniques can induce a reversion of the proliferative phenotype of culturing message cells to a quiescent or non-proliferative type that mimics the in vitro natural behavior of these cells (Kitamura M. et al., "Gene transfer of metalloproteinase transin induces aberrant behavior of cultured mesangial cells," Kidney Int., 1994; 45: 1580-1586; Turck J. et al., "Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation, "J. Biol. Cherrz, 1996; 271: 15074-15083).

MMP inhibitors (MMPi) clearly have potential applications in a multitude of diseases characterized by perturbation of extracellular matrix cellular interactions that result in abnormal tissue remodeling (Vincenti MP et al., "Using inhibitors of metalloproteinases to treat arthritis, "Arthritis Rheu., 1994; 8: 1115-1126; Grams F. et al.," X-ray structures of human neutrophil collagenase complexed with peptide hydroxyamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design, "Eur. J. BJochem., 1995, 288: 830-841). A series of tricyclic sulfonamide compounds and their derivatives have been identified which are matrix metalloproteinase inhibitors such as particularly collagenase-3, stromelysin-1 and gelatinase A, and useful as well as agents for the treatment of multiple sclerosis, rupture of atherosclerotic plaque, restenosis, aortic aneurysm, heart failure, left ventricular dilatation, periodontal disease, ulceration of the cornea, treatment of burns, decubital ulcers, wound repair, cancer, inflammation, pain, arthritis, osteoporosis, kidney disease or other autoimmune or inflammatory diseases dependent on the invention by tissue leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, sick Prion ages, myasthenia gravis, and Duchenne muscular dystrophy.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, a first aspect of the present invention is a compound of Formula I i where n is zero or an integer of 1 or 2; X is -O-, -S (O) p- where p is zero or an integer of 1 or 2, N- wherein R2 is hydrogen, alkyl is acyl, or benzyl, CH2-, or s? - »iüéi__ --- rS & f '* C-; OR R is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl, alkanoyloxyalkyl, alkanoylaminoalkyl, alkyltioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl alkylaminoalkyl, dialkylaminoalkyl, N-alkylpiperazinealkyl; N-phenylalkylpiperazinoalkyl, morpholinoalkyl, thiomorpholinoalkyl, piperidinoalkyl, pyrrolidinoalkyl, N-alkylalkylpiperidinoalkyl, pyridylalkyl, thienylalkyl, quinolinylalkyl, thiazolylalkyl, cycloalkyl, cycloalkylalkyl, phenyl phenyl substituted by one to three substituents selected from the group consisting of: hydroxy, alkoxy, alkyl, alkylthio , alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, cyano, nitro, trifluoromethyl or on adjacent carbon atoms by an alkenylenedioxy group of one to two carbons or an alkenyleneoxy group of two to three carbons, phenylalkyl, phenylalkyl wherein the phenyl it is replaced by alkyl, .. afe ».. alkoxy, halogen, or trifluoromethyl, heteroaryl, heteroaryl substituted by one to two substituents selected from the group consisting of: alkyl, or, halogen, biphenyl, biphenyl substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano, biphenylalkyl or biphenylalkyl wherein biphenyl is substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano; D is zero or an integer from 1 to 3; L is zero or an integer from 1 to 3; R1 is hydrogen, a side chain of a natural amino acid or a side chain of an unnatural amino acid Y is OR3 wherein R3 is hydrogen, methyl, ethyl, or benzyl, or NH-OR4 wherein R4 is hydrogen, alkyl, or benzyl; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. As inhibitors of matrix metalloproteinase, the compounds of Formula I are useful as agents for the treatment of multiple sclerosis. They are also useful as agents for the treatment of atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilatation, restenosis, periodontal disease, corneal ulcer, treatment of burns, decutital ulcers, wound repair, cancer metastasis, tumor angiogenesis, inflammation, pain, arthritis, osteoporosis, kidney disease and other autoimmune or inflammatory disorders dependent on the invasion by tissue leukocytes or other activated migrating cells, disorders, acute and chronic neurodegenerative disorders including attack, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion diseases, myasthenia gravis, and Duchenne muscular dystrophy. A further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the aforementioned treatment methods. Finally, the present invention is directed to methods for the production of compounds of Formula I DETAILED DESCRIPTION OF THE INVENTION In the compounds of Formula I, the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n -butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The term "alkenyl" means a linear or branched unsaturated hydrocarbon radical having from 2 to 6 carbon atoms and includes, for example, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like. "Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of 1 to 6 carbon atoms as defined above for "alkyl".

The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 7 carbon atoms optionally containing an oxygen or sulfur atom and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined above for alkyl, nitro, cyano, carboxy, guanidino, amidino, SO3H, CHO, C-alkyl as defined above for alkyl, - -NH2, OO-C-NH-alkyl, NH-C-alkyl, as defined above for O-alkyl, -CN (alkyl) 2 as defined above for alkyl , - (CH2) n2-NH2 wherein n2 is an integer from 1 to 5, - (CH2) n2-NH-alkyl as defined above for alkyl and n2, - (CH2) n2-N (alkyl) as defined above for alkyl and n2, O M s tm _! ______________ M__É__aa ______? - (CH2) n2-NH-C-alkyl as defined above for alkyl, O and n2 and - (CH2,)) n -N dC-alkyl as defined above for alkyl and n2 alkyl The term "arylalkyl" means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl) methyl, and the like. The term "acyloxymethyl" means a group of the formula -CH2-O-C-alkyl wherein alkyl is as defined above. The term "heteroaryl" means a 5- and 6-membered heteroaromatic radical containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2-, or 3-thienyl , 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pi ri m id ini lo; 3- or 4-pyrizoknyl, 1 H-indol-6-yl, 1 H-indol-5-yl, 1 H-benzimidazol-6-yl, 1 H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl optionally substituted by a selected substituent of alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, - "* • -" - '- "__- -i t- Tr_i amino, alkylamino as defined above for alkyl, dialkylamino as defined above for alkyl, nitro, cyano, carboxy, guanidino, amidino, SO3H, CHO, O - O C-alkyl, as defined above for alkyl -C-NH2, OO-C-NH-alkyl, NH-C-alkyl, as defined above for Or alkyl, -CN (alkyl) 2 as defined above for alkyl, - (CH2) n2-NH2 wherein n2 is an integer from 1 to 5, - (CH2) n2-NH-alkyl as defined above for alkyl and n '(CH 2) n 2 -N (alkyl) 2 as defined above for alkyl and n 2 O - (C HH 2.)) n 2 -NH-C-alkyl as defined above for alkyl, g ^ ^^ * t ~ 0 and n2 and - (CH2) n2-N-H.-alkyl alkyl as defined above for alkyl and n2. The term "heterocycle" means a 3- to 7-membered cycloalkyl radical containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, 2- and 3-azetidinyl, 3- and 4-azetidinyl-2-one, 4- and 5-imidazolidinyl-2-one, 2,4-dioxo-imidazolidinyl, 2, 4-di oxo-1,5,5-trimethyl-imidazolidinyl, 2-, 4-, and 5-thiazolidinyl, 4- and 5-oxazolidinyl-2-one, 2- and 3-tetrahydrofuranyl, 2- and 3-pi Ridinyl, 2-, 3-, and 4-piperidinyl, 2- and 3-morpholinyl, 2- and 3-piperazinyl, 2-, 3-, and 4-azacycloheptanyl and the like. The term "heteroarylalkyl" means a heteroaromatic radical attached to an alkyl radical wherein heteroaryl and alkyl are as defined above. The term "heterocycloalkyl" means a heterocycle radical attached to an alkyl radical wherein heterocycle and alkyl are as defined above. The term "pyrrolidinoalkyl" means a pyrrolidino group attached to an alkyl radical wherein alkyl is as defined above. The term "pyridylalkyl" means a pyridyl group attached to an alkyl radical wherein alkyl is as defined above.

