AU2015247646B2 - MDM2 inhibitors and therapeutic methods using the same - Google Patents
MDM2 inhibitors and therapeutic methods using the same Download PDFInfo
- Publication number
- AU2015247646B2 AU2015247646B2 AU2015247646A AU2015247646A AU2015247646B2 AU 2015247646 B2 AU2015247646 B2 AU 2015247646B2 AU 2015247646 A AU2015247646 A AU 2015247646A AU 2015247646 A AU2015247646 A AU 2015247646A AU 2015247646 B2 AU2015247646 B2 AU 2015247646B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- mdm2
- compounds
- cancer
- structural formula
- 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.)
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- 0 *C(**1)=C(*)C=C1N Chemical compound *C(**1)=C(*)C=C1N 0.000 description 3
- UINKXGUQRIANQN-PQCGCNLTSA-N CC(CC1)(CCC1([C@@]([C@H]1c(cccc2Cl)c2F)(c(c(N2)c3)ccc3Cl)C2=O)N[C@H]1C(NC(CC1)(CC2)CCC12C(O)=O)=O)O Chemical compound CC(CC1)(CCC1([C@@]([C@H]1c(cccc2Cl)c2F)(c(c(N2)c3)ccc3Cl)C2=O)N[C@H]1C(NC(CC1)(CC2)CCC12C(O)=O)=O)O UINKXGUQRIANQN-PQCGCNLTSA-N 0.000 description 2
- NAAGETHEXFAVCB-UHFFFAOYSA-N CC(C1)(C2)CC12C(N)=O Chemical compound CC(C1)(C2)CC12C(N)=O NAAGETHEXFAVCB-UHFFFAOYSA-N 0.000 description 1
- XQBOPWAIVOHUKI-UHFFFAOYSA-N CC(C1)(C2)CC12C(NS(C)(=O)=O)=O Chemical compound CC(C1)(C2)CC12C(NS(C)(=O)=O)=O XQBOPWAIVOHUKI-UHFFFAOYSA-N 0.000 description 1
- GCPXBFWFLFWWMP-UHFFFAOYSA-N CC(CC1)(CC2)CCC12C(NS(C)(=O)=O)=O Chemical compound CC(CC1)(CC2)CCC12C(NS(C)(=O)=O)=O GCPXBFWFLFWWMP-UHFFFAOYSA-N 0.000 description 1
- YJCZPJQGFSSFOL-MNZPCBJKSA-N CCN([C@H]([C@@H]1c(cccc2Cl)c2F)C(NC(CC2)(CC3)CCC23C(O)=O)=O)C2(CCCCC2)[C@@]1(c(ccc(Cl)c1)c1N1)C1=O Chemical compound CCN([C@H]([C@@H]1c(cccc2Cl)c2F)C(NC(CC2)(CC3)CCC23C(O)=O)=O)C2(CCCCC2)[C@@]1(c(ccc(Cl)c1)c1N1)C1=O YJCZPJQGFSSFOL-MNZPCBJKSA-N 0.000 description 1
- SHYFEBUYIACRQU-IBJHQLCKSA-N CN([C@H]([C@@H]1c(cccc2Cl)c2F)C(NC(CC2)(CC3)CCC23C(O)=O)=O)C2(CCCCC2)[C@@]1(c(c(N1)c2)ccc2Cl)C1=O Chemical compound CN([C@H]([C@@H]1c(cccc2Cl)c2F)C(NC(CC2)(CC3)CCC23C(O)=O)=O)C2(CCCCC2)[C@@]1(c(c(N1)c2)ccc2Cl)C1=O SHYFEBUYIACRQU-IBJHQLCKSA-N 0.000 description 1
- KISLXTLDZXDHNN-UHFFFAOYSA-N NC(C1)(C2)CC12C(O)=O Chemical compound NC(C1)(C2)CC12C(O)=O KISLXTLDZXDHNN-UHFFFAOYSA-N 0.000 description 1
- GWTSYKUBLGIYFN-UHFFFAOYSA-O NC(CCCCCCC1)=C1[NH3+] Chemical compound NC(CCCCCCC1)=C1[NH3+] GWTSYKUBLGIYFN-UHFFFAOYSA-O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- 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
- A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- 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
- C07D471/12—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 three hetero rings
- C07D471/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461980747P | 2014-04-17 | 2014-04-17 | |
| US61/980,747 | 2014-04-17 | ||
| PCT/US2015/026098 WO2015161032A1 (en) | 2014-04-17 | 2015-04-16 | Mdm2 inhibitors and therapeutic methods using the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2015247646A1 AU2015247646A1 (en) | 2016-10-27 |
| AU2015247646B2 true AU2015247646B2 (en) | 2019-06-06 |
Family
