CN1227010C - Usage of substituted tetrahydroisoquinoline derviation - Google Patents

Usage of substituted tetrahydroisoquinoline derviation Download PDF

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CN1227010C
CN1227010C CN 03113262 CN03113262A CN1227010C CN 1227010 C CN1227010 C CN 1227010C CN 03113262 CN03113262 CN 03113262 CN 03113262 A CN03113262 A CN 03113262A CN 1227010 C CN1227010 C CN 1227010C
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dimethoxy
tetrahydroisoquinoline
cyano group
amidino groups
benzyl
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CN1444941A (en
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黄文龙
张惠斌
李运曼
周金培
何立文
胡振
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The present invention relates to a compound shown in a general formula (I) and application of salt of the compound for preparing medicine. More specifically, the present invention relates to application for preparing reverse tumour multidrug resistance (MDR) medicine. The activity of the compound is higher than that of verapamil. The compound has no cardiovascular side effect caused by common calcium antagonist.

Description

The purposes of the tetrahydro isoquinoline derivative that replaces
Technical field the present invention relates to the tetrahydro isoquinoline derivative that the 2-amidino groups replaces, and it is used to prepare the purposes of medicine, specifically prepares the purposes of reverse multiple drug resistance of tumor medicine.
The background technology tumor is one of disease of harm humans life.Tumor can produce a kind of self-protective mechanism---drug resistance after accepting chemotherapeutic agent; drug resistance of tumor has become one of major reason of chemotherapy of tumors failure; solid tumor particularly; it is very difficult that chemotherapeutics arrives tumor tissues; drug resistance produces the back tumor cell can constantly discharge the extracellular with the chemotherapeutics that arrives target tissue; for the effect of offsetting drug resistance raising chemotherapeutic must improve dosage; this can increase the injury of chemotherapeutics to normal structure undoubtedly, and the drug resistance that therefore how to overcome tumor has become one of hot fields of current anti-tumor medicine research.Drug resistance of tumor can be divided into primary resistance (PDR) and multidrug resistance (MDR) two big classes, PDR only produces drug resistance to induced drug, and other medicines are not produced drug resistance, MDR is meant that then tumor cell is once certain chemotherapeutics is produced drug resistance, simultaneously to irrelevant on other structure, the also different medicine of the mechanism of action also produces chemical sproof phenomenon, and most of chemotherapeutics removes antimetabolite and induces generation PDR, all easily induces to produce MDR.The MDR reversal agents of clinical research at present is based on calcium antagonist, and wherein representing medicine is verapamil, and this class inversion agent has definite reverse curative effect, but it is not strong to exist the effect specificity, and reverse is active low, and is accompanied by serious cardiovascular side effects.Therefore it is active strong to seek reverse multiple drug resistance of tumor, and the low 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 a kind of purposes of tetrahydro isoquinoline derivative of new replacement, is the purposes of reverse multiple drug resistance of tumor specifically, and its cardiovascular side effects is less, safety is higher, is used to improve the curative effect of antineoplastic agent.
This seminar is that guide's thing carries out designs simplification in the eighties with natural tetrahydro isoquinoline compounds such as effective components of Chinese medicinal tetrandrine.In the research afterwards, seek by transformation in the process of new calcium antagonist, find that the benzyl tetrahydro isoquinoline compound that N-cyanogen amidino groups replaces has very strong reversion MDR activity, some chemical compound reversion MDR activity far is better than clinical inversion agent verapamil commonly used, and does not have the cardiovascular side effect.
Summary of the invention is as follows in detail:
The present invention has synthesized a series of general formulas (I) chemical compound and pharmaceutically acceptable salt thereof:
Wherein R1 representative:
Figure C0311326200051
R2 representative :-NH (CH 2) nCH 3N= 1-9
Figure C0311326200052
n＝1-2；
The R3 representative: 6,7-(OCH 3) 2, 6,7-OCH 2O-;
Preferred chemical compound is:
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3, (code name is I to the 4-tetrahydroisoquinoline 1a);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1b);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1c);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1d);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-piperidyl-N-cyano group amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1e);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1f);
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1g);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2a);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2b);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2c);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2d);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2e);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2f);
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3a);
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3b);
6,7-dimethoxy-1-Phenoxymethyl-2-(phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3c);
6,7-dimethoxy-1-Phenoxymethyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3d);
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 4b);
6,7-methylene-dioxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
The structural formula of part of compounds is:
Figure C0311326200061
R2
I 1a -NHC 5H 11-n
I 1b
I 1c
I 1d
I 1e
Figure C0311326200065
I 1f -NHC 8H 17-n
I 1g -NHC 4H 9-n
V 1 -SCH 3
Figure C0311326200071
R2
I 2a -NHC 5H 11-n
I 2b
Figure C0311326200073
I 2e -NHC 8H 17-n
I 2f -NHC 4H 9-n
V 2 -SCH 3
R2
I 3a -NHC 5H 11-n
I 3b -NHC 8H 17-n
I 3c
Figure C0311326200075
I 3d
Figure C0311326200076
V 3 -SCH 3
I 4a -NHC 5H 11-n
I 4b -NHC 8H 17-n
V 4 -SCH 3
R2
I 5a -NHC 4H 9-n
V 5 -SCH 3
Figure C0311326200083
Figure C0311326200084
Figure C0311326200087
According to the present invention, pharmaceutically acceptable salt comprises the acid-addition salts that forms with following acid: hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, maleic acid, benzenesulfonic acid.
The compound of Formula I preparation method, method is as follows: substituted phenyl ethylamine and substituted acetic acid dewater under preferred 180-200 ℃ of temperature at 150-220 ℃, generate corresponding amides (general formula I I chemical compound), II cyclization under the phosphorus oxychloride effect generates 3 of replacement, 4-dihydro-isoquinoline (compound of formula III), III is reduced into corresponding 1 with tetrahydro boron potassium, 2,3,4-tetrahydroisoquinoline (general formula I V chemical compound), IV and S,S-Dimethyl cyanoimidodithiocarbonate reaction generate intermediate V, and V and amine reaction generate goal object I.Perhaps, obtain intermediate VI, react with general formula I V chemical compound again, get goal object I the amine reaction of S,S-Dimethyl cyanoimidodithiocarbonate elder generation and replacement.
