CN106117182B - Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application - Google Patents
Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application Download PDFInfo
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- CN106117182B CN106117182B CN201610463035.8A CN201610463035A CN106117182B CN 106117182 B CN106117182 B CN 106117182B CN 201610463035 A CN201610463035 A CN 201610463035A CN 106117182 B CN106117182 B CN 106117182B
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The present invention relates to logical formula (I) compound and its salt, this kind of compound has stronger reverse multiple drug resistance of tumor (MDR) effect, part of compounds activity is much higher than Verapamil, and has lesser cytotoxicity, and the invention further relates to the pharmaceutical preparations containing them.The present invention has synthesized a series of logical formula (I) compounds and its pharmaceutically acceptable salt.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of P- glycoprotein inhibitors, the invention also discloses its systems
The application of Preparation Method and such compound in multidrug-resistance reversal agent.
Technical background
It is resistance to that multidrug resistance (multidrug resistance, MDR) refers to that tumour cell generates a kind of anti-tumor drug
After medicine, the phenomenon that crossing drug resistant is also generated to the other structures anti-tumor drug different with mechanism of action.Currently, multidrug resistance is
A main cause as tumor chemical therapy failure.Therefore, reversion MDR drug is found to have inhibited the generation of multidrug resistance
As urgent problem to be solved in oncotherapy.
The mechanism multiplicity that tumor multi-medicine drug-resistant phenomenon generates, is related to complicated molecular biology mechanism, not yet complete at present
Complete solution analysis, but wherein tumour cell transmembrane transporter --- the overexpression of P- glycoprotein (P-glycoprotein, P-gp)
It is considered as the main reason that multidrug resistance generates.The P-gp of overexpression will be entered swollen using the energy of ATP hydrolysis release
Drug in oncocyte pumps out extracellularly, is lower than effective concentration so as to cause the concentration of intracellular anti-tumor drug, keeps tumour thin
Born of the same parents are resistant to Treated with Chemotherapeutic Drugs object, generate MDR.Since first multidrug-resistance reversal agent Verapamil is found, multiple medicine is resistance to
The research of medicine reversal agent is after three generations.Using Verapamil and Ciclosporin A as representative, such inhibitor has larger the first generation
Cardiovascular side effects.The enhancing of second generation inhibitor activity, such as Valspodar and Biricodard, but such inhibitor is obvious
The plasma pharmacokinetics in conjunction using anticancer drug are influenced, its application clinically is limited.Third generation inhibitor
It is the compound designed and developed based on structure activity study, such compound inhibitor has preferable activity and selectivity,
Such as Elacridar, Tariquidar and WK-X-34.However, not having yet at present effective due to the appearance of various side effects
Reversal agent is applied to clinical treatment.
The present invention relates to the quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds of structure novel, with P- glycoprotein
Inhibitory activity, and majority of compounds activity is higher than Verapamil.Therefore the logical formula (I) compound and its pharmaceutical salts have latent
Prevent and treat tumor multi-medicine drug-resistant occur effect.
Summary of the invention
The purpose of the present invention is to provide a kind of novel novel tumor multidrug-resistance reversal agents with P-gp inhibiting effect.
Such compound has quinazoline-N- ethyl tetrahydroisoquinoline structure, has lower cytotoxicity and stronger MDR to reverse and lives
Property, be conducive to the curative effect for improving anti-tumor drug.
The purpose of the present invention is also in a kind of quinazoline-N- ethyl tetrahydroisoquinolicompounds tumor multi-drug resistance reversal agents of offer
Preparation method.
Detailed description content is as follows:
The present invention has synthesized a series of logical formula (I) compounds and its pharmaceutically acceptable salt:
Wherein R1And R2It is identical or different, it is respectively selected from: H, F, Cl, Br, I, C1-C5Alkyl or alkoxy;
Wherein R3It is selected from: aromatic radical substituted or unsubstituted, aromatic heterocyclic, carbocyclic ring, wherein the substituent group includes C1~C5
Alkyl, C1~C5Alkoxy, C1~C5Alkylamino radical, nitro, methylene-dioxy and halogen;
Wherein R4And R5It is identical or different, it is respectively selected from: H, C1~C5Alkoxy.
Preferred embodiment of the invention, a kind of compound or its pharmaceutical salt of logical formula (I) are shown in logical formula (II)
Compound or its pharmaceutical salt:
Wherein R1And R2It is identical or different, it is respectively selected from: H, F, Cl, Br, I, C1~C5Alkyl or alkoxy;
Wherein R3It is selected from: C substituted or unsubstituted5~C10Aromatic radical, C5~C10Aromatic heterocyclic, wherein the substituent group packet
Include C1~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino radical, nitro, methylene-dioxy and halogen.
Preferred compounds of the invention includes, but are not limited to:
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- phenylquinazoline -
4- amine (I-1);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (2- methoxybenzene
Base) quinazoline -4- amine (I-2);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3- methoxybenzene
Base) quinazoline -4- amine (I-3);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (4- methoxybenzene
Base) quinazoline -4- amine (I-4);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3,4- dimethoxies
Base phenyl) quinazoline -4- amine (I-5);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3,4,5- front threes
Phenyl) quinazoline -4- amine (I-6);
2- (benzo [d] [1,3] dicyclopentadienyl -5- base)-N-4 (- 2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H) -
Base-ethyl) phenyl)) quinazoline -4- amine (I-7);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3- aminomethyl phenyl)
Quinazoline -4- amine (I-8);
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (4- aminomethyl phenyl)
Quinazoline -4- amine (I-9);
2- (4- (tert-butyl) phenyl)-N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-second
Base) phenyl) quinazoline -4- amine (I-10);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridine -4-
Base) quinazoline -4- amine (I-11);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridine -3-
Base) quinazoline -4- amine (I-12);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (quinoline -2-
Base) quinazoline -4- amine (I-13);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4-, mono- dihydro-isoquinoline)-ethyl) phenyl) -2- (3- nitro
Phenyl) quinazoline -4- amine (I-14)
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- nitrobenzene
Base) quinazoline -4- amine (I-15);
2- (4- chlorphenyl)-N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) benzene
Base) quinazoline -4- amine (I-16);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- fluorobenzene
Base) quinazoline -4- amine (I-17);
The chloro- N- of 7- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- phenyl
Quinazoline -4- amine (I-18);
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -6,7- dimethoxy
Base -2- phenylquinazoline -4- amine (I-19).
