CN108690034A - A kind of fluorination benzo naphthyridones derivative, Preparation method and use - Google Patents
A kind of fluorination benzo naphthyridones derivative, Preparation method and use Download PDFInfo
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- CN108690034A CN108690034A CN201810031696.2A CN201810031696A CN108690034A CN 108690034 A CN108690034 A CN 108690034A CN 201810031696 A CN201810031696 A CN 201810031696A CN 108690034 A CN108690034 A CN 108690034A
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- DHHQDKJKDBLRPO-UHFFFAOYSA-N CN1CCN(CCN(c2c(cc3OCOc3c3)c3ncc2-c(cc2F)c3cc2F)C3=O)CC1 Chemical compound CN1CCN(CCN(c2c(cc3OCOc3c3)c3ncc2-c(cc2F)c3cc2F)C3=O)CC1 DHHQDKJKDBLRPO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
Abstract
The present invention discloses the preparation method and its purposes in the preparation of antitumor drugs of a kind of fluorination benzo naphthyridones derivative and this compound.Compound on tumor cell strain of the present invention shows good inhibitory activity, and part of compounds activity is suitable with current clinical medicine topotecan, and therefore, the compound of the present invention can be used for preparing anti-tumor drug.
Description
Technical field
The present invention relates to a kind of preparation method being fluorinated benzo naphthyridones derivative and this compound and its making
Purposes in standby antitumor drug.
Background technology
Tumour is to endanger one of the great malignant disease of people's life health at present, is counted according to the World Health Organization (WHO)
Data shows whole world cancer about 16,000,000 people of morbidity every year, dead about 6,000,000 people, and is still in rise situation, it has also become only
Inferior to the second killer of the mankind of cardiovascular disease.And chemicals will be treatment tumour in period considerably long at present and in the future
One of means the most main, play irreplaceable role in the treatment of cancer.But the most medicines launched at present
Object is often accompanied by the problems such as serious toxic side effect and drug resistance in its therapeutic process, and treatment is caused to fail to reach full
The effect or chemotherapy of meaning prove an abortion.Therefore, carry out more go deep into system antitumor drug initiative have important reality and
Strategic importance.
DNA topoisomerase Is (ToP I) are a kind of indispensable enzymes being widely present in organism, to DNA transcriptions, are replicated, again
DNA topological structures in the critical process such as group and reparation play important regulating and controlling effect.The study found that Top I in tumour cell
Content and activity be far above normal somatic cell.Top I inhibitors can then block the dissociation of the cleavable compounds of Top I-DNA,
Therefore the proliferation of energy selective depression tumour cell, to play antitumor action.Especially with Top I specific inhibitors
Extensive use of the camptothecin analogues in clinic, DNA topoisomerase Is (Top I) have become design new anticancer drug
An important function target spot, cause extensive concern (Cort the é s, F. of researcher;Pastor,N.;Mateos,S.;Domí
Nguez, I.Expert Opin.Ther.Patents, 2007,17 (5), 521~532;Bailly,
C.Curr.Med.Chem.2000,7,39~58.).Although camptothecin Top I inhibitors reach in terms of its treating cancer
Extraordinary clinical effectiveness, but by its molecular skeleton limit and it is existing as lactonic ring stability is poor, drug effect is short, poorly water-soluble,
The problems such as being also easy to produce drug resistance and toxic side effect has promoted researcher further to find the new non-CPT classes containing chinoline backbone
The shortcomings that Top I inhibitors are to overcome CPT class compounds simultaneously expands its antitumor spectra.
Through it is a large amount of the study found that benzo naphthyridones molecular skeleton and its derivative to various tumor cell strains (including
Persister) there are stronger antiproliferative effect, activity to be higher than SN-38 and topotecan, and not by common multidrug resistance egg
The influence of white MDR1 or BCRP, shows excellent development and application foreground (Sheng, C.Q.;Miao,Z.Y.;Zhang,
W.N.Curr.Med. Chem.2011,18,4389~4409.Meng, L.H.;Liao,Z.Y.;Pommier,
Y.Curr.Topics.Med.Chem.2003,3,305~320).According to people in recent years for the developmental research experience of drug
It is obtained with the structure activity study (SAR researchs) of drug:The atomic radius of its high electronegativity of fluorine atom and very little leads to fluorine-containing point
The sub polar interaction of its own, to affect various physics and chemistry and the biological property containing fluorine molecule, leads to it than stronger
Bioavilability improves, metabolic stability is more preferable, lipophilicity is more preferable and can also enhance the interaction of itself and target proteins
Power.Fluorine-containing or fluoro-containing group is introduced in drug will generate important influence in terms of the bioactivity to drug.By mesh
Before, there are 20%~25% pharmaceutical molecules to contain at least one fluorine atom, this will be attributed to important shadow of the fluorine for drug itself
It rings.
