CN102617480A - Di-(hetero)aryl-substituted tertiary amine compounds, preparation method thereof and antitumor application thereof - Google Patents
Di-(hetero)aryl-substituted tertiary amine compounds, preparation method thereof and antitumor application thereof Download PDFInfo
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- CN102617480A CN102617480A CN2011100322533A CN201110032253A CN102617480A CN 102617480 A CN102617480 A CN 102617480A CN 2011100322533 A CN2011100322533 A CN 2011100322533A CN 201110032253 A CN201110032253 A CN 201110032253A CN 102617480 A CN102617480 A CN 102617480A
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- QWDLCSZKZVQXPQ-UHFFFAOYSA-N CN(c(cc1)ccc1OC)c(nc(cc1)OC)c1C(OC)=O Chemical compound CN(c(cc1)ccc1OC)c(nc(cc1)OC)c1C(OC)=O QWDLCSZKZVQXPQ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to di-(hetero)aryl-substituted tertiary amine compounds with the general formula of formula I or pharmaceutically acceptable salts thereof, a preparation method thereof, pharmaceutical compositions containing the compounds, and an application of the compounds in the preparation of antitumor drugs. In the formula I, X, Y, Z, Ar, L, and R1-R4 are defined in the specification.
Description
Technical field
The present invention relates to have two of multiple antitumour activity-the substituted tertiary amine compounds of (mixing) aryl or its pharmacologically acceptable salt, its preparation method contains the pharmaceutical composition and the application in the preparation antitumor drug thereof of said compound.
Background technology
Malignant tumour is the common disease and the frequently-occurring disease of serious threat human health.In the whole world more than 60 hundred million 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.Along with the increase of medicine quantity and the raising of treatment means, the mortality ratio of cancer has had certain decline in developed country in recent years.For example the cancer statistical report of U.S. 2009 issue shows that the male cancer mortality ratio has descended 19.2% from nineteen ninety to 2005 year, and the women has descended 11.4%.Yet cancer incidence in developing country and mortality ratio but still are in a tangible rising stage.For example the mortality ratio of Chinese cancer has leapt to the first place of disease death rate.Lung cancer, liver cancer, the sickness rate of esophagus cancer and mammary cancer etc. obviously rises.According to World Health Organization's report, in the three big therapies (operation, chemotherapy, radiotherapy) of malignant tumour, pharmacological agent occupies critical role.In recent years along with development of molecular biology and people generation to cancer, the further understanding of the molecular level mechanism of development, antitumor drug research is just turning to the new type antineoplastic medicine to 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 the suppressor factor of target spot; The medicine of metastasis or anti-drug resistance; Differentiating inducer, targeted therapy, improving or regulating number of ways such as body's immunity and gene therapy becomes the focus of researching and developing the new type anticancer medicine.Existing a plurality of be that the cancer therapy drug of target spot goes on the market in succession with the cellular signal transduction molecule, like protein tyrosine kinase inhibitor imatinib (Gleevec), ZD1939 (Iressa), Tarceva (Tarceva) and Xarelto (Nexavar).However, existing antitumor drug still can not satisfy clinical demand far away.The most serious to the harm humans life and health, the treatment that accounts for the solid tumor of malignant tumour more than 90% also fails to reach satisfied effect.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 through carrying out various human JEG-3 (as: A459 to the synthetic micromolecular compound; DU145, KB, KB-VIN; K562) inhibition activity test; Found that series two-(mixing) the substituted tertiary amine compounds of aryl have tangible antitumour activity, and demonstrated broad spectrum or good selectivity (partial data is seen table 1), and with known listing medicine percephalotaxine, taxol and the positive contrast of imatinib.The antitumour activity of this compounds had not appeared in the newspapers and had led, and prompting might be found the new texture type, with above-mentioned contrast medicine the PTS of similar effect target spot arranged the further investigation of this compounds.
Therefore, first aspect of the present invention relates to and has two of following general formula I structure-the substituted tertiary amine compounds of (mixing) aryl or its pharmacologically acceptable salt:
Wherein,
X, Y and Z are N or CR independently of one another
4, said R
4Be H, halogen ,-NO
2,-CN ,-NH
2,-N
3, alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl ,-OH, haloalkyl, halogenated alkoxy ,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", aryl, heteroaryl, the substituted alkyl of quilt-OH; the substituted alkoxyl group of quilt-OH, the substituted alkylamino of quilt-OH, quilt-NR ' R " substituted alkyl, quilt-NR ' R " substituted alkoxyl group; quilt-NR ' R " substituted alkylamino, the substituted alkyl of quilt-C (O) OH, the substituted alkoxyl group of quilt-C (O) OH, the substituted alkylamino of quilt-C (O) OH; The substituted alkyl of quilt-C (O) OR ', the substituted alkoxyl group of quilt-C (O) OR ', the substituted alkylamino of quilt-C (O) OR '; Amido or alkylthio, wherein R ' and R " be H independently of one another, C
1-4Alkyl, C
2-4Thiazolinyl or C
2-4Alkynyl, and said aryl and heteroaryl can be selected from-CHO ,-OH ,-COOH ,-CN and-NH
2Substituting group replace;
R
1Be alkyl, thiazolinyl, alkynyl, naphthenic base, Heterocyclylalkyl, acyl group, not replacement or substituted aryl or not replacement or substituted heteroaryl, wherein the substituting group on aryl or the heteroaryl can be C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, halogen ,-NO
2,-CN ,-NH
2,-N
3,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H or-SO
2NR ' R "; Wherein R ' and R " are H or C independently of one another
1-4Alkyl;
R
2And R
3Encircle locational H capable of using, halogen ,-NO for A independently of one another
2,-CN ,-NH
2,-N
3, alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", aryl, heteroaryl, the substituted alkyl of quilt-OH; the substituted alkoxyl group of quilt-OH, the substituted alkylamino of quilt-OH, quilt-NR ' R " substituted alkyl, quilt-NR ' R " substituted alkoxyl group; quilt-NR ' R " substituted alkylamino, the substituted alkyl of quilt-C (O) OH, the substituted alkoxyl group of quilt-C (O) OH, the substituted alkylamino of quilt-C (O) OH; The substituted alkyl of quilt-C (O) OR ', the substituted alkoxyl group of quilt-C (O) OR ', the substituted alkylamino of quilt-C (O) OR '; Amido or alkylthio, wherein R ' and R " be H independently of one another, C
1-4Alkyl, and said aryl and heteroaryl can be selected from-CHO ,-OH ,-COOH ,-CN and-NH
2Substituting group replace; Perhaps
Work as X, when Y or Z are CH, R
2And R
3Can replace H independently and and X, Y or Z connect, and R
2And R
3Can form with the atom that they connected and A ring condensed aliphatic series ring, aromatic ring or hetero-aromatic ring, said aliphatic ring can comprise one; Two or more are independently selected from O, the heteroatoms of N and S, unconjugated double bond or three key; Wherein said aliphatic series ring; The optional position of aromatic ring or hetero-aromatic ring can be independently selected from halogen ,-OH ,-NH
2, C
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
L is (CR
5R
6)
n, R wherein
5And R
6Be H independently of one another, alkyl, alkenyl or alkynyl, wherein n is 0,1 or 2; With
Ar is not for replacing or by R
7Single-or many-substituted aryl or heteroaryl, the radicals R on wherein different the position of substitution
7Definition and above-mentioned R
2And R
3Definition identical; R
7Be preferably H, halogen ,-OH ,-NO
2,-CN ,-NH
2,-N
3,-CF
3,-OCF
3, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
2-4Thiazolinyl, C
2-4Alkynyl ,-C (O) OR ' or-CONR ' R "; Wherein R ' and R " are H or C independently of one another
1-4Alkyl;
Condition is not comprise following compound in the compound of general formula I:
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-phenyl amino)-3-nitropyridine.
Second aspect of the present invention relates to the preparation method of above-mentioned compound of Formula I.
The 3rd aspect of the present invention relates to the pharmaceutical composition that comprises at least a compound of Formula I of the present invention and one or more pharmaceutical carriers or vehicle.
The 4th aspect of the present invention relates to the purposes that compound of Formula I of the present invention is used to prepare the medicine of treating tumour.Preferably, said tumour is selected from lung cancer, prostate cancer, nasopharyngeal carcinoma cell and resistance nasopharyngeal carcinoma.
