2'-(1-methyl-1H-indol-3-yl)spiro(1-azabicyclo<2.2.2>octane-3,5'(4'H)-oxazole) | 128199-93-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 2'-(1-methyl-1H-indol-3-yl)spiro(1-azabicyclo<2.2.2>octane-3,5'(4'H)-oxazole)
• 英文别名: 2'-(1-Methylindol-3-yl)-spiro-<1-azabicyclo/2.2.2/octane-3,5'(4'H)-oxasole>；[2'-(methyl-1H-indol-3-yl)]spiro(1-azabicyclo[2.2.2]octane-3,5'(4'H)-oxazole)；2'-(1-Methylindol-3-yl)-spiro-(1-azabicyclo/2.2.2/octane-3,5'(4'H)-oxasole)；5-HT3 antagonist 2；2'-(1-methylindol-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-4H-1,3-oxazole]
• CAS: 128199-93-9；128200-28-2；128200-30-6
• 化学式: C₁₈H₂₁N₃O
• 分子量: 295.384
• InChiKey: GJZYDYYJSGXPCE-UHFFFAOYSA-N

物化性质

• 沸点：
  490.4±35.0 °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
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  29.8
• 氢给体数：
  0
• 氢受体数：
  3

制备方法与用途

生物活性

5-HT3 antagonist 2 是 5-HT3 受体的拮抗剂。

靶点

| 5-HT₃ Receptor |

体外研究

5-HT3 antagonist 2 来自参考化合物 21k。

反应信息

• 作为反应物：
  描述：

  2'-(1-methyl-1H-indol-3-yl)spiro(1-azabicyclo<2.2.2>octane-3,5'(4'H)-oxazole) 生成 (-)-2'-(1-methyl-1H-indol-3-yl)spiro(1-azabicyclo<2.2.2>octane-3,5'(4'H)-oxazole)
  参考文献：
  名称：

  Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)oxazoles)

  摘要：

  The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.

  DOI：

  10.1021/jm00084a007
• 作为产物：
  描述：

  3-氰基-1-甲基吲哚 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 48.0h， 生成 2'-(1-methyl-1H-indol-3-yl)spiro(1-azabicyclo<2.2.2>octane-3,5'(4'H)-oxazole)
  参考文献：
  名称：

  Swain, Christopher J.; Kneen, Clare; Herbert, Richard, Journal of the Chemical Society. Perkin transactions I, 1990, # 11, p. 3183 - 3186

  摘要：

  DOI：

文献信息

• Spirocyclic compounds incorporating five-membered rings with two
  申请人：Merck Sharp & Dohme Limited

  公开号：US04940703A1

  公开（公告）日：1990-07-10

  The present invention provides a compound of formula I or a salt or prodrug thereof: ##STR1## wherein the dotted line represents an optional chemical bond in one of the two possible positions; A represents a group of formula II: ##STR2## in which R.sup.1 represents hydrogen, hydroxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, benzyloxy, hydroxy (C.sub.1-6)alkyl, halogen, amino, cyano, nitro, --CONR.sup.6 R.sup.7 or --SO.sub.2 NR.sup.6 R.sup.7, in which R.sup.6 and R.sup.7 independently represent hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sup.2 represents hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkylcarbonyl; V represents nitrogen, --CH or --C--; and W represents oxygen, sulphur or --NR.sup.8, in which R.sup.8 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; two of X, Y and Z are the same or different and each represents oxygen, sulphur or nitrogen; and the remaining group X, Y or Z is carbon, or Y is carbonyl (C=O); and Q is the residue of an azacyclic or azabicyclic ring system; which compounds are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; movement disorders; and presenile and senile dementia.

