benzophenazine-11-carboxylic acid | 103942-90-1

• 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: benzophenazine-11-carboxylic acid
• 英文别名: 8,9-benzophenazine-1-carboxylic acid；benzo[a]phenazine-11-carboxylic acid；benzo[a]phenazine-11-carboxylic acid；Benzo[a]phenazin-11-carbonsaeure
• CAS: 103942-90-1
• 化学式: C₁₇H₁₀N₂O₂
• 分子量: 274.279
• InChiKey: FKURZSPWTBLWPK-UHFFFAOYSA-N

物化性质

• 沸点：
  579.9±15.0 °C(Predicted)
• 密度：
  1.437±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  63.1
• 氢给体数：
  1
• 氢受体数：
  4

SDS

反应信息

• 作为反应物：
  描述：

  benzophenazine-11-carboxylic acid 在 sodium azide 、 PPA 作用下， 以 二氯甲烷 为溶剂， 反应 4.33h， 生成 N-(8,9-benzophenazin-1-yl)-2-bromoacetamide
  参考文献：
  名称：

  Phenazine-1-carboxamides: Structure–cytotoxicity relationships for 9-substituents and changes in the H-bonding pattern of the cationic side chain

  摘要：

  A series of phenazine-1-carboxamides were prepared, including variations in both chromophore substituents and the nature of the cationic side chain. The novel side-chain analogues were prepared from the corresponding phenazine-1-carboxylic acids via Schmidt conversion to the 1-amines and from the corresponding 1-halides. Structure-cytotoxicity relationships for these compounds in a panel of tumor cell lines showed that there is very limited scope for variation of the structure of the 1-carboxamide side chain, consistent with the recent Structural model of flow tricyclic carboxamides bind to DNA. There was generally little difference in IC(50)s between parent and P-glycoprotein expressing cell lines, suggesting that most of the compounds are not affected by the presence of this efflux pump. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.09.032
• 作为产物：
  描述：

  1,2-萘醌 以 溶剂黄146 为溶剂， 生成 benzophenazine-11-carboxylic acid
  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，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。

  公开号：

  US20030139409A1

文献信息

• Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides
  作者：Gordon W. Rewcastle、William A. Denny、Bruce C. Baguley

  DOI：10.1021/jm00388a017

  日期：1987.5

  antitumor drugs, a series of substituted N-[2-(dimethylamino)ethyl]phenazine-1-carboxamides have been synthesized and evaluated. Fluorine-directed ring closure of N-phenyl-3-nitroanthranilic acids provided a new, unequivocal synthesis of several of the required phenazine-1-carboxylic acids, and the corresponding carboxamides were prepared and evaluated against L1210 leukemia in vitro and against P388

  在对缺乏电子的DNA插入配体作为抗肿瘤药物的进一步研究中，合成并评估了一系列取代的N- [2-（二甲基氨基）乙基]吩嗪-1-羧酰胺。N-苯基-3-硝基邻氨基苯甲酸的氟定向闭环提供了几种必需的吩嗪-1-羧酸的新的，明确的合成，并制备了相应的羧酰胺，并针对体外L1210白血病和P388白血病进行了评估。刘易斯体内肺癌。吩嗪环上的取代被广泛耐受，并且所得化合物的细胞毒性与取代基的吸电子能力正相关。取代基的位置效应甚至更加明显，其中9-取代的化合物最为活跃。一阶导数
• [EN] BENZO[A]PHENAZIN-11-CARBOXAMIDE DERIVATIVES AND THEIR USE AS JOINT INHIBITORS OF TOPOMERASE I AND II<br/>[FR] DERIVES DE BENZO[A]PHENAZINE-11-CARBOXAMIDE ET LEUR UTILISATION COMME INHIBITEURS COMMUNS DE LA TOPOMERASE I ET II
  申请人：XENOVA LTD

  公开号：WO2001046157A1

  公开（公告）日：2001-06-28

  A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R1 to R4, which are the same or different, is selected from hydrogen, halogen, hydroxyl, C¿1?-C6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C1-C6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO2R?10, CON(R12)¿2, OCON(R?12), SR10, SOR11, SO¿2(R11), SO2N(R12)2, N(R12)2, NR10SO2R11, N(SO¿2R?11)2NR10(CH2)nCN, NR?10COR11, OCOR11 or COR10¿; each of R5 to R7, which are the same or different, is selected from hydrogen, halogen, hydroxy, C¿1?-C6 alkoxy, C1-C6 alkyl, SR?10¿ and N(R12)2; Q is C1-C6 alkylene which is unsubstituted or substituted by (i) C1-C6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not α to either of the N atoms adjacent to Q in formula (I), (iii) CO2R10, or (iv) CON(R?12); R8 and R9¿, which are the same or different, are each hydrogen or C¿1?-C6 alkyl, or R?8 and R9¿ 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 R9¿ 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 R1 to R4 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.

