培利替尼 | 257933-82-7

• 物质功能分类: 生物化工 - 抑制剂 - 蛋白酪氨酸激酶
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 培利替尼
• 中文别名: (2E)-N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基氨基)-2-丁烯酰胺；贝利替尼；萘哌地尔双盐酸
• 英文名称: pelitinib
• 英文别名: 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline；(2E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide；(E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide；(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide；4-dimethylamino-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-amide
• CAS: 257933-82-7
• 化学式: C₂₄H₂₃ClFN₅O₂
• 分子量: 467.93
• InChiKey: WVUNYSQLFKLYNI-AATRIKPKSA-N

物化性质

• 熔点：
  173-178°C
• 沸点：
  655.5±55.0 °C(Predicted)
• 密度：
  1.34
• 溶解度：
  DMSO：可溶5mg/mL，澄清（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  90.3
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 危险等级：
  6.1
• 危险品标志：
  T
• 安全说明：
  S45
• 危险类别码：
  R25
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811 6.1 / PGIII
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20°C 冰箱

制备方法与用途

生物活性

培利替尼（Pelitinib）是一种有效的不可逆EGFR抑制剂，IC50为38.5 nM。其还轻微抑制Src、MEK/ERK和ErbB2，对应的IC50值分别为282 nM、800 nM和1.255 μM。Phase 2。

溶解性

体外(25℃)：

• DMSO——13 mg/mL (27.78 mM)
• 水——<1 mg/mL (<1 mM)
• 乙醇——<1 mg/mL (<1 mM)

体内(25℃)：

• 30% PEG400/0.5%Tween80/5%丙二醇——30 mg/mL

生物活性

Pelitinib (EKB-569) 是一种有效的不可逆EGFR抑制剂，IC50为38.5 nM。此外，它还轻微抑制Src、MEK/ERK和ErbB2，对应的IC50值分别为282 nM、800 nM和1.255 μM。Phase 2。

靶点

Target	Value
EGFR	38.5 nM
Src	282 nM
MEK/ERK	800 nM
ErbB2	1.255 μM
Raf	3.353 μM

体外研究

Pelitinib在抑制EGFR方面表现出比c-erbB-2等密切相关的激酶更强的活性（IC50范围为282 nM (Src) 到 >20 μM(Cdk4)）。在A431细胞中，Pelitinib治疗显著抑制了EGFR自磷酸化，而对c-Met没有作用。它有效抑制正常人角质细胞(NHEK)，以及A431和MDA-468肿瘤细胞的增殖，IC50分别为61 nM、125 nM 和 260 nM；对于MCF-7细胞则活性较低，IC50为3.6 μM。在A431和NHEK细胞中，Pelitinib抑制EGF诱导的EGFR磷酸化，IC50分别为20-80 nM，并且也抑制了STAT3的磷酸化，IC50值为30-70 nM。在75-500 nM浓度下，Pelitinib特异性抑制AKT和ERK1/2的活化而不影响NF-κB通路，在NHEK细胞中还能有效抑制TGF-α介导的EGFR激活，IC50为56 nM。此外，它还抑制STAT3和ERK1/2的活化，其IC50分别为60 nM和62 nM。

体内研究

在过表达EGFR的A431异种移植模型中，单剂量口服Pelitinib（10 mg/kg）有效抑制了EGFR磷酸化，在1小时内抑制率达到90%，24小时后抑制率超过50%。每天给予Pelitinib (20 mg/kg) 可选择性抑制体内气道上皮细胞中的EGFR信号。在病毒感染诱导的、具有延迟但永久性转变为杯状细胞化生特点的小鼠气道上皮细胞重构模型中，Pelitinib (20 mg/kg/day) 治疗能够通过完全阻断纤毛细胞增加和Clara细胞减少这三个方面纠正上皮细胞重构，并显著抑制了杯状细胞的化生。

反应信息

• 作为反应物：
  描述：

  培利替尼 、 碘甲烷 以 四氢呋喃 为溶剂， 以93%的产率得到4-trimethylammonium-but-2-enoic acid [4-(3-chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl]amide iodide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

  摘要：

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm020241c
• 作为产物：
  描述：

  (E)-2-Cyano-3-(3-ethoxy-4-nitro-phenylamino)-acrylic acid ethyl ester 在 diphenyl ether-biphenyl eutectic 、 铁粉 、 氯化铵 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 异丙醇 为溶剂， 反应 11.25h， 生成 培利替尼
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

  摘要：

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm020241c

文献信息

• THIAZOLYL-DIHYDRO-CHINAZOLINE
  申请人：Brandl Trixi

  公开号：US20070238746A1

  公开（公告）日：2007-10-11

  Disclosed are compounds of general formula (I), wherein the groups A, R 1 , R 2 , R a and R b have the meanings given in the claims and specification, the tautomers, racemates, enantiomers, diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts, solvates and hydrates thereof, and processes for preparing these thiazolyl-dihydro-quinazolines and the use thereof as pharmaceutical compositions.