Accordingly, in order to further develop the Top I inhibitors of non-camptothecine, the present invention is with Edmond J.LaVoie early period
The high activity molecule ARC-111 compounds that seminar finds are clue, and according to the structure activity study of ARC-111, considering will
8 of ARC-111 molecules or (and) 9 carry out fluorination modification, to seek the antibumor molecules with more druggability.
Invention content
The purpose of the present invention is to provide a new class of fluorination benzo naphthyridones derivatives, to seek to obtain more high activity
Antitumoral compounds.Meanwhile the present invention provides the compounds process for production thereof and its in the preparation of antitumor drugs
Purposes.
R is N, N- dimethyl-ethylenediamine bases, N, N- diethyl ethylenediamine bases, N, N- diisopropyl ethylenediamines wherein in formula 1
Base, 1- (2- aminoethyls) pyrrolidinyl, 1- (2- aminoethyls) piperidyl, 4- methyl-1s-piperazine ethanamine base, N, N- dimethyl propylenes
Two amidos, normal-butyl.
The preparation method of fluorination benzo naphthyridones derivative of the present invention is shown below:
Show the compound of formula 1 to Non-small cell lung carcinoma A549 cells, people liver through anti tumor activity in vitro the selection result
Cancer HepG2 cells, human cervical carcinoma Hela cell and human leukemia HL60 cells shows go out stronger inhibitory activity, and partization
Conjunction object activity is suitable with current clinical medicine topotecan, and therefore, the compound of the present invention can be used for preparing antitumor medicine
Object.Fluorination benzo naphthyridones derivant structure of the present invention is novel, synthesis technology is simple, product purity is high, to tumour
Cell strain shows stronger inhibiting effect, has excellent application prospect.
Below by way of specific implementation mode, the above of the present invention is described in further detail.
Specific implementation mode
Embodiment 1:The synthesis of compound 4a
The synthesis of compound 4a of the present invention is carried out by chemical equation 3:
The synthesis of intermediate 2a:4- chloroquinolines (1eq) are added in round-bottomed flask, suitable phenol is added thereto and makees
It is stirred for solvent, flow back 3h at 120 DEG C of temperature and nitrogen protection, and N, N- dimethyl second are then added into reaction solution
Diamines (5eq) continues reflux for 24 hours, TLC monitorings, until the reaction is complete.After reaction solution cooling, with 15% NaOH and chloroform
Extraction three times, organic layer is merged, is washed with water three times.Organic layer is spin-dried for afterwards to mix sample, carrying out column chromatography, (eluent system is chlorine
It is imitative:Methanol), it can get the chip solid of brown color, i.e. intermediate 2a.
The synthesis of intermediate 3a:4,5-, bis- fluoro o-iodobenzoic acids (1eq) are added in round-bottomed flask, are added thereto suitable
The thionyl chloride of amount is stirred as solvent (20ml), and the 6h that flows back under 80 DEG C and nitrogen protection, after reaction solution is removed
It is spin-dried for.Again wherein be added intermediate 2a (1eq), triethylamine (0.1eq), be added afterwards suitable dichloromethane as solvent after
It is continuous to be reacted under nitrogen protection, TLC monitorings, until the reaction is complete.After reaction solution cooling, with saturation NaHCO3And chlorine
Three times, chloroform layer is merged for imitative extraction, after be spin-dried for mixing sample, carrying out column chromatography, (eluent system is chloroform:Methanol), it can get light
Yellow solid, i.e. intermediate 3a.
