CN109516977B - Anilinopyrimidine/quinoline heterocomplex, preparation method and medical application - Google Patents

Anilinopyrimidine/quinoline heterocomplex, preparation method and medical application Download PDF

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CN109516977B
CN109516977B CN201910062995.7A CN201910062995A CN109516977B CN 109516977 B CN109516977 B CN 109516977B CN 201910062995 A CN201910062995 A CN 201910062995A CN 109516977 B CN109516977 B CN 109516977B
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韩春
吴林韬
苏峰
李梦瑶
胡晓琴
武曦
王晓霞
孙龙
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Abstract

The invention discloses an aniline pyrimidine/quinoline heterocomplex, a preparation method and a medical application thereof. The compound provided by the invention has different proliferation inhibition effects on non-small cell lung cancer cells A549, H1975, HCC827, human colon cancer cell HCT116, human liver cancer cell HepG2 and human epidermal cancer cell A431, and the proliferation inhibition effect of part of the compound on part of tumor cells is stronger than that of the positive drug gefitinib. Moreover, most of the compounds provided by the invention have weak proliferation inhibition effect on normal cells HBE, higher selectivity on tumor cells and obviously better safety than the positive drug gefitinib.

Description

Anilinopyrimidine/quinoline heterocomplex, preparation method and medical application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an aniline pyrimidine/quinoline heterocomplex, a preparation method and a medical application thereof.
Background
Cancer has become a contemporary human nightmare, and thus the discovery of anticancer drugs is an area of intense research in the scientific community.
Cancer cells are often seen as enemies invading the body and then rapidly eradicate, so the basic idea for researchers to treat cancer is to develop and clinically apply cancer cytotoxic chemicals, a strategy known as chemotherapy. Designing and synthesizing compounds with different structures and testing the antitumor activity of the compounds are important means for searching cancer chemotherapeutic drugs at present.
Disclosure of Invention
The invention aims to provide an aniline pyrimidine/quinoline heterocomplex, a preparation method and a medical application.
The above purpose of the invention is realized by the following technical scheme:
an anilinopyrimidine/quinoline hybrid having the chemical structure:
Figure BDA0001954773250000011
a process for preparing the above compound 1, comprising the steps of: adding appropriate amount of 2-methyl-6-methoxy-7- (2, 5-dichloropyrimidine-4-oxy) quinoline-3-carboxylic acid ethyl ester, 2-methoxy-4- (4-methylpiperidin-1-yl) aniline and TFA (trifluoroacetic acid) into sec-butyl alcohol, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
A process for producing the above compound 2, comprising the steps of: dissolving 2-methoxy-4-morpholinyl aniline in sec-butyl alcohol, adding a proper amount of 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, adding TFA under stirring, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
A process for producing the above compound 3, comprising the steps of: adding appropriate amount of 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, 1- (4-amino-3-methoxyphenyl) piperidine-4-ol and TFA into sec-butyl alcohol, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
A process for producing the above compound 4, comprising the steps of: adding a proper amount of sec-butyl alcohol, 2-methoxy-4- (4-allylpiperazinyl) aniline and TFA into ethyl 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate under the stirring condition, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
A process for producing the above compound 5, comprising the steps of: adding a proper amount of sec-butyl alcohol, 2-methoxy-4- (4-methylpiperidine-1-yl) aniline and TFA into ethyl 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate under the stirring condition, reacting at 105 ℃ for 30h, concentrating under reduced pressure, and purifying by column chromatography.
A process for producing the above compound 6, comprising the steps of: adding appropriate amount of 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, 2-methoxy-4-morpholinylaniline and TFA into sec-butyl alcohol, reacting at 105 ℃ for 30h under stirring, and purifying by column chromatography.
A process for producing the above compound 7, comprising the steps of: adding appropriate amount of TFA, 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester and 1- (4-amino-3-methoxyphenyl) piperidine-4-alcohol into sec-butyl alcohol under stirring, reacting at 105 ℃ for 72h, filtering, and purifying by column chromatography.
A process for preparing the above compound 8, comprising the steps of: adding a proper amount of TFA, 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester and 2-methoxy-4- (4-allylpiperazinyl) aniline into sec-butyl alcohol, reacting at 105 ℃ for 72 hours, and purifying by column chromatography.
