8-(4-phenylpiperazin-1-yl)-1,4-dioxaspiro-[4,5]-decane | 177721-56-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 8-(4-phenylpiperazin-1-yl)-1,4-dioxaspiro-[4,5]-decane
• 英文别名: 1-(1,4-Dioxaspiro[4.5]decan-8-yl)-4-phenylpiperazine
• CAS: 177721-56-1
• 化学式: C₁₈H₂₆N₂O₂
• 分子量: 302.417
• InChiKey: LLYUOXRUHWLTAG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  24.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-(4-phenylpiperazin-1-yl)-1,4-dioxaspiro-[4,5]-decane 在 盐酸 、 ammonium acetate 、 sodium cyanoborohydride 作用下， 以 甲醇 为溶剂， 反应 26.0h， 生成 4-(1-phenylpiperazin-4-yl)cyclohexylamine
  参考文献：
  名称：

  Aminopyrimidines with High Affinity for Both Serotonin and Dopamine Receptors

  摘要：

  A series of {4-[2-(4-arylpiperazin-1-yl)alkyl]cyclohexyl}pyrimidin-2-ylamines was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed, partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

  DOI：

  10.1021/jm9707378
• 作为产物：
  描述：

  1-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-4-phenyl-piperazine; hydrochloride 在 sodium cyanoborohydride 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 0.5h， 生成 8-(4-phenylpiperazin-1-yl)-1,4-dioxaspiro-[4,5]-decane
  参考文献：
  名称：

  trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines:  A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

  摘要：

  The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)-cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be-considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K-i, nM: 5-HT1A = 0.028, D-2 = 2194, alpha (1) = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D-2 and alpha (1) receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha (1a), alpha (1b), alpha (1d) receptor subtypes. They were also submitted to the [S-35]GTP gammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K-i) and in vitro activity (pD'(2)) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.

  DOI：

  10.1021/jm010866v

文献信息

• Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures¹
  作者：Ahmed F. Abdel-Magid、Kenneth G. Carson、Bruce D. Harris、Cynthia A. Maryanoff、Rekha D. Shah

  DOI：10.1021/jo960057x

  日期：1996.1.1

  triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones. Procedures for using this mild and selective reagent have been developed for a wide variety of substrates. The scope of the reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, and primary and secondary amines including a variety of weakly basic and

  存在三乙酰氧基硼氢化钠作为用于醛和酮的还原胺化的一般还原剂。已经开发了用于多种底物的使用这种温和选择性试剂的方法。反应范围包括脂族无环和环状酮，脂族和芳族醛，以及伯胺和仲胺，包括各种弱碱性和非碱性胺。局限性包括与芳族和不饱和酮以及一些位阻酮和胺的反应。1,2-二氯乙烷（DCE）是优选的反应溶剂，但是反应也可以在四氢呋喃（THF）中进行，有时也可以在乙腈中进行。乙酸可用作酮反应的催化剂，但醛类通常不需要。该过程可在对酸敏感的官能团（如乙缩醛和缩酮）的存在下有效地进行；它也可以在可还原的官能团如CC多键以及氰基和硝基的存在下进行。在DCE中，反应通常比在THF中更快，并且在两种溶剂中，在AcOH存在下反应都更快。与其他还原性胺化程序（如NaBH（3）CN / MeOH，硼烷-吡啶和催化氢化）相比，NaBH（OAc）（3）始终提供较高的收率和较少的副产物。在某些醛与伯胺发生二烷基化问题的还原胺化
• <i>trans</i>-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines:  A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines
  作者：Roberto Perrone、Francesco Berardi、Nicola A. Colabufo、Marcello Leopoldo、Enza Lacivita、Vincenzo Tortorella、Amedeo Leonardi、Elena Poggesi、Rodolfo Testa

  DOI：10.1021/jm010866v

  日期：2001.12.1

  The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)-cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be-considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K-i, nM: 5-HT1A = 0.028, D-2 = 2194, alpha (1) = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D-2 and alpha (1) receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha (1a), alpha (1b), alpha (1d) receptor subtypes. They were also submitted to the [S-35]GTP gammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K-i) and in vitro activity (pD'(2)) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.
• Aminopyrimidines with High Affinity for Both Serotonin and Dopamine Receptors
  作者：David Wustrow、Thomas Belliotti、Shelly Glase、Suzanne Ross Kesten、Don Johnson、Norman Colbry、Ronald Rubin、Anthony Blackburn、Hyacinth Akunne、Ann Corbin、M. Duff Davis、Lynn Georgic、Steven Whetzel、Kim Zoski、Thomas Heffner、Thomas Pugsley、Lawrence Wise

  DOI：10.1021/jm9707378

  日期：1998.2.1

  A series of 4-[2-(4-arylpiperazin-1-yl)alkyl]cyclohexyl}pyrimidin-2-ylamines was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed, partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.