CN103435545B - Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetrahydroisoquinoline quaternary ammonium salt derivatives, compositions containing the tetrahydroisoquinoline quaternary ammonium salt derivatives, and the derivatives or compositions as κ- Use of opioid agonists for analgesia. Pharmacodynamic tests prove that the compound of the present invention has analgesic effect without the common side effects of central sedation and anxiety of such drugs.

Description

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

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetrahydroisoquinoline quaternary ammonium salt derivatives, compositions containing the tetrahydroisoquinoline quaternary ammonium salt derivatives, and the derivatives or compositions as κ- Use of opioid agonists for analgesia.

Background technique

After the κ-opioid receptor agonist combines with the κ-opioid receptor, in addition to producing a strong analgesic effect, since the κ-opioid receptor does not participate in the analgesic and rewarding effects of morphine, it can reduce the pain of animals and humans. Morphine withdrawal symptoms, and can also antagonize the respiratory depression of μ-opioid receptor agonists, have become a hot research topic in the field of analgesia since the 1980s.

The results of the previous research of the inventors described a class of tetrahydroisoquinoline derivatives in CN1887872, which have better κ-opioid receptor affinity and μ/κ-opioid receptor selectivity. In particular the chemical name described in Example 3 is 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1, The compound of 2,3,4-tetrahydroisoquinoline (also known as indenequinolin, the following structural formula) is a highly active and selective κ-opioid receptor agonist. The radioligand binding experiment showed that the affinity of the compound for the κ-opioid receptor was Ki(M)κ=2.99×10 ^-11 , and the selectivity of the μ/κ-opioid receptor reached μKi/κKi=22341. In the pain test, it showed strong analgesic activity (ED ₅₀ =3.1ug/kg(sc)), but the mouse wheel test and the mouse elevated plus maze test found that indenequinoline showed obvious central sedative and anxiety side effects.

Studies have shown that κ-opioid receptors exist not only in the central nervous system, but also in different peripheral tissues and organs, such as internal organs and somatic afferent nerves, which are called peripheral κ-opioid receptors. Selective stimulation of peripheral κ-opioid receptors can not only relieve or eliminate inflammation, visceral and neuropathic chronic pain, but also avoid or reduce side effects such as central sedation and anxiety, and improve the quality of pain treatment. If by introducing a hydrophilic group, increasing the polarity of the molecule, reducing the logP value, effectively preventing the compound from entering the central nervous system, and avoiding the central side effects of stimulating the central κ-opioid receptor, it is believed that peripheral κ-opioids with broad application prospects can be obtained Receptor agonist analgesics.

Contents of the invention

The invention discloses a tetrahydroisoquinoline quaternary ammonium salt derivative represented by the general formula I with significantly reduced central sedation and anxiety side effects:

Wherein, R ¹ and R ² each independently represent hydrogen, halogen, hydroxyl, C _1-6 alkoxy or C _1-6 alkyl;

R ³ represents C ₁ -C ₆ alkyl, allyl or benzyl;

X represents halogen;

m and n represent 1, 2, 3 or 4 independently.

R ² preferably each independently represent hydrogen, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, methyl, ethyl or propyl.

R ³ preferably represents methyl, ethyl, propyl, cyclopropylmethyl, allyl or benzyl.

X preferably represents iodine, bromine or chlorine.

More preferred compounds are as follows:

1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroiodide Isoquinolin-1-yl)-methyl)pyrrolium;

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;

Iodide 1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-6-methoxy-1,2, 3,4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium;

Iodide 1-methyl-1-((2-(6-methoxy-7-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium;

1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-6-hydroxyl-1,2,3, iodide 4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium;

1-Benzyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydro bromide Isoquinolin-1-yl)-methyl)pyrrolium;

1-allyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrabromide Hydroisoquinolin-1-yl)-methyl)pyrrolium;

1-(4-fluorobenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3 bromide ,4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium;

1-(4-methoxybenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2 bromide ,3,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium;

1-ethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroiodide Isoquinolin-1-yl)-methyl)pyrrolium;

1-n-butyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrafluoroiodide Hydroisoquinolin-1-yl)-methyl)pyrrolium;

1-cyclopropylmethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 bromide -tetrahydroisoquinolin-1-yl)-methyl)pyrrolium.