The 5th aspect of the present invention relates to the compound of Formula I of the present invention as the medicine of treatment tumour.Preferably, said tumour is selected from lung cancer, prostate cancer, nasopharyngeal carcinoma cell and resistance nasopharyngeal carcinoma.
The 6th aspect of the present invention relates to the method for treating tumour, and said method comprises the compound of Formula I of the present invention that needs the patient treatment of this treatment significant quantity.Preferably, said tumour is selected from lung cancer, prostate cancer, nasopharyngeal carcinoma cell and resistance nasopharyngeal carcinoma.
The substituting group definition
The term that uses among this paper " alkyl " is meant saturated straight or branched alkyl, has 1-12 carbon atom, preferably has 1-10,1-8,1-6, a 1-4 or 1-3 carbon atom.The representative instance of " alkyl " includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, tert-pentyl, neo-pentyl, hexyl, heptyl, octyl group etc.
The term that uses among this paper " thiazolinyl " is meant and contains at least one carbon-carbon double bond (the unsaturated straight or branched alkyl of olefinic C=C-) has 2-12 carbon atom, preferably has 2-10,2-8,2-6, a 2-4 or 2-3 carbon atom.The representative instance of " thiazolinyl " includes but not limited to vinyl, propenyl, allyl group, butene-1-Ji, butene-2-Ji, amylene-1-base, 2-pentenyl, 1,3-pentadiene base, hexene-1-base, hexene-2-base, 1,3-hexadienyl, heptenyl, octenyl etc.
The term that uses among this paper " alkynyl " is meant the unsaturated straight or branched alkyl of acetylene series that contains at least one carbon carbon triple bond (C ≡ C-), has 2-12 carbon atom, preferably has 2-10,2-8,2-6, a 2-4 or 2-3 carbon atom.The representative instance of " alkynyl " includes but not limited to ethynyl, proyl, propargyl, butynyl, pentynyl, hexyn, heptyne base, octyne base etc.
The term that uses among this paper " alkylamino " is alkyl-NR
8R
9, R wherein
8And R
9Be selected from hydrogen and as alkyl defined herein independently of one another.The representative instance of " alkylamino " includes but not limited to methylamino-, dimethylamino, diethylin, third amino, fourth amino etc.
The term that uses among this paper " amido " means group-NR
10C (O) R
11, R wherein
10And R
11Be selected from hydrogen independently of one another, like alkyl defined herein, assorted alkyl, naphthenic base, Heterocyclylalkyl, aryl and heteroaryl.The representative instance of " amido " includes but not limited to formamido group, kharophen, and cyclohexyl-carbonyl is amino, benzamido-, benzyloxycarbonyl group amino etc.
The term that uses among this paper " alkylthio " means group-SR
12, R wherein
12Be alkyl or cycloalkyl like this paper definition.The representative instance of " alkylthio " includes but not limited to methylthio group, ethylmercapto group, rosickyite base, butylthio etc.
The term that uses among this paper " naphthenic base " means to have 3-10 carbon atom and has monocycle or the saturated cyclic alkyl of a plurality of fused rings (comprise and condensing and the bridging ring system), preferably has 3-8,5-8, a 3-6 or 5-6 carbon atom.The representative instance of " naphthenic base " includes but not limited to single ring architecture, such as cyclopropyl, and cyclobutyl, cyclopentyl, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.; And polynuclear plane, such as two ring [2.2.1] heptyl, adamantyl etc.
Term used herein " Heterocyclylalkyl " means and comprises one, and two or more are independently selected from N, the heteroatomic as naphthenic base defined herein of O and S.The representative instance of " Heterocyclylalkyl " includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, piperazinyl, piperidyl and morpholinyl etc.
Term used herein " cycloalkenyl group " means having monocycle or a plurality of fused rings (comprise and condensing and the bridging ring system) and having at least one carbon-carbon double bond (olefinic unsaturated cyclic alkyl C=C-) of 3-10 carbon atom; Preferably has 3-8; 5-8, a 3-6 or 5-6 carbon atom.The representative instance of " cycloalkenyl group " includes but not limited to single ring architecture, such as cyclohexenyl, and cyclopentenyl, cyclopropenyl radical etc.
Term used herein " heterocycloalkenyl " expression as cycloalkenyl group defined herein, one of them, two or more carbon atoms are by one, and two or more are selected from O, and the heteroatoms of S or N substitutes.The representative instance of " heterocycloalkenyl " includes but not limited to 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydrochysene-pyridyl etc.
Term used herein " aryl " means the unsaturated aromatic carbocyclyl groups of 5-14 carbon atom with a monocycle or a plurality of fused rings.Said aryl preferably has 5-10, a 5-8 or 5-6 carbon atom.The representative instance of " aryl " includes but not limited to phenyl, naphthyl and anthryl etc.
Term used herein " heteroaryl " expression as aryl defined herein, one of them, two or more carbon atoms are by one, and two or more are selected from O, and the heteroatoms of S or N substitutes.Said heteroaryl is a 5-14 unit heteroaryl, preferred 5-10 first heteroaryl, more preferably 5-or 6 yuan of heteroaryls.The representative instance of " heteroaryl " includes but not limited to furyl, thienyl ， oxazolyl, imidazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl, triazinyl, quinolyl, isoquinolyl, quinazolyl etc.
Term used herein " alkoxyl group " means group-OR
13, R wherein
13For as alkyl defined herein.The representative instance of " alkoxyl group " includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec.-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl-butoxy etc.
Term used herein " acyl group " means group-C (O) R
14, R wherein
14For hydrogen with like alkyl defined herein, assorted alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl.The representative instance of " acyl group " includes but not limited to formyl radical, ethanoyl, cyclohexyl-carbonyl, benzoyl-etc.
Term used herein " halogen " means fluorine, chlorine, bromine or iodine.Preferred halogen group is a fluorine, chlorine or bromine.
Term used herein " haloalkyl " means by halogen list defined herein or polysubstituted as alkyl defined herein.The representative instance of " haloalkyl " includes but not limited to-CF
3,-CF
2CF
3,-CH
2CCl
3Deng.
Term used herein " haloalkyl " means by halogen list defined herein or polysubstituted as alkoxyl group defined herein.The representative instance of " halogenated alkoxy " includes but not limited to-OCF
3,-OCHF
2,-OCH
2CCl
3Deng.
Above-mentioned group can be randomly by-OH ,-NH
2, C
1-4Alkyl, C
1-4Alkoxy or halogen list or polysubstituted.
The compound of general formula I of the present invention is preferably following general formula I I, the compound of III or IV:
Among the general formula I I-IV, X, Y, R
1, R
2, R
3, R
4, R
7Definition identical with the definition in the general formula I; The perhaps R on the A ring
2With R
3Can form with the atom that they connected and A ring condensed C
5-8Aromatic ring, 5-8 unit's hetero-aromatic ring or C
5-8The aliphatic series ring, said aliphatic ring can comprise one, and two or more are independently selected from O, the heteroatoms of N and S, unconjugated double bond or three key, wherein said aliphatic series ring, the optional position of aromatic ring or hetero-aromatic ring can be independently selected from halogen ,-OH ,-NH
2, C
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces.
Among the general formula I I-IV, substituent R
7Be preferably H, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkoxyl group or C
1-4Alkylthio; C more preferably
1-4Alkyl, C
1-4Alkoxyl group or C
1-4Alkylthio.R among the general formula I I
7Can be in the optional position on the phenyl ring (B ring).
According to a preferred implementation of the present invention, X in the general formula I, Y, Z is N.
According to another preferred embodiment of the present invention, X in the general formula I, Y, any two is N among the Z, another is CH;
According to another preferred embodiment of the present invention, X in the general formula I, Y, any two is CH among the Z, another is N.
According to another preferred embodiment of the present invention, X in the general formula I, Y, Z is CH.
According to another preferred embodiment of the present invention, the R in the general formula I on the A ring
2With R
3Can form with the atom that they connected and 5 yuan or 6 yuan aromatic rings of A ring condensed; 5 yuan or 6 yuan of hetero-aromatic rings or 5 yuan or 6 yuan of aliphatic series rings, said aliphatic ring can comprise one, and two or more are independently selected from O; The heteroatoms of N and S, unconjugated double bond or three key.Wherein said aliphatic series ring, the optional position of aromatic ring or hetero-aromatic ring can be independently selected from halogen ,-OH ,-NH2, C
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces.
