CEP-5214 | 402857-39-0

• 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: CEP-5214
• 英文别名: 9-(1-methylethoxy)methyl-12-(3-hydroxypropyl)-6H,7H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one；3-(5,6,7,13-Tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12h-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propanol；3-(3-hydroxypropyl)-7-(propan-2-yloxymethyl)-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4(9),5,7,11(15),17,19,21-nonaen-14-one
• CAS: 402857-39-0
• 化学式: C₂₈H₂₈N₂O₃
• 分子量: 440.542
• InChiKey: MLIFNJABMANKEU-UHFFFAOYSA-N

物化性质

• 熔点：
  224-228 °C
• 沸点：
  705.7±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  63.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N,N-二甲基甘氨酸 、 CEP-5214 在 4-二甲氨基吡啶 、 N,N-二甲基乙酰胺 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 反应 3.5h， 以78%的产率得到CEP-7055
  参考文献：
  名称：

  A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors:  Structure−Activity Relationships for a Series of 9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055

  摘要：

  A series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors from a new indenopyrrolocarbazole template is reported. The structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones revealed an optimal R9 substitution with ethoxymethyl 19 (VEGF-R2 IC50 = 4 nM) and isopropoxymethyl 21 (VEGF-R2 IC50 = 8 nM) being the most potent inhibitors in the series. The VEGF-R2 activity was reduced appreciably by increasing the size of the R9 alkoxy group or by alpha-methyl branching adjacent to the ring. The combined R9 alkoxymethyl. and N12 hydroxypropyl substitutions were required for potent VEGF-R2 activity, and the corresponding thioether analogues were weaker than their ether counterparts. Compound 21 (R9 isopropoxymethyl, CEP-5214) was identified as a potent, low-nanomolar pan inhibitor of human VEGF-R tyrosine kinases, displaying IC50 values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, respectively, with cellular activity equivalent to the isolated enzyme activity. Compound 21 exhibited good selectivity against numerous tyrosine and serine/threonine kinases including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK. To increase water solubility and oral bioavailability, the N,N-dimethylglycine ester 40 was prepared. In pharmacokinetic studies in mice and rats, increased plasma levels of 21 were observed after oral administration of 40. Compound 21 demonstrated significant in vivo antitumor activity in numerous tumor models and was advanced into phase I clinical trials as the water-soluble N,N-dimethylglycine ester prodrug 40 (CEP-7055).

  DOI：

  10.1021/jm0301641
• 作为产物：
  描述：

  2-Methoxyethyl 3-(3-hydroxypropyl)-14-oxo-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4(9),5,7,11(15),17,19,21-nonaene-7-carboxylate 在 二异丁基氢化铝 、 三乙胺 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 生成 CEP-5214
  参考文献：
  名称：

  A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors:  Structure−Activity Relationships for a Series of 9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055

  摘要：

  A series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors from a new indenopyrrolocarbazole template is reported. The structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones revealed an optimal R9 substitution with ethoxymethyl 19 (VEGF-R2 IC50 = 4 nM) and isopropoxymethyl 21 (VEGF-R2 IC50 = 8 nM) being the most potent inhibitors in the series. The VEGF-R2 activity was reduced appreciably by increasing the size of the R9 alkoxy group or by alpha-methyl branching adjacent to the ring. The combined R9 alkoxymethyl. and N12 hydroxypropyl substitutions were required for potent VEGF-R2 activity, and the corresponding thioether analogues were weaker than their ether counterparts. Compound 21 (R9 isopropoxymethyl, CEP-5214) was identified as a potent, low-nanomolar pan inhibitor of human VEGF-R tyrosine kinases, displaying IC50 values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, respectively, with cellular activity equivalent to the isolated enzyme activity. Compound 21 exhibited good selectivity against numerous tyrosine and serine/threonine kinases including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK. To increase water solubility and oral bioavailability, the N,N-dimethylglycine ester 40 was prepared. In pharmacokinetic studies in mice and rats, increased plasma levels of 21 were observed after oral administration of 40. Compound 21 demonstrated significant in vivo antitumor activity in numerous tumor models and was advanced into phase I clinical trials as the water-soluble N,N-dimethylglycine ester prodrug 40 (CEP-7055).

