CN102229563A - 4-amino quinoline derivative, preparation method and application thereof - Google Patents
4-amino quinoline derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN102229563A CN102229563A CN2011101048023A CN201110104802A CN102229563A CN 102229563 A CN102229563 A CN 102229563A CN 2011101048023 A CN2011101048023 A CN 2011101048023A CN 201110104802 A CN201110104802 A CN 201110104802A CN 102229563 A CN102229563 A CN 102229563A
- Authority
- CN
- China
- Prior art keywords
- group
- base
- preparation
- alkyl
- amido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a 4-amino quinoline derivative, a preparation method and application thereof, relating to the field of medicine synthesis. A nitrogen-containing group is introduced to a quinoline structure for synthesizing the 4-amino quinoline derivative with a novel structure. A molecular structure of the 4-amino quinoline derivative is shown in the specification, wherein R is used for representing C1-C5 fatty amido, C6-C10 aromatic amido, C1-C5 heterocyclic ring-containing amido and C1-C5 alcohol amido or benzylamine. The derivative has physiological activity similar to alkaloid and larger polarity. The invention also relates to a preparation method of a compound in the formula (1) and application of the compound in the following formula to the preparation of medicines for treating and/or preventing tumors. The derivatives possibly have physiological activity similar to alkaloid and capability of increasing polarity, present a certain alkalinity and are convenient for salt formation together with inorganic acid or organic acid so as to achieve the purpose of improving the water solubility.
Description
Technical field
The present invention relates to relate to the synthetic field of medicine.Relate in particular to class 4-aminoquinoline derivatives and preparation method thereof, relate to intermediate of synthetic described 4-aminoquinoline derivatives and preparation method thereof, and contain their pharmaceutical composition and relate to the application of described amino quinoline derivatives.
Background technology
Heterogeneous ring compound has certain biological activity mostly, and quinolines is the heterocycle compound of biologically active and pharmacologically active.Through years of researches, the quinoline antimalarial agent has had very big development, and wherein quinolylamine and derivative thereof are important component parts wherein.(some is used many medicines with quinolylamine ring clinically for J. Med. Chem. 2001,44,3187-3194) all biologically active and pharmacologically active to curing abalienation, antibiotic, anti-inflammatory, hypertension, antidepressant, anti-malarial.Recent study shows that quinoline also has tumor prevention and therapeutic action (Bioorganic ﹠amp; Medicinal Chemistry, 14 (2006), 3098 – 3105) and can be used for treating acquired immune deficiency syndrome (AIDS).Quinoline with pharmacologically active wherein has much and extracts from natural product, and the camptothecine of for example extracting from camplotheca acuminata with antitumous effect contains the compound of quinoline ring exactly.But the quinoline that more has pharmacologically active is synthesized by chemical process.Particularly since the nineties in last century, a large amount of fluorine-containing quinoline medicines have all obtained clinical verification, and example hydrochloric acid lomefloxacin, fleroxacin etc. are anti-infection drug, all are widely used in clinical treatment at present.
Nitrogen-containing heterocycle compound plays the important physical effect in animal and plant body, contain this class formation in the base of most of medium-height grass the effective elements of the medicines, nucleic acid; In modern medicines, nitrogen-containing heterocycle compound has also accounted for quite great proportion.This research and design is introduced amido or heterocycle amido in the quinoline structure, expectation can improve the water miscible while, strengthens with human body interacting and the raising antitumour activity, finds to have the PTS of quinoline effect characteristics.
Summary of the invention
The objective of the invention is to design nitrogen-containing group in the quinoline structure, the 4-aminoquinoline derivatives of composite structure novelty, this compounds structure activity relationship is inquired into, seek good water solubility, active high 4-aminoquinoline derivatives, initiative 4-quinolylamine PTS, and the preparation method who is easy to realize is provided.The inventor finds, the pharmacological activity that the formula of novel structure provided by the invention (1) compound has desirable the present invention is based on this discovery and is accomplished.
