CN102796110B - Aniline pyrimidine compound and its production and use - Google Patents
Aniline pyrimidine compound and its production and use Download PDFInfo
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- CN102796110B CN102796110B CN201110133891.4A CN201110133891A CN102796110B CN 102796110 B CN102796110 B CN 102796110B CN 201110133891 A CN201110133891 A CN 201110133891A CN 102796110 B CN102796110 B CN 102796110B
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Abstract
The invention belongs to pharmaceutical synthesis field, relate to the aniline pyrimidine compounds of general formula <b> (</b><bGreatT.Gre aT.GT I) </b>, be specifically related to a kind of 4 N-having a quaternary heterocyclic substituted [4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-benzamide compound, and preparation method thereof and application medically.The present invention is tested by anti tumor activity in vitro, and result shows, and described compound is to the anti tumor activity in vitro IC of MKN-45 gastric cancer tumor strain
50value is nM level, and the activity of the obvious inhibition tumor cell of compound energy of the present invention, can prepare new type antineoplastic medicine further.？？
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to novel Aniline pyrimidine compound, preparation method and application.Be specifically related to a kind of 4 N-having a quaternary heterocyclic substituted [4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-benzamide compound, and preparation method thereof and application medically.
Background technology
Malignant tumour has become the common disease of serious harm people's life health.According to incompletely statistics, the whole world about has the new cases of 2,000 ten thousand every year; The annual new cases of China are about 160-200 ten thousand, dead 1,300,000.Because tumour has the ability of transfer in early days, in clinical diagnosis primary tumo(u)r, the patient of about 50% has produced amphi position transfer, tumour cell growth makes a variation soon, easily, thus generation multidrug resistance, cause chemotherapy failure, according to the relevent statistics, wherein more than 90% is relevant to the multidrug resistance of tumour cell, and the antitumor drug applied clinically at present far can not meet the requirement for the treatment of.
Research discloses Philadelphia chromosome and is No. 22 karyomit(e)s and No. 9 karyomit(e) generation transpositions and the abnormal fusion gene that produces, and BCR – ABL oncogene is exactly the product of Philadelphia chromosome.Philadelphia chromosome (PhiladephiaChromosome, Ph) be the clinical diagnosis mark of chronic myelocytic leukemia, about have the chronic myelocytic leukemia people of 95 ℅ and acute lymphoblastic leukemia (AcuteLymphoblasticLeukemia, the ALL) grownup of 25% and 5% ALL children body in there is Philadelphia chromosome.The albumen (P210) of Bcr/abl oncogenes encode tool tyrosine kinase activity.This albumen and cell signaling protein-interacting, upset cellular informatics transmittance process, makes CML cell proliferation and break up out of control.
The continuously kinase activity of BCR-ABL cancer protein makes diversified substrate generation phosphorylation, comprises RAS, thus have activated many barss transduction pathway.RAS be signal from cytolemma very important reference mark to nucleus transductive process, the overexpression of the RAS that BCR-ABL causes seems to change the signal transduction in stem cell, thus cause abnormal cell mitogen and cancer cells amplification.In addition, BCR-ABL cancer protein can reduce cell adhesion on matrix base film (stromalmatrix), so just make the cytolemma signal interruption of interaction between raw blood stem cell and stroma cell and cell adhesion molecule mediation, thus make haematogonium will experience the longer time could to break up.BCR-ABL cancer protein also can make antiapoptotic signals inoperative, thus is conducive to existence and the division growth of cancer cells.Theoretically, since chronic myelocytic leukemia depends on the kinase activity of BCR-ABL protein, so an effective BCR-ABL histidine kinase inhibitor should be eliminated BCR-ABL protein positive colony and recover Philadelphia chromosome negative hemopoietic.BCR-ABL kinase inhibitor, with the ATP-binding site on ATP competitive binding BCR-ABL tyrosine kinases catalyze territory, thus can make BCR-ABL kinases does not have phosphate group shift to its substrate, and signal transmission is interrupted, reach the object of disease treatment.
