CN102010366B - 2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound as well as preparation and application thereof - Google Patents

2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound as well as preparation and application thereof Download PDF

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CN102010366B
CN102010366B CN 201010561710 CN201010561710A CN102010366B CN 102010366 B CN102010366 B CN 102010366B CN 201010561710 CN201010561710 CN 201010561710 CN 201010561710 A CN201010561710 A CN 201010561710A CN 102010366 B CN102010366 B CN 102010366B
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fluorine
fluorobenzene
fluorobenzene salicylamide
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何小钢
何晓铁
钟光祥
胡红丹
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CHANGSHAN HONGYUN CHEMICAL Co Ltd
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Abstract

The invention discloses a 2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound, and discloses an application of the 2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound in preparing anti-tumor medicaments, in particular to an application of the 2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound in preparing anti-endometrial cancer or anti-lung cancer medicaments. The invention has the main beneficial effects that: (1) the method for preparing the 2,6-dichloro-5-fluoronicotinoyl fluorobenzene salicylamide compound is provided; (2) the novel anti-tumor medicament with remarkable anti-tumor activity is provided, a research foundation is laid for novel medicament screening, and the compound has great application prospect; and (3) the preparation process is simple, and is advantageous to industrial production.

Description

A kind of 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compound and preparation and application
(1) technical field
The present invention relates to the novel substance that a class has anti-tumor activity: 2, the preparation method of 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds (I) and this compounds, and in preparation antitumor drug, the especially application in anti-carcinoma of endometrium or anti-lung-cancer medicament.
Figure BDA0000034555130000011
(2) background technology
Malignant tumour is one of common disease of serious harm human health.According to the latest news, the whole world has more than 4,000 ten thousand people to suffer from malignant tumour, annual newly-increased patient more than 900 ten thousand, dead more than 700 ten thousand wherein, the annual Incidence number of China about 1,600,000, dead about 1,300,000.Malignant tumour occurs and the dead trend that is on the rise in addition at present, and some area has become human mortality's first cause.Therefore, the novel antitumor drug of exploitation has great importance.
Fluorobenzene salicylamide compound is a kind of compound of contain fluorine atoms.Because the fluorine atom radius is little, have again maximum electronegativity, formed C-F bond energy can be much bigger than c h bond, increased the stability of organic fluorocompound; And because the volume of fluorine atom is little, thereby often think the non-classical isostere of H atom, easily produce antagonistic action, that is: do not disturb interaction between Drugs Containing Fluorine and corresponding cell receptor, can replace the eubolism medicine at molecular level, mix biomacromolecule to duplicity, it is synthetic to cause causing death.When introducing fluorine atom in the drug molecule, its electrical effect and mimic effect have not only changed the distribution of intramolecule electron density, and can also improve the fat-soluble and perviousness of compound, solvability on microbial film is enhanced, promote it to absorb in vivo and transmission speed, physiological action is changed.So Drugs Containing Fluorine has the characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong.
The research and development of Drugs Containing Fluorine mainly concentrate in the research and development of fluorine-containing aromatic, heterogeneous ring compound, have good anti-inflammatory action such as diflunisal, be widely used in clinical in.By diflunisal is carried out structural modification, preparation has the fluorine-containing new drug of anti-tumor activity, and tool has very great significance.
(3) summary of the invention
The object of the invention provide a class new have 2 of an anti-tumor activity, 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds, with the preparation method of this compounds, and in preparation antitumor drug, the especially application in anti-carcinoma of endometrium or anti-lung-cancer medicament.
The technical solution used in the present invention is:
A kind of 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds, structure is suc as formula shown in (I):
Figure BDA0000034555130000021
In the formula (I), R 1Be H, methyl or ethyl; R 2For methyl, ethyl, cyclohexyl, phenyl or contain 1～3 substituent substituted-phenyl, described substituting group is methyl, ethyl, fluorine, chlorine, nitro or methoxyl group; Perhaps R 1, R 2Connect into ring, with same R 1, R 2The N that links to each other consists of piperazinyl or morpholine base.
