(S)-6-amino-2-(1-azabicyclo<2.2.2>oct-3-yl)-2,3-dihydro-1H-benzisoquinoline-1,3-dione hydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: (S)-6-amino-2-(1-azabicyclo<2.2.2>oct-3-yl)-2,3-dihydro-1H-benzisoquinoline-1,3-dione hydrochloride
• 英文别名: (S)-6-amino-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione；6-Amino-2-(S)-1-aza-bicyclo[2.2.2]oct-3-yl-benzo[de]isoquinoline-1,3-dione；6-amino-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]benzo[de]isoquinoline-1,3-dione
• 化学式: C₁₉H₁₉N₃O₂
• 分子量: 321.379
• InChiKey: GGQMXMGHFNPCQV-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (S)-6-nitro-2-(1-azabicyclo<2.2.2>oct-3-yl)-2,3-dihydro-1H-benzisoquinoline-1,3-dione hydrochloride 在 palladium on activated charcoal 氢气 作用下， 以 溶剂黄146 为溶剂， 70.0 ℃ 、101.32 kPa 条件下， 反应 4.0h， 以70%的产率得到(S)-6-amino-2-(1-azabicyclo<2.2.2>oct-3-yl)-2,3-dihydro-1H-benzisoquinoline-1,3-dione hydrochloride
  参考文献：
  名称：

  Synthesis of quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3 receptor antagonists

  摘要：

  New potent 5-HT3 receptor antagonists have been designed from the naphthalimide moiety and a quinuclidine heterocycle and the structure-activity relationships are discussed here on the basis of the nature of the substituent on the aromatic system. The biological activity of the compounds was evaluated in binding assays with [H-3]BRL-43694 and by inhibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino substituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) enantiomer (K-i = 0.15 +/- 0.05 nM, ID50 = 1.6 mu g/kg/iv) and it is demonstrated that the additional carbonyl group is involved in the inversion of the enantioselectivity of the receptor. Conformational studies of (R)-22 demonstrated the presence of a locked structure with 4 minimal energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the presence of a second polar group in the binding site. The fluorescent properties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-HT3 receptors.

  DOI：

  10.1016/0223-5234(94)90192-9

文献信息

• Tricyclic compounds acting at serotonin receptor subtypes
  申请人：Syntex (U.S.A.) Inc.

  公开号：US05202318A1

  公开（公告）日：1993-04-13

  Compounds of Formula I: ##STR1## in which Z is CH.sub.2 or C.dbd.O; X and Y are independently selected from hydrogen, halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, aminocarbonyl, (lower alkyl)amino, di(lower alkyl)amino and (lower alkanoyl)amino; and R.sup.1 is a group selected from Formulae (a), (b), (c) (d) and (e): ##STR2## in which p is 0 or 1; n is 1, 2 or 3; R.sup.2 is hydrogen, lower alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.12 alkyl, or a group R.sup.6 -C.sub.1-2 alkyl in which R.sup.6 is thienyl, pyrrolyl or furyl optionally substituted by one or two substituents selected from lower alkyl, lower alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C.sub.1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C.sub.1-4 alkyl optionally further substituted by hydroxy, C.sub.1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; each R.sup.3 is independently selected from hydrogen, hydroxy, alkyl and alkoxy; each R.sup.4 is independently hydrogen or alkyl; and R.sup.5 is hydrogen, lower alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-2 alkyl, alkenyl, alkynyl or a group R.sup.7 -C.sub.1-3 alkyl in which R.sup.7 is phenyl or phenoxy optionally substituted by one or two substituents selected from C.sub.1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C.sub.1-4 alkyl optionally further substituted by hydroxy, C.sub.1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.

