CN1733764A - 3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy - Google Patents

3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy Download PDF

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CN1733764A
CN1733764A CN 200510041531 CN200510041531A CN1733764A CN 1733764 A CN1733764 A CN 1733764A CN 200510041531 CN200510041531 CN 200510041531 CN 200510041531 A CN200510041531 A CN 200510041531A CN 1733764 A CN1733764 A CN 1733764A
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replacement
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amino
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CN1325494C (en
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李志裕
尤启冬
郭青龙
何训贵
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

Disclosed is a 3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy, wherein the compound has antineoplastic activity and a general formula (I) with the 3-position substituted by benzimidazole and benzothiazole, the preparation process of the compound comprises condensing various substituted naphthyridine ketone-3-formylic acid, o-phenylenediamine, o-aminophenol, o-aminobenzenethiol and into polyphosphoric acids. The compound can be used in preparing anti-cancer medicaments.

Description

Naphthyridines ketone compounds that the 3-position replaces and preparation method thereof and the application in pharmacy
Technical field
The invention belongs to pharmaceutical field, relate to the naphthyridines ketone compounds that new 3-position replaces, the invention still further relates to the preparation method and the application in the preparation antitumor drug thereof of this compound.
Background technology
Quinolones is as the antimicrobial drug history of existing three more than ten years, mainly be by suppressing the DNA of bacteria topoisomerase, i.e. gyrase and bring into play anti-microbial effect.But people such as nearest Wentland find that 3-Quinolonecar boxylic acid derivatives WIN57294 also can interact with mammiferous TopII.Find its EC in the dna break test that utilizes Hela cell TopII to carry out 50Reach 7.6 μ M.And research finds that also some non-carboxylic acid derivative in 3-position also have similar anti-tumor activity, as the EC of 3-(2, the 6-dihydroxy benzyl) derivative (WIN64593) 50Value is 96 μ M.In addition, the 7-position of quinolinone replaces with other pyridines, 4-methyl isophthalic acid-piperazinyl or pyrroles, or uses NH 2Or F replaces 5-position hydrogen activity and still keeps, 8-position fluorine or methoxyl group replace can strengthen anti-tumor activity (referring to Chinese Pharmaceutical Journal, 1997,32,4529; Acta Pharmaceutica Sinica, 1998,33,121).
In patent documentation CN03132296.4, we have prepared 3 compounds that replaced by benzoglyoxaline, benzoxazole and benzothiazole of quinolinone, have showed stronger anti-tumor activity in the anti tumor activity in vitro test.But whether the replacement of naphthyridines ketone 3-position is had corresponding feature report is not arranged as yet.
Summary of the invention
The purpose of this invention is to provide the compound that benzoglyoxaline, benzoxazole and benzothiazole that a kind of new naphthyridines ketone 3-position with anti-tumor activity was substituted or do not have replacement replace.
Another object of the present invention provides the preparation method of above-claimed cpd.
A further object of the invention provides the application of above-claimed cpd in the preparation antitumor drug.
The present invention is a starting raw material with the naphthyridines ketone-3-formic acid of various replacements, with the o-amino thiophenol prepared in reaction of the Ortho-Aminophenol of the O-Phenylene Diamine of O-Phenylene Diamine, Ortho-Aminophenol, o-amino thiophenol, replacement, replacement or replacement the compounds that replaced by benzoglyoxaline, benzoxazole and benzothiazole of a series of new naphthyridines ketone 3-positions, these compounds have stronger anti-tumor activity.
The invention provides following technical scheme for solving the problems of the technologies described above:
The naphthyridines ketone compounds of following general formula (I) expression:
Figure A20051004153100071
Wherein, R 1Represent alkyl H, replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement or aryl replacement or that do not have replacement;
R 2Represent H, halogen, nitro or amino;
R 5Represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement or aryl replacement or that do not have replacement;
R 6And R 7Identical or different, represent H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, the aromatic heterocyclic that replaces or do not have replacement, nitro, amino independently of one another;
X represents O, S or NH.
Described naphthyridines ketone compounds, wherein R 1, R 5, R 6, R 7Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is a phenyl, or by F, Cl, Br, I, C 1-10Alkyl, C 1-10Alkoxyl group, nitro or amino mono-substituted phenyl;
R 1, R 5, R 6, R 7The alkyl of representative or the alkyl in the aryl refer to have the alkyl of straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom;
R 5, R 6, R 7Alkyl in alkoxyl group, aralkoxy or the heterocycle alkoxyl group of representative refers to have the alkyl of the straight or branched of 1-10 carbon atom;
R 1, R 5, R 6, R 7Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one or more heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R 1, R 5Middle alkyl, the aryl of replacement, the heterocyclic radical of replacement or the aryl of replacement that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group or amido;
R 6, R 7Aromatic heterocyclic replacement or that do not have replacement of representative is by F, Cl, Br, I, C 1～10Alkyl, C 1～10Acyl group, C 1～10Alkoxyl group, C 1～10Alkylamino, nitro or the amino ternary that contains 1～4 nitrogen-atoms～eight yuan heterocyclic aromatic heterocyclic that replace or that do not have replacement.
Described naphthyridines ketone compounds, wherein R 1, R 5, R 6, R 7The aryl of representative is the phenyl ring base, perhaps is F, Cl, Br, I, C 1～10Alkyl, C 1～10Alkoxyl group, nitro or the amino phenyl that replaces; Aromatic heterocyclic is to contain 1～3 heteroatomic fragrant heterocyclic radical, perhaps is F, Cl, Br, I, C 1～10Alkyl, C 1～10Alkoxyl group, nitro or amino replace contain 1～3 heteroatomic aromaticity heterocyclic radical.
