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Tetrahydroisoquinoline quaternary ammonium salt derivatives, preparation method and analgesic use thereof

A technology of tetrahydroisoquinoline and derivatives, applied in the field of κ-opioid receptor agonists in analgesia, tetrahydroisoquinoline quaternary ammonium salt derivatives, to achieve strong analgesic effect

Active Publication Date: 2015-10-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The radioactive ligand binding experiment showed that the affinity of the compound for the κ-opioid receptor was Ki(M)κ=2.99×10 -11 , μ / κ-opioid receptor selectivity reached μKi / κKi=22341, and showed strong analgesic activity in the mouse analgesic test (ED 50 =3.1ug / kg(s.c)), but the mouse wheel test and the mouse elevated plus maze test found that indenequinoline showed obvious central sedative and anxiety side effects

Method used

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  • Tetrahydroisoquinoline quaternary ammonium salt derivatives, preparation method and analgesic use thereof
  • Tetrahydroisoquinoline quaternary ammonium salt derivatives, preparation method and analgesic use thereof
  • Tetrahydroisoquinoline quaternary ammonium salt derivatives, preparation method and analgesic use thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1-Methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydro iodide Isoquinolin-1-yl)-methyl)pyrrolium (I-1)

[0037] With reference to the method of Chinese patent CN1887872, using phenethylamine and 3-chlorobenzaldehyde as raw materials, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3 is prepared -Dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroisoquinoline.

[0038] Add 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 to the 50ml eggplant-shaped bottle, 2,3,4-Tetrahydroisoquinoline (0.2g, 0.49mmol), acetone 10ml, methyl iodide (0.31ml, 49mmol), stirred at room temperature for 2h, a large amount of solid was precipitated, filtered to obtain white solid I-1, yield 77.4 %, m.p.170~172℃.

[0039] 1 H-NMR (300MHz, DMSO-d 6 ),δ(ppm):1.98~2.08(4H,m,2×CH 2 ),2.74~2.80(1H,d,J=15.9Hz,1 / 2CH 2 ),2.93~3.15(4H,m,2×1 / 2CH 2 ,CH 2 ),3.11(3H,s,NCH 3 ),3.48~3.79(4H,m,2×CH 2 ),3.92~4.06,4.13~4.32(2H,m,2×1 / 2CH 2 ),4.63...

Embodiment 2

[0041]1-Methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-7-fluoro-1,2,3 iodide ,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-2)

[0042] With reference to the method of Chinese patent CN1887872, 4-fluorophenethylamine and 3-chlorobenzaldehyde are used as raw materials to prepare 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo- 2,3-Dihydro-1H-indene-1-formyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline, and then react with methyl iodide, similar to the method in Example 1 to prepare I-2, white solid, yield 81.2%, m.p.190~192℃.

[0043] 1 H-NMR (300MHz, DMSO-d 6 ),δ(ppm):1.98~2.08(4H,m,2×CH 2 ),2.73~2.80(1H,d,J=18.6Hz,1 / 2CH 2 ),2.93~3.10(4H,m,1 / 2CH 2 ,CH 2 ,1 / 2CH 2 ),3.10(3H,s,NCH 3 ),3.48~3.82(4H,m,2×CH 2 ),3.92~4.06,4.13~4.32(2H,m,2×1 / 2CH 2 ),4.63~4.86(1H,m,1 / 2CH 2 ),5.04~5.06(1H,d,J=6.1Hz,CH),6.11~6.08(1H,d,J=10.1Hz,CH),7.12~7.18(1H,m,ArH),7.31~7.38(2H ,m,ArH),7.58~7.72(3H,m,ArH).

[0044] HRMS(ESI): m / z[M+H] + Calcd for C 25 H 27 ClFN 2 O 2 :...

Embodiment 3

[0046] 1-Methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-6-methoxy-1,2, iodide 3,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-3)

[0047] With reference to the method of Chinese patent CN1887872, using 3-methoxyphenethylamine and 3-chlorobenzaldehyde as raw materials, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxygen) was prepared Substituted-2,3-dihydro-1H-indene-1-formyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline, and then reacted with methyl iodide, similar to Example 1 I-3 was prepared by the method of 1-3 as a white solid with a yield of 84.7%, m.p. 266~268°C.

[0048] 1 H-NMR (500MHz, DMSO-d 6 ),δ(ppm):1.94~2.08(4H,m,2×CH 2 ),2.72~2.78(1H,d,J=18.4Hz,1 / 2CH 2 ),2.85~3.06(4H,m,1 / 2CH 2 ,CH 2 ,1 / 2CH 2 ),3.09(3H,s,NCH 3 ),

[0049] 3.40~3.70(3H,m,CH 2 ,1 / 2CH 2 ),3.75~3.85(1H,m,1 / 2CH 2 ),3.75(3H,s,OCH 3 ),3.92~3.99,4.09~4.17(2H,m,2×1 / 2CH 2 ),4.59~4.62(1H,d,J=10.6Hz,1 / 2CH 2 ),5.04~5.05(1H,d,J=5.9Hz,CH),5.99~6.02(1H,d,J=10.0Hz,CH),6.83~6.87(2H,m...

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Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to tetrahydroisoquinoline quaternary ammonium salt derivatives, a composition containing the derivatives, as well as application of the derivatives or the composition as a k-opioid receptor antagonist in the analgesia aspect. Proved by a pharmacodynamic experiment, the compound disclosed by the invention has an analgesia function but has no side effect of central sedation and anxiety which are common in the medicaments.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a class of tetrahydroisoquinoline quaternary ammonium salt derivatives, a composition containing the tetrahydroisoquinoline quaternary ammonium salt derivative, and the derivatives or compositions as κ- Use of opioid agonists for analgesia. Background technique [0002] After the κ-opioid receptor agonist binds to the κ-opioid receptor, in addition to producing a potent analgesic effect, because the κ-opioid receptor does not participate in the analgesic and rewarding effects of morphine, it can reduce the pain in animals and humans. Morphine withdrawal symptoms, and can also antagonize the respiratory depressive effect of μ-opioid agonists, have become a research hotspot in the field of analgesia since the 1980s. [0003] The results of the inventor's previous research have described a class of tetrahydroisoquinoline derivatives in CN1887872, which have good κ-opioid receptor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/14A61K31/4725A61P25/04A61P29/00
Inventor 徐云根甘宗捷宋巧陈洁贾本立杨志耿元硕张迪
Owner CHINA PHARM UNIV