The application of the compound in preparing antitumor drugs.
Has the advantages that:
the compound provided by the invention has different proliferation inhibition effects on non-small cell lung cancer cells A549, H1975, HCC827, human colon cancer cell HCT116, human liver cancer cell HepG2 and human epidermal cancer cell A431, and the proliferation inhibition effect of part of the compound on part of tumor cells is stronger than that of the positive drug gefitinib. Moreover, most of the compounds provided by the invention have weak proliferation inhibition effect on normal cells HBE, higher selectivity on tumor cells and obviously better safety than the positive drug gefitinib.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
Example 1: preparation and structure confirmation of compounds
Synthesis of ethyl 2-methyl-6-methoxy-7-benzyloxyquinoline-3-carboxylate (intermediate)
Figure BDA0001954773250000031
A250 mL round bottom flask was charged with 2-amino-5-methoxy-4-benzyloxybenzaldehyde (3.00g, 11.66mmol), absolute ethanol (75mL), ethyl acetoacetate (1.78mL, 14.00mmol), piperidine (2.88mL, 0.29mol), and heated to 90 ℃ with magnetic stirring for 30h at reflux. Stopping reaction, cooling and standing. Yellow solid is separated out, filtered, filter cake is rinsed by ethanol and water, dried and weighed to obtain 2.00g, the melting point is 137.5-139.4 ℃, and the yield is 49%.1H NMR(400MHz,d6-DMSO)δ1.37(t,3H,COOCH2CH 3,J＝7.08Hz),2.80(s,3H,ArCH 3),3.91(s,3H,OCH3),4.35(q,2H,COOCH 2CH3,J＝7.08Hz),5.30(s,2H,PhCH 2),7.45–7.36(m,4H,4×PhH),7.49(s,2H,2×PhH,),7.52(s,1H,PhH,),8.67(s,1H,ArH).
Synthesis of ethyl 2-methyl-6-methoxy-7-hydroxyquinoline-3-carboxylate (intermediate)
Figure BDA0001954773250000032
To 75mL of methanol were added ethyl 2-methyl-6-methoxy-7-benzyloxyquinoline-3-carboxylate (0.15g, 0.43mmol) and a catalytic amount of palladium on carbon, then hydrogen was introduced into the reaction apparatus, the reaction was stopped after 12 hours, the filtrate was concentrated and dried to give 0.11g of a milky white solid, melting point 129.0-129.2 ℃ and yield 98%.1H NMR(400MHz,d6-DMSO)δ1.37(t,3H,COOCH2CH 3,J＝7.08Hz),2.79(s,3H,ArCH 3),3.92(s,3H,OCH3),4.34(q,2H,COOCH 2CH3,J＝7.08Hz),7.22(s,1H,PhH),7.46(s,1H,PhH),8.64(s,1H,ArH),10.44(s,1H,OH).
Synthesis of ethyl 2-methyl-6-methoxy-7- (2, 5-dichloropyrimidine-4-yloxy) quinoline-3-carboxylate (intermediate)
Figure BDA0001954773250000033
Ethyl 2-methyl-6-methoxy-7-quinolinecarboxylic acid (600mg, 2.30mmol), potassium carbonate (630mg,3.44mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) are added into 37.5mL of DMMF, the reaction is carried out at room temperature, the reaction liquid is poured into cold water, solid is separated out, the mixture is filtered, dried and weighed, and the milky white solid 750mg is obtained, the melting point is 174.3-176.1 ℃, and the yield is 80%.1H NMR(400MHz,d6-DMSO)δ1.40(t,3H,COOCH2CH 3,J＝7.12Hz),2.84(s,3H,ArCH3),3.88(s,3H,OCH3),4.39(q,2H,COOCH 2CH3,J＝7.12Hz),7.96(s,2H,2×PhH),8.83(s,1H,ArH),8.92(s,1H,ArH).
