CN103450079A - Tetrahydroisoquinoline hydroxyl derivate, preparation method and medical application thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetrahydroisoquinoline hydroxyl derivatives, compositions containing the hydroxyl derivatives, and the analgesic effects of the derivatives or compositions as κ-opioid receptor agonists use. Pharmacodynamic tests prove that the compound of the present invention not only has strong analgesic effect, but also can significantly reduce the side effects of central sedation and anxiety, and overcome the side effects of existing analgesic drugs.

Description

Tetrahydroisoquinoline hydroxyl derivatives, preparation method and medical use thereof

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetrahydroisoquinoline hydroxyl derivatives, compositions containing the hydroxyl derivatives, and the analgesic effects of the derivatives or compositions as κ-opioid receptor agonists use.

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 alleviate the pain of morphine in animals and humans. Withdrawal symptoms, and can also antagonize the respiratory depression of μ-opioid receptor agonists, since the 1980s, it has become a research hotspot in the field of analgesia.

Indenequinoline (structural formula as follows) is a new type of κ-opioid receptor agonist, the compound has good κ-opioid receptor affinity and μ/κ-opioid receptor selectivity, but mice transfected Round test and mouse elevated plus maze test found that indenequinoline showed obvious side effects of central sedation and anxiety.

Indenequinoline

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. Indenequinoline compounds enter the central nervous system and excite central κ-opioid receptors to produce central side effects.

Contents of the invention

The present invention discloses tetrahydroisoquinoline hydroxyl derivatives represented by general formula (I):

Wherein R ₁ , R ₂ , R ₃ each independently represent hydrogen, halogen, hydroxyl or C ₁ -C ₆ alkyl, and at least one of R ₁ , R ₂ , R ₃ represents hydroxyl.

More preferred compounds are as follows:

1-(tetrahydropyrrole-1-methyl)-2-(6-hydroxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4- Tetrahydroisoquinoline;

6-Hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline;

6,7-Dihydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3 ,4-Tetrahydroisoquinoline;

6-Hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinone;

5-Chloro-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline;

7-fluoro-1-(tetrahydropyrrole-1-methyl)-2-(6-hydroxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline;

5-Bromo-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline;

5-Chloro-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)- 1,2,3,4-Tetrahydroisoquinoline.

Pharmacodynamic tests prove that the compound of the general formula (I) of the present invention not only has a strong analgesic effect, but also can significantly reduce the side effects of central sedation and anxiety, and overcome the side effects of existing analgesic drugs.

General formula (I) compound of the present invention can be prepared by following two kinds of methods:

(1) Referring to the preparation method of indenequinoline (CN1887872), using substituted tetrahydropyrrole-1-methyltetrahydroisoquinoline and substituted indanone acid as raw materials, dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) catalyzed condensation prepared Ia.

(2) Using the compound of the general formula Ia as a raw material, under the action of a dealkylating agent, demethylate the protecting group to obtain a tetrahydroisoquinoline hydroxy derivative I. The dealkylating agent is selected from 48% hydrobromic acid aqueous solution, boron tribromide dichloromethane solution, pyridine hydrochloride, hydroiodic acid or aluminum trichloride, preferably 48% hydrobromic acid aqueous solution or boron tribromide dichloromethane methane solution.

The compounds of the general formula (I) of the present invention can form acid addition salts with acids, that is, pharmaceutically acceptable salts, which have the same pharmacological efficacy as the compounds of the general formula (I). Described acid is selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid acid, malic acid, methanesulfonic acid or its analogues, etc.

Compound (I) or a pharmaceutically acceptable salt thereof can be prepared into various preparations by adding pharmaceutically acceptable carriers. It is used clinically for oral administration and injection etc.

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

The following are some pharmacodynamic tests and results of the compounds of the present invention, and the structures corresponding to the code numbers of the test parts are the same as those in the examples.

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 scintillation counter was used to measure the radioactive intensity, and the inhibition rate was calculated. Each concentration was used in triplicate 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 tetrahydroisoquinoline hydroxy derivatives of the present invention still have a strong affinity for the κ-opioid receptor, and the affinity for the κ-opioid receptor is obviously higher than that of the μ-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 indenequinoline and the test drug, the time for falling from the running wheel was recorded, and the average value was repeated twice, and the sedative _ED50 was calculated as above. The therapeutic index was used to evaluate the central sedative side effects of the test drugs. Therapeutic index = sedative ED ₅₀ /analgesic ED ₅₀ , the higher the therapeutic index, the smaller the side effects of sedation. The data are shown in Table 2.

