6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine | 179482-26-9

• 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: 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine
• 英文别名: 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine；6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1(4-nitrophenoxy)carbonylpyrimidine；6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine；5-O-methyl 3-O-(4-nitrophenyl) 4-(3,4-difluorophenyl)-2-methoxy-6-methyl-4H-pyrimidine-3,5-dicarboxylate
• CAS: 179482-26-9；200051-91-8；216311-26-1
• 化学式: C₂₁H₁₇F₂N₃O₇
• 分子量: 461.379
• InChiKey: JKLWUGFUTWTCLP-UHFFFAOYSA-N

物化性质

• 熔点：
  172-174 °C
• 沸点：
  545.5±60.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  123
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine 在 盐酸 、 碳酸氢钠 、 potassium iodide 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 10.0h， 生成 3-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-propylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester
  参考文献：
  名称：

  Design and Synthesis of Novel α_1a Adrenoceptor-Selective Antagonists. 3. Approaches To Eliminate Opioid Agonist Metabolites by Using Substituted Phenylpiperazine Side Chains

  摘要：

  Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a) adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the mu-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the mu-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the mu-opioid receptor.

  DOI：

  10.1021/jm990202+
• 作为产物：
  描述：

  乙酰乙酸甲酯 在 4-二甲氨基吡啶 、 碳酸氢钠 、 溶剂黄146 作用下， 以 正己烷 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 生成 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine
  参考文献：
  名称：

  5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines

  摘要：

  该发明涉及以下结构的二氢嘧啶化合物，这些化合物是人类α1A受体的选择性拮抗剂。该发明还涉及利用这些化合物降低眼压、抑制胆固醇合成、放松下尿路组织、治疗良性前列腺增生、阳痿、心律失常以及治疗任何需要对α1A受体进行拮抗的疾病。该发明进一步提供了一种包含上述定义化合物的治疗有效量和药用可接受载体的药物组合物。

  公开号：

  US06245773B1

文献信息

• Design and Synthesis of Novel α₁_a Adrenoceptor-Selective Antagonists. 2. Approaches To Eliminate Opioid Agonist Metabolites via Modification of Linker and 4-Methoxycarbonyl-4-phenylpiperidine Moiety
  作者：T. G. Murali Dhar、Dhanapalan Nagarathnam、Mohammad R. Marzabadi、Bharat Lagu、Wai C. Wong、George Chiu、Sriram Tyagarajan、Shou Wu Miao、Fengqi Zhang、Wanying Sun、Dake Tian、Quanrong Shen、Jack Zhang、John M. Wetzel、Carlos Forray、Raymond S. L. Chang、Theodore P. Broten、Terry W. Schorn、Tsing Bao Chen、Stacy O'Malley、Richard Ransom、Kathryn Schneck、Robert Bendesky、Charles M. Harrell、Kamlesh P. Vyas、Kanyin Zhang、John Gilbert、Douglas J. Pettibone、Michael A. Patane、Mark G. Bock、Roger M. Freidinger、Charles Gluchowski

  DOI：10.1021/jm990201h

  日期：1999.11.1

  by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did

  先前我们已经将化合物1a描述为高亲和力亚型选择性alpha（1a）拮抗剂。化合物1a的体外和体内评估表明，其主要代谢产物为mu阿片类激动剂4-甲氧基羰基-4-苯基哌啶（3）。合成了几种二氢嘧啶酮类似物，其目的是通过修饰接头来使3的形成减至最少，或寻找替代的哌啶部分，当由于代谢作用而裂解时，其不会产生μ阿片样物质的活性。接头的修饰产生了几种具有良好的alpha（1a）结合亲和力（K（i）= <1 nM）和选择性（大于alpha（1b）和alpha（1d）的300倍）的化合物。微粒体测定法中的体外分析显示，这些修饰不会显着影响N-脱烷基和哌啶3的形成。第二种方法是 然而，产生了3个哌啶替代物，它们没有显示出明显的μ阿片样物质活性。这些化合物中的几种在α（1a）肾上腺素受体上保持了良好的亲和力，并且对alpha（1b）和alpha（1d）的选择性很高。例如，（+）-73和（+）-83的哌啶片段，
• DNA encoding a human melanin concentrating hormone receptor (MCH1) and uses thereof
  申请人：——

  公开号：US20030082623A1

  公开（公告）日：2003-05-01

  This invention provides an isolated nucleic acid encoding a human MCH1 receptor, a purified human MCH1 receptor, vectors comprising isolated nucleic acid encoding a human MCH1 receptor, cells comprising such vectors, antibodies directed to a human MCH1 receptor, nucleic acid probes useful for detecting nucleic acid encoding human MCH1 receptors, antisense oligonucleotides complementary to unique sequences of nucleic acid encoding human MCH1 receptors, transgenic, nonhuman animals which express DNA encoding a normal or mutant human MCH1 receptor, methods of isolating a human MCH1 receptor, methods of treating an abnormality that is linked to the activity of a human MCH1 receptor, as well as methods of determining binding of compounds to mammalian MCH1 receptors. This invention provides a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of an MCH1 antagonist effective to decrease the body mass of the subject and/or decrease the consumption of food by the subject. This invention further provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of an MCH1 antagonist effective to treat the subject's depression and/or anxiety.

