CN102060764A - Tetrahydroisoquinoline derivative, preparation method and application thereof - Google Patents

Tetrahydroisoquinoline derivative, preparation method and application thereof Download PDF

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CN102060764A
CN102060764A CN 201010603303 CN201010603303A CN102060764A CN 102060764 A CN102060764 A CN 102060764A CN 201010603303 CN201010603303 CN 201010603303 CN 201010603303 A CN201010603303 A CN 201010603303A CN 102060764 A CN102060764 A CN 102060764A
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dimethoxy
nitro
tetrahydroisoquinoline
vinyl
compound
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黄文龙
邹志红
蓝晓步
钱海
唐春雷
朱孝云
刘保民
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to a novel tetrahydroisoquinoline derivative, i.e. a compound in a general formula (I) and a pharmaceutically acceptable salt thereof. The invention also provides application of the novel tetrahydroisoquinoline derivative, in particular application to inhibiting multidrug resistance and improving the treatment effect of antitumor drugs.

Description

Tetrahydro isoquinoline derivative, Preparation Method And The Use
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to tetrahydro isoquinoline derivative and pharmacy acceptable salt, and preparation method thereof and as the purposes of multidrug resistance reversing agent.
Background technology
Chemicals has crucial status and development prospect in the complex therapy of this systemic disease of treatment malignant tumour.At present, resistance has become one of the most common and problem of being difficult to overcome most of the failure of chemotherapy of tumors clinically.In the multiple mode of drug resistance of tumor cell, with multidrug resistance (multidrug resistance, MDR) more common.The characteristics of MDR are meant that tumour cell has also produced resistance to other structures antitumor drug different with mechanism of action simultaneously to a kind of antitumor drug is drug-fast.MDR has become the major reason that a lot of chemotherapeutics lost efficacy.The MDR reversal agents of clinical study at present is based on calcium antagonist, and wherein representing medicine is verapamil, and this class reversal agent has definite reverse curative effect, but it is single-minded not strong to exist effect, and reverse is active low, and is accompanied by serious cardiovascular side effects.In the tetrahydroisoquinolicompounds MDR reversal agents of exploitation in the past, the active compound overwhelming majority preferably shows higher fat-soluble, and pharmacokinetic property is bad, becomes deficiencies such as property of medicine difference.Therefore it is active strong to seek reversion MDR, and the low and good medicine that becomes the property of medicine of side effect becomes the technological difficulties of this research direction most critical.
Summary of the invention
The object of the present invention is to provide new tetrahydro isoquinoline derivative, i.e. general formula (I) compound and pharmacy acceptable salt thereof:
Figure BSA00000396685900011
The purposes of the tetrahydro isoquinoline derivative that the present invention also aims to provide new, the purposes of reverse multiple drug resistance of tumor specifically is used to improve the curative effect of antitumour drug.
The present invention relates to a kind of new tetrahydro isoquinoline derivative, general formula (I) compound promptly as follows and pharmacy acceptable salt thereof:
Figure BSA00000396685900012
Wherein X is selected from CH or N;
R wherein 1Be selected from:
Figure BSA00000396685900013
R wherein 2Be selected from:
Figure BSA00000396685900014
R 3Be selected from carbonatoms and be 1～8 straight chain saturated alkyl or branched-chain alkyl;
R 4Be selected from carbonatoms and be 3～6 saturated cyclic alkyls;
N is 0～4.
The preferred compound of tetrahydro isoquinoline derivative of the present invention is:
6,7-dimethoxy-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 1);
6,7-dimethoxy-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 2);
6,7-dimethoxy-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 3);
6,7-dimethoxy-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 4);
6,7-dimethoxy-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 5);
6,7-dimethoxy-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 6);
6,7-dimethoxy-2-(1-benzamido group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 7);
6,7-dimethoxy-2-{1-[1-(4-methylpiperazine base)]-the 2-nitro } vinyl-1,2,3,4-tetrahydroisoquinoline (I 8);
1,1 '-two [(6, the 7-dimethoxy)-1,2,3,4-tetrahydro isoquinolyl]-2-nitroethylene (I 9);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 10);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 11);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 12);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 13);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 14);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 15);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 16);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 17);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 18);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 19);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 20);
6,7-dimethoxy-1-Phenoxymethyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 21);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 22);
6,7-dimethoxy-1-Phenoxymethyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 23);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 24);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 25);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 26);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 27);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 28);
6,7-dimethoxy-1-(α-menaphthyl)-2-[1-(3, the 4-dimethoxy)-phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 29);
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 30);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 31);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 32);
6,7-dimethoxy-1-Phenoxymethyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 33);
6,7-dimethoxy-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 34).
Wherein the structural formula of above-claimed cpd further is:
Figure BSA00000396685900032
Figure BSA00000396685900041
According to tetrahydro isoquinoline derivative of the present invention, its pharmacy acceptable salt includes but not limited to the acid salt with following acid formation: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, citric acid, tartrate, lactic acid, pyruvic acid, toxilic acid, Phenylsulfonic acid, succsinic acid, pentanedioic acid or fumaric acid.
Embodiment: according to tetrahydro isoquinoline derivative of the present invention, its compound of Formula I can prepare according to following method:
3,4-dimethoxy-phenylethylamine (compound 2) reacts the compound of making 3 with substituted acetic acid under 190 ℃ of condition of no solvent, compound 3 refluxes in dry toluene under the phosphorus oxychloride existence condition and obtains compound 4, compound 4 is under anhydrous methanol is made solvent condition, add the catalytic amount diethylamine, obtained compound 5 by potassium borohydride reduction, compound 5 and 1,1-diformazan sulfenyl-2-nitroethylene refluxes in dry toluene and obtains compound 6, and compound 6 reacts in dry toluene with the amine that replaces and promptly obtains target compound I.Compound 5 refluxes in dehydrated alcohol with S-methyl-N-nitro isothiourea and obtains target compound I.Compound I and acid-respons promptly obtain corresponding salt.
Figure BSA00000396685900052
Pharmacologically active experiment: below be the pharmacology test data of part of compounds of the present invention:
1, external reversing tumor cell MDR activity test
[laboratory apparatus and material]
Cell strain: K562/A02 (human erythroleukemia cell's persister)
Medicine and reagent:
Verapamil (VRP): Shanghai Hefeng Pharmaceutical Co., Ltd., lot number: 0306261
RPMI Medium 1640: U.S. GIBCO BRL company product
New-born calf serum: U.S. GIBCO company product
Thiazolyl blue (MTT): Nanjing Sai Ji Science and Technology Ltd.
Dimethyl sulfoxide (DMSO) (DMSO): Shanghai Ling Feng chemical reagent company limited, lot number: 051225
Instrument:
CO 2Incubator: Forma 3111 water-jacket typ CO 2Incubator, U.S. Thermo Electron
Corporation
Bechtop: SW-CJ-1F type clean bench, SuZhou Antai Air Tech Co., Ltd. of Jiangsu Su Jing group product
Inverted microscope: CKX41 inverted phase contrast microscope, Japanese Olympus product
Microplate reader: BIO-RAD MODE 1680 type microplate reader, Britain Bio-Rad Laboratories Ltd
Electronic balance: BS224S Beijing Sai Duolisi instrument system company limited
DK-8D type electric heating constant temperature tank, precision equipment company limited in Shanghai produces
The vertical steam sterilizer of YXQ-LS-50S II digital display, Medical Equipment Plant of Shanghai Boxun Industrial Co., Ltd.