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

Table 2 data shows that indenequinoline hydroxy derivatives of the present invention are all significantly greater than indenequinoline relative to the therapeutic index of sedation, illustrating that under the analgesic treatment dose, their sedative side effects are less, and analgesia and sedation can be achieved. effectively separated.

3. Research on the effect of anxiety

experimental method

After 15 minutes of administration of the test drug, the mice were placed in 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 dwell time in the open arm or the closed arm to 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 data are shown in Table 3.

The elevated plus maze test result of table 3 compound I-1, I-2 and I-6

The data in Table 3 shows that the percentages of I-1, I-2 and I-6 staying in the closed arm at a dose of 1.25 mg/kg are basically the same as those of the blank control, indicating that there is no anxiety-inducing effect at low doses; At a dose of 2.5mg/kg, I-1, I-2 and I-6 only caused mild anxiety; at a dose of 3.75mg/kg, I-1 and I-6 only caused moderate anxiety, while I-2 Still only mild anxiety. However, indenequinoline can cause severe anxiety at high doses (5 μg/kg).

Detailed ways

Example 1

1-(tetrahydropyrrole-1-methyl)-2-(6-hydroxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4- Tetrahydroisoquinoline (I-1)

Referring to the synthetic method of indenequinoline, with 1-(tetrahydropyrrole-1-methyl)-1,2,3,4-tetrahydroisoquinoline and 6-methoxy-3-oxo-2, 3-dihydro-1H-indene-1-carboxylic acid is used as raw material, and 1-(tetrahydropyrrole-1 -Methyl)-2-(6-methoxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3,4-tetrahydroisoquinoline salt salt.

Add 1-(tetrahydropyrrole-1-methyl)-2-(6-methoxy-3-oxo-2,3-dihydro-1H-indene-1-formyl) into a 50ml eggplant-shaped bottle -1,2,3,4-Tetrahydroisoquinoline hydrochloride 0.3g, 40% HBr solution 15ml, heat up to 120°C for 2 hours, after the reaction is complete, remove hydrobromic acid by rotary evaporation, add 10ml to the residue Saturated sodium carbonate solution, a white solid precipitated, filtered, dissolved the solid in methanol, and performed column chromatography with dichloromethane:methanol=35:1 to obtain a colored solid I-1 with a yield of 27.6%, m.p.148～150℃ .

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.90～2.06(4H,m,2×CH ₂ ), 2.43～2.50(1H,m,1/2CH ₂ ), 2.86～3.10( 4H,m,CH ₂ ,2×1/2CH ₂ ),3.40～3.85(6H,m,2×CH ₂ ,2×1/2CH ₂ ),4.30～4.32(1H,d,J=9.6Hz,1 /2CH ₂ ),4.83～4.85(1H,dd,J=3.9Hz,8.3Hz,CH)5.95～5.96(1H,d,J=9.1Hz,CH),6.86～6.87(1H,d,J=9.6 Hz, ArH),7.22～7.29(3H,m,ArH),7.39～7.40(1H,d,J=6.0Hz,ArH),7.46～7.49(1H,m,ArH),9.81(1H,brs,OH ).

MS (ESI (+) 70V, m/z): 391.2 ([M+H] ⁺ , base peak).

Example 2

6-Hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline (I-2)

With 6-methoxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 , 2,3,4-Tetrahydroisoquinoline as raw material, the preparation method is the same as in Example 1, to obtain white solid I-2, the yield is 37.1%, m.p.190～192°C.

¹ H-NMR (500MHz, DMSO-d ₆ ), δ(ppm): 1.94～2.08 (4H, m, 2×CH ₂ ), 2.51～2.88 (3H, m, CH ₂ , 1/2CH ₂ ), 3.02 ～3.20(2H,m,2×1/2CH ₂ ),3.34～3.85(6H,m,2×CH ₂ ,2×1/2CH ₂ ),4.22～4.25(1H,dd,J=5.0Hz,14.2 Hz,1/2CH ₂ ),4.97～4.99(1H,dd,J=4.0Hz,8.5Hz,CH),5.79～5.82(1H,dd,J=2.7Hz,11.4Hz,CH),6.60～6.64( 2H,m,ArH),7.17～7.18(1H,d,J=8.1Hz,ArH),7.52～7.54(1H,d,J=8.1Hz,ArH),7.63～7.65(1H,d,J=8.1 Hz, ArH), 8.03 (1H, s, ArH), 9.41 (1H, brs, OH).

MS (ESI (+) 70V, m/z): 425.2 ([M+H] ⁺ , base peak).

