CN100366611C - Substitutional ramification of tetrahydro-isoquinoline, as well as its preparing method and its medication compound containing them - Google Patents

Substitutional ramification of tetrahydro-isoquinoline, as well as its preparing method and its medication compound containing them Download PDF

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CN100366611C
CN100366611C CNB031132618A CN03113261A CN100366611C CN 100366611 C CN100366611 C CN 100366611C CN B031132618 A CNB031132618 A CN B031132618A CN 03113261 A CN03113261 A CN 03113261A CN 100366611 C CN100366611 C CN 100366611C
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dimethoxy
tetrahydroisoquinoline
cyano group
amidino groups
compound
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CN1445217A (en
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黄文龙
张惠斌
周金培
何立文
胡振
李运曼
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China Pharmaceutical University
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Abstract

The present invention relates to a compound with the general formula (I) and salt thereof. The compound has good function for reversing the multi-drug resistance (MDR) of tumors, the activity of the compound is higher than the activity of verapamil, and the compound has no side effect on angiocarpy as the common calcium antagonist. The present invention also relates to a method for preparing the compound, and a medicinal preparation containing the compound.

Description

Tetrahydro isoquinoline derivative, its preparation method that replaces and contain their pharmaceutical composition
Technical field the present invention relates to the tetrahydro isoquinoline derivative that the 2-amidino groups replaces, and their synthetic method contains their pharmaceutical composition.
The background technology tumour is one of disease of harm humans life.Tumour can produce a kind of self-protective mechanism---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; resistance produces the back tumour cell can constantly discharge the extracellular with the chemotherapeutics that arrives target tissue; for the effect of offsetting resistance raising chemotherapeutic must improve dosage; this can increase the injury of chemotherapeutics to healthy tissues undoubtedly, and the resistance that therefore how to overcome tumour 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 resistance to induced drug, and other medicines are not produced resistance, MDR is meant that then tumour cell is once certain chemotherapeutics is produced 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 metabolic antagonist and induces generation PDR, all easily induces to produce MDR.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 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 novel tumor multi-drug resistant reversing agent, and its cardiovascular side effects is less, security is higher, is used to improve the curative effect of antitumour drug.
The present invention also aims to provide a kind of preparation method of synthesizing new tumor multi-drug resistant reversing agent.
Another object of the present invention is to provide a kind of pharmaceutical preparation that contains tumor multi-drug resistant reversing agent.
This study group is that guide's thing carries out designs simplification in the eighties with natural tetrahydro isoquinoline compounds such as effective components of Chinese medicinal Tetrrines.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 compound reversion MDR activity far is better than clinical reversal agent verapamil commonly used, and does not have cardiovascular side effect.
Summary of the invention is as follows in detail:
The present invention has synthesized a series of general formulas (I) compound and pharmacy acceptable salt thereof:
Wherein R1 representative:
R2 representative :-NH (CH 2) nCH 3N=1-9;
R3 representative :-H, 6,7-(OCH 3) 2Or 6,7-OCH 2O-
R4 representative :-H ,-OCH 3, 3,4-(OCH 3) 2,-OH ,-NH 2Or halogen.
Preferred 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-styroyl-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) styroyl-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 (1 2a);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2b);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-(3 ', 4 '-dimethoxy) styroyl-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 (1 2d);
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-normal-butyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2c);
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-(N-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3c);
6,7-dimethoxy-1-Phenoxymethyl-2-(N-(3 ', 4 '-dimethoxy) styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3d);
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-pentyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 4a);
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 (I 5a);
The structural formula of part of compounds is:
Figure C0311326100071
Figure C0311326100072
I 1f -NHC 8H 17-n
I 1g -NHC 4H 9-n
V 1 -SCH 3
Figure C0311326100081
Figure C0311326100082
Figure C0311326100091
According to the present invention, pharmacy acceptable salt comprises the acid salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid, Phenylsulfonic acid.
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 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 compound), IV and S,S-Dimethyl cyanoimidodithiocarbonate reaction generate intermediate V, and V and amine reaction generate object I.Perhaps, obtain intermediate VI, react with general formula I V compound again, get object I the amine reaction of S,S-Dimethyl cyanoimidodithiocarbonate elder generation and replacement.
The wherein reference method that is prepared as of general formula I V compound acquisition (Huang Wenlong, study of the Song Dynasty duty, Peng Sixun. the synthetic and biological activity of substituted tetrahydroisoquinolicompounds derivative. Acta Pharmaceutica Sinica, 1990; 25 (11): 815-823).
Concrete reactions steps is:
Figure C0311326100101
(1) 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 sulphate 100 μ g/ml place 37 ℃ to contain 5%CO 2Incubator in cultivate.This experiment is carried out with mtt assay, with logarithmic phase cell, 2 * 10 -4Porocyte is inoculated on 96 orifice plates, and volume is 0.16ml, after cultivating 24h, what add 20 μ l different concns respectively is subjected to reagent thing and ADR, sets up simultaneously to be subjected to reagent thing control group and physiological saline control group, drug effect 48h, 4h adds 1mg/ hole MTT solution before finishing, and the centrifugal nutrient solution 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+ reversal agent) expression.
Measured 13 compounds respectively under 10 μ M concentration, active in table 1 to the drug-fast reverse of the leukemia cell of resistance Zorubicin, the result shows, compound all has the activity of reverse, the reverse of 3 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 reversal agent (10 μ M) that adds table 1. reduces K562/ADR to Zorubicin IC 50(nM) effect
