methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate | 168163-99-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate
• 英文别名: methyl (2Z)-2-[1-(4-aminobenzoyl)-4,4-difluoro-2,3-dihydro-1-benzazepin-5-ylidene]acetate
• CAS: 168163-99-3
• 化学式: C₂₀H₁₈F₂N₂O₃
• 分子量: 372.371
• InChiKey: RTCUASWIMUZFCY-VBKFSLOCSA-N

物化性质

• 沸点：
  544.5±50.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate 在 吡啶 、 lithium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 (Z)-{4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ylidene}acetic acid
  参考文献：
  名称：

  V1A和V2受体的高效非口服精氨酸加压素拮抗剂：4'-[（（4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H- 1-苯并氮杂-1-基）羰基] -2-苯基苯甲腈衍生物。

  摘要：

  在结构上与4'-[（4,4-二氟-5-亚甲基-2,3,4,5-四氢-1H-1-苯并恶唑表皮-1-基）羰基] -2-苯基苯甲酰苯胺相关的一系列化合物为合成并评估了精氨酸加压素（AVP）的拮抗活性。在苯并ze庚因的5-位具有（Z）-烯烃几何结构的化合物对V1A和V2受体均具有强大的亲和力。进一步的研究表明，这些衍生物之一是（Z）-4'-（？4,4-二氟-5-[（4-二甲基氨基哌啶子基）羰基亚甲基] -2,3,4,5-四氢-1H-1 -苯并氮杂-1-基-1-羰基）-2-苯基苯甲酰苯胺单盐酸盐（29，YM-35471），即使口服给药，对V1A和V2受体也显示出极强的亲和力。该化合物的合成和药理特性在本文中有详细介绍。

  DOI：

  10.1248/cpb.48.1644
• 作为产物：
  描述：

  methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetate 在 tin(ll) chloride 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 17.0h， 生成 methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate
  参考文献：
  名称：

  Synthesis and biological activity of novel 4,4-difluorobenzazepine derivatives as non-peptide antagonists of the arginine vasopressin V1A receptor

  摘要：

  To find potent and selective antagonists of the arginine vasopressin (AVP) V-1A receptor, optimization studies of compounds structurally related to (Z)-N-{4'-[(4,4-difluoro-5-carbamoylmethylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbon-yl]phenyl}carboxamide were performed. The synthesis and phamacological properties of these compounds are described. We first investigated the effect of the carboxamide moiety, and found that a 2-methylfuran-3-carbonyl group at this position increased V-1A binding affinity and selectivity for the V-1A receptor versus the V-2 receptor. The amino group of the 5-carbamoylmethylidene moiety was also examined, and a 4-piperidinopiperidino group was found to be optimal at this position. The hemifumarate of compound 121 (YM218) was shown to exhibit potent binding affinity, V-1A receptor selectivity, and in vivo antagonist activity. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.10.035

文献信息

• Preparation of Highly Potent and Selective Non-Peptide Antagonists of the Arginine Vasopressin V1A Receptor by Introduction of a 2-Ethyl-1H-1-imidazolyl Group
  作者：Yoshiaki Shimada、Hiroaki Akane、Nobuaki Taniguchi、Akira Matsuhisa、Noriyuki Kawano、Kazumi Kikuchi、Takeyuki Yatsu、Atsuo Tahara、Yuichi Tomura、Toshiyuki Kusayama、Koh-ichi Wada、Junko Tsukada、Takashi Tsunoda、Akihiro Tanaka

  DOI：10.1248/cpb.53.764

  日期：——

  To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4′-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4′-(4,4-difluoro-5-[(N-cyclopropylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper

  为了寻找新的精氨酸加压素（AVP）V1A受体拮抗剂，研究了2-苯基-4′-[(2,3,4,5-四氢-1H-1-苯并嗪-1-基)羧酰基]苯腈（7）的2-苯基基团的影响。将2-苯基基团替换为2-乙基-1H-咪唑-1-基基团有效地产生了一个V1A选择性化合物。此外，该咪唑基团也被引入到YM-35471（6）的相同位置，针对这些化合物进行了进一步研究。因此，我们发现（Z）-4′-(4,4-二氟-5-[(N-环丙基氨基)亚甲基]-2,3,4,5-四氢-1H-1-苯并嗪-1-基}羧酰基)-2-(2-乙基-1H-1-咪唑-1-基)苯腈（9f）表现出高度的亲和力和选择性，是我们化合物中对V1A受体最有效的拮抗剂。本文描述了这些化合物的合成及药理学评估。
• Preparation of Non-peptide, Highly Potent and Selective Antagonists of Arginine Vasopressin V1A Receptor by Introduction of Alkoxy Groups
  作者：Yoshiaki Shimada、Nobuaki Taniguchi、Akira Matsuhisa、Takeyuki Yatsu、Atsuo Tahara、Akihiro Tanaka

  DOI：10.1248/cpb.51.1075

  日期：——

  A series of compounds structurally related to 4′-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2′-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V1A receptors. Consequently, we found that the (Z)-4′-(4,4-Difluoro-5-[(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl}carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4′-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper.

