CN102863438A - N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof - Google Patents
N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof Download PDFInfo
- Publication number
- CN102863438A CN102863438A CN2012101954056A CN201210195405A CN102863438A CN 102863438 A CN102863438 A CN 102863438A CN 2012101954056 A CN2012101954056 A CN 2012101954056A CN 201210195405 A CN201210195405 A CN 201210195405A CN 102863438 A CN102863438 A CN 102863438A
- Authority
- CN
- China
- Prior art keywords
- pyridine
- piperazine
- pyrimidine
- base
- take
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC1C*CC1 Chemical compound CC1C*CC1 0.000 description 4
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N Cc1nccnc1 Chemical compound Cc1nccnc1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide of a structural formula (I). When X2 is -CH3, X1 is taken from one of -H, -CH3 or -Br arbitrarily; when X2 is -H, X1 is taken from one of -H, -Br and -CI arbitrarily; X3 is taken from -H or one of -H arbitrarily; and X4 is taken from -H. Organic salt or inorganic salt such as hydrochloride, sulfate, phosphate, mesylate, sulfonate, formate, acetate, malate or lactate acceptable in pharmacy is provided. The invention further relates to a preparation method of the compound and application of the compound and the salt acceptable in the pharmacy in preparation of antineoplastic drugs and particularly in preparation of drugs for treating lung cancer, liver cancer, gastric cancer and nasopharynx cancer.
Description
Technical field
The present invention relates to the chemical synthetic drug technical field, be specifically related to an organic micromolecule N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt and preparation method thereof and the application in the preparation antitumor drug.
Background technology
Cancer is one of principal disease of serious harm human health, China every year because of the dead number of cancer more than 1,000,000 people, and be year by year ascendant trend, become the human second largest killer who is only second to cardiovascular disorder.The at present treatment for cancer mainly contains the methods such as operative treatment, radiotherapy, chemotherapy, and wherein chemotherapy occupies very important status in the treatment of cancer.
Traditional cancer therapy drug mainly is cytotoxic drug, this kind anti-cancer drugs owner will act on the materials such as cell DNA, RNA and microcosmic albumen, great majority do not have selectivity, when killing and wounding cancer cells, also can kill and wound the normal cell of body, have the poor selectivity, the toxic side effect that are difficult to avoid and by force, easily produce the shortcomings such as resistance.
For overcome traditional cancer therapy drug these are significantly not enough; the research and development of organic molecule PTS with target feature are very active; the targeting of molecule or structural points in this class research and utilization organic molecule PTS reaches the selectivity that significantly improves cancer therapy drug, the purpose that reduces the toxicity of cancer therapy drug.
Heterogeneous ring compound is that a class has bioactive material, because the singularity of its structure, many heterocycle structures unit such as morpholine, piperazinyl, pyrimidine ring, thiazole and quinazoline etc. have become structural unit indispensable in the PTS, and these structural units can also make PTS have targeting.
Although domestic, abroad at the report that utilizes existing many documents aspect the heterocycle structure unit exploitation PTS, but since the heterocyclic compound of different chemical structures in vivo distribution and the bioavailability in the different tissues be not quite similar, the kind of the organic molecule class targeted anticancer medicine that can use in cancer therapy drug at present is limited, and has the undesirable problem of inhibition of cancer cells.
Although the heterocyclic compound of report demonstrates many advantages in the supernormal growth of anticancer and the aspects such as selectivity that improve cancer cells at present, but still a lot of unsatisfactory parts are arranged.Therefore, utilize the diversity of heterocycle structure, further research and development heterocyclic anticancer new drug more, better effects if is significant.
Summary of the invention
The object of the invention is to for existing organic molecule class targeted anticancer medicine that it exists that kind is limited, cancer therapy effect undesirable problem still, a kind of N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt with better antitumour activity is provided.
Another object of the present invention provides the preparation method of above-mentioned N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt.