The invention provides the 4-aminoquinoline derivatives structure as shown in the formula (1):
Structural formula (1)
Wherein on behalf of fatty amido, the aromatic amino of C6-C10, the C1-C5 of C1-C5, R contain pure amido or the benzamido group of heterocyclic amido, C1-C5.
Preferably, the invention provides the 4-aminoquinoline derivatives of formula (1), wherein R represents fat primary amine base or the fatty primary secondary amine base of C1-C5; Anilino and 2,3,4,5,6 optional one or several substituent anilinos (2,3,4,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group) that have; Piperazinyl and 2,3, (2,3,5,6 substituting group is the C1-C5 alkyl to 4,5,6 optional one or several substituent piperazinyls that have, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; 4 substituting group is the C1-C5 alkyl, the C1-C5 alkoxyl group); Piperidyl and 2,3,4,5,6 optional one or several substituent piperidyls (substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group) that have; Morpholinyl and 2,3,5,6 optional one or several substituent morpholinyls (substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group) that have; Pyrrolidine base and 2,3,4,5 optional one or several substituent Pyrrolidine bases (substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group) that have; Imidazolyl and 2 are optional has a substituent imidazolyl (substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group); Pure amido or the benzamido group of C1-C5.
More preferably, the invention provides the 4-aminoquinoline derivatives of formula (1), wherein R represents fat primary amine base or the fatty primary secondary amine base of C1, C2, C3, C4.
Most preferably, the invention provides the 4-aminoquinoline derivatives of formula (1), wherein R represents Propylamino, butylamine base, imidazolyl, cyclohexylamino, morpholinyl, piperidyl,
N-methylpiperazine base, anilino, benzamido group.
4-aminoquinoline derivatives of the present invention or composition can be used to prepare various anti-tumor drugs.
Particularly the invention provides the purposes of 4-aminoquinoline derivatives of the present invention in the various anti-tumor drugs of preparation.
The present invention provides the preparation method of above-mentioned 4-aminoquinoline derivatives in addition, and its synthetic route is as follows
This method may further comprise the steps:
A) make 3,5-dimethoxyaniline and Benzoyl chloride react in the presence of appropriate base, obtain formula
Compound;
B) reaction product of step a) and Acetyl Chloride 98Min. are reacted in the presence of appropriate acid, obtain formula
Compound;
C) make the reaction product of step b) in the presence of appropriate base, carry out cyclization, obtain formula
Compound;
D) reaction product that makes step c) obtains formula under the phosphorus oxychloride effect
Compound;
E) reaction product of step d) and all kinds of amine are reacted under the catalysis of appropriate base, obtain corresponding nitrogen containing derivative formula
Compound.
Wherein the definition of R is described with R in the 4-aminoquinoline derivatives structure.
In the wherein said step a) 3, the mol ratio of 5-dimethoxyaniline and Benzoyl chloride is 1:0.75～2.
The mol ratio of the reaction product of step a) and Acetyl Chloride 98Min. is 1:0.75～2 in the wherein said step b).
In the wherein said step e) in the 4-aminoquinoline derivatives preparation process solvent for use be common solvent, as methylene dichloride, acetonitrile, acetone, tetrahydrofuran (THF),
N,
N-dimethyl formamide etc.Described all kinds of amine is propylamine, butylamine, imidazoles, hexahydroaniline, morpholine, piperidines,
N-methylpiperazine, aniline, benzylamine; Wherein the reaction product of step d) and all kinds of amine mol ratio be 1:0.75～2; Catalyst system therefor is an organic bases commonly used, as diazabicyclo (DBU), and 4-Dimethylamino pyridine (NMAP), pyridine, triethylamine etc.
Advantage of the present invention is: described 4-aminoquinoline derivatives, be for improving the water-soluble of quinoline and improving antitumour activity, and in its molecule, introduce nitrogen-containing group, as institute's synthetic compounds such as nitrogen heterocyclic rings, these derivatives may have some analogous alkaloid physiologically active, simultaneously can increase polarity, and make institute's synthetic derivative present certain alkalescence, be convenient to reach the water miscible purpose of improvement with mineral acid or organic acid salify.
