JP6556129B2 - ファルネソイドx受容体の阻害剤及び医薬としての使用 - Google Patents
ファルネソイドx受容体の阻害剤及び医薬としての使用 Download PDFInfo
- Publication number
- JP6556129B2 JP6556129B2 JP2016531936A JP2016531936A JP6556129B2 JP 6556129 B2 JP6556129 B2 JP 6556129B2 JP 2016531936 A JP2016531936 A JP 2016531936A JP 2016531936 A JP2016531936 A JP 2016531936A JP 6556129 B2 JP6556129 B2 JP 6556129B2
- Authority
- JP
- Japan
- Prior art keywords
- mice
- fxr
- treated
- mca
- gly
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361861109P | 2013-08-01 | 2013-08-01 | |
| US61/861,109 | 2013-08-01 | ||
| US201462004436P | 2014-05-29 | 2014-05-29 | |
| US62/004,436 | 2014-05-29 | ||
| PCT/US2014/049460 WO2015017813A2 (en) | 2013-08-01 | 2014-08-01 | Inhibitors of the farnesoid x receptor and uses in medicine |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016527277A JP2016527277A (ja) | 2016-09-08 |
| JP2016527277A5 JP2016527277A5 (https=) | 2017-09-07 |
| JP6556129B2 true JP6556129B2 (ja) | 2019-08-07 |
Family
ID=51358096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016531936A Expired - Fee Related JP6556129B2 (ja) | 2013-08-01 | 2014-08-01 | ファルネソイドx受容体の阻害剤及び医薬としての使用 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US9540415B2 (https=) |
| EP (1) | EP3027637B1 (https=) |
| JP (1) | JP6556129B2 (https=) |
| CN (2) | CN105593237B (https=) |
| AU (1) | AU2014296023B2 (https=) |
| BR (1) | BR112016002268B1 (https=) |
| CA (1) | CA2920017C (https=) |
| NZ (1) | NZ716568A (https=) |
| WO (1) | WO2015017813A2 (https=) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2545964A1 (en) | 2011-07-13 | 2013-01-16 | Phenex Pharmaceuticals AG | Novel FXR (NR1H4) binding and activity modulating compounds |
| SMT202000070T1 (it) * | 2014-05-29 | 2020-03-13 | Bar Pharmaceuticals S R L | Derivati del colano per l'uso del trattamento e/o la prevenzione di malattie mediate da fxr e tgr5/gpbar1 |
| SG11201703717SA (en) | 2014-11-06 | 2017-06-29 | Enanta Pharm Inc | Bile acid analogs an fxr/tgr5 agonists and methods of use thereof |
| EP3223823A4 (en) | 2014-11-26 | 2018-10-17 | Enanta Pharmaceuticals, Inc. | Bile acid analogs as fxr/tgr5 agonists and methods of use thereof |
| US10208081B2 (en) | 2014-11-26 | 2019-02-19 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof |
| US11578097B2 (en) | 2014-11-26 | 2023-02-14 | Enanta Pharmaceuticals, Inc. | Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof |
| EP3256134A4 (en) | 2015-02-11 | 2018-10-03 | Enanta Pharmaceuticals, Inc. | Bile acid analogs as fxr/tgr5 agonists and methods of use thereof |
| WO2016161003A1 (en) | 2015-03-31 | 2016-10-06 | Enanta Phamraceuticals, Inc. | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
| JP2018519246A (ja) * | 2015-04-28 | 2018-07-19 | ジエンス ハンセン ファーマセウティカル グループ カンパニー リミテッド | コール酸誘導体、及びその製造方法及び医薬用途 |
| US10323060B2 (en) | 2016-02-23 | 2019-06-18 | Enanta Pharmaceuticals, Inc. | Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof |
| CA3252823A1 (en) | 2016-06-13 | 2025-02-25 | Gilead Sciences, Inc. | Substituted tert-butyl-3-(2-chloro-phenyl)-3-hydroxyazetidine-1-carboxylate compounds |
| MX385718B (es) | 2016-06-13 | 2025-03-18 | Gilead Sciences Inc | Compuestos moduladores de fxr (nr1h4). |
| IT201600068742A1 (it) * | 2016-07-01 | 2018-01-01 | Bar Pharmaceuticals Soc A Responsabilita Limitata | Derivati dell'acido iodesossicolico e loro uso |
| CN106237332A (zh) * | 2016-08-11 | 2016-12-21 | 河南大学 | 核受体fxr在肝癌干细胞靶向治疗中的应用 |
| CN110121347A (zh) | 2016-11-29 | 2019-08-13 | 英安塔制药有限公司 | 制备磺酰脲胆汁酸衍生物的方法 |
| US10472386B2 (en) | 2017-02-14 | 2019-11-12 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as FXR agonists and methods of use thereof |
| PT3600309T (pt) | 2017-03-28 | 2022-10-03 | Gilead Sciences Inc | Combinações terapêuticas para o tratamento de doenças hepáticas |
