(-)-(1-benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-carbamic acid tert-butyl ester | 1020104-61-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (-)-(1-benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-carbamic acid tert-butyl ester
• 英文别名: (1-Benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-carbamic acid tert-butyl ester；tert-butyl N-[(6R)-3-(morpholin-4-ylmethyl)-7-oxo-1-phenylmethoxy-5,6-dihydro-2H-azepin-6-yl]carbamate
• CAS: 1020104-61-3
• 化学式: C₂₃H₃₃N₃O₅
• 分子量: 431.532
• InChiKey: RNIVBULGSLBXFU-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  80.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (-)-(1-benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-carbamic acid tert-butyl ester 在 吡啶 、 甲烷磺酸 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 94.0h， 生成 (-)-4-(4-chloro-phenoxy)-N-(1-hydroxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-benzenesulfonamide
  参考文献：
  名称：

  Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy

  摘要：

  The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6 nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6 nM with 34 being the most potent compound discovered (MMP-2 IC(50) = 0.39 nM and MMP-9 IC(50) = 0.22 nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.068
• 作为产物：
  描述：

  Boc-D-烯丙基甘氨酸 在 N-甲基吗啉 、 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 N-羟基-7-氮杂苯并三氮唑 、 caesium carbonate 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 38.0h， 生成 (-)-(1-benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy

  摘要：

  The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6 nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6 nM with 34 being the most potent compound discovered (MMP-2 IC(50) = 0.39 nM and MMP-9 IC(50) = 0.22 nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.068

文献信息

• HETEROCYCLIC DERIVED METALLOPROTEASE INHIBITORS
  申请人：Zhang Yue-Mei

  公开号：US20080103129A1

  公开（公告）日：2008-05-01

  This invention provides novel heterocyclic derived matrix metalloprotease inhibitors of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing matrix metalloproteases. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

  这项发明提供了一种新颖的杂环衍生物基质金属蛋白酶抑制剂的化学式，以及包含同样化合物的药物组合物，用于治疗通过拮抗基质金属蛋白酶而改善的疾病。该发明还提供了使用即时药物组合物的治疗和预防方法。
• Heterocyclic derived metalloprotease inhibitors
  申请人：Janssen Pharmaceutica NV

  公开号：US07803793B2

  公开（公告）日：2010-09-28

  This invention provides novel heterocyclic derived matrix metalloprotease inhibitors of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing matrix metalloproteases. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

  该发明提供了一种新型杂环衍生物基质金属蛋白酶抑制剂，其化学式为：以及包含其的制药组合物，用于治疗通过拮抗基质金属蛋白酶改善的疾病。此发明还提供了使用上述制药组合物的治疗和预防方法。
• US7803793B2
  申请人：——

  公开号：US7803793B2

  公开（公告）日：2010-09-28
• [EN] HETEROCYCLIC DERIVED METALLOPROTEASE INHIBITORS<br/>[FR] INHIBITEURS HÉTÉROCYCLIQUES DE MÉTALLOPROTÉASES DÉRIVÉES
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2008045668A1

  公开（公告）日：2008-04-17

  [EN] This invention provides novel heterocyclic derived matrix metalloprotease inhibitors of the formula (I) and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing matrix metalloproteases. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.
  [FR] L'objet de la présente invention propose de nouveaux inhibiteurs hétérocycliques de métalloprotéases matricielles dérivées de formule (I) et des composés pharmaceutiques comprenant ces inhibiteurs, qui sont utiles pour traiter des troubles améliorés par des métalloprotéases matricielles antagonistes. Cette invention propose également des méthodes thérapeutiques et prophylactiques mettant en oeuvre les présentes compositions pharmaceutiques.
• Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy
  作者：Lawrence J. Wilson、Bingbing Wang、Shyh-Ming Yang、Robert H. Scannevin、Sharon L. Burke、Prabha Karnachi、Kenneth J. Rhodes、William V. Murray

  DOI：10.1016/j.bmcl.2011.08.068

  日期：2011.11

  The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6 nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6 nM with 34 being the most potent compound discovered (MMP-2 IC(50) = 0.39 nM and MMP-9 IC(50) = 0.22 nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability. (C) 2011 Elsevier Ltd. All rights reserved.