ID=54321424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2015247646A Active AU2015247646B2 (en) | 2014-04-17 | 2015-04-16 | MDM2 inhibitors and therapeutic methods using the same |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9745314B2 (cg-RX-API-DMAC7.html) |
| EP (1) | EP3131544B1 (cg-RX-API-DMAC7.html) |
| JP (2) | JP6694827B2 (cg-RX-API-DMAC7.html) |
| KR (2) | KR102599945B1 (cg-RX-API-DMAC7.html) |
| CN (2) | CN106794171B (cg-RX-API-DMAC7.html) |
| AU (1) | AU2015247646B2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2945527C (cg-RX-API-DMAC7.html) |
| ES (1) | ES2712973T3 (cg-RX-API-DMAC7.html) |
| IL (2) | IL248211B (cg-RX-API-DMAC7.html) |
| MX (2) | MX373045B (cg-RX-API-DMAC7.html) |
| SG (2) | SG10201913742TA (cg-RX-API-DMAC7.html) |
| WO (1) | WO2015161032A1 (cg-RX-API-DMAC7.html) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0811643D0 (en) | 2008-06-25 | 2008-07-30 | Cancer Rec Tech Ltd | New therapeutic agents |
| CA2945527C (en) * | 2014-04-17 | 2022-05-17 | The Regents Of The University Of Michigan | Mdm2 inhibitors and therapeutic methods using the same |
| PT3183254T (pt) | 2014-08-21 | 2019-08-29 | Boehringer Ingelheim Int | Novos compostos de espiro[3h-indole-3,2¿-pirrolidin]-2(1h)-ona e derivados como inibidores de mdm2-p53 |
| US9962380B2 (en) * | 2015-09-23 | 2018-05-08 | Wisconsin Alumni Research Foundation | Methods for treating cognitive deficits associated with fragile X syndrome |
| GB201517217D0 (en) | 2015-09-29 | 2015-11-11 | Astex Therapeutics Ltd And Cancer Res Technology Ltd | Pharmaceutical compounds |
| GB201517216D0 (en) | 2015-09-29 | 2015-11-11 | Cancer Res Technology Ltd And Astex Therapeutics Ltd | Pharmaceutical compounds |
| LT3359542T (lt) | 2015-10-09 | 2021-05-25 | Boehringer Ingelheim International Gmbh | Spiro[3h-indolo-3,2 -pirolidin]-2(1h)-ono junginiai ir dariniai, kaip mdm2-p53 inhibitoriai |
| EP3440066B1 (en) * | 2016-04-06 | 2022-11-30 | The Regents of The University of Michigan | Mdm2 protein degraders |
| JP2019522633A (ja) | 2016-05-20 | 2019-08-15 | ジェネンテック， インコーポレイテッド | Ｐｒｏｔａｃ抗体コンジュゲート及び使用方法 |
| GB201704966D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| GB201704965D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| KR20200105837A (ko) * | 2017-12-29 | 2020-09-09 | 간 앤 리 파마슈티칼스 | 종양 억제제로 사용될 수 있는 화합물 및 이의 제조방법과 용도 |
| EP3511334A1 (en) * | 2018-01-16 | 2019-07-17 | Adamed sp. z o.o. | 1,2,3',5'-tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,3'-dione compounds as therapeutic agents activating tp53 |
| KR102039696B1 (ko) | 2018-04-23 | 2019-11-04 | 충남대학교산학협력단 | 세포내 결핵균 제어를 위한 p53 발현 조절 가능한 조성물 (K279-1558) 또는 방법 |
| WO2020024834A1 (en) | 2018-07-31 | 2020-02-06 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination product of bcl-2 inhibitor and chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases |
| MX2020009759A (es) | 2018-07-31 | 2020-10-08 | Ascentage Pharma Suzhou Co Ltd | Efecto antitumoral sinergico de un inhibidor de bcl-2 combinado con rituximab y/o bendamustina o un inhibidor de bcl-2 combinado con chop. |
| JP7058345B2 (ja) * | 2018-07-31 | 2022-04-21 | アセンテージ ファーマ（スーチョウ）カンパニー，リミティド | Ｂｃｌ－２阻害剤及びＭＤＭ２阻害剤の組合せ製品並びに疾患の予防及び／又治療におけるその使用 |
| CN110772521A (zh) | 2018-07-31 | 2020-02-11 | 苏州亚盛药业有限公司 | Bcl-2抑制剂或Bcl-2/Bcl-xL抑制剂与BTK抑制剂的组合产品及其用途 |
