WO2003000671A1 - Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) - Google Patents

Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) Download PDF

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Publication number
WO2003000671A1
WO2003000671A1 PCT/US2002/019231 US0219231W WO03000671A1 WO 2003000671 A1 WO2003000671 A1 WO 2003000671A1 US 0219231 W US0219231 W US 0219231W WO 03000671 A1 WO03000671 A1 WO 03000671A1
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Prior art keywords
benzofuran
naphthyl
compound
pharmaceutically acceptable
acceptable salt
Prior art date
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Ceased
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PCT/US2002/019231
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English (en)
French (fr)
Inventor
Hassan Mahmoud Elokdah
Geraldine Ruth Mcfarlane
Scott Christian Mayer
David Leroy Crandall
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Wyeth LLC
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Wyeth LLC
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Priority to MXPA03011400A priority Critical patent/MXPA03011400A/es
Priority to BR0210532-2A priority patent/BR0210532A/pt
Priority to CA002449844A priority patent/CA2449844A1/en
Priority to EP02747904A priority patent/EP1401822A1/en
Priority to JP2003507076A priority patent/JP4476624B2/ja
Publication of WO2003000671A1 publication Critical patent/WO2003000671A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • Plasminogen activator inhibitor-1 (PAI-1) is a major regulatory component of the plasminogen-plasmin system. PAI-1 is the principal physiologic inhibitor of both tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA).
  • heteroaryl groups can have a single ring, such as pyridyl, pyrrolyl or furyl groups, or multiple condensed rings, such as indolyl, indolizinyl, benzofuranyl or benzothienyl groups.
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl. It will be understood that the definitions of aryl and heteroaryl also refer to those portions of any aroyl or heteroaroyl groups described herein.
  • benzyl optionally substituted with one or more groups independently selected from CrC 6 alkyl, C C 6 alkoxy, phenyl, halogen, trifluoromethyl and trifluoromethoxy, and phenyl optionally substituted with one or more groups independently selected from C- ⁇ -C 6 alkyl, C C 6 alkoxy, phenyl, halogen, trifluoromethyl and trifluoromethoxy; or
  • Spectrozyme-tPA American Diagnostica, Greenwich, CT
  • a chromogenic substrate for tPA is added and absorbance read at 405 nm at 0 and 60 minutes.
  • Relative PAI-1 inhibition is equal to the residual tPA activity in the presence of the test compounds and PAI-1.
  • Control treatments include the complete inhibition of tPA by PAI-1 at the molar ratio employed (2:1), and the absence of any effect of the test compound on tPA alone.
  • Step 2 1 - ⁇ 2-[6-(1 HA ,2,3,4-Tetraazol-5-ylmethoxy)-2-naphthyl]-1 -benzof uran-3-yl ⁇ -1 - pentanone
  • Step 3 Ethyl 2-( ⁇ 6-[3-(2-cyclopentylacetyl)-1 -benzofuran-2-yl]-2-naphthyl ⁇ oxy)acetate

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Reproductive Health (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
PCT/US2002/019231 2001-06-20 2002-06-18 Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) Ceased WO2003000671A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MXPA03011400A MXPA03011400A (es) 2001-06-20 2002-06-18 Derivados de naftil benzofurano como inhibidores del inhibidor-1de activador de plasminogeno (pai-1).
BR0210532-2A BR0210532A (pt) 2001-06-20 2002-06-18 Derivados de naftil benzofurano como inibidores do inibidor-1 de ativador de plasminogênio (pai-1)
CA002449844A CA2449844A1 (en) 2001-06-20 2002-06-18 Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
EP02747904A EP1401822A1 (en) 2001-06-20 2002-06-18 Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
JP2003507076A JP4476624B2 (ja) 2001-06-20 2002-06-18 プラスミノゲンアクチベーターインヒビター１（ｐａｉ−１）のインヒビターとしてのナフチルベンゾフラン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29970201P 2001-06-20 2001-06-20
US60/299,702 2001-06-20

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WO2003000671A1 true WO2003000671A1 (en) 2003-01-03

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PCT/US2002/019231 Ceased WO2003000671A1 (en) 2001-06-20 2002-06-18 Naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)