Main solution:
(1) 1640 cell culture fluid: RPMI 1640 10.4g, NaHCO 32.1g, penicillin 100,000 units, Streptomycin sulphate 100,000 units, add tri-distilled water and dissolve to 1000mL, stirred filtration sterilization 4 hours.
(2) calf serum: 56 ℃ of water-baths deactivation in 30 minutes, after the packing in-20 ℃ of preservations.
(3) PBS:NaCl 8.00g, KCl 0.20g, NaHPO 412H 2O 3.49g, KH 2PO 40.20g, fully dissolve with tri-distilled water, be settled to 1000mL.Autoclaving, 4 ℃ of preservations are standby.
(4) MTT working fluid: get 25mg MTT and put into small beaker, add 5mLPBS, stirring is 30 minutes on the electromagnetic force stirrer, fully dissolving, and with the millipore filter degerming of 0.22 μ m, 4 ℃ keep in Dark Place, effective in 2 weeks.
(5) test-compound:, add PBS and be diluted to desired concn with the DMSO dissolving.
[experimental technique]
The K562A/02 cell is with containing RPMI 1640 substratum of 10% calf serum at 37 ℃, 5%CO 2Cultivate under the condition of saturated humidity.The cell of taking the logarithm vegetative period is with 1 * 10 5/ mL density is inoculated in 96 well culture plates, and every hole 160 μ L are at 37 ℃, 5%CO 2Cultivate under the condition of saturated humidity, be divided into blank group, test-compound group, positive controls.Add Zorubicin and different test-compounds in the test-compound group; Positive controls gives 10 μ mol/L verapamils; The blank group gives isopyknic PBS.The administration volume is 20 μ L.Cultivated again 48 hours, and added the MTT working fluid, centrifugal behind the 4h, the nutrient solution that inclines, every hole adds 150 μ L DMSO dissolving, reads optical density(OD) in wavelength 492nm place then on microplate reader, the influence of the survival rate of computerized compound pair cell.Cell inhibitory rate=1-(test group OD mean value/control group OD mean value) * 100%, test-results sees Table 1.
Table 1MTT method detect test-compound to the multi-medicine tolerant reversal activity of K562/A02 cell (± s, n=6)
Figure BSA00000396685900061
As can be seen from the test results, test-compound all has MDR and reverses activity, and I 2, I 13, I 19, I 20, I 29And I 33Active in verapamil.
2, cell in vitro poison test
[laboratory apparatus and material]
Instrument CO 2Incubator (U.S. Thermo Electron Corporation)
SW-CJ-1F type clean bench (SuZhou Antai Air Tech Co., Ltd.)
CKX41 inverted phase contrast microscope (Japanese Olympus)
BIO-RAD MODE 1680 type microplate reader (Britain Bio-Rad Laboratories Ltd)
BS224S electronic balance (Beijing Sai Duolisi instrument system company limited)
DK-8D type electric heating constant temperature tank (production of Shanghai precision equipment company limited)
The vertical steam sterilizer of YXQ-LS-50S II digital display (Shanghai Medical Equipment Plant of rich fast industrial corporation)
Material cell strain: K562 (human erythroleukemia cell's strain)
Vincristine sulphate: Haizheng Medicine Stock Co., Ltd., Zhejiang Prov, lot identification mark: 060702
RPMI Medium 1640: U.S. GIBCO BRL company product
New-born calf serum: U.S. GIBCO company product
MTT: Nanjing Sai Ji Science and Technology Ltd.
Dimethyl sulfoxide (DMSO) (DMSO): Shanghai Ling Feng chemical reagent company limited, lot number: 051225
[experimental technique]
The K562 cell is with containing RPMI 1640 substratum of 10% calf serum at 37 ℃, 5%CO 2Cultivate under the condition of saturated humidity.The cell of taking the logarithm vegetative period is with 1 * 10 5/ mL density is inoculated in 96 well culture plates, and every hole 180 μ L are at 37 ℃, 5%CO 2Cultivate under the condition of saturated humidity, be divided into blank group, test-compound group, positive controls.Add different test-compounds in the test-compound group, final concentration is 10 μ mol/L; Positive controls gives 1 μ mol/L vincristine(VCR); The blank group gives isopyknic PBS.The administration volume is 20 μ L.Cultivated again 48 hours, add the MTT working fluid, centrifugal behind the 4h, the nutrient solution that inclines, every hole add 150 μ L DMSO dissolving, and be centrifugal, nutrient solution inclines, every hole adds 150 μ L DMSO dissolving, reads optical density(OD) in wavelength 492nm place then on microplate reader, the influence of the survival rate of computerized compound pair cell.Cell survival rate=(test group OD mean value/control group OD mean value) * 100%, test-results sees Table 2.
Table 2 with mtt assay measure test-compound to the cytotoxicity of K562 cell strain (± s, n=9)
Test-compound concentration: 10 μ mol/L
As can be seen, most compounds do not have influence to the cell survival rate of K562 cell, do not have cytotoxicity from experimental data.
Embodiment:
Embodiment 1:6,7-dimethoxy-3,4-dihydro-isoquinoline (4a)
40g (0.22mol) 3, the 4-dimethoxy-phenylethylamine mixes with 18.4g 36% (0.22mol) formaldehyde, be warming up to 100 ℃ gradually, refluxed 30 minutes, stop heating, cold slightly back (yellow oil water mixture) suction pipe is inhaled and is removed upper water solution, add the hydrochloric acid of 4 times of amounts 23% then, the reaction solution evaporate to dryness is got pale brown look solid, with 200ml 95% ethyl alcohol recrystallization, get the 35g white, needle-shaped crystals, to go into to add strong aqua 45ml in this crystal, be heated to complete molten no dope slightly, use dichloromethane extraction, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying filters evaporate to dryness, gets yellow solid powder 28.5g, yield: 67.9%, be directly used in the next step.
Embodiment 2:6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a)
4a is dissolved in the 160ml methyl alcohol with 28.5g (0.15mol) compound, adds POTASSIUM BOROHYDRIDE 16g (0.38mol) under the ice-water bath in batches, stirs 22h under room temperature.Reaction solution is slowly poured in the 500ml icy salt solution, and standing over night allows the abundant hydrolysis of POTASSIUM BOROHYDRIDE.With methylene dichloride (100ml * 3) extraction, saturated common salt is washed to neutrality, and anhydrous sodium sulfate drying filters evaporate to dryness, gets 26.1g white solid 5a, yield: 92%.mp：74-76℃。
Embodiment 3:N-(3, the 4-dimethoxy) styroyl-(3, the 4-dimethoxy) phenylacetamide (3b)
With 3,4-dimethoxy-phenylethylamine (underpressure distillation, 140-170/1mmHg cut) 19.7g (0.106mol) and 3,4-dimethoxyphenylacetic acid 20.0g (0.102mol) mixes, logical nitrogen slowly is heated to 190 ℃, has aqueous vapor to produce, the whole fusions of solid, insulation reaction 3h is put and is chilled to room temperature, adds chloroform 150ml dissolving, chloroform solution is washed to neutrality, anhydrous Na with 3% hydrochloric acid, clear water, the 3%NaOH aqueous solution, saturated common salt successively 2SO 4Drying, decompression are steamed extremely near doing, and be cold slightly, adds ether 100ml, and jog is separated out white solid, filters, and gets white solid 32g, yield: 87%, and mp:121-123 ℃.
Embodiment 4:N-(3, the 4-dimethoxy) styroyl-benzene acetamide oxide (3c)
3,4-dimethoxy-phenylethylamine 30.5g (0.168mol), phenoxy acetic acid 25.2g (0.152mol), the preparation method gets white solid 44.2g, yield 92% with reference to embodiment 3.
