CN103450079B - Tetrahydroisoquinoline hydroxy derivatives, its preparation method and medicinal use thereof - Google Patents

Tetrahydroisoquinoline hydroxy derivatives, its preparation method and medicinal use thereof Download PDF

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CN103450079B
CN103450079B CN201310352804.3A CN201310352804A CN103450079B CN 103450079 B CN103450079 B CN 103450079B CN 201310352804 A CN201310352804 A CN 201310352804A CN 103450079 B CN103450079 B CN 103450079B
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indenes
arh
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pyrrolidine
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徐云根
甘宗捷
宋巧
陈洁
张迪
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China Pharmaceutical University
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Abstract

The invention belongs to medicinal chemistry art, be specifically related to tetrahydroisoquinoliderivatives hydroxy derivatives, composition containing this hydroxy derivatives, and described derivative or composition are as the purposes of κ-opioid receptor agonist at ease pain.Pharmacodynamics test proves compound of the present invention, and not only analgesic activity is strong, and central calmness and anxiety side effect can be made obviously to reduce, and overcomes the side effect of existing analgesic.

Description

Tetrahydroisoquinoline hydroxy derivatives, its preparation method and medicinal use thereof
Technical field
The invention belongs to medicinal chemistry art, be specifically related to tetrahydroisoquinoliderivatives hydroxy derivatives, composition containing this hydroxy derivatives, and described derivative or composition are as the purposes of κ-opioid receptor agonist at ease pain.
Background technology
After κ-opioid receptor agonist is combined with κ-opiate receptor, except can producing potent analgesic activity, because κ-opiate receptor does not participate in analgesia and the reward effect of morphine, the precipitated morphine withdrawal of animal and human can be alleviated, and can also the respiration inhibition effect of antagonism μ-opioid receptor agonist, from the 1980s, become the focus of analgesia area research.
Indenes quinolizidine morpholine (structural formula is as follows) is the novel κ-opioid receptor agonist of a class, this compound has good κ-opiate receptor affinity and μ/κ-opiate receptor selectivity, but mouse runner test and mouse elevated plus-maze experiment find, indenes quinolizidine morpholine shows the calmness of obvious central and anxiety side effect.
Indenes quinolizidine morpholine
There are some researches show at present, κ-opiate receptor does not exist only in central nervous system, and is present in the different tissues organ of periphery, as internal organ and visceral afferent volley nerve etc., is called periphery property κ-opiate receptor.Selectivity exciting periphery κ-opiate receptor, not only can alleviate or diminish inflammation, internal organ and neuropathic chronic pain, and can avoid or alleviate the side effects such as the calm and anxiety of central, the therapeutic quality of raising pain.Indenes quinolizidine morpholine compounds owing to entering central nervous system, excitomotor center κ-opiate receptor and produce maincenter side effect.
Summary of the invention
The invention discloses the tetrahydroisoquinoline hydroxy derivatives shown in general formula (I):
Wherein R 1, R 2, R 3represent hydrogen, halogen, hydroxyl or C independently of one another 1-C 6alkyl, and R 1, R 2, R 3in at least one representation hydroxy.
More preferably compound is as follows:
1-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
6-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
6,7-dihydroxyl-1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
6-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-Tetrahydroisoquinoli-s;
The chloro-8-hydroxyl of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
The fluoro-1-of 7-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
The bromo-8-hydroxyl of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
5-chloro-8-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines.
Pharmacodynamics test proves, general formula of the present invention (I) compound not only analgesic activity is strong, and central calmness and anxiety side effect can be made obviously to reduce, and overcomes the side effect of existing analgesic.
General formula of the present invention (I) compound can be prepared by following two kinds of methods:
(1) with reference to the preparation method (CN1887872) of indenes quinolizidine morpholine, sour for raw material with substituted-tetrahydro pyrroles-1-methyl tetrahydroisoquinoline and replacement indone, under dicyclohexylcarbodiimide (DCC) and DMAP (DMAP) catalysis, obtain Ia through condensation.
