9a-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A | 92594-46-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 9a-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A
• 英文别名: 9-deoxo-9a-aza-9a-(γ-aminopropyl)-9a-homoerythromycin A；9-deoxo-9a-aza-9a-demethyl-9a-(3-aminopropyl)-9a-homoerythromycin A；9a-N-(γ-aminopropyl)-9a-aza-homoerythromycin A；9-deoxo-9-dihydro-9a-aza-9a-(γ-aminopropyl)-9a-homoerithromycin A；9a-(γ-aminopropyl)-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A；(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-6-(3-aminopropyl)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one
• CAS: 92594-46-2
• 化学式: C₄₀H₇₇N₃O₁₂
• 分子量: 792.064
• InChiKey: ZXPXEXKBKUUJEK-WNXQIHLLSA-N

物化性质

• 熔点：
  108 °C(Solvent: Dichloromethane ; Methanol)
• 沸点：
  862.9±65.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  55
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.97
• 拓扑面积：
  206
• 氢给体数：
  6
• 氢受体数：
  15

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	9-deoxo-9a-aza-9a-(β-cyanoethyl)-9a-homoerythromycin A	92627-70-8	C40H73N3O12	788.033
  阿奇霉素 A	9-Deoxo-9a-aza-9a-homoerythromycin A	76801-85-9	C37H70N2O12	734.969

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	9-deoxo-9-dihydro-9a-N-[N'-(β-cyanoethyl)-γ-aminopropyl]-9a-aza-9a-homoerithromycin A	690255-34-6	C43H80N4O12	845.128
  ——	9-deoxo-9a-aza-9a-demethyl-9a-[3-(octanoylamino)propyl]-9a-homoerythromycin A	1262866-18-1	C48H91N3O13	918.263
  ——	12-amino-N-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]dodecanamide	911673-59-1	C52H100N4O13	989.385
  ——	1-butyl-3-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]thiourea	905846-56-2	C45H86N4O12S	907.263
  ——	1-[3-(diethylamino)propyl]-3-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]thiourea	905846-89-1	C48H93N5O12S	964.359
  ——	1-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]-3-ethylurea	905846-39-1	C43H82N4O13	863.143
  ——	9-deoxo-9a-aza-9a-(γ-(2-azidoacetamido)propyl)-9a-homoerythromycin A	1093739-14-0	C42H78N6O13	875.114
  ——	1-butyl-3-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]urea	1292297-08-5	C45H86N4O13	891.197
  ——	1-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]-3-prop-2-enylthiourea	905846-72-2	C44H82N4O12S	891.221
  ——	1-[3-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]propyl]-3-propan-2-ylthiourea	1292297-18-7	C44H84N4O12S	893.237

反应信息

• 作为反应物：
  描述：

  9a-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A 在 N-cyclohexanecarbodiimide-N'-propyloxymethyl polystyrene resin 作用下， 以 二氯甲烷 为溶剂， 反应 49.0h， 生成 9a-(3-{[(4-(methyloxy)phenyl)acetyl]amino}propyl)-9a-aza-9-deoxo-9-dihydro-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 A 在 platinum(IV) oxide 、 氢气 作用下， 以 乙醇 为溶剂， 反应 48.0h， 生成 9a-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  大环内酯类：一类新型的抗炎化合物

  摘要：

  通过将有效的糖皮质激素类固醇与大环内酯类化合物结合在一起，引入了安全糖皮质激素治疗设计的新概念。这些化合物是由9-deokso-9a-aza-9a-同反霉素A和3-descladinosyl-9-deokso-9a-aza-9a-的各种类固醇17β-羧酸和9a- N-（3-氨基烷基）衍生物合成的使用稳定的烷基链的同型阿霉素。结合大环内酯类化合物优先在免疫细胞（特别是吞噬细胞）中积累的特性与经典类固醇的抗炎活性，我们设计了在卵白蛋白（OVA）诱导的哮喘大鼠中表现出良好抗炎活性的分子。描述了这种新型化合物的合成，体外和体内抗炎活性。