The term "thienylalkyl" means a thienyl group attached to an alkyl radical wherein alkyl is as defined above. The term "quinolinyl alkyl" means a quinolinyl group attached to an alkyl radical wherein alkyl is as defined above. The term "thiazolylalkyl" means a thiazolyl group attached to an alkyl radical wherein alkyl is as defined above. The term "phenylalkyl" means a phenyl group attached to an alkyl radical wherein alkyl is as defined above. The term "biphenylalkyl" means a biphenyl group attached to an alkyl radical wherein alkyl is as defined above.

O The term "acyl" means a group of the formula -C-alkyl wherein alkyl is as defined above. The term "hydroxyalkyl" means a hydroxy group attached to an alkyl radical wherein alkyl is as defined above. The term "alkoxyalkyl" means an alkoxy group attached to an alkyl radical wherein alkoxy and alkyl are as defined above.

The term "aminoalkyl" means an amino group attached to an alkyl radical wherein alkyl is as defined above. The term "morpholinoalkyl" means a morpholino group attached to an alkyl radical wherein alkyl is as defined above. The term "thiomorpholinoalkyl" means a thiomorpholino group attached to an alkyl radical wherein alkyl is as defined above. The term "piperidinoalkyl" means a piperidino group attached to an alkyl radical wherein alkyl is as defined above. The term "cycloalkylalkyl" means a cycloalkyl group attached to an alkyl radical wherein cycloalkyl and alkyl are as defined above. The terms "alkylaminoalkyl" and "dialkylaminoalkyl" are respectively alkyl-NH and (alkyl) 2N- wherein alkyl is as defined above. The term "alkylamino" and "dialkylamino" are respectively alkyl NH- and (alkyl) 2N- wherein alkyl is or was previously defined. The terms "alkylthioalkyl," "alkylsulfinylalkyl,", and "alkylsulfonylalkyl" are respectively alkyl-S-alkylamino, alkyl-SO-alkyl, and alkyl-SO2-alkyl wherein alkyl is as defined above. a ___ ^ __________ B____ The terms "alkylthio," "alkylsulfinyl," and "alkylsulfonyl" are respectively alkyl-S-, alkyl-SO-, and alkyl-SO2- wherein alkyl is as defined above. O The term "alkanoyloxyalkyl" means an alkyl-C-O-alkyl wherein alkyl is as defined above.

The term "alkanoylaminoalkyl" means an alkyl-NH alkywhere alkyl is as defined above. The term "N-alkylpiperazinoalkyl" means the alkyl-N p < N where alkyl is as defined beforehand.

The term "N-phenylalkylpiperazinoalkyl" means phenylalkyl or N-N alkyl wherein alkyl is as defined above.

The term "N-alkylalkylpiperidinoalkyl" means alquilalq where alkyl is as defined above \ / The term "alkenylenedioxy" means -O-alkyl-O- wherein alkyl is as defined above. _________________________ The term "alkenyleneoxy" means -alkyl-O- wherein alkyl is as defined above. The term "side chain of a natural amino acid" (a natural amino acid) means the group Q in a natural amino acid of formula H2N-CH (Q) -COOH. Examples of side chains of natural amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and Valina A natural amino acid is an amino acid found in a living organism. Examples of such amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, asparagine, glutamine, lysine, arginine, tryptophan, histidine, cysteine, methionine, aspartic acid, and glutamic acid. The functional groups in the side chains of amino acids can be protected. For example, the carboxyl groups can be esterified, the amino groups can be converted into amides or carbamates, the hydroxyl groups can be converted into esters or ethers, and the thiol groups can be converted into thioethers or thioesters. The term "secondary chain of an unnatural amino acid" means the group R 1a in a non-naturally occurring amino acid of the formula HN- (CH 2) D-CH- (CH 2) L-COY k fc 1a is hydrogen alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl , alkanoyloxyalkyl, alkanoylaminoalkyl, alkyl Itioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylpiperazinoalkyl, N-phenylalkylpiperazinoalkyl, morpholinoalkyl, thiomorpholinoalkyl, piperidinoalkyl, pyrrolidinoalkyl, N-alkylalkylpiperidinoalkyl, pyridylalkyl, thienylalkyl, quinolinylalkyl, thiazolylalkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenyl substituted by one to three substituents selected from the group consisting of: hydroxy, alkoxy, alkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, cyano, nitro, trifluoromethyl or on adjacent carbon atoms by a one to two carbon alkenylenedioxide group or an alkenyleneoxy group of two to three carbon phenylalkyl, phenylalkyl wherein the phenyl is substituted by alkyl, alkoxy, halogen, or trifluoromethyl, heteroaryl, heteroaryl substituted by one to two substituents selected from the group consisting of: alkyl, or, halogen, biphenyl, biphenyl substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano, biphenylal chyl or biphenylalkyl wherein biphenyl is substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano; D is zero or an integer from 1 to 3; L is zero or an integer from 1 to 3; R1a is the side chain of an amino acid that does not occur naturally. Amino acids that do not occur naturally are well known in the art, for example, Roberts et al., "Unusual Amino Acids in Peptide Synthesis," T7? E Peptides, 1993; 5: 341-429, but are not naturally found in living organisms. The side chains of non-natural amino acids include, but are not limited to: hydrogen, - (CH2) n-naphthalimide where n is zero or an integer number of 1 to 2, - (CH2) n-phthalimide wherein n is as defined above, - (CH2) n-aryl wherein n is as defined above, alkyl, substituted alkyl wherein the substituent is selected from the group consisting of: SH, OR5 wherein R5 is hydrogen, alkyl, phenyl, or benzyl, SR: wherein R5 is as defined above, halogen, NR5 R5a wherein R5 and R5a are the same or different and each is the same as defined above for R5, CO2H, COR5 where R5 is as defined above, CHO, or CONR5 wherein R5 and R5a are the same ok 5a different and each is the same as defined above for R5, aryl, - (CH2) n-phenyl where n is as previously defined, alkenyl, (CH2) -n-heteroaryl wherein n is as defined above, heteroaryl, heter occyl, - (CH2) m-NH-Z-R5 wherein m is an integer from 1 to 6, Z is OS -C-, -C-, or -SO2 and R5 is as defined above, - (CH2 ) mSC (phenyl) 3 wherein m is as defined above, - (CH2) mO- (CH2) La-phenyl where La is an integer from 1 to 6 and m is as defined above, . "*« ** - **** ..- -__ -____, - O - (CH2) mC-R5 wherein m and R5 are as defined above, - (CH2) m-NHSO2-aryl wherein m is as defined above, - (CH2) m-cycloalkyl wherein m is as defined above , O - (CH2) mC-aryl wherein m is as defined above, O (C: HH2,)) rm-C- NNHH-R5 wherein m and R5 are as defined above, OR - (CH2) m-C-OR5 where m and R5 are as defined above or where n is as defined above; Y And it's OR3 where R3 is hydrogen, methyl, __________ - - "• - • • •" - 'ethyl, or benzyl, or NH-OR 4 wherein R 4 is hydrogen, alkyl, or benzyl; with the proviso that R1a is not the side chain of a natural amino acid as defined above. Additionally, side chains of amino acids and unnatural amino acids having the D or R configuration are included within this term. The functional groups in the amino acid side chains can be protected. For example, the carboxyl groups can be esterified, the amino groups can be converted into amides or carbamates, the hydroxyl groups can be converted into ethers or esters, and the thiol groups can be converted into thioethers or thioesters. "Halogen" is fluorine, chlorine, bromine or iodine. "Alkali metal" is a metal of Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like. The acyloxymethyl esters of compounds of Formula I can be prepared by methods known to one skilled in the art. For example, the corresponding carboxylic acids can be first allowed to react with a suitable base to give the carboxylate anion, followed by the reaction with a halomethylcarboxylic ester, which can be obtained from commercial suppliers or prepared by methods known to one skilled in the art, optionally in the presence of a suitable agent to activate the halomethylcarboxylic ester, which are known to one skilled in the art, to give the acyloxymethyl esters. Some of the compounds of Formula I are capable of further forming pharmaceutically acceptable acid and / or basic addition salts. All these forms are inside of the scope of the present invention. The pharmaceutically acceptable acid addition salts of the compounds of the Formula I include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, Hydrofluoric, phosphoric and the like, as well as the salts derived from the non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, alkanoic phenyl-substituted acids, hydroxyalkane acids, alkanedioic acids, aromatic acids, aliphatics and sulfonaromatic acids, etc. Such The salts thus include sulfate, pyrosulfate, disulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, mandeate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, ^ _ ^ ¡_i _ ^ ______ ^ i ^ _i_1 ____ ii _ ^^ _ i_i_liiBli_ ^ > _ ^^^ _ ^^^^^ __ ^^^^ benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are amino acid salts such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. of Pharma Sci., 1977; 66: 1). The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for purposes of the present invention. The pharmaceutically acceptable basic addition salts are formed with metals or amines, such as alkali and alkaline earth metals and organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine . * - .. - yptfan¡-. -_ SJ__ _. I "*» • __ - ^^ ^ i ^ j (see, for example, Berge SM et al, "Pharmaceutical Salts," J. of Pharma Sci., 1977; 66: 1.) The basic addition salts of the Acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner The free acid forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acids for purposes of present invention Some of the compounds of the present invention may exist in unsolvated forms as well as in solvated forms, including hydrated forms In general, solvated forms including hydrated forms are equivalent to non-hydrated forms. solvated and intended to be encompassed within the scope of the present invention. Some of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as appropriate mixtures thereof. Additionally, the compounds of the present invention can exist as geometric isomers. The present invention includes all the cis, trans, syn, anti entgegen (E), zusammen (Z) isomers as well as the appropriate mixtures thereof. A preferred compound of Formula I is wherein n, X, R, R1 and Y are as defined above. Another preferred compound of Formula I is where n is zero or an integer of 1; and X is -O-, or -CH2-. and Another preferred compound of Formula I is where n is zero or an integer of 1; X is -O-, or -CH2-; and R is hydrogen.