| TWI786322B (zh) * | 2018-08-08 | 2022-12-11 | 大陸商蘇州亞盛藥業有限公司 | 免疫療法與ｍｄｍ２抑制劑的組合及其用途 |
| TWI750539B (zh) * | 2018-11-23 | 2021-12-21 | 大陸商蘇州亞盛藥業有限公司 | 新穎藥物組成物及其用途 |
| CN111320635B (zh) * | 2018-12-14 | 2021-03-30 | 苏州亚盛药业有限公司 | 用于治疗骨关节炎的化合物 |
| WO2020169073A1 (en) * | 2019-02-24 | 2020-08-27 | Ascentage Pharma (Suzhou) Co., Ltd. | Treatment methods and biomarkers for mdm2 inhibitors |
| TWI750728B (zh) * | 2019-07-11 | 2021-12-21 | 大陸商蘇州亞盛藥業有限公司 | 2-吲哚啉螺環酮類化合物的製備方法及其中間體 |
| WO2021013028A1 (en) | 2019-07-19 | 2021-01-28 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical combination and use thereof |
| WO2021018032A1 (en) * | 2019-07-26 | 2021-02-04 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition of mdm2 inhibitor and use thereof for preventing and/or treating disease |
| US12287338B2 (en) | 2019-11-27 | 2025-04-29 | Ascentage Pharma (Suzhou) Co., Ltd. | Method and compositions for predicting anti-cancer efficacy of compounds targeting apoptosis pathway |
| US11850239B2 (en) | 2019-12-19 | 2023-12-26 | Ascentage Pharma (Suzhou) Co., Ltd. | MDM2 inhibitor and a platinum compound for cancer treatment |
| GB201919219D0 (en) | 2019-12-23 | 2020-02-05 | Otsuka Pharma Co Ltd | Cancer biomarkers |
| WO2021147982A1 (en) * | 2020-01-23 | 2021-07-29 | Ascentage Pharma (Suzhou) Co., Ltd. | Amorphous form or crystalline form of 2-indolinolinololylspironone compounds or their salts, solvent complexes |
| WO2021175192A1 (en) * | 2020-03-02 | 2021-09-10 | Ascentage Pharma (Suzhou) Co., Ltd. | Treatment methods and biomarkers for mdm2 inhibitors |
| KR20230005160A (ko) * | 2020-03-19 | 2023-01-09 | 카이메라 쎄라퓨틱스 인코포레이티드 | Mdm2 분해제 및 이의 용도 |
| WO2021208911A1 (en) * | 2020-04-14 | 2021-10-21 | Ascentage Pharma (Suzhou) Co., Ltd. | Novel medical use of mdm2 inhibitors |
| CN113801120B (zh) * | 2020-06-15 | 2024-03-22 | 苏州亚盛药业有限公司 | Mdm2抑制剂的微悬浮液以及治疗应用 |
| TW202214248A (zh) | 2020-08-27 | 2022-04-16 | 日商大塚製藥股份有限公司 | 使用ｍｄｍ２拮抗劑的癌症療法之生物標記 |
| CN112022812B (zh) * | 2020-11-03 | 2021-01-29 | 上海亚盛医药科技有限公司 | 一种包含杂环类化合物的组合物、其制备方法和应用 |
| WO2022170108A1 (en) * | 2021-02-04 | 2022-08-11 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof in prevention of radiation injury |
| WO2022178218A1 (en) | 2021-02-19 | 2022-08-25 | Mevion Medical Systems, Inc. | Gantry for a particle therapy system |
| GB202103080D0 (en) | 2021-03-04 | 2021-04-21 | Otsuka Pharma Co Ltd | Cancer biomarkers |
| EP4382126A4 (en) | 2021-08-02 | 2025-07-30 | Ascentage Pharma Suzhou Co Ltd | PHARMACEUTICAL COMBINATION AND ITS USE |
| WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
| CN116421598B (zh) * | 2022-01-11 | 2024-08-30 | 苏州亚盛药业有限公司 | 用于治疗aml-mrc和mds的方法 |
| WO2024240858A1 (en) | 2023-05-23 | 2024-11-28 | Valerio Therapeutics | Protac molecules directed against dna damage repair system and uses thereof |
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| US20120264738A1 (en) * | 2011-03-10 | 2012-10-18 | Yuuichi Sugimoto | Dispiropyrrolidine derivatives |
| US20120289494A1 (en) * | 2011-05-11 | 2012-11-15 | Sanofi | Spiro-oxindole mdm2 antagonists |
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| US3989816A (en) | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
