(9S)-6,7,10,11-tetrahydro-19-methyl-9-[(triphenylmethoxy)-methyl]-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h]-[1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione | 170277-74-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (9S)-6,7,10,11-tetrahydro-19-methyl-9-[(triphenylmethoxy)-methyl]-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h]-[1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione
• 英文别名: (S)-6,7,10,11-tetrahydro-19-methyl-9-[(triphenylmethoxy)methyl]-9H,18H,-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione；(18S)-4-methyl-18-(trityloxymethyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione
• CAS: 170277-74-4
• 化学式: C₄₆H₃₉N₃O₄
• 分子量: 697.833
• InChiKey: ZWPDSALPNVLHEK-DHUJRADRSA-N

物化性质

• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  53
• 可旋转键数：
  6
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  65.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (9S)-6,7,10,11-tetrahydro-19-methyl-9-[(triphenylmethoxy)-methyl]-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h]-[1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione 在 potassium hydroxide 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 (9S)-6,7,10,11-tetrahydro-9-[(triphenylmethoxy)methyl]-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecine-18,20(19H)-dione
  参考文献：
  名称：

  选择性可逆PKCβ抑制剂（9 S）-9-[（（二甲氨基）甲基] -6,7,10,11-四氢-9 H，18 H-5,21：12,17-二甲基二苯并[]的合成与表征e，k] pyrrolo [3,4-h] [1,4,13]草二氮杂环己癸-18,20（19 H）-二酮，黄杨黄嘌呤（LY333531）。

  摘要：

  PKCβ在介导安非他明刺激的多巴胺流出中的调节作用，调节苯丙胺诱导的多巴胺转运蛋白的运输和活性，已证明促进了选择性可逆PKCβ抑制剂（9 S）-9-[（（二甲基氨基）甲基]- 6,7,10,11-四氢-9 H，18 H-5,21：12,17-二甲二苯并[e，k]吡咯并[3,4-h] [1,4,13]草二氮杂环十六烷-18,20 （19 H）-二酮，ruboxistaurin。尽管有兴趣开发鲁贝司他林作为甲磺酸盐一水合物（Arxxant）用于治疗糖尿病性视网膜病，黄斑水肿和肾病，但理化特性中的一些关键细节是错误的或缺失的。这份报告描述了Ruboxistaurin游离碱（作为一水合物）的合成和完整表征，包括X射线晶体学以确认其绝对构型，

  DOI：

  10.1021/acschemneuro.8b00196
• 作为产物：
  描述：

  (R)-3-chloro-1-O-trityl-1,2-propanediol 在 吡啶 、 氢氧化钾 、 sodium hydroxide 、 sodium tetrahydroborate 、 (PhO)3P*Br₂ 、 sudan red 、 乙烯基溴化镁 、 potassium tert-butylate 、 caesium carbonate 、 臭氧 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.25h， 生成 (9S)-6,7,10,11-tetrahydro-19-methyl-9-[(triphenylmethoxy)-methyl]-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h]-[1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione
  参考文献：
  名称：

  Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation

  摘要：

  Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC beta(1) and beta(2) and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.

  DOI：

  10.1021/jo971980h

文献信息

• DEUTERIUM-ENRICHED RUBOXISTAURIN
  申请人：Czarnik Anthony W.

  公开号：US20120136037A1

  公开（公告）日：2012-05-31

  The present application describes deuterium-enriched ruboxistaurin, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.
• [EN] N-DESMETHYL RUBOXISTAURIN AS KINASE INHIBITOR<br/>[FR] N-DÉMÉTHYL RUBOXISTAURINE EN TANT QU'INHIBITEUR DE KINASE
  申请人：[en]4M THERAPEUTICS INC.

  公开号：WO2023192984A1

  公开（公告）日：2023-10-05

  Aspects of this invention are related to the use of N-desmethyl ruboxistaurin and pharmaceutically acceptable formulations thereof to modulate GSK3|3 signaling. Some aspects of the invention relate to the use of N-desmethyl ruboxistaurin to inhibit protein kinase C. Some aspects of the invention provide methods of using N-desmethyl ruboxistaurin in the treatment of subjects having a neurological disease and/or psychiatric disorder, including Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression, schizophrenia, Parkinson's disease, or neuroinflammation. Some aspects of this invention provide methods of using N-desmethyl ruboxistaurin in treating conditions associated with diabetes mellitus or its complications, or ischemia, inflammation, pulmonary hypertension, congestive heart failure, cardiovascular disease, dermatological disease, or cancer. Some aspects of the invention relate to the use of N-desmethyl ruboxistaurin as an alternative to ruboxistaurin, with a better pharmacokinetic profile, lower potential for prolongation of the electrocardiogram QT interval, and/or a lower potential for adverse drug interactions. In some embodiments, N-desmethyl ruboxistaurin is administered in combination with lithium or other treatments for bipolar disorder.
• Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation
  作者：Margaret M. Faul、Leonard L. Winneroski、Christine A. Krumrich、Kevin A. Sullivan、James R. Gillig、David A. Neel、Christopher J. Rito、Michael R. Jirousek

  DOI：10.1021/jo971980h

  日期：1998.3.1

  Macrocyclic bisindolylmaleimides 1-4 have been identified as competitive reversible inhibitors of PKC beta(1) and beta(2) and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1-4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1-4 by intramolecular alkylation proved less efficient, requiring 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.
• Synthesis and Characterization of the Selective, Reversible PKC_β Inhibitor (9<i>S</i>)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9<i>H</i>,18<i>H</i>-5,21:12,17-dimethenodibenzo[<i>e,k</i>]pyrrolo[3,4-<i>h</i>][1,4,13]oxadiazacyclohexadecine-18,20(19<i>H</i>)-dione, Ruboxistaurin (LY333531)
  作者：Anita H. Lewin、Larry Brieaddy、Jeffrey R. Deschamps、Gregory H. Imler、S. Wayne Mascarella、P. Anantha Reddy、F. Ivy Carroll

  DOI：10.1021/acschemneuro.8b00196

  日期：2019.1.16

  17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization

  PKCβ在介导安非他明刺激的多巴胺流出中的调节作用，调节苯丙胺诱导的多巴胺转运蛋白的运输和活性，已证明促进了选择性可逆PKCβ抑制剂（9 S）-9-[（（二甲基氨基）甲基]- 6,7,10,11-四氢-9 H，18 H-5,21：12,17-二甲二苯并[e，k]吡咯并[3,4-h] [1,4,13]草二氮杂环十六烷-18,20 （19 H）-二酮，ruboxistaurin。尽管有兴趣开发鲁贝司他林作为甲磺酸盐一水合物（Arxxant）用于治疗糖尿病性视网膜病，黄斑水肿和肾病，但理化特性中的一些关键细节是错误的或缺失的。这份报告描述了Ruboxistaurin游离碱（作为一水合物）的合成和完整表征，包括X射线晶体学以确认其绝对构型，