A more preferred compound of formula I is where n is zero or an integer of 1; X is -O-, or -CH2-; R is hydrogen; and Y is OH. A more preferred compound of Formula I is where n is zero or an integer of 1; X is -O-. or -CH2-R is hydrogen; and Y is NHOH. Particularly valuable in this embodiment of the invention is a compound selected from the group consisting of: (S) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -succinic acid; (S) Phenyl - [(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)] -acetic acid; (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -propionic acid; (S) 3- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; Acid (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfo nylamino) -4- (3,4,4-trimethyl-2,5-di-oxo-imidazolidin-1-yl) - butyric; Acid (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-su If oni lam i) -5- (3,4,4-tri-methyl-2, 5-di oxoimidazo I Din-1-yl) -pentanoic acid; (S) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (S) 4-Phenylmethanesulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4- (1I3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (S) 6-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (S) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (S) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (S) 4-Phenylsulfamoyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4-Phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4-Benzylsulfanyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 3- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (S) 4- (1H-Indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-ibenzofuran-3-sulfonylamino) -pentanoic acid; (S) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (S) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (S) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (S) 2- (2,3-Dihydro-1 H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -3-methyl-butyric acid; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-3- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -succinnamic acid; (S) N-Hydroxy-2-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -acetamide; (S) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -propionamide; (S) 3- (1, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionamide; (S) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxo-midazolidin-1-yl) ) -butyramide; Hydroxyamide (S) 2- (6,7,8,9-Tetrahydro-d i benzof uran-3-sulfonyl lam i) -5- (3,4,4-tri-methyl-2, 5-d) ioxo-imidazolidin-1-yl) -pentanoic acid; Hydroxyamide of (S) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (S) N-Hydroxy-4-phenylmetansulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) 4- (1, 3-D-ioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) - Butyramide; Hydroxyamide (S) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide; Hydroxyamide of (S) 6-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; Hydroxyamide of (S) 7-Phenyl-2- (6,7,8,9-te trah id ro-d i b in zofuran-3-sulfonyl-lamino) -heptanoic acid; Hydroxyamide of (S) 8-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (S) 4-Benzylsulfanyl-N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-4-phenylsulfamoyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-4-phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-3- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionamide; (S) N-Hydroxy-4- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; Hydroxyamide of (S) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-d i benzofuran-3-sulfonyl) -pentanoic acid; Hydroxyamide (S) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid hydroxyamide; Hydroxyamide acid (S) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-te tra h id ro-d ib in zofuran-3-sulfonium lamino) - heptane ico; (S) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (S) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -N-hydroxy-3-methyl-butyramide; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyramide; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (S) 3-Methyl-2- (9-methyl-6,7,8,9-tetrahydro-5H-carbazole-2-sulfonylamino) -butyric acid; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (S) N-Hydroxy-3-methyl-2- (9-methyl-6,7,8,9-tetrahydro-5H-carbazole-2-sulfonylamino) -butyramide; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-d i benzothiophen-3-sulfo nylamino) -butyramide; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -succinic acid; (R) Phenyl - [(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)] -acetic acid; Acid (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) - propionic; (R) 3- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -butyric acid; Acid (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -5- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) - pentanoic; (R) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (R) 4-Phenylmethanesulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; Acid (R) 4- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6, 7, 8, 9-te tra h id ro- di benzofuran-3-su I fon i la no) - butyric; (R) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; Acid (R) 6-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (R) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (R) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (R) 4-Phenylsulfamoyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 4-Phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 4-Benzylsulfanyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 3- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (R) 4- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (R) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (R) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (R) 8- (1 H-lndo) -3-yl) -2- (6,7,8,9-tetrahydro-dibenzo-furan-3-sulfonylamino) -octanoic acid; (R) 2- (2,3-Dihydro-1 H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -3-met-1-butyric acid; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulene-2-sulfonylamino) -butyric acid; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzo-furan-3-sulfonylamino) -butyramide; (R) N-Hydroxy-3- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -succinnamic acid; (R) N-Hydroxy-2-phenyl-2- (6,7,8,9-tetrahydro-dibenzo-furan-3-sulfonylamino) -acetamide; (R) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-tri-methyl-2,5-dioxo-imidazolid-1) -yl) -propionamide; (R) 3- (1, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) - propionamide; (R) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-its Ifon i mi no) -4- (3,4,4-tri-methyl-2, 5-d ioxo -imidazole din-1-yl) -butyramide; Hydroxyamide acid (R) 2- (6,7,8,9-Tetrahydro-d and benzofura n-3-sulfon i mi no) -5- (3,4,4-tri-methyl-2, 5- dioxo-imidazolidin-1-yl) -pentanoic acid; (R) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide; (R) N-Hydroxy-4-phenylmetansulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 4- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide; Hydroxyamide of (R) 6-Phenyl-2- (6,7,8,9-tetrah idro-d i b in zofuran-3-sulfonyl-lamino) -hexanoic acid; Hydroxyamide acid (R) 7-Phenyl-2- (6,7,8,9-te t rah id ro-d i benzof uran- 3 -su I fon mi la no) - heptanoic; (R) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (R) 4-Benzylsulfanyl-N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) N -H id roxy-4-f-enylsulfamyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-4-phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-3- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionamide; (R) N-Hydroxy- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzo-furan-3-sulfonylamino) -pentanoic acid; Hydroxyamide (R) 6- (1 H-l ndol-3-yl) -2- (6, 7,8,9-te tra h id ro-d ib in zofuran-3-su phonylamino) -hexanoic acid; (R) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid hydroxyamide; (R) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (R) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-its nuclopho Ufo) -N-hydroxy-3-methyl-butyra mide; (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (R) 3-Methyl-2- (9-methyl-6 > 7,8,9-tetrahydro-5H-carbazol-2-sulfonylamino) -butyric acid; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (R) N-H idroxy-3-methyl-2- (9-methyl 1-6,7,8,9-tetrahydro-rbazol-2-sulfonylamino) -butyral; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; and (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; and the corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. The compounds of Formula I are valuable inhibitors of a number of different matrix metalloproteinases. It has previously been shown that inhibitors of matrix metalloproteinases have efficiency in models of affective states such as arthritis and metastasis that depend on the modification of the extracellular matrix. In vitro experiments were carried out which demonstrated the efficiency of the compounds of Formula I as potent and specific inhibitors of a variety of matrix metalloproteinases. The experiments were carried out with the full length and catalytic domains of the proteinases. Table 1 shows the activity of Examples 1-4 versus MMP-1FL (full length enzyme collagenase-1), MMP-2CD (catalytic domain of gelatinase A), MMP-2FL (full length enzyme of gelatinase A), MMP -3CD (catalytic domain of stromelysin-1), MMP-7FL (full-length enzyme matrilysin), MMP-9-FL (full-length enzyme of gelatinase B), MMP-13CD (catalytic domain of collagenase-3), and MMP-14CD (MMP-1 membrane type). The IC50 values were determined using a thiopeptolide substrate, Ac-Pro-leu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Q.-Z- Johnson LL, Hupe DJ, and Baragi V., "Purification and Chracterization of the Human Stromelysin Catalytic Domain Expressed in Escherichia coli, "Biochemistry, 1992; 31: 11231-11235; Ye Q.-Z., Johnson LL, Yu AE, and Hupe D.," Reconstructed 19 kDa catalytic domain of gelatinase A is an active proteinase, "Biochemistry, 1995; 34: 4702-4708). MMP-13CD was expressed from a synthetic gene and purified from Escherichia coli cell culture according to the previously described method (Ye Q.-Z., Johnson LL, and Baragi V., "Gene synthesis and expression in E. coli for PMP, a human matrix matalloproteinase, "Biochemical and Biophysical Research Communications, 1992; 186: 143-149). • n * "-. ' ¥ jj¡ffrij »iagggfe!» S? «W .-- **, ..