The structure of part of compounds are as follows:
According to the present invention, pharmaceutically acceptable salt includes the addition salts formed with following acid: hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen
Bromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzene sulfonic acid, succinic acid and with it is similar
Salt formed by known acceptable acid.
Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds of the present invention the preparation method is as follows:
It is the pharmacological experiment data of part of compounds of the present invention below:
1, reverse effect of the compound to adriamycin-resistant human leukemia cell (K562/A02)
Verapamil (Verapamil, VRP) is positive control.K562/A02 adriamycin-resistant human leukemia cell line is with containing
10% calf serum and the final concentration of 1mg/L adriamycin (ADM) of addition 1640 culture medium of RPMI is in 37 DEG C, 5%CO2It is full
It is cultivated under conditions of humidity, and tests preceding drug-resistant cell strain and cultivated 14 days under conditions of no adriamycin.Take logarithmic growth
The cell of phase, with 1 × 104A/ml density is inoculated in 96 well culture plates, in 37 DEG C of 5%CO2Under the conditions of cultivate for 24 hours after, respectively
The test-compound of final concentration of 5 μm of ol/L and a series of adriamycin of concentration gradients is added, continues after being incubated for 48h, every hole adds
Enter MTT (5mg/ml), be further cultured for 4 hours, be centrifuged, board-washing machine sucks culture solution, and 150 μ L DMSO dissolution, shaking table vibration is added in every hole
20min is shaken, is then measured in microplate reader with wavelength 570nm, the concentration for inhibiting cell growth up to 50% when is calculated separately,
With IC50Value indicates that reversal index is with IC50(ADM)/IC50(ADM+ reversal agent) indicates.
19 compounds of this measuring are under 1 μm of ol/L concentration to the inverse of leukaemia cell's drug resistance of adriamycin-resistant
Turning a work property, as shown in table 1, test result show that 19 compounds all have reversion MDR activity, and the reverse of part of compounds
Activity is more than positive reference substance Wella pa (verapamil).
1 compound of table (5 μM) is to the reverse effect of adriamycin-resistant human leukemia cell's drug resistance
2, the cytotoxicity of compound
This experimental test cytotoxicity of 19 compounds to K562/A02 and K562 cell.The people of adriamycin-resistant is white
Containing 10% calf serum and final concentration of 1640 culture medium of 1mg/L adriamycin RPMI of addition of blood disease cell line K562/A02
In 37 DEG C, 5%CO2It is cultivated under conditions of saturated humidity, and tests preceding drug-resistant cell strain and cultivated under conditions of no adriamycin
14 days.The cell of logarithmic growth phase is inoculated in 96 well culture plates with 6 × 104/ml density, every 180 μ L of hole, at 37 DEG C
It is cultivated under the conditions of 5%CO2.It is grouped after overnight, respectively blank control group, test-compound group.In test-compound group respectively
A series of untested compound of final concentration of concentration gradients is added;Positive controls give adriamycin;Blank control group is given
The 0.1%DMSO of volume.Administered volume is 20 μ L.It is incubated for 48 hours, then 20 μ l MTT (5mg/ml) are added in every hole, then train
It supports 4 hours, centrifugation, board-washing machine sucks culture solution, and 150 μ l DMSO dissolution is added in every hole, and shaking table shakes 20min, then in enzyme mark
Optical density (OD) is read at wavelength 490nm on instrument, calculates the inhibiting rate of compound on intracellular, and with GraphPad Prism
Amount effect curve in 5.0 softwares calculates the IC of compound50Value.
Test result is as shown in table 2, from test result as can be seen that 19 compounds show obvious cell to K562
Toxicity, IC50 is in 2 μM~16 μM ranges, except compound I-4 and I-6 goes out weak cytotoxicity to K562/A02 cells show
40 μM of IC50s >, other compounds go out obvious cytotoxicity, IC to K562/A02 cells show50In 7.9 μM~21 μM ranges.
According to cell toxicant inhibiting rate calculated result, compound acts on the basic unrestraint of mdr cell in 1.0 μM of concentration, and such as 1.0 μM
The compound I-11 of concentration acts on the basic unrestraint of K562/A02 cell.
