3-(tert-butyloxycarbonyl)-7-(5-methyloxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine | 427891-90-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 3-(tert-butyloxycarbonyl)-7-(5-methyloxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine
• 英文别名: 3-(tert-Butyloxycarbonyl)-7-(5-methyl-oxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine；tert-butyl 7-(5-methyl-1,3-oxazol-2-yl)-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate
• CAS: 427891-90-5
• 化学式: C₁₉H₂₄N₂O₃
• 分子量: 328.411
• InChiKey: UCKIBYXGQDGIBI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(tert-butyloxycarbonyl)-7-(5-methyloxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 7-(5-methyloxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine
  参考文献：
  名称：

  1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines:  A Series of Potent and Selective Dopamine D₃ Receptor Antagonists

  摘要：

  The discovery of new highly potent and selective dopamine D-3 receptor antagonists has recently permitted characterization of the role of the dopamine D-3 receptor in a wide range, of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine- seeking behavior in the rat, reduces oral operant alcohol self- administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

  DOI：

  10.1021/jm0705612
• 作为产物：
  描述：

  3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid prop-2-ynyl amide 在 mercury(II) diacetate 、 溶剂黄146 作用下， 反应 1.5h， 以2.35 g的产率得到3-(tert-butyloxycarbonyl)-7-(5-methyloxazol-2-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine
  参考文献：
  名称：

  1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines:  A Series of Potent and Selective Dopamine D₃ Receptor Antagonists

  摘要：

  The discovery of new highly potent and selective dopamine D-3 receptor antagonists has recently permitted characterization of the role of the dopamine D-3 receptor in a wide range, of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine- seeking behavior in the rat, reduces oral operant alcohol self- administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

  DOI：

  10.1021/jm0705612

文献信息

• Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents)
  申请人：——

  公开号：US20040171606A1

  公开（公告）日：2004-09-02

  The invention provides compounds of formula (I): wherein: R 2 and R 3 independently represent various substituents; R 1 and R 4 independently represent H, F, Cl, Br, Cl 1-2 alkyl, C 1 alkoxy, OH, CN, or NO 2 ; B represents a sulfur atom or a —CH 2 -group; t represents 3 or 4; and A represents an optionally substituted 5- or 6-membered aromatic heterocyclic ring, or an optionally substituted bicyclic heterocyclic ring system in which at least the ring bound to the group B in Formula (I) is aromatic; or a salt thereof. Preferably, A is selected from one of the groups (i), (ii) or (iii): wherein X 1 and X 2 are independently N or CR 8 , and X 3 is NR 8 , O or S; Y 1 and Y 3 are independently N or CR 9 , and Y 2 is NR 9 , O or S; Z 1 is NR 10 , O or S, and Z 2 and Z 3 are independently N or CR 10 ; R 8 , R 9 , and R 10 are as herein defined, and R 7 is H, a halogen atom, OH, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylenedioxy, C 1-4 alkanoyl, or C 1-4 alkylsulfonyl, an optionally substituted 3-, 4-, 5- or 6-membered cycloalkyl ring, or a group of the formula (a), (b), (c) or (d) as defined by the formulas (a), (b), (c) or (d). The compounds are modulators of dopamine D 3 receptors and have potential in the treatment of psychotic conditions (e.g. schizophrenia) or substance abuse.

  该发明提供了以下式（I）的化合物：其中：R2和R3分别代表各种取代基；R1和R4独立地代表H、F、Cl、Br、Cl1-2烷基、C1烷氧基、OH、CN或NO2；B代表硫原子或—CH2基团；t代表3或4；A代表一个可选择取代的5-或6-成员芳香杂环环，或者一个至少与式（I）中的基团B相结合的环是芳香的可选择取代的双环杂环环系统；或其盐。最好的情况是，A选自以下组之一：其中X1和X2独立地为N或CR8，X3为NR8、O或S；Y1和Y3独立地为N或CR9，Y2为NR9、O或S；Z1为NR10、O或S，Z2和Z3独立地为N或CR10；R8、R9和R10如上所定义，R7为H、卤素原子、OH、氰基、硝基、C1-4烷基、C1-4烷氧基、C1-4烷二氧基、C1-4烷酰基或C1-4烷基磺酰基，一个可选择取代的3-、4-、5-或6-成员环烷基环，或者由式（a）、（b）、（c）或（d）定义的式（a）、（b）、（c）或（d）的基团。这些化合物是多巴胺D3受体调节剂，对治疗精神病性疾病（如精神分裂症）或物质滥用具有潜在作用。
• Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
  申请人：SmithKline Beecham, PLC

