11,12-O-[1-(dimethylamino)ethylidene]-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A | 1104201-42-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 11,12-O-[1-(dimethylamino)ethylidene]-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
• 英文别名: (1R,2R,5R,6S,7S,8R,9R,11R,14R,15R)-17-(dimethylamino)-8-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-9-hydroxy-6-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-1,5,7,9,11,13,14,17-octamethyl-3,16,18-trioxa-13-azabicyclo[13.3.0]octadecan-4-one
• CAS: 1104201-42-4
• 化学式: C₄₂H₇₉N₃O₁₂
• 分子量: 818.102
• InChiKey: MDMUZVAUILUGCF-QHDIQFIQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  57
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.98
• 拓扑面积：
  161
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  11,12-O-[1-(dimethylamino)ethylidene]-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A 在 甲醇 、 4-二甲氨基吡啶 、 platinum(IV) oxide 、 palladium 10% on activated carbon 、 水 、 氢气 、 sodium hydride 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 lithium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 mineral oil 、 叔丁醇 为溶剂， 45.0 ℃ 、500.01 kPa 条件下， 反应 155.5h， 生成 2'-O-[3-({4-[(4-quinolinyl)amino]butanoyl}amino)propyl]-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  Design, Synthesis, and in Vitro Activity of Novel 2′-O-Substituted 15-Membered Azalides

  摘要：

  Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.

  DOI：

  10.1021/jm201676t
• 作为产物：
  描述：

  1,1-二甲氧基-N,N-二甲基乙胺 、 阿奇霉素 以 氯仿 为溶剂， 反应 24.0h， 生成 11,12-O-[1-(dimethylamino)ethylidene]-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  [EN] 9-DEOXO- 9A-METHYL- 9A- AZA- 9A-H0M0ERYTHR0MYCIN A DERIVATIVES FOR THE TREATMENT OF NEUTROPHIL DOMINATED INFLAMMATORY DISEASES
  [FR] DÉRIVÉS DE 9-DÉOXO-9A-MÉTHYL-9A-AZA-9A-HOMOÉRYTHROMYCINE A POUR LE TRAITEMENT DE MALADIES INFLAMMATOIRES DOMINÉES PAR LES NEUTROPHILES

  摘要：

  式(I)中的2'-0-取代的14-或15-成员氮杂环巨环内酮类化合物，其中R6代表(i)-C1-8烷基，未取代或在末端碳原子处被羟基、-C1-3烷氧基和-C(O)OC1-3烷基中的一种选择的基团取代，或者当-C1-8烷基是支链时，替代可以选择性地由两个末端碳原子的每个都带有一个羟基基团，(ii)-CH(NH2)C1-4烷基，其中-C1-4烷基基团可以选择性地被O、S和N中选择的杂原子中断，(iii)-CH2N(R7)(R8)，其中R7和R8各自独立地代表H或-C1-3烷基，前提是R7和R8不能同时代表H，(iv)含有最多2个O、S和N中选择的杂原子的4-6成员杂环，其中该杂环未取代或被-C1-3烷基取代，(v)5-6成员杂芳环，未取代或被一个到三个独立选择的卤素、羟基、-C1-3烷基、-C1-3烷氧基、-CF3、-OCF3和-NH2基团取代，(vi)-CH(NH2)CH2-芳基，其中芳基可以未取代或被一个或两个独立选择的-C1-3烷基、-C1-3烷氧基和羟基取代，(vii)-C3-7环烷基，或(viii)苯基未取代或被一个或两个独立选择的卤素、羟基、-C1-3烷基、-C1-3烷氧基、-CF3、-OCF3和-NH2基团取代，或其盐，用于治疗中性粒细胞主导的炎症性疾病，特别是用于治疗由中性粒细胞浸润引起的中性粒细胞主导的炎症性疾病和/或与中性粒细胞功能改变相关的疾病，以及它们的制备方法，作为治疗剂的使用以及其盐。

  公开号：

  WO2010086350A1

文献信息

• Compounds
  申请人：Alihodzic Sulejman

  公开号：US20090036388A1

  公开（公告）日：2009-02-05

  The present invention relates to novel 2′-O-substituted 9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A derivatives having antimalarial activity. More particularly, the invention relates to 2′-O-substituted-9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A and 2′-O-substituted-3-O-decladinosyl-9-deoxo-9 a -methyl-9 a -aza-9 a -homoerythromycin A derivatives having antimalarial activity, to the intermediates for their preparation, to the methods for their preparation, to their use as therapeutic agents, and to salts thereof having antimalarial activity.