Cytotoxicity IC of 2 compound of table to K562 and K562/A02 cell50(μM, n=3)
3, reverse effect of the various concentration compound I-11 to K562/A02 cell adriamycin-resistant
Verapamil (Verapamil, VRP) is positive control.K562/A02 adriamycin-resistant human leukemia cell line is with containing
10% calf serum and the final concentration of 1mg/L adriamycin (ADM) of addition 1640 culture medium of RPMI is in 37 DEG C, 5%CO2It is full
It is cultivated under conditions of humidity, and tests preceding drug-resistant cell strain and cultivated 14 days under conditions of no adriamycin.Take logarithmic growth
The cell of phase, with 1 × 104A/ml density is inoculated in 96 well culture plates, in 37 DEG C, 5%CO2Under the conditions of cultivate for 24 hours after, respectively
Final concentration of 1.0 μm of ol/L, 0.5 μm of ol/L, 0.25 μm of ol/L, 0.10 μm of ol/L, 0.050 μm of ol/L, 0.025 μm of ol/L is added
Test-compound I-11 and a series of concentration gradients adriamycin, continues after being incubated for 48h, and MTT (5mg/ml) is added in every hole,
It is further cultured for 4 hours, is centrifuged, board-washing machine sucks culture solution, and 150 μ L DMSO dissolution is added in every hole, and shaking table shakes 20min, then exists
It is measured in microplate reader with wavelength 570nm, the concentration for inhibiting cell growth up to 50% when is calculated separately, with IC50Value indicates, inverse
Turn multiple with IC50(ADM)/IC50(ADM+ reversal agent) indicates.Test result is as shown in table 3, shows compound I-11 in concentration
Still having the function of higher reverse K562/A02 cellular drug resistance when being reduced to 0.31 μm of ol/L, reversal index is up to 8.6, and
Compound I-11 is significantly larger than Verapamil to the sensibility for reversing K562/A02 adriamycin-resistant cell.
3 various concentration compound I--11 of table is to K562/A02 cell adriamycin-resistant reverse effect
The above pharmacology data shows, the present invention lead to formula (I) compound with positive control drug Verapamil compared with compared with
The effect of strong reverse multiple drug resistance of tumor, and preferred compound almost no cytotoxicity.
The invention also includes pharmaceutical preparation, said preparation include as activating agent logical formula (I) compound or pharmaceutically acceptable salt thereof with
Pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier refers to one or more of inert, atoxic solids or liquid
Filler, diluent, auxiliary agent etc., they are reverse to have an effect with reactive compound or patient.
The dosage form of the present composition can be tablet, capsule, pill, suppository, soft capsule, oral solution, suspension, injection
Common dosage form in the pharmacies such as liquid.Drug and capsule for oral use contain traditional excipient such as filler, diluent, lubrication
Agent, dispersing agent and adhesive.It can be prepared according to method known in the art.
The dosage of the above activating agent will be different because of formula.
Generally, it has therefore proved that advantageous amount, it is required as a result, every kg body weight 24 hours formula (I) chemical combination being administered to reach
The total amount of object is about 0.01-80mg, preferably total amount about 0.1-40mg/kg.If necessary, it is administered in the form of single dose several times.
However, if necessary, above-mentioned dosage can be deviateed, i.e., this depends on the type of subject to be treated and weight, a
Body is to the behavior of drug, the property of disease and seriousness, preparation and the type of administration and administration time or interval.
The invention will be further described by the following examples.
Specific embodiment
Below with reference to embodiment, the invention will be further described.It should be noted that following embodiments are merely to illustrate,
And it is not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all be in this Shen
It please be within protection scope required by claim.
Embodiment 1
The preparation of compound (i)
Under ice bath, freshly prepared aroyl chloride (20mmol) is slowly added to substituted or unsubstituted ortho-aminobenzoic acid
In pyridine (15ml) solution of (30mmol), after stirring 30min under ice bath, room temperature continues to stir 12h.Reaction solution is poured into water
In (200ml), it is vigorously stirred to there are a large amount of solids to be precipitated, stands, filter, wash (20ml × 5), it is dry, obtain white solid production
Object (i).
Embodiment 2
The preparation of compound (ii)
The compound (i) that will be prepared, ammonium hydroxide (15ml) and ethyl alcohol (20ml) are added in pressure bottle, after sealing, heating
It is cooling to 80 DEG C of reaction 12h, it filters, washes (15ml × 3), it is dry, obtain white solid product (ii).
Embodiment 3
The preparation of compound (iii)
The compound being prepared (ii) (1equiv) is added in thionyl chloride (10equiv), catalytic amount is added
After DMF, it is heated to 50 DEG C of reaction 6h.It removes excessive thionyl chloride under reduced pressure, obtains faint yellow solid residue.By residue plus
Enter into suitable 1N sodium hydroxide solution, isometric methylene chloride is added after stirring, extract, organic layer with water, is satisfied respectively
And brine It, anhydrous sodium sulfate is dry, filters, and white or faint yellow solid product (iii) is obtained after evaporating solvent under reduced pressure.
Embodiment 4
The preparation of compound (iv)
By four hydrogen isoquinoline hydrochloric acid salt (1equiv), tetranitro phenethyl bromide (1.1equiv) is dissolved in acetonitrile, and nothing is added
Aqueous carbonate potassium (2.5equiv), heating reflux reaction 18h.Cooling, filtering, methylene chloride washs filter cake, and filtrate is through removing under reduced pressure
Solvent obtains yellow solid residue, and ethyl alcohol recrystallization obtains yellow needles solid (iv).
Embodiment 5
The preparation of compound (v)
By the compound being prepared (iv) (1equiv), it is dissolved in the mixed liquor of ethanol/dichloromethane (1: 1), room temperature
Lower Pd/C (0.03equiv) is catalyzed lower hydrogen reducing and reacts 48h.Diatomite makees matting layer filtering, and methylene chloride washs filter cake, filter
Liquid obtains faint yellow solid through evaporating solvent under reduced pressure, and methylene chloride/petroleum ether is recrystallized to give beige solid (v).