The compound of general formula (I) of the present invention can be prepared by the following method:

The definitions of R ¹ , R ² , R ³ , X, m and n are the same as above.

The compound of formula II is prepared according to the method of patent CN1887872; the compound of formula I is prepared by reacting the compound of formula II with an alkylating agent R ₃ X in an organic solvent. Wherein, the organic solvent is selected from one of acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethylsulfoxide or a mixed solvent of multiple compositions, preferably acetone and acetonitrile. R ₃ X is selected from iodomethane, iodoethane, iodobutane, bromomethylcyclopropane, benzyl bromide, p-methoxybenzyl bromide, p-chlorobenzyl bromide, 2,4-dichlorobenzyl bromide, p-Fluorobromobenzyl, preferably iodobutane, bromomethylcyclopropane.

The tetrahydroisoquinoline quaternary ammonium salt derivatives of the general formula (I) of the present invention can be mixed with pharmaceutically acceptable carriers to prepare various pharmaceutical preparations, including tablets, pills, granules, powders, capsules Agents, syrups, emulsions, suspensions, injections, etc. Tetrahydroisoquinoline quaternary ammonium salt derivatives of general formula (I) can also be added with other analgesics such as morphine, fentanyl, etc. to prepare compound analgesic drugs.

The clinically used dose of the compound of the present invention is 0.01 mg-1000 mg/day, and may also deviate from this range according to the severity of the disease or different dosage forms.

Pharmacodynamic tests prove that the tetrahydroisoquinoline quaternary ammonium salt derivative of the present invention not only has a strong analgesic effect, but also has almost no common sedative side effects of such drugs.

Detailed ways

Example 1

1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroiodide Isoquinolin-1-yl)-methyl)pyrrolium (I-1)

Referring to the method of Chinese patent CN1887872, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3 -dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroisoquinoline.

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

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 ),4.63～4.86(1H,dd,J=4.2Hz,14.1Hz,1/2CH ₂ ),5.05～5.06(1H,d,J=5.7Hz,CH ),6.11～6.08(1H,d,J=9.9Hz,CH),7.24～7.40(3H,m,ArH),7.41～7.44(1H,m,ArH),7.58～7.66(3H,m,ArH) .MS(ESI(+)70V,m/z):423.3([M+H] ⁺ ,base peak).

Example 2

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)

Referring to the method of Chinese patent CN1887872, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo- 2,3-dihydro-1H-indene-1-formyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline, then reacted with methyl iodide, prepared by a method similar to Example 1 I-2 is a white solid with a yield of 81.2%, m.p.190-192°C.

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).

HRMS(ESI):m/z[M+H] ⁺ Calcd for C ₂₅ H ₂₇ ClFN ₂ O ₂ :441.1740;Found:441.1746.

Example 3

Iodide 1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-6-methoxy-1,2, 3,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-3)

With reference to the method of Chinese patent CN1887872, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo Generation-2,3-dihydro-1H-indene-1-formyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline, then reacted with methyl iodide, similar to Example 1 I-3 was prepared as a white solid with a yield of 84.7%, m.p.266-268°C.

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 ),

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,ArH),7.31～7.34(1H,d,J=8.4Hz,ArH),7.58～7.60(1H,d,J=8.1 Hz, ArH), 7.65 (1H, s, ArH), 7.69～7.72 (1H, d, J=8.1Hz, ArH).

HRMS(ESI):m/z[M+H] ⁺ C ₂₆ H ₃₀ ClN ₂ O ₃ :453.1945;Found:453.1949.

