6-nitro-4-oxo-3-chromanylideneacetic acid | 189083-16-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 6-nitro-4-oxo-3-chromanylideneacetic acid
• 英文别名: 2-(6-Nitro-4-oxochroman-3-ylidene)acetic acid；(2E)-2-(6-nitro-4-oxochromen-3-ylidene)acetic acid
• CAS: 189083-16-7
• 化学式: C₁₁H₇NO₆
• 分子量: 249.18
• InChiKey: KAZJYVFNRYIHNT-ZZXKWVIFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 海关编码：
  2932999099

反应信息

• 作为反应物：
  描述：

  6-nitro-4-oxo-3-chromanylideneacetic acid 在 palladium on activated charcoal 硫酸 、 氢气 、 三乙胺 作用下， 以 氯仿 为溶剂， 60.0 ℃ 、1000.0 kPa 条件下， 反应 22.0h， 生成 ethyl 6-[(4-cyanobenzoyl)amino]chroman-3-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：

  6-硝基苯并二氢吡喃-4-酮 、 乙醛酸 在 硫酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 5.0h， 以61%的产率得到6-nitro-4-oxo-3-chromanylideneacetic acid
  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

• Amidine derivatives and platelet aggregation inhibitor containing the same
  申请人：MITSUI CHEMICALS, INC.

  公开号：EP0760364B1

  公开（公告）日：2000-07-19
• JPH10316672A
  申请人：——

  公开号：JPH10316672A

  公开（公告）日：1998-12-02
• US5719145A
  申请人：——

  公开号：US5719145A

  公开（公告）日：1998-02-17
• 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.