According to another preferred embodiment of the present invention, in general formula I,
R
2And R
3Be fluorine independently of one another, chlorine, bromine, iodine ,-NO
2,-CN ,-NH
2,-N
3, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6-alkylamino, C
2-6Thiazolinyl, C
2-6Alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", HO-C
1-6Alkyl, HO-C
1-6Alkoxyl group, HO-C
1-6Alkylamino, NR ' R " C
1-6Alkyl, NR ' R " C
1-6Alkoxyl group, NR ' R " C
1-6Alkylamino, HOOC-C
1-6Alkyl, HOOC-C
1-6Alkoxyl group, HOOC-C
1-6Alkylamino, R ' OOC-C
1-6Alkyl, R ' OOC-C
1-6Alkoxyl group or R ' OOC-C
1-6Alkylamino;
R
4Be H, halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6-alkylamino ,-NO
2,-CN ,-COOMe or-CONR ' R "; With
R
7Be H, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6-alkylamino, C
1-6Alkylthio, hydroxyl, amino ,-COOR ' or-CONR ' R "; Wherein R ' and R " are H or C
1-4Alkyl.
According to another preferred embodiment of the present invention, in general formula I,
R
2And R
3Be fluorine independently of one another, chlorine, bromine, iodine ,-NO
2,-CN ,-NH
2,-N
3, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4-alkylamino, C
2-4Thiazolinyl, C
2-4Alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", HO-C
1-4Alkyl, HO-C
1-4Alkoxyl group, HO-C
1-4Alkylamino, NR ' R " C
1-4Alkyl, NR ' R " C
1-4Alkoxyl group, NR ' R " C
1-4Alkylamino, HOOC-C
1-4Alkyl, HOOC-C
1-4Alkoxyl group, HOOC-C
1-4Alkylamino, R ' OOC-C
1-4Alkyl, R ' OOC-C
1-4Alkoxyl group or R ' OOC-C
1-4Alkylamino;
R
4Be H, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4-alkylamino ,-NO
2,-CN ,-COOMe or-CONR ' R "; With
R
7Be C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4-alkylamino, C
1-4-alkylamino, hydroxyl, amino ,-C (O) OR ' or-CONR ' R ".
Preferably, compound of Formula I of the present invention is selected from:
2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 1),
2,6-two chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 2),
4,6-two chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 3),
2-amino-6-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 4),
6-amino-2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 5),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 6),
6-chloro-2-[N-allyl group-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 7),
6-chloro-2-[N-cyclopentyl-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 8),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 9),
2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-methyl-3-nitro pyridine (compound 10),
6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 11),
2-chloro-3-cyanic acid-6-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 12),
2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-(N-methylamino-)-3-nitropyridine (compound 13),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 14),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-3-nitropyridine (compound 15),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 16),
N-(5-chloro-2-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 17),
N-(3-chloro-4-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 18),
3-bromo-4-methoxyl group-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 19),
N, N-dimethyl--3-bromo-4-methoxyl group-5-[N-(4-p-methoxy-phenyl)-N-methyl)] amino-BM (compound 20),
3-bromo-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 21),
N-(3-bromo-5-cyanic acid-2-methoxyl group) phenyl-N-(4-p-methoxy-phenyl) methylamine (compound 22),
3,4-dimethoxy-5-[N-methyl-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 23),
3,4-dimethoxy-5-[N-methyl-(3-hydroxyl-4-p-methoxy-phenyl) amino] oil of Niobe (compound 24),
N, N-dimethyl--3-(5-formyl radical-2-furyl)-5-[N '-(4 '-methoxyl group) phenyl-N '-methyl] amino-BM (compound 25),
6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-pyridine (compound 26),
1-methoxyl group-2-[N-(4-p-methoxy-phenyl)-N-methyl] amino-4-nitro-naphthalene (compound 27),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl-] amino-pyridine-3-methane amide,
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-(N, N-dimethyl-) methane amide,
6-methylamino--2-[N-(4 '-p-methoxy-phenyl)-the N-methyl-) EL-970-3-methyl-formiate,
2-(4 '-the p-methoxy-phenyl methylamino)-6-methylamino pyridine-3-(N-methyl) methane amide,
2-(4 '-the p-methoxy-phenyl methylamino)-6-methylamino pyridine-3-(N, N-dimethyl-) methane amide,
6-(5-methylol-2-furyl)-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate,
6-(5-methyl-2-pyrryl)-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate,
N-methyl-3-(4-p-methoxy-phenyl) amino-4-methoxynaphthalene methyl-formiate,
N-methyl-3-(4-anisole ylmethyl) amino-4-methoxynaphthalene methane amide,
7-(4-p-methoxy-phenyl methylamino)-1-methyl-6-nitro-2,3-dihydro-1,8-naphthyridines-4-ketone and
7-(4-p-methoxy-phenyl methylamino)-1-methyl-4-carbonyl-2,3-dihydro-1,8-naphthyridines-6-carboxylate methyl ester.
Formula I compound of the present invention can prepare through following reaction scheme:
R wherein
1, R
2, R
3, L, Ar, X is described in the definition of Y and Z such as the above-mentioned general formula I.
In the presence of alkali, the substituted halides of general formula V and the substituted aminated compounds of general formula VI are reacted in solvent, generate compound of Formula I.
More particularly, at potassium hydride KH, sodium hydride, cesium carbonate, triethylamine; Pyridine, N, the N-Dimethylamino pyridine, or salt of wormwood/halo is cuprous, salt of wormwood/two diphenylphosphino ferrocene palladium chlorides/1; 1 '-two diphenylphosphino ferrocene, sodium tert-butoxide/two diphenylphosphino ferrocene palladium chlorides/1,1 '-two diphenylphosphino ferrocene, cesium carbonate/two diphenylphosphino ferrocene palladium chlorides/1,1 '-two diphenylphosphino ferrocene; Salt of wormwood/palladium/X-Phos, cesium carbonate/palladium/X-Phos, sodium tert-butoxide/palladium/X-Phos exists down, makes substituted halides (general formula I I) and substituted aminated compounds (general formula III) at solvent DMF for example; Acetonitrile, THF, toluene, 1; Among 4-dioxane or the DMSO, below the ice bath to 220 ℃, reacted 5 minutes-24 hours, reactant V/VI molar ratio is 1: 1.1-1: 4.
This reaction also can be carried out under microwave condition, and alkali and reactant charging capacity ratio be with the above, at solvent DMF for example, and DMSO, the trimethyl carbinol, methyl alcohol, ethanol, acetonitrile or 1 in the 4-dioxane, reacted 5-60 minute.
The compounds of this invention demonstrates strong inhibitory activity in multiple cancer cells test.As mentioned below; Compound is at lung carcinoma cell (A549); Prostate cancer cell (DU145); Demonstrate in the inhibition activity test of nasopharyngeal carcinoma cell (KB) resistance nasopharyngeal carcinoma cell (KB-VIN) and leukaemia cancer cell with positive control medicine [high Fortune Plumyew Twig and Leaf ester (Homoharringtonine), taxol (Paclitaxel), imatinib (Gleevec)] 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.We further investigate these Notes of Key Datas The compounds of this invention and will be expected to develop the new anti-cancer drug thing, or have with similar mechanism of action of above-mentioned positive control drug or action target spot.
The compounds of this invention both can itself also can its pharmacologically acceptable salt or solvate forms use.The pharmacologically acceptable salt of compound of Formula I comprises and pharmaceutically acceptable mineral acid or organic acid, the salt that perhaps forms with pharmaceutically useful mineral alkali or organic bases.The example of suitable acid salt comprises and 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, Hydrocerol A; Pounce on 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, the salt that tannic acid etc. form.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethylolamine, quadrol, the salt that N-NMG and PROCAINE HCL, PHARMA GRADE etc. form.When relating to The compounds of this invention among this paper, comprise compound of Formula I and pharmacologically acceptable salt thereof or solvolyte.
According to the present invention, compound of Formula I of the present invention can become pharmaceutical composition with conventional pharmaceutical carrier or vehicle group.This pharmaceutical composition can pass through administrations such as for example oral or non-enteron aisle.Pharmaceutical composition of the present invention can be prepared into various formulations by this area ordinary method, includes but not limited to tablet, capsule, and solution, suspension-s, granule or injection etc. are through administrations such as for example oral or non-enteron aisles.