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US (1) US6599925B2 (enExample)
EP (1) EP1401822A1 (enExample)
JP (1) JP4476624B2 (enExample)
CN (1) CN1308320C (enExample)
AR (1) AR036100A1 (enExample)
BR (1) BR0210532A (enExample)
CA (1) CA2449844A1 (enExample)
MX (1) MXPA03011400A (enExample)
TW (1) TWI240723B (enExample)
WO (1) WO2003000671A1 (enExample)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030760A1 (en) * 2003-09-25 2005-04-07 Wyeth Substituted heteroaryl benzofuran acids
WO2005030750A1 (en) * 2003-09-25 2005-04-07 Wyeth Substituted naphthyl benzothiophene acids
WO2005094863A1 (en) * 2004-03-30 2005-10-13 Den Kgl.Veterinær-Og Landbohøjskole Improvements in cancer treatment and cancer treatment efficacy prediction by blocking and decting protease inhibitors
WO2006023865A1 (en) * 2004-08-23 2006-03-02 Wyeth Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (pai-1) modulators useful in the treatment of thrombosis and cardiovascular diseases
WO2006023866A3 (en) * 2004-08-23 2006-06-01 Wyeth Corp Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1
WO2008044729A1 (fr) 2006-10-12 2008-04-17 Institute Of Medicinal Molecular Design. Inc. Dérivé d'acide carboxylique
WO2008044731A1 (en) 2006-10-12 2008-04-17 Institute Of Medicinal Molecular Design. Inc. N-phenyloxamidic acid derivative
US7374886B2 (en) 1999-04-09 2008-05-20 Rigshospitalet Tissue inhibitor of matrix metalloproteinases type-1 (TIMP-1) as a cancer marker and postoperative marker for minimal residual disease or recurrent disease in patients with a prior history of cancer
WO2009054439A1 (ja) 2007-10-23 2009-04-30 Institute Of Medicinal Molecular Design, Inc. Pai-1産生抑制剤
WO2009125606A1 (ja) 2008-04-11 2009-10-15 株式会社医薬分子設計研究所 Pai-1阻害剤
WO2010129049A1 (en) * 2009-05-05 2010-11-11 Sloan-Kettering Institute For Cancer Research Benzofuran-4,5-diones as selective peptide deformylase inhibitors

Families Citing this family (28)

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TWI224101B (en) * 2001-06-20 2004-11-21 Wyeth Corp Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7291639B2 (en) * 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2003000253A1 (en) 2001-06-20 2003-01-03 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
ATE411288T1 (de) * 2002-12-10 2008-10-15 Wyeth Corp Aryl-, aryloxy- und alkyloxysubstituierte 1h- indol-3-yl-glyoxylsäurederivateals inhibitoren des plasminogenaktivatorinhibitors-1 (pai-1)
US7348351B2 (en) * 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
UA80453C2 (en) * 2002-12-10 2007-09-25 Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US7078429B2 (en) * 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7442805B2 (en) * 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7351726B2 (en) * 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7141592B2 (en) * 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7420083B2 (en) * 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7268159B2 (en) * 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7582773B2 (en) * 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7265148B2 (en) * 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7411083B2 (en) * 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7534894B2 (en) * 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7332521B2 (en) * 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) * 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
MX2007002177A (es) * 2004-08-23 2007-04-02 Wyeth Corp Acidos de pirrolo-naftilo como inhibidores de pai-1.
BRPI0614340A2 (pt) * 2005-08-17 2011-04-12 Wyeth Corp indóis substituìdos e métodos de seu uso
AU2007217363A1 (en) * 2006-02-27 2007-08-30 Wyeth Inhibitors of PAI-1 for treatment of muscular conditions
US8633245B2 (en) * 2008-04-11 2014-01-21 Institute Of Medicinal Molecular Design, Inc. PAI-1 inhibitor
CA2744555A1 (en) 2008-11-26 2010-06-03 Five Prime Therapeutics, Inc. Compositions and methods for regulating collagen and smooth muscle actin expression by serpine2
CN102850451B (zh) * 2011-06-29 2014-05-07 辽宁诺康生物制药有限责任公司 具有抑制纤溶酶活性的重组textilinin-1及其制备方法和应用
DK3395354T3 (da) 2015-12-18 2024-06-03 Talengen Int Ltd Plasminogen til anvendelse i behandling af diabetisk nefropati
CN106890324A (zh) * 2015-12-18 2017-06-27 深圳瑞健生命科学研究院有限公司 一种预防和治疗糖尿病肾病的方法
CA3047176C (en) 2016-12-15 2021-11-30 Talengen International Limited Use of plasminogen for promoting secretion of insulin in treatment of diabetes
CN114957176A (zh) * 2022-07-01 2022-08-30 河南中医药大学第一附属医院 人血管紧张素转化酶抑制剂化合物和合成方法

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US4496572A (en) * 1981-08-26 1985-01-29 Pfizer Inc. Benzo-fused thromboxane synthetase inhibitors
EP0540051A1 (en) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof
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Title
VERNER, ERIK ET AL: "Development of serine protease inhibitors displaying a multicentered shor (<2.3.ANG.) hydrogen bond binding mode: Inhibitors of urokinase-type plasminogen activator and factor Xa", JOURNAL OF MEDICINAL CHEMISTRY (2001), 44(17), 2753-2771, XP002216503 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7374886B2 (en) 1999-04-09 2008-05-20 Rigshospitalet Tissue inhibitor of matrix metalloproteinases type-1 (TIMP-1) as a cancer marker and postoperative marker for minimal residual disease or recurrent disease in patients with a prior history of cancer
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US6599925B2 (en) 2003-07-29
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CA2449844A1 (en) 2003-01-03
MXPA03011400A (es) 2004-04-05
CN1308320C (zh) 2007-04-04
BR0210532A (pt) 2004-06-22
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US20030018067A1 (en) 2003-01-23
EP1401822A1 (en) 2004-03-31

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