CA2351464A1 - 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4 - Google Patents

3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4 Download PDF

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Publication number
CA2351464A1
CA2351464A1 CA002351464A CA2351464A CA2351464A1 CA 2351464 A1 CA2351464 A1 CA 2351464A1 CA 002351464 A CA002351464 A CA 002351464A CA 2351464 A CA2351464 A CA 2351464A CA 2351464 A1 CA2351464 A1 CA 2351464A1
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CA
Canada
Prior art keywords
dioxo
compound
cyclobut
amino
pharmaceutical salt
Prior art date
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Abandoned
Application number
CA002351464A
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English (en)
French (fr)
Inventor
Joan E. Sabalski
Louis John Lombardo
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Wyeth LLC
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Individual
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Filing date
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Publication of CA2351464A1 publication Critical patent/CA2351464A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81Amides; Imides
    • C07D213/82Amides; Imides in position 3
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/40Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/24Heterocyclic 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
    • C07D213/36Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182Radicals derived from carboxylic acids
    • C07D295/185Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205Radicals derived from carbonic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/04Systems containing only non-condensed rings with a four-membered ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Indole Compounds (AREA)
CA002351464A 1998-12-14 1999-12-10 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4 Abandoned CA2351464A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21118398A 1998-12-14 1998-12-14
US09/211,183 1998-12-14
PCT/US1999/029369 WO2000035855A1 (en) 1998-12-14 1999-12-10 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4

Publications (1)

Publication Number Publication Date
CA2351464A1 true CA2351464A1 (en) 2000-06-22

Family

ID=22785877

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002351464A Abandoned CA2351464A1 (en) 1998-12-14 1999-12-10 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4

Country Status (7)

Country Link
EP (1) EP1140792A1 (ja)
JP (1) JP2002532457A (ja)
CN (1) CN1334797A (ja)
AU (1) AU2357600A (ja)
BR (1) BR9916211A (ja)
CA (1) CA2351464A1 (ja)
WO (1) WO2000035855A1 (ja)

Families Citing this family (44)