Compound blank verapamil I 1aI 1bI 1cI 1dI 1eI 2aI 2bI 2cI 2dI 3aI 3bI 3cI 3dI 4aI 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 49.92 6.33 K562/ADR reverses multiple 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 0.90 7.70
(2) 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 nutrient solution, include 10% calf serum, and penicillin 100IU/ml and Streptomycin sulphate 100 μ g/ml place 37 ℃ to contain 5%CO 2Incubator in cultivate.This experiment is carried out with mtt assay, with logarithmic 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 different concns respectively is subjected to reagent thing and ADR, sets up simultaneously to be subjected to reagent thing control group and physiological saline control group, drug effect 72h, 4h adds 1mg/ hole MTT solution before finishing, and the centrifugal nutrient solution 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+ reversal agent) expression.
Measured 7 compounds respectively under 10 μ M concentration, active to the drug-fast reverse of the human breast cancer cell of resistance Zorubicin, the results are shown in Table 2, show that 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 reversal agent (10 μ M) reduction MCF-7 or MCF-7/ADR are to Zorubicin IC 50(nM) effect
Compound blank verapamil V1 V2 I 1fI 1gI 2eI 2fI 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 reverses multiple 1.0 1.2 1.2 1.2 1.2 1.2 1.2 1.2 K562/ADR reverses multiple 10.0 14.1 13.1 30.3 5.60 4.80 9.20 8.80
2, Compound I 1fInfluence to the liver cancer cell multidrug resistance
Get human liver cancer cell multidrug resistance medicine strain SMMC-7721/ADM cell in the RPMI-1640 nutrient solution 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 s-generation cell, the SMMC-7721/ADM cell in vegetative period of taking the logarithm.Be inoculated in the flat culture plate in 96 holes, add the reagent that is subjected to of different concns, cultivated 1 hour in 37 ℃, 5%CO2 incubator.In the SMMC-7721/ADM cell, add Zorubicin then, daunorubicin (concentration is 1.5 μ g/ml).Cell concn 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 methyl-sulphoxide 150 μ l, termination reaction vibrate 10 minutes, with microplate reader detection DD value (go into=570nm).Cell survival rate=susceptibility group DD value/control group DD value * 100%.Experimental result sees Table 3.
Table 3I 1fInfluence test to the liver cancer cell multidrug resistance
Drug level (μ g/ml) Cell survival rate (%)
2.0 100
5.0 62
10.0 50
20.0 40
3. Compound I 1fExtracorporeal blood vessel shrinks inhibition test
Male SD rat, body weight 250-350g opens chest 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 reverser, logical O2, preload 1gm, every 15min changes liquid once, begins test behind the balance 1h.
1. low potassium inductive blood vessel inhibition test: adding 1mmol stimulates aortic annulus to shrink, after arterial ring is retracted to maximum amplitude and stablizes, add sample,, calculate the vasoconstriction inhibiting rate 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 maximum amplitude, wash-out, 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 inhibiting rate (table 3) that corresponding compounds causes high potassium.
Table 3 verapamil and I 1fInhibiting rate (%) to the contraction of KCl inductive rabbit aorta strip
Sample Concentration 20mmol KCl 80mmol KCl
Verapamil I 1f 10 -6mol/L 10 -6mol/L 36.3 0 46.3 0
4. Compound I 1fAnti-arrhythmia 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 4.
Table 4I 1fWith verapamil napelline is induced the heart disorder effect
Compound Dosage (mg/kg) Produce ARR napelline 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 mouse, 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 toxinosis appearance thereafter.Continue administration in high dose group, integral dose reaches 500mg/kg and does not see dead yet and the toxicity symptom appearance.
Above pharmacology data shows that general formula of the present invention (I) compound has the effect of stronger reverse multiple drug resistance of tumor, and can not cause side effects such as vasoconstriction, irregular pulse.
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 promoting agent.Pharmaceutically acceptable carrier is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and their not reverse and active compounds or patient have an effect.
The formulation of the present composition can be a formulation commonly used on the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent.Can be prepared according to the method for knowing in this area.
The dosage of above promoting agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of formula (I) 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.
Embodiment:
Embodiment 1
N-(3, the 4-dimethoxy) phenylethylamine-(3, the 4-dimethoxy) phenylacetamide (II 1) preparation:
3,4-dimethoxy-phenylethylamine (underpressure distillation, 140～170/1mmHg cut) 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, the 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) styroyl-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 1The preparation method, white solid 25.0g (75%), mp110～112 ℃.
N-(3, the 4-dimethoxy) styroyl-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 1The preparation method, white solid 9.4g (90%).
N-(3, the 4-dimethoxy) styroyl-alpha-naphthoxy ethanamide (II 4) preparation:
3,4-dimethoxy-phenylethylamine 18.6g (0.101mol) mixes with alpha-naphthoxy acetate 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) phenylethylamine-(3, the 4-dimethoxy) phenylacetamide (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, reaction solution is a reddish-brown, 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, chloroform extraction, saturated common salt is washed to the center, anhydrous Na 2SO 4Drying boils off solvent, gets reddish-brown 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) styroyl-α-phenylacetamide (II 2) 28.9g (0.0828mol), dry toluene 50ml and POCl 329ml (0.3157mol) mixing is pressed III 1The preparation method gets reddish-brown syrup thing crude product 27g (98%).
6,7-dimethoxy-1-Phenoxymethyl-3,4-dihydro-isoquinoline (III 3) preparation:
N-(3, the 4-dimethoxy) styroyl-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 reddish-brown syrup thing 6.5g (76%).
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-3,4-dihydro-isoquinoline (III 4) preparation:
N-(3, the 4-dimethoxy) styroyl-alpha-naphthoxy ethanamide (II4) 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 methyl alcohol 60ml, drips diethylamine 0.4ml, gradation adds KBH under the room temperature 49g (0.167mol) continues to stir 22h, slowly pours the 1000ml icy salt solution 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 reddish-brown oily matter 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 methyl alcohol 110ml, presses IV 1The preparation 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 methyl alcohol 100ml, drips diethylamine 0.5ml, adds KBH under the room temperature respectively 410g (0.185mol) presses IV 1The preparation method, aftertreatment gets reddish-brown oily matter 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 methyl alcohol 80ml, presses IV 1Preparation method's aftertreatment 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 dry-out benzene 150ml, adds S,S-Dimethyl cyanoimidodithiocarbonate 5.39g (0.036mol), 100 ℃ of back flow reaction 50h, the pressure reducing and steaming solvent, resistates dissolves with chloroform, uses 3% hydrochloric acid successively, and saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets reddish-brown oily matter, 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)δ 2.71-3.14(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 dry-out benzene 50ml, adds S,S-Dimethyl cyanoimidodithiocarbonate 5.39g (0.036ml), 100 ℃ of back flow reaction 30h, the pressure reducing and steaming solvent, resistates 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) isothioureido-1,2,3,4-tetrahydroisoquinoline crude product 4.0g (0.013mol) is dissolved among the dry-out benzene 50ml, add S,S-Dimethyl cyanoimidodithiocarbonate 2.1g (0.014ml), 100 ℃ of back flow reaction 50h, pressure reducing and steaming solvent, resistates dissolves with chloroform, use 3% hydrochloric acid successively, saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets light oily matter, column chromatography for separation (chloroform: methyl alcohol=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 dry-out benzene 100ml, add S,S-Dimethyl cyanoimidodithiocarbonate 4.2g (0.028ml), 100 ℃ of back flow reaction 50h, pressure reducing and steaming solvent, resistates dissolves with chloroform, use 3% hydrochloric acid successively, saturated common salt is washed to neutrality, anhydrous Na 2SO 4Drying boils off solvent, gets light oily matter, column chromatography for separation (chloroform: methyl alcohol=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 compound (V 1) 0.5g (0.0012mol) is dissolved in dry-out 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) 3 CH 3)，2.68-3.75(m，6H，2Ar-CH 2，NH CH 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-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1b) preparation:
With reference to I among the embodiment 5 1aThe preparation method, by compound V 1Make I with phenylethylamine 1b, acetone-sherwood oil 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，NH CH 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) styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 1c)
With reference to I among the embodiment 5 1aThe preparation method, by compound V 1With 3, the 4-dimethoxy-phenylethylamine makes I 1c, column chromatography for separation (ethyl acetate: sherwood oil=1: 2), acetone-sherwood oil 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 1aThe preparation method, make I by compound V1 and hexahydroaniline 1d, column chromatography for separation (ethyl acetate: sherwood oil=1: 2.5), acetone-sherwood oil 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，NH CH)，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 1aThe preparation method, by compound V 1Make I with piperidines 1e, sherwood oil-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 1aThe preparation method, by 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) 6 CH 3)，2.77-3.66(m，6H，2Ar-CH 2，NH CH 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 1aThe preparation method, by compound V 1Make I with n-Butyl Amine 99 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) 2 CH 3)，2.77-3.64(m，6H，2Ar-CH 2，NH CH 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 compound (V 2) 0.5g (0.0012mol) is dissolved among the dry-out 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，NH CH 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-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2b)
With reference to I 2aThe preparation method, by compound V 2Make I with phenylethylamine 2b, (ethyl acetate: sherwood oil=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，NH CH 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) styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 2c)
With reference to I 2aThe preparation method, by compound V 2With 3, the 4-dimethoxy-phenylethylamine makes I 2c, column chromatography for separation (ethyl acetate: sherwood oil=1: 2.5), add sherwood oil, 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 2aThe preparation method, by compound V 2Make I with hexahydroaniline 2d, column chromatography for separation (ethyl acetate: sherwood oil=1: 2.5), acetone-sherwood oil 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，NH CH 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，n/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 2aThe preparation method, by compound V 2Make I with n-Butyl Amine 99 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，NH CH 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 2aThe preparation method, by compound V 2Make I with n-octyl amine 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 compound (V 3) 0.5g (0.0013mol) is dissolved in dry-out 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，NH CH 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 3aThe preparation method, by compound V 3Make I with n-octyl amine 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，NH CH 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-(N-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3c)
With reference to I 3aThe preparation method, by compound V 3Make I with phenylethylamine 3c, column chromatography for separation (ethyl acetate: sherwood oil=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，NH CH 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) styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline (I 3d)
With reference to I 3aThe preparation method, by compound V 3With 3, the 4-dimethoxy-phenylethylamine makes I 3d, column chromatography for separation (ethyl acetate: sherwood oil=1: 3), grind, buff powder, benzene-sherwood oil 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，NH CH 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 compound V 40.5g (0.0011mol) be dissolved in dry-out 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: sherwood oil=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，NH CH 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 4aThe preparation method, by compound V 4Make I with n-octyl amine 4b, column chromatography for separation (ethyl acetate: sherwood oil=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，NH CH 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 4aThe preparation method, by compound V 5Make I with n-Butyl Amine 99 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) 2 CH 3)，2.54，2.83，3.58(m，6H，2Ar-CH 2，NH CH 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)
N-octyl amine 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) 6 CH 3)，2.77-3.66(m，6H，2Ar-CH 2，NH CH 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 promoting agent I 1fTablet:
Every contains (mg)
I 1f 50mg
Lactose 100mg
W-Gum 40mg
Magnesium Stearate 1.5mg
Ethanol is an amount of
According to a conventional method supplementary material is mixed, granulate drying, compressing tablet.