TABLE 1. Biological Activity of Compounds of Formula I Example IC50 (μM) MMP- MMP- MMP- MMP- MMP- MMP- MMP- MMP- 1FL 2CD 2FL 3CD 7FL 9FL 13CD 14CD 1 6.7 0.037 0.335 0.046 82 30 3.45 0.38 2 6.05 0.034 0.43 0.0245 7.5 100 2.3 0.155 3 16 0.0167 0.45 0.0056 3.2 100 0.97 0.048 4 25 0.018 0.15 0.0215 2.3 28 1.345 0.064 The following list contains abbreviations and acronyms used within the schemes and texts: GBM Glomerular base membrane ECM Extracellular matrix CNS Central nervous system CH.Cl. Dichloromethane EAE Experimental autoimmune encephalomyelitis MMP Metalloproteinase matrix TIMPs Metalloproteinase inhibitors tissue matrix VSMC Vascular smooth muscle cell TFA Trifluoroacetic acid IC 50 Concentration of compound required to inhibit 50% of enzymatic activity HCl Hydrogen chloride THF Tetrahydrofuran Pd Palladium Na Sodium NaH Hydride of sodium LiOH Lithium hydroxide LiCl Lithium chloride H2O Water H2 Hydrogen CDI 1,1 '-Carbonildiimidazole Hv Light . -._ - -1 SO3.DMF Dimethylformamide sulfur trioxide SOCI2 Thionyl chloride tertiary butyl tertiary BOC tertiary butoxycarbonyl LDA Diisopropylamide lithium MeOH Methanol DMF Dimethylformamide p-TsOH (p-TSA) Para-Toluenesulfonic acid CHCl3 Chloroform CDCI3 Deorred chloroform E Entgegen Z Zusammen H2NOBz O-Benzyl hydroxylamine TEA Triethylamine CH3CN Acetonitrile DBU 1,8-D-azabicyclo [5.4.0] undec-7-ene DCC Dicyclohexylcarbodiimide PPA Polyphosphoric acid BaSO4 Barium sulfate DMSO-d6 Deuterated methoxy sulphate MgSO4 Magnesium sulfate 1H -NMR proton nuclear magnetic resonance PPM parts per million MS Mass spectrum The starting materials tricyclic aryl and tricyclic heteroaryl of formula (3) where n is zero or an integer of 1 or 2; and X is -O-, -S-, -N-, wherein R2 is hydrogen, alkyl, acyl, or benzyl, are obtained from commercial sources (X = N-R2 where R2 is as defined above) or prepared using methods known in the art, for example, Bachelet J.P. and Caubere P., J. Org. Chem., 1982; 47: 234-238; Ebel F., Helv. Chim. Minutes, 1929; 12: 3-16; Vanrysselberghe V. et al., Ind. Eng. Chem. Res., 1996: 35: 3311-3318; Derouane D. et al., J. Chem. Soc, Chem.

