JP5656634B2 - タンパク質チロシンキナーゼ活性の阻害剤 - Google Patents

タンパク質チロシンキナーゼ活性の阻害剤 Download PDF

Info

Publication number
JP5656634B2
JP5656634B2 JP2010522149A JP2010522149A JP5656634B2 JP 5656634 B2 JP5656634 B2 JP 5656634B2 JP 2010522149 A JP2010522149 A JP 2010522149A JP 2010522149 A JP2010522149 A JP 2010522149A JP 5656634 B2 JP5656634 B2 JP 5656634B2
Authority
JP
Japan
Prior art keywords
alkyl
group
optionally substituted
compound
groups
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.)
Active
Application number
JP2010522149A
Other languages
English (en)
Japanese (ja)
Other versions
JP2010536887A5 (enExample
JP2010536887A (ja
Inventor
ウィリアム クラリッジ,ステファン
ウィリアム クラリッジ,ステファン
イサコヴィック,リュボミール
マニオン,マイケル
ラエペル,ステファン
マリオ サーヴェドラ,オスカー
マリオ サーヴェドラ,オスカー
ゴーデット,フレデリック
ジャン,リジエ
ゼット. ジョウ,ナンシー
ゼット. ジョウ,ナンシー
ラエペル,フランク
デジール,ロベール
ヴァイスバーグ,アルカディー
哲之 宇野
哲之 宇野
Original Assignee
メチルジーン インコーポレイテッド
メチルジーン インコーポレイテッド
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 メチルジーン インコーポレイテッド, メチルジーン インコーポレイテッド filed Critical メチルジーン インコーポレイテッド
Publication of JP2010536887A publication Critical patent/JP2010536887A/ja
Publication of JP2010536887A5 publication Critical patent/JP2010536887A5/ja
Application granted granted Critical
Publication of JP5656634B2 publication Critical patent/JP5656634B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
JP2010522149A 2007-08-29 2008-08-28 タンパク質チロシンキナーゼ活性の阻害剤 Active JP5656634B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US96867307P 2007-08-29 2007-08-29
US60/968,673 2007-08-29
PCT/CA2008/001538 WO2009026717A1 (en) 2007-08-29 2008-08-28 Inhibitors of protein tyrosine kinase activity

Publications (3)

Publication Number Publication Date
JP2010536887A JP2010536887A (ja) 2010-12-02
JP2010536887A5 JP2010536887A5 (enExample) 2011-10-13
JP5656634B2 true JP5656634B2 (ja) 2015-01-21

Family

ID=40386626

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2010522149A Active JP5656634B2 (ja) 2007-08-29 2008-08-28 タンパク質チロシンキナーゼ活性の阻害剤

Country Status (19)

