WO1998009934A1 - Inhibiteurs de metalloproteinases matricielles et leurs utilisations pharmaceutiques - Google Patents

Inhibiteurs de metalloproteinases matricielles et leurs utilisations pharmaceutiques Download PDF

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Publication number
WO1998009934A1
WO1998009934A1 PCT/US1997/014859 US9714859W WO9809934A1 WO 1998009934 A1 WO1998009934 A1 WO 1998009934A1 US 9714859 W US9714859 W US 9714859W WO 9809934 A1 WO9809934 A1 WO 9809934A1
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Prior art keywords
alkyl
sulfonylamino
patient
compound
dibenzofuran
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PCT/US1997/014859
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English (en)
Inventor
Patrick Michael O'brien
Joseph Armand Picard
Drago Robert Sliskovic
Andrew David White
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Warner-Lambert Company
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Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to US09/254,384 priority Critical patent/US6624177B1/en
Priority to NZ333063A priority patent/NZ333063A/xx
Priority to BR9711988A priority patent/BR9711988A/pt
Priority to EP97939527A priority patent/EP0931045A1/fr
Priority to JP10512709A priority patent/JP2000517341A/ja
Priority to AU41595/97A priority patent/AU735013B2/en
Publication of WO1998009934A1 publication Critical patent/WO1998009934A1/fr
Priority to US10/603,677 priority patent/US6906092B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to a method of inhibiting matrix metalloprotemases using compounds that are dibenzofuran sulfonamide derivatives. More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
  • diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leuk
  • the compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., stromelysin-1 and gelatinase A (72 kDa gelatinase).
  • matrix metalloproteinases e.g., stromelysin-1 and gelatinase A (72 kDa gelatinase).
  • Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3, and the newly discovered membrane- associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). Stromelysin-1 is also known as MMP03 and gelatinase A is known as
  • the catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design.
  • the modification of substrates by introducing chelating groups has generated potent inhibitors such as peptidehydroxamates and thiol- containing peptides.
  • Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.
  • the ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes.
  • the rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
  • Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring.
  • the shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase.
  • stromelysin RNA message has been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney A.M., Wakeley P.R., Davies M.J., 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).
  • Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine N. and Powell J.T.. "Metalloproteinases in degenerative aortic diseases,” Clin. Sci., 1991;81 :233-239).
  • Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T.H., Hamilton M.A., Stevenson L.W., Moriguchi J.D., Fonarow G.C., Child J.S., Laks H., and Walden J.A., "Impact of left ventricular size on the survival in advanced heart failure," Am. J. Cardiol., 1993;72:672-676).
  • vascular smooth muscle cells vascular smooth muscle cells
  • gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSCMs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly R.R., Passaniti A., Bilato C, Monticone R.,
  • Thiol-containing peptides inhibit the collagenase isolated from alkali-burned rabbit corneas (Bums F.R., Stack M.S., Gray R.D., and Paterson C.A., Invest. OpththamoL
  • Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U.K., Ulpu K., Pentland A.P., Birkedal-Hansen H., Parks W.C, Welgus H.G., "Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds," J. Clin. Invest.,
  • Stromelysin- 1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. Stromelysin-1 may thus prevent the epidermis from healing.
  • Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxamate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing human ovarian carcinoma xenografts.
  • a peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement membrane (Melchiori A., Albili A., Ray J.M., and Stetler- Stevenson W.G., Cancer Res.,
  • Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P.D., and Giavazzi R., Journal of the National Cancer
  • TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments
  • M is a natural (L) alpha amino acid derivative having the structure
  • X is O, S, S(O) n , CH 2 , CO, or NRQ;
  • R is hydrogen, C ⁇ -Cg alkyl, or -Ci -Cg alkyl-phenyl;
  • R is a side chain of a natural alpha amino acid;
  • R 1 is C1 -C5 alkoxy, hydroxy, or -NHOR 5 ;
  • R2 and R are independently hydrogen, -C1-C5 alkyl, phenyl -NO2, halogen, -OR 5 , -CN, -CO R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -CF3, or -NHCOR 5 ; each R 5 and R ⁇ are independently hydrogen or C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
  • X is O. In another embodiment of the invention of Formula I, X is S. In another embodiment of the invention of Formula I, X is CH 2 .
  • X is NR Q .
  • X is O and R ⁇ and R4 are hydrogen.