Embodiment:
(1) intermediate chloro quinoline
Preparation
In 100 mL round-bottomed flasks, add chrysin (281mg, 1mmol), phosphorus oxychloride, reflux 3 h.With frozen water 50 mL, ultra-sonic oscillation are filtered and are obtained the grass green crude product, get the faint yellow solid powder through the dehydrated alcohol recrystallization in system.
1H?NMR(CDCl
3)?δ:?3.97(3H,?s,?-OCH
3),?3.99(3H,?s,?-OCH
3),?6.59(1H,?d,?J=2.0Hz,?6-H),?7.41(1H,?s,?3-H),?7.52(3H,?m,?3’,?4’,5’-3H),?7.70(1H,?s,?8-H),?8.13(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?55.63(7-OCH
3),?55.94(5-OCH
3),?99.97(6-C),?101.28(8-C),?113.23(10-C),?118.93(3-C),?127.41(3’,5’-2C),?128.84(2’,6’-2C),?129.66(4’-C),?138.48(1’-C),?141.45(4-C),?152.94(9-C),?156.99(5-C),?157.33(7-C),?161.33(2-C).?FAB-MS,?
m/z?:?301(M+1).
(2) the logical method of the preparation of 4-aminoquinoline derivatives
In 100 mL round-bottomed flasks, add successively the chloro quinoline (300mg, 1mmol), amine (0.75～2mmol), (0.75～2mmol), 8～48h is stirred in oil bath (60～100 ℃) to catalyst of triethylamine.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
Embodiment's 1 is synthetic:
In 100 mL round-bottomed flasks, add successively the chloro quinoline (300mg, 1mmol), n-Butyl Amine 99 1.2mmol, catalyst of triethylamine 1.2mmol, oil bath 80
oC stirs 24h.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?1.01(3H,?t,?J=5.9Hz,?-CH
3?),?1.51(2H,?m,?-CH
2?),?1.74(2H,?m,?CH
2),?3.31(2H,?m,?CH
2),?3.92(3H,?s,?-OCH
3),?3.96(3H,?s,?-OCH
3),?6.37(1H,?d,?J=2.0Hz,?6-H),?6.62(1H,?s,?8-H),?7.04(1H,?br,?3-H),?7.41(1H,?m,?4’-H),?7.47(2H,?m,?3’,5’-2H),?8.03(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?13.90(CH
3),?20.40(CH
2),?30.93(CH
2),?42.68(CH
2),?55.53(7-OCH
3),?55.98(5-OCH
3),?95.33(6-C),?96.57(8-C),?101.34(3-C),?104.78(10-C),?127.48(3’,5’-2C),?128.51(2’,6’-2C),?128.77(4’-C),?140.70(1’-C),?152.27(4-C),?153.00(9-C),?157.51(5-C),?158.43(7-C),?160.20(2-C).?FAB-MS,?
m/z?:?337(M+1).
Embodiment's 2 is synthetic
In 100 mL round-bottomed flasks, add successively the chloro quinoline (300mg, 1mmol), imidazoles 1.3mmol, catalyst of triethylamine 1.5mmol, oil bath 90
oC stirs 12h.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?3.64(3H,?s,?-OCH
3),?3.98(3H,?s,?-OCH
3),?6.52(1H,?d,?J=2.0Hz,?6-H),?7.18-7.23(3H,?m,?3,8,4’?’-H),?7.48-7.54(4H,?m,?3’,4’,5’,5’?’-H),?7.69(1H,?S,?2’?’-H),?8.06(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?55.81(7-OCH
3),?55.87(5-OCH
3),?100.02(6-C),?101.15?(8-C),?110.67(3-C),?115.33(10-C),?121.57(5’?’-C),?127.44(3’,5’-2C),?128.60(4’?’-C),?129.02(2’,6’-2C),?130.01?(4’-C),?138.35(2’?’-C),?138.46(1’-C),?142.21(4-C),?152.96(9-C),?156.12(5-C),?158.01(7-C),?161.85(2-C).?FAB-MS,?
m/z?:?332(M+1).