Embodiment 6
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- phenyl quinazoline azoles
The preparation of quinoline -4- amine (I-1):
Resulting compound (v) (1equiv) will be prepared and dehydrated alcohol is added in the chloro- 2- phenylquinazoline (1equiv) of 4-
In, the lower Loprazolam that catalytic amount is added is stirred at room temperature, is heated to back flow reaction 4h, there is faint yellow solid precipitation, it is cooling, it takes out
Filter, dehydrated alcohol washing is dry, obtains faint yellow solid hydrochloride.Product is dissociated with the sodium hydroxide solution of 1N, and with dichloro
Methane extraction, organic layer is respectively with water, and saturated common salt water washing, anhydrous sodium sulfate is dry, filters, and evaporating solvent under reduced pressure obtains yellow
Or faint yellow solid product, yield 52.5%;1H NMR (300MHz, DMSO-d6) δ ppm:9.82 (s, 1H, NH), 8.57 (d, J
=8.4Hz, 1H, ArH), 8.46-8.43 (m, 2H, ArH), 7.91-7.85 (m, 4H, ArH), 7.51-7.49 (m, 3H, ArH),
7.37-7.34 (m, 3H, ArH), 6.66-6.64 (2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.57 (s, 2H, ArCH2N),
2.89-2.72 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:157.82,150.4,138.3,137.1,
135.8,133.11,130.21,128.62,128.35,128.06,127.84,126.65,125.9,125.8,122.9,
122.07,113.97,111.73,109.9,59.54,55.42,55.09,50.55,32.47,28.31;ESI-MS m/z:
517.2([M+H]+)。
Embodiment 7
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (2- methoxyl group
Phenyl) quinazoline -4- amine (I-2) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-2 is made, obtains faint yellow solid, yield 43.7%;1H
NMR (300MHz, DMSO-d6) δ ppm:9.73 (s, 1H, NH), 8.57 (d, J=8.1Hz, 1H, ArH), 7.94-7.79 (m, 4H,
ArH), 7.64-7.59 (m, 2H, ArH), 7.42 (dd, J=7.5,1.7Hz, 1H, ArH), 7.24 (d, J=8.4Hz, 2H, AH),
7.14 (d, J=8.4Hz, 1H, ArH), 7.03 (dd, J=7.5,7.5Hz, 1H, ArH), 6.65,6.63 (2s, 2H, ArH),
3.80 (s, 3H, OCH3), 3.73 (s, 6H, 2 × OCH3), 3.53 (s, 2H, ArCH2N), 2.80-2.49 (m, 8H, 4 × CH2);13C
NMR (75MHz, DMSO-d6) δ ppm:157.06,146.83,137.3,135.3,132.8,130.8,130.1,128.4,
127.9,126.6,125.8,122.7,121.6,119.9,113.4,111.9,111.7,109.9,59.59,55.49,
55.42,55.03,50.55,32.43,28.27;ESI-MS m/z:547.2 ([M+H]+)。
Embodiment 8
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3- methoxyl group
Phenyl) quinazoline -4- amine (I-3) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-3, faint yellow solid, yield 60.6% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.83 (s, 1H, NH), 8.56 (d, J=7.8Hz, 1H, ArH), 8..05-8.01 (m, 2H,
ArH), 7.89-7.84 (m, 4H;ArH), 7.62-7.59 (m, 1H, ArH), 7.42-7.31 (m, 3H, ArH), 7.06-7.04 (m,
1H, ArH), 6.65,6.63 (2s, 2H, ArH), 3.82 (s, 3H, OCH3), 3.68 (s, 6H, 2 × OCH3), 3.55 (s, 2H,
ArCH2N), 2.85-2.49 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:159.3,158.7,157.7,
150.4,147.1,146.8,139.8,137.1,135.8,133.0,129.3,128.5,128.0,126.6,125.9,
125.8,122.9,122.2,120.2,116.2,114.0,112.6,111.7,110.0,59.5,55.4,55.0,54.9,
50.5,32.4,28.2;ESI-MS m/z:547.2 ([M+H]+).
Embodiment 9
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- methoxyl group
Phenyl) quinazoline -4- amine (I-4) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-4, faint yellow solid, yield 63.2% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.77 (s, 1H, NH), 8.54 (d, J=8.4Hz, 1H, ArH), 8.41 (d, J=8.7Hz,
2H, ArH), 7.89 (d, J=8.7Hz, 2H, ArH), 7.82 (d, J=3.8Hz, 2H, ArH), 7.57-7.52 (m, 1H, ArH),
7.32 (d, J=8.4Hz, 2H, ArH), 7.04 (d, J=8.9Hz, 2H, ArH), 6.63,6.61 (2s, 2H, ArH), 3.82 (s,
3H, OCH3), 3.68 (s, 6H, 2 × OCH3), 3.53 (s, 2H, ArCH2N), 2.85-2.49 (m, 8H, 4 × CH2);13C NMR
(75MHz, DMSO-d6) δ ppm:161.10,158.89,157.67,150.54,147.10,146.86,137.20,129.49,
128.57,127.85,126.65,125.91,125.30,122.92,121.99,113.68,111.73,109.96,59.52,
55.44,55.40,55.19,55.08,50.51,32.48,28.30;ESI-MS m/z:547.2 ([M+H]+)。
Embodiment 10
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3,4- diformazans
