(-)-4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-1,2,3,4,4a,9b-hexahydro-γ-carboline | 75738-70-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (-)-4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-1,2,3,4,4a,9b-hexahydro-γ-carboline
• 英文别名: trans-8-Fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole；(4aR,9bR)-8-fluoro-5-(4-fluorophenyl)-1,2,3,4,4a,9b-hexahydropyrido[4,3-b]indole
• CAS: 75738-70-4
• 化学式: C₁₇H₁₆F₂N₂
• 分子量: 286.324
• InChiKey: DCTSSEIHVASKBC-DOTOQJQBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  15.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (-)-4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-1,2,3,4,4a,9b-hexahydro-γ-carboline 在 lithium aluminium tetrahydride 、 sodium carbonate 、 N,N'-二环己基碳二亚胺 、 potassium iodide 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 92.5h， 生成 4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-2-<2-(3-hydroxy-2-phenylpropionamido)ethyl>-1,2,3,4,4a,9b-trans-hexahydro-γ-carboline
  参考文献：
  名称：

  Neuroleptic activity of chiral trans-hexahydro-.gamma.-carbolines

  摘要：

  A series of trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5, 9b-hexahydro-1H-pyrido[4,3-b]indoles with various N-2 substituents has been prepared and tested for neuroleptic activity [( 3H]spiroperidol binding and amphetamine antagonism). Several members of this series showed exceptional in vivo potency, especially the hydantoin derivatives 27-30. Resolution into the enantiomers showed that neuroleptic activity is associated with the 4aS,9bS absolute configuration. These rigid neuroleptics have been correlated with other rigid neuroleptics [(+)-dexclamol, Ro 22-1319] and can serve to further define the topography of the dopamine receptor.

  DOI：

  10.1021/jm00151a002
• 作为产物：
  描述：

  trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride 、 氯甲酸乙酯 、 、 生成 (-)-4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-1,2,3,4,4a,9b-hexahydro-γ-carboline
  参考文献：
  名称：

  2-Substitute

  摘要：

  式(I)中的2-取代-5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚及其药学上可接受的盐，其中4a位和9b位的氢原子相对构型为反式，5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚基团为右旋性；X1和Y1相同或不同，分别为氢或氟；Z1为氢、氟或甲氧基；M为从以下组中选择的成员：##STR2## 其混合物和C.dbd.O，n为3或4；它们作为镇静剂的用途，包含它们的制药组合物以及它们的制备过程。

  公开号：

  US04224329A1

文献信息

• 2-Substituted-trans-5-ar
  申请人：Pfizer Inc.

  公开号：US04252812A1

  公开（公告）日：1981-02-24

  2-Substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the formula (I): ##STR1## and the pharmaceutically-acceptable salts thereof, wherein the hydrogen atoms in the 4a position and 9b positions are in a trans relationship to each other and the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety is dextrorotatory; X.sub.1 and Y.sub.1 are the same or different and are each hydrogen or fluoro; Z.sub.1 is hydrogen, fluoro or methoxy; M is a member selected from the group consisting of ##STR2## a mixture thereof and C=0 and n is 3 or 4; their use as tranquilizing agents, pharmaceutical compositions containing them and a process for their production.

  式(I)的2-取代-5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚及其药学上可接受的盐，其中4a位和9b位的氢原子相对构型为反式，5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚基团为右旋性；X.sub.1和Y.sub.1相同或不同，分别为氢或氟；Z.sub.1为氢、氟或甲氧基；M为从以下组中选择的成员之一：##STR2## 其混合物和C=0，n为3或4；它们作为镇静剂的用途，包含它们的制药组合物以及它们的制备方法。
• 5-(4-Fluorophenyl)tetrahydro-2-furanol
  申请人：Pfizer Inc.

