{(S)-6-[4-(Imino-morpholin-4-yl-methyl)-benzoylamino]-chroman-3-yl}-acetic acid ethyl ester | 790639-17-7

• 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: {(S)-6-[4-(Imino-morpholin-4-yl-methyl)-benzoylamino]-chroman-3-yl}-acetic acid ethyl ester
• 英文别名: MS-180 free base；ethyl 2-[(3S)-6-[[4-(morpholine-4-carboximidoyl)benzoyl]amino]-3,4-dihydro-2H-chromen-3-yl]acetate
• CAS: 790639-17-7
• 化学式: C₂₅H₂₉N₃O₅
• 分子量: 451.522
• InChiKey: LKMZVCXVGWBLDI-KRWDZBQOSA-N

物化性质

• 密度：
  1.30±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  ((S)-6-tert-Butoxycarbonylamino-chroman-3-yl)-acetic acid methyl ester 在 盐酸 、 硫酸 、 三乙胺 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 34.0h， 生成 {(S)-6-[4-(Imino-morpholin-4-yl-methyl)-benzoylamino]-chroman-3-yl}-acetic acid ethyl ester
  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