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WO2009039773A1 - Nouvelle utilisation thérapeutique d'une aryl-2(1h)-pyridone substituée en position 1 - Google Patents

Nouvelle utilisation thérapeutique d'une aryl-2(1h)-pyridone substituée en position 1 Download PDF

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Publication number
WO2009039773A1
WO2009039773A1 PCT/CN2008/072406 CN2008072406W WO2009039773A1 WO 2009039773 A1 WO2009039773 A1 WO 2009039773A1 CN 2008072406 W CN2008072406 W CN 2008072406W WO 2009039773 A1 WO2009039773 A1 WO 2009039773A1
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WO
WIPO (PCT)
Prior art keywords
pirfenidone
hours
flufenidone
proliferation
cancer cells
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2008/072406
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English (en)
Chinese (zh)
Inventor
Lijian Tao
Gaoyun Hu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Central South University
Original Assignee
Central South University
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 Central South University filed Critical Central South University
Priority to CN2008800110076A priority Critical patent/CN101652138B/zh
Publication of WO2009039773A1 publication Critical patent/WO2009039773A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel pharmaceutical use of a 1-substituted aryl-2(1H)-pyridone compound, in particular a novel pharmaceutical use of a fluorosubstituted phenyl 2-1(1H)-pyridone.
  • Pyridone compounds are a large family with a wide range of physiological activities and different physiological activities due to the different groups substituted on the pyridine ring. Including insecticidal, anti-inflammatory, anti-fibrotic and the like.
  • the drug is an oral active small molecule drug approved by the US FDA.
  • the treatment of pulmonary, renal and hepatic fibrotic diseases has entered Phase II clinical trials.
  • the inventors of the present application have disclosed the compound 1-(3-fluorophenyl)-5-methyl-2(1H)-pyridinone (Journal of Central South University (Medical Edition) (2004, 29(2)).
  • AKF-PD AKF-PD
  • PCT application WO2004/110245A2 discloses the use of pirfenidone for the treatment of cancer.
  • pirfenidone When pirfenidone is used in cancer treatment, it is administered in combination with a therapeutic amount of IP-10.
  • IP-10 When pirfenidone is used in cancer treatment, it is administered in combination with a therapeutic amount of IP-10.
  • the literature states that a therapeutic amount of pirfenidone in combination with a therapeutic amount of IP-10 can reduce tumors by 20%. Further, it may be administered in combination with IFN-a, an anti-proliferative agent, or as an adjuvant therapeutic agent.
  • IFN-a an anti-proliferative agent
  • the above prior art discloses a process for the preparation of the above compounds. Summary of the invention
  • the object of the present invention is to provide a new medical use of 1-(3-fluorophenyl)-5-methyl-2(1H)-pyridone (abbreviated as flufenidone).
  • the technical solution provided by the present invention is: The use of 1-(3-fluorophenyl)-5-methyl-2(1H)-pyridinone for the preparation of antitumor drugs.
  • the tumor is lung cancer.
  • the tumor is breast cancer.
  • the tumor is colon cancer.
  • the tumor is gastric cancer.
  • the tumor is liver cancer.
  • said tumor is prostate cancer.
  • the present invention discloses that 1-(3-fluorophenyl)-5-methyl-2(1H)-pyridinone has a stronger antitumor effect than the pirfenidone disclosed in the prior art.
  • Triflurane inhibits proliferation of lung cancer cells
  • Cell Human lung cancer cell (A549)
  • MTT kit is American R&D Company Second, the method:
  • a thiazole blue (MTT) method cells were cultured in DMEM medium containing 10% calf serum, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the medium containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was changed. 5 duplicate holes. After 20, 44, 68, 92, and 116 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved. The OD value was measured by microplate reader. . Statistical methods, using one-way analysis of variance.
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.01).
  • 500 ⁇ ⁇ / ⁇ 1 of flufenidone and pirfenidone inhibited the proliferation of human lung cancer cells, but flufenidone 500 ⁇ ⁇ / ⁇ 1 was stronger than the same dose of pirfenidone.
  • 100 ⁇ ⁇ / ⁇ 1 of flufenidone inhibited the proliferation of human lung cancer cells, while the same dose of pirfenidone did not inhibit the proliferation of human lung cancer cells.
  • Triflurane inhibits proliferation of breast cancer cells
  • Cells Human breast cancer cells (MCF7 cells).
  • the cells were cultured in a DMEM medium containing 10% calf serum using a thiazole blue ( ⁇ ) method, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the medium containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was changed. 5 duplicate holes. After 20 and 44 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved, and the OD value was measured by a microplate reader. Statistical methods, using one-way analysis of variance.
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.05)
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.01).
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.001)
  • Triflurane inhibits proliferation of colon cancer cells ( ⁇ -29)
  • the cells were cultured in a DMEM medium containing 10% calf serum using a thiazole blue ( ⁇ ) method, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the medium containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was changed. 5 duplicate holes. After 24, 48, and 72 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved, and the OD value was measured by a microplate reader. Statistical methods, using one-way analysis of variance. Third, the experimental results: MTT results of flufenidone inhibiting proliferation of colon cancer cells
