JP2008520742A - Vegf産生の阻害に有用なカルバゾール誘導体、カルボリン誘導体およびインドール誘導体 - Google Patents
Vegf産生の阻害に有用なカルバゾール誘導体、カルボリン誘導体およびインドール誘導体 Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
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| US11458126B2 (en) | 2017-08-01 | 2022-10-04 | Ptc Therapeutics, Inc. | DHODH inhibitor for use in treating hematologic cancers |
| JP2022163087A (ja) * | 2014-09-10 | 2022-10-25 | エピザイム インコーポレイテッド | Smyd阻害剤 |
| US11613538B2 (en) | 2009-05-27 | 2023-03-28 | Ptc Therapeutics, Inc. | Method of inhibiting or reducing a viral infection |
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| WO2011014128A1 (en) * | 2009-07-30 | 2011-02-03 | National University Of Singapore | Small molecule inhibitors of isoprenylcysteine carboxyl methyltransferase with potential anticancer activity |
| US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
| WO2011059839A1 (en) * | 2009-10-29 | 2011-05-19 | Sirtris Pharmaceuticals, Inc. | Bicyclic pyridines and analogs as sirtuin modulators |
| JP5964756B2 (ja) * | 2010-02-04 | 2016-08-03 | ラジウス ヘルス,インコーポレイテッド | 選択的アンドロゲン受容体モジュレーター |
| PL2568806T3 (pl) | 2010-05-12 | 2017-03-31 | Radius Health, Inc. | Schematy lecznicze |
| JP5951600B2 (ja) | 2010-05-21 | 2016-07-13 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | キナーゼ調節のための、化合物、組成物および方法 |
| WO2011155983A1 (en) * | 2010-06-07 | 2011-12-15 | Bikam Pharmaceuticals Inc. | Opsin-binding ligands, compositions and methods of use |
| CA2807552A1 (en) | 2010-08-06 | 2012-02-09 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| AU2011312490B2 (en) | 2010-09-28 | 2015-06-25 | Radius Pharmaceuticals, Inc. | Selective androgen receptor modulators |
| EP2857499A1 (en) | 2010-10-01 | 2015-04-08 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| WO2012064973A2 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2012071369A2 (en) | 2010-11-24 | 2012-05-31 | The Trustees Of Columbia University In The City Of New York | A non-retinoid rbp4 antagonist for treatment of age-related macular degeneration and stargardt disease |
| GB201021103D0 (en) * | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | New compounds for the treatment of neurodegenerative diseases |
| EP3238722B1 (en) | 2011-01-10 | 2019-03-13 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones |
| WO2012105610A1 (ja) * | 2011-02-02 | 2012-08-09 | 公立大学法人名古屋市立大学 | 眼内血管新生及び/又は眼内血管透過性亢進を伴う疾患の予防又は治療のための医薬 |
| TWI592411B (zh) | 2011-02-23 | 2017-07-21 | 英特爾立秦有限責任公司 | 激酶抑制劑之組合及其用途 |
| US9353113B2 (en) | 2011-03-18 | 2016-05-31 | Ono Pharmaceutical Co., Ltd. | Tetrahydrocarboline derivative |
| CA2831613A1 (en) | 2011-03-31 | 2012-10-04 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
| EP2734520B1 (en) | 2011-07-19 | 2016-09-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9056877B2 (en) | 2011-07-19 | 2015-06-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| PE20141371A1 (es) | 2011-08-29 | 2014-10-13 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos |
| WO2013077921A2 (en) | 2011-09-02 | 2013-05-30 | The Regents Of The University Of California | Substituted pyrazolo[3,4-d]pyrimidines and uses thereof |
| US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| CN103030643B (zh) * | 2011-09-29 | 2015-04-29 | 中国科学院化学研究所 | 六环吲哚类生物碱及其制备方法 |