  • X is CO. In another embodiment of the invention of Formula I, X is S(O) n .
  • R ⁇ - is hydroxy, C1-C5 alkoxy, -NHOH, or -NHObenzyl.
  • R is the side chain of the natural alpha amino acid glycine, alanine, valine, leucine, isoleucine, cysteine, aspartic acid, or phenylalanine.
  • the present invention provides a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula II
  • Z is a natural (L) amino acid derivative having the structure
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -CF3, or -NHCOR 5 ; each R 5 and R" are independently hydrogen or C1-C5 alkyl;
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR c ;
  • R" is a side chain of a natural alpha amino acid
  • R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • Z is a natural (L) amino acid derivative having the structure
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R 6 ,
  • each R 5 and R° are independently hydrogen or Ci -C5 alkyl
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR c ;
  • R" 3 is a side chain of a natural alpha amino acid; and R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. Also provided is a method of inhibiting a matrix metalloproteinase in a patient in need of matrix metalloproteinase inhibition, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula IV.
  • Z is a natural (L) amino acid derivative having the structure
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 . halogen,
  • each R 5 and R ⁇ are independently hydrogen or C]-C5 alkyl;
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR c ;
  • Rb is a side chain of a natural alpha amino acid
  • R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • Z is a natural (L) amino acid derivative having the structure
  • R ⁇ and R4 are independently hydrogen, -C1-C5 alkyl, phenyl -NO , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R6, -(CH 2 ) n NR 5 R6, -CF 3 , or -NHCOR 5 ; each R 5 and R > are independently hydrogen or C1-C5 alkyl;
  • R a is C!-C 5 alkoxy, hydroxy, or -NHOR c ;
  • R" is a side chain of a natural alpha amino acid; and R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR R6, -(CH 2 ) n NR 5 R6, -CF3, or -NHCOR 5 ; each R 5 and R ⁇ are independently hydrogen or C1-C5 alkyl;
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR c ; n is 0 to 2;
  • R D is a side chain of a natural alpha amino acid
  • R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • Z is a natural (L) amino acid derivative having the structure
  • R ⁇ and R4 are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR R ⁇ , -(CH 2 ) n NR 5 R 6 , -CF3, or -NHCOR 5 ; each R 5 and R ⁇ are independently hydrogen or C ⁇ -C5 alkyl;
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR c ;
  • RQ is hydrogen, Cj-Cg alkyl, or Cj-C ⁇ alkyl-phenyl
  • R D is a side chain of a natural alpha amino acid
  • R c is hydrogen, C1-C5 alkyl, or -CH 2 phenyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • the compound of Formula I- VIII is:
  • Also provided by the present invention is a method of treating multiple sclerosis, the method comprising administering to a patient having multiple sclerosis a therapeutically effective amount of a compound of Formula I- VIII.
  • Also provided by the present invention is a method of treating atherosclerotic plaque rupture, the method comprising administering to a patient having an atherosclerotic plaque at risk for rupture a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I-VIII. Also provided by the present invention is a method of treating aortic aneurism, the method comprising administering to a patient having aortic aneurism a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating heart failure, the method comprising administering to a patient having heart failure a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating periodontal disease, the method comprising administering to a patient having periodontal disease a therapeutically effective amount of a compound of Formula I-VIII. Also provided by the present invention is a method of treating comeal ulceration, the method comprising administering to a patient having comeal ulceration a therapeutically effective amount of a compound of Formula I-VIII. Also provided by the present invention is a method of treating burns, the method comprising administering to a patient having bums a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating decubital ulcers, the method comprising administering to a patient having decubital ulcers a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating chronic ulcers or wounds, the method comprising administering to a patient having chronic ulcers or wounds a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating cancer metastasis, the method comprising administering to a patient having cancer metastasis a therapeutically effective amount of a compound of Formula I-VIII.
  • Also provided by the present invention is a method of treating tumor angiogenesis, the method comprising administering to a patient having tumor angiogenesis a therapeutically effective amount of a compound of Formula I-VIII. Also provided by the present invention is a method of treating arthritis, the method comprising administering to a patient having arthritis a therapeutically effective amount of a compound of Formula I-VIII. Also provided by the present invention is a method of treating autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes, the method comprising administering to a patient having autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes a therapeutically effective amount of a compound of Formula I-VIII.