Example 4

Iodide 1-methyl-1-((2-(6-methoxy-7-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-4)

With reference to the method of Chinese patent CN1887872, 1-(tetrahydropyrrole-1-methyl)-2-(6-methoxy- 7-Chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroisoquinoline, then reacted with iodomethane, similar to the example The method of 1 prepared I-4 as a white solid with a yield of 75.9% and m.p.205-207°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ(ppm): 2.04～2.08(4H,m,2×CH ₂ ), 2.52～2.57(1H,m,1/2CH ₂ ), 2.90～2.95( 2H, m, CH ₂ ), 3.15 (3H, s, NCH ₃ ), 3.16～3.20 (2H, m, 2×1/2CH ₂ ), 3.48～3.87 (5H, m, 2×CH ₂ , 1/2CH ₂ ),3.84(3H,s,OCH ₃ ),4.07～4.15(1H,m,1/2CH ₂ ),4.25～4.28(1H,m,1/2CH ₂ ),4.72～4.73(1H,d,J =4.8Hz, CH), 6.06～6.09(1H,d,J=9.2Hz,CH),7.16～7.21(1H,m,ArH),7.26～7.30(3H,m,ArH),7.40～7.44(1H ,m,ArH),7.67(1H,s,ArH).

HRMS(ESI):m/z[M+H] ⁺ C ₂₆ H ₃₀ ClN ₂ O ₃ :453.1939;Found:453.1944.

Example 5

1-methyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-6-hydroxyl-1,2,3, iodide 4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-5)

With reference to the method of Chinese patent CN1887872, 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo Generation-2,3-dihydro-1H-indene-1-formyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline, then reacted with methyl iodide, similar to the method of Example 1 I-5 was obtained as a white solid with a yield of 43.2%, m.p.258-260°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.91～2.08(4H,m,2×CH ₂ ), 2.72～2.78(1H,d,J=18.7Hz,1/2CH ₂ ) ,2.88～3.15(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.09(3H,s,NCH ₃ ),

3.48～3.78(4H,m,2×CH ₂ ),3.93～4.06,4.13～4.26(2H,m,2×1/2CH ₂ ),4.56～4.60(1H,d,J=10.4Hz,1/2CH ₂ ),5.03～5.05(1H,d,J=5.5Hz,CH),5.93～5.96(1H,d,J=10.1Hz,CH),6.62～6.70(2H,m,ArH),7.20～7.23( 1H,d,J=8.4Hz,ArH),7.58～7.72(3H,m,ArH).

MS(ESI(+)70V,m/z):419.3([M+H] ⁺ ,base peak)

Example 6

1-Benzyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydro bromide Isoquinolin-1-yl)-methyl)pyrrolium (I-6)

Add 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 into a 50ml eggplant-shaped bottle, 2,3,4-Tetrahydroisoquinoline (0.2g, 0.49mmol), acetonitrile 10ml, benzyl bromide (0.58ml, 49mmol), warming up to reflux for 2h, adding the reaction solution directly to silica gel, using dichloromethane:methanol=40: 1 column chromatography, 0.16 g of white solid was obtained, the yield was 56.8%, m.p.172-174°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.72～2.08(4H,m,2×CH ₂ ), 2.73～2.80(1H,d,J=18.6Hz,1/2CH ₂ ) ,2.90～3.30(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.58～3.69(4H,m,2×CH ₂ ),4.09～4.16,4.23～4.32(2H,m,2 ×1/2CH ₂ ),4.63～4.86(3H,dd,J=9.1Hz,9.1Hz,PhCH ₂ ,1/2CH ₂ ),5.11～5.13(1H,d,J=6.7Hz,CH),6.28～ 6.31(1H,d,J=9.8Hz,CH),7.12～7.27(4H,m,ArH),7.48～7.54(5H,m,ArH),7.69～7.72(2H,m,ArH).

