CN101407467A - N-substituted arene aniline / polysubstituted diaryl ether compound, preparation and anti-tumor use thereof - Google Patents

N-substituted arene aniline / polysubstituted diaryl ether compound, preparation and anti-tumor use thereof Download PDF

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Publication number
CN101407467A
CN101407467A CNA200710163960XA CN200710163960A CN101407467A CN 101407467 A CN101407467 A CN 101407467A CN A200710163960X A CNA200710163960X A CN A200710163960XA CN 200710163960 A CN200710163960 A CN 200710163960A CN 101407467 A CN101407467 A CN 101407467A
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chloro
compound
cyano
aniline
och
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谢蓝
秦柄杰
田兴涛
李国雄
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Priority to CNA200710163960XA priority Critical patent/CN101407467A/en
Priority to PCT/CN2008/001700 priority patent/WO2009049492A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
    • C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to formula (I) N-substituted aromatic hydrocarbon phenyl amines and polysubstitution diaryl ether compounds or medicinal salt thereof, wherein, definitions of X, Y, Z, R1-R4 are shown in a claim, and also relates to a preparing method thereof, a drug combination containing the compounds and the application to anti cancer drug preparation thereof.

Description

N-substituted arene aniline/polysubstituted diaryl ether compound thing, its preparation method and antitumor application
Technical field:
The present invention relates to have N-substituted arene aniline/polysubstituted diaryl ether compound thing or its pharmacologically acceptable salt, its preparation method of multiple antitumour activity, the pharmaceutical composition that contains described compound and the application in the preparation antitumor drug thereof.
Background technology:
Malignant tumour is the common disease and the frequently-occurring disease of serious threat human health.According to World Health Organization's report, in the whole world 5,000,000,000 populations, about 9,000,000 examples of annual new cases, dead person reaches 7,000,000 people because of tumour, and the annual trend that also has increase.In three big therapies (operation, chemotherapy, radiotherapy) of malignant tumour, pharmacological agent occupies critical role.In recent years along with development of molecular biology and the people further understanding to the molecular level mechanism of the generation of cancer, development, antitumor drug research just turns to new type antineoplastic medicine at the too many levels effect of mechanism from traditional cytotoxic drug.With the cellular signal transduction molecule is that target spot or new vessel are medicine, differentiating inducer, targeted therapy, the raising of inhibitor, anti-metastasis or the anti-drug resistance of target spot or regulate the focus that number of ways such as body's immunity and gene therapy become research and development new type anticancer medicine.The protein tyrosine kinase inhibitor Gefitinib (Gefetinib) that wherein with the cellular signal transduction molecule is target spot has obtained success, becomes the medicine of first nonsmall-cell lung cancer of listing.
Although the present about kind more than 60 of clinical antitumor drug commonly used, treatment the most serious, that account for the solid tumor of malignant tumour more than 90% fails to reach satisfied effect to the harm humans life and health.Therefore the antitumor drug that continues the new high-efficiency low-toxicity of searching is still the focus in drug research field.
Summary of the invention
The inventor is in the research process of seeking PTS, by the general sieve of antitumour activity to the external many cells strain of small molecules synthetic compound, found that serial N-substituted arene aniline and polysubstituted diaryl ether compound thing all have intensive to suppress active to multiple cancer cells, and present certain structure activity relationship, in view of the above, the inventor furthers investigate this compounds.The antitumour activity of relevant this compounds had not appeared in the newspapers and had led.
Therefore, first aspect of the present invention relates to N-substituted arene aniline class and polysubstituted diaryl ether compound thing or its pharmacologically acceptable salt with following general formula (I) structure:
Figure A20071016396000061
Wherein,
Z is CH or N;
X is halogen or hydrogen;
Y is-O-or-NR '-;
R 1, R 2, R 3Be independently of one another H, halogen ,-NO 2,-CN ,-NH 2, C 1-6Alkyl, C 1-6Alkoxyl group, OH ,-OCH 2O-,-CF 3, ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Perhaps, R 1And R 2Or R 2And R 3Can form together-OCH 2O-;
R 4For-CN ,-NO 2,-CH=CH 2,-C ≡ CH ,-CH 3, C 1-6Alkyl, C 1-6Alkoxyl group, halogen ,-NH 2,-OH ,-COOH ,-SO 3H ,-C ≡ CR " or-CH=CHR ", and R 4Be single-(adjacent,, contraposition) or polysubstituted;
R ' is H, C 1-4The C that alkyl replaces 6-10Aromatic ring, five yuan or six-membered Hetero-aromatic, optional two keys or the triple-linked C of containing 1-10Aliphatic group, or optional two keys or the triple-linked C of containing 1-10Fatty acyl group;
R " contain two keys or triple-linked C for choosing wantonly 1-4Alkyl;
Condition is not comprise following compound:
5-chloro-2,4-dinitrobenzene-N-(4 '-aminomethyl phenyl)-aniline
5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline; With
6-chloro-2-(N-anilino)-3-nitropyridine.