Embodiment 5:N-(3, the 4-dimethoxy) styroyl-α-naphthalene acetamide (3d)
With 3,4-dimethoxy-phenylethylamine 47.0g (0.259mol) mixes with naphthylacetic acid 44g (0.235mol), and the preparation method gets pale solid 58.2g, yield with reference to embodiment 3: 71%, and mp:110-112 ℃.
Embodiment 6:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-3,4-dihydro-isoquinoline (4b)
Compound 3b 31.5g (0.088mol) is dissolved in dry toluene 50ml, slowly adds POCl 330ml (0.33mol), mixing, logical nitrogen stirs, and in 120 ℃ of backflow 2.5h, reaction solution is a reddish-brown, has a large amount of gases to generate, and reaction back ice bath downhill reaction liquid is slowly poured frozen water decomposed P OCl into 3, add ethyl acetate 50ml extraction, divide the water intaking layer, transfer to pH8-9 with strong aqua, use chloroform extraction again, saturated common salt is washed to the center, anhydrous Na 2SO 4Drying boils off solvent, gets reddish-brown syrup thing crude product 28.8g, yield: 97.2%, be directly used in the next step.
Embodiment 7:6,7-dimethoxy-1-Phenoxymethyl-3,4-dihydro-isoquinoline (4c)
With compound 3c 44.2g (0.140mol), dry toluene 60ml, POCl 350ml (0.532mol), preparation method get light yellow solid 40.6g, yield with reference to embodiment 6: 97%, be directly used in the next step.
Embodiment 8:6,7-dimethoxy-1-(α-menaphthyl)-3,4-dihydro-isoquinoline (4d)
With compound 3d 58.2g (0.167mol), dry toluene 65ml, POCl 358ml (0.633mol), preparation method get tawny oily matter 54.5g, yield with reference to embodiment 6: 98%, be directly used in the next step.
Embodiment 9:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-1,2,3,4-tetrahydroisoquinoline (5b)
Mix in methyl alcohol 80ml compound 4b 28.8g (0.083mol) is outstanding, drip diethylamine 0.3ml, stir down under the room temperature, add 8.8g (0.166mol) KBH in batches 4, continue to stir 25h, slowly pour the 500ml icy salt solution into, separate out yellow syrup thing, the layer that anhydrates that inclines, with methylene dichloride dissolving syrup thing, saturated appetite is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets reddish-brown oily matter 27.4g, yield: 95%, be directly used in the next step.
Embodiment 10:6,7-dimethoxy-1-Phenoxymethyl-1,2,3,4-tetrahydroisoquinoline (5c)
With compound 4c 40.6g (0.136mol), methyl alcohol 110ml, diethylamine 0.5ml, the preparation method is with reference to embodiment 10, reaction solution is poured into has solid to separate out in the icy salt solution, filter washing, oven dry, get white solid 39.8g, yield: 98%, be directly used in the next step.
Embodiment 11:6,7-dimethoxy-1-(α-naphthalene ethyl)-1,2,3,4-tetrahydroisoquinoline (5d)
With compound 4d 54.5g (0.162mol), methyl alcohol 120ml drips diethylamine 0.5ml, and the preparation method gets reddish-brown oily matter 54g, yield with reference to embodiment 9: 99%, be directly used in the next step.
Embodiment 12:6,7-dimethoxy-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 1)
Compound 5a 9.7g (50mmol), 1,1-diformazan sulfenyl-2-nitroethylene 11.6g (70mmol) is in 100ml acetone, 60 ℃ of backflows of temperature control, reaction 18h, evaporated under reduced pressure filtrate, resistates 50ml dehydrated alcohol heating for dissolving, there is yellow needle-like solid to separate out (being excessive reaction raw materials 1,1-diformazan sulfenyl-2-nitroethylene) after the cooling, filters, column chromatography for separation (sherwood oil: ethyl acetate 2: 1), get yellow solid 10.9g, yield: 70%, mp:130-132 ℃.
1HNMR(CDCl 3，300M)δ：2.51(s，3H，SCH 3)，2.94(t，2H，C 4-H)，3.84，3.86(s，6H，2×OCH 3)，3.96(t，2H，C 3-H)，4.58(s，2H，C 1-H)，6.55(s，1H，C＝CH(NO 2))，6.64，6.72(each?s，2H，C 5-H，C 8-H)；
MS(70eV)m/z：[M+H] +311.1，[M+Na] +333.1。
Embodiment 13:6,7-dimethoxy-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 2)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, and adding n-octyl amine 3.3ml (2.6g, 20mmol), temperature control 60-70 ℃, reaction 16h, pressure reducing and steaming solvent, column chromatography for separation (ethyl acetate: sherwood oil=1: 1), get white solid 0.52g, yield: 53%, mp:100-102 ℃.
1HNMR(CDCl 3，300M)δ：0.91(t，3H，CH 2 CH 3)，1.31-1.73(m，13H，N HCH 2， (CH 2) 6CH 3)，2.92(t，2H，C 4-H)，3.37，(m，2H，NH CH 2 )，3.55(t，2H，C 3-H)，3.89，3.90(s，6H，2×OCH 3)，4.35(s，2H，C 1-H)，6.58(s，1H，C＝CH(NO 2))，6.62，6.67(each?s，2H，C 5-H，C 8-H)；
IR(KBr，cm -1)：3451，2952，2924，2854，1598，1534，1518，1462，1306；
MS(70eV)m/z：[M+H] +392.1；
Anal.Calcd.for?C 21H 33N 3O 4：C?64.42，H?8.50，N?10.73；
Found：C?64.45，H?8.27，N?10.86。
Embodiment 14:6,7-dimethoxy-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 3)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, and adding normal hexyl Amine 2.0ml (1.5g, 15mmol), the preparation method gets white solid 0.51g, yield with reference to embodiment 13: 56%, mp:86-88 ℃.
1HNMR(CDCl 3，300M)δ：0.88(t，3H，CH 2 CH 3)，1.30-1.68(m，8H， (CH 2) 4CH 3)，2.88(t，2H，C 4-H)，3.33，(m，2H，NH CH 2 )，3.52(t，2H，C 3-H)，3.86(s，6H，2×OCH 3)，4.31(s，2H，C 1-H)，6.55(s，1H，C＝CH(NO 2))，6.58，6.63(each?s，2H，C 5-H，C 8-H)；
IR(KBr，cm -1)：3243，3150，2949，2926，2869，2850，1610，1518，1448，1374；
MS(70eV)m/z：[M+H] +364.1，[M+Na] +386.2；
Anal.Calcd.for?C 19H 29N 3O 4：C?62.79，H?8.04，N?11.56；
Found：C?62.54，H?5.21，N?11.64。
Embodiment 15:6,7-dimethoxy-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 4)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, and adding hexahydroaniline 1.2ml (1.0g, 10mmol), temperature control 60-70 ℃, reaction 24h, pressure reducing and steaming solvent, column chromatography for separation (ethyl acetate: sherwood oil=1: 2), get white solid 0.58g, yield: 64%, mp:146-148 ℃.