Example 3

6,7-Dihydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2,3 ,4-Tetrahydroisoquinoline (I-3)

With 6,7-dimethoxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1, 2,3,4-Tetrahydroisoquinoline was used as the raw material, and the preparation method was the same as in Example 1 to obtain white solid I-3 with a yield of 28.1% and m.p.248-250°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.75～2.09(4H,m,2×CH ₂ ), 2.50～2.60(1H,m,1/2CH ₂ ), 2.65～2.85( 2H, m, CH ₂ ), 2.88～3.15 (2H, m, 2×1/2CH ₂ ), 3.06～3.50 (4H, m, 2×CH ₂ ), 3.61～3.78 (2H, m, 2×1/2 2CH ₂ ),4.28～4.32(1H,d,J=10.5Hz,1/2CH ₂ ),4.92～4.93(1H,d,J=4.0Hz,CH),5.68～5.71(1H,d,J=9.0 Hz,CH),6.56(1H,s,ArH),6.69(1H,s,ArH),7.45～7.50(1H,m,ArH),7.63～7.78(3H,m,ArH),8.70(1H,brs ,OH), 9.15 (1H,brs,OH).

HRMS (ESI) m/z [M+H] ⁺ Calcd for C ₂₄ H ₂₇ N ₂ O ₄ : 407.1965; Found: 407.1967.

Example 4

6-Hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinone (I-4)

With 6-methoxy-1-(tetrahydropyrrole-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 , 2,3,4-Tetrahydroisoquinoline was used as raw material, and the preparation method was the same as in Example 1 to obtain white solid I-4 with a yield of 38.3% and m.p.282-284°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.85～2.10(4H,m,2×CH ₂ ), 2.52～2.60(1H,m,1/2CH ₂ ), 2.71～2.95( 2H,m,CH ₂ ),3.02～3.22(2H,m,2×1/2CH ₂ ),3.34～3.93(6H,m,2×CH ₂ ,2×1/2CH ₂ ),4.23～4.27(1H ,d,J=10.2Hz,1/2CH ₂ ),4.93～4.94(1H,m,CH),5.78～5.82(1H,d,J=9.7Hz,CH),6.60～6.65(2H,m,ArH ),7.17～7.19(1H,d,J=8.4Hz,ArH),7.34～7.37(1H,m,ArH),7.62～7.65(1H,d,J=8.1Hz,ArH),7.69～7.74(1H , m, ArH), 9.44 (1H, brs, OH.

HRMS (ESI): m/z [M+H] ⁺ Calcd for C ₂₄ H ₂₆ N ₂ O ₃ F: 409.1922; Found: 409.1928.

Example 5

5-Chloro-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline (I-5)

With 5-chloro-8-methoxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 , 2,3,4-Tetrahydroisoquinoline as raw material, the preparation method is the same as that of Example 1 to obtain white solid I-5, the yield is 28.7%, m.p.260～262°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.85～2.10(4H,m,2×CH ₂ ), 2.52～2.58(1H,m,1/2CH ₂ ), 2.68～2.99( 2H, m, CH ₂ ), 2.95～3.17 (2H, m, 2×1/2CH ₂ ), 3.18～3.30 (2H, m, CH ₂ , 3.54～3.62 (1H, m, 1/2CH ₂ ), 3.72 ～3.90(3H,m,CH ₂ ,1/2CH ₂ ),4.38～4.41(1H,d,J=9.1Hz,1/2CH ₂ ),4.98～5.00(1H,m,CH),5.97～6.00( 1H,d,J=9.8Hz,CH),6.82～6.85(1H,d,J=8.6Hz,ArH),7.22～7.25(1H,d,J=8.6Hz,ArH),7.44～7.49(1H, t, J=7.3Hz, ArH), 7.61~7.72 (2H, m, ArH), 7.99~8.01 (1H, d, J=7.6Hz, ArH).

HRMS (ESI): m/z [M+H] ⁺ Calcd for C ₂₆ H ₃₂ N ₃ O ₄ : 425.1626; Found: 425.1635.

Example 6

7-fluoro-1-(tetrahydropyrrole-1-methyl)-2-(6-hydroxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline (I-6)

With 7-fluoro-1-(tetrahydropyrrole-1-methyl)-2-(6-methoxy-3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 , 2,3,4-Tetrahydroisoquinoline was used as the raw material, and the preparation method was the same as in Example 1 to obtain a white solid I-6 with a yield of 38.9% and m.p.218-220°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.95～2.08(4H,m,2×CH ₂ ), 2.50～2.55(1H,m,1/2CH ₂ ), 2.88～3.16( 4H,m,2×1/2CH ₂ ,CH ₂ ),3.30～3.83(6H,m,2×CH ₂ ,2×1/2CH ₂ ),4.28～4.30(1H,m,1/2CH ₂ ), 4.82～4.83(1H,d,J=4.3Hz,CH),5.96～6.00(1H,d,J=9.4Hz,CH),6.86～6.89(1H,dd,J=1.7Hz,8.4Hz,ArH) ,7.11(1H,s,ArH),7.25～7.27(1H,m,ArH),7.35～7.39(1H,dd,J=2.3Hz,9.9Hz,ArH),7.47～7.50(1H,d,J= 8.4Hz, ArH), 9.73 (1H, brs, OH).

