7-Bromo-3-(3-hydroxypropyl)-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 | 638563-88-9

• 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: 7-Bromo-3-(3-hydroxypropyl)-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: 638563-88-9
• 化学式: C₂₄H₁₉BrN₂O₂
• 分子量: 447.331
• InChiKey: IIXGAGJTPXIDCW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  54.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  丙烯酸乙酯 、 7-Bromo-3-(3-hydroxypropyl)-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 在 palladium diacetate 、 三(邻甲基苯基)磷 三乙胺 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 21.0h， 生成
  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
• 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 、 N-溴代丁二酰亚胺(NBS) 、 锂硼氢 、 茴香硫醚 、 对甲苯磺酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 、 苯 为溶剂， 反应 26.0h， 生成 7-Bromo-3-(3-hydroxypropyl)-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
  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

• Novel Fused Pyrrolocarbazoles
  申请人：Becknell Nadine C.

  公开号：US20100152196A1

  公开（公告）日：2010-06-17

  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.
• US7169802B2
  申请人：——

  公开号：US7169802B2

  公开（公告）日：2007-01-30
• US7671064B2
  申请人：——

  公开号：US7671064B2

  公开（公告）日：2010-03-02
• US8044064B2
  申请人：——

  公开号：US8044064B2

  公开（公告）日：2011-10-25
• US8383813B2
  申请人：——

  公开号：US8383813B2

  公开（公告）日：2013-02-26