WO1998050348A1 - Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques - Google Patents

Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques Download PDF

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Publication number
WO1998050348A1
WO1998050348A1 PCT/US1998/009389 US9809389W WO9850348A1 WO 1998050348 A1 WO1998050348 A1 WO 1998050348A1 US 9809389 W US9809389 W US 9809389W WO 9850348 A1 WO9850348 A1 WO 9850348A1
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Prior art keywords
hydroxy
benzenesulfonyl
methyl
amino
carboxamide
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PCT/US1998/009389
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English (en)
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Steven L. Bender
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Agouron Pharmaceuticals, Inc.
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Priority to AU72940/98A priority Critical patent/AU7294098A/en
Publication of WO1998050348A1 publication Critical patent/WO1998050348A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

  • the present invention relates to compounds that inhibit metalloproteinases, particularly matrix metalloproteinases and tumor necrosis factor- ⁇ convertase, and their pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs.
  • the invention further relates to the uses of these compounds, salts, and prodrugs for the therapeutic treatment of humans or animals.
  • MMPs Matrix metalloproteinases
  • collagenases include collagenases, gelatinases, matrilysin, and stromelysins, which are involved in the degradation and remodeling of connective tissues.
  • These enzymes are found in a number of cell types that are found in or associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology.
  • Matrix metalloproteinases degrade the protein components of the extracellular matrix, i.e., the protein components found in the linings of joints, interstitial connective tissue, basement membranes, cartilage, and the like. These proteins include collagen, proteoglycan, fibronectin, and lamanin. Collagen is the major structural protein of mammalian tissue, comprising one- third of the total protein in mammalian organisms, and it is an essential component of many matrix tissues, including cartilage, bone, tendons, and skin. Interstitial collagenases catalyze the initial (rate-limiting) cleavage of native collagen types 1, 11, III, and X. These enzymes cleave collagen into two fragments which spontaneously denature at physiological temperature.
  • Denaturation of collagen involves conversion of the rigidly coiled helix to a random coil referred to as gelatin. These gelatin (denatured collagen) fragments are then subject to further cleavage and degradation by less specific enzymes. The net result of collagenase cleavage is thus the loss of structural integrity in the matrix tissue (collagen collapse), an essentially irreversible process.
  • the gelatinases include two distinct yet highly related enzymes: a 72- kiloDalton (kDa) enzyme and a 92-kiloDalton enzyme.
  • the former is released by fibroblasts while the latter is released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts, and keratinocytes.
  • Both enzymes degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectins (high molecular weight multifunctional glycoproteins found in soft connective tissue and basement membranes), and insoluble elastin (highly cross-linked hydrophobic proteins found in load bearing fibers of mammalian connective tissue).
  • Stromelysins (1 and 2) cleave a broad range of matrix substrates, including lamanin, fibronectins, proteoglycans, and collagen types IV and IX (non-helical).
  • Matrilysin (putative metalloproteinase or PUMP) also degrades a wide variety of matrix substrates, including proteoglycans, gelatins, fibronectins, elastins, and lamanin. Matrilysin has been found in mononuclear phagocytes, rat uterine explants, and tumor cells.
  • Matrix metalloproteinase inhibitors are also the subject of numerous patents and patent applications, including: U.S. Patent No. 5,189,178; U.S. Patent No. 5,183,900; U.S. Patent No. 5,506,242; U.S. Patent No. 5,552,419; U.S. Patent No. 5,455,258; European Patent Application No. 0 438 223; European Patent Application No. 0 276 436; WIPO International Publication No. WO 92/21360; WIPO International Publication No. WO 92/06966; WIPO International Publication No. WO 92/09563; WIPO International Publication No. WO 96/00214; WIPO International Publication No. 95/35276; WIPO International Publication No. WO 96/27583, WIPO International Publication No. WO 96/33172, European Patent Application No. 0 757 984, and European Patent Application No 0 757 037.
  • Tumor necrosis factor- (“TNF- ⁇ ”) is a cytokine which is produced as a 28- kDa precursor and released in an active 17-kDa form.
  • This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation, and acute phase responses, similar to those seen during acute infections and shock states.
  • Chronic administration of TNF- ⁇ can cause cachexia and anorexia; accumulation of excess of TNF- ⁇ can be fatal.
  • TNF- ⁇ convertase is a metalloproteinase involved in the biosynthesis of TNF- ⁇ . Inhibition of TNF- ⁇ convertase inhibits production of TNF- ⁇ .
  • the present invention is therefore directed to certain compounds that inhibit metalloproteinases, such as MMPs and TNF- ⁇ convertase, their pharmaceutically acceptable prodrugs, salts, and solvates, pharmaceutical compositions containing the same, and methods of using the same, as well as to methods and intermediates useful in their preparation. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description or may be learned from practice of the invention.