It may be noted that in addition The compounds of this invention using dosage and method of use depend on many factors, comprise patient's age, body weight; Sex, natural health situation, nutritional status, the activity intensity of compound; Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's subjective judgement.Preferred using dosage is between the 0.01-100mg/kg body weight/day.
Embodiment
Following embodiment is used to further specify the present invention, but it does not mean that the present invention only limits to this.
Method one: with NaH (2.3mmol; 60%) joins 1 of N-alkyl-list or multi-substituent aniline (2.3mmol) in batches; In 4-dioxane (2.5ml) solution, stirring at room add after 5 minutes N-Methyl pyrrolidone (NMP, 2.5ml); And continue to stir 10 minutes, add substituted pyrimidines (1.5mmol) then.With this mixture heating up to 120 ℃, stirred 4 hours.Reactant is poured in the frozen water, transferred pH to 3, suction filtration, ir lamp is dry, and bullion is through silica gel column chromatography (elutriant: methylene dichloride; Or sherwood oil: ETHYLE ACETATE gradient elution, sherwood oil are 5%-80%) separate.
Method two: with substituted pyrimidines (1.0mmol), N-alkyl list or polysubstituted aniline (1.2mmol), hydrochloric acid (2N, 0.75ml) and the mixed-liquor return of ethanol (3.0ml)/water (6.0ml) 4 hours.Then reactant is poured in the frozen water, dripped saturated NaHCO
3Solution is separated out until no longer including throw out, suction filtration, and ir lamp is dry.Bullion is through silica gel column chromatography (elutriant: methylene dichloride; Or sherwood oil: ETHYLE ACETATE gradient elution, sherwood oil are 5%-80%) separate.
Method three: 2-chloro-6-substituting group-3-substituent pyridine (0.5mmol), N-alkyl list or polysubstituted aniline (0.75mmol) and Anhydrous potassium carbonate (1.0mmol) join among the t-BuOH (3ml), and microwave condition 140-180 ℃ was reacted 15-30 minute.Reaction finishes the back and adds less water, transfers pH to 3, ethyl acetate extraction, anhydrous sodium sulfate drying with 2N hydrochloric acid.Removal of solvent under reduced pressure, bullion silica gel column chromatography (elutriant: methylene dichloride; Or sherwood oil: ETHYLE ACETATE gradient elution, sherwood oil are 5%-80%) separate.
Method four: with the substituted general formula V of bromine compound (1.0mmol), single or polysubstituted aniline (1.2mmol), 1; 1 '-two diphenylphosphino ferrocene palladium chloride (39mg; 0.05mmol)) and 1,1 '-(84mg is 0.15mmol) in 8ml toluene for two diphenylphosphino ferrocene; Under nitrogen protection, add t-BuONa (165mg, 1.56mmol) or Cs
2CO
3(456mg, 1.4mmol), normal temperature is heated to 100 ℃ of reaction 24h.Add a small amount of sherwood oil, remove insolubles, use the methylene dichloride wash-out through a small amount of silica gel.Concentrate the back bullion through silica gel column chromatography separate intermediate product.Get this intermediate product (0.50mmol) and methyl iodide 0.28ml (1.5mmol) is dissolved among the 7ml DMF, ice bath is cooled to 0 ℃, add in batches the 60mg sodium hydride (60%, 1.5mmol), under this temperature, stirred 1 hour.Reactant is poured in the frozen water, separated out solid, suction filtration, bullion is through silica gel column chromatography (elutriant: methylene dichloride; Or sherwood oil: ETHYLE ACETATE gradient elution, sherwood oil are 5%-80%) separate pure article.
Method five: with the substituted general formula V of bromine compound (1.0mmol), (1.0mmol), single or polysubstituted aniline (1.2mmol), palladium (6mg; 0.03mmol)), X-Phos (17mg, 0.04mmol); Zeyssatite (228mg), and t-BuONa (165mg, 1.56mmol) or Cs
2CO
3(456mg 1.4mmol), joins in the 2.5ml toluene and the 0.5ml trimethyl carbinol.Microwave condition reacted 30-60 minute down.Bullion through silica gel column chromatography separate intermediate product.Get this intermediate product (0.50mmol) and methyl iodide 0.28ml (1.5mmol) is dissolved among the 7ml DMF, ice bath is cooled to 0 ℃, add in batches the 60mg sodium hydride (60%, 1.5mmol), under this temperature, stirred 1 hour.Reactant is poured in the frozen water, separated out solid, suction filtration, bullion is through silica gel column chromatography (elutriant: methylene dichloride; Or sherwood oil: ETHYLE ACETATE gradient elution, sherwood oil are 5%-80%) separate pure article.
Embodiment 1:2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 1)
2, and the 4-dichloro pyrimidine (150mg, 1.0mmol), N-methyl-4-anisidine (165mg, 1.2mmol), NaHCO
3(2N 0.75ml) refluxed 2 hours in ethanol (4.0ml).Ethanol is removed in decompression, and reactant is poured in the frozen water, transfers pH to 3 with 2N hydrochloric acid, AcOEt extraction, saturated brine washing, anhydrous sodium sulfate drying.Filtration and removal of solvent under reduced pressure obtain bullion, separate obtaining product 176mg, productive rate 70% through silica gel column chromatography; White solid, fusing point: 119-121 ℃.
1H?NMR?δppm?3.45(3H，s，NCH
3)，3.85(3H，s，OCH
3)，6.08(1H，d，J＝6.0Hz，PyH-5)，6.98(2H，d，J＝8.8Hz，ArH-2′，6′)，7.14(2H，d，J＝8.8Hz，ArH-3′，5′)，7.85(1H，d，J＝6.0Hz，PyH-4)。
LCMS-ESI?m/z(％)：250(M+1
+，100)，252(M+3
+，33)。
Embodiment 2:2,6-two chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 2, method one)
Productive rate 74%, product are white solid, fusing point 123-124 ℃.
1H?NMR?δppm?3.45(3H，s，NCH
3)，3.86(3H，s，OCH
3)，6.07(1H，s，PyH-5)，7.00(2H，d，J＝8.8Hz，ArH-2′，6′)，7.13(2H，d，J＝8.8Hz，ArH-3′，5′)。MS?m/z(％)：284(M+1
+，100)，286(M+3
+，70)，288(M+5
+，10)。
Embodiment 3:4,6-two chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 3, method one)
White solid 37mg, productive rate: 14%, fusing point: 91-92 ℃.
1H?NMR?δppm?3.48(3H，s，NCH?
3)，3.83(3H，s，OCH
3)，6.61(1H，s，PyH-5)，6.93(2H，d，J＝8.8Hz，ArH-2′，6′)，7.18(2H，d，J＝8.8Hz，ArH-3′，5′)。
MS?m/z(％)：284(M+1
+，100)，286(M+3
+，65)，288(M+5
+，10)。
Embodiment 4:2-amino-6-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 4, method two)
Light gray solid 160mg, productive rate: 60%, fusing point: 208-211 ℃.
1H?NMR(DMSO)δppm?3.29(3H，s，NCH?
3)，3.78(3H，s，OCH
3)，5.33(1H，s，PyH-5)，6.63(2H，s，NH
2)，7.02(2H，d，J＝9.2Hz，ArH-2′，6′)，7.22(2H，d，J＝9.2Hz，ArH-3′，5′)。
MS-ESI?m/z(％)：265(M+H
+，100)，267(M+3
+，34)。
Embodiment 5:6-amino-2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 5, method two)
Light gray solid 177mg, productive rate: 80%, fusing point: 223-225 ℃.
1H?NMR(DMSO)δppm?3.28(3H，s，NCH?
3)，3.78(3H，s，OCH
3)，5.33(1H，s，PyH-5)，6.64(2H，s，NH
2)，7.02(2H，d，J＝9.2Hz，ArH-2′，6′)，7.22(2H，d，J＝9.2Hz，ArH-3′，5′)。
MS?m/z(％)：265(M+H
+，100)，267(M+3
+，34)。
Embodiment 6:6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 6, method three)
Orange solids, heavy 113mg, productive rate: 77%; Fusing point: 86-88 ℃.