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US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
ES2226413T3 (es) 1998-02-26 2005-03-16 Celltech Therapeutics Limited Derivados de fenilalanina como inhibidores de alfa-4 integrinas.
GB9805655D0 (en) 1998-03-16 1998-05-13 Celltech Therapeutics Ltd Chemical compounds
GB9811159D0 (en) 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9811969D0 (en) 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
GB9812088D0 (en) 1998-06-05 1998-08-05 Celltech Therapeutics Ltd Chemical compounds
US6518283B1 (en) * 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
NZ518886A (en) 1999-12-28 2004-02-27 Pfizer Prod Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
ATE375330T1 (de) 2000-04-17 2007-10-15 Ucb Pharma Sa Enamin-derivate als zell-adhäsionsmoleküle
US6545013B2 (en) * 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) * 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6740654B2 (en) * 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
CA2417059A1 (en) * 2000-08-02 2002-02-07 Celltech R&D Limited 3-substituted isoquinolin-1-yl derivatives
FR2815345B1 (fr) * 2000-10-12 2002-12-13 Servier Lab Nouveaux derives de cyclobutene-dione, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
GB0028844D0 (en) * 2000-11-27 2001-01-10 Celltech Chiroscience Ltd Chemical compounds
WO2002051396A1 (fr) * 2000-12-26 2002-07-04 Sankyo Company, Limited Compositions pharmaceutiques contenant des derives de cyclobutene
US7132445B2 (en) 2001-04-16 2006-11-07 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
MY149050A (en) * 2001-04-16 2013-07-15 Merck Sharp & Dohme 3,4 di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US20040106794A1 (en) * 2001-04-16 2004-06-03 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
EP1434775A1 (en) 2001-10-12 2004-07-07 Schering Corporation 3,4-di-substituted maleimide compounds as cxc-chemokine receptor antagonists
US6878709B2 (en) 2002-01-04 2005-04-12 Schering Corporation 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists
AU2003218735B2 (en) 2002-03-13 2009-03-12 Janssen Pharmaceutica N.V. Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
KR20040090981A (ko) 2002-03-13 2004-10-27 얀센 파마슈티카 엔.브이. 신규한 히스톤 디아세틸라제 저해제로서의카보닐아미노-유도체
PL213783B1 (pl) 2002-03-13 2013-05-31 Janssen Pharmaceutica Nv Podstawiona pochodna piperydyny lub piperazyny, jej zastosowanie i sposób wytwarzania oraz kompozycja farmaceutyczna
WO2003080053A1 (en) 2002-03-18 2003-10-02 Schering Corporation Combination treatments for chemokine-mediated diseases
GB0216574D0 (en) * 2002-07-17 2002-08-28 Celltech R&D Ltd Chemical compounds
CN100338032C (zh) * 2002-07-30 2007-09-19 先灵公司 作为cxc趋化因子受体配体的3,4-二取代环丁烯-1,2-二酮
PE20040570A1 (es) 2002-10-09 2004-08-30 Pharmacopeia Drug Discovery Tiadiazoldioxidos y tiadiazoloxidos como ligandos del receptor de cxc- y cc-quimiocina
ATE406356T1 (de) 2003-12-19 2008-09-15 Schering Corp Thiadiazole als cxc- und cc- chemokinrezeptorliganden
WO2005068460A1 (en) 2003-12-22 2005-07-28 Schering Corporation Isothiazole dioxides as cxc- and cc- chemokine receptor ligands
AU2005266312C1 (en) 2004-07-28 2011-06-16 Janssen Pharmaceutica N.V. Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
DE602004021404D1 (de) 2004-12-23 2009-07-16 Gpc Biotech Ag Quadratsäurederivate mit antiproliferativer Wirkung
ES2353401T3 (es) 2005-06-29 2011-03-01 Schering Corporation Oxidiazolopirazinas y tiadiazolopirazinas 5,6-di-sustituidas como ligandos del receptor de cxc-quimiocina.
MX2008000366A (es) 2005-06-29 2008-03-07 Schering Corp Oxadiazoles di-sustituidos como ligandos del receptor cxc-quimiocina.
AU2006307918B2 (en) * 2005-10-27 2012-06-21 Janssen Pharmaceutica N.V. Squaric acid derivatives as inhibitors of histone deacetylase
CA2630717C (en) 2006-01-19 2015-02-24 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
US8450348B2 (en) 2007-02-21 2013-05-28 Forma Tm, Llc Derivatives of squaric acid with anti-proliferative activity
FR2918665B1 (fr) * 2007-07-13 2009-10-02 Sod Conseils Rech Applic Derives de tri-amino-pyrimidine cyclobutenedione comme inhibiteurs de phosphatase cdc25
WO2020092401A1 (en) 2018-10-30 2020-05-07 Gilead Sciences, Inc. COMPOUNDS FOR INHIBITION OF ALPHA 4β7 INTEGRIN
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
CN112969687A (zh) 2018-10-30 2021-06-15 吉利德科学公司 作为α4β7整合素抑制剂的喹啉衍生物
AU2019373242B2 (en) 2018-10-30 2023-07-13 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
CA3148613A1 (en) 2019-08-14 2021-02-18 Gilead Sciences, Inc. Phenylalanine derived compounds and their use as inhinitors of alpha 4 beta 7 integrin

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GB9311282D0 (en) * 1993-06-01 1993-07-21 Rhone Poulenc Rorer Ltd New compositions of matter
US6140368A (en) * 1997-05-05 2000-10-31 The Regents Of The University Of California Naphthols useful in antiviral methods

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CN1334797A (zh) 2002-02-06
BR9916211A (pt) 2001-09-11
JP2002532457A (ja) 2002-10-02
EP1140792A1 (en) 2001-10-10
WO2000035855A1 (en) 2000-06-22
AU2357600A (en) 2000-07-03

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