WO1998051665A3 - Novel macrocyclic compounds as metalloprotease inhibitors - Google Patents

Novel macrocyclic compounds as metalloprotease inhibitors Download PDF

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Publication number
WO1998051665A3
WO1998051665A3 PCT/US1998/009789 US9809789W WO9851665A3 WO 1998051665 A3 WO1998051665 A3 WO 1998051665A3 US 9809789 W US9809789 W US 9809789W WO 9851665 A3 WO9851665 A3 WO 9851665A3
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WO
WIPO (PCT)
Prior art keywords
aggrecanase
compounds
cartilage
relates
macrocyclic compounds
Prior art date
Application number
PCT/US1998/009789
Other languages
French (fr)
Other versions
WO1998051665A2 (en
Inventor
Chu-Bio Xue
Carl P Decicco
Robert J Cherney
Elizabeth Arner
William F Degrado
Jingwu Duan
Xiaohua He
Irina Cipora Jacobson
Ronald L Magolda
David Nelson
Original Assignee
Du Pont Pharm Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Du Pont Pharm Co filed Critical Du Pont Pharm Co
Priority to AU73853/98A priority Critical patent/AU7385398A/en
Priority to DE69810100T priority patent/DE69810100T2/en
Priority to JP53993598A priority patent/JP2001524949A/en
Priority to CA002287923A priority patent/CA2287923A1/en
Priority to EP98921183A priority patent/EP0981521B1/en
Priority to AT98921183T priority patent/ATE229514T1/en
Publication of WO1998051665A2 publication Critical patent/WO1998051665A2/en
Publication of WO1998051665A3 publication Critical patent/WO1998051665A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
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    • 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
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
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    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
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    • C07—ORGANIC CHEMISTRY
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    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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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    • C07D403/02—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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    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

This invention relates to macrocyclic molecules of formula (I) which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases. A novel enzymatic assay was developed to detect potential inhibitors of aggrecanase. The assay uses active aggrecanase accumulated in media from stimulated bovine nasal cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or a fragment thereof as a substrate.
PCT/US1998/009789 1997-05-14 1998-05-14 Novel macrocyclic compounds as metalloprotease inhibitors WO1998051665A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU73853/98A AU7385398A (en) 1997-05-14 1998-05-14 Novel macrocyclic compounds as metalloprotease inhibitors
DE69810100T DE69810100T2 (en) 1997-05-14 1998-05-14 MACROCYCLIC COMPOUNDS AS METAL PROTEAS INHIBITORS
JP53993598A JP2001524949A (en) 1997-05-14 1998-05-14 New macrocycles as metalloprotease inhibitors
CA002287923A CA2287923A1 (en) 1997-05-14 1998-05-14 Novel macrocyclic compounds as metalloprotease inhibitors
EP98921183A EP0981521B1 (en) 1997-05-14 1998-05-14 Novel macrocyclic compounds as metalloprotease inhibitors
AT98921183T ATE229514T1 (en) 1997-05-14 1998-05-14 MACROCYCLIC COMPOUNDS AS METAL PROTEASE INHIBITORS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/856,223 1997-05-14
US08/856,223 US6281352B1 (en) 1995-11-14 1997-05-14 Macrocyclic compounds as metalloprotease inhibitors

Publications (2)

Publication Number Publication Date
WO1998051665A2 WO1998051665A2 (en) 1998-11-19
WO1998051665A3 true WO1998051665A3 (en) 1999-03-25

Family

ID=25323094

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/009789 WO1998051665A2 (en) 1997-05-14 1998-05-14 Novel macrocyclic compounds as metalloprotease inhibitors

Country Status (9)

Country Link
US (1) US6281352B1 (en)
EP (1) EP0981521B1 (en)
JP (1) JP2001524949A (en)
AT (1) ATE229514T1 (en)
AU (1) AU7385398A (en)
CA (1) CA2287923A1 (en)
DE (1) DE69810100T2 (en)
ES (1) ES2189165T3 (en)
WO (1) WO1998051665A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6649377B1 (en) 1999-05-10 2003-11-18 Syntex (U.S.A.) Llc Human aggrecanase and nucleic acid compositions encoding the same
US6808902B1 (en) 1999-11-12 2004-10-26 Amgen Inc. Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules
CA2379445C (en) 2000-06-01 2007-08-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of a.beta. protein production
PL222211B1 (en) 2001-06-26 2016-07-29 Amgen Fremont Inc Antibodies to opgl
AU2002238939A1 (en) * 2002-03-18 2003-09-29 Nihon University Cyclic etheramine derivatives as medicaments for malignant tumors
HUE026904T2 (en) 2003-04-24 2016-08-29 Incyte Holdings Corp Aza spiro alkane derivatives as inhibitors of metallproteases
WO2006113606A2 (en) * 2005-04-18 2006-10-26 Johns Hopkins University Histone deacetylase inhibitors
DK2041181T3 (en) * 2006-06-08 2011-08-29 Helmholtz Zentrum Muenchen Specific protease inhibitors and their use in cancer therapy
US20110015158A1 (en) 2007-12-11 2011-01-20 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
WO2017177144A1 (en) * 2016-04-08 2017-10-12 Yale University Novel matrix metalloproteinase inhibitors and imaging agents, and methods using same
US20210393632A1 (en) 2018-10-04 2021-12-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1992013831A1 (en) * 1991-02-07 1992-08-20 British Bio-Technology Limited Hydroxamic acid derivatives, process for their preparation and use thereof
WO1997018207A2 (en) * 1995-11-14 1997-05-22 The Du Pont Merck Pharmaceutical Company Novel macrocyclic compounds as metalloprotease inhibitors

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GB8827308D0 (en) 1988-11-23 1988-12-29 British Bio Technology Compounds
JPH06508135A (en) 1991-05-28 1994-09-14 メルク　エンド　カンパニー　インコーポレーテッド Substituted N-carboxyalkyl peptidyl derivatives as anti-denaturing active agents
US5427954A (en) 1992-04-29 1995-06-27 Shriner's Hospitals For Crippled Children Compositions and methods for detection and treatment of human osteoarthritis
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GB9215665D0 (en) 1992-07-23 1992-09-09 British Bio Technology Compounds
GB9307956D0 (en) 1993-04-17 1993-06-02 Walls Alan J Hydroxamic acid derivatives
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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1992013831A1 (en) * 1991-02-07 1992-08-20 British Bio-Technology Limited Hydroxamic acid derivatives, process for their preparation and use thereof
WO1997018207A2 (en) * 1995-11-14 1997-05-22 The Du Pont Merck Pharmaceutical Company Novel macrocyclic compounds as metalloprotease inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KSANDER G M ET AL.: "Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 4, 14 February 1997 (1997-02-14), Washington DC, US, pages 495 - 505, XP002074845 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds

Also Published As

Publication number Publication date
WO1998051665A2 (en) 1998-11-19
EP0981521A2 (en) 2000-03-01
ATE229514T1 (en) 2002-12-15
CA2287923A1 (en) 1998-11-19
ES2189165T3 (en) 2003-07-01
US6281352B1 (en) 2001-08-28
EP0981521B1 (en) 2002-12-11
DE69810100T2 (en) 2003-11-13
AU7385398A (en) 1998-12-08
JP2001524949A (en) 2001-12-04
DE69810100D1 (en) 2003-01-23

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