There are three kinds of small molecules BCR-ABL kinase inhibitor in the market, as: imatinib (imatinib mesylate, Novartis Co., Ltd) is ratified the chronic myelocytic leukemia as BCR-ABL overexpression 2001 by U.S. FDA; Dasatinib (flutters Rui Sai, Shi Guibao company) ratified the oral pharmaceutical for the treatment of chronic myelocytic leukemia (cml) as one in 2006 by U.S. FDA, also ratify it simultaneously and be used for the treatment of adult ph Chromosome Positive Acute Lymphocytic leukemia (ph+all); AMN107 (Da Xina, Novartis Co., Ltd) 2008 by U.S. FDA approval to imatinib-resistant or the chronic myelocytic leukemia that do not tolerate.
Although above three kinds of medicines show preferably curative effect, constantly increase the resistance of opening, and the difference between individual patients, force the micromolecular compound safely and effectively that people constantly go research and development new, in order to suppress BCR-ABL kinases.
Summary of the invention
The object of this invention is to provide the novel Aniline pyrimidine compound with good anti-tumor activity, be specifically related to a kind of 4 N-having a quaternary heterocyclic substituted [4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-benzamide compound.
Another object of the present invention is to provide the preparation method of above-mentioned Aniline pyrimidine compound, particularly relates to the method that preparation 4 has N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] the phenyl]-benzamide compound of quaternary heterocyclic substituted.
Aniline pyrimidine compound of the present invention has the structure of following logical formula I:
Wherein
R=
or
,
X=CH
2or O or NH or S or SO or SO
2
Y=CH
2or O or NH or S or SO or SO
2
X
1=CH
2or O or NH or S or SO or SO
2
X
2=CH
2or O or NH or S or SO or SO
2
Y
1=CH or N
Y
2=CH
2or O or NH or S or SO or SO
2
Aniline pyrimidine compound of the present invention is tested by anti tumor activity in vitro, and described compound shows good anti-tumor activity, can prepare new type antineoplastic medicine further.
In the present invention, preferred compound has the structure of following compound 1,2,3,4,5,6:
12
34
56
For compound 1, the preparation process of compound of the present invention is as follows:
The present invention is studied by Pharmacodynamic, anti tumor activity in vitro test is carried out to the strain of MKN-45 gastric cancer tumor, result shows, described 4 have the N-of quaternary heterocyclic substituted [4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-benzamide compound to have good anti tumor activity in vitro, and compound is for the anti tumor activity in vitro IC of MKN-45 gastric cancer tumor strain
50value is nM level, and wherein compound 1,2,5 and 6 is for the extracorporeal anti-tumor IC of MKN-45 gastric cancer tumor strain
50value is all less than 1nM, and the activity of compound 2 is similar to positive control anti-tumor medicine imatinib, and result shows, the activity of the obvious inhibition tumor cell of compound energy of the present invention, can prepare new type antineoplastic medicine further.
In the present invention, the pharmacodynamics test method adopted is art technology and the method known by personnel;
In the present invention, the gastric cancer tumor strain adopted is that art technology obtains by commercial approach.
Aniline pyrimidine compound of the present invention especially can prepare the medicine of relative disease caused by treatment Tyrosylprotein kinase functional disorder, in view of the product that BCR – ABL oncogene is Philadelphia chromosome, Philadelphia chromosome is the clinical diagnosis mark of chronic myelocytic leukemia, about there are the chronic myelocytic leukemia people of 95 ℅ and the acute lymphoblastic leukemia (AcuteLymphoblasticLeukemia of 25%, ALL) grownup and 5% ALL children body in there is Philadelphia chromosome, the albumen (P210) of Bcr/abl oncogenes encode tool tyrosine kinase activity, this albumen and cell signaling protein-interacting, upset cellular informatics transmittance process, make CML cell proliferation and break up out of control.Therefore relative disease comprises caused by this BCR-ABL Tyrosylprotein kinase functional disorder of the present invention, the acute lymphoblastic leukemia of Ph chromatin-positive of chronic myelogenous leukemia (CML), cancer of the stomach, gastrointestinal stromal knurl, acute lymphoblastic leukemia, intractable or recurrence, gastrointestinal stromal glucagonoma and the systemic mastocytosis just controlled and complication thereof.