  • the present invention also provides compounds of Formula I
  • M is a natural (L) alpha amino acid derivative having the structure
  • X is S, S(O) n , CH 2 , CO, or NRQ;
  • R D is a side chain of a natural alpha amino acid
  • RQ is hydrogen, Cj-Cg alkyl, or -C ⁇ -C ⁇ $ alkyl-phenyl;
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR 5 ;
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R 6 ,
  • each R 5 and R > are independently hydrogen or C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
  • the present invention also provides compounds of Formula VIII
  • M is a natural (L) alpha amino acid derivative having the structure
  • R2 and R ⁇ are independently hydrogen, -Ci -C5 alkyl, phenyl -NO 2 , halogen,
  • R" is a side chain of a natural alpha amino acid
  • R a is C1-C5 alkoxy, hydroxy, or -NHOR 5 ;
  • R2 and R4 are independently hydrogen, -C1-C5 alkyl, phenyl -NO 2 , halogen, -OR 5 , -CN, -CO 2 R 5 , -SO3R 5 , -CHO, -COR 5 , -CONR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -CF3, or -NHCOR 5 ; each R 5 and R ⁇ are independently hydrogen or C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodmgs thereof.
  • M is a natural (L) alpha amino acid derivative having the structure
  • X is O, S, S(O) n , CH , CO, or NRQ;
  • R is a side chain of a natural alpha amino acid;
  • R 1 is C1-C5 alkoxy, hydroxy, or -NHOR 5 ;
  • R2 and R ⁇ are independently hydrogen, -C1-C5 alkyl, phenyl -NO , halogen,
  • each R 5 and R ⁇ are independently hydrogen or C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodmgs thereof.
  • alkyl means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec -butyl, pentyl, and hexyl.
  • alkoxy means an alkyl group attached to an oxygen atom.
  • Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
  • halogen includes chlorine, fluorine, bromine, and iodine.
  • phenyl also includes substituted phenyl wherein one or more hydrogen on the phenyl ring is replaced with an organic radical. Examples of suitable substituents include, but are not limited to, halogen, Cj-Cg alkoxy, -CF3,
  • side chain of a natural alpha amino acid means the group Q in a natural amino acid of formula H 2 N-CH(Q)-COOH.
  • side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • a natural alpha amino acid is an amino acid found in a living organism.
  • amino acids examples include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, asparagine, glutamine, lysine, arginine, tryptophan, histidine, cysteine, methionine, aspartic acid, and glutamic acid.
  • the functional groups in the amino acid side chains can be protected.
  • carboxyl groups can be esterified
  • amino groups can be converted to amides or carbamates
  • hydroxyl groups can be converted to ethers or esters
  • thiol groups can be converted to thioethers or thioesters.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, water, alcohol, alcohol, and the like.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents such as sodium citrate or dicalcium phosphate
  • fillers or extenders as for example
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner.
  • Examples of embedding compositions which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propy
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellents as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day.
  • dosage levels in the range of about 0.1 to about 1,000 mg per day.
  • 0.01 to about 100 mg/kg of body weight per day is preferable.
  • the specific dosage used can vary.
  • the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well-known to those skilled in the art.
  • the term "patient" includes humans and animal.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodmgs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, tr iethylamine, ethylamine, and the like.
  • esters of the compounds of this invention include C ⁇ to C alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5 to C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C ⁇ to C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary
  • C 1 to C alkyl amines and secondary C ⁇ to C dialkyl amines wherein the alkyl groups are straight or branched chain.
  • the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, C ⁇ to C3 alkyl primary amines and C] to C 2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds of the present invention are administered to a patient in need of matrix metalloproteinase inhibition.
  • patients in need of matrix metalloproteinase inhibition are those patients having a disease or condition in which a matrix metalloproteinase plays a role.
  • diseases include, but are not limited to, multiple sclerosis, atherosclerotic plaque mpture, restenosis, aortic aneurism, heart failure, periodontal disease, comeal ulceration, bums, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
  • the matrix metalloproteinase is stromelysin-1 or gelatinase-A.
  • a “therapeutically effective amount” is an amount of a compound of Formula I-VIII that when administered to a patient having a disease that can be treated with a compound of Formula I-VIII ameliorates a symptom of the disease.
  • a therapeutically effective amount of a compound of Formula I-VIII is readily determined by one skilled in the art by administering a compound of Formula I-VIII to a patient and observing the results.
