exo-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: exo-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane
• 英文别名: (1S,5S,6S/1R,5R,6R)-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane；(1R,5R,6R)-1-(3,4-dichlorophenyl)-6-(ethoxymethyl)-3-azabicyclo[3.1.0]hexane
• 化学式: C₁₄H₁₇Cl₂NO
• 分子量: 286.201
• InChiKey: IBZJKEOJOGAMGJ-GYSYKLTISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  exo-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane 在 盐酸 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 生成 (1S,5S,6S/1R,5R,6R)-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane hydrochloride
  参考文献：
  名称：

  WO2008/74716

  摘要：

  公开号：
• 作为产物：
  描述：

  1,1-dimethylethyl (1S,5S,6S/1R,5R,6R)-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 exo-1-(3,4-dichlorophenyl)-6-[(ethyloxy)methyl]-3-azabicyclo[3.1.0]hexane
  参考文献：
  名称：

  1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Triple Reuptake Inhibitors

  摘要：

  The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(ary1)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SA R. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability ( > 30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

  DOI：

  10.1021/jm901818u

文献信息

• AZABICYCLIC COMPOUNDS AS SEROTONIN, DOPAMINE AND NOREPINEPHRINE RE-UPTAKE INHIBITORS
  申请人：Bonanomi Giorgio

  公开号：US20100029740A1

  公开（公告）日：2010-02-04

  Novel compounds of formula (I)′ and pharmaceutically acceptable salts, solvates and prodrugs thereof: wherein A is: K is a mono or bicyclic aryl group; R 1 is selected from halogen, C 1-4 alkyl and C 1-4 alkoxy (R 1 may assume different meanings on the basis of p value); p is an integer from 0 to 5; R 2 is a group P: R 3 is hydrogen, C 1-4 alkyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkylC 1-3 alkyl, haloC 1-2 alkyl or an optionally substituted phenyl group; X is oxygen, —NR 8 — or sulphur; n is 0 or 1; R 7 is hydrogen or methyl; R 8 is hydrogen or C 1-4 alkyl; R 4 is hydrogen or methyl; R 5 is hydrogen or C 1-4 alkyl; and R 6 is hydrogen or C 1-4 alkyl; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibitors.

  式(I)'的新化合物及其药学上可接受的盐、溶剂化合物和前药，其中： A是： K是一个单环或双环芳基基团； R1选自卤素、C1-4烷基和C1-4烷氧基（基于p值，R1可以有不同的含义）； p是0到5之间的整数； R2是一个P基团； R3是氢、C1-4烷基、C3-6环烷基、C3-6环烷基C1-3烷基、卤代C1-2烷基或一个可选择取代的苯基； X是氧、—NR8—或硫； n是0或1； R7是氢或甲基； R8是氢或C1-4烷基； R4是氢或甲基； R5是氢或C1-4烷基； R6是氢或C1-4烷基； 本发明还涉及制备这些化合物的方法、用于这些方法的中间体、包含它们的制药组合物以及它们作为5-羟色胺（5-HT）、多巴胺（DA）和去甲肾上腺素（NE）的再摄取抑制剂在治疗中的用途。
• AZABICYCLIC COMPOUNDS AS SEROTONINE, DOPAMINE AND NOREPINEPHRINE RE-UPTAKE INHIBITORS
  申请人：Glaxo Group Limited

  公开号：EP2094657A1

  公开（公告）日：2009-09-02
• [EN] AZABICYCLIC COMPOUNDS AS SEROTONINE, DOPAMINE AND NOREPINEPHRINE RE-UPTAKE INHIBITORS<br/>[FR] COMPOSÉS AZABICYCLIQUES INHIBITEURS DU RECAPTAGE DE LA SÉROTONINE, DE LA DOPAMINE ET DE LA NORÉPINÉPHRINE
  申请人：GLAXO GROUP LTD

  公开号：WO2008074716A1

  公开（公告）日：2008-06-26

  [EN] The present invention relates to novel compounds of Formula (I)' or pharmaceutically acceptable salts or a solvates thereof: wherein A is and K is a mono or bicyclic aryl group; R₁ is selected from a group consisting of: halogen, C_1-4alkyl and C_1-4alkoxy, and such R₁ may assume different meanings on the basis of p value; p is an integer from 0 to 5; R₂ is a group P wherein P is and R₃ is hydrogen, C_1-4alkyl, C_3-6cycloalkyl, C_3-6cycloalkylC_1-3alkyl, haloC_1-2alkyl or an optionally substituted phenyl group; X is oxygen, -NR₈- or sulphur; n is 0 or 1; R₇ is hydrogen or methyl; R₄ is hydrogen or methyl; R₅ is hydrogen or C_1-4alkyl; R₆ is hydrogen or C_1-4alkyl; and R₈ is hydrogen or C_1-4alkyl; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibitors.
  [FR] L'invention porte sur de nouveaux composés de formule (I) ou leurs sels pharmaceutiquement acceptables ou un de leurs solvates: dans laquelle: A et K sont un groupe aryle mono ou bicyclique; R1 est choisi parmi: halogène, C1-4alkyle et C1-4alkoxy, et R1 peut avoir des significations différentes en fonction de la valeur de p; p est un entier de 0 à 5; R2 est un groupe P où P et R3 sont hydrogène, C1-4alkyle, C3-6cycloalkyle, C3-6cycloalkyleC1-3alkyle, haloC1-2alkyle ou un groupe phényle facultativement substitué, X est oxygène,-NR8-ou soufre; n est 0 ou 1; R7 est hydrogène ou méthyle; R4 est l'hydrogène ou méthyle; R5 est l'hydrogène ou C1-4alkyle; R6 est hydrogène ou C1-4alkyle; et R8 est hydrogène ou C1-4alkyle. L'invention porte également sur leur procédé de préparation, sur les intermédiaires utilisées dans ces procédé, sur des compositions pharmaceutiques les contenant, et sur leur utilisation thérapeutique en tant qu'inhibiteurs du recaptage de la sérotonine (5-HT), de la dopamine (DA) et de la norépinéphrine (NE).
• WO2008/74716
  申请人：——

  公开号：——

  公开（公告）日：——
• 1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Triple Reuptake Inhibitors
  作者：Fabrizio Micheli、Paolo Cavanni、Roberto Arban、Roberto Benedetti、Barbara Bertani、Michela Bettati、Letizia Bettelini、Giorgio Bonanomi、Simone Braggio、Anna Checchia、Silvia Davalli、Romano Di Fabio、Elettra Fazzolari、Stefano Fontana、Carla Marchioro、Doug Minick、Michele Negri、Beatrice Oliosi、Kevin D. Read、Ilaria Sartori、Giovanna Tedesco、Luca Tarsi、Silvia Terreni、Filippo Visentini、Alessandro Zocchi、Laura Zonzini

  DOI：10.1021/jm901818u

  日期：2010.3.25

  The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(ary1)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SA R. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability ( > 30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.