Embodiment
Embodiment 1: synthetic compound 1, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(2-oxa--6-aza-spiro [3.3] heptyl-6-ylmethyl)-benzamide
1) nitrate of 2-methyl-5-nitro benzene-guanidine is synthesized
In the beaker of 100 milliliters, first add 5-nitro-2-aminotoluene (10g, 65.7mmol) He 50 milliliters of ethanol, after stirring 20 points, slowly add the salpeter solution of 4.6 milliliter 65%, continue to stir until after temperature of reaction to room temperature, add 8 milliliters of cyanamide solution, temperature rising reflux stirring reaction 24 hours.Reaction terminates, and reaction solution is chilled to room temperature, filters, then by filter cake 50 milliliters of ethanol agitator treatings, refilters collection filter cake, obtain light yellow product 7 grams after drying.
2) 3-dimethylamino-1-pyridin-3-yl-acrylketone is synthesized
5 grams of 3-acetylpyridine and 25 milliliters of DMF-DA are added, stirring and refluxing 24 hours in 50 ml flasks.After reaction terminates, water pump negative pressure pumps unnecessary reaction solution, faint yellow solid in remaining bottle; Then added by 50 milliliters of normal hexane solution, stirring at room temperature, to wash away unnecessary reactant, collecting by filtration filter cake, obtains 6.9 grams of yellow products after drying.
3) (2-methyl-5-nitrophenyl)-(4-pyridin-3-yl-pyrimidine-2-base)-amine is synthesized
In 100 ml flasks, add the nitrate of 2.57 grams of 2-methyl-5-nitro benzene-guanidines, 1.76 grams of 3-dimethylamino-1-pyridin-3-yl-acrylketone, 0.24 gram of sodium hydroxide, 40 milliliters of Virahols, reflux stirs 24 hours.Be chilled to room temperature after reaction terminates, after filtration, filter cake is added 20 ml waters, agitator treating 1 hour, refilters, then uses 30 milliliters of washing with alcohol, filters and obtains filter cake, obtain 1.2 grams of white products after drying.
4) N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-pyrimidine-amine is synthesized
-(4-pyridin-3-yl-pyrimidine-2-base)-amine, 2 milliliters of hydrazine hydrates, 60 milliliters of THF, a small amount of RaneyNi are added 0.5 gram (2-methyl-5-nitrophenyl) in 100 ml flasks.Stirring at room temperature reacts 24 hours.Reaction terminates, and after careful filtration, by mother liquor concentrations, obtains 0.4 gram of yellow product.
5) 4-chloromethyl-benzoyl chloride is synthesized
By 4-(methylol) phenylformic acid (2g), oxalyl chloride (3mL), DMF (30mg) and methylene dichloride (50mL) add down in reaction flask, at room temperature stir 2 hours.After reaction terminates, after reaction solution is concentrated, obtain white solid product (2g).
6) 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide is synthesized
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-pyrimidine-amine, THF (5mL) and TEA (0.2mL) adds down in reaction flask, being cooled to 0 ° of C and after stirring 10 minutes, the THF(2ml by 4-chloromethyl-benzoyl chloride (80mg)) solution is slowly added dropwise in above reaction solution.Remain on after 0 ° of C stirs 2 hours, reaction solution is condensed into solid.Again ethyl acetate (100ml) is added, after dissolved solids, wash with water (100ml).Concentrated organic phase, obtains product (130mg) again.
7) N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(2-oxa--6-aza-spiro [3.3] heptyl-6-ylmethyl)-benzamide is synthesized
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and 2-oxa--6-aza-spiro [3.3] heptane oxalate (50mg).70 ° of C reacting by heating 1 hour, product obtained compound 1(9mg through preparative HPLC).LC-MS(m/z):493(M+).