Described substituted-phenyl is preferably: o-tolyl, a tolyl, p-methylphenyl, adjacent ethylbenzene, an ethylbenzene, to ethylbenzene, 2,5-3,5-dimethylphenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, 2,4-dichlorophenyl, 2,5-dichlorophenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-nitrophenyl, 4-trifluoromethyl, 4-nitro-3-trifluoromethyl, o-methoxyphenyl, m-methoxyphenyl or p-methoxyphenyl.
Preferred, described R 1Be H or C 2H 5R 2For ethyl, cyclohexyl, phenyl or contain 1～2 substituent substituted-phenyl;
Described substituted-phenyl is preferably o-tolyl, a tolyl, p-methylphenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, to fluorophenyl, 2,4 difluorobenzene base, 4-nitro-3-trifluoromethyl, p-methoxyphenyl.
Further, preferred described R 1, R 2Connect into ring, with same R 1, R 2The N that links to each other consists of 4-methylpiperazine or 4-ethyl piperazidine.
Described 2, it is one of following that 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds most preferably are:
Figure BDA0000034555130000031
Figure BDA0000034555130000041
The present invention also provides described 2, the preparation method of 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds, described method is: suc as formula 2 shown in (II), 6-two chloro-5-fluorine nicotinic acids obtain 2 shown in the formula (III) through chloride, 6-two chloro-5-fluorine nicotinoyl chlorines, shown in the formula (III) 2,6-two chloro-5-fluorine nicotinoyl chlorines and diflunisal are carried out esterification and are obtained 2 shown in the formula (IV), 6-two chloro-5-fluorine nicotinoyl difunisals; Shown in the formula (IV) 2,6-two chloro-5-fluorine nicotinoyl difunisals obtain 2 shown in the formula (V) through chloride, 6-two chloro-5-fluorine nicotinoyl fluorobenzene bigcatkin willow acyl chlorides, 2 shown in the formula (V), 6-two chloro-5-fluorine nicotinoyl fluorobenzene bigcatkin willow acyl chlorides and organic amine HNR 1R 2Condensation obtains 2,6-, two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds;
Figure BDA0000034555130000051
Described organic amine HNR 1R 2In, R 1Be H, methyl or ethyl; R 2For methyl, ethyl, cyclohexyl, phenyl or contain 1～3 substituent substituted-phenyl, described substituting group is methyl, ethyl, fluorine, chlorine, nitro or methoxyl group; Perhaps R 1, R 2Connect into ring, with same R 1, R 2The N that links to each other consists of piperazinyl or morpholine base.
More specifically, said method comprising the steps of:
(1) in toluene solvant, in the presence of catalyst A, 2,6-, two chloro-5-fluorine nicotinic acids is carried out acyl chloride reaction with chloride reagent A (preferred 80 ℃) under 60～100 ℃ of temperature; Steaming desolventized after reaction finished, and obtained 2,6-, two chloro-5-fluorine nicotinoyl chlorines, and with the organic solvent A dissolving, it is stand-by to obtain solution of acid chloride A;
Described catalyst A is: DMF, pyridine, DMA;
Described chloride reagent A is: sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride;
Described organic solvent A is: tetrahydrofuran (THF), butanone, toluene;
(2) diflunisal is dissolved with organic solvent B, add organic amine, then add the solution of acid chloride A that step (1) makes, carry out esterification under the room temperature, reaction finishes afterreaction liquid separating treatment and obtains 2,6-, two chloro-5-fluorine nicotinoyl difunisals;
Described organic amine is: triethylamine, pyridine;
Described organic solvent B is: tetrahydrofuran (THF), butanone, toluene.
