<1S-(1α,2α,3α,4α)>-2-<(3-carboxy-7-oxabicyclo<2.2.1>hept-2-yl)methyl>benzenepropanoic acid methyl ester | 142757-91-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: <1S-(1α,2α,3α,4α)>-2-<(3-carboxy-7-oxabicyclo<2.2.1>hept-2-yl)methyl>benzenepropanoic acid methyl ester
• 英文别名: (1R,2S,3R,4S)-3-[2-(3-carboxy-7-oxabicyclo[2.2.1]hept-2-yl-methyl)phenyl]propionic acid methyl ester；[1S-(1α, 2α, 3α, 4α)]-2-[[3-CArboxy-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester；1S-(1α,2α,3α,4α)-2-[[2-(3-Methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid；[1S-(1α,2α,3α,4α)]-2-[(3-carboxy-7-oxabicyclo[2.2.1]hept-2-yl)methyl]benzenepropanoic acid, methyl ester；[1S-(1α,2α,3α,4α)]-2-[[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester；(1S-(1α,2α,3α,4α))-2-[(3-carboxy-7-oxabicyclo[2.2.1]hept-2-yl)methyl]benzenepropanoic acid methyl ester；(1R,2S,3R,4S)-3-(2-(3-Methoxy-3-oxopropyl)benzyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid；(1R,2S,3R,4S)-3-[[2-(3-methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid
• CAS: 142757-91-3
• 化学式: C₁₈H₂₂O₅
• 分子量: 318.37
• InChiKey: VLPHWGCHKDQJEE-MPTYRVRUSA-N

物化性质

• 沸点：
  478.5±30.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  <1S-(1α,2α,3α,4α)>-2-<(3-carboxy-7-oxabicyclo<2.2.1>hept-2-yl)methyl>benzenepropanoic acid methyl ester 在 palladium hydroxide - carbon 四氯化碳 、 草酰氯 、 氢气 、 1-羟基苯并三唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 N,N'-二环己基碳二亚胺 、 三苯基膦 、 copper(ll) bromide 作用下， 以 二氯甲烷 、 氯仿 、 乙酸乙酯 、 乙腈 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 48.25h， 生成 methyl 3-[2-[[(1S,2R,3S,4R)-3-(4-carbonochloridoyl-1,3-oxazol-2-yl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoate
  参考文献：
  名称：

  Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists

  摘要：

  A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 {BMS-180,291: [(+)-1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid} was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showed a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for >24 h.

  DOI：

  10.1021/jm00062a013
• 作为产物：
  描述：

  <1S-1α,2α,3α,4α>-2-<<3-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid, methyl ester 在 chromium(VI) oxide 、 硫酸 作用下， 以 丙酮 为溶剂， 反应 0.67h， 以82%的产率得到<1S-(1α,2α,3α,4α)>-2-<(3-carboxy-7-oxabicyclo<2.2.1>hept-2-yl)methyl>benzenepropanoic acid methyl ester
  参考文献：
  名称：

  Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists

  摘要：

  A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 {BMS-180,291: [(+)-1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid} was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showed a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for >24 h.

  DOI：

  10.1021/jm00062a013

文献信息

• Method for preparing homochiral maleimide intermediates, via silylation
  申请人：Bristol-Myers Squibb Company

  公开号：US05539126A1

  公开（公告）日：1996-07-23

  A method is provided for preparing homochiral maleimide intermediates of the structure ##STR1## wherein R.sup.7, R.sup.8 and R.sup.9 are as defined herein by reacting a homochiral amine of the structure ##STR2## with maleic anhydride and a silylating agent. The maleimide intermediate is used in the enantio-selective preparation of thromboxane A.sub.2 receptor antagonists.