1HNMR(
d 6 -DMSO,400MHz):2.22(s,3H),3.30(s,4H),3.57(s,2H),4.62(s,4H),7.28(d,J=8Hz,1H),7.37-7.45(m,4H),7.57(m,1H),7.93(d,J=8Hz,2H),8.21(s,1H),8.48(d,J=5.2Hz,1H),8.51-8.66(m,2H),9.30(s,1H),10.16(s,1H)。
13CNMR(
d 6 -DMSO,400MHz):18.120,62.051,63.416,80.475,107.979,117.189,117.671,124.250,128.075,128.535,130.485,132.681,134.143,134.883,137.664,138.256,142.465,148.670,151.855,159.943,161.654,162.069,165.678。
Embodiment 2: synthetic compound 2, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(2-thia-6-aza-spiro [3.3] heptyl-6-ylmethyl)-benzamide
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and 2-thia-6-aza-spiro [3.3] heptane oxalate (50mg).70 ° of C reacting by heating 1 hour, product obtained compound 2(16mg through preparative HPLC).LC-MS(m/z):509(M+).
1HNMR(CD
3OD,400MHz):2.33(s,3H),3.33(s,4H),3.34(s,4H),3.68(s,2H),7.27(d,J=8.4Hz,1H),7.36-7.44(m,4H),7.55(m,1H),7.92(d,J=8Hz,2H),8.22(s,1H),8.48(d,J=5.2Hz,1H),8.59-8.65(m,2H),9.29(s,1H).
13CNMR(d6-DMSO,400MHz):18.115,36.467,43.718,62.412,67.374,107.979,117.197,117.681,124.243,128.067,128.541,130.481,132.684,134.139,134.880,137.668,138.261,142.434,148.671,151.850,159.936,161.657,162.071,165.679.
Embodiment 3: synthetic compound 3, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(2-sulfoxide mix-6-aza-spiro [3.3] heptyl-6-ylmethyl)-benzamide
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and assorted-6-aza-spiro [3.3] heptane oxalate (50mg) of 2-sulfoxide.70 ° of C reacting by heating 1 hour, product obtained compound 3(8mg through preparative HPLC).LC-MS(m/z):525(M+).
1HNMR(CD
3OD,400MHz):2.34(s,3H),3.37(m,6H),3.70(s,3H),3.93(m,2H),7.27(d,J=8Hz,1H),7.36-7.44(m,4H),7.57(m,1H),7.92(d,J=8.4Hz,2H),8.21(s,1H),8.48(d,J=5.2Hz,1H),8.59-8.66(m,2H),9.29(s,1H).
13CNMR(
d 6 -DMSO,400MHz):18.118,30.086,61.920,62.312,65.315,65.630,107.984,117.676,124.251,128.084,128.545,130.490,132.681,134.183,134.886,138.262,142.235,148.676,151.859,159.948,161.655,162.071,165.663。
Embodiment 4: synthetic compound 4,4-(2-sulfone mix-6-aza-spiro [3.3] heptyl-6-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and assorted-6-aza-spiro [3.3] heptane oxalate (50mg) of 2-sulfone.70 ° of C reacting by heating 1 hour, product obtained compound 4(4mg through preparative HPLC).LC-MS(m/z):541(M+).
1HNMR(CD
3OD,400MHz):2.33(s,3H),3.51(s,4H),3.75(s,2H),4.30(s,4H),7.27(d,J=8.4Hz,1H),7.37-7.47(m,4H),7.55(m,1H),7.93(d,J=8.4Hz,2H),8.22(s,1H),8.48(d,J=5.2Hz,1H),8.59-8.65(m,2H),9.29(s,1H).
13CNMR(
d 6 -DMSO,400MHz):18.113,25.205,62.229,64.429,73.668,107.986,117.241117.688,124.247,128.113,128.573,130.491,132.684,134.233,134.885,137.649,138.264,142.117,148.676,151.859,159.945,161.659,161.115,165.654.
Embodiment 5: synthetic compound 5, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(oxetanylmethoxy-3-base aminomethyl)-benzamide
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and 3-amido are mixed oxygen tetramethylene (50mg).React 1 hour 100 ° of C microwave heatings, product obtains compound 5(3mg through preparative HPLC).LC-MS(m/z):467(M+).
1HNMR(CD
3OD,400MHz):2.33(s,3H),3.80(s,2H),4.03(m,1H),4.46(m,2H),4.73(m,2H),7.27(d,J=8.4Hz,1H),7.37-7.57(m,5H),7.93(d,J=8Hz,2H),8.22(s,1H),8.48(d,J=5.2Hz,1H),8.59-8.65(m,2H),9.29(s,1H).
