5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocycloprop-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid | 181814-90-4

• 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: 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocycloprop-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
• 英文别名: 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid；5-amino-=6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl-]1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid；5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxoquinoline-3-carboxylic acid
• CAS: 181814-90-4
• 化学式: C₁₄H₁₁F₃N₂O₃
• 分子量: 312.248
• InChiKey: LIFSIBVTJOPWMV-NKWVEPMBSA-N

物化性质

• 沸点：
  531.9±50.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  83.6
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocycloprop-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 在 盐酸 、 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 生成 5-amino-7-[(3S,4R)-4-(1-aminocycloprop-1-yl)-3-fluoropyrrolidin-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocycloprop-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 5-Amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic Acid Antibacterials Having Fluorinated 7-[(3R)-3-(1-Aminocyclopropan-1-yl)pyrrolidin-1-yl] Substituents

  摘要：

  A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyr-rolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.

  DOI：

  10.1021/jm020328y
• 作为产物：
  描述：

  ethyl 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate 在 盐酸 、 溶剂黄146 作用下， 以 水 为溶剂， 以7.52 g (79%)的产率得到5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocycloprop-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Pyridonecarboxylic acid derivatives substituted by a bicyclic amino

  摘要：

  这项发明涉及一种由以下式（I）表示的N.sub.1-(卤代环丙基)-取代吡啶酮羧酸衍生物：其中X.sup.1是卤素原子或氢原子；X.sup.2是卤素原子；R.sup.1是氢原子、羟基、硫醇基、卤代甲基基团、氨基、烷基或可能具有取代基团的烷氧基；R.sup.2是由以下式（II）表示的基团：其中R.sup.3和R.sup.4独立地是氢原子或烷基，n是1或2的整数；A是氮原子或以下式（III）的部分结构：其中X.sup.3是氢原子、卤素原子、氰基、氨基、烷基、卤代甲基基团、烷氧基或可能具有取代基团的卤代甲氧基；R是氢原子、苯基、乙酰氧甲基基团、戊酰氧甲基基团、乙氧羰基、胆碱基团、二甲氨基乙基基团、5-茚基团、邻苯二酰基团、5-烷基-2-氧代-1,3-二氧杂环戊-4-基甲基基团、3-乙酰氧基-2-氧代丁基基团、烷基、烷氧甲基或苯基烷基基团，并提供一种用作抗菌药物的杂环化合物。

  公开号：

  US05849757A1

文献信息

• Substituted aminocycloalkylpyrrolidine derivatives and cis-substituted
  申请人：Daiichi Pharmaceutical Co., Ltd.

  公开号：US06121285A1

  公开（公告）日：2000-09-19

  An antimicrobial drug having excellent antimicrobial activity and high safety is disclosed, which comprises as an active ingredient, a quinolone-derivative having a substituted aminocycloalkylpyrrolidine as a substituent and which is further substituted with various substituents, represented by formula (I), its salts and hydrates thereof: ##STR1## wherein Q is represented by formula (II) or (IV). ##STR2## Also disclosed is a quinolone derivative where R.sup.4 and the substituent on the pyrrolidine ring of the following formula: ##STR3## are located at the cis-configuration; and Q is represented by the formula: ##STR4##

  揭示了一种具有优异抗菌活性和高安全性的抗菌药物，其包括作为活性成分的奎诺酮衍生物，其具有取代氨基环烷基吡咯烷作为取代基，并且进一步取代了各种取代基，由式(I)表示，以及其盐和水合物：其中Q由式(II)或(IV)表示。还揭示了一种奎诺酮衍生物，其中R.sup.4和以下式的吡咯烷环上的取代基：位于顺式构型；Q由以下式表示：
• Tricyclic amine derivatives
  申请人：——

  公开号：US20010037030A1

  公开（公告）日：2001-11-01

  The present invention relates to a compound having a tricyclic amine substituent which may have various substituents, the compound being represented by formula (I), a salt or hydrate thereof, and a hydrate of the salt and a drug containing them as an active ingredient. They exhibit excellent antimicrobial activity against Gram negative bacteria and Gram positive bacteria with a satisfactory fate and safety and are useful in the treatment of infectious diseases. 1 wherein Q preferably represents the following partial structure which may have various substituents: 2