Commun., 1995; 10: 993-994; Miki Y. and Sugimoto Y., Seikiyu Gakkaishi, 1994; 37: 386-394; Miki Y. et al., Seikiyu Gakkaishi, 1992. 35,332-338; Rankel L.A., Fuel Sci. Technol. Int., 1991; 9: 1435-1447; Siskin M. et al., Energy Fuels, 1990; 4: 482-488; Sundaram K.M. et al., Chem. Eng. Commun., 1988; 71: 53-71; Francisco m.A. et al., J. Org. Chem., 1988; 53: 596-600; Nagai M. et al., J. Catal., 1986; 97: 52-58; Miyake M. et al., Bull. Chem. Soc. Japan, 1979; 52: 559-563; Ando W. et al., J. Chem. Soc. Chem. Commun, 1975; 17: 704-705; Fraser P.S. et al., J. Org. Che.m 1974; 39: 2509-2513; Cagniant P. et al., Bull. Soc. Chim. Fr., 1969; 2: 607-612; and Cagniant D. et al., Bull. Soc. Chim. Fr., 1969; 2: 601-606; Patents of the United States 5,721,185, 5,670,680; International Published Patent Application WO 95/27717; Smith W. et al., J. Org. Chem., 1990; 55: 5301-5302; Mlejer S., Pol. Of Chem., 1979; 53: 2385-2388; Canonne P. et al., J. Org. Chem., 1980; 45: 1828-1835; parham E.W., Synthesis, 1976; 116-117; Japanese Patent Application JP 08191063 A2; Parhan W.E., J. Org. Chem., 1969; 34: 1899-1904; McCIure K.F. et al., Bioorg. Med. Chem. Lett., 1998; 8: 143-146. The synthesis of the starting materials for a compound of Formula I wherein X is -O- is shown in Scheme 1. Thus, a compound of formula (1) wherein n is zero or an integer of 1 or 2 is it reacts with phenol in the presence of sodium, or sodium hydride and the like in the presence of a solvent such as benzene, tetrahydrofuran, and the like, to produce a compound of formula (2). The cyclization of a compound of formula (2) in the presence of an acid such as, for example, polyphosphoric acid, paratoluenesulfonic acid andjf similar in the presence of a solvent such as benzene and the like, produces a compound of formula (3). The synthesis of compounds of Formula Ia, Ib, le, and Id, are shown in Scheme 2. Thus, a compound of formula (3), wherein n is as defined above is sulphonated using a sulphonation reagent such as, for example, SO3.DMF, and the like, by reflux in a solvent such as, for example, dichloroethane and the like, to produce a compound of formula (4) wherein n is as defined above. A compound of formula (4) is treated with chlorine with a chlorinating reagent such as, for example, thionyl chloride and the like, at about room temperature to produce a compound of formula (5) wherein n is as defined above . A compound of formula (5) is reacted with an amino acid of formula (6) wherein R 1 is hydrogen, a secondary chain of a natural amino acid or a secondary chain of a non-natural amino acid in the presence of a base such as, example, triethylamine and the like in a solvent such as, for example, tetrahydrofuran / water and the like at about room temperature to produce a compound of Formula wherein n and R1 are as defined above. Alternatively, a compound of formula (5) is reacted with a C-protected amino acid of formula (7) wherein R 1 is as defined above in the presence of a base such as, for example, triethylamine and the like in the - -, «afe-i" _ & " presence of a solvent such as, for example, dichloromethane and the like to produce a compound of formula (8) wherein n and R1 are as defined above. A compound of formula (8) can be deprotected in the presence of an acid such as, for example, trifluoroacetic acid and the like, and a solvent such as, for example, dichloromethane and the like at about room temperature to produce a compound of Formula . The coupling of the acid chloride of Formula I with O-benzylhydroxylamine in a solvent such as, for example, tetrahydrofuran and the like at about -10 ° C to about 40 ° C to produce a compound of Formula le wherein n and R1 are as It was defined earlier. The reaction of a compound of Formula I with hydrogen gas in the presence of a catalyst such as, for example, palladium on barium sulfate and the like in a solvent such as, for example, methanol, tetrahydrofuran and the like, to produce a compound of Formula Id, wherein n and R1 are as defined above. The reaction of a compound of formula (8) with a compound of formula R-Hal wherein R is hydrogen alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl, alkanoyloxyalkyl, alkanoylaminoalkyl, alkylthiokyloxy, alkylsulfinylalkyl, alkylsulfonyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N -alkylpiperazinoalkyl, N-phenylalkylpiperazinoalkyl, morpholinoalkyl, thiomorpholinoalkyl, piperidinoalkyl, pyrrolidinoalkyl, N-alkylalkylpiperinoalkyl, pyridialkyl, thienylalkyl, quinolinylalkyl, thiazole and Iqloyl, cycloalkyl, cycloalkylalkyl, phenyl, phenyl substituted by one to three substituents selected from the group consisting of of: hydroxy, alkoxy, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, cyano, nitro, trifluoromethyl or on adjacent carbon atoms in either one to two carbons of the alkenylenedioxy group, or in two to three carbon of the alkenyleneoxy, phenylalkyl, phenylalkyl group wherein phenyl is substituted by alkyl, alkoxy, halogen, or trifluoromethyl, heteroaryl, heteroaryl substituted by one to two substituents selected from the group consisting of: alkyl, or halogen, biphenyl, biphenyl, substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano, biphenylalkyl or biphenylalkyl wherein biphenyl is substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano; and Hal is chlorine, bromine, or iodine in the presence of a base such as, for example, DBU and the like in a solvent such as, for example, acetonitrile and the like, to produce a compound of formula (9) wherein n, R, and R1 are as defined above. The reaction of a compound of formula (9) with an acid such as, for example, trifluoroacetic acid and the like in the presence of a solvent such as, for example, dichloromethane, produces a compound of Formula Ib wherein n, R, and R1 are as defined above. The previous methodology can be applied to natural and non-natural a-amino acids of formulas (6) and (7) which are readily available from commercial sources c can be prepared by methods known in the art. Alternatively, the natural and non-natural a-amino acids of formulas (6) and (7) can be prepared as shown in Scheme 3: Using the Evans DA method et al., J. Amer. Chem. Soc, 1982; 104: 1737-1739, N-Boc-glycine of formula (10) is coupled with the chiral benzyloxazolidine sodium salt of formula (11) in the presence of a coupling reagent such as, for example, carbonyldiimidazole in a solvent such as, for example, tetrahydrofuran and the like at about -10 ° C to about room temperature to produce the compound of formula (12). The enolate of the compound of formula (12) is formed by the reaction with lithium diisopropylamide and subsequently alkylated with a compound of formula R1-Hal wherein R1 and Ha1 are as defined above to produce a compound of formula (13) as a mixture of diastereomers. The diastereomers are separated using chromatography using an absorbent such as, for example, silica gel and the like to produce pure diastereomers. The pure diastereomers are treated with gaseous hydrogen chloride in a solvent such as dichloromethane and the like at about room temperature to produce a compound of formula (14) wherein R is as defined above. The reaction of a compound of formula (14) with a compound of formula Ar SO2Cl wherein Ar is wherein X is -O-, -S (O) p- wherein p is zero or an integer of 1 or 2, -N-, wherein R2 is hydrogen, I alkyl, R2 acyl, or benzyl, -CH2 -, or -O-, O and n is as defined above (prepared by the methodology previously described to prepare a compound of formula (5) of a compound of formula (3)) in the presence of a base such as, for example, triethylamine and the like, in a mixture of solvents such as for example, tetrahydrofuran and water at about 10 ° C at about room temperature to produce a compound of formula (15) wherein R 1 is as defined above. The auxiliary chiral oxazolidone is removed by hydrolysis with a base such as, for example, lithium hydroxide and the like, in a mixture of solvent such as, for example, dioxane / water at about room temperature to produce a compound of Formula I in where R1 is as defined above. Scheme 4 shows the preparation of a compound of Formula If using the methodology of Myers A.G. et al., Tetrahedron Lett., 1995; 36: 4555-4558. Thus, the enantiomeric glycinamide pseudoephedrine of formula (16) or its enantiomer is added to a suspension of lithium chloride and lithium diisopropylamide in a solvent such as, for example, tetrahydrofuran at about -78 ° C to produce an O, N- dianion which is heated to about 0 ° C and treated with a compound of formula R1-Hal wherein R1 and Hal are as defined above to produce a compound of formula (17) wherein R1 is as defined above, having a high degree of diastereoselectivity (99% of). A compound of formula (17) is treated with a compound of formula Ar SO2CI wherein Ar is as defined above in the presence of a base such as, for example, triethylamine and the like in a solvent such as, for example, tetrahydrofuran / water at about 10 ° C to about room temperature to produce a compound of formula (18) wherein Ar and R are as defined above. The auxiliary chiral is then removed by hydrolysis with a base such as, for example, aqueous sodium hydroxide or water / methanol mixtures at about reflux to produce a compound of Formula If wherein Ar and R1 are as defined above. Alternatively, hydrolysis can be carried out by refluxing an aqueous solution of a compound of formula (18) without adding additional base. Compounds of formula R-Hal or R1-Hal are commercially available or can be obtained by methods known in the art.

Reflux to_ Scheme 3 The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I. To prepare the pharmaceutical compositions of the compounds of In the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier may be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain from 5 or 10 to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with the encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, sacks and pills are included. The tablets, powders, capsules, pills, pouches and lozenges can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component dispersed homogeneously therein, as by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, and thereby solidify. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution, in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Also included are the solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, coloring agents, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation such as packed tablets, capsules, and powders in ampoules or ampoules. Also, the unit dosage form can be a capsule, tablet, pouch, or pill itself, or it can be the appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and potency of the active component, the composition can, if desired, contain also other compatible therapeutic agents.

For therapeutic use as agents for the treatment of multiple sclerosis, rupture of atherosclerotic plaque, aortic aneurysm, heart failure, left ventricular dilatation, restenosis, periodontal disease, corneal ulcer, treatment of burns, decubital ulcer, wound healing, cancer inflammation, pain, arthritis, osteoporosis, kidney disease or other autoimmune or inflammatory disorders, dependent on invasion by tissue leukocytes, or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion disease, severe rniastenia, and Duchenne muscular dystrophy, the compounds used in the pharmaceutical methods of the invention are administered at the dosage initial approximate 1 mg to approximately 100 mg per kilogram daily. A daily dose range of approximately 25 mg to approximately 75 mg per kilogram is preferred. The dosages, however, can be varied depending on the requirements of the patient, the severity of the condition being treated, and the compound used. The determination of the appropriate dosage for a particular situation is within the experience of the technique. Generally, the treatment starts with smaller dosages, which are less than the optimum dose of the compound. Subsequently, the dosage is increased in small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage can be divided and administered in portions during the day if desired. The following non-limiting examples illustrate the preferred methods of the inventors for preparing the compounds of the invention.