Phenyl) quinazoline -4- amine (I-5) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-5, faint yellow solid, yield 56.2% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.79 (s, 1H, NH), 8.54 (d, J=8.4Hz, 1H, ArH), 8.06-8.03 (m, 2H,
ArH), 7.79 (d, J=8.4Hz, 2H, ArH), 7.82 (d, J=3.9Hz, 2H, ArH), 7.57-7.53 (m, 1H, ArH), 7.34
(d, J=8.4Hz, 2H, ArH), 7.07 (d, J=8.7Hz, 2H, ArH), 6.66,6.64 (2s, 2H, ArH), 4.04,4.01
(2s, 6H, 2 × OCH3), 3.85-3.83 (2s, 6H, 2 × OCH3), 3.56 (s, 2H, ArCH2N), 2.85-2.49 (m, 8H, 4 ×
CH2);13C NMR (75MHz, DMSO-d6) δ ppm:158.76,157.58,150.74,148.35,147.11,146.87,
137.17,135.79,132.98,130.93,128.46,127.86,126.63,125.90,125.31,122.93,122.26,
120.92,113.70,111.75,110.97,109.96,59.63,55.50,55.42,55.11,50.55,32.46,28.28;
ESI-MS m/z:577.3 ([M+H]+)。
Embodiment 11
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3,4,5- tri-
Methoxyphenyl) quinazoline -4- amine (I-6) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-6, faint yellow solid, yield 48.4% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.86 (s, 1H, NH), 8.54 (d, J=8.4Hz, 1H, ArH), 7.89-7.81 (, 6H,
ArH), 7.61-7.56 (m, 1H, ArH), 7.33 (d, J=8.7Hz, 2H, ArH), 6.66,6.64 (2s, 2H, ArH), 3.87 (s,
6H, 2 × OCH3), 3.73,3.70 (2s, 9H, 3 × OCH3), 3.55 (s, 2H, ArCH2N), 2.87-2.68 (m, 8H, 4 × CH2)
;13C NMR (75MHz, DMSO-d6) δ ppm:158.37,157.59,152.67,147.11,146.86,139.42,137.06,
135.98,133.61,128.38,127.99,126.62,125.89,125.63,122.94,122.52,113.78,111.75,
109.97,104.97,60.04,59.68,55.57,55.44,55.08,50.55,32.46,28.27;ESI-MS m/z:
608.4([M+H]+)。
Embodiment 12
2- (benzo [d] [1,3] dicyclopentadienyl -5- base)-N- (4- (2- (6,7- dimethoxy -3,4- dihydro-isoquinolines -2
(1H)-yl)-ethyl) phenyl) and quinazoline -4- amine (I-7) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-7, faint yellow solid, yield 57.1% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.86 (s, 1H, NH), 8.57 (d, J=8.2Hz, 1H, ArH), 8.04 (dd, J=8.2,
1.6Hz, 1H, ArH), 7.89-7.86 (m, 3H, ArH), 7.81-7.93 (m, 2H, ArH), 7.59-7.53 (m, 1H, ArH),
7.35 (d, J=8.4Hz, 1H, ArH), 7.03 (d, J=8.2,1.6Hz, 1H, ArH), 6.71,6.68 (2s, 2H, ArH), 6.11
(s, 2H, OCH2), 3.82 (s, 2H, ArCH2N), 3.71,3.70 (2s, 6H, 2 × OCH3), 2.95-2.83 (m, 8H, 4 × CH2)
;13C NMR (75MHz, DMSO-d6.) δ ppm:158.48,157.67,150.41,149.15,147.48,147.08,137.36,
134.74,133.08,132.69,128.93,128.60,127.87,125.50,125.16,123.02,122.56,122,20,
113.79,111.65,109.85,108.08,107.60,101.39,58.46,56.39,55.48,55.43,54.06,
50.08,31.49,27.19;ESI-MS m/z:561.2 ([M+H]+)。
Embodiment 13
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3- methylbenzene
Base) quinazoline -4- amine (I-8) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-8, faint yellow solid, yield 53.8% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.95 (s, 1H, NH), 8.66 (d, J=8.4Hz, 1H, ArH), 8.30-8.23 (m, 2H,
ArH), 8.01 (d, J=8.4Hz, 2H, ArH), 7.86 (d, J=3.6Hz, 2H, ArH), 7.62-7.57 (m, 1H, ArH),
7.42-7.37 (m, 3H, ArH), 7.31 (d, J=8.4Hz, 1H, ArH), 6.78,6.75 (2s, 2H, ArH), 4.16 (s, 2H,
ArCH2N), 3.73,3.72 (2s, 6H, 2 × OCH3), 3.12-2.97 (m, 8H, 4 × CH2), 2.42 (s, 3H, CH3);13C NMR
(75MHz, DMSO-d6) δ ppm:159.06,157.77,150.45,148.01,147.45,138.32,137.91,137.33,
133.08,130.84,128.59,128.49,128.26,127.99,125.75,125.11,124.04,123.19,122.21,
114.01,111.59,109.75,56.91,55.54,55.49,52.32,49.30,29.96,25.58,21.21;ESI-MS
M/z:531.6 ([M+H]+)。
Embodiment 14
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- methylbenzene
Base) quinazoline -4- amine (I-9) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-9, faint yellow solid, yield 61.1% is made;1H NMR
(300MHz, DMSO-d6) δ ppm:9.80 (s, 1H, NH), 8.57 (d, J=8.1Hz, 1H, ArH), 8.35 (d, J=8.1Hz,
2H, ArH), 7.90 (d, J=8.3Hz, 2H, ArH), 7.84 (d, J=3.4Hz, 2H, ArH), 7.60-7.54 (m, 1H, ArH),
7.34-7.29 (m, 4H, ArH), 6.64,6.62 (2s, 2H, ArH), 3.78,3.75 (2s, 6H, 2 × OCH3), 3.54 (s, 2H,
ArCH2N), 2.84-2.70 (m, 8H, 4 × CH2), 1.91 (s, 3H, CH3);13C NMR (75MHz, DMSO-d6) δ ppm:
159.11,157.75,150.48,147.12,146.88,139.84,137.19,135.69,132.98,128.94,128.57,
127.97,127.88,126.67,125.93,125.54,122.95,122.00,113.93,111.76,109.98,59.48,
55.42,55.09,50.49,32.48,28.30,20.95;ESI-MS m/z:532.2 ([M+H]+).
