JP6513107B2 - 神経原線維濃縮体のイメージング剤としてのピロロ［２，３−ｃ］ピリジン - Google Patents

神経原線維濃縮体のイメージング剤としてのピロロ［２，３−ｃ］ピリジン Download PDF

Info

Publication number
JP6513107B2
JP6513107B2 JP2016572520A JP2016572520A JP6513107B2 JP 6513107 B2 JP6513107 B2 JP 6513107B2 JP 2016572520 A JP2016572520 A JP 2016572520A JP 2016572520 A JP2016572520 A JP 2016572520A JP 6513107 B2 JP6513107 B2 JP 6513107B2
Authority
JP
Japan
Prior art keywords
mmol
pyrrolo
pyridin
aryl
solution
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
JP2016572520A
Other languages
English (en)
Japanese (ja)
Other versions
JP2017521387A5 (enExample
JP2017521387A (ja
Inventor
ワルジ，アッバス・エム
ホステットラー，エリック
グレショック，トーマス
リー，ジン
ムーア，キース・ピー
ベナセフ，アイドリス
ムルハーン，ジェイムズ
セルニック，ハロルド
ウォン，ヤオディ
ヤン，クン
フー・ジァンミン
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.)
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme LLC
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 Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme LLC
Publication of JP2017521387A publication Critical patent/JP2017521387A/ja
Publication of JP2017521387A5 publication Critical patent/JP2017521387A5/ja
Application granted granted Critical
Publication of JP6513107B2 publication Critical patent/JP6513107B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Hospice & Palliative Care (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
JP2016572520A 2014-06-13 2015-06-09 神経原線維濃縮体のイメージング剤としてのピロロ［２，３−ｃ］ピリジン Active JP6513107B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CNPCT/CN2014/079834 2014-06-13
PCT/CN2014/079834 WO2015188368A1 (en) 2014-06-13 2014-06-13 Pyrrolo[2,3-c]pyridines as imaging agents for neurofibrilary tangles
PCT/US2015/034794 WO2015191506A2 (en) 2014-06-13 2015-06-09 Pyrrolo[2,3-c]pyridines as imaging agents for neurofibrilary tangles

Publications (3)

Publication Number Publication Date
JP2017521387A JP2017521387A (ja) 2017-08-03
JP2017521387A5 JP2017521387A5 (enExample) 2018-03-15
JP6513107B2 true JP6513107B2 (ja) 2019-05-15

Family

ID=54832744

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2016572520A Active JP6513107B2 (ja) 2014-06-13 2015-06-09 神経原線維濃縮体のイメージング剤としてのピロロ［２，３−ｃ］ピリジン

Country Status (15)

