CN101245061B - N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof - Google Patents
N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof Download PDFInfo
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Abstract
The invention provides an N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine derivative, in particular to a compound which is obtained by connecting the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine with an NO(nitric oxide) supply body for nitrate esters by ester bonds or amide bonds. The compound is obtained by coupling the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and the corresponding NO supply body for nitrate esters by different connecting groups for carrying out substitution reaction. The dual-coordination anti-tumor mechanism demonstrates good functions on inhibiting the cell apoptosis or inducing the apoptosis of tumor cells.
Description
Technical field
The present invention relates to N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidinamine derivatives, be specifically related to N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE and nitrate esters NO donor coupled derivative.The invention still further relates to the preparation method and the purposes aspect the preparation antitumor drug thereof of this compounds.
Background technology
Protein tyrosine kinase (protein tyrosine kinase; PTK) be one type of protein with tyrosine kinase activity of strict control in vivo; γ-phosphate on their ability catalysis adenosine triphosphate atps is transferred on the tyrosine residues of many and cell activities proteins associated matter; Make it that phosphorylation take place, thus a series of physiological processs such as regulating cell growth, differentiation, apoptosis.The imbalance of PTKs function then causes biological intravital a series of diseases.Existing data shows that proto-oncogene and oncoprotein above 70% all have protein tyrosine kinase activity, and their unconventionality expression will cause the disorder of cell proliferation adjusting, and then causes the generation of tumour.In addition, the unconventionality expression of PTKs is also closely related with the chemotherapy resistance of the generation of invasion by tumor cells and transfer, tumour neovascularity, tumour.Therefore, be that target spot carries out the focus that medicament research and development becomes the research of antitumor drug in the world with the Tyrosylprotein kinase.Exploitation ATP competitive inhibitor (ATP-competitive inhibitor) is exactly one of them important direction.Wherein pyrimidines is the competitive ptk inhibitor of one type of ATP, though the ATP of PTK combines the territory to combine the territory to have the homology of height with the ATP of serine/threonine protein kitase, miazines still has very big selectivity as ptk inhibitor.In the anilino compounds, the verivate of 3 bit substituents has stronger inhibition active (Zhou Yiming, Sun Liguang than the verivate of 2 and 4 bit substituents.The progress of tyrosine protein kinase inhibitor [J].Dissect scientific advance: 2000,6 (3): 214-217).Wherein the most successful is the imatinib mesylate (GLeevec) that is used to treat chronic myeloid leukemia CML and gastrointestinal stromal knurl GISTs of lead compound exploitation with the 2-aniline pyrimidine like Novartis Co.,Ltd; It combines through competitive inhibition ATP and LCK Abl-Bcr's; Specific prevention Abl-Bcr autophosphorylation influences cell signalling, suppresses the propagation of tumour cell.
NO (nitrogen protoxide) is messenger molecule and an effector molecule important in the organism, and it is relevant with pathologic process to participate in multiple physiology, has physiological function widely.Aspect cytotoxicity, NO can directly and contain the enzyme and the protein effect of iron, thereby suppresses the cytoactive that these enzymes are regulated, and promotes apoptosis and the reparation that stops DNA; Aspect immunity system, NO mediation scavenger cell is to outside the performance CDCCs such as tumour cell and cytopathy substance; NO can act on mitochondrial respiratory chain, and mitochondrial respiratory is obstructed, and ATP consume to increase and produces very fewly, promotes death of neoplastic cells .NO to suppress the expression of proto-oncogene, maybe be relevant with protein kinase C; NO has the pipe intestinal protection effect simultaneously; Can reduce gi tract toxic side effect (the James F.Kerwin of antitumor drug; Jr.Nitric Oxide:A New Paradigm for Second Messengers [J] .J.Med.Chem.1995,22 (38): 4342-4362.).Yet NO is as gaseous signal molecule, and the transformation period lacks in vivo, instability, and poor controllability etc. are utilized specific carrier and the coupling of NO donor so increasing research concentrates on, thereby discharge NO at the privileged site of body, reach the effect of kill cancer cell.Up to the present, the target property release of NO is still the emphasis of research.