  本发明提供了公式I的化合物或其盐或前药：其中虚线表示两种可能位置中的一个可选化学键；A代表公式II的一个基团：其中R.sup.1代表氢、羟基、C.sub.1-6烷基、C.sub.2-6烯基、C.sub.2-6炔基、C.sub.1-6烷氧基、苄氧基、羟基(C.sub.1-6)烷基、卤素、氨基、氰基、硝基、-CONR.sup.6 R.sup.7或-SO.sub.2 NR.sup.6 R.sup.7，其中R.sup.6和R.sup.7独立地代表氢、卤素、C.sub.1-6烷基、C.sub.2-6烯基或C.sub.2-6炔基；R.sup.2代表氢、卤素、C.sub.1-6烷基、C.sub.1-6烷氧基或C.sub.1-6烷基羰基；V代表氮、-CH或-C-；W代表氧、硫或-NR.sup.8，其中R.sup.8代表氢、C.sub.1-6烷基、C.sub.2-6烯基或C.sub.2-6炔基；X、Y和Z中的两个相同或不同，每个代表氧、硫或氮；剩余的X、Y或Z是碳，或Y是羰基(C=O)；Q是氮杂环或氮杂双环环系统的残基；这些化合物在治疗精神分裂症（如精神分裂症和狂躁症）；焦虑症；酒精或药物戒断或依赖；疼痛；胃排空延迟；胃功能障碍（如消化不良、消化性溃疡、反流性食道炎和胀气）；偏头痛、恶心和呕吐；运动障碍；以及老年性痴呆症和老年性痴呆症方面具有用处。
• Spirocyclic compounds incorporating five-membered rings with two heteroatoms
  申请人：MERCK SHARP & DOHME LTD.

  公开号：EP0337547A1

  公开（公告）日：1989-10-18

  The present invention provides a compound of formula I or a salt or prodrug thereof: wherein the dotted line represents an optional chemical bond in one of the two possible positions; A represents a group of formula II: in which R1 represents hydrogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, benzyloxy, hydroxy(C1-6)alkyl, halogen, amino, cyano, nitro, -CONR6R7 or -S02NR6R7, in which R6 and R7 independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R2 represents hydrogen, halogen, C1 -6 alkyl, C1 -6 alkoxy or C1-6 alkylcarbonyl; V represents nitrogen, -CH or -C-; and W represents oxygen, sulphur or -NR8, in which R8 represents hydrogen, C, -6 alkyl, C2-6 alkenyl or C2-6 alkynyl; two of X, Y and Z are the same or different and each represents oxygen, sulphur or nitrogen; and the remaining group X, Y or Z is carbon, or Y is carbonyl (C = 0); and Q is the residue of an azacyclic or azabicyclic ring system; which compounds are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or,dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; moyement disorders; and presenile and senile dementia,

  本发明提供一种式 I 的化合物或其盐或原药： 其中虚线代表两个可能位置之一的任选化学键；A 代表式 II 的基团： 其中 R1 代表氢、羟基、C1-6 烷基、C2-6 烯基、C2-6 烷炔基、C1-6 烷氧基、苄氧基、羟基（C1-6）烷基、卤素、氨基、氰基、硝基、-CONR6R7 或 -S02NR6R7，其中 R6 和 R7 独立地代表氢、C1-6 烷基、C2-6 烯基或 C2-6 烷炔基； R2 代表氢、卤素、C1-6 烷基、C1-6 烷氧基或 C1-6 烷基羰基； V 代表氮、-CH 或-C-；以及 W 代表氧、硫或-NR8，其中 R8 代表氢、C, -6 烷基、C2-6 烯基或 C2-6 烷炔基； X、Y 和 Z 中的两个相同或不同，各自代表氧、硫或氮；其余基团 X、Y 或 Z 为碳，或 Y 为羰基（C = 0）；以及 Q 是氮杂环或氮双环环系统的残基；这些化合物可用于治疗精神病（如精神分裂症和躁狂症）、焦虑症、酒精或药物戒断或依赖症、疼痛、胃淤血、胃功能障碍（如消化不良、消化性溃疡、反流性食管炎和胀气）、偏头痛、恶心和呕吐、精神错乱以及先天性和老年性痴呆症、
• Use of 5-hydroxytryptamine-antagonists in the treatment of mental disorders originating in childhood
  申请人：GLAXO GROUP LIMITED

  公开号：EP0450757A2

  公开（公告）日：1991-10-09

  The invention relates to the use of a compound which acts as an antagonist of 5-HT at 5-HT₃ receptors in the treatment of autism or another disorder originating in childhood in which there is mental retardation.

  本发明涉及一种在 5-HT₃ 受体上作为 5-HT 拮抗剂的化合物在治疗自闭症或另一种源于儿童期的精神发育迟滞疾病中的应用。
• SWAIN, CHRISTOPHER J.;KNEEN, CLARE;HERBERT, RICHARD;BAKER, RAYMOND, J. CHEM. SOC. PERKIN TRANS. PT 1,(1990) N1, C. 3183-3186
  作者：SWAIN, CHRISTOPHER J.、KNEEN, CLARE、HERBERT, RICHARD、BAKER, RAYMOND

  DOI：——

  日期：——
• US4940703A
  申请人：——

  公开号：US4940703A

  公开（公告）日：1990-07-10