MS(ESI(+)70V,m/z):499.3([M+H] ⁺ ,base peak)

Example 7

1-allyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrabromide Hydroisoquinolin-1-yl)-methyl)pyrrolium (I-7)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and allyl bromide were used as raw materials, and a white solid I-7 was obtained in a similar manner to Example 6, with a yield of 46.0%, m.p.178-180°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ(ppm): 1.88～2.08(4H,m,2×CH ₂ ), 2.57～2.64(1H,d,J=18.5Hz,1/2CH ₂ ) ,2.94～3.16(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.57～3.72(4H,m,2×CH ₂ ),3.98～4.23(4H,m,CH ₂ ,2× 1/2CH ₂ ),4.60～4.62(1H,d,J=10.1Hz,1/2CH ₂ ),5.06～5.07(1H,d,J=6.3Hz,CH),5.65～5.70(2H,m,CH =CH ₂ ),6.06～6.08(1H,d,J=9.8Hz,CH),6.17～6.20(1H,m,CH=CH ₂ ),7.24～7.30(4H,m,ArH),7.58～7.60( 1H,d,J=8.1Hz,ArH),7.65(1H,sArH),7.70～7.72(1H,d,J=8.1Hz,ArH).

MS(ESI(+)70V,m/z):449.2([M+H] ⁺ ,base peak).

Example 8

1-(4-fluorobenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3 bromide ,4-tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-8)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and 4-fluorobenzyl bromide were used as raw materials, and a white solid I-8 was obtained in a similar manner to Example 6, with a yield of 57.2%, m.p.210-212°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ(ppm): 1.72～2.04(4H,m,2×CH ₂ ), 2.72～2.76(1H,d,J=18.4Hz,1/2CH ₂ ) ,2.97～3.23(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.61～3.68(4H,m,2×CH ₂ ),4.14～4.27,4.29～4.32(2H,m,2 ×1/2CH ₂ ),4.61～4.64,4.83～4.85(3H,m,PhCH ₂ ,1/2CH ₂ ),5.11～5.12(1H,d,J=6.7Hz,CH),6.24～6.26(1H, d,J=9.3Hz,CH),7.23～7.32(6H,m,ArH),7.52(3H,s,ArH),7.67～7.70(2H,m,ArH).

MS(ESI(+)70V,m/z):517.2([M+H] ⁺ ,base peak).

Example 9

1-(4-methoxybenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2 bromide ,3,4-Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-9)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and 4-methoxybenzyl bromide were used as raw materials, and a white solid I-9 was obtained in a similar manner to Example 6, with a yield of 67.4%, m.p.220-222°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ(ppm): 1.74～2.08(4H,m,2×CH ₂ ), 2.73～2.80(1H,d,J=18.4Hz,1/2CH ₂ ) ,2.90～3.28(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.57～3.69(4H,m,2×CH ₂ ),3.81(3H,s,OCH ₃ ),4.09～4.13 ,4.17～4.26(2H,m,2×1/2CH ₂ ),4.63～4.83

(3H,dd,J=8.2Hz,8.2Hz,PhCH ₂ ,1/2CH ₂ ),5.08～5.09(1H,d,J=6.1Hz,CH),6.27～6.29(1H,d,J=9.8Hz ,CH),7.02～7.04(2H,m,ArH),7.15～7.42(4H,m,ArH),7.36～7.38(1H,d,J=8.4Hz,CH),7.53～7.55(1H,d, J=8.1Hz,CH),7.67～7.77(3H,m,ArH).

MS(ESI(+)70V,m/z):529.2([M+H] ⁺ ,base peak).