1HNMR(CDCl 3，300M)δ：1.35-1.94(m，10H，5×CH 2)，2.88(t，2H，C 4-H)，3.44(m，H，NH CH)，3.54(t，2H，C 3-H)，3.86(s，6H，2×OCH 3)，4.32(s，2H，C 1-H)，6.56(s，1H，C＝CH(NO 2))，6.58，6.64(each?s，2H，C 5-H，C 8-H)；
IR(KBr，cm -1)：3239，3155，2938，2922，2850，1614，1516，1455，1392，1369；
MS(70eV)m/z：[M+H] +362.2，[M+Na] +384.2；
Anal.Calcd.for?C 19H 27N 3O 4：C?63.14，H?7.53，N?11.63；
Found：C?62.91，H?7.70，N?11.60。
Embodiment 16:6,7-dimethoxy-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 5)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, and adding phenylethylamine 1.0ml (0.97g, 8mmol), temperature control 60-70 ℃, reaction 8h, the pressure reducing and steaming solvent, ethyl acetate-sherwood oil recrystallization gets white solid 0.54g, yield: 56%, mp:150-152 ℃.
1HNMR(CDCl 3，300M)δ：3.82-2.84(m，3H，C 4-H，N HCH 2)，2.97(t，2H，ArCH 2)，3.43(m，2H，C 3-H)，3.60(m，2H，NH CH 2 )，3.85(s，6H，2×OCH 3)，4.21(s，2H，C 1-H)，6.49-6.61(each?s，3H，C＝CH(NO 2)，C 5-H，C 8-H)，7.26(m，5H，Ar-H)；
IR(KBr，cm -1)：3415，3240，3152，3027，1612，1582，1518，1450，1374，1357；
MS(70eV)m/z：[M+H] +384.2，[M+Na] +406.1；
Anal.Calcd.for?C 21H 25N 3O 4：C?65.78，H?6.57，N?10.96；
Found：C?66.62，H?6.84，N?11.70。
Embodiment 17:6,7-dimethoxy-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 6)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, add 3,4-dimethoxy-phenylethylamine 1ml (1.1g, 5mmol), preparation method embodiment 13, get white solid 0.75g, yield: 68%, mp:152-154 ℃
1HNMR(CDCl 3，300M)δ：2.82-2.92(m，4H，C 4-H，ArCH 2)，3.41(t，2H，C 3-H)，3.57(m，2H，NH CH 2 )，3.84(s，12H，4×OCH 3)，4.19(s，2H，C 1-H)，6.56-7.30(m，6H，C＝CH(NO 2)，Ar-H)；
IR(KBr，cm -1)：3444，3241，2931，2830，1590，1520，1464，1442，1359；
MS(70eV)m/z：[M+H] +444.2，[M+Na] +466.1；
Anal.Calcd.for?C 23H 29N 3O 6：C?62.29，H?6.59，N?9.47；
Found：C?62.09，H?6.73，N?9.57。
Embodiment 18:6,7-dimethoxy-2-(1-benzamido group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 7)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, adding benzylamine 0.6ml (0.59g, 5.5mmol), temperature control 60-70 ℃, reaction 8h, it is muddy that reaction solution becomes, and naturally cooling filters, filter cake ethyl acetate-dehydrated alcohol recrystallization, get white solid 0.69g, yield: 75%, mp:134-136 ℃.
1HNMR(CDCl 3，300M)δ：2.88(t，2H，C 4-H)，3.51(t，2H，C 3-H)，3.86(s，6H，2×OCH 3)，4.33(s，2H，C 1-H)，4.55(d，2H，NH CH 2 )，6.50(s，1H，C＝CH(NO 2))，6.57，6.62(each?s，2H，Ar-H)，7.35(m，6H，Ar′-H，N HCH 2)；
IR(KBr，cm -1)：3258，3247，3184，3025，2916，2823，1614，1517，1449，1383；
MS(70eV)m/z：[M+H] +370.1，[M+Na] +392.2；
Anal.Calcd.for?C 20H 23N 3O 4：C?65.03，H?6.28，N?11.37；
Found：C?65.25，H?6.28，N11.16。
Embodiment 19:6,7-dimethoxy-2-{1-[1-(4-methylpiperazine base)]-the 2-nitro } vinyl-1,2,3,4-tetrahydroisoquinoline (I 8)
Compound I 10.78g (2.5mmol) be dissolved in dry toluene 15ml, and adding methylpiperazine 0.5ml (0.45g, 4.5mmol), the preparation method gets white solid 0.43g, yield with reference to embodiment 13: 48%, m.p:134-136 ℃.
1HNMR(CDCl 3，300M)δ：2.82(s，3H，NCH 3)，2.84-3.61(m，10H，C 4-H，2×NCH 2CH 2N)，3.86(s，6H，2×OCH 3)，4.21(s，2H，C 1-H)，4.55(d，2H，C 3-H)，6.51(s，1H，C＝CH(NO 2))，6.58，6.63(each?s，2H，Ar-H)；
IR(KBr，cm -1)：3451，2931，2844，1610，1554，1517，1449，1378；
MS(70eV)m/z：[M+H] +363.1，[M+Na] +385.1，[M+K] +401.1；
Anal.Calcd.for?C 18H 26N 4O 4：C?59.65，H?7.23，N?15.46；
Found：C?66.25，H?8.19，N?16.27。
Embodiment 20:1,1 '-two [(6, the 7-dimethoxy)-1,2,3,4-tetrahydro isoquinolyl]-2-nitroethylene (I 9)
Compound 5a 0.97g (5mmol), 1,1-diformazan sulfenyl-2-nitroethylene 0.33g (2mmol) is dissolved in the 15ml dry toluene backflow 3h, it is muddy that reaction solution becomes, and naturally cooling filters the filter cake re-crystallizing in ethyl acetate, get faint yellow solid 0.81g, yield: 89%, m.p:194-196 ℃.
1HNMR(CDCl 3，300M)δ：2.91(t，4H，C 4-H，C 4’-H)，3.63(t，4H，C 3-H，C 3’-H)，3.85(s，12H，4×OCH 3)，4.37(s，4H，C 1-H，C 1’-H)，6.46(s，1H，C＝CH(NO 2))，6.50，6.65(eachs，4H，Ar-H)；
IR(KBr，cm -1)：3458，2996，2931，2837，1610，1554，1518，1446，1445，1378；
MS(70eV)m/z：[M+H] +456.2，[M+Na] +478.1；
Anal.Calcd.for?C 24H 29N 3O 6：C?63.28，H?6.42，N?9.22；
Found：C?66.25，H?8.19，N?16.27。
Embodiment 21:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 10)
Compound 5b 10.8g (30mmol), 1,1-diformazan sulfenyl-2-nitroethylene 7.0g (42mmol) is dissolved in the 100ml dry toluene, and the preparation method gets yellow solid 7.6g, yield with reference to embodiment 12: 55%, mp:152-154 ℃.
IR(KBr，cm -1)：3458，2931，2837，1661，1557，1517，1463，1453，1380；
MS(70eV)m/z：[M+H] +461.1，[M+Na] +483.1；
Anal.Calcd.for?C 23H 28N 2O 6S：C?59.98，H?6.13，N?6.08；
Found：C?60.39，H?6.24，N?6.30。
Embodiment 22:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 11)
Compound I 100.92g (2.0mmol), and n-Butyl Amine 99 0.6ml (0.44g 6.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.58g, yield with reference to embodiment 13: 60%, and m.p:200-202 ℃.
