JP6130491B2 - ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 - Google Patents
ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 Download PDFInfo
- Publication number
- JP6130491B2 JP6130491B2 JP2015505921A JP2015505921A JP6130491B2 JP 6130491 B2 JP6130491 B2 JP 6130491B2 JP 2015505921 A JP2015505921 A JP 2015505921A JP 2015505921 A JP2015505921 A JP 2015505921A JP 6130491 B2 JP6130491 B2 JP 6130491B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- ews
- fli1
- cancer
- compound according
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261623349P | 2012-04-12 | 2012-04-12 | |
| US61/623,349 | 2012-04-12 | ||
| PCT/US2013/036234 WO2013155341A1 (en) | 2012-04-12 | 2013-04-11 | Methods and compositions for treating ewings sarcoma family of tumors |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017080017A Division JP6345301B2 (ja) | 2012-04-12 | 2017-04-13 | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2015512943A JP2015512943A (ja) | 2015-04-30 |
| JP2015512943A5 JP2015512943A5 (2) | 2017-02-23 |
| JP6130491B2 true JP6130491B2 (ja) | 2017-05-17 |
Family
ID=49328171
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015505921A Active JP6130491B2 (ja) | 2012-04-12 | 2013-04-11 | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 |
| JP2017080017A Active JP6345301B2 (ja) | 2012-04-12 | 2017-04-13 | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017080017A Active JP6345301B2 (ja) | 2012-04-12 | 2017-04-13 | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US9290449B2 (2) |
| EP (1) | EP2836481B1 (2) |
| JP (2) | JP6130491B2 (2) |
| KR (1) | KR102145835B1 (2) |
| CN (2) | CN107011242B (2) |
| AU (2) | AU2013245812B2 (2) |
| CA (1) | CA2869513C (2) |
| IL (1) | IL234993B (2) |
| IN (1) | IN2014DN09228A (2) |
| MX (1) | MX377618B (2) |
| NZ (2) | NZ700612A (2) |
| WO (1) | WO2013155341A1 (2) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3443750B2 (ja) | 1994-06-24 | 2003-09-08 | キョーラク株式会社 | ダボ付きパネル |
| US8232310B2 (en) | 2006-12-29 | 2012-07-31 | Georgetown University | Targeting of EWS-FLI1 as anti-tumor therapy |
| CN107011242B (zh) * | 2012-04-12 | 2020-08-07 | 乔治城大学 | 用于治疗尤文肉瘤家族肿瘤的方法和组合物 |
| AU2014340398A1 (en) * | 2013-10-24 | 2016-06-09 | Georgetown University | Methods and compositions for treating cancer |
| CN107108580B (zh) * | 2014-10-09 | 2020-06-30 | 英克特诺治疗公司 | 吲哚酮化合物及其用途 |
| CN107530283A (zh) | 2015-03-03 | 2018-01-02 | 奎尔波特股份有限公司 | 组合脂质体药物制剂 |
| CA2977397A1 (en) | 2015-03-03 | 2016-09-09 | Cureport, Inc. | Dual loaded liposomal pharmaceutical formulations |
| EP3795563B1 (en) * | 2016-03-31 | 2024-07-17 | Oncternal Therapeutics, Inc. | Indoline analogs and uses thereof |
| CA3029851A1 (en) | 2016-07-29 | 2018-02-01 | Oncternal Therapeutics, Inc. | Uses of indoline compounds such as tk216 for the treatment of cancer |
| EP3558266B1 (en) * | 2016-12-21 | 2022-03-30 | The Board of Regents of The University of Texas System | Altertoxin ii as a selective inhibitor of ewing family of tumor cells |
| CN108186630B (zh) * | 2017-12-18 | 2020-07-31 | 温州医科大学 | 靛红类似物在制备抗肿瘤药物中的应用 |
| CN110870917B (zh) * | 2018-09-03 | 2022-03-15 | 上海市第一人民医院 | Ews或其上调剂在制备治疗糖尿病及防治糖尿病个体肿瘤发生的药物中的应用 |