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| US6605712B1 (en) | 1990-12-20 | 2003-08-12 | Arch Development Corporation | Gene transcription and ionizing radiation: methods and compositions |
| US7759383B2 (en) | 2005-02-22 | 2010-07-20 | The Regents Of The University Of Michigan | Small molecule inhibitors of MDM2 and the uses thereof |
| EP2311814A1 (en) | 2005-12-01 | 2011-04-20 | F. Hoffmann-La Roche AG | 2,4,5-triphenyl imidazoline derivatives as inhibitors of the interaction between P53 and MDM2 proteins for use as anticancer agents |
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| UA107814C2 (uk) | 2009-11-12 | 2015-02-25 | Дзе Ріджентс Оф Дзе Юніверсіті Оф Мічіган | Спірооксіндольні антагоністи мdм2 |
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| WO2012065022A2 (en) | 2010-11-12 | 2012-05-18 | The Regents Of The University Of Michigan | Spiro-oxindole mdm2 antagonists |
| WO2013049250A1 (en) | 2011-09-27 | 2013-04-04 | Amgen Inc. | Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer |
| CN105555789B (zh) * | 2013-09-04 | 2018-08-10 | 第一三共株式会社 | 螺氧基吲哚衍生物的制备方法 |
| CA2945527C (en) * | 2014-04-17 | 2022-05-17 | The Regents Of The University Of Michigan | Mdm2 inhibitors and therapeutic methods using the same |
-
2015
- 2015-04-16 CA CA2945527A patent/CA2945527C/en active Active
- 2015-04-16 US US14/688,553 patent/US9745314B2/en active Active
- 2015-04-16 SG SG10201913742TA patent/SG10201913742TA/en unknown
- 2015-04-16 EP EP15779988.3A patent/EP3131544B1/en active Active
- 2015-04-16 KR KR1020227012871A patent/KR102599945B1/ko active Active
- 2015-04-16 CN CN201580032547.2A patent/CN106794171B/zh active Active
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| US20080188506A1 (en) * | 2007-02-07 | 2008-08-07 | Qingjie Ding | Spiroindolinone derivatives |
| US20120264738A1 (en) * | 2011-03-10 | 2012-10-18 | Yuuichi Sugimoto | Dispiropyrrolidine derivatives |
| US20120289494A1 (en) * | 2011-05-11 | 2012-11-15 | Sanofi | Spiro-oxindole mdm2 antagonists |
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| Shangary, S. et al, "Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy." Annual review of pharmacology and toxicology 49 (2009): 223-241 * |
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| IL269462B (en) | 2021-05-31 |
| KR102599945B1 (ko) | 2023-11-09 |
| CN111718354A (zh) | 2020-09-29 |
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| KR20160136450A (ko) | 2016-11-29 |
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| ES2712973T3 (es) | 2019-05-17 |
| CN106794171A (zh) | 2017-05-31 |
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| JP6909323B2 (ja) | 2021-07-28 |
| JP2020100662A (ja) | 2020-07-02 |
| MX2020003939A (es) | 2020-08-13 |
| WO2015161032A1 (en) | 2015-10-22 |
| EP3131544A4 (en) | 2017-08-30 |
| KR102389552B1 (ko) | 2022-04-22 |
| NZ724963A (en) | 2021-10-29 |
| JP2017511360A (ja) | 2017-04-20 |
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| US9745314B2 (en) | 2017-08-29 |
| CN106794171B (zh) | 2020-03-24 |
| CA2945527C (en) | 2022-05-17 |
| IL248211A0 (en) | 2016-11-30 |
| IL248211B (en) | 2019-10-31 |
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