1HNMR(CDCl 3，300M)δ：0.86(t，3H，(CH 2) 2 CH 3)，1.20-1.47(m，4H， (CH 2 ) 2 CH 3)，2.85-3.53(m，8H，C 3-H，C 4-H，NH CH 2，ArCH 2)，3.76-3.85(s，12H，4×OCH 3)，4.71(t，1H，C 1-H)，6.34(s，1H，C＝CH(NO 2))，6.41-7.26(m，5H，Ar-H)；
IR(KBr，cm -1)：3444，2951，2933，2866，2830，1592，1540，1514，1463，1450?1366；
MS(70eV)m/z：[M+H] +486.1，[M+Na] +508.2；
Anal.Calcd.for?C 26H 35N 3O 6：C?64.31，H?7.27，N?8.65；
Found：C?64.05，H?7.37，N?8.72。
Embodiment 23:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 12)
Compound I 101.1g (2.4mmol), and hexahydroaniline 0.6ml (0.51g 5.2mmol) is dissolved in dry toluene 15ml, reflux 21h, and the pressure reducing and steaming solvent, resistates acetone-dehydrated alcohol recrystallization gets white solid 0.59g, yield: 48%, mp:152-154 ℃.
1HNMR(CDCl 3，300M)δ：1.08-1.27(m，10H，5×CH 2)，3.01-3.75(m，7H，C 3-H，C 4-H，NH CH，ArCH 2)，3.85(s，12H，4×OCH 3)，4.67(t，1H，C 1-H)，6.34(s，2H，C＝CH(NO 2)，N HCH)，6.63-6.80(m，5H，Ar-H)；
IR(KBr，cm -1)：3458，2949，2930，2830，1660，1581，1557，1517，1459，1360；
MS(70eV)m/z：[M+H] +512.3，[M+Na] +534.2；
Anal.Calcd.for?C 28H 37N 3O 6·0.75H 2O：C?64.04，H?7.39，N?8.00；
Found：C?64.08，H?7.20，N?7.78。
Embodiment 24:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 13)
Compound I 100.92g (2.0mmol), and n-octyl amine 0.6ml (0.47g 3.6mmol) is dissolved in dry toluene 15ml, and the preparation method gets white crystal 0.67g, yield with reference to embodiment 13: 62%, and mp:156-158 ℃.
1HNMR(CDCl 3，300M)δ：0.88(t，3H，(CH 2) 2 CH 3)，1.24-1.55(m，15H， (CH 2 ) 6CH 3)，2.69-3.56(m，8H，C 3-H，C 4-H，NH CH 2，ArCH 2)，3.75-3.88(s，12H，4×OCH 3)，4.70(t，1H，C 1-H)，6.31(s，1H，C＝CH(NO 2))，6.41-7.26(m，5H，Ar-H)；
IR(KBr，cm -1)：3444，2996，2923，2844，1592，1544，1515，1464，1448，1356；
MS(70eV)m/z：[M+H] +542.3，[M+Na] +564.2，[M+K] +580.2；
Anal.Calcd.for?C 30H 43N 3O 6：C?66.52，H?8.00，N?7.76；
Found：C?66.48，H?8.11，N?7.74。
Embodiment 25:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 14)
Compound I 100.92g (2.0mmol), and phenylethylamine 0.5ml (0.48g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.69g, yield with reference to embodiment 13: 65%, and mp:180-181 ℃.
1HNMR(CDCl 3，300M)δ：2.64-3.49(m，10H，C 3-H，C 4-H，NH CH 2，2×ArCH 2)，3.73-3.85(s，12H，4×OCH 3)，4.65(t，1H，C 1-H)，6.26(s，1H，C＝CH(NO 2))，6.26，6.37(each?s，2H，C 5-H，C 8-H)，6.57-7.33(m，8H，Ar-H)；
IR(KBr，cm -1)：3436，2996，2924，2830，1590，1514，1498，1465，1451，1352；
MS(70eV)m/z：[M+H] +?534.2，[M+Na] +556.2；
Anal.Calcd.for?C 30H 35N 3O 6：C?67.52，H?6.61，N?7.87；
Found：C?67.30，H?6.77，N?7.92。
Embodiment 26:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 15)
Compound I 100.92g (2.0mmol), 3,4-dimethoxy-phenylethylamine 0.6ml (0.64g 3.6mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.63g, yield with reference to embodiment 13: 53%, and mp:147-149 ℃.
1HNMR(CDCl 3，300M)δ：2.63-3.43(m，10H，C 3-H，C 4-H，NH CH 2，2×ArCH 2)，3.71-3.86(s，18H，6×OCH 3)，4.63(t，1H，C 1-H)，6.22(s，1H，C＝CH(NO 2))，6.38-6.81(m，8H，Ar-H)；
IR(KBr，cm -1)：3451，2996，2934，2917，2833，1607，1588，1517，1464，1440，1357；
MS(70eV)m/z：[M+H] +594.2，[M+Na] +616.2；
Anal.Calcd.for?C 32H 39N 3O 8·0.5H 2O：C?63.77，H?6.69，N?6.97；
Found：C?63.98，H?6.77，N?6.93。
Embodiment 27:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline I 16)
Compound I 100.92g (2.0mmol), and normal hexyl Amine 0.8ml (0.62g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.55g, yield with reference to embodiment 13: 54%, and mp:165-167 ℃.
1HNMR(CDCl 3，300M)δ：0.85(t，3H，CH 2 CH 3)，1.22-1.47(m，8H， (CH 2 ) 4CH 3)，1.56(m，1H，N HCH 2)，2.69-3.09(m，8H，C 3-H，C 4-H，NH CH 2，ArCH 2)，3.75-3.88(s，12H，4×OCH 3)，4.70(t，1H，C 1-H)，6.32(s，1H，C＝CH(NO 2))，6.41-6.66(each?s，3H，C 5-H，C 8-H，C 2″-H)，6.67，6.79(d，2H，C 5″-H，C 6″-H)；
IR(KBr，cm -1)：3451，2929，2851，2837，1589，1515，1465，1449，1441，1355；
MS(70eV)m/z：[M+H] +514.2，[M+Na] +536.2；
Anal.Calcd.for?C 28H 39N 3O 6：C?65.48，H?7.65，N?8.18；
Found：C?65.39，H?7.77，N?8.21。
Embodiment 28:6,7-dimethoxy-1-Phenoxymethyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 17)
Compound 5c 9.0g (30mmol), 1,1-diformazan sulfenyl-2-nitroethylene 7.4g (45mmol) is dissolved in the 100ml dry toluene, and the preparation method gets yellow solid 6.2g, yield with reference to embodiment 12: 50%, mp:195-197 ℃.
IR(KBr，cm -1)：3451，3034，2972，2935，2874，1665，1611，1599，1555，1519，1432，1356；
MS(70eV)m/z：[M+H] +417.1，[M+Na] +439.1；
Anal.Calcd.for?C 21H 24N 2O 5S：C?60.56，H?5.81，N?6.73；
Found：C?61.65，H?5.78，N?7.10。
Embodiment 29:6,7-dimethoxy-1-Phenoxymethyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 18)
Compound I 170.83g (2.0mmol), and normal hexyl Amine 0.8ml (0.62g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.53g, yield with reference to embodiment 13: 56%, and mp:128-130 ℃.
1HNMR(CDCl 3，300M)δ：0.84(t，3H，CH 2 CH 3)，1.26-1.69(m，8H， (CH 2 ) 4CH 3)，2.72-3.87(m，6H，C 3-H，C 4-H，NH CH 2，)，3.87(s，6H，2×OCH 3)，4.17(m，2H，Ar-OCH 2)，4.89(t，1H，C 1-H)，6.52(s，1H，C＝CH(NO 2))，6.63，6.66(each?s，2H，C 5-H，C 8-H)，6.83-7.30(m，5H，Ar-H)；
IR(KBr，cm -1)：3451，2963，2946，2936，2859，1597，1551，1520，1465，1445，1354；
MS(70eV)m/z：[M+H] +470.3，[M+K] +508.3；
Anal.Calcd.for?C 26H 35N 3O 5：C?66.50，H?7.51，N?8.95；
Found：C?66.36，H?7.47，N?8.86。
Embodiment 30:6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 19)
Compound I 170.83g (2.0mmol), and n-octyl amine 0.6ml (0.47g 3.6mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.56g, yield with reference to embodiment 13: 60%, and mp:112-114 ℃.
