(2R)-2-[(tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]-3-cyclohexylpropanoic acid | 190904-21-3

• 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: (2R)-2-[(tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]-3-cyclohexylpropanoic acid
• 英文别名: N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OH；N-(tert-butoxycarbonylmethylene)-(BOC)-(D)-cyclohexylalanine；N-Boc-N-(tert-butoxycarbonylmethylene)-(D)-cyclohexylalanine；(2R)-3-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]propanoic acid
• CAS: 190904-21-3
• 化学式: C₂₀H₃₅NO₆
• 分子量: 385.501
• InChiKey: WBKLALCVDIDTIC-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  93.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R)-2-[(tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]-3-cyclohexylpropanoic acid 在 10percent Pd/C 氢气 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (2S)-1-((2R)-2-{(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino}-3-cyclohexylpropanoyl)-L-proline
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  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.

  DOI：

  10.1021/jm011110z
• 作为产物：
  描述：

  N-BOC-3-环己基-D-丙氨酸 在 sodium hydroxide 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 (2R)-2-[(tert-butoxycarbonyl)(2-tert-butoxy-2-oxoethyl)amino]-3-cyclohexylpropanoic acid
  参考文献：
  名称：

  Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(98)00650-7

文献信息

• Thrombin inhibitors
  申请人：Abbott GmbH & Co., KG

  公开号：US06740647B1

  公开（公告）日：2004-05-25

  Novel five-membered heterocyclic amidines, their preparation and use as competitive inhibitors of trypsin-like serine proteases, especially thrombin and kininogenases such as kallikrein. Pharmaceutical compositions which contain the compounds as active ingredients, and use of the compounds as thrombin inhibitors, anticoagulants and antiinflammatory agents.

  新型五元杂环胺基化物，其制备和用作胰蛋白酶样丝氨酸蛋白酶的竞争性抑制剂，特别是血栓素和激肽原酶如激肽原酶的抑制剂。含有这些化合物作为活性成分的药物组合物，以及将这些化合物用作血栓素抑制剂、抗凝剂和抗炎药剂。
• Technical Scale Synthesis of a New and Highly Potent Thrombin Inhibitor
  作者：Bernd Schäfer、Harald Bernard、Gerd Bülow、Udo E. Lange、Helmut Mack、Thomas Pfeiffer、Werner Seitz、Thomas Zierke

  DOI：10.1055/s-2004-831200

  日期：——

  In this account, we describe the development of an efficient and convergent process for the peptidomimetic thrombin inhibitor 1 on production plant scale. Starting from nicotinonitrile (13), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid (5) and (2R)-2-amino-3-cyclohexylpropanoic acid (29) compound 1 was obtained in 16 chemical steps. New methods had been developed for the preparation of the key intermediate dehydroproline 22 and the transformation of nitriles into amidines. The thrombin inhibitor 1 was isolated by special techniques (nanofiltration and spray drying). Almost all salts of 1 are amorphous, however, a crystalline complex was obtained with 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Saccharin®).

  在本报告中，我们描述了在生产工厂规模上开发一种高效且收敛的肽类模仿物 thrombin 抑制剂 1 的过程。以尼古丁腈（13）、(2S,4R)-1-(叔丁氧基碳酰基)-4-羟基-2-吡咯烷羧酸（5）和 (2R)-2-氨基-3-环己基丙酸（29）为起始材料，通过16个化学步骤合成出了化合物 1。我们开发了新方法以制备关键中间体去氢脯氨酸 22，并将腈转化为酰胺。通过特殊技术（纳滤和喷雾干燥）分离得到了 thrombin 抑制剂 1。几乎所有的 1 的盐都是无定形的，然而，我们得到了一种与 1,2-苯异噻唑-3(2H)-酮 1,1-二氧化物（糖精®）的结晶复合物。
• Method for producing 4-cyano-2-aminomethylthiazole
  申请人：Abbott GmbH & Ci, KG

  公开号：US06639081B1

  公开（公告）日：2003-10-28

  The invention relates to processes for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib in which n=1 or 2 and for n=1, X is chloride, bromide, triflate and hydrogen sulfate and for n=2, X is sulfate, which comprises the process step where the aminonitrile of the formula II is stirred with a cysteine ester of the formula III, in which R1 is branched or linear C1-10-alkyl or where n=0, 1 or 2 and R2 is branched or linear C1-C10C10-alkyl or C1-C4-alkoxy or C1-C4-dialkylamino in an inert solvent in the presence of a base at from 0° C. to 80° C. until the reaction has essentially proceeded to completion, and to the compounds of the formulae Ia and Ib.

  该发明涉及制备式Ia和Ib的2-氨甲基-4-氰基噻唑及其盐的过程，其中n＝1或2，对于n＝1，X为氯化物、溴化物、三氟甲磺酸盐和硫酸氢盐，对于n＝2，X为硫酸盐，包括在惰性溶剂中在0°C至80°C下，在存在碱的情况下，将式II的氨基腈与式III的半胱氨酸酯搅拌，其中R1为支链或直链的C1-10烷基，或n＝0、1或2，R2为支链或直链的C1-C10烷基或C1-C4烷氧基或C1-C4二烷基氨基，直至反应基本完成，以及式Ia和Ib的化合物。
• Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia
  作者：Peter Bach、Laurent Knerr、Ola Fjellström、Kenny Hansson、Christer Mattsson、David Gustafsson

  DOI：10.1016/j.bmcl.2013.12.094

  日期：2014.2

  A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 mu M. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor. (C) 2014 Elsevier Ltd. All rights reserved.
• Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety
  作者：Udo E.W. Lange、Dorit Baucke、Wilfried Hornberger、Helmut Mack、Werner Seitz、H. Wolfgang Höffken

  DOI：10.1016/j.bmcl.2006.01.046

  日期：2006.5

  Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.