  • Ar is an aryl group or a heteroaryl group
  • X is -NH-OH or -OH
  • R ⁇ is H, -CH(R 3 )(R 4 ), -C(0)R 3 , a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein R 3 is H or any suitable substituent and R 4 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
  • R 2 is CH 2 -R 5 , wherein R 5 is H or any suitable substituent, or wherein R 5 and R 4 are optionally substituted carbon atoms singly- or double-bonded to one another; or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
  • the present invention also is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable prodrug, salt, or solvate thereof; and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.
  • the present invention is further directed to a method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
  • the compound of formula I (or its pharmaceutically acceptable prodrug, salt, or solvate) may be administered in the form of a pharmaceutical composition, as described above.
  • the present invention is directed to a method of treating tumor growth, invasion, or metastasis; osteoarthritis; rheumatoid arthritis; osteoporosis; periodontitis; gingivitis; chronic dermal wounds; corneal ulceration; degenerative skin disorders; multiple sclerosis; stroke; atherosclerosis; glomerular disease; or a disease condition characterized by unwanted angiogenesis, such as diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.
  • the present invention is still further directed to a method of inhibiting the activity of a metalloproteinase that comprises contacting the metalloproteinase with an effective amount of a compound of formula (I) or a pharmaceutically acceptable prodrug, salt, or solvate thereof, optionally, in the form of a pharmaceutical composition as described above.
  • alkyl group is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
  • O-alkyl group or "alkoxy group” is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.
  • a "cycloalkyl group” is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1.]heptyl, bicyclo[2.2.1.]hept-2-en- 5-yl, bicyclo[2.2.2]octyl, bicyclo[3.2.1.]nonyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl, and the like.
  • a “heterocycloalkyl group” is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1 ,5,9- triazacycl
  • aryl group is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.
  • heteroaryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.
  • An "acyl group” is intended to mean a -C(
  • a “sulfonyl group” is intended to mean a -S(0)(0)-R 5 - radical, wherein R 5 is any suitable substituent as defined below.
  • suitable substituent is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds.
  • suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, groups of formula (A)
  • R a is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (B)
  • R a is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (C)
  • R b and R c are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (D)
  • R d is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, or an acylamino group
  • R e is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group, groups of formula (E)
  • R f is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (F)
  • R g and R h are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (G)
  • R is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (H) (defined below), or formula (K) (defined below), groups of formula (H)
  • R j wherein R j is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula (A), formula (B), formula (C) or formula (D); and wherein R k is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F), groups of formula (J)
  • R is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (C), and groups of formula (K)
  • R m and R n are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.
  • suitable organic moiety is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds.
  • suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and groups of formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), and (K), as defined above.
  • a "hydroxy group” is intended to mean the radical -OH.
  • halo group is intended to mean any of the radicals -F, -Cl, -Br, or -I.
  • a "cyano group” is intended to mean the radical -C ⁇ N.
  • a "nitro group” is intended to mean the radical -N0 2 .
  • a "trialkylsilyl group” is intended to mean the radical -SiR p R q R s , where R p , R q , and R s are each independently an alkyl group.
  • a “carboxy group” is intended to mean a group of formula (B) wherein R a is hydrogen.
  • alkoxycarbonyl group is intended to mean a group of formula (B) wherein R a is an alkyl group as defined above.
  • a “carbamoyl group” is intended to mean a group of formula (C) wherein R b and R c are both hydrogen.
  • amino group is intended to mean the radical -NH 2 .
  • alkylamino group is intended to mean the radical -NHR U , wherein R u is an alkyl group as defined above.
  • dialkylamino group is intended to mean the radical -NR U R V , wherein R u and R v , which are the same or different, are each an alkyl group as defined above.
  • a "pharmaceutically acceptable prodrug” is intended to mean a compound that is converted under physiological conditions or by solvolysis to a compound of formula I.
  • a "pharmaceutically acceptable solvate” is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula I.
  • Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • inventive compounds may exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
  • a “pharmaceutically acceptable salt” is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates,
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid; or the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; cyclic amines such as piperidine, morpholine, and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • R 3 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 10 , -SR 10 , C ⁇ C-R 10 , -C(O)OR 10 , C(O)NHR 10 , wherein R 10 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroarylgroup.
  • Preferred compounds according to the invention include compounds having the formula II:
  • R.,, R 2 and X are as defined above and Z is a halogen group, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an O-alkyl group, an S-alkyl group, an aryl group, or a heteroaryl group.