Described naphthyridines ketone compounds, wherein amino is NH 2, R 8NH, R 9R 10N; R wherein 8, R 9Or R 10Alkyl or the cycloalkyl of 3-10 carbon atom, perhaps R for straight or branched with 1-10 carbon atom 9R 10Connect into ring-type.
Described naphthyridines ketone compounds, wherein R 1, R 5, R 6, R 7Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is C 1～6Alkyl or C 1～6The phenyl that alkoxyl group replaces;
R 1, R 5, R 6, R 7The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-6 carbon atom or the cycloalkyl of 3-6 carbon atom;
R 5, R 6, R 7Alkyl in alkoxyl group, aralkoxy or the heterocycle alkoxyl group of representative refers to have the alkyl of the straight or branched of 1-6 carbon atom;
R 1, R 5, R 6, R 7Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one, two or three heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R 6, R 7Aromatic heterocyclic replacement or that do not have replacement of representative is C 1～6Alkyl, C 1～6Acyl group, C 1～6Alkoxyl group, C 1～6The aromatic heterocyclic of alkylamino, nitro, the amino ternary～hexa-member heterocycle that contains 1～3 nitrogen-atoms that replace or that do not have replacement.
Above-mentioned naphthyridines ketone compounds, wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl or decyl; Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl or ring decyl; Halogen is F, Cl, Br or I.
Described naphthyridines ketone compounds, wherein alkyl is the alkyl with straight or branched of 1-4 carbon atom; Cycloalkyl is the cycloalkyl with 3～6 carbon atoms; Heterocyclic radical is saturated heterocyclic or the aromatic heterocycle that contains 3～6 atoms; Halogen is F or Cl; R 6, R 7The ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of the replacement of representative is not replacement and the mono-substituted five yuan～hexa-member heterocycle that contains 1～2 nitrogen-atoms.
Described naphthyridines ketone compounds, wherein:
R 1Expression H, C 1-C 4Side chain or the C that replaces of the alkyl of straight chain or cyclic alkane, halogen 1-C 4Branched-chain or straight-chain alkyl;
R 2Representative is replaced by halogen, nitro, amino or H respectively or simultaneously on 5 and/or 6 of aromatic ring;
R 5And R 6Identical or different, H, amino or halogen are shown in representative independently of one another;
R 7Expression H, halogen, hydroxyl, C 1-C 4Branched-chain or straight-chain alkyl, amino or C 1-C 4The amino that replaces of branched-chain or straight-chain alkyl, C 1-C 4Branched-chain or straight-chain alkyl replace or do not have a replacement contain five yuan of 1-2 nitrogen-atoms or hexa-member heterocycle, C 1-C 4Acyl substituted or do not have five yuan or the hexa-member heterocycle containing 1-2 nitrogen-atoms of replacement;
X represents O, S, NH.
In the described naphthyridines ketone compounds, even more ideal compound is: R 1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, fluoro ethyl; R 2Representative is replaced by chlorine, nitro, amino or H on 5 and/or 6 of aromatic rings at the same time or separately; R 5And R 6Identical or different, H, amino or fluorine are shown in representative independently of one another; R 7Represent H, Cl, hydroxyl, methyl, second third; propyl group, sec.-propyl, amino, dimethylamino; diethylamino, piperazinyl is gone up the piperazinyl that is replaced by methyl, ethyl or ethanoyl for 3,4 or 5, perhaps 3,5 piperazinyls that replaced by methyl, ethyl and/or ethanoyl.
The preparation method of described naphthyridines ketone compounds:
R in general formula (I) 2When=H or F, Cl, Br, I, its preparation method can be represented by reaction formula 1:
General formula (A) general formula (I)
Reaction formula 1
Promptly get the naphthyridines ketone-3-formic acid of the various replacements of general molecular formula (A), with the O-Phenylene Diamine that replaces or do not have replacement, replace or do not have the Ortho-Aminophenol or the replacement of replacement or do not have the o-amino thiophenol of replacement, condensation in polyphosphoric acid (being called for short PPA), condensation reaction products is general formula (I) target compound;
R in general formula (I) 2Be NO 2Or NH 2The time, its preparation method can be represented by reaction formula 2:
Reaction formula 2
Promptly with R in the general formula (I) 2The compound of=H is a raw material, directly carry out nitrated, R in the general formula (I) 2=NO 2Compound; With nitroreduction, get R in the general formula (I) 2=NH 2Compound.
In the reaction formula 1,2, R 1, R 5, R 6, R 7, X is identical with above-mentioned definition, R specifically 1Expression H, alkyl, aryl, heterocyclic radical, aryl; And above-mentioned alkyl, aryl, heterocyclic radical, the aryl that has replaced.R 2Expression H, halogen, nitro, amino.R 5Expression H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl, aryl, heterocyclic radical, aryl; And above-mentioned alkyl, aryl, heterocyclic radical, the aryl that has replaced.R 6Expression H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, fragrant heterocycle, NO 2, amino, contain the ternary～eight yuan heterocycle of 1-4 nitrogen-atoms, the ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of replacement; R 7Expression H, halogen, hydroxyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, alkyl, aryl, fragrant heterocycle, NO 2, amino, contain the ternary～eight yuan heterocycle of 1-4 nitrogen-atoms, the ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of replacement; X represents O, S, NH.