The wherein list of references method that is prepared as of general formula I V chemical compound acquisition (Huang Wenlong, study of the Song Dynasty duty, Peng Sixun. the synthetic and biological activity of substituted tetrahydroisoquinolicompounds derivant. Acta Pharmaceutica Sinica, 1990; 25 (11): 815-823).
Concrete reactions steps is:
Figure C0311326200091
Another kind of preparation method is:
Figure C0311326200095
Below be the pharmacology test data of part of compounds of the present invention:
1, external reversing tumor cell MDR activity test
(1) chemical compound is to adriamycin-resistant human leukemia cell's reverse effect
The positive reference substance of verapamil (Verapamil).K562 is the human leukemia cell, the human leukemia cell of K562/ADR adriamycin-resistant, and the K562/ADR cell is that the K562 cells contacting concentration by sensitivity increases progressively inducing of ADR and forms.Two cell strains all are incubated in the RPMI-1640, include 10% calf serum, and penicillin 100IU/ml and streptomycin 100 μ g/ml place 37 ℃ to contain 5%CO 2Incubator in cultivate.This experiment is carried out with mtt assay, with exponential phase cell, 2 * 10 -4Porocyte is inoculated on 96 orifice plates, and volume is 0.16ml, after cultivating 24h, what add 20 μ l variable concentrations respectively is subjected to reagent thing and ADR, sets up simultaneously to be subjected to reagent thing matched group and normal saline matched group, drug effect 48h, 4h adds 1mg/ hole MTT solution before finishing, and the centrifugal culture fluid that inclines adds DMSO 0.15ml, after treating to dissolve colour developing fully, measure with the 570nm wavelength with enzyme connection instrument, calculate the concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC 50Value representation reverses multiple with IC 50(ADR)/IC 50(ADR+ inversion agent) expression.
Measured 13 chemical compounds respectively under 10 μ M concentration, active in table 1 to the drug-fast reverse of the leukaemia of drug resistance amycin, the result shows, chemical compound all has the activity of reverse, the reverse of 3 chemical compounds is active even surpass positive reference substance verapamil (Verapamil), wherein, and I 3cThe reverse multiple be 249, far being better than and reversing multiple is 44.1 Verapamil.
Experimental result sees Table 1
The inversion agent (10 μ M) that adds table 1. reduces K562/ADR to amycin IC 50(nM) effect
Chemical compound blank verapamil I 1a I 1b I 1c I 1d I 1e I 2a I 2b I 2c I 2d I 3a I 3b I 3c I 3d I 4b K562/ADR 44.74 1.037 0.77 3.07 8.74 39.31 34.25 8.90 44.45 0.91 43.17 6.49 6.81 0.18 1.24 6.33 K562/ADR reversal index 44.1 58.1 14.6 5.12 1.14 1.31 5.03 1.01 49.2 1.04 6.89 6.57 249 36.1 7.70
(2) chemical compound is to the reverse effect of adriamycin-resistant human breast cancer cell
The positive reference substance of verapamil (Verapamil).MCF-7 is a human breast cancer cell, and the human breast cancer cell of MCF-7/ADR adriamycin-resistant, MCF-7/ADR cell are that the MCF-7 cells contacting concentration by sensitivity increases progressively inducing of ADR and forms.Two cell strains all are incubated in the DMEM culture fluid, include 10% calf serum, and penicillin 100IU/ml and streptomycin 100 μ g/ml place 37 ℃ to contain 5%CO 2Incubator in cultivate.This experiment is carried out with mtt assay, with exponential phase cell, 0.8 * 10 -4Porocyte is inoculated on 96 orifice plates, and volume is 0.18ml, after cultivating 24h, what add 20 μ l variable concentrations respectively is subjected to reagent thing and ADR, sets up simultaneously to be subjected to reagent thing matched group and normal saline matched group, drug effect 72h, 4h adds 1mg/ hole MTT solution before finishing, and the centrifugal culture fluid that inclines adds DMSO 0.15ml, after treating to dissolve colour developing fully, measure with the 540nm wavelength with enzyme connection instrument, calculate the ADR concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC 50Value representation reverses multiple with IC 50(ADR)/IC 50(ADR+ inversion agent) expression.
Measured 7 chemical compounds respectively under 10 μ M concentration, active to the drug-fast reverse of the human breast cancer cell of drug resistance amycin, the results are shown in Table 2, show that chemical compound all has the activity of reverse, Compound I 1fThe reverse multiple be 30.3, being better than and reversing multiple is 10.0 verapamil.