Embodiment's 3 is synthetic
In 100 mL round-bottomed flasks, add successively the chloro quinoline (300mg, 1mmol), piperidinyl-1 .5mmol, catalyst of triethylamine 1.1mmol, oil bath 75
oC) stir 18h.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?1.82(2H,?s,?-CH
2),?2.74(4H,br,?2CH
2),?3.55(4H,?br,?2-CH
2-),3.94(6H,?d,?2-OCH
3),?6.48(1H,?d,?J=22.5Hz,?6-H),?7.10(1H,?s,?3-H),?7.11(1H,?d,?J=22.5Hz,?8-H),?7.42(1H,?m,?4’-H),?7.48(2H,?m,?3’,5’-2H),?8.06(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?24.51(CH
2),?26.12(2CH
2),?54.26(2CH
2),?55.49(7-OCH
3),?56.13(5-OCH
3),?98.34(6-C),?101.57?(8-C),?104.72(3-C),?109.81(10-C),?127.48(3’,5’-2C),?128.61(2’,6’-2C),?128.92?(4’-C),?140.44(1’-C),?153.52(4-C),?156.98(9-C),?158.17(5-C),?158.63(7-C),?160.26(2-C).?FAB-MS,?
m/z?:?349(M+1).
Embodiment's 4 is synthetic
In 100 mL round-bottomed flasks, add successively the chloro quinoline (300mg, 1mmol), morpholine 1.3mmol, catalyst of triethylamine 1.5mmol, oil bath 70
oC stirs 15h.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?3.28(4H,?br,?2CH
2),?3.96(10H,?s,?2-OCH
2-,?2-OCH
3),?6.50(1H,?d,?J=22.5Hz,?6-H),?7.09(1H,?s,?3-H),?7.13(1H,?d,?J=22.5Hz,?8-H),?7.43(1H,?m,?4’-H),?7.49(2H,?m,?3’,5’-2H),?8.05(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?53.30(2CH
2),?55.54(7-OCH
3),?56.08(5-OCH
3),?67.04(2CH
2),?98.86(6-C),?101.80?(8-C),?104.48(3-C),?109.50(10-C),?127.47(3’,5’-2C),?128.70(2’,6’-2C),?129.13?(4’-C),?140.13(1’-C),?153.53(4-C),?156.59(9-C),?157.51(5-C),?158.33(7-C),?160.49(2-C).?FAB-MS,?
m/z?:?351(M+1).
Embodiment's 5 is synthetic
(300mg, 1mmol), N methyl piperazine 1.2mmol, catalyst of triethylamine 1.5mmol, oil bath is stirred 20h for 80 ℃ to add the chloro quinoline in 100 mL round-bottomed flasks successively.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?2.41(3H,?s,?-CH
3),?2.96(4H,br,?2CH
2),?3.52(4H,?br,?2CH
2),3.95(6H,?d,?2-OCH
3),?6.49(1H,?d,?J=22.5Hz,?6-H),?7.09(1H,?s,?3-H),?7.12(1H,?d,?J=22.5Hz,?8-H),?7.43(1H,?m,?4’-H),?7.49(2H,?m,?3’,5’-2H),?8.06(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?46.21(CH
3),?52.73(2CH
2),?55.23(2CH
2),?55.53(7-OCH
3),?56.06(5-OCH
3),?98.64(6-C),?101.70?(8-C),?104.68(3-C),?109.57(10-C),?127.50(3’,5’-2C),?128.67(2’,6’-2C),?129.05(4’-C),?140.26(1’-C),?153.50(4-C),?156.70(9-C),?157.54(5-C),?158.28(7-C),?160.39(2-C).?FAB-MS,?
m/z?:?364(M+1).