EXAMPLE 1 Acid .R) -3-Methyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) butyric Step (a) Preparation of the acid 6.7.8.9-Tetrahydro-dibenzofuran-3-sulfonic acid To a solution of tetrahydrodibenzofuran (4 g, 0.023 mol) in dichloromethane (50 ml) was added, in one portion, DMF-sulfur dioxide complex (6 g, 0.039 mol). The reaction mixture was refluxed for 14 hours, cooled, and concentrated in vacuo. The resulting crude liquid was dissolved in diethyl ether / hot ethanol producing a precipitate upon cooling. The solid was collected by filtration, washed with diethyl ether, and dried under vacuum to give the title compound as a pink solid 82.3 g, 40%). 1HNMR (CDCl 3) d 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 2.0-1.8 (m, 4H), ppm .

Step (b) Preparation of 6.7.8.9-Tetrahydro-dibenzofuran-3-sulfonyl chloride 6,7,8,9-Tetrahydrodibenzofuran-3-sulfonic acid (2.1 g, 8.3 mmol) in thionyl chloride (25 ml) was suspended. ) and stirred at room temperature for 6 hours. The solution was concentrated in vacuo and the resulting liquid was taken up in ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was concentrated to dryness, and the crude product was triturated with hexane and collected by filtration to give the sulfonyl chloride as a tan solid (1.3 g, 58%). 1HNMR (CDCl 3) d 8.0 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 1.9-1.7 (m, 4), ppm .

Step (c) Preparation of the acid (R) -3-Methyl-2-.6.7.8.9-tetrahydro-d-benzofuran-3-sulfonylamino) -butyric acid. f-butylester To a solution of (D) -valin, .ery-butylester (0.13 g, 0.74 moles) and triethylamine (0.075 g, 0.74 mmoles) in tetrahydrofuran / water (5 ml, 1: 1) were added in one portion. at room temperature, 6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl chloride (0.20 g, 0.74 mmol). The reaction mixture was stirred at room temperature for 14 hours, followed by the addition of aqueous HCl (1M, 5 ml) and ethyl acetate (10 ml). The organic phase was separated and washed with brine, dried (MgSO4) and concentrated to dryness to give the title compound as a white solid (0.24 g, 80%). HNMR (CDCl3) d 7.9 (s, 1H9, 7.7 (d, 1H), 7.5 (d, 1H), 5.1 (d, 1H), 3.6 (dd, 1H), 2.8 (m, 2H), 2.6 (m, 2H), 2.0 (m, 1H), 1.9-1.8 (m, 4H9, 1.1 (s, 9H), 1.0 (d, 3H), 0.8 (d, 3H), ppm.

Step (d) Preparation of the acid. R) -3-Methyl-2-.6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid To a solution of anisole (0.062 g, 0.57 mmol) in trifluoroacetic acid (3 ml), stirred at room temperature, added (R) -3-methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid, fe .. -butylester (0.23 g, 0.56 mmoles). The hydrolysis of the ester was completed in 4 hours, at which time the acid solution was poured onto ice, and the resulting solid was collected by filtration. The filter cake was dried in vacuo, and the solid was recrystallized from hexane / ethyl acetate to yield a cream colored powder (0.12 g, 71%); mp 167-169 ° C. 1HNMR (CDCl 3) d 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.4 (d, 1H), 3.7 (dd, 1H), 2.7 (m, 2H), 2.5 (m , 2H), 2.1 (m, 1H), 1.9-1.7 (m, 4H), 0.9 (d, 3H), 0.8 (d, 3H), ppm. In a manner similar to that described in Example 1, the following compounds were prepared: EXAMPLE 2 ISI 3-Methyl-2-.6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid mp 162-165 ° C. 1HNMR (CDCl 3) d 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 5.1 (d, 1H), 3.8 (dd, 1H), 2.8 (m, 2H), 2.6 (m , 2H), 2.1 (m, 1H), 2.0-1.8 (m, 4H), 0.9 (d, 3H), 0.8 (d, 3H) ppm.

EXAMPLE 3 (S) 2- (6.7.8.9-Tetrahydro-dibenzofuran-3-sulfonyllamino) -succinic acid mp 176-179 ° C. HNMR (CDCI3 / DMSO-d6) d 7.8 (s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 5.9 (d, 1H), 3.9 (m, 1H), 2.9-2.5 (m, 7H), 1.9-1.7 (m, 4H), ppm. In a manner similar to that described in Example 1, but replacing D-valine, .erf-butylester with L-homophenylalanine, methyl ester and using basic hydrolysis of the ester portion, the following compound was prepared: EXAMPLE 4 SI 4-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl-amino) -butyric acid: mp 167-169 ° C. 1HNMR (CDCl 3) d 7.9 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.2 (m, 3H), 7.1 (d, 2H), 5.2 (d, 1H), 4.0 (m , 1 HOUR). Using the procedure of Example 1, the following compounds of Formula I were prepared: EXAMPLE 5 Acid (S) -Fenin - [(6.7.8.9-tetrahydro-dibenzofuran-3-sulfonyllamine)] - acetic EXAMPLE 6 Acid i = X 5-Phenyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid EXAMPLE 7 Acid. 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulphonylamino) -3-methyl-butyric EXAMPLE 8 (S) 3-Methyl-2- _ 6.7.8.9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyric acid EXAMPLE 9 Í. N-Hydroxy-4-phenyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-sijlfonylamino) -butyramide EXAMPLE 10 IS1 N-Hydroxy-3- (6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -succinnamic acid EXAMPLE 11 IR acid! 4-Phenyl-2-.6.7.8.9-tetrahydro-dibenzofuran-3-sulfo nilaminol-butyric EXAMPLE 12 Acid (R) 2- (6.7.8.9-Tetrahydro-dibenzofuran-3-sulfonylamino-V-succinic) EXAMPLE 13 M 2- (2,3-D-Hydro-1H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -3-methyl-butyric acid EXAMPLE 14 (R) 3-Methyl-2- (6.7.8.9-tetrahydro-5H-10-oxa-benzofa] azulen-2-sulfonylamino) -butyric acid EXAMPLE 15 Acid .S) -3-Methyl-2- (6.7.8.9-tetrahydro-d.benzothiophen-3-sulfonylamino) -butyric acid EXAMPLE 16 (S) 3-Methyl-2- (9-methyl-6.7.8.9-tetrahydro-5H-carbazole-2-sulfonylamino) -butyric acid (S) acid EXAMPLE 17 (S) 4-Phenyl-2-.6.7.8.9- acid tetrahydro-5H-fluoren-2-sulfonylamino) -butyric: EXAMPLE 18 (S) 3-Methyl-2-.6.7.8.9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid GENERAL PROCEDURE FOR THE PREPARATION OF HYDROXAMIC ACIDS OF FORMULA I (Y = NHOH) Step (a) Preparation of the O-Benzylhydroxylamine derivative To a solution of acid chloride of a carboxylic acid of Formula I (Y = OH) in tetrahydrofuran were added two equivalents of O-benzylhydroxylamine (the acid chloride was prepared from the corresponding acid and thionyl chloride or oxalyl chloride). The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with 1 M hydrochloric acid and ethyl acetate. The layers were separated and the ethyl acetate solution was washed with water and dried over magnesium sulfate. After filtration, the crude solid was triturated with hexane and the resulting solid was collected by filtration. Step (b) Preparation of the Hydroxamic acid of Formula I (Y = NHOH) To a solution of the product of Step (a) in methanol / tetrahydrofuran was added palladium on barium sulfate.

