JP6517693B2 - マイタンシノールをアシル化する改善された方法 - Google Patents

マイタンシノールをアシル化する改善された方法 Download PDF

Info

Publication number
JP6517693B2
JP6517693B2 JP2015534641A JP2015534641A JP6517693B2 JP 6517693 B2 JP6517693 B2 JP 6517693B2 JP 2015534641 A JP2015534641 A JP 2015534641A JP 2015534641 A JP2015534641 A JP 2015534641A JP 6517693 B2 JP6517693 B2 JP 6517693B2
Authority
JP
Japan
Prior art keywords
formula
reaction mixture
alkyl
group
desiccant
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
JP2015534641A
Other languages
English (en)
Japanese (ja)
Other versions
JP2016500657A (ja
JP2016500657A5 (enExample
Inventor
ウィディソン，ウェイン・シー．
ザオ，ロバート・ヤンシン
Original Assignee
イミュノジェン・インコーポレーテッド
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 イミュノジェン・インコーポレーテッド filed Critical イミュノジェン・インコーポレーテッド
Publication of JP2016500657A publication Critical patent/JP2016500657A/ja
Publication of JP2016500657A5 publication Critical patent/JP2016500657A5/ja
Application granted granted Critical
Publication of JP6517693B2 publication Critical patent/JP6517693B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01R—ELECTRICALLY-CONDUCTIVE CONNECTIONS; STRUCTURAL ASSOCIATIONS OF A PLURALITY OF MUTUALLY-INSULATED ELECTRICAL CONNECTING ELEMENTS; COUPLING DEVICES; CURRENT COLLECTORS
    • H01R12/00—Structural associations of a plurality of mutually-insulated electrical connecting elements, specially adapted for printed circuits, e.g. printed circuit boards [PCB], flat or ribbon cables, or like generally planar structures, e.g. terminal strips, terminal blocks; Coupling devices specially adapted for printed circuits, flat or ribbon cables, or like generally planar structures; Terminals specially adapted for contact with, or insertion into, printed circuits, flat or ribbon cables, or like generally planar structures
    • H01R12/50—Fixed connections
    • H01R12/51—Fixed connections for rigid printed circuits or like structures
    • H01R12/55—Fixed connections for rigid printed circuits or like structures characterised by the terminals
    • H01R12/58—Fixed connections for rigid printed circuits or like structures characterised by the terminals terminals for insertion into holes
    • H01R12/585—Terminals having a press fit or a compliant portion and a shank passing through a hole in the printed circuit board
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
    • H05K1/00—Printed circuits
    • H05K1/02—Details
    • H05K1/0201—Thermal arrangements, e.g. for cooling, heating or preventing overheating
    • H05K1/0203—Cooling of mounted components
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
    • H05K1/00—Printed circuits
    • H05K1/02—Details
    • H05K1/11—Printed elements for providing electric connections to or between printed circuits
    • H05K1/115—Via connections; Lands around holes or via connections
    • H05K1/116—Lands, clearance holes or other lay-out details concerning the surrounding of a via
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05K—PRINTED CIRCUITS; CASINGS OR CONSTRUCTIONAL DETAILS OF ELECTRIC APPARATUS; MANUFACTURE OF ASSEMBLAGES OF ELECTRICAL COMPONENTS
    • H05K1/00—Printed circuits
    • H05K1/18—Printed circuits structurally associated with non-printed electric components
    • H05K1/181—Printed circuits structurally associated with non-printed electric components associated with surface mounted components

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Microelectronics & Electronic Packaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polyamides (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
JP2015534641A 2012-09-26 2013-09-26 マイタンシノールをアシル化する改善された方法 Active JP6517693B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261705731P 2012-09-26 2012-09-26
US61/705,731 2012-09-26
PCT/US2013/061839 WO2014052537A1 (en) 2012-09-26 2013-09-26 Improved methods for the acylation of maytansinol

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP2018032684A Division JP2018109044A (ja) 2012-09-26 2018-02-27 マイタンシノールをアシル化する改善された方法

Publications (3)

Publication Number Publication Date
JP2016500657A JP2016500657A (ja) 2016-01-14
JP2016500657A5 JP2016500657A5 (enExample) 2018-04-12
JP6517693B2 true JP6517693B2 (ja) 2019-05-22

Family

ID=49328648

Family Applications (7)

