(3R)-10-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid | 604798-02-9

• 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: (3R)-10-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
• 英文别名: (2R)-6-[(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl]-7-fluoro-2-(fluoromethyl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid
• CAS: 604798-02-9
• 化学式: C₂₁H₂₂F₃N₃O₄
• 分子量: 437.419
• InChiKey: CZYDTCXZKQGPJZ-KNHMANMVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  82.1
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (3R)-10-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid 在 甲烷磺酸 作用下， 以 乙醇 为溶剂， 反应 1.0h， 生成 (3R)-10-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-d.e][1,4]benzoxazine-6-carboxylic acid methanesulfonate
  参考文献：
  名称：

  10-(3-CYCLOPROPYLAMINOMETHYL-1-PYRROLIDINYL)PYRIDOBENZOXAZINECARBOXYLIC ACID DERIVATIVE EFFECTIVE AGAINST RESISTANT BACTERIA

  摘要：

  公开号：

  EP1486500B1
• 作为产物：
  描述：

  (3S,4S)-3-N-cyclopropylaminomethyl-4-fluoropyrrolidine 、 bis(acetato-O)[(3R)-9,10-difluoro-3-(2-fluoromethyl)-2,3-dihydro-7-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylato-O⁶,O⁷]boron 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以72%的产率得到(3R)-10-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
  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

• 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。
• US7153851B2
  申请人：——

  公开号：US7153851B2

  公开（公告）日：2006-12-26
• Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-<i>de</i>][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 Substituent
  作者：Yoshikazu Asahina、Masaya Takei、Tetsuya Kimura、Yasumichi Fukuda

  DOI：10.1021/jm701428b

  日期：2008.6.1

  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.
• 10-(3-CYCLOPROPYLAMINOMETHYL-1-PYRROLIDINYL)PYRIDOBENZOXAZINECARBOXYLIC ACID DERIVATIVE EFFECTIVE AGAINST RESISTANT BACTERIA
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：EP1486500B1

  公开（公告）日：2009-09-16