Example 10

1-ethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroiodide Isoquinolin-1-yl)-methyl)pyrrolium (I-10)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and ethyl iodide were used as raw materials, and a white solid I-10 was obtained in a similar manner to Example 6, with a yield of 57.2%, m.p.240-242°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.29～1.32 (3H, t, J=7.0Hz, CH ₃ ), 1.98～2.04 (4H, m, 2×CH ₂ ), 2.71 ～2.75(1H,d,J=21.2Hz,1/2CH ₂ ), 2.94～3.12(4H,m,1/2CH ₂ ,CH ₂ ,1/2CH ₂ ),3.57～3.89(4H,m,2× CH ₂ ),3.62～3.65(2H,m,CH ₂ ),4.09～4.13,4.02～4.11(2H,m,2×1/2CH ₂ ),4.56～4.59(1H,d,J=10.6Hz,1 /2CH ₂ ),5.02～5.03(1H,d,J=6.1Hz,CH),5.97～5.99(1H,d,J=9.8Hz,CH),7.28～7.34(4H,m,ArH),7.59～ 7.60(1H,d,J=8.6Hz,ArH),7.66(1H,s,ArH),7.70～7.72(1H,d,J=8.2Hz,ArH).

HRMS(ESI):m/z[M+H] ⁺ Calcd for C ₂₆ H ₃₀ ClN ₂ O ₂ :437.1990;Found:437.1966.

Example 11

1-n-butyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrafluoroiodide Hydroisoquinolin-1-yl)-methyl)pyrrolium (I-11)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and iodobutane were used as raw materials, and a white solid I-11 was obtained in a similar manner to Example 6, with a yield of 40.7%, m.p.180-182°C.

¹ H-NMR(300MHz, DMSO-d ₆ ), δ(ppm): 0.89～0.94(3H,t,J=7.1Hz,CH ₃ ),1.26～1.30(2H,m,CH ₂ ),1.65～1.75 (2H,m,CH ₂ ),2.01～2.08(4H,m,2×CH ₂ ),2.72～2.75(1H,m,1/2CH ₂ ),2.94～3.12(4H,m,1/2CH ₂ , CH ₂ ,1/2CH ₂ ), 3.57～3.89(4H,m,2×CH ₂ ),3.62～3.65(2H,m,CH ₂ ),4.09～4.11(2H,m,2×1/2CH ₂ ) ,4.56～4.59(1H,d,J=9.1Hz,1/2CH ₂ ),5.02～5.03(1H,m,CH),5.77～5.79(1H,d,J=9.8Hz,CH),7.3(3H ,s,ArH),7.59～7.60(1H,d,J=8.2Hz,ArH),7.67(1H,s,ArH),7.70～7.73(1H,d,J=8.2Hz,ArH).

MS(ESI(+)70V,m/z):465.3([M+H] ⁺ ,base peak).

Example 12

1-cyclopropylmethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 bromide -Tetrahydroisoquinolin-1-yl)-methyl)pyrrolium (I-12)

With 1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4 -Tetrahydroisoquinoline and cyclopropylmethyl bromide were used as raw materials, and a white solid I-12 was obtained in a similar manner to Example 6, with a yield of 47.9%, m.p.106-108°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 0.35～0.38(2H,m,CH ₂ ), 0.71～0.73(2H,m,CH ₂ ), 1.21～1.25(1H,m, CH),1.87～2.08(4H,m,2×CH ₂ ),2.69～2.76(1H,d,J=18.5Hz,1/2CH ₂ ),2.90～3.16(5H,m,1/2CH ₂ ,2 ×CH ₂ ),3.42～3.57(3H,m,CH ₂ ,1/2CH ₂ ),3.76～3.81(2H,m,2×1/2CH ₂ ),4.01～4.08,4.18～4.27(2H,m, 2×1/2CH ₂ ),4.59～4.63(1H,d,J=11.3Hz,1/2CH ₂ ),5.04～5.06(1H,d,J=5.6Hz,CH),6.03～6.06(1H,d ,J=9.7Hz,CH),7.29～7.35(4H,m,ArH),7.59～7.73(3H,m,ArH).

HRMS(ESI):m/z[M+H] ⁺ C ₂₈ H ₃₂ ClN ₂ O ₂ :463.2147;Found:463.2156.