Second aspect of the present invention relates to the preparation method of above-mentioned formula I compound.
The 3rd aspect of the present invention relates to the pharmaceutical composition that comprises above-mentioned formula I compound and one or more pharmaceutical carrier or vehicle.
The 4th aspect of the present invention relates to the purposes that described formula I compound is used to prepare antitumor drug.
The term that is adopted among the present invention " alkyl " comprises alkyl, thiazolinyl and alkynyl.
Term " the C that is adopted among the present invention 6-10Aromatic ring " be meant and contain the single of 6-10 carbon atom or condense aromatic ring that it includes but not limited to phenyl, naphthyl.
The term that is adopted among the present invention " five yuan or six-membered Hetero-aromatic " is meant that containing at least one in the ring system is selected from O, heteroatomic five yuan or the hexa-atomic aromatic ring of S or N, and it includes but not limited to pyrroles, pyrazoles, furans, thiophene, pyridine etc.
According to an embodiment of the invention, the present invention relates to have the N-substituted arene aniline class and the polysubstituted diaryl ether compound thing of following general formula (I):
Figure A20071016396000071
Wherein,
Z is CH or N;
X is halogen or hydrogen;
Y is-O-or-NR '-;
R 1, R 2, R 3Be independently of one another H, halogen ,-NO 2,-CN ,-NH 2, C 1-6Alkyl, C 1-6Alkoxyl group, OH ,-OCH 2O-,-CF 3, ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Perhaps, R 1And R 2Or R 2And R 3Can form together-OCH 2O-;
R 4For-CN ,-NO 2,-CH=CH 2,-C ≡ CH ,-CH 3, C 1-6Alkyl, C 1-6Alkoxyl group, halogen ,-NH 2,-OH ,-COOH ,-SO 3H ,-C ≡ CR " or-CH=CHR ", and R 4Be single-(adjacent,, contraposition) or polysubstituted;
R ' is H, C 1-4The C that alkyl replaces 6-10Aromatic ring, five yuan or six-membered Hetero-aromatic, optional two keys or the triple-linked C of containing 1-10Aliphatic group, or optional two keys or the triple-linked C of containing 1-10Fatty acyl group;
R " contain two keys or triple-linked C for choosing wantonly 1-4Alkyl;
Condition is not comprise following compound:
5-chloro-2,4-dinitrobenzene-N-(4 '-aminomethyl phenyl)-aniline
5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline; With
6-chloro-2-(N-anilino)-3-nitropyridine.
According to a preferred embodiment of the present invention, wherein Z is CH.
According to another preferred embodiment of the present invention, wherein Z is N.
According to another preferred embodiment of the present invention, R wherein 4Be para-orientation.
According to another preferred embodiment of the present invention, wherein Y is-NH-.
According to another preferred embodiment of the present invention, wherein,
R 1And R 3Be independently of one another halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3, ,-COOH ,-SO 3H ,-CONH 2
R 2Be H.
According to another preferred embodiment of the present invention, wherein,
R 1For halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 2And R 3Be H.
According to another preferred embodiment of the present invention, wherein,
R 2For halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 1And R 3Be H.
According to another preferred embodiment of the present invention, wherein,
R 1And R 3Be independently of one another halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 2Be H.
According to another preferred embodiment of the present invention, wherein,
R 3For be independently halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 1And R 2Be H;
Perhaps, R 1And R 2Or R 2And R 3Formation-OCH together 2O-.
The present invention is following compounds more preferably:
N-(m-hydroxy phenyl)-5-chloro-2, the 4-dinitraniline;
5-chloro-N-(4 '-cyano-phenyl)-2, the 4-dinitraniline;
5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline;
5-chloro-N-(4 '-nitrophenyl)-2, the 4-dinitraniline;
5-chloro-N-(4 '-cyano-phenyl)-2-N-methyl-p-nitroaniline;
5-chloro-N-(4 '-cyano-phenyl)-3-N-methyl-p-nitroaniline;
4 '-cyano-benzene oxygen-5-chloro-2, the 4-dinitrodiphenyl ether;
(4 '-bromo-, 2 ', 6 '-xylyloxy)-5-chloro-2, the 4-dinitrodiphenyl ether;
(4 '-cyano group-2 ', 6 '-xylyloxy)-5-chloro-2, the 4-dinitrodiphenyl ether;
5-(4 '-cyano-benzene oxygen)-2-nitro phenylate;
4-(4 '-cyano-benzene oxygen) nitro phenylate;
2-(4 '-cyano-benzene oxygen) oil of mirbane;
6-chloro-2-(4 '-anisole amido)-3-nitropyridine;
6-chloro-2-(4 '-cyano-aniline base)-3-nitropyridine;
2-(4 '-toluidine)-3-nitropyridine;
2-(4 '-cyano-aniline base)-3-nitropyridine; With
6-chloro-2-(2 ', 4 ', 6 '-Three methyl Benzene amido)-3-nitropyridine.
