6,7,12,13-Tetrahydro-12-(3-hydroxypropyl)-9-[(1-methylpropoxy)methyl]-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one | 402857-40-3

• 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: 6,7,12,13-Tetrahydro-12-(3-hydroxypropyl)-9-[(1-methylpropoxy)methyl]-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one
• 英文别名: 7-(butan-2-yloxymethyl)-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: 402857-40-3
• 化学式: C₂₉H₃₀N₂O₃
• 分子量: 454.569
• InChiKey: PHSZEFBOTLZUMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  63.5
• 氢给体数：
  2
• 氢受体数：
  3

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 、 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 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 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 33.0h， 生成 6,7,12,13-Tetrahydro-12-(3-hydroxypropyl)-9-[(1-methylpropoxy)methyl]-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-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

• US7230026B2
  申请人：——

  公开号：US7230026B2

  公开（公告）日：2007-06-12
• 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).