N-(2-hydroxyethyl)-3-methyl-1-(2-(3-(trifluoromethyl)benzyl)-1-benzothiophen-7-yl)-1H-pyrazole-4-carboxamide | 1313195-84-4

• 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: N-(2-hydroxyethyl)-3-methyl-1-(2-(3-(trifluoromethyl)benzyl)-1-benzothiophen-7-yl)-1H-pyrazole-4-carboxamide
• 英文别名: N-(2-hydroxyethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide
• CAS: 1313195-84-4
• 化学式: C₂₃H₂₀F₃N₃O₂S
• 分子量: 459.492
• InChiKey: OOXRLZNAKGXYGI-UHFFFAOYSA-N

物化性质

• 沸点：
  629.2±55.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  95.4
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

WO-459 是一种新型的 GPR52 激动剂，在 HEK293/GPR52 细胞中表现出剂量依赖性的 cAMP 升高效应。

反应信息

• 作为产物：
  描述：

  (7-溴苯并[B]噻吩-2-基)甲醇 在 吡啶 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 copper(II) acetate monohydrate 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 N-(2-hydroxyethyl)-3-methyl-1-(2-(3-(trifluoromethyl)benzyl)-1-benzothiophen-7-yl)-1H-pyrazole-4-carboxamide
  参考文献：
  名称：

  Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists

  摘要：

  G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-D-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50 = 21 nM, E-max = 103%, logD = 2.21, Solubility at pH 6.8 = 21 mu g/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice. (c) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.02.005

文献信息

• AMIDE COMPOUND
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2518054A1

  公开（公告）日：2012-10-31

  A compound represented by the formula (I) wherein ring Cy1 is a 5-membered aromatic heterocycle optionally further substituted besides a group represented by -A-B, ring Cy2 is an optionally substituted benzene ring, ring Cy3 is an optionally substituted 5-membered aromatic heterocycle, ring Cy4 is an optionally substituted 6-membered aromatic ring, A is -CONRa- or -NRaCO-, Ra is a hydrogen atom or a substituent, B is a hydrogen atom or an optionally substituted C1-6 alkyl-group, X is an optionally substituted C1-2 alkylene, -Y-, -Y-CH2- or - CH2-Y-, Y is an oxygen atom, -NRb- or -S(O)m-, Rb is a hydrogen atom or a substituent, and m is 0, 1 or 2, provided that N-methyl-4-[2-[3,4,5-trimethoxyphenyl)amino]-1,3-benzoxazol-7-yl]thiophene-2-carboxamide is excluded, or a salt thereof, has an agonistic action on GPR52, and is useful as an agent for the prophylaxis or treatment of schizophrenia and the like.

  化合物的化学式为（I），其中环Cy1是一个5-成员芳香杂环，除了由-A-B表示的基团外，还可以进一步取代，环Cy2是一个可选取代的苯环，环Cy3是一个可选取代的5-成员芳香杂环，环Cy4是一个可选取代的6-成员芳香环，A是 -CONRa- 或 -NRaCO-，Ra是氢原子或取代基，B是氢原子或可选取代的C1-6烷基，X是可选取代的C1-2烷基，-Y-，-Y-CH2- 或 - CH2-Y-，Y是氧原子，-NRb- 或 -S(O)m-，Rb是氢原子或取代基，m为0、1或2，提供N-甲基-4-[2-[3,4,5-三甲氧基苯基)氨基]-1,3-苯并噁唑-7-基]噻吩-2-羧酰胺被排除，或其盐，对GPR52有激动作用，并且可用作预防或治疗精神分裂症等疾病的药物。
• [EN] AMIDE COMPOUND<br/>[FR] COMPOSÉ AMIDE
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2011078360A1

  公开（公告）日：2011-06-30

  　式（Ｉ） [式中、 環Ｃｙ１は、－Ａ－Ｂで表される基に加えて更に置換されていてもよい５員芳香族複素環を表し、 環Ｃｙ２は、置換されていてもよいベンゼン環を表し、 環Ｃｙ３は、置換されていてもよい５員芳香族複素環を表し、 環Ｃｙ４は、置換されていてもよい６員芳香環を表し、 Ａは、－ＣＯＮＲａ－または－ＮＲａＣＯ－を表し、 Ｒａは、水素原子または置換基を表し、 Ｂは、水素原子、または置換されていてもよいＣ１－６アルキル基を表し、 Ｘは、置換されていてもよいＣ１－２アルキレン、－Ｙ－、－Ｙ－ＣＨ２－または－ＣＨ２－Ｙ－を表し、 Ｙは、酸素原子、－ＮＲｂ－または－Ｓ（Ｏ）ｍ－を表し、 Ｒｂは、水素原子または置換基を表し、 ｍは、０、１または２を表す。] で示される化合物またはその塩は、GPR52アゴニスト活性を有し、統合失調症等の予防または治療剤として有用である。
• Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists
  作者：Takashi Nakahata、Kazuyuki Tokumaru、Yoshiteru Ito、Naoki Ishii、Masaki Setoh、Yuji Shimizu、Toshiya Harasawa、Kazunobu Aoyama、Teruki Hamada、Masakuni Kori、Kazuyoshi Aso

  DOI：10.1016/j.bmc.2018.02.005

  日期：2018.5

  G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-D-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50 = 21 nM, E-max = 103%, logD = 2.21, Solubility at pH 6.8 = 21 mu g/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice. (c) 2018 Elsevier Ltd. All rights reserved.