  化合物是公式（I）的苯并[a]菲噻唑-11-羧酰胺衍生物，其中R1至R4中的每一个，相同或不同，从氢，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中选择；R5至R7中的每一个，相同或不同，从氢，卤素，羟基，C1-C6烷氧基，C1-C6烷基，SR10和N（R12）2中选择；Q是未取代或取代的C1-C6烷基，由（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相邻的任何一个氮原子的α位上，（iii）CO2R10或（iv）CON（R12）取代的；R8和R9'，相同或不同，均为氢或C1-C6烷基，或R8和R9'与它们连接的氮原子共同形成饱和的5-或6-成员N-含杂环，该杂环可以包括从O，N和S中选择的一个额外的杂原子，或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以形成上述定义的饱和的5-或6-成员N-含杂环；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。
• Pharmaceutical compounds
  申请人：Milton John

  公开号：US20050143383A1

  公开（公告）日：2005-06-30

  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 2 ) 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 α to either of the N atoms adjacent to Q in formula (I), (iii) CO 2 R 10 , or (iv) CON(R 12 ); R 8 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; R 10 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, benzyl or phenyl; R 11 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, benzyl or phenyl; each R 12 , which are the same or different, is hydrogen, C 1 -C 6 alkyl cycloalkyl, benzyl or phenyl, or the two R 12 groups form, together with the nitrogen atom to which they are attached a 5- or 6-membered saturated N-containing heterocyclic ring which may include 1 or 2 additional heteroatoms selected from O, N and S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of 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.

  化合物为公式（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，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、叠氮基、酰肟基、CO2R10、CON(R12)2、OCON(R12)、SR10、SOR11、SO2R11、SO2N(R12)2、N(R2)2、NR10SO2R11、N(SO2R11)2NR10(CH2)nCN、NR10COR11、OCOR11或COR10；R5至R7中的每个基团，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为未取代或取代的C1-C6烷基，可以由(i)未取代或取代的C1-C6烷基，(ii)羟基，但羟基不在公式（I）中与相邻的N原子之一相邻，(iii)CO2R10，或(iv)CON(R12)取代；R8和R9，相同或不同，均为氢或C1-C6烷基，或者R8和R9与它们附着的氮原子一起形成饱和的5-或6-成员N-含杂环，其中可以包括来自O、N和S的一个额外的杂原子，或者R8和R9是由O、N或S随意中断的烷基链，它附着在由Q表示的烷基链上的碳原子上，以完成上述定义的饱和的5-或6-成员N-含杂环；R10为氢、C1-C6烷基、C3-C6环烷基、苄基或苯基；R11为C1-C6烷基、C3-C6环烷基、苄基或苯基；每个R12，相同或不同，为氢、C1-C6烷基环烷基、苄基或苯基，或两个R12基团与它们附着的氮原子一起形成一个5-或6-成员饱和N-含杂环，其中可以包括1或2个来自O、N和S的额外杂原子；n为1、2或3；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。
• Non-enzymatic immunohistochemical staining system and reagents
  申请人：Immunomedics, Inc.

  公开号：EP0250676A2

  公开（公告）日：1988-01-07

  A non-enzymatic method of immunohistochemical staining uses a bound electron transfer agent to achieve amplification of antibody binding to specific antigens of interest in a histology or cytology specimen. A preferred embodiment uses a bound phenazine, which is reduced with a soluble reducing agent, and which in turn reduces a tetrazolium salt, to precipitate a formazan dye at the site of primary antibody binding to the antigen of interest. Reagents and kits for use in the method are also provided.

  一种非酶法免疫组化染色方法使用一种结合电子转移剂来实现抗体与组织学或细胞学标本中的特异性抗原结合的放大。一个优选的实施方案是使用结合酚嗪，用可溶性还原剂将其还原，进而还原四氮唑盐，在第一抗体与相关抗原结合的部位沉淀出一种甲臢染料。还提供了用于该方法的试剂和试剂盒。
• 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.