(3) in toluene solvant, in the presence of catalyst B, with step (2) make 2,6-two chloro-5-fluorine nicotinoyl difunisals carry out acyl chloride reaction with chloride reagent B (preferred 80 ℃) under 60～100 ℃ of temperature; Steaming desolventized after reaction finished, and obtained 2 shown in the formula (V), 6-two chloro-5-fluorine nicotinoyl fluorobenzene bigcatkin willow acyl chlorides, and with organic solvent C dissolving, it is stand-by to obtain solution of acid chloride B;
Described catalyst B is: DMF, pyridine, DMA;
Described chloride reagent B is: sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride;
Described organic solvent C is: tetrahydrofuran (THF), butanone, toluene;
(4) with organic amine HNR 1R 2Join among the organic solvent D, then add the solution of acid chloride B that step (3) makes, carry out condensation reaction under the room temperature, reaction finishes afterreaction liquid separating treatment and obtains 2 shown in the formula (I), 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds.
Described organic solvent D is: tetrahydrofuran (THF), butanone, toluene.
Provided by the invention 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds can be applicable to prepare antitumor drug, especially are applied to prepare anti-carcinoma of endometrium or anti-lung-cancer medicament.
More specifically, one of following 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds are for can be applicable to prepare anti-carcinoma of endometrium:
Figure BDA0000034555130000071
Figure BDA0000034555130000081
One of following 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds can be applicable to prepare anti-lung-cancer medicament:
Figure BDA0000034555130000091
Test in an embodiment shows that the present invention 2, and 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compound obviously growths of inhibition tumor cell under finite concentration can be used as the treatment that antitumor drug is applied to the tumor diseases such as carcinoma of endometrium, lung cancer.
Beneficial effect of the present invention is mainly reflected in: (1) provides a kind of 2, the preparation method of 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds; (2) provide a kind of antitumor drug new, that obvious anti-tumor activity is arranged, for new medicament screen provides Research foundation, had the major application prospect; (3) preparation flow is simple, is beneficial to industrialization production.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1: preparation 2,6-two chloro-5-fluorine nicotinoyl difunisals (IV)
With 25.2g (0.12mol) 2,6-two chloro-5-fluorine nicotinic acids (II), 80ml toluene, 17.8g (0.15mol) thionyl chloride, 0.2ml DMF join in the reaction flask, 80 ℃ of reactions 6 hours, boil off solvent and remaining thionyl chloride, obtain white solid, be: 2,6-, two chloro-5-fluorine nicotinoyl chlorines (III), need not measure; With the dissolving of 80ml tetrahydrofuran (THF), be directly used in next step reaction.
25g (0.1mol) diflunisal with the dissolving of 20ml tetrahydrofuran (THF), is added 8g (0.1mol) pyridine, stir the lower tetrahydrofuran solution that adds the acyl chlorides (III) of previous step gained, under room temperature, react and spend the night.With the acidifying of 100ml dilute hydrochloric acid, to filter, washing gets white solid, is 2,6-, two chloro-5-fluorine nicotinoyl difunisals (IV), fusing point: 193～195 ℃ (not proofreading and correct), yield: 83.3%.
1H NMR(500MHz，DMSO，δppm)：7.26(t，1H，J＝8.5Hz，3′-H)，7.45(t，1H，J＝8.5Hz，5′-H)，7.57(d，1H，J＝8.5Hz，5-H)，7.71(q，1H，J＝8.5Hz，6′-H)，7.91(d，1H，J＝8.5Hz，6-H)，8.13(s，1H，2-H)，8.74(d，1H，J＝7.5Hz，2″-H)，13.50(s，1H，-COOH).
Reference examples 1:
With the pyridine among the triethylamine replacement embodiment 1 of identical mole number, yield 32.2%, fusing point: 190～194 ℃ (proofreading and correct).
Reference examples 2:
With the tetrahydrofuran (THF) among the butanone replacement embodiment 1 of equal volume, yield 26.1%, fusing point: 191～194 ℃ (proofreading and correct).
Reference examples 3:
With the tetrahydrofuran (THF) among the toluene replacement embodiment 1 of equal volume, yield 34.8%, fusing point: 192～195 ℃ (proofreading and correct).
Embodiment 2: preparation N-phenyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-1)
Figure BDA0000034555130000111
With 4.4g (0.01mol) IV, 1.8g (0.015mol) thionyl chloride, 15ml toluene, 0.1ml DMF added in the reaction flask, 80 ℃ of lower reactions 6 hours, boil off solvent and unnecessary thionyl chloride, obtain 2,6-, two chloro-5-fluorine nicotinoyl fluorobenzene bigcatkin willow acyl chlorides (V), need not measure; With the dissolving of 30ml tetrahydrofuran (THF), obtain the solution of V, be directly used in next step reaction.