Formula I compound of the present invention can prepare by following reaction scheme:
Figure A20071016396000101
R wherein 1, R 2, R 3And R 4Definition described with following formula I.
Under the effect of alkali, halogeno-benzene or haloperidid and formula III substituted aniline or substituted phenol compound reaction that formula II is replaced, production I compound.
More particularly, at potassium tert.-butoxide, sodium hydride, triethylamine, pyridine, N, the N dimethylamine yl pyridines, or under the cuprous existence of salt of wormwood/halo, make to have halogeno-benzene that nitro replaces or haloperidid (formula II) and substituted aniline or substituted phenol compound (formula III) at DMF, in acetonitrile, THF or the DMSO solvent, room temperature or below 130 ℃, 5 minutes-24 hours, reactant II/III molar ratio was 1: 1.1-1: 2.
This coupled reaction also can be carried out under microwave condition, and alkali and reactant charging capacity ratio are same as above, is solvent with DMF or DMSO, reacts 10-30 minute down at 150-180 ℃.
The compounds of this invention demonstrates strong inhibitory activity in multiple cancer cells test.As mentioned below, compound is at lung carcinoma cell (A549), demonstrate in the inhibition activity test of breast cancer cell (MCF-7) and nasopharyngeal carcinoma cell (KB) with positive control medicine [high Cephalotaxus fortunei ester (Homoharringtonine) and Etoposide (Etoposide, VP-16)] and quite or better suppress active.It should be noted that especially the some of them compound also demonstrates very strong inhibition activity to having chemical sproof KB-VIN cell.Therefore, The compounds of this invention is furtherd investigate to be expected to develop the cancer therapy drug that makes new advances.
The compounds of this invention both can itself also can its pharmacologically acceptable salt or solvate forms use.The pharmacologically acceptable salt of formula I compound comprises the conventional salt with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases formation.The example of suitable acid salt comprises with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, pounces on the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc. form.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, the salt that N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-methylglucosamine and PROCAINE HCL, PHARMA GRADE etc. form.When relating to The compounds of this invention herein, comprise formula I compound and pharmacologically acceptable salt thereof or solvate.
According to the present invention, formula I compound of the present invention can become pharmaceutical composition with conventional pharmaceutical carrier or vehicle group.This pharmaceutical composition can be by oral or parenteral route administration.Pharmaceutical composition of the present invention can be prepared into various formulations by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension, granule or injection etc., oral administration or parenteral route administration.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Embodiment
The following examples are used to further specify the present invention, but it does not mean that the present invention only limits to this.
Embodiment 1:N-(m-hydroxy phenyl)-5-chloro-2,4-dinitraniline (A1)
With 1,5-two chloro-2,4-dinitrobenzene (237mg 1.0mmol) and Metha Amino Phenon (230mg, 2.11mmol) be dissolved in the oil bath of 120 ℃ of the direct placements in DMF (0.5mL) back, stirring 2 minutes, reaction solution becomes redness and promptly is cooled to room temperature, add frozen water, it is 3 that rare HCl transfers pH.Filter out solid, crude product separates with silica-gel plate, developping agent: petrol ether/ethyl acetate obtains title compound 208mg, red solid, productive rate 67%. 1H?NMR(DMSO)δppm?6.77(1H，s，ArH-2’)，6.78(1H，d，J＝8.4Hz，ArH-4’)，6.81(1H，t，J＝8.4Hz，ArH-5’)，7.04(1H，s，ArH-6)，7.31(1H，d，J＝8.4Hz，ArH-6’)，8.90(1H，s，ArH-3)，9.83(1H，s，OH)，10.04(1H，s，NH)。