Embodiment's 6 is synthetic
(300mg, 1mmol), hexahydroaniline 1mmol, catalyst of triethylamine 1.2mmol, oil bath is stirred 8h for 70 ℃ to add the chloro quinoline in 100 mL round-bottomed flasks successively.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?1.44(2H,br,?CH
2),1.50(2H,br,?CH
2),1.66(2H,br,?CH
2),?1.77(2H,br,?CH
2),2.10(2H,br,?CH
2),3.56(1H,?br,?CH),3.92(3H,?s,?-OCH
3),?3.96(3H,?s,?-OCH
3),?6.36(1H,?d,?J=22.5Hz,?6-H),?6.62(1H,?s,?3-H),?7.00(1H,?s,?8-H),?7.26(1H,?m,?4’-H),?7.47(2H,?m,?3’,5’-2H),?8.00(2H,?d,?J=21.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:24.55(4’?’-C),25.93(3’?’,5’?’-C),?32.42(2’?’,6’?’-C),?55.54(7-OCH
3),?56.08(5-OCH
3),?67.04(2CH
2),?95.75(6-C),?96.47(8-C),?101.54(3-C),?104.97(10-C),?127.53(3’,5’-2C),?128.54(2’,6’-2C),?128.67?(4’-C),?141.22(1’-C),?151.94(4-C),?152.88(9-C),?158.52(5-C),?158.67(7-C),?160.08(2-C).?FAB-MS,?
m/z?:?363(M+1).
Embodiment's 7 is synthetic
(300mg, 1mmol), aniline 1.5mmol, catalyst of triethylamine 1.5mmol, oil bath is stirred 48h for 100 ℃ to add the chloro quinoline in 100 mL round-bottomed flasks successively.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?3.95(3H,?s,?-OCH
3),?4.01(3H,?s,?-OCH
3),?6.49(1H,?d,?J=22.5Hz,?6-H),?7.06(1H,?s,?3-H),?7.19(1H,?m,?8-H),?7.22(1H,m,Ar-H),?7.40-7.45(7H,?m,?3’,4’,?5’-H,?Ar-H),?7.94(2H,?d,?J=21.5Hz,?2’,6’-2H),?9.05(1H,?s,?NH).?
13C?NMR?(CDCl
3)?δ:?55.56(7-OCH
3),?56.20(5-OCH
3),?97.22(6-C),?97.67(8-C),?101.70(3-C),?105.29(10-C),?124.00(2Ar-C),?124.80(1Ar-C),?127.35(3’,5’-2C),?128.50?(2’,6’-2C),?129.09(4’-C),?130.92(2Ar-C),?139.97(1Ar-C),?140.44(1’-C),?150.70(4-C),?153.11(9-C),?158.04(5-C),?158.36(7-C),?160.33(2-C).?FAB-MS,?
m/z?:?357(M+1).
Embodiment's 8 is synthetic
(300mg, 1mmol), benzyl ammonia 1.2mmol, catalyst of triethylamine 0.75mmol, oil bath is stirred 32h for 60 ℃ to add the chloro quinoline in 100 mL round-bottomed flasks successively.Remove solvent and excessive amine under reduced pressure.The gained dark solid is separated (sherwood oil: ethyl acetate: triethylamine=160:40:1 (volume ratio)) through silica gel column chromatography, promptly obtains target product.
1H?NMR(CDCl
3)?δ:?3.91(3H,?s,?-OCH
3),?3.92(3H,?s,?-OCH
3),?6.39(1H,?d,?J=2.5Hz,?6-H),?7.64(1H,?s,?3-H),?7.04(1H,?d,?J=2.5Hz,?8-H),?7.30(1H,m,Ar-H),?7.36-7.44(7H,?m,?3’,4’,?5’-H,?Ar-H),?7.94(2H,?d,?J=1.5Hz,?2’,6’-2H).?
13C?NMR?(CDCl
3)?δ:?47.32(CH
2),55.54(7-OCH
3),?56.03(5-OCH
3),?96.00(6-C),?96.80(8-C),?101.59(3-C),?104.97(10-C),?127.19(2Ar-C),?127.44(1Ar-C),?127.49(3’,5’-2C),?128.49(2’,6’-2C),?128.74(4’-C),?128.86(2Ar-C),?138.23(1Ar-C),?140.75(1’-C),?152.53(4-C),?152.73(9-C),?158.38(5-C),?158.58(7-C),?160.24(2-C).?FAB-MS,?
m/z?:?371(M+1).