Embodiment 15
2- (4- (tert-butyl) phenyl)-N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-second
Base) phenyl) quinazoline -4- amine (I-10) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-10, faint yellow solid, yield 47.1% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.79 (s, 1H, NH), 8.57 (d, J=8.4Hz, 1H, ArH), 8.37 (d, J=
8.4Hz, 2H, ArH), 7.91 (d, J=8.4Hz, 2H, ArH), 7.84 (d, J=3.9Hz, 2H, ArH), 7.58-7.51 (m, 3H,
ArH), 7.35 (d, J=8.4Hz, 2H, ArH), 6.66,6.64 (2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.57 (s,
2H, ArCH2N), 2.87-2.49 (m, 8H, 4 × CH2), 1.33 (s, 9H, 3 × CH3);13C NMR (75MHz, DMSO-d6) δ ppm:
159.11,157.73,152.88,150.51,147.13,146.89,137.23,135.73,135.63,132.97,128.57,
128.01,127.74,126.65,125.91,125.57,125.11,122.94,121.95,113.94,111.76,109.99,
59.53,55.42,55.08,50.54,34.47,32.50,30.99,28.30;ESI-MS m/z:573.3 ([M+H]+)。
Embodiment 16
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridine -4-
Base) quinazoline -4- amine (I-11) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-11, faint yellow solid, yield 61.1% is made;1H
NMR (300MHz, DMSO-d6) δ ppm 9.94 (s, 1H, NH), 8.74 (d, J=5.5Hz, 2H, ArH), 8.64 (d, J=
8.0Hz, 2H, ArH), 7.91 (d, J=8.4Hz, 2H, ArH), 8.26 (d, J=5.5Hz, 2H, ArH), 7.91-7.85 (m, 1H,
ArH), 7.36 (d, J=8.3Hz, 2H, ArH), 6.66,6.64 (2s, 2H, ArH), 3.70,3.69 (2s, 6H, 2 × OCH3),
3.58 (s, 2H, ArCH2N), 2.90-2.49 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:158.07,
157.25,150.15,150.08,147.11,146.87,145.54,136.82,136.10,133.34,128.65,128.28,
126.66,125.91,123.07,122.28,121.72,114.41,111.77,109.98,59.47,55.46,55.43,
55.09,50.51,32.49,28.30;ESI-MS m/z:518.3 ([M+H]+)。
Embodiment 17
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridine -4-
Base) quinazoline -4- amine (I-12) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-12, faint yellow solid, yield 44.8% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.92 (s, 1H, NH), 9.54 (s, 1H, ArH), 8.68 (d, J=5.5Hz, 2H, ArH),
8.58 (d, J=8.2Hz, 1H, ArH), 7.88-7.84 (m, 4H, ArH), 7.65-7.61 (m, 1H, ArH), 7.55-7.50 (m,
1H, ArH), 7.35 (d, J=8.2Hz, 2H, ArH), 6.65,6.63 (2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.55
(s, 2H, ArCH2N), 2.88-2.50 (m, 8H, ArH);13C NMR (75MHz, DMSO-d6) δ ppm:157.89,157.44,
150.76,150.53,150.16,149.17,136.90,135.98,135.01,133.65,133.21,130.35,129.79,
128.94,128.58,128.03,126.51,7,126.15,123.48,123.07,122.43,122.31,114.13,
111.73,109.95,59.41,56.65,56.06,55.44,50.02,50.45,38.43,28.21;ESI-MS m/z:
518.2([M+H]+)。
Embodiment 18
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (quinoline -2-
Base) quinazoline -4- amine (I-13) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-13, faint yellow solid, yield 43.7% is made;1H
NMR (300MHz, DMSO-d6) δ ppm 9.94 (s, 1H, NH), 8.67 (d, J=8.4Hz, 1H, ArH), 8.57 (d, J=
8.4Hz, 1H, ArH), 8.50 (d, J=8.4Hz, 1H, ArH), 8.22-8.16 (m, 3H, ArH), 8.07-7.82 (m, 5H,
ArH), 7.72-7.65 (m, 2H, ArH), 7.37 (d, J=8.4Hz, 2H, ArH), 6.67,6.66 (2s, 2H, ArH), 3.69-
3.65 (m, 8H, 2 × OCH3, ArCH2N), 2.89-2.77 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:
158.38,158.14,154.84,149.17,148.29,147.65,147.35,138.11,136.81;133.60 132.33,
130.01,129.67,128.73,128.08,127.89,127.61,127.48,126.89,123.52,123.38,122.34,
120.72,120.03,114.27,111.52,109.66,55.95,55.57,55.52,51.26,48.85,29.05,24.53;
ESI-MS m/z:568.3 ([M+H]+)。
Embodiment 19
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3- nitrobenzene
Base) quinazoline -4- amine (I-14) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-14, faint yellow solid, yield 59.5% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:10.01 (s, 1H, NH), 9.16 (d, J=1.4Hz, 1H, ArH), 8.76 (dd, J=
7.8,1.02Hz, 1H, ArH), 8.61 (d, J=8.1Hz, 1H, ArH), 8.31-8.27 (m, 1H, ArH), 7.91-7.83 (m,
4H, ArH), 7.75 (t, J=8.0Hz, 1H, ArH), 7.65-7.60 (m, 1H, ArH), 7.36 (d, J=8.4Hz, 1H, ArH),
6.70,6.68 (2s, 2H, ArH), 3.82 (s, 2H, ArCH2N), 3.70 (s, 6H, 2 × OCH3), 2.96-2.83 (m, 8H, 4 ×
CH2);13C NMR (75MHz, DMSO-d6) δ ppm:157.94,156.80,150.09,148.01,147.45,147.09,
139.96,137.10,135.05,133.62,133.28,129.92,128.55,128.11,126.36,125.14,124.53,
123.13,122.45,122.24,114.18,111.67,109.86,58.50,55.44,54.04,50.06,31.54,
27.24;ESI-MS m/z:562.1 ([M+H]+)。
Embodiment 20