Further, above-mentioned R 1, R 5, R 6, R 7The alkyl of representative refers to have the alkyl of straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom; Wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl or decyl, preferably has the alkyl of the straight or branched of 1-4 carbon atom; Wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl or ring decyl, preferably has the cycloalkyl of 3-6 carbon atom; Above-mentioned R 1, R 5, R 6, R 7The heterocyclic radical of representative refers to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom, preferably contains the saturated heterocyclic or the aromatic heterocycle of 3-6 atom; Above-mentioned R 1, R 5, R 6, R 7The aryl of representative or the definition of alkyl in the aralkyl or alkyl are same as described above, and wherein said aryl can be benzene, also can be alkyl, the alkoxyl group of C1-10, nitro, the amino benzene that replaces of F, Cl, Br, I, C1-10; Above-mentioned R 1, R 2, R 5, R 6, R 7The halogen of representative is F, Cl, Br or I, preferred F and Cl atom; Above-mentioned R 6, R 7The ternary that contains 1-4 the nitrogen-atoms～eight yuan heterocycle of the replacement of representative can be F, Cl, Br, I, C 1-10Alkyl, C 1-10Acyl group, C 1-10Alkoxyl group, C 1-10Alkylamino, nitro, the amino ternary that contains 1-4 the nitrogen-atoms～eight yuan heterocycle that replaces, preferably contain the five yuan～hexa-member heterocycle that does not replace and replace of 1～2 nitrogen-atoms; Above-mentioned R 1, R 3, R 5Middle alkyl, aryl, heterocyclic radical, the aryl that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amido; Above-mentioned R 1, R 5, R 6, R 7The aryl of representative is a benzene, can be F, Cl, Br, I, C 1-10Alkyl, C 1-10Alkoxyl group, nitro, the amino benzene that replaces; The virtue heterocycle is to contain heteroatomic aromaticity heterocycle more than, can be F, Cl, Br, I, C 1-10Alkyl, C 1-10Alkoxyl group, nitro, amino replace contain heteroatomic aromaticity heterocycle more than; Above the amino of indication is NH 2, R 8NH, R 9R 10N, wherein R 8, R 9Or R 10Be alkyl referred to above (promptly having the alkyl of straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom), R 9R 10Can connect into ring-type.
The application of described naphthyridines ketone compounds in the preparation antitumor drug.
Beneficial effect of the present invention:
Compound provided by the invention has stronger anti-tumor activity, can be used for preparing antitumour drug, and the preparation method of this compound provided by the invention is simple, effective.
At present, the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely.
The cytotoxic activity data of The compounds of this invention:
This mensuration adopts bromination tetrazole indigo plant (MTT) method routinely, promptly use the trysinization tumour cell, to contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, and 100 μ l (containing 1000 cells/well) are inoculated in every hole in 96 well culture plates.If different pharmaceutical concentration is established three parallel holes for every group.Put to cultivate after 4 days in 37 ℃, 5%CO2 incubator and discard nutrient solution, every hole adds 100 μ l 0.5%MTT solution (RPMI 1640 preparations).37 ℃ are incubated 4 hours, abandon supernatant, and every hole adds DMSO 150 μ l dissolving Formazan particle, and vibration detects (reference wavelength 450nm, detection wavelength 570nm) with microplate reader, calculates the inhibiting rate of medicine cell growth.With the drug level logarithmic value inhibiting rate is done linear regression, get straight-line equation, therefrom obtain the half-inhibition concentration (IC of medicine cancer cells 50).
Reagent source:
MTT: bromination tetrazole indigo plant (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company; RPMI1640 substratum: GIBCO company product; Pancreatin (Trypsin): GIBCO company product; DMSO (dimethyl sulfoxide (DMSO)): the Beijing Chemical Plant produces; Calf serum: military region animal doctor's centre of prevention and cure provides.
Figure A20051004153100121
General formula (I)
Numbering General formula (I) compound IC 50(μM)
R 1 R 2 R 5 R 6 R 7 X KB A2780 Bel7402
1 Et H H F Piperazinyl-1- NH
2 Et H H F Piperazinyl-1- O 1.80 2.35 2.60
3 Et H H F Piperazinyl-1- S 0.42 0.43 0.39
4 Et 6’-Cl H F Piperazinyl-1- NH 1.87 1.13 3.91
5 Et 6’-NO 2 H F Piperazinyl-1- NH 4.30 2.35 2.06
6 Et 6’-NO 2 H F Piperazinyl-1- O 0.35 0.57
7 Et 6’-NO 2 H F Piperazinyl-1- S 1.03 0.71 0.93
8 Et 6’-NH 2 H F Piperazinyl-1- NH 9.63 17.73 39.03
9 Et 6’-NH 2 H F Piperazinyl-1- S 3.64 2.93 1.75
10 Et 6’-NO 2 H F 4-acetyl-1-piperazinyl NH 1.16 9.83 2.27
11 Et H H F 4-acetyl-1-piperazinyl O 28.63 ＞50 28.8
12 Et H H F 4-acetyl-1-piperazinyl S ＞50 ＞50 ＞50
13 The 2,4 difluorobenzene base H H F The 3-amino-pyrroles is stung base NH 0.18 ＞1
14 The 2,4 difluorobenzene base H H F The 3-amino-pyrroles is stung base O 0.19 ＞1
15 The 2,4 difluorobenzene base H H F The 3-amino-pyrroles is stung base S 0.18 0.18
Above-mentioned experimental data shows: The compounds of this invention is that (A2780) and human liver cancer cell 7402 are that (Bel7402) has strong cytotoxicity to human oral epidermoid carcinoma cell (KB), Proliferation of Human Ovarian Cell 2780.Wherein, compound 4 and 14 cytotoxic activity are suitable with the positive control drug 10-hydroxycamptothecine.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely,, can mix the preparation antitumor drug so The compounds of this invention has stronger anti-tumor activity with pharmaceutical carrier.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Agents useful for same is commercially available among the following embodiment.Naphthyridines ketone-3-formic acid the market of replacement involved in the present invention is on sale.The naphthyridines ketone of the replacement that the present invention relates to-3-formic acid (A) and O-Phenylene Diamine, Ortho-Aminophenol or the o-amino thiophenol (B) that replace or do not have replacement, condensation reaction in polyphosphoric acid (being called for short PPA), also be conventional condensation reaction, referring to J Org Chem1997,62:3552.