HRMS (ESI) m/z [M+H] ⁺ Calcd for C ₂₄ H ₂₆ FN ₂ O ₃ : 409.1922; Found: 409.1928.

Example 7

5-Bromo-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1,2, 3,4-Tetrahydroisoquinoline (I-7)

With 5-bromo-8-methoxy-1-(tetrahydropyrrole-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indene-1-formyl)-1 , 2,3,4-Tetrahydroisoquinoline was used as the raw material, and the preparation method was the same as in Example 1 to obtain white solid I-7 with a yield of 24.7% and m.p.276-278°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.91～2.08(4H,m,2×CH ₂ ), 2.52～2.58(1H,m,1/2CH ₂ ), 2.75～2.88( 2H,m,CH ₂ ),2.95～3.17(3H,m,1/2CH ₂ ,CH ₂ ),3.32～3.37(1H,m,CH ₂ ,3.50～3.54(1H,m,1/2CH ₂ ), 3.72～3.90(3H,m,CH ₂ ,1/2CH ₂ ),4.42～4.45(1H,m,1/2CH ₂ ),4.90～4.92(1H,m,CH),5.95～5.98(1H,d, J=9.6Hz, CH),6.74～6.77(1H,d,J=8.6Hz,ArH),7.39～7.42(1H,d,J=8.6Hz,ArH),7.46～7.51(1H,m,ArH) , 7.63~7.79 (3H, m, ArH), 9.62 (1H, brs, OH).

HRMS (ESI): m/z [M+H] ⁺ Calcd for C ₂₄ H ₂₆ N ₂ O ₃ : 469.1121; Found: 469.1127.

Example 8

5-Chloro-8-hydroxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-formyl)- 1,2,3,4-Tetrahydroisoquinoline (I-8)

With 5-chloro-8-methoxy-1-(tetrahydropyrrole-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indene-1-methyl Acyl)-1,2,3,4-tetrahydroisoquinoline was used as raw material, and the preparation method was the same as in Example 1 to obtain white solid I-8 with a yield of 24.7% and m.p.198-200°C.

¹ H-NMR (300MHz, DMSO-d ₆ ), δ(ppm): 1.85～2.15(4H,m,2×CH ₂ ), 2.48～2.53(1H,m,1/2CH ₂ ), 2.69～2.95( 2H,m,CH ₂ ),2.95～3.17(2H,m,2×1/2CH ₂ ),3.18～3.30(2H,m,CH ₂ ),3.51～3.62(1H,m,1/2CH ₂ ), 3.72～3.95(3H,m,CH ₂ ,1/2CH ₂ ),4.26～4.42(1H,m,1/2CH ₂ ),4.95～5.05(1H,m,CH),5.97～6.00(1H,d, J=10.1Hz, CH), 6.80～6.83(1H,d,J=8.6Hz,ArH),7.22～7.25(1H,d,J=8.6Hz,ArH),7.51～7.54(1H,d,J= 8.1Hz, ArH), 7.62～7.65 (1H, d, J=8.1Hz, ArH), 8.13 (1H, s, ArH).

HRMS (ESI): m/z [M+H] ⁺ Calcd for C ₂₄ H ₂₅ Cl ₂ N ₂ O ₃ : 459.1237; Found: 459.1247.

Claims (4)

1. Tetrahydroisoquinoline hydroxyl derivatives of the general formula (I) or pharmaceutically acceptable salts thereof:

Wherein R ₁ , R ₂ , R ₃ each independently represent hydrogen, halogen, hydroxyl or C ₁ -C ₆ alkyl, and at least one of R ₁ , R ₂ , R ₃ represents hydroxyl. 2. The tetrahydroisoquinoline hydroxyl derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ , R ₂ , R ₃ each independently represent hydrogen, fluorine, chlorine, bromine, hydroxyl or methyl. 3. A pharmaceutical composition, which contains the tetrahydroisoquinoline hydroxyl derivative or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier. 4. The use of the tetrahydroisoquinoline hydroxyl derivatives or pharmaceutically acceptable salts thereof according to claim 1 for the preparation of analgesic drugs.