  DOI：

  10.1016/j.bmc.2012.10.036

文献信息

• An automated, polymer-assisted strategy for the preparation of urea and thiourea derivatives of 15-membered azalides as potential antimalarial chemotherapeutics
  作者：Antun Hutinec、Renata Rupčić、Dinko Žiher、Kirsten S. Smith、Wilbur Milhous、William Ellis、Colin Ohrt、Zrinka Ivezić Schönfeld

  DOI：10.1016/j.bmc.2011.01.030

  日期：2011.3

  series of 15-membered azalide urea and thiourea derivatives has been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (D6), chloroquine/pyremethamine resistant (W2) and multidrug resistant (TM91C235) strains of Plasmodium falciparum. We have developed an effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide

  合成了一系列15元氮杂内酰胺脲和硫脲衍生物，并评估了它们对恶性疟原虫的氯喹敏感性（D6），氯喹/乙胺嘧啶抗性（W2）和多药耐药性（TM91C235）菌株的体外抗疟活性。我们已经开发出一种有效的自动化合成策略，用于大环内酯支架的尿素/硫脲库的快速合成。使用溶液相策略合成化合物，总收率为50–80％。大多数合成的化合物具有抑制作用。前三种化合物对所有三种菌株的效力比阿奇霉素高30-65倍，阿奇霉素具有抗疟疾活性。
• [EN] SUBSTITUTED 9a-N-[N'-(BENZENESULFONYL)CARBAMOYL-Y-AMINOPROPYL]AND 9a-N-[N'-(B-CYANEOTHYL)-N'-(BENZENESULFONYL)CARBAMOYL-Y-AMINOPROPYL]DERIVATIVES OF 9-DEOXO-9-DIHYDRO-9A-AZA-9A-HOMOERITHROMYCIN A AND 5-0-DESOSAMINYL-9-DEOXO-9-DIHYDRO-9A-AZA-HOMOERITHRONOLIDE A<br/>[FR] DERIVES DE 9-DESOXO-9-DIHYDRO-9A-AZA-9A-HOMOERITHROMYCINE A ET DE 5-0-DESOSAMINYL-9-DESOXO-9-DIHYDRO-9A-AZA-HOMOERITHRONOLIDE A SUBSTITUES PAR LE GROUPE 9A-N-[N'-(BENZENESULFONYL)CARBAMOYL-Y-AMINOPROPYL] ET PAR LE GROUPE 9A-N-[N'-(B-CYANEOTHYL)-N'-(BENZENESULFONYL)CARBAMOYL-Y-AMINOPROPYLE]
  申请人：PLIVA D D

  公开号：WO2004043984A1

  公开（公告）日：2004-05-27

  The invention relates to substituted 9a-N-[N’-(benzenesulfonyl)carbamoyl-Ϝ-aminopropyl] and 9a-N-[N’-(β-cyanoethyl)-N’-(benzenesulfonyl)carbamoyl-Ϝ-aminopropyl] derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerithromycin A and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerithronolide A, novel semisynthetic macrolide antibiotics of the azalide series, of the formula (I) wherein R represents H or cladinosyl moiety, R1 represents H or β-cyanoethyl group an R2 represents H or fluoro, chloro and methyl group, and pharmaceutically acceptable salts thereof with inorganic or organic acids, to the process for the preparation of pharmaceutical compositions as well as to the use their compositions for sterilization rooms and medical instruments as well as for protection of wall and wooden coatings.