  公开号：US04277404A1

  公开（公告）日：1981-07-07

  2-Substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the formula (I): ##STR1## and the pharmaceutically-acceptable salts thereof, wherein the hydrogen atoms in the 4a position and 9b positions are in a trans relationship to each other and the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety is dextrorotatory; X.sub.1 and Y.sub.1 are the same or different and are each hydrogen or fluoro; Z.sub.1 is hydrogen, fluoro or methoxy; M is a member selected from the group consisting of ##STR2## a mixture thereof and C.dbd.O and n is 3 or 4; their use as tranquilizing agents, pharmaceutical compositions containing them and a process for their production.

  公式（I）的2-取代-5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚及其药学上可接受的盐，其中4a位和9b位的氢原子相对于彼此处于反式关系，而5-芳基-2,3,4,4a,5,9b-六氢-1H-吡啶[4,3-b]吲哚基团为右旋性；X1和Y1相同或不同，均为氢或氟；Z1为氢、氟或甲氧基；M为从以下组中选择的成员：##STR2## 其混合物和C.dbd.O，n为3或4；其作为镇静剂的用途，包含它们的制药组合物以及它们的制备过程。
• Hexahydro-trans- and tetrahydropyridoindole neuroleptic agents
  申请人：PFIZER INC.

  公开号：EP0060610A1

  公开（公告）日：1982-09-22

  Derivatives of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and of (+)enantiomeric, mixtures of (+) and (-)-enantiomeric or (±)racemic 2,3,4,4a,5,9b-hexahydro-4a, 9b-trans-1H-pyrido[4,3-b]indole, substituted at the 5-position with an aryl group and at the 2-position with a carbonylaminoalkyl group or an aminoalkyl group, are neuroleptic agents useful in the treatment of certain psychoses and neuroses.

  2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚和(+)对映体的衍生物、(+)和(-)对映体的混合物或(±)外消旋2,3,4,4a,5,9b-六氢-4a,9b-反式-1H-吡啶并[4,3-b]吲哚的衍生物，在5位被芳基取代，在2位被羰基氨基烷基或氨基烷基取代，是治疗某些精神病和神经官能症的神经抑制剂。
• Neuroleptics from the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 3. Carboxamidoalkyl derivatives
  作者：Willard M. Welch、Charles A. Harbert、Reinhard Sarges、Albert Weissman、B. Kenneth Koe

  DOI：10.1021/jm00160a053

  日期：1986.10

  Substitution of position 2 of the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole nucleus with omega-carboxamidoalkyl substituents leads to compounds with exceedingly potent neuroleptic activity in in vitro and in vivo models. Although duration of activity is not as long as that of the analogous 4-hydroxy-4-(4-fluorophenyl)butyl derivatives reported previously, the absolute potency in vivo is greater. The ability of these compounds to bind with great affinity to dopamine (DA) receptors further defines the nature of the DA receptor auxiliary binding site as a hydrogen-bond donating site in addition to or instead of a lipophilic site as has been previously proposed.
• Neuroleptics from the 4a,9b-cis- and 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole series. 2
  作者：Willard M. Welch、Charles A. Harbert、Albert Weissman、B. Kenneth Koe

  DOI：10.1021/jm00160a050

  日期：1986.10

  Compounds derived from 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b]indole are consistently efficacious in displacing [3H]spiroperidol from striatal dopamine receptors in vitro. Derivatives bearing substituents at position 2, particularly those derived from butyrophenone moieties, are exceptionally potent in vivo. Compounds from the corresponding 4a,9b-cis series are substantially less potent in both in vivo and in vitro assays of neuroleptic activity. Although the cis and trans derivatives have, in some conformations, similar basic nitrogen atom to aromatic ring separations of about 5.1 A, the distance at which the basic nitrogen atom lies above or below the plane of the aromatic ring differs substantially between the two series. Consideration of these results in terms of this and earlier work indicates that the out-of-plane distance for the basic nitrogen in neuroleptic molecules may range from about 0 to about 0.90 A but may be optimized at about 0.55 A.