6-amino-3,4-dihydro-2H-1,5-benzodioxepine | 115464-86-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-amino-3,4-dihydro-2H-1,5-benzodioxepine
• 英文别名: 6-amino-1,5-benzodioxepin；3,4-Dihydro-2h-1,5-benzodioxepin-6-amine
• CAS: 115464-86-3
• 化学式: C₉H₁₁NO₂
• 分子量: 165.192
• InChiKey: XLAHVEFEPBILOX-UHFFFAOYSA-N

物化性质

• 沸点：
  291.6±29.0 °C(Predicted)
• 密度：
  1.193±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  44.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-amino-3,4-dihydro-2H-1,5-benzodioxepine 在 lithium aluminium tetrahydride 、 potassium carbonate 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 氯苯 为溶剂， 反应 28.0h， 生成 1-[3-(7-bicyclo[4.2.0]octa-1,3,5-trienyl)propyl]-4-(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)piperazine
  参考文献：
  名称：

  Characterization of Potent and Selective Antagonists at Postsynaptic 5-HT1A Receptors in a Series of N4-Substituted Arylpiperazines

  摘要：

  Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)pipe (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha(1)-, alpha(2)-, and beta-adrenergic receptors, as well as dopamine D-1 and D-2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. Al compounds showed high affinity at 5-HT1A sites (8.10 less than or equal to pK(i)s less than or equal to 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D-2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D-2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha(1)-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pK(i) = 8.75), marked antagonist activity, and selectivity toward alpha(1)-adrenergic (81-fold) and dopamine D-2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.

  DOI：

  10.1021/jm00020a020

文献信息

• ESTERS OF 3-HYDROXY-PIPERIDINEMETHANOL DERIVATIVES
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP0880500B1

  公开（公告）日：2002-07-31
• US6096761A
  申请人：——

  公开号：US6096761A

  公开（公告）日：2000-08-01
• [EN] ESTERS OF 3-HYDROXY-PIPERIDINEMETHANOL DERIVATIVES<br/>[FR] ESTERS DE DERIVES DE 3-HYDROXY-PIPERIDINEMETHANOL
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：WO1997030031A1

  公开（公告）日：1997-08-21

  (EN) The present invention of compounds of formula (I), a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy; R2 is hydrogen or C1-6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl; R3 is hydrogen or halo; R4 is hydrogen or C1-6alkyl; L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with aryl, or L is a radical of formula -Alk-R5-, Alk-X-R6, -Alk-Y-C(=O)-R8, or -Alk-Y-C(=O)-NR10R11 wherein each Alk is C1-12alkanediyl; and R5 is hydrogen, cyano, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, aryl, di(aryl)methyl or a heterocyclic ringsystem; R6 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, aryl or heterocyclic ringsystem; X is O, S, SO2 or NR7; said R7 being hydrogen, C1-6alkyl or aryl; R8 is hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl, arylC1-6alkyl, di(aryl)methyl, C1-6alkyloxy or hydroxy; Y is NR9 or a direct bond; said R9 being hydrogen, C1-6alkyl or aryl; R10 and R11 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl or arylC1-6alkyl, or R10 and R11 combined with the nitrogen atom bearing R10 and R11 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R10 and R11 combined with the nitrogen bearing R10 and R11 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.(FR) L'invention concerne des composés représentés par la formule (I) (I), une de leurs formes isomères sur le plan stéréochimique, une de leurs formes de N-oxyde ou un de leurs sels d'apport acide acceptable sur le plan pharmaceutique, R1 représente alkyloxy C1-6, alkényloxy C2-6 ou alkynyloxy C2-6; R2 représente hydrogène ou alkyloxy C1-6 ou, pris ensemble, R1 et R2 peuvent constituer un radical bivalent représenté par une formule dans laquelle dans lesdites radicaux bivalents, un ou deux atomes d'hydrogène peuvent être substitué par alkyle C1-6, R3 représente hydrogène ou halo; R4 représente hydrogène ou alkyle C1-6; L représente cycloalkyle C3-6, cycloalcanone C5-6, alkényle C2-6 éventuellement substitué par aryle ou L représente un radical de formule -Alk-R5-, Alk-X- R6, -Alk-Y-C(=O)- R8 ou -Alk-Y-C(=O)-NR10R11 dans laquelle chaque Alk représente alcanediyle C1-12; et R5 représente hydrogène, cyano, alkylsulfonylamino C1-6, cycloalkyle C3-6, cycloalcanone C5-6, aryle, diarylméthyle ou un système de chaîne hétérocyclique; R6 représente hydrogène, alkyle C1-6, hydrocyalkyle C1-6, cycloalkyle C3-6, aryle ou un système de chaîne hétérocyclique; X représente O, S, SO2 ou NR7; ledit R7 représentant hydrogène, alkyle C1-6 aryle; R8 représente hydrogène, alkyle C1-6, cycloalkyle C3-6, aryle, arylalkyle C1-6, diarylméthyle, alkyloxy C1-6 ou hydroxy; Y représente NR9 ou une liaison directe; ledit R9 représentant hydrogène, alkyle C1-6, ou aryle; R10 et R11 chacun indépendamment représente hydrogène, alkyle C1-6, cycloalkyle C3-6, aryle ou arylalkyle C1-6 ou R10 et R11 combinés à l'atome d'azote portant R10 et R11 peuvent constituer une chaîne pyrrolidinyle ou pipéridinyle, les deux étant éventuellement substitués par alkyle C1-6, amino ou mono ou di(alkyle C1-6)amino, ou lesdits R10 et R11 combinés à l'atome d'azote portant R10 et R11 peuvent constituer un radical pipérazinyle ou 4-morpholinyle, les deux étant éventuellement substitués par alkyle C1-6. Procédés de préparation desdits produits, formulations contenant lesdits produits et leur utilisation médicale, en particulier, dans le traitement de troubles associés au dysfonctionnement de l'évacuation gastrique.
• Characterization of Potent and Selective Antagonists at Postsynaptic 5-HT1A Receptors in a Series of N4-Substituted Arylpiperazines
  作者：Jean-Louis Peglion、Herve Canton、Karin Bervoets、Valerie Audinot、Mauricette Brocco、Alain Gobert、Sylvie Le Marouille-Girardon、Mark J. Millan

  DOI：10.1021/jm00020a020

  日期：1995.9

  Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)pipe (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha(1)-, alpha(2)-, and beta-adrenergic receptors, as well as dopamine D-1 and D-2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. Al compounds showed high affinity at 5-HT1A sites (8.10 less than or equal to pK(i)s less than or equal to 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D-2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D-2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha(1)-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pK(i) = 8.75), marked antagonist activity, and selectivity toward alpha(1)-adrenergic (81-fold) and dopamine D-2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.