| BR112019020780A2 (pt) | 2017-04-07 | 2020-04-28 | Enanta Pharm Inc | processo para preparação de derivados de ácido biliar de carbamato de sulfonila |
| US11028111B2 (en) | 2017-12-19 | 2021-06-08 | Xi' An Biocare Pharma Ltd. | Compound for treating metabolic diseases and preparation method and use thereof |
| IT201800005598A1 (it) | 2018-05-22 | 2019-11-22 | Ossadiazoli come antagonisti del recettore fxr | |
| EP3911647B1 (en) | 2019-01-15 | 2023-12-13 | Gilead Sciences, Inc. | Isoxazole compound as fxr agonist and pharmaceutical compositions comprising same |
| CA3233305A1 (en) | 2019-02-19 | 2020-08-27 | Gilead Sciences, Inc. | Solid forms of fxr agonists |
| CN112409435B (zh) * | 2019-08-23 | 2023-07-18 | 深圳云合医药科技合伙企业(有限合伙) | 胆汁酸衍生物及其组合物和应用 |
| US20220378766A1 (en) * | 2021-05-25 | 2022-12-01 | Louis Habash | Modulating expression level of a gene encoding an uncoupling protein by treating a human subject with a nitroxide |
| US20230128120A1 (en) * | 2021-10-21 | 2023-04-27 | University Of Washington | Omega muricholic acid as a pregnane x receptor ligand for treating hepato-intestinal diseases |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
| US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
| US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
| WO1987002367A2 (en) | 1985-10-18 | 1987-04-23 | The Upjohn Company | Cyclic hydrocarbons with an aminoalkyl sidechain |
| US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| IT1222395B (it) * | 1987-07-30 | 1990-09-05 | Pierrel Spa | Composizione farmaceutica per somministrazione intranasale comprendente l'ormone ghrh,un agonista colinergico e/o un sale biliare |
| IT1219733B (it) * | 1988-06-28 | 1990-05-24 | Istituto Chemioterapico Di Lod | Derivato dell' acido ursodesossicolico |
| JPH0637392B2 (ja) * | 1988-11-25 | 1994-05-18 | 健二 片桐 | 胆汁うっ滞改善剤 |
| IT1229570B (it) | 1989-04-17 | 1991-09-04 | Giuliani Spa | Derivati fluorurati di acidi biliari, loro preparazione e composizioni farmaceutiche che li contengono. |
| IT1264131B1 (it) * | 1993-04-16 | 1996-09-16 | D R Drug Research Srl | Derivato dell'acido iodesossicolico |
| US6551623B1 (en) * | 1993-09-09 | 2003-04-22 | Lorus Therapeutics Inc. | Immunomodulating compositions from bile |
| GB9320597D0 (en) * | 1993-10-06 | 1993-11-24 | Proteus Molecular Design | Improvements in and realting to vaccines |
| IT1299270B1 (it) * | 1998-05-15 | 2000-02-29 | Moreno Paolini | Acidi biliari come induttori del sistema citocromo p450-dipendente, in particolare ad attivita' anticolestatica |
| DE69940958D1 (de) | 1998-12-23 | 2009-07-16 | Glaxo Group Ltd | Bestimmungsmethode fur liganden der nuklearen rezeptoren |
| US20020132223A1 (en) * | 1999-03-26 | 2002-09-19 | City Of Hope | Methods for modulating activity of the FXR nuclear receptor |
| WO2002094865A1 (en) * | 2001-05-24 | 2002-11-28 | Smithkline Beecham Corporation | Nonhuman pregnane x receptor sequences for use in comparative pharmacology |
| US7595311B2 (en) | 2002-05-24 | 2009-09-29 | Exelixis, Inc. | Azepinoindole derivatives as pharmaceutical agents |
| JP2008509912A (ja) | 2004-08-10 | 2008-04-03 | エグゼリクシス, インコーポレイテッド | 医薬品としての複素環化合物 |
| CN101395170A (zh) * | 2006-02-14 | 2009-03-25 | 英特塞普特药品公司 | 用于预防或治疗fxr介导的疾病或状态的作为fxr配体的胆汁酸衍生物 |
| US7932244B2 (en) * | 2006-06-27 | 2011-04-26 | Intercept Pharmaceuticals, Inc. | Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions |
| WO2011022838A1 (en) | 2009-08-25 | 2011-03-03 | British Columbia Cancer Agency Branch | Polyhydroxylated bile acids for treatment of biliary disorders |
| US20110071100A1 (en) * | 2008-05-05 | 2011-03-24 | Tiltan Pharma Ltd. | Sulfobetaines for cancer, obesity, macular degeneration, neurodegenerative diseases |