Embodiment 2:5-chloro-N-(4 '-cyano-phenyl)-2,4-dinitraniline (A2)
2,4-two chloro-1, the 5-dinitrobenzene (1.2g, 5mmol) and to nitrile aniline (0.59g 5mmol) is dissolved in N, dinethylformamide (DMF, 10mL).Place ice-water bath to add potassium tert.-butoxide (1.4g, 12.5mmol), stirring at room is 45 minutes then in batches.Reaction solution is poured in the frozen water, and rare HCl adjust pH is to neutral.To separate out solid and leach, washing, drying, crude product separates (ethyl acetate/petroleum ether) with silicagel column and obtains title compound (1.44g, 90%), faint yellow solid. 1H?NMR(CDCl 3)δppm，7.41(1H，s，ArH-6)，7.57(2H，d，J＝8.8Hz，ArH-3’，5’)，7.91(2H，d，J＝8.8Hz，ArH-2’，6’)，8.90(1H，s，ArH-3)，10.07(1H，s，NH)。
Embodiment 3:5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline (A3)
With 2,4-two chloro-1, the 5-dinitrobenzene (0.5g, 2.11mmol) and P-nethoxyaniline (0.26g 2.11mmol) is dissolved among the DMSO (5mL), adds K 2CO 3(0.58g, 4.22mmol) and the metal Cu of catalytic amount, under the nitrogen protection, 115 ℃ were stirred 2 hours.Pour in the frozen water, leach solid, washed several times with water, dry back crude product separates (petrol ether/ethyl acetate wash-out) with silicagel column and obtains title compound, and it is the sorrel solid, 0.68g, yield 67%. 1H?NMR(CDCl 3)δppm?3.88(3H，s，OCH 3)，7.02(1H，s，ArH-6)，7.03(2H，d，J＝8.96Hz，ArH-3’，5’)，7.21(2H，d，J＝8.96Hz，ArH-2’，6’)，9.07(1H，s，ArH-3)，9.73(1H，s，NH)。
Embodiment 4:5-chloro-2,4-dinitrobenzene-N-(4 '-aminomethyl phenyl)-aniline (A4)
1,5-two chloro-2, the 4-dinitrobenzene (37mg, 1mmol), to monomethylaniline (128mg, 1.2mmol) and potassium tert.-butoxide (224mg, 2mmol) stirring at room 40 minutes in DMF (3mL).Pour in the water, transfer pH=5, filter crude product, obtain title compound with PTLC (petrol ether/ethyl acetate) separation, it is a faint yellow solid, 258mg, productive rate 84%. 1H?NMR(CDCl 3)δppmδ2.43(3H，s，CH 3)，7.12(1H，s，ArH-6)，7.17(2H，d，J＝8.4Hz，ArH-3’，5’)，7.32(2H，d，J＝8.4Hz，ArH-2’，6’)，9.08(1H，s，ArH-3)，9.79(1H，s，NH)。
Embodiment 5:5-chloro-N-(4 '-p-methoxy-phenyl)-1,2,4-benzene triamine (A5)
(128mg 0.4mmol) is dissolved in 2.5mL THF, and (28.3mg, methyl alcohol 0.12mmol) (1mL) solution adds in the THF solution with six water nickelous chlorides with compd A 4.This mixture cools off, stirs with ice bath, and add sodium borohydride (75.6mg, 2mmol), ice bath continues down to stir 15 minutes in batches.Reaction solution is poured in the frozen water, regulates pH and is about 5, and stirring at room leaches solid for a moment, and dry back crude product separates (chloroform/methanol) with silica-gel plate and obtains title compound, and it is light brown solid, 20mg, productive rate 19%. 1H?NMR(CDCl 3)δppm?3.78(3H，s，OCH 3)5.81(1H，s，ArH-3)，6.18(1H，s，ArH-6)，6.71(2H，d，J＝8.8Hz，ArH-3’，5’)，6.77(2H，d，J＝8.8Hz，ArH-2’，6’)。
Embodiment 6:5-chloro-N-(4 '-nitrophenyl)-2,4-dinitraniline (A6)
1,5-two chloro-2, the 4-dinitrobenzene (237mg, 1mmol), p-Nitroaniline (166mg, 1.2mmol) and potassium tert.-butoxide (236mg, 2.1mmol) in DMF (3mL), stirring at room 30 minutes.The same A5 of aftertreatment obtains title compound, and it is faint yellow product 280mg, productive rate 83%, fusing point 140-141 ℃. 1H?NMR(DMSO)δppm?7.55(1H，s，ArH-6)，7.60(2H，d，J＝9.0Hz，ArH-2’，6’)，8.29(2H，d，J＝9.0Hz，ArH-3’，5’)，8.90(1H，s，ArH-3)，10.19(1H，s，NH)。
Embodiment 7:5-chloro-N-(4 '-cyano-phenyl)-2-N-methyl-p-nitroaniline (A7)
2, the 4-dichloronitrobenzene (576mg, 3mmol), to cyano-aniline (425mg, 3.6mmol) and potassium tert.-butoxide (672mg, 6mmol) in 4mL DMF, stirring at room 20 hours,, the same A5 of aftertreatment, obtain title compound, it is the reddish yellow solid, 583mg, productive rate 71%.123 ℃ of fusing points; 1H NMR (DMSO) δ ppm 7.17 (1H, d, J=9.2Hz, ArH-4), 7.40 (2H, d, J=8.8Hz, ArH-3 ', 5 '), 7.45 (1H, s, ArH-6), 7.79 (2H, d, J=8.8Hz, ArH-2 ', 6 '), 8.14 (1H, d, J=9.2Hz, ArH-3), 9.48 (1H, s, NH).
