(R,S)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-on | 120635-47-4

• 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: (R,S)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-on
• 英文别名: 4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-one；4H-pyrido(3,2,1-jk)carbazol-11(8H)-one, 5,6,9,10-tetrahydro-10-((2-methyl-1H-imidazol-1-yl)methyl)-；5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one；cilansetron；5-HT3 antagonist 3；12-[(2-methylimidazol-1-yl)methyl]-1-azatetracyclo[7.6.1.05,16.010,15]hexadeca-5(16),6,8,10(15)-tetraen-11-one
• CAS: 120635-47-4
• 化学式: C₂₀H₂₁N₃O
• 分子量: 319.406
• InChiKey: NCNFDKWULDWJDS-UHFFFAOYSA-N

物化性质

• 沸点：
  600.6±50.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  39.8
• 氢给体数：
  0
• 氢受体数：
  2

制备方法与用途

生物活性

生物活性方面，5-HT3 antagonist 3（Compound 15b）是一种高亲和力的 5-HT3 受体拮抗剂。它能够结合到大鼠脑皮质膜中的 5-HT3 受体，其Ki 值为 0.25 nM。

靶点

| 5-HT₃ Receptor | 0.25 nM (Ki) |

体外研究

血清素（5-HT）参与多种生理和病理过程，能够与不同类型的膜受体相互作用。

反应信息

• 作为反应物：
  描述：

  (R,S)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-on 生成 d-10-<(2-methyl-1H-imidazol-1-yl)methyl>-5,6,8,9,10,11-hexahydro-4H-pyrido<3,2,1-jk>carbazol-11-one hydrochloride
  参考文献：
  名称：

  Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annulated indole derivatives. 1

  摘要：

  On the basis of the structures of ondansetron and GR 65,630, its ring-opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5-HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (K(i) = 0. 19 nM), a weak affinity for sigma-receptors (K(i) = 340 nM), muscarine M1 receptors (K(i) = 910 nM), and 5-HT4 receptors (K(i_ = 960 nM) and no affinity (K(i) greater-than-or-equal-to 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.

  DOI：

  10.1021/jm00075a026
• 作为产物：
  描述：

  2-甲基咪唑 、 d,l-10-<(dimethylamino)methyl>-5,6,8,9,10,11-hexahydro-4H-pyrido<3,2,1-jk>carbazol-11-one hydrochloride 在 2-甲基咪唑 作用下， 以87的产率得到(R,S)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-on
  参考文献：
  名称：

  Process for the preparation of enantiomerically pure imidazolyl compounds

  摘要：

  本发明涉及一种制备对映纯的咪唑基化合物的方法，其通式为：其中：n为0或1；m为1或2；R1为氢、甲基或乙基；C*表示手性中心；以及其药学上可接受的酸加成盐。该方法包括：a)将光学活性形式的羧酸加入到上述化合物I的外消旋混合物的溶液中，然后从富含一种对映体的化合物I的晶体酸加成盐中分离出来，从富含另一种对映体的母液中分离出来；b)当富含不希望的对映体的晶体酸加成盐时，通过将母液中的对映体混合物与所述光学活性羧酸分离开来，然后将获得的化合物I的异构体混合物的溶液中加入所述羧酸的外消旋混合物，然后从富含所需对映体的化合物I的晶体酸加成盐中分离出来；c)可选地，将产物重结晶，直到获得所需的对映纯度；然后d)将所需对映体的酸加成盐转化为所需的对映纯咪唑基化合物I或其药学上可接受的酸加成盐，其特征在于使用丙氨酸作为所述羧酸。本发明还涉及一种消旋化和该式I化合物和D-丙氨酸的新酸加成盐的方法。

  公开号：

  EP0768309A1

文献信息

• [EN] NOVEL PROCESS FOR THE PREPARATION OF IMIDAZOLYL COMPOUNDS<br/>[FR] PROCEDE DE PREPARATION DE COMPOSES IMIDAZOLYLE
  申请人：SOLVAY PHARM BV

