4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-methylamino-ethyl)-amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-methylamino-ethyl)-amide
• 英文别名: 4-methoxy-N-[2-(methylamino)ethyl]benzo[a]phenazine-11-carboxamide
• 化学式: C₂₁H₂₀N₄O₂
• 分子量: 360.415
• InChiKey: DXQHXRYHZWUMEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  76.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-甲基乙二胺 、 4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester 生成 4-Methoxy-benzo[a]phenazine-11-carboxylic acid (2-methylamino-ethyl)-amide
  参考文献：
  名称：

  Benzo[A] [phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II

  摘要：

  一种化合物，为公式（I）的苯并[a]菲嗪-11-羧酰胺衍生物，其中R1至R4分别选择自氢、卤素、羟基、未取代或取代的C1-C6烷氧基、杂环氧基、未取代或取代的C1-C6烷基、硝基、氰基、偶氮基、酰肟基、CO2R10、CON（R12）2、OCON（R12）、SR10、SOR11、SO2（R11）、SO2N（R12）2、N（R12）2、NR10SO2R11、N（SO2R11）2NR10（CH2）nCN、NR10COR11、OCOR11或COR10；R5至R7分别选择自氢、卤素、羟基、C1-C6烷氧基、C1-C6烷基、SR10和N（R12）2；Q为未取代或取代的C1-C6烷基，可以通过（i）未取代或取代的C1-C6烷基，（ii）羟基，但羟基不能与公式（I）中相邻的任何N原子相连，（iii）CO2R10或（iv）CON（R12）进行取代；R1和R9分别为氢或C1-C6烷基，或R8和R9与它们所连接的氮原子共同形成饱和的5-或6-成员的含氮杂环，该杂环可以包括来自O、N和S的一个额外的杂原子，或者R8和R9中的一个是由O、N或S间断的烷基链，该烷基链连接到由Q表示的烷基链上的碳原子上，以完成如上所定义的饱和的5-或6-成员的含氮杂环；或其药学上可接受的盐；但至少有一个R1至R4不是氢。这些化合物是拓扑异构酶I和/或拓扑异构酶II的抑制剂，可用于治疗肿瘤，包括表达MDR的肿瘤。

  公开号：

  US20030139409A1

文献信息

• Benzo[A] [phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II
  申请人：——

  公开号：US20030139409A1

  公开（公告）日：2003-07-24

  A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R 1 to R 4 , which are the same or different, is selected from hydrogen, halogen, hydroxyl, C 1 -C 6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C 1 -C 6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO 2 R 10 , CON(R 12 ) 2 , OCON(R 12 ), SR 10 , SOR 11 , SO 2 (R 11 ), SO 2 N(R 12 ) 2 , N(R 12 ) 2 , NR 10 SO 2 R 11 , N(SO 2 R 11 ) 2 NR 10 (CH 2 ) n CN, NR 10 COR 11 , OCOR 11 or COR 10 ; each of R 5 to R 7 , which are the same or different, is selected from hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, SR 10 and N(R 12 ) 2 ; Q is C 1 -C 6 alkylene which is unsubstituted or substituted by (i) C 1 -C 6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not, to either of the N atoms adjacent to Q in formula (I), (iii) CO 2 R 10 , or (iv) CON(R 12 ); R 1 and R 9 , which are the same or different, are each hydrogen or C 1 -C 6 alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R 8 and R 9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that at least one R 1 to R 4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.

  一种化合物，为公式（I）的苯并[a]菲嗪-11-羧酰胺衍生物，其中R1至R4分别选择自氢、卤素、羟基、未取代或取代的C1-C6烷氧基、杂环氧基、未取代或取代的C1-C6烷基、硝基、氰基、偶氮基、酰肟基、CO2R10、CON（R12）2、OCON（R12）、SR10、SOR11、SO2（R11）、SO2N（R12）2、N（R12）2、NR10SO2R11、N（SO2R11）2NR10（CH2）nCN、NR10COR11、OCOR11或COR10；R5至R7分别选择自氢、卤素、羟基、C1-C6烷氧基、C1-C6烷基、SR10和N（R12）2；Q为未取代或取代的C1-C6烷基，可以通过（i）未取代或取代的C1-C6烷基，（ii）羟基，但羟基不能与公式（I）中相邻的任何N原子相连，（iii）CO2R10或（iv）CON（R12）进行取代；R1和R9分别为氢或C1-C6烷基，或R8和R9与它们所连接的氮原子共同形成饱和的5-或6-成员的含氮杂环，该杂环可以包括来自O、N和S的一个额外的杂原子，或者R8和R9中的一个是由O、N或S间断的烷基链，该烷基链连接到由Q表示的烷基链上的碳原子上，以完成如上所定义的饱和的5-或6-成员的含氮杂环；或其药学上可接受的盐；但至少有一个R1至R4不是氢。这些化合物是拓扑异构酶I和/或拓扑异构酶II的抑制剂，可用于治疗肿瘤，包括表达MDR的肿瘤。
• Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents
  作者：Nigel Vicker、Luke Burgess、Irina S. Chuckowree、Rory Dodd、Adrian J. Folkes、David J. Hardick、Timothy C. Hancox、Warren Miller、John Milton、Sukhjit Sohal、Shouming Wang、Stephen P. Wren、Peter A. Charlton、Wendy Dangerfield、Chris Liddle、Prakash Mistry、Alistair J. Stewart、William A. Denny

  DOI：10.1021/jm010329a

  日期：2002.1.1

  A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23-parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)methyl-ethyl)-amide, XR11576 ((R)-4j"). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.