The synthesis of compound 4a:Intermediate 3a (1eq) is added in round-bottomed flask, Pd (AcO) is sequentially added2
(0.2eq), P (o-tolyl)3(0.4eq) and Ag2CO3(0.6eq), after suitable DMF be added thereto stirred as solvent
It mixes, and the 40min that flows back under nitrogen protection.After reaction, it waits for that reaction solution is cooled to room temperature, is diluted with appropriate chloroform, then
It makes it through diatomite to be filtered, is used in combination and contains 10%CH3The chloroformic solution of OH washs filter residue, collects filtrate afterwards, is spin-dried for mixing
Sample, carrying out column chromatography, (eluent system is chloroform:Methanol), it can get yellow powdery solid, as target product.
The detection data of compound 4a is as follows:Yield:25%;Faint yellow solid, fusing point:219-222℃;1H NMR
(CDCl3, 400MHz)δ:2.65(m,6H,2-CH3), 2.90 (t, 2H, J=8.0Hz ,-CH2), 4.27 (t, 2H, J=
8.0Hz,-CH2-),6.10 (s,2H,Ar-O-CH2 -O-),7.14(s,1H,Ar-H),7.45(s,2H,Ar-H),7.58(s,
1H, Ar-H), 8.10 (d, 1H, J=8.0 Hz, Ar-H) .MS-ESI m/z:398.1[M+H]+.
Embodiment 2
The synthesis of compound 4b
It is same with embodiment 1,4,5-, bis- fluoro o-iodobenzoic acids are only replaced with 5- fluoro o-iodobenzoic acids.React products therefrom
Detection data is as follows:Yield:31%;Faint yellow solid, fusing point:221-223℃;1H NMR(CDCl3,400MHz)δ:2.30
(s,6H, 2-CH3),2.97(s,2H,-CH2), 4.63 (t, 2H, J=16.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -
O-),7.38(s,1H, Ar-H),7.47(s,1H,Ar-H),7.72(s,1H,Ar-H),8.06(s,1H,Ar-H),8.30(dd,
1H, J=9.0,4.8Hz, Ar-H), 9.34 (s, 1H, Ar-H) .MS-ESI m/z:380.1[M+H]+
Embodiment 3
The synthesis of compound 4c
It is same with embodiment 1,4,5-, bis- fluoro o-iodobenzoic acids are only replaced with 4- fluoro o-iodobenzoic acids.React products therefrom
Detection data is as follows:Yield:21%;Faint yellow solid, fusing point:231-233℃;1H NMR(CDCl3,400MHz)δ:2.61
(s,6H, 2-CH3),2.84(s,2H,-CH2), 4.21 (t, 2H, J=16.0Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -
), O- 7.16 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=12.0Hz, Ar-
H).MS-ESI m/z: 380.1[M+H]+
Embodiment 4
The synthesis of compound 4d
It is same with embodiment 1, N, N- dimethyl-ethylenediamines are only replaced with 1- (2- aminoethyls) pyrrolidinyl.React products therefrom
Detection data is as follows:Yield:14%;Faint yellow solid, fusing point:236-238℃;1H NMR(CDCl3,400MHz)δ:1.71
(m,4H, 2N-CH2 -),2.64(m,4H,2-CH2), 2.90 (t, 2H, J=12.0Hz ,-CH2), 4.27 (t, 2H, J=
12.0Hz,-CH2-), 6.10(s,2H,Ar-O-CH2 -O-),7.14(s,1H,Ar-H),7.45(s,2H,Ar-H),7.58(s,
1H, Ar-H), 8.10 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI m/z:424.1[M+H]+
Embodiment 5
The synthesis of compound 4e
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodine are only replaced with 1- (2- aminoethyls) pyrrolidinyl
Benzoic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.It is as follows to react products therefrom detection data:Yield:17%;Pale yellow colored solid
Body, fusing point: 236-238℃;1H NMR(CDCl3,400MHz)δ1.79(m,4H,2N-CH2 -),2.61(m,4H,2-CH2-),
2.97(s, 2H,-CH2), 4.63 (t, 2H, J=12.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,
), Ar-H 7.47 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 8.06 (s, 1H, J=8.0Hz, Ar-H), 8.30 (dd, 1H, J
=8.8,6.4Hz, Ar-H), 9.34 (s, 1H, Ar-H) .MS-ESI m/z:406.1[M+H]+