Table 2. adding inversion agent (10 μ M) reduction MCF-7 or MCF-7/ADR are to amycin IC 50(nM) effect
Chemical compound blank verapamil V1 V2 I 1f I 1g I 2e I 2f I 5a MCF-7 96.2 92.8 81.9 80.4 79.7 78.3 80.3 79.5 79.7 MCF-7/ADR 6864.2 689.2 486.7 525.4 226.8 1224.1 1445.3 743.8 782.6 MCF-7 reversal index 1.0 1.2 1.2 1.2 1.2 1.2 1.2 1.2 K562/ADR reversal index 10.0 14.1 13.1 30.3 5.60 4.80 9.20 8.80
2, Compound I 1fInfluence to the hepatoma carcinoma cell multidrug resistance
Get human liver cancer cell multidrug resistance medicine strain SMMC-7721/ADM cell in the RPMI-1640 culture fluid that contains 20% calf serum and 0.1 μ g/ml ADM, place 37 ℃, 50%CO 2Cultivate in the incubator.The ADM that the SMMC-7721/ADM cell is increased progressively by the SMMC-7721 cells contacting concentration of sensitivity induces and forms.The final concentration of ADM is 1.5 μ g/ml, uses the fresh medium of no medicine to go down to posterity before the experiment, does experiment with second filial generation cell, the trophophase SMMC-7721/ADM cell of taking the logarithm.Be inoculated in the flat culture plate in 96 holes, add the reagent that is subjected to of variable concentrations, cultivated 1 hour in 37 ℃, 5%CO2 incubator.In the SMMC-7721/ADM cell, add amycin then, daunorubicin (concentration is 1.5 μ g/ml).Cell concentration is 1 * 106/ml, every hole total amount of liquid 200 μ l.Place 37 ℃, 5%CO 2Cultivated in the incubator 72 hours, experiment stops preceding 1 hour, and every hole adds MTT (concentration is 5mg/ml) 20 μ l, cultivate finish after, every hole adds dimethyl sulfoxine 150 μ l, cessation reaction vibrate 10 minutes, with microplate reader detection DD value (λ=570nm).Cell survival rate=susceptibility group DD value/matched group DD value * 100%.Experimental result sees Table 3.
Table 3 I 1fInfluence test to the hepatoma carcinoma cell multidrug resistance
Drug level (μ g/ml) Cell survival rate (%)
2.0 5.0 10.0 20.0 100 62 50 40
3. Compound I 1fExtracorporeal blood vessel shrinks inhibition test
Male SD rat, body weight 250-350g opens breast rapidly after the stunning, take out aortic article, be put in saturated Kreb ' the s liquid of O2, remove circumvascular nodal tissue, be cut into the volution of 4-5mm, the lower end is fixed on the 10ml bath that Kreb ' s liquid is arranged, the upper end connects the tension force diverter, logical O2, preload 1gm, every 15min changes liquid once, begins test behind the balance 1h.1. the low inductive blood vessel inhibition test of potassium: adding 1mmol stimulates aortic annulus to shrink, after arterial ring is retracted to amplitude peak and stablizes, add sample,, calculate the vasoconstriction suppression ratio that respective compound causes low potassium by measuring the shrinkage curve height change.2. high potassium induction of vascular shrinks inhibition test: add 80mmol KCl, after arterial ring is retracted to amplitude peak, eluting, stablize 20min again, add given the test agent earlier, add 80mmol KCl repetitive operation behind the 10min again, the relatively variation of shrinkage amplitude before and after the administration calculates the vasoconstriction suppression ratio (table 4) that corresponding compounds causes high potassium.
Table 4 verapamil and I 1fSuppression ratio (%) to the inductive rabbit aorta strip contraction of KCl
Sample Concentration 20mmol KCl 80mmol KCl
Verapamil I 1f 10 -6mol/L 10 -6mol/L 36.3 0 46.3 0
4. Compound I 1fArrhythmia test in the body
Rat (male and female half and half), after 1.2g/kg urethane ip anesthesia, give given the test agent (normal saline solution) from femoral vein respectively, inject Aconitine Nitrate solution (1 μ g/0.2ml/min) with the LDB-M electronic peristaltic pump by the femoral vein constant speed behind the 2min, and monitor that by electrocardioscope electrocardio changes, and the record chamber of appearance early (VP), chamber speed (VT), the consumption of Aconitine Nitrate when (VF) quivered in the chamber.The results are shown in Table 5.
Table 5 I 1fWith verapamil aconitine is induced the arrhythmia effect
Chemical compound Dosage (mg/kg) Produce ARR aconitine dosage (μ g/kg)
VP VT VF
Blank I 1fVerapamil 2 2 20.2 22.4 30.3 28.9 26.7 44.0 37.0 31.5 55.0
5. Compound I 1fAcute toxicity test
Get 12 of mices, body weight 18-22g, male and female half and half, be divided into 3 groups at random by body weight, mouse tail vein injection administration, maximum dose level group 200mg/kg (0.2ml/20g), middle dosage 100mg (0.1ml/20g) low dose group 50mg/kg (0.05ml/20g), the dosage ratio is 1: 0.5.Observed 7 days, do not see dead and the nosotoxicosis appearance thereafter.Continue administration in high dose group, accumulated dose reaches 500mg/kg and does not see dead yet and the poisoning symptom appearance.
Above pharmacology data shows that general formula of the present invention (I) chemical compound has the effect of stronger reverse multiple drug resistance of tumor, and can not cause side effect such as vasoconstriction, arrhythmia.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier as activating agent.Pharmaceutically acceptable carrier is meant one or more inert, atoxic solids or liquid filler material, diluent, auxiliary agent etc., and they are not reverse has an effect with reactive compound or patient.
The dosage form of the present composition can be a dosage form commonly used on the pharmaceuticss such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection.
Tablet for oral use and capsule contain traditional excipient such as implant, diluent, lubricant, dispersant and binding agent.Can be prepared according to the method for knowing in this area.
The dosage of above activating agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of formula (I) chemical compound of every kg body weight administration in per 24 hours is about 0.01-100mg, the preferred about 0.1-50mg/kg of total amount.If necessary, with the form administration of single dose several times.
Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time or the interval of seriousness, preparation and administration.
By the following examples the present invention is further described.
The specific embodiment:
Embodiment 1
N-(3, the 4-dimethoxy) phenethylamine-(3, the 4-dimethoxy) phenyl acetamide (II 1) preparation:
3,4-dimethoxy-phenylethylamine (distilling under reduced pressure, 140～170/1mmHg fraction) 18.6g (0.103mol) and 3,4-dimethoxyphenylacetic acid 18.9g (0.096mol) 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 80 ℃, adds chloroform 150mol dissolving, chloroform solution is washed to neutrality, anhydrous Na with 3% hydrochloric acid, clear water, 3%NaOH aqueous solution, saturated common salt successively 2SO 4Drying, decompression are steamed near and done, and be cold slightly, adds ether 100ml, and jog is separated out white solid, filters oven dry, the heavy 31.9g (84%) of crude product, mp120～122 ℃ (document mp122.5～123 ℃).