| US12076310B2 (en) * | 2021-06-09 | 2024-09-03 | University Of Rochester | Compounds and methods for the treatment of acute myelogenous leukemia |
| CN114057626B (zh) * | 2021-12-07 | 2023-06-30 | 山东第一医科大学(山东省医学科学院) | 一种吲哚-2,3-二酮的衍生物和制备方法、抑制recql4特异性表达的抗肝癌药物 |
| US20250361227A1 (en) * | 2022-03-13 | 2025-11-27 | University Of Virginia Patent Foundation | Inhibitors of fli1 and erg |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU583793B2 (en) | 1983-07-22 | 1989-05-11 | Du Pont Pharmaceuticals Company | Phenylquinolinecarboxylic acids and derivatives as antitumor agents |
| EP1135123B1 (en) | 1998-12-04 | 2004-12-29 | Neurosearch A/S | Use of isatin derivatives as ion channel activating agents |
| CN1155572C (zh) | 2001-01-19 | 2004-06-30 | 中国人民解放军军事医学科学院毒物药物研究所 | 吲哚类衍生物及其抗肿瘤用途 |
| US20030157486A1 (en) | 2001-06-21 | 2003-08-21 | Graff Jonathan M. | Methods to identify signal sequences |
| US7674778B2 (en) | 2004-04-30 | 2010-03-09 | Alnylam Pharmaceuticals | Oligonucleotides comprising a conjugate group linked through a C5-modified pyrimidine |
| AR056317A1 (es) | 2005-04-20 | 2007-10-03 | Xenon Pharmaceuticals Inc | Compuestos de oxindol y composicion farmaceutica |
| US20090217390A1 (en) | 2005-04-29 | 2009-08-27 | Fernando Lecanda Cordero | Non-human animal sarcoma model |
| WO2008046083A2 (en) * | 2006-10-12 | 2008-04-17 | Xenon Pharmaceuticals Inc. | Use of oxindole compounds as therapeutic agents |
| CA2953987A1 (en) * | 2006-12-29 | 2008-07-10 | Georgetown University | Targeting of ews-fli1 as anti-tumor therapy |
| US8232310B2 (en) | 2006-12-29 | 2012-07-31 | Georgetown University | Targeting of EWS-FLI1 as anti-tumor therapy |
| MX2009011281A (es) * | 2007-04-20 | 2010-03-08 | Univ New York State Res Found | Benzimidazol y composiciones farmaceuticas del mismo. |
| US8377992B2 (en) * | 2007-10-22 | 2013-02-19 | The Wistar Institute | TRBD-binding effectors and methods for using the same to modulate telomerase activity |
| US8710068B2 (en) | 2009-01-19 | 2014-04-29 | The Trustees Of The University Of Pennsylvania | Method of treating cancer using a survivin inhibitor |
| WO2012078519A2 (en) | 2010-12-06 | 2012-06-14 | Numerate, Inc. | 3-acylidene-2-oxoindole derivatives for inhibition of transglutaminase 2 |
| CN107011242B (zh) * | 2012-04-12 | 2020-08-07 | 乔治城大学 | 用于治疗尤文肉瘤家族肿瘤的方法和组合物 |
| CN103435606A (zh) | 2013-08-22 | 2013-12-11 | 中国药科大学 | CDK2与GSK3β双重抑制剂及用途 |
| AU2014340398A1 (en) | 2013-10-24 | 2016-06-09 | Georgetown University | Methods and compositions for treating cancer |
| CN107108580B (zh) | 2014-10-09 | 2020-06-30 | 英克特诺治疗公司 | 吲哚酮化合物及其用途 |
-
2013
- 2013-04-11 CN CN201611030609.9A patent/CN107011242B/zh active Active
- 2013-04-11 KR KR1020147031650A patent/KR102145835B1/ko active Active
- 2013-04-11 MX MX2014011583A patent/MX377618B/es active IP Right Grant
- 2013-04-11 EP EP13776244.9A patent/EP2836481B1/en active Active
- 2013-04-11 NZ NZ700612A patent/NZ700612A/en unknown
- 2013-04-11 JP JP2015505921A patent/JP6130491B2/ja active Active
- 2013-04-11 NZ NZ723971A patent/NZ723971A/en unknown