Embodiment 6: synthetic compound 6, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-4-(oxetanylmethoxy-3-yloxymethyl)-benzamide
4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-benzamide (60mg) is added, Na in reaction flask
2cO
3(250mg), acetonitrile (10ml) and 3-hydroxyl are mixed oxygen tetramethylene (50mg).React 1 hour 100 ° of C microwave heatings, product obtains compound 6(4mg through preparative HPLC).LC-MS(m/z):468(M+).
1HNMR(CD
3OD,400MHz):2.34(s,3H),4.58(s,2H),4.61(m,2H),4.71(m,1H),4.81(m,2H),7.28(d,J=8.4Hz,1H),7.37-7.58(m,5H),7.95(d,J=8Hz,2H),8.22(s,1H),8.48(d,J=5.2Hz,1H),8.60-8.65(m,2H),9.29(s,1H).
Embodiment 7: extracorporeal anti-tumor cytoactive is tested
The test of extracorporeal anti-tumor cytoactive adopts Sulforhodamine B(sulfo-hodamineB, SRB) staining.Srb assay is responsive, accurately, be specially adapted to the advantages such as large-scale medicine screening, by one of US National institute of oncology (NCI) anti-tumor i n vitro test method being classified as standard.SRB is a kind of protein bound dyestuff, can be combined by the basic aminoacids in protein, its color change be directly proportional to the albumen in viable cell.
Get be in Exponential growth stage MKN-45 gastric cancer tumor cell kind in 96 orifice plates, cultivate 24h and make cell attachment, remove supernatant, add 200 μ L/ pore area medicine fresh cultures: compound is dissolved in DMSO or physiological saline in advance, is diluted to desired concn when tested with perfect medium.Each concentration establishes 6 multiple holes, and establishes blank control wells (only adding substratum) and negative control, establishes 6 multiple holes equally.Continue to be cultured to the test design time, stop cultivating, remove supernatant, every hole adds 10% trichoroacetic acid(TCA) 200 μ L, and 4 DEG C of conditions fix lh.Rinse 5 times with redistilled water, naturally dry rear every hole and add 4mg/mLSRB solution, dye under room temperature 15min, abandons supernatant, rinses 5 times to remove the dyestuff of non-specific binding with 1% acetic acid.Every hole adds 100 μ L10mMTris solution, surveys OD value under A490 wavelength, and by following formulae discovery analyte to the inhibiting rate of growth of cancer cells.
And make regression equation with the logarithm of compound concentration and inhibiting rate, calculate IC
50, result shows, in the present invention, compound all demonstrates good antineoplastic activity (as shown in table 1), for the anti tumor activity in vitro IC of MKN-45 gastric cancer tumor strain
50value is nM level, and wherein compound 1,2,5 and 6 is for the extracorporeal anti-tumor IC of MKN-45 gastric cancer tumor strain
50value is all less than 1nM, and the activity of compound 2 is similar to positive control anti-tumor medicine imatinib, can develop new type antineoplastic medicine further.
Table 1 is the Anti-tumor angiogenesis result of the compounds of this invention.
Table 1
Claims (9)
1. Aniline pyrimidine compound, it is characterized in that, described compound is 4 N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-benzamide compounds having quaternary heterocyclic substituted, has the structure of general formula (I)
Wherein
X＝O
Y=O or NH
X
1=O or S or SO or SO
2
X
2＝CH
2
Y
1＝N
Y
2＝CH
2。
2. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 1 with following structure,
3. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 2 with following structure,
4. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 3 with following structure,
5. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 4 with following structure,
6. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 5 with following structure,
7. Aniline pyrimidine compound according to claim 1, is characterized in that, described compound is the compound 6 with following structure,
8. the purposes of Aniline pyrimidine compound in preparation tumor of claim 1.
9. by purposes according to claim 8, it is characterized in that, described tumour is relative disease caused by BCR-ABL Tyrosylprotein kinase functional disorder, and it is chronic myelogenous leukemia, cancer of the stomach, gastrointestinal stromal knurl, acute lymphoblastic leukemia and the systemic mastocytosis just controlled and complication thereof.
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