  • Ar is a heteroaryl group containing six ring atoms. More preferably, Ar is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
  • R 5 is H and R 4 is an alkyl group. Also preferred are those compounds where R 5 is a heteroaryl group and those where R 5 is -CHR 6 R 7 , wherein R 6 is H or any suitable substituent and R 7 is
  • R 8 is any suitable substituent.
  • R 4 is an alkyl group and R 3 is an alkyl group, an O-alkyl group, or an S-alkyl group. More preferably, R 3 is a CH 2 CH 2 -heteroaryl group, an -OCH 2 - heteroaryl group, or an -S-CH 2 -heteroaryl group.
  • Inventive compounds of formula I wherein X is NHOH are preferably selected from those possessing inhibitory potencies (Ki's) against human gelatinase A (Gel A), human collagenase-3 (Coll-3), and/or human stromelysin-1 (Strom) of less than 50 nM, and more preferably of less than 5 nM. Still more preferably, compounds of formula I wherein X is NHOH are selected from those possessing Ki's against Gel A and/or ColI-3 of less than 0.2 nM and/or those possessing an inhibition selectivity as defined by the ratio of Ki for human collagenase-1 (HFC) and the Ki for Coll-3, of greater than 50.
  • Ki's inhibitory potencies
  • HFC human collagenase-1
  • Coll-3 the Ki for Coll-3
  • Inventive compounds of formula I wherein X is OH are preferably selected from those possessing Ki's against Gel A of less than 1 ⁇ M, more preferably less than 200 nM, and still more preferably less than 50 nM. Assays for determining Ki's are described in greater detail infra.
  • the present invention is further directed to methods of inhibiting metalloproteinase activity, for example in mammalian tissue, by administering a compound of formula I, or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
  • metalloproteinases such as MMPs (including stromelysins, collagenases, gelatinases, and/or matrilysin) and/or TNF- ⁇ convertase
  • MMPs including stromelysins, collagenases, gelatinases, and/or matrilysin
  • TNF- ⁇ convertase may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in Anal. Biochem., vol. 147, p. 437 (1985); Anal. Biochem., vol. 180, p. 110 (1989); FEBS, vol. 96, p. 263 (1992); and European Patent Application No
  • Administration of the compounds of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates may be performed according to any of the accepted modes of administration available to those skilled in the art.
  • suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
  • the mode of administration is oral.
  • inventive compounds of formula I may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan.
  • suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, and aerosols.
  • the pharmaceutical form is a tablet or capsule for oral administration.
  • the pharmaceutical composition may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
  • compositions may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
  • steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
  • steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and
  • Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions.
  • Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water.
  • the carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of the formula I, or a pharmaceutically acceptable prodrug, salt, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units.
  • An exemplary dosage unit for a mammalian host contains an amount of from 0.1 milligram up to 500 milligrams of active compound per kilogram body weight of the host, preferably 0.1 to 200 milligrams, more preferably 50 milligrams or less, and even more preferably about 10 milligrams or less, per kilogram of the host weight.
  • the selected dose may be administered to a mammal, for example, a human patient in need of treatment mediated by inhibition of metalloproteinase activity, by any known method of administrating the dose including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
  • the amount of the inventive compounds, salts, solvates, and/or prodrugs to be administered will vary based upon a number of factors, including the specific metalloproteinase to be inhibited, the degree of inhibition desired, the characteristics of the mammalian tissue in which inhibition is desired, the metabolic stability and activity of the particular inventive compound employed, and the mode of administration.
  • One skilled in the art may readily determine a suitable dosage according to methods known to the art.
  • the amount of inventive compound of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates, administered ranges from 0.1 mg/kg body weight to 100 mg/kg body weight per day.
  • inventive compounds and the salts, solvates, and prodrugs thereof, may be prepared by employing the techniques available in the art using starting materials that are readily available. Exemplary methods of preparing the inventive compounds are described below. In the following schemes, unless otherwise indicated, R ⁇ R 2 , and Ar are as defined above. Scheme 1
  • hydroxamic acids of formula la (compounds of formula I where X is -NH-OH) can be prepared by reacting the corresponding carboxylic acids of formula lb (compounds of formula I where X is -OH) with hydroxylamine in the presence of a suitable peptide coupling reagent, for example, 1 ,1'-carbonyldimidazole, N-(dimethylaminopropyl)-N'-ethyl carbodiimide, benzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or propanephosphonic anhydride in an inert polar solvent, such as dimethylformamide.
  • a suitable peptide coupling reagent for example, 1 ,1'-carbonyldimidazole, N-(dimethylaminopropyl)-N'-ethyl carbodiimide, benzotriazol-1 -yloxy-tris
  • compounds of formula III can be reacted with hydroxylamine in a suitable solvent mixture, such as THF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0 °C, to give hydroxamic acids of formula I.