Another object of the present invention provides above-mentioned N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or the application of its pharmacy acceptable salt in the preparation cancer therapy drug.
Above-mentioned purpose of the present invention is achieved by following scheme:
A kind of N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt, its structural formula is shown in formula I.
In the formula I,
Work as X
2For-CH
3The time, X
1Take from-H ,-CH
3,
Or-among the Br any one;
Work as X
2During for-H, X
1Take from-H ,-Br ,-among the Cl any one;
X
3Take from-H or
In any one;
X
4Take from-H.
The present invention gives the title of concrete structure and corresponding N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides of 14 kinds of R, specific as follows shown in:
In the above-mentioned formula I,
X
1Take from-H X
2Take from-H this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-thiazole-5-acid amides;
In the above-mentioned formula I,
X
1Take from-CH
3, X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2,4-dimethylthiazole-5-acid amides;
In the above-mentioned formula I,
X
1Take from-H X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from
X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-phenyl-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from
X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(pyridin-3-yl)-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from
X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-chloro-phenyl-)-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from
X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-trifluorophenyl)-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from-Br X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from
X
2Take from-CH
3, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(morpholine-2-yl)-4-methylthiazol-5-acid amides;
In the above-mentioned formula I,
X
1Take from-Cl X
2Take from-H this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides;
In the above-mentioned formula I,
X
1Take from-Br X
2Take from-H this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo thiazole-5-acid amides;
In the above-mentioned formula I,
X
3Take from-H X
4Take from-H this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-thiazoline-5-acid amides;
In the above-mentioned formula I,
X
3Take from
X
4Take from-H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides called after N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-dihydro-2-(pyridin-3-yl) thiazole-5-acid amides.
The present invention also provides the preparation method of N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt, and this preparation method comprises the steps:
The preparation of step 1.2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine
Take 2-amino-4-chloropyrimide and 4-(pyridine-2-yl) piperazine as raw material, in the presence of tertiary amine catalyst and solvent, 20～80 ℃ of lower reactions 4～24 hours, reaction is filtered after finishing, collect organic phase, organic phase is used first the NaOH solution washing, it is neutral washing to organic phase with aquae destillata again, in organic phase, add at last anhydrous magnesium sulfate drying, filter, after organic phase is concentrated, with re-crystallizing in ethyl acetate, filter, collect the white powder on the filter paper, vacuum-drying obtains white powder and is 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine, and the structural formula of 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine is shown in formula II.
In the above-mentioned steps 1, the mol ratio of 2-amino-4-chloropyrimide and 4-(pyridine-2-yl) piperazine is 1:0.33～3.
In the above-mentioned steps 1, tertiary amine catalyst is selected from triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, the basic amine of N-methyl bicyclic, N-methylmorpholine, N, N-diethyl piperazine or N, one or more mixtures in the N-lupetazin etc.
In the above-mentioned steps 1, solvent is selected from ethanol, methylene dichloride, trichloromethane, ethyl acetate, pyridine, 1, one or more mixtures of 2-ethylene dichloride, benzene, toluene, acetone, butanone, cyclohexanone or DMF.
The chemical equation of above-mentioned steps 1 is as follows.
The preparation of step 2.N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides
Take 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) of step 1 gained and substituted thiazole acid or replace hydrogenation thiazole acid or substituted thiazole acyl chlorides or replace hydrogenation thiazole acyl chlorides as raw material, in the presence of catalysts and solvents, 25～85 ℃ of lower reactions 8～48 hours, reaction is used first saturated Na after finishing
2CO
3Collect organic phase behind the solution washing, be neutral with saturated NaCl solution washing organic phase to organic phase again, then in organic phase, add anhydrous magnesium sulfate drying, filter, after organic phase is concentrated, adopt the silica gel column chromatography separating-purifying, thereby obtain N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides, its structural formula is shown in formula I.