1.86g (0.02mol) aniline, 10ml tetrahydrofuran (THF) are added in the reaction flask, stir, add the tetrahydrofuran solution of the V that has prepared, reaction is spent the night.Filter, the filtrate washing boils off solvent, gets white solid.Use the butanone recrystallization, obtain N-phenyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-1), yield: 65.4%, fusing point: 178～179 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.97(t，1H，J＝8.5Hz，3′-H)，7.01(t，1H，J＝8.5Hz，5′-H)，7.16(t，1H，J＝7.5Hz，4′″-H)，7.35(t，2H，J＝8.0Hz，3′″，5′″-H)，7.40(d，1H，J＝8.5Hz，5-H)，7.45(q，1H，J＝8.5Hz，6′-H)，7.54(d，2H，J＝7.5Hz，2′″，6′″-H)，7.72(s，1H，2-H)，7.73(d，1H，J＝8.5Hz，6-H)，7.88(s，1H，-NH)，8.26(d，1H，J＝7.5Hz，4″-H)。
Reference examples 4:
With the DMF among the pyridine replacement embodiment 2 of equal volume, yield 51.4%, fusing point: 176～179 ℃ (proofreading and correct).
Reference examples 5:
With the DMF among the DMA replacement embodiment 2 of equal volume, yield 54.2%, fusing point: 175～178 ℃ (proofreading and correct).
Reference examples 6:
With the tetrahydrofuran (THF) among the toluene replacement embodiment 2 of equal volume, yield 26.7%, fusing point: 174～178 ℃ (proofreading and correct).
Reference examples 7:
With the tetrahydrofuran (THF) among the butanone replacement embodiment 2 of equal volume, yield 42.9%, fusing point: 176～179 ℃ (proofreading and correct).
Embodiment 3: preparation N-o-tolyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-2)
With the aniline among the 0.02mol Ortho Toluidine replacement embodiment 2, yield: 66.2%; Fusing point: 197～199 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：2.28(s，3H，-CH 3)，6.98(t，1H，J＝8.5Hz，3′-H)，7.02(t，1H，J＝8.5Hz，5′-H)，7.13(t，1H，J＝7.5Hz，4′″-H)，7.22(d，1H，J＝7.5Hz，3′″-H)，7.24(t，1H，J＝8.0Hz，5′″-H)，7.40(d，1H，J＝8.5Hz，5-H)，7.47(q，1H，J＝8.5Hz，6′-H)，7.53(s，1H，2-H)，7.73(d，1H，J＝8.0Hz， 6-H)，7.80(d，1H，J＝7.5Hz，6′″-H)，7.91(s，1H，-NH)，8.27(d，1H，J＝7.0Hz，4″-H)。
Embodiment 4: tolyl-2 between preparation N-, 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-3)
Figure BDA0000034555130000131
With the aniline among the 0.02mol meta-aminotoluene replacement embodiment 2,63.8%; Fusing point: 194～196 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：2.34(s，3H，-CH 3)，6.96(t，1H，J＝8.5Hz，3′-H)，6.98(d，1H，J＝8.0Hz，4′″-H)，7.01(t，1H，J＝8.5Hz，5′-H)，7.22(t，1H，J＝8.0Hz，5′″-H)，7.32(d，1H，J＝8.0Hz，6′″-H)，7.37(s，1H，2′″-H)，7.40(d，1H，J＝8.5Hz，5-H)，7.45(q，1H，J＝8.5Hz，6′-H)，7.67(s，1H，2-H)，7.71(d，1H，J＝8.5Hz，6-H)，7.86(s，1H，-NH)，8.25(d，1H，J＝7.0Hz，4″-H)。
Embodiment 5: preparation N-p-methylphenyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-4)