Embodiment 1:1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (1)
Enoxacin (3.19 grams, 0.01mol), mix porphyrize in O-Phenylene Diamine (the 1.08 gram 0.01mol) mortar, be added in the reaction flask, add 40 milliliters of polyphosphoric acid, decompression extracts the interior air of reaction flask and produces to there being bubble, feed nitrogen, stir and slowly be warming up to 140 ℃ and be incubated reaction solution and be homogeneous phase, be warmed up to 180 ℃ of reactions again after 4 hours, cool to about 100 ℃, reaction solution is stirred in the 250 gram trash ices of impouring down, leave standstill cooling, adjust pH is 9, suction filtration, dry crude product, the DMF recrystallization is the developping agent column chromatography with methyl alcohol-triethylamine again, get off-white color crystallization 0.90 gram, use recrystallizing methanol.Column chromatography gets yellow solid, yield 22.9%, mp225 ℃.
IR(cm-1)：3488，3058，2979，1634，1474，1445，1257，1139.793，738，567
1HNMR(δ，ppm，DMSO-d6)：
1.42(t，3H，-CH3)，2.98(m，4H，-CH2-*2)，3.90(m，4H，-CH2-*2)，4.51(q，2H，-CH2-)，7.14(m，2H，5`-H and 6`-H)，8.13(d，2H，4`-H and 7`-H)，9.17(s，1H，2-H)，12.70(b，1H，1-H)
Formula：C21H21N60F MW：392.44
Anal(C％，H％，N％，)Calc：64.27，5.39，21.41 Found：64.70，5.55，20.03
MS(EI，m/s)：392(M+base peak)，350
Embodiment 2:1-ethyl-3-(2-benzoxazolyl)-6-fluorine 1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (2)
With enoxacin and Ortho-Aminophenol is raw material, and the preparation method uses the DMF recrystallization with embodiment 1.Column chromatography gets faint yellow solid, yield 28.9%, mp233-5 ℃
IR(cm-1)：3412，3289，2981，1637，1473，1445，1265，792
1HNMR(δ，ppm，DMSO-d6)：
1.40(t，3H，-CH3)，2.85(m，4H，-CH2-*2)，3.67(d，4H，-CH2-*2)，4.41(q，2H，-CH2-)，7.37(m，2H，5`-H and 6`-H)，7.71(m，2H，4`-H and 7`-H)，7.98(d，1H，5-H)，8.93(s，1H，2-H)
Formula：C21H20N502F MW：393.42
Anal(C％，H％，N％，)Calc：64.11，5.12，17.80 Found：63.76，5.34，17.97
MS(EI，m/s)：393(M+)，351(base peak)
Embodiment 3:
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines [1-Ethyl-3-(benzothiazol-2-yl)-6-fluro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine] (IVf)
With enoxacin and o-amino thiophenol is raw material, and the preparation method uses recrystallizing methanol with embodiment 1.Column chromatography gets yellow solid, and mp257-9 ℃, yield 26.6%.
IR(cm-1)：3419，1627，1474，1446，1372，1276，792
1HNMR(δ，ppm，DMSO-d6)：
1.44(t，3H，-CH3)，2.87(m，4H，-CH2-*2)，3.71(m，4H，-CH2-*2)，4.53(q，2H，-CH2-)，7.37(t，1H，5`-H)，7.50(t，1H，6`-H)，7.96(d，1H，7`-H)，8.07(m，2H，5-H and 4`-H)，9.24(s，1H，2-H)
Formula：C21H20N50SF.H20 MW：427.49
Anal(C％，H％，N％，)Calc：59.00，5.15，16.38 Found：58.08，4.77，16.26
MS(EI，m/s)：409(M+)，367(base peak)。
Embodiment 4
1-ethyl-3-[2-(6-chloro benzimidazole base) 1-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (I21)
The preparation method is with embodiment 1, enoxacin (8g, 0.025mol), 4-chloro-O-Phenylene Diamine (2.7g, 0.025mol) and PPA (90ml), temperature of reaction is 190 ℃, column chromatography, tawny solid 1.7g, yield 18.1%, mp261-4 ℃.IR(cm-1)：3408，3067，2982，2867，2462，1632，1565，1525，1477，1446，1275，1256，1141，1055，921，794；HR-ESIMS(M+1)：Found 427.1444 C21H21N60FClRequires 427.1444；1HNMR(δ，ppm，DMSO-d6)：1.41(t，3H，CH3)，2.97(m，4H，CH2*2)，3.78(m，4H，CH2*2)，4.47(q，2H，CH2)，7.16(d，1H，4′-H)，7.61(m，2H，5′、7′-H)，8.03(d，1H，5-H)，9.11(s，1H，2-H)，12.79(br，NH)。
Embodiment 5
1-ethyl-3-[2-(6-nitrobenzimidazole base)]-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (according to promise nitre miaow) is (I24)
(0.8g 0.0025mol) is dissolved in an amount of vitriol oil fully, and cryosel is bathed and is chilled to about 0 ℃, and (0.26ml, 0.0037mol), interior temperature is no more than 5 ℃ of stirrings slowly to drip concentrated nitric acid with embodiment 1 gained compound.Add the back and continue to stir, be warming up to after the room temperature restir naturally 1 hour, use 35-40 ℃ of heating in water bath 2 hours then.In a large amount of trash ices of impouring under the reaction solution stirring, be neutralized to pH8 with sodium hydroxide, separate out a large amount of yellow solids, suction filtration, washing, drying.Column chromatography, (0.8g 0.0025mol) is dissolved in an amount of vitriol oil gained promise flumizole fully, and cryosel is bathed and is chilled to about 0 ℃, and (0.26ml, 0.0037mol), interior temperature is no more than 5 ℃ of stirrings slowly to drip concentrated nitric acid.Add the back and continue to stir, be warming up to after the room temperature restir naturally 1 hour, use 35-40 ℃ of heating in water bath 2 hours then.In a large amount of trash ices of impouring under the reaction solution stirring, be neutralized to pH8 with sodium hydroxide, separate out a large amount of yellow solids, suction filtration, washing, drying.Column chromatography, column chromatography must be yellow solid, mp230-33 ℃, yield 24%.