In the above-mentioned steps 2,2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) is 1:0.33～3 with the mol ratio of substituted thiazole acid or replacement hydrogenation thiazole acid or substituted thiazole acyl chlorides or replacement hydrogenation thiazole acyl chlorides.
In the above-mentioned steps 2; at first control temperature and be-5～5 ℃; in reactor, add catalysts and solvents; then under agitation in reactor, add the dichloromethane solution that contains substituted thiazole acid or replacement hydrogenation thiazole acid or substituted thiazole acyl chlorides or replace hydrogenation thiazole acyl chlorides; stir 20～50min; then under nitrogen protection, drip 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) of step 1 gained, and be warming up to 25～85 ℃ of reactions 8～48 hours.
In the above-mentioned steps 2, catalyzer is selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 4-N, one or more mixtures in N-lutidine, 1-hydroxy benzo triazole, 6-chloro-1-hydroxy benzo triazole or 1-hydroxyl-7-nitrogen heterocyclic benzotriazole etc.
In the above-mentioned steps 2, solvent is selected from methylene dichloride, trichloromethane, ethyl acetate, pyridine, 1, one or more mixtures in 2-ethylene dichloride, benzene, toluene, acetone, butanone, cyclohexanone or the DMF etc.
In the above-mentioned steps 2, the moving phase of silica gel column chromatography is one or more the mixed solvent in ethyl acetate, ether, methylene dichloride, trichloromethane, methyl alcohol, ethanol, toluene, acetone, butanone, cyclohexane or the normal hexane etc.
The chemical equation of above-mentioned steps 2 is as follows.
N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt, its described pharmaceutically acceptable organic salt or inorganic salt comprise hydrochloride, vitriol, phosphoric acid salt, (first) sulfonate, formate, acetate, malate or lactic acid salt etc.
N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt have good antitumor action through analysis of experiments, can be separately for the preparation of antitumor drug in the time of concrete the application, perhaps form composition with pharmaceutically acceptable carrier and prepare antitumor drug, as forming composition for oral administration or parenteral administration composition with pharmaceutically acceptable carrier.
Compared with prior art, the present invention has following beneficial effect:
The remarkable advantage of N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides of the present invention preparation is that the growth to four kinds of cancer cells such as Adenocarcinoma of lung cell line A549, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901 and human nasopharyngeal epithelioma 1 CNE2 has more significant restraining effect, therefore, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides of the present invention's preparation has the potential of the PTS that is developed to treatment lung cancer, liver cancer, cancer of the stomach and nasopharyngeal carcinoma.
Embodiment
Below in conjunction with specific embodiment the present invention is done further description, but specific embodiment is not done any restriction to the present invention.
Embodiment 1 N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-amide compound
The preparation method of the present embodiment N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-amide compound comprises the steps:
The preparation of step 1.2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine
Add successively 0.6475g(5mmol at 100ml in the there-necked flask of reflux condensing tube, thermometer) 2-amino-4-chloropyrimide, 2.9340g(15mmol) 4-(pyridine-2-yl) piperazine, 9.5ml N, N-dimethyl benzylamine and 50ml anhydrous pyridine, under agitation, in 20 ℃ of lower reactions 24 hours, during with thin-layer chromatography monitoring reaction degree.Reaction is filtered after finishing, and organic phase is used first the NaOH solution washing of 1M, washs with aquae destillata until organic phase is neutral again, adds at last anhydrous MgSO in organic phase
4Dried overnight, filter, after filtrate is concentrated, with re-crystallizing in ethyl acetate, filter, collect the white powder on the filter paper, vacuum-drying obtains the white powder material and is 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine, heavy 1.0488g, yield 80.0%, its structural formula shown in formula II, its m.p.408.5 ℃;
1H-NMR(CDCl
3, 300MHz): δ 3.61-3.74(m, 8H), δ 4.74(s, 2H), δ 5.97-5.99(d, 1H), δ 6.64-6.67(m, 4H), δ 7.41-7.53(t, 1H), δ 7.89-7.91(d, 1H), δ 8.19-8.22(d, 1H); ESI-MS m/e:257.3([M+H]
+), 258.3([M+2H]
+); Ultimate analysis: theoretical value C 60.29%, H 6.29%, N 32.79%, test value C 59.76%, H 6.37%, N 31.48%.