Figure BDA0000034555130000132
With the aniline among the 0.02mol para-totuidine replacement embodiment 2, yield: 48.6%; Fusing point: 195～196 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：2.32(s，3H，-CH 3)，6.97(t，1H，J＝8.5Hz，3′-H)，7.01(t，1H，J＝8.5Hz，5′-H)，7.14(d，2H，J＝8.5Hz，3′″，5′″-H)，7.39 (d，2H，J＝8.5Hz，2′″，6′″-H)，7.41(d，1H，J＝8.5Hz，5-H)，7.45(q，1H，J＝8.5Hz，6′-H)，7.66(s，1H，2-H)，7.71(d，1H，J＝8.0Hz，6-H)，7.87(s，1H，-NH)，8.25(d，1H，J＝7.0Hz，4″-H)。
Embodiment 6: preparation N-Chloro-O-Phenyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-5)
With the aniline among the 0.02mol Ortho-Chloro aniline replacement embodiment 2, yield 45.6%; Fusing point: 168～170 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.98(t，1H，J＝8.5Hz，3′-H)，7.02(t，1H，J＝8.5Hz，5′-H)，7.10(t，1H，J＝8.0Hz，4′″-H)，7.31(t，1H，J＝8.0Hz，5′″-H)，7.39(d，1H，J＝8.5Hz，3′″-H)，7.42(d，1H，J＝8.5Hz，5-H)，7.47(q，1H，J＝8.5Hz，6′-H)，7.76(d，1H，J＝8.5Hz，6-H)，7.99(s，1H，2-H)，8.27(d，1H，J＝7.0Hz，4″-H)，8.320(s，1H，-NH)，8.42(d，1H，J＝8.0Hz，6′″-H)。
Embodiment 7: chloro-phenyl--2 between preparation N-, 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-6)
Figure BDA0000034555130000142
With the aniline among the 0.02mol m-chloro aniline replacement embodiment 2, yield: 52.4%; Fusing point: 185～188 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.98(t，1H，J＝8.5Hz，3′-H)，7.02(t， 1H，J＝8.5Hz，5′-H)，7.13(d，1H，J＝8.5Hz，4′″-H)，7.27(t，1H，J＝8.0Hz，5′″-H)，7.37(d，1H，J＝8.0Hz，6′″-H)，7.40(d，1H，J＝8.0Hz，5-H)，7.45(q，1H，J＝8.5Hz，6′-H)，7.67(s，1H，2′″-H)，7.73(d，1H，J＝8.5Hz，6-H)，7.76(s，1H，-NH)，7.86(s，1H，2-H)，8.26(d，1H，J＝7.0Hz，4″-H)。
Embodiment 8: preparation N-rubigan-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-7)
Figure BDA0000034555130000151
With the aniline among the 0.02mol p-Chlorobenzoic acid amide replacement embodiment 2, yield: 58.2%; Fusing point: 200～202 ℃ (not proofreading and correct).
1HNMR(500MHz，DMSO，δppm)：7.28(t，1H，J＝8.5Hz，3′-H)，7.39(d，2H，J＝8.5Hz，3′″，5′″-H)，7.45(t，1H，J＝8.5Hz，5′-H)，7.62(d，1H，J＝8.5Hz，5-H)，7.69(d，2H，J＝8.0Hz，2′″，6′″-H)，7.75(q，1H，J＝8.5Hz，6′-H)，7.86(d，1H，J＝8.0Hz，6-H)，7.93(s，1H，2-H)，8.63(d，1H，J＝7.5Hz，4″-H)，10.66(s，1H，-NH)。
Embodiment 9: N-is to fluorophenyl-2 in preparation, 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-8)
Figure BDA0000034555130000152
With the aniline among the 0.02mol para-fluoroaniline replacement embodiment 2, yield: 63.6%; Fusing point: 198～201 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.97(t，1H，J＝8.5Hz，3′-H)，7.01(t，1H，J＝8.5Hz，5′-H)，7.03(t，2H，J＝8.5Hz，3′″，5′″-H)，7.39(d，1H，J＝8.5Hz，5-H)，7.44(q，1H，J＝8.5Hz，6′-H)，7.49(q，2H，J＝8.5Hz，2′″，6′″-H)，7.71(d，1H，J＝8.0Hz，6-H)，7.75(s，1H，-NH)，7.86(s，1H，2-H)，8.25(d，1H，J＝7.5Hz，4″-H)。