Embodiment 6
The synthesis of compound 4f
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodine are only replaced with 1- (2- aminoethyls) pyrrolidinyl
Benzoic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.It is as follows to react products therefrom detection data:Yield:28%;Pale yellow colored solid
Body, fusing point: 220-222℃;1H NMR(CDCl3,400MHz)δ:1.69(m,4H,2N-CH2 -),2.53(m,4H,2-CH2-),
2.84 (t, 2H, J=12.0Hz ,-CH2), 4.21 (t, 2H, J=12Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -O-),
7.16 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=12.0Hz, Ar-H)
.MS-ESI m/z:406.1[M+H]+
Embodiment 7
The synthesis of compound 4g
It is same with embodiment 1, N, N- dimethyl-ethylenediamines are only replaced with 1- (2- aminoethyls) piperidyl.React products therefrom inspection
Measured data is as follows:The detection data of product is as follows:Yield:29%;Faint yellow solid, fusing point:240-242℃;1H NMR
(CDCl3,400MHz) δ:1.27(s,4H,2N-CH2 ), 2.35 (t, 6H, J=12.0Hz, 3-CH2), 2.90 (t, 2H, J=
12.0Hz,-CH2), 4.27 (t, 2H, J=12.0Hz ,-CH2-),6.10(s,2H,Ar-O-CH2 -O-),7.14(s,1H,Ar-
), H 7.45 (s, 2H, Ar-H), 7.58 (s, 1H, Ar-H), 8.10 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI m/z:438.1
[M+H]+
Embodiment 8
The synthesis of compound 4h
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodobenzenes are only replaced with 1- (2- aminoethyls) piperidyl
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.It is as follows to react products therefrom detection data:Yield:17%;Faint yellow solid,
Fusing point:224-226℃;1H NMR(CDCl3,400MHz)δ:1.18(s,4H,2N-CH2 -),2.28(s,6H,3-CH2-),2.79
(s,2H, -CH2-),4.60(s,2H,-CH2-),6.09(s,2H,Ar-O-CH2 -O-),7.37(s,1H,Ar-H),7.46(s,
1H, J=12.0Hz, Ar-H), 7.86 (s, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.29 (dd, 1H, J=8.6,4.8Hz,
Ar-H),9.34(s,1H,Ar-H). MS-ESI m/z:420.1[M+H]+
Embodiment 9
The synthesis of compound 4i
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodobenzenes are only replaced with 1- (2- aminoethyls) piperidyl
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.It is as follows to react products therefrom detection data:Yield:25%;Faint yellow solid,
Fusing point: 223-225℃;1H NMR(CDCl3,400MHz)δ:1.41(s,4H,2N-CH2 ), 2.38 (t, 6H, J=12.0Hz,
3-CH2), 2.84 (t, 2H, J=12.0Hz ,-CH2), 4.21 (t, 2H, J=12.0Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -O-),7.16(s, 1H,Ar-H),7.52(s,1H,Ar-H),7.61(s,1H,Ar-H),8.12(s,1H,Ar-H).8.29
(dd, 1H, J=9.4,5.2Hz, Ar-H), 9.21 (s, 1H, Ar-H) .MS-ESI m/z:420.1[M+H]+
Embodiment 10
The synthesis of compound 4j
Same with embodiment 1, only with N, N- dimethylated propyl diethylenetriamines replace N, N- dimethyl-ethylenediamines.React products therefrom inspection
Measured data is as follows:Yield:29%;Faint yellow solid, fusing point:219-222℃;1H NMR(CDCl3,400MHz)δ:2.41(m,
8H, (CH3) 2-N-CH2 ), 2.94 (t, 2H, J=12.0Hz ,-CH2), 4.27 (t, 2H, J=12.0Hz ,-CH2-),6.10
(s,2H, Ar-O-CH2 -O-),7.14(s,1H,Ar-H),7.45(s,2H,Ar-H),7.58(s,1H,Ar-H),8.10(d,
1H, J=8.0Hz, Ar-H) .MS-ESI m/z:412.1[M+H]+
Embodiment 11
The synthesis of compound 4k
Same with embodiment 1, only with N, N- dimethylated propyl diethylenetriamines replace N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodobenzenes
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:25%;Faint yellow solid, fusing point:
225-229℃;1H NMR(CDCl3,400MHz)δ:2.30(m,8H,(CH3)2 -N-CH2 -),2.97(s,2H,-CH2-),4.63
(t, 2H, J=8.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,Ar-H),7.47(s,1H,Ar-H),
7.72 (s, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.30 (dd, 1H, J=8.8,6.4Hz, Ar-H), 9.34 (s, 1H, Ar-
H).MS-ESI m/z: 394.1[M+H]+
Embodiment 12
The synthesis of compound 4l
Same with embodiment 1, only with N, N- dimethylated propyl diethylenetriamines replace N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodobenzenes
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:25%;Faint yellow solid, fusing point:
223-225℃;1H NMR(CDCl3,400MHz)δ:2.51(m,8H,(CH3)2 -N-CH2 -),2.97(s,2H,-CH2-),4.21
(t, 2H, J=12.0Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -O-),7.16(s,1H,Ar-H),7.52(s,1H,Ar-
), H 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI m/z:394.1[M+H]+
Embodiment 13
The synthesis of compound 4m
Same with embodiment 1, only with N, N- dipropyl ethylenediamines replace N, N- dimethyl-ethylenediamines.The detection data of product is such as
Under:Yield:14%;Faint yellow solid, fusing point:211-213℃;1H NMR(CDCl3,400MHz)δ:2.65(m,6H,2-N-
CH2-CH3 ), 2.80(m,4H,2-N-CH2 -CH3), 2.90 (t, 2H, J=12.0Hz ,-CH2), 4.27 (t, 2H, J=
8.0Hz,-CH2-),6.10(s, 2H,Ar-O-CH2 -O-),7.14(s,1H,Ar-H)7.45(s,2H,Ar-H),7.58(s,1H,
), Ar-H 8.10 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI m/z:426.1[M+H]+
Embodiment 14
The synthesis of compound 4n
Same with embodiment 1, only with N, N- dipropyl ethylenediamines replace N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodobenzene first
Acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:17%;Faint yellow solid, fusing point:225-
229℃;1H NMR(CDCl3,400MHz)δ:2.30(s,6H,2-N-CH2-CH3 ),2.80(m,4H,2-N-CH2 -CH3),2.97
(s, 2H,-CH2), 4.63 (t, 2H, J=12.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,Ar-
), H 7.47 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.30 (dd, 1H, J=7.8,6.4Hz,
Ar-H),9.34(s,1H, Ar-H).MS-ESI m/z:408.1[M+H]+
Embodiment 15
The synthesis of compound 4o
Same with embodiment 1, only with N, N- dipropyl ethylenediamines replace N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodobenzene first
Acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:25%;Faint yellow solid, fusing point:223-
225℃;1H NMR(CDCl3,400MHz)δ:2.61(m,6H,2-N-CH2-CH3 ),2.80(m,4H,2-N-CH2 -CH3),2.84
(t, 2H, J=8.0Hz ,-CH2), 4.21 (t, 2H, J=12.0Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -O-),7.16
(s, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI
m/z:408.1[M+H]+
Embodiment 16
The synthesis of compound 4p
It is same with embodiment 1, N, N- dimethyl-ethylenediamines are only replaced with butylamine.The detection data of product is as follows:Yield:
15%;Faint yellow solid, fusing point:206-208℃;1H NMR(CDCl3,400MHz)δ:0.99 (t, 3H, J=12.0Hz ,-
CH3),1.62(m, 2H,-CH2-),2.09(m,2H,-CH2-),4.48(m,2H,-N-CH2-),6.10(s,2H,Ar-O-CH2 -
), O- 7.14 (s, 1H, Ar-H), 7.45 (s, 2H, Ar-H), 7.58 (s, 1H, Ar-H), 8.10 (d, 1H, J=8.0Hz, Ar-
H).MS-ESI m/z: 383.1[M+H]+
Embodiment 17
The synthesis of compound 4q
It is same with embodiment 1, only replace N, N- dimethyl-ethylenediamines to replace 4,5- bis- with 5- fluoro o-iodobenzoic acids with butylamine
Fluoro o-iodobenzoic acid.The detection data of product is as follows:Yield:35%;Faint yellow solid, fusing point:227-229℃;1H NMR