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- nitrobenzene
Base) quinazoline -4- amine (I-15) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-15, faint yellow solid, yield 55.4% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.95 (s, 1H, NH), 8.65-8.59 (m, 3H, ArH), 8.33 (d, J=7.8Hz, 1H,
ArH), 7.92-7.85 90 (m, 4H, ArH), 7.70-7.64 (m, 1H, ArH), 7.37 (d, J=8.4Hz, 2H, ArH), 6.66,
6.64 (2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.58 (s, 2H, ArCH2N), 2.88-2.73 (m, 8H, 4 × CH2);13C
NMR (75MHz, DMSO-d6) δ ppm:157.91,157.10,150.09,148.32,147.12,146.88,144.32,
136.82,136.02,133.30,128.78,128.63,128.25,126.62,125.90,123.48,123.02,122.23,
114.11 111.74,109.97,59.48,55.45,55.40,55.08,50.52,32.53,28.30;ESI-MS m/z:
562.1([M+H]+)。
Embodiment 21
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- nitrobenzene
Base) quinazoline -4- amine (I-16) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-16, faint yellow solid, yield 41.2% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.86 (s, 1H, NH), 8.57 (d, J=8.4Hz, 1H, ArH), 8.44-8.40 (m, 2H,
ArH), 7.86-7.83 (m, 4H, ArH), 7.64-7.54 (m, 3H, ArH), 7.34 (d, J=8.4Hz, 2H, ArH), 6.65,
6.63 (2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.56 (s, 2H, ArCH2N), 2.88-2.71 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:158.02,157.84,150.27,147.11,146.86,137.88,137.23,
137.02,135.80,135.01,133.08,130.38,129.81,129.52,128.95,128.57,128.34,128.01,
126.58,125.88,123.03,122.14,121.10,113.99,111.69,59.43,56.04,55.43,55.38,
55.05,50.44,32.45,28.26;ESI-MS m/z:551.2 ([M+H]+)。
Embodiment 22
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- fluorobenzene
Base) quinazoline -4- amine (I-17) preparation:
Referring to the preparation method of I-1 in embodiment 6, compound I-17, faint yellow solid, yield 61.1% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.91 (s, 1H, NH), 8.57 (d, J=8.3Hz, 1H, ArH), 8.49-8.44 (m, 2H,
ArH), 7.87-7.82 (m, 4H, ArH), 7.62-7.57 (m, 1H, ArH), 7.44-7.28 (m, 4H, ArH), 6.66,6.64
(2s, 2H, ArH), 3.69 (s, 6H, 2 × OCH3), 3.59 (s, 2H, ArCH2N), 2.89-2.50 (m, 8H, 4 × CH2);13C NMR
(75MHz, DMSO-d6) δ ppm:165.23,161.95,158.09,157.81,150.34,147.13,146.86,138.22,
137.10,135.68,134.84,133.39,132.97,130.03,128.92,128.53,127.93,126.48,125.67,
123.05,122.14,121.07,115.23,114.94,113.90,111.66,109.89,105.40,59.69,59.36,
56.50,55.95,55.40,55.34,54.98,50.35,32.39,28.20;ESI-MS m/z:536.3 ([M+H]+)。
Embodiment 23
The chloro- N- of 7- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- phenyl
The preparation of quinazoline -4- amine (I-18):
Referring to the preparation method of I-1 in embodiment 6, compound I-18, faint yellow solid, yield 61.1% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.93 (s, 1H, NH), 8.60 (d, J=8.9Hz, 1H, ArH), 8.46-8.42 (m, 2H,
ArH), 7.89-7.86 (m, 3H, ArH), 7.62 (dd, J=8.8,1.9Hz, 1H, ArH), 7.51-7.49 (m, 4H, ArH),
7.34 (d, J=8.3Hz, 2H, ArH), 6.64,6.61 (2s, 2H, ArH), 3.70 (s, 6H, 2 × OCH3), 3.54 (s, 2H,
ArCH2N), 2.87-2.70 (m, 8H, 4 × CH2);13C NMR (75MHz, DMSO-d6) δ ppm:160.22,157.67,151.48,
147.10,146.86,137.97,137.67,136.83,136.00,130.47,128.59,128.33,128.01,126.69,
126.62,125.97,125.89,125.22,122.14,112.66,111.72,109.94,59.44,55.43,55.40,
55.07,50.46,32.46,28.29;ESI-MS m/z:551.2 ([M+H]+)。
Embodiment 24N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -6,
The preparation of 7- dimethoxy -2- phenylquinazoline -4- amine (I-19):
Referring to the preparation method of I-1 in embodiment 6, compound I-19, faint yellow solid, yield 52.3% is made;1H
NMR (300MHz, DMSO-d6) δ ppm:9.50 (s, 1H, NH), 8.46-8.42 (m, 2H, ArH), 7.88-7.83 (m, 3H,
ArH), 7.51-7.44 (m, 3H, ArH), 7.34-7.27 (m, 3H, ArH), 6.63,6.63 (2s, 2H, ArH), 3.97,3.95
(2s, 6H, 2 × OCH3), 3.70,3.69 (2s, 6H, 2 × OCH3), 3.54 (s, 2H, ArCH2N), 2.87-2.69 (m, 8H, 4 ×
CH2);13C NMR (75MHz, DMSO-d6) δ ppm 157.50,156.47,154.29,148.73,147.56,147.10,
146.86,138.73,137.47,135.30,129.66,128.53,128.23,127.50,126.66,125.92,121.95,
111.71,109.94,107.64,107.50,102.09,59.51,56.18,55.70,55.43,55.39,55.08,54.84,
50.47,32.48,28.30;ESI-MS m/z:577.3 ([M+H]+)。
Embodiment 25
The tablet of the I-11 containing activating agent:
Supplementary material is mixed according to a conventional method, is pelletized, dry, tabletting.