The solution was exposed to hydrogen gas at either atmospheric pressure under a balloon or at 50 pounds per square inch (psi) in a parr apparatus. After the hydrogen uptake was completed, the mixture was filtered through celite and concentrated in vacuo to yield the hydroxamic acid. Using the general procedure for preparing hydroxamic acids described above, the following hydroxamic acids of Formula I were prepared.

EXAMPLE 19 Í. N-Hydroxy-3-methyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide EXAMPLE 20 ÍSX. N-Hydroxy-4-phenyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-s -phonyllamino) -butyramide EXAMPLE 21 (I NH id roxi-2-phenyl-2-.6.7.8.9-tetrahydro-dibenzof or ran-3-its I fonamino) -to cetamide EXAMPLE 22 (S) N-Hydroxy-2-.6.7.8.9- tetrahyd ro-d benzofuran-3-sulfonamino) -3- (3,4,4-trimethyl-2.5.-dioxo-imidazolidin-1-yl) -propionamide EXAMPLE 23 (S) 3- (1,3-D ioxo-1,3-dihydro-isoindol-2-ih-Nh id roxy-2- (6.7.8.9-tetrahydro-d-benzofuran-3-sulfonylamino ) -proponamide EXAMPLE 24 (S) 5-Phenyl-2- (6.7.8.9-tetrahydro-d? Benzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide EXAMPLE 25 (S) N-H idroxy-3-.lH-indol-3-n-2-.6.7.8.9-tetrahydro-d-benzofuran-3-sulfonyl-lane) -propionamide EXAMPLE 26 (SJ 2- (2,3-D-Hydro-1H-8-oxa-cyclopenta [a] inden-6-sijlfonylamino) -N-hydroxy-3-methyl-butyramide EXAMPLE 27 (S) NHdroxy-3-methyl-2-.6.7.8.9-tetrahydro-5H-10-oxa-benzo [a1-azulen-2-sulfonylamino) -butyramide EXAMPLE 28 N-Hydroxy- 4-phenyl-2-_ 6.7.8.9-tetrahydro-5H-fluoren-2-s -phononylamino) -butyramide EXAMPLE 29 N-Hydroxy-3-methyl-2-.6.7.8.9-tetrahydro-5H-f-luoren-2-sulfonylamino) -butyramide EXAMPLE 30 (Jü N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide EXAMPLE 31 I dropped N-Hydroxy-4-phenyl-2- (6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide EXAMPLE 32 LR N-Hydroxy-2-phenyl-2- (6.7.8.9-tetrahydro-d-benzofuran-3-sulfonylamino) -a ceta mide EXAMPLE 33 (R) NH id rox¡-2- (6.7.8.9-tetrahydro-dib in zofuran-3-sulphonyl amino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) - priopionamida , EXAMPLE 34 (R) 3-M .3-D -oxo-1,3-dihydro-iso-undol-2-yl) -N-hydroxy-2- (6.7.8.9-t trahydro-dibenzofuran- 3-sulfonylamino) -propionamide EXAMPLE 35 (R) 5-Phenyl-2-6.7.8.9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide EXAMPLE 36 (R) N-Hydroxy-3-MH-indol-3-ih-2-f6.7.8.9-tetrahydro-d-benzofuran-3-sulfonylamino) -propionamide EXAMPLE 37 (R) 2- (2,3-Dihydro-1 H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -N-Hydroxy-3-methyl-butyramide EXAMPLE 38 W- N-Hydroxy-3-methyl-2-.6.7.8.9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyramide EXAMPLE 39 NHdroxy-4-phenyl-2-.6.7.8.9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide EXAMPLE 40 a N-Hydroxy-3-methyl-2- (6.7.8.9-tetrahydro-5H-fluoren -2-sulfonylamino) -butyramide

Claims (32)

