洛曲非班 | 171049-14-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 洛曲非班
• 英文名称: lotrafiban
• 英文别名: (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid；(2S)-7-(4,4'-bipiperidinylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid；SB 214857；SB-214857；[(S)-7-([4,4']bipiperidinyl-1-carbonyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl]-acetic acid；(S)-7-[(4,4'-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid；2-[(2S)-4-methyl-3-oxo-7-(4-piperidin-4-ylpiperidine-1-carbonyl)-2,5-dihydro-1H-1,4-benzodiazepin-2-yl]acetic acid
• CAS: 171049-14-2
• 化学式: C₂₃H₃₂N₄O₄
• 分子量: 428.531
• InChiKey: PYZOVVQJTLOHDG-FQEVSTJZSA-N

物化性质

• 比旋光度：
  D -200.1° (c = 0.5 in methanol)
• 沸点：
  730.0±60.0 °C(Predicted)
• 密度：
  1.220±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  洛曲非班 在 吡啶盐酸盐 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 0.55h， 以94%的产率得到SB 214857 hydrochloride
  参考文献：
  名称：

  The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2:  Conversion of the Key Intermediate SB-235349 to SB-214857-A

  摘要：

  The process development to the manufacturing route to (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hydrochloride (SB214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2RS)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2S)-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid. The unreacted (R)-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladium-catalysed aminocarbonylation of the aryl iodide with 4,4'-pyridylpiperidine to give (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.

  DOI：

  10.1021/op034023k
• 作为产物：
  描述：

  N-boc-4,4-联哌啶 在 盐酸 、 sodium hydroxide 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 生成 洛曲非班
  参考文献：
  名称：

  对映体合成SB 214857（一种有效的口服活性非肽纤维蛋白原受体拮抗剂）

  摘要：

  据报道，SB 214857的对映体特异性合成是一种有效的非重复性纤维蛋白原受体拮抗剂。合成途径采用分子内芳基氟化物置换形成1，4-苯并二氮杂system系统的七元环作为关键步骤。

  DOI：

  10.1016/0040-4039(95)02054-3

文献信息

• Active salt forms with tyrosine kinase activity
  申请人：——

  公开号：US20040023978A1

  公开（公告）日：2004-02-05

  The present invention relates to orally active salt forms of the mesylate salt of 4-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazine-1-carboxylic acid methylamide which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, retinal ischemia, macular edema, inflammatory diseases, and the like in mammals.

  本发明涉及口服活性盐形式的甲磺酸盐，其抑制、调节和/或调控酪氨酸激酶信号传导的4-[2-(5-氰基噻唑-2-基氨基)-吡啶-4-基甲基]-哌嗪-1-羧酸甲酰胺，含有这些化合物的组合物，以及使用它们治疗酪氨酸激酶依赖性疾病和症状的方法，如血管生成、癌症、肿瘤生长、动脉粥样硬化、老年性黄斑变性、糖尿病视网膜病变、视网膜缺血、黄斑水肿、炎症性疾病等哺乳动物。
• Polymorphs with tyrosine kinase activity
  申请人：——

  公开号：US20040023980A1

  公开（公告）日：2004-02-05

  The present invention relates to active polymorphs of 4-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazine-1-carboxylic acid methylamide which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angio-genesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, retinal ischemia, macular edema, inflammatory diseases, and the like in mammals.

  本发明涉及活性多型体4-[2-(5-氰基噻唑-2-基氨基)-吡啶-4-基甲基]-哌嗪-1-羧酸甲酰胺，其抑制、调节和/或调控酪氨酸激酶信号传导，含有这些化合物的组合物，以及使用它们治疗酪氨酸激酶依赖性疾病和症状的方法，如血管生成、癌症、肿瘤生长、动脉粥样硬化、老年性黄斑变性、糖尿病视网膜病变、视网膜缺血、黄斑水肿、炎症性疾病等在哺乳动物中。
• [EN] PRODRUGS OF SECONDARY AMINE COMPOUNDS<br/>[FR] PROMÉDICAMENTS DE COMPOSÉS AMINE SECONDAIRES
  申请人：ALKERMES PHARMA IRELAND LTD

  公开号：WO2013088255A1

  公开（公告）日：2013-06-20

  The present invention relates to compounds of Formula (I).

  本发明涉及式(I)的化合物。
• Polymeric coupling agents and pharmaceutically-active polymers made therefrom
  申请人：Santerre J. Paul

  公开号：US20050255082A1

  公开（公告）日：2005-11-17

  A pharmaceutically-active polymeric compound of the general formula (I), Y-[Y n -LINK B-X] m -LINK B  (I) wherein (i) X is a coupled biological coupling agent of the general formula (II) Bio-LINK A-Bio  (II) wherein Bio is a biologically active agent fragment or precursor thereof linked to LINK A through a hydrolysable covalent bond; and LINK A is a coupled central flexible linear first segment of <2000 theoretical molecular weight linked to each of said Bio fragments; (ii) Y is LINK B-OLIGO; wherein (a) LINK B is a coupled second segment linking one OLIGO to another OLIGO and an OLIGO to X or precursor thereof; and (b) OLIGO is a short length of polymer segment having a molecular weight of less than 5,000 and comprising less than 100 monomeric repeating units; (iii) m is 1-40; and (iv) n is selected from 2-50. The compounds are useful as biomaterials, particularly, providing antibacterial activity in vivo. Also provided are biological coupling agents useful as intermediates in the preparation of the pharmaceutically-active polymeric compounds.

  一种具有一般式（I）的药用活性聚合物化合物， Y-[Y n -LINK B-X] m -LINK B  （I） 其中（i）X是一种偶联的生物偶联剂，具有一般式（II） Bio-LINK A-Bio  （II） 其中Bio是与LINK A通过可水解共价键连接的生物活性剂片段或其前体；而LINK A是与每个Bio片段连接的理论分子量小于2000的偶联中心柔性线性第一段；（ii）Y是LINK B-OLIGO；其中（a）LINK B是将一个OLIGO与另一个OLIGO以及一个OLIGO与X或其前体连接的偶联的第二段；（b）OLIGO是具有分子量小于5,000且包含少于100个单体重复单元的短聚合物段；（iii）m为1-40；（iv）n从2-50中选择。这些化合物可用作生物材料，特别是在体内提供抗菌活性。还提供了作为药用活性聚合物化合物制备中间体的生物偶联剂。
• COMPOUNDS AND COMPOSITIONS FOR DRUG RELEASE
  申请人：INTERFACE BIOLOGICS, INC.

  公开号：US20160038651A1

  公开（公告）日：2016-02-11

  The invention relates to compounds that include biologically active agents (e.g., compounds according to any of formulas (I) and (I-A) that can be used for effective drug release, e.g., as coatings for medical devices. Use of these compounds in the coating of surfaces can allow for long-term drug release as well as imparting uniform coatings with little phase separation compared to, e.g., the parent biologically active agent.

  这项发明涉及包括生物活性剂（例如，根据任何公式（I）和（I-A）的化合物）的化合物，可用作有效的药物释放，例如，作为医疗器械的涂层。在表面涂层中使用这些化合物可以实现长期药物释放，并且与原生生物活性剂相比，可以实现均匀涂层且几乎没有相分离。