(-)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid | 256950-78-4

• 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)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• 英文别名: (+)-(R)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid；(6R)-6-(3,4-difluorophenyl)-3,4-dimethyl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid
• CAS: 256950-78-4
• 化学式: C₁₃H₁₂F₂N₂O₃
• 分子量: 282.247
• InChiKey: DDRYEQZGFSAGDR-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(3-aminopropyl)-4-(2,4-difluorophenyl)-piperidine-4-carbonitrile dihydrochloride 、 (-)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 溶剂黄146 为溶剂， 生成 (R)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}-amide
  参考文献：
  名称：

  Alpha 1A adrenergic receptor antagonists

  摘要：

  这项发明涉及某些新颖化合物及其衍生物，它们的合成以及它们作为α1a肾上腺素受体拮抗剂的用途。这些化合物的一个应用是用于治疗良性前列腺增生。这些化合物在其能够放松富含α1a受体亚型的平滑肌组织方面具有选择性，同时不会引起低血压。这样的组织之一是围绕尿道内膜的组织。因此，这些化合物的一个用途是通过减少尿液流动的阻碍，为患有良性前列腺增生的男性提供急性缓解。这些化合物的另一个用途是与人类5α-还原酶抑制剂化合物结合，从而实现对良性前列腺增生影响的急性和慢性缓解。

  公开号：

  US06339090B1
• 作为产物：
  描述：

  4-(3,4-difluorophenyl)-2-methoxy-1,6-dimethyl-1,4-dihydropyrimidine-5-carboxylic acid methyl ester 在 盐酸 、 sodium hydroxide 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 10.0h， 生成 (-)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-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

• [EN] ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
  申请人：MERCK & CO INC

  公开号：WO2000006565A1

  公开（公告）日：2000-02-10

  This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha 1a adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

  本发明涉及某些新型化合物及其衍生物，它们的合成以及它们作为α1a肾上腺素能受体拮抗剂的用途。这些化合物的一个应用是治疗良性前列腺增生症。这些化合物在其选择性上具有放松充满α1a受体亚型的平滑肌组织的能力，而不会同时引起低血压。这样的组织可以在尿道内膜周围发现。因此，这些化合物的一个用途是为男性良性前列腺增生症提供急性缓解，从而使尿液流动更加顺畅。这些化合物的另一个用途是与人类5α-还原酶抑制剂化合物结合，从而实现对良性前列腺增生症的急性和慢性缓解。
• US6339090B1
  申请人：——

  公开号：US6339090B1

  公开（公告）日：2002-01-15
• Alpha 1A adrenergic receptor antagonists
  申请人：Merck & Co., Inc.

  公开号：US06339090B1

  公开（公告）日：2002-01-15

  This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha 1a adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

  这项发明涉及某些新颖化合物及其衍生物，它们的合成以及它们作为α1a肾上腺素受体拮抗剂的用途。这些化合物的一个应用是用于治疗良性前列腺增生。这些化合物在其能够放松富含α1a受体亚型的平滑肌组织方面具有选择性，同时不会引起低血压。这样的组织之一是围绕尿道内膜的组织。因此，这些化合物的一个用途是通过减少尿液流动的阻碍，为患有良性前列腺增生的男性提供急性缓解。这些化合物的另一个用途是与人类5α-还原酶抑制剂化合物结合，从而实现对良性前列腺增生影响的急性和慢性缓解。
• 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.