| PT3682905T (pt) | 2011-10-03 | 2022-04-07 | Modernatx Inc | Nucleósidos, nucleótidos e ácidos nucleicos modificados e respetivas utilizações |
| AR088377A1 (es) * | 2011-10-20 | 2014-05-28 | Siena Biotech Spa | Proceso para la preparacion de 6-cloro-2,3,4,9-tetrahidro-1h-carbazol-1-carboxamida y compuestos intermedios de esta |
| ES2923757T3 (es) | 2011-12-16 | 2022-09-30 | Modernatx Inc | Composiciones de ARNm modificado |
| EP2606726A1 (de) | 2011-12-21 | 2013-06-26 | Bayer CropScience AG | N-Arylamidine-substituierte trifluoroethylsulfid-Derivate als Akarizide und Insektizide |
| WO2013151664A1 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides for the production of proteins |
| US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
| US10501512B2 (en) | 2012-04-02 | 2019-12-10 | Modernatx, Inc. | Modified polynucleotides |
| US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
| CN104411338A (zh) | 2012-04-02 | 2015-03-11 | 现代治疗公司 | 用于产生与人类疾病相关的生物制剂和蛋白质的修饰多核苷酸 |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9333202B2 (en) | 2012-05-01 | 2016-05-10 | The Trustees Of Columbia University In The City Of New York | Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease |
| US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
| EP2690091A1 (en) | 2012-07-25 | 2014-01-29 | Studiengesellschaft Kohle mbH | Process for preparing substituted indole derivatives |
| WO2014041125A1 (en) * | 2012-09-13 | 2014-03-20 | Baden-Württemberg Stiftung Gmbh | Specific inhibitors of protein p21 as therapeutic agents |
| CA2886240A1 (en) | 2012-09-26 | 2014-04-03 | The Regents Of The University Of California | Modulation of ire1 |
| RU2702908C2 (ru) | 2012-11-01 | 2019-10-14 | Инфинити Фармасьютикалз, Инк. | Лечение злокачественных опухолей с использованием модуляторов изоформ pi3-киназы |
| PT2922554T (pt) | 2012-11-26 | 2022-06-28 | Modernatx Inc | Arn modificado nas porções terminais |
| US9938291B2 (en) | 2013-03-14 | 2018-04-10 | The Trustess Of Columbia University In The City Of New York | N-alkyl-2-phenoxyethanamines, their preparation and use |
| US9944644B2 (en) | 2013-03-14 | 2018-04-17 | The Trustees Of Columbia University In The City Of New York | Octahydropyrrolopyrroles their preparation and use |
| US10273243B2 (en) | 2013-03-14 | 2019-04-30 | The Trustees Of Columbia University In The City Of New York | 4-phenylpiperidines, their preparation and use |
| EP2968303B1 (en) | 2013-03-14 | 2018-07-04 | The Trustees of Columbia University in the City of New York | Octahydrocyclopentapyrroles, their preparation and use |
| US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
| CN105143203A (zh) | 2013-04-17 | 2015-12-09 | 辉瑞大药厂 | 用于治疗心血管疾病的n-哌啶-3-基苯甲酰胺衍生物 |
| US10561707B2 (en) * | 2013-09-08 | 2020-02-18 | Technion Research And Development Foundation Ltd. | Semaphorin 3C variants, compositions comprising said variants and methods of use thereof in treating eye diseases |
| US10023626B2 (en) | 2013-09-30 | 2018-07-17 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
| KR20160067219A (ko) | 2013-10-03 | 2016-06-13 | 모더나 세라퓨틱스, 인코포레이티드 | 저밀도 지단백질 수용체를 암호화하는 폴리뉴클레오타이드 |
| EP3964507A1 (en) | 2013-10-04 | 2022-03-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CN106456628A (zh) | 2014-03-19 | 2017-02-22 | 无限药品股份有限公司 | 用于治疗PI3K‑γ介导的障碍的杂环化合物 |
| KR102359214B1 (ko) | 2014-04-04 | 2022-02-07 | 델 마 파마슈티컬스 | 폐의 비소세포 암종 및 난소암을 치료하기 위한 디안하이드로갈락티톨 및 이의 유사체 또는 유도체 |
| WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| CN111393434B (zh) | 2014-04-30 | 2022-11-04 | 哥伦比亚大学董事会 | 取代的4-苯基哌啶及其制备和用途 |
| US11427600B2 (en) * | 2014-06-27 | 2022-08-30 | Nogra Pharma Limited | Aryl receptor modulators and methods of making and using the same |
| EP3171895A1 (en) | 2014-07-23 | 2017-05-31 | Modernatx, Inc. | Modified polynucleotides for the production of intrabodies |
| US10570146B2 (en) * | 2014-07-25 | 2020-02-25 | Northeastern University | Urea/carbamates FAAH MAGL or dual FAAH/MAGL inhibitors and uses thereof |
| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CA2963945C (en) | 2014-10-07 | 2023-01-10 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| HUE057041T2 (hu) | 2015-07-06 | 2022-04-28 | Alkermes Inc | Hiszton deacetiláz hetero-halogén gátlói |
| WO2017007755A1 (en) | 2015-07-06 | 2017-01-12 | Rodin Therapeutics, Inc. | Heterobicyclic n-aminophenyl-amides as inhibitors of histone deacetylase |
| CN114230571B (zh) | 2015-09-14 | 2025-07-08 | 无限药品股份有限公司 | 异喹啉酮的固体形式、其制备方法、包含其的组合物及其使用方法 |
| WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
| US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2017223115A1 (en) | 2016-06-22 | 2017-12-28 | Radius Health, Inc. | Ar+ breast cancer treatment methods |
| EP3474856B1 (en) | 2016-06-24 | 2022-09-14 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| EP3484528B1 (en) | 2016-07-18 | 2020-11-25 | Janssen Pharmaceutica NV | Tau pet imaging ligands |
| CN109563041B (zh) | 2016-08-26 | 2021-12-07 | 住友化学株式会社 | 1-乙酰基-3-苯基脲化合物及其用途 |
| MX2019002233A (es) | 2016-08-26 | 2019-06-17 | Sumitomo Chemical Co | Compuesto de fenil urea y uso del mismo. |
| JP2020504711A (ja) | 2016-12-21 | 2020-02-13 | バイオセリックス, インコーポレイテッド | タンパク質を標的とすることにおいて使用するための、チエノピロール誘導体、その組成物、方法、および使用 |
| HRP20220223T1 (hr) | 2017-01-11 | 2022-04-29 | Alkermes, Inc. | Biciklički inhibitori histon deacetilaze |
| WO2018165614A1 (en) | 2017-03-10 | 2018-09-13 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| EP3592736A1 (en) | 2017-03-10 | 2020-01-15 | Rutgers, the State University of New Jersey | Indole derivatives as efflux pump inhibitors |
| WO2018165612A1 (en) | 2017-03-10 | 2018-09-13 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| CN111163774A (zh) | 2017-05-26 | 2020-05-15 | 罗格斯新泽西州立大学 | 细菌外排泵抑制剂 |
| MA49421A (fr) | 2017-06-15 | 2020-04-22 | Modernatx Inc | Formulations d'arn |
| US11458121B2 (en) | 2017-06-26 | 2022-10-04 | Rutgers, The State University Of New Jersey | Therapeutic compounds and methods to treat infection |
| US11225475B2 (en) | 2017-08-07 | 2022-01-18 | Alkermes, Inc. | Substituted pyridines as inhibitors of histone deacetylase |
| MX2020002348A (es) | 2017-08-31 | 2020-10-08 | Modernatx Inc | Métodos de elaboración de nanopartículas lipídicas. |
| US10882821B1 (en) | 2017-09-26 | 2021-01-05 | The Board Of Trustees Of The Leland Stanford Junior University | Enantiomeric compound for the reduction of the deleterious activity of extended nucleotide repeat containing genes |
| EP3737361A4 (en) | 2018-01-11 | 2021-08-25 | Centaurus Therapeutics | INHIBITORS OF DIHYDROCERAMIDE DESATURASE FOR THE TREATMENT OF DISEASES |
| US12090235B2 (en) | 2018-09-20 | 2024-09-17 | Modernatx, Inc. | Preparation of lipid nanoparticles and methods of administration thereof |