N-(3, the 4-dimethoxy) phenethyl-α-naphthalene acetamide (II 2) preparation:
3,4-dimethoxy-phenylethylamine 18.6g (0.101mol) mixes with α-Nai Yisuan 17.3g (0.0957mol), presses II 1Preparation method, white solid 25.0g (75%), mp110～112 ℃.
N-(3, the 4-dimethoxy) phenethyl-benzene acetamide oxide (II 3) preparation:
3,4-dimethoxy-phenylethylamine 6.2g (0.034mol) mixes with phenoxy acetic acid 5.0g (0.033mol), presses II 1Preparation method, white solid 9.4g (90%).
N-(3, the 4-dimethoxy) phenethyl-alpha-naphthoxy acetamide (II 4) preparation:
3,4-dimethoxy-phenylethylamine 18.6g (0.101mol) mixes with alpha-naphthoxy acetic acid 19.3g (0.0957mol), presses the preparation method of II1, white solid 28.0g (80%), mp150～152 ℃.
Embodiment 2
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-3,4-dihydro-isoquinoline (III 1) preparation:
N-(3, the 4-dimethoxy) phenethylamine-(3, the 4-dimethoxy) phenyl acetamide (II 1) 24.4g (0.0213mol) is dissolved in dry toluene 40ml, POCl 330ml (0.3266mol), mixing, logical nitrogen stirs, and in 140 ℃ of backflow 2.5h, reactant liquor is a rufous, has a large amount of gases to generate, cooling, ice bath downhill reaction liquid is slowly poured clear water decomposed P OCl into 3, adding ethyl acetate 40ml, jolting divides the water intaking layer, transfers to pH8～9 with strong aqua ammonia, chloroform extraction, saturated common salt is washed to the center, anhydrous Na 2SO 4Drying boils off solvent, gets rufous syrup thing crude product 22.8g (97.8%), is directly used in the next step.
6,7-dimethoxy-1-(α-menaphthyl)-3,4-dihydro-isoquinoline (III 2) preparation:
N-(3, the 4-dimethoxy) phenethyl-α-phenyl acetamide (II 2) 28.9g (0.0828mol), dry toluene 50ml and POCl 329ml (0.3157mol) mixing is pressed III 1Preparation method gets rufous syrup thing crude product 27g (98%).
6,7-dimethoxy-1-Phenoxymethyl-3,4-dihydro-isoquinoline (III 3) preparation:
N-(3, the 4-dimethoxy) phenethyl-benzene acetamide oxide (II 3) 9.0g (0.0286mol), dry toluene 30ml and POCl 37.2ml (0.0784mol) mix, press III 1Preparation is handled, and gets rufous syrup thing 6.5g (76%).
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-3,4-dihydro-isoquinoline (III 4) preparation:
N-(3, the 4-dimethoxy) phenethyl-alpha-naphthoxy acetamide (II 4) 10g (0.0273mol), dry toluene 30ml and POCl 310ml (0.109mol) mixes, and presses III 1Preparation is handled, and gets light yellow solid 10.5g (76%).
Embodiment 3
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-1,2,3,4-tetrahydroisoquinoline (IV 1) preparation:
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-3,4-dihydro-isoquinoline (III 1) 30.7g (0.090mol) is suspended among the methanol 60ml, drips diethylamine 0.4ml, gradation adds KBH under the room temperature 49g (0.167mol) continues to stir 22h, slowly pours the 1000ml brine ice into, separates out yellow syrup thing, the layer that anhydrates that inclines, and the chloroform dissolving, saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets rufous grease 14g (64%).
6,7-dimethoxy-1-(α-menaphthyl)-1,2,3,4-tetrahydroisoquinoline (IV 2) preparation:
6,7-dimethoxy-1-α-menaphthyl-3,4-dihydro-isoquinoline (III 2) 26g (0.0781mol) is suspended among the methanol 110ml, presses IV 1Preparation method gets orange-yellow oily thing 15g (57%).
6,7-dimethoxy-1-Phenoxymethyl-1,2,3,4-tetrahydroisoquinoline (IV 3) preparation:
6,7-dimethoxy-Phenoxymethyl-3,4-dihydro-isoquinoline (III 3) 6g (0.0202mol) is suspended among the methanol 100ml, drips diethylamine 0.5ml, adds KBH under the room temperature respectively 410g (0.185mol) presses IV 1Preparation method, post processing gets rufous grease 4.0g (67%).
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-1,2,3,4-tetrahydroisoquinoline (IV 4) preparation:
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-3,4-dihydro-isoquinoline (III 4) 11g (0.030mol) is suspended among the methanol 80ml, presses IV 1The preparation method post processing gets brown oil 9g (82%).
Embodiment 4
6, the different thioamides base-1,2,3 of 7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(S-methyl-N-cyano group), 4-tetrahydroisoquinoline (V 1) preparation:
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-1,2,3,4-tetrahydroisoquinoline (IV 1) 12.5g (0.036mol) is dissolved among the anhydrous benzene 150ml, adds S,S-Dimethyl cyanoimidodithiocarbonate 5.39g (0.036mol), 100 ℃ of back flow reaction 50h, the pressure reducing and steaming solvent, residue dissolves with chloroform, uses 3% hydrochloric acid successively, and saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets rufous grease, and ethyl alcohol recrystallization gets faint yellow solid 3.8g (25%), and benzene-recrystallizing methanol gets white crystal, mp160-161 ℃.