(2) with general formula I a compound for raw material, under the effect of dealkylation agent, demethylation protecting group obtains tetrahydroisoquinoline hydroxy derivatives I.Dealkylation agent is selected from 48% hydrobromic acid aqueous solution, boron tribromide dichloromethane solution, pyridine hydrochloride, hydroiodic acid HI or aluminum chloride, preferably 48% hydrobromic acid aqueous solution or boron tribromide dichloromethane solution.
General formula of the present invention (I) compound can form acid salt with acid, and be also pharmacy acceptable salt, they have the same pharmacologic effect of same general formula (I) compound.Described acid is selected from: phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, tosic acid, oxysuccinic acid, methanesulfonic or its analogue etc.
Compound (I) or its pharmacy acceptable salt can make various preparation by adding pharmaceutically acceptable carrier.Clinical for oral, injection etc.
Compound of the present invention (I) Doses used in clinical practise is 0.01mg ~ 1000mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or formulation.
Here is part pharmacodynamics test and the result of the compounds of this invention, the same embodiment of the structure that test portion compound numbers is corresponding.
One, opiate receptor affinity research (radioligand-binding study)
Experimental technique:
Experiment point total binding pipe and non-specific binding pipe, separately establish several groups of sample hoses to add different concns competition part.Total binding pipe add the expression being equivalent to 20 μ g membrane receptor protein and [ 3h] diprenorphine (0.5nM) (1.44Pbq.mol -1wide spectrum opiate antagonist, Amersham company), corresponding non-specific binding pipe separately adds Narlan (the wide spectrum opiate antagonist of 1 μM, Sigma company), sample hose adds different concns compound to be screened, is adjusted to final volume 100 μ l with 50mM Tris (Amresco company)-HCl (pH7.4).Hatch 30min at 30 DEG C, then put termination reaction in frozen water.Through GF/ (Whatman) glass fiber filter paper negative pressure leaching on Millipore sample divider.Three times are rinsed with ice-cold 50mM Tris-HCl (pH7.4), each 4ml, after filter paper is dried, be placed in 0.5ml Eppendorff to manage, add 0.5ml lipophilic scintillation solution (Shanghai reagent one factory), Beckman LS6500 full-service fluid scintillation counter measures radioactive intensity, calculates inhibiting rate, each concentration is three multiple pipes, independent experiment 3-4 time each time.
Method of calculation:
According to inhibiting rate, with Prism4.0 computed in software IC 50value.
K i=IC 50/ (1+ [L]/K d), ([L] is the concentration of added tagged ligand, K dbalance dissociation parameters for radioligand).The results are shown in Table 1:
Table 1 part of compounds and competitive radioligand binding tests and binding affinity (the κ K to κ-acceptor i)
Above data show, tetrahydroisoquinoline hydroxy derivatives of the present invention still has stronger avidity to κ-opiate receptor, and to the avidity of κ-opiate receptor apparently higher than μ-opiate receptor.
Two, sedative effect research
Experiment establishes following several groups:
Physiological saline group: 10/group, only, 15min pneumoretroperitoneum injects 0.6% Glacial acetic acid 0.2ml to subcutaneous injection physiological saline 0.2ml/, observes writhing number of times in 15min;
Embodiment group: establish 3 various dose groups, 10/group, subcutaneous injection is by reagent 1ug/kg respectively for each group, and 5ug/kg, 10ug/kg, 15min pneumoretroperitoneum injects 0.6% Glacial acetic acid 0.2ml, observes writhing number of times in 15min, calculates analgesia ED 50value.
Utilize rotary wheel device, new mouse is placed on runner respectively, record the time that it falls down from runner, first screen before formal experiment, if the mouse fallen down in 60s, reject.Random 10 points one group of qualified mouse, give various dose indenes quinolizidine morpholine and by after reagent, record the time of falling down from runner, repeat to average for twice, calculate calm ED 50the same.The calm side effect of maincenter by reagent is evaluated by therapeutic index.Therapeutic index=calm ED 50/ analgesia ED 50, therapeutic index is higher, and calm side effect is less.Data are in table 2.
The analgesia of table 2 part of compounds and calm ED 50value and therapeutic index
Table 2 data show, indenes quinolizidine morpholine hydroxy derivatives of the present invention is all obviously greater than indenes quinolizidine morpholine relative to the therapeutic index of calmness, illustrates under analgesia therapy dosage, and their calm side effect is less, and analgesia and sedative effect can effectively separate.
Three, anxiety Effect study
Experimental technique
Mouse gave by reagent after 15 minutes, be placed on the middle junction that Elevated plus-maze open arms closes arm, face open arms, the residence time that in 5 minutes, record enters open arms or closes arm accounts for the per-cent of total time as evaluation index, enters to close arm and rest on the time of closing arm to reflect anxiety behavior.Data are in table 3.