Country Link
US (2) US9808542B2 (enExample)
EP (1) EP3154970B1 (enExample)
JP (1) JP6513107B2 (enExample)
KR (1) KR102478430B1 (enExample)
CN (1) CN106661018B (enExample)
AU (1) AU2015274843B2 (enExample)
BR (1) BR112016028345B1 (enExample)
CA (1) CA2948528C (enExample)
DK (1) DK3154970T3 (enExample)
ES (1) ES2763095T3 (enExample)
HU (1) HUE048395T2 (enExample)
MX (1) MX375282B (enExample)
PL (1) PL3154970T3 (enExample)
RU (1) RU2695373C2 (enExample)
WO (2) WO2015188368A1 (enExample)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014097474A1 (ja) 2012-12-21 2014-06-26 独立行政法人放射線医学総合研究所 脳内に蓄積したタウタンパク質をイメージングするための新規化合物
SG11201811311VA (en) 2016-07-22 2019-01-30 Ac Immune Sa Compounds for imaging tau protein aggregates
JP7059270B2 (ja) * 2016-07-22 2022-04-25 エーシー・イミューン・エス・アー タウタンパク質凝集体を画像化するための化合物
CN116473962A (zh) 2017-06-02 2023-07-25 富士胶片富山化学株式会社 脑萎缩预防或治疗剂
JPWO2018221728A1 (ja) 2017-06-02 2020-04-02 富士フイルム富山化学株式会社 アルツハイマー型認知症予防または治療剤
JP7133547B2 (ja) 2017-06-02 2022-09-08 富士フイルム富山化学株式会社 脊髄小脳変性症予防または治療剤
CN110691595A (zh) 2017-06-02 2020-01-14 富士胶片富山化学株式会社 β-淀粉样蛋白量减少剂
JP7370859B2 (ja) * 2017-06-02 2023-10-30 富士フイルム富山化学株式会社 タウオパチー予防または治療剤
WO2019088083A1 (ja) 2017-10-30 2019-05-09 富士フイルム富山化学株式会社 エモパミル結合タンパク質結合剤およびその利用
US11306089B2 (en) 2018-01-24 2022-04-19 Life Molecular Imaging Limited Gamma-carboline compounds for the detection of Tau aggregates
US20210041447A1 (en) 2018-01-24 2021-02-11 Ac Immune Sa Azacarboline compounds for the detection of tau aggregates
WO2019192533A1 (zh) * 2018-04-04 2019-10-10 深圳福沃药业有限公司 用于治疗乳腺癌的雌激素受体降解剂
KR102017324B1 (ko) 2018-04-30 2019-09-02 경북대학교 산학협력단 신규한 asm 활성 직접 억제 화합물 2-아미노-2-(1,2,3-트리아졸-4-일)프로판-1,3-디올 유도체 및 이의 용도
JP7293343B2 (ja) * 2018-05-09 2023-06-19 アプリノイア セラピューティクス リミテッド ヘテロアリール化合物及びその使用
WO2019236884A1 (en) 2018-06-07 2019-12-12 Disarm Therapeutics, Inc. Inhibitors of sarm1
CN108676007B (zh) * 2018-06-22 2020-06-26 厦门大学 放射性核素标记的苯并蝶啶类衍生物及其制备方法和应用
CA3123215C (en) 2018-12-19 2024-04-02 Disarm Therapeutics, Inc. Inhibitors of sarm1 in combination with neuroprotective agents
WO2021097243A1 (en) 2019-11-13 2021-05-20 Aprinoia Therapeutics Inc. Compounds for degrading tau protein aggregates and uses thereof
US20220008563A1 (en) * 2020-07-10 2022-01-13 The Regents Of The University Of California Radiolabelled and nonradiolabelled pegylated compounds and uses thereof
US12036292B2 (en) * 2020-08-06 2024-07-16 Chdi Foundation, Inc. Heterobiaryl compounds and imaging agents for imaging huntingtin protein
CN112939753B (zh) * 2020-09-15 2022-04-05 浙江大学 一种1-茚酮类化合物的合成方法
KR102240400B1 (ko) 2020-11-19 2021-04-15 한국원자력연구원 베타-아밀로이드 검출용 수용성 화합물
CN112745299B (zh) * 2021-01-07 2022-01-25 温州大学 4-氰基-7,8-二氢异喹啉衍生物及其制备方法和应用
TWI782769B (zh) * 2021-10-28 2022-11-01 行政院原子能委員會核能研究所 一種新穎神經纖維糾結微管相關蛋白質Tau造影化合物、其製備方法及用途
CN114149425A (zh) * 2021-11-16 2022-03-08 上海应用技术大学 5-氟甲基吡啶衍生物和18-f同位素标记的5-氟甲基吡啶衍生物及其制备与应用
CN114276259B (zh) * 2022-01-04 2022-12-06 济川(上海)医学科技有限公司 一种马来酸二甲茚定关键中间体的制备方法
CN115417816B (zh) * 2022-09-05 2024-01-26 江苏南大光电材料股份有限公司 一种3,6-二溴-1-氯-异喹啉的制备方法
WO2025230262A1 (ko) * 2024-04-29 2025-11-06 심플렉스 주식회사 신규한 헤테로아릴 유도체 및 이의 aak1 억제 용도