| WO2010014836A2 (en) | 2008-07-30 | 2010-02-04 | Intercept Pharmaceuticals, Inc. | Tgr5 modulators and methods of use thereof |
| CN101891791B (zh) * | 2009-05-22 | 2012-10-03 | 中国科学院上海应用物理研究所 | 一种标记胆汁酸衍生物及其参照化合物、制备方法和应用 |
-
2014
- 2014-08-01 BR BR112016002268-8A patent/BR112016002268B1/pt not_active IP Right Cessation
- 2014-08-01 CN CN201480054322.2A patent/CN105593237B/zh not_active Expired - Fee Related
- 2014-08-01 WO PCT/US2014/049460 patent/WO2015017813A2/en not_active Ceased
- 2014-08-01 AU AU2014296023A patent/AU2014296023B2/en not_active Ceased
- 2014-08-01 US US14/909,263 patent/US9540415B2/en not_active Expired - Fee Related
- 2014-08-01 EP EP14752716.2A patent/EP3027637B1/en active Active
- 2014-08-01 JP JP2016531936A patent/JP6556129B2/ja not_active Expired - Fee Related
- 2014-08-01 CN CN201910393592.0A patent/CN110437297B9/zh not_active Expired - Fee Related
- 2014-08-01 CA CA2920017A patent/CA2920017C/en active Active
- 2014-08-01 NZ NZ716568A patent/NZ716568A/en not_active IP Right Cessation
-
2016
- 2016-12-06 US US15/371,032 patent/US10233209B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110437297B (zh) | 2021-12-21 |
| JP2016527277A (ja) | 2016-09-08 |
| US20170152283A1 (en) | 2017-06-01 |
| CN105593237B (zh) | 2019-06-04 |
| CN105593237A (zh) | 2016-05-18 |
| WO2015017813A3 (en) | 2015-04-02 |
| US20160159851A1 (en) | 2016-06-09 |
| WO2015017813A2 (en) | 2015-02-05 |
| BR112016002268B1 (pt) | 2022-11-01 |
| US9540415B2 (en) | 2017-01-10 |
| CN110437297A (zh) | 2019-11-12 |
| EP3027637A2 (en) | 2016-06-08 |
| US10233209B2 (en) | 2019-03-19 |
| BR112016002268A2 (pt) | 2017-08-01 |
| EP3027637B1 (en) | 2019-10-09 |
| NZ716568A (en) | 2021-07-30 |
| CN110437297B9 (zh) | 2022-01-11 |
| CA2920017A1 (en) | 2015-02-05 |
| CA2920017C (en) | 2021-11-23 |
| AU2014296023A1 (en) | 2016-02-25 |
| AU2014296023B2 (en) | 2020-02-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6556129B2 (ja) | ファルネソイドx受容体の阻害剤及び医薬としての使用 | |
| US11384115B2 (en) | Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis | |
| US11319337B2 (en) | 3-desoxy derivative and pharmaceutical compositions thereof | |
| JP6125610B2 (ja) | 代謝障害、高脂血症、糖尿病、脂肪性肝疾患及びアテローム性動脈硬化症の治療のための新規コレステロール代謝物、5−コレステン−3β,25−ジオールジスルファート(25HCDS) | |
| Hui et al. | Capsaicin improves glucose homeostasis by enhancing glucagon‐like peptide‐1 secretion through the regulation of bile acid metabolism via the remodeling of the gut microbiota in male mice | |
| US9321802B2 (en) | Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis | |
| EA020140B1 (ru) | Модуляторы tgr5 и способы их применения | |
| Xin et al. | Stigmasterol protects against steatohepatitis induced by high-fat and high-cholesterol diet in mice by enhancing the alternative bile acid synthesis pathway | |
| Stefela et al. | The farnesoid X receptor (FXR) antagonist 7β-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet | |
| LA SALUTE | DOTTORATO IN SCIENZA DEL FARMACO XXXIII CICLO 2018/2020 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20160906 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20160906 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170731 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170731 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180717 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181017 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20181113 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190313 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20190510 |
|
| 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: 20190611 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190709 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6556129 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 |
|
| LAPS | Cancellation because of no payment of annual fees |