(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。
• Process for the preparation of enantiomerically pure imidazolyl compounds
  申请人：Duphar International Research B.V.

  公开号：US06365743B1

  公开（公告）日：2002-04-02

  The invention relates to a method for the preparation of an enantiomerically pure imidazolyl compound of the general formula wherein: n is 0 or 1; m is 1 or 2; R1 is hydrogen, methyl or ethyl; and C* denotes a chiral center; as well as its pharmaceutically acceptable acid addition salt. The invention further relates to a method of racemization and to a new acid addition salt of this formula I compound and D-pyroglutamic acid and to the hydrochloride monohydrate of the compound of formula I.

  本发明涉及一种制备手性纯的咪唑基化合物的方法，该化合物的一般式如下：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盐。本发明还涉及一种消旋化的方法，以及该式I化合物与D-丙氨酸盐酸盐的新酸加盐以及式I化合物的盐酸单水合物的方法。
• 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。