  本发明涉及具有抗疟活性的新型2'-O-取代的9-去氧-9a-甲基-9a-氮-9a-同异红霉素A衍生物。更具体地，本发明涉及具有抗疟活性的2'-O-取代-9-去氧-9a-甲基-9a-氮-9a-同异红霉素A和2'-O-取代-3-O-去氧-9-去氧-9a-甲基-9a-氮-9a-同异红霉素A衍生物，以及它们的制备中间体、制备方法、用作治疗剂的用途以及具有抗疟活性的盐。
• [EN] 9-DEOXO- 9A-METHYL- 9A- AZA- 9A-H0M0ERYTHR0MYCIN A DERIVATIVES FOR THE TREATMENT OF NEUTROPHIL DOMINATED INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS DE 9-DÉOXO-9A-MÉTHYL-9A-AZA-9A-HOMOÉRYTHROMYCINE A POUR LE TRAITEMENT DE MALADIES INFLAMMATOIRES DOMINÉES PAR LES NEUTROPHILES
  申请人：GLAXOSMITHKLINE ZAGREB

  公开号：WO2010086350A1

  公开（公告）日：2010-08-05

  2'-0-substituted 14- or 15-membered azalide macrolides of Formula (I) wherein R6 represents (i) -C1-8alkyl, unsubstituted or substituted at the terminal carbon atom by a group selected from hydroxy, -C1-3alkoxy and -C(O)OC1-3alkyl, or when -C1-8alkyl is branched, substitution can alternatively be by a hydroxyl group at each of two terminal carbon atoms, (ii) -CH(NH2)C1-4alkyl, wherein the -C1-4alkyl group may be optionally interrupted by a heteroatom selected from O, S and N, (iii) -CH2N(R7)(R8), wherein R7 and R8 each independently represent H or -C1-3alkyl provided that R7 and R8 cannot both simultaneously represent H, (iv) a 4-6-membered heterocyclic ring containing up to 2 heteroatoms independently selected from O, S and N, wherein the heterocyclic ring is unsubstituted or substituted by -C1-3alkyl, (v) 5-6 membered heteroaromatic ring, unsubstituted or substituted by one to three groups independently selected from halo, hydroxyl, -C1-3alkyl, -C1-3alkoxy, -CF3, -OCF3 and -NH2, (vi) -CH(NH2)CH2-aryl wherein the aryl group may be unsubstituted or substituted by one or two substituents independently selected from -C1-3alkyl, -C1-3alkoxy and hydroxyl, (vii) -C3-7cycloalkyl, or (viii) phenyl unsubstituted or substituted by one or two groups independently selected from halo, hydroxyl, -C1-3alkyl, -C1-3alkoxy, -CF3, -OCF3 and -NH2, or salts thereof, useful in the treatment of neutrophil dominated inflammatory diseases, especially in the treatment of neutrophil dominated inflammatory diseases resulting from neutrophilic infiltration and/or diseases associated with altered cellular functionality of neutrophils, to methods for their preparation, to their use as therapeutic agents, and to salts thereof.

  式(I)中的2'-0-取代的14-或15-成员氮杂环巨环内酮类化合物，其中R6代表(i)-C1-8烷基，未取代或在末端碳原子处被羟基、-C1-3烷氧基和-C(O)OC1-3烷基中的一种选择的基团取代，或者当-C1-8烷基是支链时，替代可以选择性地由两个末端碳原子的每个都带有一个羟基基团，(ii)-CH(NH2)C1-4烷基，其中-C1-4烷基基团可以选择性地被O、S和N中选择的杂原子中断，(iii)-CH2N(R7)(R8)，其中R7和R8各自独立地代表H或-C1-3烷基，前提是R7和R8不能同时代表H，(iv)含有最多2个O、S和N中选择的杂原子的4-6成员杂环，其中该杂环未取代或被-C1-3烷基取代，(v)5-6成员杂芳环，未取代或被一个到三个独立选择的卤素、羟基、-C1-3烷基、-C1-3烷氧基、-CF3、-OCF3和-NH2基团取代，(vi)-CH(NH2)CH2-芳基，其中芳基可以未取代或被一个或两个独立选择的-C1-3烷基、-C1-3烷氧基和羟基取代，(vii)-C3-7环烷基，或(viii)苯基未取代或被一个或两个独立选择的卤素、羟基、-C1-3烷基、-C1-3烷氧基、-CF3、-OCF3和-NH2基团取代，或其盐，用于治疗中性粒细胞主导的炎症性疾病，特别是用于治疗由中性粒细胞浸润引起的中性粒细胞主导的炎症性疾病和/或与中性粒细胞功能改变相关的疾病，以及它们的制备方法，作为治疗剂的使用以及其盐。
• Design, Synthesis, and in Vitro Activity of Novel 2′-<i>O</i>-Substituted 15-Membered Azalides
  作者：Dijana Pešić、Kristina Starčević、Ana Toplak、Esperanza Herreros、Jaume Vidal、Maria Jesus Almela、Dubravko Jelić、Sulejman Alihodžić、Radan Spaventi、Mihaela Perić

  DOI：10.1021/jm201676t

  日期：2012.4.12

  Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.