9-piperazinylindolo[2,1-b]quinazoline-6,12-dione

• 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: 9-piperazinylindolo[2,1-b]quinazoline-6,12-dione
• 英文别名: 9-Piperazin-1-ylindolo[2,1-b]quinazoline-6,12-dione
• 化学式: C₁₉H₁₆N₄O₂
• 分子量: 332.362
• InChiKey: XUCROCFXIJUTBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-piperazinylindolo[2,1-b]quinazoline-6,12-dione 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 72.0h， 以84%的产率得到9-Piperazin-1-ylindolo[2,1-b]quinazoline-6,12-dione;hydrochloride
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationship Studies of Tryptanthrins As Antitubercular Agents

  摘要：

  The natural product tryptanthrin (la) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

  DOI：

  10.1021/np3007167
• 作为产物：
  描述：

  6-氯靛红 在 三乙胺 、 三氟乙酸 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 甲苯 为溶剂， 反应 2.5h， 生成 9-piperazinylindolo[2,1-b]quinazoline-6,12-dione
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationship Studies of Tryptanthrins As Antitubercular Agents

  摘要：

  The natural product tryptanthrin (la) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

  DOI：

  10.1021/np3007167

文献信息

• Indolo[2,1-biquinazoline-6,12-dione antibacterial compounds and methods
  申请人：PathoGenesis Corporation

  公开号：US05441955A1

  公开（公告）日：1995-08-15

  Methods, compounds and compositions are provided form inhibiting the growth of pathogenic mycobacteria in vitro and of treatment of pathogenic mycobacterial infections in vivo using indolo[2,1-b]quinazoline-6,12-dione compounds of the formula (I): ##STR1## wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, and the pharmaceutically acceptable salts thereof. The methods, compounds and compositons are particularly useful for inhibiting the growth of Mycobacterium tuberculosis, and may be used alone, or in combination with other anti-Mycobacterium tuberculosis agents, such as isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin and ciprofloxacin, to provide new agents for the treatment of tuberculosis, including multidrug-resistant tuberculosis (MDRTB).

  提供了一种用于体外抑制病原性分枝杆菌生长和用于体内治疗病原性分枝杆菌感染的方法、化合物和组合物，使用式(I)的吲哚并[2,1-b]喹唑啉-6,12-二酮化合物：##STR1## 其中A、B、C、D、E、F、G和H独立地选自碳和氮，或A和B或C和D可以结合在一起成为氮或硫，并且其药学上可接受的盐。这些方法、化合物和组合物特别适用于抑制结核分枝杆菌的生长，并可单独使用，或与其他抗结核分枝杆菌药物（如异烟肼、利福平、吡嗪酰胺、利福布汀、链霉素和环丙沙星）结合使用，以提供用于治疗结核病的新药物，包括多药耐药结核病（MDRTB）。
• USE OF TRYPTANTHRIN COMPOUNDS FOR IMMUNE POTENTIATION
  申请人：VALIANTE Nicholas M.

  公开号：US20120244182A1

  公开（公告）日：2012-09-27

  The invention provides immunostimulatory compositions and methods of administration thereof. Also provided are methods of administering a tryptanthrin compound in an effective amount to enhance the immune response of a subject to an antigen. Also provided are methods of administering an effective amount of a tryptanthrin to stimulate the immune response in a subject for the treatment of cancer. Further provided are methods of administering a tryptanthrin compounds as an immunotherapeutic in the treatment of infectious diseases.

  本发明提供了免疫刺激组合物及其给药方法。还提供了一种给予吲哚丹宁化合物有效量的方法，以增强受体对抗原的免疫反应。还提供了一种给予有效量的吲哚丹宁化合物的方法，以刺激受体对癌症的免疫反应。此外，还提供了将吲哚丹宁化合物作为免疫治疗剂治疗传染病的方法。
• US5441955A
  申请人：——

  公开号：US5441955A

  公开（公告）日：1995-08-15
• US8193185B2
  申请人：——

  公开号：US8193185B2

  公开（公告）日：2012-06-05
• [EN] INDOLO[2,1-b]QUINAZOLINE-6,12-DIONE ANTIBACTERIAL COMPOUNDS AND METHODS OF USE THEREOF<br/>[FR] COMPOSES ANTIBACTERIENS INDOLO[2,1-B]QUINAZOLINE-6,12-DIONE ET PROCEDES D'UTILISATION DESDITS COMPOSES
  申请人：PATHOGENESIS CORPORATION

  公开号：WO1995013807A1

  公开（公告）日：1995-05-26

  (EN) Methods, compounds and compositions are provided from inhibiting the growth of pathogenic mycobacteria $i(in vitro) and of treatment of pathogenic mycobacterial infections $i(in vivo) using indolo[2,1-b]quinazoline-6,12-dione compounds of formula (I), wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, and the pharmaceutically acceptable salts thereof. The methods, compounds and compositions are particularly useful for inhibiting the growth of $i(Mycobacterium tuberculosis), and may be used alone, or in combination with other anti-$i(Mycobacterium tuberculosis) agents, such as isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin and ciprofloxacin, to provide new agents for the treatment of tuberculosis, including multidrug-resistant tuberculosis (MDRTB).(FR) Procédés, composés et compositions destinés à inhiber la croissance de mycobactéries pathogènes $i(in vitro) et à traiter des infections dues audites mycobactéries pathogènes $i(in vivo) à l'aide de composés indolo[2,1-b]quinazoline-6,12-dione de formule (I), dans laquelle A, B, C, D, E, F, G et H sont indépendamment choisis parmi carbone et azote, ou bien A et B ou C et D peuvent être ensemble azote ou soufre, et sels pharmaceutiquement acceptables desdits composés. Lesdits procédés, composés et compositions sont particulièrement utiles pour inhiber la croissance de $i(Mycobacterium tuberculosis) et peuvent être utilisés seuls ou en combinaison avec d'autres agents de lutte contre $i(Mycobacterium tuberculosis), tels qu'isoniazide, rifampine, pyrazinamide, rifabutine, streptomycine et ciproflaxine, de manière à obtenir de nouveaux agents pour le traitement de la tuberculose, y compris la tuberculose à résistance multiple aux médicaments.