Ethyl 2-[7-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]acetate | 214401-44-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: Ethyl 2-[7-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]acetate
• CAS: 214401-44-2
• 化学式: C₁₅H₁₇F₃O₅S
• 分子量: 366.358
• InChiKey: GVAIFNBXDALAGG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  78
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Ethyl 2-[7-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]acetate 在 palladium on activated charcoal 四(三苯基膦)钯 、 偶氮二异丁腈 、 氢气 、 三正丁基氢锡 、 lithium chloride 作用下， 以 乙醇 为溶剂， 25.0~100.0 ℃ 、101.33 kPa 条件下， 反应 4.0h， 生成 ethyl {7-[2-(4-cyanophenyl)ethyl]-1,2,3,4-tetrahydro-2-naphthalenyl}acetate
  参考文献：
  名称：

  New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antagonists:  Orally Active Series of N-Alkylated Amidines with a 6,6-Bicyclic Template

  摘要：

  The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4 . HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4 . HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)-4 . HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4 . HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.

  DOI：

  10.1021/jm9801859
• 作为产物：
  描述：

  7-甲氧基-1-萘满酮 在 palladium on activated charcoal 吡啶 、 sodium tetrahydroborate 、 三甲基氯硅烷 、 氢气 、 4-甲基苯磺酸吡啶 、 sodium hydride 、 碳酸氢钠 、 间氯过氧苯甲酸 、 sodium iodide 、 zinc(II) iodide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 氯仿 、 甲苯 、 乙腈 、 苯 为溶剂， 25.0 ℃ 、100.0 kPa 条件下， 反应 21.0h， 生成 Ethyl 2-[7-(trifluoromethylsulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]acetate
  参考文献：
  名称：

  New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antagonists:  Orally Active Series of N-Alkylated Amidines with a 6,6-Bicyclic Template

  摘要：

  The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4 . HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4 . HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)-4 . HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4 . HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.

  DOI：

  10.1021/jm9801859

文献信息

• New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antagonists:  Orally Active Series of <i>N</i>-Alkylated Amidines with a 6,6-Bicyclic Template
  作者：Kunio Okumura、Toshiyuki Shimazaki、Yoji Aoki、Hiroyuki Yamashita、Eishi Tanaka、Shinichi Banba、Kouhei Yazawa、Kenji Kibayashi、Hitoshi Banno

  DOI：10.1021/jm9801859

  日期：1998.10.1

  The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4 . HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4 . HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)-4 . HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4 . HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.