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.05)
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.01).
  • ⁇ ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.001)
  • Flufenidone 100ug/ml inhibited the proliferation of human colon cancer cells at 72 hours (p ⁇ 0.05 compared with the control group); pirfenidone lOOug/ml did not inhibit the proliferation of human colon cancer cells at 72 hours.
  • Flufenidone 200ug/ml inhibited the proliferation of human colon cancer cells at 48 and 72 hours (p ⁇ 0.01 compared with the control group; p ⁇ 0.001 at 72 hours); pirfenidone 200ug/ml dose at 48 The effect of inhibiting the proliferation of human colon cancer cells was inhibited by the hour, and the proliferation of human colon cancer cells was inhibited at 72 hours (p ⁇ 0.01 compared with the control group). 3.
  • Flufenidone 400ug/ml inhibited the proliferation of human colon cancer cells at 24, 48, 72 hours (p ⁇ 0.05 compared with the control group at 24 hours; p ⁇ 0.001 at 48 and 72 hours); pirfenidone 400ug/ Ml did not inhibit the proliferation of human colon cancer cells at 24 hours, inhibited the proliferation of human colon cancer cells at 48 and 72 hours (p ⁇ 0.001 compared with the control group); flufenidone 400 ug/ml dose group at 72 hours The inhibition of human colon cancer cells is greater than the equivalent dose of pirfenidone
  • Flufenidone 800ug/ml, 1600ug/ml and pirfenidone 800ug/ml, 1600ug/ml can inhibit the proliferation of human colon cancer cells at 24, 48, 72 hours (p ⁇ 0.001 compared with the control group) And with the increase of time, the inhibition rate increased; fenfluramine 800ug/ml, 1600ug/ml inhibited colon cancer cells at 24, 48, 72 hours than the same dose of pirfenidone (with the same dose) Pirfenidone was compared at 24 hours p ⁇ 0.05; 48, 72 hours p ⁇ 0.001). Fourth, the conclusion:
  • Triflurane inhibits proliferation of gastric cancer cells (BGC-803)
  • MTT kit is American R&D Company
  • a thiazole blue (MTT) method cells were cultured in DMEM medium containing 10% calf serum, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the medium containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was changed. 5 duplicate holes. After 24, 48, and 72 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved, and the OD value was measured by a microplate reader. Statistical methods, using one-way analysis of variance.
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.05)
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.001)
  • 1, flufenidone and pirfenidone 1600ug / ml dose group can inhibit the proliferation of human gastric cancer cells (BGC-803) at 24, 48, 72 hours (compared with the control group ⁇ 0.001), and over time Prolonged, increased inhibition rate;
  • flufenidone and pirfenidone 800ug / ml dose group can inhibit the proliferation of human gastric cancer cells (BGC-803) at 72 hours (compared with the control group, flufenidone ⁇ 0.01, pirfenidone? ⁇ 0.001).
  • flufenidone and pirfenidone 400ug / ml dose group can inhibit the proliferation of human gastric cancer cells (BGC-803) at 72 hours (p ⁇ 0.05 compared with the control group). 4.
  • the flufenidone 1600ug/ml dose group inhibited colon cancer cells (BGC-803) at 72 hours more than the same dose of pirfenidone (p ⁇ 0.001).
  • Triflurane inhibits proliferation of gastric cancer cells (MGC-803)
  • MTT kit is American R&D Company
  • a thiazole blue (MTT) method cells were cultured in DMEM medium containing 10% calf serum, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the medium containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was changed. 5 duplicate holes. After 24, 48, and 72 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved, and the OD value was measured by a microplate reader. Statistical methods, using one-way analysis of variance.
  • flufenidone and pirfenidone 400ug / ml dose group can inhibit the proliferation of human gastric cancer cells (MGC-803) at 72 hours (compared with the control group flufenidone p ⁇ 0.001, pirfenidone 2 ⁇ 0.05).
  • the flufenidone 800ug/ml dose group inhibited gastric cancer cells (MGC-803) at 72 hours more than the equivalent dose of pirfenidone (p ⁇ 0.05).
  • Triflurane inhibits proliferation of hepatoma cells (Bel-7402)
  • Cell Human liver cancer cell (Bel-7402)
  • MTT kit is American R&D Company
  • a thiazole blue (MTT) method cells were cultured in DMEM medium containing 10% calf serum, and the cells were made into a lx10 5 /ml cell suspension, and 100 ⁇ L per well was seeded in a 96-well plate. After the cells were attached to the wall, the serum-free DMEM medium was changed. After 24 hours, the serum-free medium was discarded, and the culture containing 10% calf serum containing different concentrations of flufenidone and pirfenidone was performed. Base, 5 replicate holes per concentration. After 24 and 48 hours after dosing, MTTlOul was added to each well. After 4 hours, MTT was aspirated. MTT solution was added to each well for 100 ul. After 15 min, MTT was completely dissolved, and the OD value was measured by a microplate reader. Statistical methods, using one-way analysis of variance.
  • ⁇ is statistically significant compared with the same dose group of pirfenidone ( ⁇ 0.05)
  • the flufenidone and pirfenidone 400ug/ml dose groups inhibited the proliferation of human hepatoma cells (Bel-7402) at 48 and 72 hours.
  • flufenidone and pirfenidone 800ug / ml, 1600ug / ml dose group can suppress people at 24, 48, 72 hours Proliferation of liver cancer cells (Bel-7402).
  • flufenidone 1600ug / ml dose group inhibited human hepatoma cells (Bel-7402) at 72 hours greater than the same dose of pirfenidone (p ⁇ 0.05).