Embodiment 8:5-chloro-N-(4 '-cyano-phenyl)-3-N-methyl-p-nitroaniline (A8)
3, the 5-dichloronitrobenzene (192mg, 1mmol) and to cyano-aniline (118mg, 1mmol) and potassium tert.-butoxide (224mg, 2mmol) in DMF (3mL), stirring at room 20 hours obtains title compound, it is the reddish yellow solid, 223mg, productive rate 82%. 1H?NMR(CDCl 3)δppm?6.25(1H，s，ArH-6)，6.78(2H，d，J＝8.8Hz，ArH-3’，5’)，7.55(2H，d，J＝8.8Hz，ArH-2’，6’)，7.83(1H，s，ArH-2)，8.02(1H，s，ArH-4)。
Embodiment 9:4 '-cyano-benzene oxygen-5-chloro-2,4-dinitrodiphenyl ether (A9)
1,5-two chloro-2, the 4-dinitrobenzene (237mg, 1mmol), 4-hydroxybenzonitrile (143mg, 1.2mmol) and salt of wormwood (276mg, 2mmol) in DMSO (2mL), 192 ℃ of following microwave reactions 10 minutes.Reaction solution is poured in the water, stirs 10 minutes, and ether extraction, organic phase are successively with 10% sodium hydroxide solution, water and the washing of saturated brine liquid, anhydrous sodium sulfate drying.After the removal of solvent under reduced pressure, obtain title compound, it is a red solid, 312mg, productive rate 97%. 1H?NMR(DMSO)δ5.98(1H，s，ArH-6)，7.12(2H，d，J＝8.8Hz，ArH-2’，6’)，7.80(2H，d，J＝8.8Hz，ArH-3’，5’)，8.73(1H，s，ArH-3)。
Embodiment 10:(4 '-bromo-2 ', 6 '-xylyloxy)-and 5-chloro-2,4-dinitrodiphenyl ether (A10)
With 1,5-two chloro-2, the 4-dinitrobenzene (250mg, 1.05mmol) and 2,6-dimethyl-4-bromophenol (250mg 1.2mmol) is dissolved among the DMF (3mL), add salt of wormwood (180mg, 1.3mmol), 180 ℃ of microwave reactions 10 minutes.Reaction solution is poured in the water, leaches solid, washing, and dry back crude product separates (petrol ether/ethyl acetate) with silicagel column and obtains title compound, and it is a yellow solid, 260mg, productive rate 65%. 1H NMR (CDCl 3) δ ppm 2.15 (6H, s, 2 * CH 3), 5.85 (1H, s, ArH-6), 7.31 (2H, s, ArH-3 ', 5 '), 8.79 (1H, s, ArH-3)
Embodiment 11:(4 '-cyano group-2 ', 6 '-xylyloxy)-5-chloro-2,4-dinitrodiphenyl ether (A11)
1,5-two chloro-2, the 4-dinitrobenzene (71mg, 0.3mmol) and 2,6-dimethyl-4-cyanophenol (59mg, 0.4mmol), Anhydrous potassium carbonate (83mg, 0.6mmol) in 3mLDMF, 180 ℃ of temperature, microwave reaction 10 minutes.Aftertreatment is the same, obtains title compound, and it is a yellow solid, 73mg, productive rate 70%. 1H?NMR(CDCl 3)δppm?2.17(6H，s，2×CH3)，5.88(1H，s，ArH-6)，7.45(2H，s，ArH-3’，5’)，8.79(1H，s，ArH-3)。
Embodiment 12:5-(4 '-cyano-benzene oxygen)-2-nitro phenylate (A12)
5-chloro-2-N-methyl-p-nitroaniline (172.5mg, 1mmol) and 4-hydroxybenzonitrile (143mg, 1.2mmol), 10 fens faint yellow solids of 180 ℃ of microwave reactions, productive rate 71%. 1H?NMR(CDCl 3)δppm?6.16(2H，s，NH 2)，6.33(1H，d，J＝2.4Hz，ArH-6)，6.36(2H，dd，J1＝9.2?&?2.4Hz，ArH-4)，7.15(2H，d，J＝8.8Hz，ArH-2’，6’)，7.71(2H，d，J＝8.8Hz，ArH-3’，5’)，8.17(1H，d，J＝9.2Hz，ArH-3)。
Embodiment 13:4-(4 '-cyano-benzene oxygen) nitro phenylate (A13)
