5-cyano-2,10,11,12-tetrahydro-2-methyl-indazolo[5,4-a]carbazole-4-carboxylic acid ethyl ester | 856694-02-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5-cyano-2,10,11,12-tetrahydro-2-methyl-indazolo[5,4-a]carbazole-4-carboxylic acid ethyl ester
• 英文别名: 5-cyano-4-ethoxycarbonyl-2,10,11,12-tetrahydro-2-methylindazolo[5,4-a]carbazole；Ethyl 11-cyano-16-methyl-3,16,17-triazapentacyclo[11.7.0.02,10.04,9.014,18]icosa-1(13),2(10),4,6,8,11,14,17-octaene-12-carboxylate
• CAS: 856694-02-5
• 化学式: C₂₂H₁₈N₄O₂
• 分子量: 370.411
• InChiKey: GURHGDSNRWCWJO-UHFFFAOYSA-N

物化性质

• 沸点：
  690.2±55.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  83.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-cyano-2,10,11,12-tetrahydro-2-methyl-indazolo[5,4-a]carbazole-4-carboxylic acid ethyl ester 在 氢气 、 硝酸 、 溶剂黄146 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 80.0 ℃ 、344.75 kPa 条件下， 反应 17.0h， 生成 11-propyl-11,12-dihydro-2-methyl-8-amino-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one
  参考文献：
  名称：

  具有免疫球蛋白和表皮生长因子样同源域2（VEGF-R / TIE-2）抑制剂11-（2-甲基丙基）-12,13-dihydro的泛血管内皮生长因子受体/酪氨酸激酶的合成和生物学特性-2-甲基-8-（嘧啶-2-基氨基）-4 H-吲唑并[5,4-a]吡咯并[3,4-c]咔唑-4-酮（CEP-11981）：新型肿瘤治疗剂

  摘要：

  大量证据支持抗血管生成抑制剂作为在多种实体和造血肿瘤中阻断或减弱肿瘤诱导的血管生成以及抑制原发性和转移性肿瘤生长的策略的实用性。鉴于肿瘤在其生长和传播的不同阶段需要不同的细胞因子和生长因子，因此最佳的抗血管生成治疗必须抑制多个，互补的和非冗余的血管生成靶标。11-（2-甲基丙基）-12,13-二氢-2-甲基-8-（嘧啶-2-基氨基）-4 H-吲唑并[5,4-a]吡咯并[3,4-c]咔唑-4 -一（11b，CEP-11981）是有效的多种靶标（TIE-2，VEGF-R1、2和3和FGF-R1）的口服活性抑制剂，在肿瘤血管生成和血管维持中具有不可或缺的作用。本文概述了11b的设计策略，合成以及生化和药理学概况，该研究完成了I期临床评估安全性和药代动力学的研究，从而可以启动概念验证研究。

  DOI：

  10.1021/jm201449n
• 作为产物：
  描述：

  在 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 乙腈 为溶剂， 生成 5-cyano-2,10,11,12-tetrahydro-2-methyl-indazolo[5,4-a]carbazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases

  摘要：

  Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.02.001

文献信息

• Novel fused pyrrolocarbazoles
  申请人：Hudkins L. Robert

  公开号：US20050143442A1

  公开（公告）日：2005-06-30

  The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

  本发明一般涉及选定的融合吡咯咯噻唑，包括其药物组合物以及用于治疗疾病的方法。本发明还涉及制备这些融合吡咯咯噻唑的中间体和方法。
• Regioselective synthesis of 2-methyl-2,5,6,11,12,13-hexahydro 4H indazolo[5,4-a]pyrrolo[3,4-c]carbazole-4-ones
  作者：Ming Tao、Chung Ho Park、Kurt Josef、Robert L. Hudkins

  DOI：10.1002/jhet.200

  日期：2009.11

  13‐hexahydro 4H indazolo[5,4‐a]pyrrolo[3,4‐c]carbazole‐4‐one was synthesized utilizing a regioselective Diels‐Alder reaction with 5‐(1H‐indol‐2‐yl)‐2‐methyl‐6,7‐dihydro‐2H‐indazole and ethyl cis‐β‐cyanoacrylate. Acetic acid and YtBr3 were the best solvent and catalyst for the regioselective Diels‐Alder reaction. The chemistry was used to synthesize novel 8‐pyrimidinyloxy‐2,5,6,11,12,13‐hexahydro 4H

  2-甲基-2-5,6,11,12,13-六氢4H吲哚并[5,4-a]吡咯并[3,4-c]咔唑-4-酮是利用区域选择性Diels-Alder反应与5合成的-（1H-吲哚-2-基）-2-甲基-6,7-二氢-2H-吲唑和顺式-β-氰基丙烯酸乙酯。乙酸和YtBr 3是区域选择性Diels-Alder反应的最佳溶剂和催化剂。该化学方法用于合成新型8-嘧啶氧基-2,5,6,11,12,13-六氢4H吲哚并[5,4-a]吡咯并[3,4-c]咔唑-4-。被发现是DLK的有效抑制剂。J.杂环化​​学，（2009）。
• Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors
  作者：Nadine C. Becknell、Allison L. Zulli、Thelma S. Angeles、Shi Yang、Mark S. Albom、Lisa D. Aimone、Candy Robinson、Hong Chang、Robert L. Hudkins

  DOI：10.1016/j.bmcl.2006.07.066

  日期：2006.10

  A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation. (c) 2006 Elsevier Ltd. All rights reserved.
• TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs
  作者：Ted L. Underiner、Bruce Ruggeri、Lisa Aimone、Mark Albom、Thelma Angeles、Hong Chang、Robert L. Hudkins、Kathryn Hunter、Kurt Josef、Candy Robinson、Linda Weinberg、Shi Yang、Allison Zulli

  DOI：10.1016/j.bmcl.2008.02.069

  日期：2008.4

  Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further pro. led in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs. (C) 2008 Elsevier Ltd. All rights reserved.
• 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors
  作者：Robert L. Hudkins、Allison L. Zulli、Ted L. Underiner、Thelma S. Angeles、Lisa D. Aimone、Sheryl L. Meyer、Daniel Pauletti、Hong Chang、Elena V. Fedorov、Steven C. Almo、Alexander A. Fedorov、Bruce A. Ruggeri

  DOI：10.1016/j.bmcl.2010.04.021

  日期：2010.6

  A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a] pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity. (C) 2010 Elsevier Ltd. All rights reserved.