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5451566A (en) 1993-11-17 1995-09-19 Zeneca Limited Herbicidal pyrrolopyridine compounds
JP5635727B2 (ja) 2004-10-07 2014-12-03 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． チアゾリルｍｇｌｕｒ５アンタゴニスト及びそれらの使用のための方法
US20080027044A1 (en) 2006-06-13 2008-01-31 Kim Lewis Prodrug antibiotic screens
WO2008103615A1 (en) 2007-02-21 2008-08-28 Kalypsys, Inc. Isoquinolines useful as inducible nitric oxide synthase inhibitors
TW200902499A (en) 2007-05-15 2009-01-16 Astrazeneca Ab New compounds
AU2009260526A1 (en) 2008-05-30 2009-12-23 Merck Sharp & Dohme Corp. Novel substituted indoles
WO2010129816A2 (en) 2009-05-07 2010-11-11 Intellikine, Inc. Heterocyclic compounds and uses thereof
GB201004311D0 (en) 2010-03-15 2010-04-28 Proximagen Ltd New enzyme inhibitor compounds
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
AU2012212323A1 (en) 2011-02-01 2013-09-12 The Board Of Trustees Of The University Of Illinois HDAC inhibitors and therapeutic methods using the same
US8684313B2 (en) 2011-02-02 2014-04-01 Ocean Rodeo Sports Inc. Inflatable kite with leading edge swept forwards at wingtip
WO2013040183A1 (en) * 2011-09-16 2013-03-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Beta-amyloid imaging agents, methods of manufacture, and methods of use thereof
US20150336948A1 (en) * 2012-05-29 2015-11-26 Merck Sharp & Dohme Corp. Isotopically Labeled Biaryl Urea Compounds
CN103450152B (zh) * 2012-06-04 2015-11-18 济南海乐医药技术开发有限公司 基于吲唑、吲哚或氮杂吲唑、氮杂吲哚的双芳基脲类结构抗肿瘤药物
GB201304526D0 (en) 2013-03-13 2013-04-24 Proximagen Ltd New compounds
GB201404498D0 (en) * 2014-03-13 2014-04-30 Proximagen Ltd New compounds

Also Published As

Publication number Publication date
DK3154970T3 (da) 2020-01-20
AU2015274843A1 (en) 2016-11-10
RU2016150404A3 (enExample) 2018-11-30
MX2016016384A (es) 2017-05-01
MX375282B (es) 2025-03-06
EP3154970A4 (en) 2017-11-15
US10022461B2 (en) 2018-07-17
AU2015274843B2 (en) 2018-11-22
EP3154970B1 (en) 2019-11-06
PL3154970T3 (pl) 2020-04-30
ES2763095T3 (es) 2020-05-27
CN106661018A (zh) 2017-05-10
US9808542B2 (en) 2017-11-07
RU2016150404A (ru) 2018-07-18
CA2948528C (en) 2022-05-31
US20170119912A1 (en) 2017-05-04
KR102478430B1 (ko) 2022-12-15
WO2015188368A1 (en) 2015-12-17
RU2695373C2 (ru) 2019-07-23
WO2015191506A3 (en) 2016-02-04
US20180071412A1 (en) 2018-03-15
WO2015191506A2 (en) 2015-12-17
BR112016028345B1 (pt) 2022-11-29
RU2019115483A (ru) 2019-06-13
BR112016028345A2 (pt) 2017-08-22
CA2948528A1 (en) 2015-12-17
EP3154970A2 (en) 2017-04-19
BR112016028345A8 (pt) 2021-06-29
JP2017521387A (ja) 2017-08-03
HUE048395T2 (hu) 2020-08-28
CN106661018B (zh) 2019-07-19
KR20170016481A (ko) 2017-02-13

Similar Documents

Publication Publication Date Title
JP6513107B2 (ja) 神経原線維濃縮体のイメージング剤としてのピロロ［２，３−ｃ］ピリジン
US8530483B2 (en) Substituted azabenzoxazoles
JP6579670B2 (ja) ９ｈ−ピロロ−ジピリジン誘導体
EP2785183B1 (en) Triazolopyridinone pde10 inhibitors
CA2741668A1 (en) Novel substituted azabenzoxazoles
CA2725934A1 (en) Novel substituted indoles
RU2788916C2 (ru) Пирроло[2,3-с]пиридины в качестве визуализирующих агентов для нейрофибриллярных клубков
NZ621092B2 (en) COMPOUNDS AND COMPOSITIONS AS c-KIT KINASE INHIBITORS

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20170210

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20180202

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20180202

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20181009

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20181004

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20181126

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20190219

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20190305

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: 20190402

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20190409

R150 Certificate of patent or registration of utility model

Ref document number: 6513107

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

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: R313111

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