Method is with embodiment 12.Adopt 158mg (1mmol) parachloronitrobenzene and 143mg (1.2mmol) 4-hydroxybenzonitrile, obtain title compound, it is a light yellow solid, 130mg, productive rate 54%. 1H?NMR(CDCl 3)δppm?7.11(2H，d，J＝9.0Hz，ArH-2’，6’)，7.15(2H，d，J＝9.2Hz，ArH-3，5)，7.72(2H，d，J＝9.0Hz，ArH-3’，5’)，8.28(2H，d，J＝9.2Hz，ArH-2，6)。
Embodiment 14:2-(4 '-cyano-benzene oxygen) oil of mirbane (A14)
Method is with embodiment 12.Adopt o-chloronitrobenzene (158mg, 1mmol) and 4-hydroxybenzonitrile (143mg, 1.2mmol) microwave reaction obtains title compound, it is a white solid, 130mg, productive rate 54%. 1H?NMR(CDCl 3)δppm?7.04(2H，d，J＝8.8Hz，ArH-2’，6’)，7.20(1H，d，J＝8.4Hz，ArH-3)，7.40(1H，t，J＝8.4Hz，ArH-4)，7.65(3H，m，ArH-5，ArH-3’，5’)，8.04(1H，d，J＝8.4Hz，ArH-6)。
Embodiment 15:6-chloro-2-(N-anilino)-3-nitropyridine (B1)
2,6-two chloro-3-nitropyridines (553.3mg, 2.867mmol), aniline (266.6mg, 286.7mg) and NaHCO 3(a large amount of red solid are separated out for 240.8mg, 2.867mmol) stirring at room 40h in dehydrated alcohol (15mL).The HCl that adds 1N in reaction solution regulates about pH to 3.Solid is filtered, distilled water wash, obtains title compound after the drying, and it is a red solid, 629.5mg, productive rate: 87.6%.TLC (ethyl acetate/petroleum ether) shows single point. 1H?NMR(CDCl3)δppm?6.81(1H，d，J＝8.4Hz，H-5)，7.21(1H，t，J＝8.0Hz，H-4’)，7.42(2H，t，J＝8.0Hz，H-3’，5’)，7.66(2H，d，J＝8.0Hz，H-2’，6’)，8.47(1H，d，J＝8.4Hz，H-4)，10.28(1H，bs，NH)。
Embodiment 16:6-chloro-2-(4 '-anisole amido)-3-nitropyridine (B2)
2,6-two chloro-3-nitropyridines (193mg, 1mmol), Para-Anisidine (123mg, 1mmol) and NaHCO 3(84mg, 1mmol) in dehydrated alcohol (10mL), stirring at room 4 days obtains title compound, and it is a red solid, 212mg, productive rate: 75.7%. 1H?NMR(CDCl 3)δ3.84(3H，s，OCH 3)，6.75(1H，d，J＝8.8Hz，H-5)，6.95(2H，d，J＝8.8Hz，H-3’，5’)，7.53(2H，d，J＝8.8Hz，H-2’，6’)，8.45(1H，d，J＝8.8Hz，H-4)，10.17(1H，bs，NH)。
Embodiment 17:6-chloro-2-(4 '-cyano-aniline base)-3-nitropyridine (B3)
2,6-two chloro-3-nitropyridines (193mg, 1mmol), to cyano-aniline (354mg, 3mmol) and Na 2CO 3(168mg, 2mmol) in the trimethyl carbinol (10mL), N 2Protection refluxed 2 days down.TLC (ethyl acetate/petroleum ether) demonstration still has raw material.Crude product separates with preparative chromatography, obtains title compound, and it is a yellow solid, 85mg, productive rate 31%. 1H?NMR(CDCl 3)δppm?6.96(1H，d，J＝8.4Hz，H-5)，7.70(2H，d，J＝8.8Hz，H-3’，5’)，7.86(2H，d，J＝8.8Hz，H-2’，6’)，8.53(1H，d，J＝8.4Hz，H-4)，10.47(1H，bs，NH)。
Embodiment 18:6-chloro-2-(2 ', 4 ', 6 '-Three methyl Benzene amido)-3-nitropyridine (B4)
2,6-two chloro-3-nitropyridines (193mg, 1mmol), 2 (0.5mL, 3.56mmol) and K 2CO 3(276mg, 2mmol) in t-BuOH (4mL), under microwave condition 200 ℃, reaction 30min, reaction solution is Vandyke brown.TLC (ethyl acetate/petroleum ether) shows new dot generation.Add the HCl adjust pH 4-5 of 1N in the reaction solution, separate out yellow solid.Filter, wash crude product, preparative chromatography obtains title compound after separating, it is a red solid, 123mg, productive rate 42.2%, fusing point 123-124.7 ℃. 1H?NMR(CDCl 3)δppm?2.07(6H，s，2×CH 3-2’，6’)，2.27(3H，s，CH3-4’)，6.85(1H，d，J＝8.4Hz，H-5)，6.95(2H，s，H-3’，H-5’)，8.50(1H，d，J＝8.4Hz，H-4)，9.75(1H，brs，NH)。
