ES2634290T3 - Pirrolidin-2-carboxamidas sustituidas - Google Patents
Pirrolidin-2-carboxamidas sustituidas Download PDFInfo
- Publication number
- ES2634290T3 ES2634290T3 ES13708466.1T ES13708466T ES2634290T3 ES 2634290 T3 ES2634290 T3 ES 2634290T3 ES 13708466 T ES13708466 T ES 13708466T ES 2634290 T3 ES2634290 T3 ES 2634290T3
- Authority
- ES
- Spain
- Prior art keywords
- chloro
- phenyl
- fluoro
- cyano
- fluorophenyl
- 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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- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical class NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- -1 (2R, 3S, 4R, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4-cyano-5-neopentylpyrrolidin-2-carboxamido Chemical group 0.000 claims description 395
- 239000002253 acid Substances 0.000 claims description 167
- TVTXCJFHQKSQQM-LJQIRTBHSA-N 4-[[(2r,3s,4r,5s)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC(=O)[C@H]1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)N1 TVTXCJFHQKSQQM-LJQIRTBHSA-N 0.000 claims description 63
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 62
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- MSKSQCLPULZWNO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN MSKSQCLPULZWNO-UHFFFAOYSA-N 0.000 claims description 21
- FNODWEPAWIJGPM-UHFFFAOYSA-N ethyl o-methoxybenzoate Natural products CCOC(=O)C1=CC=CC=C1OC FNODWEPAWIJGPM-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
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- 201000011510 cancer Diseases 0.000 claims description 6
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- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 4
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- WUEPMEXUMQVEGN-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;2,2,2-trifluoro-n-[2-[2-[(2,2,2-trifluoroacetyl)amino]ethylamino]ethyl]acetamide Chemical compound OC(=O)C(F)(F)F.FC(F)(F)C(=O)NCCNCCNC(=O)C(F)(F)F WUEPMEXUMQVEGN-UHFFFAOYSA-N 0.000 claims description 3
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- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 2
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- 229910000024 caesium carbonate Inorganic materials 0.000 description 45
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- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 32
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 32
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- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 22
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 17
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 17
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- 239000011734 sodium Substances 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
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- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
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- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Polyethers (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201261611200P | 2012-03-15 | 2012-03-15 | |
| US201261611200P | 2012-03-15 | ||
| PCT/EP2013/054920 WO2013135648A1 (en) | 2012-03-15 | 2013-03-12 | Substituted pyrrolidine-2-carboxamides |
Publications (1)
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| ES2634290T3 true ES2634290T3 (es) | 2017-09-27 |
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| KR101714856B1 (ko) | 2012-05-30 | 2017-03-09 | 에프. 호프만-라 로슈 아게 | 치환된 피롤리딘-2-카복스아미드 |
| CN105073746B (zh) | 2012-12-20 | 2017-03-22 | 默沙东公司 | 作为hdm2抑制剂的取代的咪唑并吡啶 |
| HK1214531A1 (zh) * | 2013-06-24 | 2016-07-29 | 豪夫迈．罗氏有限公司 | 稳定的静脉内制剂 |
| WO2015000945A1 (en) * | 2013-07-03 | 2015-01-08 | F. Hoffmann-La Roche Ag | Mrna-based gene expression for personalizing patient cancer therapy with an mdm2 antagonist |
| AR097584A1 (es) | 2013-09-12 | 2016-03-23 | Hoffmann La Roche | Terapia de combinación de anticuerpos contra el csf-1r humano y anticuerpos contra el pd-l1 humano |
| PL3077004T3 (pl) * | 2013-12-05 | 2020-08-10 | F.Hoffmann-La Roche Ag | Nowe leczenie skojarzone ostrej białaczki szpikowej (aml) |
| US9657351B2 (en) | 2013-12-06 | 2017-05-23 | Hoffman-La Roche Inc. | MRNA-based gene expression for personalizing patient cancer therapy with an MDM2 antagonist |