IR(cm-1)：3401，3307，2979，1633，1529，1477，1446，1310，1139，795；1HNMR(δ，ppm，DMSO-d6)：1.42(t，3H，-CH3)，3.07(m，4H，-CH2-*2)，3.82(m，4H，-CH2-*2)，4.52(q，2H，-CH2-)，7.80(m，1H，6`-H)，8.10(m，2H，7`-H and 5-H)，8.48(m，1H，4`-H)9.24(s，1H，2-H)；
Anal(C％，H％，N％，)Calc：57.66，4.61，22.41 Found：58.01，4.78，22.32；MS(EI，m/s)：437(M+ base peak)，395；
Formula：C21H20N703F
Embodiment 6
1-ethyl-3-[2-(6-Xiao base benzoxazolyl) 1-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (I31)
Embodiment 2 gained compounds are raw material, and other are operated with embodiment 5.Get yellow solid 0.3g yellow solid, yield 17%, mp258 ℃ (dec.) behind the column chromatography.
IR(cm -1)：3411，3099，3059，2983，2934，1632，1606，1584，1540，1477，1446，1383，1341，1271，1233，1163，1128，1091，1054，1003，828，794，735；
HR-ESIMS(M+1)：Found 439.1538 C 21H 20FN 6O 4 Requires 439.1524；
1HNMR(δ，ppm，DMSO-d6)：1.39(t，3H，CH 3)，3.00(m，4H，CH 2*2)，3.75(m，4H，CH 2*2)，4.42(q，2H，CH 2)，7.83(d，1H，5-H)，7.92(d，1H，4’-H)，8.23(dd，1H，5’-H)，8.49(d，1H，7’-H)，8.98(s，1H，2-H)；
Embodiment 7
1-ethyl-3-[2-(6-nitrobenzene thiazole base)]-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines [1-Ethyl-3-(6-nitrobenzothiazol-2-yl)-6-fluro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-1,8-naphthyridine] (I 40)
Embodiment 2 gained compounds are raw material, and other are operated with embodiment 5.Get yellow solid 0.51g, yield 10.2%, mp298 ℃ (dec.) behind the column chromatography.
IR(cm -1)：3413，3262，3057，2931，2712，1626，1574，1508，1477，1442，1371，1331，1276，1263，1123，792；
HR-ESIMS(M+1)：Found 455.1312 C 21H 20N 6O 3FS Requires 455.1296；
1HNMR(δ，ppm，DMSO-d6)：1.46(t，3H，CH 3)，3.30(m，1H，CH 2*2)，3.96(m，4H，CH 2*2)，4.57(q，2H，CH2)，8.04(d，1H，5-H)，8.16(d，1H，4′-H)，8.30(dd，1H，5′-H)，9.14(d，1H，7′-H)，9.35(s，1H，2-H).
Embodiment 8
1-ethyl-3-[2-(the amino benzimidazolyl-of 6-)]-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines [1-Ethyl-3-(6-aminobenzimidazol-2-yl)-6-fluro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-1,8-naphthyridine] (I 42)
(1.2g 0.0027mol) is suspended in the 1N hydrochloric acid (15ml), adds an amount of Pd-C, and normal pressure hydrogenation is to no longer inhaling hydrogen with embodiment 5 gained compounds.Filter, filtrate is neutralized to pH9 with sodium hydroxide, separates out a large amount of yellow-green colour solids, filters washing, drying.Column chromatography gets yellow solid 0.45g, yield 40.3%, mp291 ℃ (dec.).
IR(cm -1)：3414，3330，3222，3039，2965，2934，2722，1631，1570，1555，1473，1444，1273，1135，792；
HR-ESIMS(M+1)：Found 408.1938 C 21H 23N 7OF Requires 408.1943；
1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，CH 3)，3.33(m，4H，CH 2*2)，3.98(m，4H，CH 2*2)，4.52(q，2H，CH 2)，6.65(dd，1H，5′-H)，6.87(1H，7′-H)，7.36(d，1H，4′-H)，8.17(d，1H，5-H)，9.24(s，1H，2-H).
Embodiment 9
1-ethyl-3-[2-(6-aminobenzothiazole base)]-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridines (I 50)
In reaction flask, add embodiment 7 gained compounds (0.4g, 0.00104mol), 1N hydrochloric acid (5ml), stir and be heated to 95 ℃ of branches and slowly add the iron powder (0.25g that handled with dilute hydrochloric acid several times, 0.00446), add post-heating to boiling and being incubated 2 hours, till no nitro thing.Filtered while hot, filtrate is neutralized to pH8-9 with sodium hydroxide, separates out solid, filters washing, vacuum-drying, column chromatography, moral 0.2g yellow solid, yield 53.5%, mp266 ℃ (dec.).
