(R)-4-羟基-2-戊炔酸苄酯 | 226915-53-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (R)-4-羟基-2-戊炔酸苄酯
• 中文别名: 硫酸沃拉帕沙中间体
• 英文名称: (2R)-4-hydroxypentyl-2-ynoic acid benzyl ester
• 英文别名: (2R)-4-hydroxypent-2-ynoic acid benzyl ester；(R)-benzyl 4-hydroxyl-2-pentynoate；propargylic alcohol；2-Pentynoic acid, 4-hydroxy-, phenylmethyl ester, (4R)-；benzyl (4R)-4-hydroxypent-2-ynoate
• CAS: 226915-53-3
• 化学式: C₁₂H₁₂O₃
• 分子量: 204.225
• InChiKey: GTDOOLQKHXLZHQ-SNVBAGLBSA-N

物化性质

• 沸点：
  354.9±35.0 °C(Predicted)
• 密度：
  1.180±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-4-羟基-2-戊炔酸苄酯 在 Lindlar's catalyst 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 (2R)-4-hydroxypent-(Z)-2-enoic acid benzyl ester
  参考文献：
  名称：

  Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

  摘要：

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

  DOI：

  10.1021/jm061043e
• 作为产物：
  描述：

  在 硫酸 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 反应 1.0h， 以18.6 g的产率得到(R)-4-羟基-2-戊炔酸苄酯
  参考文献：
  名称：

  改进由 (R)-3-Butyn-2-ol 大规模合成 (R)-Benzyl 4-Hydroxyl-2-pentynoate

  摘要：

  为大规模生产开发了一种可靠的标题化合物一锅法。已经广泛研究了反应条件（例如温度、添加顺序和锂化试剂的量）的影响，从而产生了具有最高可达到产率的最佳工艺。

  DOI：

  10.1021/op010235a

文献信息

• Discovery of Potent Orally Active Thrombin Receptor (Protease Activated Receptor 1) Antagonists as Novel Antithrombotic Agents
  作者：Samuel Chackalamannil、Yan Xia、William J. Greenlee、Martin Clasby、Darìo Doller、Hsingan Tsai、Theodros Asberom、Michael Czarniecki、Ho-Sam Ahn、George Boykow、Carolyn Foster、Jacqueline Agans-Fantuzzi、Matthew Bryant、Janice Lau、Madhu Chintala

  DOI：10.1021/jm0502236

  日期：2005.9.1

  Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed

  描述了基于天然产物hibacine的结构新颖的凝血酶受体（蛋白酶激活受体1，PAR-1）拮抗剂。原型PAR-1拮抗剂55在结合试验中的Ki值为2.7 nM，使其成为最有效的PAR-1拮抗剂。55在几种功能测定中具有很高的活性，在大鼠和猴子模型中显示出极好的口服生物利用度，并在口服后在食蟹猴中显示出激动剂诱导的离体血小板聚集的完全抑制。
• [EN] PREPARATION AND USE OF BICYCLIC HIMBACINE DERIVATIVES AS PAR-RECEPTOR ANTAGONISTS<br/>[FR] PRÉPARATION ET UTILISATION DE DÉRIVÉS BICYCLIQUES D'HIMBACINE EN TANT QU'ANTAGONISTES DU RÉCEPTEUR DE PAR
  申请人：MERCK SHARP & DOHME

  公开号：WO2013134012A1

  公开（公告）日：2013-09-12

  The present invention relates to bicyclic himbacine derivatives of the formula or a pharmaceutically acceptable salt thereof, wherein: X is -O-, -N(R), -C(R8)(R9) or -C(O)-; and Y is -O-, -N(R), -C(R8)(R9) or -C(O)- and the remaining variables are described herein. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ACS, secondary prevention of myocardial infarction or stroke, or PAD.

  本发明涉及公式的双环希巴辛衍生物或其药用可接受盐，其中：X为-O-，-N(R)，-C(R8)(R9)或-C(O)-；Y为-O-，-N(R)，-C(R8)(R9)或-C(O)-，其余变量如本文所述。本发明的化合物是PAR-1受体的有效抑制剂。这些创新化合物可用于治疗或预防疾病状态，如急性冠状综合征（ACS），心肌梗死或中风的二级预防，或PAD。
• Heterotricyclic Himbacine Analogs as Potent, Orally Active Thrombin Receptor (Protease Activated Receptor-1) Antagonists
  作者：Mariappan V. Chelliah、Samuel Chackalamannil、Yan Xia、Keith Eagen、Martin C. Clasby、Xiaobang Gao、William Greenlee、Ho-Sam Ahn、Jacqueline Agans-Fantuzzi、George Boykow、Yunsheng Hsieh、Matthew Bryant、Jairam Palamanda、Tze-Ming Chan、David Hesk、Madhu Chintala

  DOI：10.1021/jm070704k

  日期：2007.10.1

  Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet

  遵循我们在基于组氨酸的凝血酶受体拮抗剂领域的早期努力，我们合成了一系列在三环基序的C环中掺入杂原子的化合物。这项工作已导致鉴定出几种对凝血酶受体具有优异亲和力的有效杂环类似物。这些化合物中的几种在口服给药后在食蟹猴的离体模型中显示出对血小板聚集的强烈抑制。介绍了28b（本系列的基准化合物）的详细资料，Ki为4.3 nM。
• Discovery and synthesis of a novel series of quinoline-based thrombin receptor (PAR-1) antagonists
  作者：Martin C. Clasby、Samuel Chackalamannil、Michael Czarniecki、Dario Doller、Keith Eagen、William J. Greenlee、Yan Lin、Hsingan Tsai、Yan Xia、Ho-Sam Ahn、Jacqueline Agans-Fantuzzi、George Boykow、Madhu Chintala、Carolyn Foster、Matthew Bryant、Janice Lau

  DOI：10.1016/j.bmcl.2005.12.042

  日期：2006.3

  The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.

  描述了一系列结构新颖的高效凝血酶受体（PAR-1）拮抗剂的设计，合成和SAR研究。化合物30是一种高效的凝血酶受体拮抗剂（IC（50）= 6.3 nM），一种相关的化合物36在猴离体研究中显示出功效。
• Thrombin Receptor Antagonists Based On The Modified Tricyclic Unit Of Himbacine
  申请人：Chackalamannil Samuel

  公开号：US20080085923A1

  公开（公告）日：2008-04-10

  Multiple stereoisomers of the heterocyclic-substituted tricyclics of the formula: or a pharmaceutically acceptable salt, solvate, or ester of said compound wherein R and the stereochemistry are illustrated in the structural formulas herein are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.

  公开了异环取代的三环化合物的多个立体异构体的化学式：或者其药学上可接受的盐、溶剂合物或酯，其中R和立体化学在此处的结构式中有所示，以及含有它们的药物组合物和通过给药这些化合物治疗与血栓形成、动脉粥样硬化、再狭窄、高血压、心绞痛、心律失常、心力衰竭和癌症相关的疾病的方法。还声明了与其他心血管药物的联合治疗。