Embodiment 10: preparation N-(2,4 difluorobenzene base)-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-9)
Figure BDA0000034555130000161
With 0.02mol2, the 4-difluoroaniline replaces the aniline among the embodiment 2, yield: 55.3%; Fusing point: 203～206 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.88(t，1H，J＝8.5Hz，3′″-H)，6.91(t，1H，J＝8.0Hz，5′″-H)，6.98(t，1H，J＝8.5Hz，3′-H)，7.02(t，1H，J＝8.5Hz，5′-H)，7.42(d，1H，J＝8.5Hz，5-H)，7.46(q，1H，J＝8.5Hz，6′-H)，7.75(d，1H，J＝8.0Hz，6-H)，7.95(s，1H，-NH)，7.97(s，1H，2-H)，8.26(q，1H，J＝8.5Hz，6′″-H)，8.27(d，1H，J＝7.0Hz，4″-H)
Embodiment 11: preparation N-(4-p-methoxy-phenyl)-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-10)
Figure BDA0000034555130000171
With the aniline among the 0.02mol P-nethoxyaniline replacement embodiment 2, yield: 56.4%; Fusing point: 184～187 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：3.79(s，3H，-OCH 3)，6.87(d，2H，J＝8.5Hz，3′″，5′″-H)，6.96(t，1H，J＝8.5Hz，3′-H)，7.00(t，1H，J＝8.5Hz，5′-H)，7.38(d，1H，J＝8.5Hz，5-H)，7.43(d，2H，J＝8.0Hz，2′″，6′″-H)，7.44(q，1H，J＝8.5Hz，6′-H)，7.67(s，1H，-NH)，7.70(d，1H，J＝8.0Hz，6-H)，7.86(s，1H，2-H)，8.25(d，1H，J＝7.5Hz，4″-H)。
Embodiment 12: preparation N-(4-nitro-3-trifluoromethyl)-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-11)
Figure BDA0000034555130000172
With the aniline among the 0.02mol 4-nitro-3-trifluoromethylaniline replacement embodiment 2, yield 64.1%, fusing point: 167～169 ℃ (proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：6.99(t，1H，J＝8.5Hz，3′-H)，7.03(t，1H，J＝8.5Hz，5′-H)，7.44(d，1H，J＝8.5Hz，5-H)，7.46(q，1H，J＝8.5Hz，6′-H)，7.79(d，1H，J＝8.5Hz，6-H)，7.90(s，1H，2′″-H)，7.97(s，1H，2-H)，8.00(d，1H，J＝8.5Hz，6′″-H)，8.03(d，1H，J＝8.5Hz，5′″-H)，8.11(s，1H，-NH)，8.27(d，1H， J＝8.0Hz，4″-H)。
Embodiment 13: preparation N-cyclohexyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-12)
Figure BDA0000034555130000181
With the aniline among the 0.02mol hexahydroaniline replacement embodiment 2, yield: 39.3%; Fusing point: 212～215 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：1.15(m，1H，4′″-H)，1.16(m，2H，3′″，5′″-H)，1.38(m，2H，3′″，5′″-H)，1.61(m，1H，4′″-H)，1.70(m，2H，2′″，6′″-H)，1.94(m，2H，2′″，6′″-H)，3.86(m，1H，1′″-H)，5.89(d，1H，J＝7.5Hz，-NH)，6.96(t，1H，J＝8.5Hz，3′-H)，7.00(t，1H，J＝8.5Hz，5′-H)，7.26(d，1H，J＝8.5Hz，5-H)，7.42(q，1H，J＝8.5Hz，6′-H)，7.65(d，1H，J＝8.0Hz，6-H)，7.70(s，1H，2-H)，8.34(d，1H，J＝7.0Hz，4″-H)。
Embodiment 14: preparation N, N-diethyl-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-13)
Figure BDA0000034555130000182
