[4S-(4a,4aa,5aa,12aa)]-4,7-bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide hydrochloride | 197654-04-9

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 四环素类
• 英文名称: [4S-(4a,4aa,5aa,12aa)]-4,7-bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide hydrochloride
• 英文别名: tigecycline hydrochloride；tigecycline monohydrochloride
• CAS: 197654-04-9
• 化学式: C₂₉H₃₉N₅O₈*ClH
• 分子量: 622.118
• InChiKey: ATIINCUPZOADER-KXLOKULZSA-N

物化性质

• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  0.94
• 重原子数：
  43.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  205.76
• 氢给体数：
  7.0
• 氢受体数：
  11.0

制备方法与用途

生物活性

Tigecycline hydrochloride (GAR-936 hydrochloride) 是一种广谱的甘氨酰环素抗生素。Tigecycline 对 E. coli (MG1655 菌株) 的平均抑制浓度 (MIC) 约为 125 ng/ mL。对 Acinetobacter baumannii (A. baumannii) 的 MIC50 和 MIC90 分别为 1 和 2 mg/L。

靶点

Mean MIC: 125 ng/mL ( E. coli )
MIC50: 1 mg/mL ( A. baumannii )
MIC90: 2 mg/mL ( A. baumannii )

体外研究

Tigecycline (0.63-30 µM, preincubated for 4 days, treated for 72 h) inhibits AML2 cells and HL-60 cells with IC ₅₀ s of 4.72±0.54 and 3.06±0.85 μM (freshly prepared). Tigecycline inhibits AML2 cells and HL-60 cells with IC ₅₀ s of 5.64±0.55 and 4.27±0.45 μM (1 day preincubation). Tigecycline inhibits AML2 cells and HL-60 cells with IC ₅₀ s of 5.02±0.60 and 4.39±0.44 μM (2 day preincubation). Tigecycline inhibits AML2 cells and HL-60 cells with IC ₅₀ s of 4.09±0.41 and 3.95±0.39 μM (3 day preincubation). After a 4 day preincubation of Tigecycline in saline, Tigecycline lost its ability to kill TEX human leukemia cells (from IC ₅₀ ~5 µM when freshly prepared to IC ₅₀ >50 µM after 4 days preincubation) as measured by CellTiter Flour assay.

Cell Viability Assay

Cell Line:	Human leukemic OCI-AML2, HL-60 (ATCC) and TEX cell lines
Concentration:	0.63-30 µM
Incubation Time:	Preincubated for 4 days, treated for 72 hours
Result:	Inhibited AML2 cells and HL-60 cells with IC 50 s of 4.72±0.54 and 3.06±0.85 μM (freshly prepared).

体内研究

Tigecycline (50 mg/kg; intraperitoneal injection; twice a day; for 11 days) reduces tumor volume and weight in NOD/SCID mice.
The peak plasma concentration (C _max ), the terminal half-life (t _1/2 ), area under the plasma concentration-time curve (AUC), clearance (CL) and volume of distribution (Vz) are 22.8μg/mL, 108.9 min, 1912.2min*μg/mL, 26.1 mL/min/kg, 4109.4 mL/kg for Tigecycline in saline, respectively. The peak plasma concentration (C _max ), the terminal half-life (t _1/2 ), area under the plasma concentration-time curve (AUC), clearance (CL) and volume of distribution (Vz) are15.7μg/mL, 110.3 min, 2036.5 min*μg/mL, 24.6 mL/min/kg, 3906.2 mL/kg for Tigecycline in formulation (60 mg/mL pyruvate, 3 mg/mL ascorbic acid, pH 7 in saline) , respectively.

Animal Model:	NOD/SCID mice with OCI-AML2 acute myeloid leukemia (AML) xenograft model
Dosage:	50 mg/kg
Administration:	Intraperitoneal injection; twice a day; for 11 days
Result:	Reduced tumor volume and weight.

Animal Model:	NOD/SCID mice
Dosage:	50 mg/kg
Administration:	Intraperitoneal injection; 360 minutes
Result:	The peak plasma concentration (C max ), the terminal half-life (t 1/2 ), area under the plasma concentration-time curve (AUC), clearance (CL) and volume of distribution (Vz) are 22.8 μg/mL, 108.9 min, 1912.2 min*μg/mL, 26.1 mL/min/kg, 4109.4 mL/kg, respectively.

