6-fluoro-N-methyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine | 1357348-09-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 6-fluoro-N-methyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine
• 英文别名: 6’-fluoro-4’,9’-dihydro-N-methyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amine；1r,4r-6'-fluoro-N-methyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4b]indol]-4-amine；1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole (trans)；(1r,4r)-6'-fluoro-N-methyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine
• CAS: 1357348-09-4
• 化学式: C₂₃H₂₅FN₂O
• 分子量: 364.463
• InChiKey: AMXGKMSRYLZAEO-YHBQERECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.76
• 重原子数：
  27.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  37.05
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  6-fluoro-N-methyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine 、 柠檬酸 以 乙醇 为溶剂， 反应 12.0h， 生成 6’-fluoro-4’,9’-dihydro-N-methyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amine hemicitrate
  参考文献：
  名称：

  Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

  摘要：

  In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

  DOI：

  10.1021/ml500117c
• 作为产物：
  描述：

  8-methylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile 在 盐酸 、 三氟甲磺酸 、 水 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 生成 6-fluoro-N-methyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine
  参考文献：
  名称：

  Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

  摘要：

  In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

  DOI：

  10.1021/ml500117c

文献信息

• Process for the preparation of (1r,4r)-6'-fluoro-(N,N-dimethyl- and N-methyl)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine
  申请人：Gruenenthal GmbH

  公开号：US20130150590A1

  公开（公告）日：2013-06-13

  A process for the preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine and (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]-indol]-4-amine or physiologically acceptable acid addition salts thereof.

  制备(1r,4r)-6′-氟-N,N-二甲基-4-苯基-4′,9′-二氢-3′H-螺[环己烷-1,1′-吡喃[3,4b]吲哚]-4-胺和(1r,4r)-6′-氟-N-甲基-4-苯基-4′,9′-二氢-3′H-螺[环己烷-1,1′-吡喃[3,4b]-吲哚]-4-胺或其生理上可接受的酸盐的制备方法。
• [EN] PROCESS FOR THE PREPARATION OF (1R,4R)-6'-FLUORO-(N,N-DIMETHYL- AND N-METHYL)-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO-[3,4,B]INDOL]-4-AMINE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE (1R,4R)-6'-FLUORO-(N,N-DIMÉTHYL- ET N-MÉTHYL)- 4-PHÉNYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL]- 4-AMINE
  申请人：GRUENENTHAL GMBH

  公开号：WO2013087589A1

  公开（公告）日：2013-06-20

  The present invention relates to a process for the preparation of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4b]indol]-4-amine and (1r,4r)-6'-fluoro-N-methyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4b]- indol]-4-amine or physiologically acceptable acid addition salts thereof.

  本发明涉及一种制备(1r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺和(1r,4r)-6'-氟-N-甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺或其生理上可接受的酸盐的过程。
• PHARMACEUTICAL DOSAGE FORM COMPRISING 6'-FLUORO-(N-METHYL- OR N,N-DIMETHYL-)-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4,B]INDOL]-4-AMINE FOR THE TREATMENT OF NOCICEPTIVE PAIN
  申请人：Grünenthal GmbH

  公开号：EP3459533A1

  公开（公告）日：2019-03-27

  The invention relates to a pharmaceutical dosage form for administration once daily, which contains 6'-fluoro-(N-methyl- or N,N-dimethyl)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof, for use in the treatment of nociceptive pain, preferably acute or chronic nociceptive pain.

  本发明涉及一种每日给药一次的药物剂型，其中含有6'-氟-(N-甲基或N,N-二甲基)-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃并[3,4,b]吲哚]-4-胺或其生理学上可接受的盐，用于治疗痛觉疼痛，最好是急性或慢性痛觉疼痛。
• CRYSTALLINE FORMS OF TRANS-6'-FLUORO-N-METHYL-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL]-4-AMINE
  申请人：Grünenthal GmbH

  公开号：EP3613747A1

  公开（公告）日：2020-02-26

  The present invention relates to a crystalline form of the compound according to formula (I) having at least one X-ray powder diffraction peak (CuKα radiation) in the range of from 9.3±0.2 to 11.3±0.2 (2θ) and/or 16.0±0.2 to 18.0±0.2 (2θ) and/or 17.0±0.2 to 19.5±0.2 (2θ) and/or 18.5±0.2 to 21.0±0.2 (2θ).

  本发明涉及符合式（I）的化合物结晶形式 具有至少一个 X 射线粉末衍射峰（CuKα 辐射），其范围为 9.3±0.2 至 11.3±0.2 (2θ) 和/或 16.0±0.2 至 18.0±0.2 (2θ) 和/或 17.0±0.2 至 19.5±0.2 (2θ) 和/或 18.5±0.2 至 21.0±0.2 (2θ)。
• Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
  申请人：Gruenenthal GmbH

  公开号：US10912763B2

  公开（公告）日：2021-02-09

  A pharmaceutical dosage form for administration twice daily, once daily or less frequently, which contains 6′-fluoro-(N-methyl- or N,N-dimethyl)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof.

  一种每日给药两次、一次或更少次数的药物剂型，它含有 6′-氟-(N-甲基或 N,N-二甲基)-4-苯基-4′,9′-二氢-3′H-螺[环己烷-1,1′-吡喃并[3,4,b]吲哚]-4-胺或其生理上可接受的盐。