  • a suitable solvent mixture such as THF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0 °C
  • suitable solvent mixture such as THF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0 °C
  • Compounds of formula III are generally prepared, in a form directly useful for further reaction without isolation, by allowing carboxylic acids of formula lb to react with thionyl chloride or oxalyl chloride, preferably in the presence of a catalytic amount of dimethylformamide, in dichoromethane solvent at -78 °C to room temperature.
  • the coupling reactions described above may be carried out with compounds of formula lb (or III) and O-protected derivatives of hydroxylamine (where Pg is a suitable protecting group, such as benzyl, tert-butyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl) to give compounds of formula IV.
  • Pg is a suitable protecting group, such as benzyl, tert-butyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl
  • carboxylic acids of formula lb can be prepared by reacting N-substituted- ⁇ -amino acids of formula V with arylsulfonyl chlorides of formula VI, under biphasic basic conditions as described, for example, in "The Chemistry of the Amino Acids", J.P. Greenstein and M. Winitz, Robert E. Krieger Publishing Company, 1984, p. 886-889, the disclosure of which is incorporated herein by reference.
  • carboxylic acids lb can be prepared by reacting N-substituted- ⁇ - amino acid derivatives VII, where Pg is any suitable protecting group as described, for example, in "Protective Groups in Organic Synthesis", T.W. Greene and P. G. M. Wuts, Wiley-lnterscience 1991 (the disclosure of which is incorporated herein by reference), with aryl sulfonyl chlorides VI to give sulfonamides VIM under any of a variety of reaction conditions that have been reported in the literature for the sulfonylation of amino acid derivatives (see, for example, "The Chemistry of the Amino Acids", J.P. Greenstein and M. Winitz, Robert E.
  • R 10 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group
  • Y is oxygen or sulfur.
  • the reaction scheme proceeds as follows. Sulfonylation of D- ⁇ -amino- ⁇ -hydroxy amino esters of formula XI (e.g., esters of D-serine when R 4 is H, and esters of D-allo-threonine when R 4 is Me) with sulfonyl chlorides of formula VI as described above provides compounds of formula X-a.
  • Aryl sulfonyl chlorides VI are most readily available by chlorosulfonylation of the corresponding aryl phenyl ethers XIII, as outlined in Scheme 5 above.
  • a suitable inert solvent such as 1 ,2-dichloroethane or dichloromethane
  • XIV can be further converted to the sulfonyl chloride VI by reaction with a chlorinating agent, such as oxalyl chloride or thionyl chloride, and optionally cataltyic DMF.
  • a chlorinating agent such as oxalyl chloride or thionyl chloride
  • excess chlorosulfonic acid is effective at converting XIII directly to VI via the intermediacy of XIV.
  • Compounds of the formula XIII are commercially-available or may be readily prepared by those skilled in the art from commercially-available materials by the Ullman reaction.
  • the resulting mixture was heated to 40°C for 1 hr and then allowed to cool to room temperature over a 2 hr period.
  • the reaction mixture was poured into ice-pH 7 phosphate buffer (50mL), then extracted with ethyl acetate:Hexane (4:3) (3x150mL).
  • the combined organic layers were washed with brine (75mL).
  • the aqueous layer was extracted with ethyl acetate/Hexane(4:3) (150mL).
  • the organic layer was dried over Na 2 S0 4 , then evaporated by vacuum to give crude product as white solid.
  • the reaction mixture was cooled to room temperature and slowly poured into ice cold water (5 L) while stirring. Potassium phosphate tribasic (212 g) was added as a solid to the mixture, and this was stirred for 10 minutes followed by addition of sodium hydroxide (2M) to pH 2. After stirring for 1 hour, the pH was changed to 7 by the addition of sodium hydroxide (2M)- Agitation was continued for 5 minutes, and then the organic layer was drained off and discarded. The mixture was extracted a second time with dichloromethane (2L), the mixture agitated for 5 minutes, and the organic layer drained off and discarded.
  • the remaining aqueous mixture was extracted by addition of dichloromethane (6 L), tetrabutylammonium bromide (940 g), and sodium hydroxide (2M) to pH 7.
  • the mixture was agitated for 5 minutes and the organic layer (bottom) drained into a flask.
  • the extraction procedure was repeated twice.
  • the combined organic was dried over magnesium sulfate, filtered, and the solution was concentrated under vacuum to an oil.
  • the residual oil was diluted with 20% ethanol in ethyl acetate (8 L, dry), and hydrogen chloride gas added to a pH of 1.
  • the solid was filtered off and the filter cake rinsed with 20% ethanol in ethyl acetate (2 L).
  • Dry hydrogen chloride was bubbled through a -20°C solution of 2(R)-N-(tert- butoxy)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3- methylbutanamide (750 mg, 1.27 mol) in 20 mL of dichloromethane for 10 min, and the reaction was sealed and stirred at room temperature overnight.