Pharmacological testing:
Measured target compound to the effect of five kinds of human cancer cell inhibition of proliferation with MTT (tetrazolium bromide) colorimetry method.Choose HCT-116 (human colon cancer cell), A549 (human lung carcinoma cell), DU-145 (Human Prostate Cancer Cells), 5 kinds of tumour cells of HepG2 (human liver cancer cell), LN229 (people's glioblastoma multiforme) are the test cell strain, adopt the MTT colorimetry that institute's synthetic compound is carried out the anti tumor activity in vitro evaluation, and with the positive contrast medicine of 5 FU 5 fluorouracil (5-Fu).The tumour cell of taking the logarithm vegetative period, centrifugal back is diluted to 5 * 10 with substratum (RPMI 1640 or DMEM)
4Individual/mL, be inoculated in 96 orifice plates.Add the sample of different concns after 37 ℃ of overnight incubation, hatch 72 h again, add 10.0
μ MTT solution (5 mgmL of L/well
-1), behind 37 ℃ of hatching 4 h, every hole adds 150
μ L is dissolved with purple Jia Za crystalline dimethyl sulfoxide (DMSO).After 10 minutes, orifice plate is placed on the automatic microwell plate spectrophotometer, measure the optical density value, and calculate half effective inhibition concentration (IC at 570 nm and 630 nm places
50).Every group of sample carries out parallel testing 3 times.
Measured the inhibited proliferation of 10 compounds among the embodiment with mtt assay to five kinds of human cancer cell HCT-116 (human colon cancer cell), A549 (human lung carcinoma cell), DU-145 (Human Prostate Cancer Cells), HepG2 (human liver cancer cell), LN229 (people's glioblastoma multiforme), the results are shown in Table 1, wherein Tri N-Propyl Amine, n-Butyl Amine 99, hexahydroaniline and benzyl amine derivative all have good inhibitory effect, the particularly Tri N-Propyl Amine the strongest (IC of inhibition activity to colon cancer cell HCT-116 to five kinds of tumour cells
50Value is 0.97 μ M), hexahydroaniline is to the IC of lung cell A549 and liver cancer cell HepG2
50Value only is 6.59 μ M and 3.16 μ M, is far smaller than the half-inhibition concentration of 5-Fu.The result shows by in the quinoline structure, introducing nitrogen-atoms, strengthened the external antitumour activity of quinoline really.Therefore, this compounds is expected to exploitation becomes antitumor drug.
Table 1 target compound is to the half-inhibition concentration (IC of cancer cells
50
)
Claims (7)
1.4-amino quinoline derivatives is characterized in that its structure is as shown in the formula (1):
Structural formula (1);
Wherein on behalf of fatty amido, the aromatic amino of C6-C10, the C1-C5 of C1-C5, R contain pure amido or the benzamido group of heterocyclic amido, C1-C5.
2. 4-aminoquinoline derivatives according to claim 1 is characterized in that R wherein represents fat primary amine base or the fatty primary secondary amine base of C1-C5; Anilino and 2,3,4,5,6 optional one or several substituent anilinos that have, wherein 2,3,4,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; Piperazinyl and 2,3,4,5,6 optional one or several substituent piperazinyls that have, wherein 2,3,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; 4 substituting group is the C1-C5 alkyl, the C1-C5 alkoxyl group; Piperidyl and 2,3,4,5,6 optional one or several substituent piperidyls that have, wherein 2,3,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; Morpholinyl and 2,3,5,6 optional one or several substituent morpholinyls that have, wherein 2,3,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; Pyrrolidine base and 2,3,4,5 optional one or several substituent Pyrrolidines that have, base wherein 2,3,5,6 substituting group is the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; Imidazolyl and 2 are optional has a substituent imidazolyl, and wherein 2 bit substituents are the C1-C5 alkyl, C1-C5 alkoxyl group, C6-C10 aryl, C1-C5 ester group, C1-C5 acyl group, C1-C5 amide group; Pure amido or the benzamido group of C1-C5.