| CN113939282A (zh) | 2019-01-31 | 2022-01-14 | 摩登纳特斯有限公司 | 制备脂质纳米颗粒的方法 |
| EP4267578A4 (en) | 2020-12-23 | 2024-11-20 | Recurium IP Holdings, LLC | ESTROGEN RECEPTOR MODULATORS |
| US20250034089A1 (en) * | 2021-11-19 | 2025-01-30 | Nain Biotech (Hangzhou) Co., Ltd. | Tetrahydrocarbazole compound, and pharmaceutical composition and use thereof |
| WO2024230729A1 (zh) | 2023-05-10 | 2024-11-14 | 杭州拿因生物科技有限责任公司 | 四氢咔唑衍生物、其药物组合物及用途 |
| KR20260040871A (ko) * | 2024-09-19 | 2026-03-26 | 이화여자대학교 산학협력단 | 피라지노 카바졸 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 용도 |
| EP4725481A1 (en) * | 2024-10-10 | 2026-04-15 | Leibniz-Institut für Virologie | 1,2,3,4-tetrahydrocarbazole derivatives for use in treating an adenoviral infection |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4014890A (en) * | 1976-03-23 | 1977-03-29 | Pfizer Inc. | Process for preparing indole derivatives |
| JPH04178387A (ja) * | 1989-11-01 | 1992-06-25 | Toyama Chem Co Ltd | 新規なイソインドール誘導体およびその塩 |
| US5451600A (en) * | 1994-04-19 | 1995-09-19 | Hoffmann-La Roche Inc. | Substituted tetrahydrobenzopyrrolylfuranoic acid derivatives as phospholipase A2 inhibitors |
| US6175015B1 (en) * | 1996-08-12 | 2001-01-16 | Neurogen Corporation | Fused indolecarboxamides: dopamine receptor subtype specific ligands |
| WO2004069831A1 (en) * | 2003-02-10 | 2004-08-19 | Glenmark Pharmaceuticals Ltd. | Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation |
| WO2004096766A1 (en) * | 2003-04-29 | 2004-11-11 | The Australian National University | A method of indole synthesis |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1003577B (de) * | 1955-02-11 | 1957-02-28 | Agfa Ag | Verfahren zur Herstellung seitenrichtiger positiver Bilder durch Waermeentwicklung |
| BE793493A (fr) * | 1971-12-30 | 1973-06-29 | Hoffmann La Roche | Composes tricycliques |
| BG25793A3 (bg) | 1973-07-18 | 1978-12-12 | Schering Aktiengesellschaft | Метод за получаване на карбазолови деривати |
| DE3217563A1 (de) * | 1982-05-11 | 1983-11-17 | Cassella Ag, 6000 Frankfurt | Verfahren zur herstellung gegebenenfalls substituierter 1,2,3,4-tetrahydro-9-cyanmethyl-carbazol-1-one |
| US4880817A (en) * | 1987-06-09 | 1989-11-14 | Ortho Pharmaceutical Corporation | O-functionalized derivatives of substituted isoquinolin-3-ols having cardiotonic and/or phosphodiesterase fraction III inhibiting properties and/or renal vasodilating properties |
| GB2239013B (en) * | 1989-11-01 | 1993-06-02 | Toyama Chemical Co Ltd | Novel isoindole derivatives and salts thereof,processes for producing the same and antitumor agent comprising the same |
| US5298626A (en) * | 1991-01-18 | 1994-03-29 | Hoechst-Roussel Pharmaceuticals Incorporated | Select cyclopent[b]indoles |
| US5192789A (en) * | 1991-01-18 | 1993-03-09 | Hoechst-Roussel Pharmaceuticals Incorporated | Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[b]indoles and related compounds |
| US5100891A (en) * | 1991-01-18 | 1992-03-31 | Hoechst-Roussel Pharmaceuticals Inc. | Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[B]indoles and related compounds |
| FR2763589B1 (fr) * | 1997-05-22 | 2001-01-05 | Centre Nat Rech Scient | Composes pour la preparation de medicaments destines au traitement de pathologies impliquant le glutamate extracellulaire, et leurs procedes d'obtention |