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur l'utilisation de la 1-(3-fluorophényl)-5-méthyl-2(1H)-pyridone dans la fabrication d'un médicament antitumoral, la tumeur étant un cancer des poumons, un cancer du sein, un cancer du côlon, un cancer de l'estomac, un cancer du foie et un cancer de la prostate. Selon la présente invention, l'effet dudit composé est meilleur que celui de la pirfénidone dans les états antérieurs de la technique.
PCT/CN2008/072406 2007-09-19 2008-09-18 Nouvelle utilisation thérapeutique d'une aryl-2(1h)-pyridone substituée en position 1 Ceased WO2009039773A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008800110076A CN101652138B (zh) 2007-09-19 2008-09-18 1-取代芳基-2（1h）-吡啶酮化合物的新医药用途

Applications Claiming Priority (2)

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CN200710035774 2007-09-19
CN200710035774.8 2007-09-19

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WO2009039773A1 true WO2009039773A1 (fr) 2009-04-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102241625A (zh) * 2010-05-13 2011-11-16 中南大学 1-(取代芳基)-5-((取代芳胺基)甲基)吡啶-2(1h)酮化合物、制备方法及其用途
US8304413B2 (en) 2008-06-03 2012-11-06 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198698A2 (fr) * 2015-06-12 2016-12-15 Cnic Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii Inhibiteurs de p38 pour le traitement et la prophylaxie du cancer du foie
CN113274389B (zh) * 2021-07-09 2022-11-08 中南大学 氟非尼酮在制备治疗急性肺损伤药物中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114353A (en) * 1995-03-03 2000-09-05 Margolin; Solomon B. Compositions and method for treatment of lymphomas, leukemias, and leiomyomas
CN1846699A (zh) * 2005-04-13 2006-10-18 中南大学湘雅医院 1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6114353A (en) * 1995-03-03 2000-09-05 Margolin; Solomon B. Compositions and method for treatment of lymphomas, leukemias, and leiomyomas
CN1846699A (zh) * 2005-04-13 2006-10-18 中南大学湘雅医院 1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAO, L. ET AL.: "Effects of 1-(3-fluorophenyl)-5-methyl-2(lH)-pyridone on renal fibroblast in rats", J CENT SOUTH UNIV(MED SCI), vol. 29, no. 2, 2004, pages 139 - 141 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8304413B2 (en) 2008-06-03 2012-11-06 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
CN102241625A (zh) * 2010-05-13 2011-11-16 中南大学 1-(取代芳基)-5-((取代芳胺基)甲基)吡啶-2(1h)酮化合物、制备方法及其用途
CN102241625B (zh) * 2010-05-13 2014-10-29 中南大学 1-(取代芳基)-5-((取代芳胺基)甲基)吡啶-2(1h)酮化合物、制备方法及其用途
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones

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CN101652138B (zh) 2011-07-06
CN101652138A (zh) 2010-02-17

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