- 2013-04-11 IN IN9228DEN2014 patent/IN2014DN09228A/en unknown
- 2013-04-11 CA CA2869513A patent/CA2869513C/en active Active
- 2013-04-11 CN CN201380030414.2A patent/CN104395288B/zh active Active
- 2013-04-11 WO PCT/US2013/036234 patent/WO2013155341A1/en not_active Ceased
- 2013-04-11 AU AU2013245812A patent/AU2013245812B2/en active Active
- 2013-04-11 US US14/388,671 patent/US9290449B2/en active Active
-
2014
- 2014-10-05 IL IL234993A patent/IL234993B/en active IP Right Grant
-
2016
- 2016-02-10 US US15/040,840 patent/US9714222B2/en active Active
-
2017
- 2017-03-06 AU AU2017201507A patent/AU2017201507B2/en active Active
- 2017-04-13 JP JP2017080017A patent/JP6345301B2/ja active Active
Also Published As
| Publication number | Publication date |
|---|---|
| HK1207368A1 (en) | 2016-01-29 |
| US9714222B2 (en) | 2017-07-25 |
| JP6345301B2 (ja) | 2018-06-20 |
| EP2836481A4 (en) | 2015-11-18 |
| CA2869513C (en) | 2020-07-07 |
| CN107011242B (zh) | 2020-08-07 |
| CN104395288B (zh) | 2016-12-14 |
| JP2017141290A (ja) | 2017-08-17 |
| CN107011242A (zh) | 2017-08-04 |
| NZ723971A (en) | 2018-01-26 |
| AU2017201507A1 (en) | 2017-03-23 |
| IN2014DN09228A (2) | 2015-07-10 |
| CA2869513A1 (en) | 2013-10-17 |
| KR20150007311A (ko) | 2015-01-20 |
| MX2014011583A (es) | 2016-02-09 |
| NZ700612A (en) | 2016-09-30 |
| AU2013245812A1 (en) | 2014-11-13 |
| AU2013245812A2 (en) | 2014-11-20 |
| JP2015512943A (ja) | 2015-04-30 |
| AU2013245812B2 (en) | 2017-04-06 |
| WO2013155341A1 (en) | 2013-10-17 |
| KR102145835B1 (ko) | 2020-08-20 |
| US20160159741A1 (en) | 2016-06-09 |
| EP2836481B1 (en) | 2018-12-26 |
| US20150051260A1 (en) | 2015-02-19 |
| CN104395288A (zh) | 2015-03-04 |
| MX377618B (es) | 2025-03-07 |
| US9290449B2 (en) | 2016-03-22 |
| IL234993B (en) | 2019-02-28 |
| AU2017201507B2 (en) | 2018-10-04 |
| EP2836481A1 (en) | 2015-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6345301B2 (ja) | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 | |
| JP6389884B2 (ja) | 癌を治療するための方法及び組成物 | |
| JP6795861B2 (ja) | インドリノン化合物及びその使用 | |
| CN109219594B (zh) | 吲哚啉类似物及其用途 | |
| HK1242313A1 (en) | Methods and compositions for treating ewing's sarcoma family of tumors | |
| HK1242313B (zh) | 用於治疗尤文肉瘤家族肿瘤的方法和组合物 | |
| HK40029898A (en) | Indolone compounds and uses thereof | |
| HK1207368B (en) | Compounds and compositions for treating ewings sarcoma family of tumors | |
| HK1236930B (zh) | 吲哚酮化合物及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20141225 |
|
| RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20141225 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160330 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160330 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20161013 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161018 |
|
| A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20170118 |
|
| 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: 20170314 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170413 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6130491 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 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |