4-氰基-2-甲基-1H-吲哚 | 1360883-22-2

• 物质功能分类: 医药中间体 - 杂环化合物 - 吲哚类化合物
• 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
• 中文名称: 4-氰基-2-甲基-1H-吲哚
• 英文名称: 2-methyl-1H-indole-4-carbonitrile
• 英文别名: 2-methyl-4-cyano indole
• CAS: 1360883-22-2
• 化学式: C₁₀H₈N₂
• 分子量: 156.187
• InChiKey: WQMZLOOFONQYCE-UHFFFAOYSA-N

物化性质

• 沸点：
  353.9±22.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  39.6
• 氢给体数：
  1
• 氢受体数：
  1

安全信息

• 储存条件：
  | 2-8°C |

反应信息

• 作为反应物：
  描述：

  4-氰基-2-甲基-1H-吲哚 在 tris-(dibenzylideneacetone)dipalladium(0) 、 乙醛肟 、 palladium diacetate 、 caesium carbonate 、 三苯基膦 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 14.0h， 生成 1-(4-(苄基氨基)-7,8-二氢-5H-吡喃并[4,3-D]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺
  参考文献：
  名称：

  Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer

  摘要：

  Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 mu M). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.

  DOI：

  10.1016/j.bmc.2018.12.036
• 作为产物：
  描述：

  4-溴吲哚 在 1,1'-双(二苯基膦)二茂铁 、 tris-(dibenzylideneacetone)dipalladium(0) 、 正丁基锂 、 sodium hydride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 水 为溶剂， 反应 18.0h， 生成 4-氰基-2-甲基-1H-吲哚
  参考文献：
  名称：

  Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)

  摘要：

  The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin proteasome system (ups) mediated protein degradation, endoplasmic reticulum-associated degradation (BRAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-6083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell, death. In tumor bearing mice, oral administration of 71 causes rapid accumulation Of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to Sustained antitumor activity in in vivo, xenograft models of both solid and hematological tumors. 71 has been taken into phase I clinical trials in patients with multiple myeloma and solid tumors.

  DOI：

  10.1021/acs.jmedchem.5b01346
• 作为试剂：
  描述：

  4-氰基-2-甲基-1H-吲哚 、 N-benzyl-2-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine 在 4-氰基-2-甲基-1H-吲哚 作用下， 以70的产率得到1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile
  参考文献：
  名称：

  FUSED PYRIMIDINES AS INHIBITORS OF P97 COMPLEX

  摘要：

  本发明公开了一种融合嘧啶化合物，其具有饱和，不饱和或芳香性A环融合到嘧啶环上，并在嘧啶环的2位位置具有复杂的取代基和取代胺在嘧啶环的4位位置，以及可选的脂肪烷基，功能性和/或芳香基组分取代在嘧啶环和A环的其他位置。这些化合物是AAA蛋白酶复合物的抑制剂，包含p97，并且是用于治疗与p97生物活性相关的疾病的有效药物，例如癌症。

  公开号：

  US20170258795A1

文献信息

• [EN] MONO AND BICYCLIC RING BORONIC ACID, ESTER AND SALT COMPOUNDS AS INHIBITORS OF P97 COMPLEX<br/>[FR] COMPOSÉS D'ESTER, DE SEL ET D'ACIDE BORONIQUE À NOYAU MONOCYCLIQUE ET BICYCLIQUE EN TANT QU'INHIBITEURS DE COMPLEXE P97
  申请人：CLEAVE BIOSCIENCES INC

  公开号：WO2016200840A1

  公开（公告）日：2016-12-15

  Monocyclic or bicyclic ring boronic acid or ester compounds having an arylalkyi amine substituent at the 4 position and a substituted 5:6 bicyclic group at the 2 position of the mono or bicyclic ring boronic acid or ester as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the mono or bicyclic boronic acid or ester compounds are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with the Valosin containing protein and p97 bioactivity such as cancer. Formula (I).

