<1S-1α,2α,3α,4α>-2-<<3-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid, methyl ester | 135682-53-0

• 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-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid, methyl ester
• 英文别名: <1S-(1α,2α,3α,4α)>-2-<<3-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid；[1S-(1α, 2α, 3α, 4α)]-2-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester；[1S-(1α,2α,3α,4α)]-2-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester；[1S-(1α,2α,3α,4α)]-2-[[3-(Hydroxymethyl)7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester；[1S-1α,2α,3α,4α]-2-{[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl}benzenepropanoic acid, methyl ester；methyl 3-[2-[[(1S,2R,3R,4R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoate
• CAS: 135682-53-0
• 化学式: C₁₈H₂₄O₄
• 分子量: 304.386
• InChiKey: UHSXEWUEPLXRKX-LTIDMASMSA-N

物化性质

• 沸点：
  437.3±20.0 °C(Predicted)
• 密度：
  1.159±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  <1S-1α,2α,3α,4α>-2-<<3-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid, methyl ester 在 palladium hydroxide - carbon chromium(VI) oxide 、 四氯化碳 、 草酰氯 、 硫酸 、 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 、 丙酮 、 乙腈 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 48.92h， 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：

  3-(2-溴苯基)丙酸甲酯 在 palladium dihydroxide 吡啶 、 chromium(VI) oxide 、 盐酸 、 4-二甲氨基吡啶 、 sodium hydroxide 、 硫酸 、 氢气 、 叔丁基锂 、 二异丁基氢化铝 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 、 甲苯 为溶剂， -100.0~25.0 ℃ 、101.33 kPa 条件下， 反应 21.0h， 生成 <1S-1α,2α,3α,4α>-2-<<3-(hydroxymethyl)-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid, methyl ester
  参考文献：
  名称：

  间亚苯基7-氧杂双环[2.2.1]庚烷血栓烷A2拮抗剂。Semicarbazoneω-链。

  摘要：

  制备了一系列手性联苯间7-氧杂双环[2.2.1]庚烷半咔唑酮19-26，并对其体外血栓烷（TxA2）拮抗活性和体内作用时间进行了评估。发现19-26的效力高度依赖于亚间苯环的取代模式，并且以大于间位大于邻位的顺序降低。SQ 35,091（25），[1S-（1 alpha，2 alpha，3 alpha，4 alpha）]-2-[[3-[[[[（（苯基氨基）羰基]肼基]甲基] -7-氧杂双环[2.2.1 [庚基-2-基]甲基]苯丙酸被鉴定为有效且长效的TxA2拮抗剂。在富含人血小板的血浆中，SQ 35,091抑制了花生四烯酸（800 microM）和U-46,619（10 microM）诱导的聚集，I50值分别为3和12 nM。相反，大于1000 microM时未观察到对ADP（20 microM）诱导的聚集的抑制。用[3H] -SQ 29,548进行的受体结合研究表明，SQ 35,091是

  DOI：

  10.1021/jm00113a030

文献信息

• Bioorg. Med. Chem. Lett. 1992, 2, 73-76
  作者：

  DOI：——

  日期：——
• Org. Process Res. Dev. 1997, 1, 174-175
  作者：

  DOI：——

  日期：——
• Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists
  作者：Raj N. Misra、Baerbel R. Brown、Philip M. Sher、Manorama M. Patel、Steven E. Hall、Wen Ching Han、Joel C. Barrish、Octavian Kocy、Don N. Harris

  DOI：10.1021/jm00062a013

  日期：1993.5

  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.
• Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2(TxA2)antagonists. Semicarbazone .omega.-chains
  作者：Raj N. Misra、Baerbel R. Brown、Wen Ching Han、Don N. Harris、Anders Hedberg、Maria L. Webb、Steven E. Hall

  DOI：10.1021/jm00113a030

  日期：1991.9

  A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1

  制备了一系列手性联苯间7-氧杂双环[2.2.1]庚烷半咔唑酮19-26，并对其体外血栓烷（TxA2）拮抗活性和体内作用时间进行了评估。发现19-26的效力高度依赖于亚间苯环的取代模式，并且以大于间位大于邻位的顺序降低。SQ 35,091（25），[1S-（1 alpha，2 alpha，3 alpha，4 alpha）]-2-[[3-[[[[（（苯基氨基）羰基]肼基]甲基] -7-氧杂双环[2.2.1 [庚基-2-基]甲基]苯丙酸被鉴定为有效且长效的TxA2拮抗剂。在富含人血小板的血浆中，SQ 35,091抑制了花生四烯酸（800 microM）和U-46,619（10 microM）诱导的聚集，I50值分别为3和12 nM。相反，大于1000 microM时未观察到对ADP（20 microM）诱导的聚集的抑制。用[3H] -SQ 29,548进行的受体结合研究表明，SQ 35,091是