Comprise the anilino-pyrimidine verivate example that has analog structure with this invention in the following patent: EP 0564409, WO066613, WO099187, US 0248918.
Summary of the invention
The object of the present invention is to provide one type of N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-pyrimidinamine derivatives with dual synergistic antitumor mechanism, i.e. N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE and nitrate esters NO donor coupled derivative.
The present invention is and the relevant compound of general formula (I):
Wherein, R
1Representative
R
2Be selected from: the straight or branched alkyl of carbonatoms 2-10; O, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-6 wherein, n=1-4.
Further preferred formula (I) compound, R
2Be selected from: the straight chained alkyl of carbonatoms 2-10; The branched-chain alkyl of carbonatoms 3-6; O, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-2 wherein, n=1-3.
The concrete corresponding relation such as the following table of compound number and structure:
Ph in the above-mentioned definition represents phenyl; O, m, p-Ph-CH
2-represent the phenyl of ortho position, a position, para-orientation respectively; Down together.
Special preferred formula (I) compound, R
2Be selected from: carbonatoms is 2,5,10 straight chained alkyl, and carbonatoms is 3 or 5 branched-chain alkyl, o, m, p-Ph-CH
2-.
Most preferably general formula (I) compound is from following compounds:
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base ethyl ester
N-[4-methyl-3-[[4-(3-the pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester of 6-nitre oxygen base
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-10-nitre oxygen base ester in the last of the ten Heavenly stems
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre Oxy-1-methyl ethyl ester
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base butyl ester
2-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-3-nitre oxygen methyl phenyl ester
4-[(2-nitre oxygen base oxethyl) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM
4-[(6-nitre oxygen base hexyloxy) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM
4-[(2-nitre oxygen base propoxy-) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM
4-[[(4-nitre oxygen ylmethyl)] phenoxymethyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM
The pharmaceutically acceptable salt of general formula (I) compound, said pharmacy acceptable salt is and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid; Succsinic acid, toxilic acid, tartrate, the formed salt of Phenylsulfonic acid.Pharmacy acceptable salt can the conventional salifying method preparation in this area.
Can process compsn with acceptable carrier on anticancer active constituent compound that comprises the general formula (I) of treating significant quantity and the pharmaceutics among the present invention.Compsn can the conventional preparation means preparation in this area.
Another purpose of the present invention provides the application of general formula (I) compound in treatment apoptosis disease or inducing apoptosis of tumour cell.
Further aim of the present invention provides the application of general formula (I) compound in diseases such as treatment chronic myelocytic leukemia, acute lymphoblastic leukemia, gastrointestinal stromal knurl, prostate cancer.
Another object of the present invention is to provide the preparation method of this compounds.
The present invention provides following technical scheme:
The synthetic route of lead compound N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (A) is following; Referring to [US5521184 and Zolt á n Szak á cs; Szabolcs B é ni; Zolt á n Varga, L á szlo
K é ri, B é la Nosz á l.Acid-Base profiling of Imatinib (Gleevec) and its fragment [J] .J.med.chem; 2005,48 (1): 253-254.]
Side chain nitrate esters NO donor; Be the substituted alcohols of nitric ether, can in the presence of acetate, diacetyl oxide, obtain, specifically referring to [George N.Ziakas through corresponding diol through nitric acid nitrating; Eleni A.Rekka; Antonios M.Gavalas, Phaedra T.Eleftheriou, Karyofillis C.Tsiakitzis and Panos N.Kourounakis.Nitric oxide releasing derivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile [J] .Bioorgganic&Medicinal Chemistry; 2005,13:6485-6492.]