  公开号：WO2004046116A1

  公开（公告）日：2004-06-03

  The present invention relates to a method for the preparation of an imidazolyl compound of the general formula (I), wherein: Ra and Rb each separately are (C1-C6)alkyl, (C1-C6)alkoxyalkyl, optionally substituted aryl or heteroaryl; or wherein Ra and Rb together form a further homocyclic or heterocyclic system comprising one or more rings; Ra’ and Rb’ each are hydrogen or together form a carbon-carbon double bond, said carbon-carbon double bond optionally being part of an aromatic system; Rc is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1,-C6)alkoxyalkyl or halogen; Rd is hydrogen or (C1-C4)aIkyl; Re is hydrogen or (C1-C4)aIkyl; m is 1 or 2; and R1, is hydrogen or (C1-C4)aIkyl; as well as its acid addition salt;characterized in that a compound of the general formula (II) is reacted with a compound of the formula (III), wherein: R is a hydrogen, a (C1-C4)alkyl group optionally substituted with a hydroxygroup or an optionally substituted aryl group, R', R', R'' and R'' each individually are a hydrogen or a (C1-C4)aIkyl group; followed by a reaction with a compound of the formula (IV), wherein R1, Rd and Re have the meanings defined above; and optionally followed by a reaction with a suitable acid. De method according to the present invention is especially useful for the preparation of ondansetron and cilansetron.

  本发明涉及一种制备通式（I）的咪唑基化合物的方法，其中：Ra和Rb各自分别为（C1-C6）烷基，（C1-C6）烷氧基烷基，可选择取代的芳基或杂环芳基；或者Ra和Rb一起形成进一步的同环或异环系统，包括一个或多个环；Ra'和Rb'各自为氢或一起形成碳-碳双键，所述碳-碳双键可选择地是芳香系统的一部分；Rc为氢，（C1-C6）烷基，（C1-C6）烷氧基，（C1-C6）烷氧基烷基或卤素；Rd为氢或（C1-C4）烷基；Re为氢或（C1-C4）烷基；m为1或2；R1为氢或（C1-C4）烷基；以及其酸盐；其特征在于通式（II）的化合物与通式（III）的化合物发生反应，其中：R为氢，（C1-C4）烷基，可选择地取代羟基或可选择取代的芳基的基团，R'、R''、R'''和R''''各自为氢或（C1-C4）烷基；随后与通式（IV）的化合物发生反应，其中R1、Rd和Re具有上述定义的含义；并可随后与适当的酸发生反应。根据本发明的方法特别适用于制备昂丹司特龙和西兰司特龙。
• 4-hydroxy derivatives of 5,6,9,10-tetrahydro-10-((2-methyl-1h-imidazol-1-yl)methyl)-4h-pyrido-(3,2,1-jk)-carbazol-11(8h)-one
  申请人：Solvay Pharmaceuticals GmbH

  公开号：EP1424337A1

  公开（公告）日：2004-06-02

  The present invention relates to novel 4-hydroxy derivatives of 5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido-[3,2,1-jk]-carbazol-11(8H)-one with 5-HT3-receptor antagonistic activity. Furthermore, the invention relates to a process for the preparation of the novel derivatives.

  本发明涉及具有5-HT3受体拮抗活性的新型5,6,9,10-四氢-10-[(2-甲基-1H-咪唑-1-基)甲基]-4H-吡啶并[3,2,1-jk]-咔唑-11(8H)-酮的4-羟基衍生物。此外，本发明还涉及一种制备这种新型衍生物的方法。
• Combination treatment for depression
  申请人：——

  公开号：US20020107244A1

  公开（公告）日：2002-08-08

  The present invention relates to a method of treating depression or anxiety in a mammal, including a human, by administering to the mammal a 5-HT3 receptor antagonist in combination with an SRI antidepressant agent with improvement in sexual function and/or reduction in gastro-intestinal side effects. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5-HT3 receptor antagonist and an SRI antidepressant.

  本发明涉及一种治疗哺乳动物，包括人类的抑郁症或焦虑症的方法，通过给哺乳动物同时注射5-HT3受体拮抗剂和SRI抗抑郁剂来改善性功能和/或减少胃肠道副作用。它还涉及含有药用载体、5-HT3受体拮抗剂和SRI抗抑郁剂的制药组合物。
• New anellated indole derivatives
  申请人：Duphar International Research B.V.