1HNMR(CDCl 3，300M)δ：0.83(t，3H，CH 2 CH 3)，1.24-1.68(m，12H， (CH 2 ) 6CH 3)，2.71-3.62(m，6H，C 3-H，C 4-H，NH CH 2，)，3.87(s，6H，2×OCH 3)，4.17(m，2H，Ar-OCH 2)，4.89(t，1H，C 1-H)，6.52(s，1H，C＝CH(NO 2))，6.62，6.65(each?s，2H，C 5-H，C 8-H)，6.81-7.29(m，5H，Ar-H)；
IR(KBr，cm -1)：3429，2987，2922，2853，1599，2587，1536，1516，1432，1358；
MS(70eV)m/z：[M+H] +498.1，[M+Na] +520.1，[M+K] +，536.0；
Anal.Calcd.for?C 28H 39N 3O 5：C?67.58，H?7.90，N?8.44；
Found：C?67.63，H?7.98，N?8.41。
Embodiment 31:6,7-dimethoxy-1-Phenoxymethyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 20)
Compound I 170.83g (2.0mmol), and phenylethylamine 0.5ml (0.48g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.62g, yield with reference to embodiment 13: 63%, and mp:162-164 ℃.
1HNMR(CDCl 3，300M)δ：2.35-2.97(m，8H，C 3-H，C 4-H，ArCH 2?NH CH 2)，3.87(s，6H，2×OCH 3)，4.11(d，2H，Ar-OCH 2)，4.76(t，1H，C 1-H)，6.48(s，1H，C＝CH(NO 2))，6.58，6.57(each?s，2H，C 5-H，C 8-H)，6.79-7.29(m，10H，Ar-H)；
IR(KBr，cm -1)：3465，3126，2916，2830，1594，1536，1518，1466，1433，1355；
MS(70eV)m/z：[M+H] +490.2，[M+Na] +512.2；
Anal.Calcd.for?C 28H 31N 3O 5：C?68.69，H?6.38，N?8.58；
Found：C?68.55，H，6.46，N?8.54。
Embodiment 32:6,7-dimethoxy-1-Phenoxymethyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 21)
Compound I 170.83g (2.0mmol), 3,4-dimethoxy-phenylethylamine 0.6ml (0.64g 3.6mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.66g, yield with reference to embodiment 13: 60%, and mp:162-164 ℃.
1HNMR(CDCl 3，300M)δ：2.63-3.66(m，8H，C 3-H，C 4-H，NH CH 2，ArCH 2)，3.81-3.88(s，12H，4×OCH 3)，4.11(m，2H，Ar-OCH 2)，4.77(t，1H，C 1-H)，6.51(s，1H，C＝CH(NO 2))，6.61-7.31(m，10H，Ar-H)；
IR(KBr，cm -1)：3537，3415，2931，2830，1596，1587，1517，1463，1443，1359；
MS(70eV)m/z：[M+H] +550.2，[M+Na] +572.3；
Anal.Calcd.for?C 30H 35N 3O 7：C?65.56，H?6.42，N?7.65；
Found：C?65.23，H?6.55，N?7.41。
Embodiment 33:6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 22)
Compound I 170.83g (2.0mmol), and n-Butyl Amine 99 0.5ml (0.37g 5mmol), is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.55g, yield with reference to embodiment 13: 62%, and mp:106-108 ℃.
1HNMR(CDCl 3，300M)δ：0.93(t，3H，(CH 2) 2 CH 3 )，1.41-1.70(m，4H， (CH 2 ) 2CH 3)，2.74-3.65(m，6H，C 3-H，C 4-H，NH CH 2，)，3.89(s，6H，2×OCH 3)，4.21(m，2H，Ar-OCH 2)，4.91(t，1H，C 1-H)，6.54(s，1H，C＝CH(NO 2))，6.65，6.68(each?s，2H，C 5-H，C 8-H)，6.84-7.32(m，5H，Ar-H)；
IR(KBr，cm -1)：3472，3126，2957，2932，2870，2836，1599，1518，1498，1463，1354；
MS(70eV)m/z：[M+H] +442.3，[M+Na] +464.1；
Anal.Calcd.for?C 24H 31N 3O 5：C?65.29，H?7.08，N?9.52；
Found：C?65.34，H?7.14，N?9.48。
Embodiment 34:6,7-dimethoxy-1-Phenoxymethyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline I 23)
Compound I 170.83g (2.0mmol), and hexahydroaniline 0.6ml (0.51g 5.2mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.62g, yield with reference to embodiment 13: 66%, and mp:106-108 ℃.
1HNMR(CDCl 3，300M)δ：1.20-1.99(m，10H，5×CH 2)，2.70-3.64(m，5H，C 3-H，C 4-H，NHCH)，3.87(s，6H，2×OCH 3)，4.15(m，2H，Ar-OCH 2)，4.88(t，1H，C 1-H)，6.49(s，1H，C＝CH(NO 2))，6.62-7.30(m，7H，Ar-H)；
IR(KBr，cm -1)：3451，3140，2952，2932，2855，1597，1586，1510，1459，1450，1361；
MS(70eV)m/z：[M+H] +468.2，[M+Na] +490.1；
Anal.Calcd.for?C 26H 33N 3O 5：C?66.79，H?7.11，N?8.99；
Found：C?66.78，H?7.12，N?8.95。
Embodiment 35:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 24)
Compound 5d 10.0g (30mmol), 1,1-diformazan sulfenyl-2-nitroethylene 7.4g (45mmol) is dissolved in the 100ml dry toluene, and the preparation method gets yellow solid 6.3g, yield with reference to embodiment 12: 70%, mp:148-150 ℃.
1HNMR(CDCl 3，300M)δ：1.96(s，3H，SCH 3)，2.95(m，2H，C 4-H)，3.43(s，3H，C 7-OCH 3)，3.84(s，3H，C 6-OCH 3)，3.66，4.08(m，4H，C 3-H，Ar-CH 2)，5.73(t，1H，C 1-H)，5.93(s，1H，C＝CH(NO 2))，6.62，6.71(each?s，2H，C 5-H，C 8-H)，7.22-8.02(m，7H，Ar-H)；
IR(KBr，cm -1)：3444，3112，2931，2837，1729，1607，1521，1468，1391，1348；
MS(70eV)m/z：[M+H] +451.1，[M+K] +489.0；
Anal.Calcd.for?C 25H 26N 2O 4S：C?66.64，H?5.82，N?6.22；
Found：C?66.66，H?5.90，N?6.13。
Embodiment 36:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 25)
Compound I 240.90g (2.0mmol), and hexahydroaniline 0.5ml (0.43g 4.3mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.60g, yield with reference to embodiment 13: 60%, and mp:216-218 ℃.