Country Link
US (3) US8404846B2 (enExample)
EP (1) EP2183254B1 (enExample)
JP (1) JP5656634B2 (enExample)
KR (1) KR101556269B1 (enExample)
CN (3) CN109970759A (enExample)
AR (1) AR068066A1 (enExample)
AU (1) AU2008293038B2 (enExample)
BR (1) BRPI0816064B8 (enExample)
CA (1) CA2697795C (enExample)
DK (1) DK2183254T3 (enExample)
ES (1) ES2635131T3 (enExample)
IL (1) IL204192A (enExample)
MX (1) MX2010002427A (enExample)
MY (1) MY156536A (enExample)
PL (1) PL2183254T3 (enExample)
RU (1) RU2495044C2 (enExample)
TW (1) TWI571468B (enExample)
WO (1) WO2009026717A1 (enExample)
ZA (1) ZA201001512B (enExample)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ588355A (en) * 2008-03-05 2012-03-30 Methylgene Inc Inhibitors of protein tyrosine kinase activity
AU2009303602B2 (en) 2008-10-14 2012-06-14 Sunshine Lake Pharma Co., Ltd. Compounds and methods of use
KR20110133048A (ko) * 2009-03-21 2011-12-09 닝 시 아미노 에스테르 유도체, 그의 염 및 이용 방법
US9340555B2 (en) 2009-09-03 2016-05-17 Allergan, Inc. Compounds as tyrosine kinase modulators
MX2012002591A (es) * 2009-09-03 2012-04-02 Allergan Inc Compuestos como moduladores de tirosina cinasas.
CN103025740B (zh) * 2010-04-16 2015-07-01 梅特希尔基因公司 蛋白酪氨酸激酶活性的抑制剂及其治疗眼科疾病的用途
GB201007203D0 (en) 2010-04-29 2010-06-16 Glaxo Group Ltd Novel compounds
EP2588107A1 (en) 2010-07-01 2013-05-08 Takeda Pharmaceutical Company Limited COMBINATION OF A cMET INHIBITOR AND AN ANTIBODY TO HGF AND/OR cMET
JP2013537918A (ja) * 2010-09-27 2013-10-07 エクセリクシス, インク. 去勢抵抗性前立腺癌および骨芽細胞骨転移の治療のためのmetおよびvegfの二元阻害薬
WO2012044574A1 (en) * 2010-09-27 2012-04-05 Exelixis, Inc. Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
PL2621481T5 (pl) * 2010-09-27 2023-03-13 Exelixis, Inc. Podwójne inhibitory MET i VEGF do leczenia opornego na kastrację raka prostaty i osteoblastycznych przerzutów do kości
GB201104267D0 (en) 2011-03-14 2011-04-27 Cancer Rec Tech Ltd Pyrrolopyridineamino derivatives
CN102827186A (zh) * 2011-06-16 2012-12-19 中国科学院上海药物研究所 一类吡啶并五元杂环衍生物及其制备方法和用途
AU2012310168B2 (en) 2011-09-15 2015-07-16 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
HK1207587A1 (en) 2012-05-02 2016-02-05 Exelixis, Inc. A dual met - vegf modulator for treating osteolytic bone metastases
CN103626761B (zh) * 2012-08-24 2015-07-29 上海医药工业研究院 苯并吡啶氮杂卓类化合物及其作为抗肿瘤药物的应用
GB201216018D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Pharmacologically active compounds
GB201314452D0 (en) 2013-08-13 2013-09-25 Ostara Biomedical Ltd Embryo implantation
TWI672141B (zh) 2014-02-20 2019-09-21 美商醫科泰生技 投予ros1突變癌細胞之分子
CN107207471B (zh) 2014-12-02 2020-06-26 伊尼塔公司 用于治疗神经母细胞瘤的组合
ES2764299T3 (es) 2014-12-09 2020-06-02 Inst Nat Sante Rech Med Anticuerpos monoclonales humanos contra AXL
GB201501302D0 (en) 2015-01-27 2015-03-11 Ostara Biomedical Ltd Embryo implantation
WO2016135041A1 (en) 2015-02-26 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Fusion proteins and antibodies comprising thereof for promoting apoptosis
GB201517523D0 (en) 2015-10-05 2015-11-18 Ostara Biomedical Ltd Methods and compositions for managing reproduction
JP7061068B2 (ja) 2015-12-18 2022-04-27 イグナイタ インコーポレイテッド 癌治療のための併用薬
CN108530464B (zh) * 2017-03-02 2020-10-27 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂
CN121401264A (zh) 2017-07-19 2026-01-27 伊尼塔公司 包括恩曲替尼的药物组合物
US10180422B1 (en) 2017-08-22 2019-01-15 Scripps Health Methods of treating a neuroendocrine tumor
WO2019077506A1 (en) 2017-10-17 2019-04-25 Ignyta, Inc. PHARMACEUTICAL COMPOSITIONS AND SOLID GALENIC FORMS
AU2019237715B2 (en) * 2018-03-08 2021-01-28 Wellmarker Bio Co., Ltd. Thienopyridine derivatives and pharmaceutical composition comprising same
BR112020023746A2 (pt) 2018-05-23 2021-02-17 Beigene, Ltd. anticorpo, composição farmacêutica, método para tratar câncer, ácido nucleico isolado, vetor, célula hospedeira, processo para a produção de um anticorpo e reagente de diagnóstico
CN109384799B (zh) * 2018-11-12 2020-07-14 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
JP2022554042A (ja) 2019-09-06 2022-12-28 ウェルマーカー・バイオ・カンパニー・リミテッド バイオマーカー型治療用組成物
WO2021050580A1 (en) * 2019-09-10 2021-03-18 Mirati Therapeutics, Inc. Crystalline form of a multi-tyrosine kinase inhibitor, method of preparation, and use thereof
EP4061421A4 (en) * 2019-11-21 2024-05-15 BeiGene, Ltd. Treatment of cancer with anti-ox40 antibodies and multi-kinase inhibitors
CN114945576B (zh) * 2020-01-07 2023-10-13 南京明德新药研发有限公司 氘代噻吩并吡啶类化合物
WO2022060831A1 (en) 2020-09-17 2022-03-24 Mirati Therapeutics, Inc. Combination therapies
TW202302597A (zh) * 2021-03-10 2023-01-16 美商米拉蒂醫療公司 多重酪胺酸激酶抑制劑之結晶鹽、其製備方法及用途
WO2022240802A1 (en) 2021-05-10 2022-11-17 Teva Pharmaceuticals International Gmbh Solid state forms of sitravatinib salts and processes for preparation thereof
TW202342426A (zh) * 2022-02-15 2023-11-01 大陸商百濟神州(蘇州)生物科技有限公司 N-[(6-溴吡啶-3-基)甲基]-2-甲氧基乙烷-1-胺鹽及其製備方法