3. 4-aminoquinoline derivatives according to claim 1 and 2 is characterized in that R wherein represents fat primary amine base or the fatty primary secondary amine base of C1, C2, C3, C4.
4. 4-aminoquinoline derivatives according to claim 1 and 2 is characterized in that wherein R represents diethyl alcohol radical, Propylamino, butylamine base, imidazolyl, cyclohexylamino, morpholinyl, piperidyl,
N-methylpiperazine base, anilino, benzamido group.
5.4-the purposes of amino quinoline derivatives in the various anti-tumor drugs of preparation.
6. any preparation method of 4-aminoquinoline derivatives among the claim 1-5 is characterized in that carrying out according to following step:
A) make 3,5-dimethoxyaniline and Benzoyl chloride react in the presence of appropriate base, obtain formula
Compound;
B) reaction product of step a) and Acetyl Chloride 98Min. are reacted in the presence of appropriate acid, obtain formula
Compound;
C) make the reaction product of step b) in the presence of appropriate base, carry out cyclization, obtain formula
Compound;
D) reaction product that makes step c) obtains formula under the phosphorus oxychloride effect
Compound;
E) reaction product of step d) and all kinds of amine are reacted under the catalysis of appropriate base, obtain corresponding nitrogen containing derivative formula
Compound,
Wherein the definition of R is described with R in the 4-aminoquinoline derivatives structure.
7. the preparation method of 4-aminoquinoline derivatives according to claim 6 is characterized in that in the wherein said step a) 3, and the mol ratio of 5-dimethoxyaniline and Benzoyl chloride is 1:0.75～2; The mol ratio of the reaction product of step a) and Acetyl Chloride 98Min. is 1:0.75～2 in the wherein said step b);
In the wherein said step e) in the 4-aminoquinoline derivatives preparation process solvent for use be methylene dichloride, acetonitrile, acetone, tetrahydrofuran (THF),
N,
N-dimethyl formamide; Described all kinds of amine is propylamine, butylamine, imidazoles, hexahydroaniline, morpholine, piperidines,
N-methylpiperazine, aniline, benzylamine; Wherein the reaction product of step d) and all kinds of amine mol ratio be 1:0.75～2; Catalyst system therefor is diazabicyclo (DBU), 4-Dimethylamino pyridine (NMAP), pyridine, triethylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101048023A CN102229563A (en) | 2011-04-26 | 2011-04-26 | 4-amino quinoline derivative, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101048023A CN102229563A (en) | 2011-04-26 | 2011-04-26 | 4-amino quinoline derivative, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102229563A true CN102229563A (en) | 2011-11-02 |
Family
ID=44842183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101048023A Pending CN102229563A (en) | 2011-04-26 | 2011-04-26 | 4-amino quinoline derivative, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102229563A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113349A (en) * | 2013-03-15 | 2013-05-22 | 中国药科大学 | 4-imidazolyl quinoline and quinazoline ketone aromatizing enzyme inhibitors as well as preparation method and medical application thereof |
| CN105294559A (en) * | 2015-06-24 | 2016-02-03 | 王伍顺 | Method for synthesizing medical intermediate 4-aminoquinoline compound |
| CN112867711A (en) * | 2018-10-17 | 2021-05-28 | 杜克大学 | Quinone reductase 2 inhibitor compounds and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003045920A1 (en) * | 2001-11-27 | 2003-06-05 | Merck & Co., Inc. | 4-aminoquinoline compounds |
| WO2006058201A2 (en) * | 2004-11-23 | 2006-06-01 | Reddy Us Therapeutics, Inc. | Heterocyclic and bicyclic compounds, compositions and methods |
-
2011
- 2011-04-26 CN CN2011101048023A patent/CN102229563A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003045920A1 (en) * | 2001-11-27 | 2003-06-05 | Merck & Co., Inc. | 4-aminoquinoline compounds |