IR(cm -1)：2940(CH)，2840，2180(C≡N)，1610，
1HNMR(CDCl 3)δ2.71-3.14(m，4H，2ArCH 2)，3.68(s，3H，OCH 3)，3.81(s，3H，SCH 3)，3.86(s，9H，3OCH 3)，4.05(m，2H，C 3-H)，5.65(t，1H，C 1-H)，6.23(s，1H，C 8-H)，6.62-6.79(m，4H，aromatic)；
MS(SCI，m/z)：442(M+1，base peak).
6, the different thioamides base-1,2,3 of 7-dimethoxy-1-(α-menaphthyl)-2-(S-methyl-N-cyano group), 4-tetrahydroisoquinoline (V 2) preparation:
6,7-dimethoxy-1-(α-menaphthyl)-1,2,3,4-tetrahydroisoquinoline (IV 2) 12.5g (0.037mol) is dissolved among the anhydrous benzene 50ml, adds S,S-Dimethyl cyanoimidodithiocarbonate 5.39g (0.036ml), 100 ℃ of back flow reaction 30h, the pressure reducing and steaming solvent, residue dissolves with chloroform, uses 3% hydrochloric acid successively, and saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets light brown oily thing, and re-crystallizing in ethyl acetate gets faint yellow solid 4.4g (25%), mp147-148 ℃.
IR(cm -1)：3080，2920(CH)，2180(C≡N)，1610，1520
1HNMR(CDCl 3)δ2.71-2.93(m，4H，2ArCH 2)，3.14(s，3H，OCH 3)，3.70(s，3H，SCH 3)，3.78(s，3H，OCH 3)，4.06(m，2H，C 3-H)，5.94(t，1H，C 1-H)，6.81(s，1H，C 8-H)，7.36-8.35(m，7H，aromatic)；
MS(SCI，m/z)：432(M+1，base peak).
6, the different thioamides base-1,2,3 of 7-dimethoxy-1-Phenoxymethyl-2-(S-methyl-N-cyano group), 4-tetrahydroisoquinoline (V 3) preparation:
6,7-dimethoxy-1-Phenoxymethyl 2-(S-methyl-N-cyano group) isothiourea group-1,2,3,4-tetrahydroisoquinoline crude product 4.0g (0.013mol) is dissolved among the anhydrous benzene 50ml, add S,S-Dimethyl cyanoimidodithiocarbonate 2.1g (0.014ml), 100 ℃ of back flow reaction 50h, pressure reducing and steaming solvent, residue dissolves with chloroform, use 3% hydrochloric acid successively, saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets light grease, column chromatography for separation (chloroform: methanol=16: 1), get white solid 3.6g (0%), mp133-135 ℃.
6, the different thioamides base-1,2,3 of 7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(S-methyl-N-cyano group), 4-tetrahydroisoquinoline) (V 4) preparation:
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-1,2,3,4-tetrahydroisoquinoline 9.0g (0.025mol) is dissolved among the anhydrous benzene 100ml, add S,S-Dimethyl cyanoimidodithiocarbonate 4.2g (0.028ml), 100 ℃ of back flow reaction 50h, pressure reducing and steaming solvent, residue dissolves with chloroform, use 3% hydrochloric acid successively, saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets light grease, column chromatography for separation (chloroform: methanol=18: 1), get white solid 2.0g (17%), mp129-131 ℃.
Embodiment 5
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1a) preparation:
With chemical compound (V 1) 0.5g (0.0012mol) is dissolved in anhydrous benzene 12ml, adds n-amylamine 1.5g (0.012ml), 100 ℃ of back flow reaction 14h, the pressure reducing and steaming solvent, white solid 0.40g (69%), mp144～146 ℃.
IR(cm -1)：3385(NH)，2996，2933，2835(CH)，2162(C≡N)，1610，1563，1516，(aromatic).
1HNMR(CDCl 3)δ0.82-1.61(m，9H，(CH 2) 3CH 3)，2.68-3.75(m，6H，2Ar-CH 2，NHCH 2)，3.87-3.94(s，12H，4OCH 3)，4.10(m，2H，C 3-H)，4.92(t，1H，C 1-H)，6.40(s，1H，C 8-H)，6.20-7.20(s，4H，aromatic)；MS(SCI，m/z)：515(M+1，base peak).
Embodiment 6
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1b) preparation:
With reference to I among the embodiment 5 1aPreparation method, by chemical compound V 1Make I with phenethylamine 1b, acetone-petroleum ether recrystallization, white solid, yield 48.6%, mp154～156 ℃.
IR(cm -1)：3377(NH)，3000，2936，2836(CH)，2164(C≡N)，1610，1564，1516，(aromatic).
1HNMR(CDCl 3)δ2.68-3.75(m，8H，3ArCH 2，NHCH 2)，3.77(s，3H，C 7-OCH 3)，3.87(s，9H，3OCH 3)，4.10(m，1H，C 3-H)，4.95(t，1H，C 1-H)，6.38(s，1H，C 8-H)，6.20-7.20(s，10H，aromatic)；
MS(SCI，m/z)：515(M+1，base peak).
Embodiment 7
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1c)
With reference to I among the embodiment 5 1aPreparation method, by chemical compound V 1With 3, the 4-dimethoxy-phenylethylamine makes I 1c, column chromatography for separation (ethyl acetate: petroleum ether=1: 2), acetone-petroleum ether recrystallization, white solid, yield 29.0%, mp154～156 ℃.
IR(cm -1)：3374(NH)，2965，2935(CH)，2161(C≡N)，1606，1565，1516，(aromatic).
1HNMR(CDCl 3)δ2.60-3.60(m，8H，3ArCH 2，NHCH 2)，3.72-3.90(s，18H，6OCH 3)，4.14(m，1H，C 3-H)，4.78(t，1H，C 1-H)，6.24-6.80(s，8H，aromatic)；MS(SCI，m/z)：575(M+1，base peak).