Application Number Title Priority Date Filing Date
JP2015534641A Active JP6517693B2 (ja) 2012-09-26 2013-09-26 マイタンシノールをアシル化する改善された方法
JP2018032684A Ceased JP2018109044A (ja) 2012-09-26 2018-02-27 マイタンシノールをアシル化する改善された方法
JP2020068137A Active JP6735000B1 (ja) 2012-09-26 2020-04-06 マイタンシノールをアシル化する改善された方法
JP2020118929A Pending JP2020180150A (ja) 2012-09-26 2020-07-10 マイタンシノールをアシル化する改善された方法
JP2022029253A Pending JP2022068367A (ja) 2012-09-26 2022-02-28 マイタンシノールをアシル化する改善された方法
JP2023181529A Pending JP2024010055A (ja) 2012-09-26 2023-10-23 マイタンシノールをアシル化する改善された方法
JP2025058629A Pending JP2025098242A (ja) 2012-09-26 2025-03-31 マイタンシノールをアシル化する改善された方法

Family Applications After (6)

Application Number Title Priority Date Filing Date
JP2018032684A Ceased JP2018109044A (ja) 2012-09-26 2018-02-27 マイタンシノールをアシル化する改善された方法
JP2020068137A Active JP6735000B1 (ja) 2012-09-26 2020-04-06 マイタンシノールをアシル化する改善された方法
JP2020118929A Pending JP2020180150A (ja) 2012-09-26 2020-07-10 マイタンシノールをアシル化する改善された方法
JP2022029253A Pending JP2022068367A (ja) 2012-09-26 2022-02-28 マイタンシノールをアシル化する改善された方法
JP2023181529A Pending JP2024010055A (ja) 2012-09-26 2023-10-23 マイタンシノールをアシル化する改善された方法
JP2025058629A Pending JP2025098242A (ja) 2012-09-26 2025-03-31 マイタンシノールをアシル化する改善された方法

Country Status (27)

Country Link
US (9) US9012629B2 (enExample)
EP (3) EP3904358A1 (enExample)
JP (7) JP6517693B2 (enExample)
CN (2) CN104768955B (enExample)
AU (4) AU2013323572B2 (enExample)
BR (2) BR112015006505B1 (enExample)
CA (2) CA2884873C (enExample)
CY (2) CY1121415T1 (enExample)
DK (2) DK3486248T3 (enExample)
ES (2) ES2880754T3 (enExample)
HR (2) HRP20190473T1 (enExample)
HU (2) HUE055443T2 (enExample)
IL (2) IL237899A (enExample)
LT (2) LT3486248T (enExample)
MX (2) MX390615B (enExample)
MY (1) MY169250A (enExample)
NZ (2) NZ739573A (enExample)
PL (2) PL2900676T3 (enExample)
PT (2) PT3486248T (enExample)
RS (2) RS62075B1 (enExample)
RU (2) RU2648992C2 (enExample)
SG (1) SG11201501918UA (enExample)
SI (2) SI3486248T1 (enExample)
SM (2) SMT201900170T1 (enExample)
TR (1) TR201903625T4 (enExample)
WO (1) WO2014052537A1 (enExample)
ZA (1) ZA201501898B (enExample)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020117527A (ja) * 2012-09-26 2020-08-06 イミュノジェン・インコーポレーテッド マイタンシノールをアシル化する改善された方法

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105585579A (zh) * 2014-10-24 2016-05-18 南京联宁生物制药有限公司 一种化合物及其制备方法以及美登素dm1的制备方法
WO2016149464A1 (en) * 2015-03-17 2016-09-22 Regeneron Pharmaceuticals, Inc. Amino acid acylation reagents and methods of using the same
EP3554544A4 (en) 2016-12-16 2020-07-29 Bluefin Biomedicine, Inc. ANTI-PROTEIN 1 ANTIBODY CONTAINING AN ANTI-CUB DOMAIN (CDCP1), ANTIBODY-DRUG CONJUGATES AND THEIR METHODS OF USE
EP3956332B1 (en) 2019-04-18 2023-02-22 Indena S.p.A. Diasteroselective process for the preparation of thiol- or disulfide-containing maytansinoid esters and intermediates thereof
US12473579B2 (en) 2019-11-29 2025-11-18 Microbiopharm Japan Co., Ltd. Method for enzymatically producing maytansinol
EP4685150A1 (en) 2023-04-28 2026-01-28 Chugai Seiyaku Kabushiki Kaisha Method for producing amide group-containing compound using n-carboxyamino acid anhydride