Synthesis of ethyl 2-methyl-6-methoxy-7- (2- (2-methoxy-4- (4-methyl-1-piperazinyl) anilino) -5-chloropyrimidin-4-yloxy) quinoline-3-carboxylate (Compound 1)
Ethyl 2-methyl-6-methoxy-7- (2, 5-dichloropyrimidin-4-yloxy) quinoline-3-carboxylate (16mg, 0.04mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (9mg, 0.04mmol), and TFA (6.00mL, 94.9mmol) were added to 22.5mL of sec-butanol, reacted at 105 ℃ for 24h, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 25:1) to give 7mg of a yellow solid, melting point 88.1 to 89.0 ℃ and yield 31%.1H NMR(400MHz,d6-DMSO):δ1.38(t,3H,COOCH2CH 3,J＝7.12Hz),2.17(s,3H,NCH3),2.33(br s,4H,2×NCH 2CH2N),2.80(s,7H,2×NCH 2CH2N,ArCH3),3.63(s,3H,OCH3),3.81(s,3H,OCH3),4.37(q,2H,COOCH 2CH3,J＝7.12Hz),5.54(br s,1H,PhH),6.31(s,1H,PhH),6.82(d,1H,PhH,J＝8.68Hz),7.74(s,1H,PhH),7.75(s,1H,PhH),8.05(s,1H,ArNH),8.33(s,1H,ArH),8.82(s,1H,ArH).
Synthesis of ethyl 7- ((5-chloro-2 (2-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate (Compound 2)
Figure BDA0001954773250000042
Dissolving 2-methoxy-4-morpholinylaniline (169mg, 0.81mmol) in 25ml sec-butyl alcohol, adding 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester (300mg, 0.74mmol), adding trifluoroacetic acid TFA (109. mu.l, 1.47mmol) under stirring, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography to obtain pure product 186mg, wherein the yield is 39%, and mp 190.9-192.7 ℃.1H NMR(400MHz,d6-DMSO):δ1.41(t,3H,COOCH2CH 3,J＝7.08Hz),2.82(br s,2H,NCH2),2.84(s,3H,ArCH3),2.92(t,2H,NCH2,J＝4.04Hz),3.65(br s,2H,OCH2),3.67(s,3H,OCH3),3.71(t,2H,OCH2,J＝4.36Hz),3.86(s,3H,OCH3),4.41(q,2H,COOCH 2CH3,J＝7.00Hz),5.52(br s,1H,PhH),6.37(s,1H,PhH),6.88(br s,1H,PhH),7.78(s,1H,PhH),7.79(s,1H,PhH),8.17(s,1H,ArNH),8.38(s,1H,ArH),8.86(s,1H,ArH).
Synthesis of ethyl 6-methoxy-7- (2- (2-methoxy-4- (4-hydroxy-1-piperidinyl) anilino) -5-chloropyrimidine-4-oxy) -2-methylquinoline-3-carboxylate (Compound 3)
Figure BDA0001954773250000051
To 15mL of sec-butanol were added ethyl 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate (9mg, 0.02mmol), 1- (4-amino-3-methoxyphenyl) piperidin-4-ol (5mg, 0.02mmol), and TFA (3.20mL, 43.10mmol), followed by reaction at 105 ℃ for 24 hours, followed by concentration under reduced pressure after the reaction was stopped, and column chromatography (dichloromethane: methanol ═ 25:1) gave 4.00mg of a yellow solid with a melting point of 187.8 to 189.3 ℃ in 31% yield.1H NMR(400MHz,d6-DMSO):δ1.32(m,2H,CHCH 2),1.38(t,3H,COOCH2CH 3,J＝7.12Hz),1.68(m,2H,CHCH 2),2.51(m,2H,NCH2),2.80(s,3H,ArCH3),3.17(m,2H,NCH2),3.49(m,1H,CHCH2),3.62(s,3H,OCH3),3.81(s,3H,OCH3),4.37(q,2H,COOCH 2CH3,J＝7.12Hz),4.60(d,1H,HOCH,J＝3.00Hz),5.51(br s,1H,PhH),6.31(s,1H,PhH),6.79(br s,1H,PhH),7.74(s,1H,PhH),7.75(s,1H,PhH),8.05(s,1H,ArNH),8.33(s,1H,ArH),8.82(s,1H,ArH).