  本发明涉及一种具有三环胺取代基的化合物，该化合物可以具有各种取代基，表示为式(I)的盐或水合物，盐的水合物和包含它们作为活性成分的药物。它们对革兰氏阴性菌和革兰氏阳性菌表现出优异的抗菌活性，具有令人满意的效果和安全性，适用于治疗传染病。其中Q最好表示以下可能具有各种取代基的部分结构：2
• Process for producing quinolonecarboxlic acids and intermediates thereof
  申请人：——

  公开号：US20030060631A1

  公开（公告）日：2003-03-27

  This invention relates to methods for the efficient production of quinolonecarboxylic acid based synthetic antibacterial agents which are expected for applications such as excellent medicaments and agricultural chemicals and to intermediate compounds to be used therein. According to the present invention, an amine substituent as the 7-position substituent of the quinolonecarboxylic acid derivative can be efficiently introduced.

  该发明涉及一种高效生产基于喹诺酮羧酸的合成抗菌剂的方法，这些抗菌剂可用于优良的药物和农业化学品等应用，并涉及用于其中的中间化合物。根据本发明，可以有效地引入喹诺酮羧酸衍生物的7位取代基作为胺基取代基。
• Heterocyclic spiro-derivative
  申请人：Daiichi Pharmaceutical Co., Ltd.

  公开号：US06469023B1

  公开（公告）日：2002-10-22

  The present invention provides an antibacterial compound useful as medicines, animal drugs, fisheries drugs or antibacterial preservatives and to an antibacterial agent or preparation which contains the same, more particularly a compound which possesses high safety and excellent activity against a broad range of bacterial species including quinolone-resistant strains. A quinolone derivative of the following formula (I) which has a group derived from the heterocyclic spiro-compound at the 7-positioned R2 and the halogenocyclopropyl group at the N1-position, prefereably a compound of pure isomer, and an antibacterial agent containing the derivative compound.

  本发明提供一种抗菌化合物，可用作药物、动物药品、渔业药品或抗菌防腐剂，以及含有该化合物的抗菌剂或制剂，更具体地说，是一种具有高安全性和对包括喹诺酮耐药菌株在内的广泛细菌种类表现出优异活性的化合物。公式（I）中具有来自杂环螺环化合物的衍生基在7位R2处和卤代环丙基在N1位的喹诺酮衍生物，优选为纯异构体化合物，以及含有衍生物化合物的抗菌剂。
• Process for producing 5-amino-8-alkylquinolonecarboxylic acid derivative and intermediates in the production thereof
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：US20020193591A1

  公开（公告）日：2002-12-19

  The present invention provides a process for producing intermediates of antibacterial agents in accordance with the following steps and intermediates in the production thereof. 1 (wherein R 1 : hydrogen atom or nitro group; R 2 : an alkyl group having 1 to 6 carbon atoms; R 3 , R 4 : an alkyl group having 1 to 6 carbon atoms or may form a 5-membered or 6-membered cyclic structure in combination with the nitrogen atom to which they are bonded, and the cyclic structure may contain oxygen atom, nitrogen atom, sulfinyl group, or sulfonyl group as a ring-constituting element; R 6 : a halogenocycloalkyl group having 3 to 6 carbon atoms; X 1 represents a halogen atom or hydrogen atom; X 2 , X 3 : a leaving group; and Y: an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms)

  本发明提供了一种生产抗菌剂中间体的方法，包括以下步骤和其中间体的生产。其中，步骤1中的R1表示氢原子或硝基；R2表示具有1至6个碳原子的烷基基团；R3和R4表示具有1至6个碳原子的烷基基团，或者可以与它们连接的氮原子形成5元环或6元环结构，该环结构可以包含氧原子、氮原子、亚砜基或磺酰基作为环构成元素；R6表示具有3至6个碳原子的卤代环烷基团；X1表示卤原子或氢原子；X2和X3表示离去基团；Y表示具有1至6个碳原子的烷基基团或具有2至6个碳原子的烯基基团。