With the aniline among the 0.02mol diethylamine replacement embodiment 2, yield: 38.6%; Fusing point: 125～127 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：1.13(t，3H，J＝7.0Hz，-CH 3)，1.15(t，3H，J＝7.0Hz，-CH 3)，3.31(q，2H，J＝7.0Hz，-CH 2)，3.50(q，2H，J＝7.0Hz，-CH 2)，6.95(t，1H，J＝8.5Hz，3′-H)，7.00(t，1H，J＝8.5Hz，5′-H)，7.41(d，1H， J＝8.5Hz，5-H)，7.42(q，1H，J＝8.5Hz，6′-H)，7.50(s，1H，2-H)，7.60(d，1H，J＝8.5Hz，6-H)，8.24(d，1H，J＝7.0Hz，4″-H)。
Embodiment 15: preparation N-(4-methylpiperazine base)-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-14)
Figure BDA0000034555130000191
With the aniline among the 0.02mol 1-methylpiperazine replacement embodiment 2, yield: 52.1%; Fusing point: 159～162 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：2.31(s，3H，-CH 3)，2.40(m，2H，3′″，5′″-H)，2.41(m，2H，3′″，5′″-H)，3.47(m，2H，2′″，6′″-H)，3.75(m，2H，2′″，6′″-H)，6.95(t，1H，J＝8.5Hz，3′-H)，7.00(t，1H，J＝8.5Hz，5′-H)，7.39(d，1H，J＝8.5Hz，5-H)，7.42(q，1H，J＝8.5Hz，6′-H)，7.49(s，1H，2-H)，7.62(d，1H，J＝8.0Hz，6-H)，8.25(d，1H，J＝7.0Hz，4″-H)
Embodiment 16: preparation N-(4-ethyl piperazidine base)-2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylic amides (I-15)
With the aniline among the 0.02mol 1-ethyl piperazidine replacement embodiment 2, yield: 55.3%; Fusing point: 212～215 ℃ (not proofreading and correct).
1HNMR(500MHz，CDCl 3，δppm)：1.10(t，3H，J＝2.5Hz，-CH 3)，2.42(q，2H，J＝2.5Hz，CH 2)，2.43(m，2H，3′″，5′″-H)，2.44(m，2H，3′″，5′″-H)，3.49(m，2H，2′″，6′″-H)，3.75(m，2H，2′″，6′″-H)，6.96(t，1H，J＝8.5Hz，3′-H)，7.00(t，1H，J＝8.5Hz，5′-H)，7.39(d，1H，J＝8.5Hz，5-H)，7.41(q，1H，J＝8.5Hz，6′-H)， 7.49(s，1H，2-H)，7.62(d，1H，J＝8.0Hz，6-H)，8.34(d，1H，J＝7.5Hz，4″-H)
Embodiment 17～31: anti-carcinoma of endometrium active testing
Testing method: anti tumor activity in vitro testing method:
A. principle: cell is decomposed into water-fast blue purple crystal by the plastosome lytic enzyme with Thiazolyl blue (MTT) and is deposited in the cell, crystallisate can be by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly reflect propagation situation and the number change of cell.
B. cell: Ishikawa, Endometrial carcinoma cell line.
C. experimental procedure
(1) preparation of sample: get Compound I-1～I-15, for solvable sample, every 1mg dissolves with 20 μ L DMSO, gets 2 μ L and dilutes with 1000 μ L nutrient solutions (substratum of preparation in the step (2)), making concentration is 100 μ g/mL, uses the nutrient solution serial dilution to working concentration again.
(2) cultivation of cell
The preparation of substratum: contain 800,000 unit penicillin, 1.0g Streptomycin sulphate, 10% deactivation calf serum in every 1000mL substratum.
The cultivation of cell: tumor cell inoculation in substratum, is put 37 ℃, 5%CO 2Cultivate in the incubator, 3～5d goes down to posterity.