  揭示了一般式(I)的化合物， 其中，基团A，R1，R2，Ra和Rb具有权利要求和说明中给定的含义，其互变异构体，拉克酸盐，对映体，非对映体和它们的混合物，以及可选择的药理学上可接受的酸加盐，溶剂合物和水合物，以及制备这些噻唑基-二氢喹唑啉并将其用作药物组合物的方法。
• Pteridinone derivatives as PI3-kinases inhibitors
  申请人：Boehringer Ingelheim Pharma GmbH & Co. KG

  公开号：EP1953163A1

  公开（公告）日：2008-08-06

  New compounds of formula 1 are provided which by virtue of their pharmaceutical activity as PI3-kinase modulators may be used in the therapeutic field for the treatment of inflammatory or allergic diseases. Examples of these include inflammatory and allergic respiratory complaints, inflammatory diseases of the gastro-intestinal tract and motor apparatus, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic conditions involving autoimmune reactions or inflammations of the kidney.

  根据其作为PI3-激酶调节剂的药理活性，提供了公式1的新化合物，可用于治疗炎症或过敏性疾病的治疗领域。 这些例子包括炎症和过敏性呼吸道疾病，胃肠道和运动器官的炎症性疾病，炎症性和过敏性皮肤疾病，炎症性眼病，鼻黏膜疾病，涉及自身免疫反应或肾脏炎症的炎症性或过敏性疾病。
• THIAZOLYL-DIHYDRO-INDAZOLE
  申请人：Maier Udo

  公开号：US20070259855A1

  公开（公告）日：2007-11-08

  Disclosed are compounds of general formula (I), wherein the groups R 1 , R 2 , R a and R b have the meanings given in the claims and specification, the tautomers, racemates, enantiomers, diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts, solvates and hydrates thereof, and processes for preparing these thiazolyl-dihydro-indazoles and the use thereof as pharmaceutical compositions.

  揭示了一般式(I)的化合物， 其中基团R1、R2、Ra和Rb具有权利要求和说明中给定的含义，其互变异构体、消旋体、对映体、非对映异构体及其混合物，以及可选择的药理学上可接受的酸加盐、溶剂化合物和水合物，以及制备这些噻唑基二氢吲唑烷并将其用作药物组合物的方法。
• [EN] THERAPEUTIC COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS THÉRAPEUTIQUES ET LEURS UTILISATIONS
  申请人：GENENTECH INC

  公开号：WO2015135094A1

  公开（公告）日：2015-09-17

  The present invention relates to compounds useful as inhibitors of one or more histone demethylses, such as KDM5. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

  本发明涉及作为一个或多个组蛋白去甲基化酶抑制剂的化合物。该发明还提供了包括本发明化合物的药用可接受组合物，以及使用这些组合物治疗各种疾病的方法。
• SUBSTITUTED PYRIDINYL-PYRIMIDINES AND THEIR USE AS MEDICAMENTS
  申请人：Dahmann Georg

  公开号：US20130023502A1

  公开（公告）日：2013-01-24

  The invention relates to new substituted pyridinyl-pyrimidines of formula 1 wherein ring A is a five-membered saturated or unsaturated carbocyclic ring which optionally comprises one, two or three heteroatoms each independently from each other selected from the group N, S and O, wherein R 1 , R 2 , R 4 , R 3 , R 5 and R 6 are defined as in claim 1 and wherein ring A is further optionally substituted by one or two further substituents and the pharmaceutically acceptable salts, diastereomers, enantiomers, racemates, hydrates and solvates of the aforementioned compounds.

  该发明涉及公式1中的新取代吡啶基嘧啶化合物， 其中环A是一个含有五个成员的饱和或不饱和碳环，该环可选地包含一个、两个或三个异原子，每个异原子独立地选自N、S和O组成， 其中R1、R2、R4、R3、R5和R6如权利要求书中所定义，并且环A进一步可选地被一个或两个进一步取代基取代，以及上述化合物的药用盐、二对映体、对映体、消旋体、水合物和溶剂化合物。