IR(cm -1)：3428，3326，3214，3044，2963，2931，2710，2464，1723，1625，1567，1473，1443，1371，1271，1197，1012，790；
HR-ESIMS(M+1)：Found 425.1525 C 21H 22N 6OFS Requires 425.1554；
Ultimate analysis: Found C 59.51% H 5.43% N 20.27%requires C 59.40% H 5.08%N19.98%; IR (cm-1);
1HNMR(δ，ppm，DMSO-d6)：1.41(t，3H，CH 3)，2.98(m，4H，CH 2*2)，3.75(m，4H，CH 2*2)，4.50(q，2H，CH 2)，5.32(br)，6.78(dd，1H，5′-H)，7.09(d，1H，7′-H)，7.62(d，1H，4′-H)，8.07(d，1H，5-H)，9.08(s，1H，2-H).
Embodiment 10
1-ethyl-3-[2-(6-nitrobenzimidazole base)]-6-fluoro-1; 4-dihydro-4-oxygen-7-(4-ethanoyl-1-piperazinyl)-1; 8-naphthyridines [1-Ethyl-3-(6-nitrobenzimidazol-2-yl)-6-flro-1; 4-dihydro-4-oxo-7-(4-acetyl piperazin-1-yl)-1,8-naphthridine] (II 8)
(0.18g 0.46mmol) is suspended among the DMSO (8ml), adds aceticanhydride (0.06ml then with gained compound among the embodiment 1,0.64mmol), be heated to 120 ℃ of insulations 2 hours, concentrate, add suitable quantity of water, filter, drying, column chromatography gets light yellow product 0.2g, yield 60.8%, mp289-92 ℃.
IR(cm -1)：3416，3068，2940，1632，1566，1529，1477，1443，1339，1310，1249，1187，1146，1060，995，831，795，739，589；
HR-ESIMS(M+1)：Found 480.1777 C 23H 23N 7O 4F Requires 480.1790；
1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，CH 3)，2.06(s，3H，COCH 3)，3.52(m，4H，CH 2*2)，3.78(m，4H，CH 2*2)，4.51(q，2H，CH 2)，7.66、7.70(d，1H，4′-H)，8.09(d，1H，5-H)，8.12(dd，1H，5′-H)，8.37、8.59(d，1H，7′-H)，9.18、9.22(s，1H，2-H)，13.20(s，1H，NH).
Embodiment 11
1-ethyl-3-(2-benzoxazolyl)]-6-fluoro-1; 4-dihydro-4-oxygen-7-(4-ethanoyl-1-piperazinyl)-1; 8-naphthyridines [1-Ethyl-3-(benzoxazol-2-yl)-6-fluro-1; 4-dihydro-4-oxo-7-(4-acetylpiperazin-1-yl)-1,8-naphthyridine] (II 3)
(0.18g 0.46mmol) is suspended among the DMSO (8ml), and (0.06ml 0.64mmol), is heated to 120 ℃ of insulations 2 hours to add aceticanhydride then with Yi Nuo oxazole, concentrate, add suitable quantity of water, filter drying, column chromatography gets faint yellow solid 0.085g, yield 42.7%, mp234-6 ℃.
IR(cm -1)：3056，2981，2929，1650，1626，1583，1538，1474，1440，1372，1357，1246，1158，1079，1031，995，909，834，791，742，641；
HR-ESIMS(M+1)：Found 435.1824 C 24H 24N 4O 3F Requires 435.1827；
1HNMR(δ，ppm，DMSO-d6)：1.42(t，3H，CH 3)，2.06(s，3H，CH 3)，3.65(m，4H，CH 2*2)，3.88(m，4H，CH 2*2)，4.44(q，2H，CH 2)，7.38(m，2H，5′、6′-H)，7.73(m，2H，4′、7′-H)，8.05(d，1H，5-H)，8.97(s，1H，2-H).
Embodiment 12
1-ethyl-3-(2-[4-morpholinodithio base)]-6-fluoro-1; 4-dihydro-4-oxygen-7-(4-ethanoyl-1-piperazinyl)-1; 8-naphthyridines [1-Ethyl-3-(benzothiazol-2-yl)-6-fluro-1; 4-dihydro-4-oxo-7-(4-acetylpiperazin-1-yl)-1,8-naphthyridine] (II 6)
(0.35g, 0.86mmol), (0.12ml, 1.28mmol), other operate with embodiment 11 aceticanhydride according to the promise thiazole.
Column chromatography gets light yellow product 0.21g, yield 54.4%, mp223-5 ℃.
IR(cm -1)：3100，3030，2981，2933，2870，1648，1628，1566，1492，1472，1435，1372，1252，1199，997，983，790，767，732，639，557；
HR-ESIMS(M+1)：Found 452.1532 C 23H 23N 5O 2FS Requires 452.1551； 1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，CH 3)，2.06(s，3H，CH 3)，3.65(m，4H，CH 2*2)，3.78(m，4H，CH 2*2)，4.53(q，2H，CH 2)，7.38(m，1H，6′-H)，7.50(m，1H，5′-H)，7.95(d，1H，7′-H)，8.08(s，1H，5-H)，8.11(d，1H，4′-H)，9.23(s，1H，2-H).
Embodiment 13
1-(2,4 difluorophenyl)-3-(2-benzimidazolyl-)-6-fluoro-1,4-dihydro-4-oxygen-7-(3-amino-pyrroles pyridine base)-1,8-naphthyridines (T5)
Tosufloxacin (10g, 0.025mol), O-Phenylene Diamine (2.8g, 0.025mol) and polyphosphoric acid (100ml) stirred 4 hours down in 190 ℃. after being cooled to 80 ℃. and be poured in the frozen water, sodium hydroxide is neutralized to neutrality. filter, get crude product 9.8g, vacuum-drying, column chromatography gets the 4.9g yellow solid, yield 44%, mp185-188 ℃.