Compound I
1-17Synthetic: substituted alcohols of nitric ether or phenolic cpd and halogenated acetic acids are in inert solvent; Esterification takes place in the presence of the DMAP of DCC (NSC 57182) and catalytic amount (4-dimethylamino pyridine); Make corresponding halo nitric ether, inert solvent wherein is preferably methylene dichloride; Halogenated acetic acids is preferably bromoacetic acid.In inert solvent, under the alkaline condition, in the presence of quaternary ammonium salt, with N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE generation substitution reaction, inert solvent wherein is preferably THF (THF) then; Alkali wherein is preferably TEA (triethylamine); Quaternary ammonium salt wherein is preferably TBAB (Tetrabutyl amonium bromide).
Compound I
1-14, R represents the straight chained alkyl of carbonatoms 2-10, the branched-chain alkyl of carbonatoms 3-6.
Compound I
18-33Synthetic: etherification reaction takes place with substituted alcohols of nitric ether or phenolic cpd through to monochloromethyl benzoyl halogen acidylate in N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE again in the presence of phase-transfer catalyst.Phase-transfer catalyst wherein is preferably quaternary ammonium salt, further is preferably TBAB (Tetrabutyl amonium bromide); Halogenated methyl benzoyl halogen is preferably chloromethyl benzoic acid chlorides wherein.
Compound I
18-33, R represents the straight chained alkyl of carbonatoms 2-10, the branched-chain alkyl of carbonatoms 3-6, or corresponding phenolic.
Embodiment
Below further set forth the present invention through specific embodiment and Test Example, be not construed as limiting the invention in any form.
The test of Test Example 1 antitumour activity
Test materials: JEG-3 and substratum: HL-60 (promyelocytic leukemia); K562 (promyelocytic leukemia), PC-3 (prostate), HT-29 (colon); DU145 (colon) is made into suspension with RPMI1640 nutrient solution (Gibco-BRL); Add 10% through heat-killed foetal calf serum (FCS, Gibco), 100IU/ml penicillium mould 100IU/ml Streptomycin sulphate; JEG-3 all buy in U.S. tissue culture center (ATCC, Rocksville, Maryland, USA).
Reagent: MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Sigma)
Instrument: 96 holes dull and stereotyped (CONING), the dull and stereotyped reader (Dynatech MR5000) of robotization spectrophotometric.
Medicine: according to the I of embodiment 1～5 method preparation
1～I
5, Gleevec
Experimental technique:
In dull and stereotyped every hole, 96 holes, add 0.1mL and contain the suspension-s that is made into by the RPMI1640 nutrient solution of 1000 cells, then in 37 ℃, CO
2(5%) cultivated 24 hours in the incubator, add the substratum that contains different test-compounds, in 37 ℃, CO
2(5%), cultivated 2 days, every hole adds 50 μ l MTT solution (2mg/ml); Cultivated 4 hours down for 37 ℃, the sucking-off supernatant, every hole adds 150 μ l DMSO; Jolting 15 minutes, dull and stereotyped through the dull and stereotyped reader of robotization spectrophotometric, measure the optical density(OD) (OD) in each hole in the 540nm wavelength.Do not add optical density(OD) that test-compound records as reference substance with cell in the hole, calculate the cell survival rate of each compound respectively with following formula, cell viability and drug level are made curve, and cell survival rate is 50% to be the IC50 value.(wherein dosing cell hole OD value is the OD value that records when adding cell, medicine in the hole, and blank medicine hole OD value is to add medicine in the hole, and the OD value that records when not adding cell, control cells OD value are to add cell, the OD value that records when not adding medicine in the hole).
Experimental result:
Adopt mtt assay, studied 8 external growth-inhibiting effects of target compound, comprising two kinds of rectum cancer cell strain (DU-145 to six kinds of human body tumor cell strains; HT-29), prostate cancer cell strain (PC-3); (HL-60, K562), the result sees table 1 to marrow sexual cell leukemia cell line.