  • the compounds of the present invention can be synthesized using a number of different synthetic routes.
  • the sulfonyl chloride (1) is condensed directly with a natural amino acid using a base such as triethylamine (TEA) in a mixture of tetrahydrofuran (THF) and water (3:5) at 10°C to yield the desired compound (2).
  • a base such as triethylamine (TEA) in a mixture of tetrahydrofuran (THF) and water (3:5) at 10°C to yield the desired compound (2).
  • the corresponding hydroxamic acid (5) can be conveniently prepared by coupling the acid (2) with an O-protected (usually benzyl) hydroxylamine using dicyclohexylcarbodiimide (DCC) as the coupling agent in dichloromethane at temperatures ranging from -(10) to 0°C
  • the protecting group can be removed from compound (4) by catalytic hydrogenolysis using hydrogen gas at 50 psi and Pd/BaSO4 in aqueous methanol to yield the hydroxamic acid derivative (5).
  • Method B the sulfonyl chloride (1) is condensed with a suitably
  • Step (a) (L;-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid benzyloxy-amide
  • a THF solution 50 mL of (L)-2-(Dibenzofuran-2-sulfonylamino)- 3-methyl-pentanoic acid (Example 2, 0.55 g, 0.0015 mol) and carbonyldiimidazole (0.26 g, 0.0016 mol) at room temperature under an inert nitrogen atmosphere was added O-benzylhydroxylamine (0.23 g, 0.0018 mol) in one portion. This solution was then heated to reflux for 72 hours and then allowed to stir at room temperature for 24 hours.
  • Step (b) (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide (Example 10)
  • a THF (2 mL)/methanol (10 mL) solution of the material obtained above in step (a) (0.037 g, 0.0000793 mol) was hydrogenolyzed using hydrogen gas at 50 psi with a P ⁇ V BaSO4 catalyst at room temperature for 1 hour. The catalyst was removed by filtration and the solution concentrated in vacuo. The residue was triturated with ether to yield the title compound (0.022 g, 74%).
  • EXAMPLE 12 (L)-2-(9H-Fluorene-2-sulfonyIamino)-3-methyl-butyric acid
  • (L)-leucine, tert.-butyl ester is replaced with (L)-valine, tert.-butyl ester and dibenzofi ⁇ ran-2-sulfonyl chloride is replaced with 9H-fluorene-2-sulfonyl chloride, the title compound is obtained.
  • 3-Amino-dibenzofuran (15 g, 81.9 mmoles) was added in portions to a suspension of cupric bromide (21.9 g, 98.2 mmoles) and tert.-butyl nitrite (12.66 g, 122.8 mmoles) in 350 mL of acetonitrile. This mixture was heated to reflux for 2 hours and then stirred for 16 hours at room temperature. The reaction was partitioned between 1 M HCl and diethyl ether. The diethyl ether layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography gave the title compound as a yellowish solid.
  • IC50 values were determined using a thiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson L.L., Hupe D.J., and Baragi V., "Purification and Characterization of the Human Stromelysin Catalytic Domain Expressed in Escherichia coli,"
  • MMPOl, MMP07, MMP09, and MMP13 activity was assayed in a method similar to MMP02 and MMP03 (SCD and GCD).
  • MMPOl and MMP09 can be obtained from Washington University School of Medicine, St. Louis, Missouri.
  • MMP07 can be obtained in accordance with the known procedure set forth by Ye Q-Z, Johnson L.L., and Baragi V., "Gene
  • MMP 13 can be obtained in accordance with the known procedure set forth by Freije J.M.P., et al., "Molecular Cloning and Expression of Collegenase-3, a Novel Human Matrix Metalloproteinase Produced by Breast Carcinomas" J. Bio.
  • a 100 ⁇ L reaction contains 1 mM 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), 100 ⁇ M substrate, 0.1% Brij, enzyme, and inhibitor in the appropriate reaction buffer.
  • DTNB 5,5'-dithiobis(2-nitrobenzoic acid)
  • Activated full-length enzymes are assayed at 5 nM, Stromelysin Catalytic Domain (SCD) at 10 nM, and Gelatinase A Catalytic Domain (GaCD) at 1 nM.
  • Inhibitors are screened from 100 ⁇ M to 1 nM.
