KR101707247B1 - 프로스타시클린 (ｐｇｉ2) 수용체와 관련된 장애의 치료에 유용한 상기 수용체의 조절제로서의 피라졸 치환된 탄산 유도체 - Google Patents
프로스타시클린 (ｐｇｉ2) 수용체와 관련된 장애의 치료에 유용한 상기 수용체의 조절제로서의 피라졸 치환된 탄산 유도체 Download PDFInfo
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- KR101707247B1 KR101707247B1 KR1020117014566A KR20117014566A KR101707247B1 KR 101707247 B1 KR101707247 B1 KR 101707247B1 KR 1020117014566 A KR1020117014566 A KR 1020117014566A KR 20117014566 A KR20117014566 A KR 20117014566A KR 101707247 B1 KR101707247 B1 KR 101707247B1
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/18—One oxygen or sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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| CN104262267B9 (zh) * | 2008-03-18 | 2019-04-12 | 艾尼纳制药公司 | 用于治疗前列环素(pgi2)受体相关病症的pgi2受体调节剂 |
| US20110224262A1 (en) | 2008-11-26 | 2011-09-15 | Arena Pharmaceuticals, Inc. | Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto |
| PL2370413T3 (pl) | 2008-12-08 | 2016-01-29 | Arena Pharm Inc | Modulatory receptora prostacykliny (PGI2) użyteczne w leczeniu zaburzeń z nimi związanych |
| TWI576371B (zh) | 2011-09-30 | 2017-04-01 | 日本化成股份有限公司 | 聚合性無機粒子分散劑，含有該聚合性無機粒子分散劑之無機有機複合粒子及無機有機樹脂複合材 |
| CA2851142A1 (en) | 2011-10-06 | 2013-04-11 | Bayer Intellectual Property Gmbh | Heterocyclylpyri (mi) dinylpyrazole as fungicidals |
| WO2013050434A1 (en) | 2011-10-06 | 2013-04-11 | Bayer Intellectual Property Gmbh | Heterocyclylpyri(mi)dinylpyrazole |
| EA201790905A1 (ru) | 2014-10-23 | 2017-09-29 | Арена Фармасьютикалз, Инк. | Способ лечения состояний, связанных с рецептором pgi2 |
| KR20230021186A (ko) | 2016-11-10 | 2023-02-13 | 아레나 파마슈티칼스, 인크. | 라리네팍 및 다른 제제의 조합에 의한 pah의 치료 방법 |
| CN110582271B (zh) | 2017-03-01 | 2022-06-14 | 阿瑞那制药公司 | 包含pgi2受体激动剂的组合物及其制备方法 |
| CN111699175B (zh) | 2018-02-07 | 2022-03-29 | 南京明德新药研发有限公司 | 前列环素受体受体激动剂 |
| EP3796902A1 (en) | 2018-05-16 | 2021-03-31 | Arena Pharmaceuticals, Inc. | Compositions comprising pgi2-receptor agonists and processes for the preparation thereof |
| WO2023158634A1 (en) | 2022-02-15 | 2023-08-24 | United Therapeutics Corporation | Crystalline prostacyclin (ip) receptor agonist and uses thereof |
| KR20250099113A (ko) | 2022-09-09 | 2025-07-01 | 이노보 테라퓨틱스 인코포레이티드 | CK1α 및 DUAL CK1α/GSPT1 분해 화합물 |
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| US1021451A (en) | 1911-04-22 | 1912-03-26 | James F Craven | Receptacle for containing and discharging semisolid and pasty substances. |
| DE2945530A1 (de) | 1979-11-10 | 1981-06-04 | Chemische Werke Hüls AG, 4370 Marl | Harnstoffe mit cyclischen substituenten, ihre herstellung und verwendung als herbizide |
| JPH03160438A (ja) | 1989-11-20 | 1991-07-10 | Konica Corp | ハロゲン化銀カラー写真感光材料 |
| EP0442448A3 (en) | 1990-02-13 | 1992-08-12 | Bristol-Myers Squibb Company | Heterocyclic carboxylic acids and esters |
| CA2085844A1 (en) * | 1991-12-27 | 1993-06-28 | Nobuyuki Hamanaka | Fused benzeneoxyacetic acid derivatives |
| JPH06329598A (ja) | 1993-05-19 | 1994-11-29 | Daicel Chem Ind Ltd | エステルの製造方法 |
| DE4318889A1 (de) | 1993-06-07 | 1994-12-08 | Bayer Ag | Verfahren zur Herstellung von organischen Carbamaten |
| JP3160438B2 (ja) | 1993-09-29 | 2001-04-25 | 株式会社東芝 | 交通流予測装置 |
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| US20040048844A1 (en) * | 1999-10-20 | 2004-03-11 | Bristol-Myers Squibb Pharma Company | Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents |
| WO2002055484A1 (en) | 2001-01-12 | 2002-07-18 | Takeda Chemical Industries, Ltd. | Biaryl compound, process for producing the same, and agent |
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| TW200307539A (en) * | 2002-02-01 | 2003-12-16 | Bristol Myers Squibb Co | Cycloalkyl inhibitors of potassium channel function |
| TWI293715B (en) * | 2002-10-10 | 2008-02-21 | Sipix Imaging Inc | A method for inducing or enhancing the threshold of an electrophoretic display, an electrophoretic fluid and an electrophoretic display |
| JP4675318B2 (ja) * | 2003-02-10 | 2011-04-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ｎ−アリールカルバミン酸エステルとハロ−ヘテロアリールとを反応させることによるｎ−ヘテロアリール−ｎ−アリール−アミンの調製のためのプロセスおよび類似のプロセス |
| JP4402413B2 (ja) | 2003-09-29 | 2010-01-20 | 財団法人２１あおもり産業総合支援センター | Ｕ字型化合物およびこれを含む液晶組成物 |
| DE102004006785A1 (de) | 2004-02-11 | 2005-09-08 | Mayr, Herbert, Prof. Dr. | Verfahren zur CC-Bindungsknüpfung zwischen elektrophilen Substraten und TT-Verbindungen in neutralen bis basischen wässrigen oder alkoholischen Lösungsmitteln ohne den Einsatz einer Lewis- oder Protonensäure |
| JP2008510726A (ja) * | 2004-08-20 | 2008-04-10 | エントレメッド インコーポレイテッド | プロテイナーゼ活性化受容体アンタゴニストを含む組成物および方法 |
| CN101072564A (zh) * | 2004-08-26 | 2007-11-14 | 恩希赛弗制药公司 | 内皮缩血管肽a受体(eta)拮抗剂与磷酸二酯酶5(pde5)抑制剂的联合及其用途 |
| JP2006083085A (ja) | 2004-09-15 | 2006-03-30 | Kyowa Hakko Kogyo Co Ltd | 二環性ピリミジン誘導体の製造法およびその合成中間体 |
| JP4792731B2 (ja) | 2004-11-12 | 2011-10-12 | Ｄｉｃ株式会社 | 重合性液晶組成物及び当該組成物の硬化物 |
| WO2007051255A1 (en) | 2005-11-04 | 2007-05-10 | The University Of Sydney | Process for the preparation of compounds containing an azacyclic ring system |
| JP2007161867A (ja) | 2005-12-14 | 2007-06-28 | Toyo Ink Mfg Co Ltd | インキ組成物 |
| GB0603684D0 (en) | 2006-02-23 | 2006-04-05 | Novartis Ag | Organic compounds |
| WO2007133653A2 (en) | 2006-05-09 | 2007-11-22 | Hemaquest Pharmaceuticals, Inc. | Methods for treating blood disorders |
| CN104262267B9 (zh) * | 2008-03-18 | 2019-04-12 | 艾尼纳制药公司 | 用于治疗前列环素(pgi2)受体相关病症的pgi2受体调节剂 |
| US20110224262A1 (en) | 2008-11-26 | 2011-09-15 | Arena Pharmaceuticals, Inc. | Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto |
| PL2370413T3 (pl) | 2008-12-08 | 2016-01-29 | Arena Pharm Inc | Modulatory receptora prostacykliny (PGI2) użyteczne w leczeniu zaburzeń z nimi związanych |
| WO2011037613A1 (en) | 2009-09-23 | 2011-03-31 | Arena Pharmaceuticals, Inc. | Crystalline forms and processes for the preparation of pgi2 receptor agonists |
| JP7343478B2 (ja) | 2017-08-07 | 2023-09-12 | アレーナ ファーマシューティカルズ，インク． | 処置の方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003016254A1 (en) | 2001-08-09 | 2003-02-27 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient |
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