The preparation of step 2.N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides
With 100ml with reflux condensing tube; the there-necked flask of thermometer is reaction vessel; under 5 ℃; add 0.0865g(0.5mmol) 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide; 0.0675g(0.5mmol) I-hydroxybenzotriazole and 50ml pyridine; under agitation drip and contain 0.2453g(1.5mmol) the dichloromethane solution reaction 50min of 2-chlorine thiazole-5-carboxylic acid; then under nitrogen protection; drip 0.1280g(0.5mmol) 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II); and be warmed up to 20 ℃ the reaction 48 hours, during with thin-layer chromatography monitoring reaction degree.
Reaction is used first saturated Na after finishing
2CO
3Solution washing is neutral with saturated NaCl solution washing to organic phase again, adds at last anhydrous magnesium sulfate drying and spend the night in organic phase, filter, after filtrate is concentrated, adopt silica gel column chromatography to carry out separating-purifying, moving phase is the methylene dichloride/alcohol mixed solvent of volume ratio 8/2.Collection contains the component of product, removes behind the mixed solvent to get white powder, in 50 ℃ of lower vacuum-dryings, namely gets N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides, weight 0.1080g, and yield is 53.8%.Structure is as follows:
The present embodiment N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides
1H-NMR(CDCl
3, 300MHz): δ 2.44-2.56(m, 4H), δ 3.68-3.76(t, 4H), δ 6.23-6.28(m, 1H), δ 8.00-8.03(m, 2H), δ 7.41-7.45(m, 2H), δ 8.16-8.18(d, 1H), δ 8.28-8.31(m, 1H), δ 9.22-9.23(d, 1H); ESI-MS m/e:403.8([M+2H]
+); Ultimate analysis: theoretical value C 50.81%, H 3.99%, N 24.41%, S 7.97%, test value C50.54%, H 4.05%, N 24.79%, S 7.61%.
Embodiment 2 N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt are to the restraining effect of cancer cells
The present embodiment adopts lung cancer cell line A549, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901 and human nasopharyngeal epithelioma 1 CNE2 are as experimental subjects, with 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-thiazole-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2,4-dimethylthiazole-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-phenyl-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(pyridin-3-yl)-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-chloro-phenyl-)-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-trifluoromethyl)-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(morpholine-2-yl)-4-methylthiazol-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo thiazole-5-acid amides, N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-thiazoline-5-acid amides and N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-dihydro-2-(pyridin-3-yl) thiazole-5-acid amides is Experimental agents, N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is carried out experimental study to the restraining effect of cancer cells, and concrete operations are as follows.
Adopt the MTT development process, the lung cancer cell line A549 that takes the logarithm vegetative period, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901, human nasopharyngeal epithelioma 1 CNE2, behind 0.25% tryptic digestion, add perfect medium and trypsinase, and piping and druming is prepared into single cell suspension repeatedly.Behind the tally counting, be inoculated in 96 orifice plates with 5000 cells in every hole.In 37 ℃, 5%CO
2Leave standstill in the incubator to cultivate and make cell attachment.Inhale behind the 24h and abandon original substratum, with 150 μ L PBS washing 1 time, add the fresh perfect medium that contains 10% newborn calf serum of 100 μ L, then add Experimental agents, simultaneously with the liquid medium hole of not dosing as negative control, only to add the nutrient solution hole as zeroing hole (not containing cancer cells), after cultivating 72h respectively, sucking-off substratum and liquid with PBS washing 1 time, add 200 μ L substratum and 20 μ L concentration are 5mgmL
-1MTT liquid, continue to cultivate 4h, then inhale the liquid of abandoning in the orifice plate, add 150 μ L DMSO and repeatedly blow and beat, the bluish voilet crystallization is fully dissolved; Measure absorbance value (OD value), cell survival rate (%)=(test group OD value/control group OD value) * 100%, cell inhibitory rate (%)=(1-test group OD value/control group OD value) * 100% with enzyme-linked immunosorbent assay instrument with 490nm wavelength place.