| AR016133A1 (es) * | 1997-07-31 | 2001-06-20 | Wyeth Corp | Compuesto de carbamiloxi que inhiben la adhesion de leucocitos mediada por vla-4, compuestos que son prodrogas de dichos compuestos, composicionfarmaceutica, metodo para fijar vla-4 a una muestra biologica, metodo para el tratamiento de una condicion inflamatoria |
| US6514981B1 (en) * | 1998-04-02 | 2003-02-04 | Sugen, Inc. | Methods of modulating tyrosine protein kinase function with indolinone compounds |
| GB9918962D0 (en) * | 1999-08-11 | 1999-10-13 | Cerebrus Ltd | Chemical compounds xxii |
| EP1214292B1 (en) * | 1999-09-24 | 2007-06-13 | Genentech, Inc. | Tyrosine derivatives |
| DE19962936A1 (de) * | 1999-12-24 | 2001-06-28 | Bayer Ag | Neue beta-Aminosäureverbindungen als Integrinantagonisten |
| BR0214967A (pt) * | 2001-12-14 | 2005-05-10 | Novo Nordisk As | Composto, sal famaceuticamente aceitável, processo para a preparação de um composto, composição farmacêutica, uso de um composto e método de tratar um distúrbio de um paciente |
| WO2003068223A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Corporation | Aryl ureas with raf kinase and angiogenesis inhibiting activity |
| US7626042B2 (en) * | 2002-06-06 | 2009-12-01 | Institute Of Medicinal Molecular Design, Inc. | O-substituted hydroxyaryl derivatives |
| US20060004029A1 (en) * | 2002-08-30 | 2006-01-05 | Akihiko Tsuruoka | Nitrogen-containing aromatic derivatives |
| EP1558591B1 (en) * | 2002-10-07 | 2014-05-07 | The Regents of The University of California | Modulation of anxiety through blockade of anandamide hydrolysis |
| WO2004041277A1 (en) * | 2002-11-01 | 2004-05-21 | Merck & Co., Inc. | Carbonylamino-benzimidazole derivatives as androgen receptor modulators |
| BRPI0407544A (pt) | 2003-02-17 | 2006-02-14 | Pharmacia Italia Spa | derivados de pirazol tetracìclicos como inibidores da cinase, processo para a sua preparação e composições farmacêuticas que os compreendem |
| EP1654228B1 (en) | 2003-06-10 | 2008-10-22 | Smithkline Beecham Corporation | Tetrahydrocarbazole derivatives and their pharmaceutical use |
| ES2327416T3 (es) * | 2003-06-12 | 2009-10-29 | Smithkline Beecham Corporation | Derivados de tetraidrocarbazol y su uso farmaceutico. |
| US20050074451A1 (en) * | 2003-06-25 | 2005-04-07 | Elan Pharmaceuticals, Inc. | Methods and compositions for treating rheumatoid arthritis |
| WO2005026112A2 (en) | 2003-09-12 | 2005-03-24 | Elixir Pharmaceuticals, Inc. | Methods of treating a disorder |
| JP2007509057A (ja) * | 2003-10-15 | 2007-04-12 | カイロン コーポレイション | ウイルス阻害のための組成物および方法 |
| AU2005231467A1 (en) * | 2004-04-01 | 2005-10-20 | Elan Pharmaceuticals, Inc. | Steroid sparing agents and methods of using same |
| RU2006140377A (ru) | 2004-04-16 | 2008-05-27 | Дженентек, Инк. (Us) | Способ усиления уничтожения в-клеток |
-
2005
- 2005-11-23 EP EP05852075A patent/EP1817025A2/en not_active Withdrawn
- 2005-11-23 MX MX2007006180A patent/MX2007006180A/es not_active Application Discontinuation
- 2005-11-23 US US11/720,055 patent/US8946444B2/en not_active Expired - Fee Related
- 2005-11-23 CA CA002588389A patent/CA2588389A1/en not_active Abandoned
- 2005-11-23 WO PCT/US2005/042484 patent/WO2006058088A2/en not_active Ceased
- 2005-11-23 JP JP2007543450A patent/JP2008520742A/ja active Pending
- 2005-11-23 JP JP2007543449A patent/JP2008520741A/ja active Pending