1H?NMR(CDCl
3)δppm?3.54(3H，s，NCH
3)，3.78(3H，s，OCH
3)，6.76(1H，d，J＝8.4Hz，PyH-5)，6.83(2H，d，J＝9.2Hz，ArH-2′，6′)，7.00(2H，d，J＝9.2Hz，ArH-3′，5′)，7.88(1H，d，J＝8.4Hz，PyH-4)。
MS?m/z(％)：294(M+H
+，100)，296(M+3
+，32)。
Embodiment 7:6-chloro-2-[N-allyl group-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 7, method three)
Red oil, heavy 99mg, productive rate: 58%.
1H NMR (CDCl
3): δ ppm 3.77 (3H, s, OCH
3), 4.63 (2H, d, J=5.6Hz, NCH
2CHCH
2), 5.16 (1H, dd, J=17.6 and 1.2Hz ,=CH), 5.18 (1H, dd, J=17.2 and 1.2Hz ,=CH), 5.99 (1H, m, NCH
2CHCH
2), 6.76 (1H, d, J=8.4Hz, PyH-5), 6.81 (2H, d, J=9.2Hz, ArH-2 ', 6 '), 6.98 (2H, d, J=9.2Hz, ArH-3 ', 5 '), 7.87 (1H, d, J=8.4Hz, PyH-4).
MS?m/z(％)：320(M+1
+，100)，322(M+3
+，25)。
Embodiment 8:6-chloro-2-[N-cyclopentyl-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 8, method three)
The orange solid, heavy 88mg, productive rate: 50%, fusing point: 92-93 ℃.
1H?NMR(CDCl
3)：δppm?1.49-1.61(6H，m，3*CH
2)，2.02(2H，m，CH
2)，3.79(1H，s，OCH
3)，4.93(1H，m，CH)，6.70(1H，d，J＝8.0Hz，PyH-5)，6.83(2H，d，J＝9.2Hz，ArH-2′，6′)，6.93(2H，d，J＝8.8Hz，ArH-3′，5′)，7.69(1H，d，J＝8.0Hz，PyH-4)。
MS?m/z(％)：348(M
+，100)，350(M+3
+，32)。
Embodiment 9:6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 9)
N-methyl-6-chloro-2-(4 '-p-methoxy-phenyl is amino)-the 3-nitropyridine (114mg, 0.4mmol), sodium methylate (53mg; 1.0mmol) and MeOH (3ml) stirring at room 2 hours, pour in the frozen water, separate out yellow solid; Filtration drying gets 105mg compound 10, productive rate: 72%; Fusing point: 52-54 ℃.
1H?NMR(CDCl
3)δppm?3.54(3H，s，NCH
3)，3.78(3H，s，OCH
3)，3.99(3H，s，OCH?
3)，6.19(1H，d，J＝8.8Hz，PyH-5)，6.83(2H，d，J＝8.8Hz，ArH-2′，6′)，7.02(2H，d，J＝9.2Hz，ArH-3′，5′)，8.03(1H，d，J＝8.8Hz，PyH-4)。
MS?m/z(％)：290(M+H
+，100)。
Embodiment 10:2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-methyl-3-nitro pyridine (compound 10, method three)
Yellow solid, heavy 77mg, productive rate: 56%; Fusing point: 97-98 ℃.
1H?NMR(CDCl
3)：δppm?2.53(3H，s，CH?
3)，3.53(3H，s，NCH
3)，3.77(3H，s，OCH
3)，6.64(1H，d，J＝8.0Hz，PyH-5)，6.82(2H，d，J＝9.2Hz，ArH-2′，6′)，6.99(2H，d，J＝9.2Hz，ArH-3′，5′)，7.86(1H，d，J＝8.0Hz，PyH-4)。
MS?m/z(％)：274(M
+，100)。
Embodiment 11:6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 11, method three)
White solid, 32mg, productive rate: 24%, fusing point: 137-138 ℃.
1H?NMR(CDCl
3)δppm?3.47(3H，s，NCH
3)，3.85(3H，s，OCH
3)，6.18(1H，d，J＝8.0Hz，PyH-5)，6.99(2H，d，J＝8.8Hz，ArH-2′，6′)，7.14(2H，d，J＝8.8Hz，ArH-3′，5′)，7.38(1H，d，J＝8.8Hz，PyH-4)。
MS?m/z(％)：274(M+1
+，100)，276(M+3
+，31)。
Embodiment 12:2-chloro-3-cyanic acid-6-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 12, method three)
White solid, 40mg, productive rate: 32%, fusing point: 135-136 ℃.
1H?NMR(CDCl
3)δppm?3.45(3H，s，NCH
3)，3.84(3H，s，OCH
3)，6.66(1H，d，J＝8.0Hz，PyH-5)，6.69(2H，d，J＝8.8Hz，ArH-2′，6′)，7.19(2H，d，J＝8.8Hz，ArH-3′，5′)，7.55(1H，d，J＝8.0Hz，PyH-4)。
MS?m/z(％)：274(M+H
+，100)，276(M+3
+，36)；
Embodiment 13:2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-(N-methylamino-)-3-nitropyridine (compound 13)
Compound 6 (200mg, 0.68mmol), carbinolamine (2.5ml, 30% alcoholic solution) and MeOH (3ml) back flow reaction 5 hours, solid is separated out in cooling, and filtration drying obtains product.Red solid, heavy 145mg, productive rate: 74%; Fusing point: 169-170 ℃.
1H?NMR(CDCl
3)ppm?3.03(3H，d，J＝5.2Hz，NHCH
3)，3.49(3H，s，NCH
3)，3.76(3H，s，OCH
3)，5.01(1H，s，NH)，5.87(1H，d，J＝8.8Hz，PyH-5)，6.81(2H，d，J＝8.8Hz，ArH-2′，6′)，7.02(2H，d，J＝8.8Hz，ArH-3′，5′)，8.00(1H，d，J＝9.2Hz，PyH-4)。
MS?m/z(％)：289(M+H
+，100)。
Embodiment 14:6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 14, method three)
Faint yellow solid, heavy 93mg, productive rate: 60%, fusing point: 97-98 ℃.
1H?NMR(CDCl
3)ppm?3.28(3H，s，NCH
3)，3.47(3H，s，OCH
3)，3.78(3H，s，OCH
3)，6.74(1H，d，J＝8.0Hz，PyH-5)，6.84(2H，d，J＝9.2Hz，ArH-2′，6′)，7.02(2H，d，J＝8.8Hz，ArH-3′，5′)，7.61(1H，d，J＝8.0Hz，PyH-4)。
MS?m/z(％)：275(M-31，100)，277(M+2-31，26)，307(M+H+，81)，309(M+3
+，23)。
Embodiment 15:6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-3-nitropyridine (compound 15)
(281mg 1.0mmol) is dissolved in the 8.0ml diacetyl oxide, adds 1 vitriol oil, is heated to 90 ℃, 18 hours with N-methyl-4-p-methoxy-phenyl amino-3-nitro-6-chloropyridine.Reactant is poured in the frozen water, and sodium hydroxide water liquid transfers to neutrality, separates out throw out, and suction filtration is dry, and the column chromatography separation obtains product.
Yellow solid, heavy 249mg, productive rate 77%, fusing point: 146-147 ℃.
1H?NMR?δppm?2.01(3H，s，CH
3)，3.86(3H，s，OCH
3)，6.99(2H，d，J＝8.8Hz，ArH-2′，6′)，7.31(1H，d，J＝8.4Hz，PyH-5)，7.49(2H，d，J＝8.8Hz，ArH-3′，5′)，8.22(1H，d，J＝8.4Hz，PyH-4)。
MS?m/z(％)：322(M
+，100)，324(M+2
+，28)。
Embodiment 16:6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 16)
6-methoxyl group-2-N-(4 '-p-methoxy-phenyl) EL-970-3-methyl-formiate (60mg; 0.21mmol) and methyl iodide 0.04ml (0.63mmol) be dissolved among the 3ml DMF, ice bath is cooled to 0 ℃, adds 25mg sodium hydride (60% in batches; 0.63mmol), under this temperature, stirred 1 hour.Reactant is poured in the frozen water, separated out solid, suction filtration, column chromatography for separation gets pure article.
White solid, heavy 62mg, productive rate: 98%, fusing point: 78-80 ℃.
