2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetic acid | 116833-10-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetic acid
• 英文别名: (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-<(fluoromethoxy)imino>acetic acid；2-(5-amino-1,2,4-thiathiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid；2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetic acid；2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetic acid；2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)fluoromethoxyiminoacetic acid；2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetic acid；(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetic acid
• CAS: 116833-10-4
• 化学式: C₅H₅FN₄O₃S
• 分子量: 220.184
• InChiKey: YXCUXZBVADXGBO-MBXJOHMKSA-N

物化性质

• 沸点：
  442.0±47.0 °C(Predicted)
• 密度：
  1.93±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetic acid 在 五氯化磷 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以95%的产率得到2-(5-dichlorophosphorylamino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetyl chloride
  参考文献：
  名称：

  Studies on Anti-MRSA Parenteral Cephalosporins. IV. A Novel Water-soluble N-Phosphono Type Prodrug for Parenteral Administration.

  摘要：

  描述了一种提高抗 MRSA（耐甲氧西林金黄色葡萄球菌）头孢菌素衍生物水溶性的系统方法。我们首先尝试提高7β-[2-(5-amino-1, 2, 4-thiadiazol-3-yl)-2(Z)-氟甲氧基亚氨基-乙酰氨基]-3-[(E)-的水溶性2-(1-甲基咪唑并[1, 2-b)]哒嗪鎓-6-基)硫乙烯基]-3-头孢烯-4-羧酸酯(1a)，通过取代C-3'药效团。用 1-甲基-4-吡啶基取代 C-3' 药效基团可提高水溶性，但不会降低抗 MRSA 活性。此外，我们将 N 修饰的前药策略应用于 C-7 酰基，以大幅提高水溶性。在制备的化合物中，N-膦酰基型前药2a（1-甲基咪唑[1,2-b]哒嗪鎓衍生物）和2b（1-甲基-4-吡啶衍生物）显示出适合静脉注射产品的水溶性体内抗MRSA活性与万古霉素相当。

  DOI：

  10.7164/antibiotics.54.364
• 作为产物：
  描述：

  methyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-<(fluoromethoxy)imino>acetate 在 sodium hydroxide 、 乙酸酐 作用下， 反应 18.0h， 生成 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetic acid
  参考文献：
  名称：

  Efficient Preparation of (Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-[(fluoromethoxy)imino]acetic Acid

  摘要：

  (Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-[(氟甲氧基)亚胺]乙酸（2），一种有用的头孢类抗生素化学修饰剂，已高效合成自2-[(氟甲氧基)亚胺]-1,3-丙二腈。通过X射线晶体学对2的立体化学结构进行了明确的确定。

  DOI：

  10.1246/bcsj.66.2335

文献信息

• Studies on Anti-MRSA Parenteral Cephalosporins. II. Synthesis and Antibacterial Activity of 7.BETA.-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(substituted imidazo [1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylates and Related Compounds.
  作者：TOMOYASU ISHIKAWA、KJEIJI KAMIYAMA、NOBUYUKI MATSUNAGA、HIROYUKI TAWADA、YUJI IIZAWA、KENJI OKONOGI、AKIO MIYAKE

  DOI：10.7164/antibiotics.53.1071

  日期：——

  In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1, 2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7β-[2-(5-amino-1, 2, 4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3, 6-diaminoimidazo[1, 2-b]pyridazinium-l-yl)methyl-3-cephem-4-carboxylate (20g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50=1.6 μg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20g showed activity comparable to that of VCM against MRSA. In addition, 20g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20g was considered to be the most promising CZOP derivative for further studies.

  为了发现一种对耐甲氧西林金黄色葡萄球菌（MRSA）具有出色抗菌活性、新颖的头孢唑普兰（CZOP）衍生物，我们对CZOP的烷氧亚氨基部分和咪唑并[1,2-b]哒嗪鎓基团进行了化学修饰。在制备的化合物中，环戊氧亚氨基衍生物7β-[2-(5-氨基-1,2,4-噻二唑-3-基)-2(Z)-环戊氧亚氨基乙酰胺基]-3-(3,6-二氨基咪唑并[1,2-b]哒嗪鎓-1-基)甲基-3-头孢烯-4-羧酸酯（20g）表现出最强的抗MRSA活性，反映其对青霉素结合蛋白2'（PBP2'）的高亲和力（IC50=1.6μg/ml），尽管其抗MRSA活性略逊于万古霉素（VCM）。然而，在小鼠实验性系统感染中，20g对MRSA表现出与VCM相当的活性。此外，20g无论在体外还是体内，对铜绿假单胞菌（Pseudomonas aeruginosa）的活性与CZOP相似或略逊。综合其良好的抗菌活性特征，20g被认为是最有希望的CZOP衍生物，值得进一步研究。
• Process for the preparation of aminothiadiazolylacetyl halide derivtives
  申请人：Eisai Chemical Co., Ltd.

