2-[5-amino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide

• 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: 2-[5-amino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide
• 英文别名: 2-[5-amino-2-(4-methylphenyl)-6-oxopyrimidin-1-yl]-N-(4,4,4-trifluoro-3-oxo-1-phenylbutan-2-yl)acetamide
• 化学式: C₂₃H₂₁F₃N₄O₃
• 分子量: 458.44
• InChiKey: DVLHWNUHEWGGMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-[5-benzyloxycarbonylamino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)-acetamide 在 palladium on activated charcoal 、 甲酸 作用下， 以 甲醇 为溶剂， 反应 22.0h， 以61%的产率得到2-[5-amino-6-oxo-2-(p-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide
  参考文献：
  名称：

  Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones

  摘要：

  Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (K-i = 0.0506 muM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00244-3

文献信息

• Heterocyclic amide compounds and pharmaceutical use of the same
  申请人：The Green Cross Corporation

  公开号：US05948785A1

  公开（公告）日：1999-09-07

  Heterocyclic amide compounds of the formula (I) ##STR1## wherein each symbol is as defined in the specification, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. The heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.

  式(I)的杂环酰胺化合物##STR1##，其中每个符号如规范中定义的那样，其药理学上可接受的盐，其药物组合物和其药用。本发明的杂环酰胺化合物及其药理学上可接受的盐对哺乳动物包括人类的胰蛋白酶组具有优越的抑制活性，并可经口或经肠外途径给药。因此，它们可用作胰蛋白酶抑制剂，并可有效预防和治疗由胰蛋白酶引起的各种疾病，如由II型血管紧张素引起的疾病。
• HETEROCYCLIC AMIDE COMPOUNDS AND MEDICINAL USE OF THE SAME
  申请人：THE GREEN CROSS CORPORATION

  公开号：EP0826671A1

  公开（公告）日：1998-03-04

  Heterocyclic amide compounds of the formula (I) wherein each symbol is as defined in the specification, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. The heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.

  式 (I) 的杂环酰胺化合物 其中各符号如说明书中所定义，其药理上可接受的盐、其药物组合物和其药物用途。本发明的杂环酰胺化合物及其药理学上可接受的盐类对哺乳动物（包括人类）的糜蛋白酶基团具有优异的抑制活性，并且可以口服或肠外给药。因此，它们可作为糜蛋白酶抑制剂，有效预防和治疗由糜蛋白酶引起的各种疾病，如血管紧张素 II 引起的疾病。
• US5948785A
  申请人：——

  公开号：US5948785A

  公开（公告）日：1999-09-07
• Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones
  作者：Fumihiko Akahoshi、Atsuyuki Ashimori、Takuya Yoshimura、Teruaki Imada、Masahide Nakajima、Naoko Mitsutomi、Shigeki Kuwahara、Tatsuyuki Ohtsuka、Chikara Fukaya、Mizuo Miyazaki、Norifumi Nakamura

  DOI：10.1016/s0968-0896(00)00244-3

  日期：2001.2

  Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (K-i = 0.0506 muM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease. (C) 2001 Elsevier Science Ltd. All rights reserved.