(+)-ethyl 9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate | 113400-34-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (+)-ethyl 9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate
• 英文别名: ethyl (3R)-9,10-difluoro-2,3-dihydro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]benzoxazine-6-carboxylate；ethyl (3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate；(3R)-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid ethyl ester；ethyl (2R)-6,7-difluoro-2-(fluoromethyl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylate
• CAS: 113400-34-3
• 化学式: C₁₅H₁₂F₃NO₄
• 分子量: 327.26
• InChiKey: LCYWXJLOBSPOBZ-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (+)-ethyl 9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 在 硼酸 、 溶剂黄146 、 三乙胺 、 zinc(II) chloride 作用下， 以 水 、 乙腈 为溶剂， 生成 (R)-9-fluoro-3-(fluoromethyl)-10-((R)-3-hydroxypyrrolidin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of levofloxacin core-based derivatives with potent antibacterial activity against resistant Gram-positive pathogens

  摘要：

  A series of C10 non-basic building block-substituted, levofloxacin core-based derivatives were synthesized in 43-86% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The quinolone (S)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3methyl- 7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid L-arginine tetrahydrate exhibited superior antibacterial activity against quinolone-susceptible and resistant strains compared with the clinically used fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin, penicillin, and vancomycin, especially to the methicillin-resistant Staphylococcus aureus clinical isolates, penicillin-resistant Streptococcus pneumoniae clinical isolates, and Streptococcus pyogenes. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.07.044
• 作为产物：
  描述：

  (-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 在 二乙胺基三氟化硫 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以65%的产率得到(+)-ethyl 9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate
  参考文献：
  名称：

  Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 Substituent

  摘要：

  Novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives 5-9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.

  DOI：

  10.1021/jm701428b

文献信息

• Aminoquinolones as GSK-3 inhibitors
  申请人：Cociorva Oana

  公开号：US20070254866A1

  公开（公告）日：2007-11-01

  Provided herein are aminoquinolones and pharmaceutically acceptable derivatives thereof. In certain embodiments, provided herein are compounds, compositions and methods for treating, preventing or ameliorating GSK-3 mediated diseases.

  本文提供了氨基喹啉及其药用可接受的衍生物。在某些实施例中，本文提供了用于治疗、预防或改善GSK-3介导疾病的化合物、组合物和方法。
• synthesis and antibacterial activities of optically active ofloxacin and its fluoromethyl derivative.
  作者：SHOHGO ATARASHI、SHUICHI YOKOHAMA、KEN-ICHI YAMAZAKI、KATSU-ICHI SAKANO、MASAZUMI IMAMURA、ISAO HAYAKAWA

  DOI：10.1248/cpb.35.1896

  日期：——

  Two optically active (100% enantiomeric excess) isomers (13a and 13b) of ofloxacin (1) [(±) -ofloxacin; DL-8280; (±) -9-fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid] and their fluoromethyl derivatives (14a and 14b) were prepared via their optically active intermediates resolved by use of high-performance liquid chromatography (HPLC). The isomers (13a and 13b) were also obtained efficiently by an alternative route via separation of the diastereoisomers (18, 19) prepared in the reaction of benzoxazine (17) with L-prolinyl chloride. The (-) -isomers of 1 and its fluoromethyl derivative (2) were approximately twice as active as the corresponding racemates, while the (+) -isomers were considerably less active than the racemates. The absolute configuration at the C3 position in the oxazine ring in a series of (-) -compounds (b) was confirmed by X-ray analysis of the hydrochloride of the (-) -benzoxazine derivative (15b) to be S.