  一系列与4′-[(4,4-二氟-5-亚甲基-2,3,4,5-四氢-1H-1-苯并氮杂䓬-1-基)羰基]苯甲酰苯胺结构相关的化合物被合成并评估了其对抗精氨酸加压素（AVP）的活性。在苯甲酰苯胺的2′-位具有烷氧基（特别是乙氧基）的化合物对V1A受体相对于V2受体具有强的亲和力和选择性。进一步的研究表明，在羰基亚甲基上引入4,4-二甲基氨基哌啶和吗啉基团显示出对V1A受体更强的亲和力和选择性。因此，我们发现（Z）-4′-(4,4-二氟-5-[(4-二甲基氨基哌啶)羰基亚甲基]-2,3,4,5-四氢-1H-1-苯并氮杂䓬-1-基}羰基)-2-乙氧基苯甲酰苯胺单盐酸盐（8d）和（Z）-4′-[(4,4-二氟-5-吗啉氨基羰基亚乙基-2,3,4,5-四氢-1H-1-苯并氮杂䓬-1-基)羰基]-2-乙氧基苯甲酰苯胺（8q）具有强效且选择性的V1A受体拮抗活性。这些化合物的合成及其药理学特性在本论文中详细阐述。
• Benzazepine derivative, pharmaceutical composition thereof, and
  申请人：Yamanouchi Pharmaceutical Co., Ltd.

  公开号：US05710150A1

  公开（公告）日：1998-01-20

  Benzazepine derivatives represented by the following general formula (I) useful as arginine vasopressin antagonists or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and difluorobenzazepinone derivatives represented by the following general formulae (II) and (III) which are useful as production intermediates of the compound (I). ##STR1##

  以下是通用公式（I）表示的苯并哌啶衍生物，可用作精氨酸加压素拮抗剂或其药用盐，以及其药物组合物，以及以下通用公式（II）和（III）表示的二氟苯并哌啶酮衍生物，可用作化合物（I）的生产中间体。 请注意，这是一种化学描述，内容较为专业。
• Synthesis and biological activity of novel 4,4-difluorobenzazepine derivatives as non-peptide antagonists of the arginine vasopressin V1A receptor
  作者：Yoshiaki Shimada、Nobuaki Taniguchi、Akira Matsuhisa、Hiroaki Akane、Noriyuki Kawano、Takeshi Suzuki、Takahiko Tobe、Akio Kakefuda、Takeyuki Yatsu、Atsuo Tahara、Yuichi Tomura、Toshiyuki Kusayama、Koh-ichi Wada、Junko Tsukada、Masaya Orita、Takashi Tsunoda、Akihiro Tanaka

  DOI：10.1016/j.bmc.2005.10.035

  日期：2006.3

  To find potent and selective antagonists of the arginine vasopressin (AVP) V-1A receptor, optimization studies of compounds structurally related to (Z)-N-4'-[(4,4-difluoro-5-carbamoylmethylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbon-yl]phenyl}carboxamide were performed. The synthesis and phamacological properties of these compounds are described. We first investigated the effect of the carboxamide moiety, and found that a 2-methylfuran-3-carbonyl group at this position increased V-1A binding affinity and selectivity for the V-1A receptor versus the V-2 receptor. The amino group of the 5-carbamoylmethylidene moiety was also examined, and a 4-piperidinopiperidino group was found to be optimal at this position. The hemifumarate of compound 121 (YM218) was shown to exhibit potent binding affinity, V-1A receptor selectivity, and in vivo antagonist activity. (c) 2005 Elsevier Ltd. All rights reserved.
• Highly Potent and Orally Active Non-Peptide Arginine Vasopressin Antagonists for Both V1A and V2 Receptors: Synthesis and Pharmacological Properties of 4'-[(4,4-Difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-phenylbenzanililde Derivatives.
  作者：Yoshiaki SHIMADA、Nobuaki TANIGUCHI、Akira MATSUHISA、Kenichiro SAKAMOTO、Takeyuki YATSU、Akihiro TANAKA

  DOI：10.1248/cpb.48.1644

  日期：——

  one of these derivatives, (Z)-4'-(¿4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonylmet hylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yI¿carbonyl)2- phenylbenzanilide monohydrochloride (29, YM-35471), exhibits exceptionally potent affinity for both of V1A and V2 receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.

  在结构上与4'-[（4,4-二氟-5-亚甲基-2,3,4,5-四氢-1H-1-苯并恶唑表皮-1-基）羰基] -2-苯基苯甲酰苯胺相关的一系列化合物为合成并评估了精氨酸加压素（AVP）的拮抗活性。在苯并ze庚因的5-位具有（Z）-烯烃几何结构的化合物对V1A和V2受体均具有强大的亲和力。进一步的研究表明，这些衍生物之一是（Z）-4'-（？4,4-二氟-5-[（4-二甲基氨基哌啶子基）羰基亚甲基] -2,3,4,5-四氢-1H-1 -苯并氮杂-1-基-1-羰基）-2-苯基苯甲酰苯胺单盐酸盐（29，YM-35471），即使口服给药，对V1A和V2受体也显示出极强的亲和力。该化合物的合成和药理特性在本文中有详细介绍。