1HNMR(CDCl 3，300M)δ：0.94-1.48(m，10H，5CH 2)，1.55(d，1H，N HCH)，2.75-3.58(m，6H，C 3-H，C 4-H，Ar-CH 2)，3.80(d，1H，NH CH)，3.61，3.85(s，6H，2×OCH 3)，4.86(t，1H，C 1-H)，6.14(s，1H，C 1′＝C 2′-H)，6.34，6.61(each?s，2H，C 5-H，C 8-H)，7.20-7.98(m，7H，Ar-H)；
IR(KBr，cm -1)：3476，3414，2996，2929，2851，1584，1510，1466，1451，1352；
MS(70eV)m/z：[M+H] +502.3，[M+Na] +524.2；
Anal.Calcd.for?C 30H 35N 3O 4：C?71.83，H?7.03，N?8.38；
Found：C?71.65，H?7.11，N?8.47。
Embodiment 37:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 26)
Compound I 240.90g (2.0mmol), and n-octyl amine 0.7ml (0.55g 4.1mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.52g, yield with reference to embodiment 13: 49%, and mp:216-218 ℃.
1HNMR(CDCl 3，300M)δ：0.85(t，3H，(CH 2) 6 CH 3 )，1.11-1.29(m，12H， (CH 2 ) 6CH 3)，2.75-2.84(m，4H，C 4-H，NH CH 2 )，3.48-3.54，3.73(m，4H，C 3-H，Ar-CH 2)，3.56(s，3H，C 7-OCH 3)，3.85(s，3H，C 6-OCH 3)，4.86(t，1H，C 1-H)，6.03(s，1H，C＝CH(NO 2))，6.37，6.60(each?s，2H，C 5-H，C 8-H)，7.16-7.87(m，7H，Ar-H)；
IR(KBr，cm -1)：3444，3133，2954，2919，2853，2606，2361，1608，1587，1518，1454，1441，1352；
MS(70eV)m/z：[M+H] +532.1，[M+Na] +554.1，[M+K] +570.1；
Anal.Calcd.for?C 32H 41N 3O 4：C?72.29，H?7.77，N?7.90；
Found：C72.28，H7.81，N7.86。
Embodiment 38:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 27)
Compound I 240.90g (2.0mmol), and phenylethylamine 0.5ml (0.48g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.54g, yield with reference to embodiment 13: 52%, and mp:216-218 ℃.
1HNMR(CDCl 3，300M)δ：2.62-2.72(m，4H，C 4-H，ArCH 2)，3.16-3.68(m，6H，C 3-H，Ar′CH 2，NH CH 2)，3.51(s，3H，C 7-OCH 3)，3.84(s，3H，C 6-OCH 3)，4.80(t，1H，C 1-H)，5.91(s，1H，C＝CH(NO 2))，6.33，6.58(each?s，2H，C 5-H，C 8-H)，7.04-7.88(m，12H，Ar-H)；
IR(KBr，cm -1)：3465，2996，2931，2815，2361，1585，1516，1463，1352；
MS(70eV)m/z：[M+H] +524.2；
Anal.Calcd.for?C 32H 33N 3O 4：C?73.40，H?6.35，N?8.02；
Found：C?73.43，H?6.42，N?8.00。
Embodiment 39:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 28)
Compound I 240.90g (2.0mmol), and normal hexyl Amine 0.8ml (0.62g 4.0mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.50g, yield with reference to embodiment 13: 55%, and mp:182-184 ℃.
1HNMR(CDCl 3，300M)δ：0.83(t，3H，(CH 2) 4 CH 3 )，1.12-1.33(m，8H， (CH 2 ) 4CH 3)，1.35(d，1H，N HCH)，2.76-2.99(m，4H，C 4-H，NH CH 2)，3.51-3.57(m，4H，C 3-H，Ar′CH 2，)，3.51(s，3H，C 7-OCH 3)，3.84(s，3H，C 6-OCH 3)，4.86(t，1H，C 1-H)，6.03(s，1H，C＝CH(NO 2))，6.37，6.60(each?s，2H，C 5-H，C 8-H)，7.16-7.87(m，7H，Ar-H)；
IR(KBr，cm -1)：3444，2932，2859，1589，1519，1463，1352；
MS(70eV)m/z：[M+H] +504.2；
Anal.Calcd.for?C 30H 37N 3O 4：C?71.54，H?7.40，N?8.34；
Found：71.44，H?7.44，N?8.28。
Embodiment 40:6,7-dimethoxy-1-(α-menaphthyl)-2-[1-(3, the 4-dimethoxy)-phenylethylamine base-2-nitro] vinyl-1,2,3,4-tetrahydroisoquinoline (I 29)
Compound I 240.90g (2.0mmol), 3,4-dimethoxy-phenylethylamine 0.6ml (0.64g 3.6mmol) is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.50g, yield with reference to embodiment 13: 59%, and mp:142-143 ℃.
1HNMR(CDCl 3，300M)δ：2.57-2.73(m，4H，C 4-H，Naphthyl-CH 2)，3.16-3.70(m，6H，C 3-H，NH CH 2，Ar′CH 2，)，3.49，3.83(s，12H，4×OCH 3)，4.81(t，1H，C 1-H)，5.86(s，1H，C＝CH(NO 2))，6.34，6.58(each?s，2H，C 5-H，C 8-H)，6.60-7.88(m，10H，Ar-H)；
IR(KBr，cm -1)：3429，2924，2830，1607，1589，1515，1462，1353；
MS(70eV)m/z：[M+H] +584.3，[M+Na] +606.2；
Anal.Calcd.for?C 34H 37N 3O 6：C?69.96，H?6.39，N?7.20；
Found：C?69.77，H?6.53，N?7.17。
Embodiment 41:6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline (I 30)
Compound I 240.90g (2.0mmol), and n-Butyl Amine 99 0.5ml (0.37g 5mmol), is dissolved in dry toluene 15ml, and the preparation method gets white solid 0.5.7g, yield with reference to embodiment 13: 60%, and mp:221-223 ℃.
1HNMR(CDCl 3，300M)δ：0.83(t，3H，(CH 2) 2 CH 3 )，1.12-1.35(m，4H， (CH 2 ) 2CH 3)，1.58(d，1H，N HCH)，2.76-3.00(m，4H，C 4-H，NH CH 2)，3.51-3.75(m，4H，C 3-H，Ar′CH 2，)，3.53(s，3H，C 7-OCH 3)，3.86(s，3H，C 6-OCH 3)，4.87(t，1H，C 1-H)，6.03(s，1H，C＝CH(NO 2))，6.37，6.61(each?s，2H，C 5-H，C 8-H)，7.17-7.96(m，7H，Ar-H)；
IR(KBr，cm -1)：3451，2957，2933，2866，1588，1518，1464，1452，1352；
MS(70eV)m/z：[M+H] +476.3，[M+Na] +498.2；
Anal.Calcd.for?C 28H 33N 3O 4·0.3H 2O：C?69.92，H?7.04，N?8.74；
Found：C?70.17，H?7.01，N?8.75。
Embodiment 42:6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 31)
Compound 5b 1.7g (5.0mmol) is dissolved in the 30ml dehydrated alcohol, add 0.68g (5.0mmol) S-methyl-N-nitro isothiourea, stirring and refluxing 48h, the pressure reducing and steaming solvent, column chromatography for separation (ethyl acetate: sherwood oil=1: 2), get white solid 1.2g, yield: 54%, mp:151-152 ℃.