The IC of table 1 test-compound in each JEG-3
50(μ g/ml)
Conclusion:
Can find out that from the antitumour activity test-results test-compound all has certain restraining effect to the growth of six kinds of human body tumor cell strains.Wherein to the restraining effect of leukemia cell line apparently higher than other several kinds of cell strains, explain that the main potential use of this compounds is to use compound I as anti-leukemia medicine
6, I
15, I
32To marrow sexual cell leukemia cell line (HL-60, restraining effect K562) is the most remarkable, has the value of further investigation; Several kinds of test-compounds show the restraining effect that prostate cancer is better than other two kinds of rectum cancer cell systems, show the drug use that can be used as anti-prostate cancer.
Embodiment 1
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base ethyl ester (I
1)
2-nitre ethoxy-ethanol
Under ice bath, the nitrogen protection, with terepthaloyl moietie (2.48g 40mmol) is dissolved in the 100ml ETHYLE ACETATE, add successively concentrated nitric acid (4.36g, 45mmol), Glacial acetic acid min. 99.5 12ml, acetic anhydride 10ml.Stirred overnight at room temperature.10% sodium bicarbonate aqueous solution transfers pH to neutral, tells organic layer, the saturated common salt washing, Anhydrous potassium carbonate is dry, concentrate the yellow oily bullion.Column chromatography (ETHYLE ACETATE: sherwood oil=2: 1) get 1.78g.
2-nitre oxygen monobromoethane acetic ester
2-nitre ethoxy-ethanol (1.42g 13.27mmol) is dissolved in the 40ml anhydrous methylene chloride, ice bath add down bromoacetic acid (1.83g, 13.27mmol), stirring and dissolving, add DCC (2.74g is 13.30mmol) with the DMAP of catalytic amount in batches.Settled solution becomes white milk sap, stirring at room 2.5 hours.Filter, concentrate.Residue is dissolved in the methylene dichloride, and saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying.Column chromatography (ETHYLE ACETATE: sherwood oil=2: 1) get light yellow oil 1.69g,
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (1.25g, 4.51mmol) and triethylamine (690 μ L 4.96ml) join in the 50ml THF and to stir 20 minutes; Adding 2-nitre oxygen monobromoethane acetic ester (1.34g, 5.88mmol) TBAB with catalytic amount refluxed 5 hours, filtered; Saturated sodium bicarbonate is washed, and anhydrous sodium sulfate drying concentrates; ETHYLE ACETATE: sherwood oil=column chromatography got faint yellow solid 1.12g, yield in 4: 1: 58.64%, and mp:101.3-105.6 ℃.
ESI-MS?m/z：426[M+1]
+，448[M+Na]
+；
IR(KBr，v(cm
-1))：3407(N-H)，3038(C-H，Ar)，1724(C＝O)，1579(C＝C)，1453(N-H)，1118(C-O-C)，1007(N-H)
1H-NMR?δ(ppm)：9.3(d，1H，J＝1.81，NH)，8.7(m，2H)，8.4(m，2H，)，7.5(dd，1H，J1＝4.76，J2＝7.94)，7.4(d，1H，J＝5.13)，6.9(d，1H，J＝8.20)，6.8(d，1H，J＝2.07)，6.3(dd，1H，J＝210，J＝8.06)，5.9(s，1H)，4.7(dd，2H，J1＝3.24，J2＝5.40)，4.4(dd，2H，J1＝3.15，J2＝5.47)，3.9(d，2H，J1＝6.38)，2.1(s，3H)
Embodiment 2
N-[4-methyl-3-[[4-(3-the pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester (I of 6-nitre oxygen base
5)
With reference to instance 1 preparation method, by 1, the 6-pinakon is that starting raw material prepares N-[4-methyl-3-[[4-(3-the pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester of 6-nitre oxygen base, yield: 58.64%, and mp:123.07-124.8 ℃.