Synthesis of ethyl 7- ((2- ((4- (4-acryloyl-piperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate (Compound 4)
Figure BDA0001954773250000052
To ethyl 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate (110mg, 0.27mmol) was added sec-butanol (15mL), 2-methoxy-4- (4-allyloylpiperazinyl) aniline (60mg, 0.27mmol), TFA (4.00mL, 0.05mmol) under magnetic stirring, reacted at 105 ℃ for 24h, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 25:1) to give 50mg of a yellow solid, 31% yield, melting point 93.1-94.7 ℃.1HNMR(400MHz,d6-DMSO):δ1.37(t,3H,COOCH2CH 3,J＝7.16Hz),2.80(s,3H,ArCH3),2.83(br s,4H,2×NCH 2CH2N),3.57(br s,4H,2×NCH 2CH2N),3.63(s,3H,OCH3),3.81(s,3H,OCH3),4.37(q,2H,COOCH 2CH3,J＝7.12Hz),5.61(br s,1H,PhH),5.68(dd,1H,1/2×CH 2＝CHCO,J＝2.00,10.32Hz),6.11(dd,1H,1/2×CH 2＝CHCO,J＝2.12,16.56Hz),6.38(s,1H,PhH),6.78((dd,1H,CH2＝CHCO,J＝10.40,16.68Hz),6.87(br s,1H,PhH),7.74(s,1H,PhH),7.75(s,1H,PhH),8.10(s,1H,ArNH),8.34(s,1H,ArH),8.82(s,1H,ArH).
Synthesis of ethyl 7- (2-hydroxyethyl) -6-methoxy-2-methylquinoline-3-carboxylate (intermediate)
To the synthesis of a 250mL round bottom flask was added ethyl 2-methyl-6-methoxy-7-hydroxyquinoline-3-carboxylate (1.00g, 3.83mmol)) Anhydrous potassium carbonate (2.64g, 19.15mmol), then 30mL of DMF is added for dissolution, finally 2-bromoethanol (1.087mL, 15.32mmol) is added, the mixture is heated under magnetic stirring at 90 ℃ for reflux reaction, the reaction is stopped for 6h, the reaction solution is poured into ice water, the filtration is carried out, ethyl acetate is used for extraction (3X 20mL), organic layers are combined, water washing is carried out (3X 20mL), drying and concentration are carried out, thus obtaining 0.50g of milky white solid, the melting point is 138.5-139.0 ℃, and the yield is 43%.1H NMR(400MHz,CDCl3)δ1.45(t,3H,COOCH2CH 3,J＝7.12Hz),2.88(s,1H,OH),2.95(s,3H,ArCH3),3.95(s,3H,OCH3),4.08–4.18(t,2H,OCH2CH 2OH,J＝4.28Hz),4.26–4.36(t,2H,OCH 2CH2OH,J＝4.36Hz),4.42(q,2H,COOCH 2CH3,J＝7.12Hz),7.03(s,1H,PhH),7.35(s,1H,PhH),8.57(s,1H,ArH).
Synthesis of ethyl 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (intermediate)
To 30mL of DMF was added the compound ethyl 7- (2-hydroxyethyl) -6-methoxy-2-methylquinoline-3-carboxylate (1.17g, 3.83mmol), sodium hydride (0.18g, 7.66mmol), 2,4, 5-trichloropyrimidine (0.48mL, 4.21mmol), the reaction was magnetically stirred at room temperature, the reaction mixture was poured into cold water until a solid precipitated, filtered, dried, and weighed to give a milky white solid 1.38g, m.p. 143.6-145.0 ℃ in 80% yield.1HNMR(400MHz,d6-DMSO)δ1.37(t,3H,COOCH2CH 3,J＝7.12Hz),2.83(s,3H,ArCH3),3.88(s,3H,OCH3),4.36(q,2H,COOCH 2CH3,J＝7.12Hz),4.56–4.62(m,2H,OCH2CH 2OH),4.83–4.91(m,2H,OCH 2CH2OH),7.47(s,1H,PhH),7.52(s,1H,PhH),8.68(s,1H,ArH),8.71(s,1H,ArH).
