2H-3,1-Benzoxazine-2,4(1H)-dione, 7-chloro-6-fluoro- | 97927-41-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 2H-3,1-Benzoxazine-2,4(1H)-dione, 7-chloro-6-fluoro-
• 英文别名: 7-chloro-6-fluoro-1H-3,1-benzoxazine-2,4-dione
• CAS: 97927-41-8
• 化学式: C₈H₃ClFNO₃
• 分子量: 215.568
• InChiKey: SHJIGJHFUPTPGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2H-3,1-Benzoxazine-2,4(1H)-dione, 7-chloro-6-fluoro- 在 对甲苯磺酸 、 zinc(II) chloride 作用下， 以 氯苯 、 正丁醇 为溶剂， 反应 42.0h， 生成 7-chloro-6-fluoro-3-methyl-2-[6-[4-(trifluoromethoxy)phenyl]-3-pyridyl]-1H-quinolin-4-one
  参考文献：
  名称：

  Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

  摘要：

  Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC50 = 15 nM PfNDH2; IC50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED50/ED90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

  DOI：

  10.1021/jm201184h

文献信息

• Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)
  作者：Chandrakala Pidathala、Richard Amewu、Bénédicte Pacorel、Gemma L. Nixon、Peter Gibbons、W. David Hong、Suet C. Leung、Neil G. Berry、Raman Sharma、Paul A. Stocks、Abhishek Srivastava、Alison E. Shone、Sitthivut Charoensutthivarakul、Lee Taylor、Olivier Berger、Alison Mbekeani、Alasdair Hill、Nicholas E. Fisher、Ashley J. Warman、Giancarlo A. Biagini、Stephen A. Ward、Paul M. O’Neill

  DOI：10.1021/jm201179h

  日期：2012.3.8

  the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates

  进行了一项计划来鉴定针对 NADH 的命中化合物：泛醌氧化还原酶 (PfNDH2)，这是一种疟疾寄生虫恶性疟原虫线粒体电子传递链的脱氢酶. PfNDH2 只有一种已知抑制剂，羟基-2-十二烷基-4-(1H)-喹诺酮 (HDQ)，它与一系列化学信息学方法一起用于合理选择 17000 种化合物以进行高通量筛选。确定并简要检查了 12 种不同的化学型，导致选择喹诺酮核心作为构效关系 (SAR) 发展的关键目标。广泛的结构探索导致选择 2-双芳基 3-甲基喹诺酮作为进一步生物学评价的系列。该系列中的先导化合物 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) 对 3D7 具有抗疟活性36 nM 的恶性疟原虫菌株对 PfNDH2 的选择性高于其他呼吸酶（抑制性 IC50对 PfNDH2
• QUINAZOLINES AS THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE
  申请人：Suzuki Masaki

  公开号：US20140315886A1

  公开（公告）日：2014-10-23

  Methods of treating disorders using compounds (I) that modulate stri-atal-enriched tyrosine phosphatase (STEP) are described herein. Exemplary disorders include schizophrenia and cognitive deficit. Formula (I).

  本文描述了使用调节纹状体富集的酪氨酸磷酸酶（STEP）的化合物（I）治疗疾病的方法。示例疾病包括精神分裂症和认知缺陷。公式（I）。
• Therapeutic agents
  申请人：The Boots Company PLC

  公开号：EP0135367A1

  公开（公告）日：1985-03-27

  Novel quinolones of formula I and pharmaceutically acceptable acid addition salts thereof in which the dotted line between positions 2 and 3 of the quinolone ring represents an optional bond, R is hydrogen, 1-methyl or 2-lower alkyl; R, is lower alkyl; R2 is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, cyano, difluoromethoxy, methylsulphinyl, phenylsulphinyl or the group -NR4R5 or the N-oxide thereof wherein R4 and R5, which may be the same or different, are lower alkyl or, together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino radical; and R3 is hydrogen, fluoro, lower alkyl or lower alkoxy provided that, when R3 is lower alkoxy, R2 is other than lower alkoxy have utility as antihypertensive agents. Processes for preparing the quinolones and pharmaceutical compositions containing them are disclosed.

  式 I 的新型喹诺酮类药物 及其药学上可接受的酸加成盐，其中喹诺酮环的位置2和3之间的虚线代表任选键，R是氢、1-甲基或2-低级烷基；R，是低级烷基；R2是氢、卤素、低级烷基、低级烷氧基、三氟甲基、氰基、二氟甲氧基、甲基亚磺酰基、苯基亚磺酰基或基团 -NR4R5 或其 N-氧化物，其中 R4 和 R5（可以相同或不同）是低级烷基，或与所连接的氮原子一起形成吡咯烷基、哌啶基或吗啉基；R3是氢、氟、低级烷基或低级烷氧基，但当R3是低级烷氧基时，R2是低级烷氧基以外的基团。本研究还公开了制备喹诺酮类药物和含有它们的药物组合物的工艺。
• US4659718A
  申请人：——

  公开号：US4659718A

  公开（公告）日：1987-04-21
• [EN] QUINAZOLINES AS THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE<br/>[FR] QUINAZOLINES COMME COMPOSÉS THÉRAPEUTIQUES ET PROCÉDÉS D'UTILISATION S'Y RAPPORTANT
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2013003586A1

  公开（公告）日：2013-01-03

  Methods of treating disorders using compounds (I) that modulate stri-atal-enriched tyrosine phosphatase (STEP) are described herein. Exemplary disorders include schizophrenia and cognitive deficit. Formula (I).