ESI-MS?m/z：481，504[M+Na]
+；
IR(KBr，v(cm
-1))：3407(N-H)，3038(C-H，Ar)，1724(C＝O)，1579(C＝C)，1453(N-H)，1118(C-O-C)，1007(N-H)
1H-NMR?δ(ppm)：9.3(d，1H，J＝1.81，NH)，8.7(m，2H)，8.4(m，2H，)，7.5(dd，1H，J1＝4.76，J2＝7.94)，7.4(d，1H，J＝5.13)，6.9(d，1H，J＝8.20)，6.8(d，1H，J＝2.07)，6.3(dd，1H，J＝210，J＝8.06)，5.87(s，1H)，4.76(dd，2H，J1＝3.24，J2＝5.40)，4.43(m，8H)，3.94(d，2H，J1＝6.38)，2.1(s，3H)，1.89(m，2H)
Embodiment 3
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-10-nitre oxygen base ester in the last of the ten Heavenly stems (I9)
With reference to instance 1 preparation method, be the starting raw material preparation by decamethylene-glycol, N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-10-nitre oxygen base ester in the last of the ten Heavenly stems, yield 53.43%, mp:145.3-146.7 ℃.
ESI-MS?m/z：524[M+1]
+，546[M+Na]
+；
Embodiment 4
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre Oxy-1-methyl ethyl ester (I
11)
1-hydroxyl-2-nitre oxygen base propane
Under ice bath, the nitrogen protection, with 1, the 2-Ucar 35 (3.04g 40mmol) is dissolved in the 100ml ETHYLE ACETATE, add successively concentrated nitric acid (8.73g, 80mmol), Glacial acetic acid min. 99.5 20ml, acetic anhydride 20ml stirred overnight at room temperature.10% sodium bicarbonate aqueous solution flushing is near neutral, the saturated common salt washing, Anhydrous potassium carbonate is dry, concentrate the yellow oily bullion.Column chromatography (ETHYLE ACETATE: sherwood oil=2: 1) get 258g. yield 53.31%
Bromoacetic acid-2-nitre oxygen base propyl ester
1-hydroxyl-2-nitre oxygen base propane (1.21g 10.0mmol) is dissolved in the 40ml anhydrous methylene chloride, add again under the ice bath bromoacetic acid (1.67g, 12.01mmol), stirring and dissolving, add DCC (2.06g is 10mmol) with the DMAP of catalytic amount in batches.Settled solution becomes white milk sap, stirring at room 4.5 hours.Filter, concentrate.Residue is dissolved in the methylene dichloride, saturated sodium bicarbonate flushing, anhydrous sodium sulfate drying.Column chromatography (ETHYLE ACETATE: sherwood oil=2: 1) get light yellow oil 2.12g, yield: 88.43%.
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (1.25g, 4.51mmol) and triethylamine (690 μ L 4.96ml) join in the 50ml THF; Stirred 20 minutes, and adding bromoacetic acid-2-nitre oxygen base propyl ester (1.42g, 5.88mmol) TBAB with catalytic amount refluxed 6 hours; Filter, saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying; Concentrate ETHYLE ACETATE: the faint yellow solid 1.02g of sherwood oil=4: 1 column chromatography, yield: 51.51%mp:124.6-125.7 ℃.
ESI-MS?m/z：439；
IR(KBr，v(cm
-1))：3385(N-H)，3040(C-H，Ar)，1732(C＝O)，1586(C＝C)，1457(N-H)，1200(C-O-C)，1107(N-H)，
1H-NMR?δ(ppm)：9.25(d，1H，J＝1.81，NH)，8.67(m，2H)8.4(m，2H，)，7.5(dd，1H，J1＝4.76，J2＝7.94)，7.4(d，1H，J＝5.13)，6.9(d，1H，J＝8.20)，6.8(d，1H，J＝2.07)，6.3(dd，1H，J＝210，J＝8.06)，5.87(s，1H)，5.14(dd，2H，J1＝4.24，J2＝7.40)，3.94(d，2H，J1＝6.38)，2.1(s，3H)，1.86(m，3H)
Embodiment 5
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base butyl ester (I12)
With reference to instance 5, by 1, the 2-butyleneglycol is that starting raw material is prepared into yield: 45.56%, and mp:131.2-134.5 ℃.
