Ethyl 3-(14-oxo-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-3-yl)propanoate | 263141-97-5

• 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: Ethyl 3-(14-oxo-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-3-yl)propanoate
• CAS: 263141-97-5
• 化学式: C₂₆H₂₂N₂O₃
• 分子量: 410.472
• InChiKey: ZWMJXZVJFITNSW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  60.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Ethyl 3-(14-oxo-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-3-yl)propanoate 在 1-甲基吡咯烷 、 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 锂硼氢 、 茴香硫醚 、 sodium acetate 、 二异丁基氢化铝 、 对甲苯磺酸 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 苯 为溶剂， 反应 15.0h， 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
• 作为产物：
  描述：

  丙烯酸乙酯 、 6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 以78%的产率得到Ethyl 3-(14-oxo-3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-3-yl)propanoate
  参考文献：
  名称：

  Novel fused pyrrolocarbazoles

  摘要：

  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。

  公开号：

  US20050143442A1

文献信息

• US7230026B2
  申请人：——

  公开号：US7230026B2

  公开（公告）日：2007-06-12
• US7789610B2
  申请人：——

  公开号：US7789610B2

  公开（公告）日：2010-09-07
• 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-<i>a</i>]pyrrolo[3,4-<i>c</i>]carbazole-5-ones and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055
  作者：Diane E. Gingrich、Dandu R. Reddy、Mohamed A. Iqbal、Jasbir Singh、Lisa D. Aimone、Thelma S. Angeles、Mark Albom、Shi Yang、Mark A. Ator、Sheryl L. Meyer、Candy Robinson、Bruce A. Ruggeri、Craig A. Dionne、Jeffry L. Vaught、John P. Mallamo、Robert L. Hudkins

  DOI：10.1021/jm0301641

  日期：2003.12.1

  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).
• 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。