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7019A (en) * 1850-01-15 Improvement in obstetrical supporters
US7000A (en) * 1850-01-08 Smut-machine
WO1997017329A1 (en) 1995-11-07 1997-05-15 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of growth factor receptor originating in platelet and pharmaceutical compositions containing the same
ATE419239T1 (de) 2000-10-20 2009-01-15 Eisai R&D Man Co Ltd Verfahren zur herstellung von 4-phenoxy chinolin derivaten
AU2002255284B2 (en) 2001-04-27 2007-10-04 Kyowa Kirin Co., Ltd. Quinoline derivative having azolyl group and quinazoline derivative
EP2088141A3 (en) 2001-06-22 2009-11-18 Kirin Pharma Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives capable of inhibiting autophosphorylation of hepatocyte growth factor receptors, and pharmaceutical composition comprising the same
AU2002360489A1 (en) * 2001-12-07 2003-06-23 The Regents Of The University Of California Treatment for age-related macular degeneration
UA77303C2 (en) * 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
CL2003002287A1 (es) * 2002-11-25 2005-01-14 Wyeth Corp COMPUESTOS DERIVADOS DE TIENO[3,2-b]-PIRIDINA-6-CARBONITRILOS Y TIENEO[2,3-b]-PIRIDINA-5-CARBONITRILOS, COMPOSICION FARMACEUTICA, PROCEDIMIENTO DE PREPARACION Y COMPUESTOS INTERMEDIARIOS, Y SU USO EN EL TRATAMIENTO DEL CANCER, APOPLEJIA, OSTEOPOROSIS
EP2392565B1 (en) 2003-09-26 2014-03-19 Exelixis, Inc. c-Met modulators and methods of use
AU2005217325B2 (en) 2004-02-27 2007-11-29 Eisai R & D Management Co., Ltd. Novel pyridine derivative and pyrimidine derivative (1)
US7767689B2 (en) * 2004-03-15 2010-08-03 Ptc Therapeutics, Inc. Carboline derivatives useful in the treatment of cancer
EP1732543B1 (en) * 2004-03-15 2017-05-10 PTC Therapeutics, Inc. Tetracyclic carboline deratives for inhibiting angiogenesis
US7173031B2 (en) 2004-06-28 2007-02-06 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
ES2438017T3 (es) * 2004-07-30 2014-01-15 Methylgene Inc. Inhibidores de la señalización del receptor del VEGF y del receptor del HGF
AU2006229343A1 (en) * 2005-03-28 2006-10-05 Kirin Pharma Kabushiki Kaisha Thienopyridine derivative, or quinoline derivative, or quinazoline derivative, having c-Met autophosphorylation inhibiting potency
JO2787B1 (en) * 2005-04-27 2014-03-15 امجين إنك, Alternative amide derivatives and methods of use
DK1904504T3 (da) 2005-05-20 2014-06-23 Methylgene Inc Inhibitorer af vegf-receptor- og hgf-receptorsignalering
NZ564283A (en) * 2005-05-20 2011-07-29 Methylgene Inc Inhibitors of VEGF receptor and HGF receptor signaling
TW200740820A (en) * 2005-07-05 2007-11-01 Takeda Pharmaceuticals Co Fused heterocyclic derivatives and use thereof
TWI377198B (en) 2005-08-24 2012-11-21 Eisai R&D Man Co Ltd Novel pyridine derivatives and pyrimidine derivatives (3)
EP1989211A2 (en) 2006-01-30 2008-11-12 Array Biopharma, Inc. Heterobicyclic thiophene compounds for the treatment of cancer
CA2645137A1 (en) 2006-03-07 2007-09-13 James F. Blake Heterobicyclic pyrazole compounds and methods of use
WO2007107005A1 (en) * 2006-03-22 2007-09-27 Methylgene, Inc. Inhibitors of protein tyrosine kinase activity
CA2655128A1 (en) 2006-06-08 2007-12-21 Array Biopharma Inc. Quinoline compounds and methods of use
WO2008049855A2 (en) 2006-10-27 2008-05-02 Glaxo Group Limited 7-azaindole derivatives as c-met kinase inhibitors
CN103025740B (zh) * 2010-04-16 2015-07-01 梅特希尔基因公司 蛋白酪氨酸激酶活性的抑制剂及其治疗眼科疾病的用途