Example 13

Pharmacodynamic test

1. Opioid receptor affinity research (radioligand binding experiment)

experimental method:

The experiment was divided into total binding tubes and non-specific binding tubes, and several sets of sample tubes were added with different concentrations of competing ligands. Add the equivalent of 20 μg expressed membrane receptor protein and [ ³ H]diprenorphine (0.5nM) (1.44Pbq.mol ^-1 broad-spectrum opioid antagonist, Amersham Company) to the total binding tube, and add to the corresponding non-specific binding tube 1 μM naloxone (broad-spectrum opioid antagonist, Sigma Company), the sample tube was added with different concentrations of the compound to be screened, and adjusted to a final volume of 100 μl with 50 mM Tris (Amresco Company)-HCl (pH 7.4). Incubate at 30°C for 30 min, then place in ice water to terminate the reaction. Vacuum filtration through GF/(Whatman) glass fiber filter paper on the Millipore sample collector. Rinse three times with ice-cold 50mM Tris-HCl (pH7.4), 4ml each time, dry the filter paper, put it in a 0.5ml Eppendorff tube, add 0.5ml lipophilic scintillation fluid (Shanghai Reagent No. 1 Factory), Beckman LS6500 multifunctional liquid The radioactive intensity was measured by scintillation counter, and the inhibition rate was calculated. Each concentration was three tubes, and each independent experiment was performed 3-4 times. Calculation method:

According to the inhibition rate, the IC ₅₀ value was calculated with Prism4.0 software.

K _i =IC ₅₀ /(1+[L]/K _d ), ([L] is the concentration of the added labeled ligand, K _d is the equilibrium dissociation parameter of the radioligand).

The results are shown in Table 1

Table 1 Competitive binding test of some compounds with radioligand and binding affinity to κ-receptor (κK _i )

The above data show that the indenequinoline quaternary ammonium salt derivatives of the present invention still have a strong affinity for the κ-opioid receptor.

2. Study on sedative effect

The experiment set up the following groups:

Normal saline group: 10 rats/group, subcutaneous injection of 0.2ml of normal saline per rat, intraperitoneal injection of 0.6% glacial acetic acid 0.2ml after 15 minutes, and observation of the number of writhing within 15 minutes;

Embodiment group: establish 3 different dosage groups, 10/group, each group subcutaneous injection test drug 1ug/kg, 5ug/kg, 10ug/kg respectively, intraperitoneal injection 0.6% glacial acetic acid 0.2ml after 15min, observe within 15min The number of writhing times was used to calculate the analgesic ED ₅₀ value.

Using the wheel device, put the new mice on the wheel respectively, record the time when they fall from the wheel, and screen them before the formal experiment, if the mice that fall within 60s are removed. Qualified rats were randomly divided into groups of 10, and after being given different doses of indenequinolin and the test drug, the time for falling from the running wheel was recorded, and the average value was repeated twice, and the sedation ED ₅₀ was calculated as above. The therapeutic index was used to evaluate the central sedative side effects of the test drugs. Therapeutic index = ED _{50 for sedation / ED 50 for} analgesia. The higher the therapeutic index, the less sedative side effects.

The results are shown in Table 2

Analgesic and sedative ED ₅₀ values and therapeutic index of some compounds in table 2

The data in Table 2 shows that the therapeutic index of the indenequinoline quaternary ammonium salt derivatives of the present invention is significantly greater than indenequinoline, indicating that their sedative side effects are weaker than indenequinoline, and the analgesic and sedative effects can be separated.