Adopt IC
50Value is as shown in table 1 to the antitumour activity evaluation result of N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides.By the OD value of measuring in different time points, obtain the inhibiting rate changing conditions of different time points, draw change curve, as optimum time point, the best use of time that is drawn medicine by time curve is 36h with curve arrival that time point of plateau.
Table 1 N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) IC of amides effect after 36 hours
50Value
As can be seen from Table 1, N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides all demonstrates preferably antitumour activity to Adenocarcinoma of lung cell line A549, hepatoma cell strain Bel-7402, stomach cancer cell line SGC7901 and human nasopharyngeal epithelioma 1 CNE2.
Claims (9)
1. a N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt, its structural formula is shown in formula I:
（Ⅰ）
In the formula I, R=
Or
Work as X
2For-CH
3The time, X
1Take from-H ,-CH
3,
,
,
,
,
Or-among the Br any one;
Work as X
2During for-H, X
1Take from-H ,-Br ,-among the Cl any one;
X
3Take from-H or
In any one;
X
4Take from-H;
Work as R=
, X
1Take from-H X
2Take from-during H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-thiazole-5-acid amides;
Work as R=
, X
1Take from-CH
3, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2,4-dimethylthiazole-5-acid amides;
Work as R=
, X
1Take from-H X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from
, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-phenyl-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from
, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(pyridin-3-yl)-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from
, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-chloro-phenyl-)-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from
, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(4-trifluoromethyl)-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from-Br X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from
, X
2Take from-CH
3The time, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-(morpholine-2-yl)-4-methylthiazol-5-acid amides;
Work as R=
, X
1Take from-Cl X
2Take from-during H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-diuril azoles-5-acid amides;
Work as R=
, X
1Take from-Br X
2Take from-during H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-2-bromo thiazole-5-acid amides;
Work as R=
, X
3Take from-H X
4Take from-during H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-thiazoline-5-acid amides;
Work as R=
, X
3Take from
, X
4Take from-during H, this N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides is N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base)-4,5-dihydro-2-(pyridin-3-yl) thiazole-5-acid amides.
2. described N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt according to claim 1 is characterized in that described pharmaceutically acceptable organic salt or inorganic salt comprise hydrochloride, vitriol, phosphoric acid salt, metilsulfate, sulfonate, formate, acetate, malate or lactic acid salt.
3. the preparation method of the described N-of claim 1 (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt is characterized in that this preparation method's step is as follows:
The preparation of step 1. 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine
Take 2-amino-4-chloropyrimide and 4-(pyridine-2-yl) piperazine as raw material, in the presence of tertiary amine catalyst and solvent, 20-80 ℃ of lower reaction 4-24 hour, reaction is filtered after finishing, organic phase is used first the NaOH solution washing, it is neutral washing to organic phase with aquae destillata again, in organic phase, add at last anhydrous magnesium sulfate drying, filter, after organic phase is concentrated, with re-crystallizing in ethyl acetate, filter, collect the white powder on the filter paper, dry in vacuum drying oven, obtain white powder and be 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine, its structural formula is shown in formula II:
（Ⅱ）
The preparation of step 2. N-(4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides
Take 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) of step 1 gained and substituted thiazole acid or replace hydrogenation thiazole acid or substituted thiazole acyl chlorides or replace hydrogenation thiazole acyl chlorides as raw material, in the presence of catalysts and solvents, 25～85 ℃ of lower reactions 8～48 hours, reaction is used first saturated Na after finishing
2CO
3Collect organic phase behind the solution washing, be neutral with saturated NaCl solution washing organic phase to organic phase again, then in organic phase, add anhydrous magnesium sulfate drying, filter, after organic phase is concentrated, adopt the silica gel column chromatography separating-purifying, namely get N-of the present invention (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides, its molecular structural formula is shown in formula I.
