(3S)-hexahydro-2-oxo-3-[[(phenylmethyl)sulfonyl]amino]-1H-azepine-1-acetic acid | 174960-90-8

• 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: (3S)-hexahydro-2-oxo-3-[[(phenylmethyl)sulfonyl]amino]-1H-azepine-1-acetic acid
• 英文别名: 2-[(3S)-3-(benzylsulfonylamino)-2-oxoazepan-1-yl]acetic acid
• CAS: 174960-90-8
• 化学式: C₁₅H₂₀N₂O₅S
• 分子量: 340.4
• InChiKey: WWALBFUIHLHJCF-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (3S)-hexahydro-2-oxo-3-[[(phenylmethyl)sulfonyl]amino]-1H-azepine-1-acetic acid 在 palladium on activated charcoal 氢气 、 1-羟基苯并三唑 、 溶剂黄146 、 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 乙醇 、 乙腈 为溶剂， 生成 N-((S)-1-Carbamimidoyl-2-ethoxy-piperidin-3-yl)-2-((S)-2-oxo-3-phenylmethanesulfonylamino-azepan-1-yl)-acetamide
  参考文献：
  名称：

  新型，选择性和口服可生物利用的凝血酶抑制剂的设计，合成和进化：掺有P3-P4内酰胺磺酰胺基团的P1-精氨酸衍生物。

  摘要：

  DOI：

  10.1021/jm960572n
• 作为产物：
  描述：

  苄磺酰氯 在 palladium on activated charcoal 氢气 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 (3S)-hexahydro-2-oxo-3-[[(phenylmethyl)sulfonyl]amino]-1H-azepine-1-acetic acid
  参考文献：
  名称：

  Design, synthesis, and structure–Activity relationships of unsubstituted piperazinone-Based transition state factor Xa inhibitors

  摘要：

  A series of novel transition state factor Xa inhibitors containing a variety, of lactam ring systems as central templates was synthesized in an expedient manner and allowed for a great deal of structural variability. Among them. the piperazinone-based inhibitors were found to be not only active against factor Xa but also selective over thrombin. Optimization of the P4 moiety yielded several potent compounds with IC50 below 1 nM against factor Xa. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01037-5

文献信息

• In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S₁‘ Subsite and Its Implications to Structure-Based Drug Design
  作者：Michael J. Costanzo、Harold R. Almond、Leonard R. Hecker、Mary R. Schott、Stephen C. Yabut、Han-Cheng Zhang、Patricia Andrade-Gordon、Thomas W. Corcoran、Edward C. Giardino、Jack A. Kauffman、Joan M. Lewis、Lawrence de Garavilla、Barbara J. Haertlein、Bruce E. Maryanoff

  DOI：10.1021/jm0303857

  日期：2005.3.1

  structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S(1)' region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate

  凝血酶抑制剂由于其抗凝和抗血栓形成作用而可能在医学上有用。我们基于d-Phe-Pro-Arg以及相关的凝血酶活性位点识别基序合成和评估了各种杂环活化的酮，作为候选抑制剂。基于肽的α-酮杂环通常通过亚氨酸酯或Weinreb酰胺途径制备（方案1和2），事实证明后者更为普遍。通常测定测试化合物对人α-凝血酶和牛胰蛋白酶的抑制作用。从基于结构的设计角度来看，杂环允许人们探索和调节凝血酶S1'亚位点内的相互作用。优选的α-酮杂环是富含pi的2取代的吡咯，在带有酮基的碳原子的附近至少有两个杂原子，优选的凝血酶抑制剂是2-酮基苯并噻唑3，其有效K（i）值为0.2 nM，约为1。选择性比胰蛋白酶高15倍。2-酮苯并噻唑13表现出极强的凝血酶抑制作用（K（i）= 0.000 65 nM;缓慢紧密结合）。几个α-酮杂环化合物的凝血酶K（i）值在0.1-400 nM范围内。在温和的碱性条件下，α-酮杂环的“ A
• Peptidyl heterocyclic ketones useful as tryptase inhibitors
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：US06469036B1

  公开（公告）日：2002-10-22

  The present invention relates to a series of peptidyl heterocyclic ketones which are inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

  本发明涉及一系列肽基杂环酮，它们是炎症细胞丝氨酸蛋白酶抑制剂，以及它们的组合物和用于预防和治疗各种免疫介导的炎症性疾病的方法。更具体地说，这些化合物是强效且选择性的胰蛋白酶抑制剂，因此对于预防和治疗与呼吸道相关的炎症性疾病，如哮喘和过敏性鼻炎，具有有效性。
• [EN] PEPTIDYL HETEROCYCLIC KETONES USEFUL AS TRYPTASE INHIBITORS<br/>[FR] PEPTIDYLCETONES HETEROCYCLIQUES INHIBITRICES DE LA TRYPTASE
  申请人：ORTHO MCNEIL PHARM INC

  公开号：WO2000044733A1

  公开（公告）日：2000-08-03

  The present invention relates to a series of peptidyl heterocyclic ketones which are inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

  本发明涉及一系列肽基杂环酮，它们是炎症细胞丝氨酸蛋白酶抑制剂及其组合物和预防和治疗各种免疫介导的炎症性疾病的方法。更具体地说，这些化合物是强效和选择性的替普汀酶抑制剂，因此对于预防和治疗与呼吸道有关的炎症性疾病，如哮喘和过敏性鼻炎，具有有效性。
• Novel, Potent Non-Covalent Thrombin Inhibitors Incorporating P3-Lactam Scaffolds
  作者：Jonathan Z Ho、Tony S Gibson、J.Edward Semple

  DOI：10.1016/s0960-894x(02)00010-0

  日期：2002.3

  Evolution of P-1-argininal inhibitor prototypes led to a series of non-covalent P-3-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S-1, S-2, and S-3 specificity pockets of thrombin. Rigid P-1-arginine surrogates possessing a wide range of basicity (calcd pK(a)'ssimilar toneutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety
  作者：Anton E.P. Adang、Hans Lucas、Adrianus P.A. de Man、Richard A. Engh、Peter D.J. Grootenhuis

  DOI：10.1016/s0960-894x(98)00650-7

  日期：1998.12

  Replacement of the noragmatine group in thrombin inhibitors with a beta-alanyl-guanidine group resulted in a nearly equipotent and more selective compound 8 despite the fact that the pK(a) of this P-1 moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor with this beta-alanyl guanidine group, compound 28. This is an active and selective thrombin inhibitor and in view of its nonpeptide/low basicity structure selected for further pharmacological studies. (C) 1998 Elsevier Science Ltd. All rights reserved.