[5-benzyloxycarbonylamino-6-oxo-2-(pyridin-3-yl)-1,6-dihydro-1-pyrimidinyl]acetic acid | 148747-95-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: [5-benzyloxycarbonylamino-6-oxo-2-(pyridin-3-yl)-1,6-dihydro-1-pyrimidinyl]acetic acid
• 英文别名: 5-benzyloxycarbonylamino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinylacetic acid；[5-Benzyloxycarbonylamino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]acetic acid；2-[6-oxo-5-(phenylmethoxycarbonylamino)-2-pyridin-3-ylpyrimidin-1-yl]acetic acid
• CAS: 148747-95-9
• 化学式: C₁₉H₁₆N₄O₅
• 分子量: 380.36
• InChiKey: COSBPARTEBZXIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [5-benzyloxycarbonylamino-6-oxo-2-(pyridin-3-yl)-1,6-dihydro-1-pyrimidinyl]acetic acid 在 palladium on activated charcoal 盐酸 、 二氯乙酸 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.0h， 生成 2-[5-amino-6-oxo-2-(pyridin-3-yl)-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
• 作为产物：
  描述：

  1-(2,2-Dimethoxy-ethyl)-6-oxo-2-pyridin-3-yl-1,6-dihydro-pyrimidine-5-carboxylic acid 在 盐酸 、 sodium chlorite 、 sodium dihydrogenphosphate 、 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 四氢呋喃 、 叔丁醇 为溶剂， 反应 23.0h， 生成 [5-benzyloxycarbonylamino-6-oxo-2-(pyridin-3-yl)-1,6-dihydro-1-pyrimidinyl]acetic acid
  参考文献：
  名称：

  人白细胞弹性蛋白酶的非肽抑制剂。5.一系列口服活性的含5-氨基嘧啶-6的三氟甲基酮的设计，合成和X射线晶体学。

  摘要：

  已经探索了一系列5-氨基-2-嘧啶-6-酮的取代变化对急性出血试验中体外活性和口服活性的影响。这些化合物包含三氟甲基酮或硼酸部分，以与人白细胞弹性蛋白酶（HLE）的Ser-195羟基共价结合。发现含硼酸的抑制剂在体外比相应的三氟甲基酮更有效，但是口服给药时活性较低。发现化合物13b提供了口服效力，作用持续时间和酶选择性的最佳组合，因此，选择了其用于进一步的生物学测试。

  DOI：

  10.1021/jm00001a015

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。
• Substituted 1,3-diazines as leukocyte elastase inhibitors
  申请人：Imperial Chemical Industries PLC

  公开号：US05254558A1

  公开（公告）日：1993-10-19

  The present invention relates to certain novel substituted heterocycles which are 1-pyrimidinylacetamide compounds of formula I, set out herein, which are inhibitors of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated. The invention also includes intermediates useful in the synthesis of these substituted heterocycles, processes for preparing the substituted heterocycles, pharmaceutical compositions containing such substituted heterocycles and methods for their use.

  本发明涉及某些新颖的取代杂环化合物，即公式I所示的1-嘧啶基乙酰胺化合物，这些化合物是人类白细胞弹性蛋白酶（HLE）的抑制剂，也被称为人类中性粒细胞弹性蛋白酶（HNE），使它们在需要进行此类抑制时非常有用，例如用作药理学、诊断和相关研究工具以及治疗哺乳动物中HLE有所涉及的疾病。该发明还包括在合成这些取代杂环化合物过程中有用的中间体，制备这些取代杂环化合物的方法，含有这些取代杂环化合物的药物组合物以及它们的使用方法。
• Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase
  作者：Fumihiko Akahoshi、Atsuyuki Ashimori、Hiroshi Sakashita、Takuya Yoshimura、Teruaki Imada、Masahide Nakajima、Naoko Mitsutomi、Shigeki Kuwahara、Tatsuyuki Ohtsuka、Chikara Fukaya、Mizuo Miyazaki、Norifumi Nakamura

  DOI：10.1021/jm000496v

  日期：2001.4.1

  We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed

  我们基于肽化合物（1）的结构设计了非肽糜酶抑制剂，并证明了作为P3-P2支架的嘧啶酮骨架和作为P1羰基活化基团的杂环的组合可以用作非肽糜酶抑制剂。尤其是，引入异质双环化合物（如苯并恶唑）会产生更强的糜蛋白酶抑制活性。详细的结构活性关系研究对嘧啶酮环的2位上的苯并恶唑部分和取代基表明，2r（Y-40079）具有最强的糜蛋白酶抑制活性（K（i）= 4.85 nM）。该化合物对非人类来源的乳糜也有效，并且相对于其他蛋白酶显示出对乳糜的良好选择性。大鼠的药代动力学研究表明，口服后2r吸收缓慢，并显示令人满意的生物利用度（BA）（T（max）= 6.0 +/- 2.3 h，BA = 19.3 +/- 6.6％，t（1/2）= 35.7 +/- 13.3小时）。总之，2r是一种新型的，有效的，口服活性的糜酶抑制剂，它将是阐明糜酶的病理生理作用的有用工具。
• 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。
• Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase
  作者：Fumihiko Akahoshi、Atsuyuki Ashimori、Hiroshi Sakashita、Takuya Yoshimura、Masahiro Eda、Teruaki Imada、Masahide Nakajima、Naoko Mitsutomi、Shigeki Kuwahara、Tatsuyuki Ohtsuka、Chikara Fukaya、Mizuo Miyazaki、Norifumi Nakamura

  DOI：10.1021/jm000497n

  日期：2001.4.1

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.