3-O-decladinosyl-9-deoxo-9-dihydro-9a-(β-aminoethyl)-9a-aza-9a-homoerythromycin A

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-O-decladinosyl-9-deoxo-9-dihydro-9a-(β-aminoethyl)-9a-aza-9a-homoerythromycin A
• 英文别名: 9a-(β-aminoethyl)-3-O-decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A；(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-6-(2-aminoethyl)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one
• 化学式: C₃₁H₆₁N₃O₉
• 分子量: 619.84
• InChiKey: KTNNCWHDSSAAFM-UFFIDJCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  43
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.97
• 拓扑面积：
  178
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  3-O-decladinosyl-9-deoxo-9-dihydro-9a-(β-aminoethyl)-9a-aza-9a-homoerythromycin A 在 盐酸 、 水 作用下， 以 氯仿 为溶剂， 反应 40.0h， 生成 9a-(β-aminoethyl)-3-O-decladinosyl-5-O-dedesosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  WO2007/125414

  摘要：

  公开号：
• 作为产物：
  描述：

  阿奇霉素 在 盐酸 、 双氧水 、 三乙基硼氢化锂 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 20.67h， 生成 3-O-decladinosyl-9-deoxo-9-dihydro-9a-(β-aminoethyl)-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

  摘要：

  Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N ''-substituted 9a(N'-carbamoyl-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-{N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugar; on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.

  DOI：

  10.1021/jm2001585

文献信息

• Novel Antimalarial 9A-Carbamoyl-Aminoalkyl and 9A-Thiocarbamoyl-Aminoalkyl Azalides
  申请人：Bukvic Krajacic Mirjana

  公开号：US20080200404A1

  公开（公告）日：2008-08-21

  Novel 9a-N′-substituted-carbamoyl- and thiocarbamoyl-aminoalkyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 3-O-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A compounds having antimalarial activity are claimed. More particularly, the invention relates to 9a-N′-substituted-carbamoyl- and thiocarbamoyl-β-aminoethyl- or -γ-aminopropyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 3-O-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A compounds and to pharmaceutically acceptable derivatives thereof having antimalarial activity.

  本发明涉及具有抗疟活性的9a-N'-取代-氨基甲酰基和硫代氨基甲酰基-氨基烷基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A和3-O-去氯基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A化合物。更具体地，该发明涉及具有抗疟活性的9a-N'-取代-氨基甲酰基和硫代氨基甲酰基-β-氨基乙基或-γ-氨基丙基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A和3-O-去氯基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A化合物及其具有抗疟活性的药用可接受衍生物。
• 9A-SUBSTITUTED AZALIDES FOR THE TREATMENT OF MALARIA
  申请人：Alihodzic Sulejman

  公开号：US20090105301A1

  公开（公告）日：2009-04-23

  The present invention relates to novel 9a-substituted azalides having antimalarial activity. More particularly, the invention relates to 9a-substituted 9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 3-O-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 3-O-decladinosyl-5-O-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A compounds having antimalarial activity, to the method of preparation, to the method of use, and to pharmaceutically acceptable derivatives thereof having antimalarial activity.

  本发明涉及具有抗疟活性的新型9a-取代的氮杂环己烷酮类化合物。更具体地说，本发明涉及9a-取代的9a-氮杂-9-去氧-9-二氢-9a-同麻黄霉素A、3-O-去克拉地诺糖基-9a-氮杂-9-去氧-9-二氢-9a-同麻黄霉素A和3-O-去克拉地诺糖基-5-O-去脱氨基-9a-氮杂-9-去氧-9-二氢-9a-同麻黄霉素A化合物的抗疟活性、制备方法、使用方法以及具有抗疟活性的药学上可接受的衍生物。
• WO2007/125414
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides
  作者：Mirjana Bukvić Krajačić、Mihaela Perić、Kirsten S. Smith、Zrinka Ivezić Schönfeld、Dinko Žiher、Andrea Fajdetić、Nedjeljko Kujundžić、Wolfgang Schönfeld、Goran Landek、Jasna Padovan、Dubravko Jelić、Arba Ager、Wilbur K. Milhous、William Ellis、Radan Spaventi、Colin Ohrt

  DOI：10.1021/jm2001585

  日期：2011.5.26

  Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N ''-substituted 9a(N'-carbamoyl-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugar; on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.