Also Published As

Publication number Publication date
WO2009026717A1 (en) 2009-03-05
AU2008293038B2 (en) 2013-08-29
IL204192A (en) 2016-08-31
DK2183254T3 (en) 2017-09-11
KR101556269B1 (ko) 2015-09-30
RU2010111729A (ru) 2011-10-10
CA2697795C (en) 2016-08-16
US20120108628A1 (en) 2012-05-03
CN101932586A (zh) 2010-12-29
CN109970759A (zh) 2019-07-05
MY156536A (en) 2016-02-26
US20090264440A1 (en) 2009-10-22
EP2183254A4 (en) 2011-09-28
EP2183254A1 (en) 2010-05-12
CN105777776B (zh) 2021-06-08
BRPI0816064A2 (pt) 2015-03-31
AR068066A1 (es) 2009-11-04
BRPI0816064B8 (pt) 2021-05-25
JP2010536887A (ja) 2010-12-02
MX2010002427A (es) 2010-03-30
ZA201001512B (en) 2010-11-24
EP2183254B1 (en) 2017-06-21
TWI571468B (zh) 2017-02-21
CA2697795A1 (en) 2009-03-05
TW200914458A (en) 2009-04-01
US8846927B2 (en) 2014-09-30
KR20100075873A (ko) 2010-07-05
CN105777776A (zh) 2016-07-20
AU2008293038A1 (en) 2009-03-05
RU2495044C2 (ru) 2013-10-10
ES2635131T3 (es) 2017-10-02
US8404846B2 (en) 2013-03-26
BRPI0816064B1 (pt) 2020-01-28
US8389541B2 (en) 2013-03-05
PL2183254T3 (pl) 2017-10-31
US20130165477A1 (en) 2013-06-27

Similar Documents

Publication Publication Date Title
JP5656634B2 (ja) タンパク質チロシンキナーゼ活性の阻害剤
JP5661485B2 (ja) タンパク質チロシンキナーゼ活性の阻害剤
TW201329085A (zh) 蛋白酪氨酸激酶活性抑制劑
TW201329086A (zh) 蛋白酪氨酸激酶活性抑制劑
HK1139407B (en) Inhibitors of protein tyrosine kinase activity
HK1139407A (en) Inhibitors of protein tyrosine kinase activity
HK1155977A (en) Inhibitors of protein tyrosine kinase activity

Legal Events

Date Code Title Description
A711 Notification of change in applicant

Free format text: JAPANESE INTERMEDIATE CODE: A711

Effective date: 20101222

RD02 Notification of acceptance of power of attorney

Free format text: JAPANESE INTERMEDIATE CODE: A7422

Effective date: 20110217

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20110222

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20110826

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20110826

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20130711

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20130716

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20131016

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20131106

A602 Written permission of extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A602

Effective date: 20131023

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20131118

A602 Written permission of extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A602

Effective date: 20131125

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20131216

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20140121

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20140421

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20140729

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20141003

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20141104

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20141125

R150 Certificate of patent or registration of utility model

Ref document number: 5656634

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

S111 Request for change of ownership or part of ownership

Free format text: JAPANESE INTERMEDIATE CODE: R313113

S531 Written request for registration of change of domicile

Free format text: JAPANESE INTERMEDIATE CODE: R313531

S533 Written request for registration of change of name

Free format text: JAPANESE INTERMEDIATE CODE: R313533

R350 Written notification of registration of transfer

Free format text: JAPANESE INTERMEDIATE CODE: R350

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250