(CDCl3, 400MHz)δ:1.02 (t, 3H, J=12.0Hz ,-CH3),1.64(m,2H,-CH2-),2.13(m,2H,-CH2-),
4.63(m,2H, -N-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,Ar-H),7.47(s,1H,Ar-H),
7.72 (s, 1H, Ar-H), 8.06 (s, 1H, J=8.0Hz, Ar-H), 8.30 (dd, 1H, J=8.8,6.4Hz, Ar-H), 9.34
(s,1H,Ar-H).MS-ESI m/z: 365.1[M+H]+
Embodiment 18
The synthesis of compound 4r
It is same with embodiment 1, only replace N, N- dimethyl-ethylenediamines to replace 4,5- bis- with 4- fluoro o-iodobenzoic acids with butylamine
Fluoro o-iodobenzoic acid.The detection data of product is as follows:Yield:30%;Faint yellow solid, fusing point:223-225℃;1H NMR
(CDCl3, 400MHz)δ:0.97 (t, 3H, J=12.0Hz), 1.62 (m, 2H ,-CH3),2.09(m,2H,-CH2-),2.61(m,
2H,-CH2-), 4.21(m,2H,-N-CH2-),6.05(s,2H,Ar-O-CH2 -O-),7.16(s,1H,Ar-H),7.52(s,
1H, Ar-H), 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=12.0Hz, Ar-H) .MS-ESI m/z:365.1[M+H]+
Embodiment 19
The synthesis of compound 4s
Same with embodiment 1, only with N, N- diisopropyl ethylenediamines replace N, N- dimethyl-ethylenediamines.The detection data of product
It is as follows:Yield:10%;Faint yellow solid, fusing point:251-253℃;1H NMR(CDCl3,400MHz)δ:0.86 (d, 12H, J=
12.0Hz, 2-N-CH-(CH3)2 ),2.61(m,4H,-(CH)2 -N-CH2 ), 4.27 (t, 2H, J=12.0Hz ,-CH2-),6.10
(s,2H, Ar-O-CH2 -O-),7.14(s,1H,Ar-H),7.45(s,2H,Ar-H),7.58(s,1H,Ar-H),8.10(d,
1H, J=8.0Hz, Ar-H) .MS-ESI m/z:454.2[M+H]+
Embodiment 20
The synthesis of compound 4t
Same with embodiment 1, only with N, N- diisopropyl ethylenediamines replace N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodobenzenes
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:27%;Faint yellow solid, fusing point:
250-252℃;1H NMR(CDCl3,400MHz)δ:0.87 (d, 12H, J=8.0Hz, 2-N-CH-(CH3)2 ),2.30(m,4H,
-(CH)2 -N-CH2 ), 4.63 (t, 2H, J=12.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,Ar-
), H 7.47 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.30 (dd, 1H, J=8.8,6.4Hz,
Ar-H),9.34(s,1H, Ar-H).MS-ESI m/z:436.2[M+H]+
Embodiment 21
The synthesis of compound 4u
Same with embodiment 1, only with N, N- diisopropyl ethylenediamines replace N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodobenzenes
Formic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:30%;Faint yellow solid, fusing point:
223-225℃;1H NMR(CDCl3, 400MHz) and δ 0.88 (d, 12H, J=8.0Hz, 2-N-CH-(CH3)2),2.61(m,4H,
-(CH)2 -N-CH2 ), 4.21 (t, 2H, J=12.0Hz ,-CH2-),6.05(s,2H,Ar-O-CH2 -O-),7.16(s,1H,Ar-
), H 7.52 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 8.12 (d, 1H, J=8.0Hz, Ar-H) .MS-ESI m/z:436.2
[M+H]+
Embodiment 22
The synthesis of compound 4v
It is same with embodiment 1, N, N- dimethyl-ethylenediamines are only replaced with 4- methyl-1s-piperazine ethanamine base.The testing number of product
According to as follows:Yield:41%;Faint yellow solid, fusing point:219-222℃;1HNMR(CDCl3,400MHz)δ:1.35(m,8H, 2-
N-(CH2)2 -N-CH3),2.21(s,3H,N-CH3), 2.90 (t, 2H, J=12.0Hz ,-CH2), 4.27 (t, 2H, J=
16.0Hz, -CH2-),6.10(s,2H,Ar-O-CH2 -O-),7.14(s,1H,Ar-H),7.45(s,2H,Ar-H),7.58(s,
1H, Ar-H), 8.10 (d, 1H, J=12.0Hz, Ar-H) .MS-ESI m/z:436.2[M+H]+
Embodiment 23
The synthesis of compound 4w
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 5- fluoro neighbour's iodine are only replaced with 4- methyl-1s-piperazine ethanamine base
Benzoic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:16%;Faint yellow solid, fusing point:
225-229℃;1H NMR(CDCl3,400MHz)δ:1.31(m,8H,2-N-(CH2)2 -N-CH3),2.21(s,3H,N-CH3),
2.97(s,2H, -CH2), 4.63 (t, 2H, J=12.0Hz ,-CH2-),6.08(s,2H,Ar-O-CH2 -O-),7.38(s,1H,
), Ar-H 7.47 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 8.06 (s, 1H, Ar-H), 8.30 (dd, 1H, J=8.8,
6.4Hz,Ar-H),9.34(s,1H,Ar-H). MS-ESI m/z:453.1[M+H]+
Embodiment 24
The synthesis of compound 4x
It is same with embodiment 1, N, N- dimethyl-ethylenediamines, with 4- fluoro neighbour's iodine are only replaced with 4- methyl-1s-piperazine ethanamine base
Benzoic acid replaces bis- fluoro o-iodobenzoic acids of 4,5-.The detection data of product is as follows:Yield:19%;Faint yellow solid, fusing point:
230-232℃;1H NMR(CDCl3,400MHz)δ:1.26(m,8H,2-N-(CH2)2 -N-CH3),2.24(s,3H,N-CH3),
2.84 (t, 2H, J=6.3Hz ,-CH2), 4.66 (t, 2H, J=6.3Hz ,-CH2-),6.18(s,2H,Ar-O-CH2 -O-),
7.31(s,1H,Ar-H),7.45 (s,1H,Ar-H),7.83(s,1H,Ar-H),7.96(s,1H,Ar-H),8.51(dd,1H,J
=8.8,5.8Hz, Ar-H), 9.33 (s, 1H, Ar-H) .MS-ESI m/z:435.2[M+H]+
The test method and result of the antitumor activity of 25 compound 4a-x of embodiment
The pharmacological evaluation of the present invention uses MTT colorimetric method for determining cell viabilities.Tumor cell culture selects 10% tire ox blood
The RPMI-1640 culture mediums of (FBS) clearly, logarithmic growth phase cell are digested with pancreatin/EDTA digestive juices, centrifugation, with complete
Culture solution piping and druming adjusts a concentration of 3 × 104/mL, the every accurate inoculating cell suspension 100ul in hole of 96 orifice plates at single cell suspension,
It is placed in 37 DEG C and contains 5%CO2Incubator culture 24 hours.The solution title compound to be tested of various concentration is added, is added per hole
150ul solution, maximum concentration group DMF final concentrations are not higher than 2/1000ths.Vehicle control group adds 150ul to contain 2/1000ths DMF's
Complete culture solution.After culture 72 hours, old liquid is discarded, is discarded after being cleaned with 150ul PBS per hole, the training completely of MTT storing solutions
After 10 times of dilutions of nutrient solution, the MTT 100ul of final concentration of 0.5mg/ml are added in each hole, continue culture 3 hours.Old liquid is discarded, often
150ul DMF are added in hole, and culture plate oscillator is shaken 3 minutes.Using Synergy HT types multi-function microplate readers (U.S. Bio-
Tek companies produce) measure the absorbance value measured at 492nm, 630nm per hole.All experiments set three parallel groups or repetition three
It is secondary.The cytotoxic activity test result of compound 4a-x is shown in Table 1.
The cytotoxic activity test result of 1 compound 4a-x of table
4 kinds of tumour cell in vitro cytotoxic effect test results are shown, compound of the present invention is non-to people small thin
Born of the same parents' lung cancer A549 cell, human hepatoma HepG2 cell, human cervical carcinoma Hela cell and human leukemia HL60 cells shows go out relatively strong
Inhibitory activity, and part of compounds activity is suitable with current clinical medicine topotecan, and therefore, the compound of the present invention can
It is used to prepare anti-tumor drug.
Claims (9)
1. a kind of a kind of fluorination benzo naphthyridones derivative of such as Formulas I-III shown.