1H?NMR(CDCl
3)δppm?3.28(3H，s，NCH
3)，3.48(3H，s，OCH
3)，3.78(3H，s，OCH
3)，3.96(3H，s，OCH
3)，6.18(1H，d，J＝8.4Hz，PyH-5)，6.83(2H，d，J＝8.8Hz，ArH-2′，6′)，7.03(2H，d，J＝?9.2Hz，ArH-3′，5′)，7.71(1H，d，J＝8.0Hz，PyH-4)。
MS?m/z(％)：271(M-31，100)，303(M+H
+，19).
Embodiment 17:N-(5-chloro-2-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 17)
1,5-two chloro-3-nitro-benzene (98mg, 0.5mmol), N-methyl-4-anisidine (104mg, 0.75mmol) and Anhydrous potassium carbonate (138mg, 1.0mmol) in DMF (3ml), 180 ℃ in microwave, 15 minutes.Add less water, 2N hydrochloric acid is transferred pH to 3, dichloromethane extraction, saturated salt washing, anhydrous sodium sulfate drying.Remove by filter solvent and get bullion, get product through the preparative chromatography chromatographic separation.
Red oil, heavy 50mg, productive rate 34%.
1H NMR (CDCl
3) δ ppm 3.29 (3H, s, NCH
3), 3.78 (3H, s, OCH
3), 6.82 (2H, d, J=8.8Hz, ArH-2 ', 6 '), 6.92 (2H, d, J=8.8Hz, ArH-3 ', 5 '), 6.96 (1H, dd, J=2.4Hz and 8.4Hz, ArH-4), 7.17 (1H, d, J=2.4Hz, ArH-6), 7.67 (1H, d, J=8.4Hz, ArH-3).
MS?m/z(％)：293(M+1
+，100)，295(M+3
+，27)。
Embodiment 18:N-(3-chloro-4-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 18)
1, (197mg, 0.5mmol), (208mg 0.75mmol) joins among a small amount of DMF N-methyl-4-anisidine 5-two chloro-3-nitro-benzene, and the ice bath cooling adds t-BuOK down in batches, and (134mg 1.2mmol), stirs 30min afterwards under ice bath.Add less water, 2N hydrochloric acid is transferred pH to 3, dichloromethane extraction, saturated salt washing, anhydrous sodium sulfate drying.Remove by filter solvent and get bullion, get title product with recrystallizing methanol after the preparative chromatography chromatographic separation.
Yellow solid, heavy 164mg, productive rate: 56%; Fusing point 102-103 ℃.
1H NMR (CDCl
3): δ ppm 3.34 (3H, s, NCH
3), 3.86 (3H, s, OCH
3), 6.49 (1H, dd, J=5.6Hz and 9.6Hz, ArH-4), 6.64 (1H, d, J=5.6Hz, ArH-6), 6.98 (2H, d, J=8.8Hz, ArH-2 ', 6 '), 7.12 (2H, d, J=8.8Hz, ArH-3 ', 5 '), 7.97 (1H, d, J=9.6Hz, ArH-5).
MS?m/z(％)：293(M+1
+，100)，295(M+3
+，35)。
Embodiment 19:3-bromo-4-methoxyl group-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 19, method four)
Yellow oil, heavy 75mg, productive rate: 59%.
1H?NMR(CDCl
3)：δppm?3.23(3H，s，NCH
3)，3.73(3H，s，OCH
3)，3.78(3H，s，COOCH
3)，3.79(3H，s，OCH
3)，3.87(3H，s，OCH
3)，6.78(2H，d，J＝9.2Hz，ArH-2′，6′)，6.82(2H，d，J＝9.2Hz，ArH-3′，5′)，7.75(1H，d，J＝2.0Hz，ArH-2)，7.99(1H，d，J＝2.0Hz，ArH-5)。
MS?m/z(％)：380(M+1
+，95)，382(M+3
+，100)。
Embodiment 20:N, N-dimethyl--3-bromo-4-methoxyl group-5-[N-(4-p-methoxy-phenyl)-N-methyl)] amino-BM (compound 20),
(139mg 0.4mmol) is dissolved in the 10ml ethanol, adds H with compound 19
2O
2(30%, 0.16ml) and NaOH (6N, 0.06ml).To 40-50 ℃, 4 hours, pour in the frozen water mixture heating up into accent PH to 4-5, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying.Get the tawny solid after the removal of solvent under reduced pressure.It is dissolved among the 5ml DMF, and (0.06ml, 0.98mmol), add sodium hydride during 0 ℃ of ice bath (60%, 50mg 1.25mmol), continues reaction 1 hour under this temperature in batches to add methyl iodide.Reactant is poured in the frozen water into ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying.Bullion gets product through column chromatography after the removal of solvent under reduced pressure.
Yellow oil, heavy 118mg, productive rate 75%;
1H?NMR(CDCl
3)：δppm?2.98(3H，s，CONCH
3)，3.05(3H，s，CONCH
3)，3.22(3H，s，NCH
3)，3.72(3H，s，OCH
3)，3.77(3H，s，OCH
3)，6.81(4H，s，ArH-2′，3′，5′，6′)，7.10(1H，d，J＝2.0Hz，ArH-2)，7.37(1H，d，J＝2.0Hz，ArH-5)。
MS?m/z(％)：393(M+H
+，93)，395(M+3
+，100)。
Embodiment 21:3-bromo-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 21, method four)
Yellow oil, heavy 151mg, productive rate: 58%.
1H?NMR(CDCl
3)：δppm?3.27(3H，s，NCH
3)，3.84(3H，s，OCH
3)，3.87(3H，s，OCH
3)，6.94(2H，d，J＝9.2Hz，ArH-2′，6′)，6.95(1H，s，ArH-4)，7.10(2H，d，J＝8.8Hz，ArH-3′，5′)，7.29(1H，s，ArH-6)，7.50(1H，s，ArH-5)。
MS?m/z(％)：350(M+1
+，100)，352(M+3
+，90)。
Embodiment 22:N-(3-bromo-5-cyanic acid-2-methoxyl group) phenyl-N-(4-p-methoxy-phenyl) methylamine (compound 22, method four)
White solid, heavy 187mg, productive rate 58%, fusing point 78-80 ℃;
1H?NMR(CDCl
3)：δppm(3H，s，NCH
3)，3.73(3H，s，OCH
3)，3.79(3H，s，OCH
3)，6.84(4H，s，ArH-2′，3′，5′，6′)，7.28(1H，d，J＝2.0Hz，ArH-2)，7.53(1H，d，J＝2.0Hz，ArH-5)。
MS?m/z(％)：347(M+H+，92)，349(M+3+，100)。
Embodiment 23:3,4-dimethoxy-5-[N-methyl-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 23, method five)
Faint yellow solid, heavy 282mg, productive rate: 85%, fusing point: 57-59 ℃.
1H?NMR(CDCl
3)：δppm?3.22(3H，s，NCH
3)，3.71(3H，s，OCH
3)，3.77(3H，s，OCH
3)，3.87(3H，s，OCH
3)，3.90(3H，s，OCH
3)，5.57(1H，s，OH)，6.74(2H，d，J＝9.2Hz?ArH-2′，6′)，6.80(1H，d，J＝9.2Hz，ArH-3′，5′)，7.40(1H，d，J＝2.0Hz，ArH-6)，7.48(1H，d，J＝2.0Hz，ArH-2)。
LCMS-ESI?m/z(％)：332(M+H
+，100)。
Embodiment 24:3,4-dimethoxy-5-[N-methyl-(3-hydroxyl-4-p-methoxy-phenyl) amino] oil of Niobe (compound 24, method five)
According to method five obtain 3,4-dimethoxy-5-[N-(3 '-the inferior methoxyl group-4 of methoxyl group '-methoxyl group) phenyl-N-methyl] amino-oil of Niobe joins in the Virahol, stirs 24h under the room temperature.Reactant is poured in the frozen water, and ethyl acetate extraction (3 * 20ml), wash with saturated common salt, adds anhydrous sodium sulfate drying by organic phase.Bullion gets product through column chromatography after the removal of solvent under reduced pressure.
Yellow oil, heavy 173mg, productive rate: 61%.
