2-cyanoethyl 2-methoxy-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate | 251930-31-1

• 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: 2-cyanoethyl 2-methoxy-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate
• CAS: 251930-31-1
• 化学式: C₁₆H₁₆N₄O₅
• 分子量: 344.327
• InChiKey: NYKMYRPMWCHQPC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  130
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-cyanoethyl 2-methoxy-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate 在 盐酸 、 4-二甲氨基吡啶 、 ammonium hydroxide 、 sodium hydroxide 、 碳酸氢钠 、 potassium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 为溶剂， 反应 25.0h， 生成 1-(3-{[5-Carbamoyl-4-methyl-6-(4-nitro-phenyl)-2-oxo-3,6-dihydro-2H-pyrimidine-1-carbonyl]-amino}-propyl)-4-phenyl-piperidine-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Design and Synthesis of Novel α_1a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in Dihydropyrimidinones

  摘要：

  Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K-i = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K-b(DBP)/K-b(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.

  DOI：

  10.1021/jm990200p
• 作为产物：
  描述：

  O-甲基异脲 半硫酸盐 、 2-cyanoethyl 2-acetyl-3-(4-nitrophenyl)-2-propenoate 在 碳酸氢钠 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 2-cyanoethyl 2-methoxy-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate
  参考文献：
  名称：

  Design and Synthesis of Novel α_1a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in Dihydropyrimidinones

  摘要：

  Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K-i = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K-b(DBP)/K-b(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.

  DOI：

  10.1021/jm990200p

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.
• Design and Synthesis of Novel α₁_a Adrenoceptor-Selective Antagonists. 1. Structure−Activity Relationship in Dihydropyrimidinones
  作者：Dhanapalan Nagarathnam、Shou Wu Miao、Bharat Lagu、George Chiu、James Fang、T. G. Murali Dhar、Jack Zhang、Sriram Tyagarajan、Mohammad R. Marzabadi、Fengqi Zhang、Wai C. Wong、Wanying Sun、Dake Tian、John M. Wetzel、Carlos Forray、Raymond S. L. Chang、Theodore P. Broten、Richard W. Ransom、Terry W. Schorn、Tsing B. Chen、Stacey O'Malley、Paul Kling、Kathryn Schneck、Robert Bendesky、Charles M. Harrell、Kamlesh P. Vyas、Charles Gluchowski

  DOI：10.1021/jm990200p

  日期：1999.11.1

  Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K-i = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K-b(DBP)/K-b(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.