benzo[a]phenazine-11-carboxylic acid methyl ester | 346690-91-3

• 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: benzo[a]phenazine-11-carboxylic acid methyl ester
• 英文别名: Benzo[a]phenazine-11-carboxylic Acid Methyl Ester；methyl benzo[a]phenazine-11-carboxylate
• CAS: 346690-91-3
• 化学式: C₁₈H₁₂N₂O₂
• 分子量: 288.305
• InChiKey: PLQSSOMHCIWZQD-UHFFFAOYSA-N

物化性质

• 沸点：
  512.6±15.0 °C(Predicted)
• 密度：
  1.333±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  52.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  甲胺 、 benzo[a]phenazine-11-carboxylic acid methyl ester 在 氯磺酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 10.0h， 生成 3-methylsufamoyl-benzo[a]phenazine-11-carboxylic acid 、 4-methylsufamoyl-benzo[a]phenazine-11-carboxylic acid
  参考文献：
  名称：

  Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents

  摘要：

  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.

  DOI：

  10.1021/jm010329a
• 作为产物：
  描述：

  benzophenazine-11-carboxylic acid 、 benzophenazine-8-carboxylic acid 以 甲醇 、 乙酰氯 为溶剂， 反应 1.5h， 生成 benzo[a]phenazine-11-carboxylic acid methyl ester
  参考文献：
  名称：

  Pharmaceutical compounds

  摘要：

  化合物是一种公式为（I）的苯并[a]菲噻嗪-11-羧酰胺衍生物，其中R1至R4中的每个基团，可相同或不同，选自氢、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、SO2R11、SO2N（R12）2、N（R12）2、NR10SO2R11、N（SO2R11）2 NR10（CH2）nCN、NR10COR11、OCOR11或COR10；R5至R7中的每个基团，可相同或不同，选自氢、卤素、羟基、C1-C6烷氧基、C1-C6烷基、SR10和N（R12）2；Q是未取代或取代的C1-C6烷基，该烷基由（i）未取代或取代的C1-C6烷基，（ii）羟基（前提是羟基不与公式（I）中相邻的N原子之一相邻），（iii）CO2R10或（iv）CON（R12）取代；R8和R9可相同或不同，选自氢或C1-C6烷基，或R8和R9与它们连接的氮原子一起形成饱和的5-或6-成员N-含杂环，该杂环可能包括选择自O，N和S的一个附加杂原子，或R8和R9中的一个是可选地由O，N或S中断的烷基链，该烷基链连接到由Q表示的烷基链上的碳原子，以完成上述定义的饱和的5-或6-成员N-含杂环；R10选自氢、C1-C6烷基、C3-C6环烷基、苄基或苯基；R11选自C1-C6烷基、C3-C6环烷基、苄基或苯基；每个R12，可相同或不同，选自氢、C1-C6烷基环烷基、苄基或苯基，或两个R12基团与它们连接的氮原子一起形成5-或6-成员饱和的N-含杂环，该杂环可能包括选择自O，N和S的1或2个附加杂原子；n为1、2或3；或其药学上可接受的盐；但R1至R4中至少有一个基团不是氢。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：

  US07132419B2

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，是一种公式（I）的苯并[a]菲啉-11-甲酰胺衍生物，其中R1至R4中的每一个，它们相同或不同，被选择为氢、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、叠氮基、酰肼基、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中的每一个，它们相同或不同，被选择为氢、卤素、羟基、C1-C6烷氧基、C1-C6烷基、SR10和N(R12)2；Q是未取代或取代的C1-C6烷基，其被（i）未取代或取代的C1-C6烷基，（ii）羟基、前提是羟基不是在公式（I）中与Q相邻的任一N原子，（iii）CO2R10，或（iv）CON(R12)所取代；R1和R9，它们相同或不同，分别是氢或C1-C6烷基，或R8和R9连同它们连接到的氮原子形成饱和的5-或6-成员N-含杂环戊或六元环，可能包括一个额外的由O、N和S中选择的杂原子，或R8和R9中的一个是由O、N或S随机中断的烷基链，它连接到由Q表示的烷基链上的碳原子，以完成上述定义的饱和的5-或6-成员N-含杂环戊或六元环；或其药学上可接受的盐；但至少一个R1到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。
• US7132419B2
  申请人：——

  公开号：US7132419B2

  公开（公告）日：2006-11-07