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4151042A (en) 1977-03-31 1979-04-24 Takeda Chemical Industries, Ltd. Method for producing maytansinol and its derivatives
JPS6034556B2 (ja) * 1977-03-31 1985-08-09 武田薬品工業株式会社 抗生物質ｃ−１５００３
US4137230A (en) 1977-11-14 1979-01-30 Takeda Chemical Industries, Ltd. Method for the production of maytansinoids
US4265814A (en) 1978-03-24 1981-05-05 Takeda Chemical Industries Matansinol 3-n-hexadecanoate
JPS5562090A (en) 1978-10-27 1980-05-10 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS5566585A (en) 1978-11-14 1980-05-20 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS55164687A (en) 1979-06-11 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS55162791A (en) 1979-06-05 1980-12-18 Takeda Chem Ind Ltd Antibiotic c-15003pnd and its preparation
JPS55164685A (en) 1979-06-08 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS55164686A (en) 1979-06-11 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
US4309428A (en) 1979-07-30 1982-01-05 Takeda Chemical Industries, Ltd. Maytansinoids
JPS5622790A (en) * 1979-07-31 1981-03-03 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS5645483A (en) 1979-09-19 1981-04-25 Takeda Chem Ind Ltd C-15003phm and its preparation
JP3054741B2 (ja) * 1989-09-29 2000-06-19 武田薬品工業株式会社 Ｔａｎ―１３１３およびそのアシル誘導体
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
JP4776843B2 (ja) * 1999-10-01 2011-09-21 イムノゲン インコーポレーティッド 免疫複合体及び化学療法剤を用いる癌治療用組成物及び方法
US6441163B1 (en) 2001-05-31 2002-08-27 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
TWI298067B (en) * 2002-01-31 2008-06-21 Daiso Co Ltd New optically active compound, method for kinetic resolution of carbonic acid derivatives and catalyst thereof
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
EP1651162B1 (en) * 2003-05-20 2015-10-21 ImmunoGen, Inc. Improved cytotoxic agents comprising new maytansinoids
MXPA06002088A (es) * 2003-08-22 2006-08-11 Activbiotics Inc Analogos de rifamicina y usos de los mismos.
TR201808537T4 (tr) 2004-09-23 2018-07-23 Genentech Inc Sistein değiştirilmiş antikorlar ve konjugatlar.
KR101281501B1 (ko) 2004-12-09 2013-07-15 얀센 바이오테크 인코포레이티드 항인테그린 면역 컨쥬게이트, 방법 및 용도
US7301019B2 (en) * 2005-01-21 2007-11-27 Immunogen, Inc. Method for the preparation of maytansinoid esters
WO2007011721A1 (en) * 2005-07-15 2007-01-25 Kalypsys, Inc. Inhibitors of mitotic kinesin
ATE535529T1 (de) * 2005-08-09 2011-12-15 Millennium Pharm Inc Verfahren zur acylierung von maytansinol mit chiralen aminosäuren
CA2668134A1 (en) * 2006-11-06 2008-05-15 Teva Gyogyszergyar Zartkoerueen Muekoedoe Reszvenytarsasag Ascomycin and pimecrolimus having reduced levels of des-methylascomycin and 32-deoxy-32-epichloro-desmethylascomycin respectively, and methods for preparation thereof
JP2008288289A (ja) 2007-05-16 2008-11-27 Oki Electric Ind Co Ltd 電界効果トランジスタとその製造方法
JP5784592B2 (ja) 2009-06-03 2015-09-24 イミュノジェン・インコーポレーテッド 抱合方法
US8754207B2 (en) * 2009-09-25 2014-06-17 Cadila Healthcare Limited Process for the preparation of rapamycin derivatives
EP2640727B1 (en) * 2010-11-17 2015-05-13 Genentech, Inc. Alaninyl maytansinol antibody conjugates
SMT201900170T1 (it) 2012-09-26 2019-05-10 Immunogen Inc Metodo migliorato per l'acilazione di maytansinolo

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020117527A (ja) * 2012-09-26 2020-08-06 イミュノジェン・インコーポレーテッド マイタンシノールをアシル化する改善された方法
JP2025098242A (ja) * 2012-09-26 2025-07-01 イミュノジェン・インコーポレーテッド マイタンシノールをアシル化する改善された方法