  • Full-length enzymes are assayed in 50 mM HEPES, 10 mM CaCl 2 , pH 7.0; SCD in 50 mM MES, 10 mM CaCl 2 , pH 6.0; and GaCD in 50 mM MOPS, 10 mM
  • HEPES is 4-(2-hydroxylethyl)-piperazine-l -ethane sulfonic acid
  • MES 2-morpholinoethane sulfonic acid menohydrate
  • Ac is acetyl
  • Pro is proline
  • Leu is leucine
  • Gly is glycine; Et is ethyl; and MOPS is 3-morpholinopropane sulfonic acid.
  • Soluble Proteoglycan Assay (stromelysin natural substrate assay) SCD (PG) Solubilized proteoglycan substrate is prepared from bovine cartilage powder (Sigma) using the method described by Nagase and Woessner in Anal. Biochem., 1980;107:385-392.
  • a 100 ⁇ L reaction contains 10 ⁇ g/mL proteoglycan, enzyme, and inhibitor in 50 mM MES, 10 mM CaCl 2 , pH 6.0.
  • Activated full- length stromelysin or stromelysin catalytic domain (SCD) is assayed at 100 nM.
  • Inhibitors are screened from 100 ⁇ M to 1 nM.
  • reaction products are separated from undigested substrate using ultrafree-MC polysulfone microcons with a 300,000 molecular weight cutoff membrane (Millipore) and quantified using a modified 1 ,9-dimethylene blue (DMB) assay described by Farndale, Sayers, and Barrett in Connective Tissue
  • Rat tail Type I collagen (Sigma) is denatured by heating at 95°C for 20 minutes to prepare the gelatin substrate.
  • a 50 ⁇ L reaction contains 1.12 mg/mL substrate, enzyme, inhibitor, and 80 ⁇ g/mL soy bean trypsin inhibitor as an inert internal standard in 50 mM MOPS, 10 mM CaCh, 10 ⁇ M ZnCl 2 , pH 7.0.
  • Activated full-length gelatinase A is assayed at 1 nM and gelatinase A catalytic domain (GaCD) at 10 nM.
  • Inhibitors are screened from 100 ⁇ M to 1 nM. The reactions are incubated at 37°C for 30 minutes then stopped with 50 ⁇ L at 2X Tricine gel loading buffer (Novex). Reaction products are separated from undigested substrate by electrophoresis on Tricine-SDS 10-20% polyacrylamide gradient gels (Novex). Protein bands are stained with Coomassie Brilliant Blue R and quantified using a Bio Image densitometer (Millipore). IC50 values are calculated from the disappearance of substrate using the sum of the top three bands of each reaction after normalization with the internal standard.
  • Plasma protein is precipitated with an equal volume of acetonitrile and separated by centrifugation at room temperature.
  • the supemate is evaporated to dryness and reconstituted to the original plasma volume with 50 mM Tris, pH 7.6.
  • Ten-fold serial dilutions of the reconstituted plasma samples are prepared in 50 mM Tris, pH 7.6 for dose response assays using the appropriate thiopeptolide assay.
  • the concentration of plasma which yields 50% inhibition of enzyme is determined and used to calculate the inhibitor plasma level from the known IC50 value.
  • controls for each inhibitor include normal rat plasma, normal rat plasma spiked with compound, and buffer dilutions of compound. All control samples are subjected to acetonitrile precipitation and analyzed with the thiopeptolide assay.

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Abstract

La présente invention porte sur un procédé d'inhibition de métalloprotéinases matricielles mettant en oeuvre des composés qui sont des dérivés de dibenzofurane sulfonamide ayant la formule (I). L'invention porte plus particulièrement sur un procédé de traitement de pathologies dans lesquelles interviennent les métalloprotéinases matricielles, pathologies telles que sclérose en plaques, rupture de la plaque d'athérosclérose, resténose, anévrisme de l'aorte, insuffisance cardiaque, paradontolyse, ulcération de la cornée, brûlures, ulcères de décubitus, lésions ou ulcères chroniques, métastase cancéreuse, angiogénie tumorale, arthrite ou autre maladies autoimmunes ou inflammatoires selon l'invasion des tissus par les leucocytes.