  公开号：US04939136A1

  公开（公告）日：1990-07-03

  The invention relates to new anellated indole derivatives of general formula 2, ##STR1## wherein p1 R.sub.0 is alkyl or alkoxy having 1-4 C-atoms, phenylalkoxy having 1-3 C-atoms in the alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or a group R.sub.7 S(O).sub.p, wherein R.sub.7 is alkyl having 1-4 C-atoms and p has the value 0, 1 or 2, or R.sub.0 is a group R.sub.8 R.sub.9 N, R.sub.8 R.sub.9 N--CO--CH.sub.2 -- or R.sub.8 R.sub.9 --N--CO wherein R.sub.8 and R.sub.9 are hydrogen or alkyl having 1-4 C-atoms or R.sub.8 R.sub.9 N forms a saturated 5- or 6-membered ring and n has the value 0, 1 or 2, Z together with the carbon atom and nitrogen atom to which Z is bound and the intermediate carbon atom, forms a heterocyclic group consisting of 5-8 ring atoms, in which, in addition to the nitrogen atom already present, a --CO--group or a second hetero atom from the group N, O, S, S-O or SO.sub.2 may be present, which ring may be substituted with 1-3 alkyl groups having 1-4 C-atoms, a phenyl group or a spiroalkyl group (C.sub.2 -C.sub.5), or which ring may be anellated with a saturated or non-saturated carbocyclic or heterocyclic ring which consists of 5- or 6-ring atoms and which may be substituted with halogen, alkyl or alkoxy having 1-4 C-atoms, and m has the values 1-5, one of the groups R.sub.2, R.sub.3 and R.sub.4 is hydrogen, alkyl having 1-6 C-atoms, cycloalkyl having 3-7 C-atoms, alkenyl having 2-6 C-atoms or phenylalkyl having 1-3 C-atoms in the alkyl group, and the two other groups independently of each other are hydrogen or alkyl having 1-6 C-atoms, and the pharmaceutically acceptable acid addition salts thereof. These compounds are strong and selective antagonists of "neuronal" 5-hydroxytryptamine (5-HT) receptors, and have a considerably longer-lasting effect and lower toxicity in comparison with related known compounds.

  本发明涉及一种新的环化吲哚衍生物，其通式为2，其中p1R0是具有1-4个C原子的烷基或烷氧基，具有1-3个C原子的苯基烷氧基，羟基，卤素，三氟甲基，三氟甲氧基，三氟甲基硫基或R7S（O）p基团，其中R7是具有1-4个C原子的烷基，p的值为0、1或2，或R0是R8R9N基团，R8R9N-CO-CH2-基团或R8R9-N-CO基团，其中R8和R9是氢或具有1-4个C原子的烷基，或R8R9N形成饱和的5-或6-成员环且n的值为0、1或2，Z与其所结合的碳原子和氮原子以及中间的碳原子一起形成由5-8个环原子组成的杂环基团，其中除了已经存在的氮原子外，还可以存在一个-CO-基团或来自N、O、S、S-O或SO2的第二个杂原子，该环可以用具有1-4个C原子的1-3个烷基基团，苯基或螺环烷基（C2-C5）取代，或者该环可以与由5-或6个环原子组成的饱和或非饱和碳环或杂环环并联，该环可以用卤素、具有1-4个C原子的烷基或烷氧基取代，m的值为1-5，R2、R3和R4中的一个是氢，具有1-6个C原子的烷基，具有3-7个C原子的环烷基，具有2-6个C原子的烯基或具有1-3个C原子的苯基烷基，而另外两个基团独立地是氢或具有1-6个C原子的烷基，并且其药学上可接受的酸盐。这些化合物是“神经”5-羟色胺（5-HT）受体的强效和选择性拮抗剂，并且与相关已知化合物相比，具有更长的持续作用时间和更低的毒性。
• NEUROGENESIS BY MUSCARINIC RECEPTOR MODULATION
  申请人：Barlow Carrolee

  公开号：US20070049576A1

  公开（公告）日：2007-03-01

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  该即时披露描述了通过刺激或增加神经发生来治疗中枢神经系统和外周神经系统的疾病和病症的方法。该披露包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经生成剂结合以刺激或激活新神经细胞的形成。