Embodiment 8
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1d)
With reference to I 1aPreparation method, by chemical compound V 1Make I with cyclohexylamine 1d, column chromatography for separation (ethyl acetate: petroleum ether=1: 2.5), acetone-petroleum ether recrystallization, white solid, yield 38%, mp168～170 ℃.
IR(cm -1)：3364(NH)，2995，2933(CH)，2166(C≡N)，1599，1570，1519，(aromatic).
1HNMR(CDCl 3)δ1.10-1.80(m，10H，5CH 2)，2.12-3.34(m，5H，2ArCH 2，NHCH)，3.78-3.95(s，12H，4OCH 3)，4.34(m，2H，C 3-H)，4.44(t，1H，C 1-H)，5.14(m，1H，C 1-H)，6.28-7.30(s，5H，aromatic)；MS(SCI，m/z)：493(M+1，base peak).
Embodiment 9
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-piperidyl-N-cyano group amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1e)
With reference to I 1aPreparation method, by chemical compound V 1Make I with piperidines 1e, petroleum ether-acetone recrystallization, white solid, yield 51%, mp171～173 ℃.
IR(cm -1)：3364(NH)，2995，2932(CH)，2165(C≡N)，1600，1570，1519，(aromatic).
1HNMR(CDCl 3)δ1.22-1.78(m，10H，5CH 2)，2.05-3.35(m，4H，2ArCH 2)，3.78-3.95(s，12H，4OCH 3)，4.32(m，2H，C 3-H)，4.39(t，1H，C 1-H)，5.10(m，1H，C 1-H)，6.68-7.35(s，5H，aromatic)；
MS(SCI，m/z)：507(M+1，base peak).
Embodiment 10
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1f)
With reference to I 1aPreparation method, by chemical compound V 1Make I 1f, ether-ethyl alcohol recrystallization, white solid, yield 34%, mp117～118 ℃.
IR(cm -1)：3380(NH)，3000，2920，2860(CH)，2162(C≡N)，1610，1570，1520，(aromatic).
1HNMR(CDCl 3)δ0.88-1.62(m，15H，(CH 2) 6CH 3)，2.77-3.66(m，6H，2Ar-CH 2，NHCH 2)，3.78(s，3H，OCH 3)，3.86(s，9H，3OCH 3)，4.07(m，2H，C 3-H)，4.95(t，1H，C 1-H)，6.40(s，1H，C 8-H)，6.62，6.69(each s，2H，C 5-H，C 2’-H)，6.84(d，2H，aromatic)；MS(SCI，m/z)：523(M+1，base peak).
Embodiment 11
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1g)
With reference to I 1aPreparation method, by chemical compound V 1Make I with n-butylamine 1g, ether-ethyl alcohol recrystallization, white solid, yield 56%, mp169～170 ℃.
IR(cm -1)：3380(NH)，2960，2940(CH)，2160(C≡N)，1570，1520，(aromatic).
1HNMR(CDCl 3)δ0.88-1.34(m，7H，(CH 2) 2CH 3)，2.77-3.64(m，6H，2Ar-CH 2，NHCH 2)，3.78(s，3H，OCH 3)，3.87(s，9H，3OCH 3)，4.05(m，2H，C 3-H)，4.93(t，1H，C 1-H)，6.41(s，1H，C 8-H)，6.62，6.72(each s，2H，C 5-H，C 2’-H)，6.84(d，2H，aromatic)；MS(SCI，m/z)：523(M+1，basepeak).
Embodiment 12
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2a)
With chemical compound (V 2) 0.5g (0.0012mol) is dissolved among the anhydrous benzene 12ml, adds n-amylamine 1.5g (0.012ml), 100 ℃ of back flow reaction 14h, the pressure reducing and steaming solvent, ether-ethyl alcohol recrystallization, white solid 0.4g (71%), mp153-154 ℃.
IR(cm -1)：3287(NH)，2932，2866(CH)，2166(C≡N)，1610，1560，1516，(aromatic).
1HNMR(CDCl 3)δ0.70-1.20(m，9H，(CH 2) 3CH 3)，2.77-3.66(m，6H，2ArCH 2，NHCH 2)，3.70(s，3H，C 7-OCH 3)，3.86(s，3H，C 6-OCH 3)，4.16(m，1H，C 3-H)，5.12(t，1H，C 1-H)，6.41(s，1H，C 8-H)，6.62(s，1H，C 5-H)，7.18-8.22(s，7H，aromatic)；
MS(SCI，m/z)：471(M+1，base peak).
Embodiment 13
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2b)
With reference to I 2aPreparation method, by chemical compound V 2Make I with phenethylamine 2b, (ethyl acetate: petroleum ether=1: 2), acetone-ether recrystallization gets white solid, yield 33%, mp136-138 ℃ to column chromatography for separation.
IR(cm -1)：3298(NH)，3001，2953，2866(CH)，2161(C≡N)，1610，1571，1511，(aromatic).
1HNMR(CDCl 3)δ2.24-3.60(m，8H，3ArCH 2，NHCH 2)，3.62(s，3H，C 7-OCH 3)，3.82(s，3H，C 6-OCH 3)，3.94(m，1H，C 3-H)，4.96(t，1H，C 1-H)6.18-8.18(s，14H，aromatic)；MS(SCI，m/z)：505(M+1，base peak).
Embodiment 14
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2c)
With reference to I 2aPreparation method, by chemical compound V 2With 3, the 4-dimethoxy-phenylethylamine makes I 2c, column chromatography for separation (ethyl acetate: petroleum ether=1: 2.5), add petroleum ether, grind, get pale yellow powder shape solid, yield 21%, mp112-114 ℃.
IR(cm -1)：3378(NH)，3000，2936，2836(CH)，2164(C≡N)，1609，1563，1516，(aromatic).
1HNMR(CDCl 3)δ2.26-3.56(m，8H，3ArCH 2，NHCH 2)，3.60-3.92(s，12H，4OCH 3)，3.94(m，2H，C 3-H)，5.02(t，1H，C 1-H)6.12-8.17(s，12H，aromatic)；MS(SCI，m/z)：565(M+1，base peak).