  这项发明提供了编码人类MCH1受体的孤立核酸，纯化的人类MCH1受体，包括编码人类MCH1受体的孤立核酸的载体，包含这种载体的细胞，针对人类MCH1受体的抗体，用于检测编码人类MCH1受体的核酸探针，互补于编码人类MCH1受体独特序列的反义寡核苷酸，表达编码正常或突变人类MCH1受体的转基因非人类动物，孤立人类MCH1受体的分离方法，治疗与人类MCH1受体活性相关的异常的方法，以及确定化合物与哺乳动物MCH1受体结合的方法。这项发明提供了一种修改受试者摄食行为的方法，包括向受试者投与足以减少受试者体重和/或减少受试者食物摄入量的MCH1拮抗剂的量。这项发明还提供了一种治疗患有抑郁和/或焦虑的受试者的方法，包括向受试者投与足以治疗受试者抑郁和/或焦虑的MCH1拮抗剂的量。
• Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
  申请人：——

  公开号：US20030069261A1

  公开（公告）日：2003-04-10

  This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. In an embodiment of the invention, the feeding disorder is bulimia, bulimia nervosa or obesity.

  这项发明涉及选择性拮抗黑素浓集激素-1（MCH1）受体的化合物。该发明提供了一种包括所述化合物的治疗有效量和药学可接受载体的药物组合物。该发明提供了一种通过结合本发明化合物的治疗有效量和药学可接受载体制备的药物组合物。该发明还提供了一种制备药物组合物的方法，包括结合本发明化合物的治疗有效量和药学可接受载体。该发明还提供了一种修改受试者进食行为的方法，包括向受试者投与本发明化合物的有效量以减少受试者的食物摄入量。该发明还提供了一种治疗受试者进食障碍的方法，包括向受试者投与本发明化合物的有效量以减少受试者的食物摄入量。在该发明实施方式中，进食障碍可以是暴食症、暴食症神经质或肥胖症。
• Dihydropyrimidines and uses thereof
  申请人：Synaptic Pharmaceutical Corporation

  公开号：US06274585B1

  公开（公告）日：2001-08-14

  This invention is directed to dihydropyrimidines which are selective antagonists for human &agr;1a receptors. This invention is also related to uses of these compounds for relaxing lower urinary tract tissue, treating benign prostatic hyperplasia and for the treatment of any disease where the antagonism of the &agr;1a receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

  本发明涉及选择性拮抗人α1a受体的二氢嘧啶类化合物。本发明还涉及利用这些化合物来放松下尿道组织、治疗良性前列腺增生以及治疗可能需要拮抗α1a受体的任何疾病。该发明还提供了一种包含上述定义的化合物的治疗有效量和药学上可接受的载体的药物组合物。
• [EN] DIHYDROPYRIMIDINES AND USES THEREOF<br/>[FR] DIHYDROPIRIMIDINES ET LEURS EMPLOIS
  申请人：SYNAPTIC PHARMACEUTICAL CORPORATION

  公开号：WO1997017969A1

  公开（公告）日：1997-05-22

  (EN) This invention is directed to dihydropyrimidine compounds which are selective antagonists for human $g(a)1A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of begnin prostatic hyperplasia, impotency, cardiac arrythmia and for the treatment of any disease where the antagonism of the $g(a)1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.(FR) Cette invention concerne des composés de dihydropirimidines constituants des antagonistes sélectifs des récepteurs $g(a)1A humains. Cette invention concerne également des utilisations de ces composés pour abaisser la pression intra-occulaire, inhiber la synthèse du cholestérol, décontracter les tissus des voies urinaires inférieures, le traitement de l'adénome prostatique, de l'impuissance, de l'arythmie cardiaque et dans le traitement de toutes maladies dans lesquelles l'antagonisme du récepteur $g(a)1A peut être utile. L'invention concerne en outre une composition pharmaceutique comprenant une dose thérapeutique efficace des composés ci-dessus définis ainsi qu'un excipient pharmaceutiquement acceptable.

  该发明涉及二氢嘧啶化合物，其为人类$g(a)1A受体的选择性拮抗剂。该发明还涉及使用这些化合物降低眼内压、抑制胆固醇合成、放松下尿路组织、治疗良性前列腺增生、阳痿、心律失常以及治疗任何需要拮抗$g(a)1A受体的疾病。该发明还提供了一种药物组合物，包括上述定义化合物的治疗有效剂量和药用载体。