R is N, N- dimethyl-ethylenediamine bases, N, N- diethyl ethylenediamine bases, N, N- diisopropyl ethylenediamine bases, 1- (2- ammonia in formula
Ethyl) pyrrolidinyl, 1- (2- aminoethyls) piperidyl, 4- methyl-1s-piperazine ethanamine base, N, N- dimethylated propyl diethylenetriamine bases, positive fourth
Any of base.
2. a series of preparation method of fluorination benzo naphthyridones derivatives described in the 1 of claim:By intermediate 4- chloros
Quinoline is added in round-bottomed flask, and suitable phenol is added thereto and is stirred as solvent, in 120 DEG C of temperature and nitrogen protection
Lower reflux 3h, then into reaction solution be added amino substituents (1.5mL), continue reflux for 24 hours, after amino substituents are added again
(0.5mL) is reacted, TLC monitorings, until the reaction is complete.After reaction solution cooling, three are extracted with 15% NaOH and chloroform
It is secondary, organic layer is merged, is washed with water three times.Organic layer is spin-dried for afterwards to mix sample, carrying out column chromatography, (eluent system is chloroform:First
Alcohol) to get intermediate product 4- aminoquinolines.Fluoro o-iodobenzoic acid is added in round-bottomed flask, suitable two are added thereto
Chlorine sulfoxide is stirred as solvent (20mL), and the 6h that flows back under 80 DEG C and nitrogen protection, after reaction solution removed be spin-dried for.Again
Different substituted aminoquinolines are added wherein, suitable CH is added in TEA (1.5mL) afterwards2Cl2Continue to protect in nitrogen as solvent
It is reacted under shield, TLC monitorings, until the reaction is complete.After reaction solution cooling, with saturation NaHCO3Three times with chloroform extraction,
Chloroform layer is merged, after be spin-dried for mixing sample, carrying out column chromatography, (eluent system is chloroform:Methanol) replace to get intermediate product difference
Benzamide quinoline.Different substituted fluoro neighbour's iodobenzamide quinoline are added in round-bottomed flask, Pd is sequentially added
(AcO)2, P (o-tolyl)3And Ag2CO3, after suitable DMF be added thereto be stirred as solvent, and in nitrogen protection
Lower reflux 40min.After reaction, wait for that reaction solution is cooled to room temperature, with appropriate chloroform dilute, then make it through diatomite into
Row filters, and the chloroformic solution washing filter residue containing 10% methanol is used in combination, collects filtrate afterwards, is spin-dried for mixing sample, carries out column chromatography, as mesh
It marks product and is fluorinated benzo naphthyridones derivative.
3. a series of preparation method of fluorination benzo naphthyridones derivatives according to the 2 of claim, it is characterised in that
Column chromatography is carried out after obtained target compound crude product is rinsed with chloroform, obtains target compound, eluent system used
For chloroform:The volume ratio of methanol is 90:1.
4. the method according to the 3 of claim, it is characterised in that silica gel for chromatography column is used using the column chromatography of 200-300 mesh
Silica gel.
5. a kind of fluorination benzo naphthyridones derivative application in preparation of anti-tumor drugs described in claim 1.
6. a kind of fluorination benzo naphthyridones derivative described in claim 1 is in the drug for preparing treatment Non-small cell lung carcinoma
In application.
7. a kind of fluorination benzo naphthyridones derivative answering in the drug for preparing treatment human liver cancer described in claim 1
With.
8. a kind of fluorination benzo naphthyridones derivative answering in the drug for preparing treatment human cervical carcinoma described in claim 1
With.
9. a kind of fluorination benzo naphthyridones derivative answering in the drug for preparing treatment human leukemia described in claim 1
With.
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| WO2004044174A2 (en) * | 2002-11-12 | 2004-05-27 | Rutgers, The State University | Topoisomerase-targeting agents |
| CN102395368A (en) * | 2009-01-30 | 2012-03-28 | 罗格斯，新泽西州立大学 | Methods to treat cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004044174A2 (en) * | 2002-11-12 | 2004-05-27 | Rutgers, The State University | Topoisomerase-targeting agents |
| CN102395368A (en) * | 2009-01-30 | 2012-03-28 | 罗格斯，新泽西州立大学 | Methods to treat cancer |
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