  单环或双环硼酸或硼酸酯化合物，在4位具有芳烷基胺取代基，在单环或双环硼酸或硼酸酯的2位具有取代的5:6双环基团，以及在单环或双环硼酸或硼酸酯化合物的其他位置可选地取代有脂肪族、功能性和/或芳香族组分。这些化合物是含有p97的AAA蛋白酶体的抑制剂，并且是治疗与含有Valosin蛋白和p97生物活性相关的疾病的有效药物，如癌症。公式(I)。
• [EN] SERINE/THREONINE PAK1 INHIBITORS<br/>[FR] INHIBITEURS DE SÉRINE/THRÉONINE PAK1
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013026914A1

  公开（公告）日：2013-02-28

  Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有以下式I的化合物，其中A、Z、R1a、R1b、R2、R3、R4、R5、R6、R7、R9、R10、Ra、Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了用于治疗癌症和高增殖性疾病的组合物和方法。
• [EN] FUSED PYRIMIDINES AS INHIBITORS OF p97 COMPLEX<br/>[FR] PYRIMIDINES FUSIONNÉES EN TANT QU'INHIBITEURS DU COMPLEXE P97
  申请人：ZHOU HAN-JIE

  公开号：WO2014015291A1

  公开（公告）日：2014-01-23

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明揭示了一种融合嘧啶化合物，其具有饱和、不饱和或芳香性A环与嘧啶环融合，并在嘧啶环的2位具有复杂的取代基，在4位具有取代胺基，以及在其他位置可选地具有取代的脂肪族、功能性和/或芳香性组分的嘧啶环和A环。这些化合物是包含p97的AAA蛋白酶复合物的抑制剂，是治疗与p97生物活性相关的疾病如癌症的有效药物。
• Development of Red‐Shifted and Fluorogenic Nucleoside and Oligonucleotide Diarylethene Photoswitches
  作者：Theresa Kolmar、Antonia Becker、Ronja A. Pfretzschner、Alina Lelke、Andres Jäschke

  DOI：10.1002/chem.202103133

  日期：2021.12.9

  The core structure of nucleoside based diarylethenes was modified, with the aim of bathochromically shifting the absorption wavelength in the visible range (λmax,vis) and to introduce photomodulatable fluorescence. Extending the π-system of the bridging unit resulted in a desired red shift of λmax,vis and fluorogenicity could be obtained by the introduction of a fluorescent adenosine analogue.

  对基于核苷的二芳基乙烯的核心结构进行了修改，目的是使吸收波长在可见光范围 (λ max,vis ) 发生红移，并引入可光调制的荧光。扩展桥接单元的 π 系统导致所需的 λ max,vis的红移，并且可以通过引入荧光腺苷类似物来获得荧光性。
• TRICYCLIC FUSED PYRIMIDINE COMPOUNDS AS INHIBITORS OF p97 COMPLEX
  申请人：Cleave Biosciences, Inc.

  公开号：US20170267679A1

  公开（公告）日：2017-09-21

  Tricyclic fused pyrimidine compounds having an arylalkyl amine substituent at the P4 position and a substituted 1H-indol-1-yl, 1H-indol-3-yl, indanyl, indazol-1-yl, indazol-3-yl, benzotriazol-1-yl or 1H-benz[d]imidazol-1-yl group at the P2 position well as optional aliphatic, functional and/or aromatic components substituted at other positions of the tricyclic compounds of the invention. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  具有P4位置上芳基烷基胺取代基和P2位置上取代的1H-吲哚-1-基、1H-吲哚-3-基、茚基、吲唑-1-基、吲唑-3-基、苯并三唑-1-基或1H-苯并[d]咪唑-1-基团的三环融合嘧啶化合物，以及可选的取代其他位置的脂肪、功能性和/或芳香成分的三环化合物。这些化合物是含有p97的AAA蛋白酶体复合物的抑制剂，是用于治疗与p97生物活性相关的疾病如癌症的有效药物。