1. CLAIMS 1. A compound of formula I i where n is zero or an integer of 1 or 2; X is -O-, -S (O) p where p is zero or an integer of 1 or 2, -N- wherein R2 is hydrogen, alkyl, acyl R2, or benzyl, -CH2-, or -C-; OR is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl, alkanoyloxyalkyl, alkanoylaminoalkyl, alkylthiolalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylpiperazinoalkyl, N-phenylalkylpiperazinoalkyl, morpholinoalkyl, thiomorpholinoalkyl, piperidinoalkyl, pyrrolidinoalkyl, N -alkylalkylpiperinoalkyl, pyridylalkyl, thienylalkyl, quinolinylalkyl, thiazole and Iqloyl, cycloalkyl, cycloalkylalkyl, phenyl, phenyl, substituted by one to three substituents selected from the group consisting of: hydroxy, alkoxy, alkyl, alkylthio, alkylsiinnyl, alkylsulfonyl, amino , alkylamino, dialkylamino, halogen, cyano, nitro, trifluoromethyl or on adjacent carbon atoms in either one to two carbons of the alkenylenedioxy group, or in two to three carbons of the alkenyleneoxy, phenylalkyl, phenylalkyl group wherein phenyl is substituted by alkyl, alkoxy, halogen, or trifluoromethyl, heteroaryl, heteroaryl substituted by one to two substituents selected from the group consisting of: alkyl, or halogen, biphenyl, biphenyl, substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano , biphenylalkyl or biphenylalkyl wherein biphenyl is substituted by alkyl, alkoxy, halogen, trifluoromethyl, or cyano; D is zero or an integer from 1 to 3; L is zero or an integer from 1 to 3; R1 is hydrogen a side chain or a natural amino acid or a side chain or an unnatural amino acid; Y is OR3 wherein R3 is hydrogen, methyl, ethyl, or benzyl, or NH-OR4 wherein R4 is hydrogen, alkyl, or benzyl; and corresponding isomers thereof; or a pharmaceutically salt thereof.
2. 2. The compound according to claim 1, characterized in that it is
3. 3. The compound according to claim 2, characterized in that n is zero or an integer of 1; and X is O-, or -CH2-.
4. 4. The compound according to claim 3, characterized in that n is zero or an integer of 1; X is -O-, or -CH2-; and R is hydrogen.
5. 5. The compound according to claim 4, characterized in that n is zero or an integer of 1; X is -O-, or -CH2-; R is hydrogen; and Y is OH.
6. 6. The compound according to claim 5, characterized in that n is zero or an integer of 1; X is -O-, or -CH2-; R is hydrogen; and Y is NHOH.
7. 7. A compound selected from the group consisting of: ****** PAG 65 **** Acid (S) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfo nylamino) - butyric; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfo nylamino) -butyramide; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -succinic acid; (S) Phenyl - [(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)] -acetic acid; Acid (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-tri-methyl-2,5-di-oxo-imidazolidin-1-yl) - propionic; Acid (S) 3- (1, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (, 7, 8, 9-te tra h id ro-d i benzof uran-3 -your I fon i lamino) - propion ico; Acid (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxo-imidazolidn-1-yl) -butyric; (S) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -5- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -pentanoic acid; (S) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (S) 4-Phenylmethanesulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; Acid (S) 5- (1,3-Dioxo-1,3-dihydro] -andol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) ) -pentanoic; (S) 6-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (S) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (S) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (S) 4-Phenylsulfamoyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4-Phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 4-Benzylsulfanyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 3- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (S) 4- (1H-Indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (S) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfon? Lamino) -pentanoic acid; (S) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -hexanoic acid; (S) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -heptanoic acid; (S) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -octanoic acid; (S) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -3-methyl-butyric acid; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-3- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -succinnamic acid; (S) N-H idroxy-2-phenyl-2- (6,7,8, 9-tetrahydro-d and benzofura n-3-sulfonylamino) -acetamide; (S) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-trimethyl-2,5-d-oxo-imidazolidin-1 - il) -propionamide; (S) 3- (1,3- Di oxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) - propionamide; (S) NH id roxi-2- (6, 7, 8, 9-tetrah id ro-d benzofura n-3-sulfonylamino) -4 - (3,4, 4-trimethyl-2, 5-di oxo -imidazolidin-1-yl) -butyramide; Hydroxyamide of (S) 2- (6,7,8,9-Tetrahydro-d and benzofuran-3-sulfonamino) -5- (3, 4,4-tri-methyl-2,5-d-dioxo- imidazolidin-1-yl) -pentanoic acid; Hydroxyamide of (S) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (S) N-Hydroxy-4-phenylmetansulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) 4- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; Hydroxyamide of (S) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; Hydroxyamide of (S) 6-phenyl-2- (6,7,8,9-tetrahydro-d¡benzofuran-3-sulfonylamino) -hexanoic acid; Hydroxyamide of (S) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; Hydroxyamide of (S) 8-phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (S) 4-Benzylsulfanyl-N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-H idroxy-4-phenyl-sulphonyl-2- (6, 7, 8, 9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; ?? ~ ^ »-» > -, -, «£ - •? The reaction was carried out in the following manner: (S) N-Hydroxy-4-phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (S) N-Hydroxy-3- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-d-benzofuran-3-sulfonylamino) -propionamide; (S) N-Hydroxy-4- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butramide; Hydroxyamide (S) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; Hydroxyamide (S) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid hydroxyamide; Hydroxyamide (S) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid hydroxyamide; (S) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (S) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -N-hydroxy-3-methyl-butyramide; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyramide; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (S) 3-Methyl-2- (9-methyl-6,7,8,9-tetrahydro-5H-carbazole-2-sulfonylamino) -butyric acid; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (S) 4-Phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (S) N- H id roxy-3-methyl-2- (9-methi 1-6,7,8,9-tetrahydro-5 H-carbazole-2-sulfonylamino) -butyramide; (S) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (S) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (S) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-s-l-phonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) N-H idroxy-3-methyl-2- (6, 7, 8, 9-tetrahydro-d-benzofu-3-sulfonylamino) -butyramide; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -succinic acid; (R) Phenyl - [(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino)] -acetic acid; Acid (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-s? Jphonylamino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) - propionic; (R) 3- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -butyric acid; (R) 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-sulfonylamino) -5- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -pentanoic acid; (R) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (R) 4-Phenylmethanesulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 4- (1, 3-D-Oxo-1,3-dihydro-isoindol-2-yl) -2- (, 7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; Acid (R) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6, 7, 8, 9-tetrah id ro-d ib in zofuran- 3 -su I fon i lamino) - pentanoic; (R) 6-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (R) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (R) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (R) 4-Phenylsulfamoyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 4-Phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 4-Benzylsulfanyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 3- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionic acid; (R) 4- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyric acid; (R) 5- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid; (R) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (R) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptanoic acid; (R) 8- (1H-lndo) -3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid; (R) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulfo-n-amino) -3-methyl-butyric acid; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulene-2-sulfonylamino) -butyric acid; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-d-benzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-3- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -succinnamic acid; (R) N-H id roxy-2-f eni l-2- (6, 7, 8, 9-tetrah id ro-d i benzof u ran-3-sulfonylamino) -acetamide; (R) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -propionamide; (R) 3- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionamide; (R) N-Hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -4- (3,4,4-tri-methyl-2,5-dioxo-imidazolidin-1-yl) ) -butyramide; Hydroxyamide (R) 2- (6,7,8,9-Tetrahydro-di-benzofuran-3-sulfonamine) -5- (3,4,4-tri- methyl-2, 5-d-dioxo) -imidazolidin-1-yl) -pentanoic acid; (R) 5-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide; (R) N-Hydroxy-4-phenylmetansulfinyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 4- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) 5- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -pentanoic acid hydroxyamide; Hydroxyamide of (R) 6-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid; (R) 7-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -heptaric acid hydroxyamide; (R) 8-Phenyl-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (R) 4-Benzylsulfanyl-N-hydroxy-2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-4-phenylsulfamoyl-2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-4-phenylmethanesulfonyl-2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -butyramide; (R) N-Hydroxy-3- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -propionamide; (R) N-Hydroxy- (1H-indol-3-yl) -2- (6,7,8,9-tetrahydro-d? Benzofuran-3-sulfonylamino) -butyramide; (R) 5- (1 H-l ndol-3-yl) -2- (6, 7, 8, 9-tetrahydro-d i benzofura n-3-sulfonylamino) -pentanoic acid; Hydroxyamide (R) 6- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -hexanoic acid hydroxyamide; Hydroxyamide of (R) 7- (1 H-lndol-3-yl) -2- (6,7,8,9-te tra h id ro-d ib in zofuran-3-sulfonyl lamino) -heptanoic acid; (R) 8- (1 H-lndol-3-yl) -2- (6,7,8,9-tetrahydro-dibenzofuran-3-sulfonylamino) -octanoic acid hydroxyamide; (R) 2- (2,3-Dihydro-1H-8-oxa-cyclopenta [a] inden-6-sulfonylamino) -N-hydroxy-3-methyl-butyramide; (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-10-oxa-benzo [a] azulen-2-sulfonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (R) 3-Methyl-2- (9-methyl-6,7,8,9-tetrahydro-5H-carbazole-2-sulfonylamino) -butyric acid; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyric acid; (R) 4-Phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide; (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (R) N- H id roxy-3-methyl-2- (9-methyl 1-6,7,8,9-tetrahydro-5 H-carbazole-2-sulfonylamino) -butyramide; (R) N-Hydroxy-4-phenyl-2- (6,7,8,9-tetrahydro-dibenzothiophen-3-sulfonylamino) -butyramide; (R) 3-Methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyric acid; and (R) N-Hydroxy-3-methyl-2- (6,7,8,9-tetrahydro-5H-fluoren-2-sulfonylamino) -butyramide;
8. 8. The method for inhibiting a matrix metalloproteinase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1, in unit dosage forms.
9. The method for inhibiting gelatinase A which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
10. The method for inhibiting stromelysin-1 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
11. The method for inhibiting collagenase-3 which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
12. 12. The method for preventing rupture of atherosclerotic plaque comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
13. The method for inhibiting aortic aneurysm comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
14. The method for inhibiting heart failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
15. 15. The method for preventing restenosis which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
16. 16. The method for controlling periodontal disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
17. 17. The method for treating corneal ulcer which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
18. 18. The method for treating burns comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
19. 19. The method for treating decubital ulcers comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
20. 20. The method of wound healing treatment comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
21. 21. The method of treating cancer comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
22. 22. The method of treating arthritis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
23. 23. The method for treating osteoporosis which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
24. 24. The method for treating autoimmune or inflammatory disorders dependent on invasion by leukocytes in tissue, comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
25. 25. The method for treating multiple sclerosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
26. 26. The method for treating inflammation and pain comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
27. 27. The method to treat neurodegenerative, acute and chronic disorders selected from the group consisting of: attack, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's disease, prion diseases, myasthenia gravis, and Duchenne muscular dystrophy which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
28. 28. The method for treating kidney disease which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
29. 29. The method for treating left ventricular dilatation comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form.
30. 30. The pharmaceutical composition characterized in that it comprises a compound according to claim 1, in admixture with a pharmaceutically acceptable excipient, diluent or carrier.
31. 31. The pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, in admixture with a pharmaceutically acceptable excipient, diluent or carrier.
32. 32. A method for preparing a compound of Formula where n is zero or an integer of 1 or 2; X is -O-, -S (O) p where p is zero or an integer of 1 or 2, -N- wherein R2 is hydrogen, alkyl, acyl R2, or benzyl, -CH2-, or -C-; OR R1 is hydrogen, a secondary chain of a natural amino acid or a secondary chain of an unnatural amino acid; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof which comprises treating a compound of formula (15). (15) wherein Ph is phenyl and n, X, and R1 are as defined above with a base in a solvent to give a compound of the formula le and if desired, convert a compound of Formula I to a corresponding pharmaceutically acceptable salt by conventional means and, if desired, convert the corresponding pharmaceutically acceptable salt into a compound of Formula I by conventional means.