(R)-4-amino-3-cyclohexyl-3, 4-dihydro-2H-1, 4-benzoxazine | 856703-21-4

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: (R)-4-amino-3-cyclohexyl-3, 4-dihydro-2H-1, 4-benzoxazine
• 英文别名: (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine；(3R)-3-cyclohexyl-2,3-dihydro-1,4-benzoxazin-4-amine
• CAS: 856703-21-4
• 化学式: C₁₄H₂₀N₂O
• 分子量: 232.326
• InChiKey: LHHDCQXNJQTEOJ-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  38.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  丙酮酸乙酯 、 (R)-4-amino-3-cyclohexyl-3, 4-dihydro-2H-1, 4-benzoxazine 在 硫酸 作用下， 以 乙醇 为溶剂， 以85%的产率得到ethyl (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate
  参考文献：
  名称：

  设计，合成和构象关系研究吲哚-3-羧酰胺作为新型CB1大麻素受体激动剂的构象受约束类似物

  摘要：

  新型三环吲哚-3-羧酰胺被合成为双环吲哚的结构受限类似物，并被发现是有效的CB1大麻素受体激动剂。CB1激动剂活性取决于三环手性中心的绝对构型。优选的对映异构体比结构不受限制的铅化合物更有效。还研究了吲哚C-3位置酰胺侧链的结构活性关系。

  DOI：

  10.1016/j.bmcl.2010.06.067
• 作为产物：
  描述：

  (R)-3-cyclohexyl-3, 4-dihydro-2H-1, 4-benzoxazine 在 sodium nitrite 、 盐酸 、 lithium aluminium tetrahydride 作用下， 以 DMF (N,N-dimethyl-formamide) 、 水 、 四氢呋喃 、 乙醚 为溶剂， 反应 2.0h， 生成 (R)-4-amino-3-cyclohexyl-3, 4-dihydro-2H-1, 4-benzoxazine
  参考文献：
  名称：

  [EN] TRICYCLIC 1-[(3-INDOL-3-YL)CARBONYL] PIPERAZINE DERIVATIVES AS CANNABINOID CB1 RECEPTOR AGONISTS
  [FR] DERIVES TRICYCLIQUES DE PIPERAZINE 1-[(3-INDOL-3-YL)CARBONYL] UTILES EN TANT QU'AGONISTES DU RECEPTEUR CANNABINOIDE CB1

  摘要：

  该发明涉及具有通式（I）的三环1-[(吲哚-3-基)羰基]哌嗪衍生物，其中X为CH2、O或S；R代表1-3个取自H、(C1-4)烷基、(C1-4)烷氧基和卤素的取代基；R1为(C5-8)环烷基；R2为H或(C1-4)烷基；R3、R3'、R4'、R4'、R5、R5'和R6'独立地为氢或(C1-4)烷基，可选地取代为(C1-4)烷氧基、OH或卤素；R6为氢或(C1-4)烷基，可选地取代为(C1-4)烷氧基、OH或卤素；或R6与R7一起形成一个含有O和S等进一步杂原子的4-7元饱和杂环；R7与R6一起形成一个含有O和S等进一步杂原子的4-7元饱和杂环；或R7为H、(C1-4)烷基或(C3-5)环烷基，烷基基团可选地取代为OH、卤素或(C1-4)烷氧基；或其药学上可接受的盐。该发明还涉及包含所述三环1-[(吲哚-3-基)羰基]哌嗪衍生物的药物组合物，并且涉及在治疗疼痛，如围手术疼痛、慢性疼痛、神经痛、癌症疼痛以及与多发性硬化相关的疼痛和痉挛中使用这些衍生物。

  公开号：

  WO2005058327A1

文献信息

• [EN] (INDOL-3-YL)-HETEROCYCLE DERIVATIVES AS AGONISTS OF THE CANNABINOID CB1 RECEPTOR<br/>[FR] DERIVES HETEROCYCLIQUES-(INDOL-3-YL) COMME AGONISTES DU RECEPTEUR DU CANNABINOIDE CB1
  申请人：AKZO NOBEL NV