  公开号：US07429579B2

  公开（公告）日：2008-09-30

  The invention provides compounds of formula (I): wherein: R2 and R3 independently represent various substituents; R1 and R4 independently represent H, F, Cl, Br, C1-2alkyl, C1alkoxy, OH, CN, or NO2; B represents a sulfur atom or a —CH2-group; t represents 3 or 4; and A represents an optionally substituted 5- or 6-membered aromatic heterocyclic ring, or an optionally substituted bicyclic heterocyclic ring system in which at least the ring bound to the group B in Formula (I) is aromatic; or a salt thereof. Preferably, A is selected from one of the groups (i), (ii) or (iii): wherein X1 and X2 are independently N or CR8, and X3 is NR8, O or S; Y1 and Y3 are independently N or CR9, and Y2 is NR9, O or S; Z1 is NR10, O or S, and Z2 and Z3 are independently N or CR10; R8, R9, and R10 are as herein defined, and R7 is H, a halogen atom, OH, cyano, nitro, C1-4alkyl, C1-4alkoxy, C1-4alkylenedioxy, C1-4alkanoyl, or C1-4alkylsulfonyl, an optionally substituted 3-, 4-, 5- or 6-membered cycloalkyl ring, or a group of the formula (a), (b), (c) or (d) as defined by the formulas (a), (b), (c) or (d). The compounds are modulators of dopamine D3 receptors and have potential in the treatment of psychotic conditions (e.g. schizophrenia) or substance abuse.

  本发明提供公式（I）的化合物：其中：R2和R3独立地代表各种取代基；R1和R4独立地代表H，F，Cl，Br，C1-2烷基，C1烷氧基，OH，CN或NO2；B代表硫原子或-CH2基团；t代表3或4；而A代表可选地取代的5-或6-成员芳香杂环环，或者是至少与公式（I）中的基团B相结合的环是芳香的可选地取代的双环杂环环系统；或其盐。优选地，A是从群（i），（ii）或（iii）中选择的：其中X1和X2独立地为N或CR8，X3为NR8，O或S；Y1和Y3独立地为N或CR9，Y2为NR9，O或S；Z1为NR10，O或S，而Z2和Z3独立地为N或CR10；R8，R9和R10如本文所定义，而R7为H，卤素原子，OH，氰基，硝基，C1-4烷基，C1-4烷氧基，C1-4烷二氧基，C1-4烷酰基或C1-4烷基磺酰基，可选地取代的3-, 4-, 5-或6-成员环烷基环，或由公式（a），（b），（c）或（d）定义的公式（a），（b），（c）或（d）的基团。这些化合物是多巴胺D3受体调节剂，具有在治疗精神病性疾病（例如精神分裂症）或物质滥用方面的潜力。
• TETRAHYDROBENZAZEPINE DERIVATIVES USEFUL AS MODULATORS OF DOPAMINE D3 RECEPTORS (ANTIPSYCHOTIC AGENTS)
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP1335915B1

  公开（公告）日：2008-01-02
• US7429579B2
  申请人：——

  公开号：US7429579B2

  公开（公告）日：2008-09-30
• [EN] TETRAHYDROBENZAZEPINE DERIVATIVES USEFUL AS MODULATORS OF DOPAMINE D3 RECEPTORS (ANTIPSYCHOTIC AGENTS)<br/>[FR] DERIVES DE TETRAHYDROBENZAZEPINE UTILES EN TANT QUE MODULATEURS DES RECEPTEURS D3 DE LA DOPAMINE (AGENTS ANTIPSYCHOTIQUES)
  申请人：——

  公开号：WO2002040471A9

  公开（公告）日：2003-07-31

  [EN] The invention provides compounds of formula (I), wherein R<1>-R<4>, A, B and t are as defined in claim 1. The compounds are modulators of dopamine D3 receptors and have potential in the treatment of psychotic conditions (e.g. schizophrenia) or substance abuse.
  [FR] L'invention concerne des composés de formule (I), dans laquelle : R<2> et R<3> représentent indépendamment divers substituants ; R<1> et R<4> représentent indépendamment H, F, Cl, Br, alkyle C1-2, alcoxy C1, OH, CN, ou NO2 ; B représente un atome de soufre ou un groupe CH2 ; t représente 3 ou 4 ; et A représente un noyau hétérocyclique aromatique à 5 ou 6 éléments éventuellement substitué, ou un système de noyau hétérocyclique bicyclique éventuellement substitué dans lequel au moins le noyau lié au groupe B de la formule (I) est aromatique ; ou un sel dérivé de ces composés. A est, de préférence, choisi parmi les groupes (i), (ii) ou (iii), dans lesquels : X<1> et X<2> représentent indépendamment N ou CR<8>, et X<3> représente NR<8>, O ou S ; Y<1> et Y<3> représentent indépendamment N ou CR<9>, et Y<2> représente NR<9>, O ou S ; Z<1> représente NR<10>, O ou S, et Z<2> et Z<3> représentent indépendamment N ou CR<10> ; R<8>, R<9>, et R<10 >sont définis dans la description ; et R<7> représente H, un atome d'halogène, OH, cyano, nitro, alkyle C1-4, alcoxy C1-4, alkylènedioxy C1-4, alcanoyle C1-4, ou alkylsulfonyle C1-4, un noyau cycloalkyle à 3, 4, 5 ou 6 éléments éventuellement substitué, ou un groupe représenté par les formules (a), (b), (c) ou (d) définies ci-dessous. Selon l'invention, les composés sont des modulateurs des récepteurs D3 de la dopamine et ils s'avèrent utiles pour le traitement d'états psychotiques (la schizophrénie, par exemple) ou de la toxicomanie.