ESI-MS?m/z：453；
IR(KBr，v(cm
-1))：3415，3389(N-H)，3035(C-H，Ar)，1765(C＝O)，1606(C＝C)，1447(N-H)，1215(C-O-C)，1089(N-H)，
1H-NMR?δ(ppm)：9.25(d，1H，J＝1.81，NH)，8.66(m，2H)8.4(m，2H，)，7.46(dd，1H，J1＝4.76，J2＝7.94)，7.44(d，1H，J＝5.13)，6.89(d，1H，J＝8.20)，6.82(d，1H，J＝2.07)，6.33(dd，1H，J＝210，J＝8.06)，5.87(s，1H)，5.26(dd，2H，J1＝4.24，J2＝7.40)，4.67(m，2H)，3.94(d，2H，J1＝6.38)，2.1(s，3H)，1.86(m，3H)
Embodiment 6
2-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-3-nitre oxygen methyl phenyl ester (I
16)
2-bromoacetic acid-3-nitre oxygen methyl phenyl ester
(0.70g 4.14mmol) is dissolved in the anhydrous methylene chloride 3-nitre oxygen methylphenol, and (0.84g is 4.08mmol) with the DMAP of catalytic amount to add DCC after the stirring and dissolving; Adding bromoacetic acid under the ice bath (0.86g, 6.18mmol), stirring at room 3 hours; Filter, concentrate the back and add 50ml ETHYLE ACETATE, the saturated aqueous sodium carbonate flushing; Anhydrous sodium sulfate drying, concentrate oily matter 0.92g, yield: 76.67%.
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (1.25g, 4.51mmol) and pyridine (546 μ L 6.77ml) join in the 50ml THF; Stirring and dissolving, (1.96g 3.46mmol) adds wherein with the TBAB of catalytic amount with 2-bromoacetic acid-3-nitre oxygen methyl phenyl ester; Reflux 12 hours is filtered, and column chromatography gets 1.42g; Yield: 64.84%, mp:156.7-158.6 ℃ of ESI-MS m/z:485; 508 [M+23]
+
IR(KBr，v(cm
-1))：3408(N-H)，，3038(C-H，Ar)，1778(C＝O)，1596(C＝C)，1427(N-H)，1169(C-O-C)，1159(N-H)，
1H-NMR(ppm)：9.23(d，1H，J＝1.81，NH)，8.66(m，2H)8.4(m，2H，)，7.89(m，4H)7.46(dd，1H，J1＝4.76，J2＝7.94)，7.44(d，1H，J＝5.13)，6.89(d，1H，J＝8.20)，6.82(d，1H，J＝2.07)，6.33(dd，1H，J＝210，J＝8.06)，5.87(s，1H)，5.29(dd，2H，J1＝3.24，J2＝8.76)，3.94(d，2H，J1＝6.38)，2.1(s，3H)
Embodiment 7
4-[(2-nitre oxygen base oxethyl) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM (I
18)
4-chloromethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (0.83g, 3.00mmol) and triethylamine (500 μ L 3.60ml) join in the 50ml THF and to stir 30 minutes; Add 4-chloromethyl benzoic acid chlorides (0.73g; 3.86mmol), refluxed 4 hours, filter; Ethyl alcohol recrystallization gets light yellow solid 0.82g, yield: 63.56%.
(0.86g, 2mmol), (0.32g 2.99mmol) joins in the toluene 4-chloromethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM, and 60-70 ℃ was stirred 1 hour for the TBAB of catalytic amount and 2-nitre ethoxy-ethanol.Stir and drip 20%NaOH aqueous solution 10ml in following 1 hour, continue under this temperature to stir 2 hours, tell organic layer; Water layer is used extracted in toluene, merges organic layer, uses Hydrogen chloride successively; Saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying removes toluene under reduced pressure; Re-crystallizing in ethyl acetate gets 0.53g, yield: 53.0%, and mp:145.6-148.3 ℃.
