CN1444941A - Usage of substituted tetrahydroisoquinoline derviation - Google Patents
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- CN1444941A CN1444941A CN 03113262 CN03113262A CN1444941A CN 1444941 A CN1444941 A CN 1444941A CN 03113262 CN03113262 CN 03113262 CN 03113262 A CN03113262 A CN 03113262A CN 1444941 A CN1444941 A CN 1444941A
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- dimethoxy
- tetrahydroisoquinoline
- cyano group
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Abstract
A substituted tetrahydroisoquinoline and its salts can be used to prepare the tumor-reversing medicine with multi-drug resistance (MDR). Its advantages are high activity and no calcified antagonist cardiovascular by-effect.
Description
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:
R2 representative :-NH (CH
2) nCH
3N=1-9;
N=1-2
Or
R3 representative :-H, 6,7-(OCH
3)
2, 6,7-OCH
2O-
R4 representative :-H ,-OCH
3, 3,4-(OCH
3)
2,-OH ,-NH
2, halogen.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-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:
R2I
1a -NHC
5H
11-n
I
1f -NHC
8H
17-nI
1g -NHC
4H
9-nV
1 -SCH
3
R2I
2a -NHC
5H
11-n
I
2e -NHC
8H
17-nI
2f -NHC
4H
9-nV
2 -SCH
3
R2I
3a -NHC
5H
11-nI
3b -NHC
8H
17-n
V
3 -SCH
3 
I
4a -NHC
5H
11-nI
4b -NHC
8H
17-nV
4 -SCH
3
R2I
5a -NHC
4H
9-nV
5 -SCH
3
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:
Another kind of preparation method is:
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 DMSO0.15ml, 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
(2) chemical compound is to the reverse effect of adriamycin-resistant human breast cancer cell
| Chemical 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 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 0.90 7.70 |
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 DMSO0.15ml, 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
2, Compound I
1fInfluence to the hepatoma carcinoma cell multidrug resistance
| Chemical 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 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 |
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/mlADM, 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 3I
1fInfluence test to the hepatoma carcinoma cell multidrug resistance
Drug level (μ g/ml) cell survival rate (%)
2.0 100
5.0 62
10.0 50
20.0 403. 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 3) that corresponding compounds causes high potassium.
Table 3 verapamil and I
1fSuppression ratio (%) to the inductive rabbit aorta strip contraction of KCl
Sample concentration 20mmol KCl 80mmol KCl
Verapamil 10
-6Mol/L 36.3 46.3
I
1f10
-6Mol/L 0 04. 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 4.
Table 4I
1fWith verapamil aconitine is induced the arrhythmia effect
The compound agent volume production is given birth to ARR aconitine dosage (μ g/kg)
(mg/?kg) VP VT VF
Blank 20.2 28.9 37.0
I
1f 2 22.4 26.7 31.5
Verapamil 2 30.3 44.0 55.05. 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 1N-(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 26,7-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 36,7-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 46, 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) 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), and 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) δ 2.71-2.93 (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), and 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 56,7-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)
3?CH
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 66,7-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 76,7-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 86,7-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 96,7-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 106,7-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 116,7-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)
2?CH
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 126,7-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)，4.1?6(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 136,7-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 146,7-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 156,7-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 166,7-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 176,7-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
2fThe 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 186,7-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 196,7-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 206,7-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 216,7-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 226,7-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(CDC1
3)δ0.80-1.70(m，9H，(CH
2)
3CH
3)，2.75-3.80(m，4H，ArCH2，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 236,7-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 246,7-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)
2?CH
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 256,7-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)
6?CH
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 contains 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:
Wherein R1 representative:
R2 representative :-NH (CH
2) nCH
3N=1-9,
N=1-2
Or
R3 representative :-H, 6,7-(OCH
3)
2, 6,7-OCH
2O-
R4 representative :-H ,-OCH
3, 3,4-(OCH
3)
2,-OH ,-NH
2, halogen.
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-(phenethyl-N '-cyano group) amidino groups-1,2,3, the 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-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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03113262 CN1227010C (en) | 2003-04-22 | 2003-04-22 | Usage of substituted tetrahydroisoquinoline derviation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03113262 CN1227010C (en) | 2003-04-22 | 2003-04-22 | Usage of substituted tetrahydroisoquinoline derviation |
Publications (2)
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|---|---|
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| CN1227010C CN1227010C (en) | 2005-11-16 |
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ID=27814683
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060764A (en) * | 2010-12-24 | 2011-05-18 | 中国药科大学 | Tetrahydroisoquinoline derivative, preparation method and application thereof |
| CN102459158A (en) * | 2009-04-20 | 2012-05-16 | 雅培制药有限公司 | Novel amide and amidine derivatives and uses thereof |
| 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 |
-
2003
- 2003-04-22 CN CN 03113262 patent/CN1227010C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102459158A (en) * | 2009-04-20 | 2012-05-16 | 雅培制药有限公司 | Novel amide and amidine derivatives and uses thereof |
| CN102459158B (en) * | 2009-04-20 | 2015-11-25 | Abbvie公司 | New acid amides and amidine derivative and its purposes |
| CN102060764A (en) * | 2010-12-24 | 2011-05-18 | 中国药科大学 | Tetrahydroisoquinoline derivative, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1227010C (en) | 2005-11-16 |
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