  • the starting material was prepared as follows: (i) Preparation of N-[4-(4-bromophenox .benzenesulfonyl]-D-valine t-butyl ester.
  • N-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valine hydrochloride that was used without further purification in the next step.
  • the above acid was dissolved in 8 mL of dichloromethane, treated with O-t-butyl hydroxylamine hydrochloride (600 mg, 4.8 mol), N-methylmorpholine (0.92 mL, 8.3 mol), and EDC
  • This compound can be prepared as described in Example 4 above.
  • reaction mixture was poured into sodium bicarbonate solution (1M, 10 ml), extracted with ethyl acetate/hexanes (5:1), (3 x 50 ml), and the combined organic fractions were washed with brine, then water, and dried over sodium sulfate.
  • the starting material was prepared as follows:
  • reaction mixture was poured into pH 4 citrate buffer (0.5 M), and this was extracted with dichloromethane (3 x 250 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed on silica, eluting with 8% ethanol in dichloromethane.
  • This compound can be prepared as described in Example 5 above.
  • the starting material was prepared as follows:
  • This compound can be prepared as described in Example 6 above.
  • the reaction was poured into ethyl acetate/hexanes (3:1 , 100 ml); washed with ammonium chloride (2M, 20 ml), sodium bicarbonate (2_M , 20 ml), and brine (20 ml); and dried over sodium sulfate.
  • the solvent was removed from the product oil, which was diluted with dichloromethane, isooctane was added, and the mixture was stripped down to give the product 2(R)-N-(t-butyldiphenylsilyl)oxy-1-(4- phenoxy-benzenesulfonyl)-piperidine-2-carboxamide (0.31 g) as an oil, which was used without further purification.
  • the catalytic domain of human collagenase-1 was expressed as a fusion protein with ubiquitin in E. coli (see Gehring, E.R., J. Biol. Chem., 1995, 270, 22507, which article is entirely incorporated herein by reference).
  • the fibroblast collagenase-1 catalytic domain was released either by treatment with purified, active stromelysin-1 (1 :50 w/w ratio), which generated nearly 100% N-terminal Phe1 , or by autoprocessing the concentrated collagenase-1 fusion and then incubating at 37 °C for 1 hour. Final purification was completed using zinc chelate chromatography.
  • the propeptide and catalytic domain of human collagenase-3 (Coll3) was expressed in E. coli as an N-terminal fusion protein with ubiquitin. After purification of the fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at room temperature overnight. Final purification was completed using copper chelate chromatography.
  • the catalytic domain of human stromelysin (Sin) was obtained by expression and purification of a C-terminally truncated prostromelysin-1 from E. coli host BL21 (see Marcy et al. Biochem., 1991 , 30, 6476, which article is entirely incorporated herein by reference).
  • the subsequent activation of the mature form (Sin) was completed with 2mM APMA for 1 hour at 37 °C, followed by separation using a sizing column.
  • Human matrilysin (Matr) was expressed in E. coli as a fusion protein with ubiquitin. After purification of the matrilysin/ubiquitin fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at 37 °C for 2 hours. Final purification was complete using copper chelate chromatography.
  • the catalytic and fibronectin-like portion of human progelatinase A (GelA) was expressed as a fusion protein with ubiquitin in E. Coli . Assays were carried out on autocatalytically activated material.
  • Assays were performed in assay buffer (50 mM Tricine pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate containing 2% dimethyl sulfoxide (DMSO)), once the substrate and inhibitor were diluted into it. Stock solutions of inhibitors were prepared in 100% DMSO. Stock solutions of the substrate were prepared in 100% DMSO at a concentration of 6 mM.
  • assay buffer 50 mM Tricine pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate containing 2% dimethyl sulfoxide (DMSO)
  • the assay method was based on the hydrolysis of MCA-Pro-Leu-Gly-Leu- DPA-Ala-Arg-NH 2 (American Peptide Co.) at 37 °C (see Knight, C.G. et al., FEBS, 1992, 296, 263-266, which article is entirely incorporated herein by reference).
  • the fluorescence changes were monitored with a Perkin-Elmer LS-50B fluorimeter using an excitation wavelength of 328 nm and an emission wavelength of 393 nm.
  • the substrate concentration used in the assays was 10 ⁇ M.
  • the inhibitor was diluted into the assays from a solution in 100% DMSO, and controls substituted an equal volume of DMSO so that the final DMSO concentration from inhibitor and substrate dilution in all assays was 2%.
  • concentration of enzyme in the assay ranged from 60 pM for gelatinase A to 1.5 nM for stromelysin and is a function of the enzymes respective k cat /K m for the MCA peptide substrate.