反应信息

• 作为产物：
  描述：

  替加环素 在 盐酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 生成 [4S-(4a,4aa,5aa,12aa)]-4,7-bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide hydrochloride
  参考文献：
  名称：

  [EN] CRYSTALLINE FORM C OF TIGECYCLINE DIHYDROCHLORIDE AND METHODS FOR ITS PREPARATION
  [FR] FORME CRISTALLINE C DU DICHLORHYDRATE DE TIGÉCYCLINE ET SES PROCÉDÉS DE PRÉPARATION

  摘要：

  本发明涉及替吉环素二盐酸盐的结晶形式C以及制备该结晶形式的方法。此外，本发明涉及将替吉环素二盐酸盐的结晶形式C用作抗感染药物制备的中间体。此外，本发明涉及含有替吉环素二盐酸盐的结晶形式C的有效量的药物组合物，以及将替吉环素二盐酸盐的结晶形式C用作抗感染药物的用途。

  公开号：

  WO2010070093A1

文献信息

• [EN] CRYSTALLINE FORMS OF TIGECYCLINE HYDROCHLORIDE<br/>[FR] FORMES CRISTALLINES D'HYDROCHLORURE DE TIGÉCYCLINE
  申请人：SANDOZ AG

  公开号：WO2009062963A1

  公开（公告）日：2009-05-22

  The present invention relates to crystalline forms A and B of Tigecycline hydrochloride and to methods for the preparation of the same. Furthermore the present invention relates to the use of crystalline forms A and B of Tigecycline hydrochloride as intermediates for the formulation of an anti-infective medicament. Moreover the present invention relates to pharmaceutical compositions comprising crystalline form A of Tigecycline hydrochloride in an effective amount and to the use of crystalline form A of Tigecycline hydrochloride as anti- infective medicament.

  本发明涉及替吉环素盐酸盐的晶型A和B，以及其制备方法。此外，本发明还涉及将替吉环素盐酸盐的晶型A和B用作抗感染药物配方的中间体。此外，本发明还涉及包含替吉环素盐酸盐晶型A有效量的药物组合物，以及将替吉环素盐酸盐晶型A用作抗感染药物的用途。
• [EN] OXAZOLE DERIVATIVES OF TETRACYCLINES<br/>[FR] DERIVES OXAZOLE DE TETRACYCLINES
  申请人：WYETH CORP

  公开号：WO2005056538A1

  公开（公告）日：2005-06-23

  This invention provides compounds of the formula: wherein A', X and Y are defined in the specification. These compounds are useful as antibacterial agents.

  本发明提供了以下式子的化合物：其中A'、X和Y在说明书中有定义。这些化合物可用作抗菌剂。
• TIGECYCLINE CRYSTALLINE HYDRATE AND PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：Hu Lifang

  公开号：US20140107357A1

  公开（公告）日：2014-04-17

  Provided are a Tigecycline crystalline hydrate, and a preparation method therefor and use thereof. The crystalline hydrate has high stability for storage, and is used for the manufacture of a medicament for treating or preventing the infection of respiratory system, hepatobiliary system, facial features, urogenital system, bone and joint, skin and soft tissue and endocarditis, septicemia, meningitis caused by susceptible strains of Gram-positive or Gram-negative bacteria, anaerobic bacteria, chlamydia, and mycoplasma in human or animal.

  提供了一种替格西林水合物晶体，以及其制备方法和用途。该水合物晶体具有高稳定性，可用于制造用于治疗或预防呼吸系统、肝胆系统、面部特征、泌尿生殖系统、骨骼和关节、皮肤和软组织以及由敏感的革兰氏阳性或阴性细菌、厌氧菌、沙眼衣原体和支原体引起的心内膜炎、败血症、脑膜炎等人或动物感染的药物。
• Tigecycline and methods of preparing 9-nitrominocycline
  申请人：Krishnan Lalitha

  公开号：US20070049560A1

  公开（公告）日：2007-03-01

  Methods of preparing and purifying tetracyclines, such as tigecycline, are disclosed. Also disclosed are tetracycline compositions, such as tigecycline compositions, prepared by these methods.

  公开了制备和纯化四环素类药物（如替吉奥星）的方法。同时公开了通过这些方法制备的四环素类药物组合物，例如替吉奥星组合物。
• Tigecycline and methods of preparing 9-aminominocycline
  申请人：Krishnan Lalitha

  公开号：US20070049563A1

  公开（公告）日：2007-03-01

  Methods of preparing and purifying tetracyclines, such as tigecycline, are disclosed. Also disclosed are tetracycline compositions, such as tigecycline compositions, prepared by these methods.

  本文披露了制备和纯化四环素类药物，如替吉环素的方法。同时，还披露了通过这些方法制备的四环素类药物组合物，如替吉环素组合物。