5-(formylamino)-4-(formylaminomethyl)-1-methylpyrazole | 474956-85-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 5-(formylamino)-4-(formylaminomethyl)-1-methylpyrazole
• 英文别名: N-[(5-formamido-1-methylpyrazol-4-yl)methyl]formamide
• CAS: 474956-85-9
• 化学式: C₇H₁₀N₄O₂
• 分子量: 182.182
• InChiKey: OJFUSLGZQDXBQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(formylamino)-4-(formylaminomethyl)-1-methylpyrazole 、 7Β-叔丁氧羰基氨基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯 、 三氟乙酸 在 sodium iodide 、 苯甲醚 作用下， 以 N,N-二甲基甲酰胺 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 7β-amino-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate)
  参考文献：
  名称：

  Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

  摘要：

  AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC = 1 mu g/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC = 16 mu g/mL) and ceftazidime (CAZ) (MIC = 128 mu g/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.074
• 作为产物：
  描述：

  甲酸 、 5-amino-4-(aminomethyl)-1-methylpyrazole 在 乙酸酐 作用下， 以 甲醇 为溶剂， 反应 2.5h， 以3.97 g的产率得到5-(formylamino)-4-(formylaminomethyl)-1-methylpyrazole
  参考文献：
  名称：

  Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

  摘要：

  AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC = 1 mu g/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC = 16 mu g/mL) and ceftazidime (CAZ) (MIC = 128 mu g/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.074

文献信息

• Cephem compounds
  申请人：——

  公开号：US20040248875A1

  公开（公告）日：2004-12-09

  The present invention relates to a compound of the formula [I]: wherein A is lower alkylene or lower alkenylene; R1 is lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, amino(lower)alkyl or protected amino(lower)alkyl, and R2 is hydrogen or amino protecting group, or R1 and R2 are bonded together and form lower alkylene; R3 and R5 are independently amino or protected amino; and R4 is carboxy or protected carboxy, or a pharmaceutically acceptable salt thereof, a process for preparing a compound of the formula [I], and a pharmaceutical composition comprising a compound of the formula [I] in admixture with a pharmaceutically acceptable carrier. 1

  本发明涉及一种化合物，其化学式为[I]：其中，A为较低的烷基或烯基烷基；R1为较低的烷基、羟基(较低)烷基、保护羟基(较低)烷基、氨基(较低)烷基或保护氨基(较低)烷基，R2为氢或氨基保护基，或R1和R2结合形成较低的烷基；R3和R5独立地为氨基或保护氨基；R4为羧基或保护羧基，或其药学上可接受的盐，以及制备化学式[I]的化合物的方法和包含化学式[I]的化合物与药学上可接受的载体混合的制药组合物。
• CEPHEM COMPOUNDS
  申请人：Astellas Pharma Inc.

  公开号：EP1392704B1

  公开（公告）日：2006-02-22
• US7179801B2
  申请人：——

  公开号：US7179801B2

  公开（公告）日：2007-02-20
• Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure
  作者：Kenji Murano、Toshio Yamanaka、Ayako Toda、Hidenori Ohki、Shinya Okuda、Kohji Kawabata、Kazuo Hatano、Shinobu Takeda、Hisashi Akamatsu、Kenji Itoh、Keiji Misumi、Satoshi Inoue、Tatsuya Takagi

  DOI：10.1016/j.bmc.2007.11.074

  日期：2008.3

  AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC = 1 mu g/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC = 16 mu g/mL) and ceftazidime (CAZ) (MIC = 128 mu g/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. (C) 2007 Elsevier Ltd. All rights reserved.