| WO2006058201A2 (en) * | 2004-11-23 | 2006-06-01 | Reddy Us Therapeutics, Inc. | Heterocyclic and bicyclic compounds, compositions and methods |
Non-Patent Citations (2)
| Title |
|---|
| MOHAMED HADJERI, ET AL.: "Alkylation of 2-Phenyl-4-quinolones:Synthetic and Structural Studies", 《CHEM.PHARM.BULL.》 * |
| ZENG-YUN AN, ET AL.: "Synthesis and evaluation of graveoline and graveolinine derivatives with potent anti-angiogenesis activities", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113349A (en) * | 2013-03-15 | 2013-05-22 | 中国药科大学 | 4-imidazolyl quinoline and quinazoline ketone aromatizing enzyme inhibitors as well as preparation method and medical application thereof |
| CN105294559A (en) * | 2015-06-24 | 2016-02-03 | 王伍顺 | Method for synthesizing medical intermediate 4-aminoquinoline compound |
| CN105294559B (en) * | 2015-06-24 | 2017-11-14 | 厦门法茉维特动物药业有限公司 | A kind of synthetic method of the aminoquinolines of medicine intermediate 4 |
| CN112867711A (en) * | 2018-10-17 | 2021-05-28 | 杜克大学 | Quinone reductase 2 inhibitor compounds and uses thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102075886B1 (en) | Novel pyrazolo [3,4-d] pyrimidine compounds or salts thereof | |
| AU2014350729B2 (en) | N-benzyl tryptanthrin derivative, and preparation method and application thereof | |
| CN106866571B (en) | Heterocyclic urea compound and its pharmaceutical composition and application | |
| TWI527800B (en) | 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof | |
| US9102631B2 (en) | 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs and the use thereof | |
| Mathew et al. | Novel pyridopyrazine and pyrimidothiazine derivatives as FtsZ inhibitors | |
| CN101774993A (en) | Chrysin nitrogen-containing derivative as well as preparation method and purpose thereof | |
| Badawey et al. | Benzimidazole condensed ring systems. XI. Synthesis of some substituted cycloalkyl pyrido [1, 2-a] benzimidazoles with anticipated antineoplastic activity | |
| WO2013178021A1 (en) | Pyrrole [2, 1-f][1, 2, 4] triazine derivative and antitumor effect thereof | |
| JP2022517723A (en) | Macrocycle compound as a CDK inhibitor, its production method and its application in pharmaceutical products | |
| US20190169163A1 (en) | Quinoline derivative and use thereof | |
| ES2850023T3 (en) | Amino-substituted six-membered nitric heterocyclic ring compound and preparation and use thereof | |
| Marvania et al. | The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker | |
| Liu et al. | Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property | |
| CN102229563A (en) | 4-amino quinoline derivative, preparation method and application thereof | |
| CN103224500A (en) | Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug | |
| JP6607962B2 (en) | Pyrazolo [4,3-c] quinoline derivatives for the inhibition of β-glucuronidase | |
| CN109400632B (en) | Bis-fluoroquinolone oxadiazole urea derivative containing N-methylenoxacin and preparation method and application thereof | |
| ITRM20060518A1 (en) | ISOINDOLO-KINOSALALINE DERIVATIVES WITH ANTITUMORAL ACTIVITY PROCEDURE FOR THEIR PRODUCTION AND THEIR USE | |
| WO2018159613A1 (en) | Antitumor-effect enhancer using pyrazolo[3,4-d]pyrimidine compound | |
| CN101613356B (en) | Quinazoline tetracyclic derivative, preparation method thereof and application thereof in pharmacy | |
| JP2015063476A (en) | Indolo[3, 2-c]quinoline derivative, method for producing the derivative, and antimalarial agent and anticancer agent comprising the derivative | |
| CN104211712B (en) | Artemisinin derivative containing heteroaryl piperidine, its preparation method and application | |
| JP7110335B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
| CN109369676B (en) | Bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111102 |