- 2005-11-23 EP EP05852074A patent/EP1828195A2/en not_active Withdrawn
- 2005-11-23 EP EP05852076A patent/EP1824821A2/en not_active Withdrawn
- 2005-11-23 US US11/720,061 patent/US8143257B2/en not_active Expired - Fee Related
- 2005-11-23 JP JP2007543448A patent/JP2008520740A/ja active Pending
- 2005-11-23 WO PCT/US2005/042482 patent/WO2006065479A2/en not_active Ceased
- 2005-11-23 MX MX2007006178A patent/MX2007006178A/es not_active Application Discontinuation
- 2005-11-23 CA CA002588384A patent/CA2588384A1/en not_active Abandoned
- 2005-11-23 WO PCT/US2005/042483 patent/WO2006065480A2/en not_active Ceased
- 2005-11-23 MX MX2007006179A patent/MX2007006179A/es not_active Application Discontinuation
- 2005-11-23 CA CA002588607A patent/CA2588607A1/en not_active Abandoned
-
2015
- 2015-01-26 US US14/605,721 patent/US9271960B2/en not_active Expired - Lifetime
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4014890A (en) * | 1976-03-23 | 1977-03-29 | Pfizer Inc. | Process for preparing indole derivatives |
| JPH04178387A (ja) * | 1989-11-01 | 1992-06-25 | Toyama Chem Co Ltd | 新規なイソインドール誘導体およびその塩 |
| US5451600A (en) * | 1994-04-19 | 1995-09-19 | Hoffmann-La Roche Inc. | Substituted tetrahydrobenzopyrrolylfuranoic acid derivatives as phospholipase A2 inhibitors |
| US6175015B1 (en) * | 1996-08-12 | 2001-01-16 | Neurogen Corporation | Fused indolecarboxamides: dopamine receptor subtype specific ligands |
| WO2004069831A1 (en) * | 2003-02-10 | 2004-08-19 | Glenmark Pharmaceuticals Ltd. | Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation |
| WO2004096766A1 (en) * | 2003-04-29 | 2004-11-11 | The Australian National University | A method of indole synthesis |
Non-Patent Citations (2)
| Title |
|---|
| JPN5007021001; K. SHANMUGASUNDARAM: ZEITSCHRIFT FUER NATURFORSCHUNG V54B, 1999, P1202-1204 * |
| JPN5007021002; K. SHANMUGASUNDARAM: INDIAN JOURNAL OF CHEMISTRY V37B, 199811, P1133-1136 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008536876A (ja) * | 2005-04-18 | 2008-09-11 | ピーティーシー セラピューティクス,インコーポレーテッド | 癌の治療に有用なカルボリン誘導体 |
| US11613538B2 (en) | 2009-05-27 | 2023-03-28 | Ptc Therapeutics, Inc. | Method of inhibiting or reducing a viral infection |
| JP2022163087A (ja) * | 2014-09-10 | 2022-10-25 | エピザイム インコーポレイテッド | Smyd阻害剤 |
| US11458126B2 (en) | 2017-08-01 | 2022-10-04 | Ptc Therapeutics, Inc. | DHODH inhibitor for use in treating hematologic cancers |
Also Published As
| Publication number | Publication date |
|---|---|
| US8143257B2 (en) | 2012-03-27 |
| WO2006058088A2 (en) | 2006-06-01 |
| CA2588389A1 (en) | 2006-06-22 |
| CA2588607A1 (en) | 2006-06-01 |
| EP1828195A2 (en) | 2007-09-05 |
| US20080261956A1 (en) | 2008-10-23 |
| WO2006065479A2 (en) | 2006-06-22 |
| EP1817025A2 (en) | 2007-08-15 |
| JP2008520741A (ja) | 2008-06-19 |
| US20090042866A1 (en) | 2009-02-12 |
| JP2008520740A (ja) | 2008-06-19 |
| US9271960B2 (en) | 2016-03-01 |
| MX2007006180A (es) | 2007-06-20 |
| US20150141418A1 (en) | 2015-05-21 |
| WO2006065480A3 (en) | 2006-08-03 |
| MX2007006179A (es) | 2007-06-20 |
| WO2006058088A3 (en) | 2006-12-07 |
| WO2006065480A2 (en) | 2006-06-22 |
| US8946444B2 (en) | 2015-02-03 |
| EP1824821A2 (en) | 2007-08-29 |
| WO2006065479A3 (en) | 2006-08-03 |
| MX2007006178A (es) | 2007-06-20 |
| CA2588384A1 (en) | 2006-06-22 |
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