Embodiment 19:2-(4 '-toluidine)-3-nitropyridine (B5)
2-bromo-3-nitropyridine (101.5mg, 0.5mmol), to monomethylaniline (53.5mg, 0.5mmol) and K 2CO 3(69mg, 0.5mmol) in DMSO (1.5mL), N2 protection, the outer bath are to react 4h under 110 ℃ of conditions.TLC (ethyl acetate/petroleum ether) monitoring reaction is complete.Reaction solution is poured in the distilled water, filtered out precipitation.With acetone solution gained solid, the TLC plate separate product 47mg, red solid, productive rate 40.0%, fusing point: 176-177 ℃. 1H?NMR(CDCl 3)δppm?10.04(1H，br?s，NH)；8.46-8.53(2H，m，H-4，H-6)；7.49(2H，d，J＝8.4Hz，H-2’，H-6’)；7.21(2H，d，J＝8.4Hz，H-3’，H-5’)；6.80(1H，dd，J＝8.0Hz，4.0Hz，H-5)；2.36(3H，s，CH 3)。
Embodiment 20:2-(4 '-cyano-aniline base)-3-nitropyridine (B6)
2-bromo-3-nitropyridine (203mg, 1mmol), the 4-cyano-aniline (354mg, 3mmol) and butyl alcohol-tert potassium (112mg, 1mmol) in t-BuOH (4ml), following 110 ℃ of microwave condition, the reaction 10min.TLC (ethyl acetate/petroleum ether) monitoring reaction is complete.Reaction solution is poured in the frozen water, regulated pH to slant acidity, separate out solid with rare HCl.Crude product gets yellow solid 18mg through column chromatographic isolation and purification, productive rate: 7.5%. 1H?NMR(CDCl 3)δppm?10.37(1H，br?s，NH)，8.58(2H，m，H-4，H-6)，7.90(2H，d，J＝8.4Hz，H-3’，H-5’)，7.67(2H，d，J＝8.8Hz，H-2’，H-6’)，7.00(1H，dd，J＝8.4Hz，4.4Hz，H-5)。
Embodiment 21. anticancer growth tests
Used human cancer cell (A549, MCF-7, KB, KB-VIN etc.) is placed in the single substratum (RPMI-1640 contains 10% (v/v) calf serum), checks with the morphological specificity and the upgrowth situation of microscope pair cell in nutrient solution.Cell places 2.5cm 2Culture dish in, 37 ℃, contain 5%CO 2Cultivate in the damp atmosphere.The clone adherent growth.Sample preparation and dilution and its process that is inoculated in the enchylema be should be aseptic technique.Specimen is usually with DMSO dissolving ,-70 ℃ of preservations.In 96 well culture plates, each hole places specimen and about 5000-20000 cell of different concns, places 72 hours.The ED of anticancer growth 50Value is determined by SRB (sulforhodamine B) method.Cancer therapy drug homoharringtonine and VP16 are as positive control.
A549: lung carcinoma cell; MCF-7: breast cancer cell; KB: nasopharyngeal carcinoma cell; KB-VIN: drug-fast nasopharyngeal carcinoma cell is arranged.ED 50Value is for suppressing the effective dose of half growth of cancer cells, the expression antitumour activity.The part antitumour activity test result of the compound that the present invention relates to sees Table 1.
