(2E)-3-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-2-propenoic acid | 177478-60-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (2E)-3-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-2-propenoic acid
• 英文别名: (E)-3-methoxy-4-(N-methylcarbamoyl)cinnamic acid；3-methoxy-4-(methylcarbamoyl)-cinnamic acid；(E)-3-[3-methoxy-4-(methylcarbamoyl)phenyl]prop-2-enoic acid
• CAS: 177478-60-3
• 化学式: C₁₂H₁₃NO₄
• 分子量: 235.24
• InChiKey: ZIXKKLUTWUYCPJ-GQCTYLIASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-N-[2,4-dichloro-3-({[4-(dimethylamino)-2-methyl-8-quinolinyl]oxy}methyl)phenyl]-N-methylacetamide 、 (2E)-3-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-2-propenoic acid 在 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以82.5%的产率得到4-[(1E)-3-({2-[2,4-dichloro-3-({[4-(dimethylamino)-2-methyl-8-quinolinyl]oxy}methyl)methylanilino]-2-oxoethyl}amino)-3-oxo-1-propenyl]-2-methoxy-N-methylbenzamide
  参考文献：
  名称：

  A New Class of Nonpeptide Bradykinin B₂ Receptor Ligand, Incorporating a 4-Aminoquinoline Framework. Identification of a Key Pharmacophore To Determine Species Difference and Agonist/Antagonist Profile

  摘要：

  Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B-2 receptor antagonists afforded highly potent ligands for human B-2 receptor with various affinities for guinea pig B-2 receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B-2 receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 mug/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B-2 receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B-2 receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B-2 agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

  DOI：

  10.1021/jm030326t
• 作为产物：
  描述：

  4-(羟甲基)-2-甲氧基苯甲酸 在 sodium hydroxide 、 pyridine-SO3 complex 、 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 生成 (2E)-3-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-2-propenoic acid
  参考文献：
  名称：

  A New Class of Nonpeptide Bradykinin B₂ Receptor Ligand, Incorporating a 4-Aminoquinoline Framework. Identification of a Key Pharmacophore To Determine Species Difference and Agonist/Antagonist Profile

  摘要：

  Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B-2 receptor antagonists afforded highly potent ligands for human B-2 receptor with various affinities for guinea pig B-2 receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B-2 receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 mug/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B-2 receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B-2 receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B-2 agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

  DOI：

  10.1021/jm030326t

文献信息

• Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B₂ Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks
  作者：Yuki Sawada、Hiroshi Kayakiri、Yoshito Abe、Tsuyoshi Mizutani、Noriaki Inamura、Masayuki Asano、Chie Hatori、Ichiro Aramori、Teruo Oku、Hirokazu Tanaka

  DOI：10.1021/jm030468n

  日期：2004.5.1

  human B(2) receptor at concentrations greater than 10 nM and displayed one-tenth of the intrinsic activity of BK. The agonist activity of 22b was selective for the B(2) receptor and was inhibited by selective peptide and non-peptide B(2) antagonists. On the other hand, 22b strongly suppressed BK-induced IPs formation through the cloned human B(2) receptor. Further studies on the key pharmacophore led to

  在我们对非肽缓激肽（BK）B（2）受体配体的研究过程中，研究表明喹啉环的4位取代基可能在确定人和豚鼠B（2）的结合亲和力中起关键作用。 ）受体以及激动剂/拮抗剂的特性。我们进行了广泛的研究，以阐明该关键药效基团的构效关系（SAR）。将低级烷氧基引入3的喹啉环的4-位导致鉴定出4-乙氧基衍生物22b为独特的部分激动剂。此化合物显着刺激肌醇磷酸（IPs）的形成，在中国仓鼠卵巢细胞中表达克隆的人B（2）受体的浓度大于10 nM，并显示BK固有活性的十分之一。22b的激动剂活性对B（2）受体具有选择性，并被选择性肽和非肽B（2）拮抗剂抑制。另一方面，22b强烈抑制了BK诱导的IPs通过克隆的人B（2）受体的形成。对关键药效基团的进一步研究导致鉴定出2-picolyloxy部分为强大的激动剂开关，从而导致发现了有效而有效的非肽B（2）激动剂19a。酰基侧链的连续优化得到38，其在刺激IP形成时表现出
• Benzimidazole compounds as bradykinin antagonists
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US06083961A1