Embodiment 15
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2d)
With reference to I 2aPreparation method, by chemical compound V 2Make I with cyclohexylamine 2d, column chromatography for separation (ethyl acetate: petroleum ether=1: 2.5), acetone-petroleum ether recrystallization, white solid, yield 35%, mp151～153 ℃.
IR(cm -1)：3328(NH)，3008，2965，2836(CH)，2165(C≡N)，1599，1549，1518，(aromatic).
1HNMR(CDCl 3)δ0.85-1.64(m，10H，5CH 2)，2.76-3.56(m，5H，2ArCH 2，NHCH 1)，3.86-3.93(s，6H，2OCH 3)，4.08(m，2H，C 3-H)，5.07(t，1H，C 1-H)6.48-8.24(s，9H，aromatic)；
MS(SCI，m/z)：483(M+1，base peak).
Embodiment 16
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2e)
With reference to I 2aPreparation method, by chemical compound V 2Make I with n-butylamine 2e, acetone recrystallization, white solid, yield 47%, mp212～214 ℃.
IR(cm -1)：3280(NH)，3120，2960，2920(CH)，2160(C≡N)，1580，1550，1510，(aromatic).
1HNMR(CDCl 3)δ0.75-0.93(m，7H，(CH 2) 2CH 3)，2.60-3.20，3.50-3.63(m，6H，2ArCH 2，NHCH 2)，3.70(s，3H，C 7-OCH 3)，3.86(s，3H，C 6-OCH 3)，4.08(m，2H，NCH 2)，5.13(t，1H，C 1-H)，6.37(s，1H，C 8-H)，6.64(s，1H，C 5-H)，7.13-8.25(m，7H，aromatic)；
MS(SCI，m/z)：475(M+1，base peak).
Embodiment 17
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2f)
With reference to I 2aPreparation method, by chemical compound V 2Make I with 1-Aminooctane 2f, the ether recrystallization gets white solid, yield 58%, mp108-110 ℃.
IR(cm -1)：3240(NH)，2920，2850(CH)，2160(C≡N)，1570，1520，(aromatic).
1HNMR(CDCl 3)δ0.89-1.19(m，15H，(CH 2) 6CH 3)，2.8-3.63(m，6H，2ArCH 2，NHCH 2)，3.69(s，3H，C 7-OCH 3)，3.87(s，3H，C 6-OCH 3)，4.05(m，2H，C 3-H)，5.10(t，1H，C 1-H)，6.36(s，1H，C 8-H)，6.64(s，1H，C 5-H)，7.13-8.27(s，7H，aromatic)；
MS(SCI，m/z)：513(M+1，base peak).
Embodiment 18
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3a)
With chemical compound (V 3) 0.5g (0.0013mol) is dissolved in anhydrous benzene 12ml, adds n-amylamine 1.1g (0.0135mmol), 100 ℃ of back flow reaction 14h, the pressure reducing and steaming solvent, ether-ethyl alcohol recrystallization, white solid 0.31g (54%), mp112～114 ℃.
IR(cm -1)：3284(NH)，2999，2931，2860(CH)，2163(C≡N)，1610，1572，1520，(aromatic).
1HNMR(CDCl 3)δ0.88-1.62(m，9H，(CH 2) 3CH 3)，2.77-3.64(m，6H，ArCH 2，2C 3-H，NHCH 2)，3.86(s，6H，2OCH 3)，4.30(S，2H，Ar-OCH 2)，4.40(m，1H，C 3-H)，5.16(m，1H，C 1-H)，6.41-7.40(s，7H，aromatic)；MS(SCI，m/z)：437(M+1，base peak).
Embodiment 19
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3b)
With reference to I 3aPreparation method, by chemical compound V 3Make I with 1-Aminooctane 3b, ether-ethyl alcohol recrystallization, white solid, yield 48%, mp108～109 ℃.
IR(cm -1)：3280(NH)，2999，2926，2853(CH)，2164(C≡N)，1610，1573，1521，(aromatic).
1HNMR(CDCl 3)δ0.80-1.70(s，15H，(CH 2) 6CH 3)，2.73-3.65(m，4H，ArCH 2，NHCH 2)，3.87(s，6H，2OCH 3)，4.28(m，2H，Ar-OCH 2)，4.98(t，1H，C 1-H)，6.41(s，1H，C 8-H)，6.59-6.80(s，6H，aromatic)；MS(SCI，m/z)：479(M+1，base peak).
Embodiment 20
6,7-dimethoxy-1-Phenoxymethyl-2-(phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3c)
With reference to I 3aPreparation method, by chemical compound V 3Make I with phenethylamine 3c, column chromatography for separation (ethyl acetate: petroleum ether=1: 3), ether-ethyl alcohol recrystallization, white solid, yield 41%, mp108～110 ℃.
IR(cm -1)：3369(NH)，2998，2932，2835(CH)，2167(C≡N)，1599，1566，1519，(aromatic).
1HNMR(CDCl 3)δ2.80-3.80(m，6H，2ArCH 2，NHCH 2)，3.90(s，6H，2OCH 3)，4.12(m，2H，CH 2-OAr)，4.24(m，2H，C 3-H)，4.80(t，1H，C 1-H)，6.22-7.22(s，12H，aromatic)；
MS(SCI，m/z)：471(M+1，base peak).
Embodiment 21
6,7-dimethoxy-1-Phenoxymethyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3d)
With reference to I 3aPreparation method, by chemical compound V 3With 3, the 4-dimethoxy-phenylethylamine makes I 3d, column chromatography for separation (ethyl acetate: petroleum ether=1: 3), grind, buff powder, benzene-petroleum ether recrystallization, white solid, yield 21%, mp159～160 ℃.