| PL3459933T3 (pl) * | 2014-04-15 | 2023-01-23 | F. Hoffmann-La Roche Ag | Stałe postacie farmaceutycznie czynnego związku |
| AU2015263858A1 (en) * | 2014-05-22 | 2016-12-01 | The University Of Sydney | Omega-3 analogues |
| WO2016055497A1 (en) * | 2014-10-10 | 2016-04-14 | F. Hoffmann-La Roche Ag | Methods for personalizing patient cancer therapy with an mdm2 antagonist |
| CN104496822B (zh) * | 2014-12-15 | 2016-10-26 | 扬州三友合成化工有限公司 | 一种1-氯乙基环己基丙基碳酸酯的制备方法 |
| KR20180015650A (ko) | 2015-05-07 | 2018-02-13 | 아게누스 인코포레이티드 | 항-ox40 항체 및 이의 사용 방법 |
| TWI717432B (zh) | 2015-12-02 | 2021-02-01 | 美商艾吉納斯公司 | 抗體和使用彼之方法 |
| CN118436801A (zh) | 2016-05-20 | 2024-08-06 | 豪夫迈·罗氏有限公司 | Protac抗体缀合物及其使用方法 |
| JP6848047B2 (ja) * | 2016-08-08 | 2021-03-24 | フェイ シアオ， | スピロインドロンポリエチレングリコールカーボネート系化合物及びその組成物、調製方法及びその使用 |
| CN107698598B (zh) * | 2016-08-08 | 2019-06-21 | 肖飞 | 螺环吲哚酮聚乙二醇碳酸酯类化合物和其组合物、制备方法及用途 |
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| WO2018089628A1 (en) | 2016-11-09 | 2018-05-17 | Agenus Inc. | Anti-ox40 antibodies, anti-gitr antibodies, and methods of use thereof |
| WO2018115051A1 (en) | 2016-12-22 | 2018-06-28 | F. Hoffmann-La Roche Ag | Treatment of tumors with an anti-csf-1r antibody in combination with an anti-pd-l1 antibody after failure of anti-pd-l1/pd1 treatment |
| US11358949B2 (en) * | 2017-12-20 | 2022-06-14 | Angex Pharmaceutical, Inc. | Carbamate and urea compounds as multikinase inhibitors |
| CN114230561B (zh) * | 2020-09-09 | 2024-03-19 | 中国人民解放军海军军医大学 | 一种mdm2抑制剂类小分子化合物及用途 |
| WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
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| DE69120141T2 (de) | 1990-03-28 | 1996-11-28 | Shuji Kojima | Polymerkombiniertes Arzneimittel zur Magenbehandlung und Verfahren zu dessen Herstellung |
| US5681811A (en) | 1993-05-10 | 1997-10-28 | Protein Delivery, Inc. | Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations comprising same, and method of making and using the same |
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| KR100361933B1 (ko) | 1993-09-08 | 2003-02-14 | 라 졸라 파마슈티칼 컴파니 | 화학적으로정의된비중합성결합가플랫폼분자및그것의콘주게이트 |
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| DE4435087A1 (de) | 1994-09-30 | 1996-04-04 | Deutsches Krebsforsch | Konjugat zur Behandlung von Infektions-, Autoimmun- und Hauterkrankungen |
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| TW200616604A (en) | 2004-08-26 | 2006-06-01 | Nicholas Piramal India Ltd | Nitric oxide releasing prodrugs containing bio-cleavable linker |
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| US7759383B2 (en) | 2005-02-22 | 2010-07-20 | The Regents Of The University Of Michigan | Small molecule inhibitors of MDM2 and the uses thereof |
| JP2009535462A (ja) | 2006-04-27 | 2009-10-01 | インテザイン テクノロジーズ， インコーポレイテッド | 化学的に異なる末端基を含むポリ（エチレングリコール） |
| WO2008109783A2 (en) | 2007-03-06 | 2008-09-12 | The Regents Of The University Of California | Detecting spin perturbations using magnetic resonance imaging |
| CN101357986B (zh) | 2007-06-13 | 2013-06-05 | 康达医药科技有限公司 | 聚乙二醇功能性衍生物和制造方法 |
| WO2009128789A1 (en) | 2008-04-17 | 2009-10-22 | Agency For Science, Technology And Research | Vesicles for intracellular drug delivery |
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| WO2010151269A1 (en) | 2009-06-26 | 2010-12-29 | Biotic Laboratories, Inc. | Para-xylylene based multilayer drug elution devices |
| US20110118283A1 (en) | 2009-11-17 | 2011-05-19 | Qingjie Ding | Substituted Pyrrolidine-2-Carboxamides |
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| CN101991860B (zh) | 2010-11-08 | 2013-06-19 | 中国药科大学 | 泊洛沙姆-羧酸类药物偶联物及其制备方法与应用 |
| NZ611866A (en) | 2010-11-12 | 2015-04-24 | Univ Michigan | Spiro-oxindole mdm2 antagonists |
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| WO2012116073A2 (en) | 2011-02-23 | 2012-08-30 | The Board Of Trustees Of The University Of Illinois | Amphiphilic dendron-coils, micelles thereof and uses |
| CN102247602B (zh) | 2011-06-13 | 2013-01-02 | 中山大学 | 一种超分子水凝胶双重药物载体及其制备方法和应用 |
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| KR101714856B1 (ko) * | 2012-05-30 | 2017-03-09 | 에프. 호프만-라 로슈 아게 | 치환된 피롤리딘-2-카복스아미드 |
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- 2013-03-12 HU HUE13708466A patent/HUE032864T2/en unknown
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