6-benzyloxycarbamoyl-7-isobutyl-9-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1(15),12(16),13-triene-10-carboxylic acid | 191406-82-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 6-benzyloxycarbamoyl-7-isobutyl-9-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1(15),12(16),13-triene-10-carboxylic acid
• CAS: 191406-82-3
• 化学式: C₂₇H₃₄N₂O₆
• 分子量: 482.577
• InChiKey: RANAASWMKGGLHZ-VXNXHJTFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  113.96
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  6-benzyloxycarbamoyl-7-isobutyl-9-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1(15),12(16),13-triene-10-carboxylic acid 在 Pd-BaSO₄ N-甲基吗啉 、 氢气 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~80.0 ℃ 、344.75 kPa 条件下， 反应 24.25h， 生成 (6S,7R,10S)-N⁶-hydroxy-7-isobutyl-N¹⁰-{(1S)-2-methyl-1-[(methylamino)carbonyl]propyl}-8-oxo-2-oxa-9-azabicyclo[10.2.2]hexadeca-1⁽¹⁴⁾,12,15-triene-6,10-dicarboxamide
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of Macrocyclic Hydroxamic Acids That Inhibit Tumor Necrosis Factor α Release in Vitro and in Vivo

  摘要：

  To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the PI and P2 ' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2 ' linkers. With an N-methylamide at P3 ', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3 ' -P4 ' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of less than or equal to 0.2 muM in whole blood assay (WBA). Although the P3 ' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3 ' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3 ', an N-methylamide at P4 ' provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 muM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4 ' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC50 = 0.067 muM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K-i values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

  DOI：

  10.1021/jm010127e
• 作为产物：
  描述：

  L-酪氨酸甲酯盐酸盐 在 N-甲基吗啉 、 lithium hydroxide 、 caesium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 6-benzyloxycarbamoyl-7-isobutyl-9-oxo-2-oxa-9-aza-bicyclo[10.2.2]hexadeca-1(15),12(16),13-triene-10-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of Macrocyclic Hydroxamic Acids That Inhibit Tumor Necrosis Factor α Release in Vitro and in Vivo

  摘要：

  To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the PI and P2 ' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2 ' linkers. With an N-methylamide at P3 ', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3 ' -P4 ' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC50 values of less than or equal to 0.2 muM in whole blood assay (WBA). Although the P3 ' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3 ' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3 ', an N-methylamide at P4 ' provided the best cyclophane analogue, SL422 (WBA IC50 = 0.22 muM, LPS-mouse ED50 = 15 mg/kg, po), whereas a morpholinylamide at P4 ' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC50 = 0.067 muM, LPS-mouse ED50 = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K-i values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

  DOI：

  10.1021/jm010127e

文献信息

• Matrix metalloproteinase inhibitors
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：US06656448B1

  公开（公告）日：2003-12-02

  Thus the present invention describes diagnostic agents comprising a diagnostic metal and a compound, wherein the compound comprises: 1-10 targeting moieties;a chelator; and 0-1 linking groups between the targeting moiety and chelator; wherein the targeting moiety is a matrix metalloproteinase inhibitor; and wherein the chelator is capable of conjugating to the diagnostic metal. The present invention also provides novel compositions of the compounds of the invention, kits, and their uses in diagnosis of diseases associated with MMPs.

  因此，本发明描述了包含诊断金属和化合物的诊断试剂，其中该化合物包括：1-10个靶向基团；螯合剂；以及靶向基团和螯合剂之间的0-1个连接基团；其中靶向基团是基质金属蛋白酶抑制剂；螯合剂能够与诊断金属结合。本发明还提供了该化合物的新型组合物、试剂盒以及它们在与基质金属蛋白酶相关的疾病诊断中的用途。