3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-2-methylbenzothiophene | 143203-66-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: 3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-2-methylbenzothiophene
• 英文别名: N-(1-azabicyclo[2.2.2]octan-3-yl)-2-methyl-1-benzothiophene-3-carboxamide
• CAS: 143203-66-1
• 化学式: C₁₇H₂₀N₂OS
• 分子量: 300.425
• InChiKey: VEDHJTVDBIOHFN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  60.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-2-methylbenzothiophene 在 盐酸 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 1.0h， 生成 2-(1-azabicyclo<2.2.2>oct-3-yl)-1,2-dihydrobenzothieno<3,2-c>pyridin-1-one
  参考文献：
  名称：

  2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

  摘要：

  Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pK(i) values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pK(i) 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 mug/kg iv), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

  DOI：

  10.1021/jm00070a008
• 作为产物：
  描述：

  2-methylbenzo[b]thiophene-3-carboxylic acid 在 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 乙酸乙酯 、 甲苯 为溶剂， 反应 20.0h， 生成 3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-2-methylbenzothiophene
  参考文献：
  名称：

  2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

  摘要：

  Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pK(i) values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pK(i) 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 mug/kg iv), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

  DOI：

  10.1021/jm00070a008

文献信息

• New tricyclic compounds
  申请人：SYNTEX (U.S.A.) INC.

  公开号：EP0485962A2

  公开（公告）日：1992-05-20

  5-HT receptor antagonist compounds of Formula I in which: the dashed line denotes an optional bond; X and Y are independently selected from hydrogen, halogen, hydroxy, lower alkoxy, benzyloxy, lower alkyl, nitro, amino, aminocarbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; Z is -O-, -S- or -N(R2)-; R1 and R2 are independently selected from hydrogen and lower alkyl or are together -(CH2)n- wherein n is an integer from 2 to 4; and R3 is selected from in which: p is 0 or 1; q is 1, 2 or 3; and R4 is C1 -7 alkyl; their pharmaceutically acceptable salts, individual isomers or mixtures of isomers, processes for their preparation, compositions containing them, and their use.

  式 I 的 5-HT 受体拮抗剂化合物 其中 虚线表示任选键； X 和 Y 独立选自氢、卤素、羟基、低级烷氧基、苄氧基、低级烷基、硝基、氨基、氨基羰基、（低级烷基）氨基、二（低级烷基）氨基和（低级烷酰基）氨基； Z 是-O-、-S-或-N(R2)-； R1 和 R2 分别独立地选自氢和低级烷基，或共同为-(CH2)n-，其中 n 为 2 至 4 的整数；以及 R3 选自 其中 p 是 0 或 1 q是1、2或3；和 R4 是 C1 -7 烷基； 它们的药学上可接受的盐、单个异构体或异构体混合物、它们的制备工艺、含有它们的组合物以及它们的用途。
• US5189041A
  申请人：——

  公开号：US5189041A

  公开（公告）日：1993-02-23
• 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists
  作者：Robin D. Clark、Aaron B. Miller、Jacob Berger、David B. Repke、Klaus K. Weinhardt、Bruce A. Kowalczyk、Richard M. Eglen、Douglas W. Bonhaus、Chi Ho Lee

  DOI：10.1021/jm00070a008

  日期：1993.9

  Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pK(i) values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pK(i) 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 mug/kg iv), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.