(S)-1-((R)-3-Cyclohexyl-2-ethanesulfonylamino-propionyl)-pyrrolidine-2-carboxylic acid | 172348-46-8

• 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: (S)-1-((R)-3-Cyclohexyl-2-ethanesulfonylamino-propionyl)-pyrrolidine-2-carboxylic acid
• 英文别名: 3-Cyclohexyl-N-(ethanesulfonyl)-D-alanyl-L-proline；(2S)-1-[(2R)-3-cyclohexyl-2-(ethylsulfonylamino)propanoyl]pyrrolidine-2-carboxylic acid
• CAS: 172348-46-8
• 化学式: C₁₆H₂₈N₂O₅S
• 分子量: 360.475
• InChiKey: SODKEQUHMFJKBU-KGLIPLIRSA-N

物化性质

• 沸点：
  579.6±60.0 °C(Predicted)
• 密度：
  1.262±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 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：

  (S)-1-((R)-3-Cyclohexyl-2-ethanesulfonylamino-propionyl)-pyrrolidine-2-carboxylic acid 在 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 3-{[(S)-1-((R)-3-Cyclohexyl-2-ethanesulfonylamino-propionyl)-pyrrolidine-2-carbonyl]-amino}-2-oxo-4-piperidin-4-yl-butyric acid
  参考文献：
  名称：

  Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

  摘要：

  2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P-1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 mu M, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00179-1
• 作为产物：
  描述：

  (S)-1-((R)-2-tert-Butoxycarbonylamino-3-cyclohexyl-propionyl)-pyrrolidine-2-carboxylic acid 2-oxo-2-phenyl-ethyl ester 在 四丁基氟化铵 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.17h， 生成 (S)-1-((R)-3-Cyclohexyl-2-ethanesulfonylamino-propionyl)-pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

  摘要：

  2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P-1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 mu M, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00179-1

文献信息

• Anticoagulant agents
  申请人：——

  公开号：US20010018423A1

  公开（公告）日：2001-08-30

  This invention relates to a compound of the Formula I X-C(O)-Y-G-R   I (wherein X, Y, G and R have the values defined in the description), or a pharmaceutically acceptable salt thereof, processes and intermediates for the preparation of such a compound or salt, pharmaceutical compositions comprising such a compound or salt and methods of their use as thrombin inhibitors, coagulation inhibitors and agents for the treatment of thromboembolic disorders.

  本发明涉及一种公式IX-C（O）-Y-G-R的化合物（其中X，Y，G和R的值在说明中定义），或其药学上可接受的盐，制备此类化合物或盐的过程和中间体，包含该化合物或盐的制药组合物以及它们作为凝血酶抑制剂，凝血抑制剂和治疗血栓栓塞性疾病的药剂的使用方法。
• Heterocyclic derivatives and their use as antithrombotic agents
  申请人：——

  公开号：US20030130270A1

  公开（公告）日：2003-07-10

  The present invention relates to antithrombotic compounds comprising the group Q, Q having formula (I), wherein the substructure (i) is a structure selected from (a, b and c), wherein X is 0 or S; X′ being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds of the invention are therapeutically active and in particular are antithrombotic agents. 1

  本发明涉及抗血栓化合物，包括具有公式（I）的Q基团，其中亚结构（i）是从（a、b和c）中选择的结构，其中X为0或S；X'独立地为CH或N；m为0、1、2或3；其中Q基团通过氧原子或可选择取代的氮或碳原子结合，或其药学上可接受的盐或前药。本发明的化合物具有治疗活性，特别是抗血栓剂。
• Benzisoxazole and 4-amidino-3-hydroxyphenyl chemical intermediates
  申请人：Eli Lilly and Company

  公开号：US06534650B2

  公开（公告）日：2003-03-18

  This invention relates to compounds of Formula V H—Y—G—R   V and Formula VI (wherein f, X, Y, G and R have the values defined in the description) which are useful as intermediates for the preparation of compounds, or pharmaceutically acceptable salts thereof, which are useful as thrombin inhibitors, coagulation inhibitors and agents for the treatment of thromboembolic disorders.

  本发明涉及公式VH-Y-G-R和公式VI的化合物（其中f、X、Y、G和R的值在描述中有定义），它们可用作中间体，用于制备化合物或其药学上可接受的盐，用于治疗凝血酶抑制剂、凝血抑制剂和血栓栓塞性疾病的治疗剂。
• Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics
  作者：Anton E. P. Adang、Adrianus P. A. de Man、Gerard M. T. Vogel、Peter D. J. Grootenhuis、Martin J. Smit、Co A. M. Peters、Arie Visser、Jos B. M. Rewinkel、Theo van Dinther、Hans Lucas、Jan Kelder、Sjoerd van Aelst、Dick G. Meuleman、Constant A. A. van Boeckel

  DOI：10.1021/jm011110z

  日期：2002.9.1

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.
• 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.