(3Z)-3-(3,4-dihydro-2H-quinolin-1-ylimino)cyclohexan-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (3Z)-3-(3,4-dihydro-2H-quinolin-1-ylimino)cyclohexan-1-one
• 化学式: C₁₅H₁₈N₂O
• 分子量: 242.321
• InChiKey: MXQNTTFANZXYBY-SSZFMOIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  32.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3Z)-3-(3,4-dihydro-2H-quinolin-1-ylimino)cyclohexan-1-one 以60的产率得到5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one
  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
• 作为产物：
  描述：

  1,2,3,4-四氢喹啉 在 lithium aluminium tetrahydride 、 硫酸 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (3Z)-3-(3,4-dihydro-2H-quinolin-1-ylimino)cyclohexan-1-one
  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

文献信息

• 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。
• Process for the preparation of enantiomerically pure imidazolyl compounds
  申请人：DUPHAR INTERNATIONAL RESEARCH B.V

  公开号：EP0768309A1

  公开（公告）日：1997-04-16

  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 centre; as well as its pharmaceutically acceptable acid addition salt; by a) adding a carboxylic acid in an optically active form to a solution of a racemic mixture of the above compound I, followed by separation of the crystallized acid addition salt of said mixture of enantiomers of compound I enriched in one enantiomer, from the mother liquor enriched in the other enantiomer b) when the crystallized acid addition salt is enriched in the undesired enantiomer, by then separating the mixture of enantiomers in the mother liquor from said optically active carboxylic acid, followed by addition of a racemic mixture of said carboxylic acid to a solution of the obtained mixture of isomers of I, and by separation of the crystallized acid addition salt of said mixture, enriched in the desired enantiomer, from the mother liquor, and (c) optionally recrystallizing the product until the desired enantiomeric purity is obtained, and by then (d) converting this acid-addition salt of the desired enantiomer to the desired enantiomerically pure imidazolyl compound of the general formula I or to its pharmaceutically acceptable acid addition salt,    characterized in that pyroglutamic acid is used as said carboxylic acid. The invention further relates to a method of racemisation and to a new acid addition salt of this formula I compound and D-pyroglutamic acid.

  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。
• J. Med. Chem. 1993, 36, 3693-3699
  作者：

  DOI：——

  日期：——
• Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annulated indole derivatives. 1
  作者：Ineke van Wijngaarden、Derk Hamminga、Rolf van Hes、Piet J. Standaar、Jacobus Tipker、Martin T. M. Tulp、Frans Mol、Berend Olivier、Adriaan de Jonge

  DOI：10.1021/jm00075a026

  日期：1993.11

  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.
• Drugs Fut. 1999, 24, 475
  作者：

  DOI：——

  日期：——