  公开号：WO2005089754A1

  公开（公告）日：2005-09-29

  The invention relates to (indol-3-yl)-heterocycle derivatives having general Formula (I) wherein A represents a 5-membered aromatic heterocyclic ring, wherein X1, X2 and X3 are independently selected from N, O, S and CR; R is H or (C1-4)alkyl; or R, when present in X2 or X3, may form together with R3 a 5-8 membered ring; R1 is a 5-8 mem­bered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S; R2 is H, CH3 or CH2-CH3; or R2 is joined together with R7 to form a 6-mem­bered ring, optionally containing a heteroatom selected from O and S, and which heteroatom is bonded to the 7-position of the indole ring; R3 and R4 are independent­ly H, (C1-6)alkyl or (C3-7)cycloalkyl, the alkyl groups being optionally substituted with OH, (C1-4)alkyloxy, (C1-4)alkylthio, (C1-4)alkylsulfonyl, CN or halogen; or R3 together with R4 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S, and which is optionally sub­stituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen; or R3 together with R5 forms a 4-8 membered ring optionally containing a further hetero­atom selected from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen; or R3 together with R, when present in X2 or X3, forms a 5-8 membered ring; R5 is H or (C1-4)alkyl; or R5 together with R3 forms a 4-8 membered ring optionally containing a further heteroatom select­ed from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyl­oxy, (C1-4) alkyloxy- (C1-4)alkyl, or halogen; R5' is H or (C1-4)alkyl; R6 represents 1-3 substituents independently selected from H, (C1-4 alkyl, (C1-4) alkyloxy, CN and halogen; R7 is H, (C1-4)alkyl, (C1-4)alkyloxy, CN or halogen; or R7 is joined together with R2 to form a 6-membered ring, optionally containing a further heteroatom selected from O and S, and which heteroatom is bonded to the 7-position of the indole ring; or a pharmaceutically acceptable salt thereof, as agonists of the cannabinoid CB1 receptor, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

  该发明涉及具有一般式（I）的（吲哚-3-基）-杂环衍生物，其中A代表一个5-成员芳香杂环环，其中X1、X2和X3分别选自N、O、S和CR；R为H或（C1-4）烷基；或者R，在X2或X3中时，可以与R3一起形成一个5-8成员环；R1是一个5-8成员饱和碳环，可选地含有从O和S中选取的杂原子；R2为H、CH3或CH2- ；或者R2与R7结合形成一个6-成员环，可选地含有从O和S中选取的杂原子，并且该杂原子与吲哚环的7-位置相结合；R3和R4独立地为H、（C1-6）烷基或（C3-7）环烷基，烷基基团可选地用OH、（C1-4）烷氧基、（C1-4）烷基硫醚、（C1-4）烷基磺酰基、CN或卤素取代；或者R3与R4和它们结合的N形成一个4-8成员环，可选地含有从O和S中选取的进一步杂原子，并且可选地用OH、（C1-4）烷基、（C1-4）烷氧基、（C1-4）烷氧基-（C1-4）烷基或卤素取代；或者R3与R5形成一个4-8成员环，可选地含有从O和S中选取的进一步杂原子，并且可选地用OH、（C1-4）烷基、（C1-4）烷氧基、（C1-4）烷氧基-（C1-4）烷基或卤素取代；或者R3与R，在X2或X3中时，形成一个5-8成员环；R5为H或（C1-4）烷基；或者R5与R3一起形成一个4-8成员环，可选地含有从O和S中选取的进一步杂原子，并且可选地用OH、（C1-4）烷基、（C1-4）烷氧基、（C1-4）烷氧基-（C1-4）烷基或卤素取代；R5'为H或（C1-4）烷基；R6代表独立选择的1-3个取代基，选自H、（C1-4）烷基、（C1-4）烷氧基、CN和卤素；R7为H、（C1-4）烷基、（C1-4）烷氧基、CN或卤素；或者R7与R2结合形成一个6-成员环，可选地含有从O和S中选取的进一步杂原子，并且该杂原子与吲哚环的7-位置相结合；或其药学上可接受的盐，作为大麻素CB1受体的激动剂，可用于治疗疼痛，例如围手术期疼痛、慢性疼痛、神经痛、癌症疼痛以及与多发性硬化相关的疼痛和痉挛。
• Tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives as cannabinoid cb1 receptor agonists
  申请人：Adam-Worrall Julia

  公开号：US20070088025A1

  公开（公告）日：2007-04-19

  The invention relates to tricyclic 1-[(in-dol-3-yl)carbonyl]piperazine derivative having the general Formula (I) wherein X is CH 2 , O or S; R represents 1-3 substituents independently selected from H, (C 1-4 )alkyl, (C 1-4 )alkyloxy and halogen; R 1 is (C 5-8 )cycloalkyl; R 2 is H or (C 1-4 )alkyl; R 3 , R 3 ′, R 4 ′, R 4 ′, R 5 , R 5 ′ and R 6 ′ are independently hydrogen or (C 1-4 )-alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; R 6 is hydrogen or (C 1-4 )alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; or R 6 forms together with R 7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R 7 forms together with R 6 a 4-7 membered saturated heterocydic ring, optionally containing a further heteroatom selected from O and S; or R 7 is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C 1-4 )alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.