4. described preparation method according to claim 3 is characterized in that in the described step 1, and the mol ratio of 2-amino-4-chloropyrimide and 4-(pyridine-2-yl) piperazine is 1:0.33～3; In the described step 2,2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) is 1:0.33～3 with the mol ratio of substituted thiazole acid or replacement hydrogenation thiazole acid or substituted thiazole acyl chlorides or replacement hydrogenation thiazole acyl chlorides.
5. described preparation method according to claim 3, it is characterized in that in the described step 1, tertiary amine catalyst is selected from triethylamine, triethylenediamine, tetramethyl butane diamine, N, N-dimethyl benzylamine, N-ethylmorpholine, N, N-dimethyl cyclohexyl amine, N, the basic amine of N-methyl bicyclic, N-methylmorpholine, N, N-diethyl piperazine or N, one or more mixtures in the N-lupetazin; Described solvent is selected from ethanol, methylene dichloride, trichloromethane, ethyl acetate, pyridine, 1, one or more mixtures of 2-ethylene dichloride, benzene, toluene, acetone, butanone, cyclohexanone or DMF.
6. described preparation method according to claim 3; it is characterized in that in the described step 2; at first control temperature and be-5～5 ℃; in reactor, add catalysts and solvents; then under agitation in reactor, add the dichloromethane solution that contains substituted thiazole acid or replacement hydrogenation thiazole acid or substituted thiazole acyl chlorides or replace hydrogenation thiazole acyl chlorides; stir 20～50min; then under nitrogen protection; drip 2-amido-4-(4-(pyridine-2-yl) piperazine) pyrimidine (II) of step 1 gained, and be warming up to 25～85 ℃ of reactions 8～48 hours.
7. according to claim 3 or 6 described preparation methods, it is characterized in that in the described step 2, catalyzer is selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 4-N, one or more mixtures in N-lutidine, 1-hydroxy benzo triazole, 6-chloro-1-hydroxy benzo triazole or 1-hydroxyl-7-nitrogen heterocyclic benzotriazole; Described solvent is selected from methylene dichloride, trichloromethane, ethyl acetate, pyridine, 1, one or more mixtures in 2-ethylene dichloride, benzene, toluene, acetone, butanone, cyclohexanone or the DMF.
8. described preparation method according to claim 3, it is characterized in that in the described step 2, the moving phase of silica gel column chromatography is one or more the mixed solvent in ethyl acetate, ether, methylene dichloride, trichloromethane, methyl alcohol, ethanol, toluene, acetone, butanone, cyclohexane or the normal hexane.