  提供了一种制备同手性马来酰亚胺中间体的方法，其结构为##STR1##，其中R.sup.7、R.sup.8和R.sup.9的定义如本文所述，通过将同手性胺##STR2##与马来酐和硅基化剂反应来实现。马来酰亚胺中间体用于拟手性选择性制备血栓素A.sub.2受体拮抗剂。
• Synthesis of the Chiral Pair of a Novel Thromboxane Antagonist, 3-[2-(3-Benzenesulfonylamino-7-oxabicyclo[2.2.1]hept-2-yl-methyl)phenyl] Propionic Acid
  作者：Ching-Yuh Chern、Yung Lee Yek、Ja-Ding Jan、Wai Ming Kan

  DOI：10.1002/jccs.200100132

  日期：2001.10

  Prep a ra tion of the enantiomeric pair of 3-[2-(3-benzenesulfonylamino-7-oxabicyclo[2.2.1]hept-2-ylmethyl)phenyl] propionic acid, a novel thromboxane an tag o nist is re ported. They are syn the sized from ei ther en an tio mers of known (1R,2R,3R,4S)-3-[2-(3-carboxy-7-oxabicyclo[2,2,1]hept-2-yl- methyl) phenyl]propionic acid methyl es ter via epimerization, mod i fied Curtius’ re ar range ment and

  3-[2-(3-苯磺酰氨基-7-氧杂双环[2.2.1]庚-2-基甲基)苯基]丙酸的对映异构体对的制备，一种新型血栓素和标记物被报道。它们由已知的 (1R,2R,3R,4S)-3-[2-(3-carboxy-7-oxabicyclo[2,2,1]hept-2-yl-甲基）苯基]丙酸甲酯通过差向异构化、改性的 Curtius 重排和磺酰氨基化。可以类似地准备其他衍生物。血小板异常可能导致各种可能致命的凝血障碍 1。血小板功能的调节，尤其是聚集，与二磷酸腺苷和血栓素 A2 (TXA2) 等第二信使有关。2 这些分子产生正反馈机制，导致不可逆的血小板聚集和血栓形成。在这两种放大器中，血栓素 A 2 更有效，其作用不可逆。此外，血栓素 A2 还与哮喘、心肌梗死、冠状动脉痉挛和许多其他疾病等病理生理条件有关。然后可能会出现血栓素标签
• Method for preparing 7-oxabicycloheptyl substituted heterocyclic amide
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US05260448A1

  公开（公告）日：1993-11-09

  A method is provided for preparing 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 receptor antagonists/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic disease, wherein a vinyl bromide of the formula, for example, ##STR1## wherein m, n, R.sup.1 and R.sup.2 are as defined herein is treated with a cyclizing agent to form the corresponding oxazole.

  提供了一种制备7-氧代双环庚基取代的杂环酰胺前列腺素类似物的方法，该类似物是血栓素A.sub.2（TXA.sub.2）受体拮抗剂或联合血栓素A.sub.2受体拮抗剂/血栓素合酶抑制剂，例如在治疗血栓性和/或血管痉挛性疾病中有用。其中，以式子，例如##STR1##其中m，n，R.sup.1和R.sup.2如本文所定义的乙烯基溴化物经过环化试剂处理形成相应的噁唑。
• 7-Oxabicycloheptane carboxylic acid prostaglandin analog intermediates useful in the preparation of antithrombotic and anti-vasospastic compounds and method for preparing same
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0626384A1

  公开（公告）日：1994-11-30

  A method is provided for preparing carboxylic acid intermediates of the structure wherein an aldehyde of the structure is prepared and subjected to a Horner-Emmons reaction to form the ester of the structure and the ester is hydrogenated to the carboxylic acid which may be used in making the final anti-thrombotic - anti-vasospastic compounds.

  提供了一种制备结构如下的羧酸中间体的方法 其中结构的醛 制备并进行霍纳-艾蒙斯反应以形成结构式的酯 然后将酯氢化成羧酸，羧酸可用于制造最终的抗血栓-抗血管痉挛化合物。
• Method for preparing homochiral maleimide intermediates, via silylation techniques, used in the enantioselective preparation of anti-thrombotic and anti-vasospastic compounds
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0678507A1

  公开（公告）日：1995-10-25

  A method is provided for preparing homochiral maleimide intermediates of the structure wherein R⁷, R⁸ and R⁹ are as defined herein by reacting a homochiral amine of the structure with maleic anhydride and a silylating agent. The maleimide intermediate is used in the enantioselective preparation of thromboxane A₂ receptor antagonists.

  提供了一种制备同手性马来酰亚胺中间体的方法，其结构为 其中 R⁷、R⁸ 和 R𠞙 如本文所定义，通过使结构同手性的胺反应 与马来酸酐和硅烷化剂反应。马来酰亚胺中间体可用于对映体选择性制备血栓素 A₂ 受体拮抗剂。