1HNMR(CDCl 3，300M)δ：2.67-3.51(m，6H，C 3-H，C 4-H，ArCH 2)，3.73，3.85(s，12H，4×OCH 3)，5.25(t，1H，C 1-H)，6.37-6.77(m，5H，Ar-H)，7.32(s，2H，NH 2)；
IR(KBr，cm -1)：3429，3310，2993，2958，2937，2830，1740，1615，1564，1517，1446，1382，1296；
MS(70eV)m/z：[M+H] +431.1，[M+Na] +453.1；
Anal.Calcd.for?C 21H 26N 4O 6：C?58.59，H?6.09，N?13.02；
Found：C?58.19，H?6.04，N?12.70。
Embodiment 43:6,7-dimethoxy-1-(α-menaphthyl)-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 32)
Compound 5d 1.7g (5.1mmol), dehydrated alcohol 30ml, S-methyl-N-nitro isothiourea 0.68g (5.0mmol), the preparation method gets white solid 1.3g, yield with reference to embodiment 42: 59%, mp:192-194 ℃.
1HNMR(CDCl 3，300M)δ：2.93(t，2H，C 4-H)，2.95-3.66(m，4H，C 3-H，ArCH 2)，3.79，3.86(s，6H，2×OCH 3)，5.43(t，1H，C 1-H，)，6.64，6.90(each?s，2H，C 5-H，C 8-H)，7.06-7.87(m，7H，Ar-H)，8.49(s，2H，NH 2)；
IR(KBr，cm -1)：3395，3306，2953，2830，1740，1614，1548，1518，1479，1452，1396，1293；
MS(70eV)m/z：[M+H] +421.1；
Anal.Calcd.for?C 23H 24N 4O 4：C?65.70，H?5.75，N?13.33；
Found：C?65.35，H?5.70，N?13.04。
Embodiment 44:6,7-dimethoxy-1-Phenoxymethyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 33)
Compound 5c 1.5g (5.0mmol), dehydrated alcohol 30ml, S-methyl-N-nitro isothiourea 0.68g (5.0mmol), the preparation method gets white solid 1.3g, yield with reference to embodiment 42: 53%, mp:122-124 ℃.
1HNMR(CDCl 3，300M)δ：2.80-3.46(m，4H，C 3-H，C 4-H)，3.86(s，6H，2×OCH 3)，4.25-4.37(m，3H，C 1-H，Ar-OCH 2)，6.67，6.69(each?s，2H，C 5-H，C 8-H)，6.87-7.32(m，5H，Ar-H)，7.99(s，2H，NH 2)；
IR(KBr，cm -1)：3373，3274，3198，2966，2935，2837，1747，1615，1599，1550，1516，1448，1462，1394，1372，；
MS(70eV)m/z：[M+H] +387.1，[M+Na] +409.1；
Anal.Calcd.for?C 19H 22N 4O 5：C?59.06，H?5.74，N?14.50；
Found：C?58.96，H?5.69，N?14.25。
Embodiment 45:6,7-dimethoxy-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline (I 34)
Compound 5a 0.97g (5.0mmol), dehydrated alcohol 30ml, S-methyl-N-nitro isothiourea 0.68g (5.0mmol), stirring and refluxing 12h, the reaction solution standing over night is separated out the white needles solid, filters the dehydrated alcohol recrystallization, get solid 0.77g, yield: 55%, mp:145-147 ℃.
1HNMR(CDCl 3，300M)δ：2.88(t，2H，C 4-H)，3.75(t，2H，C 3-H)，3.85(s，6H，2×OCH 3)，4.64(s，2H，C 1-H)，6.67(s，2H，Ar-H)，7.86(s，2H，NH 2)；
IR(KBr，cm -1)：3380，3281，3198，2953，2830，1744，1602，1577，1519，1484，1467，1380，1300；
MS(70eV)m/z：[M+H] +281.1，[M+Na] +303.1；
Anal.Calcd.for?C 12H 16N 4O 4：C?51.42，H?5.75，N?19.99；
Found：C?51.49，H?5.65，N?20.06。

Claims (6)

1. general formula (I) tetrahydro isoquinoline derivative or its pharmacy acceptable salt:
Wherein X is selected from CH or N;
R wherein 1Be selected from:
Figure FSA00000396685800012
R wherein 2Be selected from:
Figure FSA00000396685800013
R 3Be selected from carbonatoms and be 1～8 straight chain saturated alkyl or branched-chain alkyl;
R 4Be selected from carbonatoms and be 3～6 saturated cyclic alkyls;
N is 0～4.
2. compound according to claim 1 is selected from following compounds or its pharmacy acceptable salt:
6,7-dimethoxy-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3, the 4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(1-benzamido group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-{1-[1-(4-methylpiperazine base)]-the 2-nitro } vinyl-1,2,3, the 4-tetrahydroisoquinoline;
1,1 '-two [(6, the 7-dimethoxy)-1,2,3,4-tetrahydro isoquinolyl]-2-nitroethylenes;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3, the 4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-[1-(3, the 4-dimethoxy) phenylethylamine base-2-nitro] vinyl-1,2,3, the 4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-methylthio group-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-cyclohexylamino-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-octyl amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-phenylethylamine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-normal hexyl Amine base-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-[1-(3, the 4-dimethoxy)-phenylethylamine base-2-nitro] vinyl-1,2,3, the 4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(1-n-butylamine-based-2-nitro) vinyl-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-2-(N-nitro) guanidine radicals-1,2,3,4-tetrahydroisoquinoline.
3. tetrahydro isoquinoline derivative according to claim 1, its pharmacy acceptable salt are the salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, acetate, trifluoroacetic acid, citric acid, tartrate, lactic acid, pyruvic acid, toxilic acid, Phenylsulfonic acid, succsinic acid, pentanedioic acid or fumaric acid.
4. the preparation method of the tetrahydro isoquinoline derivative of a claim 1:
Figure FSA00000396685800021
R 1, R 2, R 3, R 4With the definition of n according to claim 1.
5. according to the preparation method of the Compound I described in the claim 4, it is characterized in that: under hot conditions, 3,4-dimethoxy-phenylethylamine (compound 2) makes compound 3 with the substituted acetic acid reaction, compound 3 refluxes in dry toluene under the phosphorus oxychloride existence condition and obtains compound 4, compound 4 is under anhydrous methanol is made solvent condition, add the catalytic amount diethylamine as catalyzer, obtained compound 5 by potassium borohydride reduction, compound 5 and 1,1-diformazan sulfenyl-2-nitroethylene refluxes in dry toluene and obtains compound 6, and compound 6 reacts in dry toluene with the amine that replaces and promptly obtains target compound I; Compound 5 refluxes in dehydrated alcohol with S-methyl-N-nitro isothiourea and obtains target compound I, and Compound I and acid-respons promptly obtain corresponding salt.
6. claim 1 and 2 tetrahydro isoquinoline derivative or its pharmacy acceptable salt purposes on the preparation multidrug resistance reversing agent.
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CN1445217A (en) * 2003-04-22 2003-10-01 中国药科大学 Substitutional ramification of tetrahydro-isoquinoline, as well as its preparing method and its medication compound containing them
CN1444941A (en) * 2003-04-22 2003-10-01 中国药科大学 Usage of substituted tetrahydroisoquinoline derviation

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CN102358731A (en) * 2011-08-27 2012-02-22 中山博闻医药科技有限公司 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof
CN102358731B (en) * 2011-08-27 2013-01-02 中山博闻医药科技有限公司 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof
CN104672136A (en) * 2013-11-30 2015-06-03 沈阳药科大学 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof
CN104672136B (en) * 2013-11-30 2017-01-25 沈阳药科大学 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof
WO2015090216A1 (en) * 2013-12-19 2015-06-25 沈阳药科大学 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative and manufacturing method thereof, pharmaceutical composition comprised thereof, and application thereof

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