9. the described N-of claim 1 (4-(4-(pyridine-2-yl) piperazine-1-yl) pyrimidine-2-base) amides or its pharmacy acceptable salt application in the preparation antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101954056A CN102863438A (en) | 2012-06-13 | 2012-06-13 | N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101954056A CN102863438A (en) | 2012-06-13 | 2012-06-13 | N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102863438A true CN102863438A (en) | 2013-01-09 |
Family
ID=47442599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101954056A Pending CN102863438A (en) | 2012-06-13 | 2012-06-13 | N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102863438A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524409A (en) * | 2013-09-26 | 2014-01-22 | 上海仁力医药科技有限公司 | Quinoline compound as well as preparation method and application thereof |
| CN111635356A (en) * | 2018-11-23 | 2020-09-08 | 厦门大学 | Compound of CARM1 small molecule inhibitor, medicinal salt, medicinal composition and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007137955A1 (en) * | 2006-05-30 | 2007-12-06 | F. Hoffmann-La Roche Ag | Piperidinyl pyrimidine derivatives |
-
2012
- 2012-06-13 CN CN2012101954056A patent/CN102863438A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007137955A1 (en) * | 2006-05-30 | 2007-12-06 | F. Hoffmann-La Roche Ag | Piperidinyl pyrimidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 谢晓琼: ""新型分子靶向抗癌药物的合成及其微胶囊化研究"", 《中国优秀硕士学位论文全文数据库（电子期刊）工程科技Ⅰ辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524409A (en) * | 2013-09-26 | 2014-01-22 | 上海仁力医药科技有限公司 | Quinoline compound as well as preparation method and application thereof |
| CN103524409B (en) * | 2013-09-26 | 2015-09-02 | 上海仁力医药科技有限公司 | Quinolines and preparation method thereof and application |
| CN111635356A (en) * | 2018-11-23 | 2020-09-08 | 厦门大学 | Compound of CARM1 small molecule inhibitor, medicinal salt, medicinal composition and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2015518011A (en) | Pyrrolo [2,1-f] [1,2,4] triazine derivatives and their antitumor applications | |
| CN104926788A (en) | Substituted piperidin derivative, and pharmaceutical composition containing substituted piperidin derivative and application thereof in antitumor | |
| CN102260260B (en) | 8-phenyl xanthine compound, preparation method, medicine composition including the compound and purpose thereof | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| CN102863438A (en) | N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof | |
| CN109400632B (en) | Bis-fluoroquinolone oxadiazole urea derivative containing N-methylenoxacin and preparation method and application thereof | |
| CN102911157B (en) | (E)-3-[2-bromo-5-(3-substituted propoxy)]phenyl-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl acrylamide compound | |
| EP3369740B1 (en) | New cytidine derivative dimers and applications thereof | |
| CN103435560B (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain | |
| WO2015021833A1 (en) | Conjugated diene derivatives, preparation method therefor, and uses thereof as anticancer drug | |
| CN110804039B (en) | Phthalimide-containing 1, 8-naphthalic anhydride derivatives, pharmaceutically acceptable salts thereof and application of anti-tumor drugs thereof | |
| CN109369676B (en) | Bis-fluoroquinolone oxadiazole urea N-acetyl norfloxacin derivative and preparation method and application thereof | |
| CN104177346A (en) | Quinazoline compound and use thereof | |
| CN102702116B (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof | |
| CN102898379A (en) | N-(4-(4-(3-chlorphenyl)piperazino-1-yl)pyrimidyl-2-yl)amide or its salts, and preparation method and use thereof | |
| CN102924441A (en) | N-(4-(4-(3-fluorophenyl)piperazin-1-yl)pyrimidin-2-yl)-amide or salts thereof, preparation method and applications | |
| CN109438482B (en) | Bis-fluoroquinolone oxadiazole urea derivative containing rufloxacin and preparation method and application thereof | |
| CN102775400A (en) | N-(4-(4-ethyl piperazine-1-yl)pyrimidine-2-yl)amide or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| CN103242321A (en) | Benzylpiperazine compound and anti-tumor application thereof | |
| CN109761998B (en) | Preparation and application of bis-fluoroquinolone thiadiazole urea Fleroxacin derivative | |
| CN109438472B (en) | Bis-fluoroquinolone oxadiazole urea derivative containing N-methyl gatifloxacin and preparation method and application thereof | |
| CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
| CN113387934B (en) | Polyaryl substituted imidazole derivative and preparation method and application thereof | |
| CN109400626B (en) | Bis-fluoroquinolone oxadiazole urea fleroxacin derivative and preparation method and application thereof | |
| CN109400627B (en) | Bis-fluoroquinolone oxadiazole urea derivative containing N-methyl lomefloxacin and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130109 |