PCT/US1997/014859 1996-09-04 1997-08-22 Inhibiteurs de metalloproteinases matricielles et leurs utilisations pharmaceutiques WO1998009934A1 (fr)

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US09/254,384 US6624177B1 (en) 1996-09-04 1997-08-22 Matrix metalloproteinase inhibitors and their therapeutic uses
NZ333063A NZ333063A (en) 1996-09-04 1997-08-22 Dibenzofuran sulfonamide derivatives as matrix metalloproteinase inhibitors
BR9711988A BR9711988A (pt) 1996-09-04 1997-08-22 Inibidores de metaloproteinase de matriz e seus empregos terap-uticos
EP97939527A EP0931045A1 (fr) 1996-09-04 1997-08-22 Inhibiteurs de metalloproteinases matricielles et leurs utilisations pharmaceutiques
JP10512709A JP2000517341A (ja) 1996-09-04 1997-08-22 マトリックスメタロプロテイナーゼ阻害剤およびそれらの治療的使用
AU41595/97A AU735013B2 (en) 1996-09-04 1997-08-22 Matrix metalloproteinase inhibitors and their therapeutic uses
US10/603,677 US6906092B2 (en) 1996-09-04 2003-06-25 Method of inhibiting matrix metalloproteinases

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998042659A2 (fr) * 1997-03-26 1998-10-01 Smithkline Beecham Plc Nouveaux composes
WO2000004892A2 (fr) * 1998-07-21 2000-02-03 Warner-Lambert Company Co-administration d'inhibiteurs de acat et de mmp pour le traitement de lesions atherosclereuses
WO2000006561A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Sulfonamides tricycliques et leurs derives utilises comme inhibiteurs des metalloproteinases matricielles
WO2000006560A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Composes heteroaromatiques tricycliques et leurs derives utilises comme inhibiteurs des metalloproteinases matricielles
WO2000015213A1 (fr) * 1998-09-11 2000-03-23 Shionogi & Co., Ltd. Agent de prevention ou de traitement de l'insuffisance cardiaque congestive
US6294674B1 (en) 1996-09-04 2001-09-25 Warner-Lambert Company Dibenzofuran sulfonamide matrix metalloproteinase inhibitors
WO2001077092A1 (fr) * 2000-04-07 2001-10-18 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
EP1233017A1 (fr) * 2001-02-14 2002-08-21 Warner-Lambert Company Sulphonamides tricycliques utiles comme inhibiteurs de métalloprotéase matricielle
WO2002085883A1 (fr) * 2001-04-23 2002-10-31 F. Hoffmann-La Roche Ag Alkylhydroxamates tricycliques, procedes de preparation et d'utilisation de ces derniers en tant qu'inhibiteurs de la proliferation cellulaire
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
WO2004089940A1 (fr) * 2003-04-11 2004-10-21 Glenmark Pharmaceuticals S.A. Nouveaux composes heterocycliques pour le traitement des affections inflammatoires et allergiques, leur procede de preparation et compositions pharmaceutiques les contenant
WO2004111044A1 (fr) * 2003-06-17 2004-12-23 Glenmark Pharmaceuticals Ltd. Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
WO2008057254A2 (fr) * 2006-10-27 2008-05-15 Wyeth Composés tricycliques servant d'inhibiteurs des métalloprotéases matricielles
WO2008137816A2 (fr) * 2007-05-04 2008-11-13 Wyeth Composés tricycliques en tant qu'inhibiteurs de métalloprotéinase matricielle
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
CN105906665A (zh) * 2016-05-16 2016-08-31 中国医学科学院医药生物技术研究所 咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用
WO2021147882A1 (fr) * 2020-01-21 2021-07-29 深圳信立泰药业股份有限公司 Inhibiteur de la cathepsine k dérivé du dibenzofurane, son procédé de préparation et son utilisation médicale

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3845097A (en) * 1969-09-06 1974-10-29 Ajinomoto Kk N-substituted amino acids and novel ester
DE2065966A1 (de) * 1969-09-06 1977-07-14 Ajinomoto Kk N-sulfonyl-aminocarbonsaeuren, sowie diese enthaltende arzneimittel
US4097472A (en) * 1974-11-08 1978-06-27 Mitsubishi Chemical Industries Limited N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof
EP0183271B1 (fr) * 1984-11-30 1990-05-16 Shosuke Okamoto Dérivé de lysine et inhibiteur de protéinase
EP0606046A1 (fr) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substitués dérivés d'acides hydroxamic
WO1996038434A1 (fr) * 1995-06-02 1996-12-05 Warner-Lambert Company Inhibiteurs tricycliques de metalloproteinases matricielles
WO1997019068A1 (fr) * 1995-11-17 1997-05-29 Warner-Lambert Company Inhibiteurs de metalloprotineases matricielles a base de sulfamide
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7013043A (fr) * 1969-09-06 1971-03-09

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3845097A (en) * 1969-09-06 1974-10-29 Ajinomoto Kk N-substituted amino acids and novel ester
DE2065966A1 (de) * 1969-09-06 1977-07-14 Ajinomoto Kk N-sulfonyl-aminocarbonsaeuren, sowie diese enthaltende arzneimittel
US4097472A (en) * 1974-11-08 1978-06-27 Mitsubishi Chemical Industries Limited N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof
EP0183271B1 (fr) * 1984-11-30 1990-05-16 Shosuke Okamoto Dérivé de lysine et inhibiteur de protéinase
EP0606046A1 (fr) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substitués dérivés d'acides hydroxamic
WO1996038434A1 (fr) * 1995-06-02 1996-12-05 Warner-Lambert Company Inhibiteurs tricycliques de metalloproteinases matricielles
WO1997019068A1 (fr) * 1995-11-17 1997-05-29 Warner-Lambert Company Inhibiteurs de metalloprotineases matricielles a base de sulfamide
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ABDEL-GHAFFAR ET AL: "Synthesis of biologically active fluoren-2-sulfonylamino acid and dipeptide derivatives", J. SERB. CHEM. SOC., vol. 55, no. 6, 1990, pages 311 - 17, XP002051688 *
EL-NAGGAR ET AL: "Synthesis and biological activity of some new dibenzofuran- and 7-nitrodibenzofuran-2-sulphonylamino acid derivatives", ACTA PHARM. JUGOSL., vol. 35, 1985, pages 15 - 22, XP002051689 *

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* Cited by examiner, † Cited by third party
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US6294674B1 (en) 1996-09-04 2001-09-25 Warner-Lambert Company Dibenzofuran sulfonamide matrix metalloproteinase inhibitors
WO1998025597A3 (fr) * 1996-12-09 2000-10-12 Warner Lambert Co Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998042659A2 (fr) * 1997-03-26 1998-10-01 Smithkline Beecham Plc Nouveaux composes
WO1998042659A3 (fr) * 1997-03-26 1999-02-25 Smithkline Beecham Plc Nouveaux composes
US6242467B1 (en) 1997-03-26 2001-06-05 Smithkline Beecham P.L.C. Compounds
WO2000004892A2 (fr) * 1998-07-21 2000-02-03 Warner-Lambert Company Co-administration d'inhibiteurs de acat et de mmp pour le traitement de lesions atherosclereuses
WO2000004892A3 (fr) * 1998-07-21 2000-05-18 Warner Lambert Co Co-administration d'inhibiteurs de acat et de mmp pour le traitement de lesions atherosclereuses
AU758619B2 (en) * 1998-07-30 2003-03-27 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases
WO2000006560A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Composes heteroaromatiques tricycliques et leurs derives utilises comme inhibiteurs des metalloproteinases matricielles
US6350885B1 (en) 1998-07-30 2002-02-26 Warner-Lambert Company Tricyclic heteroaromatics and their derivatives as inhibitors of matrix metalloproteinases
US6420408B1 (en) 1998-07-30 2002-07-16 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases
WO2000006561A1 (fr) * 1998-07-30 2000-02-10 Warner-Lambert Company Sulfonamides tricycliques et leurs derives utilises comme inhibiteurs des metalloproteinases matricielles
US6492422B2 (en) 1998-07-30 2002-12-10 Warner-Lambert Company Tricyclic sulfonamides and their derivatives as inhibitors of matrix metalloproteinases
WO2000015213A1 (fr) * 1998-09-11 2000-03-23 Shionogi & Co., Ltd. Agent de prevention ou de traitement de l'insuffisance cardiaque congestive