Table 1. formula I compound and antitumour activity data thereof
Figure A20071016396000192
Illustrate: A549: lung carcinoma cell; MCF-7: breast cancer cell; KB: nasopharyngeal carcinoma cell; KB-VIN: drug-fast nasopharyngeal carcinoma cell is arranged.Effective dose (the ED that suppresses the half growth of cancer cells 50) the expression antitumour activity.NA: unrestraint activity

Claims (10)

1. the N-substituted arene aniline class of formula I or polysubstituted diaryl ether compound thing or its pharmacologically acceptable salt:
Figure A2007101639600002C1
Wherein,
Z is CH or N;
X is halogen or hydrogen;
Y is-O-or-NR '-;
R 1, R 2, R 3Be independently of one another H, halogen ,-NO 2,-CN ,-NH 2, C 1-6Alkyl, C 1-6Alkoxyl group, OH ,-OCH 2O-,-CF 3, ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Perhaps, R 1And R 2Or R 2And R 3Can form together-OCH 2O-;
R 4For-CN ,-NO 2,-CH=CH 2,-C ≡ CH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3H ,-C ≡ CR " or-CH=CHR ", and R 4Be single-(adjacent,, contraposition) or polysubstituted;
R ' is H, C 1-4The C that alkyl replaces 6-10Aromatic ring, five yuan or six-membered Hetero-aromatic, optional two keys or the triple-linked C of containing 1-10Aliphatic group, or optional two keys or the triple-linked C of containing 1-10Fatty acyl group;
R " contain two keys or triple-linked C for choosing wantonly 1-4Alkyl;
Condition is not comprise following compound:
5-chloro-2,4-dinitrobenzene-N-(4 '-aminomethyl phenyl)-aniline
5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline; With
6-chloro-2-(N-anilino)-3-nitropyridine.
2. the compound of claim 1, wherein, R 4Be para-orientation.
3. the compound of claim 1, wherein, Y is-NH-.
4. the compound of claim 1, wherein,
R 1And R 3Be independently of one another halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3, ,-COOH ,-SO 3H ,-CONH 2
R 2Be H.
5. the compound of claim 1, wherein,
R 1For halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 2And R 3Be H.
6. the compound of claim 1, wherein,
R 1And R 3Be independently of one another halogen ,-NO 2,-CN ,-NH 2,-CH 3,-OCH 3, OH ,-OCH 2O-,-CF 3,-COOH ,-SO 3H ,-CONH 2
R 2Be H.
7. the compound of claim 1 is selected from:
N-(m-hydroxy phenyl)-5-chloro-2, the 4-dinitraniline;
5-chloro-N-(4 '-cyano-phenyl)-2, the 4-dinitraniline;
5-chloro-2,4-dinitrobenzene-N-(4 '-p-methoxy-phenyl)-aniline;
5-chloro-N-(4 '-nitrophenyl)-2, the 4-dinitraniline;
5-chloro-N-(4 '-cyano-phenyl)-2-N-methyl-p-nitroaniline;
5-chloro-N-(4 '-cyano-phenyl)-3-N-methyl-p-nitroaniline;
4 '-cyano-benzene oxygen-5-chloro-2, the 4-dinitrodiphenyl ether;
(4 '-bromo-, 2 ', 6 '-xylyloxy)-5-chloro-2, the 4-dinitrodiphenyl ether;
(4 '-cyano group-2 ', 6 '-xylyloxy)-5-chloro-2, the 4-dinitrodiphenyl ether;
5-(4 '-cyano-benzene oxygen)-2-nitro phenylate;
4-(4 '-cyano-benzene oxygen) nitro phenylate;
2-(4 '-cyano-benzene oxygen) oil of mirbane;
6-chloro-2-(4 '-anisole amido)-3-nitropyridine;
6-chloro-2-(4 '-cyano-aniline base)-3-nitropyridine;
2-(4 '-toluidine)-3-nitropyridine;
2-(4 '-cyano-aniline base)-3-nitropyridine; With
6-chloro-2-(2 ', 4 ', 6 '-Three methyl Benzene amido)-3-nitropyridine.
8. pharmaceutical composition, it comprises each described compound or pharmaceutically acceptable salt thereof of claim 1-7 and one or more pharmaceutical carriers or vehicle.
9. the preparation method of each described compound of claim 1-7:
Figure A2007101639600004C1
R wherein 1, R 2, R 3And R 4Definition described with following formula I,
Under the effect of alkali, halogeno-benzene or haloperidid and formula III substituted aniline or substituted phenol compound reaction that formula II is replaced, production I compound.
10. each the described compound of claim 1-7 that does not comprise exclusion condition described in the claim 1 is used to prepare the purposes of antitumor drug.
CNA200710163960XA 2007-10-12 2007-10-12 N-substituted arene aniline / polysubstituted diaryl ether compound, preparation and anti-tumor use thereof Pending CN101407467A (en)

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CN103301103A (en) * 2012-03-14 2013-09-18 中国中化股份有限公司 Application of cyano-containing diphenylamine compound to preparation of antitumor drugs
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