Also Published As

Publication number Publication date
US9469655B2 (en) 2016-10-18
RS62075B1 (sr) 2021-07-30
DK3486248T3 (da) 2021-07-12
AU2020203823B2 (en) 2021-12-09
JP2022068367A (ja) 2022-05-09
RS58493B1 (sr) 2019-04-30
BR122021022582B1 (pt) 2023-01-10
US20170137440A1 (en) 2017-05-18
EP3904358A1 (en) 2021-11-03
US9796731B2 (en) 2017-10-24
MX366701B (es) 2019-07-22
IL253988A0 (en) 2017-10-31
PL3486248T3 (pl) 2021-10-25
HRP20211030T1 (hr) 2021-10-01
ES2716561T3 (es) 2019-06-13
MX2019008652A (es) 2019-09-13
US10944190B2 (en) 2021-03-09
AU2018201392A1 (en) 2018-03-15
CY1121415T1 (el) 2020-05-29
RU2018109295A3 (enExample) 2021-06-24
JP2020180150A (ja) 2020-11-05
TR201903625T4 (tr) 2019-04-22
EP3486248B1 (en) 2021-04-07
CN104768955B (zh) 2018-04-27
CN108586487A (zh) 2018-09-28
SI2900676T1 (sl) 2019-04-30
AU2013323572B2 (en) 2017-12-07
IL253988B (en) 2019-02-28
HUE055443T2 (hu) 2021-11-29
DK2900676T3 (en) 2019-04-08
ZA201501898B (en) 2019-06-26
JP2024010055A (ja) 2024-01-23
US10100062B2 (en) 2018-10-16
BR112015006505A2 (pt) 2017-07-04
HRP20190473T1 (hr) 2019-05-03
SI3486248T1 (sl) 2021-10-29
LT2900676T (lt) 2019-03-25
EP3486248A1 (en) 2019-05-22
AU2018201392B2 (en) 2020-03-12
AU2013323572A1 (en) 2015-04-02
CA2884873A1 (en) 2014-04-03
US20180099980A1 (en) 2018-04-12
US20250007192A1 (en) 2025-01-02
NZ706019A (en) 2018-03-23
MX2015003745A (es) 2015-06-24
BR112015006505B1 (pt) 2022-03-15
PT3486248T (pt) 2021-07-12
MY169250A (en) 2019-03-19
HUE043285T2 (hu) 2019-08-28
US20240313444A1 (en) 2024-09-19
US9012629B2 (en) 2015-04-21
RU2648992C2 (ru) 2018-03-29
WO2014052537A1 (en) 2014-04-03
HK1212341A1 (en) 2016-06-10
LT3486248T (lt) 2021-08-25
EP2900676A1 (en) 2015-08-05
PT2900676T (pt) 2019-03-29
CN108586487B (zh) 2021-11-05
US20150191488A1 (en) 2015-07-09
JP2018109044A (ja) 2018-07-12
RU2765072C2 (ru) 2022-01-25
CA3133906A1 (en) 2014-04-03
CY1124337T1 (el) 2022-07-22
AU2022201557A1 (en) 2022-03-31
CN104768955A (zh) 2015-07-08
US20140142297A1 (en) 2014-05-22
NZ739573A (en) 2019-11-29
US20190013604A1 (en) 2019-01-10
PL2900676T3 (pl) 2019-06-28
JP2016500657A (ja) 2016-01-14
RU2018109295A (ru) 2019-02-26
IL237899A (en) 2017-08-31
ES2880754T3 (es) 2021-11-25
JP2020117527A (ja) 2020-08-06
SMT202100390T1 (it) 2021-09-14
US10461449B2 (en) 2019-10-29
AU2020203823A1 (en) 2020-07-02
JP6735000B1 (ja) 2020-08-05
JP2025098242A (ja) 2025-07-01
CA2884873C (en) 2021-11-23
CA3133906C (en) 2023-05-02
US20240145953A1 (en) 2024-05-02
SG11201501918UA (en) 2015-05-28
US20200153130A1 (en) 2020-05-14
RU2015111635A (ru) 2016-11-20
MX390615B (es) 2025-03-20
EP2900676B1 (en) 2018-12-19
SMT201900170T1 (it) 2019-05-10

Similar Documents

Publication Publication Date Title
JP6735000B1 (ja) マイタンシノールをアシル化する改善された方法
HK40061916A (en) Improved methods for the acylation of maytansinol
HK40008930A (en) Improved methods for the acylation of maytansinol
HK40008930B (en) Improved methods for the acylation of maytansinol
HK1212341B (en) Improved method for the acylation of maytansinol

Legal Events

Date Code Title Description
A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20160923

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20170831

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20170908

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20171208

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20180208

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20180227

A524 Written submission of copy of amendment under article 19 pct

Free format text: JAPANESE INTERMEDIATE CODE: A524

Effective date: 20180227

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20180724

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20181015

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20190123

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: 20190320

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20190418

R150 Certificate of patent or registration of utility model

Ref document number: 6517693

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