CEP-7055 | 402857-58-3

• 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-7055
• 英文别名: N,N-dimethylglycine 3-{5,6,7,13-tetrahydro-9-[(1-methylethoxy)methyl]-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl}propyl ester；BLP1206；Glycine, N,N-dimethyl-, 3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propyl ester；3-[14-oxo-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-3-yl]propyl 2-(dimethylamino)acetate
• CAS: 402857-58-3
• 化学式: C₃₂H₃₅N₃O₄
• 分子量: 525.648
• InChiKey: UHEBDUAFKQHUBV-UHFFFAOYSA-N

物化性质

• 熔点：
  193-194 °C
• 沸点：
  732.4±60.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

制备方法与用途

CEP-7055 是一种强效且口服活性良好的泛血管内皮生长因子受体（VEGFR）抑制剂。它是一种二甲基甘氨酸酯前药，能够转化为 CEP-5214。CEP-5214 能够抑制人类 VEGFR2/KDR、VEGFR1/FLT-1 和 VEGFR3/FLT-4 酪氨酸激酶，其 IC50 值分别为 18 nM、12 nM 和 17 nM。

反应信息

• 作为产物：
  描述：

  6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one 在 1-甲基吡咯烷 、 4-二甲氨基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 锂硼氢 、 N,N-二甲基乙酰胺 、 茴香硫醚 、 sodium acetate 、 二异丁基氢化铝 、 对甲苯磺酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 乙腈 、 苯 为溶剂， 反应 36.5h， 生成 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

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。
• METHOD FOR PREDICTION OF THE EFFICACY OF VASCULARIZATION INHIBITOR
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP1925941A1

  公开（公告）日：2008-05-28

  It is an object of the present invention to find out a method of predicting the antitumor effect of an angiogenesis inhibitor. According to the present invention, it is possible to predict the antitumor effect of an angiogenesis inhibitor by determining the number of those blood vessels which are covered with pericytes in a tumor and using the resultant number as an indicator.

  本发明的目的是找到一种预测血管生成抑制剂抗肿瘤效果的方法。根据本发明，可以通过确定肿瘤中被周细胞覆盖的血管的数量，并以该数量作为指标，来预测血管生成抑制剂的抗肿瘤效果。
• 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。