IR：3288.23，3065.34，1641.57，1558.1，1530.38，1507.71，1456.81，1321.87，1270.10，1141.67，972.99，792.58cm -1
1HNMR，δ：1.65-1.91(m，2H，-CH 2-)，3.42-3.46(m，7H，N-CH 2*2 andCH-NH 2)，7.13(s，2H，4’-H and 7’-H)，7.34(s，1H，2”-H)，7.57(s，3H，5’-H，6’-Hand 3”-H)，7.86-7.97(m，2H，5-H and 5”-H)，8.86(s，1H，2-H)，12.35(s，1H，-NH-)ppm.
Formula：C 25H 19F 3N 6O·3H 2O MW：530.5
Anal(C％，H％，N％)Calc：56.60，4.71，15.83 Found：56.88，4.53，15.09
MS[ESI(+)70V，M/Z]：477.1
Embodiment 14
1-(2,4 difluorophenyl)-3-(2-benzoxazolyl)-6-fluoro-1,4-dihydro-4-oxygen-7-(3-amino-pyrroles pyridine base)-1,8-naphthyridines (L8)
With tosufloxacin and Ortho-Aminophenol is raw material, and the preparation method is with embodiment 13.Column chromatography gets faint yellow solid 6.2 grams, yield 52%, mp.245-247 ℃
IR：3433.14，3069.45，1644.16，1613.69，1543.90，1511.38，1452.67，1381.33，1359.03，1245.11，1145.71，1098.34，791.17cm -1
1HNMR，δ1.67-1.96(m，2H，-CH 2-)，3.44-3.54(m，7H，N-CH 2*2 and-CH-NH 2)，7.36(m，3H，4’-H 7’-H and 2”-H)，7.56(d，1H，3”-H，J＝8.2HZ)，7.71(m，2H，5’-H and 6’-H)，7.84-7.96(m，2H，5-H and 5”-H)，8.71(d，1H，2-H，J＝4.1HZ)ppm
Formula：C 25H 18F 3N 5O 2·H 2O MW：495.5
Anal(C％，H％，N％)Calc：60.54，4.04，14.12 Found：60.32，4.05，13.67
MS[ESI(+)70V，m/z]：478.1
Embodiment 15:
1-(2,4 difluorophenyl)-3-(2-[4-morpholinodithio base)-6-fluoro-1,4-dihydro-4-oxygen-7-(3-amino-pyrroles pyridine base)-1,8-naphthyridines (B1)
With tosufloxacin and Ortho-Aminophenol is raw material, and the preparation method is with embodiment 13.Crude product is with the DMF recrystallization, and column chromatography gets faint yellow solid 6.7 grams, yield 54%, mp.275-277 ℃
IR：3444.44，3059.26，1632.59，1601.39，1561.99，1460.40，1341.02，1211.89，1147.69，1094.89，945.32，770.47cm -1
1HNMR，δ：2.03-2.26(m，2H，-CH 2-)，3.36-3.83(m，7H，N-CH 2*2 and-CH-NH 2)，7.38(m，2H，4’-H 7’-H)，7.49(m，1H，2”-H)，7.59(s，1H，3”-H)，7.90(m，2H，5’-H and 6’-H)，8.091(m，2H，5-H and 5”-H)，9.02(s，1H，2-H)ppm
Formula：C 25H 18F 3N 5OS·2.5H 2O MW：538g/mol
Anal(C％，H％，N％)Calc：55.81，4.27，13.01 Found：56.07，3.68，12.61
MS[ESI(+)70V，m/z]：494.0
Embodiment 16
Get embodiment 1 gained compound 0.5g, add the conventional auxiliary material of tablet, make tablet by the tablet common process.
Embodiment 17
Get embodiment 1 gained compound 0.5g, add the conventional auxiliary material of granule, make granule by the granule common process.

Claims (11)

1, the naphthyridines ketone compounds of following general formula (I) expression
Figure A2005100415310002C1
Wherein, R 1Represent alkyl H, replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement or aryl replacement or that do not have replacement;
R 2Represent H, halogen, nitro or amino;
R 5Represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement or aryl replacement or that do not have replacement;
R 6And R 7Identical or different, represent H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, the aromatic heterocyclic that replaces or do not have replacement, nitro, amino independently of one another;
X represents O, S or NH.
2, naphthyridines ketone compounds according to claim 1 is characterized in that R 1, R 5, R 6, R 7Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is a phenyl, or by F, Cl, Br, I, C 1-10Alkyl, C 1-10Alkoxyl group, nitro or amino mono-substituted phenyl;
R 1, R 5, R 6, R 7The alkyl of representative or the alkyl in the aryl refer to have the alkyl of straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom;
R 5, R 6, R 7Alkyl in alkoxyl group, aralkoxy or the heterocycle alkoxyl group of representative refers to have the alkyl of the straight or branched of 1-10 carbon atom;
R 1, R 5, R 6, R 7Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one or more heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R 1, R 5Middle alkyl, the aryl of replacement, the heterocyclic radical of replacement or the aryl of replacement that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group or amido;
R 6, R 7Aromatic heterocyclic replacement or that do not have replacement of representative is by F, Cl, Br, I, C 1～10Alkyl, C 1-10Acyl group, C 1～10Alkoxyl group, C 1～10Alkylamino, nitro or the amino ternary that contains 1～4 nitrogen-atoms～eight yuan heterocyclic aromatic heterocyclic that replace or that do not have replacement.
