6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one | 174349-13-4

• 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: 6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one
• 英文别名: 13H-indeno-[2,1-a]pyrrolo[3,4-c]carbazole；3,13-Diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one；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-14-one
• CAS: 174349-13-4
• 化学式: C₂₁H₁₄N₂O
• 分子量: 310.355
• InChiKey: NBGYLHIDCLVBHE-UHFFFAOYSA-N

物化性质

• 熔点：
  >320 °C(Solv: methanol (67-56-1); tetrahydrofuran (109-99-9))
• 沸点：
  725.9±59.0 °C(Predicted)
• 密度：
  1.433±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  24
• 可旋转键数：
  0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  44.9
• 氢给体数：
  2
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one 在 锂硼氢 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 26.0h， 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：

  2-溴化茚 在 镍 bis-triphenylphosphine-palladium(II) chloride 、 氢气 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 31.5h， 生成 6H,7H,12H,13H-indeno[2,1-a]pyrrolo[3,4-c]carbazole-5(5H)one
  参考文献：
  名称：

  茚并的合成[2,1-一个]吡咯并[3,4- c ^ ]咔唑内酰胺用乙酸乙酯区域异构体的顺式-β-氰基丙烯酸酯作为亲双烯体和内酰胺的前体

  摘要：

  这里报道的是利用与2-茚基吲哚和马来酰亚胺的Diels-Alder反应的茚并吡咯并咔唑环系统的合成和表征。Clemmensen酰亚胺10的还原反应提供了5-氧代（16）和7-氧代（17）内酰胺区域异构体。使用顺式-β-氰基丙烯酸乙酯作为亲双烯体，开发了一种新的针对5-氧代16的区域特异性途径。X射线晶体学证实了环加合物的区域和立体化学特征。

  DOI：

  10.1002/jhet.5570400118

文献信息

• 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。
• Syntheses of C12,N13 Heterocyclic Bridged Fused Indenopyrrolocarbazoles
  作者：Ted L. Underiner、John P. Mallamo、Jasbir Singh

  DOI：10.1021/jo0108360

  日期：2002.5.1

  Tandem alkylation/cyclization of indenopyrrolocarbazole 4a, a C12 carbon analogue of indolocarbazole K252c, was carried out by general solid-phase and solution-phase methods. Alkylation of fused pyrroloindenylcarbazole 4a derivatives with appropriate monoacetals of diketones afforded the corresponding C12-substituted acetal alcohols. Acid-catalyzed cyclization of these adducts yielded C12,N13-bridged

  茚并吡咯并咔唑4a（吲哚并咔唑K252c的C12碳类似物）的串联烷基化/环化反应通过常规固相和溶液相方法进行。稠合的吡咯并茚基咔唑4a衍生物与合适的二酮单缩醛烷基化，得到相应的C12-取代的缩醛醇。这些加合物的酸催化环化反应生成C12，N13桥联的四氢呋喃，吡喃和二恶烷化合物10-13。
• A simple synthetic protocol for the protection of amides, lactams, ureas, and carbamates
  作者：Dandu R Reddy、Mohamed A Iqbal、Robert L Hudkins、Patricia A Messina-McLaughlin、John P Mallamo

  DOI：10.1016/s0040-4039(02)01964-0

  日期：2002.11

  A new procedure for protecting the amide, lactam, urea, and carbamate NH group with a triphenylmethyl (Tr) group is described. The utility of this method is illustrated with molecules that contain other functional groups. A mild deprotection using trifluoroacetic acid makes this a useful method for attaching amide groups on resin for combinatorial synthesis.

  描述了用三苯甲基（Tr）基保护酰胺，内酰胺，尿素和氨基甲酸酯NH基的新方法。包含其他官能团的分子说明了该方法的实用性。使用三氟乙酸的温和脱保护使其成为在组合合成树脂上连接酰胺基的有用方法。
• Cyclic substituted fused pyrrolocarbazoles and isoindolones
  申请人：Cephalon, Inc.

  公开号：US20040186157A1

  公开（公告）日：2004-09-23

  The present invention is directed to cyclic substituted fused pyrrolocarbazoles and isoindolones. The invention also is directed to methods for making and using the cyclic substituted fused pyrrolocarbazoles and isoindolones.

  本发明涉及环替代融合吡咯咯咯吡咯咯咯和异吲哚酮。该发明还涉及制备和使用环替代融合吡咯咯咯吡咯咯咯和异吲哚酮的方法。
• Bridged indenopyrrolocarbazoles
  申请人：Cephalon, Inc.

  公开号：US06359130B1

  公开（公告）日：2002-03-19

  The present invention is directed to novel fused aryl and heteroaryl bridged indenopyrrolocarbazoles which are useful, inter alia, as therapeutic agents. The invention is also directed to methods for making and using the bridged indenopyrrolocarbazoles.

  本发明涉及新型的融合芳基和杂芳基桥联的茚吡咯咯喹唑，其可用作治疗剂等。该发明还涉及制备和使用这些桥联的茚吡咯咯喹唑的方法。