1H NMR (CDCl
3): δ ppm 3.19 (3H, s, NCH
3), 3.73 (3H, s, OCH
3), 3.83 (3H, s, OCH
3), 3.87 (3H, s, OCH
3), 3.93 (3H, s, OCH
3), 5.57 (1H, s, 0H), 6.22 (1H, dd, J=8.4Hz and 2.8Hz, ArH-6 '); (6.41 1H, d, J=3.2Hz, ArH-2 '), 6.73 (1H, d, J=8.8Hz, ArH-5 '); 7.42 (1H, d, J=2.0Hz, ArH-2), 7.50 (1H, d, J=2.0Hz, ArH-5).
LCMS-ESI?m/z(％)：348(M+H
+，100)。
Embodiment 25:N, N-dimethyl--3-(5-formyl radical-2-furyl)-5-[N '-(4 '-methoxyl group) phenyl-N '-methyl] amino-BM (compound 25)
The compound N that will obtain according to method four, and N-dimethyl--3-bromo-5-[N-(4-p-methoxy-phenyl)-N-methyl] amino-BM (111mg, 0.31mmol); 5-formyl radical-2-furans boric acid (56mg, 0.40mmol), sodium hydrogencarbonate (81mg; 0.97mmol), four (triphenylphosphines) change palladium (18mg, 5%mmol); N, the following 140 ℃ of microwave reactions of dinethylformamide (1.5ml) and water (1.5ml) nitrogen protection 10 minutes.Reactant is poured in the frozen water, and ethyl acetate extraction (3 * 20ml), wash with saturated common salt, adds anhydrous sodium sulfate drying by organic phase.Bullion gets product through column chromatography after the removal of solvent under reduced pressure.
Yellow oil, heavy 71mg, productive rate 60%.
1H NMR (CDCl
3): δ ppm 2.97 (3H, s, C (O) NCH
3), 3.08 (3H, s, C (O) NCH
3), 3.33 (3H, s, NCH
3), 3.84 (3H, s, OCH
3), 3.87 (3H, s, OCH
3), 6.73 (1H, dd, J=1.2Hz and 1.2Hz, ArH-4), 6.77 (1H, d, J=3.6Hz, FuH-3), 6.93 (2H; D, J=8.8Hz, ArH-2 ', 6 '), 7.13 (2H, d, J=8.8Hz, ArH-3 ', 5 '); 7.17 (1H, m, ArH-6), 7.19 (1H, m, ArH-5), 7.30 (1H, s, FuH-3).
MS?m/z(％)：379(M+1
+，100)
Embodiment 26:6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-pyridine (compound 26)
(281mg 1.0mmol) is dissolved in the 8.0ml diacetyl oxide, adds 1 vitriol oil, is heated to 90 ℃, 18 hours with N-methyl-4-p-methoxy-phenyl amino-3-nitro-6-chloropyridine.Reactant is poured in the frozen water, and sodium hydroxide water liquid transfers to neutrality, separates out throw out, and suction filtration is dry, and the column chromatography separation obtains pure products 249mg, productive rate 77%, fusing point: 146-147 ℃.
1H?NMRδppm?2.01(3H，s，CH
3)，3.86(3H，s，OCH
3)，6.99(2H，d，J＝8.8Hz，ArH-2′，6′)，7.31(1H，d，J＝8.4Hz，PyH-5)，7.49(2H，d，J＝8.8Hz，ArH-3′，5′)，8.22(1H，d，J＝8.4Hz，PyH-4)。
MS?m/z(％)：322(M
+，100)，324(M+2
+，28)。
Embodiment 27:1-methoxyl group-2-[N-(4-p-methoxy-phenyl)-N-methyl] amino-4-nitro-naphthalene (compound 27, method four)
Red oil, heavy 166mg, productive rate 49%.
1H?NMR?δppm?3.37(3H，s，NCH
3)，3.75(3H，s，OCH
3)，4.16(3H，s，OCH
3)，3.79(3H，s，OCH
3)，3.87(3H，s，OCH
3)，6.69(2H，d，J＝9.2Hz，ArH-2′，6′)，6.78(2H，d，J＝9.2Hz，ArH-3′，5′)，7.61(2H，m，ArH-6，7)，7.71(1H，s，ArH-3)，7.97(1H，d，J＝8.0Hz，ArH-8)，8.34(1H，d，J＝8.4Hz，ArH-5)。
MS?m/z(％)：361(M+H
+，100)。
Embodiment 28. 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 the petridish of 2.5cm, 37 ℃, contains 5%CO
2Cultivate in the damp atmosphere.The clone adherent growth.Sample preparation and dilution and its process that is inoculated in the enchylema should be aseptic technique.Specimen is usually with DMSO dissolving ,-70 ℃ of preservations.In 96 well culture plates, each hole places the specimen and about 5000-20000 cell of different concns, places 72 hours.The GI of anticancer growth
50Value is confirmed by SRB (sulphonyl rhodamine B) method.Cancer therapy drug percephalotaxine and VP16 are as positive control.
A549: lung carcinoma cell; DU145: prostate cancer cell; KB: nasopharyngeal carcinoma cell; KB-VIN: drug-fast nasopharyngeal carcinoma cell is arranged.GI
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 is seen table 1.
Table 1. compound of Formula I and antitumour activity data thereof
Explain: A549: lung carcinoma cell; DU145: prostate cancer cell; KB: nasopharyngeal carcinoma cell; KB-VIN: drug-fast nasopharyngeal carcinoma cell is arranged; K562: human granulocyte property leukemia cell.Effective dose (the GI that suppresses the half growth of cancer cells
50) the expression antitumour activity.NA: unrestraint is active.
Claims (10)
1. the compound or pharmaceutically acceptable salt thereof of general formula I
Wherein,
X, Y and Z are N or CR independently of one another
4, said R
4Be H, halogen ,-NO
2,-CN ,-NH
2,-N
3, alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl ,-OH, haloalkyl, halogenated alkoxy ,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", aryl, heteroaryl, the substituted alkyl of quilt-OH; the substituted alkoxyl group of quilt-OH, the substituted alkylamino of quilt-OH, quilt-NR ' R " substituted alkyl, quilt-NR ' R " substituted alkoxyl group; quilt-NR ' R " substituted alkylamino, the substituted alkyl of quilt-C (O) OH, the substituted alkoxyl group of quilt-C (O) OH, the substituted alkylamino of quilt-C (O) OH; The substituted alkyl of quilt-C (O) OR ', the substituted alkoxyl group of quilt-C (O) OR ', the substituted alkylamino of quilt-C (O) OR '; Amido or alkylthio, wherein R ' and R " be H independently of one another, C
1-4Alkyl, C
2-4Thiazolinyl or C
2-4Alkynyl, and said aryl and heteroaryl can be selected from-CHO ,-OH ,-COOH ,-CN and-NH
2Substituting group replace;
R
1Be alkyl, thiazolinyl, alkynyl, naphthenic base, Heterocyclylalkyl, acyl group, not replacement or substituted aryl or not replacement or substituted heteroaryl, wherein the substituting group on aryl or the heteroaryl can be C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, halogen ,-NO
2,-CN ,-NH
2,-N
3,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H or-SO
2NR ' R "; Wherein R ' and R " are H or C independently of one another
1-4Alkyl;
R
2And R
3Encircle locational H capable of using, halogen ,-NO for A independently of one another
2,-CN ,-NH
2,-N
3, alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", aryl, heteroaryl, the substituted alkyl of quilt-OH; the substituted alkoxyl group of quilt-OH, the substituted alkylamino of quilt-OH, quilt-NR ' R " substituted alkyl, quilt-NR ' R " substituted alkoxyl group; quilt-NR ' R " substituted alkylamino, the substituted alkyl of quilt-C (O) OH, the substituted alkoxyl group of quilt-C (O) OH, the substituted alkylamino of quilt-C (O) OH; The substituted alkyl of quilt-C (O) OR ', the substituted alkoxyl group of quilt-C (O) OR ', the substituted alkylamino of quilt-C (O) OR '; Amido or alkylthio, wherein R ' and R " be H independently of one another, C
1-4Alkyl, and said aryl and heteroaryl can be selected from-CHO ,-OH ,-COOH ,-CN and-NH
2Substituting group replace; Perhaps
Work as X, when Y or Z are CH, R
2And R
3Can replace H independently and and X, Y or Z connect, and R
2And R
3Can form with the atom that they connected and A ring condensed aliphatic series ring, aromatic ring or hetero-aromatic ring, said aliphatic ring can comprise one; Two or more are independently selected from O, the heteroatoms of N and S, unconjugated double bond or three key; Wherein said aliphatic series ring; The optional position of aromatic ring or hetero-aromatic ring can be independently selected from halogen ,-OH ,-NH
2, C
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
L is (CR
5R
6)
n, R wherein
5And R
6Be H independently of one another, alkyl, alkenyl or alkynyl, wherein n is 0,1 or 2; With
Ar is not for replacing or by R
7Single-or many-substituted aryl or heteroaryl, the radicals R on wherein different the position of substitution
7Definition and above-mentioned R
2And R
3Definition identical; R
7Be preferably H, halogen ,-OH ,-NO
2,-CN ,-NH
2,-N
3,-CF
3,-OCF
3, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
2-4Thiazolinyl, C
2-4Alkynyl ,-C (O) OR ' or-CONR ' R "; Wherein R ' and R " are H or C independently of one another
1-4Alkyl;
Condition is not comprise following compound in the compound of general formula I:
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-phenyl amino)-3-nitropyridine.