Synthesis of 7- (2- ((5-chloro-2- ((2-methoxy-4-methylpiperazinylphenyl) amino) -4-pyrimidinyl) oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxyethyl ester (Compound 5)
Figure BDA0001954773250000063
To the compound ethyl 7- (2- (2, 5-dichloropyrimidin-4-yloxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (0.66g, 1.46mmol) was added sec-butanol (25mL), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.30g, 1.46mmol), TFA (0.45mL, 5.97mmol) under magnetic stirring and reacted at 105 ℃ for 30 h. Concentration under reduced pressure and column chromatography (dichloromethane: methanol 25:1) gave 102mg of a yellow solid with a melting point of 247.0-248.0 ℃ in 11% yield.1HNMR(400MHz,CDCl3):δ1.48(t,3H,COOCH2CH 3,J＝7.12Hz),2.41(s,3H,NCH3),2.65(t,4H,2×NCH 2CH2N,J＝4.72Hz),2.95(s,3H,ArCH3),3.21(t,4H,2×NCH 2CH2N,J＝4.70Hz),3.90(s,3H,OCH3),4.01(s,3H,OCH3),4.46(q,2H,COOCH 2CH3,J＝7.12Hz),4.65(t,2H,OCH2,J＝5.04Hz),4.94(t,2H,OCH2,J＝4.80Hz),6.56(m,2H,2×PhH),7.12(t,1H,PhH,J＝4.56H),7.49(s,1H,PhH),7.57(s,1H,PhH),8.10(s,1H,ArNH),8.16(s,1H,ArH),8.63(s,1H,ArH).
Synthesis of 7- (2- ((5-chloro-2- ((2-methoxy-4-morpholinophenyl) amino) -4-pyrimidinyl) oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxyethyl ester (Compound 6)
Figure BDA0001954773250000071
To sec-butanol (25mL) was added ethyl 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (0.66g, 1.46mmol), 2-methoxy-4-morpholinylaniline (0.30g, 1.46mmol), TFA (0.45mL, 5.97mmol), reacted at 105 ℃ with magnetic stirring for 30h, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 25:1) to give 150mg of a yellow solid, m.p. 90.5-92.2 ℃, 16% yield.1H NMR(400MHz,d6-DMSO):δ1.34(t,3H,COOCH2CH 3,J＝7.24Hz),2.77(s,3H,ArCH3),3.03(br s,4H,2×NCH2),3.69(brs,4H,2×OCH2),3.75(s,3H,OCH3),3.85(s,3H,OCH3),4.31(q,2H,COOCH 2CH3,J＝6.88Hz),4.51(t,2H,OCH2,J＝4.24Hz),4.72(t,2H,OCH2,J＝4.64Hz),6.39(d,1H,PhH,J＝8.92H),6.59(s,1H,PhH),7.44(d,1H,PhH,J＝9.24H),7.55(s,2H,PhH),8.09(s,1H,ArNH),8.16(s,1H,ArH),8.63(s,1H,ArH).
Synthesis of ethyl 7- (2- ((5-chloro-2- ((4- (4-hydroxypiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (Compound 7)
Figure BDA0001954773250000072
Under magnetic stirring, sec-butanol was used as a solvent (25ml), and TFA (0.217ml, 2.92mmol), ethyl 7- (2- (2, 5-dichloropyrimidin-4-yloxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (660mg,1.46mmol), 1- (4-amino-3-methoxyphenyl) piperidin-4-ol (325mg, 1.46mmol) were further added to react at 105 ℃. After 72 hours of reaction, the reaction was stopped, and after filtration and column chromatography (petroleum ether: ethyl acetate: 1), 200mg of a yellow solid was obtained, m.p. 186.7-187.9 ℃, 22% yield.1H NMR(400MHz,d6-DMSO):δ1.33(t,3H,COOCH2CH 3,J＝7.12Hz),1.43(m,2H,CHCH 2),1.75(m,2H,CHCH 2),2.71(m,2H,NCH2),2.77(s,3H,ArCH3),3.42(m,2H,NCH2),3.55(m,1H,CHCH2),3.73(s,3H,OCH3),3.84(s,3H,OCH3),4.31(q,2H,COOCH 2CH3,J＝7.12Hz),4.51(t,2H,OCH2,J＝4.96Hz),4.60(d,1H,HOCH,J＝4.20Hz),4.69(t,2H,OCH2,J＝4.64Hz),6.37(d,1H,PhH,J＝8.76H),6.56(s,1H,PhH),7.43(d,2H,2×PhH,J＝8.04H),7.46(s,1H,PhH),8.12(s,1H,ArNH),8.15(s,1H,ArH),8.64(s,1H,ArH).