Claims (5)
1. the compound and its officinal salt of logical formula (I):
Wherein R1And R2It is identical or different, it is respectively selected from: H, F, Cl, Br, I, C1-C5Alkyl or alkoxy;
Wherein R3It is selected from: C substituted or unsubstituted5~C10Aromatic radical, C5~C10Aromatic heterocyclic, wherein the substituent group includes C1
~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino radical, nitro, methylene-dioxy and halogen;
Wherein R4And R5It is identical or different, it is respectively selected from: H, C1~C5Alkoxy.
2. the compound of logical formula (I) according to claim 1 or its pharmaceutical salt are chemical combination shown in logical formula (II)
Object or its pharmaceutical salt:
Wherein R1And R2It is identical or different, it is respectively selected from: H, F, Cl, Br, I, C1~C5Alkyl or alkoxy;
Wherein R3It is selected from: C substituted or unsubstituted5~C10Aromatic radical, C5~C10Aromatic heterocyclic, wherein the substituent group includes C1
~C5Alkyl, C1~C5Alkoxy, C1~C5Alkylamino radical, nitro, methylene-dioxy and halogen.
3. compound is selected from flowering structure:
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- phenylquinazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (2- methoxyphenyl) quinoline
Oxazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3- methoxyphenyl) quinoline
Oxazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (4- methoxyphenyl) quinoline
Oxazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3,4- dimethoxy benzenes
Base) quinazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3,4,5- trimethoxies
Phenyl) quinazoline -4- amine;
2- (benzo [d] [1,3] dicyclopentadienyl -5- base)-N-4 (- 2 (- 2 (1H)-bases-of 6,7- dimethoxy -3,4- dihydro-isoquinoline
Ethyl) phenyl)) quinazoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (3- aminomethyl phenyl) quinoline azoles
Quinoline -4- amine;
N- (4-2 (6,7- dimethoxy -3,4- dihydro-isoquinolines -2 (1H)-base-ethyl) phenyl) -2- (4- aminomethyl phenyl) quinoline azoles
Quinoline -4- amine;
2- (4- (tert-butyl) phenyl)-N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) benzene
Base) quinazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridin-4-yl) quinoline
Oxazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (pyridin-3-yl) quinoline
Oxazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (quinoline -2- base) quinoline
Oxazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (3- nitrobenzophenone)
Quinazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- nitrobenzophenone)
Quinazoline -4- amine;
2- (4- chlorphenyl)-N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) quinoline
Oxazoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- (4- fluorophenyl) quinoline
Oxazoline -4- amine;
The chloro- N- of 7- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -2- phenyl quinazoline azoles
Quinoline -4- amine;
N- (4- (2- (- 2 (1H)-yl of 6,7- dimethoxy -3,4- dihydro-isoquinoline)-ethyl) phenyl) -6,7- dimethoxy -2-
Phenylquinazoline -4- amine.
4. compound described in claim 1-3 any one and its pharmaceutically acceptable salt are resistance in preparation treatment tumour multiple medicine
Application in the drug of medicine.
5. a kind of pharmaceutical composition, which is characterized in that chemical combination described in the claim 1-4 any one containing therapeutically effective amount
Object and pharmaceutically acceptable auxiliary material.
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CN112876474A (en) * | 2021-01-18 | 2021-06-01 | 林剑雄 | Dimethoxy tetrahydroisoquinoline substituted purine derivative, preparation method thereof and application thereof in antitumor drugs |
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CN101094840A (en) * | 2004-12-29 | 2007-12-26 | 韩美药品株式会社 | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
CN101245050A (en) * | 2007-02-14 | 2008-08-20 | 上海艾力斯医药科技有限公司 | 4-aniline quinazoline derivative salt |
CN102887891A (en) * | 2005-11-15 | 2013-01-23 | 阿雷生物药品公司 | N4-phenyl-quinaz0line-4 -amine derivatives and related compounds |
CN102906086A (en) * | 2010-06-30 | 2013-01-30 | 和记黄埔医药(上海)有限公司 | Quinazoline compounds |
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CN101094840A (en) * | 2004-12-29 | 2007-12-26 | 韩美药品株式会社 | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
CN102887891A (en) * | 2005-11-15 | 2013-01-23 | 阿雷生物药品公司 | N4-phenyl-quinaz0line-4 -amine derivatives and related compounds |
CN101245050A (en) * | 2007-02-14 | 2008-08-20 | 上海艾力斯医药科技有限公司 | 4-aniline quinazoline derivative salt |
CN102906086A (en) * | 2010-06-30 | 2013-01-30 | 和记黄埔医药(上海)有限公司 | Quinazoline compounds |
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