  • Proper determination of steady-state rates of substrate cleavage required assay lengths of 60 minutes to allow for complete equilibration of the enzyme-inhibitor complex.
  • K m for the MCA peptide substrate with the matrix metalloproteinases is quite high and exceeds its solubility under assay conditions. Consequently, the apparent K, (K, app ) was determined to describe the strength of inhibition. However, in this case, K, app would be essentially equal to K, since [S] «K m .
  • K ⁇ app the concentration of the inhibitor was varied at a constant and low concentration of substrate, and the steady-state rates of fluorescence change were determined. In most cases, absorptive quench due to the presence of ligand was not observed. For slow-binding inhibitors, onset of inhibition curves were collected for at least 45 minutes so that equilibrium was established.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de la formule (I) dans laquelle Ar est un groupe aryle ou un groupe hétéroaryle; X désigne -NH-OH ou -OH ; R1 est H, -CH(R3)(R4), -C(O)R3, un groupe cycloalkyle, un groupe hétérocycloalkyle, un groupe aryle, ou un groupe hétéroaryle, où R3 est H ou tout substituant approprié et R4 est H, un groupe alkyle, un groupe cycloalkyle, un groupe hétérocycloalkyle, un groupe aryle, ou un groupe hétéroaryle; R2 est CH2-R5, où R5 est H ou tout substituant approprié, ou dans laquelle R5 et R4 sont des atomes de carbone éventuellement substitués, liés entre eux par une liaison simple ou une liaison double. L'invention concerne également des promédicaments pharmaceutiquement acceptables, des sels, et des solvats de ceux-ci. L'invention concerne en outre, des procédés d'utilisation de ces composés, en particulier, comme inhibiteurs de métalloprotéases.
PCT/US1998/009389 1997-05-09 1998-05-08 Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques WO1998050348A1 (fr)

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AU72940/98A AU7294098A (en) 1997-05-09 1998-05-08 Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses

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US60/045,931 1997-05-09

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EP0949246A1 (fr) * 1998-04-10 1999-10-13 Pfizer Products Inc. Procédé de préparation d'halogénures d'acides phénoxyphénylsulfoniques
WO1999058531A1 (fr) * 1998-05-14 1999-11-18 Du Pont Pharmaceuticals Company Nouveaux acides hydroxamiques a substitution aryle en tant qu'inhibiteurs de metalloproteinase
WO2000009103A2 (fr) * 1998-08-14 2000-02-24 Gpi Nil Holdings, Inc. Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009104A2 (fr) * 1998-08-14 2000-02-24 Gpi Nhl Holdings, Inc. Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
WO2000009485A1 (fr) * 1998-08-12 2000-02-24 Pfizer Products Inc. Derives d'acide hydroxamique de pipecolate hydroxy
WO2000018361A2 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Procede de traitement de la chute de cheveux par administration de sulfonamides
WO2000023443A1 (fr) * 1998-10-22 2000-04-27 Akzo Nobel N.V. Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives
WO2000051975A1 (fr) * 1999-03-03 2000-09-08 The Procter & Gamble Company Inhibiteurs de metalloproteases, contenant alcenyle et alcynale
US6235727B1 (en) * 1998-07-16 2001-05-22 Aventis Pharma Deutschland Gmbh Sulfonylaminophosphinic and sulfonylaminophosphinic acid derivatives, methods for their preparation and use
US6277987B1 (en) 1998-02-04 2001-08-21 Novartis Ag Sulfonylamino acid and sulfonylamino hydroxamic acid derivatives
EP1138680A1 (fr) * 2000-03-29 2001-10-04 Pfizer Products Inc. Acides gem-substitués alpha-sulfonylamino hydroxamiques comme inhibiteurs de métalloprotease
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
WO2001089502A2 (fr) * 2000-05-22 2001-11-29 The Regents Of The University Of Michigan Compositions et procedes a utiliser contre l'inflammation induite par l'acne et les enzymes degradant la matrice dermique
WO2001093872A1 (fr) * 2000-06-08 2001-12-13 Jomaa Pharmaka Gmbh Utilisation de derives d'acide hydroxamique organophosphores pour la fabrication de medicaments
WO2001094358A1 (fr) * 2000-06-08 2001-12-13 Jomaa Pharmaka Gmbh Derives d'acide hydroxamique organophosphores en tant qu'herbicides