Claims (5)

1. following general formula (I) compound or pharmaceutically acceptable salt thereof:
Figure C031132610002C1
Wherein R1 representative:
Figure C031132610002C2
Or
R2 representative :-NH (CH 2) nCH 3N=1-9
Figure C031132610002C4
n＝1-2
Figure C031132610002C5
Or
Figure C031132610002C6
R3 representative :-H, 6,7-(OCH 3) 2Or 6,7-OCH 2O-:
R4 representative :-H ,-OCH 3, 3,4-(OCH 3) 2,-OH ,-NH 2Or halogen.
2. the compound of claim 1 can be following arbitrary compound or pharmaceutically acceptable salt 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-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-(3 ', 4 '-dimethoxy) styroyl-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-styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(α-menaphthyl)-2-(N-(3 ', 4 ' dimethoxy) styroyl-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-(styroyl-N '-cyano group) amidino groups-1,2,3, the 4-tetrahydroisoquinoline;
6,7-dimethoxy-1-Phenoxymethyl-2-(N-(3 ', 4 '-dimethoxy) styroyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline;
6,7-dimethoxy-1-(alpha-naphthoxy methyl)-2-(N-n-pentyl-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;
6,7-dimethoxy-1-(3, the 4-dimethoxy) benzyl-2-(N-n-octyl-N '-cyano group) amidino groups-1,2,3,4-tetrahydroisoquinoline.
3. the preparation method of claim 1 or 2 compound is prepared by following method:
Definition in wherein substituent R 1, R2 and R3 such as the claim 1.
4. the preparation method of claim 1 or 2 compound is prepared by following method:
Definition in wherein substituent R 1, R2 and R3 such as the claim 1.
5. pharmaceutical composition wherein contains the formula I compound or its salt and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
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US4028363A (en) * 1975-03-13 1977-06-07 Hoffmann-La Roche Inc. Isoquinoline derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4028363A (en) * 1975-03-13 1977-06-07 Hoffmann-La Roche Inc. Isoquinoline derivatives

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