1-cyclopropyl-7-fluoro-9-methyl-8-{3-[1-(methylpiperidin-4-ylamino)cyclopropyl]pyrrolidin-1-yl}-4-oxo-4H-quinolizine-3-carboxylic acid | 922718-09-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹嗪类
• 英文名称: 1-cyclopropyl-7-fluoro-9-methyl-8-{3-[1-(methylpiperidin-4-ylamino)cyclopropyl]pyrrolidin-1-yl}-4-oxo-4H-quinolizine-3-carboxylic acid
• 英文别名: (R)-1-cyclopropyl-7-fluoro-9-methyl-8-[3-[1-(methyl-piperidin-4-yl-amino)-cyclopropyl]-pyrrolidin-1-yl]-4-oxo-4H-quinolizine-3-carboxylic acid；(R)-1-Cyclopropyl-7-fluoro-9-methyl-8-(3-(1-(methyl(piperidin-4-yl)amino)cyclopropyl)pyrrolidin-1-yl)-4-oxo-4H-quinolizine-3-carboxylic acid；1-cyclopropyl-7-fluoro-9-methyl-8-[(3R)-3-[1-[methyl(piperidin-4-yl)amino]cyclopropyl]pyrrolidin-1-yl]-4-oxoquinolizine-3-carboxylic acid
• CAS: 922718-09-0
• 化学式: C₂₇H₃₅FN₄O₃
• 分子量: 482.598
• InChiKey: KJUXXLZXLMZCKD-GOSISDBHSA-N

物化性质

• 沸点：
  612.0±55.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  76.1
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3'-hydroxy-benzoxazinorifamycin 、 1-cyclopropyl-7-fluoro-9-methyl-8-{3-[1-(methylpiperidin-4-ylamino)cyclopropyl]pyrrolidin-1-yl}-4-oxo-4H-quinolizine-3-carboxylic acid 在 manganese(IV) oxide 、 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 19.0h， 生成 (R)-5'-[3-[4-{1-[1-(3-carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-cyclopropyl]-methylamino}-piperidin-1-yl]-3'-hydroxy]-benzoxazinorifamycin
  参考文献：
  名称：

  QUINOLONE CARBOXYLIC ACID-SUBSTITUTED RIFAMYCIN DERIVATIVES

  摘要：

  这些化合物包括取代利福霉素衍生物，其中喹诺酸药效基团与苯并噁唑利福霉素或螺环哌嗪利福霉素共价键合。 利福霉素衍生物可用作抗微生物剂，对多种人类和兽医革兰氏阳性和革兰氏阴性病原体有效。 发明化合物的优点在于，利福霉素和喹诺酮抗菌药效基团都与目标感兴趣的病原体具有匹配的药代动力学。同时将多种抗菌药效基团传递到目标病原体，最大程度地实现协同作用并最小化对给药抗生素的耐药性的发展的可能性。

  公开号：

  US20090143373A1
• 作为产物：
  描述：

  (R)-1-苄基-3-吡咯烷甲腈 在 titanium(IV) isopropylate 、 Pd/C (30%) 、 氢气 、 碳酸氢钠 、 溶剂黄146 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 水 、 溶剂黄146 、 1,2-二氯乙烷 、 乙腈 为溶剂， -78.0~60.0 ℃ 、413.7 kPa 条件下， 反应 31.0h， 生成 1-cyclopropyl-7-fluoro-9-methyl-8-{3-[1-(methylpiperidin-4-ylamino)cyclopropyl]pyrrolidin-1-yl}-4-oxo-4H-quinolizine-3-carboxylic acid
  参考文献：
  名称：

  Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections

  摘要：

  The clinical management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clinical utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional molecules were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clinical development for the treatment of prosthetic joint infections.

  DOI：

  10.1021/acs.jmedchem.6b00485

文献信息

• US7226931B2
  申请人：——

  公开号：US7226931B2

  公开（公告）日：2007-06-05
• US7884099B2
  申请人：——

  公开号：US7884099B2

  公开（公告）日：2011-02-08
• [EN] QUINOLONE CARBOXYLIC ACID-SUBSTITUTED RIFAMYCIN DERIVATIVES<br/>[FR] DÉRIVÉS DE RIFAMYCINE SUBSTITUÉE PAR L'ACIDE QUINOLONE-CARBOXYLIQUE
  申请人：CUMBRE PHARMACEUTICALS INC

  公开号：WO2009064792A1

  公开（公告）日：2009-05-22

  The compounds include substituted rifamycin derivatives in which a quinolone carboxylic acid pharmacophore is covalently bonded to a benzoxazinorifamycin or a spiropiperidinorifamycin. The rifamycin derivatives are useful as antimicrobial agents and are effective against a number of human and veterinary Gram positive and Gram negative pathogens. The advantage of the inventive compounds is that both the rifamycin and quinolone antibacterial pharmacophores are co-delivered with matched pharmacokinetics to the targeted pathogens of interests. Delivery of multiple antibacterial pharmacophores simultaneously to the targeted pathogens has the maximum chance of achieving synergy and minimizing the development of resistance to the antibiotics given.
• Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections
  作者：Zhenkun Ma、Anthony Simon Lynch

  DOI：10.1021/acs.jmedchem.6b00485

  日期：2016.7.28

  The clinical management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clinical utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional molecules were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clinical development for the treatment of prosthetic joint infections.
• QUINOLONE CARBOXYLIC ACID-SUBSTITUTED RIFAMYCIN DERIVATIVES
  申请人：Ding Charles Z.

  公开号：US20090143373A1

  公开（公告）日：2009-06-04

  The compounds include substituted rifamycin derivatives in which a quinolone carboxylic acid pharmacophore is covalently bonded to a benzoxazinorifamycin or a spiropiperidinorifamycin. The rifamycin derivatives are useful as antimicrobial agents and are effective against a number of human and veterinary Gram positive and Gram negative pathogens. The advantage of the inventive compounds is that both the rifamycin and quinolone antibacterial pharmacophores are co-delivered with matched pharmacokinetics to the targeted pathogens of interests. Delivery of multiple antibacterial pharmacophores simultaneously to the targeted pathogens has the maximum chance of achieving synergy and minimizing the development of resistance to the antibiotics given.

  这些化合物包括取代利福霉素衍生物，其中喹诺酸药效基团与苯并噁唑利福霉素或螺环哌嗪利福霉素共价键合。 利福霉素衍生物可用作抗微生物剂，对多种人类和兽医革兰氏阳性和革兰氏阴性病原体有效。 发明化合物的优点在于，利福霉素和喹诺酮抗菌药效基团都与目标感兴趣的病原体具有匹配的药代动力学。同时将多种抗菌药效基团传递到目标病原体，最大程度地实现协同作用并最小化对给药抗生素的耐药性的发展的可能性。