4-(3,4-difluorophenyl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid | 289059-56-9

• 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: 4-(3,4-difluorophenyl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• 英文别名: (4R)-4-(3,4-difluorophenyl)-2-oxo-6-(trifluoromethyl)-3,4-dihydro-1H-pyrimidine-5-carboxylic acid
• CAS: 289059-56-9
• 化学式: C₁₂H₇F₅N₂O₃
• 分子量: 322.191
• InChiKey: HXEQQMNVRBSXSJ-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-(3,4-difluorophenyl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 、 2-[1-(3-aminopropyl)piperidin-4-yl]benzonitrile hydrochloride 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (4R)-N-[3-[4-(2-cyanophenyl)piperidin-1-yl]propyl]-4-(3,4-difluorophenyl)-2-oxo-6-(trifluoromethyl)-3,4-dihydro-1H-pyrimidine-5-carboxamide
  参考文献：
  名称：

  In Vitro and in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent and Selective α_1A Receptor Antagonists for the Treatment of Benign Prostatic Hyperplasia

  摘要：

  alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K-i values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1d) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

  DOI：

  10.1021/jm990612y
• 作为产物：
  描述：

  三氟乙酰乙酸甲酯 、 3,4-二氟苯甲醛 、 尿素 在 三氟化硼乙醚 、 溶剂黄146 、 copper(II) oxide 、 subtilistin enzyme 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 24.0h， 生成 4-(+)-(3,4-difluorophenyl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 、 4-(3,4-difluorophenyl)-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
  参考文献：
  名称：

  In Vitro and in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent and Selective α_1A Receptor Antagonists for the Treatment of Benign Prostatic Hyperplasia

  摘要：

  alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K-i values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1d) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

  DOI：

  10.1021/jm990612y

文献信息

• In Vitro and in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent and Selective α_1A Receptor Antagonists for the Treatment of Benign Prostatic Hyperplasia
  作者：James C. Barrow、Philippe G. Nantermet、Harold G. Selnick、Kristen L. Glass、Kenneth E. Rittle、Kevin F. Gilbert、Thomas G. Steele、Carl F. Homnick、Roger M. Freidinger、Rick W. Ransom、Paul Kling、Duane Reiss、Theodore P. Broten、Terry W. Schorn、Raymond S. L. Chang、Stacey S. O'Malley、Timothy V. Olah、Joan D. Ellis、Andrea Barrish、Kelem Kassahun、Paula Leppert、Dhanapalan Nagarathnam、Carlos Forray

  DOI：10.1021/jm990612y

  日期：2000.7.1

  alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K-i values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1d) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.