  氧氟沙星（1）[(±) -ofloxacin; DL-8280；(±)-9-氟-2, 3-二氢-3-甲基-10- (4-甲基-1-哌嗪基) -7-氧代-7H-吡啶并[1, 2, 3-de] [1, 4] 苯并恶嗪-6-羧酸]及其氟甲基衍生物 (14a 和 14b)是通过使用高效液相色谱法 (HPLC) 解析其光学活性中间体而制备的。通过苯并恶嗪（17）与 L-脯氨酰氯反应制备的非对映异构体（18、19）的分离，也可以通过另一种途径有效地获得异构体（13a 和 13b）。1 的 (-) - 异构体及其氟甲基衍生物 (2) 的活性大约是相应外消旋体的两倍，而 (+) - 异构体的活性则大大低于外消旋体。通过对 (-) - 苯并恶嗪衍生物 (15b) 的盐酸盐进行 X 射线分析，证实了一系列 (-) - 化合物 (b) 中恶嗪环 C3 位置的绝对构型为 S。
• 10-(3-cyclopropylaminomethyl-1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivative effective against resistant bacterium
  申请人：Asahina Yoshikazu

  公开号：US20050182052A1

  公开（公告）日：2005-08-18

  A compound as represented by the general formula (I) shown below exhibits high antibacterial activity against gram-positive bacteria, in particular, such drug-resistant bacteria as mRNA, PRSP and VRE: wherein R1 is a methyl group, a fluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a hydroxymethyl group or a methylene; R2 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation and an ester of a prodrug; R3 is a hydrogen atom or a halogen atom; R4 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a fluoromethyl group, a trifluoromethyl group or a fluorine atom; and R5 is a hydrogen atom or a fluorine atom, with exceptions where R1 is a methyl group, R4 and R5 are at the same time a hydrogen atom, and R3 is a fluorine atom.

  下列通式（I）所代表的化合物对革兰氏阳性细菌表现出高度的抗菌活性，特别是对那些耐药菌如mRNA、PRSP和VRE： 其中，R1是甲基、氟甲基、甲氧甲基、乙酰氧甲基、羟甲基或亚甲基；R2是氢原子、具有1至3个碳原子的低烷基或药学上可接受的阳离子和前药的酯；R3是氢原子或卤素原子；R4是氢原子、具有1至3个碳原子的低烷基、氟甲基、三氟甲基或氟原子；R5是氢原子或氟原子，除非R1是甲基、R4和R5同时为氢原子，且R3是氟原子的情况。
• 10-(3-CYCLOPROPYLAMINOMETHYL-1-PYRROLIDINYL)PYRIDOBENZOXAZINECARBOXYLIC ACID DERIVATIVE EFFECTIVE AGAINST RESISTANT BACTERIUM
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：EP1486500A1

  公开（公告）日：2004-12-15

  A compound as represented by the general formula (I) shown below exhibits high antibacterial activity against gram-positive bacteria, in particular, such drug-resistant bacteria as MRNA, PRSP and VRE: wherein R1 is a methyl group, a fluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a hydroxymethyl group or a methylene; R2 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation and an ester of a prodrug; R3 is a hydrogen atom or a halogen atom; R4 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a fluoromethyl group, a trifluoromethyl group or a fluorine atom; and R5 is a hydrogen atom or a fluorine atom, with exceptions where R1 is a methyl group, R4 and R5 are at the same time a hydrogen atom, and R3 is a fluorine atom.

  下图所示通式(I)代表的化合物对革兰氏阳性菌，特别是 MRNA、PRSP 和 VRE 等耐药菌具有很强的抗菌活性： 其中 R1 是甲基、氟甲基、甲氧基甲基、乙酰氧甲基、羟甲基或亚甲基；R2 是氢原子、具有 1 至 3 个碳原子的低级烷基或药学上可接受的阳离子和原药的酯类；R3 是氢原子或卤素原子；R4 是氢原子、1-3 个碳原子的低级烷基、氟甲基、三氟甲基或氟原子；R5 是氢原子或氟原子，但 R1 是甲基、R4 和 R5 同时是氢原子和 R3 是氟原子的情况除外。
• Aminoquinolones as GSK-3 Inhibitors
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：EP2383271A1

  公开（公告）日：2011-11-02

  Provided herein are aminoquinolones and pharmaceutically acceptable derivatives thereof. In certain embodiments, provided herein are compounds, compositions and methods for treating, preventing or ameliorating GSK-3 mediated diseases.

  本文提供的是氨基喹诺酮及其药学上可接受的衍生物。在某些实施方案中，本文提供了用于治疗、预防或改善 GSK-3 介导的疾病的化合物、组合物和方法。