2. the compound of claim 1, wherein, X, Y, Z is N; Perhaps X, Y, any two is N among the Z, another is CH; Perhaps X, Y, any two is CH among the Z, another is N; Perhaps X, Y, Z is CH.
3. the compound of claim 1, wherein, Ar is not for replacing or by R
7Replace single or polysubstituted phenyl.
4. the compound of claim 1, wherein,
R
2And R
3Be fluorine independently of one another, chlorine, bromine, iodine ,-NO
2,-CN ,-NH
2,-N
3, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6-alkylamino, C
2-6Thiazolinyl, C
2-6Alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", HO-C
1-6Alkyl, HO-C
1-6Alkoxyl group, HO-C
1-6Alkylamino, NR ' R " C
1-6Alkyl, NR ' R " C
1-6Alkoxyl group, NR ' R " C
1-6Alkylamino, HOOC-C
1-6Alkyl, HOOC-C
1-6Alkoxyl group, HOOC-C
1-6Alkylamino, R ' OOC-C
1-6Alkyl, R ' OOC-C
1-6Alkoxyl group or R ' OOC-C
1-6Alkylamino;
R
4Be H, halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6-alkylamino ,-NO
2,-CN ,-COOMe or-CONR ' R "; With
R
7Be H, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6-alkylamino, C
1-6Alkylthio, hydroxyl, amino ,-COOR ' or-CONR ' R "; Wherein R ' and R " are H or C
1-4Alkyl.
5. the compound of claim 1, wherein,
R
2And R
3Be fluorine independently of one another, chlorine, bromine, iodine ,-NO
2,-CN ,-NH
2,-N
3, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4-alkylamino, C
2-4Thiazolinyl, C
2-4Alkynyl ,-OH ,-CF
3,-OCF
3,-OCHF
2,-C (O) OH ,-C (O) OR ' ,-OCOR ' ,-CONR ' R " ,-SO
3H ,-SO
2NR ' R ", HO-C
1-4Alkyl, HO-C
1-4Alkoxyl group, HO-C
1-4Alkylamino, NR ' R " C
1-4Alkyl, NR ' R " C
1-4Alkoxyl group, NR ' R " C
1-4Alkylamino, HOOC-C
1-4Alkyl, HOOC-C
1-4Alkoxyl group, HOOC-C
1-4Alkylamino, R ' OOC-C
1-4Alkyl, R ' OOC-C
1-4Alkoxyl group or R ' OOC-C
1-4Alkylamino;
R
4Be H, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4-alkylamino ,-NO
2,-CN ,-COOMe or-CONR ' R "; With
R
7Be C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4-alkylamino, C
1-4-alkylamino, hydroxyl, amino ,-C (O) OR ' or-CONR ' R ".
6. the compound of claim 1 is selected from:
2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 1),
2,6-two chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 2),
4,6-two chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 3),
2-amino-6-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 4),
6-amino-2-chloro-4-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyrimidine (compound 5),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 6),
6-chloro-2-[N-allyl group-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 7),
6-chloro-2-[N-cyclopentyl-N-(4 '-p-methoxy-phenyl)] amino-3-nitropyridine (compound 8),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-3-nitropyridine (compound 9),
2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-methyl-3-nitro pyridine (compound 10),
6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 11),
2-chloro-3-cyanic acid-6-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine (compound 12),
2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-6-(N-methylamino-)-3-nitropyridine (compound 13),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 14),
6-chloro-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-3-nitropyridine (compound 15),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate (compound 16),
N-(5-chloro-2-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 17),
N-(3-chloro-4-nitrophenyl)-N-(4 '-p-methoxy-phenyl)-N-methylamine (compound 18),
3-bromo-4-methoxyl group-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 19),
N, N-dimethyl--3-bromo-4-methoxyl group-5-[N-(4-p-methoxy-phenyl)-N-methyl)] amino-BM (compound 20),
3-bromo-5-[N-methyl-N-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 21),
N-(3-bromo-5-cyanic acid-2-methoxyl group) phenyl-N-(4-p-methoxy-phenyl) methylamine (compound 22),
3,4-dimethoxy-5-[N-methyl-(4-p-methoxy-phenyl)] amino-oil of Niobe (compound 23),
3,4-dimethoxy-5-[N-methyl-(3-hydroxyl-4-p-methoxy-phenyl) amino] oil of Niobe (compound 24),
N, N-dimethyl--3-(5-formyl radical-2-furyl)-5-[N '-(4 '-methoxyl group) phenyl-N '-methyl] amino-BM (compound 25),
6-chloro-3-cyanic acid-2-[N-(4 '-p-methoxy-phenyl)-the N-ethanoyl] amino-pyridine (compound 26),
1-methoxyl group-2-[N-(4-p-methoxy-phenyl)-N-methyl] amino-4-nitro-naphthalene (compound 27),
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl-] amino-pyridine-3-methane amide,
6-methoxyl group-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-(N, N-dimethyl-) methane amide,
6-methylamino--2-[N-(4 '-p-methoxy-phenyl)-the N-methyl-) EL-970-3-methyl-formiate,
2-(4 '-the p-methoxy-phenyl methylamino)-6-methylamino pyridine-3-(N-methyl) methane amide,
2-(4 '-the p-methoxy-phenyl methylamino)-6-methylamino pyridine-3-(N, N-dimethyl-) methane amide,
6-(5-methylol-2-furyl)-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate,
6-(5-methyl-2-pyrryl)-2-[N-(4 '-p-methoxy-phenyl)-the N-methyl] amino-pyridine-3-methyl-formiate,
N-methyl-3-(4-p-methoxy-phenyl) amino-4-methoxynaphthalene methyl-formiate,
N-methyl-3-(4-anisole ylmethyl) amino-4-methoxynaphthalene methane amide,
7-(4-p-methoxy-phenyl methylamino)-1-methyl-6-nitro-2,3-dihydro-1,8-naphthyridines-4-ketone and
7-(4-p-methoxy-phenyl methylamino)-1-methyl-4-carbonyl-2,3-dihydro-1,8-naphthyridines-6-carboxylate methyl ester.
7. pharmaceutical composition, it comprises each compound or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers or vehicle of claim 1-6.
8. the preparation method of the compound of the general formula I of claim 1, this method comprises: in the presence of alkali, the substituted halides of general formula V and the substituted aminated compounds of general formula VI reacted in solvent, generates the compound of general formula I,
R wherein
1, R
2, R
3, L, Ar, X is described in the definition such as claim 1 of Y and Z.
9. the method for treatment tumour, said method comprises each the compound or pharmaceutically acceptable salt thereof of at least a claim 1-6 that needs the patient treatment of this treatment significant quantity.
10. each compound or pharmaceutically acceptable salt thereof of claim 1-6 is used to prepare the purposes of the medicine of treating tumour.
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| WO2008061112A2 (en) * | 2006-11-14 | 2008-05-22 | Myriad Genetics, Inc. | Pharmaceutical compounds as inhibitors of cell proliferation and the use thereof |
| CN101423513A (en) * | 2007-10-29 | 2009-05-06 | 中国医学科学院药物研究所 | Amine pyrimidine derivates, and production method thereof, and medicament composition and use |
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| US9708272B2 (en) | 2014-08-29 | 2017-07-18 | Tes Pharma S.R.L. | Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase |
| US10513499B2 (en) | 2014-08-29 | 2019-12-24 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
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