IR(cm -1)：3329(NH)，3000，2936，2836(CH)，2165(C≡N)，1599，1584，1549，1518(aromatic).
1HNMR(CDCl 3)δ2.70-3.80(m，6H，2ArCH 2，NHCH 2)，3.90(s，12H，4OCH 3)，4.12(s，2H，CH 2-OAr)，4.25(m，1H，C 3-H)，4.70(t，1H，C 1-H)，6.30-7.30(s，10H，aromatic)；
MS(SCI，m/z)：531(M+1，base peak).
Embodiment 22
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 4a)
With chemical compound V 40.5g (0.0011mol) be dissolved in anhydrous benzene 12ml, add n-amylamine 1.0g (0.012mmol), 100 ℃ of back flow reaction 22h, the pressure reducing and steaming solvent, column chromatography for separation (ethyl acetate: petroleum ether=1: 2.5), white solid 0.22g (42%), mp124～126 ℃.
IR(cm -1)：3288(NH)，3000，2870(CH)，2162(C≡N)，1610，1570，1520，(aromatic).
1HNMR(CDCl 3)δ0.80-1.70(m，9H，(CH 2) 3CH 3)，2.75-3.80(m，4H，ArCH 2，NHCH 2)，3.87(s，6H，2OCH 3)，4.30(m，H，C 3-H)，4.42(s，2H，CH 2-OAr)，5.20(t，1H，C 1-H)，6.65-8.10(s，9H，aromatic)；MS(SCI，m/z)：487(M+1，base peak).
Embodiment 23
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 4b)
With reference to I 4aPreparation method, by chemical compound V 4Make I with 1-Aminooctane 4b, column chromatography for separation (ethyl acetate: petroleum ether=1: 2.5), white solid, yield 36%, mp122～124 ℃.
IR(cm -1)：3296(NH)，3000，2930(CH)，2160(C≡N)，1611，1572，1541，1519(aromatic).
1HNMR(CDCl 3)δ0.80-1.70(m，15H，(CH 2)6CH 3)，2.73-3.65(m，4H，ArCH 2，NHCH 2)，3.87(s，6H，2OCH 3)，4.18(m，H，C 3-H)，4.22(s，2H，CH 2-OAr)，5.30(t，1H，C 1-H)，6.69-8.08(s，9H，aromatic)；MS(SCI，m/z)：529(M+1，base peak).
Embodiment 24
6,7-methylene-dioxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 5a)
With reference to I 4aPreparation method, by chemical compound V 5Make I with n-butylamine 5a, re-crystallizing in ethyl acetate, white solid, yield 47%, mp141～143 ℃.
IR(cm -1)：3260(NH)，2960，2920(CH)，2160(C≡N)，1570，1540，1500，(aromatic).
1HNMR(CDCl 3)δ0.82-1.12(m，7H，(CH 2) 2CH 3)，2.54，2.83，3.58(m，6H，2Ar-CH 2，NHCH 2)，3.67，3.94(m，2H，C 3-H)，5.57(t，1H，C 1-H)，5.94(t，2H，OCH 2O)，6.49(s，1H，C 8-H)，6.75(s，1H，C 5-H)，7.24-8.41(M，7H，aromatic)；MS(SCI，m/z)：441(M+1，base peak).
Embodiment 25
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1f)
1-Aminooctane 12.9g, S,S-Dimethyl cyanoimidodithiocarbonate 14.6g is dissolved in dehydrated alcohol 60ml, and stirring at room 2 hours is separated out a large amount of white solids gradually, filters, and gets the 19.8g compound VI 1Get 1g VI 1, 6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-1,2,3,4-tetrahydroisoquinoline 1.5g, toluene 25ml, stirring and refluxing reaction 20 hours is steamed to slip and is removed most of solvent, filter, ether-ethyl alcohol recrystallization, white solid 1.2g, mp117～118 ℃.
IR(cm -1)：3380(NH)，3000，2920，2860(CH)，2162(C≡N)，1610，1570，1520，(aromatic).
1HNMR(CDCl 3)δ0.88-1.62(m，15H，(CH 2) 6CH 3)，2.77-3.66(m，6H，2Ar-CH 2，NHCH 2)，3.78(s，3H，OCH 3)，3.86(s，9H，3OCH 3)，4.07(m，2H，C 3-H)，4.95(t，1H，C 1-H)，6.40(s，1H，C 8-H)，6.62，6.69(each s，2H，C 5-H，C 2’-H)，6.84(d，2H，aromatic)；MS(SCI，m/z)：523(M+1，base peak).
Embodiment 26
Contain activating agent I 1fTablet:
Every contains (mg)
I 1f 50mg
Lactose 100mg
Corn starch 40mg
Magnesium stearate 1.5mg
Ethanol is an amount of
According to a conventional method supplementary material is mixed, granulate drying, tabletting.

Claims (2)

1, following general formula (I) chemical compound and pharmaceutical salts thereof the purposes in preparation reverse multiple drug resistance of tumor sex pill:
Figure C031132620002C1
Wherein R1 representative:
Figure C031132620002C2
R2 representative :-NH (CH 2) nCH 3N=1-9;
Figure C031132620002C3
n＝1-2；
The R3 representative: 6,7-(OCH 3) 2, 6,7-OCH 2O-:
2, according to the purposes of claim 1, its formula of (I) chemical compound can be following arbitrary chemical compound and pharmaceutical salts thereof:
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-piperidyl-N-cyano group amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-cyclohexyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-(3 ', 4 '-dimethoxy) phenethyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-methylene-dioxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline.
CN 03113262 2003-04-22 2003-04-22 Usage of substituted tetrahydroisoquinoline derviation Expired - Fee Related CN1227010C (en)

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CN101619065B (en) * 2008-07-04 2012-07-25 上海医药工业研究院 Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof
WO2010123838A2 (en) * 2009-04-20 2010-10-28 Abbott Laboratories Novel amide and amidine derivatives and uses thereof
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