US6548667B2 (en) 2000-04-07 2003-04-15 Samsung Electronics Co. Ltd. Sulfonamide derivative as a matrix metalloproteinase inhibitor
WO2001077092A1 (fr) * 2000-04-07 2001-10-18 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
EP1233017A1 (fr) * 2001-02-14 2002-08-21 Warner-Lambert Company Sulphonamides tricycliques utiles comme inhibiteurs de métalloprotéase matricielle
US6559142B2 (en) 2001-02-14 2003-05-06 Warner-Lambert Company Sulfonamide matrix metalloproteinase inhibitors
US6512123B2 (en) 2001-04-23 2003-01-28 Hoffmann-La Roche Inc. Tricyclic alkylhydroxamate derivatives
WO2002085883A1 (fr) * 2001-04-23 2002-10-31 F. Hoffmann-La Roche Ag Alkylhydroxamates tricycliques, procedes de preparation et d'utilisation de ces derniers en tant qu'inhibiteurs de la proliferation cellulaire
CN1310904C (zh) * 2001-04-23 2007-04-18 霍夫曼-拉罗奇有限公司 三环烷基异羟肟酸酯,它们的制备和它们作为细胞增殖抑制剂的应用
US7238725B2 (en) 2002-10-23 2007-07-03 Glenmark Pharmaceuticals Ltd. Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
AP2021A (en) * 2002-10-23 2009-08-03 Glenmark Pharmaceuticals Ltd Novel tricyclic compounds useful for the treatmentof inflammatory and allergic disorders: Process f or their preparation and pharmaceutical compositions containing them
EA010408B1 (ru) * 2002-10-23 2008-08-29 Гленмарк Фармасьютикалс Лтд. Трициклические соединения для лечения воспалительных и аллергических нарушений, способы их приготовления и содержащие их фармацевтические составы
WO2004089940A1 (fr) * 2003-04-11 2004-10-21 Glenmark Pharmaceuticals S.A. Nouveaux composes heterocycliques pour le traitement des affections inflammatoires et allergiques, leur procede de preparation et compositions pharmaceutiques les contenant
US7223789B2 (en) 2003-04-11 2007-05-29 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7384962B2 (en) 2003-04-11 2008-06-10 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7393846B2 (en) 2003-04-11 2008-07-01 Glenmark Pharmaceuticals, S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders
JP2006522789A (ja) * 2003-04-11 2006-10-05 グレンマーク・ファーマシューティカルズ・エス・エー 炎症性およびアレルギー性障害の治療に有用な新規な複素環式化合物；それらの調製方法および医薬組成物
EA010634B1 (ru) * 2003-04-11 2008-10-30 Гленмарк Фармасьютикалс С.А. Новые гетероциклические соединения, применяемые для лечения нарушений аллергической или воспалительной природы: способы синтеза и содержащие их фармацевтические составы
WO2004111044A1 (fr) * 2003-06-17 2004-12-23 Glenmark Pharmaceuticals Ltd. Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
WO2008057254A3 (fr) * 2006-10-27 2009-01-08 Wyeth Corp Composés tricycliques servant d'inhibiteurs des métalloprotéases matricielles
WO2008057254A2 (fr) * 2006-10-27 2008-05-15 Wyeth Composés tricycliques servant d'inhibiteurs des métalloprotéases matricielles
WO2008137816A3 (fr) * 2007-05-04 2009-05-14 Wyeth Corp Composés tricycliques en tant qu'inhibiteurs de métalloprotéinase matricielle
WO2008137816A2 (fr) * 2007-05-04 2008-11-13 Wyeth Composés tricycliques en tant qu'inhibiteurs de métalloprotéinase matricielle
CN105906665A (zh) * 2016-05-16 2016-08-31 中国医学科学院医药生物技术研究所 咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用
WO2021147882A1 (fr) * 2020-01-21 2021-07-29 深圳信立泰药业股份有限公司 Inhibiteur de la cathepsine k dérivé du dibenzofurane, son procédé de préparation et son utilisation médicale
CN114981251A (zh) * 2020-01-21 2022-08-30 深圳信立泰药业股份有限公司 一种二苯并呋喃类衍生物组织蛋白酶k抑制剂及其制备方法和医药用途
CN114981251B (zh) * 2020-01-21 2023-11-21 深圳信立泰药业股份有限公司 一种二苯并呋喃类衍生物组织蛋白酶k抑制剂及其制备方法和医药用途

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KR20000068414A (ko) 2000-11-25
AU735013B2 (en) 2001-06-28
EP0931045A1 (fr) 1999-07-28
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AU4159597A (en) 1998-03-26
CA2256716A1 (fr) 1998-03-12
JP2000517341A (ja) 2000-12-26

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