  DOI：

  10.1021/jm0301641

文献信息

• METHOD FOR ASSAY ON THE EFFECT OF VASCULARIZATION INHIBITOR
  申请人：Uenaka Toshimitsu

  公开号：US20100092490A1

  公开（公告）日：2010-04-15

  The present invention provides a method of predicting the antitumor effect of an angiogenesis inhibitor. It is possible to predict the antitumor effect of an angiogenesis inhibitor by evaluating the EGF dependency of a tumor cell for proliferation and/or survival and using the EGF dependency as an indicator. Since the antitumor effect of an angiogenesis inhibitor correlates with the EGF dependency of a tumor cell for proliferation and/or survival, the angiogenesis inhibitors is capable of producing excellent antitumor effect when combined with a substance having EGF inhibitory activity.

  本发明提供了一种预测抗血管生成抑制剂的抗肿瘤效果的方法。通过评估肿瘤细胞对表皮生长因子（EGF）增殖和/或存活的依赖性，并将其作为指标，可以预测抗血管生成抑制剂的抗肿瘤效果。由于抗血管生成抑制剂的抗肿瘤效果与肿瘤细胞对EGF增殖和/或存活的依赖性相关，因此当与具有EGF抑制活性的物质结合时，抗血管生成抑制剂能够产生出色的抗肿瘤效果。
• JOINT USE OF SULFONAMIDE BASED COMPOUND WITH ANGIOGENESIS INHIBITOR
  申请人：Eisai Co., Ltd.

  公开号：EP1797877A1

  公开（公告）日：2007-06-20

  The present invention relates to pharmaceutical compositions comprising a sulfonamide-including compound in combination with an angiogenesis inhibitor.

  本发明涉及药物组合物，其中包括磺胺类化合物与血管生成抑制剂的组合。
• Anti-tumour pharmaceutical composition with angiogenesis inhibitors
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP2281901A2

  公开（公告）日：2011-02-09

  The present invention provides a pharmaceutical composition comprising a VEGF receptor kinase inhibitor in combination with a substance having EGF inhibitory activity. The pharmaceutical composition can be used in a method of treating cancer. The invention also provides kits containing a combination of a preparation comprising a VEGF receptor kinase inhibitor and a preparation comprising a substance having EGF inhibitory activity.

  本发明提供了一种药物组合物，它包含一种血管内皮生长因子受体激酶抑制剂与一种具有表皮生长因子抑制活性的物质。该药物组合物可用于治疗癌症的方法中。本发明还提供了包含由血管内皮生长因子受体激酶抑制剂组成的制剂和由具有 EGF 抑制活性的物质组成的制剂组合的试剂盒。
• Joint use of sulfonamide based compound with angiogenesis inhibitor
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP2364699A1

  公开（公告）日：2011-09-14

  The present invention relates to a pharmaceutical composition comprising a sulfonamide-including compound in combination with a VEGF receptor kinase inhibitor as an angiogenesis, inhibitor, wherein the sulfonamide-including compound is N-(3-cyano-4-methyl-1 H-indol-7-yl)-3-cyanobenzenesulfonaxnide (E7820), or a pharmacologically acceptable salt thereof or a solvate thereof.

  本发明涉及一种药物组合物，该药物组合物包含一种磺酰胺类化合物与一种血管内皮生长因子受体激酶抑制剂组合作为血管生成抑制剂、 其中包括磺酰胺的化合物是N-(3-氰基-4-甲基-1H-吲哚-7-基)-3-氰基苯磺酰亚胺(E7820)，或其药理上可接受的盐或其溶液。
• METHOD FOR PREDICTING EFFECTIVENESS OF ANGIOGENESIS INHIBITOR
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP2711433A1

  公开（公告）日：2014-03-26

  The purpose of the present invention is to provide a method for predicting the effectiveness of an angiogenesis inhibitor in a subject suffering from a tumor. Provided is a method comprising a step of testing for the presence or absence of an a mutation or loss of expression of B-Raf and PTEN in a sample of tumor tissue from the subject. By using the presence or absence of or a mutation or loss of expression of B-Raf and PTEN as an indicator, this method enables the antitumor effectiveness of the angiogenesis inhibitor to be predicted without administering the angiogenesis inhibitor to the subject.

  本发明的目的是提供一种预测血管生成抑制剂对肿瘤患者疗效的方法。本发明提供的方法包括检测受试者肿瘤组织样本中是否存在 B-Raf 和 PTEN 的突变或表达缺失。通过使用B-Raf和PTEN的存在或不存在或突变或表达缺失作为指标，该方法能够在不对受试者施用血管生成抑制剂的情况下预测血管生成抑制剂的抗肿瘤效果。