Synthesis of ethyl 7- (2- ((2- ((4- (4-acryloyl-piperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (Compound 8)
Figure BDA0001954773250000081
To sec-butanol (25mL) was added TFA (0.48mL, 7.84mmol), ethyl 7- (2- (2, 5-dichloropyrimidin-4-yloxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate (660mg,1.46mmol), 2-methoxy-4- (4-allylpiperazinyl) aniline (304mg, 1.17mmol), and the reaction was carried out at 105 ℃ for 72 hours, followed by stopping the reaction and performing column chromatography to obtain 200mg of a yellowish white product. The yield was 20%. Melting point: 131.4-133.2 ℃.1H NMR(400MHz,d6-DMSO):δ1.33(t,3H,COOCH2CH 3,J＝7.12Hz),2.76(s,3H,ArCH3),3.06(t,4H,2×NCH 2CH2N,J＝4.56Hz),3.64(brs,4H,2×NCH 2CH2N),3.75(s,3H,OCH3),3.84(s,3H,OCH3),4.30(q,2H,COOCH 2CH3,J＝7.08Hz),4.50(t,2H,OCH2,J＝4.24Hz),4.70(t,2H,OCH2,J＝4.64Hz),5.67(dd,1H,1/2×CH 2＝CHCO,J＝2.36,10.40Hz),6.10(dd,1H,1/2×CH 2＝CHCO,J＝2.36,16.68Hz),6.40(dd,1H,PhH,J＝2.40,8.80Hz),6.62(d,1H,PhH,J＝2.48Hz),6.80(dd,1H,CH2＝CHCO,J＝10.40,16.64Hz),7.42(s,1H,PhH),7.45(s,1H,PhH),7.52(d,1H,PhH,J＝8.76Hz),8.16(s,2H,ArNH andArH),8.64(s,1H,ArH).
Example 2: determination of proliferation inhibition effects of compounds 1-8 on different tumor cell lines by MTT (methanol to toluene) method
1. Cell line
Non-small cell lung cancer cells A549 and H1975, human colon cancer cell HCT116 and human liver cancer cell HepG2 were purchased from Shanghai cell biology institute of Chinese academy of sciences, and non-small cell lung cancer cell HCC827, human epidermal cancer cell A431 and human normal bronchial epithelial cell HBE were purchased from Shanghai Fuji Biotech Limited, and were stored and subcultured in the laboratory according to the culture data. The cells were routinely inoculated into 50mL cell culture flasks using DMEM/RPI-1640 medium containing 10% fetal bovine serum at 37 deg.C with 5% CO2Culturing under 100% humidityAnd (5) cultivating, and changing the liquid every day. When the growth reaches 80-90%, digesting with pancreatin EDTA mixed liquor, and carrying out passage 1: 3.
2. Experimental methods
In vitro cell activity proliferation inhibition experiments, the MTT method is adopted to investigate the influence of a target compound on the survival activity of each cell. Digesting each cell in logarithmic growth phase with pancreatin, collecting, blowing uniformly with a pipette, counting, and measuring to obtain a density of 1 × 104cells/mL were seeded in 96-well plates at 100. mu.l per well, at 37 ℃ with 5% CO2After overnight incubation at 100% humidity, the stock culture was discarded and the cultures were incubated for 48h (n-3) in serum-free blank medium containing the target compound (0-40 μ M) at various final concentrations. Then 5mg/mL MTT solution 10. mu.l/well was added, and after further incubation for 4h 100. mu.l of the triple was added per well and left overnight in the incubator. Measuring the light absorbance at 570nm with microplate reader, calculating the survival rate of five cells after administration, and calculating IC50The value is obtained.
3. Results of the experiment
IC (Integrated Circuit) with proliferation inhibition effect of compounds 1-8 and positive drugs on different cells (tumor cells and normal cells)50The values are given in Table 1.
