(((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)oxy)methyl (tert-butoxycarbonyl)glycyl-L-leucinate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)oxy)methyl (tert-butoxycarbonyl)glycyl-L-leucinate
• 英文别名: [(3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-3,4-dihydrochromen-3-yl]oxymethyl (2S)-4-methyl-2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]pentanoate
• 化学式: C₃₀H₄₂N₄O₈
• 分子量: 586.685
• InChiKey: FVSJIWMGNVNJLR-BYXVTNLJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  156
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)oxy)methyl (tert-butoxycarbonyl)glycyl-L-leucinate 在 盐酸 作用下， 以 水 为溶剂， 反应 0.5h， 以23%的产率得到(((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)oxy)methyl glycyl-L-leucinate
  参考文献：
  名称：

  具有体内眼部降压活性的ATP敏感性钾（K ATP）通道开放剂克罗卡林的类似物

  摘要：

  ATP敏感性钾（K ATP）通道开放剂已成为治疗青光眼，降低动物模型和培养的人前眼节的眼内压（IOP）的潜在疗法。我们已经制备了K ATP的水溶性磷酸酯和二肽衍生物开沟剂cromakalim并评估了它们在体内降低IOP的能力。通常，在血压正常的小鼠模型中，每天给药一次，磷酸盐衍生物在降低IOP方面具有更强的化学稳定性和有效性。在正常血压的兔子模型中进一步评估了其中的两种磷酸盐衍生物，观察到活性存在显着差异。用最有效的化合物（3 S，4 R）-2处理后，未观察到对房水流出通道的细胞结构或形态变化有毒害作用，表明它是发展为眼压降压药的强力候选者。 。

  DOI：

  10.1021/acs.jmedchem.6b00406
• 作为产物：
  描述：

  左色满卡林 在 磺酰氯 、 乙酸酐 作用下， 以 二氯甲烷 、 溶剂黄146 为溶剂， 反应 28.5h， 生成 (((3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-3-yl)oxy)methyl (tert-butoxycarbonyl)glycyl-L-leucinate
  参考文献：
  名称：

  具有体内眼部降压活性的ATP敏感性钾（K ATP）通道开放剂克罗卡林的类似物

  摘要：

  ATP敏感性钾（K ATP）通道开放剂已成为治疗青光眼，降低动物模型和培养的人前眼节的眼内压（IOP）的潜在疗法。我们已经制备了K ATP的水溶性磷酸酯和二肽衍生物开沟剂cromakalim并评估了它们在体内降低IOP的能力。通常，在血压正常的小鼠模型中，每天给药一次，磷酸盐衍生物在降低IOP方面具有更强的化学稳定性和有效性。在正常血压的兔子模型中进一步评估了其中的两种磷酸盐衍生物，观察到活性存在显着差异。用最有效的化合物（3 S，4 R）-2处理后，未观察到对房水流出通道的细胞结构或形态变化有毒害作用，表明它是发展为眼压降压药的强力候选者。 。

  DOI：

  10.1021/acs.jmedchem.6b00406

文献信息

• Therapeutics for the treatment of glaucoma
  申请人：MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH

  公开号：US10981951B2

  公开（公告）日：2021-04-20

  The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.

  本发明提供苯并噻二嗪和色苷衍生物，特别是用于治疗青光眼、视网膜病变、治疗年龄相关性黄斑变性、治疗、稳定和/或抑制血液和淋巴血管生成，并通过向眼睛内给予药学有效量的前药，其中前药特异性调节KATP通道以降低眼内压力。
• NOVEL THERAPEUTICS FOR THE TREATMENT OF GLAUCOMA
  申请人：MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH

  公开号：US20170002040A1

  公开（公告）日：2017-01-05

  The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.
• THERAPEUTICS FOR THE TREATMENT OF GLAUCOMA
  申请人：Mayo Foundation for Medical Education and Research

  公开号：US20210040148A1

  公开（公告）日：2021-02-11

  The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a K ATP channel to reduce an intraocular pressure.
• [EN] NOVEL THERAPEUTICS FOR THE TREATMENT OF GLAUCOMA<br/>[FR] NOUVEAUX AGENTS THÉRAPEUTIQUES POUR LE TRAITEMENT DU GLAUCOME
  申请人：MAYO FOUNDATION

  公开号：WO2015117024A1

  公开（公告）日：2015-08-06

  The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a KATP channel to reduce an intraocular pressure.
• Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity
  作者：Uttio Roy Chowdhury、Kimberly B. Viker、Kristen L. Stoltz、Bradley H. Holman、Michael P. Fautsch、Peter I. Dosa

  DOI：10.1021/acs.jmedchem.6b00406

  日期：2016.7.14

  a normotensive rabbit model, with a significant difference in activity observed. No toxic effects on cell structure or alterations in morphology of the aqueous humor outflow pathway were observed after treatment with the most efficacious compound, (3S,4R)-2, suggesting that it is a strong candidate for development as an ocular hypotensive agent.

  ATP敏感性钾（K ATP）通道开放剂已成为治疗青光眼，降低动物模型和培养的人前眼节的眼内压（IOP）的潜在疗法。我们已经制备了K ATP的水溶性磷酸酯和二肽衍生物开沟剂cromakalim并评估了它们在体内降低IOP的能力。通常，在血压正常的小鼠模型中，每天给药一次，磷酸盐衍生物在降低IOP方面具有更强的化学稳定性和有效性。在正常血压的兔子模型中进一步评估了其中的两种磷酸盐衍生物，观察到活性存在显着差异。用最有效的化合物（3 S，4 R）-2处理后，未观察到对房水流出通道的细胞结构或形态变化有毒害作用，表明它是发展为眼压降压药的强力候选者。 。