  公开号：US05428173A1

  公开（公告）日：1995-06-27

  A process is provided for the preparation of an aminothiadiazolylacetyl halide derivative represented by the following formula (II): ##STR1## wherein R.sup.1 represents a lower alkyl, cycloalkyl or halogenated lower alkyl group; and R.sup.2 represents an amino-protecting group or a hydrogen atom, or a salt thereof, which process uses as the starting material a compound represented by the following formula (I): ##STR2## wherein R.sup.1 and R.sup.2 have the same meanings as defined above, or a salt thereof.

  提供了一种制备如下式(II)所示的氨基噻二唑基乙酰卤代衍生物的方法： ##STR1## 其中R1代表低级烷基、环烷基或卤代低级烷基；R2代表氨基保护基或氢原子，或其盐，该方法使用如下式(I)所示的化合物作为起始原料： ##STR2## 其中R1和R2具有如上定义的相同含义，或其盐。
• Process for the preparation of cephem derivatives and intermediates
  申请人：Eisai Co., Ltd.

  公开号：US05128465A1

  公开（公告）日：1992-07-07

  A cephem derivative represented by the following formula: ##STR1## wherein R.sub.1 means a fluorine-substituted lower alkyl and A.sub.1 denotes a cyclic or acyclic ammonio group, or a non-toxic salt thereof, is prepared by reacting a compound represented by the following formula: ##STR2## wherein A.sub.1 has the same meaning as defined above, with another compound represented by the following formula: ##STR3## wherein R.sub.1 has the same meaning as defined above, and if necessary, removing the protecting groups.

  一种头孢烯衍生物，其结构如以下公式所示：##STR1## 其中R1表示氟取代的低级烷基，A1表示环状或非环状的铵基团，或其无毒盐，通过以下方法制备：将结构如以下公式所示的化合物：##STR2## 其中A1具有上述定义的相同含义，与结构如以下公式所示的另一化合物反应：##STR3## 其中R1具有上述定义的相同含义，并在必要时去除保护基团。
• Structure-activity Relationships of Cephalosporins Having a (Dimethylisoxazolidinio)vinyl Moiety at Their 3-Position.
  作者：RYUICHIRO HARAI、KENICHIRO SAKAMOTO、HIROYUKI HISAMICHI、NORIAKI NAGANO

  DOI：10.7164/antibiotics.49.1162

  日期：——

  A series of cephalosporins having a (dimethylisoxazolidinio)vinyl group at their 3-position were synthesized to investigate their structure-activity relationships. With regard to the olefin geometry, the (E)-vinyl compound exhibited higher in vitro activity than the (Z)-compound. Regarding the C-7 substituents, the replacement of 2-aminothiazole with 5-amino-l, 2, 4-thiadiazole increased the anti-pseudomonal activity. Determination of the absolute configuration of the C-3 substituent is also presented. Among the compounds synthesized, we selected 7β-[(Z)-2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetamido]-3-[(E)-2-((S)-2, 2-dimethyl-5-isoxazolidinio)vinyl]-3-cephem-4-carboxylate (YM-40220), which showed well-balanced in vitro activity and an excellent in vivo efficacy against Staphylococcus aureus Smith, as a candidate for further development.

  合成了一系列在其3位具有（亚甲基异噁唑啉）乙烯基基团的头孢菌素，以研究其结构-活性关系。关于烯烃几何构型，（E）-乙烯基化合物在体外活性上比（Z）-化合物表现出更高的活性。关于C-7取代基，用5-氨基-1, 2, 4-噻二唑替代2-氨基噻唑可增加抗假单胞菌活性。此外，还展示了C-3取代基的绝对构型的确定。在所合成的化合物中，我们选择了7β-[(Z)-2-(5-氨基-1, 2, 4-噻二唑-3-基)-2-(氟甲氧基亚胺)乙酰氨基]-3-[(E)-2-((S)-2, 2-二甲基-5-异噁唑啉)乙烯]-3-头孢烯-4-羧酸酯（YM-40220），该化合物在体外表现出良好的平衡活性，对金黄色葡萄球菌Smith具有优异的体内疗效，作为进一步开发的候选药物。
• CP6679, a new injectable cephalosporin. Part1: Synthesis and structure–activity relationships
  作者：Masaki Tsushima、Katsuyoshi Iwamatsu、Eijiro Umemura、Toshiaki Kudo、Yasuo Sato、Sojiro Shiokawa、Hiromasa Takizawa、Yuko Kano、Kazuko Kobayashi、Takashi Ida

  DOI：10.1016/s0968-0896(00)00214-5

  日期：2000.12

  A series of cephalosporins bearing a 5,5-fused ring system, an (imidazo/[5,1 -b]thiazolium-6-yl)methyl group, at the C-3 position were synthesized and evaluated for in vitro antibacterial activities. CP6679 (Is) and its analogues showed potent antibacterial activities against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. They were also highly active against methicillin-resistant Staphylococcus aureus (MRSA). CP6679 (Is) showed more potent antibacterial activity than ceftazidime (CAZ) or cefpirome (CPR) against Pseudomonas aeruginosa and MRSA. (C) 2000 Elsevier Science Ltd. All rights reserved.