TABLE 1 IC of Compounds 1-8 and Positive drugs for inhibition of different cell proliferations50Value of
Figure BDA0001954773250000091
The experimental results show that the compounds 1-8 have proliferation inhibition effects of different degrees on non-small cell lung cancer cells A549, H1975, HCC827, human colon cancer cell HCT116, human liver cancer cell HepG2 and human epidermal cancer cell A431, and the proliferation inhibition effect of part of the compounds on part of tumor cells is stronger than that of the positive drug gefitinib. In addition, the compounds 2-8 have weak proliferation inhibition effect on normal cells HBE, have higher selectivity on tumor cells, and are obviously superior to the positive drug gefitinib.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims (10)

1. An anilinopyrimidine/quinoline hybrid characterized by the following chemical structure:
Figure FDA0001954773240000011
2. a process for the preparation of compound 1 of claim 1, comprising the steps of: adding appropriate amount of 2-methyl-6-methoxy-7- (2, 5-dichloropyrimidine-4-oxy) quinoline-3-carboxylic acid ethyl ester, 2-methoxy-4- (4-methylpiperidin-1-yl) aniline and TFA (trifluoroacetic acid) into sec-butyl alcohol, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
3. A process for the preparation of compound 2 of claim 1, comprising the steps of: dissolving 2-methoxy-4-morpholinyl aniline in sec-butyl alcohol, adding a proper amount of 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, adding TFA under stirring, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
4. A process for the preparation of compound 3 of claim 1, comprising the steps of: adding appropriate amount of 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, 1- (4-amino-3-methoxyphenyl) piperidine-4-ol and TFA into sec-butyl alcohol, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
5. A process for the preparation of compound 4 according to claim 1, comprising the steps of: adding a proper amount of sec-butyl alcohol, 2-methoxy-4- (4-allylpiperazinyl) aniline and TFA into ethyl 7- (2- ((2, 5-dichloropyrimidin-4-yl) oxy) -6-methoxy-2-methylquinoline-3-carboxylate under the stirring condition, reacting at 105 ℃ for 24h, concentrating under reduced pressure, and purifying by column chromatography.
6. A process for the preparation of compound 5 of claim 1, comprising the steps of: adding a proper amount of sec-butyl alcohol, 2-methoxy-4- (4-methylpiperidine-1-yl) aniline and TFA into ethyl 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylate under the stirring condition, reacting at 105 ℃ for 30h, concentrating under reduced pressure, and purifying by column chromatography.
7. A process for the preparation of compound 6 of claim 1, comprising the steps of: adding appropriate amount of 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester, 2-methoxy-4-morpholinylaniline and TFA into sec-butyl alcohol, reacting at 105 ℃ for 30h under stirring, and purifying by column chromatography.
8. A process for the preparation of compound 7 of claim 1, comprising the steps of: adding appropriate amount of TFA, 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester and 1- (4-amino-3-methoxyphenyl) piperidine-4-alcohol into sec-butyl alcohol under stirring, reacting at 105 ℃ for 72h, filtering, and purifying by column chromatography.
9. A process for the preparation of compound 8 of claim 1, comprising the steps of: adding a proper amount of TFA, 7- (2- (2, 5-dichloropyrimidine-4-oxy) ethoxy) -6-methoxy-2-methylquinoline-3-carboxylic acid ethyl ester and 2-methoxy-4- (4-allylpiperazinyl) aniline into sec-butyl alcohol, reacting at 105 ℃ for 72 hours, and purifying by column chromatography.
10. The use of a compound as claimed in claim 1 for the preparation of an antineoplastic medicament.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138578A1 (en) * 2009-05-27 2010-12-02 Abbott Laboratories Pyrimidine inhibitors of kinase activity
CN108101926A (en) * 2018-02-07 2018-06-01 郑州大学 Pyrimido five-membered heterocycles containing quinolinone, preparation method and applications

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138578A1 (en) * 2009-05-27 2010-12-02 Abbott Laboratories Pyrimidine inhibitors of kinase activity
CN108101926A (en) * 2018-02-07 2018-06-01 郑州大学 Pyrimido five-membered heterocycles containing quinolinone, preparation method and applications

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
丙烯酸酯与苯胺嘧啶杂合的EGFR激酶抑制剂的研究;韩春;《长治学院学报》;20140430;24-27 *
苯胺嘧啶与肉桂酸杂合物的设计合成及抗非小细胞肺癌活性;孙龙等;《中国药学杂志》;20180531;771-775 *

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