1-(4'-hydroxy-3'-fluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione | 95333-49-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 1-(4'-hydroxy-3'-fluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione
• 英文别名: 1-(3-Fluoro-4-hydroxy-benzyl)-1,3-dihydro-imidazole-2-thione；3-[(3-fluoro-4-hydroxyphenyl)methyl]-1H-imidazole-2-thione
• CAS: 95333-49-6
• 化学式: C₁₀H₉FN₂OS
• 分子量: 224.259
• InChiKey: KLQIKJGTTNJPKN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  67.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-氟-4-甲氧基苯甲醛 在 盐酸 、 sodium tetrahydroborate 、 三溴化硼 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 27.83h， 生成 1-(4'-hydroxy-3'-fluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione
  参考文献：
  名称：

  Multisubstrate inhibitors of dopamine .beta.-hydroxylase. 2. Structure-activity relationships at the phenethylamine binding site

  摘要：

  1-Aralkylimidazole-2-thiones have been shown to be potent multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1). In the present study, a series of 1-benzylimidazole-2-thiones was prepared to explore the effects of substitution in the benzyl ring on the inhibition of DBH. A detailed structure-activity relationship for in vitro activity was discovered and this was shown by a modified Hansch analysis to correlate (r = 0.91) with four key structural features of the benzyl ring: the presence of a hydroxyl at the 4-position, molar refractivity at the 3-, 4-, and 5-positions, inductive effects of the substituents at the 3-, 4-, and 5-positions, and pi-electron density. The affinity (Kis) of eight substituted inhibitors for DBH was shown to correlate (r = 0.75) with the affinity (KD) of comparably substituted tyramines for the ternary DBH-oxygen-tyramine complex. This correlate is used to support the hypothesis that binding of inhibitor to DBH occurs in a fashion that mimics the binding of tyramine substrates. The most potent inhibitors were selected for study in vivo in the spontaneously hypertensive rat model of hypertension. The changes in vascular dopamine and norepinephrine levels that resulted from oral administration of the inhibitors corresponded to the observed reduction in mean arterial blood pressure. A divergence between in vitro potency and in vivo efficacy upon oral dosing was noted and is suggested to result from an in vivo metabolic conjugation of the phenolic group of inhibitor.

  DOI：

  10.1021/jm00386a008

文献信息

• Ester prodrugs of dopamine-beta-hydroxylase inhibitors
  申请人：SMITHKLINE BECKMAN CORPORATION

  公开号：EP0244956A1

  公开（公告）日：1987-11-11

  Compounds of structure (I) in which: Y is hydrogen, halogen, C1-4 haloalkyl, or any synthetically accessible combination thereof of up to four substituents; R is -wherein R1 is hydrogen or C1-4 alkyl: R2 is R or C1-4 alkyl; n is 0-4; or a pharmaceutically acceptable salt or hydrate thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy as dopamine β-hydroxylase inhibitors.

  结构(I)的化合物 其中 Y 是氢、卤素、C1-4 卤代烷基或最多四个取代基的任何合成组合； R 是 -其中 R1 是氢或 C1-4 烷基： R2 是 R 或 C1-4 烷基； n 为 0-4；或 它们的药学上可接受的盐或水合物、它们的制备工艺、含有它们的药物组合物以及它们作为多巴胺 β-羟化酶抑制剂在治疗中的用途。
• Dopamine-beta-hydroxylase inhibitors
  申请人：SMITHKLINE BECKMAN CORPORATION

  公开号：EP0125033B1

  公开（公告）日：1989-04-26
• US4743613A
  申请人：——

  公开号：US4743613A

  公开（公告）日：1988-05-10
• Multisubstrate inhibitors of dopamine .beta.-hydroxylase. 2. Structure-activity relationships at the phenethylamine binding site
  作者：Lawrence I. Kruse、Carl Kaiser、Walter E. DeWolf、James S. Frazee、Stephen T. Ross、Joyce Wawro、Merrie Wise、Kathryn E. Flaim、John L. Sawyer

  DOI：10.1021/jm00386a008

  日期：1987.3

  1-Aralkylimidazole-2-thiones have been shown to be potent multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1). In the present study, a series of 1-benzylimidazole-2-thiones was prepared to explore the effects of substitution in the benzyl ring on the inhibition of DBH. A detailed structure-activity relationship for in vitro activity was discovered and this was shown by a modified Hansch analysis to correlate (r = 0.91) with four key structural features of the benzyl ring: the presence of a hydroxyl at the 4-position, molar refractivity at the 3-, 4-, and 5-positions, inductive effects of the substituents at the 3-, 4-, and 5-positions, and pi-electron density. The affinity (Kis) of eight substituted inhibitors for DBH was shown to correlate (r = 0.75) with the affinity (KD) of comparably substituted tyramines for the ternary DBH-oxygen-tyramine complex. This correlate is used to support the hypothesis that binding of inhibitor to DBH occurs in a fashion that mimics the binding of tyramine substrates. The most potent inhibitors were selected for study in vivo in the spontaneously hypertensive rat model of hypertension. The changes in vascular dopamine and norepinephrine levels that resulted from oral administration of the inhibitors corresponded to the observed reduction in mean arterial blood pressure. A divergence between in vitro potency and in vivo efficacy upon oral dosing was noted and is suggested to result from an in vivo metabolic conjugation of the phenolic group of inhibitor.