EP1208092A1 (fr) * 2000-04-07 2002-05-29 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
US6410580B1 (en) 1998-02-04 2002-06-25 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
US6414011B1 (en) 1999-03-26 2002-07-02 Euro-Celtique S.A. Aryl substituted pyrazoles, and pyrroles, and the use thereof
WO2002072577A2 (fr) * 2001-03-14 2002-09-19 Novartis Ag Derives d'acide acetique substitues azacycloalkyle
US6492394B1 (en) 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US6566381B1 (en) 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
WO2003055851A1 (fr) 2001-12-27 2003-07-10 Sumitomo Pharmaceuticals Company, Limited Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active
WO2006013193A2 (fr) * 2004-08-03 2006-02-09 Abiogen Pharma S.P.A. Derives d'acide hydroxamique substitues par arylsulfonamido, utilises comme inhibiteurs des metalloproteinases matricielles
JP2008504316A (ja) * 2004-06-30 2008-02-14 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ４−トリフルオロメトキシフェノキシベンゾール−４’−スルホン酸、その製造法および薬剤としての使用
JP2009051845A (ja) * 2000-09-29 2009-03-12 Topotarget Uk Ltd Ｈｄａｃ阻害剤としてのスルホンアミド結合を含むカルバミン酸化合物
US8231858B2 (en) * 2003-02-10 2012-07-31 Ge Healthcare Limited Diagnostic imaging agents with MMP inhibitory activity
CN109678900A (zh) * 2019-01-30 2019-04-26 遵义医学院 一种磺胺衍生物及其制备方法与应用

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AU2003261319A1 (en) * 2002-08-01 2004-02-23 Bristol-Myers Squibb Company Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or tnf-alpha converting enzyme
EP2041181B1 (fr) * 2006-06-08 2011-05-18 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Inhibiteurs spécifiques de protéase et leur utilisation pour le traitement du cancer

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US6410580B1 (en) 1998-02-04 2002-06-25 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
US6277987B1 (en) 1998-02-04 2001-08-21 Novartis Ag Sulfonylamino acid and sulfonylamino hydroxamic acid derivatives
US6118016A (en) * 1998-04-10 2000-09-12 Pfizer Inc. Process for preparing phenoxyphenylsulfonyl halides
AP1155A (en) * 1998-04-10 2003-06-30 Pfizer Prod Inc Process for preparing phenoxphenysulfonyl halides.
EP0949246A1 (fr) * 1998-04-10 1999-10-13 Pfizer Products Inc. Procédé de préparation d'halogénures d'acides phénoxyphénylsulfoniques
US6365587B1 (en) 1998-05-14 2002-04-02 Matthew E. Voss Substituted aryl hydroxamic acids as metalloproteinase inhibitors
WO1999058531A1 (fr) * 1998-05-14 1999-11-18 Du Pont Pharmaceuticals Company Nouveaux acides hydroxamiques a substitution aryle en tant qu'inhibiteurs de metalloproteinase
JP2002520418A (ja) * 1998-07-16 2002-07-09 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 医薬として使用されるホスフィン酸およびホスホン酸誘導体
US6235727B1 (en) * 1998-07-16 2001-05-22 Aventis Pharma Deutschland Gmbh Sulfonylaminophosphinic and sulfonylaminophosphinic acid derivatives, methods for their preparation and use
US6500811B2 (en) 1998-07-16 2002-12-31 Aventis Pharma Deutschland Gmbh Sulfonylaminophosphinic and sulfonylaminophosphonic acid derivatives, methods for their preparation and use
WO2000009485A1 (fr) * 1998-08-12 2000-02-24 Pfizer Products Inc. Derives d'acide hydroxamique de pipecolate hydroxy
WO2000009104A2 (fr) * 1998-08-14 2000-02-24 Gpi Nhl Holdings, Inc. Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
WO2000009103A2 (fr) * 1998-08-14 2000-02-24 Gpi Nil Holdings, Inc. Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009103A3 (fr) * 1998-08-14 2000-11-16 Guilford Pharm Inc Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009104A3 (fr) * 1998-08-14 2000-12-07 Guilford Pharm Inc Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
WO2000018361A2 (fr) * 1998-09-30 2000-04-06 The Procter & Gamble Company Procede de traitement de la chute de cheveux par administration de sulfonamides
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
WO2000018361A3 (fr) * 1998-09-30 2000-05-25 Procter & Gamble Procede de traitement de la chute de cheveux par administration de sulfonamides
WO2000023443A1 (fr) * 1998-10-22 2000-04-27 Akzo Nobel N.V. Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives
US6492394B1 (en) 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US6787559B2 (en) 1998-12-22 2004-09-07 Syntex (U.S.A.) Llc. Sulfonamide compounds
US6844366B2 (en) 1998-12-22 2005-01-18 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
WO2000051975A1 (fr) * 1999-03-03 2000-09-08 The Procter & Gamble Company Inhibiteurs de metalloproteases, contenant alcenyle et alcynale
US6762198B2 (en) 1999-03-03 2004-07-13 The Procter & Gamble Company Dihetero-substituted metalloprotease inhibitors
US6566381B1 (en) 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
US6414011B1 (en) 1999-03-26 2002-07-02 Euro-Celtique S.A. Aryl substituted pyrazoles, and pyrroles, and the use thereof
EP2266960A2 (fr) 1999-03-26 2010-12-29 Euro-Celtique S.A. Pyrazoles, imidazoles, oxazoles, thiazoles et pyrroles, substitués d'aryl à titre d'anticonvulsants
US6737418B2 (en) 1999-03-26 2004-05-18 Euro-Celtique S.A. Aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles, and the use thereof
EP1138680A1 (fr) * 2000-03-29 2001-10-04 Pfizer Products Inc. Acides gem-substitués alpha-sulfonylamino hydroxamiques comme inhibiteurs de métalloprotease
EP1208092A1 (fr) * 2000-04-07 2002-05-29 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
EP1208092A4 (fr) * 2000-04-07 2003-01-02 Samsung Electronics Co Ltd Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
WO2001089502A2 (fr) * 2000-05-22 2001-11-29 The Regents Of The University Of Michigan Compositions et procedes a utiliser contre l'inflammation induite par l'acne et les enzymes degradant la matrice dermique
WO2001089502A3 (fr) * 2000-05-22 2003-01-03 Univ Michigan Compositions et procedes a utiliser contre l'inflammation induite par l'acne et les enzymes degradant la matrice dermique
WO2001093872A1 (fr) * 2000-06-08 2001-12-13 Jomaa Pharmaka Gmbh Utilisation de derives d'acide hydroxamique organophosphores pour la fabrication de medicaments
WO2001094358A1 (fr) * 2000-06-08 2001-12-13 Jomaa Pharmaka Gmbh Derives d'acide hydroxamique organophosphores en tant qu'herbicides
JP2009051845A (ja) * 2000-09-29 2009-03-12 Topotarget Uk Ltd Ｈｄａｃ阻害剤としてのスルホンアミド結合を含むカルバミン酸化合物
WO2002072577A2 (fr) * 2001-03-14 2002-09-19 Novartis Ag Derives d'acide acetique substitues azacycloalkyle
JP2009137997A (ja) * 2001-03-14 2009-06-25 Novartis Ag Ｍｍｐ阻害剤として使用するためのアザシクロアルキル置換酢酸誘導体
WO2002072577A3 (fr) * 2001-03-14 2002-11-14 Novartis Ag Derives d'acide acetique substitues azacycloalkyle
EP1466899A1 (fr) * 2001-12-27 2004-10-13 Sumitomo Pharmaceuticals Company, Limited Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active
EP1466899A4 (fr) * 2001-12-27 2010-01-06 Dainippon Sumitomo Pharma Co Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active
WO2003055851A1 (fr) 2001-12-27 2003-07-10 Sumitomo Pharmaceuticals Company, Limited Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active
US7504537B2 (en) 2001-12-27 2009-03-17 Dainippon Sumitomo Pharma Co., Ltd. Hydroxamic acid derivative and MMP inhibitor containing the same as active ingredient
US8231858B2 (en) * 2003-02-10 2012-07-31 Ge Healthcare Limited Diagnostic imaging agents with MMP inhibitory activity
JP2008504316A (ja) * 2004-06-30 2008-02-14 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ４−トリフルオロメトキシフェノキシベンゾール−４’−スルホン酸、その製造法および薬剤としての使用
JP4871273B2 (ja) * 2004-06-30 2012-02-08 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ４−トリフルオロメトキシフェノキシベンゾール−４’−スルホン酸、その製造法および薬剤としての使用
JP2008509108A (ja) * 2004-08-03 2008-03-27 アビオゲン ファルマ ソシエタ ペル アチオニ マトリックスメタロプロテイナーゼの阻害剤としての、アリールスルフォンアミド置換ヒドロキサム酸の誘導体
US7772430B2 (en) 2004-08-03 2010-08-10 Protera S.R.L. Derivatives of arylsulfonamido-substituted hydroxamic acid as matrix metalloproteinases inhibitors
WO2006013193A3 (fr) * 2004-08-03 2006-08-31 Protera S R L Derives d'acide hydroxamique substitues par arylsulfonamido, utilises comme inhibiteurs des metalloproteinases matricielles
WO2006013193A2 (fr) * 2004-08-03 2006-02-09 Abiogen Pharma S.P.A. Derives d'acide hydroxamique substitues par arylsulfonamido, utilises comme inhibiteurs des metalloproteinases matricielles
CN109678900A (zh) * 2019-01-30 2019-04-26 遵义医学院 一种磺胺衍生物及其制备方法与应用
CN109678900B (zh) * 2019-01-30 2021-05-11 遵义医科大学 一种磺胺衍生物及其制备方法与应用

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