ESI-MS?m/z：501，523[M+23]
+
IR(KBr，v(cm
-1))：3368(N-H)，，3028(C-H，Ar)，1753(C＝O)，1604(C＝C)，1454(N-H)，1216(C-O-C)，1143(N-H)，
1H-NMR?δ(ppm)：9.23(d，1H，J＝1.81，NH)，8.66(m，2H)8.4(m，2H，)，7.69(m，4H)7.46(dd，1H，J1＝4.76，J2＝7.94)，7.44(d，1H，J＝5.13)，6.89(d，1H，J＝8.20)，6.82(d，1H，J＝2.07)，6.33(dd，1H，J＝210，J＝8.06)，5.98(s，1H)，5.45(dd，2H，J1＝2.24，J2＝7.76)，3.94(d，2H，J1＝6.38)，3.32(m，2H)，2.1(s，3H)
Embodiment 8
4-[(6-nitre oxygen base hexyloxy) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM (I
22)
With reference to embodiment 7, be starting raw material with 6-nitre oxygen base hexanol, get white solid, yield 45.5%.
ESI-MS?m/z：556，[M+23]
+
Embodiment 9
4-[(2-nitre oxygen base propoxy-) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM (I
26)
With reference to embodiment 7, be starting raw material with 2-nitre oxygen base propyl alcohol, yield 54.5%.
ESI-MS?m/z：515[M+1]
+
Embodiment 10
4-[[(4-nitre oxygen ylmethyl)] phenoxymethyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM (I
32) with reference to embodiment 7, be starting raw material with 3-nitre oxygen base phenol, yield 56.6%.
ESI-MS?m/z：562，585[M+23]
+
Claims (8)
1. logical formula I compound and pharmacy acceptable salt thereof:
R
1For
R
2Be selected from: the straight or branched alkyl of carbonatoms 2-10, o, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-6 wherein, n=1-4.
2. the said logical formula I compound of claim 1, R
2Be selected from: the straight chained alkyl of carbonatoms 2-10; The branched-chain alkyl of carbonatoms 3-6; O, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-2 wherein, n=1-3.
3. the said logical formula I compound of claim 2, R
2Be selected from: the straight chained alkyl of carbonatoms 2,5,10, the branched-chain alkyl of carbonatoms 3,5, o, m, p-Ph-CH
2-.
4. the said logical formula I compound of claim 1, it is selected from:
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base ethyl ester,
N-[4-methyl-3-[[4-(3-the pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester of 6-nitre oxygen base,
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-10-nitre oxygen base ester in the last of the ten Heavenly stems,
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre Oxy-1-methyl ethyl ester,
N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-2-nitre oxygen base butyl ester,
2-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-3-nitre oxygen methyl phenyl ester,
4-[(2-nitre oxygen base oxethyl) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM,
4-[(6-nitre oxygen base hexyloxy) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM,
4-[(2-nitre oxygen base propoxy-) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM,
4-[[(4-nitre oxygen ylmethyl)] phenoxymethyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] BM.
5. the preparation method of each said logical formula I compound of claim 1-4 may further comprise the steps:
1) R
1For
The time logical formula I compound:
(1) esterification takes place in substituted alcohol compound of nitric ether and halogenated acetic acids in the presence of NSC 57182,
(2) occur in quaternary ammonium salt with N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE and have substitution reaction down;
2) R
1For
The time logical formula I compound:
(1) N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is through to halogenated methyl benzoyl halogen acidylate,
(2) with the substituted alcohol compound of nitric ether etherification reaction takes place in the presence of phase-transfer catalyst.
According in the claim 1-4 item each logical formula I compound with add the compsn that acceptable carrier is processed on the pharmaceutics.
7. the application of each logical formula I compound in preparation treatment apoptosis disease or inducing apoptosis of tumour cell medicine in the claim 1-4 item.
8. the application of each logical formula I compound in the medicine of preparation treatment chronic myelocytic leukemia, acute lymphoblastic leukemia, gastrointestinal stromal knurl, prostate cancer disease in the claim 1-4 item.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
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