2'O-acetyl-11N,12O-cyclocarbamate-11-deshydroxy-10-desmethyl-O⁶-methyl-10-methylene-3-oxodescladinosylerythromycin A | 717889-13-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2'O-acetyl-11N,12O-cyclocarbamate-11-deshydroxy-10-desmethyl-O⁶-methyl-10-methylene-3-oxodescladinosylerythromycin A
• 英文别名: 2'O-acetyl-11-amino-[11N-12O]-carbonyl-11-deshydroxy-10-desmethyl-10-methylene-6-O-methyl-3-oxo-descladinosyl-erythromycin；[(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(1S,2R,5R,7R,8R,9R,11R,14R)-2-ethyl-9-methoxy-1,5,7,9,11-pentamethyl-13-methylidene-4,6,12,16-tetraoxo-3,17-dioxa-15-azabicyclo[12.3.0]heptadecan-8-yl]oxy]-6-methyloxan-3-yl] acetate
• CAS: 717889-13-9
• 化学式: C₃₃H₅₂N₂O₁₁
• 分子量: 652.783
• InChiKey: YIRKYDDENSESEH-BYTHVMNVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  46
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  156
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  2'O-acetyl-11N,12O-cyclocarbamate-11-deshydroxy-10-desmethyl-O⁶-methyl-10-methylene-3-oxodescladinosylerythromycin A 在 甲醇 作用下， 以68%的产率得到11-amino-[11N-12O]-carbonyl-11-deshydroxy-10-desmethyl-10-methylene-6-O-methyl-3-oxo-descladinosyl-erythromycin
  参考文献：
  名称：

  [EN] 10-SUBSTITUTED MACROLIDE ANTIBIOTICS
  [FR] MACROLIDES

  摘要：

  公开号：

  WO2004056843A3
• 作为产物：
  描述：

  10-acetoxymethyl-10,11-anhydro-10-desmethyl-O6-methyldescladinosylerythromycin A 在 sodium hydride 、 戴斯-马丁氧化剂 、 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 2'O-acetyl-11N,12O-cyclocarbamate-11-deshydroxy-10-desmethyl-O⁶-methyl-10-methylene-3-oxodescladinosylerythromycin A
  参考文献：
  名称：

  Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1)

  摘要：

  Introduction: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs.Areas covered: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration.Expert opinion: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

  DOI：

  10.1517/13543776.2014.971754

文献信息

• Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group
  作者：Hany Fakhry Anwar、Mioara Andrei、Kjell Undheim

  DOI：10.1016/j.bmc.2017.02.041

  日期：2017.4

  yield a methylene α,β-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the

  据报道，在红霉素A酮醇化物的C10-甲基中有化学选择性取代。通过转化为乙酸烯丙酯，然后转化为相应的烯丙基氰化物，将克拉霉素衍生的底物10，11-脱水-O6-甲基-癸二糖基红霉素中的C10-甲基活化。乙酸烯丙基酯和氰化物都与羰基二咪唑和氨反应，得到C11，C12-环状氨基甲酸酯，同时消除了烯丙基官能团，得到亚甲基α，β-不饱和酮。与胺的共轭加成导致在末端亚甲基碳和氨基氮之间形成立体选择性CN键。在Stille条件下进行亚甲基的羰基化以与Pd催化交叉偶联。对于阴离子稳定的亲核试剂，例如丙二酸酯的钠盐，在10-取代基的形成中观察到立体选择性。与三甲基甲硅烷基重氮甲烷的立体选择性环加成反应生成了一个螺环烷，其中大环内酯骨架的C10碳已成为季螺碳。报道了针对呼吸道病原体肺炎链球菌和金黄色葡萄球菌菌株的一组选定化合物的体外抗菌数据。作为参考化合物，大多数测试化合物显示出比CLA更高的活性，可抵抗耐药的