3. Research on the effect of anxiety

experimental method

After 15 minutes of administration of the test drug, the mouse was placed at the middle link of the open arm and the closed arm of the elevated plus maze, facing the open arm, and the percentage of the residence time in the open arm or the closed arm accounted for the total time was recorded within 5 minutes as an evaluation The indicator, time to enter closed arms and stay in closed arms, reflects anxious behavior. The test results are shown in Table 3

The elevated plus maze experiment of table 3 compound I-2, I-7 and I-11

Compound code Open arm time/total time (%) Closing arm time/total time (%) control 39 61 Indenequinoline (1μg/kg) 34 66 Indenequinoline (2.5μg/kg) 17 83 Indenequinoline (5μg/kg) 3 97 I-2 (1.25mg/kg) 38 62 I-2 (2.5mg/kg) twenty three 77 I-2 (3.75mg/kg) 16 84 I-7 (1.25mg/kg) 36 64 I-7 (2.5mg/kg) twenty two 78 I-7 (3.75mg/kg) 13 87 I-11 (1.25mg/kg) 34 66 I-11 (2.5mg/kg) 25 75 I-11 (3.75mg/kg) 15 85

Table 3 data shows, I-2, I-7 and I-11 stay in the percentage of the time of closed arm under low dosage (1.25mg/kg) and blank control have no significant difference, show that above-mentioned seasonal under low dosage Ammonium salt derivatives have almost no anxiogenic effect; at a dose of 2.5mg/kg, I-2, I-7 and I-11 only cause mild anxiety; at a high dose (3.75mg/kg), I-2, I-7 and I-11 cause only moderate anxiety. However, indenequinoline can cause severe anxiety at high doses (5 μg/kg).

Claims (8)

1. tetrahydroisoquinoline quaternary ammonium salt derivatives of general formula (I): Wherein, R ¹ and R ² each independently represent hydrogen, halogen, hydroxyl, C _1-6 alkoxy or C _1-6 alkyl; R ³ represents C ₁ -C ₆ alkyl, allyl or benzyl; X represents halogen; m and n represent 1, 2, 3 or 4 independently. 2. the tetrahydroisoquinoline quaternary ammonium derivative of claim 1, wherein R ¹ , R ² each independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, methyl, ethyl or propyl. 3. the tetrahydroisoquinoline quaternary ammonium derivative of claim 1, wherein R ³ represents methyl, ethyl, propyl, allyl or benzyl. 4. The tetrahydroisoquinoline quaternary ammonium salt derivative according to claim 1, wherein X represents iodine, bromine or chlorine. 5. the tetrahydroisoquinoline quaternary ammonium derivative of claim 1, wherein the compound of general formula (I) is any of the following compounds: 1-methyl-1-(2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl )-methyl)pyrrole ammonium iodide; 1-methyl-1-((7-fluoro-2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquine Lin-1-yl)-methyl)pyrrole ammonium iodide salt; 1-methyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-6-methoxy-1,2,3,4-tetrahydro Isoquinolin-1-yl)-methyl)pyrrole ammonium iodide salt; 1-methyl-1-((2-(6-methoxy-7-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydro Isoquinolin-1-yl)-methyl)pyrrole ammonium iodide salt; 1-methyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquine Lin-1-yl)-methyl)pyrrole ammonium iodide salt; 1-Benzyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1- Base)-methyl)pyrrole ammonium bromide salt; 1-allyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1 -yl)-methyl)pyrrole ammonium bromide salt; 1-ethyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1- Base)-methyl)pyrrole ammonium iodide; 1-Butyl-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1- base)-methyl)pyrrole ammonium iodide salt. 6. Tetrahydroisoquinoline quaternary ammonium salt derivatives with any of the following structures: 1-(4-fluorobenzyl)-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetrahydroiso Quinolin-1-yl)-methyl)pyrrole ammonium bromide salt; 1-(4-methoxybenzyl)-1-((2-(6-chloro-2,3-dihydro-inden-3-one-1-carbonyl)-1,2,3,4-tetra Hydroisoquinolin-1-yl)-methyl)pyrrole ammonium bromide salt. 7. A pharmaceutical composition, which contains the tetrahydroisoquinoline quaternary ammonium salt derivative according to claim 1 or 6 and a pharmaceutically acceptable carrier. 8. Use of the tetrahydroisoquinoline quaternary ammonium salt derivative according to any one of claims 1 to 6 for the preparation of analgesic drugs.