  本发明涉及三环1-[(吲哚-3-基)羰基]哌嗪衍生物，其具有通式（I），其中X为CH2、O或S；R代表1-3个取自H、（C1-4）烷基、（C1-4）烷氧基和卤素的取代基；R1为（C5-8）环烷基；R2为H或（C1-4）烷基；R3、R3'、R4'、R4'、R5、R5'和R6'独立地为氢或（C1-4）烷基，可选地被（C1-4）烷氧基、OH或卤素取代；R6为氢或（C1-4）烷基，可选地被（C1-4）烷氧基、OH或卤素取代；或R6与R7形成4-7成员饱和杂环环，可选地包含进一步的选自O和S的杂原子；R7与R6a形成4-7成员饱和杂环环，可选地包含进一步的选自O和S的杂原子；或R7为H、（C1-4）烷基或（C3-5）环烷基，烷基基团可选地被OH、卤素或（C1-4）烷氧基取代；或其药学上可接受的盐。本发明还涉及含有上述三环1-[(吲哚-3-基)羰基]哌嗪衍生物的制药组合物，以及在治疗疼痛，如围手术期疼痛、慢性疼痛、神经病性疼痛、癌症疼痛和与多发性硬化症相关的疼痛和痉挛中使用这些衍生物的用途。
• (Indol-3-yl) heterocycle derivatives as a agonists of the cannabinoid cb1 receptor
  申请人：Adam-Worrall Julia

  公开号：US20070142446A1

  公开（公告）日：2007-06-21

  Disclosed herein are indole derivatives of the formula (I) wherein each of the substitutents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the indole derivatives and use of the derivatives for the treatment of pain.

  本文揭示了公式(I)的吲哚衍生物，其中每个取代基的定义如规范和要求所述。还揭示了含有这些吲哚衍生物的药物组合物，并且这些衍生物可用于治疗疼痛。
• Tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives as cannabinoid CB1 receptor agonists
  申请人：N.V. Organon

  公开号：US07772227B2

  公开（公告）日：2010-08-10

  The invention relates to tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative having the general Formula (I) wherein X is CH2, O or S; R represents 1-3 substituents independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy and halogen; R1 is (C5-8)cycloalkyl; R2 is H or (C1-4)alkyl; R3, R3′, R4′ R4′, R5, R5′ and R6′ are independently hydrogen or (C1-4)-alkyl, optionally substituted with (C1-4)alkyloxy, OH or halogen; R6 is hydrogen or (C1-4)alkyl, optionally substituted with (C1-4)alkyloxy, OH or halogen; or R6 forms together with R7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R7 forms together with R6 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; or R7 is H, (C1-4)alkyl or (C3-5)cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C1-4)alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.

  本发明涉及具有通式（I）的三环1-[(indol-3-yl)carbonyl]哌嗪衍生物，其中X为CH2、O或S；R代表1-3个取自H、(C1-4)烷基、(C1-4)烷氧基和卤素的取代基；R1为(C5-8)环烷基；R2为H或(C1-4)烷基；R3、R3′、R4′、R4′、R5、R5′和R6′独立地为氢或(C1-4)烷基，可选地取代(C1-4)烷氧基、OH或卤素；R6为氢或(C1-4)烷基，可选地取代(C1-4)烷氧基、OH或卤素；或R6与R7一起形成4-7成员饱和杂环环，可选地包含进一步从O和S选择的杂原子；R7与R6一起形成4-7成员饱和杂环环，可选地包含进一步从O和S选择的杂原子；或R7为H、(C1-4)烷基或(C3-5)环烷基，烷基基团可选地取代OH、卤素或(C1-4)烷氧基；或其药学上可接受的盐。本发明还涉及包含所述三环1-[(indol-3-yl)carbonyl]哌嗪衍生物的制药组合物，并且涉及使用这些衍生物治疗疼痛，例如围手术期疼痛、慢性疼痛、神经性疼痛、癌症疼痛以及与多发性硬化相关的疼痛和痉挛。
• (Indol-3-yl) heterocycle derivatives as agonists of the cannabinoid CB1 receptor
  申请人：N.V. Organon

  公开号：US07700634B2

  公开（公告）日：2010-04-20

  Disclosed herein are indole derivatives of the formula (I) wherein each of the substitutents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the indole derivatives and use of the derivatives for the treatment of pain.

  本文揭示了式(I)的吲哚衍生物，其中每个取代基的定义如规范和权利要求所述。还揭示了含有吲哚衍生物的药物组合物以及利用这些衍生物治疗疼痛的用途。