The elevated plus-maze test result of table 3 Compound I-1, I-2 and I-6
Table 3 data show, I-1, I-2 and I-6 rest on per-cent basic indifference compared with blank of the time of closing arm under 1.25mg/kg dosage, show under low dosage without causing anxiety effect; Under 2.5mg/kg dosage, I-1, I-2 and I-6 only cause LA; Under 3.75mg/kg dosage, I-1 and I-6 only causes moderate anxiety, and I-2 still only causes LA.And indenes quinolizidine morpholine can cause severe anxiety under high dosage (5 μ g/kg).
Embodiment
Embodiment 1
1-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-1)
With reference to the synthetic method of indenes quinolizidine morpholine; with 1-(Pyrrolidine-1-methyl)-1; 2; 3; 4-tetrahydroisoquinoline and 6-methoxyl group-3-oxo-2; 3-dihydro-1H-indenes-1-carboxylic acid is raw material; under dicyclohexylcarbodiimide (DCC) and DMAP (DMAP) catalysis, condensation prepares 1-(Pyrrolidine-1-methyl)-2-(6-methoxyl group-3-oxo-2; 3-dihydro-1H-indenes-1-formyl radical)-1; 2; 3,4-four hydrogen isoquinoline hydrochloric acid salt.
1-(Pyrrolidine-1-methyl)-2-(6-methoxyl group-3-oxo-2 is added in 50ml eggplant-shape bottle; 3-dihydro-1H-indenes-1-formyl radical)-1; 2; 3; 4-four hydrogen isoquinoline hydrochloric acid salt 0.3g, the HBr solution 15ml of 40%, be warming up to 120 DEG C of reaction 2h; reaction is finished; rotary evaporation removing Hydrogen bromide, in residue, add 10ml saturated sodium carbonate solution, white solid is separated out; filter; after solids with methanol dissolves, with methylene dichloride: methyl alcohol=35:1 carries out column chromatography, get Bao Se solid I-1; yield 27.6%, m.p.148 ~ 150 DEG C.
1H-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=9.6Hz,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)。
Embodiment 2
6-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-2)
With 6-methoxyl group-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-2, yield 37.1%, m.p.190 ~ 192 DEG C.
1H-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,14.2Hz,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=8.1Hz,ArH),8.03(1H,s,ArH),9.41(1H,brs,OH)。
MS(ESI(+)70V,m/z):425.2([M+H] +,base peak)。
Embodiment 3
6,7-dihydroxyl-1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-3)
With 6,7-dimethoxy-1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-3, yield 28.1%, m.p.248 ~ 250 DEG C.
1H-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,2×1/2CH 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=9.0Hz,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 24H 27N 2O 4:407.1965;Found:407.1967。
Embodiment 4
6-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-Tetrahydroisoquinoli-s (I-4)
With 6-methoxyl group-1-(Pyrrolidine-1-methyl)-2-(6-fluoro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-4, yield 38.3%, m.p.282 ~ 284 DEG C.
1H-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 24H 26N 2O 3F:409.1922;Found:409.1928。
Embodiment 5
The chloro-8-hydroxyl of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-5)
With the chloro-8-methoxyl group of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-5, yield 28.7%, m.p.260 ~ 262 DEG C.
1H-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 26H 32N 3O 4:425.1626;Found:425.1635。
Embodiment 6
The fluoro-1-of 7-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-6)
With the fluoro-1-of 7-(Pyrrolidine-1-methyl)-2-(6-methoxyl group-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-6, yield 38.9%, m.p.218 ~ 220 DEG C.
1H-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 24H 26FN 2O 3:409.1922;Found:409.1928。
Embodiment 7
The bromo-8-hydroxyl of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-7)
With the bromo-8-methoxyl group of 5--1-(Pyrrolidine-1-methyl)-2-(3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-7, yield 24.7%, m.p.276 ~ 278 DEG C.
1H-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 24H 26N 2O 3:469.1121;Found:469.1127。
Embodiment 8
5-chloro-8-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines (I-8)
With 5-chloro-8-methoxyl group-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline is raw material, and preparation method is with embodiment 1; obtain white solid I-8, yield 24.7%, m.p.198 ~ 200 DEG C.
1H-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 24H 25Cl 2N 2O 3:459.1237;Found:459.1247。

Claims (3)

1. the tetrahydroisoquinoline hydroxy derivatives of following arbitrary structure or its pharmacy acceptable salt:
1-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
6-hydroxyl-1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines;
The fluoro-1-of 7-(Pyrrolidine-1-methyl)-2-(6-hydroxyl-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinolines.
2. a pharmaceutical composition, wherein containing the tetrahydroisoquinoline hydroxy derivatives of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
3. the tetrahydroisoquinoline hydroxy derivatives of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes of analgesic.
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