  化合物的化学式I：##STR1## 其中Z为CH.sub.2或C.dbd.O；X和Y分别选自氢、卤素、羟基、低烷氧基、低烷基、硝基、氨基、氨基甲酰、(低烷基)氨基、二(低烷基)氨基和(低脂肪酰)氨基；R.sup.1为从式(a)、(b)、(c)、(d)和(e)中选择的基团：##STR2## 其中p为0或1；n为1、2或3；R.sup.2为氢、低烷基、C.sub.3-8环烷基、C.sub.3-8环烷基-C.sub.12烷基，或R.sup.6-C.sub.1-2烷基，其中R.sup.6为噻吩基、吡咯基或呋喃基，可选择地被一个或两个选自低烷基、低烷氧基、三氟甲基或卤素的取代基取代，或者为苯基，可选择地被一个或两个选自C.sub.1-4烷氧基、三氟甲基、卤素、硝基、羧基、酯化羧基和C.sub.1-4烷基的取代基取代，可选择地进一步被羟基、C.sub.1-4烷氧基、羧基、酯化羧基或体内可水解的酰氧基取代；每个R.sup.3独立地选自氢、羟基、烷基和烷氧基；每个R.sup.4独立地选自氢或烷基；R.sup.5为氢、低烷基、C.sub.3-8环烷基、C.sub.3-8环烷基-C.sub.1-2烷基、烯基、炔基或R.sup.7-C.sub.1-3烷基，其中R.sup.7为苯基或苯氧基，可选择地被一个或两个选自C.sub.1-4烷氧基、三氟甲基、卤素、硝基、羧基、酯化羧基和C.sub.1-4烷基的取代基取代，可选择地进一步被羟基、C.sub.1-4烷氧基、羧基、酯化羧基或体内可水解的酰氧基取代；以及其药学上可接受的盐、单体异构体、异构体混合物、制备方法、组合物和使用方法。
• Novel tricyclic compounds
  申请人：SYNTEX (U.S.A.) INC.

  公开号：EP0457243A1

  公开（公告）日：1991-11-21

  Compounds of Formula I: in which    Z is an oxo group or two hydrogens;    X and Y are independently selected from hydrogen, halogen, hydroxy, lower alkoxy, benzyloxy, lower alkyl, lower cycloalkyl, nitro, amino, amino-carbonyl, (lower alkyl)amino, di(lower alkyl)amino and (lower alkanoyl)amino;    R¹ is selected from in which    p is 0 or 1;    n is 1, 2 or 3; and    R² is hydrogen, lower alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₂ alkyl, or a group (CH₂)tR³ where t is 1 or 2 and R³ is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from lower alkyl, lower alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C₁₋₄ alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C₁₋₄ alkyl optionally substituted by hydroxy, C₁₋₄ alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; or their pharmaceutically acceptable salts, or an individual isomer or mixture of isomers thereof, the processes for the preparation thereof, as well as compositions containing them and their methods of use.

  式 I 的化合物： 其中 Z 是一个氧代基团或两个氢； X 和 Y 独立选自氢、卤素、羟基、低级烷氧基、苄氧基、低级烷基、低级环烷基、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； R¹ 选自 其中 p 是 0 或 1 n 是 1、2 或 3；以及 R² 是氢、低级烷基、C₃₋₈环烷基、C₃₋₈环烷基-C₁₋₂烷基或基团 (CH₂)tR³ 其中 t 是 1 或 2，R³ 是噻吩基、是噻吩基、吡咯基或呋喃基，可任选地被选自低级烷基、低级烷氧基、三氟甲基或卤素的一个或两个取代基进一步取代、或苯基，可任选被一个或两个选自 C₁₋₄烷氧基、三氟甲基、卤素、硝基、羧基、酯化羧基和 C₁₋₄烷氧基的取代基取代、C₁₋₄ 烷氧基、卤素、硝基、羧基、酯化羧基和 C₁₋₄ 烷基中任选被羟基、C₁₋₄ 烷氧基、羧基、酯化羧基或体内可水解的酰氧基取代；或它们的药学上可接受的盐，或它们的单个异构体或异构体混合物，它们的制备工艺，以及含有它们的组合物和它们的使用方法。
• US5202318A
  申请人：——

  公开号：US5202318A

  公开（公告）日：1993-04-13
• Synthesis of quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3 receptor antagonists
  作者：M Langlois、JL Soulier、V Rampillon、C Gallais、B Brémont、S Shen、D Yang、A Giudice、F Sureau

  DOI：10.1016/0223-5234(94)90192-9

  日期：1994.1

  New potent 5-HT3 receptor antagonists have been designed from the naphthalimide moiety and a quinuclidine heterocycle and the structure-activity relationships are discussed here on the basis of the nature of the substituent on the aromatic system. The biological activity of the compounds was evaluated in binding assays with [H-3]BRL-43694 and by inhibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino substituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) enantiomer (K-i = 0.15 +/- 0.05 nM, ID50 = 1.6 mu g/kg/iv) and it is demonstrated that the additional carbonyl group is involved in the inversion of the enantioselectivity of the receptor. Conformational studies of (R)-22 demonstrated the presence of a locked structure with 4 minimal energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the presence of a second polar group in the binding site. The fluorescent properties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-HT3 receptors.