(3) working sample is to the restraining effect of growth of tumour cell
Cell is digested with EDTA-trysinization liquid, and be diluted to 1 * 10 with substratum 6/ mL is added in the 96 porocyte culture plates, and every hole 100 μ L put 37 ℃, 5%CO 2Cultivate in the incubator.Behind the inoculation 24h, the substratum that inclines adds the sample with the substratum dilution, every hole 200 μ L, and each concentration adds 3 holes, puts 37 ℃, 5%CO 2Cultivate in the incubator, add the MTT of 5mg/mL behind the 72h in the cell cultures hole, every hole 10 μ L put 37 ℃ and hatch 3h, add DMSO, every hole 150 μ L, and with the vibrator vibration, Shi Jia Za dissolves fully, with microplate reader colorimetric under the 490nm wavelength.With similarity condition with do not contain sample, contain same concentration DMSO culture medium culturing cell in contrast, calculation sample is to the half-inhibition concentration (IC of growth of tumour cell 50).
The anti-tumor activity test result
With 2 of preparation, 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compound I-1～I-15 have carried out anti-Ishikawa active testing, and test-results is as follows:
Table 1: compound is to the IC of Ishikawa 50(μ mol/L)
Embodiment Compound IC 50μmol/L Estimate
17 I-1 4.71 Significantly
18 I-2 2.36 Significantly
19 I-3 7.68 Significantly
20 I-4 10.91 Effectively
21 I-5 17.54 Effectively
22 I-6 0.38 Highly significant
23 I-7 2.49 Significantly
24 I-8 7.51 Significantly
25 I-9 5.31 Significantly
26 I-10 6.45 Significantly
27 I-11 5.83 Significantly
28 I-12 48.45 Weak effect
29 I-13 77.04 Weak effect
30 I-14 110.27 Invalid
31 I-15 87.84 Weak effect
Judgement criteria according to anti-tumor activity, Compound I-6 has the anti-Ishikawa endometrial carcinoma cell activity of highly significant, it is active that Compound I-1, I-2, I-3, I-7, I-8, I-9, I-10 and I-11 have significant anti-Ishikawa endometrial carcinoma cell, Compound I-4 and I-5 have preferably anti-Ishikawa endometrial carcinoma cell activity, and it is active that Compound I-12, I-13 and I-15 have certain anti-Ishikawa endometrial carcinoma cell.
Embodiment 32～46: the anti-lung cancer activity test
Endometrial carcinoma cell line Ishikawa with among the human lung carcinoma cell line A549 replacement embodiment 17～31 carries out the anti-tumor activity test.Test-results is as follows:
Table 2: compound is to the IC of A549 50(μ mol/L)
Embodiment Compound IC 50μmol/L Estimate
32 I-1 12.52 Effectively
33 I-2 15.22 Effectively
34 I-3 51.38 Weak effect
35 I-4 16.92 Effectively
36 I-5 59.03 Weak effect
37 I-6 21.00 Effectively
38 I-7 38.07 Weak effect
39 I-8 62.72 Weak effect
40 I-9 22.12 Effectively
41 I-10 26.32 Effectively
42 I-11 9.79 Significantly
43 I-12 ＞200 Invalid
44 I-13 ＞200 Invalid
45 I-14 ＞200 Invalid
46 I-15 ＞200 Invalid
Judgement criteria according to anti-tumor activity, it is active that Compound I-11 has significant anti-A549 human lung carcinoma cell, Compound I-1, I-2, I-4, I-6, I-9 and I-10 have preferably anti-A549 human lung carcinoma cell activity, and it is active that Compound I-3, I-5, I-7 and I-8 have certain anti-A549 human lung carcinoma cell.

Claims (4)

1. one kind 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds, described 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds are one of following:
Figure FDA00001936808100021
2. as claimed in claim 12, the application of 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds in the preparation antitumor drug.
3. application as claimed in claim 2, it is characterized in that described 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds are in the application of preparation in the anti-uterine endometrium cancer drug, and are described 2, and 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds are one of following:
Figure FDA00001936808100041
4. application as claimed in claim 2, it is characterized in that described 2, the application of 6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds in the preparation anti-lung-cancer medicament, described 2,6-two chloro-5-fluorine nicotinoyl fluorobenzene salicylamide compounds are one of following:
Figure FDA00001936808100042
Figure FDA00001936808100051
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