tert-butyl 7-[N-(4-cyanophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalene-2-acetate | 178261-82-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl 7-[N-(4-cyanophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalene-2-acetate
• 英文别名: tert-butyl 2-[7-[(4-cyanophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalen-2-yl]acetate
• CAS: 178261-82-0
• 化学式: C₂₄H₂₆N₂O₃
• 分子量: 390.482
• InChiKey: DHQGTJJFTSNZRC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  79.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 7-[N-(4-cyanophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalene-2-acetate 在 盐酸 、 ammonium acetate 作用下， 生成 ethyl 7-[N-(4-amidinophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalene-2-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：

  5,6-dihydro-naphthalene-2-carboxylic acid methyl ester 在 palladium on activated charcoal 吡啶 、 4-二甲氨基吡啶 、 sodium hydroxide 、 草酰氯 、 氢气 、 sodium hydride 、 N,N-二甲基甲酰胺 、 间氯过氧苯甲酸 、 zinc(II) iodide 作用下， 以 甲醇 、 甲苯 、 苯 为溶剂， 反应 36.0h， 生成 tert-butyl 7-[N-(4-cyanophenyl)carbamoyl]-1,2,3,4-tetrahydronaphthalene-2-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

• Bicyclic compound and platelet aggregation inhibitor containing the same
  申请人：Mitsui Toatsu Chemicals, Inc.

  公开号：US05629321A1

  公开（公告）日：1997-05-13

  The invention relates to a novel compound which is represented by the formula (1) and has an excellent platelet aggregation inhibiting action based on fibrinogen antagonism. The platelet aggregation inhibitor containing the compound of the formula (1) as an effective ingredient are effective for prevention and curing of thrombosis and restenosis or reocclusion after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary recanalization.

  本发明涉及一种新型化合物，其由式（1）表示，并且基于纤维蛋白原拮抗作用具有出色的血小板聚集抑制作用。含有式（1）化合物作为有效成分的血小板聚集抑制剂对于预防和治疗血栓形成以及经皮穿透冠状动脉成形术或经皮穿透冠状动脉再通术后的再狭窄或再闭塞非常有效。
• Bicyclic compounds useful as platelet aggregation inhibitors
  申请人：MITSUI TOATSU CHEMICALS, Inc.

  公开号：EP0709370A1

  公开（公告）日：1996-05-01

  The invention relates to a novel compound which is represented by the formula (1) and has an excellent platelet aggregation inhibiting action based on fibrinogen antagonism. The platelet aggregation inhibitor containing the compound of the formula (1) as an effective ingredient is effective for prevention and therapy of thrombosis and restenosis or reocclusion after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary recanalization.

  本发明涉及一种新型化合物，该化合物由式（1）表示，在纤维蛋白原拮抗作用的基础上具有优异的血小板聚集抑制作用。含有式（1）化合物作为有效成分的血小板聚集抑制剂可有效预防和治疗血栓形成以及经皮腔内冠状动脉成形术或经皮腔内冠状动脉再通术后的再狭窄或再闭塞。
• US5629321A
  申请人：——

  公开号：US5629321A

  公开（公告）日：1997-05-13
• 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.