  该发明涉及9-去氧-9-二氢-9a-氮杂-9a-同异赤霉素A和5-O-去甘霉素-9-去氧-9-二氢-9a-氮杂-9a-同异赤霉烯醇A的替代9a-N-[N'-(苯磺酰)羰基-Ϝ-氨基丙基]和9a-N-[N'-(β-氰乙基)-N'-(苯磺酰)羰基-Ϝ-氨基丙基]衍生物，这些是一种新型半合成的氮杂环大环内酯类抗生素，属于氮杂环大环内酯系列，其化学式为(I)，其中R代表H或克拉地诺基团，R1代表H或β-氰乙基基团，R2代表H或氟、氯和甲基基团，以及它们与无机或有机酸形成的药学上可接受的盐，以及用于制备药物组合物的方法，以及将它们的组合物用于消毒房间和医疗器械以及保护墙壁和木制涂层。
• Antimalarial Activity of 9a-<i>N</i> Substituted 15-Membered Azalides with Improved in Vitro and in Vivo Activity over Azithromycin
  作者：Mihaela Perić、Andrea Fajdetić、Renata Rupčić、Sulejman Alihodžić、Dinko Žiher、Mirjana Bukvić Krajačić、Kirsten S. Smith、Zrinka Ivezić-Schönfeld、Jasna Padovan、Goran Landek、Dubravko Jelić、Antun Hutinec、Milan Mesić、Arba Ager、William Y. Ellis、Wilbur K. Milhous、Colin Ohrt、Radan Spaventi

  DOI：10.1021/jm201615t

  日期：2012.2.9

  the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant

  由于出现新的耐药性，因此需要新型的抗疟药。阿奇霉素是研究用于治疗和预防疟疾的首个大环内酯类药物，但单药治疗失败，因此新的类似物有望成为具有更高活性的下一代药物。我们使用容易获得的构建基元，通过简单且廉价的化学程序合成了具有酰胺和胺官能团的42种新的9a - N取代的15元氮杂芳族化合物。在对抗恶性疟原虫的效力方面，这些化合物在体外显示出比阿奇霉素显着的进步。（超过100倍）和对寄生虫的高选择性，并具有中等体内口服生物利用度的特征。在小鼠功效模型中进行测试时，与阿奇霉素相比，两种胺和一种酰胺衍生物显示出更高的体内效价。获得的化合物6u的结果，包括改善的体外效能，良好的药代动力学参数以及比阿奇霉素更高且与氯喹相当的体内功效，保证了其在疟疾治疗和预防上的进一步发展。
• Using chemical probes to investigate the sub-inhibitory effects of azithromycin
  作者：Freija G. Glansdorp、Richard J. Spandl、Jane E. Swatton、Olivier Loiseleur、Martin Welch、David R. Spring

  DOI：10.1039/b813157k

  日期：——

  The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.

  抗菌药物阿奇霉素在亚抑制浓度下对治疗以慢性铜绿假单胞菌感染为特征的疾病，如囊性纤维化，具有临床益处。这些效果部分是由于抑制了细菌生物膜的形成。本文报道了从红霉素出发经4步高效合成阿奇霉素，并验证了其在亚最低抑菌浓度（MIC）值下抑制生物膜形成的能力。此外，还描述了固定化和生物素标记的阿奇霉素类似物的合成。这些化学探针用于下拉实验，以努力鉴定阿奇霉素在体内的结合伙伴。正如预期的那样，这些实验结果主要揭示了与核糖体相关的蛋白质结合伙伴，表明这是该药物的主要靶点。这一发现通过使用一种含有质粒编码的ermC的铜绿假单胞菌株进一步证实，该菌株表达一种修饰23S rRNA的蛋白质，从而阻止大环内酯类进入核糖体。在这种菌株中，未观察到生物膜抑制现象。这项工作支持了阿奇霉素亚抑制效应是通过核糖体介导的假设。此外，合成这些化学探针并证明其效用，在全球目标识别中对铜绿假单胞菌和其他物种具有价值。
• [EN] 9A-AZALIDES WITH ANTI-INFLAMMATORY ACTIVITY<br/>[FR] 9A-AZALIDES AYANT UNE ACTIVITE ANTI-INFLAMMATOIRE
  申请人：ZAMBON SPA

  公开号：WO2004039821A1

  公开（公告）日：2004-05-13

  Macrolides with anti-inflammatory activity are described, and more particularly, 9a-azalides without cladinose in position 3 with anti-inflammatory activity, their pharmaceutically acceptable salts and pharmaceutical compositions that contain them as active principle.

  描述了具有抗炎活性的大环内酯类药物，尤其是在位置3没有克拉迪诺糖的9a-氮杂大环内酯类药物，它们的药用盐和包含它们作为活性成分的药物组合物。