  公开（公告）日：2000-07-04

  This invention relates to a heterocyclic compound of the formula: ##STR1## wherein a group of the formula: ##STR2## is a group of the formula: ##STR3## etc., X is O, S or N--R.sup.5, R.sup.1 is lower alkyl, etc., R.sup.5 is hydrogen, lower alkyl, etc., R.sup.2 is hydrogen, halogen, lower alkyl, etc., R.sup.3 is halogen, lower alkyl, etc., R.sup.4 is amino optionally having suitable substituent(s), and A is lower alkylene, and a salt thereof, to processes for preparation thereof, and to a pharmaceutical composition comprising the same for the prevention and/or the treatment of bradykinin or its analogues mediated diseases in human being or animals.

  这项发明涉及一种杂环化合物，其化学式为：##STR1## 其中，##STR2## 是一个化学式为：##STR3## 的基团，X为O、S或N--R.sup.5，R.sup.1为较低烷基等，R.sup.5为氢、较低烷基等，R.sup.2为氢、卤素、较低烷基等，R.sup.3为卤素、较低烷基等，R.sup.4为氨基，可选地具有适当的取代基，A为较低烷基，以及其盐，制备方法和包含该化合物的药物组合物，用于预防和/或治疗人类或动物体内由激肽酶或其类似物介导的疾病。
• Quinoline derivatives as bradykinin agonists
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US06015818A1

  公开（公告）日：2000-01-18

  This invention relates to a compound of formula (1) wherein R.sup.1 is halogen, etc., R.sup.2 is halogen, etc., R.sup.3 is amino substituted with substituent(s) selected from the group consisting of lower alkyl and acyl, etc., R.sup.4 is heterocyclic (lower)alkyl, R.sup.5 is lower alkyl, and A.sup.1 is lower alkylene, and pharmaceutically acceptable salts thereof, to processes for preparation thereof, to a pharmaceutical composition comprising the same, and to methods of using the same therapeutically in the prevention and/or the treatment of hypertension or the like. ##STR1##

  这项发明涉及一种化合物，其化学式为（1），其中R.sup.1是卤素等，R.sup.2是卤素等，R.sup.3是氨基，带有从羧甲基和酰基等组成的取代基，R.sup.4是杂环（较低）烷基，R.sup.5是较低烷基，A.sup.1是较低亚烯，并且其药学上可接受的盐，以及制备该化合物的方法，包括具有相同化合物的药物组合物，以及在预防和/或治疗高血压或类似疾病中的治疗方法。
• HETEROCYCLIC COMPOUND
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0774462A1

  公开（公告）日：1997-05-21

  This invention relates to a heterocyclic compound of the formula :    wherein    a group of the formula : is a group of the formula : etc., X is O, S or N-R5, R1 is lower alkyl, etc., R5 is hydrogen, lower alkyl, etc., R2 is hydrogen, halogen, lower alkyl, etc., R3 is halogen, lower alkyl, etc., R4 is amino optionally having suitable substituent(s), and A is lower alkylene, and a salt thereof, to processes for preparation thereof, and to a pharmaceutical composition comprising the same for the prevention and/or the treatment of bradykinin or its analogues mediated diseases in human being or animals.

  本发明涉及一种式......的杂环化合物： 其中 式中的一个基团是式中的一个基团： 等等、 X是O、S或N-R5、 R1 是低级烷基等、 R5 是氢、低级烷基等、 R2 是氢、卤素、低级烷基等、 R3 是卤素、低级烷基等、 R4 是氨基，可选择具有合适的取代基、 和 A 是低级亚烷基、 及其盐、制备工艺，以及包含上述物质的药物组合物，用于预防和/或治疗缓激肽或其类似物介导的人类或动物疾病。
• CHINOLINE AND BENZIMIDAZOLE DERIVATIVES AS BRADYKININ AGONISTS
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0879233B1

  公开（公告）日：2003-08-13