3, naphthyridines ketone compounds according to claim 1 is characterized in that R 1, R 5, R 6, R 7The aryl of representative is the phenyl ring base, perhaps is F, Cl, Br, I, C 1～10Alkyl, C 1～10Alkoxyl group, nitro or the amino phenyl that replaces; Aromatic heterocyclic is to contain 1～3 heteroatomic fragrant heterocyclic radical, perhaps is F, Cl, Br, I, C 1～10Alkyl, C 1～10Alkoxyl group, nitro or amino replace contain 1～3 heteroatomic aromaticity heterocyclic radical.
4, naphthyridines ketone compounds according to claim 1 is characterized in that the amino NH that is 2, R 8NH, R 9R 10N; R wherein 8, R 9Or R 10Alkyl or the cycloalkyl of 3-10 carbon atom, perhaps R for straight or branched with 1-10 carbon atom 9R 10Connect into ring-type.
5, naphthyridines ketone compounds according to claim 1 is characterized in that R 1, R 5, R 6, R 7Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is C 1-6Alkyl or C 1～6The phenyl that alkoxyl group replaces;
R 1, R 5, R 6, R 7The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-6 carbon atom or the cycloalkyl of 3-6 carbon atom;
R 5, R 6, R 7Alkyl in alkoxyl group, aralkoxy or the heterocycle alkoxyl group of representative refers to have the alkyl of the straight or branched of 1-6 carbon atom;
R 1, R 5, R 6, R 7Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one, two or three heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R 6, R 7Aromatic heterocyclic replacement or that do not have replacement of representative is C 1～6Alkyl, C 1～6Acyl group, C 1～6Alkoxyl group, C 1～6The aromatic heterocyclic of alkylamino, nitro, the amino ternary～hexa-member heterocycle that contains 1～3 nitrogen-atoms that replace or that do not have replacement.
6,, it is characterized in that alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl or decyl according to the arbitrary described naphthyridines ketone compounds of claim 1-5; Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl or ring decyl; Halogen is F, Cl, Br or I.
7, naphthyridines ketone compounds according to claim 6 is characterized in that: wherein alkyl is the alkyl with straight or branched of 1-4 carbon atom; Cycloalkyl is the cycloalkyl with 3～6 carbon atoms; Heterocyclic radical is saturated heterocyclic or the aromatic heterocycle that contains 3～6 atoms; Halogen is F and Cl atom; R 6, R 7The ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of the replacement of representative is not replacement and the mono-substituted five yuan～hexa-member heterocycle that contains 1～2 nitrogen-atoms.
8, naphthyridines ketone compounds according to claim 7 is characterized in that:
R 1Expression H, C 1-C 4Side chain or the C that replaces of the alkyl of straight chain or cyclic alkane, halogen 1-C 4Branched-chain or straight-chain alkyl;
R 2Representative is replaced by halogen, nitro, amino or H respectively or simultaneously on 5 and/or 6 of aromatic ring;
R 5And R 6Identical or different, H, amino or halogen are shown in representative independently of one another;
R 7Expression H, halogen, hydroxyl, C 1-C 4Branched-chain or straight-chain alkyl, amino or C 1-C 4The amino that replaces of branched-chain or straight-chain alkyl, C 1-C 4Branched-chain or straight-chain alkyl replace or do not have a replacement contain five yuan of 1-2 nitrogen-atoms or hexa-member heterocycle, C 1-C 4Acyl substituted or do not have five yuan or the hexa-member heterocycle containing 1-2 nitrogen-atoms of replacement;
X represents O, S, NH.
9, naphthyridines ketone compounds according to claim 8 is characterized in that:
R 1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, fluoro ethyl;
R 2Representative is replaced by chlorine, nitro, amino or H on 5 and/or 6 of aromatic rings at the same time or separately;
R 5And R 6Identical or different, H, amino or fluorine are shown in representative independently of one another;
R 7Represent H, Cl, hydroxyl, methyl, second third; propyl group, sec.-propyl, amino, dimethylamino; diethylamino, piperazinyl is gone up the piperazinyl that is replaced by methyl, ethyl or ethanoyl for 3,4 or 5, perhaps 3,5 piperazinyls that replaced by methyl, ethyl and/or ethanoyl.
10, the preparation method of naphthyridines ketone compounds as claimed in claim 1 is characterized in that:
R in general formula (I) 2When=H or F, Cl, Br, I, its preparation method can be represented by reaction formula 1:
Figure A2005100415310004C1
General formula (A) general formula (I)
Reaction formula 1
R wherein 1, R 5, R 6, R 7, in X and the claim 1 definition identical;
Promptly get the naphthyridines ketone-3-formic acid of the various replacements of general molecular formula (A), with the O-Phenylene Diamine that replaces or do not have replacement, replace or do not have the Ortho-Aminophenol or the replacement of replacement or do not have the o-amino thiophenol of replacement, condensation in polyphosphoric acid, condensation reaction products are general formula (I) target compound;
R in general formula (I) 2Be NO 2Or NH 2The time, its preparation method can be represented by reaction formula 2:
Figure A2005100415310005C1
Reaction formula 2
R wherein 1, R 5, R 6, R 7, in X and the claim 1 definition identical;
Promptly with R in the general formula (I) 2The compound of=H is a raw material, directly carry out nitrated, R in the general formula (I) 2=NO 2Compound; With nitroreduction, get R in the general formula (I) 2=NH 2Compound.
11, the application of arbitrary described naphthyridines ketone compounds in the preparation antitumor drug in the claim 1～9.
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JP2015522598A (en) * 2012-07-17 2015-08-06 サノフイ Use of a VEGFR-3 inhibitor to treat hepatocellular carcinoma
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